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Programme of Action for Cancer Therapy (PACT) is a programme created by the International Atomic Energy Agency (IAEA) in 2004 to build upon the Agency’s experience in radiation medicine and technology, and enable developing countries to introduce, expand or improve their cancer care capacity and services in a sustainable manner by integrating radiotherapy into a comprehensive cancer control programme that maximizes its therapeutic effectiveness and impact. Such a programme integrates and aligns cancer prevention, surveillance, screening and early detection, treatment and palliative care activities and investments, and is set up based on the Guidelines of the World Health Organization (WHO). It also addresses other challenges such as infrastructure gaps and, through partnerships, builds capacity and long term support for continuous education and training of cancer care professionals, as well as for community-based civil society action to combat cancer.
PACT has its headquarters in Vienna, Austria.
PACT and its partners are developing multidisciplinary cancer capacity building projects called PACT Model Demonstration Sites (PMDS). As of 2010, there are eight PMDS: Albania, Ghana, Mongolia, Nicaragua, Sri Lanka, United Republic of Tanzania, Vietnam and the Republic of Yemen.
== See also ==
Cancer
International Atomic Energy Agency (IAEA)
Oncology
Radiation therapy
== References ==
== External links ==
PACT Official Site
International Atomic Energy Agency Official Site | Wikipedia/Programme_of_Action_for_Cancer_Therapy |
The term "Clinical research center" (CRC) or "General clinical research center" (GCRC) refers to any designated medical facility used to conduct clinical research, such as at a hospital or medical clinic. They have been used to perform clinical trials of various medical procedures. The medical profession has had specific uses for CRC facilities, including awarding grants to support various types of research.
For example, the U.S. National Institutes of Health had, for years, issued GCRC grants, but later changed to awarding a Clinical and Translational Science Award (CTSA). Many hospitals or clinics have included a wing, ward, or other area titled as "Clinical Research Center" (with capitalized words).
== Example facilities ==
Some examples of CRC facilities are:
Harvard-Thorndike General Clinical Research Center in Massachusetts.
Mallinckrodt General Clinical Research Center in Massachusetts.
Mark O. Hatfield Clinical Research Center in Maryland.
UCLA General Clinical Research Center in California.
== References == | Wikipedia/Clinical_research_center |
Endometrial cancer is a cancer that arises from the endometrium (the lining of the uterus or womb). It is the result of the abnormal growth of cells that can invade or spread to other parts of the body. The first sign is most often vaginal bleeding not associated with a menstrual period. Other symptoms include pain with urination, pain during sexual intercourse, or pelvic pain. Endometrial cancer occurs most commonly after menopause.
Approximately 40% of cases are related to obesity. Endometrial cancer is also associated with excessive estrogen exposure, high blood pressure and diabetes. Whereas taking estrogen alone increases the risk of endometrial cancer, taking both estrogen and a progestogen in combination, as in most birth control pills, decreases the risk. Between two and five percent of cases are related to genes inherited from the parents. Endometrial cancer is sometimes called "uterine cancer", although it is distinct from other forms of cancer of the uterus such as cervical cancer, uterine sarcoma, and trophoblastic disease. The most frequent type of endometrial cancer is endometrioid carcinoma, which accounts for more than 80% of cases. Endometrial cancer is commonly diagnosed by endometrial biopsy or by taking samples during a procedure known as dilation and curettage. A pap smear is not typically sufficient to show endometrial cancer. Regular screening in those at normal risk is not called for.
The leading treatment option for endometrial cancer is abdominal hysterectomy (the total removal by surgery of the uterus), together with removal of the Fallopian tubes and ovaries on both sides, called a bilateral salpingo-oophorectomy. In more advanced cases, radiation therapy, chemotherapy or hormone therapy may also be recommended. If the disease is diagnosed at an early stage, the outcome is favorable, and the overall five-year survival rate in the United States is greater than 80%.
In 2012, endometrial cancers newly occurred in 320,000 women and caused 76,000 deaths. This makes it the third most common cause of death in cancers which only affect women, behind ovarian and cervical cancer. It is more common in the developed world and is the most common cancer of the female reproductive tract in developed countries. Rates of endometrial cancer have risen in several countries between the 1980s and 2010. This is believed to be due to the increasing number of elderly people and rising obesity rates.
== Signs and symptoms ==
Vaginal bleeding or spotting in women after menopause occurs in 90% of endometrial cancer. Bleeding is quite common with adenocarcinoma, occurring in two-thirds of all cases. Abnormal menstrual cycles or extremely long, heavy, or frequent episodes of bleeding in women before menopause may also be a sign of endometrial cancer.
Symptoms other than bleeding are not common. Other symptoms include thin white or clear vaginal discharge in postmenopausal women. More advanced disease shows more obvious symptoms or signs that can be detected on a physical examination. The uterus may become enlarged or the cancer may spread, causing lower abdominal pain or pelvic cramping. Painful sexual intercourse or painful or difficult urination are less common signs of endometrial cancer. The uterus may also fill with pus (pyometrea). Of women with these less common symptoms (vaginal discharge, pelvic pain, and pus), 10–15% have cancer.
== Risk factors ==
Risk factors for endometrial cancer include obesity, insulin resistance and diabetes mellitus, breast cancer, use of tamoxifen, never having had a child, late menopause, high levels of estrogen, and increasing age. Immigration studies (migration studies), which examine the change in cancer risk in populations moving between countries with different rates of cancer, show that there is some environmental component to endometrial cancer. These environmental risk factors are not well characterized. It is found that adiposity is associated with the earlier diagnosis of EC, particularly the endometrioid subtype.
=== Hormones ===
Most of the risk factors for endometrial cancer involve high levels of estrogens. An estimated 40% of cases are thought to be related to obesity. In obesity, the excess of adipose tissue increases conversion of androstenedione into estrone, an estrogen. Higher levels of estrone in the blood causes less or no ovulation and exposes the endometrium continuously to high levels of estrogens. Obesity also causes less estrogen to be removed from the blood. Polycystic ovary syndrome (PCOS), which also causes irregular or no ovulation, is associated with higher rates of endometrial cancer for the same reasons as obesity. Specifically, obesity, type II diabetes, and insulin resistance are risk factors for Type I endometrial cancer. Obesity increases the risk for endometrial cancer by 300–400%.
Estrogen replacement therapy during menopause when not balanced (or "opposed") with progestin is another risk factor. Higher doses or longer periods of estrogen therapy have higher risks of endometrial cancer. Women of lower weight are at greater risk from unopposed estrogen. A longer period of fertility—either from an early first menstrual period or late menopause—is also a risk factor. Unopposed estrogen raises an individual's risk of endometrial cancer by 2–10 fold, depending on weight and length of therapy. In trans men who take testosterone and have not had a hysterectomy, the conversion of testosterone into estrogen via androstenedione may lead to a higher risk of endometrial cancer. Higher circulating testosterone levels in women have also been identified as an independent endometrial cancer risk factor.
=== Genetics ===
Genetic disorders can also cause endometrial cancer. Overall, hereditary causes contribute to 2–10% of endometrial cancer cases. Lynch syndrome, an autosomal dominant genetic disorder that mainly causes colorectal cancer, also causes endometrial cancer, especially before menopause. Women with Lynch syndrome have a 40–60% risk of developing endometrial cancer, higher than their risk of developing colorectal (bowel) or ovarian cancer. Ovarian and endometrial cancer develop simultaneously in 20% of people. Endometrial cancer nearly always develops before colon cancer, on average, 11 years before. Carcinogenesis in Lynch syndrome comes from a mutation in MLH1 or MLH2: genes that participate in the process of mismatch repair, which allows a cell to correct mistakes in the DNA. Other genes mutated in Lynch syndrome include MSH2, MSH6, and PMS2, which are also mismatch repair genes. Women with Lynch syndrome represent 2–3% of endometrial cancer cases; some sources place this as high as 5%. Depending on the gene mutation, women with Lynch syndrome have different risks of endometrial cancer. With MLH1 mutations, the risk is 54%; with MSH2, 21%; and with MSH6, 16%.
Women with a family history of endometrial cancer are at higher risk. Two genes most commonly associated with some other women's cancers, BRCA1 and BRCA2, do not cause endometrial cancer. There is an apparent link with these genes. It is attributable to the use of tamoxifen, a drug that itself can cause endometrial cancer, in breast and ovarian cancers. The inherited genetic condition Cowden syndrome can also cause endometrial cancer. Women with this disorder have a 5–10% lifetime risk of developing endometrial cancer, compared to the 2–3% risk for unaffected women.
Common genetic variation has also been found to affect endometrial cancer risk in large-scale genome-wide association studies. Sixteen genomic regions have been associated with endometrial cancer and the common variants explain up to 7% of the familial relative risk.
=== Other health problems ===
Some therapies for other forms of cancer increase the lifetime risk of endometrial cancer, which is a baseline 2–3%. Tamoxifen, a drug used to treat estrogen-positive breast cancers, has been associated with endometrial cancer in approximately 0.1% of users, particularly older women. The benefits for survival from tamoxifen generally outweigh the risk of endometrial cancer. A one to two-year course of tamoxifen approximately doubles the risk of endometrial cancer, and a five-year course of therapy quadruples that risk. Raloxifene, a similar drug, did not raise the risk of endometrial cancer. Previously having ovarian cancer is a risk factor for endometrial cancer, as is having had previous radiotherapy to the pelvis. Specifically, ovarian granulosa cell tumors and thecomas are tumors associated with endometrial cancer.
Low immune function has also been implicated in endometrial cancer. High blood pressure is also a risk factor, but this may be because of its association with obesity. Sitting regularly for prolonged periods is associated with higher mortality from endometrial cancer. The risk is not negated by regular exercise, though it is lowered.
=== Protective factors ===
Smoking and the use of progestin are both protective against endometrial cancer. Smoking protects by altering the metabolism of estrogen and promoting weight loss and early menopause. This protective effect lasts long after smoking is stopped. Progestin is present in the combined oral contraceptive pill and the hormonal intrauterine device (IUD). Combined oral contraceptives reduce risk more the longer they are taken: by 56% after four years, 67% after eight years, and 72% after twelve years. This risk reduction continues for at least fifteen years after contraceptive use has been stopped. Obese women may need higher doses of progestin to be protected. Having had more than five infants (grand multiparity) is also a protective factor, and having at least one child reduces the risk by 35%. Breastfeeding for more than 18 months reduces risk by 23%. Increased physical activity reduces an individual's risk by 38–46%. There is preliminary evidence that consumption of soy is protective. Mendelian randomization analyses have established potential protective factors such as LDL cholesterol, later age of menarche and sex hormone binding globulin.
== Pathophysiology ==
Endometrial cancer forms when there are errors in normal endometrial cell growth. Usually, when cells grow old or get damaged, they die, and new cells take their place. Cancer starts when new cells form unneeded, and old or damaged cells do not die as they should. The buildup of extra cells often forms a mass of tissue called a growth or tumor. These abnormal cancer cells have many genetic abnormalities that cause them to grow excessively.
In 10–20% of endometrial cancers, mostly Grade 3 (the highest histologic grade), mutations are found in a tumor suppressor gene, commonly p53 or PTEN. In 20% of endometrial hyperplasias and 50% of endometrioid cancers, PTEN has a loss-of-function mutation or a null mutation, making it less effective or completely ineffective. Loss of PTEN function leads to up-regulation of the PI3k/Akt/mTOR pathway, which causes cell growth. The p53 pathway can either be suppressed or highly activated in endometrial cancer. When a mutant version of p53 is overexpressed, the cancer tends to be particularly aggressive. P53 mutations and chromosome instability are associated with serous carcinomas, which tend to resemble ovarian and Fallopian carcinomas. Serous carcinomas are thought to develop from endometrial intraepithelial carcinoma.
PTEN and p27 loss of function mutations are associated with a good prognosis, particularly in obese women. The Her2/neu oncogene, which indicates a poor prognosis, is expressed in 20% of endometrioid and serous carcinomas. CTNNB1 (beta-catenin; a transcription gene) mutations are found in 14–44% of endometrial cancers and may indicate a good prognosis, but the data is unclear. Beta-catenin mutations are commonly found in endometrial cancers with squamous cells. FGFR2 mutations are found in approximately 10% of endometrial cancers, and their prognostic significance is unclear. SPOP is another tumor suppressor gene found to be mutated in some cases of endometrial cancer: 9% of clear cell endometrial carcinomas and 8% of serous endometrial carcinomas have mutations in this gene.
Type I and Type II cancers (explained below) tend to have different mutations involved. ARID1A, which often carries a point mutation in Type I endometrial cancer, is also mutated in 26% of clear cell carcinomas of the endometrium and 18% of serous carcinomas. Epigenetic silencing and point mutations of several genes are commonly found in Type I endometrial cancer. Mutations in tumor suppressor genes are common in Type II endometrial cancer. PIK3CA is commonly mutated in both Type I and Type II cancers. In women with Lynch syndrome-associated endometrial cancer, microsatellite instability is common.
Development of an endometrial hyperplasia (overgrowth of endometrial cells) is a significant risk factor because hyperplasias can and often do develop into adenocarcinoma, though cancer can develop without the presence of a hyperplasia. Within ten years, 8–30% of atypical endometrial hyperplasias develop into cancer, whereas 1–3% of non-atypical hyperplasias do so. An atypical hyperplasia is one with visible abnormalities in the nuclei. Pre-cancerous endometrial hyperplasias are also referred to as endometrial intraepithelial neoplasia. Mutations in the KRAS gene can cause endometrial hyperplasia and therefore Type I endometrial cancer. Endometrial hyperplasia typically occurs after the age of 40. Endometrial glandular dysplasia occurs with an overexpression of p53, and develops into a serous carcinoma.
== Diagnosis ==
Diagnosis of endometrial cancer is made first by a physical examination, endometrial biopsy, or dilation and curettage (removal of endometrial tissue; D&C). This tissue is then examined histologically for characteristics of cancer. If cancer is found, medical imaging may be done to see whether the cancer has spread or invaded tissues like the myometrium (the muscular wall of the womb) or the uterine cervix. A study from 2024 indicates that transvaginal ultrasound provides diagnostic performance comparable to magnetic resonance imaging regarding the myometrial infiltration assessment. However, magnetic resonance imaging showed significantly better specificity in low-grade endometrial cancer.
=== Examination ===
Routine screening of asymptomatic people is not indicated since the disease is highly curable in its early, symptomatic stages. Instead, women, particularly menopausal women, should be aware of the symptoms and risk factors of endometrial cancer. A cervical screening test, such as a Pap smear, is not a useful diagnostic tool for endometrial cancer because the smear will be normal 50% of the time. A Pap smear can detect disease that has spread to the cervix. Results from a pelvic examination are frequently normal, especially in the early stages of disease. Changes in the size, shape, or consistency of the uterus or its surrounding, supporting structures may exist when the disease is more advanced. Cervical stenosis, the narrowing of the cervical opening, is a sign of endometrial cancer when pus or blood is found collected in the uterus (pyometra or hematometra).
Women with Lynch syndrome should begin to have annual biopsy screening at the age of 35. Some women with Lynch syndrome elect to have a prophylactic hysterectomy and salpingo-oophorectomy to greatly reduce the risk of endometrial and ovarian cancer.
Transvaginal ultrasound to examine the endometrial thickness in women with postmenopausal bleeding is increasingly being used to aid in the diagnosis of endometrial cancer in the United States. In the United Kingdom, both an endometrial biopsy and a transvaginal ultrasound used in conjunction are the standard of care for diagnosing endometrial cancer. The homogeneity of the tissue visible on transvaginal ultrasound can help to indicate whether the thickness is cancerous. Ultrasound findings alone are not conclusive in cases of endometrial cancer, so another screening method (for example, endometrial biopsy) must be used in conjunction. Other imaging studies are of limited use. CT scans are used for preoperative imaging of tumors that appear advanced on physical exam or have a high-risk subtype (at high risk of metastasis). They can also be used to investigate extrapelvic disease. An MRI can be of some use in determining if the cancer has spread to the cervix or if it is an endocervical adenocarcinoma. MRI is also useful for examining the nearby lymph nodes.
Dilation and curettage or an endometrial biopsy are used to obtain a tissue sample for histological examination. Endometrial biopsy is the less invasive option, but it may not give conclusive results every time. Hysteroscopy only shows the gross anatomy of the endometrium, which is often not indicative of cancer and is, therefore, not used unless in conjunction with a biopsy. Hysteroscopy can be used to confirm a diagnosis of cancer. New evidence shows that D&C has a higher false negative rate than endometrial biopsy.
Before treatment is begun, several other investigations are recommended. These include a chest x-ray, liver function tests, kidney function tests, and a test for levels of CA-125, a tumor marker that can be elevated in endometrial cancer.
=== Classification ===
Endometrial cancers may be tumors derived from epithelial cells (carcinomas), mixed epithelial and mesenchymal tumors (carcinosarcomas), or mesenchymal tumors.
Traditional classification of endometrial carcinomas is based either on clinical and endocrine features (Type I and Type II) or histopathological characteristics (endometrioid, serous, and clear-cell). Some tumors are difficult to classify and have features overlapping more than one category. High-grade endometrioid tumors, in particular, tend to have both type I and type II features.
==== Carcinoma ====
The vast majority of endometrial cancers are carcinomas (usually adenocarcinomas), meaning that they originate from the single layer of epithelial cells that line the endometrium and form the endometrial glands. There are many microscopic subtypes of endometrial carcinoma, but they are broadly organized into two categories, Type I and Type II, based on clinical features and pathogenesis. The two subtypes are genetically distinct.
Type I endometrial carcinomas occur most commonly before and around the time of menopause. In the United States, they are more common in white women, particularly those with a history of endometrial hyperplasia. Type I endometrial cancers are often low-grade, minimally invasive into the underlying uterine wall (myometrium), estrogen-dependent, and have a good outcome with treatment. Type I carcinomas represent 75–90% of endometrial cancer.
Type II endometrial carcinomas usually occur in older, post-menopausal people. In the United States, they are more common in black women and are not associated with increased exposure to estrogen or a history of endometrial hyperplasia. Type II endometrial cancers are often high-grade, with deep invasion into the underlying uterine wall (myometrium), are of the serous or clear cell type, and carry a poorer prognosis. They can appear to be epithelial ovarian cancer on evaluation of symptoms. They tend to present later than Type I tumors and are more aggressive, with a greater risk of relapse and/or metastasis.
===== Endometrioid adenocarcinoma =====
In endometrioid adenocarcinoma, the cancer cells grow in patterns reminiscent of normal endometrium, with many new glands formed from columnar epithelium with some abnormal nuclei. Low-grade endometrioid adenocarcinomas have well-differentiated cells, have not invaded the myometrium, and are seen alongside endometrial hyperplasia. The tumor's glands form very close together, without the stromal tissue that normally separates them. Higher-grade endometrioid adenocarcinomas have less well-differentiated cells, have more solid sheets of tumor cells no longer organized into glands, and are associated with an atrophied endometrium. There are several subtypes of endometrioid adenocarcinoma with similar prognoses, including villoglandular, secretory, and ciliated cell variants. There is also a subtype characterized by squamous differentiation. Some endometrioid adenocarcinomas have foci of mucinous carcinoma.
The genetic mutations most commonly associated with endometrioid adenocarcinoma are in the genes PTEN, a tumor suppressor; PIK3CA, a kinase; KRAS, a GTPase that functions in signal transduction; and CTNNB1, involved in adhesion and cell signaling. The CTNNB1 (beta-catenin) gene is most commonly mutated in the squamous subtype of endometrioid adenocarcinoma.
===== Serous carcinoma =====
Serous carcinoma is a Type II endometrial tumor that makes up 5–10% of diagnosed endometrial cancer and is common in postmenopausal women with atrophied endometrium and black women. Serous endometrial carcinoma is aggressive and often invades the myometrium and metastasizes within the peritoneum (seen as omental caking) or the lymphatic system. Histologically, it appears with many atypical nuclei, papillary structures, and, in contrast to endometrioid adenocarcinomas, rounded cells instead of columnar cells. Roughly 30% of endometrial serous carcinomas also have psammoma bodies. Serous carcinomas spread differently than most other endometrial cancers; they can spread outside the uterus without invading the myometrium.
The genetic mutations seen in serous carcinoma are chromosomal instability and mutations in TP53, an important tumor suppressor gene.
===== Clear cell carcinoma =====
Clear cell carcinoma is a Type II endometrial tumor that makes up less than 5% of diagnosed endometrial cancer. Like serous cell carcinoma, it is usually aggressive and carries a poor prognosis. Histologically, it is characterized by the features common to all clear cells: the eponymous clear cytoplasm when H&E stained and visible, distinct cell membranes. The p53 cell signaling system is not active in endometrial clear cell carcinoma. This form of endometrial cancer is more common in postmenopausal women.
===== Mucinous carcinoma =====
Mucinous carcinomas are a rare form of endometrial cancer, making up less than 1–2% of all diagnosed endometrial cancers. Mucinous endometrial carcinomas are most often stage I and grade I, giving them a good prognosis. They typically have well-differentiated columnar cells organized into glands with the characteristic mucin in the cytoplasm. Mucinous carcinomas must be differentiated from cervical adenocarcinoma.
===== Mixed or undifferentiated carcinoma =====
Mixed carcinomas are those that have both Type I and Type II cells, with one making up at least 10% of the tumor. These include the malignant mixed Müllerian tumor, which derives from endometrial epithelium and has a poor prognosis.
Undifferentiated endometrial carcinomas make up less than 1–2% of diagnosed endometrial cancers. They have a worse prognosis than grade III tumors. Histologically, these tumors show sheets of identical epithelial cells with no identifiable pattern.
===== Other carcinomas =====
Non-metastatic squamous cell carcinoma and transitional cell carcinoma are very rare in the endometrium. Squamous cell carcinoma of the endometrium has a poor prognosis. It has been reported fewer than 100 times in the medical literature since its characterization in 1892. For primary squamous cell carcinoma of the endometrium (PSCCE) to be diagnosed, there must be no other primary cancer in the endometrium or cervix, and it must not be connected to the cervical epithelium. Because of the rarity of this cancer, there are no guidelines for how it should be treated, nor any typical treatment. The common genetic causes remain uncharacterized. Primary transitional cell carcinomas of the endometrium are even more rare; 16 cases had been reported as of 2008. Its pathophysiology and treatments have not been characterized. Histologically, TCCE resembles endometrioid carcinoma and is distinct from other transitional cell carcinomas.
==== Sarcoma ====
In contrast to endometrial carcinomas, the uncommon endometrial stromal sarcomas are cancers that originate in the non-glandular connective tissue of the endometrium. They are generally non-aggressive and, if they recur, can take decades. Metastases to the lungs and pelvic or peritoneal cavities are the most frequent. They typically have estrogen and/or progesterone receptors. The prognosis for low-grade endometrial stromal sarcoma is good, with 60–90% five-year survival. High-grade undifferentiated endometrial sarcoma (HGUS) has a worse prognosis, with high rates of recurrence and 25% five-year survival. HGUS prognosis is dictated by whether or not the cancer has invaded the arteries and veins. Without vascular invasion, the five-year survival is 83%; it drops to 17% when vascular invasion is observed. Stage I ESS has the best prognosis, with a five-year survival rate of 98% and a ten-year survival rate of 89%. ESS makes up 0.2% of uterine cancers.
=== Metastasis ===
Endometrial cancer frequently metastasizes to the ovaries and Fallopian tubes when the cancer is located in the upper part of the uterus, and the cervix when the cancer is in the lower part of the uterus. The cancer usually first spreads into the myometrium and the serosa, then into other reproductive and pelvic structures. When the lymphatic system is involved, the pelvic and para-aortic nodes are usually first to become involved, but in no specific pattern, unlike cervical cancer. More distant metastases are spread by the blood and often occur in the lungs, as well as the liver, brain, and bone. Endometrial cancer metastasizes to the lungs 20–25% of the time, more than any other gynecologic cancer.
=== Histopathology ===
There is a three-tiered system for histologically classifying endometrial cancers, ranging from cancers with well-differentiated cells (grade I), to very poorly-differentiated cells (grade III). Grade I cancers are the least aggressive and have the best prognosis, while grade III tumors are the most aggressive and likely to recur. Grade II cancers are intermediate between grades I and III in terms of cell differentiation and aggressiveness of disease. There is also a separate "nuclear grade" system, where grade 1 tumors have inconspicuous cell nuclei, whereas grade 3 tumors have highly atypical nuclei.
The histopathology of endometrial cancers is highly diverse. The most common finding is a well-differentiated endometrioid adenocarcinoma, which is composed of numerous, small, crowded glands with varying degrees of nuclear atypia, mitotic activity, and stratification. This often appears on a background of endometrial hyperplasia. Frank adenocarcinoma may be distinguished from atypical hyperplasia by the finding of clear stromal invasion, or "back-to-back" glands, which represent nondestructive replacement of the endometrial stroma by the cancer. With progression of the disease, the myometrium is infiltrated.
=== Staging ===
Endometrial carcinoma is surgically staged using the FIGO cancer staging system. The 2009 FIGO staging system is commonly used. There is an updated 2023 FIGO staging system, but it is not yet universally adopted. The 2009 FIGO staging system is as follows:
Myometrial invasion and involvement of the pelvic and para-aortic lymph nodes are the most commonly seen patterns of spread. A Stage 0 is sometimes included; in this case, it is referred to as "carcinoma in situ". In 26% of presumably early-stage cancers, intraoperative staging revealed pelvic and distant metastases, making comprehensive surgical staging necessary.
== Management ==
=== Surgery ===
The initial treatment for endometrial cancer is surgery; 90% of women with endometrial cancer are treated with some form of surgery. Surgical treatment typically consists of hysterectomy including a bilateral salpingo-oophorectomy, which is the removal of the uterus, both ovaries, and the Fallopian tubes. Lymphadenectomy, or removal of pelvic and para-aortic lymph nodes, is performed for tumors of histologic grade II or above. Lymphadenectomy is routinely performed for all stages of endometrial cancer in the United States, but in the United Kingdom, the lymph nodes are typically only removed with disease of stage II or greater. The topic of lymphadenectomy and what survival benefit it offers in stage I disease is still being debated. In women with presumed stage I disease, a 2017 systematic review found no evidence that lymphadenectomy reduces the risk of death or relapse of cancer when compared with no lymphadenectomy. Women who undergo lymphadenectomy are more likely to experience systemic morbidity related to surgery or lymphoedema/lymphocyst formation. In stage III and IV cancers, cytoreductive surgery is the norm, and a biopsy of the omentum may also be included. In stage IV disease, where there are distant metastases, surgery can be used as part of palliative therapy. Laparotomy, an open-abdomen procedure, is the traditional surgical procedure; however, in those with presumed early stage primary endometrial cancer, laparoscopy (keyhole surgery) is associated with reduced operative morbidity and similar overall and disease free survival. Removal of the uterus via the abdomen is recommended over removal of the uterus via the vagina because it allows examining and obtaining washings of the abdominal cavity to detect any further evidence of cancer. Staging of the cancer is done during the surgery.
The few contraindications to surgery include inoperable tumor, massive obesity, a particularly high-risk operation, or a desire to preserve fertility. These contraindications happen in about 5–10% of cases. Women who wish to preserve their fertility and have low-grade stage I cancer can be treated with progestins, with or without concurrent tamoxifen therapy. This therapy can be continued until the cancer does not respond to treatment or until childbearing is done. Uterine perforation may occur during a D&C or an endometrial biopsy. Side effects of surgery to remove endometrial cancer can specifically include sexual dysfunction, temporary incontinence, and lymphedema, along with more common side effects of any surgery, including constipation.
=== Add-on therapy ===
There are many possible additional therapies. Surgery can be followed by radiation therapy and/or chemotherapy in cases of high-risk or high-grade cancers. This is called adjuvant therapy.
==== Chemotherapy ====
Adjuvant chemotherapy is a recent innovation, consisting of some combination of paclitaxel (or other taxanes like docetaxel), doxorubicin (and other anthracyclines), and platins (particularly cisplatin and carboplatin). Adjuvant chemotherapy has been found to increase survival in stage III and IV cancer more than added radiotherapy. Mutations in mismatch repair genes, like those found in Lynch syndrome, can lead to resistance against platins, meaning that chemotherapy with platins is ineffective in people with these mutations. Side effects of chemotherapy are common. These include hair loss, low neutrophil levels in the blood, and gastrointestinal problems.
In cases where surgery is not indicated, palliative chemotherapy is an option; higher-dose chemotherapy is associated with longer survival. Palliative chemotherapy, particularly using capecitabine and gemcitabine, is also often used to treat recurrent endometrial cancer.
Low-certainty evidence suggests that in women with recurrent endometrial cancer who have had chemotherapy, receiving drugs that inhibit the mTOR pathway may reduce the risk of disease worsening compared to having more chemotherapy or hormonal therapy. However, mTOR inhibitors may increase the chance of experiencing digestive tract ulcers.
==== Radiotherapy ====
Adjuvant radiotherapy is commonly used in early-stage (stage I or II) endometrial cancer. It can be delivered through vaginal brachytherapy (VBT), which is becoming the preferred route due to its reduced toxicity, or external beam radiotherapy (EBRT). Brachytherapy involves placing a radiation source in the organ affected; in the case of endometrial cancer a radiation source is placed directly in the vagina. External beam radiotherapy involves a beam of radiation aimed at the affected area from outside the body. VBT is used to treat any remaining cancer solely in the vagina, whereas EBRT can be used to treat remaining cancer elsewhere in the pelvis following surgery. However, the benefits of adjuvant radiotherapy are controversial. Though EBRT significantly reduces the rate of relapse in the pelvis, overall survival and metastasis rates are not improved. VBT provides a better quality of life than EBRT.
Radiotherapy can also be used before surgery in certain cases. When pre-operative imaging or clinical evaluation shows tumor invading the cervix, radiation can be given before a total hysterectomy is performed. Brachytherapy and EBRT can also be used, singly or in combination, when there is a contraindication for hysterectomy. Both delivery methods of radiotherapy are associated with side effects, particularly in the gastrointestinal tract.
==== Hormonal therapy ====
Hormonal therapy is only beneficial in certain types of endometrial cancer. It was once thought to be beneficial in most cases. If a tumor is well-differentiated and known to have progesterone and estrogen receptors, progestins may be used in treatment. There is no evidence to support the use of progestagen in addition to surgery for newly diagnosed endometrial cancer. About 25% of metastatic endometrioid cancers show a response to progestins. Also, endometrial stromal sarcomas can be treated with hormonal agents, including tamoxifen, hydroxyprogesterone caproate, letrozole, megestrol acetate, and medroxyprogesterone. This treatment is effective in endometrial stromal sarcomas because they typically have estrogen and/or progestin receptors. Progestin receptors function as tumor suppressors in endometrial cancer cells. Preliminary research and clinical trials have shown these treatments to have a high rate of response even in metastatic disease.
In 2010, hormonal therapy was of unclear effect in those with advanced or recurrent endometrial cancer. There is insufficient evidence to inform women considering hormone replacement therapy after treatment for endometrial cancer.
==== Targeted therapy ====
Dostarlimab has been approved by the FDA for therapy of endometrial cancer with specific biomarker
=== Monitoring ===
The tumor marker CA-125 is frequently elevated in endometrial cancer and can be used to monitor response to treatment, particularly in serous cell cancer or advanced disease. Periodic MRIs or CT scans may be recommended in advanced disease and women with a history of endometrial cancer should receive more frequent pelvic examinations for the five years following treatment. Examinations conducted every three to four months are recommended for the first two years following treatment, and every six months for the next three years.
Women with endometrial cancer should not have routine surveillance imaging to monitor the cancer unless new symptoms appear or tumor markers begin rising. Imaging without these indications is discouraged because it is unlikely to detect a recurrence or improve survival and because it has its costs and side effects. If a recurrence is suspected, PET/CT scanning is recommended.
== Prognosis ==
=== Survival rates ===
The five-year survival rate for endometrial adenocarcinoma following appropriate treatment is 80%. More than 70% of women diagnosed have FIGO stage I cancer, which has the best prognosis. Stage III and especially Stage IV cancers have a worse prognosis, but these are relatively rare, occurring in only 13% of cases. The median survival time for stage III–IV endometrial cancer is nine to ten months. Older age indicates a worse prognosis. In the United States, white women have a higher survival rate than black women, who tend to develop more aggressive forms of the disease by the time of their diagnosis. Tumors with high progesterone receptor expression have a good prognosis compared to tumors with low progesterone receptor expression; 93% of women with high progesterone receptor disease survived to three years, compared with 36% of women with low progesterone receptor disease. Heart disease is the most common cause of death among those who survive endometrial cancer, with other obesity-related health problems also being common. Following diagnosis, quality of life is also positively associated with a healthy lifestyle (no obesity, high-quality diet, physical activity).
=== Recurrence rates ===
Recurrence of early-stage endometrial cancer ranges from 3% to 17%, depending on primary and adjuvant treatment. Most recurrences (75–80%) occur outside of the pelvis, and most occur within two to three years of treatment—64% within two years and 87% within three years.
Higher-staged cancers are more likely to recur, as are those that have invaded the myometrium or cervix or that have metastasized into the lymphatic system. Papillary serous carcinoma, clear cell carcinoma, and endometrioid carcinoma are the subtypes at the highest risk of recurrence. High-grade histological subtypes are also at elevated risk for recurrence.
The most common site of recurrence is in the vagina; vaginal relapses of endometrial cancer have the best prognosis. If relapse occurs from a cancer that has not been treated with radiation, EBRT is the first-line treatment and is often successful. If a cancer treated with radiation recurs, pelvic exenteration is the only option for curative treatment. Palliative chemotherapy, cytoreductive surgery, and radiation are also performed. Radiation therapy (VBT and EBRT) for a local vaginal recurrence has a 50% five-year survival rate. Pelvic recurrences are treated with surgery and radiation, and abdominal recurrences are treated with radiation and, if possible, chemotherapy. Other common recurrence sites are the pelvic lymph nodes, para-aortic lymph nodes, peritoneum (28% of recurrences), and lungs, though recurrences can also occur in the brain (<1%), liver (7%), adrenal glands (1%), bones (4–7%; typically the axial skeleton), lymph nodes outside the abdomen (0.4–1%), spleen, and muscle/soft tissue (2–6%).
== Epidemiology ==
As of 2014, approximately 320,000 women are diagnosed with endometrial cancer worldwide each year and 76,000 die, making it the sixth most common cancer in women. It is more common in developed countries, where the lifetime risk of endometrial cancer in women is 1.6%, compared to 0.6% in developing countries. It occurs in 12.9 out of 100,000 women annually in developed countries.
In the United States, endometrial cancer is the most frequently diagnosed gynecologic cancer and, in women, the fourth most common cancer overall, representing 6% of all cancer cases in women. In that country, as of 2014 it was estimated that 52,630 women were diagnosed yearly and 8,590 would die from the disease. Northern Europe, Eastern Europe, and North America have the highest rates of endometrial cancer, whereas Africa and West Asia have the lowest rates. Asia saw 41% of the world's endometrial cancer diagnoses in 2012, whereas Northern Europe, Eastern Europe, and North America together comprised 48% of diagnoses. Unlike most cancers, the number of new cases has risen in recent years, including an increase of over 40% in the United Kingdom between 1993 and 2013. Some of this rise may be due to the increase in obesity rates in developed countries, increasing life expectancies, and lower birth rates. The average lifetime risk for endometrial cancer is approximately 2–3% in people with uteruses. In the UK, approximately 7,400 cases are diagnosed annually, and in the EU, approximately 88,000.
Endometrial cancer appears most frequently during perimenopause (the period just before, just after, and during menopause), between the ages of 50 and 65; overall, 75% of endometrial cancer occurs after menopause. Women younger than 40 make up 5% of endometrial cancer cases and 10–15% of cases occur in women under 50 years of age. This age group is at risk for developing ovarian cancer at the same time. The worldwide median age of diagnosis is 63 years of age; in the United States, the average age of diagnosis is 60 years of age. White American women are at higher risk for endometrial cancer than black American women, with a 2.88% and 1.69% lifetime risk, respectively. Japanese-American women and American Latina women have lower rates, and Native Hawaiian women have higher rates.
== Research ==
There are several experimental therapies for endometrial cancer under research, including immunologic, hormonal, and chemotherapeutic treatments. Trastuzumab (Herceptin), an antibody against the Her2 protein, has been used in cancers known to be positive for the Her2/neu oncogene, but research is still underway. Immunologic therapies are also under investigation, particularly in uterine papillary serous carcinoma.
Cancers can be analyzed using genetic techniques (including DNA sequencing and immunohistochemistry) to determine if certain therapies specific to mutated genes can be used to treat it. PARP inhibitors are used to treat endometrial cancer with PTEN mutations, specifically, mutations that lower the expression of PTEN. The PARP inhibitor shown to be active against endometrial cancer is olaparib. Research has been ongoing in this area as of the 2010s.
Research is ongoing on the use of metformin, a diabetes medication, in obese women with endometrial cancer before surgery. Early research has shown it to be effective in slowing the rate of cancer cell proliferation. Preliminary research has shown that preoperative metformin administration can reduce the expression of tumor markers. Long-term use of metformin has not been shown to have a preventative effect against developing cancer, but it may improve overall survival.
Temsirolimus, an mTOR inhibitor, is under investigation as a potential treatment. Research shows that mTOR inhibitors may be particularly effective for cancers with mutations in PTEN. Ridaforolimus (deforolimus) is also being researched as a treatment for people who have previously had chemotherapy. Preliminary research has been promising, and a stage II trial for ridaforolimus was completed by 2013. There has also been research on combined ridaforolimus/progestin treatments for recurrent endometrial cancer. Bevacizumab and tyrosine kinase inhibitors, which inhibit angiogenesis, are being researched as potential treatments for endometrial cancers with high levels of vascular endothelial growth factor. Ixabepilone is being researched as a possible chemotherapy for advanced or recurrent endometrial cancer. Treatments for rare high-grade undifferentiated endometrial sarcoma are being researched, as there is no established standard of care yet for this disease. Chemotherapies being researched include doxorubicin and ifosfamide.
There is also research in progress on more genes and biomarkers that may be linked to endometrial cancer. The protective effect of combined oral contraceptives and the IUD is being investigated. Preliminary research has shown that the levonorgestrel IUD placed for a year, combined with six monthly injections of gonadotropin-releasing hormone, can stop or reverse the progress of endometrial cancer in young women, specifically complex atypical hyperplasia; however, the results have been inconclusive. An experimental drug that combines a hormone with doxorubicin is also under investigation for greater efficacy in cancers with hormone receptors. Hormone therapy that is effective in treating breast cancer, including the use of aromatase inhibitors, is also being investigated for use in endometrial cancer. One such drug is anastrozole, which is currently being researched in hormone-positive recurrences after chemotherapy. Research into hormonal treatments for endometrial stromal sarcomas is ongoing as well. It includes trials of drugs like mifepristone, a progestin antagonist, and aminoglutethimide and letrozole, two aromatase inhibitors.
Research continues into the best imaging method for detecting and staging endometrial cancer. As current diagnostic methods are invasive and inaccurate, researchers are looking into new ways to catch endometrial cancer, especially in its early stages. A study found that using a technique involving infrared light on simple blood test samples detected uterine cancer with high accuracy (87%) and could detect precancerous growths in all cases. In surgery, research has shown that complete pelvic lymphadenectomy along with hysterectomy in stage 1 endometrial cancer does not improve survival and increases the risk of negative side effects, including lymphedema. Other research is exploring the potential of identifying the sentinel lymph nodes for biopsy by injecting the tumor with dye that shines under infrared light. Intensity modulated radiation therapy is currently under investigation and already used in some centers for application in endometrial cancer to reduce side effects from traditional radiotherapy. Its risk of recurrence has not yet been quantified. Research on hyperbaric oxygen therapy to reduce side effects is also ongoing. The results of the PORTEC 3 trial assessing combining adjuvant radiotherapy with chemotherapy were awaited in late 2014.
There is not enough evidence to determine if people with endometrial cancer benefit from additional behavioural and lifestyle interventions that are aimed at losing excess weight.
== History and culture ==
Endometrial cancer is not widely known by the general populace despite its frequency. There is low awareness of the symptoms, which can lead to later diagnosis and worse survival.
== References ==
== External links ==
American Cancer Society's Detailed Guide: Endometrial Cancer
U.S. National Cancer Institute: Uterine cancer
Anatomical pathology images | Wikipedia/Endometrial_cancer |
Abiraterone acetate, sold under the brand name Zytiga among others, is a medication used to treat prostate cancer. Specifically it is used together with a corticosteroid for metastatic castration-resistant prostate cancer (mCRPC) and metastatic high-risk castration-sensitive prostate cancer (mCSPC). It should either be used following removal of the testicles or along with a gonadotropin-releasing hormone (GnRH) analog. It is taken by mouth.
Common side effects include tiredness, vomiting, headache, joint pain, high blood pressure, swelling, low blood potassium, high blood sugar, hot flashes, diarrhea, and cough. Other severe side effects may include liver failure and adrenocortical insufficiency. In males whose partners can become pregnant, birth control is recommended. Supplied as abiraterone acetate it is converted in the body to abiraterone. Abiraterone acetate works by suppressing the production of androgens – specifically it inhibits CYP17A1 – and thereby decreases the production of testosterone. In doing so, it prevents the effects of these hormones in prostate cancer.
Abiraterone acetate was described in 1995, and approved for medical use in the United States and the European Union in 2011. It is on the World Health Organization's List of Essential Medicines. It is available as a generic medication.
== Medical uses ==
Abiraterone acetate is used in combination with prednisone, a corticosteroid, as a treatment for mCRPC (previously called hormone-resistant or hormone-refractory prostate cancer). This is a form of prostate cancer that is not responding to first-line androgen deprivation therapy or treatment with androgen receptor antagonists. Abiraterone acetate has received Food and Drug Administration (FDA) (28 April 2011), European Medicines Agency (EMA) (23 September 2011), Medicines and Healthcare products Regulatory Agency (MHRA) (5 September 2011) and Therapeutic Goods Administration (TGA) (1 March 2012) approval for this indication. In Australia it is covered by the Pharmaceutical Benefits Scheme when being used to treat castration-resistant prostate cancer and given in combination with prednisone/prednisolone (subject to the conditions that the patient is not currently receiving chemotherapy, is either resistant or intolerant of docetaxel, has a WHO performance status of <2, and his disease has not since become progressive since treatment with PBS-subsidised abiraterone acetate has commenced).
Abiraterone acetate/methylprednisolone, sold under the brand name Yonsa Mpred, is a composite package that contains both abiraterone acetate (Yonsa) and methylprednisolone. It was approved for medical use in Australia in March 2022.
== Contraindications ==
Contraindications include hypersensitivity to abiraterone acetate. Although documents state that it should not be taken by women who are or who may become pregnant, there is no medical reason that any woman should take it. Women who are pregnant should not even touch the pills unless they are wearing gloves. Other cautions include severe baseline hepatic impairment, mineralocorticoid excess, cardiovascular disease including heart failure and hypertension, uncorrected hypokalemia, and adrenocorticoid insufficiency.
== Side effects ==
Side effects by frequency:
Very common (>10% frequency):
Common (1-10% frequency):
Uncommon (0.1-1% frequency):
Adrenal insufficiency
Myopathy
Rhabdomyolysis
Rare (<0.1% frequency):
Allergic alveolitis
== Overdose ==
Experience with overdose of abiraterone acetate is limited. There is no specific antidote for abiraterone acetate overdose, and treatment should consist of general supportive measures, including monitoring of cardiac and liver function.
== Interactions ==
Abiraterone acetate is a CYP3A4 substrate and hence should not be administered concurrently with strong CYP3A4 inhibitors such as ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone,
saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) or inducers such as phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital. It also inhibits CYP1A2, CYP2C9, and CYP3A4 and likewise should not be taken concurrently with substrates of any of these enzymes that have a narrow therapeutic index.
Spironolactone generally exerts anti-androgenic effects, but experimental evidence exists that it acts as an androgen receptor agonist in an androgen-depleted environment, capable of inducing prostate cancer proliferation. This is supported by the observations described in several case reports.
== Pharmacology ==
=== Pharmacodynamics ===
==== Antiandrogenic activity ====
Abiraterone, the active metabolite of abiraterone acetate, inhibits CYP17A1, which manifests as two enzymes, 17α-hydroxylase (IC50Tooltip half-maximal inhibitory concentration = 2.5 nM) and 17,20-lyase (IC50 = 15 nM) (approximately 6-fold more selective for inhibition of 17α-hydroxylase over 17,20-lyase) that are expressed in testicular, adrenal, and prostatic tumor tissues. CYP17A1 catalyzes two sequential reactions: (a) the conversion of pregnenolone and progesterone to their 17α-hydroxy derivatives by its 17α-hydroxylase activity, and (b) the subsequent formation of dehydroepiandrosterone (DHEA) and androstenedione, respectively, by its 17,20-lyase activity. DHEA and androstenedione are androgens and precursors of testosterone. Inhibition of CYP17A1 activity by abiraterone acetate thus decreases circulating levels of androgens such as DHEA, testosterone, and dihydrotestosterone (DHT). Abiraterone acetate, via abiraterone, has the capacity to lower circulating testosterone levels to less than 1 ng/dL (i.e., undetectable) when added to castration. These concentrations are considerably lower than those achieved by castration alone (~20 ng/dL). The addition of abiraterone acetate to castration was found to reduce levels of DHT by 85%, DHEA by 97 to 98%, and androstenedione by 77 to 78% relative to castration alone. In accordance with its antiandrogenic action, abiraterone acetate decreases the weights of the prostate gland, seminal vesicles, and testes.
Abiraterone also acts as a partial antagonist of the androgen receptor (AR), and as an inhibitor of the enzymes 3β-hydroxysteroid dehydrogenase (3β-HSD), CYP11B1 (steroid 11β-hydroxylase), CYP21A2 (Steroid 21-hydroxylase), and other CYP450s (e.g., CYP1A2, CYP2C9, and CYP3A4). In addition to abiraterone itself, part of the activity of the drug has been found to be due to a more potent active metabolite, δ4-abiraterone (D4A), which is formed from abiraterone by 3β-HSD. D4A is an inhibitor of CYP17A1, 3β-hydroxysteroid dehydrogenase/Δ5-4 isomerase, and 5α-reductase, and has also been found to act as a competitive antagonist of the AR reportedly comparable to the potent antagonist enzalutamide. However, the initial 5α-reduced metabolite of D4A, 3-keto-5α-abiraterone, is an agonist of the AR, and promotes prostate cancer progression. Its formation can be blocked by the coadministration of dutasteride, a potent and selective 5α-reductase inhibitor.
==== Estrogenic activity ====
There has been interest in the use of abiraterone acetate for the treatment of breast cancer due to its ability to lower estrogen levels. However, abiraterone has been found to act as a direct agonist of the estrogen receptor, and induces proliferation of human breast cancer cells in vitro. If abiraterone acetate is used in the treatment of breast cancer, it should be combined with an estrogen receptor antagonist like fulvestrant. In spite of its antiandrogenic and estrogenic properties, abiraterone acetate does not appear to produce gynecomastia as a side effect.
==== Other activities ====
Due to inhibition of glucocorticoid biosynthesis, abiraterone acetate can cause glucocorticoid deficiency, mineralocorticoid excess, and associated adverse effects. This is why the medication is combined with prednisone, a corticosteroid, which serves as a means of glucocorticoid replacement and prevents mineralocorticoid excess.
Abiraterone acetate, along with galeterone, has been identified as an inhibitor of sulfotransferases (SULT2A1, SULT2B1b, SULT1E1), which are involved in the sulfation of DHEA and other endogenous steroids and compounds, with Ki values in the sub-micromolar range.
=== Pharmacokinetics ===
After oral administration, abiraterone acetate, the prodrug form in the commercial preparation, is converted into the active form, abiraterone. This conversion is likely to be esterase-mediated and not CYP-mediated. Administration with food increases absorption of the drug and thus has the potential to result in increased and highly variable exposures; the drug should be consumed on an empty stomach at least one hour before or two hours after food. The drug is highly protein bound (>99%), and is metabolized in the liver by CYP3A4 and SULT2A1 to inactive metabolites. The drug is excreted in feces (~88%) and urine (~5%), and has a terminal half-life of 12 ± 5 hours.
== Chemistry ==
Abiraterone acetate, also known as 17-(3-pyridinyl)androsta-5,16-dien-3β-ol acetate, is a synthetic androstane steroid and a derivative of androstadienol (androsta-5,16-dien-3β-ol), an endogenous androstane pheromone. It is specifically a derivative of androstadienol with a pyridine ring attached at the C17 position and an acetate ester attached to the C3β hydroxyl group. Abiraterone acetate is the C3β acetate ester of abiraterone.
== History ==
In the early 1990s, Mike Jarman, Elaine Barrie, and Gerry Potter of the Cancer Research UK Centre for Cancer Therapeutics in the Institute of Cancer Research in London set out to develop drug treatments for prostate cancer. With the nonsteroidal androgen synthesis inhibitor ketoconazole as a model, they developed abiraterone acetate, filing a patent in 1993 and publishing the first paper describing it the following year. Rights for commercialization of the drug were assigned to BTG, a UK-based specialist healthcare company. BTG then licensed the product to Cougar Biotechnology, which began development of the commercial product. In 2009, Cougar was acquired by Johnson & Johnson, which developed and sells the commercial product, and is conducting ongoing clinical trials to expand its clinical uses.
Abiraterone acetate was approved by the United States Food and Drug Administration on 28 April 2011 for mCRPC. The FDA press release made reference to a phase III clinical trial in which abiraterone acetate use was associated with a median survival of 14.8 months versus 10.9 months with placebo; the study was stopped early because of the successful outcome. Abiraterone acetate was also licensed by the European Medicines Agency. Until May 2012 the National Institute for Health and Clinical Excellence (NICE) did not recommend use of the drug within the NHS on cost-effectiveness grounds. This position was reversed when the manufacturer submitted revised costs. The use is currently limited to men who have already received one docetaxel-containing chemotherapy regimen. It was subsequently approved for the treatment of mCSPC in 2018.
== Society and culture ==
=== Names ===
Abiraterone is the INNTooltip International Nonproprietary Name and BANTooltip British Approved Name of abiraterone acetate's major active metabolite abiraterone. Abiraterone acetate is the USANTooltip United States Adopted Name, BANMTooltip British Approved Name Modified, and JANTooltip Japanese Accepted Name of abiraterone acetate. It is also known by its developmental code names CB-7630 and JNJ-212082, while CB-7598 was the developmental code name of abiraterone.
Abiraterone acetate is marketed by Janssen Biotech (a subsidiary of Johnson & Johnson) under the brand name Zytiga, and by Sun Pharmaceutical under the brand name Yonsa.
Generic versions of abiraterone acetate have been approved in the United States. Generic versions of Yonsa are not available as of November 2019. In May 2019, the United States Court of Appeals for the Federal Circuit upheld a Patent Trial and Appeal Board decision invalidating a patent by Johnson & Johnson on abiraterone acetate.
Intas Pharmaceuticals markets the drug under the brand name Abiratas, Cadila Pharmaceuticals markets the drug as Abretone, and Glenmark Pharmaceuticals as Abirapro. It is marketed as Yonsa by Sun Pharmaceutical Industries (licensed from Churchill Pharmaceuticals).
=== Brand names ===
Abiraterone acetate is marketed widely throughout the world, including in the United States, Canada, the United Kingdom, Ireland, elsewhere in Europe, Australia, New Zealand, Latin America, Asia, and Israel.
=== Economics ===
A generic version is available in India at a price of $238 a month as of 2019. The National Centre for Pharmacoeconomics initially found abiraterone acetate to not be cost effective based on prices in 2012, however following an agreement to supply at a lower price it was accepted in 2014. A generic Zytiga version is available in India at a price of under $230 a month as of 2020.
== Research ==
Abiraterone acetate is under development for the treatment of breast cancer and ovarian cancer and as of March 2018, is in phase II clinical trials for these indications. It was also under investigation for the treatment of congenital adrenal hyperplasia, but no further development has been reported for this potential use.
== Prostate cancer ==
In people previously treated with docetaxel survival is increased by 3.9 months (14.8 months versus 10.9 months for placebo).
In people with castration-refractory prostate cancer but who had not received chemotherapy those who received abiraterone acetate had a progression-free survival of 16.5 months rather than 8.3 months with placebo. After a median follow-up period of 22.2 months, overall survival was better with abiraterone acetate.
Abiraterone acetate may be useful for prevention of the testosterone flare at the initiation of GnRH agonist therapy in men with prostate cancer.
== References == | Wikipedia/Abiraterone_acetate |
Estradiol valerate (EV), sold for use by mouth under the brand name Progynova and for use by injection under the brand names Delestrogen and Progynon Depot among others, is an estrogen medication. It is used in hormone therapy for menopausal symptoms and low estrogen levels, hormone therapy for transgender people, and in hormonal birth control. It is also used in the treatment of prostate cancer. The medication is taken by mouth or by injection into muscle or fat once every 1 to 4 weeks.
Side effects of estradiol valerate include breast tenderness, breast enlargement, nausea, headache, and fluid retention. Estradiol valerate is an estrogen and hence is an agonist of the estrogen receptor, the biological target of estrogens like estradiol. It is an estrogen ester and a prodrug of estradiol in the body. Because of this, it is considered to be a natural and bioidentical form of estrogen.
Estradiol valerate was first described in 1940 and was introduced for medical use in 1954. Along with estradiol cypionate, it is one of the most widely used esters of estradiol. Estradiol valerate is used in the United States, Canada, Europe, and throughout much of the rest of the world. It is available as a generic medication.
== Medical uses ==
The medical uses of estradiol valerate are the same as those of estradiol and other estrogens. Examples of indications for the medication include hormone therapy and hormonal contraception. In regard to the latter, estradiol valerate is available in combination with a progestin as a combined estradiol-containing oral contraceptive (with dienogest) and as a combined injectable contraceptive. Along with estradiol cypionate, estradiol undecylate, and estradiol benzoate, estradiol valerate is used as a form of high-dose estrogen therapy in feminizing hormone therapy for transgender women. It is also used as a form of high-dose estrogen therapy in the treatment of prostate cancer in men. Low-dose oral estradiol valerate (2–6 mg/day) has been used in the treatment of breast cancer in women who were previously treated with and benefited from but acquired resistance to aromatase inhibitors as well. Injectable estradiol valerate has been used to suppress sex drive in sex offenders.
In the United States, the approved indications of estradiol valerate injections include the treatment of moderate to severe hot flashes and vaginal atrophy associated with menopause in women, the treatment of hypoestrogenism due to hypogonadism, castration, or primary ovarian failure in women, and the palliative treatment of advanced prostate cancer in men. Elsewhere in the world, oral estradiol valerate is similarly approved for the treatment of symptoms associated with menopause or hypoestrogenism due to castration in women. Such symptoms may include hot flashes, outbreaks of sweat, sleep disturbances, depressive moods, irritability, headaches, and dizziness.
Estradiol valerate by intramuscular injection is usually used at a dosage of 10 to 20 mg every 4 weeks in the treatment of menopausal symptoms and hypoestrogenism due to hypogonadism, castration, or primary ovarian failure in women. In the past, it was used at even higher doses of 10 to 40 every 1 to 4 weeks for estrogen replacement. Estradiol valerate is usually used in the treatment of advanced prostate cancer in men at a dosage of 30 mg or more every 1 to 2 weeks by intramuscular injection. In transgender women, estradiol valerate given by intramuscular injection is usually used at a dosage of 5 to 20 mg, but up to 30 to 40 mg, once every 2 weeks. Estradiol valerate has also been used at a dose of 10 to 40 mg by intramuscular injection to limit bleeding in women with hemorrhage due to dysfunctional uterine bleeding.: 318 : 60
=== Available forms ===
Estradiol valerate is and has been available in the form of vials and ampoules of oil solution for intramuscular injection in concentrations of 4, 5, 10, 20, and 40 mg/mL and in the form of oral tablets at doses of 0.5, 1, 2, and 4 mg per tablet. In the United States, it is specifically available in formulations of 10, 20, and 40 mg/mL in oil solution (as Delestrogen, as well as generics). Aside from estradiol valerate, the only other injectable estrogen formulations that remain available in the United States are estradiol cypionate (5 mg/mL in oil solution) and conjugated estrogens (25 mg/vial in solution). Some or all oral estradiol valerate tablets are micronized, similarly to oral estradiol tablets.
In addition to single-drug formulations, oral estradiol valerate is available in combination with the progestin dienogest as a combined oral contraceptive and intramuscular estradiol valerate is marketed at a concentration of 5 mg/mL in combination with the progestin hydroxyprogesterone caproate and with the progestin norethisterone enantate as combined injectable contraceptives. Intramuscular estradiol valerate is also marketed at a concentration of 4 mg/mL in combination with the weak androgen and neurosteroid prasterone enanthate (DHEA enanthate) and with the androgen testosterone enantate for use in menopausal hormone therapy, but the latter formulation has been discontinued. The availability of estradiol valerate-containing products varies throughout the world.
== Contraindications ==
Contraindications of estrogens include coagulation problems, cardiovascular diseases, liver disease, and certain hormone-sensitive cancers such as breast cancer and endometrial cancer, among others.
== Side effects ==
The side effects of estradiol valerate are the same as those of estradiol. Examples of such side effects include breast tenderness and enlargement, nausea, bloating, edema, headache, and melasma. High-dose estrogen therapy with estradiol valerate injections may also cause an increased risk of thromboembolism, changes in blood lipid profile, increased insulin resistance, and increased levels of prolactin.
== Overdose ==
Estradiol valerate has been used at very high doses of 40 to 100 mg once per week in women and men, without overt signs of acute toxicity observed. Symptoms of estrogen overdosage may include nausea, vomiting, bloating, increased weight, water retention, breast tenderness, vaginal discharge, heavy legs, and leg cramps. These side effects can be diminished by reducing the estrogen dosage.
== Interactions ==
Inhibitors and inducers of cytochrome P450 may influence the metabolism of estradiol and by extension circulating estradiol levels.
== Pharmacology ==
=== Pharmacodynamics ===
Estradiol valerate is an estradiol ester, or a prodrug of estradiol. As such, it is an estrogen, or an agonist of the estrogen receptors. The affinity of estradiol valerate for the estrogen receptor is approximately 50 times lower than that of estradiol. In addition, estradiol valerate is rapidly cleaved into estradiol and is unable to reach target tissues in concentrations of significance, if at all. As such, estradiol valerate is essentially inactive in terms of estrogenic effect itself, acting solely as a prodrug to estradiol. The molecular weight of estradiol valerate is about 131% of that of estradiol due to the presence of its C17β valerate ester, and hence estradiol valerate contains about 76% of the amount of estradiol of an equal dose of estradiol. Aside from dose adjustment to account for the difference in molecular weight, oral estradiol valerate is considered to be equivalent to oral estradiol. Because estradiol valerate is a prodrug of estradiol, it is considered to be a natural and bioidentical form of estrogen.
==== Effects on liver protein synthesis ====
The influence of 2 mg/day oral estradiol valerate on coagulation factors is less than that of 10 μg/day oral ethinylestradiol. Oral ethinylestradiol at 10 μg/day has been found to have about 1.5- to 2.5-fold the impact of 2 mg/day oral estradiol valerate on HDL cholesterol and triglycerides. The influence of 20 or 50 μg/day oral ethinylestradiol on coagulation factors and HDL cholesterol is markedly greater than that of 2 mg/day oral estradiol valerate.
Estradiol-containing birth control pills, which contain 1 to 3 mg/day estradiol or estradiol valerate, have been found to increase sex hormone-binding globulin (SHBG) levels by 1.5-fold. Oral estradiol valerate at 6 mg/day has been found to increase SHBG levels by 2.5- to 3-fold in transgender women. For comparison, combined birth control pills containing ethinylestradiol and a progestin with minimal androgenic or antiandrogenic activity have been found to increase SHBG levels by about 3- to 4-fold.
=== Pharmacokinetics ===
Regardless of the route of administration, estradiol valerate behaves as a prodrug of estradiol via cleavage by esterases into estradiol and the natural fatty acid valeric acid. This cleavage occurs not only in the liver, but also in the blood and in tissues, and the hydrolysis of estradiol valerate into estradiol and valeric acid is complete regardless of whether the medication is administered orally or parenterally. High levels of circulating estradiol are found after an intravenous injection of estradiol valerate, and this indicates very rapid cleavage of the medication upon entering circulation.
==== Oral administration ====
Esterification of the C17β position of estradiol as in estradiol valerate reduces the metabolism of estradiol valerate by 17β-hydroxysteroid dehydrogenase (17β-HSD). As approximately 80% of estradiol is metabolized into estrone (and estrone sulfate) by 17β-HSD during first-pass metabolism, this improves the metabolic stability and hence bioavailability of estradiol valerate. However, estradiol valerate is hydrolyzed into estradiol and valeric acid in the intestines, and hence, is still subject to extensive first-pass metabolism. As such, the oral bioavailability of estradiol valerate is only around 3 to 5%, and is similar to that of oral estradiol. All oral tablets in the cases of both estradiol and estradiol valerate seem to be micronized. Due to its nature as a rapidly converted prodrug of estradiol, the pharmacokinetics of oral estradiol valerate are similar to those of oral estradiol. Moreover, the pharmacodynamics and potency (after differences in molecular weight are taken into account) of oral estradiol valerate are considered to be equivalent to those of oral estradiol. This is also notably true for effects on hepatic protein synthesis (e.g., of SHBGTooltip sex hormone-binding globulin), again after differences in molecular weight between the two compounds are considered.
A dosage of 1 mg/day oral estradiol valerate has been found to produce approximate circulating concentrations of 50 pg/mL estradiol and 160 pg/mL estrone, while a dosage of 2 mg/day results in circulating levels of 60 pg/mL estradiol and 300 pg/mL estrone. These concentrations of estradiol and estrone are comparable to those observed with 1 and 2 mg/day oral estradiol. A review of selected studies reported a range of mean peak estradiol levels of 24 to 140 pg/mL occurring 1 to 12 hours after administration of 2 mg oral estradiol valerate. A study found that, in accordance with their differences in molecular weights, oral estradiol produced higher levels of estradiol than oral estradiol valerate. Likewise, other studies found that levels of estradiol and estrone are very similar after oral administration of roughly equimolar doses of estradiol (1.5 mg) and estradiol valerate (2 mg). A study of high-dose oral estradiol valerate found levels of estradiol of about 250 pg/mL after a single 10-mg dose in three women.
==== Sublingual administration ====
Estradiol valerate has been studied by sublingual administration in premenopausal women for the purpose of cycle control and ovulation suppression in egg donation and surrogacy. It has been investigated for this indication, along with vaginal and transdermal estradiol, because oral estradiol valerate is sometimes unable to achieve adequate estradiol levels and hence proper cycle control in this situation. Sublingual administration of estradiol valerate bypasses the first pass that occurs with the oral route and results in higher levels of estradiol and improved cycle control. Sublingual estradiol valerate is also used in hormone therapy for transgender women.
The administration of 2 mg oral micronized estradiol valerate tablets (Progynova, Schering) sublingually 3 or 4 times per day has been found to result in circulating estradiol levels of about 290 pg/mL to 460 pg/mL in premenopausal women (time of measurements not given). Steady-state levels of estradiol were achieved within about 2 or 3 days. Levels of progesterone, luteinizing hormone, and follicle-stimulating hormone were all considerably suppressed, and ovulation, as well as the associated mid-cycle hormonal surges, were prevented. Similarly to oral administration of estradiol, but in contrast to the vaginal and transdermal routes, the ratio of estradiol to estrone is decreased with sublingual administration of either estradiol valerate or estradiol.
==== Intramuscular injection ====
In contrast to oral administration, the bioavailability of estradiol valerate is complete (i.e., 100%) via intramuscular injection. Due to the far greater bioavailability of intramuscular estradiol valerate relative to oral, the former is substantially stronger (in terms of potency) than the latter. As an example, a single 4 mg intramuscular injection is said to be approximately equivalent to 2 mg/day of the medication administered orally over the course of 3 weeks. Estradiol valerate, when given intramuscularly in oil, has a relatively long duration due to the formation of an intramuscular depot from which the medication is slowly released and absorbed. Upon intramuscular injection of estradiol valerate in an oil solution, the solvent (i.e., oil) is absorbed, and a primary microcrystalline depot is formed within the muscle at the site of injection. In addition, a secondary depot may also be formed in adipose tissue. The slow release of estradiol valerate is caused by the increased lipophilicity of the medication, which in turn is due to its long fatty acid valeric acid ester moiety. The elimination half-life of estradiol valerate in oil by intramuscular injection (brand names Estradiol-Depot 10 mg, Progynon Depot-10) is about 3.5 days, with a range of 1.2 days to 7.2 days in different individuals. Α couple of older studies from the 1980s with sample sizes of only 2 or 3 individuals reported an elimination half-life of 4 to 5 days.
A single intramuscular injection of 4 mg estradiol valerate has been found to result in maximal circulating levels of estradiol of about 390 pg/mL within 3 days of administration, with levels declining to 100 pg/mL (baseline, in the study) by 12 to 13 days. Studies in general have found that a single intramuscular injection of 4 mg estradiol valerate results in peak levels of estradiol of 240 to 540 pg/mL after 1 to 5 days following administration. A study found that a single intramuscular injection of 5 mg estradiol valerate resulted in peak circulating levels of 667 pg/mL estradiol and 324 pg/mL estrone within approximately 2 and 3 days, respectively. The duration of estradiol valerate at this dose and in this study was considered to be 7 to 8 days. Other studies have found that larger doses of intramuscular estradiol valerate exceeding 20 mg have a duration of more than 15 days. A third study, in contrast to the preceding study, found that a single 10 mg intramuscular injection of estradiol valerate resulted in maximal estradiol levels of 506 to 544 pg/mL and maximal estrone levels of 205 to 219 pg/mL in postmenopausal women.
With intramuscular injections of estradiol valerate, it has been reported that a dose of 5 mg has a duration of 7 to 8 days, 10 mg a duration of 10 to 14 days, 40 mg a duration of 2 to 3 weeks (14 to 21 days), and 100 mg a duration of 3 to 4 weeks (21 to 28 days).
A study of pseudopregnancy with intramuscular injections of 40 mg/week estradiol valerate and 250 mg/week hydroxyprogesterone caproate in women with estrogen deficiency observed estradiol levels of about 3,100 pg/mL at 3 months of therapy and 2,500 pg/mL at 6 months of therapy.
==== Subcutaneous injection ====
Estradiol esters like estradiol valerate and estradiol cypionate can be given by subcutaneous injection instead of intramuscular injection.
==== Intravenous injection ====
The administration of estradiol valerate by intravenous injection has been studied. It has been found to be very rapidly cleaved into estradiol. The bioavailability and metabolism of estradiol valerate does not differ with intravenous versus intramuscular injection. Conversely, intravenous injection of estradiol valerate has a very short duration, whereas intramuscular injection has a long duration and elimination half-life.
== Chemistry ==
Estradiol valerate is a synthetic estrane steroid and the C17β valerate (pentanoate) fatty acid ester of estradiol. It is also known as estradiol 17β-valerate or as estra-1,3,5(10)-triene-3,17β-diol 17β-pentanoate. Other common esters of estradiol in use include estradiol cypionate, estradiol enantate, and estradiol acetate, the former two of which are C17β esters of estradiol similarly to estradiol valerate and the latter of which is the C3 acetate ester of estradiol.
The experimental log octanol/water partition coefficient (log P) of estradiol valerate is 5.6.
== History ==
Estradiol valerate was patented by Ciba in 1940 and 1941, with a priority date of 1936. It was synthesized and studied, along with a variety of other estradiol esters, by Karl Junkmann of Schering AG in 1953. The medication was first introduced for medical use via intramuscular injection in 1954 by Schering in Europe under the brand name Progynon Depot and by Squibb in the United States under the brand name Delestrogen. In 1966, oral estradiol valerate was introduced by Schering for medical use in Europe under the brand name Progynova. A report of its metabolism was published in 1967. Esterification of estradiol, as in estradiol valerate, has been claimed to improve its metabolic stability with oral administration. In 1968, micronized preparations of oral estradiol valerate were first introduced under the brand names Progynova 21 and Progynova 21 mite. Along with estradiol benzoate (1933) and estradiol cypionate (1952), estradiol valerate is one of the most widely used esters of estradiol.
== Society and culture ==
=== Generic names ===
Estradiol valerate is the generic name of the drug and its INNTooltip International Nonproprietary Name, USANTooltip United States Adopted Name, BANMTooltip British Approved Name, and JANTooltip Japanese Accepted Name, while oestradiol valerate was formerly its BANMTooltip British Approved Name.
=== Brand names ===
Estradiol valerate has been marketed under the brand names Altadiol, Androtardyl-Oestradiol, Ardefem, Climaval, Cyclabil, Cyclocur, Deladiol, Delahormone Unimatic, Delestrogen, Delestrogen 4X, Depogen, Diol-20, Dioval, Ditate, Dura-Estate, Dura-Estradiol, Duratrad, Duragen, Estate, Estra-L, Estradiol Depot, Estraval, Estraval Depot, Estraval PA, Estravel, Femogen, Femogex, Gynogen L.A., Gynokadin, Lastrogen, Menaval, Merimono, Neofollin, Nuvelle, Oestrogynal, Ostrin Depo, Pelanin, Pharlon, Postoval, Primogyna, Primogyn, Primogyn Depot, Progynon, Progynon Depot, Progynova, Repestrogen, Repo-Estra, Reposo-E, Retestrin, Ronfase, Span-Est, Testaval, and Valergen, among others. Neofollin is an oil solution of estradiol valerate.
=== Availability ===
Oral estradiol valerate is used primarily in Europe, under the brand name Progynova. Although oral estradiol valerate was previously available in the United States, it is no longer available in the country except in combination with dienogest as a combined oral contraceptive (under the brand name Natazia). Estradiol valerate by intramuscular injection is available under the brand name Delestrogen in the United States and Canada and under the brand name Progynon Depot in Europe and elsewhere in the world.
== Research ==
SH-834 was a combination of 90 mg estradiol valerate and 300 mg gestonorone caproate for weekly intramuscular injection that was developed by Schering in the 1970s. It was investigated clinically as a treatment for breast cancer and was found to be effective, but was never marketed.
== See also ==
Estradiol valerate/hydroxyprogesterone caproate
Estradiol valerate/norethisterone enantate
Estradiol valerate/prasterone enanthate
Estradiol valerate/testosterone enanthate
== References ==
== Further reading == | Wikipedia/Estradiol_valerate |
Endocrine therapy is a common treatment for estrogen receptor positive breast cancer. However, resistance to this therapy can develop, leading to relapse and progression of disease. This highlights the need for new strategies to combat this resistance.
== Breast cancer overview ==
=== Hormonal status in breast cancer ===
Globally, breast cancer is the second most common type of cancer, comprising 11.6% of total worldwide cancer cases in 2018. In the United Kingdom, breast cancer is the most common cancer type, affecting around 1 in 8 women. It can be loosely divided into non-invasive, where the cancer is localized to the ducts or lobules in which it originated (in-situ), or invasive, where the cancer cells have spread beyond the initial duct or lobule into the surrounding breast tissue or other part of the body. Risk factors that may predispose to breast cancer include increasing age and a family history of breast cancer. Despite the increase in incidence of breast cancer with age, there is a notable deceleration of this increase following menopause. Moreover, breast cancer risk is heightened following use of the combined oral contraceptive pill and combined hormone replacement therapy. Armed with this evidence that endogenous and exogenous changes in estrogen and progesterone levels modulate the risk of breast cancer, it is apparent that hormones can play a key role in breast cancer.
Indeed, breast tumors can express certain hormone receptors, and use these to grow and proliferate. These hormone receptors (HR) are the estrogen receptor (ER) and the progesterone receptor (PR). Immunohistochemical analysis of a tumor sample, taken via biopsy or after surgery, is utilized to determine the presence of these receptors. To classify a tumor as ER or PR negative or positive, the Allred score is utilized, which takes into account both the proportion of ERs and PRs present and the overall intensity score of the staining - this method is considered controversial, however.
Another receptor that often plays a role in breast cancer, although it is not a hormone receptor, is the human epidermal growth factor receptor 2 (HER2). The overexpression of HER2 is determined by immunohistochemistry (IHC), or with fluorescent in situ hybridization in those equivocal cases where IHC does not provide a clear result.
Different molecular subtypes of breast cancer have also been described, which loosely align with receptor status:
Luminal A (ER and/or PR positive; HER2 negative)
Luminal B (ER and/or PR positive; HER2 positive)
HER2-enriched (ER/PR negative; HER2 positive)
Basal like (triple negative).
Additionally, cancers can be ER-/PR+ or ER+/PR-, but these are unnamed and relatively rare. The receptor status of a cancer is assessed for all breast cancers as it has important implications on prognosis of the patient. It also dictates the treatment given: cancers that do express ER are likely to respond to endocrine therapy, but this type of therapy will have no effect on triple-negative breast cancers.
=== Mechanism of estrogen receptor action ===
75% of breast cancers are ER+. ER is a transcription factor containing a DNA-binding domain which allows binding DNA at specific sequences called estrogen response elements (EREs), defined as 5’-GGTCAnnnTGACC-3’, where "n" refers to any nucleotide. The N-terminal of the ER holds the activation function 1 (AF1) domain; the AF2 domain of the ER is contained within the ligand binding domain. The AF2 domain contains binding sites for coactivators.
Estrogen is a steroid hormone and can cross the cell membrane freely. It can then bind to an ER, which is located in the cytoplasm of the cell. Upon binding, the ligand-receptor complex dimerizes with another, and this homodimer moves into the nucleus. Binding of an estrogen ligand exposes a site on the AF2 domain for coactivators to attach to the ER. By recruiting coactivators and transcription factors, transcription of downstream genes, referred to as estrogen responsive genes, is initiated. These genes are of diverse function, but may potentiate aberrant cell survival and proliferation, contributing to tumorigenesis and cancer progression. For example, the ER can promote transcription of cyclin D1, an important regulator of the cell cycle. By interfering with the expression of this regulator, estrogen and estrogen receptor signaling can disrupt the cell cycle.
Endocrine therapies interrupt this pathway, blocking the binding of the receptor to the response element and subsequent transcription of these estrogen-responsive genes. ER+/PR+ cancers have been found to show better results with administration of SERMs than ER+/PR- cancers. This trend has been found with AI therapy also, albeit in fewer studies. The biological basis of this remains unknown.
== Endocrine therapy overview ==
=== Estrogen ===
Estrogens are responsible for the regulation of the female reproductive system and development of secondary sexual characteristics.
17β-Estradiol is the biologically active form of the sex hormone known as estrogen. It is secreted by granulose cells of the ovarian follicle and the corpus luteum, and is the primary form of circulating form of estrogen.
Other forms of endogenous estrogen exist, such as estrone, estriol and estretrol. Estretrol and estriol are primarily found in the body during pregnancy, and estrone is present during the menopause.
All of the forms of estrogen found in the human body are able to bind to estrogen receptors (ER) present on cells. This initiates transcription in these cells, resulting in control of gene expression.
Treatment strategies that work by blocking the effect of estrogen on breast cancer are referred to as endocrine (or hormone) therapies. These can target hormone regulation in two distinct ways.
=== Blocking estrogen synthesis ===
Firstly, some forms of endocrine therapy can be administered to block estrogen synthesis. In pre-menopausal women, this can be achieved through surgical ovarian ablation (by oophorectomy) or chemical ovarian suppression (using luteinizing hormone releasing hormone agonists, such as goserilin). In postmenopausal women, the ovaries cease to be the main source of estrogen production, with estrogen being instead synthesized from regulatory steroid hormones called androgens in tissues of the bone, fat, and breast through the activity of the enzyme aromatase. This can be blocked through the administration of aromatase inhibitors (AIs), which can be reversible inhibitors (non-steroidal) such as anastrozole and letrozole, or irreversible (steroidal) inhibitors like exemestane.
=== Influencing the effect of estrogen ===
Secondly, other endocrine therapies can directly influence the effect of estrogen in cancer cells. ER function can be chemically blocked in pre- and post-menopausal women using antiestrogens, including:
Selective ER modulators (SERMs), like tamoxifen. SERMs act as partial estrogen agonists, competing with estrogen to bind ER.
Selective ER degraders or down-regulators (SERDs), like fulvestrant. SERDs that act as full estrogen antagonists, binding to ER and leading to its degradation.
== Endocrine resistance overview ==
=== Definition of endocrine resistance ===
The term endocrine resistance describes a resistance to estrogen signaling suppression. However, in many scientific studies endocrine resistance refers to resistance to estrogen or estrogen receptor suppression. This resistance occurs due to the development of escape pathways which provide new ways for cancer cells to survive in the presence of endocrine therapy. If a patient with ER+ breast cancer develops endocrine resistance, the endocrine therapy used to treat the cancer will no longer be effective. Approximately 30-50% of ER+ breast cancer patients will relapse as a result of endocrine resistance, proving it to be a predominant challenge in the treatment of ER+ breast cancer patients.
=== Types of endocrine resistance ===
There are two types of endocrine resistance: primary and secondary. Primary resistance can also be described as de novo resistance or intrinsic resistance, which means the resistance existed before any treatment was initiated. Secondary resistance is acquired, meaning that it occurs after some initial response to treatment due to exposure to endocrine therapy.
=== Characterization of endocrine resistance ===
The table below summarizes how the two types of resistance are characterized in clinical settings.
=== Implications of resistance ===
Endocrine resistance in breast cancer leads to the progression of the disease and relapse. Resistance to endocrine therapy, leading to metastasis (spread of cancer beyond its place of origin) of breast cancer, which is one of the main reasons for death in breast cancer patients. This highlights the need for new strategies to overcome endocrine resistance and better treat ER+ breast cancer.
== Endocrine resistance mechanisms ==
=== ESR1 Modifications ===
Mutations in the ESR1 gene have been associated with the development of resistance to endocrine therapy. The ESR1 gene codes for estrogen receptors (ERα and ERβ). Whilst it is still not fully understood how ERβ impacts breast cancer development, ERα is known to have a role in tumor growth and cell survival.
Missense mutations, which are small mutations within a gene that can change the resulting protein, can lead to estrogen independence. This means that endocrine therapies blocking estrogen synthesis, such as aromatase inhibitors, lose efficacy because in a state of estrogen independence, the ER is stimulated without the need for estrogen, thus leading to constant ER activity. These mutations are rare in primary tumors; however, the frequency can be up to 30x higher in metastatic lesions.
Another mechanism by which modifications to the ESR1 gene can lead to endocrine therapy resistance is by the occurrence of translocations. During translocations, a fusion protein is formed between YAP1, a gene crucial for proliferation and apoptosis (programmed cell death) of cells, and ESR1. The creation of this fusion protein can allow the tumor to grow independent of estrogen, develop anti-estrogen resistance, have induced cell motility and constitutive expression of ER target genes.
Finally, it has been shown that there can be ESR1 gene amplification of up to 37% in breast cancer patients. However as of now there is no research showing a clear correlation between this amplification and endocrine resistance.
=== miRNA regulators ===
miRNAs are non-coding sections of RNA that are involved in gene expression. It has been shown that upregulation of some of these miRNAs may be associated with the development of anti-estrogen resistance via two potential pathways. First by activating alternative growth pathways and secondly by inhibition of ER expression. Some of examples of this are described below.
miR-155 stimulates the STAT3 signaling pathway, and this is associated with cell survival and endocrine resistance, specifically resistance to tamoxifen. In terms of inhibition, certain miRNAs are known to inhibit key inhibitors of the p27 pathway, hence allowing it carry on unchecked. Inhibition of the p27 pathway is well known for causing cell proliferation in tumors, and the levels of p27 can be measured and used as a marker for tamoxifen resistance.
In contrast to this, downregulation of other miRNAs is also associated with the development of endocrine resistance. Some miRNAs act as inhibitors to ERα-36 which acts as an ERβ antagonist and an agonist of estrogen-like SERM effects. Therefore, low levels of these mRNAs are associated with ERα-36 mediated resistance.
Another mechanism by which down-regulation of miRNAs may be implicated in the development of endocrine therapy resistance is by leading to overexpression of CDK3 and enhanced transcriptional activity of ER.
=== GPER ===
GPER is a transmembrane protein that acts as an estrogen receptor, and it is present in 50-60% of breast cancer cases. The cellular location of GPER seems to correlate somewhat with tumor prognosis, where cytoplasmic GPER is associated with lower grade tumors and nuclear GPER with higher rates of metastasis.
The signaling pathways associated with the GPER protein involve tyrosine kinases (from the Src family). Additionally, there is crosstalk between the GPER and EGFR signaling pathways.
Tamoxifen has been shown to increase expression of GPER by binding to its receptor. The signaling pathways initiated lead not only to tamoxifen resistance, but also a higher risk of metastasis and cell growth. The overall survival rate hence decreases for patients displaying high GPER expression.
=== PR expression ===
PR (progesterone receptor) is a gene expressed in around 50% of ER+ breast cancer patients. Clinical studies have shown that ER+/PR+ cases are more sensitive to endocrine therapy than ER+/PR- cases, suggesting that the loss of PR expression is associated with the development of endocrine therapy resistance. PR levels have been shown to be downregulated when there is activation of growth factors via the PI3K/Akt/mTOR pathway.
=== HER2 over-expression ===
Over-expression of HER2 is found to be present in around 30% of metastatic breast tumors and is associated with a poorer prognosis. Studies have demonstrated that there is crosstalk between HER2 and ER signaling pathways. Specifically, studies have shown there is crosstalk between HER2 and the ER coactivator A1B1 which could enhance the estrogen agonist activity of tamoxifen bound ER. Additionally, HER2 has physical associations with the cell membrane ER and interactions between them have been shown to block ER-initiated apoptosis.
== Tackling endocrine resistance ==
When tackling endocrine resistance in breast cancer, the current strategies are focused around combining hormonal agents with drugs targeting several escape pathways, as outlined in the mechanisms of endocrine resistance section. The aim is to block all the tumor survival escapes.
The main approach in overcoming endocrine resistance in those breast cancers that are both ER+ and HER2+ is by using a combination of endocrine and HER2-targeting agents.
In trials conducted with a combination of anti-HER2 agents and an aromatase inhibitor, significant clinical benefit and improved progression-free survival have been observed.
Trastuzumab is an example of an anti-HER2 agent which mainly depresses the growth of cells which are over-expressing HER2.
Many endocrine resistant breast cancers which don’t respond to aromatase inhibitors still depend on ER signaling.
Selective Estrogen Receptor Degraders (SERDs) can be used in these cases as they destabilize the ER and act as pure antagonists at the ER receptor. An example SERD is fulvestrant which binds to the ER to block its dimerization and nuclear localization. The fulvestrant-ER complex is unstable, resulting in degradation.
There has also been research into the combined inhibition of the ER and EGFR. An example of a pure EGFR inhibitor is gefitinib, which has been used in phase II trials to evaluate its addition to tamoxifen in patients with HR-positive advanced breast cancer.
The PI3K-Akt-mTOR signaling pathway and crosstalk with the ER signaling pathway is thought to be involved in the development of resistance to endocrine therapy. Therefore, studies have been done to assess the efficacy of using mTOR inhibitors, such as everolimus or temsirolimus, in ER-positive breast cancers.
Some preclinical and clinical studies have shown the possibility of mTOR inhibitors as a first step treatment to shrink the breast cancer tumor before the main treatment of an aromatase inhibitor is given. It is agreed that more clinical trials are needed to confirm this issue.
Additionally, cyclin-dependent kinase (CDK) 4/6 inhibition has shown to improve the efficacy of endocrine treatment.
== References == | Wikipedia/Endocrine_therapy_resistance_in_breast_cancer |
Niraparib/abiraterone acetate, sold under the brand name Akeega, is a fixed-dose combination anti-cancer medication used for the treatment of prostate cancer. It contains niraparib, a poly (ADP-ribose) polymerase (PARP) inhibitor (antineoplastic agent), and abiraterone acetate, a CYP17 inhibitor (hormone antagonist).
The most common side effects include anemia (low levels of red blood cells), high blood pressure, constipation, tiredness, nausea, thrombocytopenia (low levels of blood platelets), difficulty breathing, back pain, reduced appetite, neutropenia (low levels of neutrophils, a type of white blood cell), joint pain, vomiting, low levels of potassium, dizziness, difficulty sleeping, high blood glucose levels, and urinary tract infection.
Niraparib/abiraterone acetate was approved for medical use in the European Union in April 2023, and in the United States in August 2023.
== Medical uses ==
In the European Union, niraparib/abiraterone is indicated for the treatment of adults with prostate cancer. It is for people who have genetic mutations known as BRCA 1/2 mutations and who cannot have chemotherapy. It is used in combination with prednisolone or another medicine prednisone, which is converted into prednisolone.
In the United States, niraparib/abiraterone is indicated, in combination with prednisone, for adults with deleterious or suspected deleterious BRCA-mutated castration-resistant prostate cancer, as determined by an FDA-approved test.
== History ==
Efficacy was evaluated in cohort 1 of MAGNITUDE (NCT03748641), a randomized, double-blind, placebo-controlled trial enrolling 423 participants with homologous recombination repair (HRR) gene-mutated mCRPC. Participants were randomized (1:1) to receive niraparib 200 mg and abiraterone acetate 1,000 mg plus prednisone 10 mg daily or placebo and abiraterone acetate plus prednisone daily. Participants were required to have a prior orchiectomy or be receiving gonadotropin-releasing hormone (GnRH) analogues. Participants with mCRPC were eligible if they had not received prior systemic therapy in the mCRPC setting except for a short duration of prior abiraterone acetate plus prednisone (up to four months) and ongoing ADT. Participants could have received prior docetaxel or androgen-receptor (AR) targeted therapies in earlier disease settings. Randomization was stratified by prior docetaxel, prior AR targeted therapy, prior abiraterone acetate plus prednisone, and BRCA status. Of the 423 participants enrolled, 225 (53%) had prospectively determined BRCA gene mutations (BRCAm). No benefit was observed in mCRPC participants without an HRR gene mutation (Cohort 2 of MAGNITUDE) as the criterion for futility was met.
== Society and culture ==
=== Legal status ===
On 23 February 2023, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Akeega, intended for the treatment of adults with metastatic castration-resistant prostate cancer with BRCA 1/BRCA 2 mutations. The applicant for this medicinal product is Janssen-Cilag International N.V. Niraparib/abiraterone acetate was approved for medical use in the European Union in April 2023. It was approved for use in the United States in August 2023, based on the Phase 3 MAGNITUDE study.
== References == | Wikipedia/Niraparib/abiraterone_acetate |
Combinatorial ablation and immunotherapy is an oncological treatment that combines various tumor-ablation techniques with immunotherapy treatment. Combining ablation therapy of tumors with immunotherapy enhances the immunostimulating response and has synergistic effects for curative metastatic cancer treatment. Various ablative techniques are utilized including cryoablation, radiofrequency ablation, laser ablation, photodynamic ablation, stereotactic radiation therapy, alpha-emitting radiation therapy, hyperthermia therapy, HIFU. Thus, combinatorial ablation of tumors and immunotherapy is a way of achieving an autologous, in-vivo tumor lysate vaccine and treating metastatic disease.
== Mechanism of action ==
Take magnetic hyperthermia for example. By applying magnetic nanoparticle-mediated hyperthermia with a threshold of 43 °C in order not to damage surrounding normal tissues, a significant quantity of heat-shock proteins (HSP) is expressed within and around the tumor tissues, inducing tumor-specific immune responses. In vivo experiments have indicated that magnetic nanoparticle-mediated hyperthermia can induce the regression of not only a local tumor tissue exposed to heat, but also distant metastatic tumors unexposed to heat. Partially or entirely ablating primary or secondary metastatic tumors induces necrosis of tumor cells, resulting in the release of antigens and presentation of antigens to the immune system. The released tumor antigens help activate anti-tumor T cells, which can destroy remaining malignant cells in local and distant tumors. Combining immunotherapy (ie: checkpoint inhibitors, CAR-T cell therapy) and vaccine adjuvants (ie: interferon, saponin) with ablation synergizes the immune reaction, and can treat metastatic disease with curative intent.
== Ablation therapies ==
Various local ablation therapies exist to induce necrosis of tumor cells and release tumor antigens to stimulate an immunological response. These ablation therapies can be combined with a systemic immunotherapy:
Thermal ablation – local thermal ablation of tumor:
Cryoablation
Radiofrequency ablation
High-intensity focused ultrasound ablation
Laser ablation
Photodynamic ablation
Hyperthermia therapy
Ablation with alpha radiation therapy
A new type of ablation therapy that utilizes alpha radiation is now undergoing clinical trials for treatment of several types of solid tumors. Alpha particles are emitted from intratumorally-inserted seeds that have Ra-224 atoms fixed to their surface. When the radium decays, its short-lived daughter isotopes are released from the seeds by recoil energy, disperse in the tumor, and emit high energy alpha particles, which destroy the tumor. This therapy is called "Diffusing Alpha-emitting Radiation Therapy" or DaRT.
Nanotechnology in thermal ablation and immunotherapy
Currently nanotechnologies has been continuously developed for cancer immunotherapy for their versatility in integration of therapeutic and diagnostic (or termed 'theranostic') multimodalities. For example, iron oxide nanoparticles can generate heat under alternating magnetic field (100 kHz to 1 MHz); and they can also be utilized as imaging contrast agents for magnetic resonance imaging (MRI) for visualizing and monitoring the generation, distribution and biological activities of iron oxide nanoparticles. Magnetic nanoparticles can be concentrated to the tumor site via externally applied magnetic field, which is also advantageous in minimizing dose-related side effects. Localized heat can also trigger release of certain anti-cancer immuno-therapeutics loading from the nano-scale cargos if the nanomaterials are heat-responsive. From biological aspect, local heating can in addition significantly increase the extravasation of nanoscale drug carriers from tumor vessels, which enhances the performance of anti-cancer drug delivery to target cancers.
== See also ==
Cryoimmunology
Photoimmunotherapy
== References == | Wikipedia/Combinatorial_ablation_and_immunotherapy |
Isocitrate dehydrogenase (IDH) (EC 1.1.1.42) and (EC 1.1.1.41) is an enzyme that catalyzes the oxidative decarboxylation of isocitrate, producing alpha-ketoglutarate (α-ketoglutarate) and CO2. This is a two-step process, which involves oxidation of isocitrate (a secondary alcohol) to oxalosuccinate (a ketone), followed by the decarboxylation of the carboxyl group beta to the ketone, forming alpha-ketoglutarate. In humans, IDH exists in three isoforms: IDH3 catalyzes the third step of the citric acid cycle while converting NAD+ to NADH in the mitochondria. The isoforms IDH1 and IDH2 catalyze the same reaction outside the context of the citric acid cycle and use NADP+ as a cofactor instead of NAD+. They localize to the cytosol as well as the mitochondrion and peroxisome.
== Structure ==
The NAD-IDH is composed of three subunits, is allosterically regulated, and requires an integrated Mg2+ or Mn2+ ion. The closest homologue that has a known structure is the E. coli NADP-dependent IDH, which has only two subunits and a 13% identity and 29% similarity based on the amino acid sequences, making it dissimilar to human IDH and not suitable for close comparison. All the known NADP-IDHs are homodimers.
Most isocitrate dehydrogenases are dimers, to be specific, homodimers (two identical monomer subunits forming one dimeric unit). In comparing C. glutamicum and E. coli, monomer and dimer, respectively, both enzymes were found to "efficiently catalyze identical reactions." However, C. glutamicum was recorded as having ten times as much activity than E. coli and seven times more affinitive/specific for NADP. C. glutamicum favored NADP+ over NAD+. In terms of stability with response to temperature, both enzymes had a similar Tm or melting temperature at about 55 °C to 60 °C. However, the monomer C. glutamicum showed a more consistent stability at higher temperatures, which was expected. The dimer E. coli showed stability at a higher temperature than normal due to the interactions between the two monomeric subunits.
The structure of Mycobacterium tuberculosis (Mtb) ICDH-1 bound with NADPH and Mn(2+) bound has been solved by X-ray crystallography. It is a homodimer in which each subunit has a Rossmann fold, and a common top domain of interlocking β sheets. Mtb ICDH-1 is most structurally similar to the R132H mutant human ICDH found in CNS WHO grade 4 astrocytomas, formerly classified as glioblastomas. Similar to human R132H ICDH, Mtb ICDH-1 also catalyzes the formation of α-hydroxyglutarate.
== Regulation ==
The IDH step of the citric acid cycle is often (but not always) an irreversible reaction due to its large negative change in free energy. It must therefore be carefully regulated to avoid depletion of isocitrate (and therefore an accumulation of alpha-ketoglutarate). The reaction is stimulated by the simple mechanisms of substrate availability (isocitrate, NAD+ or NADP+, Mg2+ / Mn2+ ), product inhibition by NADH (or NADPH outside the citric acid cycle) and alpha-ketoglutarate, and competitive feedback inhibition by ATP. A conserved ncRNA upstream of the icd gene which codes for NADP+-dependent isocitrate dehydrogenase (IDH) has been reported in bacterial genomes, due to its characteristics this ncRNA resembles previous regulatory motifs called riboswitches, icd-II ncRNA motif has been proposed as a strong candidate riboswitch.
== Catalytic mechanisms ==
Isocitrate dehydrogenase catalyzes the chemical reactions:
Isocitrate + NAD+
⇌
{\displaystyle \rightleftharpoons }
2-oxoglutarate + CO2 + NADH + H+
Isocitrate + NADP+
⇌
{\displaystyle \rightleftharpoons }
2-oxoglutarate + CO2 + NADPH + H+
The overall free energy for this reaction is -8.4 kJ/mol.
=== Steps ===
Within the citric acid cycle, isocitrate, produced from the isomerization of citrate, undergoes both oxidation and decarboxylation. The enzyme isocitrate dehydrogenase (IDH) holds isocitrate within its active site using the surrounding amino acids, including arginine, tyrosine, asparagine, serine, threonine, and aspartic acid.
In the provided figure, the first box shows the overall isocitrate dehydrogenase reaction. The necessary reactants for this enzyme mechanism are isocitrate, NAD+/NADP+, and Mn2+ or Mg2+. The products of the reaction are alpha-ketoglutarate, carbon dioxide, and NADH + H+/NADPH + H+. Water molecules help to deprotonate the oxygen atoms of isocitrate.
The second box in the figure illustrates step 1 of the reaction, which is the oxidation of the alpha-carbon (C2 here, also called alpha-C). In this process, the alcohol group of the alpha-carbon is deprotonated and the resulting lone pair of electrons forms a ketone group on that carbon. NAD+/NADP+ acts as an electron-accepting cofactor and collects the resulting hydride from C2. The oxidation of the alpha carbon introduces a molecular arrangement where electrons (in the next step) will flow from the nearby carboxyl group and push the electrons of the double bonded oxygen up onto the oxygen atom itself, which collects a proton from a nearby lysine.
The third box illustrates step 2, which is the decarboxylation of oxalosuccinate. In this step, the carboxyl group oxygen is deprotonated by a nearby tyrosine, and those electrons flow down to C2. Carbon dioxide, the leaving group, detaches from the beta carbon of isocitrate (C3) and the electrons flow to the ketone oxygen attached to the alpha carbon, granting a negative charge to the associated oxygen atom and forming an alpha-beta unsaturated double bond between carbons 2 and 3.
The fourth and final box illustrates step 3, which is the saturation of the alpha-beta unsaturated double bond that formed in the previous step. The negatively charged oxygen (attached to the alpha-carbon) donates its electrons, reforming the ketone double bond and pushing another lone pair (the one that forms the double bond between the alpha and beta carbons) "off" the molecule. This lone pair, in turn, picks up a proton from the nearby tyrosine. This reaction results in the formation of alpha-ketoglutarate, NADH + H+/NADPH + H+, and CO2.
=== Detailed mechanism ===
Two aspartate amino acid residues (below left) are interacting with two adjacent water molecules (w6 and w8) in the Mn2+ isocitrate porcine IDH complex to deprotonate the alcohol off the alpha-carbon atom. The oxidation of the alpha-C also takes place in this picture where NAD+ accepts a hydride resulting in oxalosuccinate. Along with the sp3 to sp2 stereochemical change around the alpha-C, there is a ketone group that is formed from the alcohol group. The formation of this ketone double bond allows for resonance to take place as electrons coming down from the leaving carboxylate group move towards the ketone.
The decarboxylation of oxalosuccinate (below center) is a key step in the formation of alpha-ketoglutarate. In this reaction, the lone pair on the adjacent Tyrosine hydroxyl abstracts the proton off the carboxyl group. This carboxyl group is also referred to as the beta subunit in the isocitrate molecule. The deprotonation of the carboxyl group causes the lone pair of electrons to move down making carbon dioxide and separating from oxalosuccinate. The electrons continue to move towards the alpha carbon pushing the double bond electrons (making the ketone) up to abstract a proton off an adjacent lysine residue. An alpha-beta unsaturated double bond results between carbon 2 and three. As you can see in the picture, the green ion represents either Mg2+ or Mn2+, which is a cofactor necessary for this reaction to occur. The metal-ion forms a little complex through ionic interactions with the oxygen atoms on the fourth and fifth carbons (also known as the gamma subunit of isocitrate).
After the carbon dioxide is split from the oxalosuccinate in the decarboxylation step (below right), the enol will tautomerize to the keto from. The formation of the ketone double bond is started by the deprotonation of that oxygen off the alpha carbon (C#2) by the same lysine that protonated the oxygen in the first place. The lone pair of electrons moves down kicking off the lone pairs that were making the double bond. This lone pair of electrons abstracts a proton off the Tyrosine that deprotonated the carboxyl group in the decarboxylation step. The reason that we can say that the Lys and Tyr residues will be the same from the previous step is because they are helping in holding the isocitrate molecule in the active site of the enzyme. These two residues will be able to form hydrogen bonds back and forth as long as they are close enough to the substrate.
The isocitrate dehydrogenase enzyme as stated above produces alpha-ketoglutarate, carbon dioxide, and NADH + H+/NADPH + H+. There are three changes that occurred throughout the reaction. The oxidation of Carbon 2, the decarboxylation (loss of carbon dioxide) off Carbon 3, and the formation of a ketone group with a stereochemical change from sp3 to sp2.
=== Active site ===
The Isocitrate Dehydrogenase (IDH) enzyme structure in Escherichia coli was the first IDH ortholog structure to be elucidated and understood. Since then, the Escherichia coli IDH structure has been used by most researchers to make comparisons to other isocitrate dehydrogenase enzymes. There is much detailed knowledge about this bacterial enzyme, and it has been found that most isocitrate dehydrogenases are similar in structure and therefore also in function. This similarity of structure and function gives a reason to believe that the structures are conserved as well as the amino acids. Therefore, the active sites amongst most prokaryotic isocitrate dehydrogenase enzymes should be conserved as well, which is observed throughout many studies done on prokaryotic enzymes. Eukaryotic isocitrate dehydrogenase enzymes on the other hand, have not been fully discovered yet.
Each dimer of IDH has two active sites. Each active site binds a NAD+/NADP+ molecule and a divalent metal ion (Mg2+,Mn2+). In general, each active site has a conserved sequence of amino acids for each specific binding site. In Desulfotalea psychrophila (DpIDH) and porcine (PcIDH) there are three substrates bound to the active site.
Isocitrate binds within the active site to a conserved sequence of about eight amino acids through hydrogen bonds. These acids include (may vary in residue but with similar properties) tyrosine, serine, asparagine, arginine, arginine, arginine, tyrosine, and lysine. Their positions on the backbone vary but they are all within a close range (i.e. Arg131 DpIDH and Arg133 PcIDH, Tyr138 DpIDH and Tyr140 PcIDH).
The metal ion (Mg2+, Mn2+) binds to three conserved amino acids through hydrogen bonds. These amino acids include three Aspartate residues.
NAD+ and NADP+ bind within the active site within four regions with similar properties amongst IDH enzymes. These regions vary but are around [250–260], [280–290], [300–330], and [365–380]. Again regions vary but the proximity of regions are conserved.
== Clinical significance ==
Specific mutations in the isocitrate dehydrogenase gene IDH1 have been found in several tumor types, notably brain tumors including astrocytoma and oligodendroglioma. Patients whose tumor had an IDH1 mutation had longer survival compared to patients whose tumor had an IDH1 wild type. Furthermore, mutations of IDH2 and IDH1 were found in up to 20% of cytogenetically normal acute myeloid leukemia (AML). These mutations are known to produce D-2-hydroxyglutarate from alpha-ketoglutarate. D-2-hydroxyglutarate accumulates to very high concentrations which inhibits the function of enzymes that are dependent on alpha-ketoglutarate. This leads to a hypermethylated state of DNA and histones, which results in different gene expression that can activate oncogenes and inactivate tumor-suppressor genes. Ultimately, this may lead to the types of cancer described above. Somatic mosaic mutations of this gene have also been found associated to Ollier disease and Maffucci syndrome. However, recent studies have also shown that D-2-hydroxyglutarate may be converted back into alpha-ketoglutarate either enzymatically or non-enzymatically. Further studies are required to fully understand the roles of IDH1 mutation (and D-2-hydroxyglutarate) in cancer. Recent research highlighted cancer-causing mutations in isocitrate dehydrogenase which may cause accumulation of the metabolite D-2-hydroxyglutarate (D-2HG). Notarangelo et al. showed that such high concentrations of D-2HG could act as a direct inhibitor of lactate dehydrogenase in mouse T cells. Inhibition of this metabolic enzyme altered glucose metabolism in the T cells and inhibited their proliferation, cytokine production, and ability to kill target cells.
== Isozymes ==
The following is a list of human isocitrate dehydrogenase isozymes:
=== NADP+ dependent ===
Each NADP+-dependent isozyme functions as a homodimer:
=== NAD+ dependent ===
The isocitrate dehydrogenase 3 isozyme is a heterotetramer that is composed of two alpha subunits, one beta subunit, and one gamma subunit:
== See also ==
Oxidoreductase
Myelodysplastic syndrome#IDH1 and IDH2 mutations
Oncometabolism
Isocitrate/isopropylmalate dehydrogenase family
== References ==
== External links == | Wikipedia/Isocitrate_dehydrogenase |
Chemotherapy (often abbreviated chemo, sometimes CTX and CTx) is the type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) in a standard regimen. Chemotherapy may be given with a curative intent (which almost always involves combinations of drugs), or it may aim only to prolong life or to reduce symptoms (palliative chemotherapy). Chemotherapy is one of the major categories of the medical discipline specifically devoted to pharmacotherapy for cancer, which is called medical oncology.
The term chemotherapy now means the non-specific use of intracellular poisons to inhibit mitosis (cell division) or to induce DNA damage (so that DNA repair can augment chemotherapy). This meaning excludes the more-selective agents that block extracellular signals (signal transduction). Therapies with specific molecular or genetic targets, which inhibit growth-promoting signals from classic endocrine hormones (primarily estrogens for breast cancer and androgens for prostate cancer), are now called hormonal therapies. Other inhibitions of growth-signals, such as those associated with receptor tyrosine kinases, are targeted therapy.
The use of drugs (whether chemotherapy, hormonal therapy, or targeted therapy) is systemic therapy for cancer: they are introduced into the blood stream (the system) and therefore can treat cancer anywhere in the body. Systemic therapy is often used with other, local therapy (treatments that work only where they are applied), such as radiation, surgery, and hyperthermia.
Traditional chemotherapeutic agents are cytotoxic by means of interfering with cell division (mitosis) but cancer cells vary widely in their susceptibility to these agents. To a large extent, chemotherapy can be thought of as a way to damage or stress cells, which may then lead to cell death if apoptosis is initiated. Many of the side effects of chemotherapy can be traced to damage to normal cells that divide rapidly and are thus sensitive to anti-mitotic drugs: cells in the bone marrow, digestive tract and hair follicles. This results in the most common side-effects of chemotherapy: myelosuppression (decreased production of blood cells, hence that also immunosuppression), mucositis (inflammation of the lining of the digestive tract), and alopecia (hair loss). Because of the effect on immune cells (especially lymphocytes), chemotherapy drugs often find use in a host of diseases that result from harmful overactivity of the immune system against self (so-called autoimmunity). These include rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, vasculitis and many others.
== Treatment strategies ==
There are a number of strategies in the administration of chemotherapeutic drugs used today. Chemotherapy may be given with a curative intent or it may aim to prolong life or to palliate symptoms.
Induction chemotherapy is the first line treatment of cancer with a chemotherapeutic drug. This type of chemotherapy is used for curative intent.: 55–59
Combined modality chemotherapy is the use of drugs with other cancer treatments, such as surgery, radiation therapy, or hyperthermia therapy.
Consolidation chemotherapy is given after remission in order to prolong the overall disease-free time and improve overall survival. The drug that is administered is the same as the drug that achieved remission.: 55–59
Intensification chemotherapy is identical to consolidation chemotherapy but a different drug than the induction chemotherapy is used.: 55–59
Combination chemotherapy involves treating a person with a number of different drugs simultaneously. The drugs differ in their mechanism and side-effects. The biggest advantage is minimising the chances of resistance developing to any one agent. Also, the drugs can often be used at lower doses, reducing toxicity.: 55–59 : 17–18
Neoadjuvant chemotherapy is given prior to a local treatment such as surgery, and is designed to shrink the primary tumor.: 55–59 It is also given for cancers with a high risk of micrometastatic disease.: 42
Adjuvant chemotherapy is given after a local treatment (radiotherapy or surgery). It can be used when there is little evidence of cancer present, but there is risk of recurrence.: 55–59 It is also useful in killing any cancerous cells that have spread to other parts of the body. These micrometastases can be treated with adjuvant chemotherapy and can reduce relapse rates caused by these disseminated cells.
Maintenance chemotherapy is a repeated low-dose treatment to prolong remission.: 55–59
Salvage chemotherapy or palliative chemotherapy is given without curative intent, but simply to decrease tumor load and increase life expectancy. For these regimens, in general, a better toxicity profile is expected.: 55–59
All chemotherapy regimens require that the recipient be capable of undergoing the treatment. Performance status is often used as a measure to determine whether a person can receive chemotherapy, or whether dose reduction is required. Because only a fraction of the cells in a tumor die with each treatment (fractional kill), repeated doses must be administered to continue to reduce the size of the tumor. Current chemotherapy regimens apply drug treatment in cycles, with the frequency and duration of treatments limited by toxicity.
=== Effectiveness ===
The effectiveness of chemotherapy depends on the type of cancer and the stage. The overall effectiveness ranges from being curative for some cancers, such as some leukemias, to being ineffective, such as in some brain tumors, to being needless in others, like most non-melanoma skin cancers.
=== Dosage ===
Dosage of chemotherapy can be difficult: If the dose is too low, it will be ineffective against the tumor, whereas, at excessive doses, the toxicity (side-effects) will be intolerable to the person receiving it. The standard method of determining chemotherapy dosage is based on calculated body surface area (BSA). The BSA is usually calculated with a mathematical formula or a nomogram, using the recipient's weight and height, rather than by direct measurement of body area. This formula was originally derived in a 1916 study and attempted to translate medicinal doses established with laboratory animals to equivalent doses for humans. The study only included nine human subjects. When chemotherapy was introduced in the 1950s, the BSA formula was adopted as the official standard for chemotherapy dosing for lack of a better option.
The validity of this method in calculating uniform doses has been questioned because the formula only takes into account the individual's weight and height. Drug absorption and clearance are influenced by multiple factors, including age, sex, metabolism, disease state, organ function, drug-to-drug interactions, genetics, and obesity, which have major impacts on the actual concentration of the drug in the person's bloodstream. As a result, there is high variability in the systemic chemotherapy drug concentration in people dosed by BSA, and this variability has been demonstrated to be more than ten-fold for many drugs. In other words, if two people receive the same dose of a given drug based on BSA, the concentration of that drug in the bloodstream of one person may be 10 times higher or lower compared to that of the other person. This variability is typical with many chemotherapy drugs dosed by BSA, and, as shown below, was demonstrated in a study of 14 common chemotherapy drugs.
The result of this pharmacokinetic variability among people is that many people do not receive the right dose to achieve optimal treatment effectiveness with minimized toxic side effects. Some people are overdosed while others are underdosed. For example, in a randomized clinical trial, investigators found 85% of metastatic colorectal cancer patients treated with 5-fluorouracil (5-FU) did not receive the optimal therapeutic dose when dosed by the BSA standard—68% were underdosed and 17% were overdosed.
There has been controversy over the use of BSA to calculate chemotherapy doses for people who are obese. Because of their higher BSA, clinicians often arbitrarily reduce the dose prescribed by the BSA formula for fear of overdosing. In many cases, this can result in sub-optimal treatment.
Several clinical studies have demonstrated that when chemotherapy dosing is individualized to achieve optimal systemic drug exposure, treatment outcomes are improved and toxic side effects are reduced. In the 5-FU clinical study cited above, people whose dose was adjusted to achieve a pre-determined target exposure realized an 84% improvement in treatment response rate and a six-month improvement in overall survival (OS) compared with those dosed by BSA.
In the same study, investigators compared the incidence of common 5-FU-associated grade 3/4 toxicities between the dose-adjusted people and people dosed per BSA. The incidence of debilitating grades of diarrhea was reduced from 18% in the BSA-dosed group to 4% in the dose-adjusted group and serious hematologic side effects were eliminated. Because of the reduced toxicity, dose-adjusted patients were able to be treated for longer periods of time. BSA-dosed people were treated for a total of 680 months while people in the dose-adjusted group were treated for a total of 791 months. Completing the course of treatment is an important factor in achieving better treatment outcomes.
Similar results were found in a study involving people with colorectal cancer who have been treated with the popular FOLFOX regimen. The incidence of serious diarrhea was reduced from 12% in the BSA-dosed group of patients to 1.7% in the dose-adjusted group, and the incidence of severe mucositis was reduced from 15% to 0.8%.
The FOLFOX study also demonstrated an improvement in treatment outcomes. Positive response increased from 46% in the BSA-dosed group to 70% in the dose-adjusted group. Median progression free survival (PFS) and overall survival (OS) both improved by six months in the dose adjusted group.
One approach that can help clinicians individualize chemotherapy dosing is to measure the drug levels in blood plasma over time and adjust dose according to a formula or algorithm to achieve optimal exposure. With an established target exposure for optimized treatment effectiveness with minimized toxicities, dosing can be personalized to achieve target exposure and optimal results for each person. Such an algorithm was used in the clinical trials cited above and resulted in significantly improved treatment outcomes.
Oncologists are already individualizing dosing of some cancer drugs based on exposure. Carboplatin: 4 and busulfan dosing rely upon results from blood tests to calculate the optimal dose for each person. Simple blood tests are also available for dose optimization of methotrexate, 5-FU, paclitaxel, and docetaxel.
The serum albumin level immediately prior to chemotherapy administration is an independent prognostic predictor of survival in various cancer types.
=== Types ===
==== Alkylating agents ====
Alkylating agents are the oldest group of chemotherapeutics in use today. Originally derived from mustard gas used in World War I, there are now many types of alkylating agents in use. They are so named because of their ability to alkylate many molecules, including proteins, RNA and DNA. This ability to bind covalently to DNA via their alkyl group is the primary cause for their anti-cancer effects. DNA is made of two strands and the molecules may either bind twice to one strand of DNA (intrastrand crosslink) or may bind once to both strands (interstrand crosslink). If the cell tries to replicate crosslinked DNA during cell division, or tries to repair it, the DNA strands can break. This leads to a form of programmed cell death called apoptosis. Alkylating agents will work at any point in the cell cycle and thus are known as cell cycle-independent drugs. For this reason, the effect on the cell is dose dependent; the fraction of cells that die is directly proportional to the dose of drug.
The subtypes of alkylating agents are the nitrogen mustards, nitrosoureas, tetrazines, aziridines, cisplatins and derivatives, and non-classical alkylating agents. Nitrogen mustards include mechlorethamine, cyclophosphamide, melphalan, chlorambucil, ifosfamide and busulfan. Nitrosoureas include N-Nitroso-N-methylurea (MNU), carmustine (BCNU), lomustine (CCNU) and semustine (MeCCNU), fotemustine and streptozotocin. Tetrazines include dacarbazine, mitozolomide and temozolomide. Aziridines include thiotepa, mytomycin and diaziquone (AZQ). Cisplatin and derivatives include cisplatin, carboplatin and oxaliplatin. They impair cell function by forming covalent bonds with the amino, carboxyl, sulfhydryl, and phosphate groups in biologically important molecules. Non-classical alkylating agents include procarbazine and hexamethylmelamine.
==== Antimetabolites ====
Anti-metabolites are a group of molecules that impede DNA and RNA synthesis. Many of them have a similar structure to the building blocks of DNA and RNA. The building blocks are nucleotides; a molecule comprising a nucleobase, a sugar and a phosphate group. The nucleobases are divided into purines (guanine and adenine) and pyrimidines (cytosine, thymine and uracil). Anti-metabolites resemble either nucleobases or nucleosides (a nucleotide without the phosphate group), but have altered chemical groups. These drugs exert their effect by either blocking the enzymes required for DNA synthesis or becoming incorporated into DNA or RNA. By inhibiting the enzymes involved in DNA synthesis, they prevent mitosis because the DNA cannot duplicate itself. Also, after misincorporation of the molecules into DNA, DNA damage can occur and programmed cell death (apoptosis) is induced. Unlike alkylating agents, anti-metabolites are cell cycle dependent. This means that they only work during a specific part of the cell cycle, in this case S-phase (the DNA synthesis phase). For this reason, at a certain dose, the effect plateaus and proportionally no more cell death occurs with increased doses. Subtypes of the anti-metabolites are the anti-folates, fluoropyrimidines, deoxynucleoside analogues and thiopurines.
The anti-folates include methotrexate and pemetrexed. Methotrexate inhibits dihydrofolate reductase (DHFR), an enzyme that regenerates tetrahydrofolate from dihydrofolate. When the enzyme is inhibited by methotrexate, the cellular levels of folate coenzymes diminish. These are required for thymidylate and purine production, which are both essential for DNA synthesis and cell division.: 55–59 : 11 Pemetrexed is another anti-metabolite that affects purine and pyrimidine production, and therefore also inhibits DNA synthesis. It primarily inhibits the enzyme thymidylate synthase, but also has effects on DHFR, aminoimidazole carboxamide ribonucleotide formyltransferase and glycinamide ribonucleotide formyltransferase. The fluoropyrimidines include fluorouracil and capecitabine. Fluorouracil is a nucleobase analogue that is metabolised in cells to form at least two active products; 5-fluourouridine monophosphate (FUMP) and 5-fluoro-2'-deoxyuridine 5'-phosphate (fdUMP). FUMP becomes incorporated into RNA and fdUMP inhibits the enzyme thymidylate synthase; both of which lead to cell death.: 11 Capecitabine is a prodrug of 5-fluorouracil that is broken down in cells to produce the active drug. The deoxynucleoside analogues include cytarabine, gemcitabine, decitabine, azacitidine, fludarabine, nelarabine, cladribine, clofarabine, and pentostatin. The thiopurines include thioguanine and mercaptopurine.
==== Anti-microtubule agents ====
Anti-microtubule agents are plant-derived chemicals that block cell division by preventing microtubule function. Microtubules are an important cellular structure composed of two proteins, α-tubulin and β-tubulin. They are hollow, rod-shaped structures that are required for cell division, among other cellular functions. Microtubules are dynamic structures, which means that they are permanently in a state of assembly and disassembly. Vinca alkaloids and taxanes are the two main groups of anti-microtubule agents, and although both of these groups of drugs cause microtubule dysfunction, their mechanisms of action are completely opposite: Vinca alkaloids prevent the assembly of microtubules, whereas taxanes prevent their disassembly. By doing so, they can induce mitotic catastrophe in the cancer cells. Following this, cell cycle arrest occurs, which induces programmed cell death (apoptosis). These drugs can also affect blood vessel growth, an essential process that tumours utilise in order to grow and metastasise.
Vinca alkaloids are derived from the Madagascar periwinkle, Catharanthus roseus, formerly known as Vinca rosea. They bind to specific sites on tubulin, inhibiting the assembly of tubulin into microtubules. The original vinca alkaloids are natural products that include vincristine and vinblastine. Following the success of these drugs, semi-synthetic vinca alkaloids were produced: vinorelbine (used in the treatment of non-small-cell lung cancer), vindesine, and vinflunine. These drugs are cell cycle-specific. They bind to the tubulin molecules in S-phase and prevent proper microtubule formation required for M-phase.
Taxanes are natural and semi-synthetic drugs. The first drug of their class, paclitaxel, was originally extracted from Taxus brevifolia, the Pacific yew. Now this drug and another in this class, docetaxel, are produced semi-synthetically from a chemical found in the bark of another yew tree, Taxus baccata.
Podophyllotoxin is an antineoplastic lignan obtained primarily from the American mayapple (Podophyllum peltatum) and Himalayan mayapple (Sinopodophyllum hexandrum). It has anti-microtubule activity, and its mechanism is similar to that of vinca alkaloids in that they bind to tubulin, inhibiting microtubule formation. Podophyllotoxin is used to produce two other drugs with different mechanisms of action: etoposide and teniposide.
==== Topoisomerase inhibitors ====
Topoisomerase inhibitors are drugs that affect the activity of two enzymes: topoisomerase I and topoisomerase II. When the DNA double-strand helix is unwound, during DNA replication or transcription, for example, the adjacent unopened DNA winds tighter (supercoils), like opening the middle of a twisted rope. The stress caused by this effect is in part aided by the topoisomerase enzymes. They produce single- or double-strand breaks into DNA, reducing the tension in the DNA strand. This allows the normal unwinding of DNA to occur during replication or transcription. Inhibition of topoisomerase I or II interferes with both of these processes.
Two topoisomerase I inhibitors, irinotecan and topotecan, are semi-synthetically derived from camptothecin, which is obtained from the Chinese ornamental tree Camptotheca acuminata. Drugs that target topoisomerase II can be divided into two groups. The topoisomerase II poisons cause increased levels enzymes bound to DNA. This prevents DNA replication and transcription, causes DNA strand breaks, and leads to programmed cell death (apoptosis). These agents include etoposide, doxorubicin, mitoxantrone and teniposide. The second group, catalytic inhibitors, are drugs that block the activity of topoisomerase II, and therefore prevent DNA synthesis and translation because the DNA cannot unwind properly. This group includes novobiocin, merbarone, and aclarubicin, which also have other significant mechanisms of action.
==== Cytotoxic antibiotics ====
The cytotoxic antibiotics are a varied group of drugs that have various mechanisms of action. The common theme that they share in their chemotherapy indication is that they interrupt cell division. The most important subgroup is the anthracyclines and the bleomycins; other prominent examples include mitomycin C and actinomycin.
Among the anthracyclines, doxorubicin and daunorubicin were the first, and were obtained from the bacterium Streptomyces peucetius. Derivatives of these compounds include epirubicin and idarubicin. Other clinically used drugs in the anthracycline group are pirarubicin, aclarubicin, and mitoxantrone. The mechanisms of anthracyclines include DNA intercalation (molecules insert between the two strands of DNA), generation of highly reactive free radicals that damage intercellular molecules and topoisomerase inhibition.
Actinomycin is a complex molecule that intercalates DNA and prevents RNA synthesis.
Bleomycin, a glycopeptide isolated from Streptomyces verticillus, also intercalates DNA, but produces free radicals that damage DNA. This occurs when bleomycin binds to a metal ion, becomes chemically reduced and reacts with oxygen.: 87
Mitomycin is a cytotoxic antibiotic with the ability to alkylate DNA.
=== Delivery ===
Most chemotherapy is delivered intravenously, although a number of agents can be administered orally (e.g., melphalan, busulfan, capecitabine). According to a recent (2016) systematic review, oral therapies present additional challenges for patients and care teams to maintain and support adherence to treatment plans.
There are many intravenous methods of drug delivery, known as vascular access devices. These include the winged infusion device, peripheral venous catheter, midline catheter, peripherally inserted central catheter (PICC), central venous catheter and implantable port. The devices have different applications regarding duration of chemotherapy treatment, method of delivery and types of chemotherapeutic agent.: 94–95
Depending on the person, the cancer, the stage of cancer, the type of chemotherapy, and the dosage, intravenous chemotherapy may be given on either an inpatient or an outpatient basis. For continuous, frequent or prolonged intravenous chemotherapy administration, various systems may be surgically inserted into the vasculature to maintain access.: 113–118 Commonly used systems are the Hickman line, the Port-a-Cath, and the PICC line. These have a lower infection risk, are much less prone to phlebitis or extravasation, and eliminate the need for repeated insertion of peripheral cannulae.
Isolated limb perfusion (often used in melanoma), or isolated infusion of chemotherapy into the liver or the lung have been used to treat some tumors. The main purpose of these approaches is to deliver a very high dose of chemotherapy to tumor sites without causing overwhelming systemic damage. These approaches can help control solitary or limited metastases, but they are by definition not systemic, and, therefore, do not treat distributed metastases or micrometastases.
Topical chemotherapies, such as 5-fluorouracil, are used to treat some cases of non-melanoma skin cancer.
If the cancer has central nervous system involvement, or with meningeal disease, intrathecal chemotherapy may be administered.
== Adverse effects ==
Chemotherapeutic techniques have a range of side effects that depend on the type of medications used. The most common medications affect mainly the fast-dividing cells of the body, such as blood cells and the cells lining the mouth, stomach, and intestines. Chemotherapy-related iatrogenic toxicities can occur acutely after administration, within hours or days, or chronically, from weeks to years.: 265
=== Immunosuppression and myelosuppression ===
Virtually all chemotherapeutic regimens can cause depression of the immune system, often by paralysing the bone marrow and leading to a decrease of white blood cells, red blood cells, and platelets.
Anemia and thrombocytopenia may require blood transfusion. Neutropenia (a decrease of the neutrophil granulocyte count below 0.5 x 109/litre) can be improved with synthetic G-CSF (granulocyte-colony-stimulating factor, e.g., filgrastim, lenograstim, efbemalenograstim alfa).
In very severe myelosuppression, which occurs in some regimens, almost all the bone marrow stem cells (cells that produce white and red blood cells) are destroyed, meaning allogenic or autologous bone marrow cell transplants are necessary. (In autologous BMTs, cells are removed from the person before the treatment, multiplied and then re-injected afterward; in allogenic BMTs, the source is a donor.) However, some people still develop diseases because of this interference with bone marrow.
Although people receiving chemotherapy are encouraged to wash their hands, avoid sick people, and take other infection-reducing steps, about 85% of infections are due to naturally occurring microorganisms in the person's own gastrointestinal tract (including oral cavity) and skin.: 130 This may manifest as systemic infections, such as sepsis, or as localized outbreaks, such as Herpes simplex, shingles, or other members of the Herpesviridea. The risk of illness and death can be reduced by taking common antibiotics such as quinolones or trimethoprim/sulfamethoxazole before any fever or sign of infection appears. Quinolones show effective prophylaxis mainly with hematological cancer. However, in general, for every five people who are immunosuppressed following chemotherapy who take an antibiotic, one fever can be prevented; for every 34 who take an antibiotic, one death can be prevented. Sometimes, chemotherapy treatments are postponed because the immune system is suppressed to a critically low level.
In Japan, the government has approved the use of some medicinal mushrooms like Trametes versicolor, to counteract depression of the immune system in people undergoing chemotherapy.
Trilaciclib is an inhibitor of cyclin-dependent kinase 4/6 approved for the prevention of myelosuppression caused by chemotherapy. The drug is given before chemotherapy to protect bone marrow function.
=== Neutropenic enterocolitis ===
Due to immune system suppression, neutropenic enterocolitis (typhlitis) is a "life-threatening gastrointestinal complication of chemotherapy." Typhlitis is an intestinal infection which may manifest itself through symptoms including nausea, vomiting, diarrhea, a distended abdomen, fever, chills, or abdominal pain and tenderness.
Typhlitis is a medical emergency. It has a very poor prognosis and is often fatal unless promptly recognized and aggressively treated. Successful treatment hinges on early diagnosis provided by a high index of suspicion and the use of CT scanning, nonoperative treatment for uncomplicated cases, and sometimes elective right hemicolectomy to prevent recurrence.
=== Gastrointestinal distress ===
Nausea, vomiting, anorexia, diarrhea, abdominal cramps, and constipation are common side-effects of chemotherapeutic medications that kill fast-dividing cells. Malnutrition and dehydration can result when the recipient does not eat or drink enough, or when the person vomits frequently, because of gastrointestinal damage. This can result in rapid weight loss, or occasionally in weight gain, if the person eats too much in an effort to allay nausea or heartburn. Weight gain can also be caused by some steroid medications. These side-effects can frequently be reduced or eliminated with antiemetic drugs. Low-certainty evidence also suggests that probiotics may have a preventative and treatment effect of diarrhoea related to chemotherapy alone and with radiotherapy. However, a high index of suspicion is appropriate, since diarrhoea and bloating are also symptoms of typhlitis, a very serious and potentially life-threatening medical emergency that requires immediate treatment.
=== Anemia ===
Anemia can be a combined outcome caused by myelosuppressive chemotherapy, and possible cancer-related causes such as bleeding, blood cell destruction (hemolysis), hereditary disease, kidney dysfunction, nutritional deficiencies or anemia of chronic disease. Treatments to mitigate anemia include hormones to boost blood production (erythropoietin), iron supplements, and blood transfusions. Myelosuppressive therapy can cause a tendency to bleed easily, leading to anemia. Medications that kill rapidly dividing cells or blood cells can reduce the number of platelets in the blood, which can result in bruises and bleeding. Extremely low platelet counts may be temporarily boosted through platelet transfusions and new drugs to increase platelet counts during chemotherapy are being developed. Sometimes, chemotherapy treatments are postponed to allow platelet counts to recover.
Fatigue may be a consequence of the cancer or its treatment, and can last for months to years after treatment. One physiological cause of fatigue is anemia, which can be caused by chemotherapy, surgery, radiotherapy, primary and metastatic disease or nutritional depletion. Aerobic exercise has been found to be beneficial in reducing fatigue in people with solid tumours.
=== Nausea and vomiting ===
Nausea and vomiting are two of the most feared cancer treatment-related side-effects for people with cancer and their families. In 1983, Coates et al. found that people receiving chemotherapy ranked nausea and vomiting as the first and second most severe side-effects, respectively. Up to 20% of people receiving highly emetogenic agents in this era postponed, or even refused potentially curative treatments. Chemotherapy-induced nausea and vomiting (CINV) are common with many treatments and some forms of cancer. Since the 1990s, several novel classes of antiemetics have been developed and commercialized, becoming a nearly universal standard in chemotherapy regimens, and helping to successfully manage these symptoms in many people. Effective mediation of these unpleasant and sometimes debilitating symptoms results in increased quality of life for the recipient and more efficient treatment cycles, as patients are less likely to avoid or refuse treatment.
=== Hair loss ===
Hair loss (alopecia) can be caused by chemotherapy that kills rapidly dividing cells; other medications may cause hair to thin. These are most often temporary effects: hair usually starts to regrow a few weeks after the last treatment, but sometimes with a change in color, texture, thickness or style. Sometimes hair has a tendency to curl after regrowth, resulting in "chemo curls." Severe hair loss occurs most often with drugs such as doxorubicin, daunorubicin, paclitaxel, docetaxel, cyclophosphamide, ifosfamide and etoposide. Permanent thinning or hair loss can result from some standard chemotherapy regimens.
Chemotherapy induced hair loss occurs by a non-androgenic mechanism, and can manifest as alopecia totalis, telogen effluvium, or less often alopecia areata. It is usually associated with systemic treatment due to the high mitotic rate of hair follicles, and more reversible than androgenic hair loss, although permanent cases can occur. Chemotherapy induces hair loss in women more often than men.
Scalp cooling offers a means of preventing both permanent and temporary hair loss; however, concerns about this method have been raised.
=== Secondary neoplasm ===
Development of secondary neoplasia after successful chemotherapy or radiotherapy treatment can occur. The most common secondary neoplasm is secondary acute myeloid leukemia, which develops primarily after treatment with alkylating agents or topoisomerase inhibitors. Survivors of childhood cancer are more than 13 times as likely to get a secondary neoplasm during the 30 years after treatment than the general population. Not all of this increase can be attributed to chemotherapy.
=== Infertility ===
Some types of chemotherapy are gonadotoxic and may cause infertility. Chemotherapies with high risk include procarbazine and other alkylating drugs such as cyclophosphamide, ifosfamide, busulfan, melphalan, chlorambucil, and chlormethine. Drugs with medium risk include doxorubicin and platinum analogs such as cisplatin and carboplatin. On the other hand, therapies with low risk of gonadotoxicity include plant derivatives such as vincristine and vinblastine, antibiotics such as bleomycin and dactinomycin, and antimetabolites such as methotrexate, mercaptopurine, and 5-fluorouracil.
Female infertility by chemotherapy appears to be secondary to premature ovarian failure by loss of primordial follicles. This loss is not necessarily a direct effect of the chemotherapeutic agents, but could be due to an increased rate of growth initiation to replace damaged developing follicles.
People may choose between several methods of fertility preservation prior to chemotherapy, including cryopreservation of semen, ovarian tissue, oocytes, or embryos. As more than half of cancer patients are elderly, this adverse effect is only relevant for a minority of patients. A study in France between 1999 and 2011 came to the result that embryo freezing before administration of gonadotoxic agents to females caused a delay of treatment in 34% of cases, and a live birth in 27% of surviving cases who wanted to become pregnant, with the follow-up time varying between 1 and 13 years.
Potential protective or attenuating agents include GnRH analogs, where several studies have shown a protective effect in vivo in humans, but some studies show no such effect. Sphingosine-1-phosphate (S1P) has shown similar effect, but its mechanism of inhibiting the sphingomyelin apoptotic pathway may also interfere with the apoptosis action of chemotherapy drugs.
In chemotherapy as a conditioning regimen in hematopoietic stem cell transplantation, a study of people conditioned with cyclophosphamide alone for severe aplastic anemia came to the result that ovarian recovery occurred in all women younger than 26 years at time of transplantation, but only in five of 16 women older than 26 years.
=== Teratogenicity ===
Chemotherapy is teratogenic during pregnancy, especially during the first trimester, to the extent that abortion usually is recommended if pregnancy in this period is found during chemotherapy. Second- and third-trimester exposure does not usually increase the teratogenic risk and adverse effects on cognitive development, but it may increase the risk of various complications of pregnancy and fetal myelosuppression.
Female patients of reproductive potential should use effective contraception during chemotherapy and for a few months after the last dose (e.g. 6 month for doxorubicin).
In males previously having undergone chemotherapy or radiotherapy, there appears to be no increase in genetic defects or congenital malformations in their children conceived after therapy. The use of assisted reproductive technologies and micromanipulation techniques might increase this risk. In females previously having undergone chemotherapy, miscarriage and congenital malformations are not increased in subsequent conceptions. However, when in vitro fertilization and embryo cryopreservation is practised between or shortly after treatment, possible genetic risks to the growing oocytes exist, and hence it has been recommended that the babies be screened.
=== Peripheral neuropathy ===
Between 30 and 40 percent of people undergoing chemotherapy experience chemotherapy-induced peripheral neuropathy (CIPN), a progressive, enduring, and often irreversible condition, causing pain, tingling, numbness and sensitivity to cold, beginning in the hands and feet and sometimes progressing to the arms and legs. Chemotherapy drugs associated with CIPN include thalidomide, epothilones, vinca alkaloids, taxanes, proteasome inhibitors, and the platinum-based drugs. Whether CIPN arises, and to what degree, is determined by the choice of drug, duration of use, the total amount consumed and whether the person already has peripheral neuropathy. Though the symptoms are mainly sensory, in some cases motor nerves and the autonomic nervous system are affected. CIPN often follows the first chemotherapy dose and increases in severity as treatment continues, but this progression usually levels off at completion of treatment. The platinum-based drugs are the exception; with these drugs, sensation may continue to deteriorate for several months after the end of treatment. Some CIPN appears to be irreversible. Pain can often be managed with drug or other treatment but the numbness is usually resistant to treatment.
=== Cognitive impairment ===
Some people receiving chemotherapy report fatigue or non-specific neurocognitive problems, such as an inability to concentrate; this is sometimes called post-chemotherapy cognitive impairment, referred to as "chemo brain" in popular and social media.
=== Tumor lysis syndrome ===
In particularly large tumors and cancers with high white cell counts, such as lymphomas, teratomas, and some leukemias, some people develop tumor lysis syndrome. The rapid breakdown of cancer cells causes the release of chemicals from the inside of the cells. Following this, high levels of uric acid, potassium and phosphate are found in the blood. High levels of phosphate induce secondary hypoparathyroidism, resulting in low levels of calcium in the blood. This causes kidney damage and the high levels of potassium can cause cardiac arrhythmia. Although prophylaxis is available and is often initiated in people with large tumors, this is a dangerous side-effect that can lead to death if left untreated.: 202
=== Organ damage ===
Cardiotoxicity (heart damage) is especially prominent with the use of anthracycline drugs (doxorubicin, epirubicin, idarubicin, and liposomal doxorubicin). The cause of this is most likely due to the production of free radicals in the cell and subsequent DNA damage. Other chemotherapeutic agents that cause cardiotoxicity, but at a lower incidence, are cyclophosphamide, docetaxel and clofarabine.
Hepatotoxicity (liver damage) can be caused by many cytotoxic drugs. The susceptibility of an individual to liver damage can be altered by other factors such as the cancer itself, viral hepatitis, immunosuppression and nutritional deficiency. The liver damage can consist of damage to liver cells, hepatic sinusoidal syndrome (obstruction of the veins in the liver), cholestasis (where bile does not flow from the liver to the intestine) and liver fibrosis.
Nephrotoxicity (kidney damage) can be caused by tumor lysis syndrome and also due direct effects of drug clearance by the kidneys. Different drugs will affect different parts of the kidney and the toxicity may be asymptomatic (only seen on blood or urine tests) or may cause acute kidney injury.
Ototoxicity (damage to the inner ear) is a common side effect of platinum based drugs that can produce symptoms such as dizziness and vertigo. Children treated with platinum analogues have been found to be at risk for developing hearing loss.
=== Other side-effects ===
Less common side-effects include red skin (erythema), dry skin, damaged fingernails, a dry mouth (xerostomia), water retention, and sexual impotence. Some medications can trigger allergic or pseudoallergic reactions.
Specific chemotherapeutic agents are associated with organ-specific toxicities, including cardiovascular disease (e.g., doxorubicin), interstitial lung disease (e.g., bleomycin) and occasionally secondary neoplasm (e.g., MOPP therapy for Hodgkin's disease).
Hand-foot syndrome is another side effect to cytotoxic chemotherapy.
Nutritional problems are also frequently seen in cancer patients at diagnosis and through chemotherapy treatment. Research suggests that in children and young people undergoing cancer treatment, parenteral nutrition may help with this leading to weight gain and increased calorie and protein intake, when compared to enteral nutrition.
== Limitations ==
Chemotherapy does not always work, and even when it is useful, it may not completely destroy the cancer. People frequently fail to understand its limitations. In one study of people who had been newly diagnosed with incurable, stage 4 cancer, more than two-thirds of people with lung cancer and more than four-fifths of people with colorectal cancer still believed that chemotherapy was likely to cure their cancer.
The blood–brain barrier poses an obstacle to delivery of chemotherapy to the brain. This is because the brain has an extensive system in place to protect it from harmful chemicals. Drug transporters can pump out drugs from the brain and brain's blood vessel cells into the cerebrospinal fluid and blood circulation. These transporters pump out most chemotherapy drugs, which reduces their efficacy for treatment of brain tumors. Only small lipophilic alkylating agents such as lomustine or temozolomide are able to cross this blood–brain barrier.
Blood vessels in tumors are very different from those seen in normal tissues. As a tumor grows, tumor cells furthest away from the blood vessels become low in oxygen (hypoxic). To counteract this they then signal for new blood vessels to grow. The newly formed tumor vasculature is poorly formed and does not deliver an adequate blood supply to all areas of the tumor. This leads to issues with drug delivery because many drugs will be delivered to the tumor by the circulatory system.
== Resistance ==
Resistance is a major cause of treatment failure in chemotherapeutic drugs. There are a few possible causes of resistance in cancer, one of which is the presence of small pumps on the surface of cancer cells that actively move chemotherapy from inside the cell to the outside. Cancer cells produce high amounts of these pumps, known as p-glycoprotein, in order to protect themselves from chemotherapeutics. Research on p-glycoprotein and other such chemotherapy efflux pumps is currently ongoing. Medications to inhibit the function of p-glycoprotein are undergoing investigation, but due to toxicities and interactions with anti-cancer drugs their development has been difficult. Another mechanism of resistance is gene amplification, a process in which multiple copies of a gene are produced by cancer cells. This overcomes the effect of drugs that reduce the expression of genes involved in replication. With more copies of the gene, the drug can not prevent all expression of the gene and therefore the cell can restore its proliferative ability. Cancer cells can also cause defects in the cellular pathways of apoptosis (programmed cell death). As most chemotherapy drugs kill cancer cells in this manner, defective apoptosis allows survival of these cells, making them resistant. Many chemotherapy drugs also cause DNA damage, which can be repaired by enzymes in the cell that carry out DNA repair. Upregulation of these genes can overcome the DNA damage and prevent the induction of apoptosis. Mutations in genes that produce drug target proteins, such as tubulin, can occur which prevent the drugs from binding to the protein, leading to resistance to these types of drugs. Drugs used in chemotherapy can induce cell stress, which can kill a cancer cell; however, under certain conditions, cells stress can induce changes in gene expression that enables resistance to several types of drugs. In lung cancer, the transcription factor NFκB is thought to play a role in resistance to chemotherapy, via inflammatory pathways.
== Cytotoxics and targeted therapies ==
Targeted therapies are a relatively new class of cancer drugs that can overcome many of the issues seen with the use of cytotoxics. They are divided into two groups: small molecule and antibodies. The massive toxicity seen with the use of cytotoxics is due to the lack of cell specificity of the drugs. They will kill any rapidly dividing cell, tumor or normal. Targeted therapies are designed to affect cellular proteins or processes that are utilised by the cancer cells. This allows a high dose to cancer tissues with a relatively low dose to other tissues. Although the side effects are often less severe than that seen of cytotoxic chemotherapeutics, life-threatening effects can occur. Initially, the targeted therapeutics were supposed to be solely selective for one protein. Now it is clear that there is often a range of protein targets that the drug can bind. An example target for targeted therapy is the BCR-ABL1 protein produced from the Philadelphia chromosome, a genetic lesion found commonly in chronic myelogenous leukemia and in some patients with acute lymphoblastic leukemia. This fusion protein has enzyme activity that can be inhibited by imatinib, a small molecule drug.
== Mechanism of action ==
Cancer is the uncontrolled growth of cells coupled with malignant behaviour: invasion and metastasis (among other features). It is caused by the interaction between genetic susceptibility and environmental factors. These factors lead to accumulations of genetic mutations in oncogenes (genes that control the growth rate of cells) and tumor suppressor genes (genes that help to prevent cancer), which gives cancer cells their malignant characteristics, such as uncontrolled growth.: 93–94
In the broad sense, most chemotherapeutic drugs work by impairing mitosis (cell division), effectively targeting fast-dividing cells. As these drugs cause damage to cells, they are termed cytotoxic. They prevent mitosis by various mechanisms including damaging DNA and inhibition of the cellular machinery involved in cell division. One theory as to why these drugs kill cancer cells is that they induce a programmed form of cell death known as apoptosis.
As chemotherapy affects cell division, tumors with high growth rates (such as acute myelogenous leukemia and the aggressive lymphomas, including Hodgkin's disease) are more sensitive to chemotherapy, as a larger proportion of the targeted cells are undergoing cell division at any time. Malignancies with slower growth rates, such as indolent lymphomas, tend to respond to chemotherapy much more modestly. Heterogeneic tumours may also display varying sensitivities to chemotherapy agents, depending on the subclonal populations within the tumor.
Cells from the immune system also make crucial contributions to the antitumor effects of chemotherapy. For example, the chemotherapeutic drugs oxaliplatin and cyclophosphamide can cause tumor cells to die in a way that is detectable by the immune system (called immunogenic cell death), which mobilizes immune cells with antitumor functions. Chemotherapeutic drugs that cause cancer immunogenic tumor cell death can make unresponsive tumors sensitive to immune checkpoint therapy.
== Other uses ==
Some chemotherapy drugs are used in diseases other than cancer, such as in autoimmune disorders, and noncancerous plasma cell dyscrasia. In some cases they are often used at lower doses, which means that the side effects are minimized, while in other cases doses similar to ones used to treat cancer are used. Methotrexate is used in the treatment of rheumatoid arthritis (RA), psoriasis, ankylosing spondylitis and multiple sclerosis. The anti-inflammatory response seen in RA is thought to be due to increases in adenosine, which causes immunosuppression; effects on immuno-regulatory cyclooxygenase-2 enzyme pathways; reduction in pro-inflammatory cytokines; and anti-proliferative properties. Although methotrexate is used to treat both multiple sclerosis and ankylosing spondylitis, its efficacy in these diseases is still uncertain. Cyclophosphamide is sometimes used to treat lupus nephritis, a common symptom of systemic lupus erythematosus. Dexamethasone along with either bortezomib or melphalan is commonly used as a treatment for AL amyloidosis. Recently, bortezomid in combination with cyclophosphamide and dexamethasone has also shown promise as a treatment for AL amyloidosis. Other drugs used to treat myeloma such as lenalidomide have shown promise in treating AL amyloidosis.
Chemotherapy drugs are also used in conditioning regimens prior to bone marrow transplant (hematopoietic stem cell transplant). Conditioning regimens are used to suppress the recipient's immune system in order to allow a transplant to engraft. Cyclophosphamide is a common cytotoxic drug used in this manner and is often used in conjunction with total body irradiation. Chemotherapeutic drugs may be used at high doses to permanently remove the recipient's bone marrow cells (myeloablative conditioning) or at lower doses that will prevent permanent bone marrow loss (non-myeloablative and reduced intensity conditioning). When used in non-cancer setting, the treatment is still called "chemotherapy", and is often done in the same treatment centers used for people with cancer.
== Occupational exposure and safe handling ==
In the 1970s, antineoplastic (chemotherapy) drugs were identified as hazardous, and the American Society of Health-System Pharmacists (ASHP) has since then introduced the concept of hazardous drugs after publishing a recommendation in 1983 regarding handling hazardous drugs. The adaptation of federal regulations came when the U.S. Occupational Safety and Health Administration (OSHA) first released its guidelines in 1986 and then updated them in 1996, 1999, and, most recently, 2006.
The National Institute for Occupational Safety and Health (NIOSH) has been conducting an assessment in the workplace since then regarding these drugs. Occupational exposure to antineoplastic drugs has been linked to multiple health effects, including infertility and possible carcinogenic effects. A few cases have been reported by the NIOSH alert report, such as one in which a female pharmacist was diagnosed with papillary transitional cell carcinoma. Twelve years before the pharmacist was diagnosed with the condition, she had worked for 20 months in a hospital where she was responsible for preparing multiple antineoplastic drugs. The pharmacist did not have any other risk factor for cancer, and therefore, her cancer was attributed to the exposure to the antineoplastic drugs, although a cause-and-effect relationship has not been established in the literature. Another case happened when a malfunction in biosafety cabinetry is believed to have exposed nursing personnel to antineoplastic drugs. Investigations revealed evidence of genotoxic biomarkers two and nine months after that exposure.
=== Routes of exposure ===
Antineoplastic drugs are usually given through intravenous, intramuscular, intrathecal, or subcutaneous administration. In most cases, before the medication is administered to the patient, it needs to be prepared and handled by several workers. Any worker who is involved in handling, preparing, or administering the drugs, or with cleaning objects that have come into contact with antineoplastic drugs, is potentially exposed to hazardous drugs. Health care workers are exposed to drugs in different circumstances, such as when pharmacists and pharmacy technicians prepare and handle antineoplastic drugs and when nurses and physicians administer the drugs to patients. Additionally, those who are responsible for disposing antineoplastic drugs in health care facilities are also at risk of exposure.
Dermal exposure is thought to be the main route of exposure due to the fact that significant amounts of the antineoplastic agents have been found in the gloves worn by healthcare workers who prepare, handle, and administer the agents. Another noteworthy route of exposure is inhalation of the drugs' vapors. Multiple studies have investigated inhalation as a route of exposure, and although air sampling has not shown any dangerous levels, it is still a potential route of exposure. Ingestion by hand to mouth is a route of exposure that is less likely compared to others because of the enforced hygienic standard in the health institutions. However, it is still a potential route, especially in the workplace, outside of a health institute. One can also be exposed to these hazardous drugs through injection by needle sticks. Research conducted in this area has established that occupational exposure occurs by examining evidence in multiple urine samples from health care workers.
=== Hazards ===
Hazardous drugs expose health care workers to serious health risks. Many studies show that antineoplastic drugs could have many side effects on the reproductive system, such as fetal loss, congenital malformation, and infertility. Health care workers who are exposed to antineoplastic drugs on many occasions have adverse reproductive outcomes such as spontaneous abortions, stillbirths, and congenital malformations. Moreover, studies have shown that exposure to these drugs leads to menstrual cycle irregularities. Antineoplastic drugs may also increase the risk of learning disabilities among children of health care workers who are exposed to these hazardous substances.
Moreover, these drugs have carcinogenic effects. In the past five decades, multiple studies have shown the carcinogenic effects of exposure to antineoplastic drugs. Similarly, there have been research studies that linked alkylating agents with humans developing leukemias. Studies have reported elevated risk of breast cancer, nonmelanoma skin cancer, and cancer of the rectum among nurses who are exposed to these drugs. Other investigations revealed that there is a potential genotoxic effect from anti-neoplastic drugs to workers in health care settings.
=== Safe handling in health care settings ===
As of 2018, there were no occupational exposure limits set for antineoplastic drugs, i.e., OSHA or the American Conference of Governmental Industrial Hygienists (ACGIH) have not set workplace safety guidelines.
==== Preparation ====
NIOSH recommends using a ventilated cabinet that is designed to decrease worker exposure. Additionally, it recommends training of all staff, the use of cabinets, implementing an initial evaluation of the technique of the safety program, and wearing protective gloves and gowns when opening drug packaging, handling vials, or labeling. When wearing personal protective equipment, one should inspect gloves for physical defects before use and always wear double gloves and protective gowns. Health care workers are also required to wash their hands with water and soap before and after working with antineoplastic drugs, change gloves every 30 minutes or whenever punctured, and discard them immediately in a chemotherapy waste container.
The gowns used should be disposable gowns made of polyethylene-coated polypropylene. When wearing gowns, individuals should make sure that the gowns are closed and have long sleeves. When preparation is done, the final product should be completely sealed in a plastic bag.
The health care worker should also wipe all waste containers inside the ventilated cabinet before removing them from the cabinet. Finally, workers should remove all protective wear and put them in a bag for their disposal inside the ventilated cabinet.
==== Administration ====
Drugs should only be administered using protective medical devices such as needle lists and closed systems and techniques such as priming of IV tubing by pharmacy personnel inside a ventilated cabinet. Workers should always wear personal protective equipment such as double gloves, goggles, and protective gowns when opening the outer bag and assembling the delivery system to deliver the drug to the patient, and when disposing of all material used in the administration of the drugs.
Hospital workers should never remove tubing from an IV bag that contains an antineoplastic drug, and when disconnecting the tubing in the system, they should make sure the tubing has been thoroughly flushed. After removing the IV bag, the workers should place it together with other disposable items directly in the yellow chemotherapy waste container with the lid closed. Protective equipment should be removed and put into a disposable chemotherapy waste container. After this has been done, one should double bag the chemotherapy waste before or after removing one's inner gloves. Moreover, one must always wash one's hands with soap and water before leaving the drug administration site.
==== Employee training ====
All employees whose jobs in health care facilities expose them to hazardous drugs must receive training. Training should include shipping and receiving personnel, housekeepers, pharmacists, assistants, and all individuals involved in the transportation and storage of antineoplastic drugs. These individuals should receive information and training to inform them of the hazards of the drugs present in their areas of work. They should be informed and trained on operations and procedures in their work areas where they can encounter hazards, different methods used to detect the presence of hazardous drugs and how the hazards are released, and the physical and health hazards of the drugs, including their reproductive and carcinogenic hazard potential. Additionally, they should be informed and trained on the measures they should take to avoid and protect themselves from these hazards. This information ought to be provided when health care workers come into contact with the drugs, that is, perform the initial assignment in a work area with hazardous drugs. Moreover, training should also be provided when new hazards emerge as well as when new drugs, procedures, or equipment are introduced.
==== Housekeeping and waste disposal ====
When performing cleaning and decontaminating the work area where antineoplastic drugs are used, one should make sure that there is sufficient ventilation to prevent the buildup of airborne drug concentrations. When cleaning the work surface, hospital workers should use deactivation and cleaning agents before and after each activity as well as at the end of their shifts. Cleaning should always be done using double protective gloves and disposable gowns. After employees finish up cleaning, they should dispose of the items used in the activity in a yellow chemotherapy waste container while still wearing protective gloves. After removing the gloves, they should thoroughly wash their hands with soap and water. Anything that comes into contact or has a trace of the antineoplastic drugs, such as needles, empty vials, syringes, gowns, and gloves, should be put in the chemotherapy waste container.
==== Spill control ====
A written policy needs to be in place in case of a spill of antineoplastic products. The policy should address the possibility of various sizes of spills as well as the procedure and personal protective equipment required for each size. A trained worker should handle a large spill and always dispose of all cleanup materials in the chemical waste container according to EPA regulations, not in a yellow chemotherapy waste container.
=== Occupational monitoring ===
A medical surveillance program must be established. In case of exposure, occupational health professionals need to ask for a detailed history and do a thorough physical exam. They should test the urine of the potentially exposed worker by doing a urine dipstick or microscopic examination, mainly looking for blood, as several antineoplastic drugs are known to cause bladder damage.
Urinary mutagenicity is a marker of exposure to antineoplastic drugs that was first used by Falck and colleagues in 1979 and uses bacterial mutagenicity assays. Apart from being nonspecific, the test can be influenced by extraneous factors such as dietary intake and smoking and is, therefore, used sparingly. However, the test played a significant role in changing the use of horizontal flow cabinets to vertical flow biological safety cabinets during the preparation of antineoplastic drugs because the former exposed health care workers to high levels of drugs. This changed the handling of drugs and effectively reduced workers' exposure to antineoplastic drugs.
Biomarkers of exposure to antineoplastic drugs commonly include urinary platinum, methotrexate, urinary cyclophosphamide and ifosfamide, and urinary metabolite of 5-fluorouracil. In addition to this, there are other drugs used to measure the drugs directly in the urine, although they are rarely used. A measurement of these drugs directly in one's urine is a sign of high exposure levels and that an uptake of the drugs is happening either through inhalation or dermally.
== Available agents ==
There is an extensive list of antineoplastic agents. Several classification schemes have been used to subdivide the medicines used for cancer into several different types.
== History ==
The first use of small-molecule drugs to treat cancer was in the early 20th century, although the specific chemicals first used were not originally intended for that purpose. Mustard gas was used as a chemical warfare agent during World War I and was discovered to be a potent suppressor of hematopoiesis (blood production). A similar family of compounds known as nitrogen mustards were studied further during World War II at the Yale School of Medicine. It was reasoned that an agent that damaged the rapidly growing white blood cells might have a similar effect on cancer. Therefore, in December 1942, several people with advanced lymphomas (cancers of the lymphatic system and lymph nodes) were given the drug by vein, rather than by breathing the irritating gas. Their improvement, although temporary, was remarkable. Concurrently, during a military operation in World War II, following a German air raid on the Italian harbour of Bari, several hundred people were accidentally exposed to mustard gas, which had been transported there by the Allied forces to prepare for possible retaliation in the event of German use of chemical warfare. The survivors were later found to have very low white blood cell counts. After WWII was over and the reports declassified, the experiences converged and led researchers to look for other substances that might have similar effects against cancer. The first chemotherapy drug to be developed from this line of research was mustine. Since then, many other drugs have been developed to treat cancer, and drug development has exploded into a multibillion-dollar industry, although the principles and limitations of chemotherapy discovered by the early researchers still apply.
=== The term chemotherapy ===
The word chemotherapy without a modifier usually refers to cancer treatment, but its historical meaning was broader. The term was coined in the early 1900s by Paul Ehrlich as meaning any use of chemicals to treat any disease (chemo- + -therapy), such as the use of antibiotics (antibacterial chemotherapy). Ehrlich was not optimistic that effective chemotherapy drugs would be found for the treatment of cancer. The first modern chemotherapeutic agent was arsphenamine, an arsenic compound discovered in 1907 and used to treat syphilis. This was later followed by sulfonamides (sulfa drugs) and penicillin. In today's usage, the sense "any treatment of disease with drugs" is often expressed with the word pharmacotherapy.
== Research ==
=== Targeted delivery vehicles ===
Specially targeted delivery vehicles aim to increase effective levels of chemotherapy for tumor cells while reducing effective levels for other cells. This should result in an increased tumor kill or reduced toxicity or both.
==== Antibody-drug conjugates ====
Antibody-drug conjugates (ADCs) comprise an antibody, drug and a linker between them. The antibody will be targeted at a preferentially expressed protein in the tumour cells (known as a tumor antigen) or on cells that the tumor can utilise, such as blood vessel endothelial cells. They bind to the tumor antigen and are internalised, where the linker releases the drug into the cell. These specially targeted delivery vehicles vary in their stability, selectivity, and choice of target, but, in essence, they all aim to increase the maximum effective dose that can be delivered to the tumor cells. Reduced systemic toxicity means that they can also be used in people who are sicker and that they can carry new chemotherapeutic agents that would have been far too toxic to deliver via traditional systemic approaches.
The first approved drug of this type was gemtuzumab ozogamicin (Mylotarg), released by Wyeth (now Pfizer). The drug was approved to treat acute myeloid leukemia. Two other drugs, trastuzumab emtansine and brentuximab vedotin, are both in late clinical trials, and the latter has been granted accelerated approval for the treatment of refractory Hodgkin's lymphoma and systemic anaplastic large cell lymphoma.
==== Nanoparticles ====
Nanoparticles are 1–1000 nanometer (nm) sized particles that can promote tumor selectivity and aid in delivering low-solubility drugs. Nanoparticles can be targeted passively or actively. Passive targeting exploits the difference between tumor blood vessels and normal blood vessels. Blood vessels in tumors are "leaky" because they have gaps from 200 to 2000 nm, which allow nanoparticles to escape into the tumor. Active targeting uses biological molecules (antibodies, proteins, DNA and receptor ligands) to preferentially target the nanoparticles to the tumor cells. There are many types of nanoparticle delivery systems, such as silica, polymers, liposomes and magnetic particles. Nanoparticles made of magnetic material can also be used to concentrate agents at tumor sites using an externally applied magnetic field. They have emerged as a useful vehicle in magnetic drug delivery for poorly soluble agents such as paclitaxel.
=== Electrochemotherapy ===
Electrochemotherapy is the combined treatment in which injection of a chemotherapeutic drug is followed by application of high-voltage electric pulses locally to the tumor. The treatment enables the chemotherapeutic drugs, which otherwise cannot or hardly go through the membrane of cells (such as bleomycin and cisplatin), to enter the cancer cells. Hence, greater effectiveness of antitumor treatment is achieved.
Clinical electrochemotherapy has been successfully used for treatment of cutaneous and subcutaneous tumors irrespective of their histological origin. The method has been reported as safe, simple and highly effective in all reports on clinical use of electrochemotherapy. According to the ESOPE project (European Standard Operating Procedures of Electrochemotherapy), the Standard Operating Procedures (SOP) for electrochemotherapy were prepared, based on the experience of the leading European cancer centres on electrochemotherapy. Recently, new electrochemotherapy modalities have been developed for treatment of internal tumors using surgical procedures, endoscopic routes or percutaneous approaches to gain access to the treatment area.
=== Hyperthermia therapy ===
Hyperthermia therapy is heat treatment for cancer that can be a powerful tool when used in combination with chemotherapy (thermochemotherapy) or radiation for the control of a variety of cancers. The heat can be applied locally to the tumor site, which will dilate blood vessels to the tumor, allowing more chemotherapeutic medication to enter the tumor. Additionally, the tumor cell membrane will become more porous, further allowing more of the chemotherapeutic medicine to enter the tumor cell.
Hyperthermia has also been shown to help prevent or reverse "chemo-resistance." Chemotherapy resistance sometimes develops over time as the tumors adapt and can overcome the toxicity of the chemo medication. "Overcoming chemoresistance has been extensively studied within the past, especially using CDDP-resistant cells. In regard to the potential benefit that drug-resistant cells can be recruited for effective therapy by combining chemotherapy with hyperthermia, it was important to show that chemoresistance against several anticancer drugs (e.g. mitomycin C, anthracyclines, BCNU, melphalan) including CDDP could be reversed at least partially by the addition of heat.
== Other animals ==
Chemotherapy is used in veterinary medicine similar to how it is used in human medicine.
== See also ==
== References ==
== External links ==
Chemotherapy, American Cancer Society
Hazardous Drug Exposures in Health Care, National Institute for Occupational Safety and Health
NIOSH List of Antineoplastic and Other Hazardous Drugs in Healthcare Settings, 2016, National Institute for Occupational Safety and Health
Wikiversity page for the International Ototoxicity Management Group: https://en.wikiversity.org/wiki/International_Ototoxicity_Management_Group_(IOMG) | Wikipedia/Chemotherapy_medication |
Cancer immunotherapy (immuno-oncotherapy) is the stimulation of the immune system to treat cancer, improving the immune system's natural ability to fight the disease. It is an application of the fundamental research of cancer immunology (immuno-oncology) and a growing subspecialty of oncology.
Cancer immunotherapy exploits the fact that cancer cells often have tumor antigens, molecules on their surface that can bind to antibody proteins or T-cell receptors, triggering an immune system response. The tumor antigens are often proteins or other macromolecules (e.g., carbohydrates). Normal antibodies bind to external pathogens, but the modified immunotherapy antibodies bind to the tumor antigens marking and identifying the cancer cells for the immune system to inhibit or kill. The clinical success of cancer immunotherapy is highly variable between different forms of cancer; for instance, certain subtypes of gastric cancer react well to the approach whereas immunotherapy is not effective for other subtypes.
In 2018, American immunologist James P. Allison and Japanese immunologist Tasuku Honjo received the Nobel Prize in Physiology or Medicine for their discovery of cancer therapy by inhibition of negative immune regulation.
== History ==
"During the 17th and 18th centuries, various forms of immunotherapy in cancer became widespread... In the 18th and 19th centuries, septic dressings enclosing ulcerative tumours were used for the treatment of cancer. Surgical wounds were left open to facilitate the development of infection, and purulent sores were created deliberately... One of the most well-known effects of microorganisms on ... cancer was reported in 1891, when an American surgeon, William Coley, inoculated patients having inoperable tumours with [ Streptococcus pyogenes ]." "Coley [had] thoroughly reviewed the literature available at that time and found 38 reports of cancer patients with accidental or iatrogenic feverish erysipelas. In 12 patients, the sarcoma or carcinoma had completely disappeared; the others had substantially improved. Coley decided to attempt the therapeutic use of iatrogenic erysipelas..." "Coley developed a toxin that contained heat-killed bacteria [ Streptococcus pyogenes and Serratia marcescens ]. Until 1963, this treatment was used for the treatment of sarcoma." "Coley injected more than 1000 cancer patients with bacteria or bacterial products." 51.9% of [Coley's] patients with inoperable soft-tissue sarcomas showed complete tumour regression and survived for more than 5 years, and 21.2% of the patients had no clinical evidence of tumour at least 20 years after this treatment..." Research continued in the 20th century under Maria O'Connor Hornung at Tulane Medical School.
In the 1980's, researchers at the National Cancer Institute's Center for Cancer Research (CCR) began exploring the then-heretical idea that a patient’s immune system could be harnessed to fight cancer. These researchers included Michael Potter, Ira Pastan, and Steven Rosenberg who developed approaches including monoclonal antibody-based immunotoxins, checkpoint blockade drugs, cytokine-based therapies, and adoptive cell therapy studies.
== Types and categories ==
There are several types of immunotherapy used to treat cancer:
Immune checkpoint inhibitors: drugs that block immune system checkpoints to allow immune cells to respond more strongly to the cancer.
T-cell transfer therapy: a treatment that takes T-cells from the tumor and selects or changes them in the lab to better attack cancer cells, then reintroduces them into the patient.
Monoclonal antibodies: designed to bind to specific targets on cancer cells, marking cancer cells so that they will be better seen and destroyed by the immune system.
Treatment vaccines: also known as therapeutic cancer vaccines, help the immune system learn to recognize and react to mutant proteins specific to the tumor and destroy cancer cells containing them.
Immune system modulators: agents that enhance the body’s immune response against cancer.
Immunotherapies can be categorized as active or passive based on their ability to engage the host immune system against cancer. Active immunotherapy specifically targets tumor cells via the immune system. Examples include therapeutic cancer vaccines (also known as treatment vaccines, which are designed to boost the body's immune system to fight cancer), CAR-T cells, and targeted antibody therapies. In contrast, passive immunotherapy does not directly target tumor cells, but enhances the ability of the immune system to attack cancer cells. Examples include checkpoint inhibitors and cytokines.
Active cellular therapies aim to destroy cancer cells by recognition of distinct markers known as antigens. In cancer vaccines, the goal is to generate an immune response to these antigens through a vaccine. Currently, only one vaccine (sipuleucel-T for prostate cancer) has been approved. In cell-mediated therapies like CAR-T cell therapy, immune cells are extracted from the patient, genetically engineered to recognize tumor-specific antigens, and returned to the patient. Cell types that can be used in this way are natural killer (NK) cells, lymphokine-activated killer cells, cytotoxic T cells, and dendritic cells. Finally, specific antibodies can be developed that recognize cancer cells and target them for destruction by the immune system. Examples of such antibodies include rituximab (targeting CD-20), trastuzumab (targeting HER-2), and cetuximab (targeting EGFR).
Passive antibody therapies aim to increase the activity of the immune system without specifically targeting cancer cells. For example, cytokines directly stimulate the immune system and increase immune activity. Checkpoint inhibitors target proteins (immune checkpoints) that normally dampen the immune response. This enhances the ability of the immune system to attack cancer cells. Current research is identifying new potential targets to enhance immune function. Approved checkpoint inhibitors include antibodies such as ipilimumab, nivolumab, and pembrolizumab.
== Cellular immunotherapy ==
=== Dendritic cell therapy ===
Dendritic cell therapy provokes anti-tumor responses by causing dendritic cells to present tumor antigens to lymphocytes, which activates them, priming them to kill other cells that present the antigen. Dendritic cells are antigen-presenting cells (APCs) in the mammalian immune system. In cancer treatment, they aid cancer antigen targeting. The only approved cellular cancer therapy based on dendritic cells is sipuleucel-T.
One method of inducing dendritic cells to present tumor antigens is by vaccination with autologous tumor lysates or short peptides (small parts of the protein that correspond to the protein antigens on cancer cells). These peptides are often given in combination with adjuvants (highly immunogenic substances) to increase the immune and anti-tumor responses. Other adjuvants include proteins or other chemicals that attract and/or activate dendritic cells, such as granulocyte-macrophage colony-stimulating factor (GM-CSF). The most common sources of antigens used for dendritic cell vaccine in glioblastoma (GBM) as an aggressive brain tumor were whole tumor lysate, CMV antigen RNA and tumor-associated peptides like EGFRvIII.
Dendritic cells can also be activated in vivo by making tumor cells express GM-CSF. This can be achieved by either genetically engineering tumor cells to produce GM-CSF or by infecting tumor cells with an oncolytic virus that expresses GM-CSF.
Another strategy is to remove dendritic cells from the blood of a patient and activate them outside the body. The dendritic cells are activated in the presence of tumor antigens, which may be a single tumor-specific peptide/protein or a tumor cell lysate (a solution of broken-down tumor cells). These cells (with optional adjuvants) are infused and provoke an immune response.
Dendritic cell therapies include the use of antibodies that bind to receptors on the surface of dendritic cells. Antigens can be added to the antibody and can induce the dendritic cells to mature and provide immunity to the tumor. Dendritic cell receptors such as TLR3, TLR7, TLR8 or CD40 have been used as antibody targets. Dendritic cell-NK cell interface also has an important role in immunotherapy. The design of new dendritic cell-based vaccination strategies should also encompass NK cell-stimulating potency. It is critical to systematically incorporate NK cells monitoring as an outcome in antitumor DC-based clinical trials.
==== Drugs ====
Sipuleucel-T (Provenge) was approved for treatment of asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer in 2010. The treatment consists of removal of antigen-presenting cells from blood by leukapheresis and growing them with the fusion protein PA2024 made from GM-CSF and prostate-specific prostatic acid phosphatase (PAP) and reinfused. This process is repeated three times.
=== Adoptive T-cell therapy ===
Adoptive T cell therapy is a form of passive immunization by the transfusion of T-cells. They are found in blood and tissue and typically activate when they find foreign pathogens. Activation occurs when the T-cell's surface receptors encounter cells that display parts of foreign proteins (either on their surface or intracellularly). These can be either infected cells or other antigen-presenting cells (APCs). The latter are found in normal tissue and in tumor tissue, where they are known as tumor-infiltrating lymphocytes (TILs). They are activated by the presence of APCs such as dendritic cells that present tumor antigens. Although these cells can attack tumors, the tumor microenvironment is highly immunosuppressive, interfering with immune-mediated tumour death.
Multiple ways of producing tumour-destroying T-cells have been developed. Most commonly, T-cells specific to a tumor antigen can be removed from a tumor sample (TILs) or filtered from blood. The T-cells can optionally be modified in various ways, cultured and infused into patients. T cells can be modified via genetic engineering, producing CAR-T cell or TCR T cells or by exposing the T cells to tumor antigens in a non-immunosuppressive environment, that they recognize as foreign and learn to attack.
Another approach is transfer of haploidentical γδ T cells or natural killer cells from a healthy donor. The major advantage of this approach is that these cells do not cause graft-versus-host disease. The disadvantage is that transferred cells frequently have impaired function.
==== Tumor-derived T cell therapy ====
The simplest example involves removing TILs from a tumor, culturing but not modifying them, and infusing the result back into the tumour. The first therapy of this type, Lifileucel, achieved US Food and Drug Administration (FDA) approval in February 2024.
==== CAR-T cell therapy ====
The premise of CAR-T immunotherapy is to modify T cells to recognize cancer cells in order to target and destroy them. Scientists harvest T cells from people, genetically alter them to add a chimeric antigen receptor (CAR) that specifically recognizes cancer cells, then infuse the resulting CAR-T cells into patients to attack their tumors.
Tisagenlecleucel (Kymriah), a chimeric antigen receptor (CAR-T) therapy, was approved by the FDA in 2017 to treat acute lymphoblastic leukemia (ALL). This treatment removes CD19 positive cells (B-cells) from the body (including the diseased cells, but also normal antibody-producing cells).
Axicabtagene ciloleucel (Yescarta) is another CAR-T therapeutic, approved in 2017 for treatment of diffuse large B-cell lymphoma (DLBCL).
==== Multifunctional alginate scaffolds ====
Multifunctional alginate scaffolds for T cell engineering and release (MASTER) is a technique for in situ engineering, replication and release of genetically engineered T cells. It is an evolution of CAR T cell therapy. T cells are extracted from the patient and mixed with a genetically engineered virus that contains a cancer-targeting gene (as with CAR T). The mixture is then added to a MASTER (scaffold), which absorbs them. The MASTER contains antibodies that activate the T cells and interleukins that trigger cell proliferation. The MASTER is then implanted into the patient. The activated T cells interact with the viruses to become CAR T cells. The interleukins stimulate these CAR T cells to proliferate, and the CAR T cells exit the MASTER to attack the cancer. The technique takes hours instead of weeks. And because the cells are younger, they last longer in the body, show stronger potency against cancer, and display fewer markers of exhaustion. These features were demonstrated in mouse models. The treatment was more effective and longer-lasting against lymphoma.
==== T cell receptor T cell therapy ====
== Antibody therapy ==
=== Antibody types ===
==== Conjugation ====
Two types are used in cancer treatments:
Naked monoclonal antibodies are antibodies without added elements. Most antibody therapies use this antibody type.
Conjugated monoclonal antibodies are joined to another molecule, which is either cytotoxic or radioactive. The toxic chemicals are those typically used as chemotherapy drugs, but other toxins can be used. The antibody binds to specific antigens on cancer cell surfaces, directing the therapy to the tumor. Radioactive compound-linked antibodies are referred to as radiolabelled. Chemolabelled or immunotoxins antibodies are tagged with chemotherapeutic molecules or toxins, respectively. Research has also demonstrated conjugation of a TLR agonist to an anti-tumor monoclonal antibody.
==== Fc regions ====
Fc's ability to bind Fc receptors is important because it allows antibodies to activate the immune system. Fc regions are varied: they exist in numerous subtypes and can be further modified, for example with the addition of sugars in a process called glycosylation. Changes in the Fc region can alter an antibody's ability to engage Fc receptors and, by extension, will determine the type of immune response that the antibody triggers. For example, immune checkpoint blockers targeting PD-1 are antibodies designed to bind PD-1 expressed by T cells and reactivate these cells to eliminate tumors. Anti-PD-1 drugs contain not only a Fab region that binds PD-1 but also an Fc region. Experimental work indicates that the Fc portion of cancer immunotherapy drugs can affect the outcome of treatment. For example, anti-PD-1 drugs with Fc regions that bind inhibitory Fc receptors can have decreased therapeutic efficacy. Imaging studies have further shown that the Fc region of anti-PD-1 drugs can bind Fc receptors expressed by tumor-associated macrophages. This process removes the drugs from their intended targets (i.e. PD-1 molecules expressed on the surface of T cells) and limits therapeutic efficacy. Furthermore, antibodies targeting the co-stimulatory protein CD40 require engagement with selective Fc receptors for optimal therapeutic efficacy. Together, these studies underscore the importance of Fc status in antibody-based immune checkpoint targeting strategies.
==== Human/non-human antibodies ====
Antibodies can come from a variety of sources, including human cells, mice, and a combination of the two (chimeric antibodies). Different sources of antibodies can provoke different kinds of immune responses. For example, the human immune system can recognize mouse antibodies (also known as murine antibodies) and trigger an immune response against them. This could reduce the effectiveness of the antibodies as a treatment and cause an immune reaction. Chimeric antibodies attempt to reduce murine antibodies' immunogenicity by replacing part of the antibody with the corresponding human counterpart. Humanized antibodies are almost completely human; only the complementarity determining regions of the variable regions are derived from murine sources. Human antibodies have been produced using unmodified human DNA.
=== Mechanism of action ===
==== Antibody-dependent cell-mediated cytotoxicity (ADCC) ====
Antibody-dependent cell-mediated cytotoxicity (ADCC) requires antibodies to bind to target cell surfaces. Antibodies are formed of a binding region (Fab) and the Fc region that can be detected by immune system cells via their Fc surface receptors. Fc receptors are found on many immune system cells, including NK cells. When NK cells encounter antibody-coated cells, the latter's Fc regions interact with their Fc receptors, releasing perforin and granzyme B to kill the tumor cell. Examples include rituximab, ofatumumab, elotuzumab, and alemtuzumab. Antibodies under development have altered Fc regions that have higher affinity for a specific type of Fc receptor, FcγRIIIA, which can dramatically increase effectiveness.
=== Anti-CD47 therapy ===
Many tumor cells overexpress CD47 to escape immunosurveilance of host immune system. CD47 binds to its receptor signal-regulatory protein alpha (SIRPα) and downregulate phagocytosis of tumor cell. Therefore, anti-CD47 therapy aims to restore clearance of tumor cells. Additionally, growing evidence supports the employment of tumor antigen-specific T cell response in response to anti-CD47 therapy. A number of therapeutics are being developed, including anti-CD47 antibodies, engineered decoy receptors, anti-SIRPα antibodies and bispecific agents. As of 2017, wide range of solid and hematologic malignancies were being clinically tested.
=== Anti-GD2 antibodies ===
Carbohydrate antigens on the surface of cells can be used as targets for immunotherapy. GD2 is a ganglioside found on the surface of many types of cancer cell including neuroblastoma, retinoblastoma, melanoma, small cell lung cancer, brain tumors, osteosarcoma, rhabdomyosarcoma, Ewing's sarcoma, liposarcoma, fibrosarcoma, leiomyosarcoma and other soft tissue sarcomas. It is not usually expressed on the surface of normal tissues, making it a good target for immunotherapy. As of 2014, clinical trials were underway.
==== Complement Activation ====
The complement system includes blood proteins that can cause cell death after an antibody binds to the cell surface (the classical complement pathway, among the ways of complement activation). Generally, the system deals with foreign pathogens but can be activated with therapeutic antibodies in cancer. The system can be triggered if the antibody is chimeric, humanized, or human; as long as it contains the IgG1 Fc region. Complement can lead to cell death by activation of the membrane attack complex, known as complement-dependent cytotoxicity; enhancement of antibody-dependent cell-mediated cytotoxicity; and CR3-dependent cellular cytotoxicity. Complement-dependent cytotoxicity occurs when antibodies bind to the cancer cell surface, the C1 complex binds to these antibodies and subsequently, protein pores are formed in cancer cell membrane.
Blocking
Antibody therapies can also function by binding to proteins and physically blocking them from interacting with other proteins. Checkpoint inhibitors (CTLA-4, PD-1, and PD-L1) operate by this mechanism. Briefly, checkpoint inhibitors are proteins that normally help to slow immune responses and prevent the immune system from attacking normal cells. Checkpoint inhibitors bind these proteins and prevent them from functioning normally, which increases the activity of the immune system. Examples include durvalumab, ipilimumab, nivolumab, and pembrolizumab.
=== FDA-approved antibodies ===
==== Alemtuzumab ====
Alemtuzumab (Campath-1H) is an anti-CD52 humanized IgG1 monoclonal antibody indicated for the treatment of fludarabine-refractory chronic lymphocytic leukemia (CLL), cutaneous T-cell lymphoma, peripheral T-cell lymphoma and T-cell prolymphocytic leukemia. CD52 is found on >95% of peripheral blood lymphocytes (both T-cells and B-cells) and monocytes, but its function in lymphocytes is unknown. It binds to CD52 and initiates its cytotoxic effect by complement fixation and ADCC mechanisms. Due to the antibody target (cells of the immune system), common complications of alemtuzumab therapy are infection, toxicity and myelosuppression.
==== Atezolizumab ====
==== Atezolizumab/hyaluronidase ====
==== Avelumab ====
==== Durvalumab ====
Durvalumab (Imfinzi) is a human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody that blocks the interaction of programmed cell death ligand 1 (PD-L1) with the PD-1 and CD80 (B7.1) molecules. Durvalumab is approved for the treatment of patients with locally advanced or metastatic urothelial carcinoma who:
have disease progression during or following platinum-containing chemotherapy.
have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
On 16 February 2018, the Food and Drug Administration approved durvalumab for patients with unresectable stage III non-small cell lung cancer (NSCLC) whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy.
==== Elotuzumab ====
==== Ipilimumab ====
Ipilimumab (Yervoy) is a human IgG1 antibody that binds the surface protein CTLA4. In normal physiology T-cells are activated by two signals: the T-cell receptor binding to an antigen-MHC complex and T-cell surface receptor CD28 binding to CD80 or CD86 proteins. CTLA4 binds to CD80 or CD86, preventing the binding of CD28 to these surface proteins and therefore negatively regulates the activation of T-cells.
Active cytotoxic T-cells are required for the immune system to attack melanoma cells. Normally inhibited active melanoma-specific cytotoxic T-cells can produce an effective anti-tumor response. Ipilimumab can cause a shift in the ratio of regulatory T-cells to cytotoxic T-cells to increase the anti-tumor response. Regulatory T-cells inhibit other T-cells, which may benefit the tumor.
==== Nivolumab ====
Nivolumab is a human IgG4 antibody that prevents T-cell inactivation by blocking the binding of programmed cell death 1 ligand 1 or programmed cell death 1 ligand 2 (PD-L1 or PD-L2), a protein expressed by cancer cells, with PD-1, a protein found on the surface of activated T-cells. Nivolumab is used in advanced melanoma, metastatic renal cell carcinoma, advanced lung cancer, advanced head and neck cancer, and Hodgkin's lymphoma.
==== Ofatumumab ====
Ofatumumab is a second generation human IgG1 antibody that binds to CD20. It is used in the treatment of chronic lymphocytic leukemia (CLL) because the cancerous cells of CLL are usually CD20-expressing B-cells. Unlike rituximab, which binds to a large loop of the CD20 protein, ofatumumab binds to a separate, small loop. This may explain their different characteristics. Compared to rituximab, ofatumumab induces complement-dependent cytotoxicity at a lower dose with less immunogenicity.
==== Pembrolizumab ====
As of 2019, pembrolizumab, which blocks PD-1, programmed cell death protein 1, has been used via intravenous infusion to treat inoperable or metastatic melanoma, metastatic non-small cell lung cancer (NSCLC) in certain situations, as a second-line treatment for head and neck squamous cell carcinoma (HNSCC), after platinum-based chemotherapy, and for the treatment of adult and pediatric patients with refractory classic Hodgkin's lymphoma (cHL). It is also indicated for certain patients with urothelial carcinoma, stomach cancer and cervical cancer.
==== Rituximab ====
Rituximab is a chimeric monoclonal IgG1 antibody specific for CD20, developed from its parent antibody Ibritumomab. As with ibritumomab, rituximab targets CD20, making it effective in treating certain B-cell malignancies. These include aggressive and indolent lymphomas such as diffuse large B-cell lymphoma and follicular lymphoma and leukemias such as B-cell chronic lymphocytic leukemia. Although the function of CD20 is relatively unknown, CD20 may be a calcium channel involved in B-cell activation. The antibody's mode of action is primarily through the induction of ADCC and complement-mediated cytotoxicity. Other mechanisms include apoptosis and cellular growth arrest. Rituximab also increases the sensitivity of cancerous B-cells to chemotherapy.
==== Trastuzumab ====
== Immune checkpoint antibody therapy or immune checkpoint blockade ==
Immune checkpoints affect the immune system function. Immune checkpoints can be stimulatory or inhibitory. Tumors can use these checkpoints to protect themselves from immune system attacks. Checkpoint therapies approved as of 2012 block inhibitory checkpoint receptors. Blockade of negative feedback signaling to immune cells thus results in an enhanced immune response against tumors. As of 2020, immune checkpoint blockade therapies have varied effectiveness. In Hodgkin lymphoma and natural killer T-cell lymphoma, response rates are high, at 50–60%. Response rates are quite low for breast and prostate cancers, however. A major challenge are the large variations in responses to immunocheckpoint inhibitors, some patients showing spectacular clinical responses while no positive effects are seen in others. A plethora of possible reasons for the absence of efficacy in many patients have been proposed, but the biomedical community has still to begin to find consensus in this respect. For instance, a recent paper documented that infection with Helicobacter pylori would negatively influence the effects of immunocheckpoint inhibitors in gastric cancer., but this notion was quickly challenged by others.
One ligand-receptor interaction under investigation is the interaction between the transmembrane programmed cell death 1 protein (PDCD1, PD-1; also known as CD279) and its ligand, PD-1 ligand 1 (PD-L1, CD274). PD-L1 on the cell surface binds to PD1 on an immune cell surface, which inhibits immune cell activity. Among PD-L1 functions is a key regulatory role on T cell activities. It appears that (cancer-mediated) upregulation of PD-L1 on the cell surface may inhibit T cells that might otherwise attack. PD-L1 on cancer cells also inhibits FAS- and interferon-dependent apoptosis, protecting cells from cytotoxic molecules produced by T cells. Antibodies that bind to either PD-1 or PD-L1 and therefore block the interaction may allow the T-cells to attack the tumor.
=== CTLA-4 blockade ===
The first checkpoint antibody approved by the FDA was ipilimumab, approved in 2011 to treat melanoma. It blocks the immune checkpoint molecule CTLA-4. As of 2012, clinical trials have also shown some benefits of anti-CTLA-4 therapy on lung cancer or pancreatic cancer, specifically in combination with other drugs. In on-going trials the combination of CTLA-4 blockade with PD-1 or PD-L1 inhibitors is tested on different types of cancer.
However, as of 2015 it is known that patients treated with checkpoint blockade (specifically CTLA-4 blocking antibodies), or a combination of check-point blocking antibodies, are at high risk of having immune-related adverse events such as dermatologic, gastrointestinal, endocrine, or hepatic autoimmune reactions. These are most likely due to the breadth of the induced T-cell activation when anti-CTLA-4 antibodies are administered by injection in the bloodstream.
A 2024 cohort study of ICI use during pregnancy showed no overreporting of specific adverse effects on pregnancy, fetal, and/or newborn outcomes, interestingly.
Using a mouse model of bladder cancer, researchers have found that a local injection of a low dose anti-CTLA-4 in the tumour area had the same tumour inhibiting capacity as when the antibody was delivered in the blood. At the same time the levels of circulating antibodies were lower, suggesting that local administration of the anti-CTLA-4 therapy might result in fewer adverse events.
=== PD-1 inhibitors ===
Initial clinical trial results with IgG4 PD1 antibody nivolumab were published in 2010. It was approved in 2014. Nivolumab is approved to treat melanoma, lung cancer, kidney cancer, bladder cancer, head and neck cancer, and Hodgkin's lymphoma. A 2016 clinical trial for non-small cell lung cancer failed to meet its primary endpoint for treatment in the first-line setting, but is FDA-approved in subsequent lines of therapy.
Pembrolizumab (Keytruda) is another PD1 inhibitor that was approved by the FDA in 2014. Pembrolizumab is approved to treat melanoma and lung cancer.
Antibody BGB-A317 is a PD-1 inhibitor (designed to not bind Fc gamma receptor I) in early clinical trials.
=== PD-L1 inhibitors ===
In May 2016, PD-L1 inhibitor atezolizumab was approved for treating bladder cancer.
Anti-PD-L1 antibodies currently in development include avelumab and durvalumab, in addition to an inhibitory affimer.
=== CISH ===
=== Combinations ===
Many cancer patients do not respond to immune checkpoint blockade. Response rate may be improved by combining that with additional therapies, including those that stimulate T cell infiltration. For example, targeted therapies such as radiotherapy, vasculature targeting agents, and immunogenic chemotherapy can improve immune checkpoint blockade response in animal models.
Combining immunotherapies such as PD1 and CTLA4 inhibitors can create to durable responses.
Combinatorial ablation and immunotherapy enhances the immunostimulating response and has synergistic effects for metastatic cancer treatment.
Combining checkpoint immunotherapies with pharmaceutical agents has the potential to improve response, and as of 2018 were a target of clinical investigation. Immunostimulatory drugs such as CSF-1R inhibitors and TLR agonists have been effective.
Two independent 2024 clinical trials reported that combinations of JAK inhibitors with anti–PD-1 immunotherapy could improve efficacy. A phase 2 trial investigated the combination as a first-line therapy for metastatic non-small-cell lung cancer. Administration of itacitinib after treatment with pembrolizumab improved therapeutic response. A separate phase 1/2 trial with patients with relapsed/refractory Hodgkin’s lymphoma combined ruxolitinib and nivolumab, yielding improved clinical efficacy in patients who had previously failed checkpoint blockade immunotherapy.
== Cytokine therapy ==
Cytokines are proteins produced by many types of cells present within a tumor. They can modulate immune responses. The tumor often employs them to allow it to grow and reduce the immune response. These immune-modulating effects allow them to be used as drugs to provoke an immune response. Two commonly used cytokines are interferons and interleukins.
Interleukin-2 and interferon-α are cytokines, proteins that regulate and coordinate the behavior of the immune system. They have the ability to enhance anti-tumor activity and thus can be used as passive cancer treatments. Interferon-α is used in the treatment of hairy-cell leukaemia, AIDS-related Kaposi's sarcoma, follicular lymphoma, chronic myeloid leukaemia and malignant melanoma. Interleukin-2 is used in the treatment of malignant melanoma and renal cell carcinoma.
=== Interferon ===
Interferons are produced by the immune system. They are usually involved in anti-viral response, but also have use for cancer. They fall in three groups: type I (IFNα and IFNβ), type II (IFNγ) and type III (IFNλ). IFNα has been approved for use in hairy-cell leukaemia, AIDS-related Kaposi's sarcoma, follicular lymphoma, chronic myeloid leukaemia and melanoma. Type I and II IFNs have been researched extensively and although both types promote anti-tumor immune system effects, only type I IFNs have been shown to be clinically effective. IFNλ shows promise for its anti-tumor effects in animal models.
Unlike type I IFNs, Interferon gamma is not approved yet for the treatment of any cancer. However, improved survival was observed when Interferon gamma was administered to patients with bladder carcinoma and melanoma cancers. The most promising result was achieved in patients with stage 2 and 3 of ovarian carcinoma. The in vitro study of IFN-gamma in cancer cells is more extensive and results indicate anti-proliferative activity of IFN-gamma leading to the growth inhibition or cell death, generally induced by apoptosis but sometimes by autophagy.
=== Interleukin ===
Interleukins have an array of immune system effects. Interleukin-2 is used in the treatment of malignant melanoma and renal cell carcinoma. In normal physiology it promotes both effector T cells and T-regulatory cells, but its exact mechanism of action is unknown.
== Genetic pre-treatment testing for therapeutic significance ==
Because of the high cost of many of immunotherapy medications and the reluctance of medical insurance companies to prepay for their prescriptions various test methods have been proposed, to attempt to forecast the effectiveness of these medications. In some cases the FDA has approved genetic tests for medication specific to certain genetic markers. For example, the FDA approved BRAF-associated medication for metastatic melanoma, to be administered to patients after testing for the BRAF genetic mutation.
As of 2018, the detection of PD-L1 protein seemed to be an indication of cancer susceptible to several immunotherapy medications, but research found that both the lack of this protein or its inclusion in the cancerous tissue was inconclusive, due to the little-understood varying quantities of the protein during different times and locations within the infected cells and tissue.
In 2018, some genetic indications such as Tumor Mutational Burden (TMB, the number of mutations within a targeted genetic region in the cancerous cell's DNA), and microsatellite instability (MSI, the quantity of impaired DNA mismatch leading to probable mutations), have been approved by the FDA as good indicators for the probability of effective treatment of immunotherapy medication for certain cancers, but research is still in progress. As of 2020, the patient prioritization for immunotherapy based on TMB was still highly controversial.
Tests of this sort are being widely advertised for general cancer treatment and are expensive. In the past, some genetic testing for cancer treatment has been involved in scams such as the Duke University Cancer Fraud scandal, or claimed to be hoaxes.
== Research ==
=== Oncolytic virus ===
An oncolytic virus is a virus that preferentially infects and kills cancer cells. As the infected cancer cells are destroyed by oncolysis, they release new infectious virus particles or virions to help destroy the remaining tumour. Oncolytic viruses are thought not only to cause direct destruction of the tumour cells, but also to stimulate host anti-tumour immune responses for long-term immunotherapy.
The potential of viruses as anti-cancer agents was first realized in the early twentieth century, although coordinated research efforts did not begin until the 1960s. A number of viruses including adenovirus, reovirus, measles, herpes simplex, Newcastle disease virus and vaccinia have now been clinically tested as oncolytic agents. T-Vec is the first FDA-approved oncolytic virus for the treatment of melanoma. A number of other oncolytic viruses are in Phase II-III development.
=== Polysaccharides ===
Certain compounds found in mushrooms, primarily polysaccharides, can up-regulate the immune system and may have anti-cancer properties. For example, beta-glucans such as lentinan have been shown in laboratory studies to stimulate macrophage, NK cells, T cells and immune system cytokines and have been investigated in clinical trials as immunologic adjuvants.
=== Neoantigens ===
Many tumors express mutations. These mutations potentially create new targetable antigens (neoantigens) for use in T-cell immunotherapy. The presence of CD8+ T cells in cancer lesions, as identified using RNA sequencing data, is higher in tumors with a high mutational burden. The level of transcripts associated with the cytolytic activity of natural killer cells and T cells positively correlates with mutational load in many human tumors. In non–small cell lung cancer patients treated with lambrolizumab, mutational load shows a strong correlation with clinical response. In melanoma patients treated with ipilimumab, the long-term benefit is also associated with a higher mutational load, although less significantly. The predicted MHC binding neoantigens in patients with a long-term clinical benefit were enriched for a series of tetrapeptide motifs that were not found in tumors of patients with no or minimal clinical benefit. However, human neoantigens identified in other studies do not show the bias toward tetrapeptide signatures.
=== Polysaccharide-K ===
In the 1980s, Japan's Ministry of Health, Labour and Welfare approved polysaccharide-K extracted from the mushroom, Coriolus versicolor, to stimulate the immune systems of patients undergoing chemotherapy. It is a dietary supplement in the US and other jurisdictions.
== See also ==
Cancer vaccine
Antigen 5T4
Coley's toxins
Combinatorial ablation and immunotherapy
Cryoimmunotherapy
Photoimmunotherapy
Radioimmunotherapy
== References ==
== External links ==
A primer on "Immunotherapy to Treat Cancer", NIH
Immunotherapy – Using the Immune System to Treat Cancer Archived 4 April 2017 at the Wayback Machine
Cancer Research Institute – What is Cancer Immunotherapy
Association for Immunotherapy of Cancer
Society for Immunotherapy of Cancer
"And Then There Were Five". Economist.
"Discover the Science of Immuno-Oncology". Bristol-Myers Squibb. Archived from the original on 10 October 2014. Retrieved 13 March 2014.
Eggermont A, Finn O (September 2012). "Advances in immuno-oncology. Foreword". Annals of Oncology. 23 (Suppl 8): viii5. doi:10.1093/annonc/mds255. PMID 22918929.
"Cancer Immunotherapy in Gujarat" | Wikipedia/Adoptive_T-cell_therapy |
Virulent Newcastle disease (VND), formerly exotic Newcastle disease, is a contagious viral avian disease affecting many domestic and wild bird species; it is transmissible to humans. Though it can infect humans, most cases are non-symptomatic; rarely it can cause a mild fever and influenza-like symptoms and/or conjunctivitis in humans. Its effects are most notable in domestic poultry due to their high susceptibility and the potential for severe impacts of an epizootic on the poultry industries. It is endemic to many countries. No treatment for VND is known, but the use of prophylactic vaccines and sanitary measures reduces the likelihood of outbreaks.
The disease is caused by Newcastle disease virus (NDV), an avulavirus. Strains of Newcastle disease virus have been used to treat cancer in humans, since the virus appears to preferentially infect and kill cancerous cells. Strains of Newcastle disease virus have also been used to create viral vector vaccine candidates against Ebola and COVID-19.
== History ==
Newcastle disease was first identified in Java, Indonesia, in 1926, and in Newcastle upon Tyne, England, in 1927. However, it may have been prevalent as early as 1898, when a disease wiped out all the domestic fowl in northwest Scotland.
The policy of slaughter ceased in England and Wales on 31 March 1963, except for the peracute form of Newcastle disease and for fowl plague. In Scotland the slaughter policy continued for all types of fowl pest.
Interest in the use of NDV as an anticancer agent has arisen from the ability of NDV to selectively kill human tumour cells with limited toxicity to normal cells.
Since May 2018, California Department of Food and Agriculture staff and the United States Department of Agriculture have been working on eliminating VND in South California and more than 400 birds have been confirmed to have VND. On February 27, 2019, the California state veterinarian, Annette Jones, increased the quarantine area in Southern California and on March 15, 2019, and April 5, 2019, cases of VND in Northern California and Arizona respectively.
== Causal agent ==
The causal agent, Newcastle disease virus (NDV), is a variant of the species Orthoavulavirus javaense, a negative-sense, single-stranded RNA virus. NDV belongs to the subfamily Avulavirinae, which infect birds. Transmission occurs by exposure to faecal and other excretions from infected birds, and through contact with contaminated food, water, equipment, and clothing.
=== Strains ===
NDV strains can be categorised as velogenic (highly virulent), mesogenic (intermediate virulence), or lentogenic (nonvirulent). Velogenic strains produce severe nervous and respiratory signs, spread rapidly, and cause up to 90% mortality. Mesogenic strains cause coughing, affect egg quality and production, and result in up to 10% mortality. Lentogenic strains produce mild signs with negligible mortality.
== Transmission ==
NDV is spread primarily through direct contact between healthy birds and the bodily discharges of infected birds. The disease is transmitted through infected birds' droppings and secretions from the nose, mouth, and eyes. NDV spreads rapidly among birds kept in confinement, such as commercially raised chickens.
High concentrations of the NDV are found in birds' bodily discharges; therefore, the disease can be spread easily by mechanical means. Virus-bearing material can be picked up on shoes and clothing and carried from an infected flock to a healthy one.
NDV can survive for several weeks in a warm and humid environment on birds' feathers, manure, and other materials. It can survive indefinitely in frozen material. However, the virus is destroyed rapidly by dehydration and by the ultraviolet rays in sunlight.
Smuggled pet birds, especially Amazon parrots from Latin America, pose a great risk of introducing NDV into the US. Amazon parrots are carriers of the disease, but do not show symptoms, and are capable of shedding NDV for more than 400 days.
== Clinical findings ==
=== Clinical signs ===
Signs of infection with NDV vary greatly depending on factors such as the strain of virus and the health, age and species of the host.
The incubation period for the disease ranges from 2 to 15 days. An infected bird may exhibit several signs, including respiratory signs (gasping, coughing), nervous signs (depression, inappetence, muscular tremors, drooping wings, twisting of head and neck, circling, complete paralysis), swelling of the tissues around the eyes and neck, greenish, watery diarrhoea, misshapen, rough- or thin-shelled eggs and reduced egg production.
In acute cases, the death is very sudden, and, in the beginning of the outbreak, the remaining birds do not seem to be sick. In flocks with good immunity, however, the signs (respiratory and digestive) are mild and progressive, and are followed after seven days by nervous symptoms, especially twisted heads.
=== Postmortem lesions ===
Petechiae in the proventriculus and on the submucosae of the gizzard are typical; also, severe enteritis of the duodenum occurs. The lesions are scarce in hyperacute cases (first day of outbreak).
== Diagnosis ==
=== Immunological tests ===
Enzyme-linked immunosorbent assay, polymerase chain reaction, and sequence technology tests have been developed.
== Virus isolation ==
=== Samples ===
For routine isolation of NDV from chickens, turkeys, and other birds, samples are obtained by swabbing the trachea and the cloaca. Cotton swabs can be used. The virus can also be isolated from the lungs, brain, spleen, liver, and kidneys.
=== Handling ===
Prior to shipping, samples should be stored at 4 °C (refrigerator). Samples must be shipped in a padded envelope or box. Samples may be sent by regular mail, but overnight is recommended.
== Prevention ==
Any animals showing symptoms of Newcastle disease should be isolated immediately. New birds should also be vaccinated before being introduced to a flock. An inactivated viral vaccine is available, as well as various combination vaccines. A thermotolerant vaccine is available for controlling Newcastle disease in underdeveloped countries. Schiappacasse et al. 2020 demonstrates successful, complete inactivation of the virus in a space using a nonthermal plasma generator.
== History of NDV in cancer research ==
Though the oncolytic effect of NDV was already documented in the 1950s, later advances in research into using viruses in cancer therapy came with the advent of reverse genetics technologies. Later on it was Csatary LK and his colleagues to document anti-cancer effects in patients with brain gliomas.
One of the main issues using NDV would be the host/patient immune response against the virus itself, which prior to the time of the reverse genetics technology, decreased the potential applicability of NDV as a cancer treatment.
As of 2018 there had been several clinical studies into the use of NDV for cancer treatment, but the research quality was low and the outcomes inconclusive.
== References ==
== External links ==
Current status of Newcastle disease worldwide at OIE. WAHID Interface - OIE World Animal Health Information Database
Disease card
Department of Environment, Food and Rural Affairs, UK
Newcastle Disease, Iowa State University, Center for Food Security and Public Health
Newcastle Disease in Poultry, Merck Veterinary Manual
Species Profile—Virulent Newcastle Disease, National Invasive Species Information Center, United States National Agricultural Library. Lists general information and resources for Exotic Newcastle Disease. | Wikipedia/Newcastle_disease |
PCR inhibitors are any factor which prevent the amplification of nucleic acids through the polymerase chain reaction (PCR). PCR inhibition is the most common cause of amplification failure when sufficient copies of DNA are present. PCR inhibitors usually affect PCR through interaction with DNA or interference with the DNA polymerase. Inhibitors can escape removal during the DNA purification procedure by binding directly to single or double-stranded DNA. Alternatively, by reducing the availability of cofactors (such as Mg2+) or otherwise interfering with their interaction with the DNA polymerase, PCR is inhibited.
In a multiplex PCR reaction, it is possible for the different sequences to suffer from different inhibition effects to different extents, leading to disparity in their relative amplifications.
== Types of inhibitors ==
Inhibitors may be present in the original sample, such as blood, fabrics, tissues and soil but may also be added as a result of the sample processing and DNA extraction techniques used. Excess salts including KCl and NaCl, ionic detergents such as sodium deocycholate, sarkosyl and SDS, ethanol, isopropanol and phenol among others, all contribute via various inhibitory mechanisms, to the reduction of PCR efficiency.
== Quantifying extent of inhibition ==
In order to try to assess the extent of inhibition that occurs in a reaction, a control can be performed by adding a known amount of a template to the investigated reaction mixture (based on the sample under analysis). By comparing the amplification of this template in the mixture to the amplification observed in a separate experiment in which the same template is used in the absence of inhibitors, the extent of inhibition in the investigated reaction mixture can be inferred. Of course, if any part of the inhibition occurring in the sample-derived reaction mixture is sequence-specific, then this method will yield an underestimate of the inhibition as it applies to the investigate sequence(s).
== Preventing PCR inhibition ==
=== Sample collection ===
The method of sample acquisition can be refined to avoid unnecessary collection of inhibitors. For example, in forensics, swab-transfer of blood on fabric or saliva on food, may prevent or reduce contamination with inhibitors present in the fabric or food.
=== DNA purification ===
Techniques exist and kits are commercially available to enable extraction of DNA to the exclusion of some inhibitors.
=== PCR reaction components ===
As well as methods for the removal of inhibitors from samples before PCR, some DNA polymerases offer varying resistance to different inhibitors and increasing the concentration of the chosen DNA polymerase also confers some resistance to polymerase-targeted inhibitors.
For PCR based on blood samples, the addition of bovine serum albumin reduces the effect of some inhibitors on PCR.
== See also ==
PCR optimization
== References == | Wikipedia/DNA_polymerase_inhibitor |
Cryoimmunotherapy, also referred to as cryoimmunology, is an oncological treatment for various cancers that combines cryoablation of tumor with immunotherapy treatment. In-vivo cryoablation of a tumor, alone, can induce an immunostimulatory, systemic anti-tumor response, resulting in a cancer vaccine—the abscopal effect. Thus, cryoablation of tumors is a way of achieving autologous, in-vivo tumor lysate vaccine and treat metastatic disease. However, cryoablation alone may produce an insufficient immune response, depending on various factors, such as high freeze rate. Combining cryotherapy with immunotherapy enhances the immunostimulating response and has synergistic effects for cancer treatment.
Although, cryoblation and immunotherapy has been used successfully in oncological clinical practice for over 100 years, and can treat metastatic disease with curative intent, it has been ignored in modern practice. Only recently has cryoimmunotherapy been resurrected to become an established cancer treatment for all stages of disease.
== History ==
Immunological effects resulting from the cryoablation of tumors was first observed in the 1960s. Since the 1960s, Tanaka treated metastatic breast cancer patients with cryotherapy and reported cryoimmunological reaction resulting from cryotherapy. In the 1970s, systemic immunological response from local cryoablation of prostate cancer was also clinically observed. In the 1980s, Tanaka, of Japan, continued to advance the clinical practice of cryoimmunology with combination treatments including: cryochemotherapy and cryoimmunotherapy. In 1997, Russian scientists confirmed the efficacy of cryoimmunotherapy in inhibiting metastases in advanced cancer. In 2000s, China, following closely with the exciting developments, enthusiastically embraced cryoablation treatment for cancer and has been leading the practice ever since with cryoimmunotherapy treatments available for cancer patients in numerous hospitals and medical clinics throughout China. In the 2010s, American researchers and medical professionals, started to explore cryoimmunotherapy for systemic treatment of cancer.
== Mechanisms of actions ==
Cryoablation of tumor induces necrosis of tumor cells. The immunotherapeutic effect of cryoablation of tumor is the result of the release of intracellular tumor antigens from within the necrotized tumor cells. The released tumor antigens help activate anti-tumor T cells, which destroy remaining malignant cells. Thus, cryoablation of tumor elicits a systemic anti-tumor immunologic response.
The resulting immunostimulation from cryoablation may not be sufficient to induce sustained, systemic regression of metastases, and can be synergised with the combination of immunotherapy treatment and vaccine adjuvants.
Various adjuvant immunotherapy and chemotherapy treatments can be combined with cryoablation to sustain systemic anti-tumor response with regression of metastases, including:
Injection of immunomodulating drugs (i.e.: therapeutic antibodies) and vaccine adjuvants (saponins) directly into the cryoablated, necrotized tumor lysate, immediately after cryoablation
Administration of autologous immune enhancement therapy, including: dendritic cell therapy, CIK cell therapy
== See also ==
Combinatorial ablation and immunotherapy
Photoimmunotherapy
== References ==
== External links ==
The Great Prostate Hoax: How Big Medicine Hijacked...
Immunologic Response to Cryoablation of Breast Cancer
Modern Cryosurgery for Cancer
Percutaneous Cryotherapy of Renal Cell Carcinoma Under an Open MRI System
Modern Cryosurgery for Cancer
Tumor Ablation: Effects on Systemic and Local Anti-Tumor Immunity and on Other Tumor-Microenvironment Interactions
Basics of Cryosurgery
Cryosurgery: A Practical Manual
Dermatological Cryosurgery and Cryotherapy
The Abscopal Effect and the Prospect of Using Cancer Against Itself
Tumor Ablation: Principles and Practice
Cryoimmunologie: Cryoimmunology: colloque
Metastatic Bone Disease: An Integrated Approach to Patient Care
Musculoskeletal Cancer Surgery: Treatment of Sarcomas and Allied Diseases
Prospects for cryo-immunotherapy in cases of metastasizing carcinoma of the prostate . | Wikipedia/Cryoimmunotherapy |
T cell receptor T cell therapy (TCR-T) is a type of adoptive T-cell therapy that targets some cancers. TCR-T therapies use heterodimers made of alpha and beta peptide chains to recognize MHC-presented polypeptide fragment molecules. Unlike CAR-T, which uses cell surface antigens, TCR-T can recognize MHC's larger set of intracellular antigen fragments. However, TCR-T cell therapy depends on MHC molecules, limiting its usefulness.
Each T cell's TCR is specific to one antigen and sits on the T cell's surface. The affinity of human TCRs to tumor antigens is relatively low, rendering them unable to recognize and kill tumor cells effectively. The modified T cell has much higher affinity, which enhances both recognition and affinity supporting the recognition of tumor cells.
== History ==
Michael Steinmetz was the first to move TCR genes across T cells. The recipient T cell then recognized a different antigen, enabling the use of these cells to target non-surface antigens.
One clinical trial modified multiple amino acids, increasing the T cell's affinity for New York esophageal squamous cell carcinoma (NY-ESO-1). This TCR was used to attack NY-ESO-1-overexpressing cancers, such as multiple myeloma. 80% of multiple myeloma patients had at least a good clinical response, and 70% had complete or near-complete response.
In 2024, the US Food and Drug Administration approved afamitresgene autoleucel (Tecelra) as the first TCR-T therapy for the treatment of synovial sarcoma.
== Process ==
Appropriate target antigens are identified by subtraction. First the entire set of antigens presented by tumor cells is identified. Next, those presented by normal cells are screened out, leaving only those unique to the tumorous cells. Then a TCR phage display library is used to pick TCRs with high affinity and specificity. A preclinical safety test watches for off-target effects and cross-reactivity.
Challenges include target selection, TCR identification, affinity screening, safety, time, and cost.
Most targets are limited by MHC class.
== Side effects ==
Hybridization (mismatch) between exogenous and endogenous chains may induce harmful recognition of autoantigens, triggering graft-vs.-host disease. Increased affinity poses a risk of false targeting.
== Target malignancies ==
Malignant myelomas appear qualified, but the appropriate epitopes have not been identified. Published studies and their target antigens include:
Acute myeloid leukemia (WT1)
Solid tumors:
In solid tumors local injection is more effective than systemic drug administration, such as injecting T cells into the cerebrospinal fluid in brain tumors. Published studies include:
Esophageal cancer (MAGE-E4)
Metastatic colorectal cancer (TGFβII)
Metastatic melanoma (Gp100)
Metastatic/malignant melanoma (MAGE-A3)
Metastatic melanoma (MART-1)
Metastatic melanova/synovial cell carcinoma (NY-ESO-1)
Multiple myeloma (NY-ESO-1)
== References ==
== Further reading == | Wikipedia/T_cell_receptor_T_cell_therapy |
Monospecific antibodies are antibodies whose specificity to antigens is singular (mono- + specific) in any of several ways: antibodies that all have affinity for the same antigen; antibodies that are specific to one antigen or one epitope; or antibodies specific to one type of cell or tissue. Monoclonal antibodies are monospecific, but monospecific antibodies may also be produced by other means than producing them from a common germ cell. Regarding antibodies, monospecific and monovalent overlap in meaning; both can indicate specificity to one antigen, one epitope, or one cell type (including one microorganism species). However, antibodies that are monospecific to a certain tissue, or all monospecific to the same tissue because clones, can be polyvalent in their epitope binding.
== Production ==
=== Hybridoma cell ===
Monoclonal antibodies are typically made by fusing the spleen cells from a mouse that has been immunized with the desired antigen with myeloma cells. However, recent advances have allowed the use of rabbit B-cells.
=== PrEST ===
Another way of producing monospecific antibodies are by PrESTs. A PrEST (protein epitope signature tag) is a type of recombinantly produced human protein fragment. They are inserted into an animal, e.g. rabbit, which produces antibodies against the fragment. These antibodies are monospecific against the human protein.
== Cautions ==
Recent research has led to the discovery that unstable hinged monospecific antibodies may engage in a process leading to a decrease in their apparent avidity/affinity. This process, termed Fab arm exchange, has led to theories about the dissemination of viral infections in patients given monospecific IgG4 therapeutic antibodies. Evidence is suggestive that this process is linked to the dissemination of PML in patients given Tysabri for MS. Following dosing unpredictability still reigns and mutations in the hinge of the antibody which may prevent Fab-arm exchange in-vivo should be considered when designing therapeutic antibodies.
== References ==
== See also ==
Monoclonal antibodies | Wikipedia/Monospecific_antibody |
Signal regulatory protein α (SIRPα) is a regulatory membrane glycoprotein from SIRP family expressed mainly by myeloid cells and also by stem cells or neurons.
SIRPα acts as inhibitory receptor and interacts with a broadly expressed transmembrane protein CD47 also called the "don't eat me" signal. This interaction negatively controls effector function of innate immune cells such as host cell phagocytosis. SIRPα diffuses laterally on the macrophage membrane and accumulates at a phagocytic synapse to bind CD47 and signal 'self', which inhibits the cytoskeleton-intensive process of phagocytosis by the macrophage. This is analogous to the self signals provided by MHC class I molecules to NK cells via Ig-like or Ly49 receptors. NB. Protein shown to the right is CD47 not SIRP α.
== Structure ==
The cytoplasmic region of SIRPα is highly conserved between rats, mice and humans. Cytoplasmic region contains a number of tyrosine residues, which likely act as ITIMs. Upon CD47 ligation, SIRPα is phosphorylated and recruits phosphatases like SHP1 and SHP2. The extracellular region contains three Immunoglobulin superfamily domains – single V-set and two C1-set IgSF domains. SIRP β and γ have the similar extracellular structure but different cytoplasmic regions giving contrasting types of signals. SIRP α polymorphisms are found in ligand-binding IgSF V-set domain but it does not affect ligand binding. One idea is that the polymorphism is important to protect the receptor of pathogens binding.
== Ligands ==
SIRPα recognizes CD47, an anti-phagocytic signal that distinguishes live cells from dying cells. CD47 has a single Ig-like extracellular domain and five membrane spanning regions. The interaction between SIRPα and CD47 can be modified by endocytosis or cleavage of the receptor, or interaction with surfactant proteins. Surfactant protein A and D are soluble ligands, highly expressed in the lungs, that bind to the same region of SIRPα as CD47 and can therefore competitively block binding.
== Signalling ==
The extracellular domain of SIRP α binds to CD47 and transmits intracellular signals through its cytoplasmic domain. CD47-binding is mediated through the NH2-terminal V-like domain of SIRP α. The cytoplasmic region contains four ITIMs that become phosphorylated after binding of ligand. The phosphorylation mediates activation of tyrosine kinase SHP2. SIRP α has been shown to bind also phosphatase SHP1, adaptor protein SCAP2 and FYN-binding protein. Recruitment of SHP phosphatases to the membrane leads to the inhibition of myosin accumulation at the cell surface and results in the inhibition of phagocytosis.
== Cancer ==
Cancer cells highly expressed CD47 that activate SIRP α and inhibit macrophage-mediated destruction. In one study, they engineered high-affinity variants of SIRP α that antagonized CD47 on cancer cells and caused increase phagocytosis of cancer cells. Another study (in mice) found anti-SIRPα antibodies helped macrophages to reduce cancer growth and metastasis, alone and in synergy with other cancer treatments.
== References ==
== Further reading ==
This article incorporates text from the United States National Library of Medicine, which is in the public domain. | Wikipedia/Signal-regulatory_protein_alpha |
Targeted therapy of lung cancer refers to using agents specifically designed to selectively target molecular pathways responsible for, or that substantially drive, the malignant phenotype of lung cancer cells, and as a consequence of this (relative) selectivity, cause fewer toxic effects on normal cells.
Most previous chemotherapy drugs for cancer were (relatively) nonselective in their activity. Although their exact mechanisms of action were varied and complex, they generally worked by damaging cells undergoing mitosis, which is usually more common in malignant tumors than in most normal tissues. Targeted agents are designed to be selective in their effects by modulating the activity of proteins necessary and essential for oncogenesis and maintenance of cancer, particularly enzymes driving the uncontrolled growth, angiogenesis, invasiveness, and metastasis characteristic of malignant tumors. The increased differential activity usually results in fewer troubling side effects for cancer patients, particularly less nausea, vomiting, and death of cells in the bone marrow and gastrointestinal tract, and increased effectiveness against tumor cells.
== Traditional lung cancer classification and treatment ==
Lung cancer is an extremely heterogeneous family of malignant neoplasms, with well over 50 different histological variants recognized under the 4th revision of the World Health Organization (WHO) typing system, currently the most widely used lung cancer classification scheme. Because these variants have differing genetic, biological, and clinical properties, including response to treatment, correct classification of lung cancer cases are necessary to assure that lung cancer patients receive optimum management.
Approximately 98% of lung cancers are carcinoma, a term describing malignancies derived from transformed cells exhibiting characteristics of epithelium. About 2% of all lung cancers are non-carcinoma (mainly sarcoma, tumors of hematopoietic origin, or germ cell tumors. These forms of lung cancer are usually treated differently from carcinomas. Because of the ubiquity of lung carcinomas, however, the term "lung cancer" generally refers to carcinomas in everyday clinical practice.
Despite the large number of histological variants of lung carcinoma, oncologists have long tended to favor a dichotomous division into small cell and non-small cell forms, based on differences in clinical behavior and response to treatment. Most small cell lung carcinomas (SCLC's) metastasize to distant organs early on in their course, rendering surgery ineffective in curing the cancer. In contrast, non-small cell lung carcinomas (NSCLC's) are more likely to remain localized to the thorax during development, and are thus more amenable to cure using radical surgical resection. Additionally, SCLC's are typically much more sensitive to chemotherapy and/or radiation therapy than are NSCLC's. Therefore, current traditional treatment guidelines and standards of care recommend, when possible, the use of surgery for NSCLC, and chemotherapy with or without radiotherapy for SCLC.
== Agents in current use ==
While a very large number of agents targeting various molecular pathways are being developed and tested, the main classes and agents that are now being used in lung cancer treatment include:
Inhibitors of Epidermal growth factor receptor (EGFR)
tyrosine kinase inhibitors (TKI's):
erlotinib (Tarceva)
gefitinib (Iressa)
osimertinib (Tagrisso)
monoclonal antibody against EGFR:
cetuximab (Erbitux)
Inhibitors of vascular endothelial growth factor (VEGF)
bevacizumab (Avastin)
Inhibitor of EML4-ALK
crizotinib shows benefit in a subset of non-small cell lung cancer that is characterized by the EML4-ALK fusion oncogene, found in some relatively young, never or light smokers with adenocarcinoma.
== Non-small cell lung cancer ==
Targeted agents are beginning to permit the design of more rational treatment regimens for non-small cell lung cancer (NSCLC), which comprises about 80% to 85% of all lung cancers.
While there have been no randomized clinical trials of targeted agents in combined small-cell lung carcinoma (c-SCLC), some small case series suggest that some may be useful in c-SCLC. Many targeted agents appear more active in certain NSCLC variants. Given that c-SCLC contains components of NSCLC, and that the chemoradioresistance of NSCLC components impact the effectiveness of c-SCLC treatment, these agents may permit the design of more rational treatment regimens for c-SCLC.
EGFR-TKI's have been found to be active against variants exhibiting certain mutations in the EGFR gene. While EGFR mutations are very rare (<5%) in "pure" SCLC, they are considerably more common (about 15–20%) in c-SCLC, particularly in non-smoking females whose c-SCLC tumors contain an adenocarcinoma component. These patients are much more likely to have classical EGFR mutations in the small cell component of their tumors as well, and their tumors seem to be more likely to respond to treatment with EGFR-TKI's. EGFR-targeted agents appear particularly effective in papillary adenocarcinoma, non-mucinous bronchioloalveolar carcinoma, and adenocarcinoma with mixed subtypes.
Bevacizumab may improve some measures of survival in both SCLC and non-squamous cell variants of NSCLC.
Pemetrexed, although not classified as a targeted agent, has been shown to have improve survival in non-squamous cell NSCLC, and is the first drug to reveal differential survival benefit in large cell lung carcinoma.
C-SCLC appear to express female hormone (i.e. estrogen and/or progesterone) receptors in a high (50%-67%) proportion of cases, similar to breast carcinomas However, it is at present unknown whether blockade of these receptors affects the growth of c-SCLC.
Several studies have shown that EGFR-TKI's are particularly active in papillary and non-mucinous bronchioloalveolar carcinoma variants of adenocarcinoma.
Bevacizumab is contraindicated in squamous cell carcinoma and its variants.
Pemetrexed has been approved for treating non-squamous lung carcinomas, and is the first drug that has been specifically shown to improve survival in large cell carcinoma.
== Small-cell lung cancer ==
To date, most clinical trials of newer targeted agents - both alone and in combination with previously tested treatment regimens - have either been less effective, or no more effective, than older platinum-based doublets in SCLC.
== Combined small-cell lung cancer ==
The term "combined small-cell lung carcinoma" (c-SCLC) refers to a multiphasic lung cancer that contains a component of SCLC admixed with one (or more) components of NSCLC. It is currently considered a variant of SCLC under the current World Health Organization lung tumor classification scheme. While the true incidence of c-SCLC is unknown, case series suggest that they may account for as many as 25% to 30% of all cases of SCLC, and for 4% to 6% of all lung cancer cases.
Traditionally, c-SCLC have been treated according to guidelines established for "pure" SCLC.
To date, most clinical trials of targeted agents, alone and in combination with previously tested treatment regimens, have either been ineffective in SCLC or no more effective than standard platinum-based doublets.
While there have been no randomized clinical trials of targeted agents in c-SCLC, some small case series suggest that some agents currently in use may be beneficial in c-SCLC. Many targeted agents appear more active in certain NSCLC variants. Given that c-SCLC contains components of NSCLC, and that the chemoradioresistance of NSCLC components impact the effectiveness of c-SCLC treatment, these agents may permit the design of more rational treatment regimens for c-SCLC.
== References ==
== External links ==
World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of the Lung, Pleura, Thymus and Heart.
Lung Cancer page at the National Cancer Institute. | Wikipedia/Targeted_therapy_of_lung_cancer |
The Journal of Clinical Oncology is a peer-reviewed medical journal published 3 times a month by ASCO Publications. It covers research on all aspects of clinical oncology. The journal was established in 1983 and the editor-in-chief is Jonathan W. Friedberg (University of Rochester).
== History ==
In 1981 Emil Frei III proposed that the American Society of Clinical Oncology should publish an official journal. The first issue was published on January 1, 1983, containing 70 pages of research and an editorial by the then editor-in-chief, Joseph Bertino. Bertino was succeeded by George P. Canellos in 1987. In 1998, a Spanish language edition of the journal started quarterly publication, followed by a Chinese language edition. Currently there are 10 international editions. Daniel Haller became editor-in-chief in 2001 and during his tenure the journal moved from its publisher Grune & Stratton to in-house publication by society staff. Stephen A. Cannistra was editor-in-chief from 2011 to 2021.
== Abstracting and indexing ==
The journal is abstracted and indexed in:
According to the Journal Citation Reports, the journal has a 2023 impact factor of 42.1, ranking it 6th out of 322 journals in the category "Oncology".
== See also ==
JCO Clinical Cancer Informatics
Journal of Oncology Practice
JCO Global Oncology
== References ==
== External links ==
Official website | Wikipedia/Journal_of_Clinical_Oncology |
Directed enzyme prodrug therapy (DEPT) uses enzymes artificially introduced into the body to convert prodrugs, which have no or poor biologically activity, to the active form in the desired location within the body. Many chemotherapy drugs for cancer lack tumour specificity and the doses required to reach therapeutic levels in the tumour are often toxic to other tissues. DEPT strategies are an experimental method of reducing the systemic toxicity of a drug, by achieving high levels of the active drug only at the desired site. This article describes the variations of DEPT technology.
== Antibody-directed enzyme prodrug therapy (ADEPT) ==
ADEPT is a strategy to overcome the problems of lack of tumor selectivity. An antibody designed/developed against a tumor antigen is linked to an enzyme and injected to the blood, resulting in selective binding of the enzyme in the tumor. When the discrimination between tumor and normal tissue enzyme levels is sufficient, a prodrug is administered into the blood circulation, which is converted to an active cytotoxic drug by the enzyme, only within the tumor. Selectivity is achieved by the tumor specificity of the antibody and by delaying prodrug administration until there is a large differential between tumor and normal tissue enzyme levels.
ADEPT has shown antitumor activity in animal tumor models of human choriocarcinoma and colonic and breast carcinoma.
=== ADEPT history ===
The first pilot-scale clinical trial of ADEPT was carried out at Charing Cross Hospital, London, using an anti-CEA F(ab′)2 antibody conjugated to the bacterial enzyme carboxypeptidase G2 (CPG2).
The antibody used in the first ADEPT clinical trial was of murine origin and the enzyme was bacterial. Host antibodies to both components of the AEC were present in the blood of all non-immunosuppressed patients by day 10 after AEC infusion. Several patients received ciclosporin since it had been shown in rabbits that this could delay the appearance of host antibodies to soluble proteins.
A subsequent, small-scale trial at the Royal Free Hospital, London, used the same agents as in the Charing Cross Hospital trial but the protocol was modified to provide additional pharmacokinetic data and most patients received only a single course of treatment.
== Gene-directed enzyme prodrug therapy (GDEPT) ==
GDEPT is a suicide gene therapy in which the enzyme required for prodrug conversion is produced within the target cell, using a gene delivered to it by gene therapy. When an adequate differential exists between the targeted cell and endogenous tissue, non-toxic prodrug is administered and is subsequently converted into its toxic form within the target cell. Systems that use viral vectors to deliver the gene are known as VDEPT.
== Virus-directed enzyme prodrug therapy (VDEPT) ==
VDEPT is the term given to the use of a virus to deliver the gene for GDEPT. VDEPT can potentially be used to enhance the therapeutic potential of oncolytic viruses.
== Lectin-directed Enzyme-Activated Prodrug Therapy (LEAPT) ==
LEAPT is a variant of DEPT in which the manipulation of carbohydrates on the surface of the enzyme is used to target the enzyme activity to the cell in question. This allows exploitation of the sometimes highly specific sugar-lectin interactions found in organisms, including humans. Proof-of-principle examples have shown delivery to target organs of enzymes that specifically release cytotoxics to treat tumours.
== Polymer-directed enzyme prodrug therapy (PDEPT) ==
PDEPT uses polymer-drug conjugates, drugs contained within a polymer 'shell' such as pHPMA and designed to be released only by a specific enzyme.
== Clostridia-directed enzyme prodrug therapy (CDEPT) ==
CDEPT is the use of Clostridia to convert prodrugs into active drug agents. CDEPT exploits the hypoxic environment of solid tumors to target drugs to tumors using anaerobic bacteria resident in the tumour to convert the pro-drug to the active form. Intravenously injected clostridial spores exhibit a specificity for tumours, colonising the hypoxic areas of the tumours.
=== The CDEPT strategy ===
Perhaps the most challenging issue in cancer treatment is how to reduce the side effects of the injected anti-cancer agents, which are of a high cytotoxicity potential. A widely used solution is to use enzymes which are able to convert a relatively non-toxic prodrug precursor into the active drug form(s). Clostridial-directed enzyme prodrug therapy (CDEPT) is one of the possible approaches.
Solid tumors, in contrast to normal tissues, grow rapidly. As a result, the cancerous tissues may suffer from inadequate blood and oxygen supply. Therefore, clostridia can grow in tumor and destroy it specifically. (Originally, Parker and co-workers showed that the injection of Clostridium histolyticum spores to the transplanted sarcomas of mice results in significant tumour lysis. Soon after, it was shown that a direct injection is not necessary, and that tumour colonization was readily obtained after intravenous administration of spores).
In CDEPT, a prodrug-converting enzyme expressed by a clostridial expression plasmid converts a prodrug into an active drug form within the tumor. While the prodrug is the inactive form and can be administrated to the blood, the products of the prodrug cleavage are highly cytotoxic and show their effect only in the vicinity of tumor cells.
Difficulties in the engineering of clostridial strains have restricted the application of other enzyme prodrug systems. So far, two enzymes have been applied in CDEPT: cytosine deaminase and nitroreductase.
== References == | Wikipedia/Antibody-directed_enzyme_prodrug_therapy |
Treatment of lung cancer refers to the use of medical therapies, such as surgery, radiation, chemotherapy, immunotherapy, percutaneous ablation, and palliative care, alone or in combination, in an attempt to cure or lessen the adverse impact of malignant neoplasms originating in lung tissue.
Lung cancer is an extremely heterogeneous family of malignant neoplasms, and well over 50 different histopathological variants are currently recognized under the most widely used typing system. Because these variants have differing genetic, biological, and clinical properties, including response to treatment, correct classification of lung cancer cases are necessary to assure that lung cancer patients receive optimum management.
Approximately 95% of lung cancers are carcinoma, or tumors derived from transformed cells of epithelial lineage. Currently, nearly four dozen different histopathological variants of lung carcinoma are recognized. For clinical and treatment purposes, however, most oncologists tend to classify lung carcinomas into two major groups, namely small cell carcinoma (SCLC) and non-small cell lung cancer (NSCLC). This is done because of differing responses to treatment—NSCLC is comparatively less sensitive to chemotherapy and/or radiation, so surgery is the treatment of choice in these tumors. SCLC, in contrast, usually initially responds well to chemotherapy and/or radiation, but has usually metastasized widely by the time it is discovered, making surgery ineffective.
In a 2010 study of patients with metastatic non–small-cell lung cancer, "early palliative care led to significant improvements in both quality of life and mood. As compared with patients receiving standard care, patients receiving early palliative care had less aggressive care at the end of life but longer survival" which was increased by approximately three months.
There are typically three objectives applied to the treatment of lung cancer and can vary by patient or individual diagnosis: (1) curing lung cancer, (2) controlling lung cancer, and (3) being comfortable.
== Surgery ==
In most cases, the goal of lung cancer surgery is to remove the entire tumor, including a small amount of normal tissue (about 2 centimetres, 0.8 in) at the margin. The general name for surgery that enters the chest is thoracotomy, and specific named types of surgical interventions may be performed as part of the thoracotomy, such as wedge resection, segmentectomy, "sleeve resection", lobectomy, or pneumonectomy, depending on the tumor and patient characteristics.
Surgery is very rarely used in cases of stage 3b or stage 4 non-small cell lung carcinoma.
== Chemotherapy ==
In patients with stage 3 lung cancer that cannot be removed, treatment with combined radiotherapy and chemotherapy improves survival significantly.
=== Chemotherapeutic Agents Used for Treatment of stage IV NSCLC ===
Chemotherapy for NSCLC usually includes combination of two drugs (chemotherapy doublet), with one of the agents is cisplatin or carboplatin. In 2002, Schiller at al. published in the New England Journal of Medicine, a study that compared four chemotherapy regimens for advanced NSCLC, cisplatin and paclitaxel, cisplatin and gemcitabine, cisplatin and docetaxel, and carboplatin and paclitaxel. The study was well powered, with 1207 patients enrolled. None of the four chemotherapy regimens offered a significant advantage over the others. In 2008, Scagliotti et al. published in the Journal of Clinical Oncology a study that compared cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced NSCLC. Overall survival was statistically superior for cisplatin/pemetrexed versus cisplatin/gemcitabine in patients with adenocarcinoma and large-cell carcinoma histology, while patients with squamous cell histology had a significant improvement in survival with cisplatin/gemcitabine versus cisplatin/pemetrexed. These two studies made significant impact on the chemotherapy choices for treating NSCLC, with cisplatin or carboplatin as the backbone of all the chemotherapy treatments protocols. Pemetrexed is provided with platinum-based chemotherapy to patients with nonsquamous NSCLC. Gemcitabine is provided with platinum-based drug to patients with squamous NSCLC.
Cisplatin
Cisplatin is composed of a central atom of platinum with two chloride atoms and two ammonia molecules attached to it. Cisplatin is provided intravenously and exerts its cell-killing effects through disrupting transcription and translation of the cell's DNA. Kidney damage (nephrotoxicity) in the form of proximal tubular injury is the main reason to stop cisplatin. Other side effects of cisplatin include nausea and vomiting which usually necessitate premedication with antiemetic medications before infusion; ear damage (ototoxicity), which could manifest in varying levels of hearing loss; peripheral neuropathy; and bone marrow suppression (myelosuppression).
Carboplatin
Carboplatin, like cisplatin, is composed of a central atom of platinum and two ammonia molecules, but it has a cyclobutanedicarboxylate moiety instead of chloride. Carboplatin is also provided intravenously and also kills cells by disrupting the cell's DNA. Bone marrow suppression is the dose-limiting toxicity of carboplatin. Carboplatin is much less damaging to kidneys compared to cisplatin and is used as an alternative to cisplatin for patients with preexisting kidney failure.
Taxanes
Taxanes are microtubule-stabilizing drugs which induces mitotic arrest at the G2/M transition phase of the cell cycle, resulting in cell death. Paclitaxel was isolated from bark extract of the Pacific yew tree. Docetaxel is a semisynthetic taxane and nab-paclitaxel is a nanoparticle albumin-bound paclitaxel.
Paclitaxel
Paclitaxel binds to tubulin and stabilizes the microtubules which leads to inhibition of cell division. Paclitaxel is provided intravenously, with a dose limiting toxicity of peripheral neuropathy. Peripheral sensory neuropathy presents with numbness and tingling in a stocking-and-glove distribution, which may disturb daily function of the patients. Hematologic toxicity include anemia, neutropenia, and less frequently thrombocytopenia.
Docetaxel
Docetaxel is provided intravenously, and acts in similar manner to paclitaxel. Docetaxel binds to tubulin, the protein component of the microtubules, and inhibits its disassembly, which results in disruption of mitosis and cell death. Hematological toxicities are the dose limiting toxicity of Docetaxel with neutropenia and anemia. Other side effects include alopecia, stomatitis, diarrhea, nausea, vomiting, fluid retention, onycholysis, and skin toxicity.
Nanoparticle Albumin-Bound Paclitaxel
Nanoparticle albumin-bound (nab) paclitaxel is an Albumin bound with high affinity to the hydrophobic molecules of paclitaxel, which results in higher accumulation of the cytotoxic drug in tumors. A recent meta-analysis showed that when compared to Paclitaxel, nab-paclitaxel has significant beneficial effects in terms of overall response rate, progression free survival, and overall survival. Side effects of nab-paclitaxel include anemia, neutropenia, alopecia, and peripheral neuropathy.
Gemcitabine
Gemcitabine is structurally similar to cytarabine and functions as a pyrimidine analogue, and blocks the progression of cells through the G1/S-phase. Gemcitabine is metabolized by nucleoside kinases to Gemcitabine diphosphate and Gemcitabine triphosphate. Gemcitabine diphosphate inhibits ribonucleotide reductase, resulting in reductions in deoxynucleotide concentrations, including deoxycytidine triphosphate. Gemcitabine triphosphate competes with deoxycytidine triphosphate for incorporation into DNA. Side effects of Gemcitabine includes myelosuppression manifested by neutropenia, thrombocytopenia, and anemia; pulmonary toxicity, including interstitial pneumonitis, pulmonary fibrosis, pulmonary edema, and adult respiratory distress syndrome; capillary leak syndrome; and posterior reversible encephalopathy syndrome.
Pemetrexed
Pemetrexed functions as an antimetabolite. Pemetrexed inhibits thymidylate synthase, dihydrofolate reductase and glycinamide ribonucleotide formyltransferase. Pemetrexed induces cell cycle arrest in the G1/S phase. Side effects of Pemetrexed includes myelosuppression, renal failure, bullous and exfoliative skin toxicity, diarrhea, nausea, and vomiting.
Tumor Treating Fields might improve chemotherapy treatment, though it is still experimental.
== Targeted therapy ==
In recent years, various molecular targeted therapies have been developed for the treatment of advanced lung cancer. Gefitinib (Iressa; withdrawn from the U.S. market) is one such drug, which targets the tyrosine kinase domain of the epidermal growth factor receptor (EGFR), expressed in many cases of non-small cell lung carcinoma. It was not shown to increase survival, although females, Asians, nonsmokers, and those with bronchioloalveolar carcinoma appear to derive the most benefit from gefitinib.
Erlotinib (Tarceva), another EGFR tyrosine kinase inhibitor, increased survival in non-small cell lung cancer and was approved by the FDA in 2004 for second-line treatment of advanced non-small cell lung carcinoma. Similar to gefitinib, it also appeared to work best in females, Asians, nonsmokers, and those with bronchioloalveolar carcinoma, particularly those with specific mutations in EGFR.
The angiogenesis inhibitor bevacizumab (Avastin), (in combination with paclitaxel and carboplatin), improves the survival of patients with advanced non-small cell lung carcinoma. However, this increases the risk of lung bleeding, particularly in patients with squamous cell carcinoma.
Crizotinib shows benefit in a subset of non-small cell lung cancer that is characterized by the EML4-ALK fusion oncogene, and is approved by the FDA. EML4-ALK is found in some relatively young, never or light smokers with adenocarcinoma.
Advances in cytotoxic drugs, pharmacogenetics and targeted drug design show promise. A number of targeted agents are at the early stages of clinical research, such as cyclo-oxygenase-2 inhibitors, the apoptosis promoter exisulind, proteasome inhibitors, bexarotene, the epidermal growth factor receptor inhibitor cetuximab, and vaccines. Sorafenib (marketed as Nexavar for use in renal and liver cancer) showed promise in a clinical trial matching targeted treatment to the cancer's genetic profile. Future areas of research include ras proto-oncogene inhibition, phosphoinositide 3-kinase inhibition, histone deacetylase inhibition, and tumor suppressor gene replacement.
== Immunotherapy ==
Immunotherapy is a type of cancer treatment that activates the immune system to fight cancer.
Nivolumab is a fully human IgG4 antibody targeting programmed death receptor 1 (PD-1). In 2015, nivolumab was approved for the treatment of people with metastatic squamous non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy.
In 2016, the FDA approved atezolizumab for the treatment of people with metastatic non-small cell lung cancer (NSCLC) whose disease progressed during or following platinum-containing chemotherapy and pembrolizumab for the treatment of people with metastatic non-small cell lung cancer (NSCLC) whose tumors express programmed death-ligand 1 (PD-L1) as determined by an FDA-approved test.
In 2017, the FDA granted accelerated approval to pembrolizumab in combination with pemetrexed and carboplatin for the treatment of people with previously untreated metastatic non-squamous non-small cell lung cancer (NSCLC).
In 2018, the FDA approved durvalumab for people with unresectable stage III NSCLC whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy.
In 2018, the FDA granted accelerated approval to nivolumab for people with metastatic SCLC with progression after platinum-based chemotherapy and at least one other line of therapy, and approved pembrolizumab in combination with pemetrexed and platinum-based antineoplastic (carboplatin or cisplatin) as first-line treatment of people with metastatic, NSCLC with no EGFR or ALK genomic tumor aberrations.
In 2018, the FDA approved pembrolizumab in combination with carboplatin and either paclitaxel or nab-paclitaxel as first-line treatment of metastatic squamous non-small cell lung cancer (NSCLC).
In 2018, the FDA approved atezolizumab in combination with bevacizumab, paclitaxel, and carboplatin for the first-line treatment of people with metastatic non-squamous, non-small cell lung cancer (NSCLC) with no EGFR or ALK genomic tumor aberrations.
In 2019, the FDA approved atezolizumab in combination with carboplatin and etoposide for the first-line treatment of adult people with extensive-stage SCLC.
In 2019, the FDA approved pembrolizumab for the first-line treatment of people with stage III non-small cell lung cancer (NSCLC) who are not candidates for surgical resection or definitive chemoradiation or metastatic NSCLC. people' tumors must have no EGFR or ALK genomic aberrations and express PD-L1 (Tumor Proportion Score [TPS] >1%) determined by an FDA-approved test.
In 2019, the FDA granted accelerated approval to pembrolizumab for people with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy and at least one other prior line of therapy.
In 2021, the FDA approved amivantamab as the first treatment for patients with metastatic non-small cell lung cancer with epidermal growth factor receptor exon 20 insertion mutation.
The first line treatment of advanced/metastatic NSCLC can incorporates immunotherapy either as a single modality or with chemotherapy. Patients with PD-L1 ≥ 50% have multiple immunotherapy treatment options. Pembrolizumab monotherapy is an appealing approach for these patients, with median OS of 30 months with pembrolizumab single agent compared to 14.2 months with chemotherapy in KEYNOTE-024. Atezolizumab for first-line treatment of metastatic NSCLC with PD-L1 ≥ 50% was approved recently by the FDA, after the IMPOWER110 trial showed a median OS of 20.2 months for patients in the atezolizumab arm, compared with 13.1 months in the chemotherapy arm (p = 0.0106). For patients with tumor PD-L1 expression level of 1–49%, monotherapy with pembrolizumab as per KEYNOTE-042 is an appealing option, especially for smoker males.
Atezolizumab/hyaluronidase (Tecentriq Hybreza) was approved for medical use in the United States in September 2024.
== Keynote-024 ==
Keynote-024 was a phase 3 trial that compared Pembrolizumab versus platinum-based chemotherapy-doublet for PD-L1 positive NSCLC. The chemotherapy used was the investigator’s choice of platinum-based chemotherapy doublet. The trial included patients with squamous (18%) and nonsquamous (82%) histology with PD-L1 expression on at least 50% of tumor cells. Most patients were current or former smokers (92%). Median overall survival (OS) was 30.0 months with pembrolizumab and 14.2 months with chemotherapy, hazard ratio 0.63, p = 0.002. Pembrolizumab was associated with significantly fewer adverse events than was platinum-based chemotherapy.
== Keynote-042 ==
KEYNOTE-042 included NSCLC patients with locally advanced or metastatic disease without previous treatment and without a driving mutation in EGFR or ALK translocation, and with PD-L1 tumor proportion score (TPS) of 1% or greater. The trial included patients with squamous and nonsquamous histology, most of them current or former smokers. This phase 3 trial compared Pembrolizumab versus the investigator’s choice of platinum-based chemotherapy doublet. Median overall survival was 16.7 months with Pembrolizumab and 12.1 months with chemotherapy, hazard ratio 0.81, p = 0.0018.
== Keynote-189 ==
This study compared chemotherapy to chemotherapy and pembrolizumab in patients with nonsquamous NSCLC as first line therapy. The chemotherapy used was Pemetrexed + Cisplatin/Carboplatin. Among patients with nonsquamous NSCLC with any PD-L1 expression level, overall survival was 22 versus 10.7 months with Pembrolizumab and chemotherapy compared to chemotherapy alone, HR 0.56.
== Keynote-407 ==
Keynote-407 compared chemotherapy to chemotherapy and pembrolizumab in patients with squamous NSCLC as first line therapy. The chemotherapy used was Carboplatin + paclitaxel or nab–paclitaxel. Among patients with squamous NSCLC with any PD-L1 expression level, OS was 15.9 versus 11.3 months with Pembrolizumab and chemotherapy compared to chemotherapy alone, respectively, HR 0.64. More than 92% of the patients were current or former smokers.
== IMpower110 ==
IMpower110 randomized patients with stage IV NSCLC with PD-L1 expression ≥ 1% to Atezolizumab single agent or to chemotherapy. The chemotherapy used was Cisplatin or Carboplatin, combined with Gemcitabine for patient with squamous cell NSCLC, or pemetrexed for patients with nonsquamous disease. Atezolizumab was better tolerated than chemotherapy. In the subgroup of patients with EGFR and ALK wild-type tumors who had PD-L1 stained ≥ 50% of tumor cells (205 patients), the OS was 20.2 months with Atezolizumab, and 13.1 months with chemotherapy.
IMpower150
IMpower150 randomized patients with nonsquamous NSCLC to treatment with chemotherapy plus Bevacizumab, chemotherapy plus atezolizumab or chemotherapy plus Bevacizumab and atezolizumab. The chemotherapy used was Carboplatin, and Paclitaxel. Median OS was 19.8 and 14.9 months for patients treated with chemotherapy plus Bevacizumab, with or without atezolizumab, respectively. Median OS with Atezolizumab and chemotherapy alone was 19.5 months, raising question with regard to the added value of Bevacizumab to this combination for the general patients population.
Survival outcomes for stage 4 non-small lung cancer patients treated with immunotherapy alone or combined with chemotherapy in the first line:
== Radiation ==
In patients with stage one or two non-small cell lung carcinoma, radiotherapy alone results in 13–39% of patients surviving to five years.
== Percutaneous ablation ==
Percutaneous image-guided ablation is a minimally invasive treatment that can be offered to patients with early stage NSCLC or for palliative treatment for patients with metastatic disease. There are various types of ablation used for treating lung malignancies including radiofrequency ablation (RFA), cryoablation, and microwave ablation. Thermal ablation is typically recommended for patients who are higher risk surgical patients due to cardiopulmonary disease. Ablation is generally a lower risk procedure compared to surgery; it requires only local anesthesia and sometimes conscious sedation, and it is minimally invasive. The procedure is performed by interventional radiology in an outpatient setting. Under CT or ultrasound guidance, a probe is advanced through the anesthetized skin until the tip of the probe is positioned within the tumor. Extreme temperature is then created through electrical current (radiofrequency ablation and microwave ablation) or gas (cryoablation), which triggers destruction of the cancerous cells. Major complications are uncommon, but include partial collapse of the lung and hemothorax. While there is growing evidence supportive of ablation as treatment for NSCLC, high rates of local recurrence and new metastatic disease in the treatment areas leads to reliance on more traditional treatment modalities. The pitfalls of ablation stem from the lack of complete and homogenous destruction of tumor cells, often leading to residual malignant cells on the periphery of the tumor. For that reason, lesions greater than 5 centimetres (2.0 in) should be excluded, and lesions 3 to 5 cm (1.2 to 2.0 in) should be considered with caution, given high risk of recurrence. Additionally, for safety reasons, lesions less than 1 cm (3⁄8 in) from the trachea, main bronchi, esophagus and central vessels should be excluded from RFA, given high risk of complications and frequent incomplete ablation. An animal tumor model demonstrated improved survival after combined treatment with RFA and radiation therapy compared to either treatment alone. It is possible that the two modalities have a synergistic effect and patients may benefit from combined treatment.
== History ==
Prior to the early part of the 20th century lung cancer was considered a very rare disease, and all malignant lung tumors were treated identically. Radical surgical resection (i.e. lobectomy or pneumonectomy) was the only effective intervention available for lung cancer prior to the 1940s, when the era of modern cytotoxic chemotherapy began.
Palliative radiotherapy has been used since the 1940s. Radical radiotherapy, initially used in the 1950s, was an attempt to use larger radiation doses in patients with relatively early-stage lung cancer, but who were otherwise unfit for surgery. With SCLC, initial attempts in the 1960s at surgical resection and radical radiotherapy were unsuccessful.
It was not until 1962 that small cell lung carcinoma (SCLC), then called "oat cell carcinoma" was recognized for its unique biological behavior, including a much higher frequency of widespread metastases at presentation, and exquisite sensitivity to cytotoxic chemotherapy and radiation.
Early studies suggested that patients with small cell lung carcinoma (SCLC) fared better when treated with chemotherapy and/or radiation than when treated surgically. While this approach to treating SCLC remains the current standard of care, the role of surgery in SCLC is being re-examined, with recent studies indicating that surgery may improve outcomes in some patients with early stage SCLC and combined forms of SCLC and NSCLC.
== Trials ==
Squalamine is undergoing trials for treatment of non-small cell lung cancer (stage I/IIA).
In December 2012, Merck published the results of its current study. Although the Phase III Trial of L-BLP25 (Stimuvax) did not meet satisfying primary endpoints for patients with Non-Small Cell Lung Cancer, notable treatment effects have been observed for L-BLP25 in certain subgroups in the START study.
In 2023 the American Society of Clinical Oncology announced a new pill that cut the risks of a patient dying from lung cancer by over 50%. The comprehensive study was conducted with patients between the ages of 30 and 86 in 26 different countries. Researchers on the project from the Yale School of Medicine believed that the treatment could become the standard of care for lung cancer patients.
== Funding of Research ==
From 2003-2014, a study conducted by the Global Lung Cancer Coalition found that the total number of articles published in independent journals regarding lung cancer treatment research only increased ~1%. Money that is put forth for cancer research by taxpayers is generally misplaced into organizations such as the American Cancer Society rather than going to organizations that are specifically focused on a specific type of cancer. While lung cancer is the deadliest cancer, a stigma surrounds the disease that it is highly preventable by not smoking. Lung cancer receives much less press time then other cancers such as breast cancer due to this stigma, with a survey of 1,000 participants finding that only 14% of those participants were the most concerned about lung cancer. This stigma has resulted in less time and money being put into treatment research and focusing more so on smoking prevention, despite lung cancer having a multitude of other causes such as genetics or air pollution. Governing bodies place taxpayer funds into generalized organizations and the public focuses less heavily on the disease, resulting in less research into treatment.
== References ==
== External links ==
"Pathology and Genetics of Tumours of the Lung, Pleura, Thymus and Heart". World Health Organization Classification of Tumours. (Download Page).
"Lung Cancer Surgery Demystified". Where's the Funding for Lung Cancer?. Archived from the original on 2019-07-08. Retrieved 2012-08-14. (Download Page). | Wikipedia/Treatment_of_lung_cancer |
Targeted molecular therapy for neuroblastoma involves treatment aimed at molecular targets that have a unique expression in this form of cancer. Neuroblastoma, the second most common pediatric malignant tumor, often involves treatment through intensive chemotherapy. A number of molecular targets have been identified for the treatment of high-risk forms of this disease. Aiming treatment in this way provides a more selective way to treat the disease, decreasing the risk for toxicities that are associated with the typical treatment regimen. Treatment using these targets can supplement or replace some of the intensive chemotherapy that is used for neuroblastoma. These molecular targets of this disease include GD2, ALK, and CD133. GD2 is a target of immunotherapy, and is the most fully developed of these treatment methods, but is also associated with toxicities. ALK has more recently been discovered, and drugs in development for this target are proving to be successful in neuroblastoma treatment. The role of CD133 in neuroblastoma has also been more recently discovered and is an effective target for treatment of this disease.
== Identifying High-Risk Patients ==
High-risk cases of neuroblastoma are difficult to treat, even through intensive chemotherapy. For this reason, molecular targets have been identified and are being developed for treatment in patients who have more difficulty responding to treatment. There are a number of genetic factors that can be used to identify high-risk patients. In neuroblastoma cells, there can be amplification of genomic DNA regions, loss of genomic DNA regions, and genetic abnormalities. All of these factors can contribute to an advanced disease state in high-risk patients.
Amplification occurs within a protein called the MYCN oncogene. This protein is amplified in approximately 20% of primary neuroblastoma tumors and is associated with advanced disease state and treatment failure.
Loss of genomic regions by deletion can occur at chromosomes 1p and 11q. Loss at 1p is correlated with MYCN amplification and advanced disease state. The loss at 11q is not related to MYCN, but is correlated with adverse patient outcomes.
Genetic abnormalities frequently occur in a tumor-suppressor gene called caspase 8. Inactivation of this gene will result in tumor cell survival.
Table 1 summarizes the genomic factors used to identify high-risk patients.
== Treatment Using Molecular Targets ==
=== Anti-GD2 Immunotherapy ===
GD2 is a glycolipid that is expressed on the surface of neuroblastoma cells. It is targeted through immunotherapy in neuroblastoma treatment using monoclonal antibodies. These monoclonal antibodies are used to block GD2 expression, and are thus referred to as anti-GD2 agents. They can be used for tumor-specific therapy because GD2 expression is weak and limited to certain areas in normal human tissue. Therefore, its expression can be easily targeted in tumor cells. While anti-GD2 antibodies are effective in clearing the remaining tumors in neuroblastoma patients, there have also been major toxicities associated with the use of this form of treatment. These toxicities include neuropathic pain, capillary leak syndrome, and hypersensitivity reaction.
Anti-GD2 antibodies have been developed for immunotherapy treatment of neuroblastoma and can be grouped into first-generation and second-generation antibodies.
First-Generation:
14G2a
ch14.18
3F8
Second-Generation:
Hu14.18-IL-2
Hu14.18K332A
mAb1A7
All of these antibodies are going through clinical trial processes for the treatment of neuroblastoma. The most extensively studied of these antibodies is ch14.18. Through randomized trials, it has been found that treatment with ch14.18 is most effective when combined with cytokines, such as granulocyte macrophage colony-stimulating factor (GM-CSF) and interleukin-2 (IL-2). This combination therapy improves the outcome of high-risk neuroblastoma, but does not decrease the risk of toxicities. For this reason, the second-generation antibodies have been developed, which have fewer associated toxicities but are continuing trials to determine their therapeutic efficacy.
=== ALK in Familial Neuroblastoma ===
Mutations in the anaplastic lymphoma kinase (ALK) oncogene can be inherited and are a major cause of neuroblastoma. These mutations occur in approximately 5-15% of neuroblastoma cases. ALK has recently been discovered as a molecular target of chemotherapy in the treatment of neuroblastoma patients. Drugs that target ALK are referred to as ALK inhibitors. ALK is expressed on the surface of neuroblastoma tumor cells, making it easily accessible as a target for cancer treatment. In neuroblastoma patients who do not possess a mutated form of ALK, targeting the non-mutated form of ALK on a tumor cell can also be beneficial. This will cause the tumor to undergo apoptosis, which is programmed cell death. ALK inhibitors can also be used to treat another cause of neuroblastoma referred to as MYCN gene amplification. Amplification of the MYCN protein is a genetic mutation associated with neuroblastoma tumors. MYCN amplification is correlated with a specific mutation in ALK, referred to as the F1174L mutation. ALK inhibitors can target this mutation and suppress the MYCN protein in the tumor cell.
The following is a list of ALK inhibitors currently in clinical trials for treatment of neuroblastoma:
Crizotinib (Pfizer)
CH5424802 (Chugai Pharmaceutical Co.)
ASP3026 (Astellas Pharma Inc.)
Ceritinib (LDK378, Novartis Pharmaceuticals)
AP26113 (Ariad Pharmaceuticals)
Crizotinib was the first of these drugs to enter clinical trials and is the sole available ALK inhibitor, approved by the FDA on August 26, 2011. Thus far, it has proven its efficacy in treating adults with non-small-cell lung carcinoma (NSCLC), another form of cancer in which ALK plays a role. The drug is currently in phase III clinical trials to test its use in treating pediatric cancer types, such as neuroblastoma.
CH542802 is currently in phase I/II trials and is being shown to inhibit the growth of neuroblastoma cells with the amplified expression of ALK.
ASP3026 is in phase I trials for ALK-related malignancies. It is currently being tested in adults but also can be a viable treatment for neuroblastoma due to its ALK inhibiting characteristics.
Ceritinib was approved by the FDA in April 2014 for treatment of ALK-positive metastatic non-small cell lung cancer. Like crizotinib, it has proven to be efficacious in adults and is also being tested for its efficacy in pediatric neuroblastoma cells.
AP26113 is a dual inhibitor of ALK and epidermal growth factor receptor. It is going through phase I/II clinical trials for treatment of neuroblastoma and NSCLC.
=== CD133 Biomarker ===
CD133 is shown to be a marker of tumor-initiating or cancer stem cells in neuroblastoma. The tumor-initiating properties of CD133 have been discovered through studies such as the one performed by Cournoyer et al. The cells from neuroblastoma patients have been examined, comparing those with a high expression of the CD133 glycoprotein to those with a low expression of CD133. The following are the characteristics of high-expression CD133 that provide evidence for its tumor-initiating properties:
Increased neurosphere formation
Large neurosphere size
Increased colony formation
Tumor formation when injected into mice
Presence of genetic abnormalities
The tumor-initiating properties of CD133 provide evidence for it to be a practical target of chemotherapeutic treatment for neuroblastoma. Through genotype analysis CD133 expression is found to be associated with the expression of the EFNA2 protein. This protein can play a role in cancer development. It is expressed in stem cells and can promote the formation of tumors. For these reasons, it can also be used for chemotherapy treatment in neuroblastoma patients. Through genotype analysis, the presence of this protein can be detected in neuroblastoma patients who also have high-expression CD133. In developing drugs for the treatment of neuroblastoma, pharmaceutical companies are experimenting with the use of CD133 and the associated EFNA2 protein as targets.
== References == | Wikipedia/Targeted_molecular_therapy_for_neuroblastoma |
Gallbladder diseases are diseases involving the gallbladder and is closely linked to biliary disease, with the most common cause being gallstones (cholelithiasis).
The gallbladder is designed to aid in the digestion of fats by concentrating and storing the bile made in the liver and transferring it through the biliary tract to the digestive system through bile ducts that connect the liver, gallbladder, and the Sphincter of Oddi. The gallbladder is controlled on a neurohormonal basis, with Cholecystokinin (CCK) leading to the contraction and release of bile into the bile ducts. Other hormones allow for the relaxation and further storing of bile. A disruption in the hormones, ducts, or gallbladder can lead to disease. Gallstones are the most common disease and can lead to other diseases, including Cholecystitis, inflammation of the gallbladder, and gallstone pancreatitis when the gallstone blocks the pancreatic duct. Treatment is considered for symptomatic disease and can vary from surgical to non-surgical treatment.
About 104 million new cases of gallbladder and biliary disease occurred in 2013.
== Signs and symptoms ==
Gallbladder disease presents chiefly with abdominal pain located in the right upper abdomen. This pain is described as biliary colic. Pain typically occurs suddenly and radiates to the right shoulder and back, depending on several factors, including specific diseases. It can either be constant or episodic and last from minutes to hours. This pain is described as biliary colic pain. Other common symptoms with gallbladder disease and biliary colic are nausea and vomiting. With conditions such as cholecystitis and choledocholithiasis, fever may be present.
During the physical examination, the patient will present with Murphy's sign. This maneuver requires the physician to grab the lower part of the right ribs and curl their fingers under them. A positive test elicits pain with deep inspiration and is indicative of inflammation of the gallbladder, cholecystitis. With positive Murphy's sign, deep palpation of the abdomen also elicits pain. In these cases, physicians will need to rule out peritonitis, inflammation of the abdominal cavity. A negative Murphy's sign does not rule out all gallbladder diseases such as ascending cholangitis. Using an ultrasound transducer supplanting a physician's hands during an abdominal ultrasound can detect a positive Murphy's sign. The sign also has over a 90% positive and negative predictive value for acute cholecystitis
=== Gallstones ===
Gallstones may develop in the gallbladder as well as elsewhere in the biliary tract. If gallstones in the gallbladder are symptomatic, surgical removal of the gallbladder, known as cholecystectomy may be indicated.
Gallstones form when the tenuous balance of solubility of biliary lipids tips in favor of precipitation of cholesterol, unconjugated bilirubin, or bacterial degradation products of biliary lipids. For cholesterol gallstones, metabolic alterations in hepatic cholesterol secretion combine with changes in gallbladder motility and intestinal bacterial degradation of bile salts to destabilize cholesterol carriers in bile and produce cholesterol crystals. For black pigment gallstones, changes in heme metabolism or bilirubin absorption lead to increased bilirubin concentrations and precipitation of calcium bilirubinate. In contrast, mechanical obstruction of the biliary tract is the major factor leading to bacterial degradation and precipitation of biliary lipids in brown pigment stones.
== Risk factors ==
=== Pregnancy ===
During pregnancy when female sex hormones are naturally raised, biliary sludge (particulate material derived from bile that is composed of cholesterol, calcium bilirubinate, and mucin) appears in 5% to 30% of women. Resolution frequently transpires during the post-partum period: sludge disappears in two-thirds; small (<1 cm) gallstones (microlithiasis) vanish in one-third, but definitive gallstones become established in ~5%. Additional risk factors for stone formation during pregnancy include obesity (prior to the pregnancy), reduced high density lipoprotein (HDL) cholesterol and the metabolic syndrome.
=== Hormonal contraceptives ===
Women are almost twice as likely as men to form gallstones especially during the fertile years; the gap narrows after the menopause. The underlying mechanism is female sex hormones; parity, oral contraceptive use and estrogen replacement therapy are established risk factors for cholesterol gallstone formation. Female sex hormones adversely influence hepatic bile secretion and gallbladder function. Estrogens increase cholesterol secretion and diminish bile salt secretion, while progestins act by reducing bile salt secretion and impairing gallbladder emptying leading to stasis. A new 4th generation progestin, drospirenone, used in some oral contraceptives may further heighten the risk of gallstone disease and cholecystectomy; however, the increased risk is quite modest and not likely to be clinically meaningful.
A retrospective (historical) cohort study was performed on a very large data base including 1980 and 1981 Medicaid billing data from the states of Michigan and Minnesota in which 138,943 users of OCs were compared with 341,478 nonusers. Oral contraceptives were shown as risk factors for gallbladder disease, although the risk is of sufficient magnitude to be of potential clinical importance only in young women.
The 1984 Royal College of General Practitioners' Oral Contraception Study suggests that, in the long-term, oral contraceptives are not associated with any increased risk of gallbladder disease, although there is an acceleration of the disease in those women susceptible to it.
Newer research suggests otherwise. A 1993 meta-analysis concludes that oral contraceptive use is associated with a slightly and transiently increased rate of gallbladder disease, but laters confirms that modern low-dose oral contraceptives are safer than older formulas, though an effect cannot be excluded.
A 2001 comparative study of the IMS LifeLink Health Plan Claims Database interpreted that in a large cohort of women using oral contraceptives, there was found a small, statistically significant increase in the risk of gallbladder disease associated with desogestrel, drospirenone and norethisterone compared with levonorgestrel. No statistically significant increase in risk was associated with the other formulations of oral contraceptive (etynodiol diacetate, norgestrel and norgestimate).
=== Menopausal hormone therapy ===
While some observational studies had suggested that estrogens increase the risk for gallbladder disease by as much as twofold to fourfold, such an association had not been reported consistently. More recent randomized clinical trial data among postmenopausal women now support a causal role for oral menopausal hormone therapy estrogens. Confirming the positive finding of another large study, the landmark Women's Health Initiative (WHI) reported very significant increases (p < 0.001) for risk of gallbladder disease or surgery attributed to treatments with both estrogen alone (conjugated equine estrogen; CEE) and estrogen-plus-progestin (conjugated equine estrogen with medroxyprogesterone; CEE+MPA ). Specifically, a 67% increase (CEE versus placebo) and 59% increase (CEE+MPA versus placebo) among healthy postmenopausal women that reported either having had a hysterectomy (n = 8376) or not (n = 14203) prior to randomization, respectively.
=== Other factors ===
A prospective study in 1994 noted that body mass index remains the strongest predictor of symptomatic gallstones among young women. Other risk factors are having over four pregnancies, weight gain, and cigarette smoking. Alcohol was shown to have an inverse relationship between use and gallbladder disease.
== Diseases of the gallbladder ==
Cholelithiasis (gallstones) are typically asymptomatic but can cause biliary pain episodically combined with other signs and symptoms of gallbladder disease such as nausea, vomiting, and pain radiating to the back. The curative treatment of symptomatic gallstones is a cholecystectomy. Abdominal pain can be confused with other gut disorders and will not relieve the pain in these instances.
Cholecystitis, inflammation of the gallbladder can occur in both acute and chronic cases. Ultrasound is the diagnostic test of choice by showing an increased gallbladder wall thickness. Additionally, in acute cases, a leukocytosis, an increase in white blood cell count, is found. In chronic cases, a cholecystectomy is curative but is treated with medication as an alternative therapy for older patients. While in acute cases, patients take antibiotics for complications such as abscesses, pain control, and nothing to eat until a cholecystectomy.
Gallbladder polyp is a growth in the gallbladder from various causes, with the most common being cholesterol polyp. Some can cause upper abdominal pain, while others remain asymptomatic. The size and symptoms determine the course of treatment, and those with smaller polyps may undergo routine monitoring for the growth of polyps. Larger polyps greater than 10mm will require cholecystectomy, gallbladder removal due to potential malignant qualities.
Gallbladder cancer (Malignant neoplasm of the gallbladder) is rare, and most of the time is adenocarcinoma. As most early-stage cancers are asymptomatic, neoplasm of the gallbladder is found in late stages and has a poor prognosis. Multiple hypotheses have been formed about an individual's susceptibility to cancer with notations of increased susceptibility in patients with cholecystitis, gallstones, specific ethnicities, gallbladder polyps, and lifestyle diseases such as obesity. Symptoms include persistent right upper quadrant pain, jaundice, palpable mass.
Biliary dyskinesia is a disease with the abnormal release of bile from the gallbladder leading to chronic biliary colic. Diagnosis is based on several studies examining the most common cause of gallstones and looking at the ejection fraction through a HIDA scan with cholecystokinin. This hormone causes bile release from the gallbladder.
Postcholecystectomy syndrome (cholesterosis, hydrops, perforation, fistula)
Xanthogranulomatous cholecystitis is a rare form of gallbladder disease which mimics gallbladder cancer although it is not cancerous. It was first discovered and reported in the medical literature in 1976 by J.J. McCoy, Jr., and colleagues.
== Diagnosis ==
A diagnostic workup is based on the most likely diagnosis. In testing for gallbladder disease, specifically, liver panel tests and pancreatic enzymes such as lipase will be within normal limits. There can be a mild elevation in alkaline phosphatase and bilirubin in some instances, such as cholecystitis. If gallstones are blocking other biliary tract areas causing pancreatic gallstones or choledocholithiasis, elevated liver panel, pancreatic enzymes, and bilirubin will be noted.
Ultrasound is the diagnostic imaging of choice to examine for thickening of the gallbladder walls, polyps, pericholecystic fluid, and gallstones. A positive Murphy's sign may also be noted using the ultrasound transducer. Another imaging modality is using cholescintigraphy to examine hepatic function. This scan assesses if the gallbladder is functioning as it is supposed to with a controlled amount of hormone. In regards to a suspected choledocholithiasis, a endoscopic retrograde cholangiopancreatography (ERCP) is used in both the diagnosis and treatment as it can remove the stones that are blocking the bile ducts causing choledocholithiasis.
== Treatment ==
In patients with an asymptomatic disease where a gallstone or small polyp was found incidentally, no further treatment is undertaken until symptoms arise. When an individual has symptomatic gallbladder disease and early-stage cancer, a cholecystectomy is utilized. A cholecystectomy is controversial in advanced cancer due to the low 5-year survival rate, especially if regional lymph nodes are involved. Symptoms of gallbladder disease typically decrease after cholecystectomy unless the abdominal pain was caused by other digestive tract diseases such as irritable bowel syndrome.
Nonsurgical treatment of gallstones and cholecystitis includes medication (for example chenodeoxycholic acid and ursodiol) to dissolve the stones. Because of side effects, ursodiol is more commonly chosen. It will take approximately two years to dissolve small stones with medications. Other avenues to reduce the modifiable risk factors that one may have for gallstones by reducing weight, dietary changes to lower cholesterol, and triglycerides.
== See also ==
Gallbladder polyp
== References ==
Yes
== External links ==
Gallstones - Topic Overview
Cholecystectomy: Surgical Removal of the Gallbladder Archived 2014-06-10 at the Wayback Machine
Surgery Questions on gallbladder | Wikipedia/Gallbladder_diseases |
Virology is the scientific study of biological viruses. It is a subfield of microbiology that focuses on their detection, structure, classification and evolution, their methods of infection and exploitation of host cells for reproduction, their interaction with host organism physiology and immunity, the diseases they cause, the techniques to isolate and culture them, and their use in research and therapy.
The identification of the causative agent of tobacco mosaic disease (TMV) as a novel pathogen by Martinus Beijerinck (1898) is now acknowledged as being the official beginning of the field of virology as a discipline distinct from bacteriology. He realized the source was neither a bacterial nor a fungal infection, but something completely different. Beijerinck used the word "virus" to describe the mysterious agent in his 'contagium vivum fluidum' ('contagious living fluid'). Rosalind Franklin proposed the full structure of the tobacco mosaic virus in 1955.
One main motivation for the study of viruses is because they cause many infectious diseases of plants and animals. The study of the manner in which viruses cause disease is viral pathogenesis. The degree to which a virus causes disease is its virulence. These fields of study are called plant virology, animal virology and human or medical virology.
Virology began when there were no methods for propagating or visualizing viruses or specific laboratory tests for viral infections. The methods for separating viral nucleic acids (RNA and DNA) and proteins, which are now the mainstay of virology, did not exist. Now there are many methods for observing the structure and functions of viruses and their component parts. Thousands of different viruses are now known about and virologists often specialize in either the viruses that infect plants, or bacteria and other microorganisms, or animals. Viruses that infect humans are now studied by medical virologists. Virology is a broad subject covering biology, health, animal welfare, agriculture and ecology.
== History ==
Louis Pasteur was unable to find a causative agent for rabies and speculated about a pathogen too small to be detected by microscopes. In 1884, the French microbiologist Charles Chamberland invented the Chamberland filter (or Pasteur-Chamberland filter) with pores small enough to remove all bacteria from a solution passed through it. In 1892, the Russian biologist Dmitri Ivanovsky used this filter to study what is now known as the tobacco mosaic virus: crushed leaf extracts from infected tobacco plants remained infectious even after filtration to remove bacteria. Ivanovsky suggested the infection might be caused by a toxin produced by bacteria, but he did not pursue the idea. At the time it was thought that all infectious agents could be retained by filters and grown on a nutrient medium—this was part of the germ theory of disease.
In 1898, the Dutch microbiologist Martinus Beijerinck repeated the experiments and became convinced that the filtered solution contained a new form of infectious agent. He observed that the agent multiplied only in cells that were dividing, but as his experiments did not show that it was made of particles, he called it a contagium vivum fluidum (soluble living germ) and reintroduced the word virus. Beijerinck maintained that viruses were liquid in nature, a theory later discredited by Wendell Stanley, who proved they were particulate. In the same year, Friedrich Loeffler and Paul Frosch passed the first animal virus, aphthovirus (the agent of foot-and-mouth disease), through a similar filter.
In the early 20th century, the English bacteriologist Frederick Twort discovered a group of viruses that infect bacteria, now called bacteriophages (or commonly 'phages'), and the French-Canadian microbiologist Félix d'Herelle described viruses that, when added to bacteria on an agar plate, would produce areas of dead bacteria. He accurately diluted a suspension of these viruses and discovered that the highest dilutions (lowest virus concentrations), rather than killing all the bacteria, formed discrete areas of dead organisms. Counting these areas and multiplying by the dilution factor allowed him to calculate the number of viruses in the original suspension. Phages were heralded as a potential treatment for diseases such as typhoid and cholera, but their promise was forgotten with the development of penicillin. The development of bacterial resistance to antibiotics has renewed interest in the therapeutic use of bacteriophages.
By the end of the 19th century, viruses were defined in terms of their infectivity, their ability to pass filters, and their requirement for living hosts. Viruses had been grown only in plants and animals. In 1906 Ross Granville Harrison invented a method for growing tissue in lymph, and in 1913 E. Steinhardt, C. Israeli, and R.A. Lambert used this method to grow vaccinia virus in fragments of guinea pig corneal tissue. In 1928, H. B. Maitland and M. C. Maitland grew vaccinia virus in suspensions of minced hens' kidneys. Their method was not widely adopted until the 1950s when poliovirus was grown on a large scale for vaccine production.
Another breakthrough came in 1931 when the American pathologist Ernest William Goodpasture and Alice Miles Woodruff grew influenza and several other viruses in fertilised chicken eggs. In 1949, John Franklin Enders, Thomas Weller, and Frederick Robbins grew poliovirus in cultured cells from aborted human embryonic tissue, the first virus to be grown without using solid animal tissue or eggs. This work enabled Hilary Koprowski, and then Jonas Salk, to make an effective polio vaccine.
The first images of viruses were obtained upon the invention of electron microscopy in 1931 by the German engineers Ernst Ruska and Max Knoll. In 1935, American biochemist and virologist Wendell Meredith Stanley examined the tobacco mosaic virus and found it was mostly made of protein. A short time later, this virus was separated into protein and RNA parts.
The tobacco mosaic virus was the first to be crystallised and its structure could, therefore, be elucidated in detail. The first X-ray diffraction pictures of the crystallised virus were obtained by Bernal and Fankuchen in 1941. Based on her X-ray crystallographic pictures, Rosalind Franklin discovered the full structure of the virus in 1955. In the same year, Heinz Fraenkel-Conrat and Robley Williams showed that purified tobacco mosaic virus RNA and its protein coat can assemble by themselves to form functional viruses, suggesting that this simple mechanism was probably the means through which viruses were created within their host cells.
The second half of the 20th century was the golden age of virus discovery, and most of the documented species of animal, plant, and bacterial viruses were discovered during these years. In 1957 equine arterivirus and the cause of bovine virus diarrhoea (a pestivirus) were discovered. In 1963 the hepatitis B virus was discovered by Baruch Blumberg, and in 1965 Howard Temin described the first retrovirus. Reverse transcriptase, the enzyme that retroviruses use to make DNA copies of their RNA, was first described in 1970 by Temin and David Baltimore independently. In 1983 Luc Montagnier's team at the Pasteur Institute in France, first isolated the retrovirus now called HIV. In 1989 Michael Houghton's team at Chiron Corporation discovered hepatitis C.
== Detecting viruses ==
There are several approaches to detecting viruses and these include the detection of virus particles (virions) or their antigens or nucleic acids and infectivity assays.
=== Electron microscopy ===
Viruses were seen for the first time in the 1930s when electron microscopes were invented. These microscopes use beams of electrons instead of light, which have a much shorter wavelength and can detect objects that cannot be seen using light microscopes. The highest magnification obtainable by electron microscopes is up to 10,000,000 times whereas for light microscopes it is around 1,500 times.
Virologists often use negative staining to help visualise viruses. In this procedure, the viruses are suspended in a solution of metal salts such as uranium acetate. The atoms of metal are opaque to electrons and the viruses are seen as suspended in a dark background of metal atoms. This technique has been in use since the 1950s. Many viruses were discovered using this technique and negative staining electron microscopy is still a valuable weapon in a virologist's arsenal.
Traditional electron microscopy has disadvantages in that viruses are damaged by drying in the high vacuum inside the electron microscope and the electron beam itself is destructive. In cryogenic electron microscopy the structure of viruses is preserved by embedding them in an environment of vitreous water. This allows the determination of biomolecular structures at near-atomic resolution, and has attracted wide attention to the approach as an alternative to X-ray crystallography or NMR spectroscopy for the determination of the structure of viruses.
=== Growth in cultures ===
Viruses are obligate intracellular parasites and because they only reproduce inside the living cells of a host these cells are needed to grow them in the laboratory. For viruses that infect animals (usually called "animal viruses") cells grown in laboratory cell cultures are used. In the past, fertile hens' eggs were used and the viruses were grown on the membranes surrounding the embryo. This method is still used in the manufacture of some vaccines. For the viruses that infect bacteria, the bacteriophages, the bacteria growing in test tubes can be used directly. For plant viruses, the natural host plants can be used or, particularly when the infection is not obvious, so-called indicator plants, which show signs of infection more clearly.
Viruses that have grown in cell cultures can be indirectly detected by the detrimental effect they have on the host cell. These cytopathic effects are often characteristic of the type of virus. For instance, herpes simplex viruses produce a characteristic "ballooning" of the cells, typically human fibroblasts. Some viruses, such as mumps virus cause red blood cells from chickens to firmly attach to the infected cells. This is called "haemadsorption" or "hemadsorption". Some viruses produce localised "lesions" in cell layers called plaques, which are useful in quantitation assays and in identifying the species of virus by plaque reduction assays.
Viruses growing in cell cultures are used to measure their susceptibility to validated and novel antiviral drugs.
=== Serology ===
Viruses are antigens that induce the production of antibodies and these antibodies can be used in laboratories to study viruses. Related viruses often react with each other's antibodies and some viruses can be named based on the antibodies they react with. The use of the antibodies which were once exclusively derived from the serum (blood fluid) of animals is called serology. Once an antibody–reaction has taken place in a test, other methods are needed to confirm this. Older methods included complement fixation tests, hemagglutination inhibition and virus neutralisation. Newer methods use enzyme immunoassays (EIA).
In the years before PCR was invented immunofluorescence was used to quickly confirm viral infections. It is an infectivity assay that is virus species specific because antibodies are used. The antibodies are tagged with a dye that is luminescencent and when using an optical microscope with a modified light source, infected cells glow in the dark.
=== Polymerase chain reaction (PCR) and other nucleic acid detection methods ===
PCR is a mainstay method for detecting viruses in all species including plants and animals. It works by detecting traces of virus specific RNA or DNA. It is very sensitive and specific, but can be easily compromised by contamination. Most of the tests used in veterinary virology and medical virology are based on PCR or similar methods such as transcription mediated amplification. When a novel virus emerges, such as the covid coronavirus, a specific test can be devised quickly so long as the viral genome has been sequenced and unique regions of the viral DNA or RNA identified. The invention of microfluidic tests as allowed for most of these tests to be automated, Despite its specificity and sensitivity, PCR has a disadvantage in that it does not differentiate infectious and non-infectious viruses and "tests of cure" have to be delayed for up to 21 days to allow for residual viral nucleic acid to clear from the site of the infection.
=== Diagnostic tests ===
In laboratories many of the diagnostic test for detecting viruses are nucleic acid amplification methods such as PCR. Some tests detect the viruses or their components as these include electron microscopy and enzyme-immunoassays. The so-called "home" or "self"-testing gadgets are usually lateral flow tests, which detect the virus using a tagged monoclonal antibody. These are also used in agriculture, food and environmental sciences.
== Quantitation and viral loads ==
Counting viruses (quantitation) has always had an important role in virology and has become central to the control of some infections of humans where the viral load is measured. There are two basic methods: those that count the fully infective virus particles, which are called infectivity assays, and those that count all the particles including the defective ones.
=== Infectivity assays ===
Infectivity assays measure the amount (concentration) of infective viruses in a sample of known volume. For host cells, plants or cultures of bacterial or animal cells are used. Laboratory animals such as mice have also been used particularly in veterinary virology. These are assays are either quantitative where the results are on a continuous scale or quantal, where an event either occurs or it does not. Quantitative assays give absolute values and quantal assays give a statistical probability such as the volume of the test sample needed to ensure 50% of the hosts cells, plants or animals are infected. This is called the median infectious dose or ID 50. Infective bacteriophages can be counted by seeding them onto "lawns" of bacteria in culture dishes. When at low concentrations, the viruses form holes in the lawn that can be counted. The number of viruses is then expressed as plaque forming units. For the bacteriophages that reproduce in bacteria that cannot be grown in cultures, viral load assays are used.
The focus forming assay (FFA) is a variation of the plaque assay, but instead of relying on cell lysis in order to detect plaque formation, the FFA employs immunostaining techniques using fluorescently labeled antibodies specific for a viral antigen to detect infected host cells and infectious virus particles before an actual plaque is formed. The FFA is particularly useful for quantifying classes of viruses that do not lyse the cell membranes, as these viruses would not be amenable to the plaque assay. Like the plaque assay, host cell monolayers are infected with various dilutions of the virus sample and allowed to incubate for a relatively brief incubation period (e.g., 24–72 hours) under a semisolid overlay medium that restricts the spread of infectious virus, creating localized clusters (foci) of infected cells. Plates are subsequently probed with fluorescently labeled antibodies against a viral antigen, and fluorescence microscopy is used to count and quantify the number of foci. The FFA method typically yields results in less time than plaque or fifty-percent-tissue-culture-infective-dose (TCID50) assays, but it can be more expensive in terms of required reagents and equipment. Assay completion time is also dependent on the size of area that the user is counting. A larger area will require more time but can provide a more accurate representation of the sample. Results of the FFA are expressed as focus forming units per milliliter, or FFU/
=== Viral load assays ===
When an assay for measuring the infective virus particle is done (Plaque assay, Focus assay), viral titre often refers to the concentration of infectious viral particles, which is different from the total viral particles. Viral load assays usually count the number of viral genomes present rather than the number of particles and use methods similar to PCR. Viral load tests are an important in the control of infections by HIV. This versatile method can be used for plant viruses.
== Molecular biology ==
Molecular virology is the study of viruses at the level of nucleic acids and proteins. The methods invented by molecular biologists have all proven useful in virology. Their small sizes and relatively simple structures make viruses an ideal candidate for study by these techniques.
=== Purifying viruses and their components ===
For further study, viruses grown in the laboratory need purifying to remove contaminants from the host cells. The methods used often have the advantage of concentrating the viruses, which makes it easier to investigate them.
==== Centrifugation ====
Centrifuges are often used to purify viruses. Low speed centrifuges, i.e. those with a top speed of 10,000 revolutions per minute (rpm) are not powerful enough to concentrate viruses, but ultracentrifuges with a top speed of around 100,000 rpm, are and this difference is used in a method called differential centrifugation. In this method the larger and heavier contaminants are removed from a virus mixture by low speed centrifugation. The viruses, which are small and light and are left in suspension, are then concentrated by high speed centrifugation.
Following differential centrifugation, virus suspensions often remain contaminated with debris that has the same sedimentation coefficient and are not removed by the procedure. In these cases a modification of centrifugation, called buoyant density centrifugation, is used. In this method the viruses recovered from differential centrifugation are centrifuged again at very high speed for several hours in dense solutions of sugars or salts that form a density gradient, from low to high, in the tube during the centrifugation. In some cases, preformed gradients are used where solutions of steadily decreasing density are carefully overlaid on each other. Like an object in the Dead Sea, despite the centrifugal force the virus particles cannot sink into solutions that are more dense than they are and they form discrete layers of, often visible, concentrated viruses in the tube. Caesium chloride is often used for these solutions as it is relatively inert but easily self-forms a gradient when centrifuged at high speed in an ultracentrifuge. Buoyant density centrifugation can also be used to purify the components of viruses such as their nucleic acids or proteins.
==== Electrophoresis ====
The separation of molecules based on their electric charge is called electrophoresis. Viruses and all their components can be separated and purified using this method. This is usually done in a supporting medium such as agarose and polyacrylamide gels. The separated molecules are revealed using stains such as coomasie blue, for proteins, or ethidium bromide for nucleic acids. In some instances the viral components are rendered radioactive before electrophoresis and are revealed using photographic film in a process known as autoradiography.
=== Sequencing of viral genomes ===
As most viruses are too small to be seen by a light microscope, sequencing is one of the main tools in virology to identify and study the virus. Traditional Sanger sequencing and next-generation sequencing (NGS) are used to sequence viruses in basic and clinical research, as well as for the diagnosis of emerging viral infections, molecular epidemiology of viral pathogens, and drug-resistance testing. There are more than 2.3 million unique viral sequences in GenBank. NGS has surpassed traditional Sanger as the most popular approach for generating viral genomes. Viral genome sequencing as become a central method in viral epidemiology and viral classification.
=== Phylogenetic analysis ===
Data from the sequencing of viral genomes can be used to determine evolutionary relationships and this is called phylogenetic analysis. Software, such as PHYLIP, is used to draw phylogenetic trees. This analysis is also used in studying the spread of viral infections in communities (epidemiology).
=== Cloning ===
When purified viruses or viral components are needed for diagnostic tests or vaccines, cloning can be used instead of growing the viruses. At the start of the COVID-19 pandemic the availability of the severe acute respiratory syndrome coronavirus 2 RNA sequence enabled tests to be manufactured quickly. There are several proven methods for cloning viruses and their components. Small pieces of DNA called cloning vectors are often used and the most common ones are laboratory modified plasmids (small circular molecules of DNA produced by bacteria). The viral nucleic acid, or a part of it, is inserted in the plasmid, which is the copied many times over by bacteria. This recombinant DNA can then be used to produce viral components without the need for native viruses.
=== Phage virology ===
The viruses that reproduce in bacteria, archaea and fungi are informally called "phages", and the ones that infect bacteria – bacteriophages – in particular are useful in virology and biology in general. Bacteriophages were some of the first viruses to be discovered, early in the twentieth century, and because they are relatively easy to grow quickly in laboratories, much of our understanding of viruses originated by studying them. Bacteriophages, long known for their positive effects in the environment, are used in phage display techniques for screening proteins DNA sequences. They are a powerful tool in molecular biology.
== Genetics ==
All viruses have genes which are studied using genetics. All the techniques used in molecular biology, such as cloning, creating mutations RNA silencing are used in viral genetics.
=== Reassortment ===
Reassortment is the switching of genes from different parents and it is particularly useful when studying the genetics of viruses that have segmented genomes (fragmented into two or more nucleic acid molecules) such as influenza viruses and rotaviruses. The genes that encode properties such as serotype can be identified in this way.
=== Recombination ===
Often confused with reassortment, recombination is also the mixing of genes but the mechanism differs in that stretches of DNA or RNA molecules, as opposed to the full molecules, are joined during the RNA or DNA replication cycle. Recombination is not as common as reassortment in nature but it is a powerful tool in laboratories for studying the structure and functions of viral genes.
=== Reverse genetics ===
Reverse genetics is a powerful research method in virology. In this procedure complementary DNA (cDNA) copies of virus genomes called "infectious clones" are used to produce genetically modified viruses that can be then tested for changes in say, virulence or transmissibility.
== Virus classification ==
A major branch of virology is virus classification. It is artificial in that it is not based on evolutionary phylogenetics but it is based shared or distinguishing properties of viruses. It seeks to describe the diversity of viruses by naming and grouping them on the basis of similarities. In 1962, André Lwoff, Robert Horne, and Paul Tournier were the first to develop a means of virus classification, based on the Linnaean hierarchical system. This system based classification on phylum, class, order, family, genus, and species. Viruses were grouped according to their shared properties (not those of their hosts) and the type of nucleic acid forming their genomes. In 1966, the International Committee on Taxonomy of Viruses (ICTV) was formed. The system proposed by Lwoff, Horne and Tournier was initially not accepted by the ICTV because the small genome size of viruses and their high rate of mutation made it difficult to determine their ancestry beyond order. As such, the Baltimore classification system has come to be used to supplement the more traditional hierarchy. Starting in 2018, the ICTV began to acknowledge deeper evolutionary relationships between viruses that have been discovered over time and adopted a 15-rank classification system ranging from realm to species. Additionally, some species within the same genus are grouped into a genogroup.
=== ICTV classification ===
The ICTV developed the current classification system and wrote guidelines that put a greater weight on certain virus properties to maintain family uniformity. A unified taxonomy (a universal system for classifying viruses) has been established. Only a small part of the total diversity of viruses has been studied. As of 2021, 6 realms, 10 kingdoms, 17 phyla, 2 subphyla, 39 classes, 65 orders, 8 suborders, 233 families, 168 subfamilies, 2,606 genera, 84 subgenera, and 10,434 species of viruses have been defined by the ICTV.
The general taxonomic structure of taxon ranges and the suffixes used in taxonomic names are shown hereafter. As of 2021, the ranks of subrealm, subkingdom, and subclass are unused, whereas all other ranks are in use.
Realm (-viria)
Subrealm (-vira)
Kingdom (-virae)
Subkingdom (-virites)
Phylum (-viricota)
Subphylum (-viricotina)
Class (-viricetes)
Subclass (-viricetidae)
Order (-virales)
Suborder (-virineae)
Family (-viridae)
Subfamily (-virinae)
Genus (-virus)
Subgenus (-virus)
Species
=== Baltimore classification ===
The Nobel Prize-winning biologist David Baltimore devised the Baltimore classification system.
The Baltimore classification of viruses is based on the mechanism of mRNA production. Viruses must generate mRNAs from their genomes to produce proteins and replicate themselves, but different mechanisms are used to achieve this in each virus family. Viral genomes may be single-stranded (ss) or double-stranded (ds), RNA or DNA, and may or may not use reverse transcriptase (RT). In addition, ssRNA viruses may be either sense (+) or antisense (−). This classification places viruses into seven groups:
I: dsDNA viruses (e.g. Adenoviruses, Herpesviruses, Poxviruses)
II: ssDNA viruses (+ strand or "sense") DNA (e.g. Parvoviruses)
III: dsRNA viruses (e.g. Reoviruses)
IV:(+)ssRNA viruses (+ strand or sense) RNA (e.g. Coronaviruses, Picornaviruses, Togaviruses)
V: (−)ssRNA viruses (− strand or antisense) RNA (e.g. Orthomyxoviruses, Rhabdoviruses)
VI: ssRNA-RT viruses (+ strand or sense) RNA with DNA intermediate in life-cycle (e.g. Retroviruses)
VII: dsDNA-RT viruses DNA with RNA intermediate in life-cycle (e.g. Hepadnaviruses)
== References ==
=== Bibliography ===
== External links ==
Media related to Virology at Wikimedia Commons
Official website of the International Committee on Taxonomy of Viruses | Wikipedia/virology |
Hepadnaviridae is a family of viruses. Humans, apes, and birds serve as natural hosts. The family contains five genera. Its best-known member is hepatitis B virus. Diseases associated with this family include: liver infections, such as hepatitis, hepatocellular carcinomas (chronic infections), and cirrhosis. It is the sole accepted family in the order Blubervirales.
== Taxonomy ==
The following genera are recognized:
Avihepadnavirus
Orthohepadnavirus
Herpetohepadnavirus
Metahepadnavirus
Parahepadnavirus
== History and discovery ==
Although liver diseases transmissible among human populations were identified early in the history of medicine, the first known hepatitis with a viral etiological agent was Hepatitis A, in the picornaviridae family. Hepatitis B Virus (HBV) was identified as an infection distinct from Hepatitis A through its contamination of yellow fever vaccine. The vaccine contained human serum as a stabilizing agent which was HBV-infected. HBV was identified as a new DNA virus in the 1960s, followed a couple of decades later by the discovery of the flavivirus hepatitis C. HBV was first identified in the lab as the "Australia agent" by Blumberg and colleagues in the blood of an Aboriginal transfusion patient. This work earned Blumberg the 1976 Nobel Prize in Medicine.
== Genome ==
Hepadnaviruses have very small genomes of partially double-stranded, partially single stranded circular DNA (pdsDNA). The genome consists of two strands, a longer negative-sense strand and a shorter and positive-sense strand of variable length. In the virion these strands are arranged such that the two ends of the long strand meet but are not covalently bonded together. The shorter strand overlaps this divide and is connected to the longer strand on either side of the split through a direct repeat (DR) segment that pairs the two strands together. In replication, the viral pdsDNA is converted in the host cell nucleus to covalently-closed-circular DNA (cccDNA) by the viral polymerase.
Replication involves an RNA intermediate, as in viruses belonging to group VII of Baltimore classification. Four main open reading frames are encoded (ORFs) and the virus has four known genes which encode seven proteins: the core capsid protein, the viral polymerase, surface antigens—preS1, preS2, and S, the X protein and HBeAg. The X protein is thought to be non-structural. Its function and significance are poorly understood but it is suspected to be associated with host gene expression modulation.
=== Viral polymerase ===
Members of the family Hepadnaviridae encode their own polymerase, rather than co-opting host machinery as some other viruses do. This enzyme is unique among viral polymerases in that it has reverse transcriptase activity to convert RNA into DNA to replicate the genome (the only other human-pathogenic virus family encoding a polymerase with this capability is Retroviridae), RNAse activity (used when the DNA genome is synthesized from pgRNA that was packaged in virions for replication to destroy the RNA template and produce the pdsDNA genome), and DNA-dependent-DNA-polymerase activity (used to create cccDNA from pdsDNA in the first step of the replication cycle).
=== Envelope proteins ===
The hepatitis envelope proteins are composed of subunits made from the viral preS1, preS2, and S genes. The L (for "large") envelope protein contains all three subunits. The M (for "medium") protein contains only preS2 and S. The S (for "small") protein contains only S. The genome portions encoding these envelope protein subunits share both the same frame and the same stop codon, generating nested transcripts on a single open reading frame. The pre-S1 is encoded first (closest to the 5' end), followed directly by the pre-S2 and the S. When a transcript is made from the beginning of the pre-S1 region, all three genes are included in the transcript and the L protein is produced. When the transcript starts after the pro-S1 at the beginning of the pre-S2 the final protein contains the pre-S2 and S subunits only and therefore is an M protein. The smallest envelope protein containing just the S subunit is made most because it is encoded closest to the 3' end and comes from the shortest transcript. These envelope proteins can assemble independently of the viral capsid and genome into non-infectious virus-like particles that give the virus a pleomorphic appearance and promote a strong immune response in hosts.
== Replication ==
Hepadnaviruses replicate through an RNA intermediate (which they transcribe back into cDNA using reverse transcriptase). The reverse transcriptase becomes covalently linked to a short 3- or 4-nucleotide primer. Most hepadnaviruses will only replicate in specific hosts, and this makes experiments using in vitro methods very difficult.
The virus binds to specific receptors on cells and the core particle enters the cell cytoplasm. This is then translocated to the nucleus, where the partially double stranded DNA is 'repaired' by the viral polymerase to form a complete circular dsDNA genome (called covalently-closed-circular DNA or cccDNA). The genome then undergoes transcription by the host cell RNA polymerase and the pregenomicRNA (pgRNA) is sent out of the nucleus. The pgRNA is inserted into an assembled viral capsid containing the viral polymerase. Inside this capsid the genome is converted from RNA to pdsDNA through activity of the polymerase as an RNA-dependent-DNA-polymerase and subsequently as an RNAse to eliminate the pgRNA transcript. These new virions either leave the cell to infect others or are immediately dismantled so the new viral genomes can enter the nucleus and magnify the infection. The virions that leave the cell egress through budding.
== Structure ==
Viruses in Hepadnaviridae are enveloped, with spherical geometries, and T=4 symmetry. The diameter is around 42 nm. Genomes are circular, around 3.2kb in length. The genome codes for 7 proteins.
== Evolution ==
Based on the presence of viral genomes in bird DNA it appears that the hepadnaviruses evolved >82 million years ago. Birds may be the original hosts of the Hepadnaviridae with mammals becoming infected after a bird (see host switch).
Endogenous hepatitis B virus genomes have been described in crocodilian, snake and turtle genomes. This suggests that these viruses have infected vertebrates for over 200 million years ago.
Hepadnaviruses have been described in fish and amphibians also. This suggests that this family has co-evolved with the vertebrates.
Phylogenetic trees suggest that the bird viruses originated from those infecting reptiles. Those affecting mammals appear to be more closely related to those found in fish.
=== Nackednaviridae ===
A proposed family of viruses – the Nackednaviridae – has been isolated from fish. This family has a similar genomic organisation to that of members of the family Hepadnaviridae. These two families separated over 400 million years ago, suggesting an ancient origin for the family Hepadnaviridae.
Viruses in the family have non-enveloped, isosahedral structure with T=3 symmetry, smaller than typical Hepadnaviridae virions (about 5% of the latter show a T=3 symmetry). The circular, monopartite genome is about 3 kb much like Hepadnaviridae. The envelop protein S is accordingly not present, likely the ancestral state by sequence analysis. Unlike Hepadnaviridae viruses that usually diverge alongside their hosts, viruses in the family jump hosts more frequently. The "type" for this family is African cichlid nackednavirus'(ACNDV), formerly African cichlid hepadnavirus (ACHBV), a proposed and not-yet-accepted species.
== Cell tropism ==
Hepadnaviruses, as their "hepa" name implies, infect liver cells and cause hepatitis. This is true not only of the human pathogen Hepatitis B Virus but also the hepadnaviruses that infect other organisms. The "adhesion" step of the dynamic phase—in which an exterior viral protein stably interacts with a host cell protein—determines cell tropism. In the case of HBV the host receptor is human sodium taurocholate receptor (NTCP), a mediator of bile acid uptake, and the virus anti-receptor is the abundant HB-AgS envelope protein.
== See also ==
Transmission of hepadnaviruses
== Notes ==
== References ==
== External links ==
ICTV Report: Hepadnaviridae
Viralzone: Hepadnaviridae
"Hepadnaviridae". NCBI Taxonomy Browser. 10404. | Wikipedia/Hepadnavirus |
Foot-and-mouth disease (FMD) or hoof-and-mouth disease (HMD) is an infectious and sometimes fatal viral disease that primarily affects even-toed ungulates, including domestic and wild bovids. The virus causes a high fever lasting two to six days, followed by blisters inside the mouth and near the hoof that may rupture and cause lameness.
FMD has very severe implications for animal farming, since it is highly infectious and can be spread by infected animals comparatively easily through contact with contaminated farming equipment, vehicles, clothing, and feed, and by domestic and wild predators. Its containment demands considerable efforts in vaccination, strict monitoring, trade restrictions, quarantines, and the culling of both infected and healthy (uninfected) animals.
Susceptible animals include cattle, water buffalo, sheep, goats, pigs, antelope, deer, and bison. It has also been known to infect hedgehogs and elephants; llamas and alpacas may develop mild symptoms, but are resistant to the disease and do not pass it on to others of the same species. In laboratory experiments, mice, rats, and chickens have been artificially infected, but they are not believed to contract the disease under natural conditions. Cattle, Asian and African buffalo, sheep, and goats can become carriers following an acute infection, meaning they are still infected with a small amount of virus but appear healthy. Animals can be carriers for up to 1–2 years and are considered very unlikely to infect other animals, although laboratory evidence suggests that transmission from carriers is possible.
Humans are only extremely rarely infected by foot-and-mouth disease virus (FMDV). Humans, particularly young children, can be affected by hand, foot, and mouth disease (HFMD), which is often confused with FMD. HFMDV also affects cattle, sheep, and swine. HFMD is also a viral infection caused by multiple viruses belonging to the Picornaviridae family, but it is distinct from FMD.
The virus responsible for FMD is an aphthovirus, foot-and-mouth disease virus. Infection occurs when the virus particle is taken into a cell of the host. The cell is then forced to manufacture thousands of copies of the virus, and eventually bursts, releasing the new particles in the blood. The virus is genetically highly variable, which limits the effectiveness of vaccination. The disease was first documented in 1870.
== Signs and symptoms ==
The incubation period for FMD virus has a range between one and 12 days. The disease is characterized by high fever that declines rapidly after two to three days, blisters inside the mouth that lead to excessive secretion of stringy or foamy saliva and to drooling, and blisters on the feet that may rupture and cause lameness. Adult animals may suffer weight loss from which they do not recover for several months, as well as swelling in the testicles of mature males, and cows' milk production can decline significantly. Though most animals eventually recover from FMD, the disease can lead to myocarditis (inflammation of the heart muscle) and death, especially in newborn animals. Some infected ruminants remain asymptomatic carriers, but they nonetheless carry the virus and may be able to transmit it to others. Pigs cannot serve as asymptomatic carriers.
=== Subclinical infection ===
Subclinical (asymptomatic) infections can be classified as neoteric or persistent based on when they occur and whether the animal is infectious. Neoteric subclinical infections are acute infections, meaning they occur soon after an animal is exposed to the FMD virus (about 1 to 2 days) and last about 8 to 14 days. Acute infections are characterized by a high degree of replicating virus in the pharynx. In a neoteric subclinical infection, the virus remains in the pharynx and does not spread into the blood as it would in a clinical infection. Although animals with neoteric subclinical infections do not appear to have disease, they shed substantial amounts of virus in nasal secretions and saliva, so they are able to transmit the FMD virus to other animals. Neoteric subclinical infections often occur in vaccinated animals but can occur in unvaccinated animals as well.
Persistent subclinical infection (also referred to as a carrier state) occurs when an animal recovers from an acute infection but continues to have a small amount of replicating virus present in the pharynx. Cattle, buffalo, sheep, and goats can all become carriers, but pigs cannot. Animals can become carriers following acute infections with or without symptoms. Both vaccinated and unvaccinated animals can become carriers. Transmission of the FMD virus from carriers to susceptible animals is considered very unlikely under natural conditions and has not been conclusively demonstrated in field studies.
However, in an experiment where virus was collected from the pharynx of carrier cattle and inserted in the pharynx of susceptible cattle, the susceptible cattle became infected and developed characteristic blisters in the mouth and on the feet. This supports the theory that while the likelihood of a carrier spreading FMD is quite low, it is not impossible. It is not fully understood why ruminants but not pigs can become carriers or why some animals develop persistent infection while others do not. Both are areas of ongoing study.
Because vaccinated animals can become carriers, the waiting period to prove FMD-freedom is longer when vaccination rather than slaughter is used as an outbreak-control strategy. As a result, many FMD-free countries are resistant to emergency vaccination in case of in outbreak out of concern for the serious trade and economic implications of a prolonged period without FMD-free status.
Although the risk of transmission from an individual FMD carrier is considered to be very low, there are many carriers in FMD-endemic regions, possibly increasing the number of chances for carrier transmission to occur. Also, it can be difficult to determine if an asymptomatic infection is neoteric or persistent in the field, as both would be apparently healthy animals that test positive for the FMD virus. This fact complicates disease control, as the two types of subclinical infections have significantly different risks of spreading disease.
== Cause ==
Of the seven serotypes of this virus, A, C, O, Asia 1, and SAT3 appear to be distinct lineages; SAT 1 and SAT 2 are unresolved clades. The mutation rate of the protein-encoding sequences of strains isolated between 1932 and 2007 has been estimated to be 1.46 × 10−3 substitutions/site/year, a rate similar to that of other RNA viruses. The most recent common ancestor appears to have evolved about 481 years ago (early 16th century). This ancestor then diverged into two clades which have given rise to the extant circulating Euro-Asiatic and South African. SAT 1 diverged first 397 years ago, followed by sequential divergence of serotype SAT 2 (396 years ago), A (147 years ago), O (121 years ago), Asia 1 (89 years ago), C (86 years ago), and SAT 3 (83 years ago). Bayesian skyline plot reveals a population expansion in the early 20th century that is followed by a rapid decline in population size from the late 20th century to the present day. Within each serotype, there was no apparent periodic, geographic, or host species influence on the evolution of global FMD viruses. At least seven genotypes of serotype Asia 1 are known.
=== Transmission ===
The FMD virus can be transmitted in a number of ways, including close-contact, animal-to-animal spread, long-distance aerosol spread and fomites, or inanimate objects, typically fodder and motor vehicles. The clothes and skin of animal handlers such as farmers, standing water, and uncooked food scraps and feed supplements containing infected animal products can harbor the virus, as well. Cows can also catch FMD from the semen of infected bulls. Control measures include quarantine and destruction of both infected and healthy (uninfected) livestock, and export bans for meat and other animal products to countries not infected with the disease.
There is significant variation in both susceptibility to infection and ability to spread disease between different species, virus strains, and transmission routes. For example, cattle are far more vulnerable than pigs to infection with aerosolized virus, and infected pigs produce 30 times the amount of aerosolized virus compared to infected cattle and sheep. Also, pigs are particularly vulnerable to infection through the oral route. It has been demonstrated experimentally that FMD can be spread to pigs when they eat commercial feed products contaminated by the FMD virus. Also, the virus can remain active for extended periods of time in certain feed ingredients, especially soybean meal. Feed biosecurity practices have become an important area of study since a 2013 outbreak of Porcine Epidemic Diarrhea Virus (PEDV) in the US, thought to be introduced through contaminated feed.
Just as humans may spread the disease by carrying the virus on their clothes and bodies, animals that are not susceptible to the disease may still aid in spreading it. This was the case in Canada in 1952, when an outbreak flared up again after dogs had carried off bones from dead animals. Wolves are thought to play a similar role in the former Soviet Union.
Daniel Rossouw Kannemeyer (1843–1925) published a note in the Transactions of the South African Philosophical Society volume 8 part 1 in which he links saliva-covered locusts with the spread of the disease.
Transmission of the FMD virus is possible before an animal has apparent signs of disease, a factor that increases the risk that significant spread of the virus has occurred before an outbreak is detected. A 2011 experiment measured transmission timing in cattle infected with serotype O virus by exposing susceptible cattle in 24-hour increments. It estimated the infectious period of the infected cattle to be 1.7 days, but showed the cattle were only infectious for a few hours before they developed fevers or classic FMD lesions. The authors also showed that the infectious period would have been estimated to be much higher (4.2 to 8.2 days) if detection of virus had been used as a substitute for infectiousness. A similar 2016 experiment using serotype A virus exposed susceptible pigs to infected pigs for 8 hour periods and found that pigs were able to spread disease for a full day before developing signs of disease. Analysis of this experimental data estimated the infectious period to be approximately 7 days. Again, the study showed that detection of virus was not an accurate substitution for infectiousness. An accurate understanding of the parameters of infectiousness is an important component of building epidemiological models which inform disease control strategies and policies.
=== Infecting humans ===
Humans can be infected with FMD through contact with infected animals, but this is extremely rare. Some cases were caused by laboratory accidents. Because the virus that causes FMD is sensitive to stomach acid, it cannot spread to humans via consumption of infected meat, except in the mouth before the meat is swallowed. In the UK, the last confirmed human case occurred in 1966, and only a few other cases have been recorded in countries of continental Europe, Africa, and South America. Symptoms of FMD in humans include malaise, fever, vomiting, red ulcerative lesions (surface-eroding damaged spots) of the oral tissues, and sometimes vesicular lesions (small blisters) of the skin. According to a newspaper report, FMD killed two children in England in 1884, supposedly due to infected milk.
Another viral disease with similar symptoms, hand, foot and mouth disease, occurs more frequently in humans, especially in young children; certain other non-polio enteroviruses than the FMD virus are its cause. These viruses belong to the Enterovirus genus within the Picornaviridae.
Because FMD rarely infects humans, but spreads rapidly among animals, it is a much greater threat to the agriculture industry than to human health. It has been argued that FMD is a zoonotic disease, but it is not considered among them by the U.S. Centers for Disease Control and Prevention and the U.S. Department of Agriculture due to the rarity of interspecies transmission.
== Prevention ==
Like other RNA viruses, the FMD virus continually evolves and mutates, thus one of the difficulties in vaccinating against it is the huge variation between, and even within, serotypes. No cross-protection has been seen between serotypes (a vaccine for one serotype will not protect against any others) and in addition, two strains within a given serotype may have nucleotide sequences that differ by as much as 30% for a given gene. This means FMD vaccines must be highly specific to the strain involved. Vaccination only provides temporary immunity that lasts from months to years.
Currently, the World Organisation for Animal Health recognizes countries to be in one of three disease states with regard to FMD: FMD present with or without vaccination, FMD-free with vaccination, and FMD-free without vaccination. Countries designated FMD-free without vaccination have the greatest access to export markets, so many developed nations, including Canada, the United States, and the UK, work hard to maintain their current status. Some countries such as Brazil and Argentina, which have large beef-exporting industries, practise vaccination in some areas, but have other vaccination-free zones.
Reasons cited for restricting export from countries using FMD vaccines include, probably most importantly, routine blood tests relying on antibodies cannot distinguish between an infected and a vaccinated animal, which severely hampers screening of animals used in export products, risking a spread of FMD to importing countries. A widespread preventive vaccination would also conceal the existence of the virus in a country. From there, it could potentially spread to countries without vaccine programs. Lastly, an animal infected shortly after being vaccinated can harbor and spread FMD without showing symptoms itself, hindering containment and culling of sick animals as a remedy.
Many early vaccines used dead samples of the FMD virus to inoculate animals, but those early vaccines sometimes caused real outbreaks. In the 1970s, scientists discovered that a vaccine could be made using only a single key protein from the virus. The task was to produce enough quantities of the protein to be used in the vaccination. On June 18, 1981, the US government announced the creation of a vaccine targeted against FMD, the world's first genetically engineered vaccine.
The North American FMD Vaccine Bank is housed at the United States Department of Agriculture's Foreign Animal Disease Diagnostic Laboratory at Plum Island Animal Disease Center. The center, located 1.5 mi (2.4 km) off the coast of Long Island, New York, is the only place in the United States where scientists can conduct research and diagnostic work on highly contagious animal diseases such as FMD. Because of this limitation, US companies working on FMD usually use facilities in other countries where such diseases are endemic.
== Epidemiology ==
=== United States (1870–1929) ===
The US has had nine FMD outbreaks since it was first recognized on the northeastern coast in 1870; the most devastating happened in 1914. It originated from Michigan, but its entry into the stockyards in Chicago turned it into an epizootic. About 3,500 livestock herds were infected across the US, totaling over 170,000 cattle, sheep, and swine. The eradication came at a cost of US$4.5 million (equivalent to $141 million in 2024).
A 1924 outbreak in California resulted not only in the slaughter of 109,000 farm animals, but also 22,000 deer.
The US had its latest FMD outbreak in Montebello, California, in 1929. This outbreak originated in hogs that had eaten infected meat scraps from a tourist steamship that had stocked meat in Argentina. Over 3,600 animals were slaughtered and the disease was contained in less than a month.
=== Mexico–U.S. border (1947) ===
On December 26, 1946, the United States and Mexico jointly declared that FMD had been found in Mexico. Initially, proposals from Texans were for an animal-proof wall, to prevent animals from crossing the border and spreading the disease, but the two countries eventually managed to cooperate in a bilateral effort and eradicated the disease without building a wall. To prevent tension between ranchers and the veterinarians, public broadcasts over the radio and with speakers on trucks were used to inform Mexican ranchers why the U.S. veterinarians were working on their livestock. Ranchers who lost cattle due to being culled by the vets would receive financial compensation. However, the tension remained and resulted in clashes between local citizens and the military-protected U.S. veterinarians. These teams of veterinarians worked from outside the infection zone of the disease and worked their way to the heart of the epidemic. Over 60,000,000 injections were administered to livestock by the end of 1950.
=== United Kingdom (1967) ===
In October 1967, a farmer in Shropshire reported a lame sow, which was later diagnosed with FMD. The source was believed to be remains of legally imported infected lamb from Argentina and Chile. The virus spread, and in total, 442,000 animals were slaughtered and the outbreak had an estimated cost of £370 million (equivalent to £8 billion in 2023).
=== Taiwan (1997) ===
Taiwan had previous epidemics of FMD in 1913–14 and 1924–29, but had since been spared, and considered itself free of FMD as late as in the 1990s. On the 19th of March 1997, a sow at a farm in Hsinchu, Taiwan, was diagnosed with a strain of FMD that only infects swine. Mortality was high, nearing 100% in the infected herd. The cause of the epidemic was not determined, but the farm was near a port city known for its pig-smuggling industry and illegal slaughterhouses. Smuggled swine or contaminated meat are thus likely sources of the disease.
The disease spread rapidly among swine herds in Taiwan, with 200–300 new farms being infected daily. Causes for this include the high swine density in the area, with up to 6,500 hogs per square mile, feeding of pigs with untreated garbage, and the farms' proximity to slaughterhouses. Other systemic issues, such as lack of laboratory facilities, slow response, and initial lack of a vaccination program, contributed.
A complicating factor is the endemic spread of swine vesicular disease (SVD) in Taiwan. The symptoms are indistinguishable from FMD, which may have led to previous misdiagnosing of FMD as SVD. Laboratory analysis was seldom used for diagnosis, and FMD may thus have gone unnoticed for some time.
The swine depopulation was a massive undertaking, with the military contributing substantial manpower. At peak capacity, 200,000 hogs per day were disposed of, mainly by electrocution. Carcasses were disposed of by burning and burial, but burning was avoided in water resource-protection areas. In April, industrial incinerators were running around the clock to dispose of the carcasses.
Initially, 40,000 combined vaccine doses for the strains O-1, A-24, and Asia-1 were available and administered to zoo animals and valuable breeding hogs. At the end of March, half a million new doses for O-1 and Asia-1 were made available. On the May 3rd, 13 million doses of O-1 vaccine arrived, and both the March and May shipments were distributed free of charge. With a danger of vaccination crews spreading the disease, only trained farmers were allowed to administer the vaccine under veterinary supervision.
Taiwan had previously been the major exporter of pork to Japan, and among the top 15 pork producers in the world in 1996. During the outbreak, over 3.8 million swine were destroyed at a cost of US$6.9 billion (equivalent to $13.5 billion in 2024). The Taiwanese pig industry was devastated as a result, and the export market was in ruins.
In 2007, Taiwan was considered free of FMD, but was still conducting a vaccination program, which restricts the export of meat from Taiwan.
=== United Kingdom (2001) ===
The epidemic of FMD in the United Kingdom in the spring and summer of 2001 was caused by the "Type O pan Asia" strain of the disease. This episode resulted in more than 2,000 cases of the disease in farms throughout the British countryside. More than six million sheep and cattle were killed in an eventually successful attempt to halt the disease. The county of Cumbria was the most seriously affected area of the country, with 843 cases. By the time the disease was halted in October 2001, the crisis was estimated to have cost Britain £8 billion (equivalent to £17 billion in 2023) to the agricultural and support industries, and to the outdoor industry. What made this outbreak so serious was the amount of time between infection being present at the first outbreak locus, and when countermeasures were put into operation against the disease, such as transport bans and detergent washing of both vehicles and personnel entering livestock areas. The epidemic was probably caused by pigs that had been fed infected rubbish that had not been properly heat-sterilized. Further, the rubbish is believed to have contained remains of infected meat that had been illegally imported to Britain.
=== China (2005) ===
In April 2005, an Asia-1 strain of FMD appeared in the eastern provinces of Shandong and Jiangsu. During April and May, it spread to suburban Beijing, the northern province of Hebei, and the Xinjiang autonomous region in northwest China. On 13 May, China reported the FMD outbreak to the World Health Organization and the OIE. This was the first time China has publicly admitted to having FMD. China is still reporting FMD outbreaks. In 2007, reports filed with the OIE documented new or ongoing outbreaks in the provinces of Gansu, Qinghai and Xinjiang. This included reports of domestic yak showing signs of infection. FMD is endemic in pastoral regions of China from Heilongjiang Province in the northeast to Sichuan Province and the Tibetan Autonomous region in the southwest. Chinese domestic media reports often use a euphemism "Disease Number Five" (五号病 wǔhàobìng) rather than FMD in reports because of the sensitivity of the FMD issue. In March 2010, Southern Rural News (Nanfang Nongcunbao), in an article "Breaking the Hoof and Mouth Disease Taboo", noted that FMD has long been covered up in China by referring to it that way. FMD is also called canker (口疮, literally "mouth ulcers" kǒuchuāng) or hoof jaundice (蹄癀 tíhuáng) in China, so information on FMD in China can be found online using those words as search terms. One can find online many provincial orders and regulations on FMD control antedating China's acknowledgment that the disease existed in China, for example Guangxi Zhuang Autonomous Region 1991 regulation on preventing the spread of Disease No.5.
=== United Kingdom (2007) ===
An infection of FMD in the United Kingdom was confirmed by the Department for Environment, Food and Rural Affairs, on 3 August 2007, on farmland located in Normandy, Surrey. All livestock in the vicinity were culled on 4 August. A nationwide ban on the movement of cattle and pigs was imposed, with a 3-km (1.9-mi) protection zone placed around the outbreak sites and the nearby virus research and vaccine production establishments, together with a 10-km (6.2-mi) increased surveillance zone.
On 4 August, the strain of the virus was identified as a "01 BFS67-like" virus, one linked to vaccines and not normally found in animals, and isolated in the 1967 outbreak. The same strain was used at the nearby Institute for Animal Health and Merial Animal Health Ltd at Pirbright, 2.5 miles (4.0 km) away, which is an American/French-owned BSL-4 vaccine manufacturing facility, and was identified as the likely source of infection.
On 12 September, a new outbreak of the disease was confirmed in Egham, Surrey, 19 km (12 mi) from the original outbreak, with a second case being confirmed on a nearby farm on 14 September.
These outbreaks caused a cull of all at-risk animals in the area surrounding Egham, including two farms near the famous four-star hotel Great Fosters. These outbreaks also caused the closure of Windsor Great Park due to the park containing deer; the park remained closed for three months. On 19 September 2007, a suspected case of FMD was found in Solihull, where a temporary control zone was set up by Defra.
=== Japan and Korea (2010–2011) ===
In April 2010, a report of three incursions of FMD in Japan and South Korea led the United Nations Food and Agriculture Organization (FAO) to issue a call for increased global surveillance. Japan veterinary authorities confirmed an outbreak of type O FMD virus, currently more common in Asian countries where FMD is endemic.
South Korea was hit by the rarer type A FMD in January, and then the type O infection in April. The most serious case of foot-and-mouth outbreak in South Korea's history started in November 2010 in pig farms in Andong city of Gyeongsangbuk-do, and has since spread in the country rapidly. More than 100 cases of the disease have been confirmed in the country so far, and in January 2011, South Korean officials started a mass cull of approximately 12%, or around three million in total, of the entire domestic pig population, and 107,000 of three million cattle of the country to halt the outbreak.
According to the report based on complete 1D gene sequences, Korean serotype A virus was linked with those from Laos. Korean serotype O viruses were divided into three clades and were closely related to isolates from Japan, Thailand, the UK, France, Ireland, South Africa, and Singapore, as well as Laos.
On 10 February 2011, North Korea reported an outbreak affecting pigs in the region around Pyongyang, by then ongoing since at least December 2010. Efforts to control the outbreak were hampered by illicit sales of infected meat.
=== Indonesia (2022) ===
After being eradicated there in 1986, FMD was again detected in Indonesia in May 2022. The Australian government has offered its assistance but remains unconcerned, considering the risk to the country's biosecurity to be low. The Department of Agriculture (DAWE) is the responsible body and has been monitoring the situation. DAWE has determined there is only a low risk and has stockpiled vaccines since 2004 anyhow.
In response to the Indonesian outbreak, Australian authorities began checking parcels and baggage from Indonesia and China. Disinfectant floormats were also installed at Australian airports to clean footwear. The Albanese Government rejected calls by opposition parties to close the border to travel from Indonesia. In addition, New Zealand authorities have banned travellers from Indonesia from bringing meat products, have screened baggage from Indonesia, and installed floor mats. New Zealand Prime Minister Jacinda Ardern and Biosecurity Minister Damien O'Connor have expressed concern about the impact of foot and mouth disease on New Zealand's substantial cattle, sheep and pig populations as well as wildlife.
=== Germany (2025) ===
In January 2025, an outbreak of foot-and-mouth disease was reported in a herd of water buffalo near Berlin. A 3 kilometre exclusion zone and a 10 kilometre monitoring zone were imposed, and after four days no further cases had been detected within 1 kilometre of the original case.
=== Hungary and Slovakia (2025) ===
On March 8th, 2025, a confirmed case of foot-and-mouth disease was reported at a cattle farm in Kisbajcs, located in the northwestern corner of Hungary, the first such case in 50 years. Immediate counter-measures were made to mitigate the spread of the disease, including the liquidation of all 1400 animals in the affected herd and the burial of their carcasses. The government of the United Kingdom subsequently banned all imports of cattle, sheep, pigs and deer, as well as banning travellers from bringing meat and dairy products with them, from both Hungary and neighbouring Slovakia due to the farm's proximity to the country's border. As of March 10th, 2025, the eradication of the disease was still in progress. On March 21st, 2025, the foot-and-mouth disease was confirmed to cross the Hungarian-Slovak border with three cattle farms in villages Medveďov, Ňárad and Baka in Dunajská Streda district having the cases of the disease. The Fourth Slovak farm with infected cattle confirmed was in village Lúč na Ostrove on March 25, with another source of the disease confirmed in Hungarian village Levél on March 26. A Fifth infected farm in Slovakia was confirmed on March 30 in Plavecký Štvrtok. Both countries started with strict border controls, including stopping of traffic on several border crossings. All Slovak zoological gardens were closed temporarily.
== History ==
The cause of FMD was first shown to be viral in 1897 by Friedrich Loeffler. He passed the blood of an infected animal through a Chamberland filter and found the collected fluid could still cause the disease in healthy animals.
FMD occurs throughout much of the world, and while some countries have been free of FMD for some time, its wide host range and rapid spread represent cause for international concern. After World War II, the disease was widely distributed throughout the world. In 1996, endemic areas included Asia, Africa, and parts of South America; as of August 2007, Chile is disease-free, and Uruguay and Argentina have not had an outbreak since 2001. In May 2014, the FAO informed that Bolivia, Colombia, Ecuador and Peru were "just one step away" from eradication; North America and Australia have been free of FMD for many years. New Zealand has never had a case of foot-and-mouth disease. Most European countries have been recognized as disease-free, and countries belonging to the European Union have stopped FMD vaccination.
However, in 2001, a serious outbreak of FMD in Britain resulted in the slaughter of many animals, the postponing of the general election for a month, and the cancellation of many sporting events and leisure activities, such as the Isle of Man TT. Due to strict government policies on sale of livestock, disinfection of all persons leaving and entering farms, and the cancellation of large events likely to be attended by farmers, a potentially economically disastrous epizootic was avoided in Ireland, with just one case recorded in Proleek, County Louth. As one result, the Animal Health Act 2002 was designed by Parliament to provide the regulators with more powers to deal with FMD.
In August 2007, FMD was found at two farms in Surrey, England. All livestock were culled and a quarantine erected over the area. Two other suspected outbreaks have occurred since, although these seem now not to be related to FMD. The only reported case in 2010 was a false alarm from GIS Alex Baker, as proven false by the Florida Farm and Agricultural Department, and quarantine/slaughter of cattle and pigs was confirmed from Miyazaki Prefecture in Japan in June after three cows tested positive. Some 270,000 cattle have been ordered slaughtered following the disease's outbreak.
In 2022, the disease was once again seen in cattle in Indonesia. Other countries are worried that it might spread to their countries soon.
== Ethical considerations ==
Great Britain's response to the 2001 outbreak of foot and mouth disease was a controversial policy of culling all animals within 3 km of an infected farm within 48 hours, leading to the slaughter of over 4 million animals. This was stated to be "a response to a desperate situation, not a pre-meditated response to a known, assessed risk". FMD is usually nonfatal to adult animals. Pigs are capable of airborne transmission of the virus in one extreme case 250 km across the English Channel, although not usually more than 10 km. There are no known cases of cattle or sheep spreading the virus beyond 3 km. The 2007 outbreak was caught much earlier, and was able to be contained after culling only 1,578 animals.
For the farmer, culling animals often results in financial devastation with no ability to honor existing contractual arrangements, thus facing the prospective loss of farm, equipment, and future earning potential. Farmers, especially in more traditional systems, may also have emotional attachments to some of the animals. On the ethical side, one must also consider that FMD is a painful disease for the affected animals. The vesicles and blisters are painful in themselves, and restrict both eating and movement. Through ruptured blisters, the animal is also at risk from secondary bacterial infections. Production loss and vaccination in areas where the disease is endemic costs and estimated US$6.5 billion to 21 billion yearly, and controlling outbreaks in countries normally free of it costs and additional >US$1.5 billion per year. This cost is disproportionately borne by some of the poorest countries in the world. Controlling the virus with vaccines is difficult because there are multiple serotypes of the virus which require distinct vaccines. When an outbreak occurs, the virus must be analyzed before the correct vaccine can be identified. Research is ongoing to improve vaccination technology.
== See also ==
Animal virology
Hand, foot and mouth disease (HFMD)
Swine vesicular disease (SVD)
Blain, an archaic disease of uncertain etiology
== References ==
== External links ==
FMD Myocarditis in Pigs
Stenfeldt, C.; Pacheco, J. M.; Smoliga, G. R.; Bishop, E.; Pauszek, S. J.; Hartwig, E. J.; Rodriguez, L. L.; Arzt, J. (2014). "Detection of Foot-and-mouth Disease Virus RNA and Capsid Protein in Lymphoid Tissues of Convalescent Pigs Does Not Indicate Existence of a Carrier State". Transboundary and Emerging Diseases. 63 (2): 152–164. doi:10.1111/tbed.12235. PMID 24943477.
Foot-and-Mouth Disease Archived 2013-05-20 at the Wayback Machine 12-part comprehensive overview from the Center for Infectious Disease Research and Policy
FMD portal
2007 Outbreak Foot and Mouth Disease Timeline
Armstrong R, Davie J, Hedger RS (1967). "Foot-and-mouth disease in man". Br Med J. 4 (5578): 529–30. doi:10.1136/bmj.4.5578.529. PMC 1749100. PMID 4294412.
Current status of Foot and Mouth Disease worldwide at OIE. WAHID Interface—OIE World Animal Health Information Database
Disease card Archived 2014-10-10 at the Wayback Machine
The European Commission for the Control of Foot-and-Mouth Disease (EuFMD)
Species Profile – Foot and Mouth Disease, National Invasive Species Information Center, United States National Agricultural Library. | Wikipedia/Foot-and-mouth_disease |
Tobacco mosaic virus (TMV) is a positive-sense single-stranded RNA virus species in the genus Tobamovirus that infects a wide range of plants, especially tobacco and other members of the family Solanaceae. The infection causes characteristic patterns, such as "mosaic"-like mottling and discoloration on the leaves (hence the name). TMV was the first virus to be discovered. Although it was known from the late 19th century that a non-bacterial infectious disease was damaging tobacco crops, it was not until 1930 that the infectious agent was determined to be a virus. It is the first pathogen identified as a virus. The virus was crystallised by Wendell Meredith Stanley. It has a similar size to the largest synthetic molecule, known as PG5 with comparable length and diameter.
== History ==
In 1886, Adolf Mayer first described the tobacco mosaic disease that could be transferred between plants, similar to bacterial infections. In 1892, Dmitri Ivanovsky gave the first concrete evidence for the existence of a non-bacterial infectious agent, showing that infected sap remained infectious even after filtering through the finest Chamberland filters. Later, in 1903, Ivanovsky published a paper describing abnormal crystal intracellular inclusions in the host cells of the affected tobacco plants and argued the connection between these inclusions and the infectious agent. However, Ivanovsky remained rather convinced, despite repeated failures to produce evidence, that the causal agent was an unculturable bacterium, too small to be retained on the employed Chamberland filters and to be detected in the light microscope. In 1898, Martinus Beijerinck independently replicated Ivanovsky's filtration experiments and then showed that the infectious agent was able to reproduce and multiply in the host cells of the tobacco plant. Beijerinck adopted the term of "virus" to indicate that the causal agent of tobacco mosaic disease was of non-bacterial nature. Tobacco mosaic virus was the first virus to be crystallized. It exhibits liquid crystal phases above a critical density. It was achieved by Wendell Meredith Stanley in 1935 who also showed that TMV remains active even after crystallization. For his work, he was awarded 1/4 of the Nobel Prize in Chemistry in 1946, even though it was later shown some of his conclusions (in particular, that the crystals were pure protein, and assembled by autocatalysis) were incorrect. The first electron microscopical images of TMV were made in 1939 by Gustav Kausche, Edgar Pfankuch and Helmut Ruska – the brother of Nobel Prize winner Ernst Ruska. In 1955, Heinz Fraenkel-Conrat and Robley Williams showed that purified TMV RNA and its capsid (coat) protein assemble by themselves to functional viruses, indicating that this is the most stable structure (the one with the lowest free energy).
The crystallographer Rosalind Franklin worked for Stanley for about a month at Berkeley, and later designed and built a model of TMV for the 1958 World's Fair at Brussels. In 1958, she speculated that the virus was hollow, not solid, and hypothesized that the RNA of TMV is single-stranded. This conjecture was proven to be correct after her death and is now known to be the + strand. The investigations of tobacco mosaic disease and subsequent discovery of its viral nature were instrumental in the establishment of the general concepts of virology.
== Structure ==
Tobacco mosaic virus has a rod-like appearance. Its capsid is made from 2130 molecules of coat protein and one molecule of genomic single strand RNA, 6400 bases long. The coat protein self-assembles into the rod-like helical structure (16.3 proteins per helix turn) around the RNA, which forms a hairpin loop structure (see the electron micrograph above). The structural organization of the virus gives stability. The protein monomer consists of 158 amino acids which are assembled into four main alpha-helices, which are joined by a prominent loop proximal to the axis of the virion. Virions are ~300 nm in length and ~18 nm in diameter. Negatively stained electron microphotographs show a distinct inner channel of radius ~2 nm. The RNA is located at a radius of ~4 nm and is protected from the action of cellular enzymes by the coat protein. X-ray fiber diffraction structure of the intact virus was studied based on an electron density map at 3.6 Å resolution. Inside the capsid helix, near the core, is the coiled RNA molecule, which is made up of 6,395 ±10 nucleotides. The structure of the virus plays an important role in the recognition of the viral DNA. This happens due to the formation of an obligatory intermediate produced from a protein allows the virus to recognize a specific RNA hairpin structure. The intermediate induces the nucleation of TMV self-assembly by binding with the hairpin structure.
== Genome ==
The TMV genome consists of a 6.3–6.5 kbp single-stranded (ss) RNA. The 3’-terminus has a tRNA-like structure, and the 5’-terminus has a methylated nucleotide cap. (m7G5’pppG). The genome encodes 4 open reading frames (ORFs), two of which produce a single protein due to ribosomal readthrough of a leaky UAG stop codon. The 4 genes encode a replicase (with methyltransferase [MT] and RNA helicase [Hel] domains), an RNA-dependent RNA polymerase, a so-called movement protein (MP) and a capsid protein (CP). The coding sequence starts with the first reading frame, which is 69 nucleotides away from the 5' end of the RNA. The noncoding region at the 5' end can be varied in different individual virions, but there hasn't been any variation found between virions in the noncoding region at the 3' end.
== Physicochemical properties ==
TMV is a thermostable virus. On a dried leaf, it can withstand up to 50 °C (120 degree Fahrenheit) for 30 minutes.
TMV has an index of refraction of about 1.57.
== Disease cycle ==
TMV does not have a distinct overwintering structure. Rather, it will over-winter in infected tobacco stalks and leaves in the soil, on the surface of contaminated seed (TMV can even survive in contaminated tobacco products for many years, so smokers can accidentally transmit it by touch, although not in the smoke itself). With the direct contact with host plants through its vectors (normally insects such as aphids and leafhoppers), TMV will go through the infection process and then the replication process.
=== Infection and transmission ===
After its multiplication, it enters the neighboring cells through plasmodesmata. The infection does not spread through contact with insects, but instead spreads by direct contact to the neighboring cells. For its smooth entry, TMV produces a 30 kDa movement protein called P30 which enlarges the plasmodesmata. TMV most likely moves from cell-to-cell as a complex of the RNA, P30, and replicate proteins.
It can also spread through phloem for longer distance movement within the plant. Moreover, TMV can be transmitted from one plant to another by direct contact. Although TMV does not have defined transmission vectors, the virus can be easily transmitted from the infected hosts to the healthy plants by human handling.
=== Replication ===
Following entry into its host via mechanical inoculation, TMV uncoats itself to release its viral [+]RNA strand. As uncoating occurs, the MetHel:Pol gene is translated to make the capping enzyme MetHel and the RNA Polymerase. Then the viral genome will further replicate to produce multiple mRNAs via a [-]RNA intermediate primed by the tRNAHIS at the [+]RNA 3' end. The resulting mRNAs encode several proteins, including the coat protein and an RNA-dependent RNA polymerase (RdRp), as well as the movement protein. Thus TMV can replicate its own genome.
After the coat protein and RNA genome of TMV have been synthesized, they spontaneously assemble into complete TMV virions in a highly organized process. The protomers come together to form disks or 'lockwashers' composed of two layers of protomers arranged in a helix. The helical capsid grows by the addition of protomers to the end of the rod. As the rod lengthens, the RNA passes through a channel in its center and forms a loop at the growing end. In this way the RNA can easily fit as a spiral into the interior of the helical capsid.
== Host and symptoms ==
Like other plant pathogenic viruses, TMV has a very wide host range and has different effects depending on the host being infected. Tobacco mosaic virus has been known to cause a production loss for flue cured tobacco of up to two percent in North Carolina. It is known to infect members of nine plant families, and at least 125 individual species, including tobacco, tomato, pepper (all members of the Solanaceae), cucumbers, a number of ornamental flowers, and beans including Phaseolus vulgaris and Vigna unguiculata. There are many different strains. The first symptom of this virus disease is a light green coloration between the veins of young leaves. This is followed quickly by the development of a "mosaic" or mottled pattern of light and dark green areas in the leaves. Rugosity may also be seen where the infected plant leaves display small localized random wrinkles. These symptoms develop quickly and are more pronounced on younger leaves. Its infection does not result in plant death, but if infection occurs early in the season, plants are stunted. Lower leaves are subjected to "mosaic burn" especially during periods of hot and dry weather. In these cases, large dead areas develop in the leaves. This constitutes one of the most destructive phases of Tobacco mosaic virus infection. Infected leaves may be crinkled, puckered, or elongated. However, if TMV infects crops like grape and apple, it is almost symptomless. TMV is able to infect and complete its replication cycle in a plant pathogenic fungus, TMV is able to enter and replicate in cells of the fungi species Colletotrichum acutatum, C. clavatum, and C. theobromicola, which may not be an exception, although it has neither been found nor probably searched for in nature.
== Environment ==
TMV is one of the most stable viruses and has a wide survival range. As long as the surrounding temperature remains below approximately 40 degrees Celsius, TMV can sustain its stable form. All it needs is a host to infect. If necessary, greenhouses and botanical gardens would provide the most favorable condition for TMV to spread out, due to the high population density of possible hosts and the constant temperature throughout the year. It also could be useful to culture TMV in vitro in sap because it can survive up to 3000 days.
== Treatment and management ==
One of the common control methods for TMV is sanitation, which includes removing infected plants and washing hands in between each planting. Crop rotation should also be employed to avoid infected soil/seed beds for at least two years. As for any plant disease, looking for resistant strains against TMV may also be advised. Furthermore, the cross protection method can be administered, where the stronger strain of TMV infection is inhibited by infecting the host plant with a mild strain of TMV, similar to the effect of a vaccine.
In the past ten years, the application of genetic engineering on a host plant genome has been developed to allow the host plant to produce the TMV coat protein within their cells. It was hypothesized that the TMV genome will be re-coated rapidly upon entering the host cell, thus it prevents the initiation of TMV replication. Later it was found that the mechanism that protects the host from viral genome insertion is through gene silencing.
TMV is inhibited by a product of the myxomycete slime mold Physarum polycephalum. Both tobacco and the beans P. vulgaris and V. sinensis suffered almost no lesioning in vitro from TMV when treated with a P. polycephalum extract.
Research has shown that Bacillus spp. can be used to reduce the severity of symptoms from TMV in tobacco plants. In the study, treated tobacco plants had more growth and less build-up of TMV virions than tobacco plants that hadn't been treated.
A research has been conducted by H.Fraenkel-Conrat to show the influence of acetic acid on the Tobacco Mosaic Virus. According to the research, 67% acetic acid resulted as degradation of the virus.
Another possible source of prevention for TMV is the use of salicylic acid. A study completed by a research team at the University of Cambridge found that treating plants with salicylic acid reduced the amount of TMV viral RNAs and viral coat protein present in the tobacco plants. Their research showed that salicylic acid most likely was disrupting replication and transcription and more specifically, the RdRp complex.
A research was conducted and revealed that humans have antibodies against Tobacco Mosaic Virus.
== Scientific and environmental impact ==
The large amount of literature about TMV and its choice for many pioneering investigations in structural biology (including X-ray diffraction and X-ray crystallography), virus assembly and disassembly, and so on, are fundamentally due to the large quantities that can be obtained, plus the fact that it does not infect animals. After growing several hundred infected tobacco plants in a greenhouse, followed by a few simple laboratory procedures, a scientist can produce several grams of the virus. In fact, tobacco mosaic virus is so proliferate that the inclusion bodies can be seen with only a light microscope.
James D. Watson, in his memoir The Double Helix, cites his x-ray investigation of TMV's helical structure as an important step in deducing the nature of the DNA molecule.
== Applications ==
Plant viruses can be used to engineer viral vectors, tools commonly used by molecular biologists to deliver genetic material into plant cells; they are also sources of biomaterials and nanotechnology devices. Viral vectors based on TMV include those of the magnICON and TRBO plant expression technologies. Due to its cylindrical shape, high aspect ratio, self-assembling nature, and ability to incorporate metal coatings (nickel and cobalt) into its shell, TMV is an ideal candidate to be incorporated into battery electrodes. Addition of TMV to a battery electrode increases the reactive surface area by an order of magnitude, resulting in an increase in the battery's capacity by up to six times compared to a planar electrode geometry. The TMV-based vector also enabled C. acutatum to transiently express exogenous GFP up to six subcultures and for at least 2 mo after infection, without the need to develop transformation technology, RNAi can be expressed in the phytopathogenic fungus Colletotrichum acutatum by VIGS using a recombinant vector based on TMV in which the ORF of the gene encoding the green fluorescent protein (GFP) was transcribed in fungal cells from a duplicate of the TMV coat protein (CP) subgenomic mRNA promoter and demonstrated that the approach could be used to obtain foreign protein expression in fungi.
== Notes ==
== References ==
== Further reading ==
== External links ==
Description of plant viruses – TMV Archived 2007-09-26 at the Wayback Machine – contains information on symptoms, hosts species, purification etc.
Further information
Electron microscope image of TM | Wikipedia/Tobacco_mosaic_disease |
In biochemistry and cell biology, differential centrifugation (also known as differential velocity centrifugation) is a common procedure used to separate organelles and other sub-cellular particles based on their sedimentation rate. Although often applied in biological analysis, differential centrifugation is a general technique also suitable for crude purification of non-living suspended particles (e.g. nanoparticles, colloidal particles, viruses). In a typical case where differential centrifugation is used to analyze cell-biological phenomena (e.g. organelle distribution), a tissue sample is first lysed to break the cell membranes and release the organelles and cytosol. The lysate is then subjected to repeated centrifugations, where particles that sediment sufficiently quickly at a given centrifugal force for a given time form a compact "pellet" at the bottom of the centrifugation tube.
After each centrifugation, the supernatant (non-pelleted solution) is removed from the tube and re-centrifuged at an increased centrifugal force and/or time. Differential centrifugation is suitable for crude separations on the basis of sedimentation rate, but more fine grained purifications may be done on the basis of density through equilibrium density-gradient centrifugation. Thus, the differential centrifugation method is the successive pelleting of particles from the previous supernatant, using increasingly higher centrifugation forces. Cellular organelles separated by differential centrifugation maintain a relatively high degree of normal functioning, as long as they are not subject to denaturing conditions during isolation.
== Theory ==
In a viscous fluid, the rate of sedimentation of a given suspended particle (as long as the particle is denser than the fluid) is largely a function of the following factors:
Gravitational force
Difference in density
Fluid viscosity
Particle size and shape
Larger particles sediment more quickly and at lower centrifugal forces. If a particle is less dense than the fluid (e.g., fats in water), the particle will not sediment, but rather will float, regardless of strength of the g-force experienced by the particle. Centrifugal force separates components not only on the basis of density, but also of particle size and shape. In contrast, a more specialized equilibrium density-gradient centrifugation produces a separation profile dependent on particle-density alone, and therefore is suitable for more fine-grained separations.
High g-force makes sedimentation of small particles much faster than Brownian diffusion, even for very small (nanoscale) particles. When a centrifuge is used, Stokes' law must be modified to account for the variation in g-force with distance from the center of rotation.
D
=
18
η
ln
(
R
f
/
R
i
)
(
ρ
p
−
ρ
f
)
ω
2
t
{\displaystyle D={\sqrt {\frac {18\eta \,\ln(R_{f}/R_{i})}{(\rho _{p}-\rho _{f})\omega ^{2}t}}}}
where
D is the minimum diameter of the particles expected to sediment (m)
η (or μ) is the fluid dynamic viscosity (Pa.s)
Rf is the final radius of rotation (m)
Ri is the initial radius of rotation (m)
ρp is particle volumetric mass density (kg/m3)
ρf is the fluid volumetric mass density (kg/m3)
ω is the angular velocity (radian/s)
t is the time required to sediment from Ri to Rf (s)
== Procedure ==
Differential centrifugation can be used with intact particles (e.g. biological cells, microparticles, nanoparticles), or used to separate the component parts of a given particle. Using the example of a separation of eukaryotic organelles from intact cells, the cell must first be lysed and homogenized (ideally by a gentle technique, such as Dounce homogenization; harsher techniques or over homogenization will lead to a lower proportion of intact organelles). Once the crude organelle extract is obtained, it may be subjected to a varying centrifugation speeds to separate the organelles:
== Ultracentrifugation ==
The lysed sample is now ready for centrifugation in an ultracentrifuge. An ultracentrifuge consists of a refrigerated, low-pressure chamber containing a rotor which is driven by an electrical motor capable of high speed rotation. Samples are placed in tubes within or attached to the rotor. Rotational speed may reach up to 100,000 rpm for floor model, 150,000 rpm for bench-top model (Beckman Optima Max-XP or Sorvall MTX150 or himac CS150NX), creating centrifugal speed forces of 800,000g to 1,000,000g. This force causes sedimentation of macromolecules, and can even cause non-uniform distributions of small molecules.
Since different fragments of a cell have different sizes and densities, each fragment will settle into a pellet with different minimum centrifugal forces. Thus, separation of the sample into different layers can be done by first centrifuging the original lysate under weak forces, removing the pellet, then exposing the subsequent supernatants to sequentially greater centrifugal fields. Each time a portion of different density is sedimented to the bottom of the container and extracted, and repeated application produces a rank of layers which includes different parts of the original sample. Additional steps can be taken to further refine each of the obtained pellets.
Sedimentation depends on mass, shape, and partial specific volume of a macromolecule, as well as solvent density, rotor size and rate of rotation. The sedimentation velocity can be monitored during the experiment to calculate molecular weight.
Values of sedimentation coefficient (S) can be calculated. Large values of S (faster sedimentation rate) correspond to larger molecular weight. Dense particle sediments more rapidly. Elongated proteins have larger frictional coefficients, and sediment more slowly to ensure accuracy.
== Differences between differential and density gradient centrifugation ==
The difference between differential and density gradient centrifugation techniques is that the latter method uses solutions of different densities (e.g. sucrose, Ficoll, Percoll) or gels through which the sample passes. This separates the sample into layers by relative density, based on the principle that molecules settle down under a centrifugal force until they reach a medium with the density the same as theirs. The degree of separation or number of layers depends on the solution or gel. Differential centrifugation, on the other hand, does not utilize a density gradient, and the centrifugation is taken in increasing speeds. The different centrifugation speeds often create separation into not more than two fractions, so the supernatant can be separated further in additional centrifugation steps. For that, each step the centrifugation speed has to be increased until the desired particles are separated. In contrast, the density gradient centrifugation is usually performed with just one centrifugation speed.
== See also ==
Buoyant density ultracentrifugation
Jerome Vinograd
Svedberg
== References == | Wikipedia/Differential_centrifugation |
Swine vesicular disease (SVD) is an acute, contagious viral disease of swine caused by swine vesicular disease virus, an Enterovirus. It is characterized by fever and vesicles with subsequent ulcers in the mouth and on the snout, feet, and teats. The pathogen is relatively resistant to heat, and can persist for a long time in salted, dried, and smoked meat products. Swine vesicular disease does not cause economically important disease, but is important due to its similarity to foot-and-mouth disease.
== Transmission ==
Swine vesicular disease is most commonly brought into a herd by the introduction of a subclinically infected pig.
The disease can be transmitted in feed containing infected meat scraps, or by direct contact with infected feces (such as in an improperly cleaned truck).
== Clinical signs ==
After an incubation period up to 7 days, the signs associated with swine vesicular disease occur. The first sign is a transient mild fever. Other signs include:
Vesicles in the mouth and on the snout and feet
Lameness and an unsteady gait, shivering, and jerking–type leg movements
Ruptured vesicles can cause ulcers on limbs and feet, and foot pads may be loosened.
Young animals are more severely affected. Recovery often occurs within a week. Mortality is negligible.
Swine vesicular disease has the same clinical signs as foot-and-mouth disease, and can only be diagnosed by laboratory testing.
== Prevention and control ==
No vaccine exists for SVD. Prevention measures are similar to those for foot-and-mouth disease: controlling animals imported from infected areas, sanitary disposal of garbage from international aircraft and ships, and thorough cooking of garbage. Infected animals should be placed in strict quarantine. Eradication measures for the disease include quarantining infected areas, depopulation and disposal of infected and contact pigs, and cleaning and disinfecting contaminated premises.
== History ==
Swine vesicular disease was first identified in Italy in 1966. In 1971, an outbreak occurred in Hong Kong, and the disease was subsequently found other countries in Europe and Asia.
== References == | Wikipedia/Swine_vesicular_disease |
Blain was an animal disease of unknown etiology that was well known in the 18th and 19th centuries. It is unclear whether it is still extant, or what modern disease it corresponds to.
According to Ephraim Chambers' 18th-century Cyclopaedia, or an Universal Dictionary of Arts and Sciences, blain was "a distemper" (in the archaic eighteenth-century sense of the word, meaning "disease") occurring in animals, consisting of a "Bladder growing on the Root of the Tongue against the Wind-Pipe", which "at length swelling, stops the Wind". It was thought to occur "by great chafing, and heating of the Stomach".
Blain is also mentioned in Cattle: Their Breeds, Management, and Diseases, published in 1836, where it is also identified as "gloss-anthrax". W. C. Spooner's 1888 book The History, Structure, Economy and Diseases of the Sheep also identifies blain as being the same as gloss-anthrax.
A description of blain is provided in the Horticulture column of the Monday Morning edition of the Belfast News-Letter, September 13, 1852. Headline: The Prevailing Epidemic Disease in Horned Cattle - The Mouth and Food Disease. "There are two diseases of the mouth - one of a very serious character, which is called blain (gloss anthrax) or inflammation of the tongue. This is a very virulent disease, and sometimes of a very rapid action, and which should be at once attended to, and not trifled with; but though it always exhibits itself in inflammation of the membranes of the mouth, beneath or above the tongue, and the sides of the tongue itself, it soon extends through the whole system, and, according to the best veterinarians, involves inflammation and gangrene of the oesophagus and intestines. The symptoms are many, the eyes are inflamed, and constantly weeping; swellings appear round the eyes and some other parts of the body; the pulse quick, heaving of the flanks, and the bowels sometimes constipated. Such are the general symptoms of this formidable disease, more or less aggravated by neglect of inattention in mitigation." It continues to describe treatment including deep lancing of blisters, blood letting, Epsom salt doses, chloride of lime rinses, tincture of diluted myrrh, fever treatments supplied in the animals feed, etc.
Modern scholarship suggests that "gloss-anthrax" was not the same disease as modern-day anthrax, but instead could have been foot-and-mouth disease, or a viral infection with a secondary Fusobacterium necrophorum infection. It has also been suggested that it may have been due to an extinct variant strain of true anthrax. Other sources also report epizootics known as "blain" or "black-blain" in the 13th and 14th centuries, but it is not clear if the disease involved was the same as "gloss-anthrax".
== References ==
This article incorporates text from a publication now in the public domain: Chambers, Ephraim, ed. (1728). "Blain". Cyclopædia, or an Universal Dictionary of Arts and Sciences (1st ed.). James and John Knapton, et al. p. 106. | Wikipedia/Blain_(animal_disease) |
Foot-and-mouth disease (FMD) or hoof-and-mouth disease (HMD) is an infectious and sometimes fatal viral disease that primarily affects even-toed ungulates, including domestic and wild bovids. The virus causes a high fever lasting two to six days, followed by blisters inside the mouth and near the hoof that may rupture and cause lameness.
FMD has very severe implications for animal farming, since it is highly infectious and can be spread by infected animals comparatively easily through contact with contaminated farming equipment, vehicles, clothing, and feed, and by domestic and wild predators. Its containment demands considerable efforts in vaccination, strict monitoring, trade restrictions, quarantines, and the culling of both infected and healthy (uninfected) animals.
Susceptible animals include cattle, water buffalo, sheep, goats, pigs, antelope, deer, and bison. It has also been known to infect hedgehogs and elephants; llamas and alpacas may develop mild symptoms, but are resistant to the disease and do not pass it on to others of the same species. In laboratory experiments, mice, rats, and chickens have been artificially infected, but they are not believed to contract the disease under natural conditions. Cattle, Asian and African buffalo, sheep, and goats can become carriers following an acute infection, meaning they are still infected with a small amount of virus but appear healthy. Animals can be carriers for up to 1–2 years and are considered very unlikely to infect other animals, although laboratory evidence suggests that transmission from carriers is possible.
Humans are only extremely rarely infected by foot-and-mouth disease virus (FMDV). Humans, particularly young children, can be affected by hand, foot, and mouth disease (HFMD), which is often confused with FMD. HFMDV also affects cattle, sheep, and swine. HFMD is also a viral infection caused by multiple viruses belonging to the Picornaviridae family, but it is distinct from FMD.
The virus responsible for FMD is an aphthovirus, foot-and-mouth disease virus. Infection occurs when the virus particle is taken into a cell of the host. The cell is then forced to manufacture thousands of copies of the virus, and eventually bursts, releasing the new particles in the blood. The virus is genetically highly variable, which limits the effectiveness of vaccination. The disease was first documented in 1870.
== Signs and symptoms ==
The incubation period for FMD virus has a range between one and 12 days. The disease is characterized by high fever that declines rapidly after two to three days, blisters inside the mouth that lead to excessive secretion of stringy or foamy saliva and to drooling, and blisters on the feet that may rupture and cause lameness. Adult animals may suffer weight loss from which they do not recover for several months, as well as swelling in the testicles of mature males, and cows' milk production can decline significantly. Though most animals eventually recover from FMD, the disease can lead to myocarditis (inflammation of the heart muscle) and death, especially in newborn animals. Some infected ruminants remain asymptomatic carriers, but they nonetheless carry the virus and may be able to transmit it to others. Pigs cannot serve as asymptomatic carriers.
=== Subclinical infection ===
Subclinical (asymptomatic) infections can be classified as neoteric or persistent based on when they occur and whether the animal is infectious. Neoteric subclinical infections are acute infections, meaning they occur soon after an animal is exposed to the FMD virus (about 1 to 2 days) and last about 8 to 14 days. Acute infections are characterized by a high degree of replicating virus in the pharynx. In a neoteric subclinical infection, the virus remains in the pharynx and does not spread into the blood as it would in a clinical infection. Although animals with neoteric subclinical infections do not appear to have disease, they shed substantial amounts of virus in nasal secretions and saliva, so they are able to transmit the FMD virus to other animals. Neoteric subclinical infections often occur in vaccinated animals but can occur in unvaccinated animals as well.
Persistent subclinical infection (also referred to as a carrier state) occurs when an animal recovers from an acute infection but continues to have a small amount of replicating virus present in the pharynx. Cattle, buffalo, sheep, and goats can all become carriers, but pigs cannot. Animals can become carriers following acute infections with or without symptoms. Both vaccinated and unvaccinated animals can become carriers. Transmission of the FMD virus from carriers to susceptible animals is considered very unlikely under natural conditions and has not been conclusively demonstrated in field studies.
However, in an experiment where virus was collected from the pharynx of carrier cattle and inserted in the pharynx of susceptible cattle, the susceptible cattle became infected and developed characteristic blisters in the mouth and on the feet. This supports the theory that while the likelihood of a carrier spreading FMD is quite low, it is not impossible. It is not fully understood why ruminants but not pigs can become carriers or why some animals develop persistent infection while others do not. Both are areas of ongoing study.
Because vaccinated animals can become carriers, the waiting period to prove FMD-freedom is longer when vaccination rather than slaughter is used as an outbreak-control strategy. As a result, many FMD-free countries are resistant to emergency vaccination in case of in outbreak out of concern for the serious trade and economic implications of a prolonged period without FMD-free status.
Although the risk of transmission from an individual FMD carrier is considered to be very low, there are many carriers in FMD-endemic regions, possibly increasing the number of chances for carrier transmission to occur. Also, it can be difficult to determine if an asymptomatic infection is neoteric or persistent in the field, as both would be apparently healthy animals that test positive for the FMD virus. This fact complicates disease control, as the two types of subclinical infections have significantly different risks of spreading disease.
== Cause ==
Of the seven serotypes of this virus, A, C, O, Asia 1, and SAT3 appear to be distinct lineages; SAT 1 and SAT 2 are unresolved clades. The mutation rate of the protein-encoding sequences of strains isolated between 1932 and 2007 has been estimated to be 1.46 × 10−3 substitutions/site/year, a rate similar to that of other RNA viruses. The most recent common ancestor appears to have evolved about 481 years ago (early 16th century). This ancestor then diverged into two clades which have given rise to the extant circulating Euro-Asiatic and South African. SAT 1 diverged first 397 years ago, followed by sequential divergence of serotype SAT 2 (396 years ago), A (147 years ago), O (121 years ago), Asia 1 (89 years ago), C (86 years ago), and SAT 3 (83 years ago). Bayesian skyline plot reveals a population expansion in the early 20th century that is followed by a rapid decline in population size from the late 20th century to the present day. Within each serotype, there was no apparent periodic, geographic, or host species influence on the evolution of global FMD viruses. At least seven genotypes of serotype Asia 1 are known.
=== Transmission ===
The FMD virus can be transmitted in a number of ways, including close-contact, animal-to-animal spread, long-distance aerosol spread and fomites, or inanimate objects, typically fodder and motor vehicles. The clothes and skin of animal handlers such as farmers, standing water, and uncooked food scraps and feed supplements containing infected animal products can harbor the virus, as well. Cows can also catch FMD from the semen of infected bulls. Control measures include quarantine and destruction of both infected and healthy (uninfected) livestock, and export bans for meat and other animal products to countries not infected with the disease.
There is significant variation in both susceptibility to infection and ability to spread disease between different species, virus strains, and transmission routes. For example, cattle are far more vulnerable than pigs to infection with aerosolized virus, and infected pigs produce 30 times the amount of aerosolized virus compared to infected cattle and sheep. Also, pigs are particularly vulnerable to infection through the oral route. It has been demonstrated experimentally that FMD can be spread to pigs when they eat commercial feed products contaminated by the FMD virus. Also, the virus can remain active for extended periods of time in certain feed ingredients, especially soybean meal. Feed biosecurity practices have become an important area of study since a 2013 outbreak of Porcine Epidemic Diarrhea Virus (PEDV) in the US, thought to be introduced through contaminated feed.
Just as humans may spread the disease by carrying the virus on their clothes and bodies, animals that are not susceptible to the disease may still aid in spreading it. This was the case in Canada in 1952, when an outbreak flared up again after dogs had carried off bones from dead animals. Wolves are thought to play a similar role in the former Soviet Union.
Daniel Rossouw Kannemeyer (1843–1925) published a note in the Transactions of the South African Philosophical Society volume 8 part 1 in which he links saliva-covered locusts with the spread of the disease.
Transmission of the FMD virus is possible before an animal has apparent signs of disease, a factor that increases the risk that significant spread of the virus has occurred before an outbreak is detected. A 2011 experiment measured transmission timing in cattle infected with serotype O virus by exposing susceptible cattle in 24-hour increments. It estimated the infectious period of the infected cattle to be 1.7 days, but showed the cattle were only infectious for a few hours before they developed fevers or classic FMD lesions. The authors also showed that the infectious period would have been estimated to be much higher (4.2 to 8.2 days) if detection of virus had been used as a substitute for infectiousness. A similar 2016 experiment using serotype A virus exposed susceptible pigs to infected pigs for 8 hour periods and found that pigs were able to spread disease for a full day before developing signs of disease. Analysis of this experimental data estimated the infectious period to be approximately 7 days. Again, the study showed that detection of virus was not an accurate substitution for infectiousness. An accurate understanding of the parameters of infectiousness is an important component of building epidemiological models which inform disease control strategies and policies.
=== Infecting humans ===
Humans can be infected with FMD through contact with infected animals, but this is extremely rare. Some cases were caused by laboratory accidents. Because the virus that causes FMD is sensitive to stomach acid, it cannot spread to humans via consumption of infected meat, except in the mouth before the meat is swallowed. In the UK, the last confirmed human case occurred in 1966, and only a few other cases have been recorded in countries of continental Europe, Africa, and South America. Symptoms of FMD in humans include malaise, fever, vomiting, red ulcerative lesions (surface-eroding damaged spots) of the oral tissues, and sometimes vesicular lesions (small blisters) of the skin. According to a newspaper report, FMD killed two children in England in 1884, supposedly due to infected milk.
Another viral disease with similar symptoms, hand, foot and mouth disease, occurs more frequently in humans, especially in young children; certain other non-polio enteroviruses than the FMD virus are its cause. These viruses belong to the Enterovirus genus within the Picornaviridae.
Because FMD rarely infects humans, but spreads rapidly among animals, it is a much greater threat to the agriculture industry than to human health. It has been argued that FMD is a zoonotic disease, but it is not considered among them by the U.S. Centers for Disease Control and Prevention and the U.S. Department of Agriculture due to the rarity of interspecies transmission.
== Prevention ==
Like other RNA viruses, the FMD virus continually evolves and mutates, thus one of the difficulties in vaccinating against it is the huge variation between, and even within, serotypes. No cross-protection has been seen between serotypes (a vaccine for one serotype will not protect against any others) and in addition, two strains within a given serotype may have nucleotide sequences that differ by as much as 30% for a given gene. This means FMD vaccines must be highly specific to the strain involved. Vaccination only provides temporary immunity that lasts from months to years.
Currently, the World Organisation for Animal Health recognizes countries to be in one of three disease states with regard to FMD: FMD present with or without vaccination, FMD-free with vaccination, and FMD-free without vaccination. Countries designated FMD-free without vaccination have the greatest access to export markets, so many developed nations, including Canada, the United States, and the UK, work hard to maintain their current status. Some countries such as Brazil and Argentina, which have large beef-exporting industries, practise vaccination in some areas, but have other vaccination-free zones.
Reasons cited for restricting export from countries using FMD vaccines include, probably most importantly, routine blood tests relying on antibodies cannot distinguish between an infected and a vaccinated animal, which severely hampers screening of animals used in export products, risking a spread of FMD to importing countries. A widespread preventive vaccination would also conceal the existence of the virus in a country. From there, it could potentially spread to countries without vaccine programs. Lastly, an animal infected shortly after being vaccinated can harbor and spread FMD without showing symptoms itself, hindering containment and culling of sick animals as a remedy.
Many early vaccines used dead samples of the FMD virus to inoculate animals, but those early vaccines sometimes caused real outbreaks. In the 1970s, scientists discovered that a vaccine could be made using only a single key protein from the virus. The task was to produce enough quantities of the protein to be used in the vaccination. On June 18, 1981, the US government announced the creation of a vaccine targeted against FMD, the world's first genetically engineered vaccine.
The North American FMD Vaccine Bank is housed at the United States Department of Agriculture's Foreign Animal Disease Diagnostic Laboratory at Plum Island Animal Disease Center. The center, located 1.5 mi (2.4 km) off the coast of Long Island, New York, is the only place in the United States where scientists can conduct research and diagnostic work on highly contagious animal diseases such as FMD. Because of this limitation, US companies working on FMD usually use facilities in other countries where such diseases are endemic.
== Epidemiology ==
=== United States (1870–1929) ===
The US has had nine FMD outbreaks since it was first recognized on the northeastern coast in 1870; the most devastating happened in 1914. It originated from Michigan, but its entry into the stockyards in Chicago turned it into an epizootic. About 3,500 livestock herds were infected across the US, totaling over 170,000 cattle, sheep, and swine. The eradication came at a cost of US$4.5 million (equivalent to $141 million in 2024).
A 1924 outbreak in California resulted not only in the slaughter of 109,000 farm animals, but also 22,000 deer.
The US had its latest FMD outbreak in Montebello, California, in 1929. This outbreak originated in hogs that had eaten infected meat scraps from a tourist steamship that had stocked meat in Argentina. Over 3,600 animals were slaughtered and the disease was contained in less than a month.
=== Mexico–U.S. border (1947) ===
On December 26, 1946, the United States and Mexico jointly declared that FMD had been found in Mexico. Initially, proposals from Texans were for an animal-proof wall, to prevent animals from crossing the border and spreading the disease, but the two countries eventually managed to cooperate in a bilateral effort and eradicated the disease without building a wall. To prevent tension between ranchers and the veterinarians, public broadcasts over the radio and with speakers on trucks were used to inform Mexican ranchers why the U.S. veterinarians were working on their livestock. Ranchers who lost cattle due to being culled by the vets would receive financial compensation. However, the tension remained and resulted in clashes between local citizens and the military-protected U.S. veterinarians. These teams of veterinarians worked from outside the infection zone of the disease and worked their way to the heart of the epidemic. Over 60,000,000 injections were administered to livestock by the end of 1950.
=== United Kingdom (1967) ===
In October 1967, a farmer in Shropshire reported a lame sow, which was later diagnosed with FMD. The source was believed to be remains of legally imported infected lamb from Argentina and Chile. The virus spread, and in total, 442,000 animals were slaughtered and the outbreak had an estimated cost of £370 million (equivalent to £8 billion in 2023).
=== Taiwan (1997) ===
Taiwan had previous epidemics of FMD in 1913–14 and 1924–29, but had since been spared, and considered itself free of FMD as late as in the 1990s. On the 19th of March 1997, a sow at a farm in Hsinchu, Taiwan, was diagnosed with a strain of FMD that only infects swine. Mortality was high, nearing 100% in the infected herd. The cause of the epidemic was not determined, but the farm was near a port city known for its pig-smuggling industry and illegal slaughterhouses. Smuggled swine or contaminated meat are thus likely sources of the disease.
The disease spread rapidly among swine herds in Taiwan, with 200–300 new farms being infected daily. Causes for this include the high swine density in the area, with up to 6,500 hogs per square mile, feeding of pigs with untreated garbage, and the farms' proximity to slaughterhouses. Other systemic issues, such as lack of laboratory facilities, slow response, and initial lack of a vaccination program, contributed.
A complicating factor is the endemic spread of swine vesicular disease (SVD) in Taiwan. The symptoms are indistinguishable from FMD, which may have led to previous misdiagnosing of FMD as SVD. Laboratory analysis was seldom used for diagnosis, and FMD may thus have gone unnoticed for some time.
The swine depopulation was a massive undertaking, with the military contributing substantial manpower. At peak capacity, 200,000 hogs per day were disposed of, mainly by electrocution. Carcasses were disposed of by burning and burial, but burning was avoided in water resource-protection areas. In April, industrial incinerators were running around the clock to dispose of the carcasses.
Initially, 40,000 combined vaccine doses for the strains O-1, A-24, and Asia-1 were available and administered to zoo animals and valuable breeding hogs. At the end of March, half a million new doses for O-1 and Asia-1 were made available. On the May 3rd, 13 million doses of O-1 vaccine arrived, and both the March and May shipments were distributed free of charge. With a danger of vaccination crews spreading the disease, only trained farmers were allowed to administer the vaccine under veterinary supervision.
Taiwan had previously been the major exporter of pork to Japan, and among the top 15 pork producers in the world in 1996. During the outbreak, over 3.8 million swine were destroyed at a cost of US$6.9 billion (equivalent to $13.5 billion in 2024). The Taiwanese pig industry was devastated as a result, and the export market was in ruins.
In 2007, Taiwan was considered free of FMD, but was still conducting a vaccination program, which restricts the export of meat from Taiwan.
=== United Kingdom (2001) ===
The epidemic of FMD in the United Kingdom in the spring and summer of 2001 was caused by the "Type O pan Asia" strain of the disease. This episode resulted in more than 2,000 cases of the disease in farms throughout the British countryside. More than six million sheep and cattle were killed in an eventually successful attempt to halt the disease. The county of Cumbria was the most seriously affected area of the country, with 843 cases. By the time the disease was halted in October 2001, the crisis was estimated to have cost Britain £8 billion (equivalent to £17 billion in 2023) to the agricultural and support industries, and to the outdoor industry. What made this outbreak so serious was the amount of time between infection being present at the first outbreak locus, and when countermeasures were put into operation against the disease, such as transport bans and detergent washing of both vehicles and personnel entering livestock areas. The epidemic was probably caused by pigs that had been fed infected rubbish that had not been properly heat-sterilized. Further, the rubbish is believed to have contained remains of infected meat that had been illegally imported to Britain.
=== China (2005) ===
In April 2005, an Asia-1 strain of FMD appeared in the eastern provinces of Shandong and Jiangsu. During April and May, it spread to suburban Beijing, the northern province of Hebei, and the Xinjiang autonomous region in northwest China. On 13 May, China reported the FMD outbreak to the World Health Organization and the OIE. This was the first time China has publicly admitted to having FMD. China is still reporting FMD outbreaks. In 2007, reports filed with the OIE documented new or ongoing outbreaks in the provinces of Gansu, Qinghai and Xinjiang. This included reports of domestic yak showing signs of infection. FMD is endemic in pastoral regions of China from Heilongjiang Province in the northeast to Sichuan Province and the Tibetan Autonomous region in the southwest. Chinese domestic media reports often use a euphemism "Disease Number Five" (五号病 wǔhàobìng) rather than FMD in reports because of the sensitivity of the FMD issue. In March 2010, Southern Rural News (Nanfang Nongcunbao), in an article "Breaking the Hoof and Mouth Disease Taboo", noted that FMD has long been covered up in China by referring to it that way. FMD is also called canker (口疮, literally "mouth ulcers" kǒuchuāng) or hoof jaundice (蹄癀 tíhuáng) in China, so information on FMD in China can be found online using those words as search terms. One can find online many provincial orders and regulations on FMD control antedating China's acknowledgment that the disease existed in China, for example Guangxi Zhuang Autonomous Region 1991 regulation on preventing the spread of Disease No.5.
=== United Kingdom (2007) ===
An infection of FMD in the United Kingdom was confirmed by the Department for Environment, Food and Rural Affairs, on 3 August 2007, on farmland located in Normandy, Surrey. All livestock in the vicinity were culled on 4 August. A nationwide ban on the movement of cattle and pigs was imposed, with a 3-km (1.9-mi) protection zone placed around the outbreak sites and the nearby virus research and vaccine production establishments, together with a 10-km (6.2-mi) increased surveillance zone.
On 4 August, the strain of the virus was identified as a "01 BFS67-like" virus, one linked to vaccines and not normally found in animals, and isolated in the 1967 outbreak. The same strain was used at the nearby Institute for Animal Health and Merial Animal Health Ltd at Pirbright, 2.5 miles (4.0 km) away, which is an American/French-owned BSL-4 vaccine manufacturing facility, and was identified as the likely source of infection.
On 12 September, a new outbreak of the disease was confirmed in Egham, Surrey, 19 km (12 mi) from the original outbreak, with a second case being confirmed on a nearby farm on 14 September.
These outbreaks caused a cull of all at-risk animals in the area surrounding Egham, including two farms near the famous four-star hotel Great Fosters. These outbreaks also caused the closure of Windsor Great Park due to the park containing deer; the park remained closed for three months. On 19 September 2007, a suspected case of FMD was found in Solihull, where a temporary control zone was set up by Defra.
=== Japan and Korea (2010–2011) ===
In April 2010, a report of three incursions of FMD in Japan and South Korea led the United Nations Food and Agriculture Organization (FAO) to issue a call for increased global surveillance. Japan veterinary authorities confirmed an outbreak of type O FMD virus, currently more common in Asian countries where FMD is endemic.
South Korea was hit by the rarer type A FMD in January, and then the type O infection in April. The most serious case of foot-and-mouth outbreak in South Korea's history started in November 2010 in pig farms in Andong city of Gyeongsangbuk-do, and has since spread in the country rapidly. More than 100 cases of the disease have been confirmed in the country so far, and in January 2011, South Korean officials started a mass cull of approximately 12%, or around three million in total, of the entire domestic pig population, and 107,000 of three million cattle of the country to halt the outbreak.
According to the report based on complete 1D gene sequences, Korean serotype A virus was linked with those from Laos. Korean serotype O viruses were divided into three clades and were closely related to isolates from Japan, Thailand, the UK, France, Ireland, South Africa, and Singapore, as well as Laos.
On 10 February 2011, North Korea reported an outbreak affecting pigs in the region around Pyongyang, by then ongoing since at least December 2010. Efforts to control the outbreak were hampered by illicit sales of infected meat.
=== Indonesia (2022) ===
After being eradicated there in 1986, FMD was again detected in Indonesia in May 2022. The Australian government has offered its assistance but remains unconcerned, considering the risk to the country's biosecurity to be low. The Department of Agriculture (DAWE) is the responsible body and has been monitoring the situation. DAWE has determined there is only a low risk and has stockpiled vaccines since 2004 anyhow.
In response to the Indonesian outbreak, Australian authorities began checking parcels and baggage from Indonesia and China. Disinfectant floormats were also installed at Australian airports to clean footwear. The Albanese Government rejected calls by opposition parties to close the border to travel from Indonesia. In addition, New Zealand authorities have banned travellers from Indonesia from bringing meat products, have screened baggage from Indonesia, and installed floor mats. New Zealand Prime Minister Jacinda Ardern and Biosecurity Minister Damien O'Connor have expressed concern about the impact of foot and mouth disease on New Zealand's substantial cattle, sheep and pig populations as well as wildlife.
=== Germany (2025) ===
In January 2025, an outbreak of foot-and-mouth disease was reported in a herd of water buffalo near Berlin. A 3 kilometre exclusion zone and a 10 kilometre monitoring zone were imposed, and after four days no further cases had been detected within 1 kilometre of the original case.
=== Hungary and Slovakia (2025) ===
On March 8th, 2025, a confirmed case of foot-and-mouth disease was reported at a cattle farm in Kisbajcs, located in the northwestern corner of Hungary, the first such case in 50 years. Immediate counter-measures were made to mitigate the spread of the disease, including the liquidation of all 1400 animals in the affected herd and the burial of their carcasses. The government of the United Kingdom subsequently banned all imports of cattle, sheep, pigs and deer, as well as banning travellers from bringing meat and dairy products with them, from both Hungary and neighbouring Slovakia due to the farm's proximity to the country's border. As of March 10th, 2025, the eradication of the disease was still in progress. On March 21st, 2025, the foot-and-mouth disease was confirmed to cross the Hungarian-Slovak border with three cattle farms in villages Medveďov, Ňárad and Baka in Dunajská Streda district having the cases of the disease. The Fourth Slovak farm with infected cattle confirmed was in village Lúč na Ostrove on March 25, with another source of the disease confirmed in Hungarian village Levél on March 26. A Fifth infected farm in Slovakia was confirmed on March 30 in Plavecký Štvrtok. Both countries started with strict border controls, including stopping of traffic on several border crossings. All Slovak zoological gardens were closed temporarily.
== History ==
The cause of FMD was first shown to be viral in 1897 by Friedrich Loeffler. He passed the blood of an infected animal through a Chamberland filter and found the collected fluid could still cause the disease in healthy animals.
FMD occurs throughout much of the world, and while some countries have been free of FMD for some time, its wide host range and rapid spread represent cause for international concern. After World War II, the disease was widely distributed throughout the world. In 1996, endemic areas included Asia, Africa, and parts of South America; as of August 2007, Chile is disease-free, and Uruguay and Argentina have not had an outbreak since 2001. In May 2014, the FAO informed that Bolivia, Colombia, Ecuador and Peru were "just one step away" from eradication; North America and Australia have been free of FMD for many years. New Zealand has never had a case of foot-and-mouth disease. Most European countries have been recognized as disease-free, and countries belonging to the European Union have stopped FMD vaccination.
However, in 2001, a serious outbreak of FMD in Britain resulted in the slaughter of many animals, the postponing of the general election for a month, and the cancellation of many sporting events and leisure activities, such as the Isle of Man TT. Due to strict government policies on sale of livestock, disinfection of all persons leaving and entering farms, and the cancellation of large events likely to be attended by farmers, a potentially economically disastrous epizootic was avoided in Ireland, with just one case recorded in Proleek, County Louth. As one result, the Animal Health Act 2002 was designed by Parliament to provide the regulators with more powers to deal with FMD.
In August 2007, FMD was found at two farms in Surrey, England. All livestock were culled and a quarantine erected over the area. Two other suspected outbreaks have occurred since, although these seem now not to be related to FMD. The only reported case in 2010 was a false alarm from GIS Alex Baker, as proven false by the Florida Farm and Agricultural Department, and quarantine/slaughter of cattle and pigs was confirmed from Miyazaki Prefecture in Japan in June after three cows tested positive. Some 270,000 cattle have been ordered slaughtered following the disease's outbreak.
In 2022, the disease was once again seen in cattle in Indonesia. Other countries are worried that it might spread to their countries soon.
== Ethical considerations ==
Great Britain's response to the 2001 outbreak of foot and mouth disease was a controversial policy of culling all animals within 3 km of an infected farm within 48 hours, leading to the slaughter of over 4 million animals. This was stated to be "a response to a desperate situation, not a pre-meditated response to a known, assessed risk". FMD is usually nonfatal to adult animals. Pigs are capable of airborne transmission of the virus in one extreme case 250 km across the English Channel, although not usually more than 10 km. There are no known cases of cattle or sheep spreading the virus beyond 3 km. The 2007 outbreak was caught much earlier, and was able to be contained after culling only 1,578 animals.
For the farmer, culling animals often results in financial devastation with no ability to honor existing contractual arrangements, thus facing the prospective loss of farm, equipment, and future earning potential. Farmers, especially in more traditional systems, may also have emotional attachments to some of the animals. On the ethical side, one must also consider that FMD is a painful disease for the affected animals. The vesicles and blisters are painful in themselves, and restrict both eating and movement. Through ruptured blisters, the animal is also at risk from secondary bacterial infections. Production loss and vaccination in areas where the disease is endemic costs and estimated US$6.5 billion to 21 billion yearly, and controlling outbreaks in countries normally free of it costs and additional >US$1.5 billion per year. This cost is disproportionately borne by some of the poorest countries in the world. Controlling the virus with vaccines is difficult because there are multiple serotypes of the virus which require distinct vaccines. When an outbreak occurs, the virus must be analyzed before the correct vaccine can be identified. Research is ongoing to improve vaccination technology.
== See also ==
Animal virology
Hand, foot and mouth disease (HFMD)
Swine vesicular disease (SVD)
Blain, an archaic disease of uncertain etiology
== References ==
== External links ==
FMD Myocarditis in Pigs
Stenfeldt, C.; Pacheco, J. M.; Smoliga, G. R.; Bishop, E.; Pauszek, S. J.; Hartwig, E. J.; Rodriguez, L. L.; Arzt, J. (2014). "Detection of Foot-and-mouth Disease Virus RNA and Capsid Protein in Lymphoid Tissues of Convalescent Pigs Does Not Indicate Existence of a Carrier State". Transboundary and Emerging Diseases. 63 (2): 152–164. doi:10.1111/tbed.12235. PMID 24943477.
Foot-and-Mouth Disease Archived 2013-05-20 at the Wayback Machine 12-part comprehensive overview from the Center for Infectious Disease Research and Policy
FMD portal
2007 Outbreak Foot and Mouth Disease Timeline
Armstrong R, Davie J, Hedger RS (1967). "Foot-and-mouth disease in man". Br Med J. 4 (5578): 529–30. doi:10.1136/bmj.4.5578.529. PMC 1749100. PMID 4294412.
Current status of Foot and Mouth Disease worldwide at OIE. WAHID Interface—OIE World Animal Health Information Database
Disease card Archived 2014-10-10 at the Wayback Machine
The European Commission for the Control of Foot-and-Mouth Disease (EuFMD)
Species Profile – Foot and Mouth Disease, National Invasive Species Information Center, United States National Agricultural Library. | Wikipedia/Foot-and-mouth_vaccine |
A blocking antibody is an antibody that does not have a reaction when combined with an antigen, but prevents other antibodies from combining with that antigen. This function of blocking antibodies has had a variety of clinical and experimental uses.
The term can also be used for inhibiting antibody, prozone phenomenon and, agglutination reaction.
Blocking antibodies have been described as a mechanism for HSV-1 to evade the immune system.
== Uses ==
Blocking antibodies can be used in a variety of medical and scientific manners, thus far been to treat cancer, Graves' disease, and prevent the growth of malaria in mosquitoes.
=== Cancer treatment ===
Blocking antibodies have been used in clinical trials of cancer treatments. The blocking antibody ipilimumab has been effectively used in the clinical treatment of melanoma, RCC, and NSCLC with some degree of success. This is accomplished through the blocking of the coinhibitory molecule CTLA-4. The blocking antibody does not directly target tumor cells, but rather blocks the regulatory functions of CTLA-4, resulting in enhanced T-cell function.
Some new treatments hypothesize the blocking of PD-1, a programmed cell-death protein, which will result in longer-lived T-cells. The blocking antibody BMS-936559 has been shown to bind to PD-L1 and prevent its binding to PD-1.
These new treatments are not without side-effects and immune-related adverse events have been observed in a variety of patients. The tolerance that immune cells normally have to host tissues can be lost, resulting in permanent damage to host cells.
=== Graves' disease ===
Studies have shown that blocking antibodies can bind to and prevent thyrotropin binding, resulting in reduced cAMP levels in human thyroid cells. This interaction has been used primarily as a method of indicating that Graves' disease immunoglobulins are pluritopic, meaning that they have multiple effects, rather than indicating a possible treatment for this disease.
=== Malaria ===
Blocking antibodies have a variety of functions on the merozoite form of parasitic malaria. While in the merozoite form, malaria parasites invade erythrocytes and reproduce in them. Some blocking antibodies may inhibit the invasion of erythrocytes, while other blocking antibodies prevent the binding of inhibitory antibodies, allowing merozoite invasion of erythrocytes despite the presence of inhibitory antibodies. The monoclonal antibodies that prevent the invasion of merozoites bind to the parasitic antigen MSP-1 (merozoite surface protein 1). The binding of blocking antibodies to MSP-1 is shown to result in the inhibition of secondary processing, resulting in the inability for merozoites to invade host erythrocytes. Secondary processing involves a single proteolytic cleavage on the merozoite surface of the carboxy-terminal component of MSP-1. The blocking of MSP-1 has been proposed to be a method of creating a vaccine against malaria by preventing its invasion and multiplication.
== See also ==
Neutralizing antibody
== References ==
== External links ==
Media related to Blocking antibodies at Wikimedia Commons | Wikipedia/Blocking_antibody |
A capsid is the protein shell of a virus, enclosing its genetic material. It consists of several oligomeric (repeating) structural subunits made of protein called protomers. The observable 3-dimensional morphological subunits, which may or may not correspond to individual proteins, are called capsomeres. The proteins making up the capsid are called capsid proteins or viral coat proteins (VCP). The virus genomic component inside the capsid, along with occasionally present virus core protein, is called the virus core. The capsid and core together are referred to as a nucleocapsid (cf. also virion).
Capsids are broadly classified according to their structure. The majority of the viruses have capsids with either helical or icosahedral structure. Some viruses, such as bacteriophages, have developed more complicated structures due to constraints of elasticity and electrostatics. The icosahedral shape, which has 20 equilateral triangular faces, approximates a sphere, while the helical shape resembles the shape of a spring, taking the space of a cylinder but not being a cylinder itself. The capsid faces may consist of one or more proteins. For example, the foot-and-mouth disease virus capsid has faces consisting of three proteins named VP1–3.
Some viruses are enveloped, meaning that the capsid is coated with a lipid membrane known as the viral envelope. The envelope is acquired by the capsid from an intracellular membrane in the virus' host; examples include the inner nuclear membrane, the Golgi membrane, and the cell's outer membrane.
Once the virus has infected a cell and begins replicating itself, new capsid subunits are synthesized using the protein biosynthesis mechanism of the cell. In some viruses, including those with helical capsids and especially those with RNA genomes, the capsid proteins co-assemble with their genomes. In other viruses, especially more complex viruses with double-stranded DNA genomes, the capsid proteins assemble into empty precursor procapsids that include a specialized portal structure at one vertex. Through this portal, viral DNA is translocated into the capsid.
Structural analyses of major capsid protein (MCP) architectures have been used to categorise viruses into lineages. For example, the bacteriophage PRD1, the algal virus Paramecium bursaria Chlorella virus-1 (PBCV-1), mimivirus and the mammalian adenovirus have been placed in the same lineage, whereas tailed, double-stranded DNA bacteriophages (Caudovirales) and herpesvirus belong to a second lineage.
== Specific shapes ==
=== Icosahedral ===
The icosahedral structure is extremely common among viruses. The icosahedron consists of 20 triangular faces delimited by 12 fivefold vertexes and consists of 60 asymmetric units. Thus, an icosahedral virus is made of 60N protein subunits. The number and arrangement of capsomeres in an icosahedral capsid can be classified using the "quasi-equivalence principle" proposed by Donald Caspar and Aaron Klug. Like the Goldberg polyhedra, an icosahedral structure can be regarded as being constructed from pentamers and hexamers. The structures can be indexed by two integers h and k, with
h
≥
1
{\displaystyle h\geq 1}
and
k
≥
0
{\displaystyle k\geq 0}
; the structure can be thought of as taking h steps from the edge of a pentamer, turning 60 degrees counterclockwise, then taking k steps to get to the next pentamer. The triangulation number T for the capsid is defined as:
T
=
h
2
+
h
⋅
k
+
k
2
{\displaystyle T=h^{2}+h\cdot k+k^{2}}
In this scheme, icosahedral capsids contain 12 pentamers plus 10(T − 1) hexamers. The T-number is representative of the size and complexity of the capsids. Geometric examples for many values of h, k, and T can be found at List of geodesic polyhedra and Goldberg polyhedra.
Many exceptions to this rule exist: For example, the polyomaviruses and papillomaviruses have pentamers instead of hexamers in hexavalent positions on a quasi T = 7 lattice. Members of the double-stranded RNA virus lineage, including reovirus, rotavirus and bacteriophage φ6 have capsids built of 120 copies of capsid protein, corresponding to a T = 2 capsid, or arguably a T = 1 capsid with a dimer in the asymmetric unit. Similarly, many small viruses have a pseudo T = 3 (or P = 3) capsid, which is organized according to a T = 3 lattice, but with distinct polypeptides occupying the three quasi-equivalent positions
=== Prolate ===
An elongated icosahedron is a common shape for the heads of bacteriophages. Such a structure is composed of a cylinder with a cap at either end. The cylinder is composed of 10 elongated triangular faces. The Q number (or Tmid), which can be any positive integer, specifies the number of triangles, composed of asymmetric subunits, that make up the 10 triangles of the cylinder. The caps are classified by the T (or Tend) number.
The bacterium E. coli is the host for bacteriophage T4 that has a prolate head structure. The bacteriophage encoded gp31 protein appears to be functionally homologous to E. coli chaperone protein GroES and able to substitute for it in the assembly of bacteriophage T4 virions during infection. Like GroES, gp31 forms a stable complex with GroEL chaperonin that is absolutely necessary for the folding and assembly in vivo of the bacteriophage T4 major capsid protein gp23.
=== Helical ===
Many rod-shaped and filamentous plant viruses have capsids with helical symmetry. The helical structure can be described as a set of n 1-D molecular helices related by an n-fold axial symmetry. The helical transformation are classified into two categories: one-dimensional and two-dimensional helical systems. Creating an entire helical structure relies on a set of translational and rotational matrices which are coded in the protein data bank. Helical symmetry is given by the formula P = μ x ρ, where μ is the number of structural units per turn of the helix, ρ is the axial rise per unit and P is the pitch of the helix. The structure is said to be open due to the characteristic that any volume can be enclosed by varying the length of the helix. The most understood helical virus is the tobacco mosaic virus. The virus is a single molecule of (+) strand RNA. Each coat protein on the interior of the helix binds three nucleotides of the RNA genome. Influenza A viruses differ by comprising multiple ribonucleoproteins, the viral NP protein organizes the RNA into a helical structure. The size is also different; the tobacco mosaic virus has a 16.33 protein subunits per helical turn, while the influenza A virus has a 28 amino acid tail loop.
== Functions ==
The functions of the capsid are to:
protect the genome,
deliver the genome, and
interact with the host.
The virus must assemble a stable, protective protein shell to protect the genome from lethal chemical and physical agents. These include extremes of pH or temperature and proteolytic and nucleolytic enzymes. For non-enveloped viruses, the capsid itself may be involved in interaction with receptors on the host cell, leading to penetration of the host cell membrane and internalization of the capsid. Delivery of the genome occurs by subsequent uncoating or disassembly of the capsid and release of the genome into the cytoplasm, or by ejection of the genome through a specialized portal structure directly into the host cell nucleus.
== Origin and evolution ==
It has been suggested that many viral capsid proteins have evolved on multiple occasions from functionally diverse cellular proteins. The recruitment of cellular proteins appears to have occurred at different stages of evolution so that some cellular proteins were captured and refunctionalized prior to the divergence of cellular organisms into the three contemporary domains of life, whereas others were hijacked relatively recently. As a result, some capsid proteins are widespread in viruses infecting distantly related organisms (e.g., capsid proteins with the jelly-roll fold), whereas others are restricted to a particular group of viruses (e.g., capsid proteins of alphaviruses).
A computational model (2015) has shown that capsids may have originated before viruses and that they served as a means of horizontal transfer between replicator communities since these communities could not survive if the number of gene parasites increased, with certain genes being responsible for the formation of these structures and those that favored the survival of self-replicating communities. The displacement of these ancestral genes between cellular organisms could favor the appearance of new viruses during evolution.
== See also ==
Geodesic polyhedron
Goldberg–Coxeter construction
Fullerene#Other buckyballs
== References ==
== Further reading ==
== External links ==
IRAM-Virus Capsid Database and Analysis Resource Archived 2019-10-23 at the Wayback Machine | Wikipedia/Capsid_proteins |
Cardiology (from Ancient Greek καρδίᾱ (kardiā) 'heart' and -λογία (-logia) 'study') is the study of the heart. Cardiology is a branch of medicine that deals with disorders of the heart and the cardiovascular system. The field includes medical diagnosis and treatment of congenital heart defects, coronary artery disease, heart failure, valvular heart disease, and electrophysiology. Physicians who specialize in this field of medicine are called cardiologists, a sub-specialty of internal medicine. Pediatric cardiologists are pediatricians who specialize in cardiology. Physicians who specialize in cardiac surgery are called cardiothoracic surgeons or cardiac surgeons, a specialty of general surgery.
== Specializations ==
All cardiologists in the branch of medicine study the disorders of the heart, but the study of adult and child heart disorders each require different training pathways. Therefore, an adult cardiologist (often simply called "cardiologist") is inadequately trained to take care of children, and pediatric cardiologists are not trained to treat adult heart disease. Surgical aspects outside of cardiac rhythm device implant are not included in cardiology and are in the domain of cardiothoracic surgery. For example, coronary artery bypass surgery (CABG), cardiopulmonary bypass and valve replacement are surgical procedures performed by surgeons, not cardiologists. Typically a cardiologist would first identify who is in need of cardiac surgery and refer them to a cardiac surgeon for the procedure. However, some invasive procedures such as cardiac catheterization and pacemaker implantation are performed by cardiologists.
=== Adult cardiology ===
Cardiology is a specialty of internal medicine.
To become a cardiologist in the United States, a three-year residency in internal medicine is followed by a three-year fellowship in cardiology. It is possible to specialize further in a sub-specialty. Recognized sub-specialties in the U.S. by the Accreditation Council for Graduate Medical Education are clinical cardiac electrophysiology, interventional cardiology, adult congenital heart disease, and advanced heart failure and transplant cardiology. Cardiologists may further become certified in echocardiography by the National Board of Echocardiography, in nuclear cardiology by the Certification Board of Nuclear Cardiology, in cardiovascular computed tomography by the Certification Board of Cardiovascular Computed Tomography in cardiovascular MRI by the Certification Board of Cardiovascular Magnetic Resonance. Recognized subspecialties in the U.S. by the American Osteopathic Association Bureau of Osteopathic Specialists include clinical cardiac electrophysiology and interventional cardiology.
In India, a three-year residency in General Medicine or Pediatrics after M.B.B.S. and then three years of residency in cardiology are needed to be a D.M. (holder of a Doctorate of Medicine [D.M.])/Diplomate of National Board (DNB) in Cardiology.
Per Doximity, adult cardiologists earn an average of $436,849 per year in the U.S.
==== Cardiac electrophysiology ====
Cardiac electrophysiology is the science of elucidating, diagnosing, and treating the electrical activities of the heart. The term is usually used to describe studies of such phenomena by invasive (intracardiac) catheter recording of spontaneous activity as well as of cardiac responses to programmed electrical stimulation (PES). These studies are performed to assess complex arrhythmias, elucidate symptoms, evaluate abnormal electrocardiograms, assess risk of developing arrhythmias in the future, and design treatment. These procedures increasingly include therapeutic methods (typically radiofrequency ablation, or cryoablation) in addition to diagnostic and prognostic procedures.
Other therapeutic modalities employed in this field include antiarrhythmic drug therapy and implantation of pacemakers and automatic implantable cardioverter-defibrillators (AICD).
The cardiac electrophysiology study typically measures the response of the injured or cardiomyopathic myocardium to PES on specific pharmacological regimens in order to assess the likelihood that the regimen will successfully prevent potentially fatal sustained ventricular tachycardia (VT) or ventricular fibrillation (VF) in the future. Sometimes a series of electrophysiology-study drug trials must be conducted to enable the cardiologist to select the one regimen for long-term treatment that best prevents or slows the development of VT or VF following PES. Such studies may also be conducted in the presence of a newly implanted or newly replaced cardiac pacemaker or AICD.
==== Clinical cardiac electrophysiology ====
Clinical cardiac electrophysiology is a branch of the medical specialty of cardiology and is concerned with the study and treatment of rhythm disorders of the heart. Cardiologists with expertise in this area are usually referred to as electrophysiologists. Electrophysiologists are trained in the mechanism, function, and performance of the electrical activities of the heart. Electrophysiologists work closely with other cardiologists and cardiac surgeons to assist or guide therapy for heart rhythm disturbances (arrhythmias). They are trained to perform interventional and surgical procedures to treat cardiac arrhythmia.
The training required to become an electrophysiologist is long and requires eight years after medical school (within the U.S.). Three years of internal medicine residency, three years of cardiology fellowship, and two years of clinical cardiac electrophysiology.
==== Cardiogeriatrics ====
Cardiogeriatrics, or geriatric cardiology, is the branch of cardiology and geriatric medicine that deals with the cardiovascular disorders in elderly people.
Cardiac disorders such as coronary heart disease, including myocardial infarction, heart failure, cardiomyopathy, and arrhythmias such as atrial fibrillation, are common and are a major cause of mortality in elderly people. Vascular disorders such as atherosclerosis and peripheral arterial disease cause significant morbidity and mortality in aged people.
==== Imaging ====
Cardiac imaging includes echocardiography (echo), cardiac magnetic resonance imaging (CMR), and computed tomography of the heart.
Those who specialize in cardiac imaging may undergo more training in all imaging modes or focus on a single imaging modality.
Echocardiography (or "echo") uses standard two-dimensional, three-dimensional, and Doppler ultrasound to create images of the heart. It is used to evaluate and quantify cardiac size and function, valvular function, and can assist with diagnosis and treatment of conditions including heart failure, heart attack, valvular heart disease, congenital heart defects, pericardial disease, and aortic disease.
Those who specialize in echo may spend a significant amount of their clinical time reading echos and performing transesophageal echo, in particular using the latter during procedures such as insertion of a left atrial appendage occlusion device. Transesophageal echo provides higher spatial resolution than trans thoracic echocardiography and because the probe is located in the esophagus, it is not limited by attenuation due to anterior chest structures such as the ribs, chest wall, breasts, lungs that can hinder the quality of trans thoracic echocardiography. It is generally indicated for a variety of indications including: when the standard transthoracic echocardiogram is non diagnostic, for detailed evaluation of abnormalities that are typically in the far field, such as the aorta, left atrial appendage, evaluation of native or prosthetic heart valves, evaluation of cardiac masses, evaluation of endocarditis, valvular abscesses, or for the evaluation of cardiac source of embolus. It is frequently used in the setting of atrial fibrillation or atrial flutter to facilitate the clinical decision with regard to anticoagulation, cardioversion and/or radio frequency ablation.
Cardiac MRI utilizes special protocols to image heart structure and function with specific sequences for certain diseases such as hemochromatosis and amyloidosis.
Cardiac CT utilizes special protocols to image heart structure and function with particular emphasis on coronary arteries.
==== Interventional cardiology ====
Interventional cardiology is a branch of cardiology that deals specifically with the catheter based treatment of structural heart diseases. A large number of procedures can be performed on the heart by catheterization, including angiogram, angioplasty, atherectomy, and stent implantation. These procedures all involve insertion of a sheath into the femoral artery or radial artery (but, in practice, any large peripheral artery or vein) and cannulating the heart under X-ray visualization (most commonly fluoroscopy). This cannulation allows indirect access to the heart, bypassing the trauma caused by surgical opening of the chest.
The main advantages of using the interventional cardiology or radiology approach are the avoidance of the scars and pain, and long post-operative recovery. Additionally, interventional cardiology procedure of primary angioplasty is now the gold standard of care for an acute myocardial infarction. This procedure can also be done proactively, when areas of the vascular system become occluded from atherosclerosis. The Cardiologist will thread this sheath through the vascular system to access the heart. This sheath has a balloon and a tiny wire mesh tube wrapped around it, and if the cardiologist finds a blockage or stenosis, they can inflate the balloon at the occlusion site in the vascular system to flatten or compress the plaque against the vascular wall. Once that is complete a stent is placed as a type of scaffold to hold the vasculature open permanently.
==== Cardiomyopathy/heart failure ====
A relatively newer specialization of cardiology is in the field of heart failure and heart transplant. Cardiomyopathy is a disease of the heart muscle that make it larger or stiffer, sometimes making the heart worse at pumping blood. Specialization of general cardiology to just that of the cardiomyopathies leads to also specializing in heart transplant and pulmonary hypertension.
==== Cardiooncology ====
A recent specialization of cardiology is that of cardiooncology.
This area specializes in the cardiac management in those with cancer and in particular those with plans for chemotherapy or those who have experienced cardiac complications of chemotherapy.
=== Preventive cardiology and cardiac rehabilitation ===
In recent times, the focus is gradually shifting to preventive cardiology due to increased cardiovascular disease burden at an early age. According to the WHO, 37% of all premature deaths are due to cardiovascular diseases and out of this, 82% are in low and middle income countries. Clinical cardiology is the sub specialty of cardiology which looks after preventive cardiology and cardiac rehabilitation. Preventive cardiology also deals with routine preventive checkup though noninvasive tests, specifically electrocardiography, fasegraphy, stress tests, lipid profile and general physical examination to detect any cardiovascular diseases at an early age, while cardiac rehabilitation is the upcoming branch of cardiology which helps a person regain their overall strength and live a normal life after a cardiovascular event. A subspecialty of preventive cardiology is sports cardiology. Because heart disease is the leading cause of death in the world including United States (cdc.gov), national health campaigns and randomized control research has developed to improve heart health.
=== Pediatric cardiology ===
Helen B. Taussig is known as the founder of pediatric cardiology. She became famous through her work with Tetralogy congenital heart defect in which oxygenated and deoxygenated blood enters the circulatory system resulting from a ventricular septal defect (VSD) right beneath the aorta. This condition causes newborns to have a bluish-tint, cyanosis, and have a deficiency of oxygen to their tissues, hypoxemia. She worked with Alfred Blalock and Vivien Thomas at the Johns Hopkins Hospital where they experimented with dogs to look at how they would attempt to surgically cure these "blue babies". They eventually figured out how to do just that by the anastomosis of the systemic artery to the pulmonary artery and called this the Blalock-Taussig Shunt.
Tetralogy of Fallot, pulmonary atresia, double outlet right ventricle, transposition of the great arteries, persistent truncus arteriosus, and Ebstein's anomaly are various congenital cyanotic heart diseases, in which the blood of the newborn is not oxygenated efficiently, due to the heart defect.
=== Adult congenital heart disease ===
As more children with congenital heart disease are surviving into adulthood, a hybrid of adult and pediatric cardiology has emerged called adult congenital heart disease (ACHD).
This field can be entered as either adult or pediatric cardiology.
ACHD specializes in congenital diseases in the setting of adult diseases (e.g., coronary artery disease, COPD, diabetes) that is, otherwise, atypical for adult or pediatric cardiology.
== The heart ==
As the center focus of cardiology, the heart has numerous anatomical features (e.g., atria, ventricles, heart valves) and numerous physiological features (e.g., systole, heart sounds, afterload) that have been encyclopedically documented for many centuries. The heart is located in the middle of the abdomen with its tip slightly towards the left side of the abdomen.
Disorders of the heart lead to heart disease and cardiovascular disease and can lead to a significant number of deaths: cardiovascular disease is the leading cause of death in the U.S. and caused 24.95% of total deaths in 2008.
The primary responsibility of the heart is to pump blood throughout the body.
It pumps blood from the body — called the systemic circulation — through the lungs — called the pulmonary circulation — and then back out to the body. This means that the heart is connected to and affects the entirety of the body. Simplified, the heart is a circuit of the circulation. While plenty is known about the healthy heart, the bulk of study in cardiology is in disorders of the heart and restoration, and where possible, of function.
The heart is a muscle that squeezes blood and functions like a pump. The heart's systems can be classified as either electrical or mechanical, and both of these systems are susceptible to failure or dysfunction.
The electrical system of the heart is centered on the periodic contraction (squeezing) of the muscle cells that is caused by the cardiac pacemaker located in the sinoatrial node.
The study of the electrical aspects is a sub-field of electrophysiology called cardiac electrophysiology and is epitomized with the electrocardiogram (ECG/EKG).
The action potentials generated in the pacemaker propagate throughout the heart in a specific pattern. The system that carries this potential is called the electrical conduction system.
Dysfunction of the electrical system manifests in many ways and may include Wolff–Parkinson–White syndrome, ventricular fibrillation, and heart block.
The mechanical system of the heart is centered on the fluidic movement of blood and the functionality of the heart as a pump.
The mechanical part is ultimately the purpose of the heart and many of the disorders of the heart disrupt the ability to move blood.
Heart failure is one condition in which the mechanical properties of the heart have failed or are failing, which means insufficient blood is being circulated. Failure to move a sufficient amount of blood through the body can cause damage or failure of other organs and may result in death if severe.
=== Coronary circulation ===
Coronary circulation is the circulation of blood in the blood vessels of the heart muscle (the myocardium). The vessels that deliver oxygen-rich blood to the myocardium are known as coronary arteries. The vessels that remove the deoxygenated blood from the heart muscle are known as cardiac veins. These include the great cardiac vein, the middle cardiac vein, the small cardiac vein and the anterior cardiac veins.
As the left and right coronary arteries run on the surface of the heart, they can be called epicardial coronary arteries. These arteries, when healthy, are capable of autoregulation to maintain coronary blood flow at levels appropriate to the needs of the heart muscle. These relatively narrow vessels are commonly affected by atherosclerosis and can become blocked, causing angina or myocardial infarction (a.k.a., a heart attack). The coronary arteries that run deep within the myocardium are referred to as subendocardial.
The coronary arteries are classified as "end circulation", since they represent the only source of blood supply to the myocardium; there is very little redundant blood supply, which is why blockage of these vessels can be so critical.
=== Cardiac examination ===
The cardiac examination (also called the "precordial exam"), is performed as part of a physical examination, or when a patient presents with chest pain suggestive of a cardiovascular pathology. It would typically be modified depending on the indication and integrated with other examinations especially the respiratory examination.
Like all medical examinations, the cardiac examination follows the standard structure of inspection, palpation and auscultation.
== Heart disorders ==
Cardiology is concerned with the normal functionality of the heart and the deviation from a healthy heart. Many disorders involve the heart itself, but some are outside of the heart and in the vascular system. Collectively, the two are jointly termed the cardiovascular system, and diseases of one part tend to affect the other.
=== Coronary artery disease ===
Coronary artery disease, also known as "ischemic heart disease", is a group of diseases that includes: stable angina, unstable angina, myocardial infarction, and is one of the causes of sudden cardiac death. It is within the group of cardiovascular diseases of which it is the most common type. A common symptom is chest pain or discomfort which may travel into the shoulder, arm, back, neck, or jaw. Occasionally it may feel like heartburn. Usually symptoms occur with exercise or emotional stress, last less than a few minutes, and get better with rest. Shortness of breath may also occur and sometimes no symptoms are present. The first sign is occasionally a heart attack. Other complications include heart failure or an irregular heartbeat.
Risk factors include: high blood pressure, smoking, diabetes, lack of exercise, obesity, high blood cholesterol, poor diet, and excessive alcohol, among others. Other risks include depression. The underlying mechanism involves atherosclerosis of the arteries of the heart. A number of tests may help with diagnoses including: electrocardiogram, cardiac stress testing, coronary computed tomographic angiography, and coronary angiogram, among others.
Prevention is by eating a healthy diet, regular exercise, maintaining a healthy weight and not smoking. Sometimes medication for diabetes, high cholesterol, or high blood pressure are also used. There is limited evidence for screening people who are at low risk and do not have symptoms. Treatment involves the same measures as prevention. Additional medications such as antiplatelets including aspirin, beta blockers, or nitroglycerin may be recommended. Procedures such as percutaneous coronary intervention (PCI) or coronary artery bypass surgery (CABG) may be used in severe disease. In those with stable CAD it is unclear if PCI or CABG in addition to the other treatments improve life expectancy or decreases heart attack risk.
In 2013 CAD was the most common cause of death globally, resulting in 8.14 million deaths (16.8%) up from 5.74 million deaths (12%) in 1990. The risk of death from CAD for a given age has decreased between 1980 and 2010 especially in developed countries. The number of cases of CAD for a given age has also decreased between 1990 and 2010. In the U.S. in 2010 about 20% of those over 65 had CAD, while it was present in 7% of those 45 to 64, and 1.3% of those 18 to 45. Rates are higher among men than women of a given age.
=== Cardiomyopathy ===
Heart failure, or formally cardiomyopathy, is the impaired function of the heart, and there are numerous causes and forms of heart failure.
The causes of cardiomyopathy can be genetic, viral, or lifestyle-related. Key symptoms of cardiomyopathy include shortness of breath, fatigue, and irregular heartbeats. Understanding the specific function of cardiac muscle is crucial, as the heart muscle's main role is to pump blood throughout the body efficiently.
=== Cardiac arrhythmia ===
Cardiac arrhythmia, also known as "cardiac dysrhythmia" or "irregular heartbeat", is a group of conditions in which the heartbeat is too fast, too slow, or irregular in its rhythm. A heart rate that is too fast – above 100 beats per minute in adults – is called tachycardia. A heart rate that is too slow – below 60 beats per minute – is called bradycardia. Many types of arrhythmia present no symptoms. When symptoms are present, they may include palpitations, or feeling a pause between heartbeats. More serious symptoms may include lightheadedness, passing out, shortness of breath, or chest pain. While most types of arrhythmia are not serious, some predispose a person to complications such as stroke or heart failure. Others may result in cardiac arrest.
There are four main types of arrhythmia: extra beats, supraventricular tachycardias, ventricular arrhythmias, and bradyarrhythmias. Extra beats include premature atrial contractions, premature ventricular contractions, and premature junctional contractions. Supraventricular tachycardias include atrial fibrillation, atrial flutter, and paroxysmal supraventricular tachycardia. Ventricular arrhythmias include ventricular fibrillation and ventricular tachycardia. Arrhythmias are due to problems with the electrical conduction system of the heart. Arrhythmias may occur in children; however, the normal range for the heart rate is different and depends on age. A number of tests can help diagnose arrhythmia, including an electrocardiogram and Holter monitor.
Most arrhythmias can be effectively treated. Treatments may include medications, medical procedures such as a pacemaker, and surgery. Medications for a fast heart rate may include beta blockers or agents that attempt to restore a normal heart rhythm such as procainamide. This later group may have more significant side effects especially if taken for a long period of time. Pacemakers are often used for slow heart rates. Those with an irregular heartbeat are often treated with blood thinners to reduce the risk of complications. Those who have severe symptoms from an arrhythmia may receive urgent treatment with a jolt of electricity in the form of cardioversion or defibrillation.
Arrhythmia affects millions of people. In Europe and North America, as of 2014, atrial fibrillation affects about 2% to 3% of the population. Atrial fibrillation and atrial flutter resulted in 112,000 deaths in 2013, up from 29,000 in 1990. Sudden cardiac death is the cause of about half of deaths due to cardiovascular disease or about 15% of all deaths globally. About 80% of sudden cardiac death is the result of ventricular arrhythmias. Arrhythmias may occur at any age but are more common among older people.
=== Cardiac arrest ===
Cardiac arrest is a sudden stop in effective blood flow due to the failure of the heart to contract effectively. Symptoms include loss of consciousness and abnormal or absent breathing. Some people may have chest pain, shortness of breath, or nausea before this occurs. If not treated within minutes, death usually occurs.
The most common cause of cardiac arrest is coronary artery disease. Less common causes include major blood loss, lack of oxygen, very low potassium, heart failure, and intense physical exercise. A number of inherited disorders may also increase the risk including long QT syndrome. The initial heart rhythm is most often ventricular fibrillation. The diagnosis is confirmed by finding no pulse. While a cardiac arrest may be caused by heart attack or heart failure these are not the same.
Prevention includes not smoking, physical activity, and maintaining a healthy weight. Treatment for cardiac arrest is immediate cardiopulmonary resuscitation (CPR) and, if a shockable rhythm is present, defibrillation. Among those who survive targeted temperature management may improve outcomes. An implantable cardiac defibrillator may be placed to reduce the chance of death from recurrence.
In the United States, cardiac arrest outside of hospital occurs in about 13 per 10,000 people per year (326,000 cases). In hospital cardiac arrest occurs in an additional 209,000 Cardiac arrest becomes more common with age. It affects males more often than females. The percentage of people who survive with treatment is about 8%. Many who survive have significant disability. Many U.S. television shows, however, have portrayed unrealistically high survival rates of 67%.
=== Hypertension ===
Hypertension, also known as "high blood pressure", is a long term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms. Long term high blood pressure, however, is a major risk factor for coronary artery disease, stroke, heart failure, peripheral vascular disease, vision loss, and chronic kidney disease.
Lifestyle factors can increase the risk of hypertension. These include excess salt in the diet, excess body weight, smoking, and alcohol consumption. Hypertension can also be caused by other diseases, or occur as a side-effect of drugs.
Blood pressure is expressed by two measurements, the systolic and diastolic pressures, which are the maximum and minimum pressures, respectively. Normal blood pressure when at rest is within the range of 100–140 millimeters mercury (mmHg) systolic and 60–90 mmHg diastolic. High blood pressure is present if the resting blood pressure is persistently at or above 140/90 mmHg for most adults. Different numbers apply to children. When diagnosing high blood pressure, ambulatory blood pressure monitoring over a 24-hour period appears to be more accurate than "in-office" blood pressure measurement at a physician's office or other blood pressure screening location.
Lifestyle changes and medications can lower blood pressure and decrease the risk of health complications. Lifestyle changes include weight loss, decreased salt intake, physical exercise, and a healthy diet. If changes in lifestyle are insufficient, blood pressure medications may be used. A regimen of up to three medications effectively controls blood pressure in 90% of people. The treatment of moderate to severe high arterial blood pressure (defined as >160/100 mmHg) with medication is associated with an improved life expectancy and reduced morbidity. The effect of treatment for blood pressure between 140/90 mmHg and 160/100 mmHg is less clear, with some studies finding benefits while others do not. High blood pressure affects between 16% and 37% of the population globally. In 2010, hypertension was believed to have been a factor in 18% (9.4 million) deaths.
==== Essential vs Secondary hypertension ====
Essential hypertension is the form of hypertension that by definition has no identifiable cause. It is the most common type of hypertension, affecting 95% of hypertensive patients, it tends to be familial and is likely to be the consequence of an interaction between environmental and genetic factors. Prevalence of essential hypertension increases with age, and individuals with relatively high blood pressure at younger ages are at increased risk for the subsequent development of hypertension.
Hypertension can increase the risk of cerebral, cardiac, and renal events.
Secondary hypertension is a type of hypertension which is caused by an identifiable underlying secondary cause. It is much less common than essential hypertension, affecting only 5% of hypertensive patients. It has many different causes including endocrine diseases, kidney diseases, and tumors. It also can be a side effect of many medications.
==== Complications of hypertension ====
Complications of hypertension are clinical outcomes that result from persistent elevation of blood pressure. Hypertension is a risk factor for all clinical manifestations of atherosclerosis since it is a risk factor for atherosclerosis itself. It is an independent predisposing factor for heart failure, coronary artery disease, stroke, renal disease, and peripheral arterial disease. It is the most important risk factor for cardiovascular morbidity and mortality, in industrialized countries.
=== Congenital heart defects ===
A congenital heart defect, also known as a "congenital heart anomaly" or "congenital heart disease", is a problem in the structure of the heart that is present at birth. Signs and symptoms depend on the specific type of problem. Symptoms can vary from none to life-threatening. When present they may include rapid breathing, bluish skin, poor weight gain, and feeling tired. It does not cause chest pain. Most congenital heart problems do not occur with other diseases. Complications that can result from heart defects include heart failure.
The cause of a congenital heart defect is often unknown. Certain cases may be due to infections during pregnancy such as rubella, use of certain medications or drugs such as alcohol or tobacco, parents being closely related, or poor nutritional status or obesity in the mother. Having a parent with a congenital heart defect is also a risk factor. A number of genetic conditions are associated with heart defects including Down syndrome, Turner syndrome, and Marfan syndrome. Congenital heart defects are divided into two main groups: cyanotic heart defects and non-cyanotic heart defects, depending on whether the child has the potential to turn bluish in color. The problems may involve the interior walls of the heart, the heart valves, or the large blood vessels that lead to and from the heart.
Congenital heart defects are partly preventable through rubella vaccination, the adding of iodine to salt, and the adding of folic acid to certain food products. Some defects do not need treatment. Other may be effectively treated with catheter based procedures or heart surgery. Occasionally a number of operations may be needed. Occasionally heart transplantation is required. With appropriate treatment outcomes, even with complex problems, are generally good.
Heart defects are the most common birth defect. In 2013 they were present in 34.3 million people globally. They affect between 4 and 75 per 1,000 live births depending upon how they are diagnosed. About 6 to 19 per 1,000 cause a moderate to severe degree of problems. Congenital heart defects are the leading cause of birth defect-related deaths. In 2013 they resulted in 323,000 deaths down from 366,000 deaths in 1990.
==== Tetralogy of Fallot ====
Tetralogy of Fallot is the most common congenital heart disease arising in 1–3 cases per 1,000 births. The cause of this defect is a ventricular septal defect (VSD) and an overriding aorta. These two defects combined causes deoxygenated blood to bypass the lungs and going right back into the circulatory system. The modified Blalock-Taussig shunt is usually used to fix the circulation. This procedure is done by placing a graft between the subclavian artery and the ipsilateral pulmonary artery to restore the correct blood flow.
==== Pulmonary atresia ====
Pulmonary atresia happens in 7–8 per 100,000 births and is characterized by the aorta branching out of the right ventricle. This causes the deoxygenated blood to bypass the lungs and enter the circulatory system. Surgeries can fix this by redirecting the aorta and fixing the right ventricle and pulmonary artery connection.
There are two types of pulmonary atresia, classified by whether or not the baby also has a ventricular septal defect.
Pulmonary atresia with an intact ventricular septum: This type of pulmonary atresia is associated with complete and intact septum between the ventricles.
Pulmonary atresia with a ventricular septal defect: This type of pulmonary atresia happens when a ventricular septal defect allows blood to flow into and out of the right ventricle.
==== Double outlet right ventricle ====
Double outlet right ventricle (DORV) is when both great arteries, the pulmonary artery and the aorta, are connected to the right ventricle. There is usually a VSD in different particular places depending on the variations of DORV, typically 50% are subaortic and 30%. The surgeries that can be done to fix this defect can vary due to the different physiology and blood flow in the defected heart. One way it can be cured is by a VSD closure and placing conduits to restart the blood flow between the left ventricle and the aorta and between the right ventricle and the pulmonary artery. Another way is systemic-to-pulmonary artery shunt in cases associated with pulmonary stenosis. Also, a balloon atrial septostomy can be done to relieve hypoxemia caused by DORV with the Taussig-Bing anomaly while surgical correction is awaited.
==== Transposition of great arteries ====
There are two different types of transposition of the great arteries, Dextro-transposition of the great arteries and Levo-transposition of the great arteries, depending on where the chambers and vessels connect. Dextro-transposition happens in about 1 in 4,000 newborns and is when the right ventricle pumps blood into the aorta and deoxygenated blood enters the bloodstream. The temporary procedure is to create an atrial septal defect. A permanent fix is more complicated and involves redirecting the pulmonary return to the right atrium and the systemic return to the left atrium, which is known as the Senning procedure. The Rastelli procedure can also be done by rerouting the left ventricular outflow, dividing the pulmonary trunk, and placing a conduit in between the right ventricle and pulmonary trunk. Levo-transposition happens in about 1 in 13,000 newborns and is characterized by the left ventricle pumping blood into the lungs and the right ventricle pumping the blood into the aorta. This may not produce problems at the beginning, but will eventually due to the different pressures each ventricle uses to pump blood. Switching the left ventricle to be the systemic ventricle and the right ventricle to pump blood into the pulmonary artery can repair levo-transposition.
==== Persistent truncus arteriosus ====
Persistent truncus arteriosus is when the truncus arteriosus fails to split into the aorta and pulmonary trunk. This occurs in about 1 in 11,000 live births and allows both oxygenated and deoxygenated blood into the body. The repair consists of a VSD closure and the Rastelli procedure.
==== Ebstein anomaly ====
Ebstein's anomaly is characterized by a right atrium that is significantly enlarged and a heart that is shaped like a box. This is very rare and happens in less than 1% of congenital heart disease cases. The surgical repair varies depending on the severity of the disease.
Pediatric cardiology is a sub-specialty of pediatrics. To become a pediatric cardiologist in the U.S., one must complete a three-year residency in pediatrics, followed by a three-year fellowship in pediatric cardiology. Per doximity, pediatric cardiologists make an average of $303,917 in the U.S.
== Diagnostic tests in cardiology ==
Diagnostic tests in cardiology are the methods of identifying heart conditions associated with healthy vs. unhealthy, pathologic heart function. The starting point is obtaining a medical history, followed by Auscultation. Then blood tests, electrophysiological procedures, and cardiac imaging can be ordered for further analysis. Electrophysiological procedures include electrocardiogram, cardiac monitoring, cardiac stress testing, and the electrophysiology study.
== Trials ==
Cardiology is known for randomized controlled trials that guide clinical treatment of cardiac diseases. While dozens are published every year, there are landmark trials that shift treatment significantly. Trials often have an acronym of the trial name, and this acronym is used to reference the trial and its results. Some of these landmark trials include:
V-HeFT (1986) — use of vasodilators (hydralazine and isosorbide dinitrate) in heart failure
ISIS-2 (1988) — use of aspirin in myocardial infarction
CASE I (1991) — use of antiarrhythmic agents after a heart attack increases mortality
SOLVD (1991) — use of ACE inhibitors in heart failure
4S (1994) — statins reduce risk of heart disease
CURE (1991) — use of dual antiplatelet therapy in NSTEMI
MIRACLE (2002) — use of cardiac resynchronization therapy in heart failure
SCD-HeFT (2005) — the use of implantable cardioverter-defibrillator in heart failure
RELY (2009), ROCKET-AF (2011), ARISTOTLE (2011) — use of DOACs in atrial fibrillation instead of warfarin
PARADIGM-HF (2014) — use of angiotensin-neprilysin inhibitor in heart failure
ISCHEMIA (2020) — medical therapy is as good as coronary stents in stable heart disease
EMPEROR-Preserved (2021) — SGLT2 receptors in heart failure
== Cardiology community ==
=== Associations ===
American College of Cardiology
American Heart Association
European Society of Cardiology
Heart Rhythm Society
Canadian Cardiovascular Society
Indian Heart Association
National Heart Foundation of Australia
Cardiology Society of India
=== Journals ===
Acta Cardiologica
American Journal of Cardiology
Annals of Cardiac Anaesthesia
Current Research: Cardiology
Cardiology in Review
Circulation
Circulation Research
Clinical and Experimental Hypertension
Clinical Cardiology
EP – Europace
European Heart Journal
Heart
Heart Rhythm
International Journal of Cardiology
Journal of the American College of Cardiology
Pacing and Clinical Electrophysiology
Indian Heart Journal
=== Cardiologists ===
Robert Atkins (1930–2003), known for the Atkins diet
Christiaan Barnard (1922–2001), cardiac surgeon who performed the world's first human-to-human heart transplant operation
Eugene Braunwald (born 1929), editor of Braunwald's Heart Disease and 1000+ publications
Wallace Brigden (1916–2008), identified cardiomyopathy
Manoj Durairaj (1971– ), cardiologist from Pune, India who received Pro Ecclesia et Pontifice
Willem Einthoven (1860–1927), a physiologist who built the first practical ECG and won the 1924 Nobel Prize in Physiology or Medicine ("for the discovery of the mechanism of the electrocardiogram")
Werner Forssmann (1904–1979), who infamously performed the first human catheterization on himself that led to him being let go from Berliner Charité Hospital, quitting cardiology as a speciality, and then winning the 1956 Nobel Prize in Physiology or Medicine ("for their discoveries concerning heart catheterization and pathological changes in the circulatory system")
Andreas Gruentzig (1939–1985), first developed balloon angioplasty
William Harvey (1578–1657), wrote Exercitatio Anatomica de Motu Cordis et Sanguinis in Animalibus that first described the closed circulatory system and whom Forssmann described as founding cardiology in his Nobel lecture
Murray S. Hoffman (1924–2018) As president of the Colorado Heart Association, he initiated one of the first jogging programs promoting cardiac health
Max Holzmann (1899–1994), co-founder of the Swiss Society of Cardiology, president from 1952 to 1955
Samuel A. Levine (1891–1966), recognized the sign known as Levine's sign as well as the current grading of the intensity of heart murmurs, known as the Levine scale
Henry Joseph Llewellyn "Barney" Marriott (1917–2007), ECG interpretation and Practical Electrocardiography
Bernard Lown (1921–2021), original developer of the defibrillator
Woldemar Mobitz (1889–1951), described and classified the two types of second-degree atrioventricular block often called "Mobitz Type I" and "Mobitz Type II"
Jacqueline Noonan (1928–2020), discoverer of Noonan syndrome that is the top syndromic cause of congenital heart disease
John Parkinson (1885–1976), known for Wolff–Parkinson–White syndrome
Helen B. Taussig (1898–1986), founder of pediatric cardiology and extensively worked on blue baby syndrome
Paul Dudley White (1886–1973), known for Wolff–Parkinson–White syndrome
Fredrick Arthur Willius (1888–1972), founder of the cardiology department at the Mayo Clinic and an early pioneer of electrocardiography
Louis Wolff (1898–1972), known for Wolff–Parkinson–White syndrome
Karel Frederik Wenckebach (1864–1940), first described what is now called type I second-degree atrioventricular block in 1898
== See also ==
Glossary of medicine
List of cardiac pharmaceutical agents
List of cardiovascular clinical trials
Outline of cardiology
== References ==
== Sources ==
Braunwald, Eugene, ed. (2019). Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine. Elsevier. ISBN 978-0-323-46299-0.
Ramrakha, Punit; Hill, Jonathan, eds. (2012). Oxford Handbook of Cardiology (2nd ed.). Oxford University Press. ISBN 978-0-19-964321-9.
== External links ==
American Heart Association | Wikipedia/cardiology |
Excess dietary salt (sodium chloride) consumption has been extensively studied for its potential impact on human health. Chronic, high intake of dietary salt is associated with hypertension and cardiovascular disease, among other adverse health outcomes. Major health and scientific organizations, such as the World Health Organization, the US Centers for Disease Control and Prevention, and the American Heart Association, have established high salt consumption as a major risk factor for cardiovascular diseases and stroke.
== Effect of salt on blood pressure ==
Salt fulfills several important biological functions in humans. The human body has evolved to compensate for high salt intake through regulatory systems such as the renin–angiotensin system. Salt is particularly involved with maintaining body fluid volume, including the regulation of osmotic balance in the blood, extracellular and intracellular fluids, and resting membrane potential.
When salt is ingested, it is dissolved in the blood as two separate ions – Na+ and Cl−. While the kidney reacts to excrete excess sodium and chloride in the body, water retention causes blood pressure to increase.
=== Reducing salt intake in chronic kidney disease ===
A 2021 Cochrane review of people with chronic kidney disease, including those on dialysis, demonstrated robust evidence that salt reduction decreases systolic and diastolic blood pressure and albuminuria. However, there was moderate certainty evidence that some people may experience hypotensive symptoms, such as dizziness, following sudden reduction of salt intake. The effect of salt restriction on extracellular fluid, edema, and total body weight was uncertain.
=== Dietary Approaches to Stop Hypertension-Sodium study ===
The DASH-Sodium study was a sequel to the original DASH (Dietary Approaches to Stop Hypertension) study. Both studies were designed and conducted by the National Heart, Lung, and Blood Institute in the United States, each involving a large, randomized sample. While the original study was designed to test the effects of several varying nutrients on blood pressure, DASH-Sodium varies only in salt content in the diet.
Participants were pre-hypertensive or at stage 1 hypertension and either ate a DASH Diet or a diet reflecting an "average American Diet". During the intervention phase, participants ate their assigned diets containing three distinct levels of sodium in random order. Their blood pressure was monitored during the control period and at all three intervention phases.
The study concluded that the effect of a reduced dietary sodium intake alone on blood pressure is substantial and that the largest decrease in blood pressure occurred in those eating the DASH Diet at the lowest sodium level (1,500 milligrams per day). However, this study is especially significant because participants in both the control and DASH diet groups showed lowered blood pressure with decreased sodium alone.
In agreement with studies regarding salt sensitivity, participants of African descent showed high reductions in blood pressure.
== Hypertension and cardiovascular disease ==
In 2018, the American Heart Association published an advisory stating that "if people in the U.S. consume an average 1,500 mg/day sodium, it could result in a 25.6% decrease in high blood pressure and an estimated $26.2 billion in health care savings. Another estimate projects that achieving this goal would reduce cardiovascular disease deaths from 500,000 to nearly 1.2 million over the next 10 years." There has been evidence from epidemiological studies, human and animal intervention experiments, supporting the links between high rate of salt intake and hypertension. A Cochrane review and meta-analysis of clinical trials showed that reduced sodium intake reduces blood pressure in hypertensive and normotensive subjects. Since controlling hypertension is related to a reduced risk of cardiovascular disease, it is plausible that salt consumption is a risk factor for cardiovascular health. However, to properly study the effects of sodium intake levels on the risk of development of cardiovascular disease, long-term studies of large groups using both dietary and biochemical measures are necessary.
As of 2019, major government research organizations, such as the US Centers for Disease Control and Prevention and the European Food Safety Authority, advise consumers to reduce their salt consumption to lower the risk of cardiovascular diseases.
One 2016 review found that five studies supported the evidence that reduced sodium intake lowers cardiovascular disease incidence and mortality, three contradicted this evidence, and two found insufficient evidence to conclude. The survey found 27 primary studies and 106 letters in academic journals in support of the salt evidence, 34 primary studies and 51 letters contradicting the evidence, and 7 primary studies and 19 letters that were inconclusive. There are several long-term studies which found that groups with sodium-reduced diets have lower incidence of cardiovascular disease in all demographics.
Some researchers cast doubts on the link between lowering sodium intake and the health of a given population.
=== Current trends and campaigns ===
Government regulatory agencies and clinical organizations, the European Food Safety Authority, the US Centers for Disease Control, and the American Heart Association recommend that consumers use less salt in their diets, mainly to reduce the risk of high blood pressure and associated cardiovascular diseases in adults and children. The World Health Organization issued a 2016 fact sheet to encourage reducing global salt consumption by 30% through 2025.
In 2015, the United States Centers for Disease Control and Prevention began an initiative encouraging Americans to reduce their consumption of salty foods. The American Heart Association defined a daily sodium consumption limit of 1,500 milligrams (contained in less than 0.75 teaspoon of table salt).
According to a 2012 Health Canada report, Canadians in all age groups are consuming 3400 mg per day of sodium, more than twice as much as needed. The US Centers for Disease Control and Prevention stated that the average daily sodium intake for Americans over 2 years of age is 3,436 milligrams. The majority of sodium consumed by North Americans is from processed and restaurant foods, while only a small portion is added during cooking or at the table.
In the European Union, half of the member states legislated change in the form of taxation, mandatory nutrition labeling, and regulated nutrition and health claims to address overconsumption of sodium in response to a 2012 EU Salt Reduction Framework.
== Sodium sensitivity ==
A diet high in sodium increases the risk of hypertension in people with sodium sensitivity, which in turn raises the risk of health issues associated with hypertension, including cardiovascular disease.
Unfortunately, there is no universally accepted definition of sodium sensitivity, and the methods used to assess it vary across studies. In most studies, sodium sensitivity is defined by changes in mean blood pressure in response to variations in sodium intake, either through an increase or decrease. Typically, sodium sensitivity is assessed by measuring circulating fluid volume and peripheral vascular resistance. Several studies have shown a relationship between sodium sensitivity and the increase in circulating fluid volume or peripheral vascular resistance.
Several factors are associated with sodium sensitivity, including demographic variables such as race, gender, and age. One study shows that the American population of African descent is significantly more salt-sensitive than Caucasians. Women are found to be more sodium-sensitive than men; one possible explanation is based on the fact that women tend to consume more salt per unit weight, as women weigh less than men on average. Several studies have shown that an increase in age is also associated with the occurrence of sodium sensitivity.
The difference in genetic makeup and family history has a significant impact on salt sensitivity and is being studied more with improvement on the efficiencies and techniques of genetic testing. In both hypertensive and non-hypertensive individuals, those with haptoglobin 1-1 phenotype are more likely to have sodium sensitivity than people with haptoglobin 2-1 or 2-2 phenotypes. More specifically, haptoglobin 2-2 phenotypes contribute to the characteristic of sodium resistance in humans. Moreover, the prevalence of a family history of hypertension is strongly linked with the occurrence of sodium sensitivity.
The influence of physiological factors including renal function and insulin levels on sodium sensitivity are shown in various studies. One study concludes that the effect of kidney failure on sodium sensitivity is substantial due to the contribution of decreasing the Glomerular filtration rate (GFR) in the kidney. Moreover, insulin resistance is found to be related to sodium sensitivity; however, the actual mechanism is still unknown.
Approximately 15% of adults have inverse salt sensitivity, with blood pressure increasing from eating less salt.
== Potassium and hypertension ==
Possible mechanisms by which high dietary potassium intake reduces the risk of hypertension and cardiovascular disease have been proposed but remain insufficiently studied. However, studies have found a strong inverse association between long-term adequate to high rates of potassium intake and the development of cardiovascular diseases.
The recommended dietary intake of potassium is higher than that of sodium. However, the average absolute intake of potassium of studied populations is lower than that of sodium intake. According to Statistics Canada in 2007, Canadians' potassium intake in all age groups was lower than recommended, while sodium intake greatly exceeded recommended intake in every age group.
The ratio of potassium to sodium intake may help explain the large differences in hypertension rates between populations that primarily consume unprocessed or minimally processed foods (such as certain Indigenous and traditional rural communities) and those following Western diets, which are typically high in processed foods.
== Salt substitutes ==
The growing awareness of excessive sodium consumption in connection with hypertension and cardiovascular disease has increased the usage of salt substitutes at both a consumer and industrial level.
On a consumer level, salt substitutes, which usually substitute a portion of sodium chloride content with potassium chloride, can be used to increase the potassium-to-sodium consumption ratio. This change has been shown to blunt the effects of excess salt intake on hypertension and cardiovascular disease. It has also been suggested that salt substitutes can be used to provide an essential portion of daily potassium intake and may even be more economical than prescription potassium supplements.
In the food industry, processes have been developed to create low-sodium versions of existing products. The meat industry especially has developed and fine-tuned methods to decrease salt contents in processed meats without sacrificing consumer acceptance. Research demonstrates that salt substitutes such as potassium chloride and synergistic compounds such as phosphates can be used to decrease salt content in meat products.
There have been concerns with certain populations' use of potassium chloride as a substitute for salt, as high potassium loads are dangerous for groups with diabetes, renal diseases, or heart failure. The use of salts with minerals such as natural salts has also been tested, but, like salt substitutes partially containing potassium, mineral salts produce a bitter taste above certain levels.
== See also ==
Salt
Hypertension
Cardiovascular disease
== References == | Wikipedia/Salt_and_cardiovascular_disease |
The Society for Vascular Surgery (SVS) an American academic society for vascular surgery. Its mission includes education, research, career development and advocacy. The SVS is the national organization for more than 6,000 vascular surgeons and other medical professionals involved in the prevention and cure of vascular disease. The association was founded in 1947. The SVS is the sponsor organization for the Journal of Vascular Surgery (JVS) and for the national Vascular Annual Meeting (VAM).
== History ==
The Society for Vascular Surgery was founded in 1947 as the Society for Cardiovascular Surgery. The society changed its name to the Society for Vascular Surgery in 1953 to reflect its focus on vascular disease.
In the early years of the society, the focus was primarily on the surgical treatment of arterial occlusive disease. However, over time, the scope of the society's work expanded to include the treatment of all types of vascular disease.
== Organization ==
The Society for Vascular Surgery is a professional medical society that represents vascular surgeons in the United States and around the world. The society has over 5,500 members, including vascular surgeons, trainees, and allied health professionals. The society is governed by a board of directors, which is made up of elected members of the society.
The society has several committees that are responsible for various aspects of the society's work, including research, education, advocacy, and quality improvement. The society also has a foundation, the SVS Foundation, which funds research into vascular disease and advocates for improved patient care.
The Society for Vascular Surgery develops clinical practice guidelines for the diagnosis and management of vascular disease. The society's guidelines are developed by expert panels, based on the best available evidence, and are designed to help healthcare providers make informed decisions about the care of patients with vascular disease.
The SVS publishes of the Journal of Vascular Surgery and its associated co-journals. In addition, the society also has an active Patient Safety Organization and Vascular Quality Improvement program.
=== Journal of Vascular Surgery ===
JVS is a subscription based, peer reviewed academic journal published by Elsevier. It has been in circulation since 1984 and has published several of the most notable academic papers in the field of vascular surgery. The journal publishes original research articles, review articles, case reports, and editorials related to the diagnosis, treatment, and prevention of vascular diseases. In 2013, JVS had an impact factor of 2.98. In 2014, JVS launched an additional journal, "JVS: Venous and Lymphatic Disorders".
In addition to the JVS, the SVS also publishes several co-journals:
Journal of Vascular Surgery: Venous and Lymphatic Disorders - focuses on the diagnosis, treatment, and prevention of venous and lymphatic diseases.
Journal of Vascular Surgery: Cases and Innovative Techniques - showcases original case reports, technical notes, and surgical innovations.
Journal of Vascular Surgery: Vascular Innovations- explores the epidemiology, prevention, and treatment of vascular diseases on a global scale.
=== SVS Patient Safety Organization ===
The SVS Patient Safety Organization (PSO) was established in 2011 as a response to the growing need for improved patient safety in vascular surgery. The PSO is dedicated to improving patient outcomes and reducing medical errors by collecting and analyzing data on adverse events and near misses in vascular surgery. The PSO provides its members with tools and resources to promote a culture of safety and to reduce the risk of medical errors. The organization also conducts research and provides educational programs focused on patient safety.
=== Vascular Quality Improvement Program ===
The SVS Vascular Quality Improvement Program (VQI) was established in 2011. The VQI is a national registry that collects and analyzes data on the outcomes of vascular surgeries performed at participating institutions. The registry enables participating institutions to track their own performance and compare it to national benchmarks. The VQI provides feedback to participating institutions to help them improve patient outcomes and reduce the risk of medical errors. In addition, the VQI conducts research and provides educational programs focused on improving the quality of vascular surgery.
== Structure ==
The SVS is governed by a Board of Directors and is supported by a number of committees, task forces, and sections. The Board of Directors is responsible for setting the strategic direction of the society and overseeing its operations. The committees, task forces, and sections are responsible for carrying out specific functions and activities of the society. These include activities such as education, research, advocacy, and quality improvement. The society also has regional chapters and international affiliates that provide additional support to its members.
The SVS offers educational programs and resources for its members. These include the SVS Vascular Annual Meeting and online educational resources, including webinars, podcasts, and online courses.
=== List of presidents ===
1940s
1947 Alton Ochsner, MD
1948 Arthur Allen, MD
1949 Emile Holman, MD
1950s
1950 Daniel Elkin, MD
1951 Ross Veal, MD
1952 Alfred Blalock, MD
1953 Geza de Takats, MD
1954 Michael DeBakey, MD
1955 Robert Linton, MD
1956 George Lilly, MD
1957 Arthur Blakemore, MD
1958 Frank Gerbode, MD
1959 Harris B. Shumaker, Jr., MD
1960s
1960 Richard Warren, MD
1961 Julian Johnson, MD
1962 F.A. Simeone, MD
1963 Earle B. Mahoney, MD
1964 Richard L. Varco, MD
1965 John Heysham Gibbon, MD
1966 Clarence Dennis, MD
1967 William H. Muller Jr., MD
1968 Wilfred Gordon Bigelow, MD
1969 C. Rollins Hanlon, MD
1970s
1970 W. Sterling Edwards, MD
1971 F. Henry Ellis, Jr., MD
1972 Andrew G. Morrow, MD
1973 Wiley F. Barker, MD
1974 W. Andrew Dale, MD
1975 Russell M. Nelson, MD
1976 Worthington G. Schenk, MD
1977 Jesse E. Thompson, MD
1978 James A DeWeese, MD
1979 F. William Blaisdell, MD
1980s
1980 Edwin J. Wylie, MD
1981 John A. Mannick, MD
1982 H. Edward Garrett, MD
1983 D. Emerick Szilagyi, MD
1984 John J. Bergan, MD
1985 Anthony M. Imparato, MD
1986 Allan D. Callow, MD
1987 Wesley S. Moore, MD
1988 E. Stanley Crawford, MD
1989 D. Eugene Strandness, Jr., MD
1990s
1990 William J. Fry, MD
1991 Calvin B. Ernst, MD
1992 Malcolm O. Perry, MD
1993 James S.T. Yao, MD
1994 Norman R. Hertzer, MD
1995 Thomas J. Fogarty, MD
1996 Frank Veith, MD
1997 James C. Stanley, MD
1998 William M. Abbott, MD
1999 Christopher Zarins, MD
2000's
2000 Jonathan B. Towne, MD
2001 Ramon Berguer, MD
2002 Thomas F. O’Donnell, MD
2003 Jack L. Cronenwett, MD
2004 Richard Green, MD
2005 Gregorio A. Sicard, MD
2006 Enrico Ascher, MD
2007 K. Craig Kent, MD
2008 K. Wayne Johnston, MD
2009 G. Patrick Clagett, MD
2010's
2010 Anton N. Sidawy, MD
2011 Robert M. Zwolak, MD
2012 Richard P. Cambria, MD
2013 Peter Gloviczki, MD
2014 Julie Ann Freischlag, MD
2015 Peter F. Lawrence, MD
2016 Bruce A. Perler, MD
2017 Ronald M. Fairman, MD
2018 R. Clement Darling III, MD
2019 Michel Makaroun, MD
2020s
2020 Kim J. Hodgson, MD
2021 Ronald L. Dalman, MD
2022 Ali AbuRahma, MD
2023 Mike Dalsing, MD
2024 Joseph Mills, MD
== References == | Wikipedia/Journal_of_Vascular_Surgery |
Right atrial enlargement (RAE) is a form of cardiomegaly, or heart enlargement. It can broadly be classified as either right atrial hypertrophy (RAH), overgrowth, or dilation, like an expanding balloon. Common causes include pulmonary hypertension, which can be the primary defect leading to RAE, or pulmonary hypertension secondary to tricuspid stenosis; pulmonary stenosis or Tetralogy of Fallot i.e. congenital diseases; chronic lung disease, such as cor pulmonale. Other recognised causes are: right ventricular failure, tricuspid regurgitation, and atrial septal defect. Right atrial enlargement (RAE) is clinically significant due to its prevalence in diagnosing supraventricular arrhythmias. Further, early diagnosis using risk factors like RAE may decrease mortality because patients with RAE are at 9x more risk of arrhythmias and other cardiac conditions compared to their healthy counterparts. Treatment for RAE can include taking certain medications such as diuretics, beta-blockers, anticoagulants, and anti-arrhythmics. If medications are not effective enough, procedures such as implanting a pacemaker, cardioverter-defibrillator (ICD), or a left ventricular assist device (LVAD), heart valve surgery, and coronary bypass surgery may be needed. The last resort treatment option would be a complete heart transplant. Prevention for RAE comes from maintaining a healthy lifestyle with plenty of exercise and eating plenty of vegetables, fruits, and whole grains and avoiding or limiting alcohol and caffeine. It is also important to control heart disease risk factors including diabetes, high cholesterol, and high blood pressure. Exercise, pregnancy, and prior health conditions like ASD II can also promote cardiac remodeling, so routine primary care visits are important to distinguish between physiological and pathological atrial enlargement. Regular primary care visits and routine testing has also been shown to protect against the development of cardiovascular disease and may play a key role in early identification and treatment.
== Signs and symptoms ==
Symptoms of right atrial enlargement include palpitations, dyspnea, paroxysmal tachycardia, general malaise, shortness of breath, syncope, chest pain, fatigue, cyanosis, loss of appetite, tachycardia, fever, and cough. Many patients with right atrial enlargement are asymptomatic.
== Causes ==
Most authors have classified this condition as congenital, but the etiology is still unknown.
== Diagnosis ==
Right Atrial Enlargement (RAE) increases the p wave, representing atrial depolarization, on an ECG to an amplitude > 2.5mm in lead II, an abnormality referred to as p-pulmonale, likely due to weakened right atrial myocardium close to the Sinoatrial (SA) node.
ECG criteria for RAE: P wave amplitude in lead II > 2.5 mm and upward deflection of the P wave in lead V1 > 1.5 mm in amplitude.
Large "a" waves on the JVP waveform can also aid in diagnosis.
== See also ==
Cardiomegaly
Left atrial enlargement
== References ==
== Further reading ==
J, Zhang; L, Zhang; L, He; H, Li; Y, Li; L, Zhang; M, Xie (2021). "Clinical Presentation, Diagnosis, and Management of Idiopathic Enlargement of the Right Atrium: An Analysis Based on Systematic Review of 153 Reported Cases". Cardiology. 146 (1): 88–97. doi:10.1159/000511434. ISSN 1421-9751. PMID 33242857.
Hughes, William E.; Casey, Darren P.; Baldini, Francesca; Vergani, Laura; Guo, Junxia; Fan, Zhenping; Wang, Zhenwei; Liu, Nai-Feng; Motoki, Hirohiko; Klein, Allan L.; Tandaju, Jeremy R.; Raeisi-Dehkordi, Hamidreza (February 1, 2022). "Right atrium enlargement is related to increased heart damage and mortality in well-controlled hypertension". Nutrition, Metabolism and Cardiovascular Diseases. 32 (2). Elsevier: 420–428. doi:10.1016/j.numecd.2021.10.004. ISSN 0939-4753. PMID 34893418. Retrieved December 29, 2023.
== External links ==
Cleveland Clinic
Life in the Fast Lane | Wikipedia/Right_atrial_enlargement |
Wandering atrial pacemaker (WAP) is an atrial rhythm where the pacemaking activity of the heart originates from different locations within the atria. This is different from normal pacemaking activity, where the sinoatrial node (SA node) is responsible for each heartbeat and keeps a steady rate and rhythm. Causes of wandering atrial pacemaker are unclear, but there may be factors leading to its development. It is often seen in the young, the old, and in athletes, and rarely causes symptoms or requires treatment. Diagnosis of wandering atrial pacemaker is made by an ECG.
== Pathophysiology ==
The SA node is considered the primary pacemaker of the heart. In wandering atrial pacemaker, there are other locations within the atria besides the SA node that are responsible for each heartbeat. This is unusual because the SA node, AV node, bundle of His, bundle branches, and Purkinje fibers are the structures that have pacemaking capability. The atrial and ventricular muscle tissue do not have this capability.
Originally, it was believed that the atria had different ectopic foci that were spontaneously depolarizing, each foci acting as a pacemaker for the heart. However, the atrial muscle tissue isn't able to spontaneously depolarize. Therefore, the mechanism is by extension of the self-depolarizing tissue between the SA and AV node. Over time, the extension of tissue becomes a tract with spontaneous depolarization capability. This allows for any location along the tract to spontaneously depolarize, hence different locations that are responsible for each heartbeat.
== Causes ==
Wandering atrial pacemaker may be seen in young, healthy individuals as well as in the elderly and those with lung disease. The cause of wandering atrial pacemaker is unclear.
Increased tone from the vagus nerve may factor into the rhythm appearing in young, healthy individuals who exercise. The vagus nerve is a part of the parasympathetic nervous system that helps control heart rate and contractility of the heart. Through exercise, there is increased input to the heart from the vagus nerve, which causes the heart to beat at a slower rate. This is manifested by a lower resting heart rate than may be seen in the average person. For elderly individuals, the rhythm may be caused by sinus node dysfunction. This is where the heart's pacemaker, the SA node, has become damaged. For individuals with lung disease, the rhythm could be related to the underlying lung pathology. In rare cases, digoxin toxicity can cause wandering atrial pacemaker.
== Symptoms ==
Wandering atrial pacemaker doesn't usually have symptoms because it is commonly a benign rhythm. It is usually found incidentally on an ECG for other medical indications that require a heart rhythm screening. If a patient does have symptoms, it may manifest as skipped heartbeats. Upon physical examination, it can be found by having an irregularly irregular rhythm, similar to how atrial fibrillation is described. An ECG would then be performed to find the underlying cause of the rhythm disturbance.
== Diagnosis ==
The heart rhythm is seen through an electrocardiogram. To make the diagnosis, there must be at least 3 different P-wave morphologies in a single ECG lead due to the shifting of the pacemaker in the atria. This is different from normal sinus rhythm where one will see the same P-wave morphology through the same lead because each beat is started from the SA node. The P-wave is normally upright or positive in leads I and II, and therefore may be the helpful when determining changing P-wave morphologies. Other common changes that are seen on ECG with wandering atrial pacemaker include differing PR intervals and PP intervals.
Another heart rhythm similar to wandering atrial pacemaker is multifocal atrial tachycardia. Both arrhythmias have at least 3 different P-wave morphologies in a single ECG lead, but the heart rate is different. When the heart rate is lower than 100 beats per minute, the heart rhythm is considered wandering atrial pacemaker. When the heart rate is greater than 100 beats per minute, the heart rhythm is considered multifocal atrial tachycardia.
== Treatment ==
Treatment is rarely required because, in most cases, it is asymptomatic. If symptoms develop, medication can be pursued for symptomatic relief. In the setting of suspected sinus node dysfunction manifesting as wandering atrial pacemaker, evaluation for pacemaker placement may be done due to sinus node damage. In cases of digoxin toxicity, a physician may decrease the dose, change medications, or cease digoxin therapy.
== References ==
== External links == | Wikipedia/Wandering_atrial_pacemaker |
A computed tomography scan (CT scan), formerly called computed axial tomography scan (CAT scan), is a medical imaging technique used to obtain detailed internal images of the body. The personnel that perform CT scans are called radiographers or radiology technologists.
CT scanners use a rotating X-ray tube and a row of detectors placed in a gantry to measure X-ray attenuations by different tissues inside the body. The multiple X-ray measurements taken from different angles are then processed on a computer using tomographic reconstruction algorithms to produce tomographic (cross-sectional) images (virtual "slices") of a body. CT scans can be used in patients with metallic implants or pacemakers, for whom magnetic resonance imaging (MRI) is contraindicated.
Since its development in the 1970s, CT scanning has proven to be a versatile imaging technique. While CT is most prominently used in medical diagnosis, it can also be used to form images of non-living objects. The 1979 Nobel Prize in Physiology or Medicine was awarded jointly to South African-American physicist Allan MacLeod Cormack and British electrical engineer Godfrey Hounsfield "for the development of computer-assisted tomography".
== Types ==
On the basis of image acquisition and procedures, various type of scanners are available in the market.
=== Sequential CT ===
Sequential CT, also known as step-and-shoot CT, is a type of scanning method in which the CT table moves stepwise. The table increments to a particular location and then stops which is followed by the X-ray tube rotation and acquisition of a slice. The table then increments again, and another slice is taken. The table movement stops while taking slices. This results in an increased time of scanning.
=== Spiral CT ===
Spinning tube, commonly called spiral CT, or helical CT, is an imaging technique in which an entire X-ray tube is spun around the central axis of the area being scanned. These are the dominant type of scanners on the market because they have been manufactured longer and offer a lower cost of production and purchase. The main limitation of this type of CT is the bulk and inertia of the equipment (X-ray tube assembly and detector array on the opposite side of the circle) which limits the speed at which the equipment can spin. Some designs use two X-ray sources and detector arrays offset by an angle, as a technique to improve temporal resolution.
=== Electron beam tomography ===
Electron beam tomography (EBT) is a specific form of CT in which a large enough X-ray tube is constructed so that only the path of the electrons, travelling between the cathode and anode of the X-ray tube, are spun using deflection coils. This type had a major advantage since sweep speeds can be much faster, allowing for less blurry imaging of moving structures, such as the heart and arteries. Fewer scanners of this design have been produced when compared with spinning tube types, mainly due to the higher cost associated with building a much larger X-ray tube and detector array and limited anatomical coverage.
=== Dual energy CT ===
Dual energy CT, also known as spectral CT, is an advancement of computed Tomography in which two energies are used to create two sets of data. A dual energy CT may employ dual source, single source with dual detector layer, single source with energy switching methods to get two different sets of data.
Dual source CT is an advanced scanner with a two X-ray tube detector system, unlike conventional single tube systems. These two detector systems are mounted on a single gantry at 90° in the same plane. Dual source CT scanners allow fast scanning with higher temporal resolution by acquiring a full CT slice in only half a rotation. Fast imaging reduces motion blurring at high heart rates and potentially allowing for shorter breath-hold time. This is particularly useful for ill patients having difficulty holding their breath or unable to take heart-rate lowering medication.
Single source with energy switching is another mode of dual energy CT in which a single tube is operated at two different energies by switching the energies frequently.
=== CT perfusion imaging ===
CT perfusion imaging is a specific form of CT to assess flow through blood vessels whilst injecting a contrast agent. Blood flow, blood transit time, and organ blood volume, can all be calculated with reasonable sensitivity and specificity. This type of CT may be used on the heart, although sensitivity and specificity for detecting abnormalities are still lower than for other forms of CT. This may also be used on the brain, where CT perfusion imaging can often detect poor brain perfusion well before it is detected using a conventional spiral CT scan. This is better for stroke diagnosis than other CT types.
=== PET CT ===
Positron emission tomography–computed tomography is a hybrid CT modality which combines, in a single gantry, a positron emission tomography (PET) scanner and an X-ray computed tomography (CT) scanner, to acquire sequential images from both devices in the same session, which are combined into a single superposed (co-registered) image. Thus, functional imaging obtained by PET, which depicts the spatial distribution of metabolic or biochemical activity in the body can be more precisely aligned or correlated with anatomic imaging obtained by CT scanning.
PET-CT gives both anatomical and functional details of an organ under examination and is helpful in detecting different type of cancers.
== Medical use ==
Since its introduction in the 1970s, CT has become an important tool in medical imaging to supplement conventional X-ray imaging and medical ultrasonography. It has more recently been used for preventive medicine or screening for disease, for example, CT colonography for people with a high risk of colon cancer, or full-motion heart scans for people with a high risk of heart disease. Several institutions offer full-body scans for the general population although this practice goes against the advice and official position of many professional organizations in the field primarily due to the radiation dose applied.
The use of CT scans has increased dramatically over the last two decades in many countries. An estimated 72 million scans were performed in the United States in 2007 and more than 80 million in 2015.
=== Head ===
CT scanning of the head is typically used to detect infarction (stroke), tumors, calcifications, haemorrhage, and bone trauma. Of the above, hypodense (dark) structures can indicate edema and infarction, hyperdense (bright) structures indicate calcifications and haemorrhage and bone trauma can be seen as disjunction in bone windows. Tumors can be detected by the swelling and anatomical distortion they cause, or by surrounding edema. CT scanning of the head is also used in CT-guided stereotactic surgery and radiosurgery for treatment of intracranial tumors, arteriovenous malformations, and other surgically treatable conditions using a device known as the N-localizer.
=== Neck ===
Contrast CT is generally the initial study of choice for neck masses in adults. CT of the thyroid plays an important role in the evaluation of thyroid cancer. CT scan often incidentally finds thyroid abnormalities, and so is often the preferred investigation modality for thyroid abnormalities.
=== Lungs ===
A CT scan can be used for detecting both acute and chronic changes in the lung parenchyma, the tissue of the lungs. It is particularly relevant here because normal two-dimensional X-rays do not show such defects. A variety of techniques are used, depending on the suspected abnormality. For evaluation of chronic interstitial processes such as emphysema, and fibrosis, thin sections with high spatial frequency reconstructions are used; often scans are performed both on inspiration and expiration. This special technique is called high resolution CT that produces a sampling of the lung, and not continuous images.
Bronchial wall thickening can be seen on lung CTs and generally (but not always) implies inflammation of the bronchi.
An incidentally found nodule in the absence of symptoms (sometimes referred to as an incidentaloma) may raise concerns that it might represent a tumor, either benign or malignant. Perhaps persuaded by fear, patients and doctors sometimes agree to an intensive schedule of CT scans, sometimes up to every three months and beyond the recommended guidelines, in an attempt to do surveillance on the nodules. However, established guidelines advise that patients without a prior history of cancer and whose solid nodules have not grown over a two-year period are unlikely to have any malignant cancer. For this reason, and because no research provides supporting evidence that intensive surveillance gives better outcomes, and because of risks associated with having CT scans, patients should not receive CT screening in excess of those recommended by established guidelines.
=== Angiography ===
Computed tomography angiography (CTA) is a type of contrast CT to visualize the arteries and veins throughout the body. This ranges from arteries serving the brain to those bringing blood to the lungs, kidneys, arms and legs. An example of this type of exam is CT pulmonary angiogram (CTPA) used to diagnose pulmonary embolism (PE). It employs computed tomography and an iodine-based contrast agent to obtain an image of the pulmonary arteries. CT scans can reduce the risk of angiography by providing clinicians with more information about the positioning and number of clots prior to the procedure.
=== Cardiac ===
A CT scan of the heart is performed to gain knowledge about cardiac or coronary anatomy. Traditionally, cardiac CT scans are used to detect, diagnose, or follow up coronary artery disease. More recently CT has played a key role in the fast-evolving field of transcatheter structural heart interventions, more specifically in the transcatheter repair and replacement of heart valves.
The main forms of cardiac CT scanning are:
Coronary CT angiography (CCTA): the use of CT to assess the coronary arteries of the heart. The subject receives an intravenous injection of radiocontrast, and then the heart is scanned using a high-speed CT scanner, allowing radiologists to assess the extent of occlusion in the coronary arteries, usually to diagnose coronary artery disease.
Coronary CT calcium scan: also used for the assessment of severity of coronary artery disease. Specifically, it looks for calcium deposits in the coronary arteries that can narrow arteries and increase the risk of a heart attack. A typical coronary CT calcium scan is done without the use of radiocontrast, but it can possibly be done from contrast-enhanced images as well.
To better visualize the anatomy, post-processing of the images is common. Most common are multiplanar reconstructions (MPR) and volume rendering. For more complex anatomies and procedures, such as heart valve interventions, a true 3D reconstruction or a 3D print is created based on these CT images to gain a deeper understanding.
=== Abdomen and pelvis ===
CT is an accurate technique for diagnosis of abdominal diseases like Crohn's disease, GIT bleeding, and diagnosis and staging of cancer, as well as follow-up after cancer treatment to assess response. It is commonly used to investigate acute abdominal pain.
Non-contrast-enhanced CT scans are the gold standard for diagnosing kidney stone disease. They allow clinicians to estimate the size, volume, and density of stones, helping to guide further treatment; with size being especially important in predicting the time to spontaneous passage of a stone.
=== Axial skeleton and extremities ===
For the axial skeleton and extremities, CT is often used to image complex fractures, especially ones around joints, because of its ability to reconstruct the area of interest in multiple planes. Fractures, ligamentous injuries, and dislocations can easily be recognized with a 0.2 mm resolution. With modern dual-energy CT scanners, new areas of use have been established, such as aiding in the diagnosis of gout.
=== Biomechanical use ===
CT is used in biomechanics to quickly reveal the geometry, anatomy, density and elastic moduli of biological tissues.
== Other uses ==
=== Industrial use ===
Industrial CT scanning (industrial computed tomography) is a process which uses X-ray equipment to produce 3D representations of components both externally and internally. Industrial CT scanning has been used in many areas of industry for internal inspection of components. Some of the key uses for CT scanning have been flaw detection, failure analysis, metrology, assembly analysis, image-based finite element methods and reverse engineering applications. CT scanning is also employed in the imaging and conservation of museum artifacts.
=== Aviation security ===
CT scanning has also found an application in transport security (predominantly airport security) where it is currently used in a materials analysis context for explosives detection CTX (explosive-detection device) and is also under consideration for automated baggage/parcel security scanning using computer vision based object recognition algorithms that target the detection of specific threat items based on 3D appearance (e.g. guns, knives, liquid containers). Its usage in airport security pioneered at Shannon Airport in March 2022 has ended the ban on liquids over 100 ml there, a move that Heathrow Airport plans for a full roll-out on 1 December 2022 and the TSA spent $781.2 million on an order for over 1,000 scanners, ready to go live in the summer.
=== Geological use ===
X-ray CT is used in geological studies to quickly reveal materials inside a drill core. Dense minerals such as pyrite and barite appear brighter and less dense components such as clay appear dull in CT images.
=== Paleontological use ===
Traditional methods of studying fossils are often destructive, such as the use of thin sections and physical preparation. X-ray CT is used in paleontology to non-destructively visualize fossils in 3D. This has many advantages. For example, we can look at fragile structures that might never otherwise be able to be studied. In addition, one can freely move around models of fossils in virtual 3D space to inspect it without damaging the fossil.
=== Cultural heritage use ===
X-ray CT and micro-CT can also be used for the conservation and preservation of objects of cultural heritage. For many fragile objects, direct research and observation can be damaging and can degrade the object over time. Using CT scans, conservators and researchers are able to determine the material composition of the objects they are exploring, such as the position of ink along the layers of a scroll, without any additional harm. These scans have been optimal for research focused on the workings of the Antikythera mechanism or the text hidden inside the charred outer layers of the En-Gedi Scroll. However, they are not optimal for every object subject to these kinds of research questions, as there are certain artifacts like the Herculaneum papyri in which the material composition has very little variation along the inside of the object. After scanning these objects, computational methods can be employed to examine the insides of these objects, as was the case with the virtual unwrapping of the En-Gedi scroll and the Herculaneum papyri. Micro-CT has also proved useful for analyzing more recent artifacts such as still-sealed historic correspondence that employed the technique of letterlocking (complex folding and cuts) that provided a "tamper-evident locking mechanism". Further examples of use cases in archaeology is imaging the contents of sarcophagi or ceramics.
Recently, CWI in Amsterdam has collaborated with Rijksmuseum to investigate art object inside details in the framework called IntACT.
=== Microorganism research ===
Varied types of fungus can degrade wood to different degrees, one Belgium research group has been used X-ray CT 3 dimension with sub-micron resolution unveiled fungi can penetrate micropores of 0.6 μm under certain conditions.
=== Timber sawmill ===
Sawmills use industrial CT scanners to detect round defects, for instance knots, to improve total value of timber productions. Most sawmills are planning to incorporate this robust detection tool to improve productivity in the long run, however initial investment cost is high.
== Interpretation of results ==
=== Presentation ===
The result of a CT scan is a volume of voxels, which may be presented to a human observer by various methods, which broadly fit into the following categories:
Slices (of varying thickness). Thin slice is generally regarded as planes representing a thickness of less than 3 mm. Thick slice is generally regarded as planes representing a thickness between 3 mm and 5 mm.
Projection, including maximum intensity projection and average intensity projection
Volume rendering (VR)
Technically, all volume renderings become projections when viewed on a 2-dimensional display, making the distinction between projections and volume renderings a bit vague. The epitomes of volume rendering models feature a mix of for example coloring and shading in order to create realistic and observable representations.
Two-dimensional CT images are conventionally rendered so that the view is as though looking up at it from the patient's feet. Hence, the left side of the image is to the patient's right and vice versa, while anterior in the image also is the patient's anterior and vice versa. This left-right interchange corresponds to the view that physicians generally have in reality when positioned in front of patients.
==== Grayscale ====
Pixels in an image obtained by CT scanning are displayed in terms of relative radiodensity. The pixel itself is displayed according to the mean attenuation of the tissue(s) that it corresponds to on a scale from +3,071 (most attenuating) to −1,024 (least attenuating) on the Hounsfield scale. A pixel is a two dimensional unit based on the matrix size and the field of view. When the CT slice thickness is also factored in, the unit is known as a voxel, which is a three-dimensional unit. Water has an attenuation of 0 Hounsfield units (HU), while air is −1,000 HU, cancellous bone is typically +400 HU, and cranial bone can reach 2,000 HU. The attenuation of metallic implants depends on the atomic number of the element used: Titanium usually has an amount of +1000 HU, iron steel can completely block the X-ray and is, therefore, responsible for well-known line-artifacts in computed tomograms. Artifacts are caused by abrupt transitions between low- and high-density materials, which results in data values that exceed the dynamic range of the processing electronics.
==== Windowing ====
CT data sets have a very high dynamic range which must be reduced for display or printing. This is typically done via a process of "windowing", which maps a range (the "window") of pixel values to a grayscale ramp. For example, CT images of the brain are commonly viewed with a window extending from 0 HU to 80 HU. Pixel values of 0 and lower, are displayed as black; values of 80 and higher are displayed as white; values within the window are displayed as a gray intensity proportional to position within the window. The window used for display must be matched to the X-ray density of the object of interest, in order to optimize the visible detail. Window width and window level parameters are used to control the windowing of a scan.
==== Multiplanar reconstruction and projections ====
Multiplanar reconstruction (MPR) is the process of converting data from one anatomical plane (usually transverse) to other planes. It can be used for thin slices as well as projections. Multiplanar reconstruction is possible as present CT scanners provide almost isotropic resolution.
MPR is used almost in every scan. The spine is frequently examined with it. An image of the spine in axial plane can only show one vertebral bone at a time and cannot show its relation with other vertebral bones. By reformatting the data in other planes, visualization of the relative position can be achieved in sagittal and coronal plane.
New software allows the reconstruction of data in non-orthogonal (oblique) planes, which help in the visualization of organs which are not in orthogonal planes. It is better suited for visualization of the anatomical structure of the bronchi as they do not lie orthogonal to the direction of the scan.
Curved-plane reconstruction (or curved planar reformation = CPR) is performed mainly for the evaluation of vessels. This type of reconstruction helps to straighten the bends in a vessel, thereby helping to visualize a whole vessel in a single image or in multiple images. After a vessel has been "straightened", measurements such as cross-sectional area and length can be made. This is helpful in preoperative assessment of a surgical procedure.
For 2D projections used in radiation therapy for quality assurance and planning of external beam radiotherapy, including digitally reconstructed radiographs, see Beam's eye view.
==== Volume rendering ====
A threshold value of radiodensity is set by the operator (e.g., a level that corresponds to bone). With the help of edge detection image processing algorithms a 3D model can be constructed from the initial data and displayed on screen. Various thresholds can be used to get multiple models, each anatomical component such as muscle, bone and cartilage can be differentiated on the basis of different colours given to them. However, this mode of operation cannot show interior structures.
Surface rendering is limited technique as it displays only the surfaces that meet a particular threshold density, and which are towards the viewer. However, In volume rendering, transparency, colours and shading are used which makes it easy to present a volume in a single image. For example, Pelvic bones could be displayed as semi-transparent, so that, even viewing at an oblique angle one part of the image does not hide another.
=== Image quality ===
==== Dose versus image quality ====
An important issue within radiology today is how to reduce the radiation dose during CT examinations without compromising the image quality. In general, higher radiation doses result in higher-resolution images, while lower doses lead to increased image noise and unsharp images. However, increased dosage raises the adverse side effects, including the risk of radiation-induced cancer – a four-phase abdominal CT gives the same radiation dose as 300 chest X-rays. Several methods that can reduce the exposure to ionizing radiation during a CT scan exist.
New software technology can significantly reduce the required radiation dose. New iterative tomographic reconstruction algorithms (e.g., iterative Sparse Asymptotic Minimum Variance) could offer super-resolution without requiring higher radiation dose.
Individualize the examination and adjust the radiation dose to the body type and body organ examined. Different body types and organs require different amounts of radiation.
Higher resolution is not always suitable, such as detection of small pulmonary masses.
==== Artifacts ====
Although images produced by CT are generally faithful representations of the scanned volume, the technique is susceptible to a number of artifacts, such as the following:Chapters 3 and 5
Streak artifact
Streaks are often seen around materials that block most X-rays, such as metal or bone. Numerous factors contribute to these streaks: under sampling, photon starvation, motion, beam hardening, and Compton scatter. This type of artifact commonly occurs in the posterior fossa of the brain, or if there are metal implants. The streaks can be reduced using newer reconstruction techniques. Approaches such as metal artifact reduction (MAR) can also reduce this artifact. MAR techniques include spectral imaging, where CT images are taken with photons of different energy levels, and then synthesized into monochromatic images with special software such as GSI (Gemstone Spectral Imaging).
Partial volume effect
This appears as "blurring" of edges. It is due to the scanner being unable to differentiate between a small amount of high-density material (e.g., bone) and a larger amount of lower density (e.g., cartilage). The reconstruction assumes that the X-ray attenuation within each voxel is homogeneous; this may not be the case at sharp edges. This is most commonly seen in the z-direction (craniocaudal direction), due to the conventional use of highly anisotropic voxels, which have a much lower out-of-plane resolution, than in-plane resolution. This can be partially overcome by scanning using thinner slices, or an isotropic acquisition on a modern scanner.
Ring artifact
Probably the most common mechanical artifact, the image of one or many "rings" appears within an image. They are usually caused by the variations in the response from individual elements in a two dimensional X-ray detector due to defect or miscalibration. Ring artifacts can largely be reduced by intensity normalization, also referred to as flat field correction. Remaining rings can be suppressed by a transformation to polar space, where they become linear stripes. A comparative evaluation of ring artefact reduction on X-ray tomography images showed that the method of Sijbers and Postnov can effectively suppress ring artefacts.
Noise
This appears as grain on the image and is caused by a low signal to noise ratio. This occurs more commonly when a thin slice thickness is used. It can also occur when the power supplied to the X-ray tube is insufficient to penetrate the anatomy.
Windmill
Streaking appearances can occur when the detectors intersect the reconstruction plane. This can be reduced with filters or a reduction in pitch.
Beam hardening
This can give a "cupped appearance" when grayscale is visualized as height. It occurs because conventional sources, like X-ray tubes emit a polychromatic spectrum. Photons of higher photon energy levels are typically attenuated less. Because of this, the mean energy of the spectrum increases when passing the object, often described as getting "harder". This leads to an effect increasingly underestimating material thickness, if not corrected. Many algorithms exist to correct for this artifact. They can be divided into mono- and multi-material methods.
== Advantages ==
CT scanning has several advantages over traditional two-dimensional medical radiography. First, CT eliminates the superimposition of images of structures outside the area of interest. Second, CT scans have greater image resolution, enabling examination of finer details. CT can distinguish between tissues that differ in radiographic density by 1% or less. Third, CT scanning enables multiplanar reformatted imaging: scan data can be visualized in the transverse (or axial), coronal, or sagittal plane, depending on the diagnostic task.
The improved resolution of CT has permitted the development of new investigations. For example, CT angiography avoids the invasive insertion of a catheter. CT scanning can perform a virtual colonoscopy with greater accuracy and less discomfort for the patient than a traditional colonoscopy. Virtual colonography is far more accurate than a barium enema for detection of tumors and uses a lower radiation dose.
CT is a moderate-to-high radiation diagnostic technique. The radiation dose for a particular examination depends on multiple factors: volume scanned, patient build, number and type of scan protocol, and desired resolution and image quality. Two helical CT scanning parameters, tube current and pitch, can be adjusted easily and have a profound effect on radiation. CT scanning is more accurate than two-dimensional radiographs in evaluating anterior interbody fusion, although they may still over-read the extent of fusion.
== Adverse effects ==
=== Cancer ===
The radiation used in CT scans can damage body cells, including DNA molecules, which can lead to radiation-induced cancer. The radiation doses received from CT scans is variable. Compared to the lowest dose X-ray techniques, CT scans can have 100 to 1,000 times higher dose than conventional X-rays. However, a lumbar spine X-ray has a similar dose as a head CT. Articles in the media often exaggerate the relative dose of CT by comparing the lowest-dose X-ray techniques (chest X-ray) with the highest-dose CT techniques. In general, a routine abdominal CT has a radiation dose similar to three years of average background radiation.
Large scale population-based studies have consistently demonstrated that low dose radiation from CT scans has impacts on cancer incidence in a variety of cancers. For example, in a large population-based Australian cohort it was found that up to 3.7% of brain cancers were caused by CT scan radiation. Some experts project that in the future, between three and five percent of all cancers would result from medical imaging. An Australian study of 10.9 million people reported that the increased incidence of cancer after CT scan exposure in this cohort was mostly due to irradiation. In this group, one in every 1,800 CT scans was followed by an excess cancer. If the lifetime risk of developing cancer is 40% then the absolute risk rises to 40.05% after a CT. The risks of CT scan radiation are especially important in patients undergoing recurrent CT scans within a short time span of one to five years.
Some experts note that CT scans are known to be "overused," and "there is distressingly little evidence of better health outcomes associated with the current high rate of scans." On the other hand, a recent paper analyzing the data of patients who received high cumulative doses showed a high degree of appropriate use. This creates an important issue of cancer risk to these patients. Moreover, a highly significant finding that was previously unreported is that some patients received >100 mSv dose from CT scans in a single day, which counteracts existing criticisms some investigators may have on the effects of protracted versus acute exposure.
There are contrarian views and the debate is ongoing. Some studies have shown that publications indicating an increased risk of cancer from typical doses of body CT scans are plagued with serious methodological limitations and several highly improbable results, concluding that no evidence indicates such low doses cause any long-term harm.
One study estimated that as many as 0.4% of cancers in the United States resulted from CT scans, and that this may have increased to as much as 1.5 to 2% based on the rate of CT use in 2007. Others dispute this estimate, as there is no consensus that the low levels of radiation used in CT scans cause damage. Lower radiation doses are used in many cases, such as in the investigation of renal colic.
A person's age plays a significant role in the subsequent risk of cancer. Estimated lifetime cancer mortality risks from an abdominal CT of a one-year-old is 0.1%, or 1:1000 scans. The risk for someone who is 40 years old is half that of someone who is 20 years old with substantially less risk in the elderly. The International Commission on Radiological Protection estimates that the risk to a fetus being exposed to 10 mGy (a unit of radiation exposure) increases the rate of cancer before 20 years of age from 0.03% to 0.04% (for reference a CT pulmonary angiogram exposes a fetus to 4 mGy). A 2012 review did not find an association between medical radiation and cancer risk in children noting however the existence of limitations in the evidences over which the review is based. CT scans can be performed with different settings for lower exposure in children with most manufacturers of CT scans as of 2007 having this function built in. Furthermore, certain conditions can require children to be exposed to multiple CT scans.
Current recommendations are to inform patients of the risks of CT scanning. However, employees of imaging centers tend not to communicate such risks unless patients ask.
=== Contrast reactions ===
In the United States half of CT scans are contrast CTs using intravenously injected radiocontrast agents. The most common reactions from these agents are mild, including nausea, vomiting, and an itching rash. Severe life-threatening reactions may rarely occur. Overall reactions occur in 1 to 3% with nonionic contrast and 4 to 12% of people with ionic contrast. Skin rashes may appear within a week to 3% of people.
The old radiocontrast agents caused anaphylaxis in 1% of cases while the newer, low-osmolar agents cause reactions in 0.01–0.04% of cases. Death occurs in about 2 to 30 people per 1,000,000 administrations, with newer agents being safer.
There is a higher risk of mortality in those who are female, elderly or in poor health, usually secondary to either anaphylaxis or acute kidney injury.
The contrast agent may induce contrast-induced nephropathy. This occurs in 2 to 7% of people who receive these agents, with greater risk in those who have preexisting kidney failure, preexisting diabetes, or reduced intravascular volume. People with mild kidney impairment are usually advised to ensure full hydration for several hours before and after the injection. For moderate kidney failure, the use of iodinated contrast should be avoided; this may mean using an alternative technique instead of CT. Those with severe kidney failure requiring dialysis require less strict precautions, as their kidneys have so little function remaining that any further damage would not be noticeable and the dialysis will remove the contrast agent; it is normally recommended, however, to arrange dialysis as soon as possible following contrast administration to minimize any adverse effects of the contrast.
In addition to the use of intravenous contrast, orally administered contrast agents are frequently used when examining the abdomen. These are frequently the same as the intravenous contrast agents, merely diluted to approximately 10% of the concentration. However, oral alternatives to iodinated contrast exist, such as very dilute (0.5–1% w/v) barium sulfate suspensions. Dilute barium sulfate has the advantage that it does not cause allergic-type reactions or kidney failure, but cannot be used in patients with suspected bowel perforation or suspected bowel injury, as leakage of barium sulfate from damaged bowel can cause fatal peritonitis.
Side effects from contrast agents, administered intravenously in some CT scans, might impair kidney performance in patients with kidney disease, although this risk is now believed to be lower than previously thought.
=== Scan dose ===
The table reports average radiation exposures; however, there can be a wide variation in radiation doses between similar scan types, where the highest dose could be as much as 22 times higher than the lowest dose. A typical plain film X-ray involves radiation dose of 0.01 to 0.15 mGy, while a typical CT can involve 10–20 mGy for specific organs, and can go up to 80 mGy for certain specialized CT scans.
For purposes of comparison, the world average dose rate from naturally occurring sources of background radiation is 2.4 mSv per year, equal for practical purposes in this application to 2.4 mGy per year. While there is some variation, most people (99%) received less than 7 mSv per year as background radiation. Medical imaging as of 2007 accounted for half of the radiation exposure of those in the United States with CT scans making up two thirds of this amount. In the United Kingdom it accounts for 15% of radiation exposure. The average radiation dose from medical sources is ≈0.6 mSv per person globally as of 2007. Those in the nuclear industry in the United States are limited to doses of 50 mSv a year and 100 mSv every 5 years.
Lead is the main material used by radiography personnel for shielding against scattered X-rays.
==== Radiation dose units ====
The radiation dose reported in the gray or mGy unit is proportional to the amount of energy that the irradiated body part is expected to absorb, and the physical effect (such as DNA double strand breaks) on the cells' chemical bonds by X-ray radiation is proportional to that energy.
The sievert unit is used in the report of the effective dose. The sievert unit, in the context of CT scans, does not correspond to the actual radiation dose that the scanned body part absorbs but to another radiation dose of another scenario, the whole body absorbing the other radiation dose and the other radiation dose being of a magnitude, estimated to have the same probability to induce cancer as the CT scan. Thus, as is shown in the table above, the actual radiation that is absorbed by a scanned body part is often much larger than the effective dose suggests. A specific measure, termed the computed tomography dose index (CTDI), is commonly used as an estimate of the radiation absorbed dose for tissue within the scan region, and is automatically computed by medical CT scanners.
The equivalent dose is the effective dose of a case, in which the whole body would actually absorb the same radiation dose, and the sievert unit is used in its report. In the case of non-uniform radiation, or radiation given to only part of the body, which is common for CT examinations, using the local equivalent dose alone would overstate the biological risks to the entire organism.
==== Effects of radiation ====
Most adverse health effects of radiation exposure may be grouped in two general categories:
deterministic effects (harmful tissue reactions) due in large part to the killing/malfunction of cells following high doses;
stochastic effects, i.e., cancer and heritable effects involving either cancer development in exposed individuals owing to mutation of somatic cells or heritable disease in their offspring owing to mutation of reproductive (germ) cells.
The added lifetime risk of developing cancer by a single abdominal CT of 8 mSv is estimated to be 0.05%, or 1 one in 2,000.
Because of increased susceptibility of fetuses to radiation exposure, the radiation dosage of a CT scan is an important consideration in the choice of medical imaging in pregnancy.
==== Excess doses ====
In October, 2009, the US Food and Drug Administration (FDA) initiated an investigation of brain perfusion CT (PCT) scans, based on radiation burns caused by incorrect settings at one particular facility for this particular type of CT scan. Over 200 patients were exposed to radiation at approximately eight times the expected dose for an 18-month period; over 40% of them lost patches of hair. This event prompted a call for increased CT quality assurance programs. It was noted that "while unnecessary radiation exposure should be avoided, a medically needed CT scan obtained with appropriate acquisition parameter has benefits that outweigh the radiation risks." Similar problems have been reported at other centers. These incidents are believed to be due to human error.
== Procedure ==
CT scan procedure varies according to the type of the study and the organ being imaged. The patient lies on the CT table and the centering of the table is done according to the body part. The IV line is established in case of contrast-enhanced CT. After selecting proper and rate of contrast from the pressure injector, the scout is taken to localize and plan the scan. Once the plan is selected, the contrast is given. The raw data is processed according to the study and proper windowing is done to make scans easy to diagnose.
=== Preparation ===
Patient preparation may vary according to the type of scan. The general patient preparation includes.
Signing the informed consent.
Removal of metallic objects and jewelry from the region of interest.
Changing to the hospital gown according to hospital protocol.
Checking of kidney function, especially creatinine and urea levels (in case of CECT).
== Mechanism ==
Computed tomography operates by using an X-ray generator that rotates around the object; X-ray detectors are positioned on the opposite side of the circle from the X-ray source. As the X-rays pass through the patient, they are attenuated differently by various tissues according to the tissue density. A visual representation of the raw data obtained is called a sinogram, yet it is not sufficient for interpretation. Once the scan data has been acquired, the data must be processed using a form of tomographic reconstruction, which produces a series of cross-sectional images. These cross-sectional images are made up of small units of pixels or voxels.
Pixels in an image obtained by CT scanning are displayed in terms of relative radiodensity. The pixel itself is displayed according to the mean attenuation of the tissue(s) that it corresponds to on a scale from +3,071 (most attenuating) to −1,024 (least attenuating) on the Hounsfield scale. A pixel is a two dimensional unit based on the matrix size and the field of view. When the CT slice thickness is also factored in, the unit is known as a voxel, which is a three-dimensional unit.
Water has an attenuation of 0 Hounsfield units (HU), while air is −1,000 HU, cancellous bone is typically +400 HU, and cranial bone can reach 2,000 HU or more (os temporale) and can cause artifacts. The attenuation of metallic implants depends on the atomic number of the element used: Titanium usually has an amount of +1000 HU, iron steel can completely extinguish the X-ray and is, therefore, responsible for well-known line-artifacts in computed tomograms. Artifacts are caused by abrupt transitions between low- and high-density materials, which results in data values that exceed the dynamic range of the processing electronics. Two-dimensional CT images are conventionally rendered so that the view is as though looking up at it from the patient's feet. Hence, the left side of the image is to the patient's right and vice versa, while anterior in the image also is the patient's anterior and vice versa. This left-right interchange corresponds to the view that physicians generally have in reality when positioned in front of patients.
Initially, the images generated in CT scans were in the transverse (axial) anatomical plane, perpendicular to the long axis of the body. Modern scanners allow the scan data to be reformatted as images in other planes. Digital geometry processing can generate a three-dimensional image of an object inside the body from a series of two-dimensional radiographic images taken by rotation around a fixed axis. These cross-sectional images are widely used for medical diagnosis and therapy.
=== Contrast ===
Contrast media used for X-ray CT, as well as for plain film X-ray, are called radiocontrasts. Radiocontrasts for CT are, in general, iodine-based. This is useful to highlight structures such as blood vessels that otherwise would be difficult to delineate from their surroundings. Using contrast material can also help to obtain functional information about tissues. Often, images are taken both with and without radiocontrast.
== History ==
The history of X-ray computed tomography goes back to at least 1917 with the mathematical theory of the Radon transform. In October 1963, William H. Oldendorf received a U.S. patent for a "radiant energy apparatus for investigating selected areas of interior objects obscured by dense material". The first commercially viable CT scanner was invented by Godfrey Hounsfield in 1972.
It is often claimed that revenues from the sales of The Beatles' records in the 1960s helped fund the development of the first CT scanner at EMI. The first production X-ray CT machines were in fact called EMI scanners.
=== Etymology ===
The word tomography is derived from the Greek tome 'slice' and graphein 'to write'. Computed tomography was originally known as the "EMI scan" as it was developed in the early 1970s at a research branch of EMI, a company best known today for its music and recording business. It was later known as computed axial tomography (CAT or CT scan) and body section röntgenography.
The term CAT scan is no longer in technical use because current CT scans enable for multiplanar reconstructions. This makes CT scan the most appropriate term, which is used by radiologists in common vernacular as well as in textbooks and scientific papers.
In Medical Subject Headings (MeSH), computed axial tomography was used from 1977 to 1979, but the current indexing explicitly includes X-ray in the title.
The term sinogram was introduced by Paul Edholm and Bertil Jacobson in 1975.
== Society and culture ==
=== Campaigns ===
In response to increased concern by the public and the ongoing progress of best practices, the Alliance for Radiation Safety in Pediatric Imaging was formed within the Society for Pediatric Radiology. In concert with the American Society of Radiologic Technologists, the American College of Radiology and the American Association of Physicists in Medicine, the Society for Pediatric Radiology developed and launched the Image Gently Campaign which is designed to maintain high-quality imaging studies while using the lowest doses and best radiation safety practices available on pediatric patients. This initiative has been endorsed and applied by a growing list of various professional medical organizations around the world and has received support and assistance from companies that manufacture equipment used in Radiology.
Following upon the success of the Image Gently campaign, the American College of Radiology, the Radiological Society of North America, the American Association of Physicists in Medicine and the American Society of Radiologic Technologists have launched a similar campaign to address this issue in the adult population called Image Wisely.
The World Health Organization and International Atomic Energy Agency (IAEA) of the United Nations have also been working in this area and have ongoing projects designed to broaden best practices and lower patient radiation dose.
=== Prevalence ===
Use of CT has increased dramatically over the last two decades. An estimated 72 million scans were performed in the United States in 2007, accounting for close to half of the total per-capita dose rate from radiologic and nuclear medicine procedures. Of the CT scans, six to eleven percent are done in children, an increase of seven to eightfold from 1980. Similar increases have been seen in Europe and Asia. In Calgary, Canada, 12.1% of people who present to the emergency with an urgent complaint received a CT scan, most commonly either of the head or of the abdomen. The percentage who received CT, however, varied markedly by the emergency physician who saw them from 1.8% to 25%. In the emergency department in the United States, CT or MRI imaging is done in 15% of people who present with injuries as of 2007 (up from 6% in 1998).
The increased use of CT scans has been the greatest in two fields: screening of adults (screening CT of the lung in smokers, virtual colonoscopy, CT cardiac screening, and whole-body CT in asymptomatic patients) and CT imaging of children. Shortening of the scanning time to around 1 second, eliminating the strict need for the subject to remain still or be sedated, is one of the main reasons for the large increase in the pediatric population (especially for the diagnosis of appendicitis). As of 2007, in the United States a proportion of CT scans are performed unnecessarily. Some estimates place this number at 30%. There are a number of reasons for this including: legal concerns, financial incentives, and desire by the public. For example, some healthy people avidly pay to receive full-body CT scans as screening. In that case, it is not at all clear that the benefits outweigh the risks and costs. Deciding whether and how to treat incidentalomas is complex, radiation exposure is not negligible, and the money for the scans involves opportunity cost.
== Manufacturers ==
Major manufacturers of CT scanning devices and equipment are:
Canon Medical Systems Corporation
Fujifilm Healthcare
GE HealthCare
Neusoft Medical Systems
Philips
Siemens Healthineers
United Imaging
== Research ==
Photon-counting computed tomography is a CT technique currently under development. Typical CT scanners use energy integrating detectors; photons are measured as a voltage on a capacitor which is proportional to the X-rays detected. However, this technique is susceptible to noise and other factors which can affect the linearity of the voltage to X-ray intensity relationship. Photon counting detectors (PCDs) are still affected by noise but it does not change the measured counts of photons. PCDs have several potential advantages, including improving signal (and contrast) to noise ratios, reducing doses, improving spatial resolution, and through use of several energies, distinguishing multiple contrast agents. PCDs have only recently become feasible in CT scanners due to improvements in detector technologies that can cope with the volume and rate of data required. As of February 2016, photon counting CT is in use at three sites. Some early research has found the dose reduction potential of photon counting CT for breast imaging to be very promising. In view of recent findings of high cumulative doses to patients from recurrent CT scans, there has been a push for scanning technologies and techniques that reduce ionising radiation doses to patients to sub-milliSievert (sub-mSv in the literature) levels during the CT scan process, a goal that has been lingering.
== See also ==
== References ==
== External links ==
Development of CT imaging
CT Artefacts—PPT by David Platten
Filler A (2009-06-30). "The History, Development and Impact of Computed Imaging in Neurological Diagnosis and Neurosurgery: CT, MRI, and DTI". Nature Precedings: 1. doi:10.1038/npre.2009.3267.4. ISSN 1756-0357.
Boone JM, McCollough CH (2021). "Computed tomography turns 50". Physics Today. 74 (9): 34–40. Bibcode:2021PhT....74i..34B. doi:10.1063/PT.3.4834. ISSN 0031-9228. S2CID 239718717. | Wikipedia/Computed_tomography_of_the_heart |
Pulmonary heart disease, also known as cor pulmonale, is the enlargement and failure of the right ventricle of the heart as a response to increased vascular resistance (such as from pulmonic stenosis) or high blood pressure in the lungs.
Chronic pulmonary heart disease usually results in right ventricular hypertrophy (RVH), whereas acute pulmonary heart disease usually results in dilatation. Hypertrophy is an adaptive response to a long-term increase in pressure. Individual muscle cells grow larger (in thickness) and change to drive the increased contractile force required to move the blood against greater resistance. Dilatation is a stretching (in length) of the ventricle in response to acute increased pressure.
To be classified as pulmonary heart disease, the cause must originate in the pulmonary circulation system; RVH due to a systemic defect is not classified as pulmonary heart disease. Two causes are vascular changes as a result of tissue damage (e.g. disease, hypoxic injury), and chronic hypoxic pulmonary vasoconstriction. If left untreated, then death may result. The heart and lungs are intricately related; whenever the heart is affected by a disease, the lungs risk following and vice versa.
== Signs and symptoms ==
The symptoms/signs of pulmonary heart disease (cor pulmonale) can be non-specific and depend on the stage of the disorder, and can include blood backing up into the systemic venous system, including the hepatic vein. As pulmonary heart disease progresses, most individuals will develop symptoms like:
Shortness of breath
Wheezing
Cyanosis
Ascites
Jaundice
Enlargement of the liver
Raised jugular venous pressure (JVP)
Third heart sound
Intercostal recession
Presence of abnormal heart sounds
== Causes ==
The causes of pulmonary heart disease (cor pulmonale) are the following:
Acute respiratory distress syndrome (ARDS)
COPD
Primary pulmonary hypertension
Blood clots in lungs/Pulmonary embolism
Kyphoscoliosis
Interstitial lung disease
Cystic fibrosis
Sarcoidosis
Obstructive sleep apnea (untreated)
Sickle cell anemia
Bronchopulmonary dysplasia (in infants)
== Pathophysiology ==
The pathophysiology of pulmonary heart disease (cor pulmonale) has always indicated that an increase in right ventricular afterload causes RV failure (pulmonary vasoconstriction, anatomic disruption/pulmonary vascular bed and increased blood viscosity are usually involved), however most of the time, the right ventricle adjusts to an overload in chronic pressure. According to Voelkel, et al., pressure overload is the initial step for changes in RV, other factors include:
Ischemia
Inflammation
Oxidative damage
Epigenetics
Abnormal cardiac energetics
== Diagnosis ==
Investigations available to determine the cause of cor pulmonale include the following:
Chest x-ray – right ventricular hypertrophy, right atrial dilatation, prominent pulmonary artery
ECG – right ventricular hypertrophy, dysrhythmia, P pulmonale (characteristic peaked P wave)
Thrombophilia screen- to detect chronic venous thromboembolism (proteins C and S, antithrombin III, homocysteine levels)
=== Differential diagnosis ===
The diagnosis of pulmonary heart disease is not easy as both lung and heart disease can produce similar symptoms. Therefore, the differential diagnosis (DDx) should assess:
Atrial myxoma
Congestive heart failure
Constrictive pericarditis
Infiltrative cardiomyopathies
Right heart failure (right ventricular infarction)
Ventricular septal defect
== Treatment ==
The treatment for cor pulmonale can include the following: antibiotics, expectorants, oxygen therapy, diuretics, digitalis, vasodilators, and anticoagulants. Some studies have indicated that Shenmai injection with conventional treatment is safe and effective for cor pulmonale (chronic).
Treatment requires diuretics (to decrease strain on the heart). Oxygen is often required to resolve the shortness of breath. Additionally, oxygen to the lungs also helps relax the blood vessels and eases right heart failure. When wheezing is present, the majority of individuals require a bronchodilator. A variety of medications have been developed to relax the blood vessels in the lung, calcium channel blockers are used but only work in few cases and according to NICE are not recommended for use at all.
Anticoagulants are used when venous thromboembolism is present. Venesection is used in severe secondary polycythemia (because of hypoxia), which improves symptoms though survival rate has not been proven to increase. Finally, transplantation of single/double lung in extreme cases of cor pulmonale is also an option.
== Epidemiology ==
The epidemiology of pulmonary heart disease (cor pulmonale) accounts for 7% of all heart disease in the U.S. According to Weitzenblum, et al., the mortality that is related to cor pulmonale is not easy to ascertain, as it is a complication of COPD.
== See also ==
Bilharzial cor pulmonale.
== References ==
== Further reading ==
Forfia, Paul R.; Vaidya, Anjali; Wiegers, Susan E. (2013-01-01). "Pulmonary heart disease: The heart-lung interaction and its impact on patient phenotypes". Pulmonary Circulation. 3 (1): 5–19. doi:10.4103/2045-8932.109910. ISSN 2045-8932. PMC 3641739. PMID 23662171.
Taussig, Lynn M.; Landau, Louis I. (2008-04-09). Pediatric Respiratory Medicine. Elsevier Health Sciences. ISBN 978-0323070720.
Jamal, K.; Fleetham, J. A.; Thurlbeck, W. M. (1990-05-01). "Cor Pulmonale: Correlation with Central Airway Lesions, Peripheral Airway Lesions, Emphysema, and Control of Breathing". American Review of Respiratory Disease. 141 (5_pt_1): 1172–1177. doi:10.1164/ajrccm/141.5_Pt_1.1172. ISSN 0003-0805. PMID 2339840.
== External links == | Wikipedia/Pulmonary_heart_disease |
Endocrine diseases are disorders of the endocrine system. The branch of medicine associated with endocrine disorders is known as endocrinology. Interconnected
== Types of disease ==
Broadly speaking, endocrine disorders may be subdivided into three groups:
Endocrine gland hypofunction/hyposecretion (leading to hormone deficiency)
Endocrine gland hyperfunction/hypersecretion (leading to hormone excess)
Tumours (benign or malignant) of endocrine glands
Endocrine disorders are often quite complex, involving a mixed picture of hyposecretion and hypersecretion because of the feedback mechanisms involved in the endocrine system. For example, most forms of hyperthyroidism are associated with an excess of thyroid hormone and a low level of thyroid stimulating hormone.
== List of diseases ==
=== Glucose homeostasis disorders ===
Diabetes
Type 1 Diabetes
Type 2 Diabetes
Gestational Diabetes
Mature Onset Diabetes of the Young
Diabetic myopathy
Hypoglycemia
Idiopathic hypoglycemia
Insulinoma
Glucagonoma
=== Thyroid disorders ===
Goitre
Hyperthyroidism
Graves-Basedow disease
Toxic multinodular goitre
Thyrotoxic myopathy
Hypothyroidism
Hypothyroid myopathies
Kocher-Debre-Semelaigne syndrome
Hoffmann syndrome
Myasthenic syndrome
Atrophic form
Thyroiditis
Hashimoto's thyroiditis
Thyroid cancer
Thyroid hormone resistance
=== Calcium homeostasis disorders and Metabolic bone disease ===
Parathyroid gland disorders
Hyperparathyroidism
Primary hyperparathyroidism
Secondary hyperparathyroidism
Tertiary hyperparathyroidism
Hyperparathyroid myopathy
Hypoparathyroidism
Pseudohypoparathyroidism
Hypoparathyroid myopathy
Osteoporosis
Osteitis deformans (Paget's disease of bone)
Rickets
Osteomalacia
=== Pituitary gland disorders ===
==== Posterior pituitary ====
Diabetes insipidus
Syndrome of inappropriate antidiuretic hormone secretion (SIADH)
==== Anterior pituitary ====
Hypopituitarism (or Panhypopituitarism)
Pituitary tumors
Pituitary adenomas
Prolactinoma (or Hyperprolactinemia)
Acromegaly, gigantism, dwarfism
Cushing's disease
=== Adrenal gland disorders ===
Addison's disease
Adrenal crisis
Adrenal insufficiency
Adrenal tumour
Congenital adrenal hyperplasia
Hypercortisolism (Cushing's disease)
Steroid myopathy
Hypoaldosteronism
Hyperaldosteronism
=== Sex hormone disorders ===
Disorders of sex development or intersex disorders
Hermaphroditism
Gonadal dysgenesis
Androgen insensitivity syndromes
Hypogonadism (Gonadotropin deficiency)
Inherited (genetic and chromosomal) disorders
Kallmann syndrome
Klinefelter syndrome
Turner syndrome
Acquired disorders
Ovarian failure (also known as Premature Menopause)
Testicular failure
Testosterone deficiency myopathy
Disorders of Puberty
Delayed puberty
Precocious puberty
Menstrual function or fertility disorders
Amenorrhea
Polycystic ovary syndrome (PCOS)
=== Tumours of the endocrine glands not mentioned elsewhere ===
Multiple endocrine neoplasia
MEN type 1
MEN type 2a
MEN type 2b
Carcinoid syndrome
=== See also separate organs ===
Autoimmune polyendocrine syndromes
Incidentaloma - an unexpected finding on diagnostic imaging, often of endocrine glands
== Endocrine emergencies ==
In endocrinology, medical emergencies include diabetic ketoacidosis, hyperosmolar hyperglycemic state, hypoglycemic coma, acute adrenocortical insufficiency, phaeochromocytoma crisis, hypercalcemic crisis, thyroid storm, myxoedema coma and pituitary apoplexy.
Emergencies arising from decompensated pheochromocytomas or parathyroid adenomas are sometimes referred for emergency resection when aggressive medical therapies fail to control the patient's state, however the surgical risks are significant, especially blood pressure lability and the possibility of cardiovascular collapse after resection (due to a brutal drop in respectively catecholamines and calcium, which must be compensated with gradual normalization). It remains debated when emergency surgery is appropriate as opposed to urgent or elective surgery after continued attempts to stabilize the patient, notably in view of newer and more efficient medications and protocols.
== See also ==
List of MeSH codes (C19)
List of ICD-9 codes 240-279: Endocrine, nutritional and metabolic diseases, and immunity disorders
Diabetes self-management
== References ==
== External links ==
Endocrine+system+diseases at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
MedlinePlus Overview endocrinediseases | Wikipedia/Endocrine_diseases |
Bentham Science Publishers is a company that publishes scientific, technical, and medical journals and e-books. It publishes over 120 subscription-based academic journals and around 40 open access journals.
As of 2023, 66 Bentham Science journals have received JCR impact factors, and they are a member of the Committee on Publication Ethics. Bentham Open, its open access division, has received criticism for questionable peer-review practices as well as invitation spam; it was listed as a "potential, possible, or probable predatory scholarly open access publisher" in Jeffrey Beall's list of predatory publishers, before the list went defunct.
== History ==
Bentham was incorporated in 1994 by Atta-ur-Rahman and his friend Matthew Honan as a private business entity at the Sharjah Airport International Free Trade Zone in the United Arab Emirates. An investigative profile from Sujag notes the publisher to have operated out of Pakistan — for the first six years, from the premises of International Center for Chemical and Biological Sciences and then, from private residential blocks at Karachi — in reality, under the banner of a tax-exempt proxy firm, owned by Rahman's sons.
As of 2022, the publisher publishes more than 120 subscription-based journals, indexed in Scopus, Chemical Abstracts, MEDLINE, EMBASE, etc. Bentham Open Access published more than 150 peer-reviewed, free-to-view online journals under Bentham Open.
== Criticism of Bentham Open ==
Bentham Open journals claim to employ peer review; however, a fake paper that was generated using SCIgen in 2009 was accepted for publication, though it was never officially published and the publisher has since contended that the acceptance was a play-along to catch the author. The author, a graduate student at Cornell University, was motivated into the submission after being bombarded with unsolicited invitations to publish in Bentham's journals and offers to serve in their editorial boards for topics beyond his expertise. In consequence, some editors quit the collaboration with Bentham. In 2013, the now-discontinued The Open Bioactive Compounds Journal again accepted a blatantly bogus paper submitted as part of the Who's Afraid of Peer Review? sting.
Bentham Open has been accused of spamming scientists to become members of the editorial boards of its journals since 2008. In a 2017 study of invitation spam by publishers, Bentham Open was noted to be a habitual offender.
In 2009, the Bentham Open Science journal The Open Chemical Physics Journal published a study contending dust from the World Trade Center attacks contained "active nanothermite", a well known 9/11 conspiracy theory. The journal's editor-in-chief Marie-Paule Pileni claimed the article was published without her authorization, and resigned. In a July 2009 review of Bentham Open for The Charleston Advisor, Jeffrey Beall accused Bentham Open of exploiting the Open Access model to make quick money, and rejected that they employed any meaningful peer-review. Beall had since added Bentham Open to his list of "Potential, possible, or probable predatory scholarly open-access publishers".
== Notes ==
== References ==
== External links ==
Official website
Bentham Open Archives website | Wikipedia/Current_Drug_Targets |
An antiplatelet drug (antiaggregant), also known as a platelet agglutination inhibitor or platelet aggregation inhibitor, is a member of a class of pharmaceuticals that decrease platelet aggregation and inhibit thrombus formation. They are effective in the arterial circulation where classical Vitamin K antagonist anticoagulants have minimal effect.
Antiplatelet drugs are widely used in primary and secondary prevention of thrombotic disease, especially myocardial infarction and ischemic stroke.
Antiplatelet therapy with one or more of these drugs decreases the ability of blood clots to form by interfering with the platelet activation process in primary hemostasis. Antiplatelet drugs can reversibly or irreversibly inhibit the process involved in platelet activation resulting in decreased tendency of platelets to adhere to one another and to damaged blood vessels' endothelium.
== Choice ==
Antiplatelet medications are one of the primary recommendations for treatment of both stable and unstable ischemic heart disease. Most commonly, aspirin is used as a single medication in cases of uncomplicated stable angina, and in some cases of unstable angina. If a patient does not tolerate aspirin, ADP/P2Y inhibitors may be used as single-drug therapy instead. More severe and complicated cases are treated with dual antiplatelet therapy, or in some cases triple therapy that includes direct oral anticoagulants. Clinicians must make a choice that balances patient risk with the increased risks of bleeding associated with combination therapy.
== Dual antiplatelet therapy ==
Often a combination of aspirin plus an ADP/P2Y inhibitor (such as clopidogrel, prasugrel, ticagrelor, or another) is used to obtain greater effectiveness than with either agent alone. This is known as "dual antiplatelet therapy" (or DAPT). DAPT is used in patients who have, or are at high risk of developing, unstable angina, NSTEMI myocardial infarctions, and other high-risk thrombotic conditions. Dual antiplatelet therapy has been found to significantly reduce rates of heart attacks, strokes, and overall cardiovascular death, but is not used in low-risk patients because it significantly increases the risks of major bleeding.
== Classification ==
Classes of antiplatelet drugs include:
Adenosine diphosphate (ADP) receptor inhibitors
Cangrelor (Kengreal)
Clopidogrel (Plavix)
Prasugrel (Effient)
Ticagrelor (Brilinta)
Ticlopidine (Ticlid)
Adenosine reuptake inhibitors
Dipyridamole (Persantine)
Glycoprotein IIB/IIIA inhibitors (intravenous use only)
Abciximab (ReoPro)
Eptifibatide (Integrilin)
Tirofiban (Aggrastat)
Irreversible cyclooxygenase inhibitors
Aspirin
Triflusal (Disgren)
Phosphodiesterase inhibitors
Cilostazol (Pletaal)
Protease-activated receptor-1 antagonists (which inhibit the protease-activated receptor 1 a.k.a. PAR-1)
Vorapaxar (Zontivity)
Thromboxane inhibitors
Thromboxane receptor antagonists
Terutroban
Thromboxane synthase inhibitors
== Usage ==
=== Prevention and treatment of arterial thrombosis ===
Prevention and treatment of arterial thrombosis is essential in patients with certain medical conditions whereby the risk of thrombosis or thromboembolism may result in disastrous consequences such as heart attack, pulmonary embolism or stroke. Patients who require the use of antiplatelet drugs are: stroke with or without atrial fibrillation, any heart surgery (especially prosthetic replacement heart valve), Coronary Heart Disease such as stable angina, unstable angina and heart attack, patients with coronary stent, Peripheral Vascular Disease/Peripheral Arterial Disease and apical/ventricular/mural thrombus.
Treatment of established arterial thrombosis includes the use of antiplatelet drugs and thrombolytic therapy. Antiplatelet drugs alter the platelet activation at the site of vascular damage crucial to the development of arterial thrombosis.
Aspirin and Triflusal irreversibly inhibits the enzyme COX, resulting in reduced platelet production of TXA2 (thromboxane – powerful vasoconstrictor that lowers cyclic AMP and initiates the platelet release reaction).
Clopidogrel affects the ADP-dependent activation of IIb/IIIa complex
Dipyridamole inhibits platelet phosphodiesterase, causing an increase in cyclic AMP with potentiation of the action of PGI2 – opposes actions of TXA2
Epoprostenol is a prostacyclin that is used to inhibit platelet aggregation during renal dialysis (with or without heparin) and is also used in primary pulmonary hypertension.
Glycoprotein IIb/IIIa receptor antagonists block a receptor on the platelet for fibrinogen and von Willebrand factor. 3 classes:
Murine-human chimeric antibodies (e.g., abciximab)
Synthetic non-peptides (e.g., tirofiban)
Synthetic peptides (e.g., eptifibatide)
== Management in the perioperative period ==
Antiplatelet therapy may increase the risk of a bleed during surgery, however, stopping therapy may increase the risk of other thrombotic problems including myocardial infarction. When considering these medications and the risk-benefit ratio in the perioperative period, one must consider the risk of stopping the medication and a clot forming versus the risk of bleeding during or after the surgery if medication is continued. A 2018 Cochrane Review that included five randomized controlled trials found low-certainty evidence to suggest that continuing or discontinuing antiplatelet therapy for a non-cardiac surgery does not make a difference in mortality, major bleeds that require surgery, or ischaemic events. The same review found moderate certainty evidence that continuing or discontinuing therapy also did not have a big difference on the incidence of bleeds requiring a blood transfusion.
Balloon angioplasty in the preoperative period – patients can proceed to surgery two weeks after the procedure.
Bare metal stents required at least one month of DAPT
CABG: Patients may proceed with surgery as soon as they are healed from the coronary artery bypass procedure and they do not need any specific amount of time on DAPT
In patients with truly time-sensitive disease (defined in the 2014 ACC/AHA guidelines as needing to proceed in 2–6 weeks), DAPT can be stopped 3 (three) months (90 days) after a coronary stent is placed if postponing surgery any longer would result in significant morbidity. Examples of these types of surgeries include some cancer surgery and possibly some orthopedic surgery (non-urgent/emergent fracture management). Preferably 6 to 12 months of DAPT should be continued in patients having elective surgery.
== Dental management of patients on antiplatelet drugs ==
Dentists should be aware of the risk of prolonged bleeding time in patients taking antiplatelet drugs when planning dental treatments that are likely to cause bleeding. Therefore, it is important for dentists to know how to assess patient's bleeding risk and how to manage them.
=== Assess bleeding risk ===
Identify the likelihood and risk of dental treatment causing bleeding complications.
== Drug toxicity ==
Antiplatelet drugs effect may be affected by patient's medications, current medical conditions, food and supplements taken. Antiplatelet drugs effect may be increased or decreased. An increase in antiplatelet effect would increase the risk of bleeding and could cause prolonged or excessive bleeding. A decrease in antiplatelet effect would reduce the risk of bleeding, but increase the thromboembolic risk. Drug toxicity may increase when multiple antiplatelet drugs are used. Gastrointestinal bleeding is a common adverse event seen in many patients.
=== Medications ===
Medications that may increase antiplatelet drug effect:
Cytotoxic drugs or drugs associated with bone marrow suppression (e.g.: leflunomide, hydroxychloroquine, adalimumab, infliximab, etanercept, sulfasalazine, penicillamine, gold, methotrexate, azathioprine, mycophenolate)
Drugs affecting the nervous system (e.g.: Selective serotonin reuptake inhibitors (SSRIs))
NSAIDS (e.g.: aspirin, ibuprofen, diclofenac, naproxen)
Other anticoagulants or antiplatelet drugs
Medications that may decrease antiplatelet drug effect:
Carbamazepine
Erythromycin
Fluconazole
Omeprazole
Use of NSAIDs as part of dental management of patients with vascular disease should be discouraged as NSAIDs have antiplatelet effect. Instead, simple analgesics such as paracetamol or co-codamol should be of first choice. If NSAIDs are required, the risk of bleeding increases with duration of dental treatment.
=== Medical conditions ===
Medical conditions that may increase antiplatelet drugs' effect include:
Chronic kidney failure, liver disease, haematological malignancy, recent or current chemotherapy, advanced heart failure, mild forms of inherited bleeding disorders (e.g. haemophilia, Von Willebrand's disease) and idiopathic thrombocytopenic purpura.
=== Food and supplements ===
Food and supplements that may increase antiplatelet drugs' effect:
St. John's wort, ginkgo biloba, garlic.
== Oral antiplatelet drugs available in the UK ==
== See also ==
Anticoagulant drug
Nitrophorin
Thrombolytic drug
== References == | Wikipedia/Dual_antiplatelet_therapy |
Kidney disease, or renal disease, technically referred to as nephropathy, is damage to or disease of a kidney. Nephritis is an inflammatory kidney disease and has several types according to the location of the inflammation. Inflammation can be diagnosed by blood tests. Nephrosis is non-inflammatory kidney disease. Nephritis and nephrosis can give rise to nephritic syndrome and nephrotic syndrome respectively. Kidney disease usually causes a loss of kidney function to some degree and can result in kidney failure, the complete loss of kidney function. Kidney failure is known as the end-stage of kidney disease, where dialysis or a kidney transplant is the only treatment option.
Chronic kidney disease is defined as prolonged kidney abnormalities (functional and/or structural in nature) that last for more than three months. Acute kidney disease is now termed acute kidney injury and is marked by the sudden reduction in kidney function over seven days.
Rates for both chronic kidney disease and mortality have increased, associated with the rising prevalence of diabetes and the ageing global population. The World Health Organization has reported that "kidney diseases have risen from the world’s nineteenth leading cause of death to the ninth, with the number of deaths increasing by 95% between 2000 and 2021." In the United States, prevalence has risen from about one in eight in 2007, to one in seven in 2021.
== Causes ==
Causes of kidney disease include deposition of the Immunoglobulin A antibodies in the glomerulus, administration of analgesics, xanthine oxidase deficiency, toxicity of chemotherapy agents, and a long-term exposure to lead or its salts. Chronic conditions that can produce nephropathy include systemic lupus erythematosus, diabetes mellitus and high blood pressure (hypertension), which lead to diabetic nephropathy and hypertensive nephropathy, respectively.
=== Analgesics ===
One cause of nephropathy is the long term usage of pain medications known as analgesics. The pain medicines which can cause kidney problems include aspirin, acetaminophen, and nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen and naproxen. This form of nephropathy is "chronic analgesic nephritis", a chronic inflammatory change characterized by loss and atrophy of tubules and interstitial fibrosis and inflammation (BRS Pathology, 2nd ed.).
Specifically, long-term use of the analgesic phenacetin has been linked to renal papillary necrosis (necrotizing papillitis).
=== Diabetes ===
Diabetic nephropathy is a progressive kidney disease caused by angiopathy of the capillaries in the glomeruli. It is characterized by nephrotic syndrome and diffuse scarring of the glomeruli. It is particularly associated with poorly managed diabetes mellitus and is a primary reason for dialysis in many developed countries. It is classified as a small blood vessel complication of diabetes.
=== Autosomal dominant polycystic kidney disease ===
Gabow 1990 talks about autosomal dominant polycystic kidney disease and how this disease is genetic. They go on to say "Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic disease, affecting a half million Americans. The clinical phenotype can result from at least two different gene defects. One gene that can cause ADPKD has been located on the short arm of chromosome 16." The same article also goes on to say that millions of Americans are affected by this disease and it is very common.
=== COVID-19 ===
COVID-19 is associated with kidney disease. In patients hospitalized with COVID-19, the prevalence of acute kidney injury is estimated to be 28%, and the prevalence of renal replacement therapy is estimated to be 9%.
=== Diet ===
Higher dietary intake of animal protein, animal fat, and cholesterol may increase risk for microalbuminuria, a sign of kidney function decline, and generally, diets higher in fruits, vegetables, and whole grains but lower in meat and sweets may be protective against kidney function decline. This may be because sources of animal protein, animal fat, and cholesterol, and sweets are more acid-producing, while fruits, vegetables, legumes, and whole grains are more base-producing.
=== IgA nephropathy ===
IgA nephropathy is the most common glomerulonephritis throughout the world Primary IgA nephropathy is characterized by deposition of the IgA antibody in the glomerulus. The classic presentation (in 40–50% of the cases) is episodic frank hematuria which usually starts within a day or two of a non-specific upper respiratory tract infection (hence synpharyngitic) as opposed to post-streptococcal glomerulonephritis which occurs some time (weeks) after initial infection. Less commonly gastrointestinal or urinary infection can be the inciting agent. All of these infections have in common the activation of mucosal defenses and hence IgA antibody production.
=== Iodinated contrast media ===
Kidney disease induced by iodinated contrast media (ICM) is called contrast induced nephropathy (CIN) or contrast-induced acute kidney injury (AKI). Currently, the underlying mechanisms are unclear. But there is a body of evidence that several factors including apoptosis-induction seem to play a role.
=== Lithium ===
Lithium, a medication commonly used to treat bipolar disorder and schizoaffective disorders, can cause nephrogenic diabetes insipidus; its long-term use can lead to nephropathy.
=== Lupus ===
Despite expensive treatments, lupus nephritis remains a major cause of morbidity and mortality in people with relapsing or refractory lupus nephritis.
=== Xanthine oxidase deficiency ===
Another possible cause of Kidney disease is due to decreased function of xanthine oxidase in the purine degradation pathway. Xanthine oxidase will degrade hypoxanthine to xanthine and then to uric acid. Xanthine is not very soluble in water; therefore, an increase in xanthine forms crystals (which can lead to kidney stones) and result in damage to the kidney. Xanthine oxidase inhibitors, like allopurinol, can cause nephropathy.
=== Polycystic disease of the kidneys ===
Additional possible cause of nephropathy is due to the formation of cysts or pockets containing fluid within the kidneys. These cysts become enlarged with the progression of aging causing renal failure. Cysts may also form in other organs including the liver, brain, and ovaries. Polycystic kidney disease is a genetic disease caused by mutations in the PKD1, PKD2, and PKHD1 genes. This disease affects about half a million people in the US. Polycystic kidneys are susceptible to infections and cancer.
=== Toxicity of chemotherapy agents ===
Nephropathy can be associated with some therapies used to treat cancer. The most common form of kidney disease in cancer patients is acute kidney injury (AKI) which can usually be due to volume depletion from vomiting and diarrhea that occur following chemotherapy or occasionally due to kidney toxicities of chemotherapeutic agents. Kidney failure from break down of cancer cells, usually after chemotherapy, is unique to onconephrology. Several chemotherapeutic agents, for example cisplatin, are associated with acute and chronic kidney injuries. Newer agents such as anti-vascular endothelial growth factor (anti-VEGF) are also associated with similar injuries, as well as proteinuria, hypertension, and thrombotic microangiopathy.
== Diagnosis ==
The standard diagnostic workup of suspected kidney disease includes a medical history, physical examination, a urine test, and an ultrasound of the kidneys (renal ultrasonography). An ultrasound is essential in the diagnosis and management of kidney disease.
== Treatment ==
Treatment approaches for kidney disease focus on managing the symptoms, controlling the progression, and also treating co-morbidities that a person may have.
=== Dialysis ===
=== Transplantation ===
Millions of people across the world have kidney disease. Of those millions, several thousand will need dialysis or a kidney transplant at its end-stage. In the United States, as of 2008, 16,500 people needed a kidney transplant. Of those, 5,000 died while waiting for a transplant. Currently, there is a shortage of donors, and in 2007 there were only 64,606 kidney transplants in the world. This shortage of donors is causing countries to place monetary value on kidneys. Countries such as Iran and Singapore are eliminating their lists by paying their citizens to donate. Also, the black market accounts for 5–10 percent of transplants that occur worldwide. The act of buying an organ through the black market is illegal in the United States. To be put on the waiting list for a kidney transplant, patients must first be referred by a physician, then they must choose and contact a donor hospital. Once they choose a donor hospital, patients must then receive an evaluation to make sure they are sustainable to receive a transplant. In order to be a match for a kidney transplant, patients must match blood type and human leukocyte antigen factors with their donors. They must also have no reactions to the antibodies from the donor's kidneys.
== Prognosis ==
Kidney disease can have serious consequences if it cannot be controlled effectively. Generally, the progression of kidney disease is from mild to serious. Some kidney diseases can cause kidney failure.
== See also ==
Hematologic Diseases Information Service
Mesoamerican nephropathy, an enigmatic chronic kidney disease of Central America
Protein toxicity
== References ==
== External links == | Wikipedia/Kidney_diseases |
Left atrial enlargement (LAE) or left atrial dilation refers to enlargement of the left atrium (LA) of the heart, and is a form of cardiomegaly.
== Signs and symptoms ==
Left atrial enlargement can be mild, moderate or severe depending on the extent of the underlying condition. Although other factors may contribute, left atrium size has been found to be a predictor of mortality due to both cardiovascular issues as well as all-cause mortality. Research suggests that left atrium size as measured by an echo-cardiograph may be linked to cardiovascular disease. However, studies that have found LAE to be a predictor for mortality recognize the need for more standardized left atrium measurements than those found in an echo-cardiogram.
== Causes ==
In the general population, obesity appears to be the most important risk factor for LAE. LAE has been found to be correlated to body size, independent of obesity, meaning that LAE is more common in people with a naturally large body size. Also, a study found that LAE can occur as a consequence of atrial fibrillation (AF), although another study found that AF by itself does not cause LAE. The latter study also showed that the persistent type of AF was associated with LAE, but the number of years that a subject had AF was not.
Obstructive sleep apnea (OSA) may be a cause of LAE in some cases. When an OSA event occurs, an attempt is made to breathe with an obstructed airway and the pressure inside the chest is suddenly lowered. The negative intrathoracic pressure may cause the left atrium to expand and stretch its walls during each OSA event. Over time, the repetitive stretching of the left atrium may result in a persistent left atrial enlargement.
== Diagnosis ==
LAE is suggested by an electrocardiogram (ECG) that has a pronounced notch in the P wave. However, if atrial fibrillation is present, a P wave would not be present. In any case, LAE can be diagnosed and measured using an echocardiogram (ECHO) by measuring the left atrial volume (LAVI).
Characterizing the size of the left atrium according to its volume is preferred over a single linear dimension since enlargement can be different for different directions. For example, because of the smaller distance in the thoracic cavity between the sternum and spine, compared to the other directions, less room exists for enlargement of the left atrium along the anteroposterior axis. By approximating the shape of the left atrium as an ellipsoid, its volume can be calculated from measurements of its dimensions along three perpendicular directions.
Indexing the left atrial volume to body surface area (volume/BSA) is recommended by the American Society of Echocardiography and the European Association of Echocardiography. The values for volume/BSA in the following table are the best validated, and are the same for both men and women.
== References == | Wikipedia/Left_atrial_enlargement |
Peripheral artery disease (PAD) is a vascular disorder that causes abnormal narrowing of arteries other than those that supply the heart or brain. PAD can happen in any blood vessel, but it is more common in the legs than the arms.
When narrowing occurs in the heart, it is called coronary artery disease (CAD), and in the brain, it is called cerebrovascular disease. Peripheral artery disease most commonly affects the legs, but other arteries may also be involved, such as those of the arms, neck, or kidneys.
Peripheral artery disease (PAD) is a form of peripheral vascular disease. Vascular refers to the arteries and veins within the body. PAD differs from peripheral veinous disease. PAD means the arteries are narrowed or blocked—the vessels that carry oxygen-rich blood as it moves from the heart to other parts of the body. Peripheral veinous disease, on the other hand, refers to problems with veins—the vessels that bring the blood back to the heart.
The classic symptom is leg pain when walking, which resolves with rest and is known as intermittent claudication. Other symptoms include skin ulcers, bluish skin, cold skin, or abnormal nail and hair growth in the affected leg. Complications may include an infection or tissue death, which may require amputation; coronary artery disease; or stroke. Up to 50% of people with PAD do not have symptoms.
The greatest risk factor for PAD is cigarette smoking. Other risk factors include diabetes, high blood pressure, kidney problems, and high blood cholesterol. PAD is primarily caused by the buildup of fatty plaque in the arteries, which is called atherosclerosis, especially in individuals over 40 years old. Other mechanisms include artery spasm, blood clots, trauma, fibromuscular dysplasia, and vasculitis. PAD is typically diagnosed by finding an ankle-brachial index (ABI) less than 0.90, which is the systolic blood pressure at the ankle divided by the systolic blood pressure of the arm. Duplex ultrasonography and angiography may also be used. Angiography is more accurate and allows for treatment at the same time; however, it is associated with greater risks.
It is unclear if screening for peripheral artery disease in people without symptoms is useful, as it has not been properly studied. For those with intermittent claudication from PAD, stopping smoking and supervised exercise therapy may improve outcomes. Medications, including statins, ACE inhibitors, and cilostazol, may also help. Aspirin, which helps with thinning the blood and thus improving blood flow, does not appear to help those with mild disease but is usually recommended for those with more significant disease due to the increased risk of heart attacks. Anticoagulants (blood thinners) such as warfarin show no definitive scientific evidence of benefit in PAD. Surgical procedures used to treat PAD include bypass grafting, angioplasty, and atherectomy.
In 2015, about 155 million people had PAD worldwide. It becomes more common with age. In the developed world, it affects about 5.3% of 45- to 50-year-olds and 18.6% of 85- to 90-year-olds. In the developing world, it affects 4.6% of people between the ages of 45 and 50 and 15% of people between the ages of 85 and 90. PAD in the developed world is equally common among men and women, though in the developing world, women are more commonly affected. In 2015, PAD resulted in about 52,500 deaths, which is an increase from the 16,000 deaths in 1990.
== Signs and symptoms ==
The signs and symptoms of peripheral artery disease are based on the affected body part. About 66% of patients affected by PAD either do not have symptoms or have atypical symptoms. The most common presenting symptom is intermittent claudication (IC), which typically refers to lower extremity skeletal muscle pain that occurs during exercise. IC presents when there is insufficient oxygen delivery to meet the metabolic requirements of the skeletal muscles. IC is a common manifestation of peripheral arterial disease (PAD). The pain is usually located in the calf muscles of the affected leg and is relieved by rest. This occurs because during exercise, the muscles require more oxygen. Normally, the arteries would be able to increase the amount of blood flow and therefore increase the amount of oxygen going to the exercised muscle. However, in PAD, the artery cannot respond appropriately to the increased muscular demand for oxygen. Therefore, the muscles are deprived of oxygen, leading to muscle pain that subsides with rest.
Other symptoms may include:
Pain, aches, and/or cramps in the buttocks, hip, or thigh
Muscle atrophy (muscle loss) of the affected limb
Hair loss of the affected limb
Skin that is smooth, shiny, or cool to the touch in the affected area
Decreased or absent pulse in the feet
Cold and/or numbness in the toes
Sores/ulcers on the affected limb that do not heal
In individuals with severe PAD, complications may arise, including critical limb ischemia and gangrene. Critical limb ischemia occurs when the obstruction of blood flow in the artery is compromised to the point where the blood cannot maintain oxygenation of the tissue at rest. This can lead to pain at rest, a feeling of coldness, or numbness in the affected foot and toes. Other complications of severe PAD include lower limb tissue loss (amputation), arterial insufficiency ulcers, erectile dysfunction, and gangrene. People with diabetes are affected by gangrene of the feet at a rate that is 30 times higher than the unaffected population. Many of these severe complications, such as those leading to amputation, are irreversible.
== Causes ==
=== Risk factors ===
Factors contributing to an increased risk of PAD are the same as those for atherosclerosis. These include age, sex, and ethnicity. PAD is twice as common in males as in females. In terms of ethnicity, PAD is more common in people of color compared to the white population in a 2:1 ratio. The factors with the greatest risk associations are hyperlipidemia, hypertension, diabetes mellitus, chronic kidney disease, and smoking. Presenting three of these factors or more increases the risk of developing PAD tenfold.
Smoking – Tobacco use in any form is the single greatest risk factor for peripheral artery disease internationally. Smokers have up to a 10-fold increase in the risk of PAD in a dose-response relationship. Exposure to second-hand smoke has also been shown to promote changes in the lining of blood vessels (endothelium), which can lead to atherosclerosis. Smokers are 2–3 times more likely to have lower extremity PAD than coronary artery disease. Greater than 80%–90% of patients with lower extremity peripheral arterial disease are current or former smokers. The risk of PAD increases with the number of cigarettes smoked per day and the number of years smoked.
High blood sugar – Diabetes mellitus is shown to increase the risk of PAD by 2–4 fold. It does this by causing endothelial and smooth-muscle cell dysfunction in peripheral arteries. The risk of developing lower extremity peripheral arterial disease is proportional to the severity and duration of diabetes.
High blood cholesterol – Dyslipidemia is an unhealthy pattern of cholesterol or fat in the blood. Dyslipidemia is characterized by a high level of a protein called low-density lipoprotein (LDL cholesterol), low levels of high-density lipoprotein (HDL cholesterol), elevation of total cholesterol, and/or high triglyceride levels. This abnormality in blood cholesterol levels has been correlated with accelerated peripheral artery disease. Management of dyslipidemia by diet, exercise, and/or medication is associated with a major reduction in rates of heart attack and stroke.
High blood pressure – Hypertension or elevated blood pressure can increase a person's risk of developing PAD. Similarly to PAD, there is a known association between high blood pressure and heart attacks, strokes, and abdominal aortic aneurysms. High blood pressure increases the risk of intermittent claudication, the most common symptom of PAD, by 2.5- to 4-fold in men and women, respectively.
Other risk factors that are being studied include levels of various inflammatory mediators such as C-reactive protein, fibrinogen, homocysteine, and lipoprotein A. Individuals with increased levels of homocysteine in their blood have a 2-fold risk of developing peripheral artery disease. While there are genetic factors leading to risk factors for peripheral artery disease, including diabetes and high blood pressure, there have been no specific genes or gene mutations directly associated with the development of peripheral artery disease.
=== High risk populations ===
Peripheral arterial disease is more common in these populations:
All people who have leg symptoms with exertion (suggestive of claudication) or ischemic rest pain
All people aged 65 years and over, regardless of risk factor status
All people between 50 and 69 who have a cardiovascular risk factor (particularly diabetes or smoking)
Age less than 50 years, with diabetes and one other atherosclerosis risk factor (smoking, dyslipidemia, hypertension, or hyperhomocysteinemia)
Individuals with an abnormal lower extremity pulse examination
Those with known atherosclerotic coronary, carotid, or renal artery disease
All people with a Framingham risk score of 10%–20%
All people who have previously experienced chest pain
== Etiology and pathophysiology ==
Peripheral arterial disease is considered to be a set of chronic or acute syndromes, generally derived from the presence of occlusive arterial disease, which causes inadequate blood flow to the limbs.
As previously mentioned, the most common etiology of peripheral artery disease, especially in patients over 40 years old, is atherosclerosis. Atherosclerosis is a narrowing of the arteries caused by lipid or fat buildup and calcium deposition in the wall of the affected arteries.
The pathophysiology of atherosclerosis involves complex interactions between cholesterol and vascular cells. In the early stages of PAD, the arteries compensate for plaque buildup by dilating to preserve flow through the vessel. Eventually, the artery cannot dilate further, and the atherosclerotic plaque narrows the arterial flow lumen.
When there is an imbalance between the needs of the peripheral tissues and the blood supply, the affected person is faced with ischemia.
From the pathophysiologic point of view, a restriction of blood supply (ischemia) to the lower limbs can be classified as either functional or critical. Functional ischemia occurs when the blood flow is normal at rest but insufficient during exercise, presenting clinically as intermittent claudication. Critical ischemia is produced when the reduction in blood flow results in a perfusion deficit at rest and is defined by the presence of pain at rest or trophic lesions in the legs. In this situation, precise diagnosis is fundamental, as there is a clear risk of limb loss if adequate blood flow is not re-established, either by surgery or endovascular therapy. Differentiating between the two concepts is important to establish the therapeutic indication and the prognosis in patients with PAD.
Other causes include vasculitis and in situ thrombosis related to hypercoagulable states. Additional mechanisms of peripheral artery disease include arterial spasm and fibromuscular dysplasia. The cause and pathophysiology of arterial spasm are not fully understood, but it is hypothesized that they can occur secondary to trauma. The symptoms of claudication ensue when the artery spasms, or clamps down on itself, creating an obstruction. Like atherosclerosis, this leads to decreased blood flow to the tissue downstream of the obstruction. Thrombosis, or the formation of a blood clot, usually occurs due to stasis or trauma.
== Diagnosis ==
Diagnosing or identifying peripheral artery disease requires a history of symptoms and a physical exam, followed by confirmatory testing. These tests could include CT scans (Computed Tomographic Angiography), MRA scans (Magnetic Resonance Angiography), or ultrasounds for imaging. A physician will examine an individual for specific exam findings if symptoms are consistent with peripheral artery disease. Abnormal physical exam findings can lead a healthcare provider to consider the diagnosis. However, to confirm a diagnosis, confirmatory testing is required.
These findings are associated with peripheral artery disease:
Decreased or absent pulses
Muscle atrophy or wasting
Noticeable blueness of the affected limb
Decreased temperature (coolness) in the affected limb when compared to the other
Thickened nails
Smooth or shiny skin and hair loss
Buerger's test can check for pallor when the affected limb is in an elevated position. The limb is then moved from an elevated to a sitting position and checked for redness, which is called reactive hyperemia. Buerger's test is an assessment of arterial sufficiency, which is the ability of the artery to supply oxygenated blood to the tissue that it goes to.
Nonhealing lower extremity wound
If peripheral artery disease is suspected, the initial study is the ankle–brachial index (ABI). The ABI is a simple, non-invasive test that measures the ratio of systolic blood pressure in the ankle to the systolic blood pressure in the upper arm. This is based on the idea that if blood pressure readings in the ankle are lower than those in the arm, a blockage in the arteries that provide blood from the heart to the ankle is suspected. An ABI range of 0.90 to 1.40 is considered normal. A person is considered to have PAD when the ABI is ≤ 0.90. However, PAD can be further graded as mild to moderate if the ABI is between 0.41 and 0.90, and severe if the ABI is less than 0.40. These categories can provide insight into the disease course. Furthermore, ABI values of 0.91 to 0.99 are considered borderline, and values >1.40 indicate noncompressible arteries. If an ABI >1.40 is calculated, this could indicate vessel wall stiffness caused by calcification, which can occur in people with uncontrolled diabetes. Abnormally high ABIs (>1.40) are usually considered false negatives, and thus, such results merit further investigation and higher-level studies. Individuals with noncompressible arteries have an increased risk of cardiovascular mortality within two years.
Individuals with suspected PAD with normal ABIs can undergo exercise testing for ABI. A baseline ABI is obtained before exercise. The patient is then asked to exercise (usually patients are made to walk on a treadmill at a constant speed) until claudication pain occurs (for a maximum of 5 minutes), after which the ankle pressure is again measured. A decrease in ABI of 15%–20% would be diagnostic of PAD.
If ABIs are abnormal, the next step is generally a lower limb Doppler ultrasound to look at the site of obstruction and the extent of atherosclerosis. Other imaging can be performed by angiography, where a catheter is inserted into the common femoral artery and selectively guided to the artery in question. While injecting a radio-dense contrast agent, an X-ray is taken. Any blood flow-limiting blockage found in the X-ray can be identified and treated by procedures including atherectomy, angioplasty, or stenting. Contrast angiography is the most readily available and widely used imaging technique. Modern computerized tomography (CT) scanners provide direct imaging of the arterial system. Studies have shown the sensitivity and specificity of CT in identifying lesions with >50% stenosis to be 95% and 96%, respectively. As such, CT may be considered as an alternative to invasive angiography. An important distinction between the two is that, unlike invasive angiography, assessment of the arterial system with CT does not allow for vascular intervention.
Magnetic resonance angiography (MRA) is a noninvasive diagnostic procedure that uses a combination of a large magnet, radio frequencies, and a computer to produce detailed images of blood vessels inside the body. The advantages of MRA include its safety and ability to provide high-resolution, three-dimensional imaging of the entire abdomen, pelvis, and lower extremities in one sitting.
=== Classification ===
The two most commonly used methods to classify peripheral artery disease are the Fontaine and Rutherford classification systems. The Fontaine stages were introduced by René Fontaine in 1954 to define the severity of chronic limb ischemia:
Stage I: asymptomatic
Stage IIa: intermittent claudication after walking a distance of more than 200 meters
Stage IIb: intermittent claudication after walking a distance of less than 200 meters
Stage III: rest pain
Stage IV: ulcers or gangrene of the limb
The Rutherford classification was created by the Society for Vascular Surgery and the International Society of Cardiovascular Surgery, introduced in 1986 and revised in 1997 (and known as the Rutherford classification after the lead author, Robert B. Rutherford). This classification system consists of four grades and seven categories (categories 0–6):
Grade 0, Category 0: asymptomatic
Grade I, Category 1: mild claudication
Grade I, Category 2: moderate claudication
Grade I, Category 3: severe claudication
Grade II, Category 4: rest pain
Grade III, Category 5: minor tissue loss; ischemic ulceration not exceeding ulcer of the digits of the foot
Grade IV, Category 6: major tissue loss; severe ischemic ulcers or frank gangrene
Moderate to severe PAD, classified by Fontaine's stages III to IV or Rutherford's categories 4 to 5, presents a limb threat (risk of limb loss) in the form of critical limb ischemia.
Recently, the Society for Vascular Surgery came out with a classification system based on "wound, ischemia and foot infection" (WIfI). This classification system, published in 2013, was created to account for the demographic changes that have occurred over the past forty years, including the increased incidence of high blood sugar and evolving techniques and abilities for revascularization. This system was created on the basis that ischemia and angiographic disease patterns are not the sole determinants of amputation risk. The WIfI classification system is broken up into two parts: wounds and ischemia. Wounds are graded 0 through 3 based on the presence of ulceration, gangrene, and ischemia.
Grade 0: no ulcer, no gangrene
Grade 1: small, shallow ulcer; no gangrene
Grade 2: deep ulcer with exposed tendon or bone, gangrene limited to toes
Grade 3: extensive, full-thickness ulcer; gangrene extending to the forefoot or midfoot
Ischemia is graded 0 through 3 based on ABI, ankle systolic pressure, and toe pressure.
Grade 0: ABI ≥0.80, ankle systolic pressure ≥100 mm Hg, toe pressure ≥60 mm Hg
Grade 1: arterial brachial index 0.6 to 0.79, ankle systolic pressure 70 to 100 mm Hg, toe pressure 40 to 59 mm Hg
Grade 2: ABI 0.4–0.59, ankle systolic pressure 50 to 70 mm Hg, toe pressure 30 to 39 mm Hg
Grade 3: ABI ≤0.39, ankle systolic pressure <50 mm Hg, toe pressure <30 mm Hg
The TASC (and TASC II) classification suggests PAD treatment is based on the severity of the disease seen on an angiogram.
=== Screening ===
It is unclear if screening for disease in the general population is useful, as it has not been extensively studied. This includes screening with the ankle-brachial index (ABI), although a systematic review of the literature did not support the use of routine ABI screening in asymptomatic patients.
Testing for coronary artery disease or carotid artery disease is of unclear benefit. While PAD is a risk factor for abdominal aortic aneurysms (AAA), there is no data on screening individuals with asymptomatic PAD for abdominal aortic aneurysms. For people with symptomatic PAD, screening by ultrasound for AAA is not unreasonable.
=== Wearable devices and remote patient monitoring ===
A 2022 review found that a variety of wearable medical devices measuring different parameters (such as body temperature) were being combined with remote patient monitoring of PAD patients, to improve health outcomes.
Some studies propose the development of devices measuring oxygen continuously during exercise. This is because resting perfusion and metabolic activity are extremely low and differences between non-patients and PAD patients are barely measurable. As such, testing of vascular function and energetics requires a physiological challenge. Pulse oximeters can be inconvenient to wear during exercise and only give oxygen values at discrete time points, nor is there sufficient evidence to support any use in identifying PAD. Some publications and studies therefore discuss the use of wearable sensors measuring oxygen levels continuously in PAD patients, such as through transcutaneous means. However, because transcutaneous measurements are affected by movement (such as during exercise) and body temperature, the use of oxygen sensors that are inserted subcutaneously as opposed to transcutaneously may most effectively help monitor a PAD patient's progress and direct therapy decisions. To date, one oxygen sensing system has been approved for use in Europe to measure tissue perfusion in all PAD patients.
== Treatment ==
Depending on the severity of the disease, these steps can be taken, according to these guidelines:
=== Lifestyle ===
Stopping smoking (cigarettes promote PAD and are a risk factor for cardiovascular disease)
Regular exercise for those with claudication helps open up alternative small vessels (collateral flow), and the limitation in walking often improves. Treadmill exercise (35 to 50 minutes, three or four times per week) has been reviewed as another treatment with several positive outcomes, including a reduction in cardiovascular events and improved quality of life. Supervised exercise programs increase pain-free walking time and the maximum walking distance in people with PAD.
=== Medication ===
Management of diabetes
Management of hypertension
Management of high cholesterol, and antiplatelet drugs such as aspirin and clopidogrel. Statins reduce clot formation and cholesterol levels, respectively, and can help with disease progression and address the other cardiovascular risks that the affected person is likely to have.
According to guidelines, taking aspirin or clopidogrel is recommended to reduce AMI ("heart attack"), stroke, and other causes of vascular death in people with symptomatic peripheral artery disease. It is recommended that aspirin and clopidogrel be taken alone and not in conjunction with one another (i.e., not as dual antiplatelet therapy). The recommended daily dosage of aspirin for treating PAD is between 75 and 325 mg, while the recommended daily dosage for clopidogrel is 75 mg. The effectiveness of both aspirin and clopidogrel to reduce the risk of cardiovascular ischemic events in people with symptomatic PAD is not well established. Research also suggests that low-dose rivaroxaban plus aspirin is effective as a new anti-thrombotic regimen for PAD.
Cilostazol can improve symptoms in some people. Pentoxifylline is of unclear benefit. Cilostazol may improve walking distance for people who experience claudication due to peripheral artery disease, but no strong evidence suggests that it improves the quality of life, decreases mortality, or decreases the risk of cardiovascular events.
Treatment with other drugs or vitamins is unsupported by clinical evidence, "but trials evaluating the effect of folate and vitamin B12 on hyperhomocysteinemia, a putative vascular risk factor, are near completion".
=== Revascularization ===
After a trial of the best medical treatment outlined above, if symptoms persist, patients may be referred to a vascular or endovascular surgeon. The benefit of revascularization is thought to correspond to the severity of ischemia and the presence of other risk factors for limb loss, such as wound and infection severity.
Angioplasty (or percutaneous transluminal angioplasty) can be done on solitary lesions in large arteries, such as the femoral artery, but may not have sustained benefits. Patency rates following angioplasty are highest for iliac arteries and decrease with arteries towards the toes. Other criteria that affect the outcome following revascularization are the length of the lesion and the number of lesions. There do not appear to be any long-term advantages or sustained benefits to placing a stent following angioplasty in order to hold the narrowing of the subsartorial artery open.
Atherectomy, in which the plaque is scraped off the inside of the vessel wall (albeit with no better results than angioplasty).
Vascular bypass grafting can be performed to circumvent a diseased area of the arterial vasculature. The great saphenous vein is used as a conduit if available, although artificial (Gore-Tex or PTFE) material is often used for long grafts when adequate venous conduit is unavailable.
When gangrene has set in, amputation may be required to prevent infected tissues from causing sepsis, a life-threatening illness.
Thrombolysis and thrombectomy are used in cases of arterial thrombosis or embolism.
shockwave intravascular lithotripsy, a minimally invasive method that uses ultrasound waves to break up plaque within the artery without the need for penetration. The method was first approved by the US Food and Drug Administration in February 2021, and has been used as a complement to more widely-used methods of atherectomy.
=== Guidelines ===
A guideline from the American College of Cardiology and American Heart Association for the diagnosis and treatment of lower extremity, renal, mesenteric, and abdominal aortic PAD was compiled in 2013, combining the 2005 and 2011 guidelines. For chronic limb-threatening ischemia, the ACCF/AHA guidelines recommend balloon angioplasty only for people with a life expectancy of 2 years or less or those who do not have an autogenous vein available. For those with a life expectancy greater than 2 years or who have an autogenous vein, bypass surgery is recommended.
== Prognosis ==
Individuals with PAD have an "exceptionally elevated risk for cardiovascular events and the majority will eventually die of a cardiac or cerebrovascular etiology". Prognosis is correlated with the severity of the PAD as measured by an ABI. Large-vessel PAD increases mortality from cardiovascular disease significantly. PAD carries a greater than "20% risk of a coronary event in 10 years".
The risk is low that an individual with claudication will develop severe ischemia and require amputation, but the risk of death from coronary events is three to four times higher than matched controls without claudication. Of patients with intermittent claudication, only "7% will undergo lower-extremity bypass surgery, 4% major amputations, and 16% worsening claudication", but stroke and heart attack events are elevated, and the "5-year mortality rate is estimated to be 30% (versus 10% in controls)".
== Epidemiology ==
The prevalence of PAD in the general population is 3–7%, affecting up to 20% of those over 70; 70%–80% of affected individuals are asymptomatic; only a minority ever require revascularization or amputation. Peripheral artery disease affects one in three diabetics over the age of 50. In the US, it affects 12–20 percent of Americans age 65 and older. Around 10 million Americans have PAD. Despite its prevalence and implications for cardiovascular risk, there are still low levels of awareness of risk factors and symptoms, with 26% of the population in the US reported to have knowledge of PAD.
In 2000, among people aged 40 years and older in the United States, rates of PAD were 4.3%. Rates were 14.5% for people aged 70 years or over. Within age groups, rates were generally higher for women than men. Non-Hispanic blacks had a rate of 7.9% compared to 4.4% in Non-Hispanic whites and 3.0% (1.4%–4.6%) in Mexican Americans.
The incidence of symptomatic PAD increases with age, from about 0.3% per year for men aged 40–55 years to about 1% per year for men aged over 75 years. The prevalence of PAD varies considerably depending on how PAD is defined and the age of the population being studied. People diagnosed with PAD have a greater risk of a MACE (Major Adverse Cardiac Event) and stroke. Their risk of developing a reinfarction, stroke, or transient ischemic attack within one year following a heart attack increases to 22.9%, compared to 11.4% for those without PAD.
The Diabetes Control and Complications Trial and the UK Prospective Diabetes Study trials in people with type 1 and type 2 diabetes, respectively, demonstrated that glycemic control is more strongly associated with microvascular disease than macrovascular disease. Pathologic changes occurring in small vessels may be more sensitive to chronically elevated glucose levels than atherosclerosis occurring in larger arteries.
== Research ==
Research is being done on therapies to prevent the progression of PAD. In those who have developed critically poor blood flow to the legs, the benefit of autotransplantation of autologous mononuclear cells is unclear.
Only one randomized controlled trial has been conducted comparing vascular bypass to angioplasty for the treatment of severe PAD. The trial found no difference in amputation-free survival between vascular bypass and angioplasty at the planned clinical endpoint, but the trial has been criticized as being underpowered, limiting endovascular options, and comparing inappropriate endpoints. As of 2017, two randomized clinical trials are being conducted to better understand the optimal revascularization technique for severe PAD and critical limb ischemia (CLI), the BEST-CLI (Best Endovascular Versus Best Surgical Therapy for Patients With Critical Limb Ischemia) Trial and the BASIL-2 (Bypass Versus Angioplasty in Severe Ischaemia of the Leg – 2 )Trial.
In 2011, pCMV-vegf165 was registered in Russia as the first-in-class gene therapy drug for the treatment of PAD, including the advanced stage of critical limb ischemia.
== References ==
== External links ==
"Peripheral Arterial Disease" at the National Heart, Lung and Blood Institute
Peripheral Arterial Disease (P.A.D.) at the American College of Foot and Ankle Surgeons
Gerhard-Herman MD, Gornik HL, Barrett C, Barshes NR, Corriere MA, Drachman DE, et al. (March 2017). "2016 AHA/ACC Guideline on the Management of Patients With Lower Extremity Peripheral Artery Disease: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines". Circulation. 135 (12): e686 – e725. doi:10.1161/CIR.0000000000000470. PMC 5479414. PMID 27840332. | Wikipedia/Peripheral_arterial_disease |
Familial atrial fibrillation is an autosomal dominant heart condition that causes disruptions in the heart's normal rhythm. This condition is characterized by uncoordinated electrical activity in the heart's upper chambers (the atria), which causes the heartbeat to become fast and irregular.
== Cause ==
It is associated with multiple genes:
Mutations in the KCNQ1 gene cause familial atrial fibrillation. The KCNE2 and KCNJ2 genes are associated with familial atrial fibrillation. A small percentage of all cases of familial atrial fibrillation are associated with changes in the KCNE2, KCNJ2, and KCNQ1 genes. These genes provide instructions for making proteins that act as channels across the cell membrane. These channels transport positively charged potassium ions into and out of cells. In heart muscle, the ion channels produced from the KCNE2, KCNJ2, and KCNQ1 genes play critical roles in maintaining the heart's normal rhythm. Mutations in these genes have been identified in only a few families worldwide. These mutations increase the activity of the channels, which changes the flow of potassium ions between cells. This disruption in ion transport alters the way the heart beats, increasing the risk of syncope, stroke, and sudden death.
Most cases of atrial fibrillation are not caused by mutations in a single gene. This condition is often related to structural abnormalities of the heart or underlying heart disease. Additional risk factors for atrial fibrillation include high blood pressure (hypertension), diabetes mellitus, a previous stroke, or an accumulation of fatty deposits and scar-like tissue in the lining of the arteries (atherosclerosis). Although most cases of atrial fibrillation are not known to run in families, studies suggest that they may arise partly from genetic risk factors. Researchers are working to determine which genetic changes may influence the risk of atrial fibrillation.
Familial atrial fibrillation appears to be inherited in an autosomal dominant pattern, which means the defective gene is located on an autosome, and only one copy of the defective gene - inherited from one parent - is sufficient to cause the disorder.
== Diagnosis ==
If untreated, this abnormal heart rhythm can lead to dizziness, chest pain, a sensation of fluttering or pounding in the chest (palpitations), shortness of breath, or fainting (syncope). Atrial fibrillation also increases the risk of stroke. Complications of familial atrial fibrillation can occur at any age, although some people with this heart condition never experience any health problems associated with the disorder. Atrial fibrillation is the most common type of sustained abnormal heart rhythm (arrhythmia), affecting more than 3 million people in the United States. The risk of developing this irregular heart rhythm increases with age. The incidence of the familial form of atrial fibrillation is unknown; however, recent studies suggest that up to 30 percent of all people with atrial fibrillation may have a history of the condition in their family.
== Treatment ==
== References ==
== External links == | Wikipedia/Familial_atrial_fibrillation |
Peripheral artery disease (PAD) is a vascular disorder that causes abnormal narrowing of arteries other than those that supply the heart or brain. PAD can happen in any blood vessel, but it is more common in the legs than the arms.
When narrowing occurs in the heart, it is called coronary artery disease (CAD), and in the brain, it is called cerebrovascular disease. Peripheral artery disease most commonly affects the legs, but other arteries may also be involved, such as those of the arms, neck, or kidneys.
Peripheral artery disease (PAD) is a form of peripheral vascular disease. Vascular refers to the arteries and veins within the body. PAD differs from peripheral veinous disease. PAD means the arteries are narrowed or blocked—the vessels that carry oxygen-rich blood as it moves from the heart to other parts of the body. Peripheral veinous disease, on the other hand, refers to problems with veins—the vessels that bring the blood back to the heart.
The classic symptom is leg pain when walking, which resolves with rest and is known as intermittent claudication. Other symptoms include skin ulcers, bluish skin, cold skin, or abnormal nail and hair growth in the affected leg. Complications may include an infection or tissue death, which may require amputation; coronary artery disease; or stroke. Up to 50% of people with PAD do not have symptoms.
The greatest risk factor for PAD is cigarette smoking. Other risk factors include diabetes, high blood pressure, kidney problems, and high blood cholesterol. PAD is primarily caused by the buildup of fatty plaque in the arteries, which is called atherosclerosis, especially in individuals over 40 years old. Other mechanisms include artery spasm, blood clots, trauma, fibromuscular dysplasia, and vasculitis. PAD is typically diagnosed by finding an ankle-brachial index (ABI) less than 0.90, which is the systolic blood pressure at the ankle divided by the systolic blood pressure of the arm. Duplex ultrasonography and angiography may also be used. Angiography is more accurate and allows for treatment at the same time; however, it is associated with greater risks.
It is unclear if screening for peripheral artery disease in people without symptoms is useful, as it has not been properly studied. For those with intermittent claudication from PAD, stopping smoking and supervised exercise therapy may improve outcomes. Medications, including statins, ACE inhibitors, and cilostazol, may also help. Aspirin, which helps with thinning the blood and thus improving blood flow, does not appear to help those with mild disease but is usually recommended for those with more significant disease due to the increased risk of heart attacks. Anticoagulants (blood thinners) such as warfarin show no definitive scientific evidence of benefit in PAD. Surgical procedures used to treat PAD include bypass grafting, angioplasty, and atherectomy.
In 2015, about 155 million people had PAD worldwide. It becomes more common with age. In the developed world, it affects about 5.3% of 45- to 50-year-olds and 18.6% of 85- to 90-year-olds. In the developing world, it affects 4.6% of people between the ages of 45 and 50 and 15% of people between the ages of 85 and 90. PAD in the developed world is equally common among men and women, though in the developing world, women are more commonly affected. In 2015, PAD resulted in about 52,500 deaths, which is an increase from the 16,000 deaths in 1990.
== Signs and symptoms ==
The signs and symptoms of peripheral artery disease are based on the affected body part. About 66% of patients affected by PAD either do not have symptoms or have atypical symptoms. The most common presenting symptom is intermittent claudication (IC), which typically refers to lower extremity skeletal muscle pain that occurs during exercise. IC presents when there is insufficient oxygen delivery to meet the metabolic requirements of the skeletal muscles. IC is a common manifestation of peripheral arterial disease (PAD). The pain is usually located in the calf muscles of the affected leg and is relieved by rest. This occurs because during exercise, the muscles require more oxygen. Normally, the arteries would be able to increase the amount of blood flow and therefore increase the amount of oxygen going to the exercised muscle. However, in PAD, the artery cannot respond appropriately to the increased muscular demand for oxygen. Therefore, the muscles are deprived of oxygen, leading to muscle pain that subsides with rest.
Other symptoms may include:
Pain, aches, and/or cramps in the buttocks, hip, or thigh
Muscle atrophy (muscle loss) of the affected limb
Hair loss of the affected limb
Skin that is smooth, shiny, or cool to the touch in the affected area
Decreased or absent pulse in the feet
Cold and/or numbness in the toes
Sores/ulcers on the affected limb that do not heal
In individuals with severe PAD, complications may arise, including critical limb ischemia and gangrene. Critical limb ischemia occurs when the obstruction of blood flow in the artery is compromised to the point where the blood cannot maintain oxygenation of the tissue at rest. This can lead to pain at rest, a feeling of coldness, or numbness in the affected foot and toes. Other complications of severe PAD include lower limb tissue loss (amputation), arterial insufficiency ulcers, erectile dysfunction, and gangrene. People with diabetes are affected by gangrene of the feet at a rate that is 30 times higher than the unaffected population. Many of these severe complications, such as those leading to amputation, are irreversible.
== Causes ==
=== Risk factors ===
Factors contributing to an increased risk of PAD are the same as those for atherosclerosis. These include age, sex, and ethnicity. PAD is twice as common in males as in females. In terms of ethnicity, PAD is more common in people of color compared to the white population in a 2:1 ratio. The factors with the greatest risk associations are hyperlipidemia, hypertension, diabetes mellitus, chronic kidney disease, and smoking. Presenting three of these factors or more increases the risk of developing PAD tenfold.
Smoking – Tobacco use in any form is the single greatest risk factor for peripheral artery disease internationally. Smokers have up to a 10-fold increase in the risk of PAD in a dose-response relationship. Exposure to second-hand smoke has also been shown to promote changes in the lining of blood vessels (endothelium), which can lead to atherosclerosis. Smokers are 2–3 times more likely to have lower extremity PAD than coronary artery disease. Greater than 80%–90% of patients with lower extremity peripheral arterial disease are current or former smokers. The risk of PAD increases with the number of cigarettes smoked per day and the number of years smoked.
High blood sugar – Diabetes mellitus is shown to increase the risk of PAD by 2–4 fold. It does this by causing endothelial and smooth-muscle cell dysfunction in peripheral arteries. The risk of developing lower extremity peripheral arterial disease is proportional to the severity and duration of diabetes.
High blood cholesterol – Dyslipidemia is an unhealthy pattern of cholesterol or fat in the blood. Dyslipidemia is characterized by a high level of a protein called low-density lipoprotein (LDL cholesterol), low levels of high-density lipoprotein (HDL cholesterol), elevation of total cholesterol, and/or high triglyceride levels. This abnormality in blood cholesterol levels has been correlated with accelerated peripheral artery disease. Management of dyslipidemia by diet, exercise, and/or medication is associated with a major reduction in rates of heart attack and stroke.
High blood pressure – Hypertension or elevated blood pressure can increase a person's risk of developing PAD. Similarly to PAD, there is a known association between high blood pressure and heart attacks, strokes, and abdominal aortic aneurysms. High blood pressure increases the risk of intermittent claudication, the most common symptom of PAD, by 2.5- to 4-fold in men and women, respectively.
Other risk factors that are being studied include levels of various inflammatory mediators such as C-reactive protein, fibrinogen, homocysteine, and lipoprotein A. Individuals with increased levels of homocysteine in their blood have a 2-fold risk of developing peripheral artery disease. While there are genetic factors leading to risk factors for peripheral artery disease, including diabetes and high blood pressure, there have been no specific genes or gene mutations directly associated with the development of peripheral artery disease.
=== High risk populations ===
Peripheral arterial disease is more common in these populations:
All people who have leg symptoms with exertion (suggestive of claudication) or ischemic rest pain
All people aged 65 years and over, regardless of risk factor status
All people between 50 and 69 who have a cardiovascular risk factor (particularly diabetes or smoking)
Age less than 50 years, with diabetes and one other atherosclerosis risk factor (smoking, dyslipidemia, hypertension, or hyperhomocysteinemia)
Individuals with an abnormal lower extremity pulse examination
Those with known atherosclerotic coronary, carotid, or renal artery disease
All people with a Framingham risk score of 10%–20%
All people who have previously experienced chest pain
== Etiology and pathophysiology ==
Peripheral arterial disease is considered to be a set of chronic or acute syndromes, generally derived from the presence of occlusive arterial disease, which causes inadequate blood flow to the limbs.
As previously mentioned, the most common etiology of peripheral artery disease, especially in patients over 40 years old, is atherosclerosis. Atherosclerosis is a narrowing of the arteries caused by lipid or fat buildup and calcium deposition in the wall of the affected arteries.
The pathophysiology of atherosclerosis involves complex interactions between cholesterol and vascular cells. In the early stages of PAD, the arteries compensate for plaque buildup by dilating to preserve flow through the vessel. Eventually, the artery cannot dilate further, and the atherosclerotic plaque narrows the arterial flow lumen.
When there is an imbalance between the needs of the peripheral tissues and the blood supply, the affected person is faced with ischemia.
From the pathophysiologic point of view, a restriction of blood supply (ischemia) to the lower limbs can be classified as either functional or critical. Functional ischemia occurs when the blood flow is normal at rest but insufficient during exercise, presenting clinically as intermittent claudication. Critical ischemia is produced when the reduction in blood flow results in a perfusion deficit at rest and is defined by the presence of pain at rest or trophic lesions in the legs. In this situation, precise diagnosis is fundamental, as there is a clear risk of limb loss if adequate blood flow is not re-established, either by surgery or endovascular therapy. Differentiating between the two concepts is important to establish the therapeutic indication and the prognosis in patients with PAD.
Other causes include vasculitis and in situ thrombosis related to hypercoagulable states. Additional mechanisms of peripheral artery disease include arterial spasm and fibromuscular dysplasia. The cause and pathophysiology of arterial spasm are not fully understood, but it is hypothesized that they can occur secondary to trauma. The symptoms of claudication ensue when the artery spasms, or clamps down on itself, creating an obstruction. Like atherosclerosis, this leads to decreased blood flow to the tissue downstream of the obstruction. Thrombosis, or the formation of a blood clot, usually occurs due to stasis or trauma.
== Diagnosis ==
Diagnosing or identifying peripheral artery disease requires a history of symptoms and a physical exam, followed by confirmatory testing. These tests could include CT scans (Computed Tomographic Angiography), MRA scans (Magnetic Resonance Angiography), or ultrasounds for imaging. A physician will examine an individual for specific exam findings if symptoms are consistent with peripheral artery disease. Abnormal physical exam findings can lead a healthcare provider to consider the diagnosis. However, to confirm a diagnosis, confirmatory testing is required.
These findings are associated with peripheral artery disease:
Decreased or absent pulses
Muscle atrophy or wasting
Noticeable blueness of the affected limb
Decreased temperature (coolness) in the affected limb when compared to the other
Thickened nails
Smooth or shiny skin and hair loss
Buerger's test can check for pallor when the affected limb is in an elevated position. The limb is then moved from an elevated to a sitting position and checked for redness, which is called reactive hyperemia. Buerger's test is an assessment of arterial sufficiency, which is the ability of the artery to supply oxygenated blood to the tissue that it goes to.
Nonhealing lower extremity wound
If peripheral artery disease is suspected, the initial study is the ankle–brachial index (ABI). The ABI is a simple, non-invasive test that measures the ratio of systolic blood pressure in the ankle to the systolic blood pressure in the upper arm. This is based on the idea that if blood pressure readings in the ankle are lower than those in the arm, a blockage in the arteries that provide blood from the heart to the ankle is suspected. An ABI range of 0.90 to 1.40 is considered normal. A person is considered to have PAD when the ABI is ≤ 0.90. However, PAD can be further graded as mild to moderate if the ABI is between 0.41 and 0.90, and severe if the ABI is less than 0.40. These categories can provide insight into the disease course. Furthermore, ABI values of 0.91 to 0.99 are considered borderline, and values >1.40 indicate noncompressible arteries. If an ABI >1.40 is calculated, this could indicate vessel wall stiffness caused by calcification, which can occur in people with uncontrolled diabetes. Abnormally high ABIs (>1.40) are usually considered false negatives, and thus, such results merit further investigation and higher-level studies. Individuals with noncompressible arteries have an increased risk of cardiovascular mortality within two years.
Individuals with suspected PAD with normal ABIs can undergo exercise testing for ABI. A baseline ABI is obtained before exercise. The patient is then asked to exercise (usually patients are made to walk on a treadmill at a constant speed) until claudication pain occurs (for a maximum of 5 minutes), after which the ankle pressure is again measured. A decrease in ABI of 15%–20% would be diagnostic of PAD.
If ABIs are abnormal, the next step is generally a lower limb Doppler ultrasound to look at the site of obstruction and the extent of atherosclerosis. Other imaging can be performed by angiography, where a catheter is inserted into the common femoral artery and selectively guided to the artery in question. While injecting a radio-dense contrast agent, an X-ray is taken. Any blood flow-limiting blockage found in the X-ray can be identified and treated by procedures including atherectomy, angioplasty, or stenting. Contrast angiography is the most readily available and widely used imaging technique. Modern computerized tomography (CT) scanners provide direct imaging of the arterial system. Studies have shown the sensitivity and specificity of CT in identifying lesions with >50% stenosis to be 95% and 96%, respectively. As such, CT may be considered as an alternative to invasive angiography. An important distinction between the two is that, unlike invasive angiography, assessment of the arterial system with CT does not allow for vascular intervention.
Magnetic resonance angiography (MRA) is a noninvasive diagnostic procedure that uses a combination of a large magnet, radio frequencies, and a computer to produce detailed images of blood vessels inside the body. The advantages of MRA include its safety and ability to provide high-resolution, three-dimensional imaging of the entire abdomen, pelvis, and lower extremities in one sitting.
=== Classification ===
The two most commonly used methods to classify peripheral artery disease are the Fontaine and Rutherford classification systems. The Fontaine stages were introduced by René Fontaine in 1954 to define the severity of chronic limb ischemia:
Stage I: asymptomatic
Stage IIa: intermittent claudication after walking a distance of more than 200 meters
Stage IIb: intermittent claudication after walking a distance of less than 200 meters
Stage III: rest pain
Stage IV: ulcers or gangrene of the limb
The Rutherford classification was created by the Society for Vascular Surgery and the International Society of Cardiovascular Surgery, introduced in 1986 and revised in 1997 (and known as the Rutherford classification after the lead author, Robert B. Rutherford). This classification system consists of four grades and seven categories (categories 0–6):
Grade 0, Category 0: asymptomatic
Grade I, Category 1: mild claudication
Grade I, Category 2: moderate claudication
Grade I, Category 3: severe claudication
Grade II, Category 4: rest pain
Grade III, Category 5: minor tissue loss; ischemic ulceration not exceeding ulcer of the digits of the foot
Grade IV, Category 6: major tissue loss; severe ischemic ulcers or frank gangrene
Moderate to severe PAD, classified by Fontaine's stages III to IV or Rutherford's categories 4 to 5, presents a limb threat (risk of limb loss) in the form of critical limb ischemia.
Recently, the Society for Vascular Surgery came out with a classification system based on "wound, ischemia and foot infection" (WIfI). This classification system, published in 2013, was created to account for the demographic changes that have occurred over the past forty years, including the increased incidence of high blood sugar and evolving techniques and abilities for revascularization. This system was created on the basis that ischemia and angiographic disease patterns are not the sole determinants of amputation risk. The WIfI classification system is broken up into two parts: wounds and ischemia. Wounds are graded 0 through 3 based on the presence of ulceration, gangrene, and ischemia.
Grade 0: no ulcer, no gangrene
Grade 1: small, shallow ulcer; no gangrene
Grade 2: deep ulcer with exposed tendon or bone, gangrene limited to toes
Grade 3: extensive, full-thickness ulcer; gangrene extending to the forefoot or midfoot
Ischemia is graded 0 through 3 based on ABI, ankle systolic pressure, and toe pressure.
Grade 0: ABI ≥0.80, ankle systolic pressure ≥100 mm Hg, toe pressure ≥60 mm Hg
Grade 1: arterial brachial index 0.6 to 0.79, ankle systolic pressure 70 to 100 mm Hg, toe pressure 40 to 59 mm Hg
Grade 2: ABI 0.4–0.59, ankle systolic pressure 50 to 70 mm Hg, toe pressure 30 to 39 mm Hg
Grade 3: ABI ≤0.39, ankle systolic pressure <50 mm Hg, toe pressure <30 mm Hg
The TASC (and TASC II) classification suggests PAD treatment is based on the severity of the disease seen on an angiogram.
=== Screening ===
It is unclear if screening for disease in the general population is useful, as it has not been extensively studied. This includes screening with the ankle-brachial index (ABI), although a systematic review of the literature did not support the use of routine ABI screening in asymptomatic patients.
Testing for coronary artery disease or carotid artery disease is of unclear benefit. While PAD is a risk factor for abdominal aortic aneurysms (AAA), there is no data on screening individuals with asymptomatic PAD for abdominal aortic aneurysms. For people with symptomatic PAD, screening by ultrasound for AAA is not unreasonable.
=== Wearable devices and remote patient monitoring ===
A 2022 review found that a variety of wearable medical devices measuring different parameters (such as body temperature) were being combined with remote patient monitoring of PAD patients, to improve health outcomes.
Some studies propose the development of devices measuring oxygen continuously during exercise. This is because resting perfusion and metabolic activity are extremely low and differences between non-patients and PAD patients are barely measurable. As such, testing of vascular function and energetics requires a physiological challenge. Pulse oximeters can be inconvenient to wear during exercise and only give oxygen values at discrete time points, nor is there sufficient evidence to support any use in identifying PAD. Some publications and studies therefore discuss the use of wearable sensors measuring oxygen levels continuously in PAD patients, such as through transcutaneous means. However, because transcutaneous measurements are affected by movement (such as during exercise) and body temperature, the use of oxygen sensors that are inserted subcutaneously as opposed to transcutaneously may most effectively help monitor a PAD patient's progress and direct therapy decisions. To date, one oxygen sensing system has been approved for use in Europe to measure tissue perfusion in all PAD patients.
== Treatment ==
Depending on the severity of the disease, these steps can be taken, according to these guidelines:
=== Lifestyle ===
Stopping smoking (cigarettes promote PAD and are a risk factor for cardiovascular disease)
Regular exercise for those with claudication helps open up alternative small vessels (collateral flow), and the limitation in walking often improves. Treadmill exercise (35 to 50 minutes, three or four times per week) has been reviewed as another treatment with several positive outcomes, including a reduction in cardiovascular events and improved quality of life. Supervised exercise programs increase pain-free walking time and the maximum walking distance in people with PAD.
=== Medication ===
Management of diabetes
Management of hypertension
Management of high cholesterol, and antiplatelet drugs such as aspirin and clopidogrel. Statins reduce clot formation and cholesterol levels, respectively, and can help with disease progression and address the other cardiovascular risks that the affected person is likely to have.
According to guidelines, taking aspirin or clopidogrel is recommended to reduce AMI ("heart attack"), stroke, and other causes of vascular death in people with symptomatic peripheral artery disease. It is recommended that aspirin and clopidogrel be taken alone and not in conjunction with one another (i.e., not as dual antiplatelet therapy). The recommended daily dosage of aspirin for treating PAD is between 75 and 325 mg, while the recommended daily dosage for clopidogrel is 75 mg. The effectiveness of both aspirin and clopidogrel to reduce the risk of cardiovascular ischemic events in people with symptomatic PAD is not well established. Research also suggests that low-dose rivaroxaban plus aspirin is effective as a new anti-thrombotic regimen for PAD.
Cilostazol can improve symptoms in some people. Pentoxifylline is of unclear benefit. Cilostazol may improve walking distance for people who experience claudication due to peripheral artery disease, but no strong evidence suggests that it improves the quality of life, decreases mortality, or decreases the risk of cardiovascular events.
Treatment with other drugs or vitamins is unsupported by clinical evidence, "but trials evaluating the effect of folate and vitamin B12 on hyperhomocysteinemia, a putative vascular risk factor, are near completion".
=== Revascularization ===
After a trial of the best medical treatment outlined above, if symptoms persist, patients may be referred to a vascular or endovascular surgeon. The benefit of revascularization is thought to correspond to the severity of ischemia and the presence of other risk factors for limb loss, such as wound and infection severity.
Angioplasty (or percutaneous transluminal angioplasty) can be done on solitary lesions in large arteries, such as the femoral artery, but may not have sustained benefits. Patency rates following angioplasty are highest for iliac arteries and decrease with arteries towards the toes. Other criteria that affect the outcome following revascularization are the length of the lesion and the number of lesions. There do not appear to be any long-term advantages or sustained benefits to placing a stent following angioplasty in order to hold the narrowing of the subsartorial artery open.
Atherectomy, in which the plaque is scraped off the inside of the vessel wall (albeit with no better results than angioplasty).
Vascular bypass grafting can be performed to circumvent a diseased area of the arterial vasculature. The great saphenous vein is used as a conduit if available, although artificial (Gore-Tex or PTFE) material is often used for long grafts when adequate venous conduit is unavailable.
When gangrene has set in, amputation may be required to prevent infected tissues from causing sepsis, a life-threatening illness.
Thrombolysis and thrombectomy are used in cases of arterial thrombosis or embolism.
shockwave intravascular lithotripsy, a minimally invasive method that uses ultrasound waves to break up plaque within the artery without the need for penetration. The method was first approved by the US Food and Drug Administration in February 2021, and has been used as a complement to more widely-used methods of atherectomy.
=== Guidelines ===
A guideline from the American College of Cardiology and American Heart Association for the diagnosis and treatment of lower extremity, renal, mesenteric, and abdominal aortic PAD was compiled in 2013, combining the 2005 and 2011 guidelines. For chronic limb-threatening ischemia, the ACCF/AHA guidelines recommend balloon angioplasty only for people with a life expectancy of 2 years or less or those who do not have an autogenous vein available. For those with a life expectancy greater than 2 years or who have an autogenous vein, bypass surgery is recommended.
== Prognosis ==
Individuals with PAD have an "exceptionally elevated risk for cardiovascular events and the majority will eventually die of a cardiac or cerebrovascular etiology". Prognosis is correlated with the severity of the PAD as measured by an ABI. Large-vessel PAD increases mortality from cardiovascular disease significantly. PAD carries a greater than "20% risk of a coronary event in 10 years".
The risk is low that an individual with claudication will develop severe ischemia and require amputation, but the risk of death from coronary events is three to four times higher than matched controls without claudication. Of patients with intermittent claudication, only "7% will undergo lower-extremity bypass surgery, 4% major amputations, and 16% worsening claudication", but stroke and heart attack events are elevated, and the "5-year mortality rate is estimated to be 30% (versus 10% in controls)".
== Epidemiology ==
The prevalence of PAD in the general population is 3–7%, affecting up to 20% of those over 70; 70%–80% of affected individuals are asymptomatic; only a minority ever require revascularization or amputation. Peripheral artery disease affects one in three diabetics over the age of 50. In the US, it affects 12–20 percent of Americans age 65 and older. Around 10 million Americans have PAD. Despite its prevalence and implications for cardiovascular risk, there are still low levels of awareness of risk factors and symptoms, with 26% of the population in the US reported to have knowledge of PAD.
In 2000, among people aged 40 years and older in the United States, rates of PAD were 4.3%. Rates were 14.5% for people aged 70 years or over. Within age groups, rates were generally higher for women than men. Non-Hispanic blacks had a rate of 7.9% compared to 4.4% in Non-Hispanic whites and 3.0% (1.4%–4.6%) in Mexican Americans.
The incidence of symptomatic PAD increases with age, from about 0.3% per year for men aged 40–55 years to about 1% per year for men aged over 75 years. The prevalence of PAD varies considerably depending on how PAD is defined and the age of the population being studied. People diagnosed with PAD have a greater risk of a MACE (Major Adverse Cardiac Event) and stroke. Their risk of developing a reinfarction, stroke, or transient ischemic attack within one year following a heart attack increases to 22.9%, compared to 11.4% for those without PAD.
The Diabetes Control and Complications Trial and the UK Prospective Diabetes Study trials in people with type 1 and type 2 diabetes, respectively, demonstrated that glycemic control is more strongly associated with microvascular disease than macrovascular disease. Pathologic changes occurring in small vessels may be more sensitive to chronically elevated glucose levels than atherosclerosis occurring in larger arteries.
== Research ==
Research is being done on therapies to prevent the progression of PAD. In those who have developed critically poor blood flow to the legs, the benefit of autotransplantation of autologous mononuclear cells is unclear.
Only one randomized controlled trial has been conducted comparing vascular bypass to angioplasty for the treatment of severe PAD. The trial found no difference in amputation-free survival between vascular bypass and angioplasty at the planned clinical endpoint, but the trial has been criticized as being underpowered, limiting endovascular options, and comparing inappropriate endpoints. As of 2017, two randomized clinical trials are being conducted to better understand the optimal revascularization technique for severe PAD and critical limb ischemia (CLI), the BEST-CLI (Best Endovascular Versus Best Surgical Therapy for Patients With Critical Limb Ischemia) Trial and the BASIL-2 (Bypass Versus Angioplasty in Severe Ischaemia of the Leg – 2 )Trial.
In 2011, pCMV-vegf165 was registered in Russia as the first-in-class gene therapy drug for the treatment of PAD, including the advanced stage of critical limb ischemia.
== References ==
== External links ==
"Peripheral Arterial Disease" at the National Heart, Lung and Blood Institute
Peripheral Arterial Disease (P.A.D.) at the American College of Foot and Ankle Surgeons
Gerhard-Herman MD, Gornik HL, Barrett C, Barshes NR, Corriere MA, Drachman DE, et al. (March 2017). "2016 AHA/ACC Guideline on the Management of Patients With Lower Extremity Peripheral Artery Disease: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines". Circulation. 135 (12): e686 – e725. doi:10.1161/CIR.0000000000000470. PMC 5479414. PMID 27840332. | Wikipedia/Peripheral_vascular_disease |
A functional murmur (innocent murmur, physiologic murmur) is a heart murmur that is primarily due to physiologic conditions outside the heart, as opposed to structural defects in the heart itself. Serious conditions can arise even in the absence of a primary heart defect, and it is possible for peripheral conditions to generate abnormalities in the heart. Therefore, caution should be applied to use of the terms "innocent" or "benign" in this context.Use of the term dates to the mid 19th century.
== Benign pediatric heart murmur ==
Functional murmurs are an important consideration in the precordial examination of an infant or child.
=== Presentation ===
Soft, less than 3/6 in intensity (although note that even when structural heart disease is present, intensity does not predict severity.)
Often position-dependent. Murmurs heard while supine and may disappear when upright or sitting.
Otherwise healthy individual, no concerns about growth, no symptoms of heart failure such as dyspnea on exertion. (In infants, ask if the baby cries during feeding, becomes diaphoretic, or develops a rapid respiratory rate. In older children, this can be elucidated by asking whether or not the child can keep up with peers during play.)
Occurs during systole or continuously during both systole and diastole. (Murmurs occurring only during diastole are usually pathologic, but can also be heard during hyperdynamic states.)
Physiologic splitting of S2 (A2 and P2 components should only be resolvable during inspiration and should merge during expiration.)
No palpable thrill (A thrill is a vibration caused by turbulent blood flow.)
=== Diagnosis ===
==== Types, and DDx ====
In the adult, hyperdynamic circulation of the blood may also produce a functional murmur, such as in anemia or thyrotoxicosis.
=== Prognosis ===
Innocent murmurs are inconsequential and usually disappear as the child grows. ECG and Chest XRAY are normal.
== See also ==
Heart murmur
Precordial examination
Ventricular septal defect
== References ==
6. Circulation 2005: Innocent Murmurs http://circ.ahajournals.org/cgi/content/full/111/3/e20
== External links ==
Heart Murmurs in Pediatric Patients: When Do You Refer? Archived 2010-02-10 at the Wayback Machine - AAFP | Wikipedia/Functional_murmur |
A developed country, or advanced country, is a sovereign state that has a high quality of life, developed economy, and advanced technological infrastructure relative to other less industrialized nations. Most commonly, the criteria for evaluating the degree of economic development are the gross domestic product (GDP), gross national product (GNP), the per capita income, level of industrialization, amount of widespread infrastructure and general standard of living. Which criteria are to be used and which countries can be classified as being developed are subjects of debate. Different definitions of developed countries are provided by the International Monetary Fund and the World Bank; moreover, HDI ranking is used to reflect the composite index of life expectancy, education, and income per capita. In 2025, 40 countries fit all three criteria, while an additional 21 countries fit two out of three.
Developed countries have generally more advanced post-industrial economies, meaning the service sector provides more wealth than the industrial sector. They are contrasted with developing countries, which are in the process of industrialisation or are pre-industrial and almost entirely agrarian, some of which might fall into the category of Least Developed Countries. As of 2023, advanced economies comprise 57.3% of global GDP based on nominal values and 41.1% of global GDP based on purchasing-power parity (PPP) according to the IMF.
== Definition and criteria ==
Economic criteria have tended to dominate discussions. One such criterion is the income per capita; countries with the high gross domestic product (GDP) per capita would thus be described as developed countries. Another economic criterion is industrialisation; countries in which the tertiary and quaternary sectors of industry dominate would thus be described as developed. More recently, another measure, the Human Development Index (HDI), which combines an economic measure, national income, with other measures, indices for life expectancy and education has become prominent. This criterion would define developed countries as those with a very high (HDI) rating. The index, however, does not take into account several factors, such as the net wealth per capita or the relative quality of goods in a country. This situation tends to lower the ranking of some of the most advanced countries, such as the G7 members and others.
According to the United Nations Statistics Division:
There is no established convention for the designation of "developed" and "developing" countries or areas in the United Nations system.
And it notes that:
The designations "developed" and "developing" are intended for statistical convenience and do not necessarily express a judgement about the stage reached by a particular country or area in the development process.
Nevertheless, the UN Trade and Development considers that this categorization can continue to be applied:
The developed economies broadly comprise Northern America and Europe, Israel, Japan, the Republic of Korea, Australia, and New Zealand.
=== Similar terms ===
Terms linked to the concept developed country include "advanced country", "industrialized country", "more developed country" (MDC), "more economically developed country" (MEDC), "Global North country", "first world country", and "post-industrial country". The term industrialized country may be somewhat ambiguous, as industrialisation is an ongoing process that is hard to define. The first industrialized country was the United Kingdom, followed by Belgium. Later it spread further to Germany, United States, France and other Western European countries. According to some economists such as Jeffrey Sachs, however, the current divide between the developed and developing world is largely a phenomenon of the 20th century.
Mathis Wackernagel calls the binary labeling of countries as "neither descriptive nor explanatory. It is merely a thoughtless and destructive endorsement of GDP fetish. In reality, there are not two types of countries, but over 200 countries, all faced with the same laws of nature, yet each with unique features."
A 2021 analysis proposes the term emerged to describe markets, economies, or countries that have graduated from emerging market status, but have not yet reached the level equivalent to developed countries. Multinational corporations from these emerging markets present unique patterns of overseas expansion and knowledge acquisition from foreign countries.
== Economy lists by various criteria ==
=== Human Development Index (HDI) ===
The UN HDI is a statistical measure that gauges an economy's level of human development. While there is a strong correlation between having a high HDI score and being a prosperous economy, the UN points out that the HDI accounts for more than income or productivity. Unlike GDP per capita or per capita income, the HDI takes into account how income is turned "into education and health opportunities and therefore into higher levels of human development."
Since 1990, Norway (2001–2006, 2009–2019), Japan (1990–1991 and 1993), Canada (1992 and 1994–2000) and Iceland (2007–2008) have had the highest HDI score.
The following countries in the year 2023 are considered to be of "very high human development":
=== WESP developed economies ===
According to the United Nations Department of Economic and Social Affairs' World Economic Situation and Prospects report, the following 37 countries are classified as "developed economies" as of January 2024:
31 countries in Europe:
two countries in Northern America:
four countries in Asia and the Pacific:
=== World Bank high-income economies ===
According to the World Bank, the following 85 sovereign states and territories across are classified as high-income economies, having a nominal GNI per capita in excess of $14,005 as of 2024:
Unsovereign Territories are denoted with an asterisk (*).
=== Development Assistance Committee members ===
There are 29 OECD member countries and the European Union—in the Development Assistance Committee (DAC), a group of the world's major donor countries that discusses issues surrounding development aid and poverty reduction in developing countries. The following OECD member countries are DAC members:
25 countries in Europe:
two countries in the Americas:
two countries in Asia:
two countries in Oceania:
=== IMF advanced economies ===
According to the International Monetary Fund, 41 countries and territories are officially listed as "advanced economies", with the addition of 7 microstates and dependencies modified by the CIA which were omitted from the IMF version:
29 countries and dependencies in Europe classified by the IMF, 6 others given by the CIA:
seven countries and territories in Asia:
three countries and territories in the Americas classified by the IMF, one territory given by the CIA :
two countries in Oceania:
d The CIA has modified an older version of the IMF's list of 38 Advanced Economies, noting that the IMF's Advanced Economies list "would presumably also cover the following nine smaller countries of Andorra, Bermuda, Faroe Islands, Guernsey, Holy See, Jersey, Liechtenstein, Monaco, and San Marino[...]". San Marino (2012) and Andorra (2021) were later included in the IMF's list.
=== Paris Club members ===
There are 22 permanent members in the Paris Club (French: Club de Paris), a group of officials from major creditor countries whose role is to find coordinated and sustainable solutions to the payment difficulties experienced by debtor countries.
15 countries in Europe:
three countries in the Americas:
three countries in Asia:
one country in Oceania:
== Comparative table (2025) ==
Comparative table of countries with a "very high" human development (0.800 or higher), according to UNDP; "advanced" economies, according to the IMF; "high-income" economies, according to the World Bank.
== See also ==
== Notes ==
== References ==
== External links ==
Quotations related to Developed country at Wikiquote
IMF (advanced economies)
The World Factbook Archived 9 April 2008 at the Wayback Machine (developed countries)
United Nations Statistics Division (definition)
List of countries, United Nations Statistics Division (developed regions)
World Bank (high-income economies) | Wikipedia/Industrialized_countries |
Coronary CT angiography (CTA or CCTA) is the use of computed tomography (CT) angiography to assess the coronary arteries of the heart. The patient receives an intravenous injection of radiocontrast and then the heart is scanned using a high speed CT scanner, allowing physicians to assess the extent of occlusion in the coronary arteries, usually in order to diagnose coronary artery disease.
CTA is superior to coronary CT calcium scan in determining the risk of Major Adverse Cardiac Events (MACE).
== Medical uses ==
Faster CT machines, due to multidetector capabilities, have made imaging of the heart and circulatory system very practical in a number of clinical settings. The faster capability has allowed the imaging of the heart with minimal involuntary motion, which creates motion blur on the image, and has a number of practical applications. It may be useful in the diagnosis of suspected coronary heart disease, for follow-up of a coronary artery bypass, for the evaluation of valvular heart disease and for the evaluation of cardiac masses.
It is uncertain whether this modality will replace invasive coronary catheterization. At present, it appears that the greatest utility of cardiac CT lies in ruling out coronary artery disease rather than ruling it in. This is because the test is highly sensitive (over 90% detection rate), so a negative test result largely rules out coronary artery disease (i.e. the test has a high negative predictive value). The test is somewhat less specific, however, so a positive result is less conclusive and may need to be confirmed by subsequent invasive angiography.
The positive predictive value of cardiac CTA is approximately 82% and the negative predictive value is around 93%. This means for every 100 patients who appear to have coronary artery disease after CT angiography, 18 of them actually won't have it, and that for every 100 patients who have a negative CT angio test result (i.e. the test says they do not have coronary artery disease), 7 will actually have the disease as defined by the reference standard of invasive coronary angiography via cardiac catheterization. Both coronary CT angiography and invasive angiography via cardiac catheterization yield similar diagnostic accuracy when both are being compared to a third reference standard such as intravascular ultrasound or fractional flow reserve.
In addition to the diagnostic abilities, cardiac CTA beholds important prognostic information. Stenosis severity and extent of coronary artery disease are important prognostic indicators. However, one of the unique features of cardiac CTA is the fact that it enables the visualization of the vessel wall, in a non-invasive manner. Therefore, the technique is able to identify characteristics of coronary artery disease that are associated to the development of acute coronary syndrome.
== Side effects ==
Because the heart is effectively imaged more than once (described above), cardiac CT angiography can result in a relatively high radiation exposure (around 12 millisievert), although newer acquisition protocols, have recently been developed which drastically reduce this exposure to around 1 mSv (cfr. Pavone, Fioranelli, Dowe: Computed Tomography or Coronary Arteries, Springer 2009). By comparison, a chest X-ray carries a dose of approximately 0.02-0.2 mSv and natural background radiation exposure is around 2.3 mSv/year. Thus, each cardiac CT scan carried out with current protocols (dose approximately 1 mSv) is equivalent to approximately 5-50 chest X-rays or less than 1 year of background radiation. Methods are available to decrease this exposure, however, such as prospectively decreasing radiation output based on the concurrently acquired ECG (i.e. tube current modulation.) This can result in a significant decrease in radiation exposure, at the risk of compromising image quality if there is any arrhythmia during the acquisition.
The significance of the low radiation doses used in diagnostic imaging is unknown, although the possibility of increasing cancer incidence across a population is of significant concern. This potential risk must be weighed against the competing risk of not diagnosing a significant health problem in a particular individual, such as coronary artery disease.
=== Contraindications ===
Pregnancy is considered a relative contraindication, similarly to many forms of medical imaging in pregnancy. The potential harms to a fetus include the application of X-rays in addition to radiocontrast. Since an iodine-containing contrast agent is used, severe contrast agent allergy, uncontrolled hyperthyroidism or renal function impairment are also relative contraindications. Cardiac arrhythmias, coronary artery stents and tachycardia may result in a reduced image quality.
== Improved resolution ==
With the advent of subsecond rotation combined with multi-slice CT (up to 320 slices), high resolution and high speed can be obtained at the same time, allowing excellent imaging of the coronary arteries (cardiac CT angiography). Images with even higher temporal resolution can be obtained using multi-cycle (also called multi-segmental) image reconstruction.
In this technique, a portion of the heart is imaged during one heart cycle while an ECG trace is recorded. During the next heart cycle, the next portion of the heart is scanned for up to 5 total cycles until the entire heart is imaged. The reconstruction algorithm then combines the images from these different cycles to generate one complete image. The advantage of this method is that each image segment is acquired in less time as compared to acquiring the entire heart in one heart cycle, thus improving temporal resolution. The disadvantages are 1) the potential for image artifacts from fusing the image segments and 2) the requirement of additional X-ray radiation for image acquisition.
Dual Source CT scanners, introduced in 2005, allow higher temporal resolution by acquiring a full CT slice in only half a rotation, thus reducing motion blurring at high heart rates and potentially allowing for shorter breath-hold time. This is particularly useful for ill patients having difficulty holding their breath or unable to take heart-rate lowering medication.
The speed advantages of 64-slice MSCT have rapidly established it as the minimum standard for newly installed CT scanners intended for cardiac scanning. Manufacturers have developed 320-slice and true 'volumetric' scanners, primarily for their improved cardiac scanning performance.
Introduction of a CT scanner with a 160 mm detector in 2014 allows for imaging of the whole heart in a single beat without motion of the coronary arteries, regardless of patient heart rate.
The latest MSCT scanners acquire images only at 70-80% of the R-R interval (late diastole). This prospective gating can reduce effective dose from 10 to 15 mSv to as little as 1.2 mSv in follow-up patients acquiring at 75% of the R-R interval. Effective dose using MSCT coronary imaging can average less than the dose in conventional coronary angiography.
== References == | Wikipedia/Coronary_computed_tomographic_angiography |
Accelerated idioventricular rhythm is a ventricular rhythm with a rate of between 40 and 120 beats per minute. Idioventricular means “relating to or affecting the cardiac ventricle alone” and refers to any ectopic ventricular arrhythmia. Accelerated idioventricular arrhythmias are distinguished from ventricular rhythms with rates less than 40 (ventricular escape) and those faster than 120 (ventricular tachycardia). Though some other references limit to between 60 and 100 beats per minute. It is also referred to as AIVR and "slow ventricular tachycardia."
It can be present at birth, however, it is more commonly associated with reperfusion after myocardial injury. AIVR is generally considered to be a benign abnormal heart rhythm. It is typically temporary and does not require treatment.
== Pathophysiology ==
The accelerated idioventricular rhythm occurs when depolarization rate of a normally suppressed focus increases to above that of the "higher order" focuses (the sinoatrial node and the atrioventricular node). This most commonly occurs in the setting of a sinus bradycardia.
Accelerated idioventricular rhythm is the most common reperfusion arrhythmia in humans. However, ventricular tachycardia and ventricular fibrillation remain the most important causes of sudden death following spontaneous restoration of antegrade flow. Prior to the modern practice of percutaneous coronary intervention for acute coronary syndrome, pharmacologic thrombolysis was more common and accelerated idioventricular rhythms were used as a sign of successful reperfusion. It is considered a benign arrhythmia especially in the setting of STEMI(where it is conventionally thought to be an indicator of reperfusion) that does not require intervention, though atrioventricular dyssynchrony can cause hemodynamic instability, which can be treated through overdrive pacing or atropine.
== Diagnosis ==
=== Differential diagnosis ===
AIVR appears similar to ventricular tachycardia with wide QRS complexes (QRS >0.12s) and a regular rhythm. It can most easily be distinguished from VT in that the rate is less than 120 and usually less than 100 bpm. There may or may not be AV dissociation depending on whether it is due to ventricular escape or AV block.
== References ==
== External links == | Wikipedia/Accelerated_idioventricular_rhythm |
Antiarrhythmic agents, also known as cardiac dysrhythmia medications, are a class of drugs that are used to suppress abnormally fast rhythms (tachycardias), such as atrial fibrillation, supraventricular tachycardia and ventricular tachycardia.
Many attempts have been made to classify antiarrhythmic agents. Many of the antiarrhythmic agents have multiple modes of action, which makes any classification imprecise.
== Action potential ==
The cardiac myocyte has two general types of action potentials: conduction system and working myocardium. The action potential is divided into 5 phases and shown in the diagram. The sharp rise in voltage ("0") corresponds to the influx of sodium ions, whereas the two decays ("1" and "3", respectively) correspond to the sodium-channel inactivation and the repolarizing efflux of potassium ions. The characteristic plateau ("2") results from the opening of voltage-sensitive calcium channels. Each phase utilizes different channels and it is useful to compare these phases to the most common classification system — Vaughan Williams — described below.
== Vaughan Williams classification ==
The Vaughan Williams classification was introduced in 1970 by Miles Vaughan Williams.
Vaughan Williams was a pharmacology tutor at Hertford College, Oxford. One of his students, Bramah N. Singh, contributed to the development of the classification system. The system is therefore sometimes known as the Singh-Vaughan Williams classification.
The five main classes in the Vaughan Williams classification of antiarrhythmic agents are:
Class I agents interfere with the sodium (Na+) channel.
Class II agents are anti-sympathetic nervous system agents. Most agents in this class are beta blockers.
Class III agents affect potassium (K+) efflux.
Class IV agents affect calcium channels and the AV node.
Class V agents work by other or unknown mechanisms.
With regard to management of atrial fibrillation, classes I and III are used in rhythm control as medical cardioversion agents, while classes II and IV are used as rate-control agents.
=== Class I agents ===
The class I antiarrhythmic agents interfere with the sodium channel.
Class I agents are grouped by what effect they have on the Na+ channel, and what effect they have on cardiac action potentials.
Class I agents are called membrane-stabilizing agents, "stabilizing" referring to the decrease of excitogenicity of the plasma membrane which is brought about by these agents. (Also noteworthy is that a few class II agents like propranolol also have a membrane stabilizing effect.)
Class I agents are divided into three groups (Ia, Ib, and Ic) based upon their effect on the length of the action potential.
Class Ia drugs lengthen the action potential (right shift)
Class Ib drugs shorten the action potential (left shift)
Class Ic drugs do not significantly affect the action potential (no shift)
=== Class II agents ===
Class II agents are conventional beta blockers. They act by blocking the effects of catecholamines at the β1-adrenergic receptors, thereby decreasing sympathetic activity on the heart, which reduces intracellular cAMP levels and hence reduces Ca2+ influx. These agents are particularly useful in the treatment of supraventricular tachycardias. They decrease conduction through the AV node.
Class II agents include atenolol, esmolol, propranolol, and metoprolol.
=== Class III agents ===
Class III agents predominantly block the potassium channels, thereby prolonging repolarization. Since these agents do not affect the sodium channel, conduction velocity is not decreased. The prolongation of the action potential duration and refractory period, combined with the maintenance of normal conduction velocity, prevent re-entrant arrhythmias. (The re-entrant rhythm is less likely to interact with tissue that has become refractory). The class III agents exhibit reverse-use dependence (their potency increases with slower heart rates, and therefore improves maintenance of sinus rhythm). Inhibiting potassium channels results in slowed atrial-ventricular myocyte repolarization. Class III agents have the potential to prolong the QT interval of the EKG, and may be proarrhythmic (more associated with development of polymorphic VT).
Class III agents include: bretylium, amiodarone, ibutilide, sotalol, dofetilide, vernakalant, and dronedarone.
=== Class IV agents ===
Class IV agents are slow non-dihydropyridine calcium channel blockers. They decrease conduction through the AV node, and shorten phase two (the plateau) of the cardiac action potential. They thus reduce the contractility of the heart, so may be inappropriate in heart failure. However, in contrast to beta blockers, they allow the body to retain adrenergic control of heart rate and contractility.
Class IV agents include verapamil and diltiazem.
=== Class V and others ===
Since the development of the original Vaughan Williams classification system, additional agents have been used that do not fit cleanly into categories I through IV. Such agents include:
Adenosine is used intravenously for terminating supraventricular tachycardias.
Digoxin decreases conduction of electrical impulses through the AV node and increases vagal activity via its action on the central nervous system. Via indirect action, it leads to an increase in acetylcholine production, stimulating M2 receptors on AV node leading to an overall decrease in speed of conduction.
Magnesium sulfate is an antiarrhythmic drug, but only used against very specific arrhythmias such as torsades de pointes.
=== History ===
The initial classification system had 4 classes, although their definitions different from the modern classification. Those proposed in 1970 were:
Drugs with a direct membrane action: the prototype was quinidine, and lignocaine was a key example. Differing from other authors, Vaughan-Williams describe the main action as a slowing of the rising phase of the action potential.
Sympatholytic drugs (drugs blocking the effects of the sympathetic nervous system): examples included bretylium and adrenergic beta-receptors blocking drugs. This is similar to the modern classification, which focuses on the latter category.
Compounds that prolong the action potential: matching the modern classification, with the key drug example being amiodarone, and a surgical example being thyroidectomy. This was not a defining characteristic in an earlier review by Charlier et al. (1968), but was supported by experimental data presented by Vaughan Williams (1970).: 461 The figure illustrating these findings was also published in the same year by Singh and Vaughan Williams.
Drugs acting like diphenylhydantoin (DPH): mechanism of action unknown, but others had attributed its cardiac action to an indirect action on the brain; this drug is better known as antiepileptic drug phenytoin.
== Sicilian gambit classification ==
Another approach, known as the "Sicilian gambit", placed a greater approach on the underlying mechanism.
It presents the drugs on two axes, instead of one, and is presented in tabular form. On the Y axis, each drug is listed, in roughly the Singh-Vaughan Williams order. On the X axis, the channels, receptors, pumps, and clinical effects are listed for each drug, with the results listed in a grid. It is, therefore, not a true classification in that it does not aggregate drugs into categories.
== Modernized Oxford classification by Lei, Huang, Wu, and Terrar ==
A recent publication (2018) has now emerged with a fully modernised drug classification. This preserves the simplicity of the original Vaughan Williams framework while capturing subsequent discoveries of sarcolemmal, sarcoplasmic reticular and cytosolic biomolecules. The result is an expanded but pragmatic classification that encompasses approved and potential anti-arrhythmic drugs. This will aid our understanding and clinical management of cardiac arrhythmias and facilitate future therapeutic developments. It starts by considering the range of pharmacological targets, and tracks these to their particular cellular electrophysiological effects. It retains but expands the original Vaughan Williams classes I to IV, respectively covering actions on Na+ current components, autonomic signalling, K+ channel subspecies, and molecular targets related to Ca2+ homeostasis. It now introduces new classes incorporating additional targets, including:
Class 0: ion channels involved in automaticity
Class V: mechanically sensitive ion channels
Class VI: connexins controlling electrotonic cell coupling
Class VII: molecules underlying longer term signalling processes affecting structural remodeling.
It also allows for multiple drug targets/actions and adverse pro-arrhythmic effects. The new scheme will additionally aid development of novel drugs under development and is illustrated here.
== See also ==
Antiarrhythmic agents (category)
Cardiac Arrhythmia Suppression Trial (CAST)
Electrocardiogram
Management of atrial fibrillation
Proarrhythmic agent
== References == | Wikipedia/Antiarrhythmic_drug |
Multiple organ dysfunction syndrome (MODS) is altered organ function in an acutely ill patient requiring immediate medical intervention.
There are different stages of organ dysfunction for certain different organs, both in acute and in chronic onset, whether or not there are one or more organs affected. Each stage of dysfunction (whether it be the heart, lung, liver, or kidney) has defined parameters, in terms of laboratory values based on blood and other tests, as to what it is (each of these organs' levels of failure is divided into stage I, II, III, IV, and V). The word "failure" is commonly used to refer to the later stages, especially IV and V, when artificial support usually becomes necessary to sustain life; the damage may or may not be fully or partially reversible.
== Signs and symptoms ==
Multiple organ dysfunction syndrome can trigger a variety of symptoms throughout the body. Because MODS can impact any organ system, the specific symptoms experienced will depend on which organs are affected. Initially, these signs may be mild as the underlying illness progresses towards MODS. However, as the condition worsens, the symptoms can become more severe.
These symptoms include low urine output, nausea, vomiting, and loss of appetite. Some patients experience mental symptoms like confusion and may feel fatigued. Symptoms like fever, chills, irregular heartbeat, and quick/shallow breathing are also common. Multiple cases of MODS also suffer chest and abdominal pain, and patients may even lose consciousness.
== Cause ==
The condition results from infection, injury (accident, surgery), hypoperfusion and hypermetabolism. The primary cause triggers an uncontrolled inflammatory response.
Sepsis is the most common cause of multiple organ dysfunction syndrome and may result in septic shock. In the absence of infection, a sepsis-like disorder is termed systemic inflammatory response syndrome (SIRS). Both SIRS and sepsis could ultimately progress to multiple organ dysfunction syndrome. In one-third of the patients, however, no primary focus can be found. Multiple organ dysfunction syndrome is well established as the final stage of a continuum: SIRS + infection → sepsis → severe sepsis → Multiple organ dysfunction syndrome.
Currently, investigators are looking into genetic targets for possible gene therapy to prevent the progression to multiple organ dysfunction syndrome. Some authors have conjectured that the inactivation of the transcription factors NF-κB and AP-1 would be appropriate targets in preventing sepsis and SIRS. These two genes are pro-inflammatory. They are essential components of a normal healthy immune response, however, so there is risk of increasing vulnerability to infection, which can also cause clinical deterioration.
== Pathophysiology ==
A definite explanation has not been found. Local and systemic responses are initiated by tissue damage. Respiratory failure is common in the first 72 hours. Subsequently, one might see liver failure (5–7 days), gastrointestinal bleeding (10–15 days) and kidney failure (11–17 days).
=== Gut hypothesis ===
The most popular hypothesis by Deitch to explain MODS in critically ill patients is the gut hypothesis. Due to splanchnic hypoperfusion and the subsequent mucosal ischaemia there are structural changes and alterations in cellular function. This results in increased gut permeability, changed immune function of the gut and increased translocation of bacteria. Liver dysfunction leads to toxins escaping into the systemic circulation and activating an immune response. This results in tissue injury and organ dysfunction.
=== Endotoxin macrophage hypothesis ===
Gram-negative infections in MODS patients are relatively common, hence endotoxins have been advanced as principal mediator in this disorder. It is thought that following the initial event cytokines are produced and released. The pro-inflammatory mediators are: tumor necrosis factor-alpha (TNF-α), interleukin-1, interleukin-6, thromboxane A2, prostacyclin, platelet activating factor, and nitric oxide.
=== Tissue hypoxia-microvascular hypothesis ===
As a result of macro- and microvascular changes insufficient supply of oxygen occurs. Hypoxemia causes cell death and organ dysfunction.
=== Mitochondrial DNA hypothesis ===
According to findings of Professor Zsolt Balogh and his team at the University of Newcastle (Australia), mitochondrial DNA is the leading cause of severe inflammation due to a massive amount of mitochondrial DNA that leaks into the bloodstream due to cell death of patients who survived major trauma.
Mitochondrial DNA resembles bacterial DNA. If bacteria triggers leukocytes, mitochondrial DNA may do the same. When confronted with bacteria, white blood cells, or neutrophil granulocytes, behave like predatory spiders. They spit out a web, or net, to trap the invaders, then hit them with a deadly oxidative blast, forming neutrophil extracellular traps (NETs).
This results in catastrophic immune response leading to multiple organ dysfunction syndrome.
=== Integrated hypothesis ===
Since in most cases no primary cause is found, the condition could be part of a compromised homeostasis involving the previous mechanisms.
== Diagnosis ==
The European Society of Intensive Care organized a consensus meeting in 1994 to create the "Sepsis-Related Organ Failure Assessment (SOFA)" score to describe and quantitate the degree of organ dysfunction in six organ systems. Using similar physiologic variables the Multiple Organ Dysfunction Score was developed.
Four clinical phases have been suggested:
Stage 1: the patient has increased volume requirements and mild respiratory alkalosis, which is accompanied by oliguria, hyperglycemia and increased insulin requirements.
Stage 2: the patient is tachypneic, hypocapnic and hypoxemic; develops moderate liver dysfunction and possible hematologic abnormalities.
Stage 3: the patient develops shock with azotemia and acid–base disturbances; has significant coagulation abnormalities.
Stage 4: the patient is vasopressor dependent and oliguric or anuric; subsequently develops ischemic colitis and lactic acidosis.
== Management ==
At present, there is no drug or device that can reverse organ failure that has been judged by the health care team to be medically and/or surgically irreversible (organ function can recover, at least to a degree, in patients whose organs are very dysfunctional, where the patient has not died; and some organs, like the liver or the skin, can regenerate better than others),- with the possible exception of single or multiple organ transplants or the use of artificial organs or organ parts, in certain candidates in specific situations. Therapy, therefore, is usually mostly limited to supportive care, i.e. safeguarding hemodynamics, and respiration. Maintaining adequate tissue oxygenation is a principal target. Starting enteral nutrition within 36 hours of admission to an intensive care unit has reduced infectious complications.
== Prognosis ==
Mortality, though it has lessened to a limited degree, at least in developed countries with timely access to initial and tertiary care, varies where the chance of survival is diminished as the number of organs involved increases. Mortality in MODS from septic shock (which itself has a high mortality of 25–50%), and from multiple traumas, especially if not rapidly treated, appear to be especially severe. If more than one organ system is affected, the mortality rate is still higher, and this is especially the case when five or more systems or organs are affected. Old age is a risk factor in and of itself, and immunocompromised patients, such as with cancer or AIDS or a transplant, are at risk. Prognosis must take into account any co-morbidities the patient may have, their past and current health status, any genetic or environmental vulnerabilities they have, the nature and type of the illness or injury (as an example, data from COVID-19 is still being analyzed, whereas other cases from long-existing illnesses are much better understood), and any resistance to drugs used to treat microbial infections or any hospital-acquired co-infection. Earlier and aggressive treatment, the use of experimental treatments, or at least modern tools such as ventilators, ECMO, dialysis, bypass, and transplantation, especially at a trauma center, may improve outcomes in certain cases, but this depends in part on speedy and affordable access to high-quality care, which many areas lack. Measurements of lactate, cytokines, albumin and other proteins, urea, blood oxygen and carbon dioxide levels, insulin, and blood sugar, adequate hydration, constant monitoring of vital signs, good communication within and between facilities and staff, and adequate staffing, training, and charting are important in MODS, as in any serious illness.
In patients with sepsis, septic shock, or multiple organ dysfunction syndrome that is due to major trauma, the rs1800625 polymorphism is a functional single nucleotide polymorphism, a part of the receptor for advanced glycation end products (RAGE) transmembrane receptor gene (of the immunoglobulin superfamily) and confers host susceptibility to sepsis and MODS in these patients.
== History ==
For many years, some patients were loosely classified as having sepsis or the sepsis syndrome. In more recent years, these concepts have been refined – so that there are specific definitions of sepsis – and two new concepts have been developed: the SIRS and MODS.
Although Irwin and Rippe cautioned in 2005 that the use of "multiple organ failure" or "multisystem organ failure" should be avoided, both Harrison's (2015) and Cecil's (2012) medical textbooks still use the terms "multi-organ failure" and "multiple organ failure" in several chapters and do not use "multiple organ dysfunction syndrome" at all.
== References ==
== Further reading ==
The ICU Book by Marino
Cecil Textbook of Medicine
The Oxford Textbook of Medicine
== External links == | Wikipedia/Multiple_organ_dysfunction_syndrome |
The Renal Support Network (RSN) is an American nonprofit, kidney patient-focused, kidney patient-run organization that focuses on individuals affected by chronic kidney disease (CKD).
RSN hosts its national patient meeting and regional patient lifestyle meetings and the RSN Patients Educating Patients & Professionals (PEPP) Patient Speakers Program. Information and education programs include the Kidney Times website and the KidneyTalk biweekly podcast. RSN sponsors Renal Teen Proms in Los Angeles and Washington, DC.
The Renal Support Network also provides lawmakers and policymakers with patient perspectives on the needs and capabilities of people with CKD through their Wellness & Education Kidney Advocacy Network (weKAN).
== History ==
The Renal Support Network was founded in 1993 by Lori Hartwell.
== Meetings ==
The national meeting is a three-day conference held in conjunction with the National Renal Administrators Association (NRAA) annual meeting. Regional Patient Lifestyle meetings are free to attend.
== Activities ==
In addition to contributing to educational and scientific publications, the Wellness & Education Kidney Advocacy Network (weKAN) consists of chronic kidney disease (CKD) patient activists from across the country.
The PEPP Patient Speakers Program was initiated by RSN in 2005. Since then, there have been over 100 speaking engagements to more than 9800 listeners. These educational programs are led by CKD patient-speakers who have been professionally authorized to deliver these programs at meetings of renal patients and healthcare professionals. PEPP speakers are available at no charge to organizations that meet the RSN criteria.
"Kidney Times" is the organization's CKD information website; all articles are all written by people with CKD or health care professionals. A stipend is paid for articles published. Kidney Talk is a biweekly webcast hosted by Stephen Furst and RSN Founder and President Lori Hartwell.
Renal Teen Proms are free events are for teens ages 14 to 24 who have CKD and a guest of their choice.
== References ==
== External links ==
Renal Support Network | Wikipedia/Renal_Support_Network |
Kidney disease, or renal disease, technically referred to as nephropathy, is damage to or disease of a kidney. Nephritis is an inflammatory kidney disease and has several types according to the location of the inflammation. Inflammation can be diagnosed by blood tests. Nephrosis is non-inflammatory kidney disease. Nephritis and nephrosis can give rise to nephritic syndrome and nephrotic syndrome respectively. Kidney disease usually causes a loss of kidney function to some degree and can result in kidney failure, the complete loss of kidney function. Kidney failure is known as the end-stage of kidney disease, where dialysis or a kidney transplant is the only treatment option.
Chronic kidney disease is defined as prolonged kidney abnormalities (functional and/or structural in nature) that last for more than three months. Acute kidney disease is now termed acute kidney injury and is marked by the sudden reduction in kidney function over seven days.
Rates for both chronic kidney disease and mortality have increased, associated with the rising prevalence of diabetes and the ageing global population. The World Health Organization has reported that "kidney diseases have risen from the world’s nineteenth leading cause of death to the ninth, with the number of deaths increasing by 95% between 2000 and 2021." In the United States, prevalence has risen from about one in eight in 2007, to one in seven in 2021.
== Causes ==
Causes of kidney disease include deposition of the Immunoglobulin A antibodies in the glomerulus, administration of analgesics, xanthine oxidase deficiency, toxicity of chemotherapy agents, and a long-term exposure to lead or its salts. Chronic conditions that can produce nephropathy include systemic lupus erythematosus, diabetes mellitus and high blood pressure (hypertension), which lead to diabetic nephropathy and hypertensive nephropathy, respectively.
=== Analgesics ===
One cause of nephropathy is the long term usage of pain medications known as analgesics. The pain medicines which can cause kidney problems include aspirin, acetaminophen, and nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen and naproxen. This form of nephropathy is "chronic analgesic nephritis", a chronic inflammatory change characterized by loss and atrophy of tubules and interstitial fibrosis and inflammation (BRS Pathology, 2nd ed.).
Specifically, long-term use of the analgesic phenacetin has been linked to renal papillary necrosis (necrotizing papillitis).
=== Diabetes ===
Diabetic nephropathy is a progressive kidney disease caused by angiopathy of the capillaries in the glomeruli. It is characterized by nephrotic syndrome and diffuse scarring of the glomeruli. It is particularly associated with poorly managed diabetes mellitus and is a primary reason for dialysis in many developed countries. It is classified as a small blood vessel complication of diabetes.
=== Autosomal dominant polycystic kidney disease ===
Gabow 1990 talks about autosomal dominant polycystic kidney disease and how this disease is genetic. They go on to say "Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic disease, affecting a half million Americans. The clinical phenotype can result from at least two different gene defects. One gene that can cause ADPKD has been located on the short arm of chromosome 16." The same article also goes on to say that millions of Americans are affected by this disease and it is very common.
=== COVID-19 ===
COVID-19 is associated with kidney disease. In patients hospitalized with COVID-19, the prevalence of acute kidney injury is estimated to be 28%, and the prevalence of renal replacement therapy is estimated to be 9%.
=== Diet ===
Higher dietary intake of animal protein, animal fat, and cholesterol may increase risk for microalbuminuria, a sign of kidney function decline, and generally, diets higher in fruits, vegetables, and whole grains but lower in meat and sweets may be protective against kidney function decline. This may be because sources of animal protein, animal fat, and cholesterol, and sweets are more acid-producing, while fruits, vegetables, legumes, and whole grains are more base-producing.
=== IgA nephropathy ===
IgA nephropathy is the most common glomerulonephritis throughout the world Primary IgA nephropathy is characterized by deposition of the IgA antibody in the glomerulus. The classic presentation (in 40–50% of the cases) is episodic frank hematuria which usually starts within a day or two of a non-specific upper respiratory tract infection (hence synpharyngitic) as opposed to post-streptococcal glomerulonephritis which occurs some time (weeks) after initial infection. Less commonly gastrointestinal or urinary infection can be the inciting agent. All of these infections have in common the activation of mucosal defenses and hence IgA antibody production.
=== Iodinated contrast media ===
Kidney disease induced by iodinated contrast media (ICM) is called contrast induced nephropathy (CIN) or contrast-induced acute kidney injury (AKI). Currently, the underlying mechanisms are unclear. But there is a body of evidence that several factors including apoptosis-induction seem to play a role.
=== Lithium ===
Lithium, a medication commonly used to treat bipolar disorder and schizoaffective disorders, can cause nephrogenic diabetes insipidus; its long-term use can lead to nephropathy.
=== Lupus ===
Despite expensive treatments, lupus nephritis remains a major cause of morbidity and mortality in people with relapsing or refractory lupus nephritis.
=== Xanthine oxidase deficiency ===
Another possible cause of Kidney disease is due to decreased function of xanthine oxidase in the purine degradation pathway. Xanthine oxidase will degrade hypoxanthine to xanthine and then to uric acid. Xanthine is not very soluble in water; therefore, an increase in xanthine forms crystals (which can lead to kidney stones) and result in damage to the kidney. Xanthine oxidase inhibitors, like allopurinol, can cause nephropathy.
=== Polycystic disease of the kidneys ===
Additional possible cause of nephropathy is due to the formation of cysts or pockets containing fluid within the kidneys. These cysts become enlarged with the progression of aging causing renal failure. Cysts may also form in other organs including the liver, brain, and ovaries. Polycystic kidney disease is a genetic disease caused by mutations in the PKD1, PKD2, and PKHD1 genes. This disease affects about half a million people in the US. Polycystic kidneys are susceptible to infections and cancer.
=== Toxicity of chemotherapy agents ===
Nephropathy can be associated with some therapies used to treat cancer. The most common form of kidney disease in cancer patients is acute kidney injury (AKI) which can usually be due to volume depletion from vomiting and diarrhea that occur following chemotherapy or occasionally due to kidney toxicities of chemotherapeutic agents. Kidney failure from break down of cancer cells, usually after chemotherapy, is unique to onconephrology. Several chemotherapeutic agents, for example cisplatin, are associated with acute and chronic kidney injuries. Newer agents such as anti-vascular endothelial growth factor (anti-VEGF) are also associated with similar injuries, as well as proteinuria, hypertension, and thrombotic microangiopathy.
== Diagnosis ==
The standard diagnostic workup of suspected kidney disease includes a medical history, physical examination, a urine test, and an ultrasound of the kidneys (renal ultrasonography). An ultrasound is essential in the diagnosis and management of kidney disease.
== Treatment ==
Treatment approaches for kidney disease focus on managing the symptoms, controlling the progression, and also treating co-morbidities that a person may have.
=== Dialysis ===
=== Transplantation ===
Millions of people across the world have kidney disease. Of those millions, several thousand will need dialysis or a kidney transplant at its end-stage. In the United States, as of 2008, 16,500 people needed a kidney transplant. Of those, 5,000 died while waiting for a transplant. Currently, there is a shortage of donors, and in 2007 there were only 64,606 kidney transplants in the world. This shortage of donors is causing countries to place monetary value on kidneys. Countries such as Iran and Singapore are eliminating their lists by paying their citizens to donate. Also, the black market accounts for 5–10 percent of transplants that occur worldwide. The act of buying an organ through the black market is illegal in the United States. To be put on the waiting list for a kidney transplant, patients must first be referred by a physician, then they must choose and contact a donor hospital. Once they choose a donor hospital, patients must then receive an evaluation to make sure they are sustainable to receive a transplant. In order to be a match for a kidney transplant, patients must match blood type and human leukocyte antigen factors with their donors. They must also have no reactions to the antibodies from the donor's kidneys.
== Prognosis ==
Kidney disease can have serious consequences if it cannot be controlled effectively. Generally, the progression of kidney disease is from mild to serious. Some kidney diseases can cause kidney failure.
== See also ==
Hematologic Diseases Information Service
Mesoamerican nephropathy, an enigmatic chronic kidney disease of Central America
Protein toxicity
== References ==
== External links == | Wikipedia/Kidney_disease |
Chronic kidney disease–mineral and bone disorder (CKD–MBD) is one of the many complications associated with chronic kidney disease. It represents a systemic disorder of mineral and bone metabolism due to CKD manifested by either one or a combination of the following:
Abnormalities of calcium, phosphorus (phosphate), parathyroid hormone, or vitamin D metabolism
Abnormalities in bone turnover, mineralization, volume, linear growth, or strength
Vascular or other soft-tissue calcification
CKD–MBD explains, at least in part, the high morbidity and mortality of CKD patients, linking kidney and bone disease with cardiovascular complications. It is a matter of discussion whether CKD–MBD may be considered a real syndrome or not.
CKD–MBD broadens the "old" concept of "renal osteodystrophy", which now should be restricted to describing the bone pathology associated with CKD. Thus, renal osteodystrophy is currently considered one measure of the skeletal component of the systemic disorder of CKD–MBD that is quantifiable by histomorphometry of bone biopsy. New guidelines have been recently released.
== Presentation ==
== Pathophysiology ==
It is well known that as kidney function declines, there is a progressive deterioration in mineral homeostasis, with a disruption of normal serum and tissue concentrations of phosphorus and calcium, and changes in circulating levels of hormones. These include parathyroid hormone (PTH), 25-hydroxyvitamin D (25(OH) vitamin D; calcidiol), 1,25-dihydroxyvitamin D (1,25(OH)2 vitamin D; calcitriol), and other vitamin D metabolites, fibroblast growth factor 23 (FGF-23), and growth hormone. Beginning in CKD stage 3, the ability of the kidneys to appropriately excrete a phosphate load is diminished, leading to hyperphosphatemia, elevated PTH (secondary hyperparathyroidism), and decreased 1,25(OH)2 vitamin D with associated elevations in the levels of FGF-23. The conversion of 25(OH) vitamin D to 1,25(OH)2 vitamin D is impaired, reducing intestinal calcium absorption and increasing PTH. The kidney fails to respond adequately to PTH, which normally promotes phosphaturia and calcium reabsorption, or to FGF-23, which also enhances phosphate excretion. In addition, there is evidence at the tissue level of a downregulation of vitamin D receptor and of resistance to the actions of PTH. Therapy is generally focused on correcting biochemical and hormonal abnormalities in an effort to limit their consequences.
The mineral and endocrine functions disrupted in CKD are critically important in the regulation of both initial bone formation during growth (bone modeling) and bone structure and function during adulthood (bone remodeling). As a result, bone abnormalities are found almost universally in patients with CKD requiring dialysis (stage 5D), and in the majority of patients with CKD stages 3–5. More recently, there has been an increasing concern of extraskeletal calcification that may result from the deranged mineral and bone metabolism of CKD and from the therapies used to correct these abnormalities.
Numerous cohort studies have shown associations between disorders of mineral metabolism and fractures, cardiovascular disease, and mortality. These observational studies have broadened the focus of CKD-related mineral and bone disorders (MBDs) to include cardiovascular disease (which is the leading cause of death in patients at all stages of CKD). All three of these processes (abnormal mineral metabolism, abnormal bone, and extraskeletal calcification) are closely interrelated and together make a major contribution to the morbidity and mortality of patients with CKD. The traditional definition of renal osteodystrophy did not accurately encompass this more diverse clinical spectrum, based on serum biomarkers, noninvasive imaging, and bone abnormalities. The absence of a generally accepted definition and diagnosis of renal osteodystrophy prompted Kidney Disease: Improving Global Outcomes (KDIGO) to sponsor a controversies conference, entitled Definition, Evaluation, and Classification of Renal Osteodystrophy, in 2005. The principal conclusion was that the term CKD–Mineral and Bone Disorder (CKD–MBD) should now be used to describe the "broader clinical syndrome encompassing mineral, bone, and calcific cardiovascular abnormalities that develop as a complication of CKD".
== Diagnosis ==
== Treatment ==
Treatment efforts may involve many clinical and diagnostic manoeuvers, such as trying to decrease phosphate, normalize vitamin D (calcidiol levels) or decrease PTH and/or alkaline phosphatase levels. However, there is an important lack of randomized clinical studies and recent guidelines (KDIGO 2017) have been recently released on the topic. Although it was previously considered, normalization of calcemia is not included in modern treatment goals since the advent of calcimimetics.
== References ==
== External links ==
Chronic Kidney Disease–Mineral and Bone Disorder (NIDDKD)
Current Concepts and Management Strategies in Chronic Kidney Disease–Mineral and Bone Disorder (Medscape) | Wikipedia/Chronic_kidney_disease–mineral_and_bone_disorder |
Erectile dysfunction (ED), also referred to as impotence, is a form of sexual dysfunction in males characterized by the persistent or recurring inability to achieve or maintain a penile erection with sufficient rigidity and duration for satisfactory sexual activity. It is the most common sexual problem in males and can cause psychological distress due to its impact on self-image and sexual relationships.
The majority of ED cases are attributed to physical risk factors and predictive factors. These factors can be categorized as vascular, neurological, local penile, hormonal, and drug-induced. Notable predictors of ED include aging, cardiovascular disease, diabetes mellitus, high blood pressure, obesity, abnormal lipid levels in the blood, hypogonadism, smoking, depression, and medication use. Approximately 10% of cases are linked to psychosocial factors, encompassing conditions such as depression, stress, and problems within relationships.
The term erectile dysfunction does not encompass other erection-related disorders, such as priapism.
Treatment of ED encompasses addressing the underlying causes, lifestyle modification, and addressing psychosocial issues. In many instances, medication-based therapies are used, specifically PDE5 inhibitors such as sildenafil. These drugs function by dilating blood vessels, facilitating increased blood flow into the spongy tissue of the penis, analogous to opening a valve wider to enhance water flow in a fire hose. Less frequently employed treatments encompass prostaglandin pellets inserted into the urethra, the injection of smooth-muscle relaxants and vasodilators directly into the penis, penile implants, the use of penis pumps, and vascular surgery.
ED is reported in 18% of males aged 50 to 59 years, and 37% in males aged 70 to 75.
== Signs and symptoms ==
ED is characterized by the persistent or recurring inability to achieve or maintain an erection of the penis with sufficient rigidity and duration for satisfactory sexual activity. It is defined as the "persistent or recurrent inability to achieve and maintain a penile erection of sufficient rigidity to permit satisfactory sexual activity for at least 3 months."
=== Psychological impact ===
ED often has an impact on the emotional well-being of both males and their partners. Many males do not seek treatment due to feelings of embarrassment. About 75% of diagnosed cases of ED go untreated.
== Causes ==
Causes of or contributors to ED include the following:
Diets high in saturated fat are linked to heart diseases, and males with heart diseases are more likely to experience ED. By contrast, plant-based diets show a lower risk for ED.
Prescription drugs (e.g., SSRIs, beta blockers, antihistamines, alpha-2 adrenergic receptor agonists, thiazides, hormone modulators, and 5α-reductase inhibitors)
Neurogenic disorders (e.g., diabetic neuropathy, temporal lobe epilepsy, multiple sclerosis, Parkinson's disease, multiple system atrophy)
Cavernosal disorders (e.g., Peyronie's disease)
Hyperprolactinemia (e.g., due to a prolactinoma)
Psychological causes: performance anxiety, stress, and mental disorders
Surgery (e.g., radical prostatectomy)
Ageing: after age 40 years, ageing itself is a risk factor for ED, although numerous other pathologies that may occur with ageing, such as testosterone deficiency, cardiovascular diseases, or diabetes, among others, appear to have interacting effects
Kidney disease: ED and chronic kidney disease have pathological mechanisms in common, including vascular and hormonal dysfunction, and may share other comorbidities, such as hypertension and diabetes mellitus that can contribute to ED
Lifestyle habits, particularly smoking, which is a key risk factor for ED as it promotes arterial narrowing. Due to its propensity for causing detumescence and erectile dysfunction, some studies have described tobacco as an anaphrodisiacal substance.
COVID-19: preliminary research indicates that COVID-19 viral infection may affect sexual and reproductive health.
Surgical intervention for a number of conditions may remove anatomical structures necessary to erection, damage nerves, or impair blood supply. ED is a common complication of treatments for prostate cancer, including prostatectomy and destruction of the prostate by external beam radiation, although the prostate gland itself is not necessary to achieve an erection. As far as inguinal hernia surgery is concerned, in most cases, and in the absence of postoperative complications, the operative repair can lead to a recovery of the sexual life of people with preoperative sexual dysfunction, while, in most cases, it does not affect people with a preoperative normal sexual life.
ED can also be associated with bicycling due to both neurological and vascular problems due to compression. The increased risk appears to be about 1.7-fold.
Concerns that use of pornography can cause ED have little support in epidemiological studies, according to a 2015 literature review. According to Gunter de Win, a Belgian professor and sex researcher, "Put simply, respondents who watch 60 minutes a week and think they're addicted were more likely to report sexual dysfunction than those who watch a care-free 160 minutes weekly."
In seemingly rare cases, medications such as SSRIs, isotretinoin (Accutane) and finasteride (Propecia) are reported to induce long-lasting iatrogenic disorders characterized by sexual dysfunction symptoms, including erectile dysfunction in males; these disorders are known as post-SSRI sexual dysfunction (PSSD), post-retinoid sexual dysfunction/post-Accutane syndrome (PRSD/PAS), and post-finasteride syndrome (PFS). These conditions remain poorly understood and lack effective treatments, although they have been suggested to share a common etiology.
Rarely impotence can be caused by aromatase being active. See Androgen replacement therapy.
== Pathophysiology ==
Penile erection is managed by two mechanisms: the reflex erection, which is achieved by directly touching the penile shaft, and the psychogenic erection, which is achieved by erotic or emotional stimuli. The former involves the peripheral nerves and the lower parts of the spinal cord, whereas the latter involves the limbic system of the brain. In both cases, an intact neural system is required for a successful and complete erection. Stimulation of the penile shaft by the nervous system leads to the secretion of nitric oxide (NO), which causes the relaxation of the smooth muscles of the corpora cavernosa (the main erectile tissue of the penis), and subsequently penile erection. Additionally, adequate levels of testosterone (produced by the testes) and an intact pituitary gland are required for the development of a healthy erectile system. As can be understood from the mechanisms of a normal erection, impotence may develop due to hormonal deficiency, disorders of the neural system, lack of adequate penile blood supply or psychological problems.
== Diagnosis ==
In many cases, the diagnosis can be made based on the person's history of symptoms. In other cases, a physical examination and laboratory investigations are done to rule out more serious causes such as hypogonadism or prolactinoma.
One of the first steps is to distinguish between physiological and psychological ED. Determining whether involuntary erections are present is important in eliminating the possibility of psychogenic causes for ED. Obtaining full erections occasionally, such as nocturnal penile tumescence when asleep (that is, when the mind and psychological issues, if any, are less present), tends to suggest that the physical structures are functionally working. Similarly, performance with manual stimulation, as well as any performance anxiety or acute situational ED, may indicate a psychogenic component to ED.
Another factor leading to ED is diabetes mellitus, a well known cause of neuropathy. ED is also related to generally poor physical health, poor dietary habits, obesity, and most specifically cardiovascular disease, such as coronary artery disease and peripheral vascular disease. Screening for cardiovascular risk factors, such as smoking, dyslipidemia, hypertension, and alcoholism, is helpful.
In some cases, the simple search for a previously undetected groin hernia can prove useful since it can affect sexual functions in males and is relatively easily curable.
The current – as of April 2025 – edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5-TR) lists Erectile Disorder (ICD-10-CM code: F52.21) as a diagnosis. According to the DSM, it "is the more specific DSM-5 diagnostic category in which erectile dysfunction persists for at least 6 months and causes distress in the individual." The ICD-10, to which the DSM refers regarding Erectile dysfunction, lists it under Failure of genital response (F52.2). The latest edition of the ICD – namely, the ICD-11 – lists the condition as Male erectile dysfunction (HA01.1).
=== Ultrasonography ===
Penile ultrasonography with doppler can be used to examine the erect penis. Most cases of ED of organic causes are related to changes in blood flow in the corpora cavernosa, represented by occlusive artery disease (in which less blood is allowed to enter the penis), most often of atherosclerotic origin, or due to failure of the veno-occlusive mechanism (in which too much blood circulates back out of the penis). Before the Doppler sonogram, the penis should be examined in B mode, in order to identify possible tumors, fibrotic plaques, calcifications, or hematomas, and to evaluate the appearance of the cavernous arteries, which can be tortuous or atheromatous.
Erection can be induced by injecting 10–20 μg of prostaglandin E1, with evaluations of the arterial flow every five minutes for 25–30 min (see image). The use of prostaglandin E1 is contraindicated in patients with predisposition to priapism (e.g., those with sickle cell anemia), anatomical deformity of the penis, or penile implants. Phentolamine (2 mg) is often added. Visual and tactile stimulation produces better results. Some authors recommend the use of sildenafil by mouth to replace the injectable drugs in cases of contraindications, although the efficacy of such medication is controversial.
Before the injection of the chosen drug, the flow pattern is monophasic, with low systolic velocities and an absence of diastolic flow. After injection, systolic and diastolic peak velocities should increase, decreasing progressively with vein occlusion and becoming negative when the penis becomes rigid (see image below). The reference values vary across studies, ranging from > 25 cm/s to > 35 cm/s. Values above 35 cm/s indicate the absence of arterial disease, values below 25 cm/s indicate arterial insufficiency, and values of 25–35 cm/s are indeterminate because they are less specific (see image below). The data obtained should be correlated with the degree of erection observed. If the peak systolic velocities are normal, the final diastolic velocities should be evaluated, those above 5 cm/s being associated with venogenic ED.
=== Other workup methods ===
Penile nerves function
Tests such as the bulbocavernosus reflex test are used to ascertain whether there is enough nerve sensation in the penis. The physician squeezes the glans (head) of the penis, which immediately causes the anus to contract if nerve function is normal. A physician measures the latency between squeeze and contraction by observing the anal sphincter or by feeling it with a gloved finger in the anus.
Nocturnal penile tumescence (NPT)
It is normal for a man to have five to six erections during sleep, especially during rapid eye movement (REM). Their absence may indicate a problem with nerve function or blood supply in the penis. There are two methods for measuring changes in penile rigidity and circumference during nocturnal erection: snap gauge and strain gauge. A significant proportion of males who have no sexual dysfunction nonetheless do not have regular nocturnal erections.
Penile biothesiometry
This test uses electromagnetic vibration to evaluate sensitivity and nerve function in the glans and shaft of the penis.
Dynamic infusion cavernosometry (DICC)
Technique in which fluid is pumped into the penis at a known rate and pressure. It gives a measurement of the vascular pressure in the corpus cavernosum during an erection.
Corpus cavernosometry
Cavernosography measurement of the vascular pressure in the corpus cavernosum. Saline is infused under pressure into the corpus cavernosum with a butterfly needle, and the flow rate needed to maintain an erection indicates the degree of venous leakage. The leaking veins responsible may be visualized by infusing a mixture of saline and x-ray contrast medium and performing a cavernosogram. In Digital Subtraction Angiography (DSA), the images are acquired digitally.
Magnetic resonance angiography (MRA)
This is similar to magnetic resonance imaging. Magnetic resonance angiography uses magnetic fields and radio waves to provide detailed images of the blood vessels. The doctor may inject into the patient's bloodstream a contrast agent, which causes vascular tissues to stand out against other tissues, so that information about blood supply and vascular anomalies is easier to gather.
Erection Hardness Score
== Treatment ==
Treatment depends on the underlying cause. In general, exercise, particularly of the aerobic type, is effective for preventing ED during midlife. Counseling can be used if the underlying cause is psychological, including how to lower stress or anxiety related to sex. Medications by mouth and vacuum erection devices are first-line treatments,: 20, 24 followed by injections of drugs into the penis, as well as penile implants.: 25–26 Vascular reconstructive surgeries are beneficial in certain groups. Treatments, other than surgery, do not fix the underlying physiological problem, but are used as needed before sex.
=== Medications ===
The PDE5 inhibitors sildenafil (Viagra), vardenafil (Levitra) and tadalafil (Cialis) are prescription drugs which are taken by mouth.: 20–21 As of 2018, sildenafil is available in the UK without a prescription. Additionally, a cream combining alprostadil with the permeation enhancer DDAIP has been approved in Canada as a first line treatment for ED. Penile injections, on the other hand, can involve one of the following medications: papaverine, phentolamine, and prostaglandin E1, also known as alprostadil. In addition to injections, there is an alprostadil suppository that can be inserted into the urethra. Once inserted, an erection can begin within 10 minutes and last up to an hour. Medications to treat ED may cause a side effect called priapism.
==== Prevalence of medical diagnosis ====
In a study published in 2016, based on US health insurance claims data, out of 19,833,939 US males aged ≥18 years, only 1,108,842 (5.6%), were medically diagnosed with erectile dysfunction or on a PDE5I prescription (μ age 55.2 years, σ 11.2 years). Prevalence of diagnosis or prescription was the highest for age group 60–69 at 11.5%, lowest for age group 18–29 at 0.4%, and 2.1% for 30–39, 5.7% for 40–49, 10% for 50–59, 11% for 70–79, 4.6% for 80–89, 0.9% for ≥90, respectively.
=== Focused shockwave therapy ===
Focused shockwave therapy involves passing short, high frequency acoustic pulses through the skin and into the penis. These waves break down any plaques within the blood vessels, encourage the formation of new vessels, and stimulate repair and tissue regeneration.
Focused shockwave therapy appears to work best for males with vasculogenic ED, which is a blood vessel disorder that affects blood flow to tissue in the penis. The treatment is painless and has no known side effects. Treatment with shockwave therapy can lead to a significant improvement of the IIEF (International Index of Erectile Function).
=== Testosterone ===
Men with low levels of testosterone can experience ED. Taking testosterone may help maintain an erection. Males with type 2 diabetes are twice as likely to have lower levels of testosterone, and are three times more likely to experience ED than non-diabetic men.
=== Pumps ===
A vacuum erection device helps draw blood into the penis by applying negative pressure. This type of device is sometimes referred to as penis pump and may be used just prior to sexual intercourse. Several types of FDA approved vacuum therapy devices are available under prescription. When pharmacological methods fail, a purpose-designed external vacuum pump can be used to attain erection, with a separate compression ring fitted to the base of the penis to maintain it. These pumps should be distinguished from other penis pumps (supplied without compression rings) which, rather than being used for temporary treatment of impotence, are claimed to increase penis length if used frequently, or vibrate as an aid to masturbation. More drastically, inflatable or rigid penile implants may be fitted surgically.
=== Vibrators ===
The vibrator was invented in the late 19th century as a medical instrument for pain relief and the treatment of various ailments. Sometimes described as a massager, the vibrator is used on the body to produce sexual stimulation. Several clinical studies have found vibrators to be an effective solution for Erectile Dysfunction. Examples of FDA registered vibrators for erectile dysfunction include MysteryVibe's Tenuto and Reflexonic's Viberect.
=== Surgery ===
Often, as a last resort, if other treatments have failed, the most common procedure is prosthetic implants which involves the insertion of artificial rods into the penis.: 26 Some sources show that vascular reconstructive surgeries are viable options for some people.
=== Alternative medicine ===
The Food and Drug Administration (FDA) does not recommend alternative therapies to treat sexual dysfunction. Many products are advertised as "herbal viagra" or "natural" sexual enhancement products, but no clinical trials or scientific studies support the effectiveness of these products for the treatment of ED, and synthetic chemical compounds similar to sildenafil have been found as adulterants in many of these products. The FDA has warned consumers that any sexual enhancement product that claims to work as well as prescription products is likely to contain such a contaminant. A 2021 review indicated that ginseng had "only trivial effects on erectile function or satisfaction with intercourse compared to placebo".
== History ==
Attempts to treat the symptoms described by ED date back well over 1,000 years. In the 8th century, males of Ancient Rome and Greece wore talismans of rooster and goat genitalia, believing these talismans would serve as an aphrodisiac and promote sexual function. In the 13th century, Albertus Magnus recommended ingesting roasted wolf penis as a remedy for impotence. During the late 16th and 17th centuries in France, male impotence was considered a crime, as well as legal grounds for a divorce. The practice, which involved inspection of the complainants by court experts, was declared obscene in 1677.
The first major publication describing a broad medicalization of sexual disorders was the first edition of the Diagnostic and Statistical Manual of Mental Disorders in 1952. In the early 20th century, medical folklore held that 90-95% of cases of ED were psychological in origin, but around the 1980s research took the opposite direction of searching for physical causes of sexual dysfunction, which also happened in the 1920s and 30s. Physical causes as explanations continue to dominate literature when compared with psychological explanations as of 2022.
Treatments in the 80s for ED included penile implants and intracavernosal injections. The first successful vacuum erection device, or penis pump, was developed by Vincent Marie Mondat in the early 1800s. A more advanced device based on a bicycle pump was developed by Geddings Osbon, a Pentecostal preacher, in the 1970s. In 1982, he received FDA approval to market the product. John R. Brinkley initiated a boom in male impotence treatments in the U.S. in the 1920s and 1930s, with radio programs that recommended expensive goat gland implants and "mercurochrome" injections as the path to restored male virility, including operations by surgeon Serge Voronoff.
Modern drug therapy for ED made a significant advance in 1983, when British physiologist Giles Brindley dropped his trousers and demonstrated to a shocked Urodynamics Society audience showing his papaverine-induced erection. The current most common treatment for ED, the oral PDE5 inhibitor known as sildenafil (Viagra) was approved for use for Pfizer by the FDA in 1998, which at the time of release was the fastest selling drug in history. Sildenafil largely replaced SSRI treatments for ED at the time and proliferated new types of specialised pharmaceutical marketing which emphasised social connotations of ED and Viagra rather than its physical effects.
== Anthropology ==
Anthropological research presents ED not as a disorder but, as a normal, and sometimes even welcome sign of healthy aging. Wentzell's study of 250 Mexican males in their 50s and 60s found that "most simply did not see decreasing erectile function as a biological pathology". The males interviewed described the decrease in erectile function "as an aid for aging in socially appropriate ways". A common theme amongst the interviewees showed that respectable older males shifted their focus toward the domestic sphere into a "second stage of life". The Mexican males of this generation often pursued sex outside of marriage; decreasing erectile function acted as an aid to overcoming infidelity thus helping to attain the ideal "second stage" of life. A 56-year-old about to retire from the public health service said he would now "dedicate myself to my wife, the house, gardening, caring for the grandchildren—the Mexican classic". Wentzell found that treating ED as a pathology was antithetical to the social view these males held of themselves, and their purpose at this stage of their lives.
In the 20th and 21st centuries, anthropologists investigated how common treatments for ED are built upon assumptions of institutionalized social norms. In offering a range of clinical treatments to 'correct' a person's ability to produce an erection, biomedical institutions encourage the public to strive for prolonged sexual function. Anthropologists argue that a biomedical focus places emphasis on the biological processes of fixing the body thereby disregarding holistic ideals of health and aging. By relying on a wholly medical approach, Western biomedicine can become blindsided by bodily dysfunctions which can be understood as appropriate functions of age, and not as a medical problem. Anthropologists understand that a biosocial approach to ED considers a person's decision to undergo clinical treatment more likely a result of "society, political economy, history, and culture" than a matter of personal choice. In rejecting biomedical treatment for ED, males can challenge common forms of medicalized social control by deviating from what is considered the normal approach to dysfunction.
== Lexicology ==
The Latin term impotentia coeundi describes simple inability to insert the penis into the vagina; it is now mostly replaced by more precise terms, such as erectile dysfunction (ED). The study of ED within medicine is covered by andrology, a sub-field within urology. Research indicates that ED is common, and it is suggested that approximately 40% of males experience symptoms compatible with ED, at least occasionally. The condition is also on occasion called phallic impotence. Its antonym, or opposite condition, is priapism.
== References ==
== Further reading ==
Carson C, Faria G, Hellstrom WJ, Krishnamurti S, Minhas S, Moncada I, et al. (1 January 2010). "Implants, Mechanical Devices, and Vascular Surgery for Erectile Dysfunction". Journal of Sexual Medicine. 7 (1). Wiley: 501–523. doi:10.1111/j.1743-6109.2009.01626.x. PMID 20092450.
== External links == | Wikipedia/Erectile_dysfunction |
Organ dysfunction is a condition where an organ does not perform its expected function. Organ failure is organ dysfunction to such a degree that normal homeostasis cannot be maintained without external clinical intervention or life support. It is not a diagnosis. It can be classified by the cause, but when the cause is not known, it can also be classified by whether the onset is chronic or acute.
Multiple organ failure can be associated with sepsis and is often fatal. Countries such as Spain have shown a rise in mortality risk due to a large elderly population there. There are tools physicians use when diagnosing multiple organ failure and when prognosing the outcome. The Sequential Organ Failure Assessment (SOFA) score uses early lab values in a patient's hospitalization (within 24 hours) to predict fatal outcomes for a patient.
== References ==
== External links ==
Sequential Organ Failure Assessment (SOFA) Score | Wikipedia/Organ_dysfunction |
Assessment of kidney function occurs in different ways, using the presence of symptoms and signs, as well as measurements using urine tests, blood tests, and medical imaging.
Functions of a healthy kidney include maintaining a person's fluid balance, maintaining an acid-base balance; regulating electrolytes sodium, and other electrolytes; clearing toxins; regulating blood pressure; and regulating hormones, such as erythropoietin; and activation of vitamin D. The kidney is also involved in maintaining blood pH balance.
== Description ==
The functions of the kidney include maintenance of acid-base balance; regulation of fluid balance; regulation of sodium, potassium, and other electrolytes; clearance of toxins; absorption of glucose, amino acids, and other small molecules; regulation of blood pressure; production of various hormones, such as erythropoietin; and activation of vitamin D.
The Glomerular filtration rate (GFR) is regarded as the best overall measure of the kidney's ability to carry out these numerous functions. An estimate of the GFR is used clinically to determine the degree of kidney impairment and to track the progression of the disease. The GFR, however, does not reveal the source of the kidney disease. This is accomplished by urinalysis, measurement of urine protein excretion, kidney imaging, and, if necessary, kidney biopsy.
Much of renal physiology is studied at the level of the nephron – the smallest functional unit of the kidney. Each nephron begins with a filtration component that filters the blood entering the kidney. This filtrate then flows along the length of the nephron, which is a tubular structure lined by a single layer of specialized cells and surrounded by capillaries. The major functions of these lining cells are the reabsorption of water and small molecules from the filtrate into the blood, and the secretion of wastes from the blood into the urine.
Proper function of the kidney requires that it receives and adequately filters blood. This is performed at the microscopic level by many hundreds of thousands of filtration units called renal corpuscles, each of which is composed of a glomerulus and a Bowman's capsule. A global assessment of renal function is often ascertained by estimating the rate of filtration, called the glomerular filtration rate (GFR).
== Clinical assessment ==
Clinical assessment can be used to assess the function of the kidneys. This is because a person with abnormally functioning kidneys may have symptoms that develop. For example, a person with chronic kidney disease may develop oedema due to failure of the kidneys to regulate water balance. They may develop evidence of chronic kidney disease, that can be used to assess its severity, for example high blood pressure, osteoporosis or anaemia. If the kidneys are unable to excrete urea, a person may develop a widespread itch or confusion.
== Urine tests ==
Part of the assessment of kidney function includes the measurement of urine and its contents. Abnormal kidney function may cause too much or too little urine to be produced. The ability of the kidneys to filter protein is often measured, as urine albumin or urine protein levels, measured either at a single instance or, because of variation throughout the day, as 24-hour urine tests.
== Blood tests ==
Blood tests are also used to assess kidney function. These include tests that are intended to directly measure the function of the kidneys, as well as tests that assess the function of the kidneys by looking for evidence of problems associated with abnormal function. One of the measures of kidney function is the glomerular filtration rate (GFR). Other tests that can assess the function of the kidneys include assessment of electrolyte levels such as potassium and phosphate, assessment of acid-base status by the measurement of bicarbonate levels from a vein, and assessment of the full blood count for anaemia.
=== Glomerular filtration rate ===
The glomerular filtration rate (GFR) describes the volume of fluid filtered from the renal (kidney) glomerular capillaries into the Bowman's capsule per unit time. Creatinine clearance (CCr) is the volume of blood plasma that is cleared of creatinine per unit time and is a useful measure for approximating the GFR. Creatinine clearance exceeds GFR due to creatinine secretion, which can be blocked by cimetidine. Both GFR and CCr may be accurately calculated by comparative measurements of substances in the blood and urine, or estimated by formulas using just a blood test result (eGFR and eCCr) The results of these tests are used to assess the excretory function of the kidneys. Staging of chronic kidney disease is based on categories of GFR as well as albuminuria and cause of kidney disease.
Central to the physiologic maintenance of GFR is the differential basal tone of the afferent and efferent arterioles (see diagram). In other words, the filtration rate is dependent on the difference between the higher blood pressure created by vasoconstriction of the input or afferent arteriole versus the lower blood pressure created by lesser vasoconstriction of the output or efferent arteriole.
GFR is equal to the renal clearance ratio when any solute is freely filtered and is neither reabsorbed nor secreted by the kidneys. The rate therefore measured is the quantity of the substance in the urine that originated from a calculable volume of blood. Relating this principle to the below equation – for the substance used, the product of urine concentration and urine flow equals the mass of substance excreted during the time that urine has been collected. This mass equals the mass filtered at the glomerulus as nothing is added or removed in the nephron. Dividing this mass by the plasma concentration gives the volume of plasma which the mass must have originally come from, and thus the volume of plasma fluid that has entered Bowman's capsule within the aforementioned period of time. The GFR is typically recorded in units of volume per time, e.g., milliliters per minute (mL/min). Compare to filtration fraction.
G
F
R
=
Urine Concentration
×
Urine Flow
Plasma Concentration
{\displaystyle GFR={\frac {{\mbox{Urine Concentration}}\times {\mbox{Urine Flow}}}{\mbox{Plasma Concentration}}}}
There are several different techniques used to calculate or estimate the glomerular filtration rate (GFR or eGFR). The above formula only applies for GFR calculation when it is equal to the clearance rate.
The normal range of GFR, adjusted for body surface area, is 100–130 average 125 (mL/min)/(1.73 m2) in men and 90–120 (mL/min)/(1.73 m2) in women younger than the age of 40. In children, GFR measured by inulin clearance is 110 (mL/min)/(1.73 m2) until 2 years of age in both sexes, and then it progressively decreases. After age 40, GFR decreases progressively with age, by 0.4–1.2 mL/min per year.
Estimated GFR (eGFR) is now recommended by clinical practice guidelines and regulatory agencies for routine evaluation of GFR whereas measured GFR (mGFR) is recommended as a confirmatory test when more accurate assessment is required.
== Medical imaging ==
The kidney function can also be assessed with medical imaging. Some forms of imaging, such as kidney ultrasound or CT scans, may assess kidney function by indicating chronic disease that can impact function, by showing a small or shrivelled kidney.. Other tests, such as nuclear medicine tests, directly assess the function of the kidney by measuring the perfusion and excretion of radioactive substances through the kidneys.
== Kidney function in disease ==
A decreased renal function can be caused by many types of kidney disease. Upon presentation of decreased renal function, it is recommended to perform a history and physical examination, as well as performing a renal ultrasound and a urinalysis. The most relevant items in the history are medications, edema, nocturia, gross hematuria, family history of kidney disease, diabetes and polyuria. The most important items in a physical examination are signs of vasculitis, lupus erythematosus, diabetes, endocarditis and hypertension.
A urinalysis is helpful even when not showing any pathology, as this finding suggests an extrarenal etiology. Proteinuria and/or urinary sediment usually indicates the presence of glomerular disease. Hematuria may be caused by glomerular disease or by a disease along the urinary tract.
The most relevant assessments in a renal ultrasound are renal sizes, echogenicity and any signs of hydronephrosis. Renal enlargement usually indicates diabetic nephropathy, focal segmental glomerular sclerosis or myeloma. Renal atrophy suggests longstanding chronic renal disease.
=== Chronic kidney disease stages ===
Risk factors for kidney disease include diabetes, high blood pressure, family history, older age, ethnic group and smoking.
For most patients, a GFR over 60 (mL/min)/(1.73 m2) is adequate. But significant decline of the GFR from a previous test result can be an early indicator of kidney disease requiring medical intervention. The sooner kidney dysfunction is diagnosed and treated the greater odds of preserving remaining nephrons, and preventing the need for dialysis.
The severity of chronic kidney disease (CKD) is described by six stages; the most severe three are defined by the MDRD-eGFR value, and first three also depend on whether there is other evidence of kidney disease (e.g., proteinuria):
0) Normal kidney function – GFR above 90 (mL/min)/(1.73 m2) and no proteinuria
1) CKD1 – GFR above 90 (mL/min)/(1.73 m2) with evidence of kidney damage
2) CKD2 (mild) – GFR of 60 to 89 (mL/min)/(1.73 m2) with evidence of kidney damage
3) CKD3 (moderate) – GFR of 30 to 59 (mL/min)/(1.73 m2)
4) CKD4 (severe) – GFR of 15 to 29 (mL/min)/(1.73 m2)
5) CKD5 kidney failure – GFR less than 15 (mL/min)/(1.73 m2) Some people add CKD5D for those stage 5 patients requiring dialysis; many patients in CKD5 are not yet on dialysis.
Note: others add a "T" to patients who have had a transplant regardless of stage.
Not all clinicians agree with the above classification, suggesting that it may mislabel patients with mildly reduced kidney function, especially the elderly, as having a disease. A conference was held in 2009 regarding these controversies by Kidney Disease: Improving Global Outcomes (KDIGO) on CKD: Definition, Classification and Prognosis, gathering data on CKD prognosis to refine the definition and staging of CKD.
== See also ==
== References ==
== External links ==
=== Reference links ===
National Kidney Disease Education Program website. Includes professional references and GFR calculators
eGFR at Lab Tests Online | Wikipedia/Kidney_function |
Renal functions include maintaining an acid–base balance; regulating fluid balance; regulating sodium, potassium, and other electrolytes; clearing toxins; absorption of glucose, amino acids, and other small molecules; regulation of blood pressure; production of various hormones, such as erythropoietin; and activation of vitamin D.
The kidney has many functions, which a well-functioning kidney realizes by filtering blood in a process known as glomerular filtration. A major measure of kidney function is the glomerular filtration rate (GFR).
The glomerular filtration rate is the flow rate of filtered fluid through the kidney. The creatinine clearance rate (CCr or CrCl) is the volume of blood plasma that is cleared of creatinine per unit time and is a useful measure for approximating the GFR. Creatinine clearance exceeds GFR due to creatinine secretion, which can be blocked by cimetidine. Both GFR and CCr may be accurately calculated by comparative measurements of substances in the blood and urine, or estimated by formulas using just a blood test result (eGFR and eCCr) The results of these tests are used to assess the excretory function of the kidneys. Staging of chronic kidney disease is based on categories of GFR as well as albuminuria and cause of kidney disease.
Estimated GFR (eGFR) is recommended by clinical practice guidelines and regulatory agencies for routine evaluation of GFR whereas measured GFR (mGFR) is recommended as a confirmatory test when more accurate assessment is required.
== Definition ==
Glomerular filtration rate (GFR) is the volume of fluid filtered from the renal (kidney) glomerular capillaries into the Bowman's capsule per unit time. Central to the physiologic maintenance of GFR is the differential basal tone of the afferent (input) and efferent (output) arterioles (see diagram). In other words, the filtration rate is dependent on the difference between the higher blood pressure created by vasoconstriction of the afferent arteriole versus the lower blood pressure created by lesser vasoconstriction of the efferent arteriole.
GFR is equal to the renal clearance rate when any solute is freely filtered and is neither reabsorbed nor secreted by the kidneys. The rate therefore measured is the quantity of the substance in the urine that originated from a calculable volume of blood. Relating this principle to the below equation – for the substance used, the product of urine concentration and urine flow equals the mass of substance excreted during the time that urine has been collected. This mass equals the mass filtered at the glomerulus as nothing is added or removed in the nephron. Dividing this mass by the plasma concentration gives the volume of plasma which the mass must have originally come from, and thus the volume of plasma fluid that has entered Bowman's capsule within the aforementioned period of time. The GFR is typically recorded in units of volume per time, e.g., milliliters per minute (mL/min). Compare to filtration fraction.
G
F
R
=
Urine Concentration
×
Urine Flow
Plasma Concentration
{\displaystyle GFR={\frac {{\mbox{Urine Concentration}}\times {\mbox{Urine Flow}}}{\mbox{Plasma Concentration}}}}
There are several different techniques used to calculate or estimate the glomerular filtration rate (GFR or eGFR). The above formula only applies for GFR calculation when it is equal to the Clearance Rate.
== Measurement ==
=== Creatinine ===
In clinical practice, however, creatinine clearance or estimates of creatinine clearance based on the serum creatinine level are used to measure GFR. Creatinine is produced naturally by the body (creatinine is a breakdown product of creatine phosphate, which is found in muscle). It is freely filtered by the glomerulus, but also actively secreted by the peritubular capillaries in very small amounts such that creatinine clearance overestimates actual GFR by 10–20%. This margin of error is acceptable, considering the ease with which creatinine clearance is measured. Unlike precise GFR measurements involving constant infusions of inulin, creatinine is already at a steady-state concentration in the blood, and so measuring creatinine clearance is much less cumbersome. However, creatinine estimates of GFR have their limitations. All of the estimating equations depend on a prediction of the 24-hour creatinine excretion rate, which is a function of muscle mass which is quite variable. One of the equations, the Cockcroft and Gault equation (see below) does not correct for race. With a higher muscle mass, serum creatinine will be higher for any given rate of clearance.
=== Inulin ===
The GFR can be determined by injecting inulin or the inulin-analog sinistrin into the blood stream. Since both inulin and sinistrin are neither reabsorbed nor secreted by the kidney after glomerular filtration, their rate of excretion is directly proportional to the rate of filtration of water and solutes across the glomerular filter. Incomplete urine collection is an important source of error in inulin clearance measurement.
Using inulin to measure kidney function is the "gold standard" for comparison with other means of estimating glomerular filtration rate. In 2018, the French pharmacovigilance agency withdrew inulin and sinistrin-based products from the market after some patients experienced hypersensitivity reactions including a fatal outcome. Consequently, the contrast agents Iohexol and Iothalamate have become more popular alternatives to determine GFR and are considered to show sufficient accuracy to determine GFR.
=== Radioactive tracers ===
GFR can be accurately measured using radioactive substances, in particular chromium-51 and technetium-99m. These come close to the ideal properties of inulin (undergoing only glomerular filtration) but can be measured more practically with only a few urine or blood samples. Measurement of renal or plasma clearance of 51Cr-EDTA is widely used in Europe but not available in the United States, where 99mTc-DTPA may be used instead. Renal and plasma clearance 51Cr-EDTA has been shown to be accurate in comparison with the gold standard, inulin. Use of 51Cr‑EDTA is considered a reference standard measure in UK guidance.
=== Cystatin C ===
Problems with creatinine (varying muscle mass, recent meat ingestion (much less dependent on the diet than urea), etc.) have led to evaluation of alternative agents for estimation of GFR. One of these is cystatin C, a ubiquitous protein secreted by most cells in the body (it is an inhibitor of cysteine protease).
Cystatin C is freely filtered at the glomerulus. After filtration, Cystatin C is reabsorbed and catabolized by the tubular epithelial cells, with only small amounts excreted in the urine. Cystatin C levels are therefore measured not in the urine, but in the bloodstream.
Equations have been developed linking estimated GFR to serum cystatin C levels. Most recently, some proposed equations have combined sex, age, adjusted cystatin C and creatinine. In 2022, the National Kidney Foundation (NKF) and American Society of Nephrology (ASN)'s Joint Task Force on Reassessing the Inclusion of Race in Diagnosing Kidney Diseases recommended national efforts to facilitate increased, routine, and timely use of cystatin C. They noted that cystatin C would be useful particularly to confirm estimated GFR in adults who are at risk for or have chronic kidney disease. They suggested that combining filtration markers (creatinine and cystatin C) is more accurate and would support better clinical decisions than either marker alone.
== Calculation ==
More precisely, GFR is the fluid flow rate between the glomerular capillaries and the Bowman's capsule:
Q
=
d
V
d
t
=
K
f
×
(
P
G
−
P
B
−
Π
G
+
Π
B
)
{\displaystyle Q={\operatorname {d} V \over \operatorname {d} t}=K_{f}\times (P_{G}-P_{B}-\Pi _{G}+\Pi _{B})}
Where:
Q
{\displaystyle Q}
is the GFR.
K
f
{\displaystyle K_{f}}
is called the filtration constant and is defined as the product of the hydraulic conductivity and the surface area of the glomerular capillaries.
P
G
{\displaystyle P_{G}}
is the hydrostatic pressure within the glomerular capillaries.
P
B
{\displaystyle P_{B}}
is the hydrostatic pressure within the Bowman's capsule.
Π
G
{\displaystyle \Pi _{G}}
is the colloid osmotic pressure within the glomerular capillaries.
and
Π
B
{\displaystyle \Pi _{B}}
is the colloid osmotic pressure within the Bowman's capsule.
=== Kf ===
Because this constant is a measurement of hydraulic conductivity multiplied by the capillary surface area, it is almost impossible to measure physically. However, it can be determined experimentally. Methods of determining the GFR are listed in the above and below sections and it is clear from our equation that
K
f
{\displaystyle K_{f}}
can be found by dividing the experimental GFR by the net filtration pressure:
K
f
=
GFR
Net Filt. Pressure
=
GFR
(
P
G
−
P
B
−
Π
G
+
Π
B
)
{\displaystyle K_{f}={\frac {\textrm {GFR}}{\text{Net Filt. Pressure}}}={\frac {\textrm {GFR}}{(P_{G}-P_{B}-\Pi _{G}+\Pi _{B})}}}
=== PG ===
The hydrostatic pressure within the glomerular capillaries is determined by the pressure difference between the fluid entering immediately from the afferent arteriole and leaving through the efferent arteriole. The pressure difference is approximated by the product of the total resistance of the respective arteriole and the flux of blood through it:
P
a
−
P
G
=
R
a
×
Q
a
{\displaystyle P_{a}-P_{G}=R_{a}\times Q_{a}}
P
G
−
P
e
=
R
e
×
Q
e
{\displaystyle P_{G}-P_{e}=R_{e}\times Q_{e}}
Where:
P
a
{\displaystyle P_{a}}
is the afferent arteriole pressure.
is the hydrostatic pressure within the glomerular capillaries.
P
e
{\displaystyle P_{e}}
is the efferent arteriole pressure.
R
a
{\displaystyle R_{a}}
is the afferent arteriole resistance.
R
e
{\displaystyle R_{e}}
is the efferent arteriole resistance.
Q
a
{\displaystyle Q_{a}}
is the afferent arteriole flux.
And,
Q
e
{\displaystyle Q_{e}}
is the efferent arteriole flux.
=== PB ===
The pressure in the Bowman's capsule and proximal tubule can be determined by the difference between the pressure in the Bowman's capsule and the descending tubule:
P
B
−
P
d
=
R
d
×
(
Q
a
−
Q
e
)
{\displaystyle P_{B}-P_{d}=R_{d}\times (Q_{a}-Q_{e})}
Where:
P
d
{\displaystyle P_{d}}
is the pressure in the descending tubule.
And,
R
d
{\displaystyle R_{d}}
is the resistance of the descending tubule.
=== ΠG ===
Blood plasma has a good many proteins in it and they exert an inward directed force called the osmotic pressure on the water in hypotonic solutions across a membrane, i.e., in the Bowman's capsule. Because plasma proteins are virtually incapable of escaping the glomerular capillaries, this oncotic pressure is defined, simply, by the ideal gas law:
Π
G
=
R
T
c
{\displaystyle \Pi _{G}=RTc}
Where:
R is the universal gas constant
T is the temperature.
And, c is concentration in mol/L of plasma proteins (remember the solutes can freely diffuse through the glomerular capsule).
=== ΠB ===
This value is almost always taken to be equal to zero because in a healthy nephron, there should be no proteins in the Bowman's capsule.
== Clearance and filtration fraction ==
=== Filtration fraction ===
The filtration fraction is the amount of plasma that is actually filtered through the kidney. This can be defined using the equation:
FF=GFR/RPF
FF is the filtration fraction
GFR is the glomerular filtration rate
RPF is the renal plasma flow
Normal human FF is 20%.
=== Renal clearance ===
Cx=(Ux)V/Px
Cx is the clearance of X (normally in units of mL/min).
Ux is the urine concentration of X.
Px is the plasma concentration of X.
V is the urine flow rate.
== Estimation ==
In clinical practice, however, creatinine clearance or estimates of creatinine clearance based on the serum creatinine level are used to measure GFR. Creatinine is produced naturally by the body (creatinine is a breakdown product of creatine phosphate, which is found in muscle). It is freely filtered by the glomerulus, but also actively secreted by the peritubular capillaries in very small amounts such that creatinine clearance overestimates actual GFR by 10–20%. This margin of error is acceptable, considering the ease with which creatinine clearance is measured. Unlike precise GFR measurements involving constant infusions of inulin, creatinine is already at a steady-state concentration in the blood, and so measuring creatinine clearance is much less cumbersome. However, creatinine estimates of GFR have their limitations. All of the estimating equations depend on a prediction of the 24-hour creatinine excretion rate, which is a function of muscle mass which is quite variable. The Cockcroft-Gault and CKD-EPI 2021 equations (see below) do not correct for race. With a higher muscle mass, serum creatinine will be higher for any given rate of clearance.
A common mistake made when just looking at serum creatinine is the failure to account for muscle mass. Hence, an older woman with a serum creatinine of 1.4 mg/dL may actually have a moderately severe chronic kidney disease, whereas a young muscular male can have a normal level of renal function at this serum creatinine level. Creatinine-based equations should be used with caution in cachectic patients and patients with cirrhosis. They often have very low muscle mass and a much lower creatinine excretion rate than predicted by the equations below, such that a cirrhotic patient with a serum creatinine of 0.9 mg/dL may have a moderately severe degree of chronic kidney disease.
Estimated GFR (eGFR) is now recommended by clinical practice guidelines and regulatory agencies for routine evaluation of GFR whereas measured GFR (mGFR) is recommended as a confirmatory test when more accurate assessment is required.
=== Creatinine clearance CCr ===
One method of determining GFR from creatinine is to collect urine (usually for 24 h) to determine the amount of creatinine that was removed from the blood over a given time interval. If one removes 1440 mg in 24 h, this is equivalent to removing 1 mg/min. If the blood concentration is 0.01 mg/mL (1 mg/dL), then one can say that 100 mL/min of blood is being "cleared" of creatinine, since, to get 1 mg of creatinine, 100 mL of blood containing 0.01 mg/mL would need to have been cleared.
Creatinine clearance (CCr) is calculated from the creatinine concentration in the collected urine sample (UCr), urine flow rate (Vdt), and the plasma concentration (PCr). Since the product of urine concentration and urine flow rate yields creatinine excretion rate, which is the rate of removal from the blood, creatinine clearance is calculated as removal rate per min (UCr×Vdt) divided by the plasma creatinine concentration. This is commonly represented mathematically as
C
C
r
=
U
C
r
×
V
˙
P
C
r
{\displaystyle C_{Cr}={\frac {U_{Cr}\times {\dot {V}}}{P_{Cr}}}}
Example: A person has a plasma creatinine concentration of 0.01 mg/mL and in 1 hour produces 60 mL of urine with a creatinine concentration of 1.25 mg/mL.
C
C
r
=
1.25
m
g
/
m
L
×
60
m
L
60
m
i
n
0.01
m
g
/
m
L
=
1.25
m
g
/
m
L
×
1
m
L
/
m
i
n
0.01
m
g
/
m
L
=
1.25
m
g
/
m
i
n
0.01
m
g
/
m
L
=
125
m
L
/
m
i
n
{\displaystyle C_{Cr}={\frac {\mathrm {1.25\ mg/mL\times {\frac {60\ mL}{60\ min}}} }{\mathrm {0.01\ mg/mL} }}={\frac {\mathrm {{1.25\ mg/mL}\times {1\ mL/min}} }{\mathrm {0.01\ mg/mL} }}={\frac {\mathrm {1.25\ mg/min} }{\mathrm {0.01\ mg/mL} }}=\mathrm {125\ mL/min} }
The common procedure involves undertaking a 24-hour urine collection, from empty-bladder one morning to the contents of the bladder the following morning, with a comparative blood test then taken. The urinary flow rate is still calculated per minute, hence:
C
C
r
=
U
C
r
×
24-hour volume
P
C
r
×
24
×
60
m
i
n
{\displaystyle C_{Cr}={\frac {U_{Cr}\ \times \ {\text{24-hour volume}}}{\mathrm {P_{Cr}\ \times \ 24\times 60\ min} }}}
To allow comparison of results between people of different sizes, the CCr is often corrected for the body surface area (BSA) and expressed compared to the average sized man as mL/min/1.73 m2. While most adults have a BSA that approaches 1.7 m2 (1.6 m2 to 1.9 m2), extremely obese or slim patients should have their CCr corrected for their actual BSA.
C
Cr-corrected
=
C
C
r
×
B
S
A
1.73
{\displaystyle C_{\text{Cr-corrected}}={\frac {{C_{Cr}}\ \times \ {BSA}}{\mathrm {1.73} }}}
BSA can be calculated on the basis of weight and height.
Twenty-four-hour urine collection to assess creatinine clearance is no longer widely performed, due to difficulty in assuring complete specimen collection. To assess the adequacy of a complete collection, one always calculates the amount of creatinine excreted over a 24-hour period. This amount varies with muscle mass and is higher in young people/old, and in men/women. An unexpectedly low or high 24-hour creatinine excretion rate voids the test. Nevertheless, in cases where estimates of creatinine clearance from serum creatinine are unreliable, creatinine clearance remains a useful test. These cases include "estimation of GFR in individuals with variation in dietary intake (vegetarian diet, creatine supplements) or muscle mass (amputation, malnutrition, muscle wasting), since these factors are not specifically taken into account in prediction equations."
A number of formulae have been devised to estimate GFR or Ccr values on the basis of serum creatinine levels. Where not otherwise stated serum creatinine is assumed to be stated in mg/dL, not μmol/L—divide by 88.4 to convert from μmol/Lto mg/dL.
=== Cockcroft–Gault formula ===
A commonly used surrogate marker for the estimation of creatinine clearance is the Cockcroft–Gault (CG) formula, which in turn estimates GFR in ml/min: It is named after the scientists, the asthmologist Donald William Cockcroft (b. 1946) and the nephrologist Matthew Henry Gault (1925–2003), who first published the formula in 1976, and it employs serum creatinine measurements and a patient's weight to predict the creatinine clearance.
The formula, as originally published, is:
e
C
C
r
=
(
140
−
A
g
e
)
×
Mass (in kilograms)
×
[
0.85 if Female
]
72
×
[
Serum Creatinine (in mg/dL)
]
{\displaystyle eC_{Cr}={\frac {\mathrm {(140-Age)} \ \times \ {\text{Mass (in kilograms)}}\ \times \ [{\text{0.85 if Female}}]}{\mathrm {72} \ \times \ [{\text{Serum Creatinine (in mg/dL)}}]}}}
This formula expects weight to be measured in kilograms and creatinine to be measured in mg/dL, as is standard in the US. The resulting value is multiplied by a constant of 0.85 if the patient is female. This formula is useful because the calculations are simple and can often be performed without the aid of a calculator.
When serum creatinine is measured in μmol/L:
e
C
C
r
=
(
140
−
A
g
e
)
×
Mass (in kilograms)
×
Constant
[
Serum Creatinine (in
μ
m
o
l
/
L
)
]
{\displaystyle eC_{Cr}={\frac {\mathrm {(140-Age)} \ \times \ {\text{Mass (in kilograms)}}\ \times \ {\text{Constant}}}{[{\text{Serum Creatinine (in }}\mu \mathrm {mol/L)} ]}}}
Where Constant is 1.23 for men and 1.04 for women.
One interesting feature of the Cockcroft and Gault equation is that it shows how dependent the estimation of CCr is based on age. The age term is (140 – age). This means that a 20-year-old person (140 – 20 = 120) will have twice the creatinine clearance as an 80-year-old (140 – 80 = 60) for the same level of serum creatinine. The C-G equation assumes that a woman will have a 15% lower creatinine clearance than a man at the same level of serum creatinine.
=== Modification of Diet in Renal Disease (MDRD) formula ===
Another formula for calculating the GFR is the one developed by the Modification of Diet in Renal Disease Study Group. Most laboratories in Australia, and the United Kingdom now calculate and report the estimated GFR along with creatinine measurements and this forms the basis of diagnosis of chronic kidney disease. The adoption of the automatic reporting of MDRD-eGFR has been widely criticised.
The most commonly used formula is the "4-variable MDRD", which estimates GFR using four variables: serum creatinine, age, ethnicity, and gender. The original MDRD used six variables with the additional variables being the blood urea nitrogen and albumin levels. The equations have been validated in patients with chronic kidney disease; however, both versions underestimate the GFR in healthy patients with GFRs over 60 mL/min. The equations have not been validated in acute renal failure.
For creatinine in μmol/L:
eGFR
=
32788
×
[
Serum Creatinine
]
−
1.154
×
Age
−
0.203
×
[1.212 if Black]
×
[0.742 if Female]
{\displaystyle {\text{eGFR}}={\text{32788}}\ \times \ [{\text{Serum Creatinine}}]^{-1.154}\ \times \ {\text{Age}}^{-0.203}\ \times {\text{[1.212 if Black]}}\ \times {\text{[0.742 if Female]}}}
For creatinine in mg/dL:
eGFR
=
186
×
[
Serum Creatinine
]
−
1.154
×
Age
−
0.203
×
[1.212 if Black]
×
[0.742 if Female]
{\displaystyle {\text{eGFR}}={\text{186}}\ \times \ [{\text{Serum Creatinine}}]^{-1.154}\ \times \ {\text{Age}}^{-0.203}\ \times {\text{[1.212 if Black]}}\ \times {\text{[0.742 if Female]}}}
Creatinine levels in μmol/L can be converted to mg/dL by dividing them by 88.4. The 32788 number above is equal to 186×88.41.154.
A more elaborate version of the MDRD equation also includes serum albumin and blood urea nitrogen (BUN) levels:
eGFR
=
170
×
[
Serum Creatinine
]
−
0.999
×
Age
−
0.176
×
[0.762 if Female]
×
[1.180 if Black]
×
BUN
−
0.170
×
Albumin
+
0.318
{\displaystyle {\text{eGFR}}={\text{170}}\ \times \ [{\text{Serum Creatinine}}]^{-0.999}\ \times \ {\text{Age}}^{-0.176}\ \times {\text{[0.762 if Female]}}\ \times {\text{[1.180 if Black]}}\ \times \ {\text{BUN}}^{-0.170}\ \times \ {\text{Albumin}}^{+0.318}}
where the creatinine and blood urea nitrogen concentrations are both in mg/dL. The albumin concentration is in g/dL.
These MDRD equations are to be used only if the laboratory has NOT calibrated its serum creatinine measurements to isotope dilution mass spectrometry (IDMS). When IDMS-calibrated serum creatinine is used (which is about 6% lower), the above equations should be multiplied by 175/186 or by 0.94086.
Since these formulae do not adjust for body size, results are given in units of mL/min per 1.73 m2, 1.73 m2 being the estimated body surface area of an adult with a mass of 63 kg and a height of 1.7 m.
=== CKD-EPI formula ===
The CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) formula was first published in May 2009. It was developed in an effort to create a formula more accurate than the MDRD formula, especially when actual GFR is greater than 60 mL/min per 1.73 m2. This is the formula currently recommended by NICE in the UK.
Researchers pooled data from multiple studies to develop and validate this new equation. They used 10 studies that included 8254 participants, randomly using 2/3 of the data sets for development and the other 1/3 for internal validation. Sixteen additional studies, which included 3896 participants, were used for external validation.
The CKD-EPI equation performed better than the MDRD (Modification of Diet in Renal Disease Study) equation, especially at higher GFR, with less bias and greater accuracy. When looking at NHANES (National Health and Nutrition Examination Survey) data, the median estimated GFR was 94.5 mL/min per 1.73 m2 vs. 85.0 mL/min per 1.73 m2, and the prevalence of chronic kidney disease was 11.5% versus 13.1%. Despite its overall superiority to the MDRD equation, the CKD-EPI equations performed poorly in certain populations, including black women, the elderly and the obese, and was less popular among clinicians than the MDRD estimate.
The 2009 CKD-EPI equation is:
e
G
F
R
=
141
×
min
(
S
C
r
/
k
,
1
)
a
×
max
(
S
C
r
/
k
,
1
)
−
1.209
×
0.993
Age
×
[1.018 if Female]
×
[1.159 if Black]
{\displaystyle \mathrm {eGFR} =141\ \times \ \mathrm {\min(SCr/k,1)} ^{a}\ \times \ \mathrm {\max(SCr/k,1)} ^{-1.209}\ \times \ 0.993^{\text{Age}}\ \times {\text{[1.018 if Female]}}\ \times {\text{[1.159 if Black]}}\ }
where SCr is serum creatinine (mg/dL), k is 0.7 for females and 0.9 for males, a is −0.329 for females and −0.411 for males, min indicates the minimum of SCr/k or 1, and max indicates the maximum of SCr/k or 1.
As separate equations for different populations:
For creatinine (IDMS calibrated) in mg/dL:
Male, not black
If serum creatinine (Scr) ≤ 0.9
e
G
F
R
=
141
×
(
S
C
r
/
0.9
)
−
0.411
×
0.993
Age
{\displaystyle \mathrm {eGFR} =141\ \times \ \mathrm {(SCr/0.9)} ^{-0.411}\ \times \ 0.993^{\text{Age}}\ }
If serum creatinine (Scr) > 0.9
e
G
F
R
=
141
×
(
S
C
r
/
0.9
)
−
1.209
×
0.993
Age
{\displaystyle \mathrm {eGFR} =141\ \times \ \mathrm {(SCr/0.9)} ^{-1.209}\ \times \ 0.993^{\text{Age}}\ }
Female, not black
If serum creatinine (Scr) ≤ 0.7
e
G
F
R
=
144
×
(
S
C
r
/
0.7
)
−
0.329
×
0.993
Age
{\displaystyle \mathrm {eGFR} =144\ \times \ \mathrm {(SCr/0.7)} ^{-0.329}\ \times \ 0.993^{\text{Age}}\ }
If serum creatinine (Scr) > 0.7
e
G
F
R
=
144
×
(
S
C
r
/
0.7
)
−
1.209
×
0.993
Age
{\displaystyle \mathrm {eGFR} =144\ \times \ \mathrm {(SCr/0.7)} ^{-1.209}\ \times \ 0.993^{\text{Age}}\ }
Black male
If serum creatinine (Scr) ≤ 0.9
e
G
F
R
=
163
×
(
S
C
r
/
0.9
)
−
0.411
×
0.993
Age
{\displaystyle \mathrm {eGFR} =163\ \times \ \mathrm {(SCr/0.9)} ^{-0.411}\ \times \ 0.993^{\text{Age}}\ }
If serum creatinine (Scr) > 0.9
e
G
F
R
=
163
×
(
S
C
r
/
0.9
)
−
1.209
×
0.993
Age
{\displaystyle \mathrm {eGFR} =163\ \times \ \mathrm {(SCr/0.9)} ^{-1.209}\ \times \ 0.993^{\text{Age}}\ }
Black female
If serum creatinine (Scr) ≤ 0.7
e
G
F
R
=
166
×
(
S
C
r
/
0.7
)
−
0.329
×
0.993
Age
{\displaystyle \mathrm {eGFR} =166\ \times \ \mathrm {(SCr/0.7)} ^{-0.329}\ \times \ 0.993^{\text{Age}}\ }
If serum creatinine (Scr) > 0.7
e
G
F
R
=
166
×
(
S
C
r
/
0.7
)
−
1.209
×
0.993
Age
{\displaystyle \mathrm {eGFR} =166\ \times \ \mathrm {(SCr/0.7)} ^{-1.209}\ \times \ 0.993^{\text{Age}}\ }
This formula was developed by Levey et al.
The 2009 CKD-EPI formula was suggested to improve cardiovascular risk prediction over the MDRD Study formula in a middle-age population.
The 2021 CKD-EPI formula does not include a race coefficient (see discussion below).
The 2021 CKD-EPI equation is:
e
G
F
R
=
142
×
min
(
S
C
r
/
k
,
1
)
a
×
max
(
S
C
r
/
k
,
1
)
−
1.209
×
0.9938
Age
×
[1.012 if Female]
{\displaystyle \mathrm {eGFR} =142\ \times \ \mathrm {\min(SCr/k,1)} ^{a}\ \times \ \mathrm {\max(SCr/k,1)} ^{-1.209}\ \times \ 0.9938^{\text{Age}}\ \times {\text{[1.012 if Female]}}\ }
where SCr is serum creatinine (mg/dL), k is 0.7 for females and 0.9 for males, a is −0.241 for females and −0.302 for males, min indicates the minimum of SCr/k or 1, and max indicates the maximum of SCr/k or 1.
As separate equations for different populations:
For creatinine (IDMS calibrated) in mg/dL:
Male
If serum creatinine (Scr) ≤ 0.9
e
G
F
R
=
142
×
(
S
C
r
/
0.9
)
−
0.302
×
0.9938
Age
{\displaystyle \mathrm {eGFR} =142\ \times \ \mathrm {(SCr/0.9)} ^{-0.302}\ \times \ 0.9938^{\text{Age}}\ }
If serum creatinine (Scr) > 0.9
e
G
F
R
=
142
×
(
S
C
r
/
0.9
)
−
1.2
×
0.9938
Age
{\displaystyle \mathrm {eGFR} =142\ \times \ \mathrm {(SCr/0.9)} ^{-1.2}\ \times \ 0.9938^{\text{Age}}\ }
Female
If serum creatinine (Scr) ≤ 0.7
e
G
F
R
=
143
×
(
S
C
r
/
0.7
)
−
0.241
×
0.9938
Age
{\displaystyle \mathrm {eGFR} =143\ \times \ \mathrm {(SCr/0.7)} ^{-0.241}\ \times \ 0.9938^{\text{Age}}\ }
If serum creatinine (Scr) > 0.7
e
G
F
R
=
143
×
(
S
C
r
/
0.7
)
−
1.2
×
0.9938
Age
{\displaystyle \mathrm {eGFR} =143\ \times \ \mathrm {(SCr/0.7)} ^{-1.2}\ \times \ 0.9938^{\text{Age}}\ }
=== Mayo Quadratic formula ===
Another estimation tool to calculate GFR is the Mayo Quadratic formula. This formula was developed by Rule et al., in an attempt to better estimate GFR in patients with preserved kidney function. It is well recognized that the MDRD formula tends to underestimate GFR in patients with preserved kidney function. Studies in 2008 found that the Mayo Clinic Quadratic Equation compared moderately well with radionuclide GFR, but had inferior bias and accuracy than the MDRD equation in a clinical setting.
The equation is:
eGFR
=
exp
(
1.911
+
5.249
/
[
Serum Creatinine
]
−
2.114
/
[
Serum Creatinine
]
2
−
0.00686
×
Age
−
[0.205 if Female]
)
{\displaystyle {\text{eGFR}}={\text{exp}}{(1.911+5.249/[{\text{Serum Creatinine}}]-2.114/[{\text{Serum Creatinine}}]^{2}-0.00686\ \times \ {\text{Age}}-{\text{[0.205 if Female]}})}}
If Serum Creatinine < 0.8 mg/dL, use 0.8 mg/dL for Serum Creatinine.
=== Schwartz formula ===
In children, the Schwartz formula is used. This employs the serum creatinine (mg/dL), the child's height (cm) and a constant to estimate the glomerular filtration rate:
eGFR
=
k
×
Height
Serum Creatinine
{\displaystyle {\text{eGFR}}={\frac {{k}\times {\text{Height}}}{\text{Serum Creatinine}}}}
Where k is a constant that depends on muscle mass, which itself varies with a child's age:
In first year of life, for pre-term babies k=0.33 and for full-term infants k=0.45
For infants and children of age 1 to 12 years, k=0.55.
The method of selection of the constant k has been questioned as being dependent upon the gold-standard of renal function used (i.e. inulin clearance, creatinine clearance, etc.) and also may be dependent upon the urinary flow rate at the time of measurement.
In 2009 the formula was updated to use standardized serum creatinine (recommend k=0.413) and additional formulas that allow improved precision were derived if serum cystatin C is measured in addition to serum creatinine.
=== IDMS standardization effort ===
One problem with any creatinine-based equation for GFR is that the methods used to assay creatinine in the blood differ widely in their susceptibility to non-specific chromogens, which cause the creatinine value to be overestimated. In particular, the MDRD equation was derived using serum creatinine measurements that had this problem. The NKDEP program in the United States has attempted to solve this problem by trying to get all laboratories to calibrate their measures of creatinine to a "gold standard", which in this case is isotope dilution mass spectrometry (IDMS). In late 2009 not all labs in the U.S. had changed over to the new system. There are two forms of the MDRD equation that are available, depending on whether or not creatinine was measured by an IDMS-calibrated assay. The CKD-EPI equation is designed to be used with IDMS-calibrated serum creatinine values only.
== Normal ranges ==
The normal range of GFR, adjusted for body surface area, is 100–130 average 125 mL/min/1.73m2 in men and 90–120 ml/min/1.73m2 in women younger than the age of 40. In children, GFR measured by inulin clearance is 110 mL/min/1.73 m2 until 2 years of age in both sexes, and then it progressively decreases. After age 40, GFR decreases progressively with age, by 0.4–1.2 mL/min per year.
== Decreased GFR ==
A decreased renal function can be caused by many types of kidney disease. Upon presentation of decreased renal function, it is recommended to perform a history and physical examination, as well as performing a renal ultrasound and a urinalysis. The most relevant items in the history are medications, edema, nocturia, gross hematuria, family history of kidney disease, diabetes and polyuria. The most important items in a physical examination are signs of vasculitis, lupus erythematosus, diabetes, endocarditis and hypertension.
A urinalysis is helpful even when not showing any pathology, as this finding suggests an extrarenal etiology. Proteinuria and/or urinary sediment usually indicates the presence of glomerular disease. Hematuria may be caused by glomerular disease or by a disease along the urinary tract.
The most relevant assessments in a renal ultrasound are renal sizes, echogenicity and any signs of hydronephrosis. Renal enlargement usually indicates diabetic nephropathy, focal segmental glomerular sclerosis or myeloma. Renal atrophy suggests longstanding chronic renal disease.
=== Chronic kidney disease stages ===
Risk factors for kidney disease include diabetes, high blood pressure, family history, older age, ethnic group and smoking.
For most patients, a GFR over 60 mL/min/1.73 m2 is adequate. But significant decline of the GFR from a previous test result can be an early indicator of kidney disease requiring medical intervention. The sooner kidney dysfunction is diagnosed and treated the greater odds of preserving remaining nephrons, and preventing the need for dialysis.
The severity of chronic kidney disease (CKD) is described by six stages; the most severe three are defined by the MDRD-eGFR value, and first three also depend on whether there is other evidence of kidney disease (e.g., proteinuria):
0) Normal kidney function – GFR above 90 mL/min/1.73 m2 and no proteinuria
1) CKD1 – GFR above 90 mL/min/1.73 m2 with evidence of kidney damage
2) CKD2 (mild) – GFR of 60 to 89 mL/min/1.73 m2 with evidence of kidney damage
3) CKD3 (moderate) – GFR of 30 to 59 mL/min/1.73 m2
4) CKD4 (severe) – GFR of 15 to 29 mL/min/1.73 m2
5) CKD5 kidney failure – GFR less than 15 mL/min/1.73 m2 Some people add CKD5D for those stage 5 patients requiring dialysis; many patients in CKD5 are not yet on dialysis.
Note: others add a "T" to patients who have had a transplant regardless of stage.
Not all clinicians agree with the above classification, suggesting that it may mislabel patients with mildly reduced kidney function, especially the elderly, as having a disease. A conference was held in 2009 regarding these controversies by Kidney Disease: Improving Global Outcomes (KDIGO) on CKD: Definition, Classification and Prognosis, gathering data on CKD prognosis to refine the definition and staging of CKD.
== Removal of race from eGFR Calculations ==
In 2017, Beth Israel Deaconess Medical Center dropped the Black race coefficient in their estimated glomerular filtration rate (eGFR) report, resulting in a steady increase in the percentage of Black patients listed before starting dialysis. Hoenig et al said on the topic "Race is a social construct that cannot be measured, can be used imprecisely and may contribute to disparities in kidney transplant access for Black patients."
In 2020, Vyas et al published an article in The New England Journal of Medicine criticizing the use of race in eGFR calculations which resulted in higher reported eGFR values for black-identifying patients. They noted that "The algorithm developers justified these outcomes with evidence of higher average serum creatinine concentrations among black people than among white people. Explanations that have been given for this finding include the notion that black people release more creatinine into their blood at baseline, in part because they are reportedly more muscular. Analyses have cast doubt on this claim, but the "race-corrected" eGFR remains the standard." They concluded saying "As long as uncertainty persists about the cause of racial differences in serum creatinine levels, we should favor practices that may alleviate health inequities over those that may exacerbate them."
In February 2022, the National Kidney Foundation (NKF) and American Society of Nephrology (ASN)'s Joint Task Force on Reassessing the Inclusion of Race in Diagnosing Kidney Diseases recommended use of the 2021 CKD-EPI equation which discontinues using a race modifier.
In July 2022 the OPTN Board eliminated race-based calculations for transplant candidate listing across all transplant hospitals in the US.
== See also ==
Clearance
Dialysis
Filtration fraction
Kt/V
Pharmacokinetics
Renal clearance ratio
Renal failure
Standardized Kt/V
Tubuloglomerular feedback
Urea reduction ratio
== References ==
== External links ==
=== Reference links ===
National Kidney Disease Education Program website. Includes professional references and GFR calculators
eGFR at Lab Tests Online | Wikipedia/Glomerular_filtration_rate |
The chronic kidney disease of the cat (CKD or CNE) – also called chronic renal insufficiency (CRI or CNI) or chronic renal failure (CRF) in the older literature – is an incurable, progressive disease characterized by a gradual decrease in the nephrons and thus to a decreasing function (insufficiency) of the kidneys. It is one of the most common causes of death in older domestic cats. In current literature, the term "kidney disease" is preferred to the term "renal insufficiency" because the disease initially progresses without any measurable decline in kidney function. Due to the different type of diet and the resulting metabolic peculiarities, the clinical picture and treatment sometimes differ significantly from chronic renal failure in humans.
Chronic kidney disease occurs in cats as a result of inflammation of the renal tubules and the renal interstitial tissue without an identifiable cause (idiopathic tubulointerstitial nephritis). The main symptoms are a reluctance to eat, increased drinking, increased urine output, fatigue, vomiting and weight loss. Chronic kidney disease in cats is divided into four main stages based on the creatinine concentration in the blood plasma, which are further subdivided according to the protein-creatinine quotient in the urine and blood pressure. Treatment is mainly based on reducing the protein and phosphate content of the diet to the basic requirement ("renal diet"). In addition, the numerous secondary symptoms resulting from renal dysfunction, such as disorders of the water, electrolyte and acid-base balance, increased blood pressure, anemia and digestive disorders are treated with medication. If detected and treated early, the progression of the disease can be slowed, the quality of life improved and the life expectancy of the animals increased.
== Physiological basics ==
The kidney is a vital organ with a variety of tasks. It plays an important role in maintaining the water, electrolyte and acid-base balance, in the excretion of toxic metabolic degradation products such as urea and in the recovery of valuable substances such as glucose, amino acids, peptides and minerals initially filtered out of the blood during ultrafiltration in the renal corpuscles. In addition, endogenous and exogenous substances are metabolized and broken down in the kidneys - the kidney is therefore a central metabolic organ alongside the liver. Finally, some hormone-active substances such as renin, erythropoietin and calcitriol (active form of vitamin D3). As a result, the organ plays an important role in the regulation of blood pressure, new blood formation and the calcium and phosphorus balance and thus the bonemetabolism. As carnivores, cats are particularly dependent on the intake of animal proteins because glucose formation from amino acids is their most important energy source. The enzymes of amino acid degradation are adapted to the high protein intake and their activity is largely independent of the protein supply in the diet, so that cats break down endogenous proteins (especially from the muscles) when there is a lack of protein intake (catabolic metabolic state). Fleisch und Innereien enthalten darüber hinaus für die Katze lebensnotwendige Nährstoffe wie beispielsweise Vitamin A, Taurin or arachidonic acid. Compared to a normal human diet, cats consume around six times as much phosphate in their diet with standard cat food. This makes it difficult to achieve a similar phosphorus reduction in cat food as is aimed at in human medicine for human kidney diets.
== Pathophysiological basics ==
Symptoms of the disease only appear at an advanced stage, when more than two-thirds of the original kidney function has already been lost. This is due to the body's own compensatory mechanisms and the kidney's reserve capacity, which can compensate for the reduced kidney function for a long time and maintain the excretion of urine-requiring substances. With the loss of functioning nephrons - the functional structural unit of the kidney - the filtering capacity of the renal corpuscles (glomerular filtration rate) decreases and with it the excretory capacity for urinary substances. Acute damage to the tubules can regenerate again if the basement membrane is preserved. However, if a section of the nephron is irreversibly damaged, the entire nephron dies.
The increased urea levels in the blood (uremia) lead to nausea and vomiting for various reasons. Firstly, they directly irritate chemoreceptors in the chemoreceptor trigger zone in the brain. Secondly, they increase gastrinsecretion and thus lead to an increase in gastric acid production and thus to hyperacidity of the stomach. Finally, they cause vascular inflammation (uraemic vasculitis), which leads to further damage to the digestive tract.
As a result of the accumulation of phosphate in the blood (hyperphosphatemia) and the reduced formation of calcitriol in the remaining main parts, there is a drop in the calcium blood level (hypocalcemia) and increased parathyroid hormone is released from the parathyroid gland. Chronic kidney disease leads to hyperparathyroidism in 84% of cases (secondary renal hyperparathyroidism). Among other things, the parathyroid hormone causes calcium and phosphate to be released from the bones, which ultimately leads to renal bone disorders and calcification of the kidneys, skin, heart and blood vessels. In the kidneys, this calcification contributes to further destruction of the kidney tissue. The reduced responsiveness of the parathyroid cells to calcium disrupts the negative feedback of parathyroid hormone secretion, so that parathyroid hormone continues to be secreted despite the increase in calcium levels. As less phosphate reaches the renal tubules due to the reduced filtration rate, the inhibitory effect of parathyroid hormone on reabsorption in the main body has only a minor effect on the blood phosphate level.
The loss of nephrons and the associated decrease in the number of sodium ion channels leads to a decrease in the concentration gradient in the kidney. However, this is the driving force for water reabsorption in the mid-piece and - in the presence of ADH - also in the collecting ducts. The result is a loss of water via the urine and thus drying out of the body, which is exacerbated by the loss of fluid during vomiting.
One consequence of the kidneys' reduced ability to excrete hydrogen ions, phosphate and sulphate and the excessive loss of bicarbonate is the metabolic acidification of the blood (metabolic acidosis). Metabolic acidosis occurs in 80% of cats with chronic kidney disease.
With increasing kidney damage, the autoregulation of renal blood flow, which normally ensures that the blood flow and thus the filtering capacity up to a threshold of 60 mm Hg are independent of the general blood pressure, is also impaired. As a result, kidney performance is reduced at low blood pressure and, in the case of high blood pressure often associated with chronic kidney disease, further damage occurs due to pressure overload of the renal corpuscles. The increase in blood pressure is due to hardening of the blood vessels in the area of the renal corpuscles, the reduced formation of vasodilating prostaglandins and activation of the renin-angiotensin-aldosterone system.
== Occurrence and causes ==
Chronic kidney disease is one of the most common causes of death in older domestic cats. In many animals, however, the disease initially remains unrecognized, as clinical symptoms are often absent in the early stages of chronic kidney disease due to the kidney's reserve capacity and sufficiently sensitive diagnostic tests are not available for routine use. The data on the frequency of the disease in cats is contradictory, varying between 1.6 and 20%. Chronic kidney disease occurs more frequently in older cats: Over 50% of affected cats are seven years old or older and 30% of all cats over 9 years of age show elevated blood levels of nitrogen compounds (azotemia). However, the disease can occur as early as 9 months of age. Disposition predisposition has been proven for Maine Coon, Abyssinian, Siamese, Russian Blue and Burmese.
Since the kidneys have a high reserve capacity and clinical symptoms only appear when two thirds of the original kidney function has been lost, the triggering factors must damage both kidneys.
Chronic kidney disease in cats is an idiopathic tubulointerstitial nephritis, i.e. an inflammation of the renal tubules and the renal interstitial tissue without an identifiable cause. In addition to the damage that this primary disease causes directly to the kidney tissue, activated endogenous repair mechanisms such as connective tissue formation lead to further, partially self-sustaining destruction of functional kidney tissue. The reduced ability of the kidneys to excrete sodium and water causes retention (medicine) of these substances and thus an increase in blood volume, which ultimately leads to an increase in blood pressure. About two thirds of all cats with CNE are affected. High blood pressure in turn leads to increased connective tissue formation. A potassium deficiency or excess calcium secondary to other kidney damage also causes further damage to the kidney tissue.
Other diseases can also be triggers of renal dysfunction, for example infections, autoimmune diseases, poisonings or tumors. Virtually any infection or even lupus erythematosus can lead to the deposition of antigen-antibody complexes in the basal membrane of the renal corpuscles and thus to their damage. Many lily species, ethylene glycol, melamine, cyanuric acid and some heavy metals (cadmium, lead, mercury) have a strong toxic effect on the kidneys (renal toxicity) in cats. But also many drugs such as amphotericin B, cholecalciferol, doxorubicin, polymyxins, aminoglycosides and numerous non-steroidal anti-inflammatory drugs (→ analgesic nephropathy) can cause kidney damage.
== Symptoms ==
The main symptoms of chronic kidney disease in cats are lack of appetite (anorexia), increased drinking (polydipsia), increased urine output (polyuria), fatigue (apathy), vomiting and weight loss. In addition, diarrhea, inflammation of the oral mucosa (stomatitis) with the formation of ulcers (ulcera), increased salivation (hypersalivation) and bad breath may occur as a result of uremia. Increased blood pressure (arterial hypertension) with damage to the eye (fundus hypertonicus, hypertensive retinopathy), anemia (anemia), itching, dehydration, soft tissue calcifications, bleedings and accumulation of water in the tissues (oedemas) are also more frequent accompanying symptoms. In the case of severe uremia, neurological neurology manifestations such as apathy, seizures, delirium, coma, abnormal movements and muscle disorders (myopathys). Typically, the symptoms - in contrast to acute renal failure - occur gradually over weeks, months or even years, and the general condition is poor. In addition, acute kidney failure is initially characterized by reduced urine production. However, an existing mild or moderate chronic kidney disease is often suddenly worsened by an acute event ("exacerbation") and thus becomes conspicuous to the cat owner. This can be the case, for example, if one kidney has already become a non-functioning shrunken kidney due to urinary retention and the second suddenly swells acutely due to urinary retention (hydronephrosis) and is damaged ("large kidney-small kidney syndrome") or if hyperthyroidism is treated and the glomerular filtration rate is suddenly reduced as a result.
By palpation, the kidneys can be checked for pain, firmness (consistency), enlargement or reduction in size and changes in surface structure. A healthy kidney is about 4 cm long, 3 cm wide and 2–3.5 cm thick. In the most common form - CNE due to tubulointerstitial nephritis - the kidneys are usually reduced in size and have an irregular surface; in the case of tumors or pyelonephritis, they may be enlarged and sensitive to pain. Since the degree of protein loss via the urine is directly related to the increase in blood pressure, regular blood pressure measurement is advisable.
An X-ray examination can be used to detect changes in the size, density and position of the kidneys as well as some urinary stones (struvite and calcium oxalate stones are "radiopaque") and soft tissue calcifications. In severely emaciated cats or fluid accumulations in the retroperitoneal space, however, the kidney can only be visualized to a limited extent on the X-ray image due to the resulting reduction in contrast. Excretory urography, in which a radiopaque contrast medium (e.g. Iopamidol, Iohexol) is injected into the bloodstream and its excretion via the kidneys is recorded radiographically. This makes it possible to detect circulatory disorders, dysfunctions of the renal corpuscles and obstructions of the outflow pathways.
The ultrasound examination allows morphological changes in the kidneys in more detail. In addition to changes in size and shape, renal cysts, localized (focal) organ damage, water sac kidneys and urinary retention as well as tumors can also be visualized. Hardly defined (diffuse) organ changes are accompanied by changes in echogenicity, but can only rarely be assigned to defined diseases. Pulsed Wave Doppler" can also be used to detect circulatory disorders. Calcification (nephrocalcinosis) is also common in chronic kidney disease and can also be detected sonographically.
Renal biopsy is not routinely used, but may be indicated in certain preliminary reports—for example, young Abyssinian cats with symptoms of kidney disease for the detection of amyloidosis. Although computed tomography and magnetic resonance imaging have very good detail recognition, they only play a subordinate role in veterinary medicine due to their high costs and limited availability.
== Laboratory diagnostic findings ==
Urinalysis is essential in chronic kidney disease in cats. Damage to as little as two thirds of the nephrons results in a reduced ability to concentrate urine and the specific weight falls below 1030 N-m−3. Protein loss via the kidney is detected by an increase in the protein/creatinine ratio in the urine (UPC), as 24-hour collection samples are impractical in cats. The UPC is a good marker for the early detection of CNE, as it reveals renal dysfunction even before the creatinine in the blood rises. The urine sediment can also show effusions from the renal tubules (cylinder), and in chronic bacterial renal pelvic inflammation bacteria or pus can also be detected. The detection of small amounts of albumin (< 300 mg/l, "microalbuminuria") is very sensitive, but not very specific for chronic kidney disease.
In blood serum, the content of nitrogenous substances such as urea and creatinine (uremia or azotemia) and phosphate (hyperphosphatemia). The increased phosphate concentration is the result of the reduced glomerular filtration rate. Among other things, fibroblast growth factor 23 (FGF-23) is involved here, which is more sensitive than the phosphate level in the event of an incipient disorder. The potassium content is usually reduced (hypokalemia), but can also be increased - the reverse is true for the sodium content. If the cause of the kidney disease lies in the renal corpuscles, albumin deficiency (hypalbuminemia) and excess cholesterol (hypercholesterolemia) also occur. The determination of cystatin C is not evaluated for cats, this protein can also be elevated in cats with hyperthyroidism or with glucocorticoids and drop sharply for several hours after food intake. Recent studies suggest that symmetric dimethylarginine (SDMA) is a suitable marker for renal function in cats. The SDMA concentration in serum shows close correlations with the glomerular filtration rate and the creatinine concentration. It can already detect a 40% loss of kidney function, i.e. before there is an increase in creatinine in the blood.
The most sensitive method of kidney function diagnostics is the direct determination of the glomerular filtration rate via the clearance, which is already reduced in chronic kidney disease before azotemia occurs. Various substances have been evaluated for cats, the most practical being creatinine and iohexol. Although creatinine is eliminated more slowly than iohexol, it can be determined immediately in many veterinary practices photometric even without the involvement of a specialized laboratory.
In advanced kidney disease, the blood count shows a decrease in the number of red blood cells and thus the hematocrit without a change in the blood pigment load and the cell sizes of the red blood cells and without signs of new blood cell formation (normochromic, normocytic, aregenerative anemia).
== Classification ==
Chronic kidney disease in cats is currently divided into four main stages by the International Renal Interest Society (IRIS) and adapted by the European Society of Veterinary Nephrology and Urology, with the creatinine concentration in blood plasma being used as the main criterion. In addition, sub-stages are defined on the basis of the protein-creatinine quotient in the urine and blood pressure. The plasma creatinine concentration should be ensured by at least two measurements at intervals of one to two weeks, the protein-creatinine quotient in the urine by two or three measurements over a period of two to four weeks. As creatinine is also influenced by other factors, since 2019 the Symmetric dimethylarginine (SDMA) is also used for assessment. In diabetic cats SDMA may be reduced.
In stage 1, creatinine and SDMA values are still within the normal range. However, there are other disorders of kidney function, such as an inadequate ability to concentrate, protein loss via the urine, morphological kidney changes or an increase in the values on repeated measurements. Creatinine and SDMA values often indicate a different stage. This may be due to the biological fluctuation range, concomitant diseases, influencing factors outside the kidney and pre-analytical causes. In this case, staging should be based on the higher value and the determination should be repeated after two to four weeks.
== Differential diagnosis ==
In the sum of all examination findings, chronic kidney disease can hardly be confused with any other disease. There is only extensive agreement with acute renal insufficiency. Here, the clinical course (see symptoms) is particularly suitable as a differentiation criterion. In addition, in acute renal failure the blood pressure and red blood cell count are unchanged and the kidneys are often enlarged and painful.
The main feature that determines the staging - azotemia - can have a number of other causes that can be localized "before the kidney" (prerenal) or "after the kidney" (postrenal). Prerenal causes in cats are mainly blood loss, dehydration, shock, congestive heart failure, hyperthyroidism, but also fever or severe physical exertion. Possible postrenal causes include obstruction of the urinary tract due to bladder stones or tumors, tears of the urinary bladder, ureter, or urethra.
== Treatment ==
The options for Kidney replacement therapy are severely limited in cats, as kidney transplants or Hemodialysis In veterinary medicine, kidney tests are only carried out in exceptional cases due to the high equipment, logistical and financial costs involved. The aim is therefore to detect chronic kidney disease at the earliest possible stage, when the kidneys still have sufficient reserve capacity. At the same time, attempts are made to reduce the amount of urinary substances - especially nitrogen compounds and phosphate - in the diet by means of dietaryetic measures. Finally, metabolic imbalances and sequelae must be buffered. From a plasma creatinine level of 7 mg/dL (618.8 μmol/L), however, drug therapy is not very promising.
=== Dietary measures ===
One problem with dietary therapy with phosphate- and protein-reduced diets is that they are usually not very palatable. In addition, cats with kidney disease have little appetite and getting used to a new food is made even more difficult due to the negative imprinting (behavior) - the cat associates its own physical discomfort with the new food -. The loss of protein via the urine also results in a negative nitrogen balance, which also reduces appetite. Finally, affected animals often show gastrointestinal tract problems. In a clinical study by Elliott et al. 34% of cats could not be switched to the renal diet and in Plantinga et al. the figure was as high as 54%. An attempt can be made to increase the acceptability of the feed by warming it or by adding tasty additives such as tuna juice or sardines. It is therefore recommended to start the feed change only after the uraemia has been eliminated and to extend it over three weeks by gradually mixing it in to avoid feed aversion. Sorptionsuch as activated charcoal or probiotics can be used in an attempt to reduce the formation of uraemic substances in the gastrointestinal tract. Cyproheptadine or mirtazapine may be used for a short time to increase appetite; if these measures do not work, force-feeding via an esophageal or gastric tube is necessary. The administration of feed supplements based on Chinese rhubarb or with prebiotics and probiotics had no discernible effect in clinical studies; there is only one small manufacturer's study on the activated charcoal-based absorber for indole in the large intestine (trade name Porus one), but this did not include any cats with kidney disease.
==== Phosphate reduction ====
A key goal in the management of chronic kidney disease in cats is to reduce dietary phosphate intake early in the course of the disease. As a rule of thumb, the phosphate content can be reduced to 170 mg/MJ UE (Megajoule metabolizable energy, see also Physiological calorific value), i.e. to two thirds of the maintenance requirement. Commercially available cat food usually contains twice the maintenance requirement and should therefore not be mixed with the diet food. If the phosphate levels in the plasma remain elevated despite the renal diet, absorption in the intestine can be reduced by using calcium salts and phosphate binders such as aluminum hydroxide, aluminum carbonate or lanthanum carbonate. Calcium carbonate can compensate for calcium deficiency in the early stages, but can lead to hypercalcemia in advanced stages. The use of phosphate binders should be monitored by blood tests and their dose adjusted on the basis of phosphate levels.
Several studies have shown that a reduction of phosphate in the diet is sufficient to slow down the progression of the disease. If the general condition continues to deteriorate during phosphate reduction, a phosphate deficiency should also be considered. This manifests itself in a similar way to chronic kidney disease: shaggy coat, loss of appetite, weakness, exhaustion and anaemia. Calcitriol can also be used to treat secondary hyperparathyroidism, but only if parathyroid hormone and calcium levels are monitored. For cats in the early stages with normal blood phosphate levels, a less phosphate-reduced diet ("Senior", "Early-Renal" or a mixture of kidney and normal food) is usually sufficient.
==== Protein reduction ====
In order to combat uraemia, the amount of protein in the diet and thus the amount of nitrogen supplied to the body can be reduced. However, this is only possible to a limited extent in cats, as their energy balance is dependent on protein (see above). The protein content should be adjusted to the maintenance requirement of 15 g digestible crude protein per MJ UE and should never be reduced below 11 g/MJ UE, whereby the amount of protein declared on feed must be multiplied by a factor of 0.86 to obtain the digestible crude protein. High-quality animal protein also reduces the amount of nitrogen compounds entering the large intestine and thus the amount of ammonia produced by bacterial degradation processes through the intestinal flora. If there are severe acceptance problems or there is a loss of body mass and muscle, complicating factors (metabolic acidosis, intestinal bleeding) must be clarified. The necessary nutritional requirements must be guaranteed in any case, in problematic cases even without a kidney diet.
=== Treatment of the accompanying symptoms ===
==== Dehydration ====
To combat dehydration, sufficient fresh drinking water should be provided. Here, too, you can try to increase the cat's voluntary water intake by adding meat broth or tuna juice. Switching to wet food also often leads to increased fluid intake. Dehydrated cats or animals with volume deficiency require fluid administration with correction of electrolytes. Renal azotemia cannot be influenced in this way. The administration of sterile infusion solutions under the skin by the owner must be viewed critically. These also ultimately enter the vascular system and conventional infusion solutions inevitably lead to a permanent excess of sodium. This form of treatment should therefore only be carried out if the condition and hydration status improve and there are no disturbances in blood pressure or potassium levels. Infusion solutions for cats in stage IV should contain a maximum of 40 mmol/L sodium and about 13 mmol/L (max. 30 mmol/L) potassium (half-electrolyte solution with potassium substitution).
==== Metabolic acidosis and potassium ====
The bicarbonate content should ideally be between 17 and 22 mEq/L. Sodium bicarbonate or potassium citrate is administered for buffering, whereby the latter also compensates for any existing potassium deficiency. A diet rich in potassium and magnesium is recommended and is already used in most commercial kidney diets. Potassium gluconate can also be used to compensate for a potassium deficiency, but potassium chloride is usually poorly accepted by cats and often causes gastrointestinal disorders. The restriction of renal excretion in stage IV, ACE inhibitors or aldosterone deficiency due to renin deficiency can also lead to hyperkalemia, which is why potassium levels must be checked regularly and a low-potassium diet may also need to be used.
==== High blood pressure ====
Over 60% of cats with kidney disease develop high blood pressure. Amlodipine is the main drug used for treatment. If the antihypertensive effect is not sufficient, the AT1 antagonist, which has been approved for cats since 2014 telmisartan can also be used to treat high blood pressure and proteinuria. Telmisartan can significantly reduce the extent of proteinuria. However, the active ingredient can only be used as the sole antihypertensive agent if the blood pressure is below 200 mg Hg. It is important to monitor the effect of telmisartan at the beginning and after one week if the dose is changed by determining creatitinine, blood pressure and potassium levels; after four weeks, the urine protein-creatinine quotient should be checked. The reduction in systolic blood pressure must not be lowered below 120 mm Hg; it should be around 140 mm Hg. Telmisartan should also be discontinued in phases of volume or fluid deficiency, during acute episodes of illness or before anesthesia.
ACE inhibitors such as benazepril, enalapril or ramipril alone do not usually lead to a sufficient reduction in blood pressure, but they can slow down the progression of the disease up to stage III. In stage IV, ACE inhibitors are considered relatively contraindicated. Of these active substances, benazepril and ramipril are currently approved for cats in Germany, all others must be reclassified. Dietetically, the tendency to high blood pressure can be reduced by reducing the sodium content of the feed.
==== Anemia ====
To combat anaemia, an ironaddition to the feed in the form of organic iron compounds or iron sulphate is particularly useful. The iron content in the feed should be slightly above the maintenance requirement of 5 mg/MJ UE. However, the parenteral administration of iron is more potent. If the hematocrit (Hct) nevertheless falls, blood transfusions are indicated. Anabolic steroids Steroids to increase new blood formation are slow-acting in cats and their benefit is questionable. recombinant human erythropoietin may be indicated from a hematocrit < 20%. However, the treatment is expensive and around a third of all cats form antibodies against this substance, which results in anemia that can no longer be treated. With darbepoetin, the risk of antibody formation is apparently significantly lower, it also has a longer plasma half-life and is more potent. Darbepoetin is used when the hematocrit is permanently below 20, the target range is a Hct of 25–35. This is usually achieved after two to three weeks, then the dose can be gradually reduced.
==== Gastrointestinal tract ====
Secondary consequences of uremia on the gastrointestinal tract in cats are mainly fibrosis and mineralization of the gastric mucosa, but no gastric ulcers, so that the gastric acid blockers such as omeprazole, which have long been recommended for therapy, are no longer indicated. Mirtazapine has been shown to stimulate the appetite and reduce uraemic nausea.
=== Nierentransplantation ===
Kidney transplantation is only possible in a few specialized facilities and is cost-intensive. The basic requirements are decompensated renal insufficiency at an early stage that no longer responds to conventional treatment, a previous weight loss of no more than 20%, the absence of serious concomitant diseases and negative tests for chronic viral infections such as feline leukemia or feline immunodeficiency syndrome. Urinary tract infections should also not have occurred in the recent past.
== Interactions with other treatments ==
Since the kidney is also an important excretory organ for numerous drugs, chronic kidney disease must be taken into account in the drug therapy of other diseases. For example, the plasma half-life may be significantly prolonged (e.g. with numerous antibiotics) and the dose must be reduced accordingly. Drugs that can only be administered with caution in cats with kidney disease include atenolol, carbimazole, chlorothiazide, digoxin and thiamazole.
== Treatment prospects ==
It is not possible to restore lost nephrons, so that all therapeutic measures only result in an increase in quality of life and lifespan. The treatment prospects is strongly dependent on the degree of azotemia, protein loss via the urine, hyperphosphatemia and uremia as well as the hematocrit. In stage 2, a low hematocrit and a high urine protein-creatinine ratio, and in stage 3 hyperphosphatemia are prognostic for progression of CNE. A new prognostic parameter is fibroblast growth factor 23, as it indicates an early derailment of mineral metabolism. The average survival time in a recent study was 1151 days in stage IIb cats, 778 days in stage III and only 103 days in stage IV. The consistent use of phosphate-reduced kidney diets shows quite good results up to stage III. If the measures taken do not work, the only option for advanced kidney disease is often euthanasia.
== Further reading ==
Sarah Steinbach and Reto Neiger: Chronische Nierenerkrankung: In: Hans Lutz et al. (Ed.): Krankheiten der Katze. Enke, 5. Aufl. 2014, ISBN 978-3-8304-1243-4, S. 751–755.
Gregory F. Grauer: Chronic renal failure. In: R. W. Nelson und C. G. Couto (Hrsg.): Small animal internal medicine. Mosby, 3. 2003, ISBN 0-323-01724-X, p. 615–623.
== See also ==
List of feline diseases
== References ==
== External links ==
International Renal Interest Society | Wikipedia/Chronic_kidney_disease_in_cats |
Metabolic bone disease is an abnormality of bones caused by a broad spectrum of disorders. Most commonly these disorders are caused by deficiencies of minerals such as calcium, phosphorus, magnesium or vitamin D leading to dramatic clinical disorders that are commonly reversible once the underlying defect has been treated. These disorders are to be differentiated from a larger group of genetic bone disorders where there is a defect in a specific signaling system or cell type that causes the bone disorder. There may be overlap. For example, genetic or hereditary hypophosphatemia may cause the metabolic bone disorder osteomalacia. Although there is currently no treatment for the genetic condition, replacement of phosphate often corrects or improves the metabolic bone disorder. Metabolic bone disease in captive reptiles is also common, and is typically caused by calcium deficiency in a reptile's diet.
== Conditions considered to be metabolic bone disorders ==
osteoporosis
osteopenia
osteomalacia (adults) and rickets (children)
osteitis fibrosa cystica
Paget's disease of bone
pyramiding (turtles)
Osteoporosis is due to causal factors like atrophy of disuse and gonadal deficiency. Hence, osteoporosis is common in postmenopausal women and in men above 50 years. Hypercorticism may also be a causal factor, as osteoporosis may be seen as a feature of Cushing's syndrome.
== References ==
== External links == | Wikipedia/Metabolic_bone_disease |
Polycystic kidney disease (PKD or PCKD, also known as polycystic kidney syndrome) is a genetic disorder in which the renal tubules become structurally abnormal, resulting in the development and growth of multiple cysts within the kidney. These cysts may begin to develop in utero, in infancy, in childhood, or in adulthood. Cysts are non-functioning tubules filled with fluid pumped into them, which range in size from microscopic to enormous, crushing adjacent normal tubules and eventually rendering them non-functional as well.
PKD is caused by abnormal genes that produce a specific abnormal protein; this protein has an adverse effect on tubule development. PKD is a general term for two types, each having their own pathology and genetic cause: autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD). The abnormal gene exists in all cells in the body; as a result, cysts may occur in the liver, seminal vesicles, and pancreas. This genetic defect can also cause aortic root aneurysms, and aneurysms in the circle of Willis cerebral arteries, which if they rupture, can cause a subarachnoid hemorrhage.
Diagnosis may be suspected from one, some, or all of the following: new onset flank pain or red urine; a positive family history; palpation of enlarged kidneys on physical exam; an incidental finding on abdominal sonogram; or an incidental finding of abnormal kidney function on routine lab work (BUN, serum creatinine, or eGFR). Definitive diagnosis is made by abdominal CT exam.
Complications include hypertension due to the activation of the renin–angiotensin–aldosterone system (RAAS), frequent cyst infections, urinary bleeding, and declining renal function. Hypertension is treated with angiotensin converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs). Infections are treated with antibiotics. Declining renal function is treated with renal replacement therapy (RRT): dialysis and/or transplantation. Management from the time of the suspected or definitive diagnosis is by an appropriately trained doctor.
== Signs and symptoms ==
Signs and symptoms include high blood pressure, headaches, abdominal pain, blood in the urine, and excessive urination. Other symptoms include pain in the back, and cyst formation (renal and other organs).
== Cause ==
PKD is caused by abnormal genes which produce a specific abnormal protein which has an adverse effect on tubule development. PKD is a general term for two types, each having their own pathology and genetic cause: autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD).
=== Autosomal dominant ===
Autosomal dominant polycystic kidney disease (ADPKD) is the most common of all the inherited cystic kidney diseases with an incidence of 1:500 live births. Studies show that 10% of end-stage kidney disease (ESKD) patients being treated with dialysis in Europe and the U.S. were initially diagnosed and treated for ADPKD.
Genetic mutations in any of the three genes PKD1, PKD2, and PKD3 have similar phenotypical presentations.
Gene PKD1 is located on chromosome 16 and codes for a protein involved in cell cycle regulation and intracellular calcium transport in epithelial cells and is responsible for 85% of the cases of ADPKD.
Gene PKD2 is identified, using genetic linkage study, on chromosome 4. A group of voltage-linked cation channels, with inward selectivity for K>Na>>Ca and outward selectivity for Ca2+ ≈ Ba2+ > Na+ ≈ K+, are coded for by PKD2 on chromosome 4.
PKD3 recently appeared in research papers as a postulated third gene. Fewer than 10% of cases of ADPKD appear in non-ADPKD families. Cyst formation begins in utero from any point along the nephron, although fewer than 5% of nephrons are thought to be involved. As the cysts accumulate fluid, they enlarge, separate from the nephron, compress the neighboring kidney parenchyma, and progressively compromise kidney function.
=== Autosomal recessive ===
Autosomal recessive polycystic kidney disease (ARPKD) (OMIM #263200) is the less common of the two types of PKD, with an incidence of 1:20,000 live births and is typically identified in the first few weeks after birth. Unfortunately, the kidneys are often underdeveloped, resulting in a 30% death rate in newborns with ARPKD. PKHD1 is involved.
== Mechanism ==
Both autosomal dominant and autosomal recessive polycystic kidney disease cyst formation are tied to abnormal cilia-mediated signaling. The polycystin-1 and polycystin-2 proteins appear to be involved in both autosomal dominant and recessive polycystic kidney disease due to defects in both proteins. Both proteins have communication with calcium channel proteins, and cause reduction in resting (intracellular) calcium and endoplasmic reticulum storage of calcium.
The disease is characterized by a 'second hit' phenomenon, in which a mutated dominant allele is inherited from a parent, with cyst formation occurring only after the normal, wild-type gene sustains a subsequent second genetic 'hit', resulting in renal tubular cyst formation and disease progression.
PKD results from defects in the primary cilium, an immotile, hair-like cellular organelle present on the surface of most cells in the body, anchored in the cell body by the basal body. In the kidney, primary cilia have been found to be present on most cells of the nephron, projecting from the apical surface of the renal epithelium into the tubule lumen. The cilia were believed to bend in the urine flow, leading to changes in signalling, however this has since been shown to be an experimental error (the bending of cilia was an artifact of focal plane compensation, and also the actual effect on micturition by severe hypertension and cardiac arrest) and that bending of cilia does not contribute to alterations in Ca flux. While it is not known how defects in the primary cilium lead to cyst development, it is thought to possibly be related to disruption of one of the many signaling pathways regulated by the primary cilium, including intracellular calcium, Wnt/β-catenin, cyclic adenosine monophosphate (cAMP), or planar cell polarity (PCP). Function of the primary cilium is impaired, resulting in disruption of a number of intracellular signaling cascades which produce differentiation of cystic epithelium, increased cell division, increased apoptosis, and loss of resorptive capacity.
== Diagnosis ==
Polycystic kidney disease can be ascertained via a CT scan of abdomen, as well as an MRI and ultrasound of the same area. A physical exam/test can reveal enlarged liver, heart murmurs and elevated blood pressure.
=== Natural history ===
Most cases progress to bilateral disease in adulthood.
== Treatment ==
In 2018, Jynarque (Tolvaptan) was introduced as the first FDA-approved treatment for PKD. In a recent long-term study, patients using Tolvaptan had a 6.4% higher kidney function after 5 years compared to standard of care. In 2019, a team of researchers at UCSB found that a ketogenic diet might be able to halt, or even reverse progression in mice, and the results of a first human case series study are showing potential benefit. The results of a 3-month randomized, prospective dietary intervention clinical trial are pending. In addition, recent research indicates that mild to moderate calorie restriction or time-restricted feeding slow the progression of autosomal dominant polycystic kidney disease (ADPKD) in mice.
Patient communities have been combining both ketogenic diets and time-restricted feeding with a low-oxalate diet to prevent the formation of stones and early reports show an average of 17% increase in kidney function after approximately one year on a ketogenic, time-restricted dietary regimen. If and when the disease progresses enough in a given case, the nephrologist or other practitioner and the patient will have to decide what form of renal replacement therapy will be used to treat end-stage kidney disease (kidney failure, typically stage 4 or 5 of chronic kidney disease).
That will either be some form of dialysis, which can be done at least two different ways at varying frequencies and durations (whether it is done at home or in the clinic depends on the method used and the patient's stability and training) and eventually, if they are eligible because of the nature and severity of their condition and if a suitable match can be found, unilateral or bilateral kidney transplantation.
A Cochrane Review study of autosomal dominant polycystic kidney disease made note of the fact that it is important at all times, while avoiding antibiotic resistance, to control infections of the cysts in the kidneys, and if affected, the liver, when needed for a certain duration to combat infection, by using, "bacteriostatic and bacteriocidal drugs".
== Prognosis ==
ADPKD individuals might have a normal life; conversely, ARPKD can cause kidney dysfunction and can lead to kidney failure by the age of 40–60. ADPKD1 and ADPKD2 are very different, in that ADPKD2 is much milder.
Currently, there are no therapies proven effective to prevent the progression of ADPKD.
== Epidemiology ==
PKD is one of the most common hereditary diseases in the United States, affecting more than 600,000 people. It is the cause of nearly 10% of all end-stage renal disease. It equally affects men, women, and all races. It causes about 5% of all kidney failure PKD occurs in some animals as well as humans.
== See also ==
Autosomal recessive polycystic kidney disease
== References ==
== Further reading ==
== External links == | Wikipedia/Polycystic_kidney_disease |
Sexual dysfunction is difficulty experienced by an individual or partners during any stage of normal sexual activity, including physical pleasure, desire, preference, arousal, or orgasm. The World Health Organization defines sexual dysfunction as a "person's inability to participate in a sexual relationship as they would wish". This definition is broad and is subject to many interpretations. A diagnosis of sexual dysfunction under the DSM-5 requires a person to feel extreme distress and interpersonal strain for a minimum of six months (except for substance- or medication-induced sexual dysfunction). Sexual dysfunction can have a profound impact on an individual's perceived quality of sexual life. The term sexual disorder may not only refer to physical sexual dysfunction, but to paraphilias as well; this is sometimes termed disorder of sexual preference.
A thorough sexual history and assessment of general health and other sexual problems (if any) are important when assessing sexual dysfunction, because it is usually correlated with other psychiatric issues, such as mood disorders, eating and anxiety disorders, and schizophrenia. Assessing performance anxiety, guilt, stress, and worry are integral to the optimal management of sexual dysfunction. Many of the sexual dysfunctions that are defined are based on the human sexual response cycle proposed by William H. Masters and Virginia E. Johnson, and modified by Helen Singer Kaplan.
== Types ==
Sexual dysfunction can be classified into four categories: sexual desire disorders, arousal disorders, orgasm disorders, and pain disorders. Dysfunction among men and women are studied in the fields of andrology and gynecology respectively.
=== Sexual desire disorders ===
Sexual desire disorders or decreased libido are characterized by a lack of sexual desire, libido for sexual activity, or sexual fantasies for some time. The condition ranges from a general lack of sexual desire to a lack of sexual desire for the current partner. The condition may start after a period of normal sexual functioning, or the person may always have had an absence or a lesser intensity of sexual desire.
The causes vary considerably but include a decrease in the production of normal estrogen in women, or testosterone in both men and women. Other causes may be aging, fatigue, pregnancy, medications (such as SSRIs), or psychiatric conditions, such as depression and anxiety. While many causes of low sexual desire are cited, only a few of these have ever been the object of empirical research.
=== Sexual arousal disorders ===
Sexual arousal disorders were previously known as frigidity in women and impotence in men, though these have now been replaced with less judgmental terms. Impotence is now known as erectile dysfunction, and frigidity has been replaced with a number of terms describing specific problems that can be broken down into four categories as described by the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders: lack of desire, lack of arousal, pain during intercourse, and lack of orgasm.
For both men and women, these conditions can manifest themselves as an aversion to and avoidance of sexual contact with a partner. In men, there may be partial or complete failure to attain or maintain an erection, or a lack of sexual excitement and pleasure in sexual activity.
There may be physiological origins to these disorders, such as decreased blood flow or lack of vaginal lubrication. Chronic disease and the partners' relationship can also contribute to dysfunction.
Additionally, postorgasmic illness syndrome (POIS) may cause symptoms when aroused, including adrenergic-type presentation: rapid breathing, paresthesia, palpitations, headaches, aphasia, nausea, itchy eyes, fever, muscle pain and weakness, and fatigue.
From the onset of arousal, symptoms can persist for up to a week in patients.
The cause of this condition is unknown; however, it is believed to be a pathology of either the immune system or autonomic nervous systems. It is defined as a rare disease by the National Institute of Health, but the prevalence is unknown. It is not thought to be psychiatric in nature, but it may present as anxiety relating to coital activities and may be incorrectly diagnosed as such. There is no known cure or treatment.
==== Erectile dysfunction ====
Erectile dysfunction (ED), or impotence, is a sexual dysfunction characterized by the inability to develop or maintain an erection of the penis. There are various underlying causes of ED, including damage to anatomical structures, psychological causes, medical disease, and drug use. Many of these causes are medically treatable.
Psychological ED can often be treated by almost anything that the patient believes in; there is a very strong placebo effect. Physical damage can be more difficult to treat. One leading physical cause of ED is continual or severe damage taken to the nervi erigentes, which can prevent or delay erection. These nerves course beside the prostate arising from the sacral plexus and can be damaged in prostatic and colorectal surgeries.
Diseases are also common causes of erectile dysfunction. Diseases such as cardiovascular disease, multiple sclerosis, kidney failure, vascular disease, and spinal cord injury can cause erectile dysfunction. Cardiovascular disease can decrease blood flow to penile tissues, making it difficult to develop or maintain an erection.
Due to the shame and embarrassment felt by some with erectile dysfunction, the subject was taboo for a long time and is the focus of many urban legends. Folk remedies have long been advocated, with some being advertised widely since the 1930s. The introduction of perhaps the first pharmacologically effective remedy for impotence, sildenafil (trade name Viagra), in the 1990s caused a wave of public attention, propelled in part by the newsworthiness of stories about it and heavy advertising.
It is estimated that around 30 million men in the United States and 152 million men worldwide have erectile dysfunction. However, social stigma, low health literacy, and social taboos lead to under reporting which makes an accurate prevalence rate hard to determine.
The Latin term impotentia coeundi describes the inability to insert the penis into the vagina, and has been mostly replaced by more precise terms.
ED from vascular disease is seen mainly amongst older individuals who have atherosclerosis. Vascular disease is common in individuals who smoke or have diabetes, peripheral vascular disease, or hypertension. Any time blood flow to the penis is impaired, ED can occur.
Drugs are also a cause of erectile dysfunction. Individuals who take drugs that lower blood pressure, antipsychotics, antidepressants, sedatives, narcotics, antacids, or alcohol can have problems with sexual function and loss of libido.
Hormone deficiency is a relatively rare cause of erectile dysfunction. In individuals with testicular failure, as in Klinefelter syndrome, or those who have had radiation therapy, chemotherapy, or childhood exposure to the mumps virus, the testes may fail to produce testosterone. Other hormonal causes of erectile failure include brain tumors, hyperthyroidism, hypothyroidism, or adrenal gland disorders.
=== Orgasm disorders ===
==== Anorgasmia ====
Anorgasmia is classified as persistent delays or absence of orgasm following a normal sexual excitement phase in at least 75% of sexual encounters.: 368 The disorder can have physical, psychological, or pharmacological origins. SSRI antidepressants are a common pharmaceutical culprit, as they can delay orgasm or eliminate it entirely. A common physiological cause of anorgasmia is menopause; one in three women report problems obtaining an orgasm during sexual stimulation following menopause.
==== Premature ejaculation ====
Premature ejaculation is when ejaculation occurs before the partner achieves orgasm, or a mutually satisfactory length of time has passed during intercourse. There is no correct length of time for intercourse to last, but generally, premature ejaculation is thought to occur when ejaculation occurs in under two minutes from the time of the insertion of the penis. For a diagnosis, the patient must have a chronic history of premature ejaculation, poor ejaculatory control, and the problem must cause feelings of dissatisfaction as well as distress for the patient, the partner, or both.
Premature ejaculation has historically been attributed to psychological causes, but newer theories suggest that premature ejaculation may have an underlying neurobiological cause that may lead to rapid ejaculation.
==== Post-orgasmic disorders ====
Post-orgasmic disorders cause symptoms shortly after orgasm or ejaculation. Post-coital tristesse (PCT) is a feeling of melancholy and anxiety after sexual intercourse that lasts for up to two hours. Sexual headaches occur in the skull and neck during sexual activity, including masturbation, arousal or orgasm.
In men, post orgasmic illness syndrome (POIS) causes severe muscle pain throughout the body and other symptoms immediately following ejaculation. These symptoms last for up to a week. Some doctors speculate that the frequency of POIS "in the population may be greater than has been reported in the academic literature", and that many with POIS are undiagnosed.
POIS may involve adrenergic symptoms: rapid breathing, paresthesia, palpitations, headaches, aphasia, nausea, itchy eyes, fever, muscle pain and weakness, and fatigue.
The etiology of this condition is unknown; however, it is believed to be a pathology of either the immune system or autonomic nervous systems. It is defined as a rare disease by the NIH, but the prevalence is unknown. It is not thought to be psychiatric in nature, but it may present as anxiety relating to coital activities and thus may be incorrectly diagnosed as such. There is no known cure or treatment.
Dhat syndrome is another condition which occurs in men: it is a culture-bound syndrome which causes anxious and dysphoric mood after sex. It is distinct from the low-mood and concentration problems (acute aphasia) seen in POIS.
=== Sexual pain disorders ===
Sexual pain disorders in women include dyspareunia (painful intercourse) and vaginismus (an involuntary spasm of the muscles of the vaginal wall that interferes with intercourse).
Dyspareunia may be caused by vaginal dryness. Poor lubrication may result from insufficient excitement and stimulation, or from hormonal changes caused by menopause, pregnancy, or breastfeeding. Irritation from contraceptive creams and foams can also cause dryness, as can fear and anxiety about sex.
It is unclear exactly what causes vaginismus, but it is thought that past sexual trauma (such as rape or abuse) may play a role. Another female sexual pain disorder is vulvodynia, or vulvar vestibulitis when localized to the vulval vestibule. In this condition, women experience burning pain during sex, which seems to be related to problems with the skin in the vulvar and vaginal areas. Its cause is unknown.
In men, structural abnormalities of the penis like Peyronie's disease can make sexual intercourse difficult and/or painful. The disease is characterized by thick fibrous bands in the penis that lead to excessive curvature during erection. It has an incidence estimated at 0.4–3% or more, is most common in men 40–70, and has no certain cause. Risk factors include genetics, minor trauma (potentially during cystoscopy or transurethral resection of the prostate), chronic systemic vascular diseases, smoking, and alcohol consumption.
Priapism is a painful erection that occurs for several hours and occurs in the absence of sexual stimulation. This condition develops when blood is trapped in the penis and is unable to drain. If the condition is not promptly treated, it can lead to severe scarring and permanent loss of erectile function. The disorder is most common in young men and children. Individuals with sickle-cell disease and those who use certain medications can often develop this disorder.
== Causes ==
There are many factors which may result in a person experiencing a sexual dysfunction. These may result from emotional or physical causes. Emotional factors include interpersonal or psychological problems, which include depression, sexual fears or guilt, past sexual trauma, and sexual disorders.
Sexual dysfunction is especially common among people who have anxiety disorders. Ordinary anxiety can cause erectile dysfunction in men without psychiatric problems, but clinically diagnosable disorders such as panic disorder commonly cause avoidance of intercourse and premature ejaculation. Pain during intercourse is often a comorbidity of anxiety disorders among women.
Physical factors that can lead to sexual dysfunctions include the use of drugs, such as alcohol, nicotine, narcotics, stimulants, antihypertensives, antihistamines, and some psychotherapeutic drugs. For women, almost any physiological change that affects the reproductive system—premenstrual syndrome, pregnancy and the postpartum period, and menopause—can have an adverse effect on libido. Back injuries may also impact sexual activity, as can problems with an enlarged prostate gland, problems with blood supply, or nerve damage (as in sexual dysfunction after spinal cord injuries). Diseases such as diabetic neuropathy, multiple sclerosis, tumors, and, rarely, tertiary syphilis may also impact activity, as can the failure of various organ systems (such as the heart and lungs), endocrine disorders (thyroid, pituitary, or adrenal gland problems), hormonal deficiencies (low testosterone, other androgens, or estrogen), and some birth defects.
In the context of heterosexual relationships, one of the main reasons for the decline in sexual activity among these couples is the male partner experiencing erectile dysfunction. This can be very distressing for the male partner, causing poor body image, and it can also be a major source of low desire for these men. In aging women, it is natural for the vagina to narrow and atrophy. If a woman does not participate in sexual activity regularly (in particular, activities involving vaginal penetration), she will not be able to immediately accommodate a penis without risking pain or injury if she decides to engage in penetrative intercourse. This can turn into a vicious cycle that often leads to female sexual dysfunction.
According to Emily Wentzell, American culture has anti-aging sentiments that have caused sexual dysfunction to become "an illness that needs treatment" instead of viewing it as a natural part of the aging process. Not all cultures seek treatment; for example, a population of men living in Mexico often accept ED as a normal part of their maturing sexuality.
=== With SSRI medication ===
Sexual problems are common with SSRIs, which can cause anorgasmia, erectile dysfunction, diminished libido, genital numbness, and sexual anhedonia (pleasureless orgasm). Poor sexual function is also one of the most common reasons people stop the medication. In some cases, symptoms of sexual dysfunction may persist after discontinuation of SSRIs.: 14 This combination of symptoms is sometimes referred to as post-SSRI sexual dysfunction.
=== Pelvic floor dysfunction ===
Pelvic floor dysfunction can be an underlying cause of sexual dysfunction in both women and men, and is treatable by pelvic floor physical therapy, a type of physical therapy designed to restore the health and function of the pelvic floor and surrounding areas.
=== Female sexual dysfunction ===
Several theories have looked at female sexual dysfunction, from medical to psychological perspectives. Three social psychological theories include: the self-perception theory, the overjustification hypothesis, and the insufficient justification hypothesis:
Self-perception theory: people make attributions about their own attitudes, feelings, and behaviours by relying on their observations of external behaviours and the circumstances in which those behaviours occur
Overjustification hypothesis: when an external reward is given to a person for performing an intrinsically rewarding activity, the person's intrinsic interest will decrease
Insufficient justification: based on the classic cognitive dissonance theory (inconsistency between two cognitions or between a cognition and a behavior will create discomfort), this theory states that people will alter one of the cognitions or behaviours to restore consistency and reduce distress
The prevalence of sexual dysfunction in women is not well known due to a paucity of epidemiological studies, inconsistent criteria for sexual dysfunction across different studies and incomplete recruitment, with studies often excluding women who were without a partner or who were sexually inactive. However, based on incomplete population based studies from the United States, Europe and Australia, unspecified arousal dysfunction (in which a woman is unable to achieve desirable genital or non-genital sexual arousal despite adequate stimulation and desire) was present in 3-9% of women aged 18–44, 5-7.5% aged 45–64 and 3-6% in women older than 65. Anorgasmia with distress (in which women were unable to achieve an orgasm) was present in 7-8% of women younger than 40, 5-7% aged 40–64 and 3-6% of those older than 65. Poor sexual self image leading to distress was seen in 13.4% of women younger than 40 in an Australian population based study.
The importance of how a woman perceives her behavior should not be underestimated. Many women perceive sex as a chore as opposed to a pleasurable experience, and they tend to consider themselves sexually inadequate, which in turn does not motivate them to engage in sexual activity. Several factors influence a women's perception of her sexual life. These can include race, gender, ethnicity, educational background, socioeconomic status, sexual orientation, financial resources, culture, and religion. Cultural differences are also present in how women view menopause and its impact on health, self-image, and sexuality. A study found that African American women are the most optimistic about menopausal life; Caucasian women are the most anxious, Asian women are the most inhibited about their symptoms, and Hispanic women are the most stoic.
Since these women have sexual problems, their sexual lives with their partners can become a burden without pleasure, and may eventually lose complete interest in sexual activity. Some of the women found it hard to be aroused mentally, while others had physical problems. Several factors can affect female dysfunction, such as situations in which women do not trust their sex partners, the environment where sex occurs being uncomfortable, or an inability to concentrate on the sexual activity due to a bad mood or burdens from work. Other factors include physical discomfort or difficulty in achieving arousal, which could be caused by aging or changes in the body's condition.
Sexual assault has been associated with excessive menstrual bleeding, genital burning, and painful intercourse (attributable to disease, injury, or otherwise), medically unexplained dysmenorrhea, menstrual irregularity, and lack of sexual pleasure. Physically violent assaults and those committed by strangers were most strongly related to reproductive symptoms. Multiple assaults, assaults accomplished by persuasion, spousal assault, and completed intercourse were most strongly related to sexual symptoms. Assault was occasionally associated more strongly with reproductive symptoms among women with lower income or less education, possibly because of economic stress or differences in assault circumstances. Associations with unexplained menstrual irregularity were strongest among African American women; ethnic differences in reported circumstances of assault appeared to account for these differences. Assault was associated with sexual indifference only among Latinas.
=== Menopause ===
The most prevalent of female sexual dysfunctions that have been linked to menopause include lack of desire and libido; these are predominantly associated with hormonal physiology. Specifically, the decline in serum estrogens causes these changes in sexual functioning. Androgen depletion may also play a role, but current knowledge about this is less clear. The hormonal changes that take place during the menopausal transition have been suggested to affect women's sexual response through several mechanisms, some more conclusive than others.
=== Aging in women ===
Whether or not aging directly affects women's sexual functioning during menopause is controversial. However, many studies have demonstrated that aging has a powerful impact on sexual function and dysfunction in women, specifically in the areas of desire, sexual interest, and frequency of orgasm. The primary predictor of sexual response throughout menopause is prior sexual functioning, which means that it is important to understand how the physiological changes in men and women can affect sexual desire. Despite the apparent negative impact that menopause can have on sexuality and sexual functioning, sexual confidence and well-being can improve with age and menopausal status.
Testosterone, along with its metabolite dihydrotestosterone, is important to normal sexual function in men and women. Dihydrotestosterone is the most prevalent androgen in both men and women. Testosterone levels in women at age 60 are on average about half of what they were before the women were 40. Although this decline is gradual for most women, those who have undergone bilateral oophorectomy experience a sudden drop in testosterone levels, as the ovaries produce 40% of the body's circulating testosterone.
Sexual desire has been related to three separate components: drive, beliefs and values, and motivation. Particularly in postmenopausal women, drive fades and is no longer the initial step in a woman's sexual response.
== Diagnosis ==
=== List of disorders ===
==== DSM ====
The fourth edition of the Diagnostic and Statistical Manual of Mental Disorders lists the following sexual dysfunctions:
Hypoactive sexual desire disorder (see also asexuality, which is not classified as a disorder)
Sexual aversion disorder (avoidance of or lack of desire for sexual intercourse)
Female sexual arousal disorder (failure of normal lubricating arousal response)
Male erectile disorder
Female orgasmic disorder (see anorgasmia)
Male orgasmic disorder (see anorgasmia)
Premature ejaculation
Dyspareunia
Vaginismus
Additional DSM sexual disorders that are not sexual dysfunctions include:
Paraphilias
PTSD due to genital mutilation or childhood sexual abuse
==== Other sexual problems ====
Sexual dissatisfaction (non-specific)
Lack of sexual desire
Anorgasmia
Impotence
Sexually transmitted infections
Delay or absence of ejaculation, despite adequate stimulation
Inability to control timing of ejaculation
Inability to relax vaginal muscles enough to allow intercourse
Inadequate vaginal lubrication preceding and during intercourse
Burning pain on the vulva or in the vagina with contact to those areas
Unhappiness or confusion related to sexual orientation
Transsexual and transgender people may have sexual problems before or after surgery.
Persistent sexual arousal syndrome
Sexual addiction
Hypersexuality
All forms of female genital cutting
Post-orgasmic diseases, such as Dhat syndrome, PCT, POIS, and sexual headaches.
Hard flaccid syndrome
== Treatment ==
=== Males ===
Several decades ago, the medical community believed most sexual dysfunction cases were related to psychological issues. Although this may be true for a portion of men, the vast majority of cases have now been identified to have a physical cause or a correlation. If the sexual dysfunction is deemed to have a psychological component or cause, psychotherapy can help. Situational anxiety arises from an earlier bad incident or lack of experience, and often leads to development of fear towards sexual activity and avoidance which enters a cycle of increased anxiety and desensitization of the penis. In some cases, erectile dysfunction may be due to marital disharmony. Marriage counseling sessions are recommended in this situation.
Lifestyle changes such as discontinuing tobacco smoking or substance use can also treat some types of ED. Several oral medications like Viagra, Cialis, and Levitra have become available to alleviate ED and have become first line therapy. These medications provide an easy, safe, and effective treatment solution for approximately 60% of men. In the rest, the medications may not work because of wrong diagnosis or chronic history.
Another type of medication that is effective in roughly 85% of men is called intracavernous pharmacotherapy, which involves injecting a vasodilator drug directly into the penis to stimulate an erection. This method has an increased risk of priapism if used in conjunction with other treatments, and localized pain.
Premature ejaculations are treated by behavioural techniques Squeeze technique and Stop Start Technique. In Squeeze technique the area between head and shaft of penis is pressed using index finger and thumb just before ejaculation. In Stop Start Technique the male partner stops having sexual intercourse just before ejaculation and waits for the sense of ejaculation to pass away. Both Techniques are repeated many times.
When conservative therapies fail, are an unsatisfactory treatment option, or are contraindicated for use, the insertion of a penile implant may be selected by the patient. Technological advances have made the insertion of a penile implant a safe option for the treatment of ED, which provides the highest patient and partner satisfaction rates of all available ED treatment options.
Pelvic floor physical therapy has been shown to be a valid treatment for men with sexual problems and pelvic pain.
The 2020 guidelines from the American College of Physicians support the discussion of testosterone treatment in adult men with age-related low levels of testosterone who have sexual dysfunction. They recommend yearly evaluation regarding possible improvement and, if none, to discontinue testosterone; intramuscular treatments should be considered rather than transdermal treatments due to costs and since the effectiveness and harm of either method is similar. Testosterone treatment for reasons other than possible improvement of sexual dysfunction may not be recommended.
=== Females ===
In 2015, flibanserin was approved in the US to treat decreased sexual desire in women. While it is effective for some women, it has been criticized for its limited efficacy, and has many warnings and contraindications that limit its use. Flibanserin was found to increase pleasurable sexual experiences by 0.5 events per month in trials. Possible side effects include dizziness, drowsiness, nausea and fatigue. Flibanserin should not be taken with alcohol. Bremelanotide has been shown to modestly increase sexual desire in women, but it has not shown evidence of increasing the number of satisfactory sexual experiences per month. Possible side effects include nausea, flushing and headaches. Women experiencing pain with intercourse are often prescribed pain relievers or desensitizing agents; others are prescribed vaginal lubricants. Many women with sexual dysfunction are also referred to a counselor or sex therapist. Counselling for female sexual dysfunction, including sexual counselling, cognitive behavioral therapy, body awareness counselling, and couples counselling have been found to be helpful.
Estrogen replacement therapy, outside of the indicated use for menopausal symptoms, is not recommended for the treatment of sexual dysfunction in women.
==== Menopause ====
Estrogens are responsible for the maintenance of collagen, elastic fibers, and vasculature of the urogenital tract, all of which are important in maintaining vaginal structure and functional integrity; they are also important for maintaining vaginal pH and moisture levels, both of which help to keep the tissues lubricated and protected. Prolonged estrogen deficiency leads to atrophy, fibrosis, and reduced blood flow to the urogenital tract, which cause menopausal symptoms such as vaginal dryness and pain related to sexual activity and/or intercourse. Women experiencing vaginal dryness who cannot use commercial lubricants may be able to use coconut oil as an alternative.
Androgen therapy for hypoactive sexual desire disorder has a small benefit but its safety is not known. It is not approved as a treatment in the United States. It is more commonly used among women who have had an oophorectomy or are in a postmenopausal state. However, like most treatments, this is also controversial. One study found that after a 24-week trial, women taking androgens had higher scores of sexual desire compared to a placebo group. As with all pharmacological drugs, there are side effects in using androgens, which include hirsutism, acne, polycythaemia, increased high-density lipoproteins, cardiovascular risks, and endometrial hyperplasia. Alternative treatments include topical estrogen creams and gels that can be applied to the vulva or vagina area to treat vaginal dryness and atrophy.
== Research ==
In modern times, clinical study of sexual problems is usually dated back no earlier than 1970 when Masters and Johnson's Human Sexual Inadequacy was published. It was the result of over a decade of work at the Reproductive Biology Research Foundation in St. Louis, involving 790 cases. The work grew from Masters and Johnson's earlier Human Sexual Response (1966).
Prior to Masters and Johnson, the clinical approach to sexual problems was largely derived from Sigmund Freud. It was held to be psychopathology and approached with a certain pessimism regarding the chance of help or improvement. Sexual problems were merely symptoms of a deeper malaise, and the diagnostic approach was from the psychopathological viewpoint. There was little distinction between difficulties in function and variations nor between perversion and problems. Despite work by psychotherapists such as Balint sexual difficulties were crudely split into frigidity or impotence, terms which acquired negative connotations in popular culture.
Human Sexual Inadequacy moved thinking from psychopathology to learning; psychopathological problems would only be considered if a problem did not respond to educative treatment. Treatment was directed at couples, whereas before partners would be seen individually. Masters and Johnson believed that sex was a joint act, and that sexual communication was the key issue to sexual problems, not the specifics of an individual problem. They also proposed co-therapy, with a pair of therapists to match the clients, arguing that a lone male therapist could not fully comprehend female difficulties.
The basic Masters and Johnson treatment program was an intensive two-week program to develop efficient sexual communication. The program is couple-based and therapist-led, and began with discussion and sensate focus between the couple to develop shared experiences. From the experiences, specific difficulties could be determined and approached with a specific therapy. In a limited number of male-only cases (41) Masters and Johnson developed the use of a female surrogate, which was abandoned over the ethical, legal, and other problems it raised.
In defining the range of sexual problems, Masters and Johnson defined a boundary between dysfunction and deviations. Dysfunctions were transitory and experienced by most people, and included male primary or secondary impotence, premature ejaculation, and ejaculatory incompetence; female primary orgasmic dysfunction and situational orgasmic dysfunction; pain during intercourse (dyspareunia) and vaginismus. According to Masters and Johnson, sexual arousal and climax are a normal physiological process of every functionally intact adult, but they can be inhibited despite being autonomic responses. Masters and Johnson's treatment program for dysfunction was 81.1% successful.
Despite Masters and Johnson's work, sexual therapy in the US was overrun by enthusiastic rather than systematic approaches, blurring the space between "enrichment" and therapy.
== See also ==
== References ==
== External links ==
Media related to Sexual disorders at Wikimedia Commons
NIH site on sexual problems (archived 18 October 2013) | Wikipedia/Sexual_dysfunction |
Hyperlipidemia is abnormally high levels of any or all lipids (e.g. fats, triglycerides, cholesterol, phospholipids) or lipoproteins in the blood. The term hyperlipidemia refers to the laboratory finding itself and is also used as an umbrella term covering any of various acquired or genetic disorders that result in that finding. Hyperlipidemia represents a subset of dyslipidemia and a superset of hypercholesterolemia. Hyperlipidemia is usually chronic and requires ongoing medication to control blood lipid levels.
Lipids (water-insoluble molecules) are transported in a protein capsule. The size of that capsule, or lipoprotein, determines its density. The lipoprotein density and type of apolipoproteins it contains determines the fate of the particle and its influence on metabolism.
Hyperlipidemias are divided into primary and secondary subtypes. Primary hyperlipidemia is usually due to genetic causes (such as a mutation in a receptor protein), while secondary hyperlipidemia arises due to other underlying causes such as diabetes. Lipid and lipoprotein abnormalities are common in the general population and are regarded as modifiable risk factors for cardiovascular disease due to their influence on atherosclerosis. In addition, some forms may predispose to acute pancreatitis.
== Signs and symptoms ==
Hyperlipidemia, on its own, is typically asymptomatic. However, it can predispose one to more serious medical problems via lipid buildup, such as atherosclerosis (blood vessels), heart attack, or stroke (brain).
Some indicators of hyperlipidemia are xanthomas, which are yellow "bumps" on the arms, legs, or trunk, or xanthelasmas, which are yellowish deposits of fat on the eyelids.
== Causes ==
The major causes of hyperlipidemia are either genetic or lifestyle causes. Individuals with a genetic predisposition for hyperlipidemia or a family history are more at risk for this disease. However, unhealthy habits can lead to secondary hyperlipidemia: A diet heavy in trans fats or saturated fats, contained in red meats and dairy, can lead to secondary hyperlipidemia. Not getting enough exercise can also be a risk factor. Stress and alcohol can lead to elevated levels of cholesterol. Smoking damages blood vessels, contributing to atherosclerosis and lowers HDL (good cholesterol) levels. An increase in age also increases the risk of hyperlipidemia.
== Classification ==
Hyperlipidemias may basically be classified as either familial (also called primary) when caused by specific genetic abnormalities or acquired (also called secondary) when resulting from another underlying disorder that leads to alterations in plasma lipid and lipoprotein metabolism. Also, hyperlipidemia may be idiopathic, that is, without a known cause.
Hyperlipidemias are also classified according to which types of lipids are elevated, that is hypercholesterolemia, hypertriglyceridemia or both in combined hyperlipidemia. Elevated levels of Lipoprotein(a) may also be classified as a form of hyperlipidemia.
=== Familial (primary) ===
Familial hyperlipidemias are classified according to the Fredrickson classification, which is based on the pattern of lipoproteins on electrophoresis or ultracentrifugation. It was later adopted by the World Health Organization (WHO). It does not directly account for HDL, and it does not distinguish among the different genes that may be partially responsible for some of these conditions.
==== Type I ====
Type I hyperlipoproteinemia exists in several forms:
Lipoprotein lipase deficiency (type Ia), due to a deficiency of lipoprotein lipase (LPL) or altered apolipoprotein C2, resulting in elevated chylomicrons, the particles that transfer fatty acids from the digestive tract to the liver
Familial apoprotein CII deficiency (type Ib), a condition caused by a lack of lipoprotein lipase activator.: 533
Chylomicronemia due to circulating inhibitor of lipoprotein lipase (type Ic)
Type I hyperlipoproteinemia usually presents in childhood with eruptive xanthomata and abdominal colic. Complications include retinal vein occlusion, acute pancreatitis, steatosis, and organomegaly, and lipemia retinalis.
==== Type II ====
Hyperlipoproteinemia type II is further classified into types IIa and IIb, depending mainly on whether elevation in the triglyceride level occurs in addition to LDL cholesterol.
===== Type IIa =====
This may be sporadic (due to dietary factors), polygenic, or truly familial as a result of a mutation either in the LDL receptor gene on chromosome 19 (0.2% of the population) or the ApoB gene (0.2%). The familial form is characterized by tendon xanthoma, xanthelasma, and premature cardiovascular disease. The incidence of this disease is about one in 500 for heterozygotes, and one in 1,000,000 for homozygotes.
HLPIIa is a rare genetic disorder characterized by increased levels of LDL cholesterol in the blood due to the lack of uptake (no Apo B receptors) of LDL particles. This pathology, however, is the second-most common disorder of the various hyperlipoproteinemias, with individuals with a heterozygotic predisposition of one in every 500 and individuals with homozygotic predisposition of one in every million. These individuals may present with a unique set of physical characteristics such as xanthelasmas (yellow deposits of fat underneath the skin often presenting in the nasal portion of the eye), tendon and tuberous xanthomas, arcus juvenilis (the graying of the eye often characterized in older individuals), arterial bruits, claudication, and of course atherosclerosis. Laboratory findings for these individuals are significant for total serum cholesterol levels two to three times greater than normal, as well as increased LDL cholesterol, but their triglycerides and VLDL values fall in the normal ranges.
To manage persons with HLPIIa, drastic measures may need to be taken, especially if their HDL cholesterol levels are less than 30 mg/dL and their LDL levels are greater than 160 mg/dL. A proper diet for these individuals requires a decrease in total fat to less than 30% of total calories with a ratio of monounsaturated:polyunsaturated:saturated fat of 1:1:1. Cholesterol should be reduced to less than 300 mg/day, thus the avoidance of animal products and to increase fiber intake to more than 20 g/day with 6g of soluble fiber/day. Exercise should be promoted, as it can increase HDL. The overall prognosis for these individuals is in the worst-case scenario if uncontrolled and untreated individuals may die before the age of 20, but if one seeks a prudent diet with correct medical intervention, the individual may see an increased incidence of xanthomas with each decade, and Achilles tendinitis and accelerated atherosclerosis will occur.
===== Type IIb =====
The high VLDL levels are due to overproduction of substrates, including triglycerides, acetyl-CoA, and an increase in B-100 synthesis. They may also be caused by the decreased clearance of LDL. Prevalence in the population is 10%.
Familial combined hyperlipoproteinemia (FCH)
Lysosomal acid lipase deficiency (often called Cholesteryl ester storage disease)
Secondary combined hyperlipoproteinemia (usually in the context of metabolic syndrome, for which it is a diagnostic criterion)
==== Type III ====
This form is due to high chylomicrons and IDL (intermediate density lipoprotein). Also known as broad beta disease or dysbetalipoproteinemia, the most common cause for this form is the presence of ApoE E2/E2 genotype. It is due to cholesterol-rich VLDL (β-VLDL). Its prevalence has been estimated to be approximately 1 in 10,000.
It is associated with hypercholesterolemia (typically 8–12 mmol/L), hypertriglyceridemia (typically 5–20 mmol/L), a normal ApoB concentration, and two types of skin signs (palmar xanthomata or orange discoloration of skin creases, and tuberoeruptive xanthomata on the elbows and knees). It is characterized by the early onset of cardiovascular disease and peripheral vascular disease. Remnant hyperlipidemia occurs as a result of abnormal function of the ApoE receptor, which is normally required for clearance of chylomicron remnants and IDL from the circulation. The receptor defect causes levels of chylomicron remnants and IDL to be higher than normal in the blood stream. The receptor defect is an autosomal recessive mutation or polymorphism.
==== Type IV ====
Familial hypertriglyceridemia is an autosomal dominant condition occurring in approximately 1% of the population. This form is due to high triglyceride level. Other lipoprotein levels are typically within the normal reference range or slightly increased. Treatment include diet control, fibrates and niacins. Although statins are typically the first line treatment for hyperlipidemias, fibrates are actually better at reducing elevated triglyceride levels and are considered first line.
==== Type V ====
Hyperlipoproteinemia type V, also known as mixed hyperlipoproteinemia familial or mixed hyperlipidemia, is very similar to type I, but with high VLDL in addition to chylomicrons.
It is also associated with glucose intolerance and hyperuricemia.
In medicine, combined hyperlipidemia (or -aemia) (also known as "multiple-type hyperlipoproteinemia") is a commonly occurring form of hypercholesterolemia (elevated cholesterol levels) characterized by increased LDL and triglyceride concentrations, often accompanied by decreased HDL. On lipoprotein electrophoresis (a test now rarely performed) it shows as a hyperlipoproteinemia type IIB. It is the most common inherited lipid disorder, occurring in about one in 200 persons. In fact, almost one in five individuals who develop coronary heart disease before the age of 60 has this disorder. The elevated triglyceride levels (>5 mmol/L) are generally due to an increase in very low density lipoprotein (VLDL), a class of lipoprotein prone to cause atherosclerosis.
Both conditions are treated with fibrate drugs, which act on the peroxisome proliferator-activated receptors (PPARs), specifically PPARα, to decrease free fatty acid production.
Statin drugs, especially the synthetic statins (atorvastatin and rosuvastatin) can decrease LDL levels by increasing hepatic reuptake of LDL due to increased LDL-receptor expression.
==== Unclassified familial forms ====
These unclassified forms are extremely rare:
Hyperalphalipoproteinemia
Polygenic hypercholesterolemia
=== Acquired (secondary) ===
Acquired hyperlipidemias (also called secondary dyslipoproteinemias) often mimic primary forms of hyperlipidemia and can have similar consequences. They may result in increased risk of premature atherosclerosis or, when associated with marked hypertriglyceridemia, may lead to pancreatitis and other complications of the chylomicronemia syndrome. The most common causes of acquired hyperlipidemia are:
Diabetes mellitus
Use of drugs such as thiazide diuretics, beta blockers, and estrogens
Other conditions leading to acquired hyperlipidemia include:
Hypothyroidism
Kidney failure
Nephrotic syndrome
Alcohol consumption
Some rare endocrine disorders and metabolic disorders
Treatment of the underlying condition, when possible, or discontinuation of the offending drugs usually leads to an improvement in the hyperlipidemia.
Another acquired cause of hyperlipidemia, although not always included in this category, is postprandial hyperlipidemia, a normal increase following ingestion of food.
== Screening and diagnosis ==
Adults 20 years and older should have the cholesterol checked every four to six years. Serum level of Low Density Lipoproteins (LDL) cholesterol, High Density Lipoproteins (HDL) Cholesterol, and triglycerides are commonly tested in primary care setting using a lipid panel. Quantitative levels of lipoproteins and triglycerides contribute toward cardiovascular disease risk stratification via models/calculators such as Framingham Risk Score, ACC/AHA Atherosclerotic Cardiovascular Disease Risk Estimator, and/or Reynolds Risk Scores. These models/calculators may also take into account of family history (heart disease and/or high blood cholesterol), age, gender, Body-Mass-Index, medical history (diabetes, high cholesterol, heart disease), high sensitivity CRP levels, coronary artery calcium score, and ankle-brachial index. The cardiovascular stratification further determines what medical intervention may be necessary to decrease the risk of future cardiovascular disease.
=== Total cholesterol ===
The combined quantity of LDL and HDL. A total cholesterol of higher than 240 mg/dL is abnormal, but medical intervention is determined by the breakdown of LDL and HDL levels.
=== LDL cholesterol ===
LDL, commonly known as "bad cholesterol", is associated with increased risk of cardiovascular disease. LDL cholesterol transports cholesterol particles throughout the body, and can build up in the walls of the arteries, making them hard and narrow. LDL cholesterol is produced naturally by the body, but eating a diet high in saturated fat, trans fats, and cholesterol can increase LDL levels. Elevated LDL levels are associated with diabetes, hypertension, hypertriglyceridemia, and atherosclerosis. In a fasting lipid panel, a LDL greater than 160 mg/dL is abnormal.
=== HDL cholesterol ===
HDL, also known as "good cholesterol", is associated with decreased risk of cardiovascular disease. HDL cholesterol carries cholesterol from other parts of the body back to the liver and then removes the cholesterol from the body. It can be affected by acquired or genetic factors, including tobacco use, obesity, inactivity, hypertriglyceridemia, diabetes, high carbohydrate diet, medication side effects (beta-blockers, androgenic steroids, corticosteroids, progestogens, thiazide diuretics, retinoic acid derivatives, oral estrogens, etc.) and genetic abnormalities (mutations ApoA-I, LCAT, ABC1). Low level is defined as less than 40 mg/dL.
=== Triglycerides ===
Triglyceride level is an independent risk factor for cardiovascular disease and/or metabolic syndrome. Food intake prior to testing may cause elevated levels, up to 20%. Normal level is defined as less than 150 mg/dL. Borderline high is defined as 150 to 199 mg/dL. High level is between 200 and 499 mg/dL. Greater than 500 mg/dL is defined as very high, and is associated with pancreatitis and requires medical treatment.
=== Screening age ===
Health organizations does not have a consensus on the age to begin screening for hyperlipidemia. The CDC recommends cholesterol screenings once between ages 9 and 11, once again between 17 and 21, and every 4 to 6 years in adulthood. Doctors may recommend more frequent screenings for people with a family history of early heart attacks, heart disease, or if a child has obesity or diabetes. USPSTF recommends men older than 35 and women older than 45 to be screened. NCE-ATP III recommends all adults older than 20 to be screened as it may lead potential lifestyle modification that can reduce risks of other diseases. However, screening should be done for those with known CHD or risk-equivalent conditions (e.g. Acute Coronary Syndrome, history of heart attacks, Stable or Unstable angina, Transient ischemic attacks, Peripheral arterial disease of atherosclerotic origins, coronary or other arterial revascularization).
=== Screening frequency ===
Adults 20 years and older should have the cholesterol checked every four to six years, and most screening guidelines recommends testing every 5 years. USPSTF recommends increased frequency for people with elevated risk of CHD, which may be determined using cardiovascular disease risk scores.
== Management ==
Management of hyperlipidemia includes maintenance of a normal body weight, increased physical activity, and decreased consumption of refined carbohydrates and simple sugars. Prescription drugs may be used to treat some people having significant risk factors, such as cardiovascular disease, LDL cholesterol greater than 190 mg/dL or diabetes. Common medication therapy is a statin.
=== Lifestyle Modification ===
The first step in managing hyperlipidemia should be lifestyle modification, which, if not proven to be effective, can be used in conjunction with medical management. One diet that was specifically developed to help lower cholesterol levels is called the TLC diet (therapeutic lifestyle changes diet). This was created by the National Heart, Lung, and Blood Institute in 1985 and combines physical activity, diet, and weight management to help lower cholesterol levels.
=== HMG-CoA reductase inhibitors ===
Competitive inhibitors of HMG-CoA reductase, such as lovastatin, atorvastatin, fluvastatin, pravastatin, simvastatin, rosuvastatin, and pitavastatin, inhibit the synthesis of mevalonate, a precursor molecule to cholesterol. This medication class is especially effective at decreasing elevated LDL cholesterol. Major side effects include elevated transaminases and myopathy.
=== Fibric acid derivatives ===
Fibric acid derivatives, such as gemfibrozil and fenofibrate, function by increasing the lipolysis in adipose tissue via activation of peroxisome proliferator-activated receptor-α. They decrease VLDL – very low density lipoprotein – and LDL in some people. Major side effects include rashes, GI upset, myopathy, or increased transaminases. Fibrates may be prescribed in conjunction with statins to further reduce cholesterol if monotherapy is not successful; however, the combination of statins and fibrates may increase myopathy.
=== Niacin ===
Niacin, or vitamin B3 has a mechanism of action that is poorly understood, however it has been shown to decrease LDL cholesterol and triglycerides, and increase HDL cholesterol. The most common side effect is flushing secondary to skin vasodilation. This effect is mediated by prostaglandins and can be decreased by taking concurrent aspirin.
=== Bile acid binding resins ===
Bile acid binding resins, such as colestipol, cholestyramine, and colesevelam, function by binding bile acids, increasing their excretion. They are useful for decreasing LDL cholesterol. The most common side effects include bloating and diarrhea.
=== Sterol absorption inhibitors ===
Inhibitors of intestinal sterol absorption, such as ezetimibe, function by decreasing the absorption of cholesterol in the GI tract by targeting NPC1L1, a transport protein in the gastrointestinal wall. This results in decreased LDL cholesterol.
=== PCSK9 inhibitors ===
PCSK9 inhibitors are a newer drug class, approved by the FDA in 2015, which inhibit the liver-made enzyme (PCSK9), which typically breaks down LDL receptors. LDL receptors function to remove cholesterol from the bloodstream. Thus, by inhibiting the enzyme (PCSK9) that breaks down LDL receptors, more LDL receptors are available to lower lipids in the bloodstream. PCSK9 inhibitors are usually prescribed as adjunct therapy to first-line statins. Side effects can include flu-like symptoms and pain/swelling at the injection site.
== Prognosis ==
=== Relation to cardiovascular disease ===
Hyperlipidemia predisposes a person to atherosclerosis. Atherosclerosis is the accumulation of lipids, cholesterol, calcium, fibrous plaques within the walls of arteries. This accumulation narrows the blood vessel and reduces blood flow and oxygen to muscles of the heart. Over time fatty deposits can build up, hardening and narrowing the arteries until organs and tissues don't receive enough blood to properly function. If arteries that supply the heart with blood are affected, a person might have angina (chest pain). Complete blockage of the artery causes infarction of the myocardial cells, also known as heart attack. Fatty buildup in the arteries can also lead to stroke, if a blood clot blocks blood flow to the brain.
== Prevention ==
Quitting smoking, lowering intake of saturated fat and alcohol, losing excess body weight, and eating a low-salt diet that emphasizes fruits, vegetables, and whole grains can help reduce blood cholesterol.
== See also ==
== References ==
== External links == | Wikipedia/Hyperlipoproteinemia |
Women should speak to their doctor or healthcare professional before starting or stopping any medications while pregnant. Drugs taken in pregnancy including over-the counter-medications, prescription medications, nutritional supplements, recreational drugs, and illicit drugs may cause harm to the mother or the unborn child. Non-essential drugs and medications should be avoided while pregnant. Tobacco, alcohol, marijuana, and illicit drug use while pregnant may be dangerous for the unborn baby and may lead to severe health problems and/or birth defects. Even small amounts of alcohol, tobacco, and marijuana have not been proven to be safe when taken while pregnant. In some cases, for example, if the mother has epilepsy or diabetes, the risk of stopping a medication may be worse than risks associated with taking the medication while pregnant. The mother's healthcare professional will help make these decisions about the safest way to protect the health of both the mother and unborn child. In addition to medications and substances, some dietary supplements are important for a healthy pregnancy, however, others may cause harm to the unborn child.
The Food and Drug Administration (FDA) in the United States reports that there are six million pregnancies with at least 50% of the women taking at least one medication. In addition a reported 5–10% of women of childbearing age use alcohol or other addictive substances. Of those who bear children, recreational drug use can have serious consequences to the health of not only the mother, but also the fetus as many medications can cross the placenta and reach the fetus. Some of the consequences on the babies include physical and mental abnormalities, higher risk of stillbirth, neonatal abstinence syndrome (NAS), sudden infant death syndrome (SIDS), low birthweight, and others.
== Medications ==
Medications during pregnancy must be carefully considered. Many types of drugs, medications, and even nutritional supplements can affect fetal development or cause complications. For over-the-counter and prescription medications, healthcare professionals can help weigh the potential risks and benefits of taking medication while pregnant and if it is needed. Some medications may be necessary for the health and well being of both the mother and the unborn child, and some medications may come with a risk of harm to the unborn baby, but in some instances the benefits may outweigh the risks to the baby or mother.
=== Medications used to treat diabetes ===
Women who have diabetes mellitus may still need intensive therapy with insulin to prevent complications to the mother and baby. Gestational diabetes is a form of diabetes that is first diagnosed during pregnancy and can accordingly cause high blood sugar that affects the woman and the baby. In 10 - 20% of women whose diet and exercise are not adequate enough to control blood sugar, insulin injections may be required to lower blood sugar levels. Medications that can be used in diabetes during pregnancy include insulin, glyburide and metformin.
Pregnant women who use prescription medications containing opioids while pregnant may cause serious harm to the mother or unborn child. For some people, the risk of stopping a medication such as prescription opioids may be more serious than the risk of taking a medication.
==== Acetaminophen ====
Short-term use of acetaminophen as directed is one of the only medications recommended for treating pain and fever in women who are pregnant. There is no established association with teratogenicity or elevated occurrence of birth defects and the usage of acetaminophen at any point during a pregnancy. There is potential for fetal liver toxicity in cases of maternal overdose, where the mother consumes more than the recommended daily dose.
==== Non-steroidal anti-inflammatory medications (NSAIDs) ====
Ibuprofen and naproxen have not frequently been studied during pregnancy, but recent studies do not show increased risk of spontaneous abortion within the first six weeks of pregnancy. However, all NSAIDs showed association with structural cardiac defects with usage during the early weeks of pregnancy. When ibuprofen and naproxen are used within the third trimester, there is a significant increase in the risk of premature closure of the ductus arteriosus with primary pulmonary hypertension in the newborn. Between the lack of studies of the effect of ibuprofen and naproxen on pregnancy, it is recommended that pregnant women avoid these medications or use them sparingly per physician recommendations.
==== Aspirin ====
Usage of aspirin for pain relief during pregnancy is not recommended. Aspirin use during pregnancy has not demonstrated an increased risk of spontaneous abortion within the early weeks of pregnancy. However, its usage during organogenesis and the third trimester can lead to elevated risk of intrauterine growth retardation and maternal hemorrhage.
While aspirin should be avoided for use pain relief, low dose aspirin is used for prevention of preeclampsia and fetal growth restriction (FGR) in patients with previous risk factors (e.g. previous preeclampsia, multiple pregnancies, hypertension and diabetes).
==== Pain medications containing opioids ====
For more information, see the below section on Recreational drugs
Any medications containing opioids may be dangerous for the unborn baby and should not be taken while pregnant.
=== Anticonvulsant medications ===
Many commonly prescribed anticonvulsant medications are associated with an increased risk of birth defects such as neural tube defects, however, most women with epilepsy deliver healthy babies and have a healthy pregnancy. Women who have epilepsy often still require treatment to control or prevent seizures and therefore require very early advice (ideally before conceiving the child) from their doctor to determine the safest way to protect both the mother and unborn child.
Valproic acid and its derivatives such as sodium valproate and divalproex sodium, commonly used to prevent seizures and treat mood disorders, increase the risk of congenital malformations (birth defects) including neural tube defects if taken during pregnancy. There is evidence that an increased dose or increased exposure in utero is associated with an increased risk of lower scores on neurodevelopmental tests. Valproic acid use during pregnancy increases the risk of neural tube defects by approximately 20-fold. Evidence is conflicting for carbamazepine regarding any increased risk of congenital physical anomalies or neurodevelopmental disorders by intrauterine exposure. Similarly, children exposed to lamotrigine or phenytoin in the womb do not seem to differ in their skills compared to those who were exposed to carbamazepine.
=== Antacids ===
Heartburn is a common symptom of late term pregnancy during which up to 80% of pregnant women have experienced it by the end of their third trimester. Heartburn often indicates the development of gastro-esophageal reflux disease (GERD), where the lower esophageal sphincter relaxes due to elevated progesterone levels causing increased frequency and severity of gastric reflux or heartburn. If heartburn appears after 20 weeks of gestational age or is severe and persistent, this can indicate other conditions including HELLP syndrome and preeclampsia.
Common antacids include aluminum hydroxide/magnesium hydroxide (Maalox) and calcium carbonate (Tums). Histamine H2 blockers and proton pump inhibitors, such as famotidine (Pepcid) and omeprazole (Prilosec), respectively, can also be used to help relieve heartburn, with no known teratogenic effects or congenital malformations. Aluminum hydroxide/magnesium hydroxide and calcium carbonate, when consumed, do not cross the placenta and are regarded as safe pharmacological options to treat heartburn, since there are no significant association with maldevelopment or injury to fetus.
Ginger and acupressure are common non-pharmacological options used to treat nausea and vomiting as alternatives to antacids, histamine H2 blockers, and proton pump inhibitors. Lifestyle modifications are often recommended as well. Recommended modifications can include avoiding fatty food, reducing size and frequency of meals, and reducing caffeine intake.
=== Antiacne ===
Acne vulgaris (acne) can occur in pregnancy possibly due to the hormonal changes influencing sebum production. There are limited antiacne medications that are safe in pregnancy. External applications of azelaic acid, glycolic acid, or benzoyl peroxide (alone or combined with clindamycin or erythromycin) are the safest options to treat mild to moderate acne. Erythromycin is the antibiotic of choice for severe acne, barring the use of its estolate salt which risks maternal hepatotoxicity. Topical nicotinamide and topical zinc are safe, however, there are no FDA pregnancy category ratings. Topical salicylic acid and topical dapsone are classified as FDA pregnancy category C. Acne medications to avoid during pregnancy include oral isotretinoin and topical tazarotene as there have been reports of birth defects. As safety data is lacking, the use of topical retinoids, such as adapalene and tretinoin, is not recommended. Antiandrogenic drugs, including spironolactone and cyproterone acetate, should be avoided. If planning to conceive while using contraindicated medications, a washout and waiting period before conception is advised. A herbal product, vitex agnus-castus should not be used during gestation due to undesirable hormonal effects.
Safety data supports the use of blue and red light therapy as non-drug treatments to consider. Personal hygiene and a healthy lifestyle also help, however dietary restriction and abrasive agents found in facial cleaning products are not beneficial. As there are limited options to safely treat acne in pregnancy, shared decision-making between the health care provider and client is recommended.
=== Anticoagulants ===
Anticoagulants are medications that prevent the blood from forming clots and are also known as blood thinners. These medications are commonly used for both prevention and treatment in people who are at risk for or have experienced a heart attack, stroke, or venous thromboembolism. Pregnancy increases the risk of clot formation in women due to elevated levels of certain clotting factors and compounds in the body, and the risk increases even more immediately after birth and remains elevated up to 3 months after delivery. Anticoagulants must be prescribed with caution as these medications can have negative health consequences for the developing baby and need to consider dosing and medication management options.
==== Warfarin ====
Warfarin (brand name Coumadin) is a commonly prescribed blood thinner both in the inpatient and outpatient hospital settings. In pregnant women, warfarin is contraindicated and should be avoided as it crosses the placental barrier. Additionally, warfarin is listed as Pregnancy Category D, which means it has a risk of harming the fetus. However, it has been shown that daily warfarin doses up to 5 mg may be beneficial for pregnant women who are at higher risk of thromboembolism.
==== Low Molecular Weight Heparin (LMWH) ====
A common low molecular weight heparin drug is called enoxaparin (brand name Lovenox). Enoxaparin is listed as Pregnancy Category B, meaning animal studies have failed to show harmful effects to the fetus and therefore are safe to use in pregnant women. However, pregnant women taking LMWH may not experience the full anticoagulant effect due to the nature of the medication compared to other anticoagulants (i.e. warfarin) and may be less favorable for users as it is an injectable medication.
==== Unfractionated Heparin (UFH) ====
Unfractionated heparin is another type of anticoagulant that has been widely used. UFH is classified as Pregnancy Category C, which means animal studies have shown potential for adverse effects to the fetus; however, there needs to be more studies done to confirm the presence of a risk to the fetus. UFH can be used in pregnant women as long as the benefits outweigh the risk.
==== Direct Oral Anticoagulants (DOACs) ====
Direct oral anticoagulants are newer types of anticoagulants that are available as oral medications and are widely used in non-pregnant populations. As many studies looking at DOACs exclude pregnant women, there is not enough evidence to demonstrate the safety and efficacy of DOACs in pregnant women. Currently, rivaroxaban (Xarelto), dabigatran (Pradaxa), and edoxaban (Savaysa) are DOACs listed under Pregnancy Category C, and apixaban (Eliquis) is listed under Pregnancy Category B.
=== Antidepressants ===
=== Antidiarrheal ===
Diarrhea is not a common symptom of pregnancy; however, it can occur as a result of reduced gastric acidity and slowed intestinal motility. Bismuth subsalicylate (Pepto-Bismol), loperamide (Imodium), and atropine/diphenoxylate (Lomotil) are antidiarrheal agents that can be used to treat diarrhea. However, not all of them are safe to use during pregnancy. One of the components of bismuth subsalicylate is salicylate, which is a component that crosses the placenta. Due to this, there is an increased risk for intrauterine growth retardation, fetal hemorrhage, and maternal hemorrhage within organogenesis and in the second/third trimester. Loperamide has limited data on the impact it has on pregnancy, but there is an association with cardiovascular malformation in the first trimester. Atropine/diphenoxylate currently has insufficient evidence of teratogenicity in humans, but trials with animals showed evidence of teratogenic effects.
=== Antihistamines ===
Antihistamines may be prescribed in early pregnancy for the treatment of nausea and vomiting along with symptoms of asthma and allergies. First generation antihistamines include diphenhydramine (Benadryl), chlorpheniramine (Diabetic Tussin), hydroxyzine (Atarax), and doxepin (Sinequan). Second generation antihistamines include loratadine (Claritin), cetrizine (Zyrtec), and fexofenadine (Allegra). First generation antihistamines have the ability to cross the blood-brain barrier which can result in sedative and anticholinergic effects while effectively treating allergic reactions and nausea and vomiting related to pregnancy. On the other hand, second generation antihistamines do not cross the blood-brain barrier, thus eliminating sedating effects. Currently, there is a lack of association between prenatal antihistamine exposure and birth defects.
Antihistamines during pregnancy have not been linked to birth defects; however, further research is necessary for some antihistamine medications to determine safety during pregnancy. It is suggested that women speak to their healthcare professionals before taking any over-the-counter or prescription medication while pregnant to ensure that there are no adverse health outcomes.
=== Anti-hypertensives ===
Hypertensive issues are the most common cardiovascular disorders during pregnancy, occurring within 5 to 10% of all pregnant females. Anti-hypertensives are blood pressure medications used to treat high blood pressure in pregnant women. This class of medication is commonly used to treat problems such as heart failure, heart attack, and kidney failure. Caution must be exercised with the use of various hypertensive agents for the treatment of blood pressure. While the drug classes of Angiotensin Converting Enzyme inhibitors (ACEi), Angiotensin Receptor Blockers (ARB), and angiotensin receptor neprilysin inhibitors (ARNI) have been shown to be potent anti-hypertensive agents, their use is advised against during pregnancy. ACEi and ARB have known fetotoxicities when used during the second or third trimester or both. Signs and symptoms of ACEi and ARB use during pregnancy include kidney damage or failure, oligohydramnios, anuria, joint contractures, and hypoplasia of the skull. Common, alternative agents for high blood pressure in pregnant women include anti-adrenergic and beta-blocking medications, such as methyldopa or metoprolol, respectively.
=== Decongestants ===
Decongestants are often used in conjunction with cold medications or to combat pregnancy rhinitis in pregnant women. Common decongestants include pseudoephedrine and phenylephrine. Pseudoephedrine is an alpha-adrenergic receptor agonist that enacts a vasoconstrictive effect to reduce airflow resistance in the nasal cavity and allow easier breathing by relieving a stuffy or congested nose. When taken in early trimesters, there has been limited evidence to associate pseudoephedrine with birth defects. However, studies often found it difficult to isolate pseudoephedrine's involvement, due to the variety of combination products that contain pseudoephedrine in conjunction with other medications. Since pseudoephedrine activates alpha adrenergic receptors, it has the ability to elevate blood pressure and cause vasoconstriction within the uterine arteries. This can negatively affect blood flow to the fetus. Due to the lack of studies, decongestants in combination drugs or isolated forms are suggested to be used sparingly during pregnancy. Saline nasal sprays, among other non-pharmacological treatments, are considered to be safe alternatives for decongestants.
== Dietary supplements ==
Dietary supplements such as folic acid and iron are important for a healthy pregnancy. Some dietary supplements can cause side effects and harm to the mother or unborn child. Pregnant women should discuss all dietary supplements with their health care professional to determine the appropriate dosage and which supplements are safe during pregnancy.
Caution should be taken before consuming dietary supplements while pregnant as dietary supplements are considered "foods" rather than medications and are not regulated for safety and efficacy by the FDA.
=== Folic Acid ===
Many countries such as the USA, Canada, Chile, and Costa Rica have fortified foods with folic acid and have seen a reduced incidence of neural tube defect (NTD).
The Center for Disease Control and Prevention (CDC) recommends that all women of child-barring age receive 400 μg of folic acid supplement (even if they are not planning on getting pregnant). Women who have already had an NTD-affected pregnancy and are planning to become pregnant again should receive 4000 μg each day for a month before and for the first three months of pregnancy. The recommendation came from a study conducted by the British Medical Research Council (MRC) Vitamin Study Group from July 1983 to April 1991 involving 33 centers (17 of which in the UK and the remaining 16 in 6 different countries) that compared pregnancy outcomes of folic acid and other vitamins interventions with placebo. That study found a risk reduction of 71% of NTD-affected pregnancies in groups receiving folic acid when compared to groups receiving placebo. In the study, there were four intervention groups, Group A received 4 mg of folic acid; Group B received a multivitamin that contained folic acid; Group C placebo and Group D received a multivitamin without folic acid. In the groups that received folic acid, 6 out of 593 (1%) infants and fetuses had NTD reoccurrence compared to the groups that received no folic acid, which had 21 infants and fetuses with NTD out of 602 (3.5%). There were no significant benefit found in the vitamin intervention groups.
=== Iron ===
Iron deficiency is common in pregnancy, with the highest occurrence rate during the third trimester as iron demand increases to support the placenta, fetal development and the iron stores for the first six months after birth. Low iron levels can cause fatigue, reduced work capacity, cardiovascular stress, lower resistance to infection and iron deficiency anemia. Iron deficiency anemia in pregnancy can lead to an increased risk of premature delivery, low birth weight and increased risk of perinatal mortality.
The Recommended Dietary Allowance (RDA) suggests 27 mg of iron a day which would account for normal iron losses, iron used by the fetus and related tissues during gestation and increased maternal hemoglobin mass changes. WHO recommends taking supplements of 30–60 mg of elemental iron a day throughout pregnancy for all pregnant individuals. Iron demand depends on individual specific factors and risk of deficiency; for specific dose recommendations, individuals should discuss with their doctors.
Dietary sources of iron include meat, poultry, fish, eggs, legumes, vegetables, fruits, grains, nuts and iron-fortified grain products. Eating at least one source of vitamin C with each meal is also recommended, as it can help increase iron absorption. Examples of vitamin C sources include broccoli, cantaloupe, citrus fruits and their juices, kiwis, mangos, potatoes, strawberries, sweet peppers, tomatoes, and tomato sauce. On the contrary, caffeine, calcium supplements and antacids should be separated from meals and iron supplements by 1–2 hours as they can decrease iron absorption.
== Illicit and recreational drugs ==
According to the World Health Organization, substance abuse refers to the damaging or risky consumption of psychoactive substances, which includes alcohol and illegal drugs. When pregnant women use psychotropic substances, whether they are prescribed or not, it can have adverse effects on the developing fetus. These effects may include causing birth defects, delayed development, and intrauterine growth restriction. Additionally, it raises the likelihood of various pregnancy complications, including spontaneous miscarriage, preterm birth, and puts the mother at an increased risk of medical issues such as postpartum bleeding and placental abruption.
=== Alcohol ===
Alcohol should not be consumed while pregnant. Even a small amount of alcohol is not known to be safe for the unborn baby. Alcohol passes easily from the mother's bloodstream through the placenta and into the bloodstream of the fetus. Since the fetus is smaller and does not have a fully developed liver, the concentration of alcohol in its bloodstream lasts longer, increasing the chances of detrimental side effects. The severity of effects alcohol may have on a developing fetus depends upon the amount and frequency of alcohol consumed as well as the stage of pregnancy. Rates of alcohol consumption can generally be categorized in one of three ways: heavy drinking (more than 48-60 grams of ethanol/day), moderately high drinking (24-48 grams of ethanol/day), and binge drinking (4-5 drinks/90 grams of ethanol at a time).
==== Fetal alcohol spectrum disorder ====
Heavy drinking and binge drinking are closely associated with a higher risk of fetal alcohol spectrum disorders (FASDs). The most severe form of FASD is fetal alcohol syndrome (FAS). This used to be the only diagnosis for fetal disorders due to alcohol consumption, but the term was broadened to a "spectrum" due to the variety of abnormalities observed in newborns. This was most likely because of the different amounts of alcohol ingested during pregnancy indicating that there is not a clear, specific dose that determines if a fetus will be affected by alcohol or not. FAS is characterized by slower physical growth, distinct facial abnormalities including smooth philtrum, thin vermilion, and short palpebral fissures, neurological deficits, or smaller head circumference. Other problems associated with FASD include delayed or uncoordinated motor skills, hearing or vision problems, learning disabilities, behavior problems, and inappropriate social skills compared to same-age peers. Those affected are more likely to have trouble in school, legal problems, participate in high-risk behaviors, and develop substance use disorders themselves.
==== Miscarriage ====
Alcohol consumption is a risk factor for miscarriage.
==== Neonatal withdrawal ====
Babies exposed to alcohol, benzodiazepines, barbiturates, and some antidepressants (SSRIs) during pregnancy may experience neonatal withdrawal.
The onset of clinical presentation typically appears within 48 to 72 hours of birth but may take up to 8 days.
==== Sudden infant death syndrome ====
Drinking of alcohol by parents is linked to sudden infant death syndrome (SIDS). One study found a positive correlation between the two during New Years celebrations and weekends. Another found that alcohol use disorder was linked to a more than doubling of risk.
=== Caffeine ===
Caffeine is a widespread drug consumed by adults due to its behavioral and stimulating effects. According to the American College of Obstetricians and Gynecologists, an acceptable intake of caffeine for pregnant women is less than or equal to 200 mg per day. Consumption of caffeine is not associated with adverse reproductive and developmental effects. The half-life of caffeine is longer in pregnancy by 8 to 16 more hours, which means that caffeine stays in the person longer, increases fetal exposure to caffeine, and is eliminated slower in the body. Other comprehensive reviews reported that caffeine intake of more than 300 mg per day have been associated with spontaneous abortions and low birth weight, but further research is needed to establish this causal relationship.
=== Cannabis ===
Cannabis use during pregnancy should be avoided. There is no known safe dose of cannabis while pregnant and use of cannabis may lead to birth defects, pre-term birth, or low birth weight. Tetrahydrocannabinol (THC), an active ingredient in cannabis, can both cross the placenta and accumulates in high concentrations in breast milk. Cannabis consumption in pregnancy might be associated with restrictions in growth of the fetus, miscarriage, and cognitive deficits. Infants exposed to prenatal cannabis may show signs of increased tremors and altered sleep patterns. Cannabis is the most frequently used illicit drug amongst pregnant women. There are significant limitations to the current research available. One limitation is because most studies done are dated in the 1980s. Additionally, many studies done on cannabis that evaluate its safety often fail to account for confounding factors, a variable that could also be having an effect on an outcome that is not the test variable. For example, tobacco use and sociodemographic differences are often not adjusted for accordingly in many studies.
=== Cocaine ===
Use of cocaine in pregnant women is dangerous and can lead to cardiovascular complications like hypertension, myocardial infarction and ischemia, kidney failure, liver rupture, cerebral ischemia, cerebral infarction, and maternal death. Cardiac muscles become more sensitive to cocaine in pregnancy, in the presence of increasing progesterone concentrations. Cocaine use leads to increased risk for perinatal outcomes: preterm delivery, low birth weight (less than 2500 grams) or reduced birth rate, small size and earlier gestational age at delivery.
Prenatal cocaine exposure (PCE) is associated with premature birth, birth defects, attention deficit hyperactivity disorder (ADHD), and other conditions.
=== Methamphetamine ===
Use of methamphetamine is dangerous for pregnant women and to the fetus. Methamphetamines are a class of drugs that provide stimulant-like effects, including euphoria and alertness. The drug crosses the placenta and affects the fetus during the gestational stage of pregnancy. Methamphetamine use in pregnancy may lead to babies born with an earlier gestational age at delivery (pre-term), lower birth weight, and smaller head circumference. Methamphetamine use during pregnancy also negatively impacts brain development and behavioral functioning and increases the risk of the baby having ADHD and lower mental processing speed.
=== Opioids ===
Opioids such as heroin, fentanyl, oxycodone and methadone should not be taken while pregnant. Opioid use during pregnancy may cause adverse outcomes for the women and unborn child. Women who use opioids during pregnancy in a non-medical fashion are at a higher risk for premature birth, lower birth weight, still birth, specific birth defects, and withdrawal (neonatal abstinence syndrome).
Opioids can cross the placenta and the blood brain barrier to the fetus. Opioid use is the main cause of neonatal abstinence syndrome, which is where the baby experiences withdrawals from the opioid they were exposed to during the pregnancy. Typical symptoms may include tremors, convulsions, twitching, excessive crying, poor feeding or sucking, slow weight gain, breathing problems, fever, diarrhea, and vomiting. There is no consensus on the effects on cognitive abilities. Further research is required to determine the long-term effects of in utero exposure to opioid medications on children.
=== Tobacco ===
Smoking during pregnancy is dangerous to the unborn baby and may cause pre-term birth, birth defects such as cleft lip or cleft palate, or miscarriage. Tobacco is the most commonly used substance among pregnant women, at 25%. Nicotine crosses the placenta and accumulates within fetal tissues. Children born to women who smoked heavily were more susceptible to behavioral problems such as ADHD, poor impulse control, and aggressive behaviors. Tobacco contains carbon monoxide, which has the potential to prevent the fetus from receiving sufficient oxygen. Other health concerns tobacco poses are premature birth, low birth weight, and an increased risk of sudden infant death syndrome (SIDS) of up to three times compared to infants not exposed to tobacco. Smoking and pregnancy, combined, cause twice the risk of premature rupture of membranes, placental abruption and placenta previa. In addition to the fetus, women in general who smoke heavily are less likely to become pregnant.
== Pregnancy categories ==
Until 2014, the U.S. Code of Federal Regulations required that certain drugs and biological products be labelled specifically with respect to their effects on pregnant populations, including a definition of a "pregnancy category". These rules were enforced by the FDA, and medications that have been studied for their effects in pregnancy fell under the following Pregnancy Categories: A, B, C, D, or X depending on how they have been studied and what kind of results were found from the studies. In 2014, however, the FDA has developed a "Pregnancy and Lactation Labeling Rule (PLLR)" which requires product labels to include specific information related to the safety and effectiveness of medications to pregnant and lactating women. This ruling has removed the requirement of stating pregnancy categories in prescription drug labels.
Australia's categorization system takes into account birth defects, the effects around birth or when the mother gives birth, and problems that will arise later in the child's life due to the drug taken. The system places them into a category based on the severity of the consequences that the drug can have on the infant when it crosses the placenta.
== References ==
== Further reading == | Wikipedia/Drugs_in_pregnancy |
A pre-existing disease in pregnancy is a disease that is not directly caused by the pregnancy, in contrast to various complications of pregnancy, but which may become worse or be a potential risk to the pregnancy (such as causing pregnancy complications). A major component of this risk can result from the necessary use of drugs in pregnancy to manage the disease.
In such circumstances, women who wish to continue with a pregnancy require extra medical care, often from an interdisciplinary team. Such a team might include (besides an obstetrician) a specialist in the disorder and other practitioners (for example, maternal-fetal specialists or obstetric physicians, dieticians, etc.).
== Chronic hypertension ==
Chronic hypertension in pregnancy can lead to increased complications for both the mother and fetus. Maternal complications include superimposed pre-eclampsia and caesarean delivery. Fetal complications include preterm delivery, low birth weight, and death. Increasing rates of obesity and metabolic syndrome play a key role in the increased prevalence of chronic hypertension and associated complications. Women who have chronic hypertension before their pregnancy are at increased risk of complications such as premature birth, low birthweight or stillbirth. Women who have high blood pressure and had complications in their pregnancy have three times the risk of developing cardiovascular disease compared to women with normal blood pressure who had no complications in pregnancy. Monitoring pregnant women's blood pressure can help prevent both complications and future cardiovascular diseases. While high blood pressure treatment has been shown to decrease the incidence of severe hypertension during pregnancy, there was no significant difference in pregnancy complications (for example, superimposed pre-eclampsia, stillbrith/neonatal death, small for gestational age).
== Endocrine disorders ==
=== Diabetes mellitus ===
Diabetes mellitus and pregnancy deals with the interactions of diabetes mellitus (not restricted to gestational diabetes) and pregnancy. Risks for the child include miscarriage, growth restriction, growth acceleration, fetal obesity (macrosomia), polyhydramnios, and birth defects.
=== Thyroid disease ===
Thyroid disease in pregnancy can, if uncorrected, cause adverse effects on fetal and maternal well-being. The deleterious effects of thyroid dysfunction can also extend beyond pregnancy and delivery to affect neurointellectual development in the early life of the child. Demand for thyroid hormones is increased during pregnancy, which may cause a previously unnoticed thyroid disorder to worsen. The most effective way of screening for thyroid dysfunction is not known. A review found that more women were diagnosed with thyroid dysfunction when all pregnant women were tested instead of just testing those at 'high-risk' of thyroid problems (those with family history, signs or symptoms). Finding more women with thyroid dysfunction meant that the women could have treatment and management through their pregnancies. However, the outcomes of the pregnancies were surprisingly similar so more research is needed to look at the effects of screening all pregnant women for thyroid problems.
== Hypercoagulability ==
Hypercoagulability in pregnancy is the propensity of pregnant women to develop thrombosis (blood clots), such as a deep vein thrombosis with a potential subsequent pulmonary embolism. Pregnancy itself is a factor of hypercoagulability (pregnancy-induced hypercoagulability), as a physiologically adaptive mechanism to prevent postpartum bleeding. The pregnancy-associated hypercoagulability is attributed to an increased synthesis of coagulation factors, such as fibrinogen, by the liver through the effects of estrogen.
When combined with any additional underlying hypercoagulable state, the risk of thrombosis or embolism may become substantial. Multiple pre-existing genetic disorders can worsen the hypercoagulable state observed in pregnancy. Examples include:
Factor V Leiden
Prothrombin G20210A
Protein C deficiency
Protein S deficiency
Antithrombin III deficiency
== Infections ==
=== Vertically transmitted infections ===
Many infectious diseases have a risk of vertical transmission to the fetus, known as TORCH infections. Examples based on the TORCHES acronym include:
Toxoplasma
Other: Parvovirus B19, Zika, Chickenpox
Rubella
Cytomegalovirus
Herpes simplex or Neonatal herpes simplex
HIV
Syphilis
Infections in pregnancy also raise particular concerns about whether or not to use drugs in pregnancy (that is, antibiotics or antivirals) to treat them. For example, pregnant women who contract H1N1 influenza infection are recommended to receive antiviral therapy with either oseltamivir (which is the preferred medication) or zanamivir. Both amantadine and rimantadine have been found to be teratogenic and embryotoxic when given at high doses in animal studies.
=== Candidal vulvovaginitis ===
In pregnancy, changes in the levels of female sex hormones, such as estrogen, make a woman more likely to develop candidal vulvovaginitis. During pregnancy, the Candida fungus is more prevalent (common), and recurrent infection is also more likely. There is no clear evidence that treatment of asymptomatic candidal vulvovaginitis in pregnancy reduces the risk of preterm birth. Candidal vulvovaginitis in pregnancy should be treated with intravaginal clotrimazole or nystatin for at least 7 days.
=== Bacterial vaginosis ===
Bacterial vaginosis is an imbalance of naturally occurring bacterial flora in the vagina. Bacterial vaginosis occurring during pregnancy may increase the risk of pregnancy complications, most notably premature birth or miscarriage. However, this risk is small overall and appears more significant in women who have had such complications in an earlier pregnancy.
== Valvular heart disease ==
In the case of valvular heart disease in pregnancy, the maternal physiological changes in pregnancy confer additional load on the heart and may lead to complications.
In individuals who require an artificial heart valve, consideration must be made for deterioration of the valve over time (for bioprosthetic valves) versus the risks of blood clotting in pregnancy with mechanical valves with the resultant need of drugs in pregnancy in the form of anticoagulants.
== Other autoimmune disorders ==
=== Celiac disease ===
Untreated celiac disease can cause spontaneous abortion (miscarriage), intrauterine growth restriction, small for gestational age, low birthweight and preterm birth. Often, reproductive disorders are the only manifestation of undiagnosed celiac disease, and most cases are not recognized. Complications or failures of pregnancy cannot be explained simply by malabsorption, but by the autoimmune response elicited by the exposure to gluten, which causes damage to the placenta. The gluten-free diet avoids or reduces the risk of developing reproductive disorders in pregnant women with celiac disease. Also, pregnancy can be a trigger for the development of celiac disease in genetically susceptible women who are consuming gluten.
=== Systemic lupus erythematosus ===
Systemic lupus erythematosus and pregnancy confers an increased rate of fetal death in utero and spontaneous abortion (miscarriage), as well as of neonatal lupus.
=== Behçet's disease ===
Pregnancy does not worsen the course of Behçet's disease and may ameliorate it. Still, there is substantial variability in clinical course between patients and even for different pregnancies in the same patient. Also, the other way around, Behçet's disease confers an increased risk of pregnancy complications, miscarriage and Cesarean section.
=== Multiple sclerosis ===
Being pregnant decreases the risk of relapse in multiple sclerosis; however, during the first months after delivery, the risk increases. Overall, pregnancy does not seem to influence long-term disability. Multiple sclerosis does not increase the risk of congenital abnormality or miscarriage.
== Mental health ==
=== Depression in pregnancy ===
The effects of depression during pregnancy are difficult to parse from depression before pregnancy, as the symptoms of the two overlap. However, the biggest risk factor for depression during pregnancy is a prior history of depression. Most of the research is focused on the consequences of untreated depression regardless if the depression developed during pregnancy or if it was there before conception. Untreated depression has been linked to premature birth, low birth weight, fetal growth restriction, and postnatal complications. On the other hand, however, anti-depressant medications also come with a small risk of pre-term birth, low birth weight, and persistent pulmonary hypertension.
== Respiratory disease ==
=== Asthma ===
In the United States, the prevalence of asthma among pregnant women is between 8.4% and 8.8%. Asthma in pregnant women is strongly associated with multiple adverse health outcomes, including pre-eclampsia, preterm birth, and low birth weight. Other conditions such as gestational diabetes, placenta previa, and hemorrhage are inconsistently correlated to asthma. Additionally, women with Asthma face a higher likelihood of complications during labor and delivery, such as breech presentation and caesarean delivery. Poorly controlled and severe asthma may exacerbate conditions associated with maternal and neonate morbidity and mortality. Asthma treatment recommendations during pregnancy are similar to those in non-pregnant women.
As of 2018, Asthma was the most prevalent respiratory disorder to complicate pregnancy, remaining a high-risk condition despite therapeutic advancements. Preventing asthma exacerbations during pregnancy is crucial to reduce the risk of complications and poor outcomes.
==== The course of asthma during pregnancy ====
The course of asthma during pregnancy can vary, with some patients experiencing worsening symptoms while others see improvement.
As of 2006, it was believed the course of asthma during pregnancy varied with a similar proportion of women improving, remaining stable, or worsening. However, as of 2013, it was found that deterioration may manifest in approximately 20% of women, improvement in around 30%, and no significant change observed in the remaining 50%.
== Structural (congenital) abnormalities of the uterus ==
Structural abnormalities of the uterus include conditions like a septate uterus, a bicornuate uterus, an arcuate uterus, and a didelphys uterus. Most of these abnormalities occur when the Müllerian ducts are fused improperly or incompletely. Women with these congenital abnormalities are usually unaware, as these conditions do not usually present any symptoms. During pregnancy, these conditions are associated with infertility, preterm birth, fetal malpresentation, and early miscarriages. Among these uterine abnormalities, those with canalization defects, i.e., not having a normal uterine canal, such as septate defects, have the worst pregnancy outcomes. Surgical treatment is only recommended for individuals who have had recurrent miscarriages and have a septate uterus; however, the risks of surgery, especially scarring of the womb, should be considered. Further evidence from randomized controlled trials is required to establish conclusively whether surgery is the better option when its risks and rewards are compared with the risks of adverse pregnancy outcomes.
== Others ==
The following conditions may also become worse or be a potential risk to the pregnancy:
Cancer
Chronic hypertension
Cirrhosis
Congenital disorders that may be passed on to offspring
Heart defects, especially primary pulmonary hypertension and Eisenmenger's syndrome
Kidney disorders
Mental health.
Depression has been linked to higher rates of preterm delivery.
Respiratory disorders and diseases (associated, for example, with placental abruption)
Asthma
Seizure disorders
Structural abnormalities in the cervix
Structural abnormalities in the uterus
Viral hepatitis
== References == | Wikipedia/Pre-existing_disease_in_pregnancy |
Valvular heart disease is any cardiovascular disease process involving one or more of the four valves of the heart (the aortic and mitral valves on the left side of heart and the pulmonic and tricuspid valves on the right side of heart). These conditions occur largely as a consequence of aging, but may also be the result of congenital (inborn) abnormalities or specific disease or physiologic processes including rheumatic heart disease and pregnancy.
Anatomically, the valves are part of the dense connective tissue of the heart known as the cardiac skeleton and are responsible for the regulation of blood flow through the heart and great vessels. Valve failure or dysfunction can result in diminished heart functionality, though the particular consequences are dependent on the type and severity of valvular disease. Treatment of damaged valves may involve medication alone, but often involves surgical valve repair or valve replacement.
== Classification ==
Stenosis and insufficiency/regurgitation represent the dominant functional and anatomic consequences associated with valvular heart disease. Irrespective of disease process, alterations to the valve occur that produce one or a combination of these conditions. Insufficiency and regurgitation are synonymous terms that describe an inability of the valve to prevent backflow of blood as leaflets of the valve fail to join (coapt) correctly. Stenosis is characterized by a narrowing of the valvular orifice that prevents adequate outflow of blood. Stenosis can also result in insufficiency if thickening of the annulus or leaflets results in inappropriate leaf closure.
=== Aortic and mitral valve disorders ===
Aortic and mitral valve disorders are left heart diseases that are more prevalent than diseases of the pulmonary or tricuspid valve in the right heart due to the higher pressures in the left heart.
Stenosis of the aortic valve is characterized by a thickening of the valvular annulus or leaflets that limits the ability of blood to be ejected from the left ventricle into the aorta. Stenosis is typically the result of valvular calcification but may be the result of a congenitally malformed bicuspid aortic valve. This defect is characterized by the presence of only two valve leaflets. It may occur in isolation or in concert with other cardiac anomalies.
Aortic insufficiency, or regurgitation, is characterized by an inability of the valve leaflets to appropriately close at the end systole, thus allowing blood to flow inappropriately backward into the left ventricle. Causes of aortic insufficiency in the majority of cases are unknown, or idiopathic. It may be the result of connective tissue or immune disorders, such as Marfan syndrome or systemic lupus erythematosus, respectively. Processes that lead to aortic insufficiency usually involve dilation of the valve annulus, thus displacing the valve leaflets, which are anchored in the annulus.
Mitral stenosis is caused largely by rheumatic heart disease, though is rarely the result of calcification. In some cases, vegetations form on the mitral leaflets as a result of endocarditis, an inflammation of the heart tissue. Mitral stenosis is uncommon and not as age-dependent as other types of valvular disease.
Mitral insufficiency can be caused by dilation of the left heart, often a consequence of heart failure. In these cases, the left ventricle of the heart becomes enlarged and causes displacement of the attached papillary muscles, which control the mitral.
=== Pulmonary and tricuspid valve disorders ===
Pulmonary and tricuspid valve diseases are right heart diseases. Pulmonary valve diseases are the least common heart valve disease in adults.
Pulmonary valve stenosis is often the result of congenital malformations and is observed in isolation or as part of a larger pathologic process, as in Tetralogy of Fallot, Noonan syndrome, and congenital rubella syndrome. Unless the degree of stenosis is severe, individuals with pulmonary stenosis usually have excellent outcomes and better treatment options. Often patients do not require intervention until later in adulthood as a consequence of calcification that occurs with aging.
Pulmonary valve insufficiency occurs commonly in healthy individuals to a very mild extent and does not require intervention. More appreciable insufficiency is typically the result of damage to the valve due to cardiac catheterization, intra-aortic balloon pump insertion, or other surgical manipulations. Additionally, insufficiency may be the result of carcinoid syndrome, inflammatory processes such a rheumatoid disease or endocarditis, or congenital malformations. It may also be secondary to severe pulmonary hypertension.
Tricuspid valve stenosis without co-occurrent regurgitation is highly uncommon and typically the result of rheumatic disease. It may also be the result of congenital abnormalities, carcinoid syndrome, obstructive right atrial tumors (typically lipomas or myxomas), or hypereosinophilic syndromes.
Minor tricuspid insufficiency is common in healthy individuals. In more severe cases it is a consequence of dilation of the right ventricle, leading to displacement of the papillary muscles which control the valve's ability to close. Dilation of the right ventricle occurs secondary to ventricular septal defects, right to left shunting of blood, eisenmenger syndrome, hyperthyroidism, and pulmonary stenosis. Tricuspid insufficiency may also be the result of congenital defects of the tricuspid valve, such as Ebstein's anomaly.
== Signs and symptoms ==
=== Aortic stenosis ===
Symptoms of aortic stenosis may include heart failure symptoms, such as dyspnea on exertion (most frequent symptom), orthopnea and paroxysmal nocturnal dyspnea, angina pectoris, and syncope, usually exertional.
Medical signs of aortic stenosis include pulsus parvus et tardus, that is, diminished and delayed carotid pulse, fourth heart sound, decreased A2 sound, sustained apex beat, precordial thrill. Auscultation may reveal a systolic murmur of a harsh crescendo-decrescendo type, heard in 2nd right intercostal space and radiating to the carotid arteries.
=== Aortic regurgitation ===
Patients with aortic regurgitation may experience heart failure symptoms, such as dyspnea on exertion, orthopnea and paroxysmal nocturnal dyspnea, palpitations, and angina pectoris. In acute cases patients may experience cyanosis and circulatory shock.
Medical signs of aortic regurgitation include increased pulse pressure by increased systolic and decreased diastolic blood pressure, but these findings may not be significant if acute. The patient may have a diastolic decrescendo murmur best heard at left sternal border, water hammer pulse, Austin Flint murmur, and a displaced apex beat down and to the left. A third heart sound may be present
=== Mitral stenosis ===
Patients with mitral stenosis may present with heart failure symptoms, such as dyspnea on exertion, orthopnea and paroxysmal nocturnal dyspnea, palpitations, chest pain, hemoptysis, thromboembolism, or ascites and edema (if right-sided heart failure develops). Symptoms of mitral stenosis increase with exercise and pregnancy
On auscultation of a patient with mitral stenosis, typically the most prominent sign is a loud S1. Another finding is an opening snap followed by a low-pitched diastolic rumble with presystolic accentuation. The opening snap follows closer to the S2 heart tone with worsening stenosis. The murmur is heard best with the bell of the stethoscope lying on the left side and its duration increases with worsening disease. Advanced disease may present with signs of right-sided heart failure such as parasternal heave, jugular venous distension, hepatomegaly, ascites and/or pulmonary hypertension (presenting with a loud P2). Signs increase with exercise and pregnancy.
=== Mitral regurgitation ===
Patients with mitral regurgitation may present with heart failure symptoms, such as dyspnea on exertion, orthopnea and paroxysmal nocturnal dyspnea, palpitations, or pulmonary edema.
On auscultation of a patient with mitral stenosis, there may be a holosystolic murmur at the apex, radiating to the back or clavicular area, a third heart sound, and a loud, palpable P2, heard best when lying on the left side. Patients also commonly have atrial fibrillation. Patients may have a laterally displaced apex beat, often with heave In acute cases, the murmur and tachycardia may be only distinctive signs.
=== Tricuspid regurgitation ===
Patients with tricuspid regurgitation may experience symptoms of right-sided heart failure, such as ascites, hepatomegaly, edema and jugular venous distension.
Signs of tricuspid regurgitation include pulsatile liver, prominent V waves and rapid y descents in jugular venous pressure. Auscultatory findings include inspiratory third heart sound at left lower sternal border (LLSB) and a blowing holosystolic murmur at LLSB, intensifying with inspiration, and decreasing with expiration and Valsalva maneuver. Patients may have a parasternal heave along LLSB. Atrial fibrillation is usually present in patients with tricuspid regurgitation
== Causes ==
=== Calcific disease ===
Calcification of the leaflets of the aortic valve is a common with increasing age, but the mechanism is likely to be more related to increased lipoprotein deposits and inflammation than the "wear and tear" of advance age. Aortic stenosis due to calcification of tricuspid aortic valve with age comprises >50% of the disease. Aortic stenosis due to calcification of a bicuspid aortic valve comprises about 30–40% of the disease. Hypertension, diabetes mellitus, hyperlipoproteinemia and uremia may speed up the process of valvular calcification.
=== Dysplasia ===
Heart valve dysplasia is an error in the development of any of the heart valves, and a common cause of congenital heart defects in humans as well as animals; tetralogy of Fallot is a congenital heart defect with four abnormalities, one of which is stenosis of the pulmonary valve. Ebstein's anomaly is an abnormality of the tricuspid valve, and its presence can lead to tricuspid valve regurgitation. A bicuspid aortic valve is an aortic valve with only 2 cusps as opposed to the normal 3. It is present in about 0.5% to 2% of the general population and causes increased calcification due to higher turbulent flow through the valve.
=== Connective tissue disorders ===
Marfan's Syndrome is a connective tissue disorder that can lead to chronic aortic or mitral regurgitation. Osteogenesis imperfecta is a disorder in formation of type I collagen and can also lead to chronic aortic regurgitation.
=== Inflammatory disorders ===
Inflammation of the heart valves due to any cause is called valvular endocarditis; this is usually due to bacterial infection but may also be due to cancer (marantic endocarditis), certain autoimmune conditions (Libman-Sacks endocarditis, seen in systemic lupus erythematosus) and hypereosinophilic syndrome (Loeffler endocarditis). Endocarditis of the valves can lead to regurgitation through that valve, which is seen in the tricuspid, mitral, and aortic valves. Certain medications have been associated with valvular heart disease, most prominently ergotamine derivatives pergolide and cabergoline.
Valvular heart disease resulting from rheumatic fever is referred to as rheumatic heart disease. Acute rheumatic fever, which frequently manifests with carditis and valvulitis, is a late sequela of Group A beta-hemolytic streptococcus infection in the throat, often lagging the initial infection by weeks to months. Cardiac involvement is dependent on the cross-reaction of antibodies directed against M proteins produced by bacteria with human proteins present in the myocardium or endocardium (although acute rheumatic fever may present as pancarditis with additional involvement of the pericardium). This results in generalized inflammation in the heart, producing acute erosions and vegetations with fibrin deposition in the mitral valve that may be followed by chronic changes over years to decades, including shortening of the chordae tendinae and thickening or fusion of the mitral leaflets, leading to a severely compromised "buttonhole" or "fish mouth" valve.
In 70% of cases rheumatic heart disease involves only the mitral valve, while 25% of cases involve both the aortic and mitral valves. Involvement of other heart valves without damage to the mitral is exceedingly rare. Mitral stenosis is almost always caused by rheumatic heart disease. Less than 10% of aortic stenosis is caused by rheumatic heart disease. Rheumatic fever can also cause chronic mitral and aortic regurgitation.
While developed countries once had a significant burden of rheumatic fever and rheumatic heart disease, medical advances and improved social conditions have dramatically reduced their incidence. Many developing countries, as well as indigenous populations within developed countries, still carry a significant burden of rheumatic fever and rheumatic heart disease and there has been a resurgence in efforts to eradicate the diseases in these populations. Among persons who have experienced rheumatic fever, long-term intramuscular antibiotic therapy is used as secondary prophylaxis against additional streptococcal infections, which can contribute to progression of rheumatic heart disease. In people with severe valvular disease, however, short-term risks of cardiovascular compromise after intramuscular injections may outweigh the benefits, and oral therapy may be considered instead of IM injections in this subset of patients.
Diseases of the aortic root can cause chronic aortic regurgitation. These diseases include syphilitic aortitis, Behçet's disease, and reactive arthritis.
=== Heart disease ===
Tricuspid regurgitation is usually secondary to right ventricular dilation which may be due to left ventricular failure (the most common cause), right ventricular infarction, inferior myocardial infarction, or cor pulmonale Other causes of tricuspid regurgitation include carcinoid syndrome and myxomatous degeneration.
== Diagnosis ==
=== Aortic stenosis ===
Patients with aortic stenosis can have chest X-ray findings showing dilation of the ascending aorta, but they may also have a completely normal chest X-ray. Direct visualization of calcifications on chest X-ray is uncommon. Other findings include dilation of the left ventricle. ECG typically shows left ventricular hypertrophy in patients with severe stenosis, but it may also show signs of left heart strain. Echocardiography is the diagnostic gold standard, which shows left ventricular hypertrophy, leaflet calcification, and abnormal leaflet closure.
=== Aortic regurgitation ===
Chest X-ray is not as sensitive as other tests, but it may show aortic root dilation (especially in causes involving the aortic root) and apex displacement. An ECG may show left ventricular hypertrophy and signs of left heart strain. Left axis deviation can be a sign of advanced disease. An echocardiogram can be helpful in determining the root cause of the disease, as it will clearly show aortic root dilation or dissection if it exists. Typically the pump function of the heart during systole is normal, but an echocardiogram will show flow reversal during diastole. This disease is classified using regurgitant fraction (RF), or the amount of volume that flows back through the valve divided by the total forward flow through the valve during systole. Severe disease has an RF of >50%, while progressive aortic regurgitation has an RF of 30–49%.
=== Mitral stenosis ===
Chest x-ray in mitral stenosis will typically show an enlarged left atrium, and may show dilation of the pulmonary veins. ECG can show left atrial enlargement, due to increased pressures in the left atrium. Echocardiography is helpful in determining the severity of the disease by estimating the pulmonary artery systolic pressure. This test can also show leaflet calcification and the pressure gradient over the mitral valve. Severe mitral stenosis is defined as a mitral valve area <1.5 cm2. Progressive mitral stenosis has a normal valve area but will have increased flow velocity across the mitral valve.
=== Mitral regurgitation ===
Chest x-ray in mitral regurgitation can show an enlarged left atrium, as well as pulmonary venous congestion. It may also show valvular calcifications specifically in combined mitral regurgitation and stenosis due to rheumatic heart disease. ECG typically shows left atrial enlargement, but can also show right atrial enlargement if the disease is severe enough to cause pulmonary hypertension. Echocardiography is useful in visualizing the regurgitant flow and calculating the RF. It can also be used to determine the degree of calcification, and the function and closure of the valve leaflets. Severe disease has an RF of >50%, while progressive mitral regurgitation has an RF of <50%.
== Treatment ==
Some of the most common treatments of valvular heart disease are avoiding smoking and excessive alcohol consumption, antibiotics, antithrombotic medications such as aspirin, anticoagulants, balloon dilation, and water pills.
In some cases, surgery may be necessary.
=== Aortic stenosis ===
Treatment of aortic stenosis is not necessary in asymptomatic patients, unless the stenosis is classified as severe based on valve hemodynamics. Both asymptomatic severe and symptomatic aortic stenosis are treated with aortic valve replacement (AVR) surgery. AVR surgery can be performed using mechanical or tissue valves depending on age and other relevant factors. Trans-catheter Aortic Valve Implantation (TAVI) is an alternative to AVR and is recommended in high risk patients who may not be suitable for surgical AVR. Any angina is treated with short-acting nitrovasodilators, beta-blockers and/or calcium blockers, although nitrates can drastically decrease blood pressure in patients with severe aortic stenosis and are therefore contraindicated. Any hypertension is treated aggressively, but caution must be taken in administering beta-blockers. Any heart failure is treated with digoxin, diuretics, nitrovasodilators and, if not contraindicated, cautious inpatient administration of ACE inhibitors. Moderate stenosis is monitored with echocardiography every 1–2 years, possibly with supplementary cardiac stress test. Severe stenosis should be monitored with echocardiography every 3–6 months. In patients with non-severe asymptomatic aortic valve stenosis, increased age- and sex adjusted N-terminal pro-brain natriuretic peptide (NT-proBNP) levels alone and combined with a 50% or greater increase from baseline had been found associated with increased event rates of aortic valve stenosis related events (cardiovascular death, hospitalization with heart failure due to progression of aortic valve stenosis, or aortic valve replacement surgery). In patients with non-severe asymptomatic aortic valve stenosis and no overt coronary artery disease, the increased troponin T (above 14 pg/mL) was found associated with an increased 5-year event rate of ischemic cardiac events (myocardial infarction, percutaneous coronary intervention, or coronary artery bypass surgery).
=== Aortic regurgitation ===
Aortic regurgitation is treated with aortic valve replacement, which is recommended in patients with symptomatic severe aortic regurgitation. Aortic valve replacement is also recommended in patients that are asymptomatic but have chronic severe aortic regurgitation and left ventricular ejection fraction of less than 50%. Hypertension is treated in patients with chronic aortic regurgitation, with the anti-hypersensives of choice being calcium channel blockers, ACE inhibitors, or ARBs. Also, endocarditis prophylaxis is indicated before dental, gastrointestinal or genitourinary procedures. Mild to moderate aortic regurgitation should be followed with echocardiography and a cardiac stress test once every 1–2 years. In severe moderate/severe cases, patients should be followed with echocardiography and cardiac stress test and/or isotope perfusion imaging every 3–6 months.
=== Mitral stenosis ===
For patients with symptomatic severe mitral stenosis, percutaneous balloon mitral valvuloplasty (PBMV) is recommended. If this procedure fails, then it may be necessary to undergo mitral valve surgery, which may involve valve replacement, repair, or commisurotomy. Anticoagulation is recommended for patients that have mitral stenosis in the setting of atrial fibrillation or a previous embolic event. No therapy is required for asymptomatic patients. Diuretics may be used to treat pulmonary congestion or edema.
=== Mitral regurgitation ===
Surgery is recommended for chronic severe mitral regurgitation in symptomatic patients with left ventricular ejection fraction (LVEF) of greater than 30%, and asymptomatic patients with LVEF of 30-60% or left ventricular end diastolic volume (LVEDV) > 40%. Surgical repair of the leaflets is preferred to mitral valve replacement as long as the repair is feasible. Mitral regurgitation may be treated medically with vasodilators, diuretics, digoxin, antiarrhythmics, and chronic anticoagulation. Mild to moderate mitral regurgitation should be followed with echocardiography and cardiac stress test every 1–3 years. Severe mitral regurgitation should be followed with echocardiography every 3–6 months.
== Epidemiology ==
In the United States, about 2.5% of the population has moderate to severe valvular heart disease. The prevalence of these diseases increase with age, and 75 year-olds in the United States have a prevalence of about 13%. In industrially underdeveloped regions, rheumatic disease is the most common cause of valve diseases, and it can cause up to 65% of the valve disorders seen in these regions.
=== Aortic stenosis ===
Aortic stenosis is typically the result of aging, occurring in 12.4% of the population over 75 years of age, and represents the most common cause of outflow obstruction in the left ventricle. Bicuspid aortic valves are found in up to 1% of the population, making it one of the most common cardiac abnormalities.
=== Aortic regurgitation ===
The prevalence of aortic regurgitation also increases with age. Moderate to severe disease has a prevalence of 13% in patients between the ages of 55 and 86. This valve disease is primarily caused by aortic root dilation, but infective endocarditis has been an increased risk factor. It has been found to be the cause of aortic regurgitation in up to 25% of surgical cases.
=== Mitral stenosis ===
Mitral stenosis is caused almost exclusively by rheumatic heart disease, and has a prevalence of about 0.1% in the United States. Mitral stenosis is the most common valvular heart disease in pregnancy.
=== Mitral regurgitation ===
Mitral regurgitation is significantly associated with normal aging, rising in prevalence with age. It is estimated to be present in over 9% of people over 75.
== Special populations ==
=== Pregnancy ===
The evaluation of individuals with valvular heart disease who are or wish to become pregnant is a difficult issue. Issues that have to be addressed include the risks during pregnancy to the mother and the developing fetus by the presence of maternal valvular heart disease as a pre-existing disease in pregnancy.
Normal physiological changes during pregnancy require, on average, a 50% increase in circulating blood volume that is accompanied by an increase in cardiac output that usually peaks between the midportion of the second and third trimesters. The increased cardiac output is due to an increase in the stroke volume, and a small increase in heart rate, averaging 10 to 20 beats per minute. Additionally uterine circulation and endogenous hormones cause systemic vascular resistance to decrease and a disproportionately lowering of diastolic blood pressure causes a wide pulse pressure. Inferior vena caval
obstruction from a gravid uterus in the supine position can result in an abrupt decrease in cardiac preload, which leads to hypotension with weakness and lightheadedness. During labor and delivery cardiac output increases more in part due to the associated anxiety and pain, as well as due to uterine contractions which will cause an increase in systolic and diastolic blood pressure.
Valvular heart lesions associated with high maternal and fetal risk during pregnancy include:
Severe aortic stenosis with or without symptoms
Aortic regurgitation with NYHA functional class III-IV symptoms
Mitral stenosis with NYHA functional class II-IV symptoms
Mitral regurgitation with NYHA functional class III-IV symptoms
Aortic and/or mitral valve disease resulting in severe pulmonary hypertension (pulmonary pressure greater than 75% of systemic pressures)
Aortic and/or mitral valve disease with severe LV dysfunction (EF less than 0.40)
Mechanical prosthetic valve requiring anticoagulation
Marfan syndrome with or without aortic regurgitation
In individuals who require an artificial heart valve, consideration must be made for deterioration of the valve over time (for bioprosthetic valves) versus the risks of blood clotting in pregnancy with mechanical valves with the resultant need of drugs in pregnancy in the form of anticoagulation.
== References == | Wikipedia/Rheumatic_heart_disease |
The ostium primum atrial septal defect is a defect in the atrial septum at the level of the tricuspid and mitral valves. This is sometimes known as an endocardial cushion defect because it often involves the endocardial cushion, which is the portion of the heart where the atrial septum meets the ventricular septum and the mitral valve meets the tricuspid valve.
Endocardial cushion defects are associated with abnormalities of the atrioventricular valves (the mitral valve and the tricuspid valve). These include the cleft mitral valve, and the single atrioventricular valve (a single large, deformed valve that flows into both the right ventricle and the left ventricle).
Endocardial cushion defects are the most common congenital heart defect that is associated with Down syndrome.
== Signs and symptoms ==
On ECG a left axis deviation is generally found in ostium primum ASD, but an RSR pattern (M pattern) in V1 is characteristic. Fixed splitting of the second heart sound (S2) occurs because of equal filling of the left and right atria during all phases of the respiratory cycle.
Patients with atrial Septal Defects may have atrial fibrillation, atrial tachycardia, or atrial flutter, but these abnormal heart rhythms are not usually seen until the affected individual grows older. Features also seen on the ECG include right atrial enlargement and varying degrees of atrioventricular block. When a person is suspected of having an ASD based on the findings of an incomplete right bundle branch block with a rSr' or rSR', the frontal plane QRS should be examined. The frontal plane QRS is the most helpful clue to distinguish between an ostium secundum ASD and an ostium primum ASD. In primum defects left axis deviation is seen in most patients with an axis of > -30 degrees and very few patients have right axis deviation. In contrast ostium secundum defects have an axis between 0 degrees and 180 degrees with most cases to the right of 100 degrees.
In the ECG above, you can see an example of the rSR' pattern in V1 with a R' greater than S with T wave inversion which is commonly seen in volume overload right ventricular hypertrophy.
== Diagnosis ==
=== Classification ===
A defect in the ostium primum is occasionally classified as an atrial septal defect, but it is more commonly classified as an atrioventricular septal defect.
== Treatment ==
Hemodynamically significant ASDs (flow ratio 1.5:1) are large enough to be closed surgically. The long term prognosis is excellent. Pulmonary hypertension with shunt reversal is a contraindication for surgery, however the pulmonary hypertension can frequently be treated with medicines. The hole can then be closed safely with a good long term prognosis.
== References ==
Notes
== External links ==
This article incorporates text available under the CC BY-SA 3.0 license. | Wikipedia/Ostium_primum_atrial_septal_defect |
Bradycardia, also called bradyarrhythmia, is a resting heart rate under 60 beats per minute (BPM). While bradycardia can result from various pathological processes, it is commonly a physiological response to cardiovascular conditioning or due to asymptomatic type 1 atrioventricular block.
Resting heart rates of less than 50 BPM are often normal during sleep in young and healthy adults and athletes. In large population studies of adults without underlying heart disease, resting heart rates of 45–50 BPM appear to be the lower limits of normal, dependent on age and sex. Bradycardia is most likely to be discovered in the elderly, as age and underlying cardiac disease progression contribute to its development.
Bradycardia may be associated with symptoms of fatigue, dyspnea, dizziness, confusion, and syncope due to reduced blood flow to the brain. The types of symptoms often depend on the etiology of the slow heart rate, classified by the anatomical location of a dysfunction within the cardiac conduction system. Generally, these classifications involve the broad categories of sinus node dysfunction, atrioventricular block, and other conduction tissue diseases. However, bradycardia can also result without dysfunction of the conduction system, arising secondarily to medications, including beta blockers, calcium channel blockers, antiarrythmics, and other cholinergic drugs. Excess vagus nerve activity or carotid sinus hypersensitivity are neurological causes of transient symptomatic bradycardia. Hypothyroidism and metabolic derangements are other common extrinsic causes of bradycardia.
The management of bradycardia is generally reserved for people with symptoms, regardless of minimum heart rate during sleep or the presence of concomitant heart rhythm abnormalities (See: Sinus pause), which are common with this condition. Untreated sinus node dysfunction increases the risk of heart failure and syncope, sometimes warranting definitive treatment with an implanted pacemaker. In atrioventricular causes of bradycardia, permanent pacemaker implantation is often required when no reversible causes of disease are found. In both SND and atrioventricular blocks, there is little role for medical therapy unless a person is hemodynamically unstable, which may require the use of medications such as atropine and isoproterenol and interventions such as transcutenous pacing until such time that an appropriate workup can be undertaken and long-term treatment selected. While asymptomatic bradycardias rarely require treatment, consultation with a physician is recommended, especially in the elderly.
The term "relative bradycardia" can refer to a heart rate lower than expected in a particular disease state, often a febrile illness. Chronotropic incompetence (CI) refers to an inadequate rise in heart rate during periods of increased demand, often due to exercise, and is an important sign of SND and an indication for pacemaker implantation.
The word "bradycardia" is from the Greek βραδύς bradys "slow", and καρδία kardia "heart".
== Normal cardiac conduction ==
The heart is a specialized muscle containing repeating units of cardiomyocytes, or heart muscle cells. Like most cells, cardiomyocytes maintain a highly regulated negative voltage at rest and are capable of propagating action potentials, much like neurons. While at rest, the negative cellular voltage of a cardiomyocyte can be raised above a certain threshold (so-called depolarization) by an incoming action potential, causing the myocyte to contract. When these contractions occur in a coordinated fashion, the atria and ventricles of the heart will pump, delivering blood to the rest of the body.
Normally, the origination of the action potential causing cardiomyocyte contraction originates from the sinoatrial node (SA node). This collection of specialized conduction tissue is located in the right atrium, near the entrance of the superior vena cava. The SA node contains pacemaker cells that demonstrate "automaticity" and can generate impulses that travel through the heart and create a steady heartbeat.
At the beginning of the cardiac cycle, the SA node generates an electrical action potential that spreads across the right and left atria, causing the atrial contraction of the cardiac cycle. This electrical impulse carries on to the atrioventricular node (AV node), another specialized grouping of cells located in the base of the right atrium, which is the only anatomically normal electrical connection between the atria and ventricles. Impulses coursing through the AV node are slowed before carrying on to the ventricles, allowing for appropriate filling of the ventricles before contraction. The SA and AV nodes are both closely regulated by the autonomic nervous system's fibres, allowing for adjustment of cardiac output by the central nervous system in times of increased metabolic demand.
Following slowed conduction through the atrioventricular node, the action potential produced initially at the SA node now flows through the His-Purkinje system. The bundle of His originates in the AV node and rapidly splits into a left and right branch, each destined for a different ventricle. Finally, these bundle branches terminate in the small Purkinje fibers that innervate myocardial tissue. The His-Purkinje system conducts action potentials much faster than can be propagated between myocardial cells, allowing the entire ventricular myocardium to contract in less time, improving pump function.
== Classification ==
Most pathological causes of bradycardia result from damage to this normal cardiac conduction system at various levels: the sinoatrial node, the atrioventricular node, or damage to conduction tissue between or after these nodes.
=== Sinus node ===
Bradycardia caused by the alterations of sinus node activity is divided into three types.
==== Sinus bradycardia ====
Sinus bradycardia is a sinus rhythm of less than 50 BPM. Cardiac action potentials are generated from the SA node and propagated through an otherwise normal conduction system, but they occur at a slow rate. It is a common condition found in both healthy individuals and those considered well-conditioned athletes. Studies have found that 50–85% of conditioned athletes have benign sinus bradycardia, as compared to 23% of the general population studied. The heart muscle of athletes has a higher stroke volume, requiring fewer contractions to circulate the same volume of blood. Asymptomatic sinus bradycardia decreases in prevalence with age.
==== Sinus arrhythmia ====
Sinus arrhythmias are heart rhythm abnormalities characterized by variations in the cardiac cycle length over 120 milliseconds (longest cycle - shortest cycle). These are the most common type of arrhythmia in the general population and usually have no significant consequences. They typically occur in the young, athletes or after administration of medications such as morphine. The types of sinus arrhythmia are separated into the respiratory and non-respiratory categories.
===== Respiratory sinus arrhythmia =====
Respiratory sinus arrhythmia refers to the physiologically normal variation in heart rate due to breathing. During inspiration, vagus nerve activity decreases, reducing parasympathetic innervation of the sinoatrial node and causing an increase in heart rate. During expiration, heart rates fall due to the converse occurring.
===== Non-respiratory sinus arrhythmia =====
Non-respiratory causes of sinus arrhythmia include sinus pause, sinus arrest, and sinoatrial exit block. Sinus pause and arrest involve slowing or arresting of automatic impulse generation from the sinus node. This can lead to asystole or cardiac arrest if ventricular escape rhythms do not create backup sources of cardiac action potentials.
Sinoatrial exit block is a similar non-respiratory phenomenon of temporarily lost sinoatrial impulses. However, in contrast to a sinus pause, the action potential is still generated at the SA node but is either unable to leave or delayed from leaving the node, preventing or delaying atrial depolarization and subsequent ventricular systole. Therefore, the length of the pause in heartbeats is usually a multiple of the P-P interval, as seen on electrocardiography. Like a sinus pause, a sinoatrial exit block can be symptomatic, especially with prolonged pause length.
==== Sinus node dysfunction ====
A syndrome of intrinsic disease of the sinus node, referred to as sick sinus syndrome or sinus node dysfunction, covers conditions that include symptomatic sinus bradycardia or persistent chronotropic incompetence, sinoatrial block, sinus arrest, and tachycardia-bradycardia syndrome. These conditions can be caused by damage to the native sinus node itself and are frequently accompanied by damaged AV node conduction and reduced backup pacemaker activity. The condition can also be caused by dysfunction of the autonomic nervous system that regulates the node and is commonly exacerbated by medications.
=== Atrioventricular node ===
Bradycardia can also result from the inhibition of the flow of action potentials through the atrioventricular (AV) node. While this can be normal in young people due to excessive vagus nerve tone, symptomatic bradycardia due to AV node dysfunction in older people is commonly due to structural heart disease, myocardial ischemia, or age-related fibrosis.
==== Atrioventricular block ====
Atrioventricular blocks are divided into three categories, ranked by severity. AV block is diagnosed via surface ECG, which is usually sufficient to locate the causal lesion of the block without the need for an invasive electrophysiology study.
In 1st degree AV block, electrical impulses originating in the SA node (or other ectopic focus above the ventricles) are conducted with significant delay through the AV node. This condition is diagnosed via ECG, with PR intervals in excess of 200 milliseconds. The PR interval represents the length of time between the start of atrial depolarization and the start of ventricular depolarization, representing the flow of electrical impulses between the SA and AV nodes. Despite the term "block," no impulses are fully lost in this conduction but are merely delayed. The location of the causal lesion can be anywhere between the AV node and the His-Purkinje system but is most commonly found in the AV node itself. Generally, isolated PR prolongation in 1st degree AV block is not associated with increased mortality or hospitalization.
2nd degree AV block is characterized by intermittently lost conduction of impulses between the SA node and the ventricles. 2nd degree block is classified into two types. Mobitz type 1 block, otherwise known by the eponym Wenckebach, classically demonstrates grouped patterns of heartbeats on ECG. Throughout the group, the PR interval gradually lengthens until a dropped conduction occurs, resulting in no QRS complex seen on surface ECG following the last P wave. After a delay, the grouping repeats, with the PR interval shortening again to baseline. Type 1 2nd degree AV block due to disease in the AV node (as opposed to in the His-purkinje system) rarely needs intervention with pacemaker implantation.
2nd degree, Mobitz type 2 AV block is another phenomenon of intermittently dropped QRS complexes after characteristic groupings of beats seen on surface ECG. The PR and RR intervals are consistent in this condition, followed by a sudden AV block and dropped QRS complex. Because type 2 blocks are typically due to lesions below the AV node, the ability for ventricular escape rhythms to maintain cardiac output is compromised. Permanent pacemaker implantation is often required.
==== Junctional rhythms ====
An AV-junctional rhythm, or atrioventricular nodal bradycardia, is usually caused by the absence of the electrical impulse from the sinus node. This usually appears on an electrocardiogram with a normal QRS complex accompanied by an inverted P wave either before, during, or after the QRS complex.
An AV-junctional escape beat is a delayed heartbeat originating from an ectopic focus somewhere in the AV junction. It occurs when the rate of depolarization of the SA node falls below the rate of the AV node. This dysrhythmia may also occur when the electrical impulses from the SA node fail to reach the AV node because of SA or AV block. This is a protective mechanism for the heart to compensate for an SA node that is no longer handling the pacemaking activity and is one of a series of backup sites that can take over pacemaker function when the SA node fails to do so. This would present with a longer PR interval. An AV-junctional escape complex is a normal response that may result from excessive vagal tone on the SA node. Pathological causes include sinus bradycardia, sinus arrest, sinus exit block, or AV block.
=== Ventricular ===
Idioventricular rhythm, also known as atrioventricular bradycardia or ventricular escape rhythm, is a heart rate of less than 50 BPM. This is a safety mechanism when a lack of electrical impulse or stimuli from the atrium occurs. Impulses originating within or below the bundle of His in the AV node will produce a wide QRS complex with heart rates between 20 and 40 BPM. Those above the bundle of His, also known as junctional, will typically range between 40 and 60 BPM with a narrow QRS complex. In a third-degree heart block, about 61% take place at the bundle branch-Purkinje system, 21% at the AV node, and 15% at the bundle of His. AV block may be ruled out with an ECG indicating "a 1:1 relationship between P waves and QRS complexes." Ventricular bradycardias occurs with sinus bradycardia, sinus arrest, and AV block. Treatment often consists of the administration of atropine and cardiac pacing.
=== Infantile ===
For infants, bradycardia is defined as a heart rate less than 100 BPM (normal is around 120–160 BPM). Premature babies are more likely than full-term babies to have apnea and bradycardia spells; their cause is not clearly understood. The spells may be related to centers inside the brain that regulate breathing which may not be fully developed. Touching the baby gently or rocking the incubator slightly will almost always get the baby to start breathing again, which increases the heart rate. The neonatal intensive-care unit standard practice is to electronically monitor the heart and lungs.
== Causes ==
Bradycardia arrhythmia may have many causes, both cardiac and non-cardiac.
Non-cardiac causes are usually secondary and can involve recreational drug use or abuse, metabolic or endocrine issues, especially hypothyroidism, an electrolyte imbalance, neurological factors, autonomic reflexes, situational factors, such as prolonged bed rest, and autoimmunity. At rest, although tachycardia is more commonly seen in fatty acid oxidation disorders, acute bradycardia can occur more rarely.
Cardiac causes include acute or chronic ischemic heart disease, vascular heart disease, valvular heart disease, or degenerative primary electrical disease. Ultimately, the causes act by three mechanisms: depressed automaticity of the heart, conduction block, or escape pacemakers and rhythms.
In general, two types of problems result in bradycardias: disorders of the SA node and disorders of the AV node.
With SA node dysfunction (sometimes called sick sinus syndrome), there may be disordered automaticity or impaired conduction of the impulse from the SA node into the surrounding atrial tissue (an "exit block"). Second-degree sinoatrial blocks can be detected only by use of a 12-lead ECG. It is difficult and sometimes impossible to assign a mechanism to any particular bradycardia, but the underlying mechanism is not clinically relevant to treatment, which is the same in both cases of sick sinus syndrome: a permanent pacemaker.
AV conduction disturbances (AV block; primary AV block, secondary type I AV block, secondary type II AV block, tertiary AV block) may result from impaired conduction in the AV node or anywhere below it, such as in the bundle of His. The clinical relevance pertaining to AV blocks is greater than that of SA blocks.
A variety of medications can induce or exacerbate bradycardia. These include beta blockers like propranolol, calcium channel blockers like verapamil and diltiazem, cardiac glycosides like digoxin, alpha-2 agonists like clonidine, and lithium, among others. Beta blockers may slow the heart rate to a dangerous level if prescribed with calcium channel blockers.
Chronic cocaine use has been associated with bradycardia. Desensitization of β-adrenergic receptors has been suggested as a possible cause of this. In contrast to cocaine however, methamphetamine has not been associated with bradyarrhythmias.
Bradycardia is also part of the mammalian diving reflex.
COVID-19 has been found to be a cause of bradycardia.
== Diagnosis ==
A diagnosis of bradycardia in adults is based on a heart rate of less than 60 BPM, although some studies use a heart rate of less than 50 BPM. This is usually determined either by palpation or ECG. If symptoms occur, a determining electrolytes may help determine the underlying cause.
Many healthy young adults, and particularly well-trained athletes, have sinus bradycardia that is without symptoms. This can include heart rates of less than 50 or 60 bpm or even less than 40 bpm. Such individuals, without symptoms, do not require treatment.
Temporal correlation of symptoms with bradycardia is necessary for diagnosis of symptomatic bradycardia. This can sometimes be difficult. Challenge with oral theophylline can be used as a diagnostic agent in people with bradycardia caused by sinus node dysfunction (SND) to help correlate symptoms. Theophylline increases resting heart rate and improves subjective symptoms in most people with bradycardia due to SND.
== Management ==
The treatment of bradycardia depends on whether the person is stable or unstable.
=== Chronic or stable ===
Emergency treatment is not needed if the person is asymptomatic or minimally symptomatic.
Treatment of chronic symptomatic bradycardia first necessitates correlation of symptoms. Once symptoms have been clearly linked to bradycardia, permanent cardiac pacing can be provided to increase heart rate and symptoms will improve.
In people who are unwilling to undergo pacemaker implantation or are not candidates for cardiac pacing, chronic oral theophylline, an adenosine receptor antagonist, can be considered for treatment of symptomatic bradycardia. Other positive chronotropes have also been used to treat bradycardia, including the vasodilator and antihypertensive agent hydralazine, the alpha-1 blocker prazosin, anticholinergics, and sympathomimetic agents like beta-1 agonists. However, side effects, like orthostatic hypotension with hydralazine, prazosin, and anticholinergics and myocardial toxicity with sympathomimetics, as well as limited data for this indication, hinder their routine and long-term use.
If hypothyroidism is present and is the cause of symptomatic bradycardia, symptoms respond well to replacement therapy with thyroid hormone.
Discontinuation of medications that induce or exacerbate bradycardia, such as beta blockers, calcium channel blockers, sodium channel blockers, and potassium channel blockers, can improve symptoms. If discontinuation of these medications is not possible due to clinical need, cardiac pacing can be considered with continuation of the medications. Beta blockers with intrinsic sympathomimetic activity (i.e., partial agonist activity), like pindolol, have less risk of bradycardia and may be useful as replacements of pure beta blockers, like propranolol, atenolol, and metoprolol.
=== Acute or unstable ===
If a person is unstable, the initial recommended treatment is intravenous atropine. Doses less than 0.5 mg should not be used, which may further decrease the rate. If this is ineffective, intravenous inotrope infusion (dopamine, epinephrine) or transcutaneous pacing should be used. Transvenous pacing may be required if the cause of the bradycardia is not rapidly reversible. Methylxanthines like theophylline and aminophylline are also used in the treatment of acute bradycardia due to sinus node dysfunction (SND).
In children, giving oxygen, supporting their breathing, and chest compressions are recommended.
== Epidemiology ==
In clinical practice, elderly people over age 65 and young athletes of both sexes may have sinus bradycardia. The US Centers for Disease Control and Prevention reported in 2011 that 15.2% of adult males and 6.9% of adult females had clinically defined bradycardia (a resting pulse rate below 60 BPM).
== Society and culture ==
=== Records ===
Daniel Green holds the world record for the slowest heartbeat in a healthy human, with a heart rate measured in 2014 of 26 BPM.
Martin Brady holds the Guinness world record for the slowest heart rate, with a certified rate over a minute duration of 27 BPM.
During his career, professional cyclist Miguel Indurain had a resting heart rate of 28 BPM.
== See also ==
Bezold–Jarisch reflex – Processes which cause hypopnea
== References == | Wikipedia/Low_heart_rate |
Antiarrhythmic agents, also known as cardiac dysrhythmia medications, are a class of drugs that are used to suppress abnormally fast rhythms (tachycardias), such as atrial fibrillation, supraventricular tachycardia and ventricular tachycardia.
Many attempts have been made to classify antiarrhythmic agents. Many of the antiarrhythmic agents have multiple modes of action, which makes any classification imprecise.
== Action potential ==
The cardiac myocyte has two general types of action potentials: conduction system and working myocardium. The action potential is divided into 5 phases and shown in the diagram. The sharp rise in voltage ("0") corresponds to the influx of sodium ions, whereas the two decays ("1" and "3", respectively) correspond to the sodium-channel inactivation and the repolarizing efflux of potassium ions. The characteristic plateau ("2") results from the opening of voltage-sensitive calcium channels. Each phase utilizes different channels and it is useful to compare these phases to the most common classification system — Vaughan Williams — described below.
== Vaughan Williams classification ==
The Vaughan Williams classification was introduced in 1970 by Miles Vaughan Williams.
Vaughan Williams was a pharmacology tutor at Hertford College, Oxford. One of his students, Bramah N. Singh, contributed to the development of the classification system. The system is therefore sometimes known as the Singh-Vaughan Williams classification.
The five main classes in the Vaughan Williams classification of antiarrhythmic agents are:
Class I agents interfere with the sodium (Na+) channel.
Class II agents are anti-sympathetic nervous system agents. Most agents in this class are beta blockers.
Class III agents affect potassium (K+) efflux.
Class IV agents affect calcium channels and the AV node.
Class V agents work by other or unknown mechanisms.
With regard to management of atrial fibrillation, classes I and III are used in rhythm control as medical cardioversion agents, while classes II and IV are used as rate-control agents.
=== Class I agents ===
The class I antiarrhythmic agents interfere with the sodium channel.
Class I agents are grouped by what effect they have on the Na+ channel, and what effect they have on cardiac action potentials.
Class I agents are called membrane-stabilizing agents, "stabilizing" referring to the decrease of excitogenicity of the plasma membrane which is brought about by these agents. (Also noteworthy is that a few class II agents like propranolol also have a membrane stabilizing effect.)
Class I agents are divided into three groups (Ia, Ib, and Ic) based upon their effect on the length of the action potential.
Class Ia drugs lengthen the action potential (right shift)
Class Ib drugs shorten the action potential (left shift)
Class Ic drugs do not significantly affect the action potential (no shift)
=== Class II agents ===
Class II agents are conventional beta blockers. They act by blocking the effects of catecholamines at the β1-adrenergic receptors, thereby decreasing sympathetic activity on the heart, which reduces intracellular cAMP levels and hence reduces Ca2+ influx. These agents are particularly useful in the treatment of supraventricular tachycardias. They decrease conduction through the AV node.
Class II agents include atenolol, esmolol, propranolol, and metoprolol.
=== Class III agents ===
Class III agents predominantly block the potassium channels, thereby prolonging repolarization. Since these agents do not affect the sodium channel, conduction velocity is not decreased. The prolongation of the action potential duration and refractory period, combined with the maintenance of normal conduction velocity, prevent re-entrant arrhythmias. (The re-entrant rhythm is less likely to interact with tissue that has become refractory). The class III agents exhibit reverse-use dependence (their potency increases with slower heart rates, and therefore improves maintenance of sinus rhythm). Inhibiting potassium channels results in slowed atrial-ventricular myocyte repolarization. Class III agents have the potential to prolong the QT interval of the EKG, and may be proarrhythmic (more associated with development of polymorphic VT).
Class III agents include: bretylium, amiodarone, ibutilide, sotalol, dofetilide, vernakalant, and dronedarone.
=== Class IV agents ===
Class IV agents are slow non-dihydropyridine calcium channel blockers. They decrease conduction through the AV node, and shorten phase two (the plateau) of the cardiac action potential. They thus reduce the contractility of the heart, so may be inappropriate in heart failure. However, in contrast to beta blockers, they allow the body to retain adrenergic control of heart rate and contractility.
Class IV agents include verapamil and diltiazem.
=== Class V and others ===
Since the development of the original Vaughan Williams classification system, additional agents have been used that do not fit cleanly into categories I through IV. Such agents include:
Adenosine is used intravenously for terminating supraventricular tachycardias.
Digoxin decreases conduction of electrical impulses through the AV node and increases vagal activity via its action on the central nervous system. Via indirect action, it leads to an increase in acetylcholine production, stimulating M2 receptors on AV node leading to an overall decrease in speed of conduction.
Magnesium sulfate is an antiarrhythmic drug, but only used against very specific arrhythmias such as torsades de pointes.
=== History ===
The initial classification system had 4 classes, although their definitions different from the modern classification. Those proposed in 1970 were:
Drugs with a direct membrane action: the prototype was quinidine, and lignocaine was a key example. Differing from other authors, Vaughan-Williams describe the main action as a slowing of the rising phase of the action potential.
Sympatholytic drugs (drugs blocking the effects of the sympathetic nervous system): examples included bretylium and adrenergic beta-receptors blocking drugs. This is similar to the modern classification, which focuses on the latter category.
Compounds that prolong the action potential: matching the modern classification, with the key drug example being amiodarone, and a surgical example being thyroidectomy. This was not a defining characteristic in an earlier review by Charlier et al. (1968), but was supported by experimental data presented by Vaughan Williams (1970).: 461 The figure illustrating these findings was also published in the same year by Singh and Vaughan Williams.
Drugs acting like diphenylhydantoin (DPH): mechanism of action unknown, but others had attributed its cardiac action to an indirect action on the brain; this drug is better known as antiepileptic drug phenytoin.
== Sicilian gambit classification ==
Another approach, known as the "Sicilian gambit", placed a greater approach on the underlying mechanism.
It presents the drugs on two axes, instead of one, and is presented in tabular form. On the Y axis, each drug is listed, in roughly the Singh-Vaughan Williams order. On the X axis, the channels, receptors, pumps, and clinical effects are listed for each drug, with the results listed in a grid. It is, therefore, not a true classification in that it does not aggregate drugs into categories.
== Modernized Oxford classification by Lei, Huang, Wu, and Terrar ==
A recent publication (2018) has now emerged with a fully modernised drug classification. This preserves the simplicity of the original Vaughan Williams framework while capturing subsequent discoveries of sarcolemmal, sarcoplasmic reticular and cytosolic biomolecules. The result is an expanded but pragmatic classification that encompasses approved and potential anti-arrhythmic drugs. This will aid our understanding and clinical management of cardiac arrhythmias and facilitate future therapeutic developments. It starts by considering the range of pharmacological targets, and tracks these to their particular cellular electrophysiological effects. It retains but expands the original Vaughan Williams classes I to IV, respectively covering actions on Na+ current components, autonomic signalling, K+ channel subspecies, and molecular targets related to Ca2+ homeostasis. It now introduces new classes incorporating additional targets, including:
Class 0: ion channels involved in automaticity
Class V: mechanically sensitive ion channels
Class VI: connexins controlling electrotonic cell coupling
Class VII: molecules underlying longer term signalling processes affecting structural remodeling.
It also allows for multiple drug targets/actions and adverse pro-arrhythmic effects. The new scheme will additionally aid development of novel drugs under development and is illustrated here.
== See also ==
Antiarrhythmic agents (category)
Cardiac Arrhythmia Suppression Trial (CAST)
Electrocardiogram
Management of atrial fibrillation
Proarrhythmic agent
== References == | Wikipedia/Anti-arrhythmic_drug |
Atrial natriuretic peptide (ANP) or atrial natriuretic factor (ANF) is a natriuretic peptide hormone secreted from the cardiac atria that in humans is encoded by the NPPA gene. Natriuretic peptides (ANP, BNP, and CNP) are a family of hormone/paracrine factors that are structurally related. The main function of ANP is causing a reduction in expanded extracellular fluid (ECF) volume by increasing renal sodium excretion. ANP is synthesized and secreted by cardiac muscle cells in the walls of the atria in the heart. These cells contain volume receptors which respond to increased stretching of the atrial wall due to increased atrial blood volume.
Reduction of blood volume by ANP can result in secondary effects such as reduction of extracellular fluid (ECF) volume, improved cardiac ejection fraction with resultant improved organ perfusion, decreased blood pressure, and increased serum potassium. These effects may be blunted or negated by various counter-regulatory mechanisms operating concurrently on each of these secondary effects.
Brain natriuretic peptide (BNP) – a misnomer; it is secreted by cardiac muscle cells in the heart ventricles – is similar to ANP in its effect. It acts via the same receptors as ANP does, but with 10-fold lower affinity than ANP. The biological half-life of BNP, however, is twice as long as that of ANP, and that of NT-proBNP is even longer, making these peptides better choices than ANP for diagnostic blood testing.
== Clinical significance ==
A member of the natriuretic peptide gene family, NPPA encodes an important cardiac signaling molecule known as atrial natriuretic peptide/factor (ANP). ANP carries out endocrine functions of the heart. It acts as a diuretic by inhibiting sodium reabsorption in the kidneys. ANP also acts in the heart to prevent cardiac hypertrophy and to regulate vascular remodeling and energy metabolism. NPPA expression is varied throughout mammalian development into adulthood. Fetal expression of NPPA is associated with the formation of chamber myocardium, muscle cells of the atria and ventricles in the early developing heart. Early expression of this gene has been associated with ventricular hypertrophy in both in vitro and in vivo models. NPPA variants affect plasma ANP concentrations, blood pressure levels, and cardiovascular diseases such as atrial fibrillation (AF). ANP-deficient mice were found to have a large increase in heart and left ventricular weight in response to volume overload, which is normally prevented by proper regulation of blood pressure. Using a knock-in (KI) rat model, researchers found an AF-associated human variant in NPPA caused inflammation, fibroblast activation, atrial fibrosis, and AF in KI rats. These findings suggest NPPA is a critical gene in cardiac development and dysfunction of this gene can lead to heart problems via altered ANP levels.
== Discovery ==
The discovery of a natriuretic factor (one that promotes kidney excretion of salt and water) was first reported by Adolfo José de Bold in 1981 when rat atrial extracts were found to contain a substance that increased salt and urine output in the kidney. Later, the substance was purified from heart tissue by several groups and named atrial natriuretic factor (ANF) or ANP.
== Structure ==
ANP is a 28-amino acid peptide with a 17-amino acid ring in the middle of the molecule. The ring is formed by a disulfide bond between two cysteine residues at positions 7 and 23. ANP is closely related to BNP (brain natriuretic peptide) and CNP (C-type natriuretic peptide), which all share a similar amino acid ring structure. ANP is one of a family of nine structurally similar natriuretic hormones: seven are atrial in origin.
== Production ==
ANP is synthesized as an inactive preprohormone, encoded by the human NPPA gene located on the short arm of chromosome 1. The NPPA gene is expressed primarily in atrial myocytes and consists of 2 introns and three exons, with translation of this gene yielding a high molecular mass 151 amino acid polypeptide known as preproANP. The preprohormone is activated via post-translational modification that involves cleavage of the 25 amino acid signal sequence to produce proANP, a 126 amino acid peptide that is the major form of ANP stored in intracellular granules of the atria. Following stimulation of atrial cells, proANP is released and rapidly converted to the 28-amino-acid C-terminal mature ANP on the cell surface by the cardiac transmembrane serine protease corin. Recently, it was discovered that ANP also can be O-glycosylated.
ANP is secreted in response to:
Stretching of the atrial wall, via Atrial volume receptors
Increased Sympathetic stimulation of β-adrenoceptors
Increased sodium concentration (hypernatremia), though sodium concentration is not the direct stimulus for increased ANP secretion
Endothelin, a potent vasoconstrictor
== Receptors ==
Three types of atrial natriuretic peptide receptors have been identified on which natriuretic peptides act. They are all cell surface receptors and designated:
guanylyl cyclase-A (GC-A) also known as natriuretic peptide receptor-A (NPRA/ANPA) or NPR1
guanylyl cyclase-B (GC-B) also known as natriuretic peptide receptor-B (NPRB/ANPB) or NPR2
natriuretic peptide clearance receptor (NPRC/ANPC) or NPR3
NPR-A and NPR-B have a single membrane-spanning segment with an extracellular domain that binds the ligand. The intracellular domain maintains two consensus catalytic domains for guanylyl cyclase activity. Binding of a natriuretic peptide induces a conformational change in the receptor that causes receptor dimerization and activation.
The binding of ANP to its receptor causes the conversion of GTP to cGMP and raises intracellular cGMP. As a consequence, cGMP activates a cGMP-dependent kinase (PKG or cGK) that phosphorylates proteins at specific serine and threonine residues. In the medullary collecting duct, the cGMP generated in response to ANP may act not only through PKG but also via direct modulation of ion channels.
NPR-C functions mainly as a clearance receptor by binding and sequestering ANP from the circulation. All natriuretic peptides are bound by the NPR-C.
== Physiological effects ==
Maintenance of the ECF volume (space), and its subcompartment the vascular space, is crucial for survival. These compartments are maintained within a narrow range, despite wide variations in dietary sodium intake. There are three volume regulating systems: two salt saving systems, the renin angiotensin aldosterone system (RAAS) and the renal sympathetic system (RSS); and the salt excreting natriuretic peptide (NP) hormone system. When the vascular space contracts, the RAAS and RSS are "turned on"; when the atria expand, NPs are "turned on". Each system also suppresses its counteracting system(s). NPs are made in cardiac, intestinal, renal, and adrenal tissue: ANP in one of a family of cardiac NPs: others are BNP, CNP, and DNP.
ANP binds to a specific set of receptors – ANP receptors. Receptor-agonist binding causes the increase in renal sodium excretion, which results in a decreased ECF and blood volume. Secondary effects may be an improvement in cardiac ejection fraction and reduction of systemic blood pressure.
=== Renal ===
ANP acts on the kidney to increase sodium and water excretion (natriuresis) in the following ways:
The medullary collecting duct is the main site of ANP regulation of sodium excretion. ANP effects sodium channels at both the apical and basolateral sides. ANP inhibits ENaC on the apical side and the sodium potassium ATPase pump on the basolateral side in a cGMP PKG dependent manner resulting in less sodium re-absorption and more sodium excretion.
ANP increases glomerular filtration rate and glomerular permeability. ANP directly dilates the afferent arteriole and counteracts the norepinephrine induced vasoconstriction of the afferent arteriole. Some studies suggest that ANP also constricts the efferent arteriole, but this is not a unanimous finding. ANP inhibits the effect of Angiotensin II on the mesangial cells, thereby relaxing them. ANP increases the radius and number of glomerular pores, thereby increasing glomerular permeability and resulting in greater filter load of sodium and water.
Increases blood flow through the vasa recta, which will wash the solutes (sodium chloride (NaCl), and urea) out of the medullary interstitium. The lower osmolarity of the medullary interstitium leads to less reabsorption of tubular fluid and increased excretion.
Decreases sodium reabsorption at least in the thick ascending limb (interaction with NKCC2) and cortical collecting duct of the nephron via guanosine 3',5'-cyclic monophosphate (cGMP) dependent phosphorylation of ENaC.
It inhibits renin secretion, thereby inhibiting the production of angiotensin and aldosterone.
It inhibits the renal sympathetic nervous system.
ANP has the opposite effect of angiotensin II on the kidney: angiotensin II increases renal sodium retention and ANP increases renal sodium loss.
=== Adrenal ===
Reduces aldosterone secretion by the zona glomerulosa of the adrenal cortex.
=== Vascular ===
Relaxes vascular smooth muscle in arterioles and venules by:
Membrane Receptor-mediated elevation of vascular smooth muscle cGMP
Inhibition of the effects of catecholamines
Promotes uterine spiral artery remodeling, which is important for preventing pregnancy-induced hypertension.
=== Cardiac ===
ANP inhibits cardiac hypertrophy in heart failure as well as fibrosis. Fibrosis is inhibited by preventing fibroblasts from entering heart tissue and replicating, as well as decreasing inflammation. ANP prevents hypertrophy by inhibiting calcium influx that is caused by norepinephrine.
Re-expression of NPRA rescues the phenotype.
=== Adipose tissue ===
Increases the release of free fatty acids from adipose tissue. Plasma concentrations of glycerol and nonesterified fatty acids are increased by i.v. infusion of ANP in humans.
Activates adipocyte plasma membrane type A guanylyl cyclase receptors NPR-A
Increases intracellular cGMP levels that induce the phosphorylation of a hormone-sensitive lipase and perilipin A via the activation of a cGMP-dependent protein kinase-I (cGK-I)
Does not modulate cAMP production or PKA activity.
=== Immune System ===
ANP is produced locally by several immune cells. ANP is shown to regulate several functions of innate and adaptive immune system as well as shown to have cytoprotective effects.
ANP modulates innate immunity by raising defence against extracellular microbes and inhibiting the release of pro-inflammatory markers and expression of adhesion molecules.
There is evidence of cytoprotective effects of ANP in myocardial, vascular smooth, endothelial, hepatocytes and tumour cells.
== Degradation ==
Modulation of the effects of ANP is achieved through gradual degradation of the peptide by the enzyme neutral endopeptidase (NEP). Recently, NEP inhibitors have been developed, such as Sacubitril and Sacubitril/valsartan. They may be clinically useful in treating patients in heart failure with reduced ejection fraction .
== Biomarker ==
Fragments derived from the ANP precursor, including the signal peptide, N-terminal pro-ANP and ANP, have been detected in human blood. ANP and related peptides are used as biomarkers for cardiovascular diseases such as stroke, coronary artery disease, myocardial infarction and heart failure. A specific ANP precursor called mid-regional pro-atrial natriuretic peptide (MRproANP) is a highly sensitive biomarker in heart failure. MRproANP levels below 120 pmol/L can be used to effectively rule out acute heart failure.
Large amounts of ANP secretion has been noted to cause electrolyte disturbances (hyponatremia) and polyuria. These indications can be a marker of a large atrial myxoma.
== Therapeutic use and drug development ==
Opinions regarding the use of ANP for the treatment of acute heart failure and kidney disease are varied. While this molecule has been shown to successfully restore some hemodynamic parameters following heart failure, and yield clinical improvement for kidney injury, whether it ultimately reduces mortality and its long-term effects are unknown. Therefore, more studies need to be conducted to better understand the therapeutic effects of ANP. Newly synthesized homologues of ANP molecule are being assessed for the treatment of acute heart failure. Preliminary research on one of such molecules, ularitide, has shown that this drug is safe, well tolerated, and effective in the treatment of acute heart failure.
== Other natriuretic peptides ==
Brain natriuretic peptide (BNP) – a misnomer; it is secreted by ventricular myocytes – is similar to ANP in its effect. It acts via atrial natriuretic peptide receptors but with 10-fold lower affinity than ANP. The biological half-life of BNP, however, is twice as long as that of ANP, and that of NT-proBNP is even longer, making these peptides better choices than ANP for diagnostic blood testing.
In addition to the mammalian natriuretic peptides (ANP, BNP, CNP), other natriuretic peptides with similar structure and properties have been isolated elsewhere in the animal kingdom. A salmon natriuretic peptide known as salmon cardiac peptide has been described, and dendroaspis natriuretic peptide (DNP) has been found in the venom of the green mamba, as well as an NP in a species of African snake.
Beside these four, five additional natriuretic peptides have been identified: long-acting natriuretic peptide (LANP), vessel dilator, kaliuretic peptide, urodilatin, and adrenomedullin.
== Pharmacological modulation ==
Neutral endopeptidase (NEP) also known as neprilysin is the enzyme that metabolizes natriuretic peptides. Several inhibitors of NEP are currently being developed to treat disorders ranging from hypertension to heart failure. Most of them are dual inhibitors (NEP and ACE). In 2014, PARADIGM-HF study was published in NEJM. This study considered as a landmark study in treatment of heart failure. The study was double blinded; compared LCZ696 versus enalapril in patients with heart failure. The study showed lower all cause mortality, cardiovascular mortality and hospitalization in LCZ696 arm.
Omapatrilat (dual inhibitor of NEP and angiotensin-converting enzyme) developed by BMS did not receive FDA approval due to angioedema safety concerns. Other dual inhibitors of NEP with ACE/angiotensin receptor are (in 2003) being developed by pharmaceutical companies.
== Synonyms ==
ANP is also called atrial natriuretic factor (ANF), atrial natriuretic hormone (ANH), cardionatrine, cardiodilatin (CDD), and atriopeptin.
== See also ==
Renin-angiotensin system: When the blood flow through the juxtaglomerular apparatus decreases, blood pressure is considered low, and the adrenal cortex secretes aldosterone to increase sodium reabsorption in the collecting duct, thereby increasing blood pressure.
Bainbridge reflex: In response to stretching of the right atrium wall, heart rate increases, lowering venous blood pressure.
Baroreflex: When the stretch receptors in the aortic arch and carotid sinus increase, the blood pressure is considered to be elevated and the heart rate decreases to lower blood pressure.
Antidiuretic hormone: The hypothalamus detects the extracellular fluid hyperosmolality and the posterior pituitary gland secretes antidiuretic hormone to increase water reabsorption in the collecting duct.
== Notes ==
== References ==
== External links ==
Atrial+Natriuretic+Factor at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
Human NPPA genome location and NPPA gene details page in the UCSC Genome Browser.
Overview of all the structural information available in the PDB for UniProt: P01160 (Natriuretic peptides A) at the PDBe-KB. | Wikipedia/Atrial_natriuretic_peptide |
A therapy or medical treatment is the attempted remediation of a health problem, usually following a medical diagnosis. Both words, treatment and therapy, are often abbreviated tx, Tx, or Tx.
As a rule, each therapy has indications and contraindications. There are many different types of therapy. Not all therapies are effective. Many therapies can produce unwanted adverse effects.
Treatment and therapy are often synonymous, especially in the usage of health professionals. However, in the context of mental health, the term therapy may refer specifically to psychotherapy.
== Semantic field ==
The words care, therapy, treatment, and intervention overlap in a semantic field, and thus they can be synonymous depending on context. Moving rightward through that order, the connotative level of holism decreases and the level of specificity (to concrete instances) increases. Thus, in health-care contexts (where its senses are always noncount), the word care tends to imply a broad idea of everything done to protect or improve someone's health (for example, as in the terms preventive care and primary care, which connote ongoing action), although it sometimes implies a narrower idea (for example, in the simplest cases of wound care or postanesthesia care, a few particular steps are sufficient, and the patient's interaction with the provider of such care is soon finished). In contrast, the word intervention tends to be specific and concrete, and thus the word is often countable; for example, one instance of cardiac catheterization is one intervention performed, and coronary care (noncount) can require a series of interventions (count). At the extreme, the piling on of such countable interventions amounts to interventionism, a flawed model of care lacking holistic circumspection—merely treating discrete problems (in billable increments) rather than maintaining health. Therapy and treatment, in the middle of the semantic field, can connote either the holism of care or the discreteness of intervention, with context conveying the intent in each use. Accordingly, they can be used in both noncount and count senses (for example, therapy for chronic kidney disease can involve several dialysis treatments per week).
The words aceology and iamatology are obscure and obsolete synonyms referring to the study of therapies.
The English word therapy comes via Latin therapīa from Ancient Greek: θεραπεία and literally means "curing" or "healing". The term therapeusis is a somewhat archaic doublet of the word therapy.
== Types of therapies ==
Therapy as a treatment for physical or mental condition is based on knowledge usually from one of three separate fields (or a combination of them): conventional medicine (allopathic, Western biomedicine, relying on scientific approach and evidence-based practice), traditional medicine (age-old cultural practices), and alternative medicine (healthcare procedures "not readily integrated into the dominant healthcare model").
=== By chronology, priority, or intensity ===
==== Levels of care ====
Levels of care classify health care into categories of chronology, priority, or intensity, as follows:
Urgent care handles health issues that need to be handled today but are not necessarily emergencies; the urgent care venue can send a patient to the emergency care level if it turns out to be needed.
In the United States (and possibly various other countries), urgent care centers also serve another function as their other main purpose: U.S. primary care practices have evolved in recent decades into a configuration whereby urgent care centers provide portions of primary care that cannot wait a month, because getting an appointment with the primary care practitioner is often subject to a waitlist of 2 to 8 weeks.
Emergency care handles medical emergencies and is a first point of contact or intake for less serious problems, which can be referred to other levels of care as appropriate. This therapy is often given to patients before a definitive diagnosis is made.
Intensive care, also called critical care, is care for extremely ill or injured patients. It thus requires high resource intensity, knowledge, and skill, as well as quick decision making.
Ambulatory care is care provided on an outpatient basis. Typically patients can walk into and out of the clinic under their own power (hence "ambulatory"), usually on the same day. This care type also involves surgery which, according to recent research, offers "generally superior 30-day outcomes relative to inpatient-based care".
Home care is care at home, including care from providers (such as physicians, nurses, and home health aides) making house calls, care from caregivers such as family members, and patient self-care.
Primary care is meant to be the main kind of care in general, and ideally a medical home that unifies care across referred providers. The current trend in this area is digitalization aiming to ensure open access to information about therapy, issues, and recent progress on biomedical research.
Secondary care is care provided by medical specialists and other health professionals who generally do not have first contact with patients, for example, cardiologists, urologists and dermatologists. A patient reaches secondary care as a next step from primary care, typically by provider referral although sometimes by patient self-initiative. According to a systematic review, fields for development secondary care from patients' viewpoint may be classified into four domains that should usefully guide future improvement of this care stage: "barriers to care, communication, coordination, and relationships and personal value".
Tertiary care is specialized consultative care, usually for inpatients and on referral from a primary or secondary health professional, in a facility that has personnel and facilities for advanced medical investigation and treatment, such as a tertiary referral hospital.
Follow-up care is additional care during or after convalescence. Aftercare is generally synonymous with follow-up care. One of the key areas of development–Telehealth, including non-clinical services: provider training, administrative meetings, and continuing medical education–offers opportunities to improve access to care, increase provider and patient productivity through reduced travel, potential expenses savings, and the ability to expand services.
End-of-life care is care near the end of one's life. It often includes the following:
Palliative care is supportive care, most especially (but not necessarily) near the end of life.
Hospice care is palliative care very near the end of life when cure is very unlikely. Its main goal is comfort, both physical and mental. A systematic meta review showed that the most cost-efficient one relates to home-based end-of-life care, including reduced overall "resource use and improved patient and carer outcomes".
==== Lines of therapy ====
Treatment decisions often follow formal or informal algorithmic guidelines. Treatment options can often be ranked or prioritized into lines of therapy: first-line therapy, second-line therapy, third-line therapy, and so on. First-line therapy (sometimes referred to as induction therapy, primary therapy, or front-line therapy) is the first therapy that will be tried. Its priority over other options is usually either: (1) formally recommended on the basis of clinical trial evidence for its best-available combination of efficacy, safety, and tolerability or (2) chosen based on the clinical experience of the physician. If a first-line therapy either fails to resolve the issue or produces intolerable side effects, additional (second-line) therapies may be substituted or added to the treatment regimen, followed by third-line therapies, and so on.
An example of a context in which the formalization of treatment algorithms and the ranking of lines of therapy is very extensive is chemotherapy regimens. Because of the great difficulty in successfully treating some forms of cancer, one line after another may be tried. In oncology the count of therapy lines may reach 10 or even 20.
Often multiple therapies may be tried simultaneously (combination therapy or polytherapy). Thus combination chemotherapy is also called polychemotherapy, whereas chemotherapy with one agent at a time is called single-agent therapy or monotherapy. Single-agent therapy is a care algorithm that focuses on one specific drug or procedure. It utilizes a single therapeutic agent rather than combining multiple ones. Multiagent Therapy is a treatment by two or more drugs or procedures. Comprehensive therapy combines various forms of medical treatment to provide the most effective care for patients.
Adjuvant therapy is therapy given in addition to the primary, main, or initial treatment, but simultaneously (as opposed to second-line therapy). Neoadjuvant therapy is therapy that is begun before the main therapy. Thus one can consider surgical excision of a tumor as the first-line therapy for a certain type and stage of cancer even though radiotherapy is used before it; the radiotherapy is neoadjuvant (chronologically first but not primary in the sense of the main event). Premedication is conceptually not far from this, but the words are not interchangeable; cytotoxic drugs to put a tumor "on the ropes" before surgery delivers the "knockout punch" are called neoadjuvant chemotherapy, not premedication, whereas things like anesthetics or prophylactic antibiotics before dental surgery are called premedication.
Step therapy or stepladder therapy is a specific type of prioritization by lines of therapy. It is controversial in American health care because unlike conventional decision-making about what constitutes first-line, second-line, and third-line therapy, which in the U.S. reflects safety and efficacy first and cost only according to the patient's wishes, step therapy attempts to mix cost containment by someone other than the patient (third-party payers) into the algorithm.
Therapy freedom refers to prescription for use of an unlicensed medicine (without a marketing authorization issued by the licensing authority of the country) and the negotiation between individual and group rights are involved. A comprehensive research in Australia, Czech Republic, India, Israel, Italy, Netherlands, Spain, Serbia, Sweden, UK, and USA showed that the rate of the unlicensed medicine prescription has been reported to range from 0.3 to 35% depending on the country. In many jurisdictions, therapy freedom is limited to cases of no treatment existing that is both well-established and more efficacious.
=== By intent ===
=== By intervention ===
Invasive therapy is achieved either through surgery or through the use of drugs. Medical invasive treatments can be divided into two main categories: pharmacotherapy and surgery.
Noninvasive therapies are medical treatments that do not involve entry into the body. It can be classified into five main categories: neurotherapy, physical therapy, occupational therapy, radiation therapy, and psychotherapy.
=== By therapy composition ===
Treatments can be classified according to the method of treatment:
==== By matter ====
by drugs: pharmacotherapy, chemotherapy (also, medical therapy often means specifically pharmacotherapy)
by medical devices: implantation
cardiac resynchronization therapy
by specific molecules: molecular therapy (although most drugs are specific molecules, molecular medicine refers in particular to medicine relying on molecular biology)
by specific biomolecular targets: targeted therapy
molecular chaperone therapy
by chelation: chelation therapy
by specific chemical elements:
by metals:
by heavy metals:
by gold: chrysotherapy (aurotherapy)
by platinum-containing drugs: platin therapy
by biometals
by lithium: lithium therapy
by potassium: potassium supplementation
by magnesium: magnesium supplementation
by chromium: chromium supplementation; phonemic neurological hypochromium therapy
by copper: copper supplementation
by nonmetals:
by diatomic oxygen: oxygen therapy, hyperbaric oxygen therapy (hyperbaric medicine)
transdermal continuous oxygen therapy
by triatomic oxygen (ozone): ozone therapy
by fluoride: fluoride therapy
by other gases: medical gas therapy
by water:
hydrotherapy
aquatic therapy
rehydration therapy
oral rehydration therapy
water cure (therapy)
by biological materials (biogenic substances, biomolecules, biotic materials, natural products), including their synthetic equivalents: biotherapy
by whole organisms
by viruses: virotherapy
by bacteriophages: phage therapy
by animal interaction: see animal interaction section
by constituents or products of organisms
by plant parts or extracts (but many drugs are derived from plants, even when the term phytotherapy is not used)
scientific type: phytotherapy
traditional (prescientific) type: herbalism
by animal parts: quackery involving shark fins, tiger parts, and so on, often driving threat or endangerment of species
by genes: gene therapy
gene therapy for epilepsy
gene therapy for osteoarthritis
gene therapy for color blindness
gene therapy of the human retina
gene therapy in Parkinson's disease
by epigenetics: epigenetic therapy
by proteins: protein therapy (but many drugs are proteins despite not being called protein therapy)
by enzymes: enzyme replacement therapy
by hormones: hormone therapy
hormonal therapy (oncology)
hormone replacement therapy
estrogen replacement therapy
androgen replacement therapy
hormone replacement therapy (menopause)
transgender hormone therapy
feminizing hormone therapy
masculinizing hormone therapy
antihormone therapy
androgen deprivation therapy
by whole cells: cell therapy (cytotherapy)
by stem cells: stem cell therapy
by immune cells: see immune system products below
by immune system products: immunotherapy, host modulatory therapy
by immune cells:
T-cell vaccination
cell transfer therapy
autologous immune enhancement therapy
TK cell therapy
by humoral immune factors: antibody therapy
by whole serum: serotherapy, including antiserum therapy
by immunoglobulins: immunoglobulin therapy
by monoclonal antibodies: monoclonal antibody therapy
by urine: urine therapy (some scientific forms; many prescientific or pseudoscientific forms)
by food and dietary choices:
medical nutrition therapy
grape therapy (quackery)
by salts (but many drugs are the salts of organic acids, even when drug therapy is not called by names reflecting that)
by salts in the air
by natural dry salt air: "taking the cure" in desert locales (especially common in prescientific medicine; for example, one 19th-century way to treat tuberculosis)
by artificial dry salt air:
low-humidity forms of speleotherapy
negative air ionization therapy
by moist salt air:
by natural moist salt air: seaside cure (especially common in prescientific medicine)
by artificial moist salt air: water vapor forms of speleotherapy
by salts in the water
by mineral water: spa cure ("taking the waters") (especially common in prescientific medicine)
by seawater: seaside cure (especially common in prescientific medicine)
by aroma: aromatherapy
by other materials with mechanism of action unknown
by occlusion with duct tape: duct tape occlusion therapy
==== By energy ====
by electric energy as electric current: electrotherapy, electroconvulsive therapy
Transcranial magnetic stimulation
Vagus nerve stimulation
by magnetic energy:
magnet therapy
pulsed electromagnetic field therapy
magnetic resonance therapy
by electromagnetic radiation (EMR):
by light: light therapy (phototherapy)
ultraviolet light therapy
PUVA therapy
photodynamic therapy
photothermal therapy
cytoluminescent therapy
blood irradiation therapy
by darkness: dark therapy
by lasers: laser therapy
low level laser therapy
by gamma rays: radiosurgery
Gamma Knife radiosurgery
stereotactic radiation therapy
cobalt therapy
by radiation generally: radiation therapy (radiotherapy)
intraoperative radiation therapy
by EMR particles:
particle therapy
proton therapy
electron therapy
intraoperative electron radiation therapy
Auger therapy
neutron therapy
fast neutron therapy
neutron capture therapy of cancer
by radioisotopes emitting EMR:
by nuclear medicine
by brachytherapy
quackery type: electromagnetic therapy (alternative medicine)
by mechanical: manual therapy as massotherapy and therapy by exercise as in physical therapy
inversion therapy
by sound:
by ultrasound:
ultrasonic lithotripsy
extracorporeal shockwave therapy
sonodynamic therapy
by music: music therapy
by temperature
by heat: heat therapy (thermotherapy)
by moderately elevated ambient temperatures: hyperthermia therapy
by dry warm surroundings: Waon therapy
by dry or humid warm surroundings: sauna, including infrared sauna, for sweat therapy
by cold:
by extreme cold to specific tissue volumes: cryotherapy
by ice and compression: cold compression therapy
by ambient cold:
hypothermia therapy for neonatal encephalopathy (in newborns)
targeted temperature management (therapeutic hypothermia, protective hypothermia)
by hot and cold alternation: contrast bath therapy
==== By procedure and human interaction ====
Surgery
by counseling, such as psychotherapy (see also: list of psychotherapies)
systemic therapy
by group psychotherapy
by cognitive behavioral therapy
by cognitive therapy
by behaviour therapy
by dialectical behavior therapy
by cognitive emotional behavioral therapy
by cognitive rehabilitation therapy
by family therapy
by education
by psychoeducation
by information therapy
by speech therapy, physical therapy, occupational therapy, vision therapy, massage therapy, chiropractic or acupuncture
by lifestyle modifications, such as avoiding unhealthy food or maintaining a predictable sleep schedule
by coaching
==== By animal interaction ====
by pets, assistance animals, or working animals: animal-assisted therapy
by horses: equine therapy, hippotherapy
by dogs: pet therapy with therapy dogs, including grief therapy dogs
by cats: pet therapy with therapy cats
by fish: ichthyotherapy (wading with fish), aquarium therapy (watching fish)
by maggots: maggot therapy
by worms:
by internal worms: helminthic therapy
by leeches: leech therapy
by immersion: animal bath
==== By meditation ====
by mindfulness: mindfulness-based cognitive therapy
==== By reading ====
by bibliotherapy
==== By creativity ====
by expression: expressive therapy
by writing: writing therapy
journal therapy
by play: play therapy
by art: art therapy
sensory art therapy
comic book therapy
by gardening: horticultural therapy
by dance: dance therapy
by drama: drama therapy
by recreation: recreational therapy
by music: music therapy
==== By sleeping and waking ====
by deep sleep: deep sleep therapy
by sleep deprivation: wake therapy
== See also ==
== References ==
== External links ==
The dictionary definition of therapy at Wiktionary
"Chapter Nine of the Book of Medicine Dedicated to Mansur, with the Commentary of Sillanus de Nigris" is a Latin book by Rhazes, from 1483, that is known for its ninth chapter, which is about therapeutics | Wikipedia/First-line_treatment |
Antiparasitics are a class of medications which are indicated for the treatment of parasitic diseases, such as those caused by helminths, amoeba, ectoparasites, parasitic fungi, and protozoa, among others. Antiparasitics target the parasitic agents of the infections by destroying them or inhibiting their growth; they are usually effective against a limited number of parasites within a particular class. Antiparasitics are one of the antimicrobial drugs which include antibiotics that target bacteria, and antifungals that target fungi. They may be administered orally, intravenously or topically. Overuse or misuse of antiparasitics can lead to the development of antimicrobial resistance.
Broad-spectrum antiparasitics, analogous to broad-spectrum antibiotics for bacteria, are antiparasitic drugs with efficacy in treating a wide range of parasitic infections caused by parasites from different classes.
== Types ==
=== Broad-spectrum ===
Nitazoxanide
=== Antiprotozoals ===
Melarsoprol (for treatment of sleeping sickness caused by Trypanosoma brucei)
Eflornithine (for sleeping sickness)
Metronidazole (for vaginitis caused by Trichomonas)
Tinidazole (for intestinal infections caused by Giardia lamblia)
Miltefosine (for the treatment of visceral and cutaneous leishmaniasis, currently undergoing investigation for Chagas disease)
=== Antihelminthic ===
==== Antinematodes ====
Mebendazole (for most nematode infections)
Pyrantel pamoate (for most nematode infections)
Thiabendazole (for roundworm infections)
Diethylcarbamazine (for treatment of Lymphatic filariasis)
Ivermectin (for prevention of river blindness)
Fenbendazole
==== Anticestodes ====
Niclosamide (for tapeworm infections)
Praziquantel (for tapeworm infections)
Albendazole (broad spectrum)
==== Antitrematodes ====
Praziquantel
=== Antiamoebics ===
Rifampin
Amphotericin B
=== Antifungals ===
Fumagillin (for microsporidiosis)
== Medical uses ==
Antiparasitics treat parasitic diseases, which impact an estimated 2 billion people.
=== Administration ===
Antiparastics may be given via a variety of routes depending on the specific medication, including oral, topical, and intravenous.
Resistance to antiparasitics has been a growing concern, especially in veterinary medicine. The Egg hatch assay can be used to determine whether a parasite causing an infection has become resistant to standard drug treatments.
== Drug development history ==
Early antiparasitics were ineffective, frequently toxic to patients, and difficult to administer due to the difficulty in distinguishing between the host and the parasite.
Between 1975 and 1999 only 13 of 1,300 new drugs were antiparasitics, which raised concerns that insufficient incentives existed to drive development of new treatments for diseases that disproportionately target low-income countries. This led to new public sector and public-private partnerships (PPPs), including investment by the Bill and Melinda Gates Foundation. Between 2000 and 2005, twenty new antiparasitic agents were developed or in development. Metal-containing compounds are the subject of another avenue of approach.
== Research ==
In the last decades, triazolopyrimidines and their metal complexes have been looked at as an alternative drug to the existing commercial antimonials, searching for a decrease in side effects and the development of parasite drug resistance.
== See also ==
Balsam of Peru, which has antiparasitic attributes
Naegleria fowleri
Balamuthia mandrillaris
== References == | Wikipedia/Antiparasitic_drug |
Xenodiagnosis is a diagnostic method used to document the presence of infectious disease microorganisms or pathogens by exposing possibly infected tissue to a vector and then examining the vector for the presence of the microorganisms or pathogens it may have ingested.
== Uses ==
Xenodiagnosis has not been commonly used in diagnosing Lyme disease because in vitro cell culturing now serves the purpose, however the process is commonly used to diagnose infections involving microorganisms such as trypanosomiasis.
== Study ==
Émile Brumpt introduced the xenodiagnosis technique into parasitological research and extensively studied such diseases as bilharzia, Chagas disease, onchocerciasis and leishmaniasis.
Medical professionals primarily use xenodiagnosis in determining the presence of a chronic infection of Trypanosoma cruzi (the flagellate that causes Chagas disease). Directly and definitively demonstrating the presence of this causative agent in a patient proves difficult. Therefore, the doctor allows a triatominae, a vector of the flagellate, to take a blood meal from the patient. The doctor later inspects the gut of the triatominae for growth of Trypanosoma cruzi.
Medical professionals historically successfully identified babesiosis with xenodiagnosis, both in hamsters for Babesia microti and in gerbils for Babesia divergens. They now use faster diagnostic measures.
Xenodiagnosis for filariasis is now obsolete.
== References ==
== External links ==
Xenodiagnosis at the U.S. National Library of Medicine Medical Subject Headings (MeSH) | Wikipedia/Xenodiagnosis |
The phases of clinical research are the stages in which scientists conduct experiments with a health intervention to obtain sufficient evidence for a process considered effective as a medical treatment. For drug development, the clinical phases start with testing for drug safety in a few human subjects, then expand to many study participants (potentially tens of thousands) to determine if the treatment is effective. Clinical research is conducted on drug candidates, vaccine candidates, new medical devices, and new diagnostic assays.
== Description ==
Clinical trials testing potential medical products are commonly classified into four phases. The drug development process will normally proceed through all four phases over many years. When expressed specifically, a clinical trial phase is capitalized both in name and Roman numeral, such as "Phase I" clinical trial.
If the drug successfully passes through Phases I, II, and III, it will usually be approved by the national regulatory authority for use in the general population. Phase IV trials are 'post-marketing' or 'surveillance' studies conducted to monitor safety over several years.
== Preclinical studies ==
Before clinical trials are undertaken for a candidate drug, vaccine, medical device, or diagnostic assay, the product candidate is tested extensively in preclinical studies. Such studies involve in vitro (test tube or cell culture) and in vivo (animal model) experiments using wide-ranging doses of the study agent to obtain preliminary efficacy, toxicity and pharmacokinetic information. Such tests assist the developer to decide whether a drug candidate has scientific merit for further development as an investigational new drug.
== Phase 0 ==
Phase 0 is a designation for optional exploratory trials, originally introduced by the United States Food and Drug Administration's (FDA) 2006 Guidance on Exploratory Investigational New Drug (IND) Studies, but now generally adopted as standard practice. Phase 0 trials are also known as human microdosing studies and are designed to speed up the development of promising drugs or imaging agents by establishing very early on whether the drug or agent behaves in human subjects as was expected from preclinical studies. Distinctive features of Phase 0 trials include the administration of single subtherapeutic doses of the study drug to a small number of subjects (10 to 15) to gather preliminary data on the agent's pharmacokinetics (what the body does to the drugs).
A Phase 0 study gives no data on safety or efficacy, being by definition a dose too low to cause any therapeutic effect. Drug development companies carry out Phase 0 studies to rank drug candidates to decide which has the best pharmacokinetic parameters in humans to take forward into further development. They enable go/no-go decisions to be based on relevant human models instead of relying on sometimes inconsistent animal data.
== Phase I ==
Phase I trials were formerly referred to as "first-in-man studies" but the field generally moved to the gender-neutral language phrase "first-in-humans" in the 1990s; these trials are the first stage of testing in human subjects. They are designed to test the safety, side effects, best dose, and formulation method for the drug. Phase I trials are not randomized, and thus are vulnerable to selection bias.
Normally, a small group of 20–100 healthy volunteers will be recruited. These trials are often conducted in a clinical trial clinic, where the subject can be observed by full-time staff. These clinical trial clinics are often run by contract research organization (CROs) who conduct these studies on behalf of pharmaceutical companies or other research investigators.
The subject who receives the drug is usually observed until several half-lives of the drug have passed. This phase is designed to assess the safety (pharmacovigilance), tolerability, pharmacokinetics, and pharmacodynamics of a drug. Phase I trials normally include dose-ranging, also called dose escalation studies, so that the best and safest dose can be found and to discover the point at which a compound is too poisonous to administer. The tested range of doses will usually be a fraction of the dose that caused harm in animal testing.
Phase I trials most often include healthy volunteers. However, there are some circumstances when clinical patients are used, such as patients who have terminal cancer or HIV and the treatment is likely to make healthy individuals ill. These studies are usually conducted in tightly controlled clinics called Central Pharmacological Units, where participants receive 24-hour medical attention and oversight. In addition to the previously mentioned unhealthy individuals, "patients who have typically already tried and failed to improve on the existing standard therapies" may also participate in Phase I trials. Volunteers are paid a variable inconvenience fee for their time spent in the volunteer center.
Before beginning a Phase I trial, the sponsor must submit an Investigational New Drug application to the FDA detailing the preliminary data on the drug gathered from cellular models and animal studies.
Phase I trials can be further divided:
=== Phase Ia ===
Single ascending dose (Phase Ia): In single ascending dose studies, small groups of subjects are given a single dose of the drug while they are observed and tested for a period of time to confirm safety. Typically, a small number of participants, usually three, are entered sequentially at a particular dose. If they do not exhibit any adverse side effects, and the pharmacokinetic data are roughly in line with predicted safe values, the dose is escalated, and a new group of subjects is then given a higher dose.
If unacceptable toxicity is observed in any of the three participants, an additional number of participants, usually three, are treated at the same dose. This is continued until pre-calculated pharmacokinetic safety levels are reached, or intolerable side effects start showing up (at which point the drug is said to have reached the maximum tolerated dose (MTD)). If an additional unacceptable toxicity is observed, then the dose escalation is terminated and that dose, or perhaps the previous dose, is declared to be the maximally tolerated dose. This particular design assumes that the maximally tolerated dose occurs when approximately one-third of the participants experience unacceptable toxicity. Variations of this design exist, but most are similar.
=== Phase Ib ===
Multiple ascending dose (Phase Ib): Multiple ascending dose studies investigate the pharmacokinetics and pharmacodynamics of multiple doses of the drug, looking at safety and tolerability. In these studies, a group of patients receives multiple low doses of the drug, while samples (of blood, and other fluids) are collected at various time points and analyzed to acquire information on how the drug is processed within the body. The dose is subsequently escalated for further groups, up to a predetermined level.
=== Food effect ===
A short trial designed to investigate any differences in absorption of the drug by the body, caused by eating before the drug is given. These studies are usually run as a crossover study, with volunteers being given two identical doses of the drug while fasted, and after being fed.
== Phase II ==
Once a dose or range of doses is determined, the next goal is to evaluate whether the drug has any biological activity or effect. Phase II trials are performed on larger groups (50–300 individuals) and are designed to assess how well the drug works, as well as to continue Phase I safety assessments in a larger group of volunteers and patients. Genetic testing is common, particularly when there is evidence of variation in metabolic rate. When the development process for a new drug fails, this usually occurs during Phase II trials when the drug is discovered not to work as planned, or to have toxic effects.
Phase II studies are sometimes divided into Phase IIa and Phase IIb. There is no formal definition for these two sub-categories, but generally:
Phase IIa studies are usually pilot studies designed to find an optimal dose and assess safety ('dose finding' studies).
Phase IIb studies determine how well the drug works in subjects at a given dose to assess efficacy ('proof of concept' studies).
=== Trial design ===
Some Phase II trials are designed as case series, demonstrating a drug's safety and activity in a selected group of participants. Other Phase II trials are designed as randomized controlled trials, where some patients receive the drug/device and others receive placebo/standard treatment. Randomized Phase II trials have far fewer patients than randomized Phase III trials.
==== Example: cancer design ====
In the first stage, the investigator attempts to rule out drugs that have no or little biologic activity. For example, the researcher may specify that a drug must have some minimal level of activity, say, in 20% of participants. If the estimated activity level is less than 20%, the researcher chooses not to consider this drug further, at least not at that maximally tolerated dose. If the estimated activity level exceeds 20%, the researcher will add more participants to get a better estimate of the response rate. A typical study for ruling out a 20% or lower response rate enters 14 participants. If no response is observed in the first 14 participants, the drug is considered not likely to have a 20% or higher activity level. The number of additional participants added depends on the degree of precision desired, but ranges from 10 to 20. Thus, a typical cancer phase II study might include fewer than 30 people to estimate the response rate.
==== Efficacy vs effectiveness ====
When a study assesses efficacy, it is looking at whether the drug given in the specific manner described in the study is able to influence an outcome of interest (e.g. tumor size) in the chosen population (e.g. cancer patients with no other ongoing diseases). When a study is assessing effectiveness, it is determining whether a treatment will influence the disease. In an effectiveness study, it is essential that participants are treated as they would be when the treatment is prescribed in actual practice. That would mean that there should be no aspects of the study designed to increase compliance above those that would occur in routine clinical practice. The outcomes in effectiveness studies are also more generally applicable than in most efficacy studies (for example does the patient feel better, come to the hospital less or live longer in effectiveness studies as opposed to better test scores or lower cell counts in efficacy studies). There is usually less rigid control of the type of participant to be included in effectiveness studies than in efficacy studies, as the researchers are interested in whether the drug will have a broad effect in the population of patients with the disease.
=== Success rate ===
Phase II clinical programs historically have experienced the lowest success rate of the four development phases. In 2010, the percentage of Phase II trials that proceeded to Phase III was 18%, and only 31% of developmental candidates advanced from Phase II to Phase III in a study of trials over 2006–2015.
== Phase III ==
This phase is designed to assess the effectiveness of the new intervention and, thereby, its value in clinical practice. Phase III studies are randomized controlled multicenter trials on large patient groups (300–3,000 or more depending upon the disease/medical condition studied) and are aimed at being the definitive assessment of how effective the drug is, in comparison with current 'gold standard' treatment. Because of their size and comparatively long duration, Phase III trials are the most expensive, time-consuming and difficult trials to design and run, especially in therapies for chronic medical conditions. Phase III trials of chronic conditions or diseases often have a short follow-up period for evaluation, relative to the period of time the intervention might be used in practice. This is sometimes called the "pre-marketing phase" because it actually measures consumer response to the drug.
It is common practice that certain Phase III trials will continue while the regulatory submission is pending at the appropriate regulatory agency. This allows patients to continue to receive possibly lifesaving drugs until the drug can be obtained by purchase. Other reasons for performing trials at this stage include attempts by the sponsor at "label expansion" (to show the drug works for additional types of patients/diseases beyond the original use for which the drug was approved for marketing), to obtain additional safety data, or to support marketing claims for the drug. Studies in this phase are by some companies categorized as "Phase IIIB studies."
While not required in all cases, it is typically expected that there be at least two successful Phase III trials, demonstrating a drug's safety and efficacy, to obtain approval from the appropriate regulatory agencies such as FDA (US), or the EMA (European Union).
Once a drug has proved satisfactory after Phase III trials, the trial results are usually combined into a large document containing a comprehensive description of the methods and results of human and animal studies, manufacturing procedures, formulation details, and shelf life. This collection of information makes up the "regulatory submission" that is provided for review to the appropriate regulatory authorities in different countries. They will review the submission, and if it is acceptable, give the sponsor approval to market the drug.
Most drugs undergoing Phase III clinical trials can be marketed under FDA norms with proper recommendations and guidelines through a New Drug Application (NDA) containing all manufacturing, preclinical, and clinical data. In case of any adverse effects being reported anywhere, the drugs need to be recalled immediately from the market. While most pharmaceutical companies refrain from this practice, it is not abnormal to see many drugs undergoing Phase III clinical trials in the market.
=== Adaptive design ===
The design of individual trials may be altered during a trial – usually during Phase II or III – to accommodate interim results for the benefit of the treatment, adjust statistical analysis, or to reach early termination of an unsuccessful design, a process called an "adaptive design". Examples are the 2020 World Health Organization Solidarity trial, European Discovery trial, and UK RECOVERY Trial of hospitalized people with severe COVID-19 infection, each of which applies adaptive designs to rapidly alter trial parameters as results from the experimental therapeutic strategies emerge.
Adaptive designs within ongoing Phase II–III clinical trials on candidate therapeutics may shorten trial durations and use fewer subjects, possibly expediting decisions for early termination or success, and coordinating design changes for a specific trial across its international locations.
=== Success rate ===
For vaccines, the probability of success ranges from 7% for non-industry-sponsored candidates to 40% for industry-sponsored candidates.
A 2019 review of average success rates of clinical trials at different phases and diseases over the years 2005–15 found a success range of 5–14%. Separated by diseases studied, cancer drug trials were on average only 3% successful, whereas ophthalmology drugs and vaccines for infectious diseases were 33% successful. Trials using disease biomarkers, especially in cancer studies, were more successful than those not using biomarkers.
A 2010 review found about 50% of drug candidates either fail during the Phase III trial or are rejected by the national regulatory agency.
== Cost of trials by phases ==
In the early 21st century, a typical Phase I trial conducted at a single clinic in the United States ranged from $1.4 million for pain or anesthesia studies to $6.6 million for immunomodulation studies. Main expense drivers were operating and clinical monitoring costs of the Phase I site.
The amount of money spent on Phase II or III trials depends on numerous factors, with therapeutic area being studied and types of clinical procedures as key drivers. Phase II studies may cost as low as $7 million for cardiovascular projects, and as much as $20 million for hematology trials.
Phase III trials for dermatology may cost as low as $11 million, whereas a pain or anesthesia Phase III trial may cost as much as $53 million. An analysis of Phase III pivotal trials leading to 59 drug approvals by the US Food and Drug Administration over 2015–16 showed that the median cost was $19 million, but some trials involving thousands of subjects may cost 100 times more.
Across all trial phases, the main expenses for clinical trials were administrative staff (about 20% of the total), clinical procedures (about 19%), and clinical monitoring of the subjects (about 11%).
== Phase IV ==
A Phase IV trial is also known as a postmarketing surveillance trial or drug monitoring trial to assure long-term safety and effectiveness of the drug, vaccine, device or diagnostic test. Phase IV trials involve the safety surveillance (pharmacovigilance) and ongoing technical support of a drug after it receives regulatory approval to be sold. Phase IV studies may be required by regulatory authorities or may be undertaken by the sponsoring company for competitive (finding a new market for the drug) or other reasons (for example, the drug may not have been tested for interactions with other drugs, or on certain population groups such as pregnant women, who are unlikely to subject themselves to trials). The safety surveillance is designed to detect any rare or long-term adverse effects over a much larger patient population and longer time period than was possible during the Phase I-III clinical trials. Harmful effects discovered by Phase IV trials may result in a drug being withdrawn from the market or restricted to certain uses; examples include cerivastatin (brand names Baycol and Lipobay), troglitazone (Rezulin) and rofecoxib (Vioxx).
== Overall cost ==
The entire process of developing a drug from preclinical research to marketing can take approximately 12 to 18 years and often costs well over $1 billion.
== References == | Wikipedia/Phase_II_clinical_trial |
The Drugs for Neglected Diseases initiative (DNDi) is a collaborative, patients' needs-driven, non-profit drug research and development (R&D) organization that is developing new treatments for neglected diseases, notably leishmaniasis, sleeping sickness (human African trypanosomiasis, HAT), Chagas disease, malaria, filarial diseases, mycetoma, paediatric HIV, cryptococcal meningitis, hepatitis C, and dengue. DNDi's malaria activities were transferred to Medicines for Malaria Venture (MMV) in 2015.
Led by Executive Director Luis Pizarro, DNDi has offices in Switzerland (Geneva), Brazil, the Democratic Republic of Congo, India, Japan, Kenya, Malaysia, and an affiliate in the United States.
== Origins ==
Despite the major progress achieved in medicine during the past 50 years, many tropical diseases affecting the poorest are still neglected. More than a billion people – more than a seventh of the world's population – are infected with one of the 20 diseases listed by the World Health Organization (WHO) as neglected tropical diseases. Although neglected tropical diseases can be fatal, there is a lack of modern, safe and effective medications to treat these illnesses.
Evidence of the lack of new drugs for diseases that cause high mortality and morbidity among people living in poor areas has been published in the scientific literature. One publication reported that only 1.1% of new drugs were approved specifically for neglected diseases over a period of 25 years (1975 to 1999) despite the fact that these diseases represented 11.4% of the global burden. Another indicated that this trend remained the same between 2000 and 2011 with only 1.2% of the new chemical entities brought to market indicated for neglected diseases.
DNDi was created in 2003 to develop new treatments for neglected diseases. The organization was set up by key research and health institutions, notably from the public sector in neglected-disease-endemic countries – the Oswaldo Cruz Foundation from Brazil, the Indian Council of Medical Research, the Kenya Medical Research Institute, the Ministry of Health of Malaysia and France's Pasteur Institute, with seed funding from Médecins Sans Frontières' (MSF) 1999 Nobel Peace Prize. The WHO Special Programme for Research and Training in Tropical Diseases (TDR) acts as a permanent observer to the initiative.
DNDi's founder Bernard Pécoul led the organization from 2003 until 2022.
From 2022 until now, the organization has a new director, a Chilean doctor called Luis Pizarro.
== Non-profit drug development model ==
As people with neglected diseases do not represent a lucrative market for pharmaceutical companies, incentives to invest in research and development are lacking for these diseases.
Alternatives to profit-driven drug development emerged in the early 2000s to meet the needs of these neglected patients. Product development partnerships (PDPs), also called public-private partnerships (PPPs) aim to implement and accelerate research and development (R&D) into health tools (diagnostics, vaccines, drugs) for diseases that are neglected, by enabling new collaborations between private industry, academia, and the public sector. Examples of PDPs include the International AIDS Vaccine Initiative, MMV, the Global Alliance for TB Drug Development (TB Alliance), and DNDi.
PDPs act as 'conductors of a virtual orchestra', leveraging partners' specific assets, capacities, and expertise to implement projects at all stages of the R&D process, integrating capabilities from academia; public-sector research institutions, particularly in neglected disease-endemic countries; pharmaceutical and biotechnology companies; non-governmental organizations including other PDPs; and governments worldwide.
To overcome the lack of commercial research into drug development, PDPs can apply "delinkage" principles that aim to separate the cost of research and development from the price of products. This allows the incentive for investing in a particular disease to be independent of the price at which any developed products will be sold.
== Key achievements ==
DNDi has built a large drug pipeline for neglected diseases with both improvements on existing drugs and entirely new chemical entities. To date, their 13 key achievements are
Treatments delivered to date:
=== ASAQ, fixed-dose combination for malaria, 2007 ===
Launched in 2007, this antimalarial product is a fixed-dose combination of artesunate/amodiaquine (ASAQ). The result of a partnership between DNDi and French pharmaceutical company Sanofi, ASAQ, which is produced in Morocco, is affordable (available for only $0.05 for children, $1 for adults), is administered in a simple regimen (1 or 2 tablets per day for three days), meets the latest WHO guidelines for malaria treatment in Africa and was granted "pre-qualified" status in 2008. Although developed without a patent, ASAQ is included in the WHO Model List of Essential Medicines and Essential Medicines List for Children, is registered in 32 African countries, India, Ecuador, and in Colombia, and more than 437 million treatments have been distributed.
A technology transfer agreement has been signed with industrial partner Zenufa in Tanzania in order to provide an additional source of ASAQ. ASAQ was handed over to the MMV Access and Product Management Team in May 2015.
=== ASMQ, fixed-dose combination for malaria, 2008 ===
The second antimalarial treatment developed by DNDi is a fixed-dose combination of artesunate and mefloquine launched in 2008. It was developed by an international collaboration within the FACT Project Consortium. It has a simple and adapted regimen, a three-year shelf-ife and a very high compliance rate. ASMQ is produced in Brazil by Farmanguinhos/Fiocruz and thanks to a South–South technology transfer, it is now also produced by Cipla. The latter was granted "pre-qualified" status by the WHO in 2012 and included on the WHO Model List of Essential Medicines and Essential Medicines List for Children in 2013. By 2015 it was registered in Brazil, India, Malaysia, Myanmar, Tanzania, Vietnam, Niger, Burkina Faso, Thailand and Cambodia. By the end of 2015 more than one million treatments had been distributed. ASMQ was handed over to the MMV Access and Product Management Team in May 2015.
=== NECT, improved treatment for sleeping sickness, 2009 ===
Nifurtimox-eflornithine combination treatment (NECT), a combination therapy of nifurtimox and eflornithine, is the first new, improved treatment option in 25 years for stage 2 (advanced stage) human African trypanosomiasis (HAT) also known as sleeping sickness. It is the result of a six-year partnership between NGOs, governments, pharmaceutical companies, and the WHO. It was launched in 2009 and included on the WHO Model List of Essential Medicines and WHO Essential Medicines List for Children in 2009 and 2013 respectively. It requires shorter hospitalization than previous treatment, and is much safer than previously widely used arsenic-based melarsoprol that killed about 5% of patients. NECT is now used to treat 100% of the patients infected with HAT stage 2 in all 13 endemic countries.
=== SSG&PM, combination treatment for visceral leishmaniasis, 2010 ===
SSG&PM, a sodium stibogluconate plus paromomycin combination therapy, is a shorter-course, cost-efficient treatment option against visceral leishmaniasis (VL) in East Africa available since 2010. It is the result of a six-year partnership between DNDi, the Leishmaniasis East Africa Platform (LEAP), the National Control Programmes of Kenya, Sudan, Ethiopia, and Uganda, Médecins Sans Frontières (MSF) and the WHO. It was recommended by the WHO Expert Committee on the Control of Leishmaniasis in 2010 as the first-line treatment in East Africa, and more than 10,000 patients have been treated. Sudan, Ethiopia, South Sudan and Somalia have released revised guidelines recommending SSG&PM as the first-line treatment for VL.
=== Combination treatments for visceral leishmaniasis in Asia, 2011 ===
Single dose amphotericin B and paromomycin/miltefosine/amphotericin B combinations were recommended by the WHO Expert Committee on the Control of Leishmaniasis (2010). These treatments are less toxic than previous mainstay treatments, useful in areas of antimonial resistance, are shorter course and their cost is comparable with previous treatments. In 2010, a study investigating the three possible 2-drug combinations of amphotericin B, miltefosine and paromomycin was completed in India. All three combination treatments were shown to be highly efficacious (> 97.5% cure rate). A WHO Expert committee recommended these treatments to be used preferentially to current established monotherapy treatments for VL in South Asia. DNDi is working with TDR and WHO to facilitate their introduction and support VL elimination strategies. DNDi conducted more studies, including a pilot project in the Bihar State of India (2012–2015) that demonstrated the safety and effectiveness of combination therapies based on amphotericin B, miltefosine, and paromomycin at the primary healthcare level, and single dose amphotericin B at the hospital level. Based on the study results, the Indian National Roadmap for Kala-Azar Elimination in August 2014 recommended use of single dose amphotericin B as a first option treatment for the treatment of VL patients, with paromomycin and miltefosine as a second option at all levels; a policy also reflected in Bangladesh and Nepal. This removal of miltefosine monotherapy is an important policy change. This project has been a collaboration with a consortium of partners.
=== Paediatric benznidazole for Chagas disease, 2011 ===
This is the only paediatric dosage treatment for Chagas disease, launched in 2011 through a collaboration between DNDi and Laboratório Farmacêutico do Estado de Pernambuco (LAFEPE). In November 2013, the Mundo Sano Foundation and DNDi signed a collaboration agreement to deliver a second source of the treatment in partnership with ELEA. The paediatric dosage form of benznidazole is designed for infants and young children under two years of age (20 kg body weight) infected congenitally. Thanks to its age-adapted, easy-to-use, affordable, and non-patented tablet, the new treatment contributes to improved dosing accuracy, safety, and adherence to treatment. The paediatric dosage form of benznidazole was granted registration by Brazil's National Health Surveillance Agency in 2011, and further endemic countries are targeted for obtaining registration. It was included on the WHO Essential Medicines List for Children in July 2013.
=== Superbooster therapy for children living with HIV and tuberculosis, 2016 ===
Among the many challenges of treating children co-infected with both tuberculosis (TB) and HIV is the fact that a key TB drug negates the effectiveness of ritonavir, one of the main antiretrovirals to treat HIV. A DNDi-sponsored study at five hospitals in South Africa demonstrated the effectiveness of 'super-boosting' or adding extra ritonavir to a child's treatment regimen. WHO has since strengthened recommendations to use super-boosting in TB/HIV co-infected children.
=== Fexinidazole, 2018 ===
Fexinidazole is the first entirely oral treatment for sleeping sickness (or human African trypanosomiase) due to Trypanosoma brucei gambiense. It was developed in partnership by DNDi, Sanofi, and others. The clinical trials enrolled 749 patients from the Democratic Republic of the Congo and the Central African Republic. Results published in The Lancet showed high efficacy and safety for both stages of the disease. Fexinidazole is administered as oral tablets for 10 days.
In November 2018, the European Medicines Agency adopted a positive scientific opinion of fexinidazole. In December 2018, fexinidazole was approved in the Democratic Republic of the Congo.
Other project:
=== Global Antibiotic Research & Development Partnership ===
In 2016, the WHO and DNDi collaborated to launch the Global Antibiotic Research and Development Partnership (GARDP), a not-for-profit research and development organization that addresses global public health needs by developing and delivering new or improved antibiotic treatments, while endeavouring to ensure their sustainable access. In 2018, GARDP was organized as an independent legal entity.
=== Ravidasvir, 2021 ===
Access to affordable hepatitis C treatment with highly efficacious direct-acting antivirals (DAAs) remains extremely limited in many low- and middle-income countries. In 2016, DNDi signed agreements with US biopharmaceutical company Presidio Pharmaceuticals, developer of the DAA drug candidate ravidasvir, and its licensing partner, the Egyptian generic manufacturer Pharco Pharmaceuticals, to enable testing of a new combination treatment optimised for public health use: ravidasvir + sofosbuvir. A Phase II/III study in Malaysia and Thailand, co-sponsored by the Malaysian and Thai Ministries of Health and co-financed by the MSF Transformational Investment Capacity (TIC) initiative, showed that 12 weeks after the end of treatment, 97% of participants were cured. Patients with multiple risk factors were cured, and no unexpected safety signals were detected. In June 2021, Malaysia granted a conditional registration for ravidasvir.
=== New treatments for HIV/VL, 2022 ===
Leishmania-HIV coinfection has been reported from 35 endemic countries [http://www.who.int/news-room/fact-sheets/detail/leishmaniasis]. People co-infected with HIV and visceral leishmaniasis have poor response to treatment, higher risk of death, and often experience multiple relapse episodes. Based on the results of two studies, in June 2022 WHO released new treatment guidelines for the treatment of people co-infected with visceral leishmaniasis and HIV, recommending a combination of liposomal amphotericin B with miltefosine.
=== Leishmaniasis in Latin America, 2022 ===
Previously, first-line treatment recommendations for visceral leishmaniasis in Brazil included the use of meglumine antimoniate, which has serious limitations due to toxicity, parenteral administration, and the need for hospitalization. Results of a trial in partnership with the University of Brasilia and the Oswaldo Cruz Foundation of Brazil showed that due to lower toxicity and acceptable efficacy, liposomal amphotericin B would be a more suitable first-line treatment for visceral leishmaniasis than standard treatment. In June 2022, the Pan American Health Organization (PAHO) published new guidelines for the treatment of leishmaniasis in the Americas, which recommend liposomal amphotericin B for the treatment of visceral leishmaniasis instead of pentavalent antimonials.
=== 4-in-1 for paediatric HIV, 2022 ===
This '4-in-1' fixed-dose combination combines the protease inhibitors lopinavir and ritonavir with the nucleoside reverse transcriptase inhibitors (NRTIs) lamivudine and abacavir for the treatment of paediatric HIV. The 4-in-1 is a significant improvement over currently available lopinavir-based regimens, because it is formulated as a granule-filled capsule, which is heat-stable, taste-masked, solid, and does not contain alcohol or inappropriate solvents. It was developed for infants and young children weighing from 3 to 25 kg, in partnership with Cipla Limited. It can be administered by opening the capsules and sprinkling the granules on soft food, water, or milk. The South African Health Products Regulatory Authority (SAHPRA) approved the 4-in-1 in June 2022.
== Awards ==
In 2013, DNDi won the BBVA Foundation Frontiers of Knowledge Award in the Development Cooperation category for developing and delivering new treatments for poverty-related diseases including Chagas disease, sleeping sickness, malaria and leishmaniasis.
DNDi received the Carlos Slim Health Award in 2013. Created in 2008 by the Carlos Slim Foundation, the aim of the award is to distinguish the people and institutions who are committed to improving the levels of health among the population of Latin America and the Caribbean.
In 2013, The Rockefeller Foundation asked the global community to nominate organizations and individuals who were making a difference for poor and vulnerable populations through innovation. From those nominations, and the votes of individuals around the world, The Rockefeller Foundation selected three winners of the 2013 Next Century Innovators Award. DNDi was one of the awardees.
On December 11, 2015, DNDi won the national FINEP Award for Innovation. The award was in recognition of an innovative R&D model that has delivered a new antimalarial drug developed in Brazil.
DNDi received the prize for innovation in 2017 and the 'cuvée 2018 de la Vigne des Nations' in 2018, both from the Canton of Geneva.
The publication Oral fexinidazole for late-stage African Trypanosoma brucei gambiense trypanosomiasis: a pivotal multicentre, randomised, non-inferiority trial published November 4, 2017 in The Lancet was one of the two winners of the 2018 edition of the Anne Maurer-Cecchini Award.
A short film about fexinidazole, a new treatment for sleeping sickness, was awarded the Grand Prix at the inaugural World Health Organization 'Health for All' film festival in 2020. 'A doctor's dream' was produced by DNDi with Scholars and Gentlemen, a production company from South Africa.
In 2023, the organization was awarded the Princess of Asturias Award in the category of "International Cooperation".
== Regional clinical trial platforms ==
DNDi works with partners in disease-endemic countries to strengthen existing clinical research capacity and build new capacity where necessary. DNDi helped in the setting up of four regional disease-specific platforms in Africa and Latin America including the Leishmaniasis East Africa Platform (LEAP) on leishmaniasis. the HAT Platform on sleeping sickness (human African trypanosomiasis), the Chagas Clinical Research Platform (CCRP), and the RedeLeish Network on leishmaniasis in Latin America and continues to work with them.
Their mission is to define patient needs, taking into consideration the local conditions, bring together key regional actors in the field of health, reinforce clinical capacities in endemic regions, address infrastructural requirements where necessary and provide on-site training.
== Long-term objective ==
As part of its Strategic Plan 2021–2028, DNDi aims to deliver 15 to 18 new treatments, for a total of 25 new treatments in its first 25 years.
== See also ==
Neglected tropical diseases
Fexinidazole
Artemisinin
Quinine
== Notes and references ==
== External links ==
Drugs for Neglected Diseases Initiative
WHO Tropical Disease Research
Global Antibiotic Research & Development Partnership (GARDP) | Wikipedia/Drugs_for_Neglected_Diseases_initiative |
Neglected tropical diseases (NTDs) are a diverse group of tropical infections that are common in low-income populations in developing regions of Africa, Asia, and the Americas. They are caused by a variety of pathogens, such as viruses, bacteria, protozoa, and parasitic worms (helminths). These diseases are contrasted with the "big three" infectious diseases (HIV/AIDS, tuberculosis, and malaria), which generally receive greater treatment and research funding. In sub-Saharan Africa, the effect of neglected tropical diseases as a group is comparable to that of malaria and tuberculosis. NTD co-infection can also make HIV/AIDS and tuberculosis more deadly.
Some treatments for NTDs are relatively inexpensive. For example, praziquantel for schistosomiasis costs about US $0.20 per child per year. Nevertheless, in 2010 it was estimated that control of neglected diseases would require funding of between US$2 billion and $3 billion over the subsequent five to seven years. Some pharmaceutical companies have committed to donating all the drug therapies required, and mass drug administration efforts (for example, mass deworming) have been successful in several countries. While preventive measures are often more accessible in the developed world, they are not universally available in poorer areas.
Within developed countries, neglected tropical diseases affect the very poorest in society. In the United States, there are up to 1.46 million families, including 2.8 million children, living on less than two dollars per day. In developed countries, the burdens of neglected tropical diseases are often overshadowed by other public health issues. However, many of the same issues put populations at risk in developed as well as developing nations. For example, other problems stemming from poverty, such as lack of adequate housing, can expose individuals to the vectors of these diseases.
Twenty neglected tropical diseases are prioritized by the World Health Organization (WHO), though other organizations define NTDs differently. Chromoblastomycosis and other deep mycoses, scabies and other ectoparasites, and snakebite envenomation were added to the WHO list in 2017. These diseases are common in 149 countries, affecting more than 1.4 billion people (including more than 500 million children) and costing developing economies billions of dollars every year. They resulted in 142,000 deaths in 2013, down from 204,000 deaths in 1990.
== Reasons for neglect ==
The importance of neglected tropical diseases has been underestimated since many are asymptomatic and have long incubation periods. The connection between death and a neglected tropical disease that has been latent for a long period is often not realized. Areas of high endemicity are often geographically isolated, making treatment and prevention much more difficult.
There are three other major reasons that these diseases have been overlooked: they mainly affect the poorest countries of the developing world; in recent years public health efforts have focused heavily on decreasing the prevalence of HIV/AIDS, tuberculosis, and malaria (far more resources are given to those three diseases because of their higher mortality rates and higher public awareness of them); and neglected tropical diseases do not currently have a prominent cultural figure to champion their elimination.
=== Stigma ===
Neglected tropical diseases are often associated with social stigma, making their treatment more complex. Public health research has only recently begun to focus on stigma as a component of the issue. From the 1960s onward, approximately one citation a year related to social stigma. In 2006, there were 458.
Stigma greatly affects disease control by decreasing help-seeking and treatment adherence. Disease control programs since the 1980s have begun to integrate stigma mitigation into their offerings. In India, a leprosy program prioritized the message that "leprosy is curable, not hereditary" in order to inspire optimism in highly affected communities. The goal was to make leprosy a disease "like any other", so as to reduce stigma. At the same time, medical resources were optimized to fulfill the promise that the disease could be cured.
=== Economic incentives ===
Treatment and prevention of neglected tropical diseases are not seen as profitable, so patents and profit play a reduced role in stimulating innovation compared to other diseases. Like all non-commercial areas, communities affected by these diseases are reliant on governments and philanthropy. Currently, the pharmaceutical industry views research and development as highly risky. For this reason, resources are not often put into the field of NTDs, and new chemical products are often expensive. A review of public and private initiatives found that of the 1,393 new chemical products that were marketed between 1975 and 1999, only 16 were related to tropical diseases or tuberculosis. The same review found that there was a 13-fold greater chance of a newly marketed drug being for central nervous system disorders or cancer than for an NTD.
Because of a lack of economic incentives for the pharmaceutical industry, successful NTD treatment programs have often relied on donations. For instance, the Mectizan Donation Program has donated over 1.8 billion tablets of ivermectin. While developed countries often rely on government-run and private partnerships to fund such projects, developing nations frequently have significantly lower per-person spending on these diseases.
A 2006 report found that the Gates Foundation funded most extra activities to counter these diseases.
=== Neglected diseases in developed nations ===
Since 2008, the concept of "neglected diseases of poverty" has been developed and explored. This group of diseases, which overlaps with neglected tropical diseases, also pose a threat to human health in developed nations. In the United States alone, there are at least 12 million people with neglected parasitic infections. They make up a hidden disease burden among the poorest people in wealthy societies. In developed nations, lack of knowledge in the healthcare industry and lack of conclusive diagnostic tests perpetuate the neglect of this group of diseases.
In the United States, rates of parasitic infection can be distributed along geographic, racial, and socio-economic lines. Among African Americans, there may be up to 2.8 million cases of toxocariasis. Toxocariasis, trichomoniasis, and some other neglected infections occur in the United States at the same rate as in Nigeria. Within the Hispanic community, neglected infections are concentrated near the US–Mexico border. Vector-borne illnesses are especially high, with some rates approaching those of Latin America. Chagas disease was found in the US as early as the 1970s. However, in the developed world, diseases that are associated with poverty are often not addressed comprehensively. This may be due to a lack of economic incentives and public policy failings. A lack of awareness prevents effective policy generation and leaves healthcare services unequipped to address the issue. Additionally, little effort is put into creating and maintaining large data sets on neglected diseases in the United States and other developed nations. The first summit on the issue was held by the Adler Institute on Social Exclusion in the United States in 2009.
In Europe, a similar trend is seen. Neglected tropical diseases are concentrated in eastern and southern Europe, where poverty levels are highest. The most prevalent diseases in this region are ascariasis, trichuriasis, zoonotic helminth infections, and visceral leishmaniasis. Migration paths to Europe, most notably to Spain, have brought diseases to Europe as well. As many as 6,000 cases of Chagas disease have been introduced in this way. In response to a growing awareness of the burden on these populations, the European Centre for Disease Prevention and Control has laid out ten public health guidelines. They cover a variety of topics, from health education and promotion to community partnerships and the development of a minority healthcare workforce.
== List of diseases ==
There is some debate among the WHO, CDC, and infectious disease experts over which diseases are classified as neglected tropical diseases. Feasey, a researcher in neglected tropical diseases, notes 13 neglected tropical diseases: ascariasis, Buruli ulcer, Chagas disease, dracunculiasis, hookworm infection, human African trypanosomiasis, leishmaniasis, leprosy, lymphatic filariasis, onchocerciasis, schistosomiasis, trachoma, and trichuriasis. Fenwick recognizes 12 "core" neglected tropical diseases: the same as above, excluding hookworm.
These diseases result from four classes of causative pathogens: (i) protozoa (Chagas disease, human African trypanosomiasis, and leishmaniasis); (ii) bacteria (Buruli ulcer, leprosy, trachoma, and yaws), (iii) helminths or metazoan worms (cysticercosis/taeniasis, dracunculiasis, echinococcosis, foodborne trematodiases, lymphatic filariasis, onchocerciasis, schistosomiasis, and soil-transmitted helminthiasis); and (iv) viruses (dengue, chikungunya, and rabies).
The WHO recognizes the twenty diseases below as neglected tropical diseases.
The World Health Organization's 2010 report on neglected tropical diseases offers an expanded list including dengue, rabies, yaws, cysticercosis, echinococcosis, and foodborne trematode infections.
=== Buruli ulcer ===
Buruli ulcer is caused by the bacterium Mycobacterium ulcerans. It is related to the bacteria that cause tuberculosis and leprosy. Mycobacterium ulcerans produces a toxin, mycolactone, that destroys tissue. The prevalence of Buruli ulcer is unknown. The risk of mortality is low, although secondary infections can be lethal. Morbidity takes the form of deformity, disability, and skin lesions, which can be prevented through early treatment with antibiotics and surgery. It is found in Africa, Asia, Australia, and Latin America.
=== Chagas disease ===
Chagas disease is also known as American trypanosomiasis. There are approximately 15 million people infected with Chagas disease. Morbidity rates are higher for immunocompromised individuals, children, and the elderly, but can be very low if the disease is treated early. Chagas disease does not kill victims rapidly, instead causing years of debilitating chronic symptoms.
It is caused by the vector-borne protozoa Trypanosoma cruzi. It is spread by contact with Trypanosoma cruzi-infected feces of the triatomine (assassin bug). The protozoan can enter the body via the bug's bite, skin breaks, or mucous membranes. Infection can result from eating infected food or coming into contact with contaminated bodily fluids.
There are two phases of Chagas disease. The acute phase is usually asymptomatic. The first symptoms are usually skin chancres, unilateral purplish orbital oedema, local lymphadenopathy, and fever, accompanied by a variety of other symptoms depending on the infection site. The chronic phase occurs in 30 percent of all infections and can take three forms: asymptomatic (most prevalent), cardiac, and digestive lesions.
Chagas disease can be prevented by avoiding insect bites through insecticide spraying, home improvement, bed nets, hygienic food, medical care, laboratory practices, and testing. It can be diagnosed through a serological test, although the test is not very accurate. Treatment is with medication, which may have severe side effects.
=== Dengue and chikungunya ===
There are 50–100 million dengue virus infections annually. Dengue fever is usually not fatal, but infection with one of four serotypes can increase later susceptibility to other serotypes, resulting in a potentially fatal disease called severe dengue. Dengue fever is caused by a flavivirus which is spread mostly by the bite of the Aedes aegypti mosquito. No treatment for either dengue or severe dengue exists beyond palliative care. The symptoms are high fever and flu-like symptoms. It is found in Asia, Latin America, and Northern Australia.
Chikungunya is an arboviral disease transmitted by A. albopictus and A. aegypti mosquitoes. The virus was first isolated from an outbreak in Tanzania in 1952. Chikungunya virus is a member of the genus Alphavirus and family Togaviridae. The word "chikungunya" is from the Makonde language and means "that which bends up", referring to the effect of debilitating joint pain on the patient. Symptoms, generally appearing 5–7 days after exposure, can be confused with dengue and include fever, rash, headache, joint pain, and swelling. The disease mainly occurs in Africa and Asia.
=== Dracunculiasis ===
Dracunculiasis is also known as Guinea-worm disease. In 2019, 53 cases were reported across four countries, a substantial decrease from 3,500,000 cases in 1986. It is not fatal, but can cause months of inactivity. It is caused by drinking water contaminated by water fleas infected with guinea-worm larvae. Approximately one year after infection, a painful blister forms and one or more worms emerge. Worms can be up to 1 metre long.
It is usually treated by World Health Organization volunteers who clean and bandage wounds caused by worms and return daily to pull the worm out a few more inches. Dracunculiasis is preventable by water filtration, immediate case identification to prevent spread, health education, and treating ponds with larvicide. An eradication program has been able to reduce prevalence. As of 2014, the four endemic countries are Chad, Ethiopia, Mali, and South Sudan.
=== Echinococcosis ===
The rate of echinococcosis is higher in rural areas, and there are more than one million people infected currently. It is caused by ingesting parasites in animal feces.
There are two versions of the disease: cystic and alveolar. Both versions involve an asymptomatic incubation period of several years. In the cystic version, liver cysts cause abdominal pain, nausea, and vomiting, while cysts in the lungs cause chronic cough, chest pain, and shortness of breath. In alveolar echinococcosis, a primary cyst develops, usually in the liver, in addition to weight loss, abdominal pain, malaise, and signs of liver failure. Untreated alveolar echinococcosis is fatal.
Surgery and drugs can be used to treat echinococcosis. It can be prevented by deworming dogs, sanitation, proper disposal of animal feces, health education, and livestock vaccination. Cystic echinococcosis is found in the eastern portion of the Mediterranean region, northern Africa, southern and eastern Europe, the southern portion of South America, and Central Asia. Alveolar echinococcosis is found in western and northern China, Russia, Europe, and northern North America. It can be diagnosed through imaging techniques and serological tests.
=== Yaws ===
There are limited data available on the prevalence of yaws, although it primarily affects children. The mortality risk is very low, but the disease causes disfigurement and disability if untreated. The most common symptom is skin lesions. It is a chronic bacterial infection, transmitted by skin contact, and caused by the spirochete bacterium Treponema pallidum pertenue. It is treated with antibiotics and can be prevented through hygiene and sanitation. Yaws is most prevalent in warm, moist tropical regions of the Americas, Africa, Asia, and the Pacific.
=== Foodborne trematodiases ===
Foodborne trematode infections include clonorchiasis, opisthorchiasis, fascioliasis, and paragonimiasis. These infections are all zoonotic, primarily affecting domestic or wild animals, but can also be transmitted to humans. They are acquired by eating food, such as raw fish, contaminated with the larval stages of the parasites. At least 40 million people are thought to be infected.
=== Human African trypanosomiasis ===
African trypanosomiasis (African sleeping sickness) is a somewhat rare protozoal disease, with fewer than 10,000 cases currently. Human African trypanosomiasis is vector-borne and spreads through the bite of the tsetse fly. The most common symptoms are fever, headache, lymphadenopathy, sleeping disturbances, personality changes, cognitive decline, and coma. The disease is always fatal if untreated. The current forms of treatment are highly toxic and ineffective, as resistance is spreading. It is diagnosed through an inexpensive serological test.
=== Leishmaniasis ===
The three forms of leishmaniasis, a protozoal disease, are visceral (Kala-azar), cutaneous, and mucocutaneous. There are an estimated 12 million people infected. It is fatal if untreated, and 20,000 deaths from visceral leishmaniasis occur annually. It is a vector-borne disease caused by the bite of sandflies. At least 90 percent of visceral leishmaniasis occurs in Bangladesh, Brazil, Ethiopia, India, South Sudan, and Sudan. Cutaneous leishmaniasis occurs in Afghanistan, Algeria, Brazil, Colombia, Iran, Pakistan, Peru, Saudi Arabia, and Syria. Around 90 percent of mucocutaneous leishmaniasis occurs in Bolivia, Brazil, and Peru.
A vaccine is under development to prevent leishmaniasis. The only other method of prevention is avoidance of sandfly bites. Diagnosis can be made by clinical signs, serological tests, or parasitological tests. Leishmaniasis can be treated with expensive medications.
=== Leprosy ===
According to recent figures from the WHO, 208,619 new cases of leprosy were reported in 2018 from 127 countries. It is most prevalent in India (69% of cases), Brazil, Indonesia, Nigeria, the Democratic Republic of the Congo, Madagascar, and East Africa from Mozambique to Ethiopia, with the highest relative incidence in India, Brazil, and Nepal. There are one to two million individuals currently disabled or disfigured due to past or present leprosy. It is caused by bacteria and transmitted through droplets from the mouth and nose of infected individuals.
Leprosy causes disfigurement and physical disabilities if untreated. It is curable if treated early. Treatment requires multidrug therapy. The BCG vaccine has some preventative effect against leprosy. Leprosy has a 5–20 year incubation period, and the symptoms are damage to the skin, nerves, eyes, and limbs.
=== Lymphatic filariasis ===
Lymphatic filariasis is also known as elephantiasis. There are approximately 120 million individuals infected and 40 million with deformities. Approximately two-thirds of cases are in Southwest Asia, and one-third are in Africa. Lymphatic filariasis is rarely fatal but has lifelong implications, such as lymphoedema of the limbs, genital disease, and painful recurrent attacks. Most people are asymptomatic but have lymphatic damage. Up to 40 percent of infected individuals have kidney damage. It is a vector-borne disease, caused by nematode worms that are transmitted by mosquitoes.
It can be treated with cost-effective antihelminthic treatments, and washing skin can slow or even reverse damage. It is diagnosed with a finger-prick blood test.
=== Noma ===
Noma, an opportunistic bacterial infection causing gangrenous necrosis of the mouth, was added to the World Health Organization's list of neglected tropical diseases in December 2023.
=== Onchocerciasis ===
Onchocerciasis is also known as river blindness. There are 20.9 million people infected, and prevalence is higher in rural areas. Over 99 percent of cases are in sub-Saharan Africa. It causes blindness, skin rashes, lesions, intense itching, and skin depigmentation. It is a vector-borne disease, caused by blackflies infected with filarial worms.
It can be treated with ivermectin and prevented by insecticide spraying or preventative dosing with ivermectin.
=== Rabies ===
There are two forms of rabies: furious and paralytic. It is mostly found in Asia and Africa. There is a higher prevalence in rural areas, and it disproportionately affects children. Rabies is fatal after symptoms develop. It is caused by a lyssavirus transmitted through wounds or bites from infected animals.
The first symptoms are fever and pain near the infection site, which occur after a one- to three-month incubation period. Furious rabies (the more common type) causes hyperactivity, hydrophobia, and aerophobia; death by cardio-respiratory arrest occurs within days. Paralytic rabies causes a slow progression from paralysis to coma to death. There are 60,000 deaths from rabies annually.
It can be prevented in dogs by vaccination and by cleaning and disinfecting bite wounds and post-exposure prophylaxis. Rabies is undiagnosable before symptoms develop. It can be detected through tissue testing after symptoms develop.
=== Schistosomiasis ===
There are over 200 million cases of schistosomiasis. Approximately 85 percent of cases are in sub-Saharan Africa. The disease can be fatal by causing bladder cancer and hematemesis. Schistosoma species have a complex life cycle that alternates between humans and freshwater snails. Infection occurs when the skin comes into contact with contaminated fresh water in which snails that carry the parasite are living. Symptoms for schistosomiasis are not caused by the worms but by the body's reaction to the eggs. The eggs that do not pass out of the body can become lodged in the intestine or bladder, causing inflammation or scarring. Children who are repeatedly infected can develop anemia, malnutrition, and learning difficulties. The symptoms are usually haematuria, bladder obstruction, renal failure, bladder cancer, periportal fibrosis, bladder fibrosis, liver fibrosis, portal hypertension, cervical lesions, ascites, and esophageal varices.
Inexpensive praziquantel can be used to treat individuals with schistosomiasis, but it cannot prevent reinfection. The cost of prevention is US$0.32 per child per year. Mass deworming treatment with praziquantel, better access to safe water, sanitation, and health education can all be used to prevent schistosomiasis. Vaccines are under development. It can be diagnosed through a serological test, but the test often produces false negatives.
=== Soil-transmitted helminthiasis ===
Soil-transmitted helminthiasis is the most prevalent neglected tropical disease. The four major worm species responsible for soil-transmitted helminthiasis are Ascaris (roundworms), Trichuris (whipworm), the hookworms Necator americanus and Ancylostoma duodenale, and Strongyloides stercoralis. There are 1.5 billion people currently infected. Soil-transmitted helminthiasis occurs in sub-Saharan Africa, the Americas, China, and East Asia. The mortality risk is very low. The most common symptoms are anemia, stunted growth, intestinal problems, lack of energy, and compromised physical and cognitive development. Infected children often fall behind in schooling. The severity of symptoms depends on the number of worms in the body.
Parasitic worms are generally transmitted via exposure to infected human feces and soil that are spread in the environment, for example, due to open defecation. The most common treatment is medicine. It can be prevented through hygienically prepared food and clean water, improved sanitation, periodic deworming, and health education. The World Health Organization recommends mass deworming without prior diagnosis.
=== Taeniasis/cysticercosis ===
Cysticercosis is a tapeworm larvae infection, while taeniasis is infection with adult tapeworms. Both are found in Asia, Africa, and Latin America, particularly on farms in which pigs are exposed to human excrement.
Cysticercosis is the most common preventable cause of epilepsy in the developing world. Cysticercosis occurs after ingestion of contaminated food, water, or soil. Cysts and lesions can cause headaches, blindness, seizures, hydrocephalus, meningitis, and dementia. Neurocysticercosis, or the parasitic infection of the nervous system, can be fatal. Taeniasis is not fatal. It is usually contracted after eating undercooked contaminated pork. Taeniasis has mild symptoms, including abdominal pain, nausea, diarrhea, or constipation.
Drugs are used to treat both diseases. Infection can be prevented through stricter meat-inspection standards, livestock confinement, improved hygiene and sanitation, health education, safe meat preparation, and identifying and treating human and pig carriers.
=== Trachoma ===
There are 21.4 million people infected with trachoma, of whom 2.2 million are partially blind and 1.2 million are blind. It is found in Africa, Asia, Central and South America, the Middle East, and Australia. The disease disproportionately affects women and children. The mortality risk is very low, although multiple re-infections eventually lead to blindness. The symptoms are internally scarred eyelids, followed by eyelids turning inward. Trachoma is caused by a micro-organism that spreads through eye discharges (on hands, cloth, etc.) and by "eye-seeking flies".
It is treated with antibiotics. The only known prevention method is interpersonal hygiene.
=== Chromoblastomycosis and other deep mycoses ===
Other important endemic mycoses with common systemic involvement are histoplasmosis, paracoccidioidomycosis, coccidioidomycosis, blastomycosis and talaromycosis. These infections are also seldomly seen in returning travelers in western countries
=== Scabies ===
=== Snakebite envenoming ===
Snakebite was added to the list in 2017, after years of criticism of the WHO by activists for not making it a priority. The greatest burden of snakebite morbidity is in India and Southeast Asia. Snakebite envenoming (SBE) affects as many as 2.7 million people every year, most of whom live in some of the world’s most remote, poorly developed, and politically marginalised tropical communities. With annual mortality of 81,000 to 138,000 and 400,000 surviving victims suffering permanent physical and psychological disabilities, SBE is a disease in urgent need of attention. <Gutierrez JM, Calvete JJ, Habib AG, Harrison RA, Williams DJ, Warrell DA. Snakebite envenoming. Nat Rev Dis Primers. 2017;3:17063. Epub 2017/09/15. pmid:28905944.> but snakebites often go unreported. A policy analysis however found that the placement of snakebite in the global health agenda of WHO is fragile due to reluctance acceptance of the disease in the neglected tropical disease community and the perceived colonial nature of the network driving the agenda.
== Effects for patients ==
=== Social effects ===
==== Social stigma ====
Several NTDs, such as leprosy, cause severe deformities that result in social stigma. Stigma is considered to be the "hidden burden" of NTDs and is not accounted for in measures such as disability-adjusted life years (DALYs). Other NTDs that carry heavy social stigma include onchocerciasis, lymphatic filariasis, plague, Buruli ulcer, leishmaniasis, and Chagas disease. Lymphatic filariasis, for example, causes severe deformities that can result in denial of marriage and inability to work. Studies in Ghana and Sri Lanka have demonstrated that support groups for patients with lymphatic filariasis can increase participants' self-esteem, quality of life, and social relations through social support and providing practical advice on how to manage their illness. The social effects of neglected tropical diseases have been shown to affect men and women in different ways. Men are socially stigmatized in a way that detrimentally affects their economic prospects. Women are more likely to be affected in the areas of marriage and family.
==== Mental health ====
A 2012 review found that infection with a neglected tropical disease predisposes individuals to poor mental health. This is partially due to the social stigma that surrounds NTDs, but is also likely caused by the subsequent lack of access to health and social services. Overall, being a member of the infected community was found to cut individuals off from multiple aspects of society via civic rights, educational opportunities, and employment. A high prevalence of post-traumatic stress disorder (PTSD) and depression was found among people who had survived snakebites. More research needs to be directed to understanding psychological aspects of NTDs to understand their effects more fully and to direct strategies to manage them better in healthcare systems where mental health professionals are scarce.
==== Gender ====
NTDs disproportionately affect women and children. There is also added risk of hookworm infection during pregnancy and potential to transfer diseases such as Chagas during pregnancy. A study in Uganda found that women were able to obtain treatment more easily than men because they had fewer occupational responsibilities and were more trusting of treatments, but ignorance of the effects of medicines during pregnancy prevented adequate care. The paper concludes that gender should be considered when designing treatment programs in Uganda. Additionally, women often bear a heavier social stigma in relation to the pressure to marry.
=== Economic effects ===
The cost of treatment of some of these diseases, such as Buruli ulcer, can be almost the average household income for families in the highest quarter of incomes, while for those in the lowest quarter it can be over twice the yearly income. These enormous financial costs often cause deferral of treatment and financial ruin. These diseases also cost the government in terms of healthcare provision and lost worker productivity through morbidity and shortened life spans. In Kenya, for example, deworming is estimated to increase average adult income by 40 percent, which is a benefit-to-cost ratio of 100. Each untreated case of trachoma is estimated to cost US$118 in lost productivity. Each case of schistosomiasis causes a loss of 45.4 days of work per year. Most of the diseases cost the economies of developing countries millions of dollars. Large-scale prevention campaigns are predicted to increase agricultural output and education levels.
The low cost of treatment for NTDs can be attributed to the large scale of the programs, free provision of drugs by pharmaceutical companies, delivery modes of drugs, and unpaid volunteers who distribute the drugs. The economic burden of NTDs is undervalued and therefore the corresponding economic effect and cost-effectiveness of decreasing prevalence of NTDs is underestimated. The investment return on measures to control NTDs is estimated to be between 14 and 30 percent, depending on the disease and region.
=== Health effects ===
==== Coinfection ====
Coinfection is a major concern with NTDs, making them more damaging than their mortality rates might suggest. Because factors such as poverty, inadequate healthcare and inadequate sanitation practices contribute to all NTDs, they are often found in overlapping distributions. Helminth infections, as the most common infection of humans, are often found to be in multi-infection systems. For example, in Brazil, low socioeconomic status contributes to overcrowded housing. In these same areas, coinfection by Necator americanus and Schistosoma mansoni is common. The effect of each worm weakens the immune system, making infection from the other more likely and more severe. For this reason, coinfection carries a higher risk of mortality. NTDs may also play a role in infection with other diseases, such as malaria, HIV/AIDS, and tuberculosis. The ability of helminths to manipulate the immune system may create a physiological environment that could exacerbate the progression of HIV/AIDS. Some evidence from Senegal, Malawi, and Thailand has shown that helminth infections raise the risk of malarial infection.
== Prevention, treatment and eradication ==
Prevention and eradication are important because "of the appalling stigma, disfigurement, blindness and disabilities caused by NTDs." The principal aim of the London Declaration on Neglected Tropical Diseases was the elimination or eradication of dracunculiasis, leprosy, lymphatic filariasis, onchocerciasis, trachoma, sleeping sickness, visceral leishmaniasis, and canine rabies within ten years of its launch in January 2012. The declaration is a collaborative effort involving the WHO, the World Bank, the Bill & Melinda Gates Foundation, the world's 13 leading pharmaceutical companies, and government representatives from the US, UK, United Arab Emirates, Bangladesh, Brazil, Mozambique, and Tanzania.
While there has been a noticeable uptick in biological research into NTDs, prevention may be supplemented by social and development outreach. Spiegel and coauthors advocated for "social offset", which reallocates some funding for biotechnological research to social programs. This attempts to alleviate some of the factors (such as poverty, poor sanitation, overcrowding and poor healthcare) that greatly exacerbate conditions brought on by NTDs. Projects such as these also strengthen the goal of sustained eliminations rather than quickly addressing symptoms.
=== Policy initiatives ===
There are many prevention and eradication campaigns funded by organizations such as the World Health Organization, US Agency for International Development, Bill & Melinda Gates Foundation, and UK Department for International Development.
Sustainable Development Goal 3 has the target: "By 2030, [to] end the epidemics of AIDS, tuberculosis, malaria and neglected tropical diseases and combat hepatitis, water-borne diseases and other communicable diseases."
==== WHO Roadmap of 2012 ====
In 2012, WHO published an NTD "roadmap", which contained milestones for 2015 and 2020, and specified targets for eradication, elimination and intensified control of the different NTDs. For example:
NTDs planned to be eradicated: dracunculiasis by the year 2015, endemic treponematoses (yaws) by 2020
NTDs planned to be eliminated globally by 2020: blinding trachoma, leprosy, human African trypanosomiasis, and lymphatic filariasis
NTDs planned to be eliminated in certain regions: rabies (by 2015 in Latin America, by 2020 in Southeast Asia and the western Pacific), Chagas disease (transmission through blood transfusion by 2015, intra-domiciliary transmission by 2020 in the Americas), visceral leishmaniasis (by 2020 in the Indian subcontinent), onchocerciasis (by 2015 in Latin America), and schistosomiasis (by 2015 in the eastern Mediterranean region, the Caribbean, Indonesia, and the Mekong River basin, and by 2020 in the Americas and western Pacific)
NTDs planned to be eliminated in certain countries: human African trypanosomiasis (by 2015 in 80 percent of areas in which it occurs), onchocerciasis (by 2015 in Yemen, by 2020 in selected countries in Africa), and schistosomiasis (by 2020 in selected countries in Africa)
Intensified control with specific targets for 2015 and 2020 are provided for these NTDs: dengue, Buruli ulcer, cutaneous leishmaniasis, taeniasis/cysticercosis and echinococcosis/hydatidosis, foodborne trematode infections, and soil-transmitted helminthiases.
In 2021, WHO updated their NTD roadmap "Together towards 2030", outlining their approach for 2021–2030.: v–vi
==== Others ====
The U.S. Food and Drug Administration priority review voucher is an incentive for companies to invest in new drugs and vaccines for tropical diseases. A provision of the Food and Drug Administration Amendments Act of 2007 awards a transferable "priority review voucher" to any company that obtains approval for a treatment for one of the listed diseases. The voucher can later be used to accelerate the review of an unrelated drug. This program is for all tropical diseases and includes medicines for malaria and tuberculosis. The first voucher given was for Coartem, a malaria treatment.
The prize was proposed by Duke University faculty Henry Grabowski, Jeffrey Moe, and David Ridley in their 2006 Health Affairs paper "Developing Drugs for Developing Countries". In 2007, United States Senators Sam Brownback (R-KS) and Sherrod Brown (D-OH) sponsored an amendment to the Food and Drug Administration Amendments Act of 2007. President George W. Bush signed the bill in September 2007.
=== Deworming treatment ===
Deworming treatments in infected children may have some nutritional benefit, as worms are often partially responsible for malnutrition. However, in areas where these infections are common, there is strong evidence that mass deworming campaigns do not have a positive effect on children's average nutritional status, levels of blood haemoglobin, cognitive abilities, performance at school, or survival. To achieve health gains in the longer term, improvements in sanitation and hygiene behaviours are also required, together with deworming treatments.
The effect of mass deworming on school attendance is disputed. It has been argued that mass deworming has a positive effect on school attendance. The long-term benefits of deworming include a decrease in school absenteeism by 25 percent and an increase in adult earnings by 20 percent. A systematic review, however, found that there is little or no difference in attendance in children who receive mass deworming compared to children who did not. One study found that boys were enrolled in primary school for more years than boys who were in schools that did not offer such programs. Girls in the same study were about a quarter more likely to attend secondary school if they received treatment. Both groups went on to participate in more skilled sectors of the labor market. The economic growth generated from school programs such as this may balance out the actual expenses of the program. However, the results of this study are disputed (due to a high risk of bias in the study), and the positive long-term outcomes of mass deworming remain unclear.
=== Integration of treatment ===
Inclusion of NTDs into initiatives for malaria, HIV/AIDS, and tuberculosis, as well as integration of NTD treatment programs, may have advantages given the strong link between these diseases and NTDs. Some neglected tropical diseases share common vectors (sandflies, black flies, and mosquitos). Both medicinal and vector control efforts may be combined.
A four-drug rapid-impact package has been proposed that targets multiple diseases together. This package is estimated to cost US$0.40 per patient, with estimated saving of 26–47% compared to treating the diseases separately. While more research must be done in order to understand how NTDs and other diseases interact in both the vector and the human stages, safety assessments have so far produced positive results.
Many neglected tropical diseases and other prevalent diseases share common vectors, creating another opportunity for treatment and control integration. One such example of this is malaria and lymphatic filariasis, which are both transmitted by the same or related mosquito vectors. Vector control, through the distribution of insecticide-treated nets, reduces human contact with a wide variety of disease vectors. Integrated vector control may also alleviate pressure on mass drug administration, especially with respect to rapidly evolving drug resistance. Combining vector control and mass drug administration deemphasizes both, making each less susceptible to resistance evolution.
=== Integration with water, sanitation and hygiene (WASH) programs ===
Water, sanitation, and hygiene (WASH) interventions are essential in preventing many NTDs, such as soil-transmitted helminthiasis. Mass drug administration alone will not protect people from re-infection. A more holistic and integrated approach to NTDs and WASH efforts will benefit both sectors along with the communities they are aiming to serve. This is especially true in areas where more than one NTD is endemic.
In August 2015, the World Health Organization unveiled a global strategy and action plan to integrate WASH with other public health interventions to accelerate the elimination of NTDs. The plan aimed to intensify control or eliminate certain NTDs in specific regions by 2020, and referred to the NTD "roadmap" milestones from 2012 that included eradication of dracunculiasis by 2015 and of yaws by 2020, elimination of trachoma and lymphatic filariasis as public health problems by 2020, and intensified control of dengue, schistosomiasis, and soil-transmitted helminthiases.
Closer collaboration between WASH and NTD programmes can lead to synergies. They can be achieved through collaborative planning, delivery and evaluation of programmes, strengthening and sharing of evidence, and using monitoring tools to improve the equity of health services.
Reasons why WASH plays an important role in NTD prevention and patient care include:
NTDs affect more than one billion people in 149 countries. They occur mainly in regions with a lack of basic sanitation. About 2.4 billion people worldwide do not have adequate sanitation facilities. 663 million do not have access to improved drinking water sources.
A leading cause of preventable blindness is trachoma. The bacterial infection is transmitted through contact with eye-seeking flies, fingers, and fomites. Prevention components are facial cleanliness, which requires water for face washing, and environmental improvement, which includes safe disposal of excreta to reduce fly populations.
Improved sanitation prevents soil-transmitted helminthiases. It impedes fecal pathogens such as intestinal worm eggs from contaminating the environment and infecting people through contaminated food, water, dirty hands, and direct skin contact with the soil.
Improved sanitation and water management can contribute to reduced proliferation of mosquitoes that transmit diseases, such as lymphatic filariasis, dengue, and chikungunya. Breeding of the Culex mosquito, which transmits filarial parasites, is facilitated through poorly constructed latrines. Breeding of the Aedes aegypti and Aedes albopictus mosquitoes, which transmit dengue and chikungunya, can be prevented through safe storage of water.
Feces and urine that contain worm eggs can contaminate surface water and lead to transmission of schistosomiasis. This can be prevented through improved sanitation. Not only human but also animal (cow, buffalo) urine or feces can transmit some schistosome species. Therefore, it is important to protect freshwater from animals and animal waste.
Treatment of many NTDs requires clean water and hygienic conditions for healthcare facilities and households. For Guinea-worm disease, Buruli ulcer, and cutaneous leishmaniasis, wound management is needed to speed up healing and reduce disability. Lymphatic filariasis causes chronic disabilities. People who have this disease need to maintain rigorous personal hygiene with water and soap to prevent secondary infections.
NTDs that lead to permanent disabilities make tasks such as carrying water long distances or accessing toilets difficult. However, people affected by these diseases often face stigma and can be excluded from accessing water and sanitation facilities. This increases their risk of poverty and severe illness. Clean water and soap are essential for these groups to maintain personal hygiene and dignity. Therefore, additional efforts to reduce stigma and exclusion are needed. In this manner, WASH can improve the quality of life of people affected by NTDs.
In a meta-analysis, safe water was associated with significantly reduced odds of Schistosoma infection, and adequate sanitation was associated with significantly lower odds of infection with both S. mansoni and S. haematobium.
A systematic review and meta-analysis showed that better hygiene in children is associated with lower odds of trachoma. Access to sanitation was associated with 15 percent lower odds of active trachoma and 33 percent lower odds of C. trachomatis infection of the eyes.
Another systematic review and meta-analysis found a correlation between WASH access and practices, and lower odds of soil-transmitted helminthiasis infections by 33 to 77 percent. Persons who washed their hands after defecating were less than half as likely to be infected as those who did not. Traditionally, preventive chemotherapy is used as a measure of control, although this measure does not stop the transmission cycle and cannot prevent reinfection. In contrast, improved sanitation can.
=== Pharmaceutical market ===
Biotechnology companies in the developing world have targeted neglected tropical diseases due to a need to improve global health.
Mass drug administration is considered a possible method for eradication, especially for lymphatic filariasis, onchocerciasis, and trachoma, although drug resistance is a potential problem. According to Fenwick, Pfizer donated 70 million doses of drugs in 2011 to eliminate trachoma through the International Trachoma Initiative. Merck has helped The African Programme for the Control of Onchocerciasis (APOC) and Oncho Elimination Programme for the Americas to greatly diminish the effect of onchocerciasis by donating ivermectin. Merck KGaA pledged to give 200 million tablets of praziquantel, the only cure for schistosomiasis, over 10 years. GlaxoSmithKline has donated two billion tablets of medicine for lymphatic filariasis and pledged 400 million deworming tablets per year for five years in 2010. Johnson & Johnson has pledged 200 million deworming tablets per year. Novartis has pledged leprosy treatment, and EISAI pledged two billion tablets to help treat lymphatic filariasis.
=== NGO initiatives ===
Non-governmental organizations that focus exclusively on NTDs include the Schistosomiasis Control Initiative, Deworm the World, and the END Fund. Despite under-funding, treatment and prevention of many neglected diseases is cost-effective. The cost of treating a child for infection of soil-transmitted helminths and schistosomes (some of the main causes of neglected diseases) is less than US$0.50 per year when administered as part of school-based mass deworming by Deworm the World. This programme is recommended by Giving What We Can and the Copenhagen Consensus Centre as one of the most efficient and cost-effective solutions. The efforts of the Schistosomiasis Control Initiative to combat neglected diseases include the use of rapid-impact packages: supplying schools with packages including four or five drugs, and training teachers in how to administer them.
Health Action International based in Amsterdam worked with the WHO to get snakebite envenoming on the list of neglected tropical diseases.
=== Public-private initiatives ===
An alternative to the profit-driven drug development model emerged in 2000 to address the needs of these neglected patients. Product development partnerships (PDPs) aim at implementing and accelerating the research and development (R&D) of safe and effective health tools (diagnostics, vaccines, drugs) to combat neglected diseases. Drugs for Neglected Disease initiative (DNDi) is one of these PDPs that has already developed new treatments for NTDs.
The Sabin Vaccine Institute, founded in 1993, works to address the issues of vaccine-preventable diseases as well as NTDs. They run three main programs: Sabin Vaccine Development, Global Network for Neglected Tropical Diseases, and Vaccine Advocacy and Education. Their product development partnership affiliates them with the Texas Children's Hospital as well as the Baylor College of Medicine. Their major campaign, End7, aims to end seven of the most common NTDs (elephantiasis, river blindness, snail fever, trachoma, roundworm, whipworm, and hookworm) by 2020. Through End7, college campuses undertake fundraising and educational initiatives for the broader goals of the campaign.
WIPO Re:Search was established in 2011 by the World Intellectual Property Organization in collaboration with BIO Ventures for Global Health (BVGH) and with the active participation of leading pharmaceutical companies and other private and public sector research organizations. It allows organizations to share their intellectual property, compounds, expertise, facilities, and know-how royalty-free with qualified researchers worldwide working on new solutions for NTDs, malaria, and tuberculosis.
In 2013, the Government of Japan, five Japanese pharmaceutical companies, the Bill and Melinda Gates Foundation, and the UNDP established a new public–private partnership, the Global Health Innovative Technology Fund. They pledged over US$100 million to the fund over five years, to be awarded as grants to R&D partnerships across sectors in Japan and elsewhere, working to develop new drugs and vaccines for 17 neglected diseases, in addition to HIV, malaria, and tuberculosis. Affordability of the resulting drugs and vaccines is one of the key criteria for grant awards.
==== London Declaration on Neglected Tropical Diseases ====
The London Declaration on Neglected Tropical Diseases, initiated by the Bill and Melinda Gates Foundation launched on 30 January 2012 in London. Inspired by the WHO roadmap to eradicate or prevent transmission for neglected tropical diseases, it aimed to eradicate or reduce NTDs by the year 2020. It was endorsed by governments and organisations around the world, as well as major pharmaceutical companies including Abbott, AstraZeneca, Bayer HealthCare Pharmaceuticals, Becton Dickinson, Bristol-Myers Squibb, Eisai, Gilead Sciences, GlaxoSmithKline, Johnson & Johnson, Merck KGaA, Merck Sharp & Dohme, MSD, Novartis, Pfizer, and Sanofi. It was not a complete success, but millions of lives were saved, the burden of the infections was reduced, and 42 countries eliminated at least one disease. To commemorate the programme, WHO adopted 30 January as the World NTD Day.
==== Kigali Declaration on Neglected Tropical Diseases ====
The Kigali Declaration on Neglected Tropical Diseases was launched at the Kigali Summit on Malaria and Neglected Tropical Diseases (NTDs) hosted by the Government of Rwanda at its capital city Kigali on 23 June 2022. It was signed as a support for the World Health Organization's 2021–30 road map for NTDs and the target of Sustainable Development Goal 3 to end NTD epidemics; and as a follow-up project of the London Declaration . Supported by WHO, governments of the Commonwealth of Nations pledged the endorsement, along with commitments from GSK plc, Novartis, and Pfizer.
=== Others ===
An open-access journal dedicated to neglected tropical diseases called PLoS Neglected Tropical Diseases first began publication in 2007.
One of the first large-scale initiatives to address NTDs came from a collaboration between Kenneth Warren and the Rockefeller Foundation. Ken Warren is regarded as a pioneer in neglected tropical disease research. The Great Neglected Tropical Diseases Network was a consortium of scientists from all over the world, hand-picked by Warren, working to expand the research base in neglected diseases. Many of the scientists that he recruited had not been involved in NTD research before. The network ran from 1978 to 1988. Warren's vision was to establish units within biological labs across the world, dedicated to R&D. By forming a critical mass of scientists in NTD research, he hoped to attract new students into the field. The interdisciplinary group met annually to update the community on research progress. Much of the work done by this group focused on understanding the mechanisms behind infection. At these informally structured meetings, research partnerships were formed. Warren himself encouraged these partnerships, especially if they bridged the divide between developed and developing nations. Through the Great Neglected Tropical Disease Network, a great number of scientists were brought into the field of parasitology.
== Epidemiology ==
The distribution of neglected tropical disease disproportionally affects about one billion of the world's poorest populations, causing mortality, disability, and morbidity. Lack of funding, resources, and attention can result in treatable and preventable diseases causing death. Factors like political dynamics, poverty, and geographical conditions can make the delivery of NTD control programs difficult. Intersectional collaboration of poverty reduction policies and neglected tropical diseases creates cross-sector approaches to simultaneously address these issues.
The six most common NTDs include soil-transmitted helminths (STHs)—specifically roundworms (Ascaris lumbricoides), whipworm (Trichuris trichiura), and hookworms (Necator americanus and Ancylostoma duodenale)—schistosomiasis, trachoma, and lymphatic filariasis (LF). These diseases affect one-sixth of the world's population, with 90 percent of the disease burden occurring in sub-Saharan Africa.
Information on the frequency of neglected tropical diseases is of low quality. It is currently difficult to summarize all of the information on this family of diseases. One effort to do so is the Global Burden of Disease framework. It aims to create a standardized method of measurement. The principle components of the approach involve 1) the measuring of premature mortality as well as disability, 2) the standardized usage of DALYs (disability-adjusted life years), and 3) widespread inclusion of diseases and injury causes with the estimation of missing data. However, the DALY has been criticized as a "systematic undervaluation" of disease burden. King asserts that DALY emphasizes the individual too much while ignoring the effects of the ecology of the disease. In order for the measure to become more valid, it may have to take the context of poverty more into account. King also emphasizes that DALYs may not capture the non-linear effects of poverty on the cost-utility analysis of disease control. The Socio-Demographic Index (SDI) and Healthy Life Expectancy (HALE) are other summary measures that can be used to take into account other factors. HALE is a metric that weights years lived and health loss before death to provide a summary of population health. SDI is a measurement that includes lag-distributed income per capita, average education, and fertility rate. Socioeconomic factors greatly influence the distribution of neglected tropical diseases, and not addressing these factors in models and measurements can lead to ineffective public health policy.
== Research and development ==
NTD interventions include programs to address environmental and social determinants of health (e.g., vector control, water quality, sanitation) as well as programs offering mass drug administration for disease prevention and treatment. Drug treatments exist to confront many of the NTDs and represent some of the world's essential medicines. Despite significant health and economic improvements using available medicines, the low number of new compounds being researched and developed for NTDs is an ongoing and significant challenge. The dearth of candidates in pharmaceutical company drug pipelines is primarily attributed to the high costs of drug development and the fact that NTDs are concentrated among the world's poor. Other disincentives to investment include weak existing infrastructure for distribution and sales as well as concerns regarding intellectual property protection. However, the major stakeholders in NTD drug development—governments, foundations, pharmaceutical companies, academia, and NGOs—are involved in activities to help address the research and development shortfall and meet the many challenges presented by neglected tropical diseases. Initiatives include public-private partnerships, global R&D capacity building, priority vouchers to speed drug approval processes, open source scientific collaborations, and harmonization of global governance structures concerning NTDs.
The diseases considered neglected tropical diseases vary. Some researchers no longer consider malaria, HIV, and tuberculosis to be neglected due to the amount of public attention and increased funding they have received. Outside "The Big Three", the seven most prevalent neglected tropical diseases in order of their global prevalence are ascariasis, trichuriasis, hookworm infection, schistosomiasis, lymphatic filariasis, and trachoma. These seven are among a larger list of thirteen major NTDs: onchocerciasis, leishmaniasis, Chagas disease, leprosy, human African trypanosomiasis (sleeping sickness), dracunculiasis, and Buruli ulcer.
=== Deficient market ===
In their 2002 review of the U.S. Food and Drug Administration (FDA) databases and the European Agency for the Evaluation of Medicinal Products, Troullier et al. found that 16 out of 1393 new chemical entities were approved for NTDs between 1975 and 1999 (~1%). Cohen et al. revisited the data and using the same methodology found 32 new chemical entities during the time period. In a second analysis using an expanded list of NTDs based on the G-FINDER survey, the number was slightly higher, with 46 new drugs and vaccines approved (~3% of the total including HIV drugs). Between 2000 and 2009, there has been some increase with an additional 26 newly approved drugs and vaccines for NTDs.
A number of factors are recognized as contributing to the low number. The barrier most reported is the high cost of drug development. Estimates are that pharmaceutical companies' development costs to approval fall between $500 million and $2 billion. DiMasi, Hansen, and Grabowski calculated an average of $802 million in year 2000 dollars. Furthermore, the time that drugs are approved for use averages seven years out of the twenty years on patent, meaning a tendency for the market to focus on diseases of developed nations where high prices can be used to recoup research and development costs, and subsidize failed R&D efforts. In short, NTD research and development is considered a high investment risk, given that NTDs predominantly affect the poor in low- and middle-income countries. Additional barriers include drug safety regulatory requirements, intellectual property protection problems, and poor infrastructure for distribution and sales.
Although drug companies have not invested heavily in NTDs, in several cases, rather than focus on profits, some have decided to donate key drugs to address NTDs. For example, Merck has had a program since the mid-1980s to donate ivermectin (Mectizan) indefinitely to support the global fight against onchocerciasis. GlaxoSmithKline and several other large pharmaceutical companies have donation programs as well. Drug donation, however, does not ameliorate the deficiency of new chemical entities being researched and developed. This is especially of concern with reports of emerging resistance among existing drugs.
=== Policy initiatives ===
==== Public–private partnerships ====
Governments, foundations, the non-profit sector, and the private sector have found new connections to help address market deficiencies by providing funding support and spreading both the costs and risks of NTD research and development. The proliferation of public–private partnerships (PPPs) has been recognized as a key innovation in the past decade, helping to unlock existing and new resources.
Major PPPs for NTDs include: the Sabin Vaccine Institute, Norvartis Vaccines Institute for Global Health, MSD Wellcome Trust Hilleman Laboratories, Infectious Diseases Research Institute, Institut Pasteur and INSERM, WIPO Re:Search, and the International Vaccine Institute. Likewise, a number of new academic drug development centers have been created in recent years drawing in industry partners. Support for these centers is frequently traced to the Bill & Melinda Gates Foundation, the Sandler Foundation, and the Wellcome Trust.
==== R&D capacity building in middle-income countries ====
Growing NTD research and development capacity in middle-income countries is an area of policy interest. A 2009 study of biotechnology companies in India, China, Brazil, and South Africa revealed 62 NTD products in development and on the market out of approximately 500 products offered (~14%). When products to fight HIV, malaria, and TB were included in the analysis, the number increased to 123 products, approximately 25% of the total products offered.
Researchers have argued that, unlike most multinationals, small and mid-sized "Global South" companies see significant business opportunities in the development of NTD-related diagnostics, biologics, pharmaceuticals, and services. Potential actions to improve and expand this R&D capacity have been recommended, including expansion of human capital, increased private investment, knowledge and patent sharing, infrastructure building for business incubation, and innovation support.
==== Innovation prizes and grants ====
Competitive innovation prizes have been used to spur development in a range of fields such as aerospace engineering, clean technology, and genomics. The X-Prize Foundation is launching a competition for high-speed, point-of-care diagnostics for tuberculosis. A more widely defined annual "Global Health EnterPrize" for neglected tropical diseases has been proposed to reward health innovators, particularly those based in countries where NTDs represent a serious health burden.
The Bill & Melinda Gates Foundation offers the Grand Challenges Explorations Opportunities on a rolling basis. This grant program allows individuals from any organization or background to apply to address priority global health issues. Each project award is $100,000 and is drawn from a Foundation funding pool of $100 million. Awardees have tended to offer research projects on topics that are highly speculative but offer potentially game-changing breakthroughs in global health.
==== FDA priority review vouchers (PRV) ====
In 2006, Ridley et al. recommended the development of a priority review voucher (PRV) in the journal Health Affairs. It gained interest from Senator Sam Brownback of Kansas, who championed its introduction in the FDA Amendments Act of 2007. Under the enacted law, FDA approval of a non-NTD drug can be accelerated through the drug review process if paired with a drug that addresses an NTD. The potential economic benefit to a pharmaceutical company is estimated to be potentially as high as $300 million per drug. Three drugs have earned NTD PRVs to date (December 2014): Coartem (by Novartis, for malaria); bedaquiline (by Janssen, for TB); and miltefosine (by Knight, for leishmaniasis). However, the success of the PRV system is now under much scrutiny, given that Knight benefitted by $125 million from the sale of a PRV earned from a drug (miltefosine) that was largely researched and developed by the WHO. Médecins Sans Frontières are now pressuring Knight to guarantee to supply miltefosine at cost price, thus far without success.
The PRV isn't limited to the pairing of drugs within a single company as it can be transferred between companies. Companies with NTD drug candidates in their pipelines but without a blockbuster drug are able to sell their vouchers, producing financial returns. In the EU, similar priority review incentives are now under consideration to increase the speed of regulatory pricing and reimbursement decisions.
However, PRVs have been criticized as being open to manipulation and possibly encouraging errors through too rapid regulatory decision-making.
==== Open source collaboration initiatives ====
Several companies and scientific organizations are participating in open-source initiatives to share drug data and patent information over the web, and facilitate virtual collaboration on NTD research.
One rich area to explore is the wealth of genomic data resulting from the sequencing of parasite genomes. These data offer opportunities for the exploration of new therapeutic products using computational and open-source collaboration methods for drug discovery. The Tropical Disease Initiative, for example, has used large amounts of computing power to generate the protein structures for ten parasite genomes. An open-source drug bank was matched algorithmically to determine compounds with protein interaction activity, and two candidates were identified. In general, such methods may hold important opportunities for off-label use of existing approved drugs.
== History ==
In 1977, Kenneth S. Warren, an American researcher, invented the concept of what is now "neglected tropical diseases".
In 2005 Lorenzo Savioli, a senior United Nations civil servant, was appointed director of the "Department of Control of Neglected Tropical Diseases".
The World Health Organization definition of neglected tropical disease has been criticised to be restrictive and described as a form of epistemic injustice.
== See also ==
Contagious disease
Fecal–oral route transmission
Neglected Tropical Disease Research and Development
Drugs for Neglected Diseases Initiative
Eradication of infectious diseases
Global Network for Neglected Tropical Diseases
Orphan diseases
== References ==
== External links ==
WHO – Control of neglected tropical disease
PLOS Neglected Tropical Diseases
United Nations World Health Organization
U.S. Food and Drug Administration
India's neglected tropical diseases
Neglected tropical disease targets must include morbidity
Global health policy and neglected tropical diseases: Then, now, and in the years to come
UK's One Health Vector-Borne Diseases Hub | Wikipedia/Neglected_tropical_disease |
Electrocardiography is the process of producing an electrocardiogram (ECG or EKG), a recording of the heart's electrical activity through repeated cardiac cycles. It is an electrogram of the heart which is a graph of voltage versus time of the electrical activity of the heart using electrodes placed on the skin. These electrodes detect the small electrical changes that are a consequence of cardiac muscle depolarization followed by repolarization during each cardiac cycle (heartbeat). Changes in the normal ECG pattern occur in numerous cardiac abnormalities, including:
Cardiac rhythm disturbances, such as atrial fibrillation and ventricular tachycardia;
Inadequate coronary artery blood flow, such as myocardial ischemia and myocardial infarction;
and electrolyte disturbances, such as hypokalemia.
Traditionally, "ECG" usually means a 12-lead ECG taken while lying down as discussed below.
However, other devices can record the electrical activity of the heart such as a Holter monitor but also some models of smartwatch are capable of recording an ECG.
ECG signals can be recorded in other contexts with other devices.
In a conventional 12-lead ECG, ten electrodes are placed on the patient's limbs and on the surface of the chest. The overall magnitude of the heart's electrical potential is then measured from twelve different angles ("leads") and is recorded over a period of time (usually ten seconds). In this way, the overall magnitude and direction of the heart's electrical depolarization is captured at each moment throughout the cardiac cycle.
There are three main components to an ECG:
The P wave, which represents depolarization of the atria.
The QRS complex, which represents depolarization of the ventricles.
The T wave, which represents repolarization of the ventricles.
During each heartbeat, a healthy heart has an orderly progression of depolarization that starts with pacemaker cells in the sinoatrial node, spreads throughout the atrium, and passes through the atrioventricular node down into the bundle of His and into the Purkinje fibers, spreading down and to the left throughout the ventricles. This orderly pattern of depolarization gives rise to the characteristic ECG tracing. To the trained clinician, an ECG conveys a large amount of information about the structure of the heart and the function of its electrical conduction system. Among other things, an ECG can be used to measure the rate and rhythm of heartbeats, the size and position of the heart chambers, the presence of any damage to the heart's muscle cells or conduction system, the effects of heart drugs, and the function of implanted pacemakers.
== Medical uses ==
The overall goal of performing an ECG is to obtain information about the electrical functioning of the heart. Medical uses for this information are varied and often need to be combined with knowledge of the structure of the heart and physical examination signs to be interpreted. Some indications for performing an ECG include the following:
Chest pain or suspected myocardial infarction (heart attack), such as ST elevated myocardial infarction (STEMI) or non-ST elevated myocardial infarction (NSTEMI)
Symptoms such as shortness of breath, murmurs, fainting, seizures, funny turns, or arrhythmias including new onset palpitations or monitoring of known cardiac arrhythmias
Medication monitoring (e.g., drug-induced QT prolongation, digoxin toxicity) and management of overdose (e.g., tricyclic overdose)
Electrolyte abnormalities, such as hyperkalemia
Perioperative monitoring in which any form of anesthesia is involved (e.g., monitored anesthesia care, general anesthesia). This includes preoperative assessment and intraoperative and postoperative monitoring.
Cardiac stress testing
Computed tomography angiography (CTA) and magnetic resonance angiography (MRA) of the heart (ECG is used to "gate" the scanning so that the anatomical position of the heart is steady)
Clinical cardiac electrophysiology, in which a catheter is inserted through the femoral vein and can have several electrodes along its length to record the direction of electrical activity from within the heart.
ECGs can be recorded as short intermittent tracings or continuous ECG monitoring. Continuous monitoring is used for critically ill patients, patients undergoing general anesthesia, and patients who have an infrequently occurring cardiac arrhythmia that would unlikely be seen on a conventional ten-second ECG. Continuous monitoring can be conducted by using Holter monitors, internal and external defibrillators and pacemakers, and/or biotelemetry.
=== Screening ===
For adults, evidence does not support the use of ECGs among those without symptoms or at low risk of cardiovascular disease as an effort for prevention. This is because an ECG may falsely indicate the existence of a problem, leading to misdiagnosis, the recommendation of invasive procedures, and overtreatment. However, persons employed in certain critical occupations, such as aircraft pilots, may be required to have an ECG as part of their routine health evaluations. Hypertrophic cardiomyopathy screening may also be considered in adolescents as part of a sports physical out of concern for sudden cardiac death.
== Electrocardiograph machines ==
Mechanical cardiographs (apex cardiogram), developed in the 19th century, recorded heart movements by transmitting heart or chest wall motions to a spring and air chamber system. A writing lever traced these movements onto a smoked rotating cylinder, producing a cardiogram. Their accuracy was limited, as they captured all body movements, introducing errors.
Modern day electrocardiograms are recorded by machines that consist of a set of electrodes connected to a central unit.
In the late 19th century, scientists discovered the heart’s electrical activity, leading to the electrocardiograph’s development. Willem Einthoven’s 1903 string galvanometer enabled precise measurement of these signals, revolutionizing cardiography. He received the 1924 Nobel Prize for this work.
Early ECG machines were constructed with analog electronics, where the signal drove a motor to print out the signal onto paper. Today, electrocardiographs use analog-to-digital converters to convert the electrical activity of the heart to a digital signal. Many ECG machines are now portable and commonly include a screen, keyboard, and printer on a small wheeled cart. Recent advancements in electrocardiography include developing even smaller devices for inclusion in fitness trackers and smart watches. These smaller devices often rely on only two electrodes to deliver a single lead I. Portable twelve-lead devices powered by batteries are also available.
Recording an ECG is a safe and painless procedure. The machines are powered by mains power but they are designed with several safety features including an earthed (ground) lead.
Other features include:
Defibrillation protection: any ECG used in healthcare may be attached to a person who requires defibrillation and the ECG needs to protect itself from this source of energy.
Electrostatic discharge is similar to defibrillation discharge and requires voltage protection up to 18,000 volts.
Additionally, circuitry called the right leg driver can be used to reduce common-mode interference (typically the 50 or 60 Hz mains power).
ECG voltages measured across the body are very small. This low voltage necessitates a low noise circuit, instrumentation amplifiers, and electromagnetic shielding.
Simultaneous lead recordings: earlier designs recorded each lead sequentially, but current models record multiple leads simultaneously.
Most modern ECG machines include automated interpretation algorithms. This analysis calculates features such as the PR interval, QT interval, corrected QT (QTc) interval, PR axis, QRS axis, rhythm and more. The results from these automated algorithms are considered "preliminary" until verified and/or modified by expert interpretation. Despite recent advances, computer misinterpretation remains a significant problem and can result in clinical mismanagement.
=== Cardiac monitors ===
Besides the standard electrocardiograph machine, there are other devices that can record ECG signals. Portable devices have existed since the Holter monitor was introduced in 1962.
Traditionally, these monitors have used electrodes with patches on the skin to record the ECG, but new devices can stick to the chest as a single patch without need for wires, developed by Zio (Zio XT), TZ Medical (Trident), Philips (BioTel) and BardyDx (CAM) among many others.
Implantable devices such as the artificial cardiac pacemaker and implantable cardioverter-defibrillator are capable of measuring a "far field" signal between the leads in the heart and the implanted battery/generator that resembles an ECG signal (technically, the signal recorded in the heart is called an electrogram, which is interpreted differently).
The development of the Holter monitor led to the creation of the implantable loop recorder, which performs the same function but is an implantable device with batteries that last for years.
Additionally, there are available various Arduino kits with ECG sensor modules and smartwatch devices that are capable of recording an ECG signal as well, such as with the 4th generation Apple Watch (2018), Samsung Galaxy Watch 4 (2021) and newer devices.
== Electrodes and leads ==
Electrodes are the actual conductive pads attached to the body surface. Any pair of electrodes can measure the electrical potential difference between the two corresponding locations of attachment. Such a pair forms a lead. However, "leads" can also be formed between a physical electrode and a virtual electrode, which is the average of numerous leads. All clinical ECGs use Wilson's central terminal (WCT) as the virtual electrode from which the precordial leads are measured, whose potential is defined as the average potential measured by the three standard limb leads.
Commonly, 10 electrodes attached to the body are used to form 12 ECG leads, with each lead measuring a specific electrical potential difference.
=== 12-Lead ECG ===
Leads are broken down into three types: limb; augmented limb; and precordial or chest. The 12-lead ECG has a total of three limb leads and three augmented limb leads arranged like spokes of a wheel in the coronal plane (vertical), and six precordial leads or chest leads that lie on the perpendicular transverse plane (horizontal).
Electrodes should be placed in standard positions, with 'left' or 'right' referring to anatomical directions, being the patient's left or right. Exceptions due to emergency or other issues should be recorded to avoid erroneous analysis.
The 12 standard ECG leads and electrodes are listed below. All leads are effectively bipolar, with one positive and one negative electrode; the term "unipolar" is not true, nor useful.
Two types of electrodes in common use are a flat paper-thin sticker and a self-adhesive circular pad.
The former are typically used in a single ECG recording while the latter are for continuous recordings as they stick longer.
Each electrode consists of an electrically conductive electrolyte gel and a silver/silver chloride conductor.
The gel typically contains potassium chloride – sometimes silver chloride as well – to permit electron conduction from the skin to the wire and to the electrocardiogram.
=== Virtual Electrode ===
The virtual electrode is used to obtain useful measurements from the precordial leads, and also allows the creation of the augmented limb leads.
The virtual electrode is known as Wilson's Central Terminal (WCT). For the precordial leads, WCT is formed by averaging the three standard limb leads (I, II, and III):
V
W
=
1
3
(
R
A
+
L
A
+
L
L
)
{\displaystyle V_{W}={\frac {1}{3}}(RA+LA+LL)}
WCT is therefore a virtual electrode which sits slightly posteriorly to the heart. It is a useful point, from which the electrical potential of the precordial leads is measured.
WCT used to be used as a reference for the virtual limb leads, however use in this way produced leads with very small amplitudes. Goldberger's modification is now used to produce each augmented limb lead, aVF, aVR, and aVL, which produces 50% larger amplitude leads than the standard WCT. Goldberger's WCT is formed according to the following:
a
V
R
=
L
A
+
L
L
2
{\displaystyle aVR={\frac {LA+LL}{2}}}
a
V
L
=
R
A
+
L
L
2
{\displaystyle aVL={\frac {RA+LL}{2}}}
a
V
F
=
R
A
+
L
A
2
{\displaystyle aVF={\frac {RA+LA}{2}}}
In a 12-lead ECG, all leads except the limb leads are assumed to be unipolar (aVR, aVL, aVF, V1, V2, V3, V4, V5, and V6).
The measurement of a voltage requires two contacts and so, electrically, the unipolar leads are measured from the common lead (negative) and the unipolar lead (positive).
This averaging for the common lead and the abstract unipolar lead concept makes for a more challenging understanding and is complicated by sloppy usage of "lead" and "electrode".
In fact, instead of being a constant reference, VW has a value that fluctuates throughout the heart cycle. It also does not truly represent the center-of-heart potential due to the body parts the signals travel through. Because voltage is by definition a bipolar measurement between two points, describing an electrocardiographic lead as "unipolar" makes little sense electrically and should be avoided. The American Heart Association states "All leads are effectively 'bipolar,' and the term 'unipolar' in description of the augmented limb leads and the precordial leads lacks precision."
=== Limb leads ===
Leads I, II and III are called the limb leads. The electrodes that form these signals are located on the limbs – one on each arm and one on the left leg. The limb leads form the points of what is known as Einthoven's triangle.
Lead I is the voltage between the (positive) left arm (LA) electrode and right arm (RA) electrode:
I
=
L
A
−
R
A
{\displaystyle I=LA-RA}
Lead II is the voltage between the (positive) left leg (LL) electrode and the right arm (RA) electrode:
I
I
=
L
L
−
R
A
{\displaystyle II=LL-RA}
Lead III is the voltage between the (positive) left leg (LL) electrode and the left arm (LA) electrode:
I
I
I
=
L
L
−
L
A
{\displaystyle III=LL-LA}
=== Augmented limb leads ===
Leads aVR, aVL, and aVF are the augmented limb leads. They are derived from the same three electrodes as leads I, II, and III, but they use Goldberger's central terminal as their negative pole. Goldberger's central terminal is a combination of inputs from two limb electrodes, with a different combination for each augmented lead. It is referred to immediately below as "the negative pole".
Lead augmented vector right (aVR) has the positive electrode on the right arm. The negative pole is a combination of the left arm electrode and the left leg electrode:
a
V
R
=
R
A
−
1
2
(
L
A
+
L
L
)
=
3
2
(
R
A
−
V
W
)
{\displaystyle aVR=RA-{\frac {1}{2}}(LA+LL)={\frac {3}{2}}(RA-V_{W})}
Lead augmented vector left (aVL) has the positive electrode on the left arm. The negative pole is a combination of the right arm electrode and the left leg electrode:
a
V
L
=
L
A
−
1
2
(
R
A
+
L
L
)
=
3
2
(
L
A
−
V
W
)
{\displaystyle aVL=LA-{\frac {1}{2}}(RA+LL)={\frac {3}{2}}(LA-V_{W})}
Lead augmented vector foot (aVF) has the positive electrode on the left leg. The negative pole is a combination of the right arm electrode and the left arm electrode:
a
V
F
=
L
L
−
1
2
(
R
A
+
L
A
)
=
3
2
(
L
L
−
V
W
)
{\displaystyle aVF=LL-{\frac {1}{2}}(RA+LA)={\frac {3}{2}}(LL-V_{W})}
Together with leads I, II, and III, augmented limb leads aVR, aVL, and aVF form the basis of the hexaxial reference system, which is used to calculate the heart's electrical axis in the frontal plane.
Older versions of the nodes (VR, VL, VF) use Wilson's central terminal as the negative pole, but the amplitude is too small for the thick lines of old ECG machines. The Goldberger terminals scale up (augments) the Wilson results by 50%, at the cost of sacrificing physical correctness by not having the same negative pole for all three.
=== Precordial leads ===
The precordial leads lie in the transverse (horizontal) plane, perpendicular to the other six leads. The six precordial electrodes act as the positive poles for the six corresponding precordial leads: (V1, V2, V3, V4, V5, and V6). Wilson's central terminal is used as the negative pole. Recently, unipolar precordial leads have been used to create bipolar precordial leads that explore the right to left axis in the horizontal plane.
=== Specialized leads ===
Additional electrodes may rarely be placed to generate other leads for specific diagnostic purposes. Right-sided precordial leads may be used to better study pathology of the right ventricle or for dextrocardia (and are denoted with an R (e.g., V5R). Posterior leads (V7 to V9) may be used to demonstrate the presence of a posterior myocardial infarction. The Lewis lead or S5-lead (requiring an electrode at the right sternal border in the second intercostal space) can be used to better detect atrial activity in relation to that of the ventricles.
An esophageal lead can be inserted to a part of the esophagus where the distance to the posterior wall of the left atrium is only approximately 5–6 mm (remaining constant in people of different age and weight). An esophageal lead avails for a more accurate differentiation between certain cardiac arrhythmias, particularly atrial flutter, AV nodal reentrant tachycardia and orthodromic atrioventricular reentrant tachycardia. It can also evaluate the risk in people with Wolff-Parkinson-White syndrome, as well as terminate supraventricular tachycardia caused by re-entry.
An intracardiac electrogram (ICEG) is essentially an ECG with some added intracardiac leads (that is, inside the heart). The standard ECG leads (external leads) are I, II, III, aVL, V1, and V6. Two to four intracardiac leads are added via cardiac catheterization. The word "electrogram" (EGM) without further specification usually means an intracardiac electrogram.
=== Lead locations on an ECG report ===
A standard 12-lead ECG report (an electrocardiograph) shows a 2.5 second tracing of each of the twelve leads. The tracings are most commonly arranged in a grid of four columns and three rows. The first column is the limb leads (I, II, and III), the second column is the augmented limb leads (aVR, aVL, and aVF), and the last two columns are the precordial leads (V1 to V6).
Additionally, a rhythm strip may be included as a fourth or fifth row.
The timing across the page is continuous and notes tracings of the 12 leads for the same time period.
In other words, if the output were traced by needles on paper, each row would switch which leads as the paper is pulled under the needle.
For example, the top row would first trace lead I, then switch to lead aVR, then switch to V1, and then switch to V4, and so none of these four tracings of the leads are from the same time period as they are traced in sequence through time.
=== Contiguity of leads ===
Each of the 12 ECG leads records the electrical activity of the heart from a different angle, and therefore align with different anatomical areas of the heart. Two leads that look at neighboring anatomical areas are said to be contiguous.
In addition, any two precordial leads next to one another are considered to be contiguous. For example, though V4 is an anterior lead and V5 is a lateral lead, they are contiguous because they are next to one another.
== Electrophysiology ==
The study of the conduction system of the heart is called cardiac electrophysiology (EP). An EP study is performed via a right-sided cardiac catheterization: a wire with an electrode at its tip is inserted into the right heart chambers from a peripheral vein, and placed in various positions in close proximity to the conduction system so that the electrical activity of that system can be recorded.
Standard catheter positions for an EP study include "high right atrium" or hRA near the sinus node, a "His" across the septal wall of the tricuspid valve to measure bundle of His, a "coronary sinus" into the coronary sinus, and a "right ventricle" in the apex of the right ventricle.
== Interpretation ==
Interpretation of the ECG is fundamentally about understanding the electrical conduction system of the heart.
Normal conduction starts and propagates in a predictable pattern, and deviation from this pattern can be a normal variation or be pathological.
An ECG does not equate with mechanical pumping activity of the heart; for example, pulseless electrical activity produces an ECG that should pump blood but no pulses are felt (and constitutes a medical emergency and CPR should be performed).
Ventricular fibrillation produces an ECG but is too dysfunctional to produce a life-sustaining cardiac output. Certain rhythms are known to have good cardiac output and some are known to have bad cardiac output.
Ultimately, an echocardiogram or other anatomical imaging modality is useful in assessing the mechanical function of the heart.
Like all medical tests, what constitutes "normal" is based on population studies. The heartrate range of between 60 and 100 beats per minute (bpm) is considered normal since data shows this to be the usual resting heart rate.
=== Theory ===
Interpretation of the ECG is ultimately that of pattern recognition.
In order to understand the patterns found, it is helpful to understand the theory of what ECGs represent.
The theory is rooted in electromagnetics and boils down to the four following points:
depolarization of the heart toward the positive electrode produces a positive deflection
depolarization of the heart away from the positive electrode produces a negative deflection
repolarization of the heart toward the positive electrode produces a negative deflection
repolarization of the heart away from the positive electrode produces a positive deflection
Thus, the overall direction of depolarization and repolarization produces positive or negative deflection on each lead's trace.
For example, depolarizing from right to left would produce a positive deflection in lead I because the two vectors point in the same direction.
In contrast, that same depolarization would produce minimal deflection in V1 and V2 because the vectors are perpendicular, and this phenomenon is called isoelectric.
Normal rhythm produces four entities – a P wave, a QRS complex, a T wave, and a U wave – that each have a fairly unique pattern.
The P wave represents atrial depolarization.
The QRS complex represents ventricular depolarization.
The T wave represents ventricular repolarization.
The U wave represents papillary muscle repolarization.
Changes in the structure of the heart and its surroundings (including blood composition) change the patterns of these four entities.
The U wave is not typically seen and its absence is generally ignored. Atrial repolarization is typically hidden in the much more prominent QRS complex and normally cannot be seen without additional, specialized electrodes.
=== Background grid ===
ECGs are normally printed on a grid.
The horizontal axis represents time and the vertical axis represents voltage.
The standard values on this grid are shown in the adjacent image at 25mm/sec (or 40ms per mm):
A small box is 1 mm × 1 mm and represents 0.1 mV × 0.04 seconds.
A large box is 5 mm × 5 mm and represents 0.5 mV × 0.20 seconds.
The "large" box is represented by a heavier line weight than the small boxes.
The standard printing speed in the United States is 25 mm per sec (5 big boxes per second), but in other countries it can be 50 mm per sec.
Faster speeds such as 100 and 200 mm per sec are used during electrophysiology studies.
Not all aspects of an ECG rely on precise recordings or having a known scaling of amplitude or time.
For example, determining if the tracing is a sinus rhythm only requires feature recognition and matching, and not measurement of amplitudes or times (i.e., the scale of the grids are irrelevant).
An example to the contrary, the voltage requirements of left ventricular hypertrophy require knowing the grid scale.
=== Rate and rhythm ===
In a normal heart, the heart rate is the rate at which the sinoatrial node depolarizes since it is the source of depolarization of the heart.
Heart rate, like other vital signs such as blood pressure and respiratory rate, change with age.
In adults, a normal heart rate is between 60 and 100 bpm (normocardic), whereas it is higher in children.
A heart rate below normal is called "bradycardia" (<60 in adults) and above normal is called "tachycardia" (>100 in adults).
A complication of this is when the atria and ventricles are not in synchrony and the "heart rate" must be specified as atrial or ventricular (e.g., the ventricular rate in ventricular fibrillation is 300–600 bpm, whereas the atrial rate can be normal [60–100] or faster [100–150]).
In normal resting hearts, the physiologic rhythm of the heart is normal sinus rhythm (NSR).
Normal sinus rhythm produces the prototypical pattern of P wave, QRS complex, and T wave.
Generally, deviation from normal sinus rhythm is considered a cardiac arrhythmia.
Thus, the first question in interpreting an ECG is whether or not there is a sinus rhythm.
A criterion for sinus rhythm is that P waves and QRS complexes appear 1-to-1, thus implying that the P wave causes the QRS complex.
Once sinus rhythm is established, or not, the second question is the rate.
For a sinus rhythm, this is either the rate of P waves or QRS complexes since they are 1-to-1.
If the rate is too fast, then it is sinus tachycardia, and if it is too slow, then it is sinus bradycardia.
If it is not a sinus rhythm, then determining the rhythm is necessary before proceeding with further interpretation.
Some arrhythmias with characteristic findings:
Absent P waves with "irregularly irregular" QRS complexes are the hallmark of atrial fibrillation.
A "saw tooth" pattern with QRS complexes is the hallmark of atrial flutter.
A sine wave pattern is the hallmark of ventricular flutter.
Absent P waves with wide QRS complexes and a fast heart rate are ventricular tachycardia.
Determination of rate and rhythm is necessary in order to make sense of further interpretation.
=== Axis ===
The heart has several axes, but the most common by far is the axis of the QRS complex (references to "the axis" imply the QRS axis).
Each axis can be computationally determined to result in a number representing degrees of deviation from zero, or it can be categorized into a few types.
The QRS axis is the general direction of the ventricular depolarization wavefront (or mean electrical vector) in the frontal plane.
It is often sufficient to classify the axis as one of three types: normal, left deviated, or right deviated.
Population data shows that a normal QRS axis is from −30° to 105°, with 0° being along lead I and positive being inferior and negative being superior (best understood graphically as the hexaxial reference system).
Beyond +105° is right axis deviation and beyond −30° is left axis deviation (the third quadrant of −90° to −180° is very rare and is an indeterminate axis).
A shortcut for determining if the QRS axis is normal is if the QRS complex is mostly positive in lead I and lead II (or lead I and aVF if +90° is the upper limit of normal).
The normal QRS axis is generally down and to the left, following the anatomical orientation of the heart within the chest. An abnormal axis suggests a change in the physical shape and orientation of the heart or a defect in its conduction system that causes the ventricles to depolarize in an abnormal way.
The extent of a normal axis can be +90° or 105° depending on the source.
=== Amplitudes and intervals ===
All of the waves on an ECG tracing and the intervals between them have a predictable time duration, a range of acceptable amplitudes (voltages), and a typical morphology. Any deviation from the normal tracing is potentially pathological and therefore of clinical significance.
For ease of measuring the amplitudes and intervals, an ECG is printed on graph paper at a standard scale: each 1 mm (one small box on the standard 25mm/s ECG paper) represents 40 milliseconds of time on the x-axis, and 0.1 millivolts on the y-axis.
=== Time-Frequency Analysis in ECG Signal Processing ===
In electrocardiogram (ECG) signal processing, Time-Frequency Analysis (TFA) is an important technique used to reveal how the frequency characteristics of ECG signals change over time, especially in non-stationary signals such as arrhythmias or transient cardiac events.
Common Methods for Time-Frequency Analysis
Steps for Time-Frequency Analysis
Step1: Preprocessing
Signal Denoising: Use wavelet denoising, band-pass filtering (0.5–50 Hz), or Principal Component Analysis (PCA) to remove electromyographic (EMG) noise.
Signal Segmentation: Segment the signal based on heartbeat cycles (e.g., R-wave detection).
Step2: Select an Appropriate TFA Method
Choose methods such as STFT, WT, or HHT based on the application requirements.
Step3: Compute the Time-Frequency Spectrum
Calculate the time-frequency distribution using the selected method to generate a time-frequency representation.
Step4: Feature Extraction
Extract power features from specific frequency bands, such as low-frequency (LF: 0.04–0.15 Hz) and high-frequency (HF: 0.15–0.4 Hz) components.
Step5: Pattern Recognition or Diagnosis
Apply machine learning or deep learning models to detect or classify cardiac events based on the time-frequency features.
Application Scenarios
Heart Rate Variability Analysis (HRV):
Time-frequency analysis helps to separate sympathetic and parasympathetic nervous system activity.
Atrial Fibrillation Detection:
Analyze the time-frequency characteristics of atrial activity.
Ventricular Fibrillation Analysis:
Detect time-frequency changes in high-frequency abnormal components.
=== Limb leads and electrical conduction through the heart ===
The animation shown to the right illustrates how the path of electrical conduction gives rise to the ECG waves in the limb leads.
What is green zone ?
Recall that a positive current (as created by depolarization of cardiac cells) traveling towards the positive electrode and away from the negative electrode creates a positive deflection on the ECG. Likewise, a positive current traveling away from the positive electrode and towards the negative electrode creates a negative deflection on the ECG. The red arrow represents the overall direction of travel of the depolarization. The magnitude of the red arrow is proportional to the amount of tissue being depolarized at that instance. The red arrow is simultaneously shown on the axis of each of the 3 limb leads. Both the direction and the magnitude of the red arrow's projection onto the axis of each limb lead is shown with blue arrows. Then, the direction and magnitude of the blue arrows are what theoretically determine the deflections on the ECG. For example, as a blue arrow on the axis for Lead I moves from the negative electrode, to the right, towards the positive electrode, the ECG line rises, creating an upward wave. As the blue arrow on the axis for Lead I moves to the left, a downward wave is created. The greater the magnitude of the blue arrow, the greater the deflection on the ECG for that particular limb lead.
Frames 1–3 depict the depolarization being generated in and spreading through the sinoatrial node. The SA node is too small for its depolarization to be detected on most ECGs. Frames 4–10 depict the depolarization traveling through the atria, towards the atrioventricular node. During frame 7, the depolarization is traveling through the largest amount of tissue in the atria, which creates the highest point in the P wave. Frames 11–12 depict the depolarization traveling through the AV node. Like the SA node, the AV node is too small for the depolarization of its tissue to be detected on most ECGs. This creates the flat PR segment.
Frame 13 depicts an interesting phenomenon in an over-simplified fashion. It depicts the depolarization as it starts to travel down the interventricular septum, through the bundle of His and bundle branches. After the Bundle of His, the conduction system splits into the left bundle branch and the right bundle branch. Both branches conduct action potentials at about 1 m/s. However, the action potential starts traveling down the left bundle branch about 5 milliseconds before it starts traveling down the right bundle branch, as depicted by frame 13. This causes the depolarization of the interventricular septum tissue to spread from left to right, as depicted by the red arrow in frame 14. In some cases, this gives rise to a negative deflection after the PR interval, creating a Q wave such as the one seen in lead I in the animation to the right. Depending on the mean electrical axis of the heart, this phenomenon can result in a Q wave in lead II as well.
Following depolarization of the interventricular septum, the depolarization travels towards the apex of the heart. This is depicted by frames 15–17 and results in a positive deflection on all three limb leads, which creates the R wave. Frames 18–21 then depict the depolarization as it travels throughout both ventricles from the apex of the heart, following the action potential in the Purkinje fibers. This phenomenon creates a negative deflection in all three limb leads, forming the S wave on the ECG. Repolarization of the atria occurs at the same time as the generation of the QRS complex, but it is not detected by the ECG since the tissue mass of the ventricles is so much larger than that of the atria. Ventricular contraction occurs between ventricular depolarization and repolarization. During this time, there is no movement of charge, so no deflection is created on the ECG. This results in the flat ST segment after the S wave.
Frames 24–28 in the animation depict repolarization of the ventricles. The epicardium is the first layer of the ventricles to repolarize, followed by the myocardium. The endocardium is the last layer to repolarize. The plateau phase of depolarization has been shown to last longer in endocardial cells than in epicardial cells. This causes repolarization to start from the apex of the heart and move upwards. Since repolarization is the spread of negative current as membrane potentials decrease back down to the resting membrane potential, the red arrow in the animation is pointing in the direction opposite of the repolarization. This therefore creates a positive deflection in the ECG, and creates the T wave.
=== Ischemia and infarction ===
Ischemia or non-ST elevation myocardial infarctions (non-STEMIs) may manifest as ST depression or inversion of T waves. It may also affect the high frequency band of the QRS.
ST elevation myocardial infarctions (STEMIs) have different characteristic ECG findings based on the amount of time elapsed since the MI first occurred. The earliest sign is hyperacute T waves, peaked T waves due to local hyperkalemia in ischemic myocardium. This then progresses over a period of minutes to elevations of the ST segment by at least 1 mm. Over a period of hours, a pathologic Q wave may appear and the T wave will invert. Over a period of days the ST elevation will resolve. Pathologic Q waves generally will remain permanently.
The coronary artery that has been occluded can be identified in an STEMI based on the location of ST elevation. The left anterior descending (LAD) artery supplies the anterior wall of the heart, and therefore causes ST elevations in anterior leads (V1 and V2). The LCx supplies the lateral aspect of the heart and therefore causes ST elevations in lateral leads (I, aVL and V6). The right coronary artery (RCA) usually supplies the inferior aspect of the heart, and therefore causes ST elevations in inferior leads (II, III and aVF).
=== Artifacts ===
An ECG tracing is affected by patient motion. Some rhythmic motions (such as shivering or tremors) can create the illusion of cardiac arrhythmia. Artifacts are distorted signals caused by a secondary internal or external sources, such as muscle movement or interference from an electrical device.
Distortion poses significant challenges to healthcare providers, who employ various techniques and strategies to safely recognize these false signals. Accurately separating the ECG artifact from the true ECG signal can have a significant impact on patient outcomes and legal liabilities.
Improper lead placement (for example, reversing two of the limb leads) has been estimated to occur in 0.4% to 4% of all ECG recordings, and has resulted in improper diagnosis and treatment including unnecessary use of thrombolytic therapy.
=== A Method for Interpretation ===
Whitbread, consultant nurse and paramedic, suggests ten rules of the normal ECG, deviation from which is likely to indicate pathology. These have been added to, creating the 15 rules for 12-lead (and 15- or 18-lead) interpretation.
Rule 1: All waves in aVR are negative.
Rule 2: The ST segment (J point) starts on the isoelectric line (except in V1 & V2 where it may be elevated by not greater than 1 mm).
Rule 3: The PR interval should be 0.12–0.2 seconds long.
Rule 4: The QRS complex should not exceed 0.11–0.12 seconds.
Rule 5: The QRS and T waves tend to have the same general direction in the limb leads.
Rule 6: The R wave in the precordial (chest) leads grows from V1 to at least V4 where it may or may not decline again.
Rule 7: The QRS is mainly upright in I and II.
Rule 8: The P wave is upright in I II and V2 to V6.
Rule 9: There is no Q wave or only a small q (<0.04 seconds in width) in I, II and V2 to V6.
Rule 10: The T wave is upright in I II and V2 to V6. The end of the T wave should not drop below the isoelectric baseline.
Rule 11: Does the deepest S wave in V1 plus the tallest R wave in V5 or V6 equal >35 mm?
Rule 12: Is there an Epsilon wave?
Rule 13: Is there an J wave?
Rule 14: Is there a Delta wave?
Rule 15: Are there any patterns representing an occlusive myocardial infarction (OMI)?
== Diagnosis ==
Numerous diagnoses and findings can be made based upon electrocardiography, and many are discussed above. Overall, the diagnoses are made based on the patterns. For example, an "irregularly irregular" QRS complex without P waves is the hallmark of atrial fibrillation; however, other findings can be present as well, such as a bundle branch block that alters the shape of the QRS complexes. ECGs can be interpreted in isolation but should be applied – like all diagnostic tests – in the context of the patient. For example, an observation of peaked T waves is not sufficient to diagnose hyperkalemia; such a diagnosis should be verified by measuring the blood potassium level. Conversely, a discovery of hyperkalemia should be followed by an ECG for manifestations such as peaked T waves, widened QRS complexes, and loss of P waves. The following is an organized list of possible ECG-based diagnoses.
Rhythm disturbances or arrhythmias:
Atrial fibrillation and atrial flutter without rapid ventricular response
Premature atrial contraction (PACs) and premature ventricular contraction (PVCs)
Sinus arrhythmia
Sinus bradycardia and sinus tachycardia
Sinus pause and sinoatrial arrest
Sinus node dysfunction and bradycardia-tachycardia syndrome
Supraventricular tachycardia
Atrial fibrillation with rapid ventricular response
Atrial flutter with rapid ventricular response
AV nodal reentrant tachycardia
Atrioventricular reentrant tachycardia
Junctional ectopic tachycardia
Atrial tachycardia
Ectopic atrial tachycardia (unicentric)
Multifocal atrial tachycardia
Paroxysmal atrial tachycardia
Sinoatrial nodal reentrant tachycardia
Wide complex tachycardia
Ventricular flutter
Ventricular fibrillation
Ventricular tachycardia (monomorphic ventricular tachycardia)
Torsades de pointes (polymorphic ventricular tachycardia)
Pre-excitation syndrome
Lown–Ganong–Levine syndrome
Wolff–Parkinson–White syndrome
J wave (Osborn wave)
Heart block and conduction problems:
Sinoatrial block: first, second, and third-degree
AV node
First-degree AV block
Second-degree AV block (Mobitz [Wenckebach] I and II)
Third-degree AV block or complete AV block
Right bundle
Incomplete right bundle branch block (IRBBB)
Complete right bundle branch block (RBBB)
Left bundle
Incomplete left bundle branch block (ILBBB)
Complete left bundle branch block (LBBB)
Left anterior fascicular block (LAFB)
Left posterior fascicular block (LPFB)
Bifascicular block (LAFB plus LPFB)
Trifascicular block (LAFP plus FPFB plus RBBB)
QT syndromes
Brugada syndrome
Short QT syndrome
Long QT syndromes, genetic and drug-induced
Right and left atrial abnormality
Electrolytes disturbances and intoxication:
Digitalis intoxication
Calcium: hypocalcemia and hypercalcemia
Potassium: hypokalemia and hyperkalemia
Serotonin toxicity
Ischemia and infarction:
Wellens' syndrome (LAD occlusion)
de Winter T waves (LAD occlusion)
ST elevation and ST depression
High frequency QRS changes
Myocardial infarction (heart attack)
Non-Q wave myocardial infarction
NSTEMI
STEMI
Sgarbossa's criteria for ischemia with a LBBB
Structural:
Acute pericarditis
Right and left ventricular hypertrophy
Right ventricular strain or S1Q3T3 (can be seen in pulmonary embolism)
Other phenomena:
Cardiac aberrancy
Ashman phenomenon
Concealed conduction
Electrical alternans
== History ==
In 1872, Alexander Muirhead is reported to have attached wires to the wrist of a patient with fever to obtain an electronic record of their heartbeat.
In 1882, John Burdon-Sanderson working with frogs, was the first to appreciate that the interval between variations in potential was not electrically quiescent and coined the term "isoelectric interval" for this period.
In 1887, Augustus Waller invented an ECG machine consisting of a Lippmann capillary electrometer fixed to a projector. The trace from the heartbeat was projected onto a photographic plate that was itself fixed to a toy train. This allowed a heartbeat to be recorded in real time.
In 1895, Willem Einthoven assigned the letters P, Q, R, S, and T to the deflections in the theoretical waveform he created using equations which corrected the actual waveform obtained by the capillary electrometer to compensate for the imprecision of that instrument. Using letters different from A, B, C, and D (the letters used for the capillary electrometer's waveform) facilitated comparison when the uncorrected and corrected lines were drawn on the same graph. Einthoven probably chose the initial letter P to follow the example set by Descartes in geometry. When a more precise waveform was obtained using the string galvanometer, which matched the corrected capillary electrometer waveform, he continued to use the letters P, Q, R, S, and T, and these letters are still in use today. Einthoven also described the electrocardiographic features of a number of cardiovascular disorders.
In 1897, the string galvanometer was invented by the French engineer Clément Ader.
In 1901, Einthoven, working in Leiden, the Netherlands, used the string galvanometer: the first practical ECG. This device was much more sensitive than the capillary electrometer Waller used.
In 1924, Einthoven was awarded the Nobel Prize in Medicine for his pioneering work in developing the ECG.
By 1927, General Electric had developed a portable apparatus that could produce electrocardiograms without the use of the string galvanometer. This device instead combined amplifier tubes similar to those used in a radio with an internal lamp and a moving mirror that directed the tracing of the electric pulses onto film.
In 1937, Taro Takemi invented a new portable electrocardiograph machine.
In 1942, Emanuel Goldberger increases the voltage of Wilson's unipolar leads by 50% and creates the augmented limb leads aVR, aVL and aVF. When added to Einthoven's three limb leads and the six chest leads we arrive at the 12-lead electrocardiogram that is used today.
In the late 1940s, Rune Elmqvist invented an inkjet printer involving thin jets of ink deflected by electrical potentials from the heart, with good frequency response and direct recording of ECG on paper. The device, called the Mingograf, was sold by Siemens Elema until the 1990s.
=== Etymology ===
The word is derived from the Greek electro, meaning related to electrical activity; kardia, meaning heart; and graph, meaning "to write".
== See also ==
Signal-averaged electrocardiogram
Electrical conduction system of the heart
Electroencephalography
Electrogastrogram
Electropalatography
Electroretinography
Emergency medicine
Forward problem of electrocardiology
Heart rate
Heart rate monitor
Wireless ambulatory ECG
== Notes ==
== References ==
== External links ==
The whole ECG course on 1 A4 paper from ECGpedia, a wiki encyclopedia for a course on interpretation of ECG
Wave Maven – a large database of practice ECG questions provided by Beth Israel Deaconess Medical Center
PysioBank – a free scientific database with physiologic signals (here ecg)
EKG Academy – free EKG lectures, drills and quizzes
ECG Learning Center created by Eccles Health Sciences Library at University of Utah | Wikipedia/Electrocardiograph |
Heart rate variability (HRV) is the physiological phenomenon of variation in the time interval between heartbeats. It is measured by the variation in the beat-to-beat interval.
Other terms used include "cycle length variability", "R–R variability" (where R is a point corresponding to the peak of the QRS complex of the ECG wave; and R–R is the interval between successive Rs), and "heart period variability". Measurement of the RR interval is used to derive heart rate variability.
Methods used to detect beats include ECG, blood pressure, ballistocardiograms, and the pulse wave signal derived from a photoplethysmograph (PPG). ECG is considered the gold standard for HRV measurement because it provides a direct reflection of cardiac electric activity.
== Variability ==
Variability (or Variation) in the beat-to-beat interval is a physiological phenomenon. Power spectral analysis of the beat-to-beat variations of heart rate or the heart period (R–R interval) partitions the total variance (the “power”) of a continuous series of beats into its frequency components, typically identifying two or three main peaks: Very Low Frequency (VLF) <0.04 Hz, Low Frequency (LF), 0.04–0.15 Hz, and High Frequency (HF) 0.15–0.4 Hz.
The HF peak is widely believed to reflect cardiac parasympathetic nerve (PSNS) activity while the LF, although more complex, is often assumed to have a dominant sympathetic (SNS) component. Though LF was previously thought to reflect primarily SNS activity, it is now widely accepted that it reflects a mixture of both the SNS and PSNS.
Decreased PSNS activity or increased SNS activity will result in reduced HRV. High frequency (HF) activity (0.15 to 0.40 Hz), especially, has been linked to PSNS activity. Activity in this range is associated with the respiratory sinus arrhythmia (RSA), a vagally mediated modulation of heart rate (which increases during inspiration and decreases during expiration). Less is known about the physiological inputs of the low frequency (LF) activity (0.04 to 0.15 Hz).
The SA node receives several different inputs and the instantaneous heart rate or RR interval and its variation are the results of such inputs. The main inputs are the sympathetic and the parasympathetic nervous system (PSNS) and humoral factors. Respiration gives rise to waves in heart rate mediated primarily via the PSNS, and it is thought that the lag in the baroreceptor feedback loop may give rise to 10 second waves in heart rate (associated with Mayer waves of blood pressure), but this remains controversial.
Factors that affect the input are the baroreflex, thermoregulation, hormones, sleep–wake cycle, meals, physical activity, and stress.
== Clinical significance ==
Reduced HRV has been shown to be a predictor of mortality after myocardial infarction although others have shown that the information in HRV relevant to acute myocardial infarction survival is fully contained in the mean heart rate.
A range of other outcomes and conditions may also be associated with modified (usually lower) HRV, including congestive heart failure, diabetic neuropathy, post–cardiac-transplant depression, susceptibility to SIDS and poor survival in premature babies, as well as fatigue severity in chronic fatigue syndrome. On the other hand, for patients having high blood pressure (hypertension), higher HRV is a risk factor for atrial fibrillation.
== Psychological and social aspects ==
There is interest in HRV in the field of psychophysiology. For example, HRV is related to emotional arousal. High-frequency (HF) activity has been found to decrease under conditions of acute time pressure and emotional strain and elevated anxiety state, presumably related to focused attention and motor inhibition. HRV has been shown to be reduced in individuals reporting to worry more. In individuals with post-traumatic stress disorder (PTSD), HRV and its HF component is reduced whilst the low-frequency (LF) component is elevated. Furthermore, PTSD patients demonstrated no LF or HF reactivity to recalling a traumatic event. Statistical quantitative differences have also been found among healthy, depressed, and psychotic people.
The neurovisceral integration is a model of HRV that views the central autonomic network as the decision maker of cognitive, behavioral and physiological regulation as they pertain to a continuum of emotion. The neurovisceral integration model describes how the prefrontal cortex regulates activity in limbic structures which act to suppress parasympathetic nervous system (PSNS) activity and activate sympathetic nervous system (SNS) circuits. Variation in the output of these two branches of the autonomic system produces HRV and activity in the prefrontal cortex can hence modulate HRV.
HRV is reported to be an index of the influence of both the parasympathetic and the sympathetic nervous system. For example, high HRV is shown to reflect proper emotion regulation, decision-making, and attention, and low HRV reflects the opposite. The parasympathetic nervous system works to decrease the heart rate, while the SNS works to increase the heart rate. For example, someone with high HRV may reflect increased parasympathetic activity, and someone with low HRV may reflect increased sympathetic activity.
Emotions stem from the time and impact of a situation on a person. The ability to regulate emotions is essential for social environments and well-being. HRV has provided a window to the physiological components associated with emotional regulation. HRV has been shown to reflect emotional regulation at two different levels, while resting and while completing a task. Research suggests that a person with higher HRV while resting can provide more appropriate emotional responses compared to those that have low HRV at rest. Empirical research found that HRV can reflect better emotional regulation by those with higher resting HRV, particularly with negative emotions. However, HRV is elevated by negative news in persons who react more strongly to negative news than to positive news. When completing a task, HRV is subject to change, especially when people need to regulate their emotions. Most importantly, individual differences are related to the ability to regulate emotions.
Previous research has suggested that a large part of the attention regulation is due to the default inhibitory properties of the prefrontal cortex. Top-down processes from the prefrontal cortex provide parasympathetic influences, and if for some reason, those influences are active, attention can suffer. Researchers have suggested that HRV can index attention. It was found that groups with high anxiety and low HRV have poor attention. In line with this research, it has also been suggested that increased attention has been linked to high HRV and increased vagus nerve activity. The vagus nerve activity reflects the physiological modulation of the parasympathetic and sympathetic nervous system. The activity behind the prefrontal cortex and the parasympathetic and sympathetic nervous system can influence heart activity. However, people are not all affected the same. A systematic review of HRV and cognitive function suggested that resting HRV can predict individual differences in attentional performance. Furthermore, HRV has been able to index the role of attention and performance, supporting high HRV as a biomarker of increased attention and performance.
Decision-making skills are found to be indexed by HRV in several studies. Previous research has suggested that both emotion and attention are linked to decision making; for example, poor decision making is linked to the inability to regulate or control emotions and attention and vice versa. Decision making is negatively affected by lower HRV and positively affected by higher levels of HRV. Most importantly, resting-state HRV was found to be a significant predictor of cognitive functions such as decision making. HRV, accompanied by a psychological state such as anxiety, has been found to lead to poor decisions. For example, a group of researchers found that low HRV was an index of higher uncertainty leading to poor decision-making skills, especially those with higher levels of anxiety. HRV was also used to assess decision-making skills in a high-risk game and was found to be an index higher sympathetic activation (lower HRV) when making decisions involving risk. HRV can index psychological concepts, such as the ones outlined above, to assess the demand for the situations that people experience.
The polyvagal theory is another way to describe the pathways in the autonomic nervous system that mediate HRV. The polyvagal theory highlights three main ordinal processes, inactive response to an environmental threat, the active response to an environmental threat, and the fluctuation between the connect and disconnect to an environmental threat. This theory, like others, decomposes heart rate variability based on frequency domain characteristics. However, it places more emphasis on respiratory sinus arrhythmia and its transmission by a hypothesized neural pathway distinct from other components of HRV. There is anatomic and physiological evidence for a polyvagal control of the heart.
== Phenomena ==
There are two primary fluctuations:
Respiratory arrhythmia (or respiratory sinus arrhythmia) is directly caused by the central respiratory rhythm, which tracks the respiratory rate across a range of frequencies and is a major cause of heart rate variability in humans. The respiratory rhythm contributes to sinus arrhythmia in normal unanesthetized subjects during mechanical hyperventilation with positive pressure.
Low-frequency oscillations are associated with Mayer waves (Traube–Hering–Mayer waves) of blood pressure and is usually at a frequency of 0.1 Hz, or a 10-second period.
=== Pattern formation in heart rate ===
The regulation of heart rate, encompassing both acceleration and deceleration of the heartbeat, is highly specific. Distinct patterns in heart rate can be observed during everyday movements, such as kneeling down or standing up. These patterns reflect highly sensitive physiological regulatory mechanisms that enable a healthy heart to adapt to various life influences.
== Artifact ==
Errors in the location of the instantaneous heart beat will result in errors in the calculation of the HRV. HRV is highly sensitive to artifact and errors in as low as even 2% of the data will result in unwanted biases in HRV calculations. To ensure accurate results therefore it is critical to manage artifact and RR errors appropriately prior to performing any HRV analyses.
Robust management of artifacts, including RWave identification, interpolation and exclusion requires a high degree of care and precision. This can be very time-consuming in large studies with data recorded over long durations. Software packages are able to assist users with a variety of robust and tested artifact management tools. These software programs also include some automated capability but it is important that a human review any automated artifact management and edit accordingly.
== Analysis ==
The most widely used methods can be grouped under time-domain and frequency-domain. A joint European and American task-force described standards in HRV measurements in 1996. Other methods have been proposed, such as non-linear methods.
=== Time-domain methods ===
Time-domain methods are based on the beat-to-beat or NN intervals, which are analysed to give variables such as:
SDNN (standard deviation of NN intervals). Often calculated over a 24-hour period. SDNN reflects all the cyclic components responsible for variability in the period of recording, therefore it represents total variability.
SDANN (standard deviation of the average NN intervals) calculated over short periods, usually 5 minutes. SDANN is therefore a measure of changes in heart rate due to cycles longer than 5 minutes.
RMSSD (root mean square of successive differences), the square root of the mean of the squares of the successive differences between adjacent NNs.
SDSD (standard deviation of successive differences), the standard deviation of the successive differences between adjacent NNs.
NN50, the number of pairs of successive NNs that differ by more than 50 ms.
pNN50, the proportion of NN50 divided by total number of NNs.
NN20, the number of pairs of successive NNs that differ by more than 20 ms.
pNN20, the proportion of NN20 divided by total number of NNs.
EBC (estimated breath cycle), the range (max-min) within a moving window of a given time duration within the study period. The windows can move in a self-overlapping way or be strictly distinct (sequential) windows. EBC is often provided in data acquisition scenarios where HRV feedback in real time is a primary goal. EBC derived from PPG over 10-second and 16-second sequential and overlapping windows has been shown to correlate highly with SDNN.
=== Geometric methods ===
The series of NN intervals also can be converted into a geometric pattern such as:
Geometric Measures HRV triangular index: integral of density distribution / maximum of density distribution maximum
HRV triangular index = Number of all NN intervals / maximum number. Dependent on the length of the bin -> quote the bin size+ relative insensitive to the analytic quality of the series of NN intervals – need of reasonable number of NN intervals to generate the geometric pattern (in practice 20 min to 24 h) – not appropriate to assess short-term changes in HRV
the sample density distribution of NN interval durations;
sample density distribution of differences between adjacent NN intervals;
a scatterplot of each NN (or RR) interval with the immediately preceding NN (or RR) interval – also called "Poincare plot" or (apparently in error) a "Lorenz plot"; and so forth. A simple formula is then used that judges the variability on the basis of the geometric and/or graphics properties of the resulting pattern.
=== Frequency-domain methods ===
Frequency domain methods assign bands of frequency and then count the number of NN intervals that match each band. The bands are typically high frequency (HF) from 0.15 to 0.4 Hz, low frequency (LF) from 0.04 to 0.15 Hz, and the very low frequency (VLF) from 0.0033 to 0.04 Hz. HF power reflects stimulation by the parasympathetic nervous system (PNS), whereas LF power reflects stimulation by both the sympathetic nervous system (SNS) and the PNS. VLF power is associated with thermoregulation, the renin–angiotensin system. and peripheral vasomotor activity.
Several methods of analysis are available. Power spectral density (PSD), using parametric or nonparametric methods, provides basic information on the power distribution across frequencies. One of the most commonly used PSD methods is the discrete Fourier transform.
Methods for the calculation of PSD may be generally classified as nonparametric and parametric. In most instances, both methods provide comparable results. The advantages of the nonparametric methods are (1) the simplicity of the algorithm used (fast Fourier transform [FFT] in most of the cases) and (2) the high processing speed. The advantages of parametric methods are (1) smoother spectral components that can be distinguished independent of preselected frequency bands, (2) easy postprocessing of the spectrum with an automatic calculation of low- and high-frequency power components with an easy identification of the central frequency of each component, and (3) an accurate estimation of PSD even on a small number of samples on which the signal is supposed to maintain stationarity. The basic disadvantage of parametric methods is the need of verification of the suitability of the chosen model and of its complexity (that is, the order of the model).
In addition to classical FFT-based methods used for the calculation of frequency parameters, a more appropriate PSD estimation method is the Lomb–Scargle periodogram. Analysis has shown that the LS periodogram can produce a more accurate estimate of the PSD than FFT methods for typical RR data. Since the RR data is an unevenly sampled data, another advantage of the LS method is that in contrast to FFT-based methods it is able to be used without the need to resample and detrend the RR data.
Alternatively, to avoid artefacts that are created when calculating the power of a signal that includes a single high-intensity peak (for example caused by an arrhythmic heart beat), the concept of the 'instantaneous Amplitude' has been introduced, which is based on the Hilbert transform of the RR data.
A newly used HRV index, which depends on the wavelet entropy measures, is an alternative choice. The wavelet entropy measures are calculated using a three-step procedure defined in the literature. First, the wavelet packet algorithm is implemented using the Daubechies 4 (DB4) function as the mother wavelet with a scale of 7. Once the wavelet coefficients are obtained, the energy for each coefficient are calculated as described in the literature. After calculating the normalized values of wavelet energies, which represent the relative wavelet energy (or the probability distribution), the wavelet entropies are obtained using the definition of entropy given by Shannon.
=== Non-linear methods ===
Given the complexity of the mechanisms regulating heart rate, it is reasonable to assume that applying HRV analysis based on methods of non-linear dynamics will yield valuable information. Although chaotic behavior has been assumed, more rigorous testing has shown that heart rate variability cannot be described as a low dimensional chaotic process. However, application of chaotic globals to HRV has been shown to predict diabetes status. The most commonly used non-linear method of analysing heart rate variability is the Poincaré plot. Each data point represents a pair of successive beats, the x-axis is the current RR interval, while the y-axis is the previous RR interval. HRV is quantified by fitting mathematically defined geometric shapes to the data. Other methods used are the correlation dimension, symbolic dynamics, nonlinear predictability, pointwise correlation dimension, approximate entropy, sample entropy, multiscale entropy analysis, sample asymmetry and memory length (based on inverse statistical analysis). It is also possible to represent long range correlations geometrically.
=== Long term correlations ===
Sequences of RR intervals have been found to have long-term correlations. However, one flaw with these analyses is their lack of goodness-of-fit statistics, i.e. values are derived that may or may not have adequate statistical rigor. Different types of correlations have been found during different sleep stages.
== Heart rate dependence of HRV parameters ==
A basic problem is that all the parameters used to characterize HRV strongly depend on heart rate, but many articles have not adjusted properly or at all for HR differences when comparing HRV in multiple circumstances.
However, the exact HRV(HR) relationship is still a matter of debate. For time domain parameters (RMSSD, SDNN, etc.) the results imply that, if there exists a universal function, it should be either exponential or hyperbolic in nature. The evaluation procedures used to determine HRV(HR) function have not allowed to decide between these options, so far.
A new evaluation method has recently allowed to determine a HRV(HR) function with unprecedented precision: it can be described by two descending exponential components for healthy individuals, in general.
== Duration and circumstances of ECG recording ==
Time domain methods are preferred to frequency domain methods when short-term recordings are investigated. This is due to the fact that the recording should be at least 10 times the wavelength of the lowest frequency bound of interest. Thus, recording of approximately 1 minute is needed to assess the HF components of HRV (i.e., a lowest bound of 0.15 Hz is a cycle of 6.6 seconds and so 10 cycles require ~60 seconds), while more than 4 minutes are needed to address the LF component (with a lower bound of 0.04 Hz).
Although time domain methods, especially the SDNN and RMSSD methods, can be used to investigate recordings of long durations, a substantial part of the long-term variability is day–night differences. Thus, long-term recordings analyzed by time domain methods should contain at least 18 hours of analyzable ECG data that include the whole night.
== Physiological correlates of HRV components ==
=== Autonomic influences of heart rate ===
Although cardiac automaticity is intrinsic to various pacemaker tissues, heart rate and rhythm are largely under the control of the autonomic nervous system. The parasympathetic influence on heart rate is mediated via release of acetylcholine by the vagus nerve. Muscarinic acetylcholine receptors respond to this release mostly by an increase in cell membrane K+ conductance. Acetylcholine also inhibits the hyperpolarization-activated "pacemaker" current. The "Ik decay" hypothesis proposes that pacemaker depolarization results from slow deactivation of the delayed rectifier current, Ik, which, due to a time-independent background inward current, causes diastolic depolarization. Conversely, the "If activation" hypothesis suggests that after action potential termination, If provides a slowly activating inward current predominating over decaying Ik, thus initiating slow diastolic depolarization.
The sympathetic influence on heart rate is mediated by release of epinephrine and norepinephrine. Activation of β-adrenergic receptors results in cAMP-mediated phosphorylation of membrane proteins and increases in ICaL and in If the result is an acceleration of the slow diastolic depolarization.
Under resting conditions, vagal tone prevails and variations in heart period are largely dependent on vagal modulation. The vagal and sympathetic activity constantly interact. Because the sinus node is rich in acetylcholinesterase, the effect of any vagal impulse is brief because the acetylcholine is rapidly hydrolyzed. Parasympathetic influences exceed sympathetic effects probably through two independent mechanisms: a cholinergically induced reduction of norepinephrine released in response to sympathetic activity, and a cholinergic attenuation of the response to an adrenergic stimulus.
=== Components ===
The RR interval variations present during resting conditions represent beat-by-beat variations in cardiac autonomic inputs. However, efferent vagal (parasympathetic) activity is a major contributor to the HF component, as seen in clinical and experimental observations of autonomic maneuvers such as electrical vagal stimulation, muscarinic receptor blockade, and vagotomy. More problematic is the interpretation of the LF component, which was considered by some as a marker of sympathetic modulation (especially when expressed in normalized units) but is now known to include both sympathetic and vagal influences. For example, during sympathetic activation the resulting tachycardia is usually accompanied by a marked reduction in total power, whereas the reverse occurs during vagal activation. Thus the spectral components change in the same direction and do not indicate that LF faithfully reflects sympathetic effects.
HRV measures fluctuations in autonomic inputs to the heart rather than the mean level of autonomic inputs. Thus, both withdrawal and saturatingly high levels of autonomic input to the heart can lead to diminished HRV.
== Changes related to biologic states and pathologies ==
A reduction of HRV has been reported in several cardiovascular and noncardiovascular diseases.
=== Myocardial infarction ===
Depressed HRV after MI may reflect a decrease in vagal activity directed to the heart. HRV in patients surviving an acute MI reveal a reduction in total and in the individual power of spectral components. The presence of an alteration in neural control is also reflected in a blunting of day-night variations of RR interval. In post-MI patients with a very depressed HRV, most of the residual energy is distributed in the VLF frequency range below 0.03 Hz, with only a small respiration-related variations.
=== Diabetic neuropathy ===
In neuropathy associated with diabetes mellitus characterized by alteration in small nerve fibers, a reduction in time domain parameters of HRV seems not only to carry negative prognostic value but also to precede the clinical expression of autonomic neuropathy. In diabetic patients without evidence of autonomic neuropathy, reduction of the absolute power of LF and HF during controlled conditions was also reported. Similarly, diabetic patients can be differentiated from normal controls on the basis of reduction in HRV.
=== Heart transplants ===
A very reduced HRV with no definite spectral components has been reported in patients with a recent heart transplant. The appearance of discrete spectral components in a few patients is considered to reflect cardiac reinnervation. This reinnervation may occur as early as 1 to 2 years after transplantation and is assumed to be of sympathetic origin. In addition, a correlation between respiratory rate and the HF component of HRV observed in some transplanted patients also indicates that a nonneural mechanism may generate a respiration-related rhythmic oscillation.
=== Myocardial dysfunction ===
A reduced HRV has been observed consistently in patients with cardiac failure. In this condition characterized by signs of sympathetic activation such as faster heart rates and high levels of circulating catecholamines, a relation between changes in HRV and the extent of left ventricular dysfunction was reported. In fact, whereas the reduction in time domain measures of HRV seemed to parallel the severity of the disease, the relationship between spectral components and indices of ventricular dysfunction appears to be more complex. In particular, in most patients with a very advanced phase of the disease and with a drastic reduction in HRV, an LF component could not be detected despite the clinical signs of sympathetic activation. This reflects that, as stated above, the LF may not accurately reflect cardiac sympathetic tone.
=== Liver cirrhosis ===
Liver cirrhosis is associated with decreased HRV. Decreased HRV in patients with cirrhosis has a prognostic value and predicts mortality. Loss of HRV is also associated with higher plasma pro-inflammatory cytokine levels and impaired neurocognitive function in this patient population.
=== Sepsis ===
HRV is decreased in patients with sepsis. Loss of HRV has both diagnostic and prognostic value in neonates with sepsis. The pathophysiology of decreased HRV in sepsis is not well understood but there is experimental evidence to show that partial uncoupling of cardiac pacemaker cells from autonomic neural control may play a role in decreased HRV during acute systemic inflammation. (Decreased HRV is generally lower in inflammatory conditions).
=== Tetraplegia ===
Patients with chronic complete high cervical spinal cord lesions have intact efferent vagal neural pathways directed to the sinus node. However, an LF component can be detected in HRV and arterial pressure variabilities of some tetraplegic patients. Thus, the LF component of HRV in those without intact sympathetic inputs to the heart represent vagal modulation.
=== Sudden cardiac death ===
Victims of sudden cardiac death have been found to have had lower HRV than healthy individuals. HRV can be observed to be depressed prior to the development of SCD, which raises questions about whether or not altered autonomic function plays a role in the development of electrical instability. HRV is also depressed in SCD survivors, who are at high risk for subsequent episodes. HRV is markedly decreased prior to both fatal and non-fatal arrhythmias.
=== Cancer ===
HRV correlates with the progression of disease and outcome of cancer patients, according to a systematic review of published studies. Patients in the early stages of cancer have a significantly higher HRV when compared to patients in the later stages of cancer, suggesting disease severity influences HRV. Different ranges of HRV can be observed between cancer types.
=== Pregnancy ===
HRV alterations occur in healthy pregnancies as well as similar changes in pregnancies with gestational diabetes that include lower HRV mean values.
=== Mood and anxiety disorders ===
Low RMSSD, thought to represent vagal tone, have been associated with major depression. Lower SDNN and elevated LF/HF were found in those with bipolar disorder, and in particular those characterized as having greater illness severity due to greater number of episodes, illness duration and whether there had been psychosis. Patients with PTSD also had lower HF, a measure of vagal tone.
== Modifications by specific interventions ==
Interventions that augment HRV may be protective against cardiac mortality and sudden cardiac death. Although the rationale for changing HRV is sound, it also contains the inherent danger of leading to the unwarranted assumption that modification of HRV translates directly into cardiac protection, which may not be the case. Despite the growing consensus that increases in vagal activity can be beneficial, it is not as yet known how much vagal activity (or HRV as a marker) has to increase in order to provide adequate protection.
=== β-Adrenergic blockade ===
The data on the effect of β-blockers on HRV in post-MI patients are surprisingly scant. Despite the observation of statistically significant increases, the actual changes are very modest. In conscious post-MI dogs, β-blockers do not modify HRV. The unexpected observation that before MI, β-blockade increases HRV only in the animals destined to be at low risk for lethal arrhythmias after MI may suggest novel approaches to post-MI risk stratification.
=== Antiarrhythmic drugs ===
Data exist for several antiarrhythmic drugs. Flecainide and propafenone but not amiodarone were reported to decrease time domain measures of HRV in patients with chronic ventricular arrhythmia. In another study, propafenone reduced HRV and decreased LF much more than HF. A larger study confirmed that flecainide, also encainide and moricizine, decreased HRV in post-MI patients but found no correlation between the change in HRV and mortality during follow-up. Thus, some antiarrhythmic drugs associated with increased mortality can reduce HRV. However, it is not known whether these changes in HRV have any direct prognostic significance.
=== Scopolamine ===
Low-dose muscarinic receptor blockers, such as atropine and scopolamine, may produce a paradoxical increase in vagal effects on the heart, as suggested by a decrease in heart rate. In addition, scopolamine and low dose atropine can markedly increase HRV. However, though the heart rate slowing in proportional to the (low) dose of atropine, the increase in HRV varies widely across and within individuals. This suggests that even for vagal activity to the heart, HRV may be a limited marker.
=== Thrombolysis ===
The effect of thrombolysis on HRV (assessed by pNN50) was reported in 95 patients with acute MI. HRV was higher 90 minutes after thrombolysis in the patients with patency of the infarct-related artery. However, this difference was no longer evident when the entire 24 hours were analyzed.
=== Exercise training ===
Exercise training may decrease cardiovascular mortality and sudden cardiac death. Regular exercise training is also thought to modify cardiac autonomic control. Individuals who exercise regularly have a 'training bradycardia' (i.e., low resting heart rate) and generally have higher HRV than sedentary individuals.
=== Biofeedback ===
The technique called resonant breathing biofeedback teaches how to recognize and control involuntary heart rate variability. A randomized study by Sutarto et al. assessed the effect of resonant breathing biofeedback among manufacturing operators; depression, anxiety and stress significantly decreased. A first overall meta-analysis by Goessl VC et al. (24 studies, 484 individuals, 2017) indicates ''HRV biofeedback training is associated with a large reduction in self-reported stress and anxiety'', while mentioning that more well-controlled studies are needed.
=== Wind instruments ===
One study that surveyed the physiological effects of playing Native American flutes found a significant HRV increase when playing both low-pitched and high-pitched flutes.
== Normal HRV values ==
Even though there are no widely accepted standard values for HRV that can be used for clinical purposes, multiple studies have measured and reported normal values for various populations:
Time Domain Analysis Abbreviations
IBI is InterBeat Interval, the time period between successive heartbeats (Normal-to-Normal interbeat interval, also known as the R–R interval), measured in milliseconds (ms). SDNN is Standard Deviation of Normal-to-Normal interbeat intervals measured in milliseconds. RMSSD is Root Mean Square of Successive Differences between normal heartbeats measured in milliseconds. The conventional recording time is five minutes.
Spectral Analysis Abbreviations
LF is Power of the Low Frequency range [ms squared (ms2) or normal units (nu)] HF is Power of the High Frequency range [ms squared (ms2) or normal units (nu)] LF/HF is the ratio of LF-to-HF power
== See also ==
Heart rate turbulence
Sinus rhythm
== References ==
== External links ==
Association for Applied Psychophysiology and Biofeedback
Biofeedback Federation of Europe
1996 guidelines
Review on the mechanisms of cardiovascular variability in the Journal of Physiology | Wikipedia/Heart_rate_variability |
In medicine, the pulse refers to the rhythmic pulsations (expansion and contraction) of an artery in response to the cardiac cycle (heartbeat). The pulse may be felt (palpated) in any place that allows an artery to be compressed near the surface of the body close to the skin, such as at the neck (carotid artery), wrist (radial artery or ulnar artery), at the groin (femoral artery), behind the knee (popliteal artery), near the ankle joint (posterior tibial artery), and on foot (dorsalis pedis artery). The pulse is most commonly measured at the wrist or neck for adults and at the brachial artery (inner upper arm between the shoulder and elbow) for infants and very young children. A sphygmograph is an instrument for measuring the pulse.
== Physiology ==
Claudius Galen was perhaps the first physiologist to describe the pulse. The pulse is an expedient tactile method of determination of systolic blood pressure to a trained observer. Diastolic blood pressure is non-palpable and unobservable by tactile methods, occurring between heartbeats.
Pressure waves generated by the heart in systole move the arterial walls. Forward movement of blood occurs when the boundaries are pliable and compliant. These properties form enough to create a palpable pressure wave.
Pulse velocity, pulse deficits and much more physiologic data are readily and simplistically visualized by the use of one or more arterial catheters connected to a transducer and oscilloscope. This invasive technique has been commonly used in intensive care since the 1970s.
The pulse may be further indirectly observed under light absorbances of varying wavelengths with assigned and inexpensively reproduced mathematical ratios. Applied capture of variances of light signal from the blood component hemoglobin under oxygenated vs. deoxygenated conditions allows the technology of pulse oximetry.
== Characteristics ==
=== Rate ===
The rate of the pulse can be observed and measured on the outside of an artery by tactile or visual means. It is recorded as arterial beats per minute or BPM. Although the pulse and heart beat are related, they are not the same. For example, there is a delay between the onset of the heart beat and the onset of the pulse, known as the pulse transit time, which varies by site. Similarly measurements of heart rate variability and pulse rate variability differ.
In healthy people, the pulse rate is close to the heart rate, as measured by ECG. Measuring the pulse rate is therefore a convenient way to estimate the heart rate. Pulse deficit is a condition in which a person has a difference between their pulse rate and heart rate. It can be observed by simultaneous palpation at the radial artery and auscultation using a stethoscope at the PMI, near the heart apex, for example. Typically, in people with pulse deficit, heart beats do not result in pulsations at the periphery, meaning the pulse rate is lower than the heart rate. Pulse deficit has been found to be significant in the context of premature ventricular contraction and atrial fibrillation.
=== Rhythm ===
A normal pulse is regular in rhythm and force. An irregular pulse may be due to sinus arrhythmia, ectopic beats, atrial fibrillation, paroxysmal atrial tachycardia, atrial flutter, partial heart block etc. Intermittent dropping out of beats at pulse is called "intermittent pulse". Examples of regular intermittent (regularly irregular) pulse include pulsus bigeminus, second-degree atrioventricular block. An example of irregular intermittent (irregularly irregular) pulse is atrial fibrillation.
=== Volume ===
The degree of expansion displayed by artery during diastolic and systolic state is called volume. It is also known as amplitude, expansion or size of pulse.
==== Hypokinetic pulse ====
A weak pulse signifies narrow pulse pressure. It may be due to low cardiac output (as seen in shock, congestive cardiac failure), hypovolemia, valvular heart disease (such as aortic outflow tract obstruction, mitral stenosis, aortic arch syndrome) etc.
==== Hyperkinetic pulse ====
A bounding pulse signifies high pulse pressure. It may be due to low peripheral resistance (as seen in fever, anemia, thyrotoxicosis, hyperkinetic heart syndrome, A-V fistula, Paget's disease, beriberi, liver cirrhosis), increased cardiac output, increased stroke volume (as seen in anxiety, exercise, complete heart block, aortic regurgitation), decreased distensibility of arterial system (as seen in atherosclerosis, hypertension and coarctation of aorta).
The strength of the pulse can also be reported:
0 = Absent
1 = Barely palpable
2 = Easily palpable
3 = Full
4 = Aneurysmal or bounding pulse
=== Force ===
Also known as compressibility of pulse. It is a rough indication of systolic blood pressure.
=== Tension ===
Determined mainly by mean arterial blood pressure; corresponds to diastolic blood pressure. A low tension pulse (pulsus mollis), the vessel is soft or impalpable between beats. In high tension pulse (pulsus durus), vessels feel rigid even between pulse beats.
=== Form ===
A form or contour of a pulse is palpatory estimation of arteriogram. A quickly rising and quickly falling pulse (pulsus celer) is seen in aortic regurgitation. A slow rising and slowly falling pulse (pulsus tardus) is seen in aortic stenosis.
=== Equality ===
Comparing pulses and different places gives valuable clinical information.
A discrepant or unequal pulse between left and right radial artery is observed in anomalous or aberrant course of artery, coarctation of aorta, aortitis, dissecting aneurysm, peripheral embolism etc. An unequal pulse between upper and lower extremities is seen in coarctation to aorta, aortitis, block at bifurcation of aorta, dissection of aorta, iatrogenic trauma and arteriosclerotic obstruction.
=== Condition of arterial wall ===
A normal artery is not palpable after flattening by digital pressure. A thick radial artery which is palpable 7.5–10 cm up the forearm is suggestive of arteriosclerosis.
=== Radio-femoral delay ===
In coarctation of aorta, femoral pulse may be significantly delayed as compared to radial pulse (unless there is coexisting aortic regurgitation). The delay can also be observed in supravalvar aortic stenosis.
== Patterns ==
Several pulse patterns can be of clinical significance. These include:
Anacrotic pulse: notch on the upstroke of the carotid pulse. Two distinct waves (slow initial upstroke and delayed peak, which is close to S2). Present in AS.
Dicrotic pulse: is characterized by two beats per cardiac cycle, one systolic and the other diastolic. Physiologically, the dicrotic wave is the result of reflected waves from the lower extremities and aorta. Conditions associated with low cardiac output and high systemic vascular resistance can produce a dicrotic pulse.
Pulse deficit: difference in the heart rate by direct cardiac ausculation and by palpation of the peripheral arterial pulse rate when in atrial fibrillation (AF).
Pulsus alternans: an ominous medical sign that indicates progressive systolic heart failure. To trained fingertips, the examiner notes a pattern of a strong pulse followed by a weak pulse over and over again. This pulse signals a flagging effort of the heart to sustain itself in systole. It also can be detected in HCM with obstruction.
Pulsus bigeminus: indicates a pair of hoofbeats within each heartbeat. Concurrent auscultation of the heart may reveal a gallop rhythm of the native heartbeat.
Pulsus bisferiens: is characterized by two beats per cardiac cycle, both systolic, unlike the dicrotic pulse. It is an unusual physical finding typically seen in patients with aortic valve diseases if the aortic valve does not normally open and close. Trained fingertips will observe two pulses to each heartbeat instead of one.
Pulsus tardus et parvus, also pulsus parvus et tardus, slow-rising pulse and anacrotic pulse, is weak (parvus), and late (tardus) relative to its expected characteristics. It is caused by a stiffened aortic valve that makes it progressively harder to open, thus requiring increased generation of blood pressure in the left ventricle. It is seen in aortic valve stenosis.
Pulsus paradoxus: a condition in which some heartbeats cannot be detected at the radial artery during the inspiration phase of respiration. It is caused by an exaggerated decrease in blood pressure during this phase, and is diagnostic of a variety of cardiac and respiratory conditions of varying urgency, such as cardiac tamponade.
Tachycardia: an elevated resting heart rate. In general an electrocardiogram (ECG) is required to identify the type of tachycardia.
Pulsatile This description of the pulse implies the intrinsic physiology of systole and diastole. Scientifically, systole and diastole are forces that expand and contract the pulmonary and systemic circulations.
A collapsing pulse is a sign of hyperdynamic circulation, which can be seen in AR or PDA.
== Common palpable sites ==
Sites can be divided into peripheral pulses and central pulses. Central pulses include the carotid and femoral pulses.
=== Upper limb ===
Axillary pulse: located inferiorly of the lateral wall of the axilla
Brachial pulse: located on the inside of the upper arm near the elbow, frequently used in place of carotid pulse in infants (brachial artery)
Radial pulse: located on the lateral of the wrist (radial artery). It can also be found in the anatomical snuff box. Commonly, the radial pulse is measured with three fingers. The finger closest to the heart is used to occlude the pulse pressure, the middle finger is used get a crude estimate of the blood pressure, and the finger most distal to the heart (usually the ring finger) is used to nullify the effect of the ulnar pulse as the two arteries are connected via the palmar arches (superficial and deep).
Ulnar pulse: located on the medial of the wrist (ulnar artery).
=== Lower limb ===
Femoral pulse: located in the inner thigh, at the mid-inguinal point, halfway between the pubic symphysis and anterior superior iliac spine (femoral artery).
Popliteal pulse: Above the knee in the popliteal fossa, found by holding the bent knee. The patient bends the knee at approximately 124°, and the health care provider holds it in both hands to find the popliteal artery in the pit behind the knee (popliteal artery).
Dorsalis pedis pulse: located on top of the foot, immediately lateral to the extensor of hallucis longus (dorsalis pedis artery).
Tibialis posterior pulse: located on the medial side of the ankle, 2 cm inferior and 2 cm posterior to the medial malleolus (posterior tibial artery). It is easily palpable over Pimenta's Point.
=== Head and neck ===
Carotid pulse: located in the neck (carotid artery). The carotid artery should be palpated gently and while the patient is sitting or lying down. Stimulating its baroreceptors with low palpitation can provoke severe bradycardia or even stop the heart in some sensitive persons. Also, a person's two carotid arteries should not be palpated at the same time. Doing so may limit the flow of blood to the head, possibly leading to fainting or brain ischemia. It can be felt between the anterior border of the sternocleidomastoid muscle, above the hyoid bone and lateral to the thyroid cartilage.
Facial pulse: located on the mandible (lower jawbone) on a line with the corners of the mouth (facial artery).
Temporal pulse: located on the temple directly in front of the ear (superficial temporal artery).
Although the pulse can be felt in multiple places in the head, people should not normally hear their heartbeats within the head. This is called pulsatile tinnitus, and it can indicate several medical disorders.
=== Torso ===
Apical pulse: located in the 5th left intercostal space, 1.25 cm lateral to the mid-clavicular line. In contrast with other pulse sites, the apical pulse site is unilateral, and measured not under an artery, but below the heart itself (more specifically, the apex of the heart). See also apex beat.
== History ==
Pulse rate was first measured by ancient Greek physicians and scientists. The first person to measure the heart beat was Herophilus of Alexandria, Egypt (c. 335–280 BC) who designed a water clock to time the pulse. Rumi has mentioned in a poem that "The wise physician measured the patient's pulse and became aware of his condition." It shows the practice was common during Rumi's era and geography.
The first person to accurately measure the pulse rate was Santorio Santorii who invented the pulsilogium, a form of pendulum which was later studied by Galileo Galilei. A century later another physician, de Lacroix, used the pulsilogium to test cardiac function.
== See also ==
Pulse meter
Tempo
Pulse diagnosis – a practice in various types of traditional medicine
Pulse pressure
== References ==
== External links ==
Measure Pulse Online Tap along with your pulse | Wikipedia/Pulse_rate |
In pharmacology, the fibrates are a class of amphipathic carboxylic acids and esters. They are derivatives of fibric acid (phenoxyisobutyric acid). They are used for a range of metabolic disorders, mainly hypercholesterolemia (high cholesterol), and are therefore hypolipidemic agents.
== Medical uses ==
Fibrates improve atherogenic dyslipidemia characterized by high triglyceride and/or low HDL-C levels and elevated concentrations of small dense LDL particles, with or without high LDL-C levels. Fibrates may be compared to statin drugs, which reduce LDL-cholesterol (LDL-C) and have only limited effects on other lipid parameters. Clinical trials have shown that the combination of statins and fibrates results in a significantly greater reduction in LDL-C and triglyceride levels and greater increases in high-density lipoprotein cholesterol (HDL-C) compared with monotherapy with either drug. Fibrates are used in accessory therapy in many forms of hypercholesterolemia, but the combination of some fibrates (e.g., gemfibrozil) with statins is contraindicated due to an increased risk of rhabdomyolysis.
Fibrates stimulate peroxisome proliferator activated receptor (PPAR) alpha, which controls the expression of gene products that mediate the metabolism of triglycerides (TG) and high-density lipoprotein (HDL). As a result, synthesis of fatty acids, TG and VLDL is reduced, whilst that of lipoprotein lipase, which catabolises TG, is enhanced. In addition, production of Apo A1 and ATP binding cassette A1 is up-regulated, leading to increased reverse cholesterol transport via HDL. Consequently, fibrates reduce TG by up to 50% and increase HDL-C by up to 20%, but LDL-C changes are variable.
Fewer large-scale trials have been conducted with fibrates than with statins and the results are less conclusive, but reduced rates of cardiovascular disease have been reported with fibrate therapy in the subgroup of patients with low HDL-C levels and elevated TG (e.g. TG > 2.3 mmol/L (200 mg/dL)). Fibrates are usually well tolerated but share a similar side-effect profile to statins. In addition, they may increase the risk of cholelithiasis and prolong the action of anticoagulants. Accumulating evidence suggests that they may also have a protective effect against diabetic microvascular complications.
Clinical trials do support their use as monotherapy agents. Fibrates reduce the number of non-fatal heart attacks, but do not improve all-cause mortality and are therefore indicated only in those not tolerant to statins.
Although less effective in lowering LDL levels, the ability of fibrates to increase HDL and lower triglyceride levels seems to reduce insulin resistance when the dyslipidemia is associated with other features of the metabolic syndrome (hypertension and diabetes mellitus type 2). They are therefore used in many hyperlipidemias. Due to a rare paradoxical decrease in HDL-C seen in some patients on fenofibrate, as per US FDA label change, it is recommended that the HDL-C levels be checked within the first few months after initiation of fibrate therapy. If a severely depressed HDL-C level is detected, fibrate therapy should be withdrawn, and the HDL-C level monitored until it has returned to baseline.
== Side effects ==
Most fibrates can cause mild stomach upset and myopathy (muscle pain with CPK elevations). Fibrates decrease the synthesis of bile acid by down-regulation of cholesterol 7 alpha-hydroxylase and sterol 27-hydroxylase expression, therefore making it easier for cholesterol to precipitate and increasing the risk for gallstones.
In combination with statin drugs, fibrates cause an increased risk of rhabdomyolysis, idiosyncratic destruction of muscle tissue, leading to kidney failure. The less lipophilic statins are less prone to cause this reaction, and are probably safer to be combined with fibrates than the more lipophilic statins are.
Drug toxicity includes acute kidney injury.
== Pharmacology ==
Although used clinically since at least 1962, the mechanism of action of fibrates remained unelucidated until the 1990s, when it was discovered that fibrates activate peroxisome proliferator-activated receptors (PPARs), especially PPARα. The PPARs are a class of intracellular receptors that modulate carbohydrate and fat metabolism and adipose tissue differentiation.
Activating PPARs induces the transcription of a number of genes that facilitate lipid metabolism.
Fibrates are pharmacologically related to the thiazolidinediones, a novel class of anti-diabetic drugs that also act on PPARs (more specifically PPARγ)
Fibrates are a substrate of (metabolized by) CYP3A4.
Fibrates have been shown to extend lifespan in the roundworm C. elegans.
== Members ==
== See also ==
Statin
Hypertriglyceridemia
== References == | Wikipedia/Fibrates |
In a 2018 study on 599,912 drinkers, a roughly linear association was found with alcohol consumption and a higher risk of stroke, coronary artery disease excluding myocardial infarction, heart failure, fatal hypertensive disease, and fatal aortic aneurysm, even for moderate drinkers. Alcohol abuse may also cause occupational cardiovascular disease. The American Heart Association states that people who are currently non-drinkers should not start drinking alcohol.
Excessive alcohol intake is associated with an elevated risk of alcoholic liver disease (ALD), heart failure, some cancers, and accidental injury, and is a leading cause of preventable death in industrialized countries. Some studies have suggested that one drink per day may have cardiovascular benefits. However, these studies are controversial, and the common view is that no level of alcohol consumption improves health. There is far more evidence for the harmful effects of alcohol than for any beneficial effects. It is also recognized that the alcohol industry may promote the unsubstantiated benefits of moderate drinking.
== Alcohol intake and cardiovascular disease ==
Some early reviews showed that light alcohol consumption may have a protective effect on cardiovascular health. For instance, a meta-analysis from 2010 found that patients with cardiovascular disease who were light to moderate alcohol consumers, were less likely to suffer from cardiovascular and all-cause mortality. However, the researchers warned against encouraging cardiovascular patients who do not regularly consume alcohol to start drinking due to lack of controlled intervention studies and evidence.
Several possible mechanisms have been suggested for the cardioprotective effect of alcohol. These include glucose control, lipid metabolism, and metabolism as a whole. However, another possible explanation is that the cardioprotective effect is only a confounding research result. A logical possibility is that some of the alcohol abstainers in research studies previously drank excessively and had undermined their health. After they quit they were categorized as non-drinkers, which in turn lead to more sick people in the non-drinkers category. To test this hypothesis, a 2019 meta analysis has recategorized people accordingly. As a result, no benefit was found for alcohol consumption of any dosage, moreover, alcohol was detrimental to health even at low doses.
The American Heart Association states that drinking too much alcohol increases health risks including cardiovascular disease precursors such as obesity, high blood pressure, high triglycerides and also heart attacks and strokes. They warn that "We’ve all seen the headlines about studies associating light or moderate drinking with health benefits and reduced mortality. Some researchers have suggested there are health benefits from wine, especially red wine, and that a glass a day can be good for the heart. But there’s more to the story. No research has proved a cause-and-effect link between drinking alcohol and better heart health."
The World Heart Federation (2022) recommends against any alcohol intake for optimal heart health.
It has also been pointed out that the studies suggesting a positive link between red wine consumption and heart health had flawed methodology in the form of comparing two sets of people which were not actually appropriately paired.
== Alcohol reduction ==
It is well known that alcohol consumption increases the risk of hypertension. Hence, many clinical trials examined the effect of reduction in alcohol consumption on blood pressure. Systematic review and meta-analysis have shown that effect of alcohol reduction on blood pressure is dose dependent.
I. For people who consumed 2 or fewer drinks per day, blood pressure was not significantly decreased when they reduced alcohol consumption close to abstinence.
II. For people who consumed 3 or more drinks per day, blood pressure was significantly decreased when they reduced alcohol consumption close to abstinence.
III. For people who consumed 6 or more drinks per day, reduction rate on blood pressure was the strongest when they reduced alcohol consumption close to abstinence.
IV. The effect of alcohol reduction on blood pressure is still unclear for women and hypertensive patients who consume less than three drinks per day due to limited clinical trials.
== History ==
In 2010, a systematic review reported that moderate consumption of alcohol does not cause harm to people with cardiovascular disease. However, the authors did not encourage people to start drinking alcohol in the hope of any benefit.
== See ==
French paradox
Long-term effects of alcohol consumption
== References ==
== External links ==
USDA Dietary Guidelines for Americans 2005: Chapter 9 Alcoholic Beverages
Alcohol and heart health: Separating fact from fiction, Johns Hopkins Medicine | Wikipedia/Alcohol_and_cardiovascular_disease |
Pleural disease occurs in the pleural space, which is the thin fluid-filled area in between the two pulmonary pleurae in the human body. There are several disorders and complications that can occur within the pleural area, and the surrounding tissues in the lung.
== Pleural content anomalies ==
Pneumothorax: a collection of air within the pleural cavity, arising either from the outside or from the lung. Pneumothoraces may be traumatic, iatrogenic, or spontaneous. A tension pneumothorax is a particular type of pneumothorax where the air may enter (though a defect of the chest wall, lung, or airways) on inspiration, but cannot exit on expiration. Each breath increases the amount of trapped air in the chest cavity, leading to further lung compression. This is often an urgent situation and may progress to a medical emergency if there is compromise of the venous return to the heart causing hypotension and rarely shock.
Pleural effusion: a fluid accumulation within the pleural space. Abnormal collections of pleural fluid may be due to excessive fluid volume (i.e. excess intravenous fluids, kidney failure), decreased fluid protein (e.g. cirrhosis, proteinuria), heart failure, bleeding (hemothorax), infections (parapneumonic effusions, pleural empyema), inflammation, malignancies, or perforation of thoracic organs (i.e. chylothorax, esophageal rupture).
== Pleural tumors ==
Pleural tumors may be benign (i.e. solitary fibrous tumor) or malignant in nature. Pleural mesothelioma is a type of malignant cancer associated with asbestos exposure. Under most other circumstances, pleural cancers are secondary malignancies associated with lung cancer due to its nearby location or as metastasis such as with breast cancer.
Mesothelial tumors: pleural malignant mesothelioma.
Pleural sarcomas
Pleural angiosarcoma
Pleural desmoplastic small round cell tumor (pleural DSRCT)
Pleural synovial sarcoma
Pleural solitary fibrous tumor (pleural SFT, can be benign or less commonly malignant)
Smooth muscle tumors of the pleura
Pleural carcinomas
Pleural mucoepidermoid carcinoma
Pleural pseudomesotheliomatous adenocarcinoma
== Other pleural diseases ==
Pulmonary embolism
Pleurisy
Pneumonia
Pleural infections
Pleural endometriosis
Pleuritis
Pleural mesothelial hyperplasia
Pleural calcified fibrous pseudotumor
Pleural thickening, including pleural plaques
== See also ==
Pleural cavity
== References ==
== External links == | Wikipedia/Pleural_disease |
A placental disease is any disease, disorder, or pathology of the placenta.
Ischemic placental disease leads to the attachment of the placenta to the uterine wall to become under-perfused, causing uteroplacental ischemia. Where the term overarches the pathology associated with preeclampsia, placental abruptions and intrauterine growth restriction (IUGR). These factors are known to be the primary pathophysiology cause placental disease. Which is considered to be associated with more than half of premature births.
Abnormalities present within the spiral arteries lead to higher velocities in blood, in turn causes the maternal villi to shred. Which trigger pro-coagulator molecules to be released into the blood stream causing action of the coagulator cascade, eventually leading to placental infarction. Risk factors such as diabetes, chronic blood pressure and multiple pregnancies can increase the risk of developing placental disease. Also, exposure to sudden trauma can increase the risk of placental abruption which coincides with placental disease.
There is no target treatment available for placental disease. Associative prevention mechanisms can be a method of minimising the risk of developing the disease, within early stages of pregnancy.
Placental syndromes include pregnancy loss, fetal growth restriction, preeclampsia, preterm delivery, premature rupture of membranes, placental abruption and intrauterine fetal demise.
== Signs and symptoms ==
The abnormal spiral arteries lead decreased level of oxygen diffusion through the placental villus, which cause chronic hypoxia. The abnormal trophoblast invasion, lead to overall uteroplacental insufficiencies and uteroplacental underperfusion. It is due to the decreased vascularisation, there are reduced levels of nutrient delivery to the foetus. Also, cases of still births can be associated with placental disease.
== Causes ==
Preeclampsia is considered to be linked with Placental Disease, as well as intrauterine growth restriction (IUGR) and placental abruptions are risk factors that lead to placental disease. Especially when these symptoms are evident at early stages of pregnancy. The abnormal invasion of the trophoblast cells, lack of important growth factors such as vascular endothelial growth factor (VEGF) and placental growth factor (PlGF), has an association with the onset of placental disease.
=== Risk factors ===
Risk factors associated with placental disease are as follows:
Smoking cigarettes and use other forms of drugs such as cocaine.
Diabetes mellitus
Maternal age less than 20 years or over the age of 35
Multiple pregnancies
Chronic high blood pressure
Being underweight or obese
Also, chronic renal disease, collagen vascular disease, thrombophilia, and cardiovascular disease increase the risk of developing placental disease. Moreover, being exposed to severe trauma within the pregnancy period, rapid acceleration and deceleration and uterine compression increase the risk of placental abruption, in turn leading to placental disease.
=== Adherence/penetration ===
Abruptio placentae
Placenta accreta
Placenta increta
Placenta percreta
=== Inflammatory/infectious ===
Placentitis
Villitis of unknown etiology
TORCH infections
=== Placental development ===
Circumvallate placenta
Placental villous immaturity
=== Obstruction of os ===
Placenta previa
Vasa previa
=== Vascular ===
Fetal thrombotic vasculopathy
Hypertrophic decidual vasculopathy
Chorangiosis
Chorangioma
Placental infarction
=== Neoplastic ===
Trophoblastic neoplasms derive from trophoblastic tissue. Examples include:
Choriocarcinoma
Hydatidiform mole
== Mechanism ==
In placental disease, there's abnormalities present within the spiral arties of the uterus, where the terminal part of the spinal arteries does not dilate. This leads to decrease oxygen carried past the maternal villi into the intervillus space. The lack of terminal dilation and inclining blood velocity causes shredding of the villi into the maternal blood, releasing blood coagulants activating the coagulation cascade. Which then leads to blocking of the blood vessels causing placental infarction.
== Diagnosis ==
Placental Disease can be diagnosed through technologies such as, Prenatal ultrasound evaluation and invasive foetal testing. The size of the foetus is taken into account through ultrasonography in terms of intrauterine growth restriction (IUGR). In conjunction with taking into account the maternal history. Suspicions may be confirmed by postpartum examination of the placenta.
== Prevention ==
The following factors can be linked with reducing the likelihood of developing placental disease:
Use of aspirin, can reduce the risks associated with preeclampsia
Low calcium intake can reduce the risk of preeclampsia
Reducing oxidative stress present within the body
Intake of prenatal multivitamins
== Treatment ==
Treatment of placental disease would require a premature birth, in order to avoid a still birth.
== Epidemiology ==
Placental disease is more common in preterm gestation than with full term. Which leads to serious injuries to both the mother and the new-born. Women who endured placental disease within the first pregnancy has an increased risk of the disease progressing within future pregnancies. The onset of the disease within the first trimester leads to preterm delivery of a premature baby. Preeclampsia is diagnosed in 3-5% of pregnancies that place them at risk of developing placental disease. Ischemic placental disease is linked with approximately more than half of premature births.
== References ==
== External links == | Wikipedia/Placental_disease |
A saturated fat is a type of fat in which the fatty acid chains have all single bonds between the carbon atoms. A fat known as a glyceride is made of two kinds of smaller molecules: a short glycerol backbone, and fatty acids that each contain a long linear or branched chain of carbon (C) atoms. Along the chain, some carbon atoms are linked by single bonds (-C-C-) and others are linked by double bonds (-C=C-). A double bond along the carbon chain can react with a pair of hydrogen atoms to change into a single -C-C- bond, with each H atom now bonded to one of the two C atoms. Glyceride fats without any carbon chain double bonds are called saturated because they are "saturated with" hydrogen atoms, having no double bonds available to react with more hydrogen. Saturated fats are generally solid. All fats, both saturated and unsaturated, contain 9kcal per gram making them more energy dense than both proteins and carbohydrates.
Most animal fats are saturated. The fats of plants and fish are generally unsaturated. Various foods contain different proportions of saturated and unsaturated. Many processed foods, like foods deep-fried in hydrogenated oil and sausages, are high in saturated fat content. Some store-bought baked goods are as well, especially those containing partially hydrogenated oils. Other examples of foods containing a high proportion of saturated fat and dietary cholesterol include animal fat products such as lard or schmaltz, fatty meats and dairy products made with whole or reduced fat milk like yogurt, ice cream, cheese and butter. Certain vegetable products have high saturated fat content, such as coconut oil and palm kernel oil.
Guidelines released by many medical organizations, including the World Health Organization, have advocated for reduction in the intake of saturated fat to promote health and reduce the risk from cardiovascular diseases.
== Fat profiles ==
While nutrition labels regularly combine them, the saturated fatty acids appear in different proportions among food groups. Lauric and myristic acids are most commonly found in "tropical" oils (e.g., palm kernel, coconut) and dairy products. The saturated fat in meat, eggs, cacao, and nuts is primarily the triglycerides of palmitic and stearic acids.
== Examples of saturated fatty acids ==
Some common examples of saturated fatty acids:
Lauric acid with 12 carbon atoms (contained in coconut oil, palm kernel oil, cow's milk, and breast milk)
Myristic acid with 14 carbon atoms (contained in cow's milk and dairy products)
Palmitic acid with 16 carbon atoms (contained in palm oil and meat)
Stearic acid with 18 carbon atoms (also contained in meat and cocoa butter)
== Association with diseases ==
=== Cardiovascular disease ===
The effect of saturated fat on heart disease has been extensively studied. Saturated fat intake increases low-density lipoprotein cholesterol (LDL-C) concentrations. The American Heart Association have stated that "the scientific rationale for decreasing saturated fat in the diet has been and remains based on well-established effects of saturated fat to raise low-density lipoprotein (LDL) cholesterol, a leading cause of atherosclerosis".
Many health authorities, such as the American Heart Association, the Academy of Nutrition and Dietetics, the British Dietetic Association, the World Heart Federation, the British National Health Service, among others, advise that saturated fat is a risk factor for cardiovascular diseases. In 2020, the World Health Organization recommended lowering dietary intake of saturated fats to less than 10% of total energy consumption, and increasing intake of unsaturated fats. There is moderate-quality evidence that reducing the proportion of saturated fat in the diet and replacing it with unsaturated fats or carbohydrates for a period of at least two years leads to a reduction in the risk of cardiovascular disease.
A 2017 review by the Sax Institute for the National Heart Foundation of Australia found that saturated fat consumption is associated with higher mortality and that replacement of saturated fat with polyunsaturated fat decreases risk of cardiovascular disease events and mortality. In 2019, the UK Scientific Advisory Committee on Nutrition concluded that higher saturated fat consumption is associated with raised blood cholesterol and increased risk of cardiovascular disease.
A 2021 review found that diets high in saturated fat were associated with higher mortality from all causes, as well as from cardiovascular disease.
A 2023 review by the World Health Organization found convincing evidence that higher saturated fat consumption is associated with higher coronary heart disease incidence and mortality.
A 2023 review by the Academy of Nutrition and Dietetics found moderate certainty evidence to support reducing saturated fat intake for reduced risk of CVD and CVD events.
A scoping review for Nordic Nutrition Recommendations 2023 found that partial replacement of saturated fatty acid with omega-6 fatty acid decreases the risk of cardiovascular disease and improves the blood lipid profile.
A 2024 meta-analysis found that odd-chain and longer-chain saturated fatty acids were negatively associated with the risk of cardiovascular disease, including stroke.
=== Dyslipidemia ===
The consumption of saturated fat is generally considered a risk factor for dyslipidemia, which in turn is a risk factor for some types of cardiovascular disease.
Abnormal blood lipid levels – high total cholesterol, high levels of triglycerides, high levels of low-density lipoprotein (LDL) or low levels of high-density lipoprotein (HDL) cholesterol – are associated with increased risk of heart disease and stroke.
Meta-analyses have found a significant relationship between saturated fat and serum cholesterol levels. High total cholesterol levels, which may be caused by many factors, are associated with an increased risk of cardiovascular disease.
There are other pathways involving obesity, triglyceride levels, insulin sensitivity, endothelial function, and thrombogenicity, among others, that play a role in cardiovascular disease. Different saturated fatty acids have differing effects on various lipid levels. There is strong evidence that lauric, myristic, and palmitic acids raise LDL-C, while stearic acid is more neutral.
=== Type 2 diabetes ===
A 2022 review of cohort studies found that the risk of type 2 diabetes was not associated with dietary intake of total saturated fats, palmitic acid, and stearic acid. Dietary lauric acid and myristic acid, present in plant oils and also in dairy fat, were associated with reduced risk of diabetes.
=== Cancer ===
Several reviews of case–control studies have found that saturated fat intake is associated with breast cancer risk and mortality. Observational studies have shown that a diet high in saturated fat is associated with increased prostate cancer risk.
A 2024 systematic review found that higher levels of myristic acid, palmitic acid and stearic acid are associated with increased cancer risk.
== Dietary sources ==
== Dietary recommendations ==
Recommendations to reduce, limit or replace dietary intake of trans fats and saturated fats, in favor of unsaturated fats, are made by the World Health Organization, American Heart Association, Health Canada, the US Department of Health and Human Services, the UK National Health Service, the UK Scientific Advisory Committee on Nutrition, the Australian Department of Health and Aging, the Singapore Ministry of Health, the Indian Ministry of Health and Family Welfare, the New Zealand Ministry of Health, and Hong Kong's Department of Health.
In 2003, the World Health Organization (WHO) and Food and Agriculture Organization (FAO) expert consultation report concluded:
The evidence shows that intake of saturated fatty acids is directly related to cardiovascular risk. The traditional target is to restrict the intake of saturated fatty acids to less than 10% of daily energy intake and less than 7% for high-risk groups. If populations are consuming less than 10%, they should not increase that level of intake. Within these limits, the intake of foods rich in myristic and palmitic acids should be replaced by fats with a lower content of these particular fatty acids. In developing countries, however, where energy intake for some population groups may be inadequate, energy expenditure is high and body fat stores are low (BMI <18.5 kg/m2). The amount and quality of fat supply have to be considered keeping in mind the need to meet energy requirements. Specific sources of saturated fat, such as coconut and palm oil, provide low-cost energy and may be an important source of energy for the poor.
A 2004 statement released by the Centers for Disease Control (CDC) determined that "Americans need to continue working to reduce saturated fat intake…" In addition, reviews by the American Heart Association led the Association to recommend reducing saturated fat intake to less than 7% of total calories according to its 2006 recommendations. This concurs with similar conclusions made by the US Department of Health and Human Services, which determined that reduction in saturated fat consumption would positively affect health and reduce the prevalence of heart disease.
The United Kingdom, National Health Service claims the majority of British people eat too much saturated fat. The British Heart Foundation also advises people to cut down on saturated fat, and to read labels on the food they buy. The British Nutrition Foundation have said that based on the totality of available evidence the saturated fatty acids should make up no more than 10% of total dietary energy.
A 2004 review stated that "no lower safe limit of specific saturated fatty acid intakes has been identified" and recommended that the influence of varying saturated fatty acid intakes against a background of different individual lifestyles and genetic backgrounds should be the focus in future studies.
Blanket recommendations to lower saturated fat were criticized at a 2010 conference debate of the American Dietetic Association for focusing too narrowly on reducing saturated fats rather than emphasizing increased consumption of healthy fats and unrefined carbohydrates. Concern was expressed over the health risks of replacing saturated fats in the diet with refined carbohydrates, which carry a high risk of obesity and heart disease, particularly at the expense of polyunsaturated fats which may have health benefits. None of the panelists recommended heavy consumption of saturated fats, emphasizing instead the importance of overall dietary quality to cardiovascular health.
In a 2017 comprehensive review of the literature and clinical trials, the American Heart Association published a recommendation that saturated fat intake be reduced or replaced by products containing monounsaturated and polyunsaturated fats, a dietary adjustment that could reduce the risk of cardiovascular diseases by 30%.
== Molecular description ==
The two-dimensional illustration has implicit hydrogen atoms bonded to each of the carbon atoms in the polycarbon tail of the myristic acid molecule (there are 13 carbon atoms in the tail; 14 carbon atoms in the entire molecule).
Carbon atoms are also implicitly drawn, as they are portrayed as intersections between two straight lines. "Saturated," in general, refers to a maximum number of hydrogen atoms bonded to each carbon of the polycarbon tail as allowed by the Octet Rule. This also means that only single bonds (sigma bonds) will be present between adjacent carbon atoms of the tail.
== See also ==
== Notes ==
== References == | Wikipedia/Saturated_fat_and_cardiovascular_disease |
Superficial thrombophlebitis is a thrombosis and inflammation of superficial veins presenting as a painful induration (thickening) with erythema, often in a linear or branching configuration with a cordlike appearance.: 826–7
Superficial thrombophlebitis is due to inflammation and/or thrombosis, and, less commonly, infection of the vein. It is generally a benign, self-limiting disorder; however, it can be complicated by deep vein thrombosis (DVT) and even pulmonary embolism (PE) Migratory superficial thrombophlebitis is known as Trousseau's syndrome, which can be an early sign of cancer.
When it (rarely) occurs on the breast or anterior chest wall it has been called Mondor's disease. It sometimes occurs in the arm or penis.: 827 In axilla, this condition is known as axillary web syndrome.
== Eponym ==
Mondor's disease is named after Henri Mondor (1885–1962), a surgeon in Paris, France who first described the disease in 1939.
== Signs and symptoms ==
Findings of tenderness, induration, pain, or erythema (redness) along the course of a superficial vein usually establish a clinical diagnosis, especially in patients with known risk factors. In addition, there is often a palpable, sometimes nodular "cord", due to thrombus (blood clot) within the affected vein. Persistence of this cord when the extremity is raised suggests the presence of thrombus.
On the chest wall, patients with this disease often have abrupt onset of superficial pain, with possible swelling and redness of a limited area of their anterior chest wall or breast. There is usually a lump present, which may be somewhat linear and tender. Because of the possibility of the lump being from another cause, patients are often referred for mammogram and/or breast ultrasound.
=== Complications ===
Superficial vein thrombosis (SVT) extension to the deep vein system and/or recurrence of SVT.
Suppurative thrombophlebitis is suspected when erythema extends significantly beyond the margin of the vein and is likely to be associated with significant fever. If suspected, antibiotic treatment, surgical drainage, and potentially vein excision are indicated.
Venous thromboembolism can occur with superficial vein thrombosis. Estimates of the percentage of patients with SVT who also have DVT vary between 6% and 53%, and symptomatic pulmonary embolism has been reported in 0% to 10% of patients with SVT. Deep venous system, and may lead to pulmonary embolism.
On the breast, there have been occasional cases of associated cancer.
== Risk factors ==
Patient characteristics and predisposing factors for thrombophlebitis nearly mirror those for DVT; thrombophlebitis is a risk factor for the development of DVT, and vice versa.
Lower extremity superficial phlebitis (inflamed vein) is associated with conditions that increase the risk of thrombosis, including abnormalities of coagulation or of fibrinolysis, endothelial dysfunction, infection, venous stasis, intravenous therapy, and intravenous drug use.
== Diagnosis ==
Clinical evaluation is the primary diagnostic tool for thrombophlebitis. People with thrombophlebitis complain of pain along the affected area. Some report constitutional symptoms, such as low-grade fever and aches. On physical examination, the skin over the affected vein exhibits erythema, warmth, swelling, and tenderness. Later in the disease, as induration subsides, erythema gives way to a ruddy or bruised color.
Duplex ultrasound identifies the presence, location and extent of venous thrombosis, and can help identify other pathology that may be a source of the patient's complaints. Ultrasound is indicated if superficial phlebitis involves or extends into the proximal one-third of the medial thigh, there is evidence for clinical extension of phlebitis, lower extremity swelling is greater than would be expected from a superficial phlebitis alone or diagnosis of superficial thrombophlebitis in question.
== Treatment ==
Treatment with compression stockings should be offered to patients with lower extremity superficial phlebitis, if not contraindicated (e.g., peripheral artery disease). Patients may find them helpful for reducing swelling and pain once the acute inflammation subsides.
Nonsteroidal anti-inflammatory drugs (NSAID) are effective in relieving the pain associated with venous inflammation and were found in a randomized trial to significantly decrease extension and/or recurrence of superficial vein thrombosis.
Anticoagulation is recommended for patients with lower extremity superficial thrombophlebitis at increased risk for thromboembolism (affected venous segment of ≥5 cm, in proximity to deep venous system, positive medical risk factors).
Treatment with fondaparinux reduces the risk of subsequent venous thromboembolism.
Surgery is reserved for patients with extension of the clot to within 1 cm of the saphenofemoral junction, in patients deemed unreliable for anticoagulation, upon failure of anticoagulation, and in patients with intense pain. Surgical therapy with ligation of the saphenofemoral junction or stripping of thrombosed superficial veins appears to be associated with higher rates of venous thromboembolism compared with treatment with anticoagulants.
== Epidemiology ==
Some 125,000 cases a year have been reported in the United States, but actual incidence of spontaneous thrombophlebitis is unknown. A fourfold increased incidence from the third to the eight decade in men and a preponderance among women of approximately 55-70%. The average mean age of affected patients is 60 years.
Thrombophlebitis can develop along the arm, back, or neck veins, the leg is by far the most common site. When it occurs in the leg, the great saphenous vein is usually involved, although other locations are possible.
== See also ==
Septic thrombophlebitis
Superficial vein thrombosis
== References ==
== External links == | Wikipedia/Mondor's_disease |
Hemolytic disease of the newborn (anti-Rhc) can range from a mild to a severe disease. It is the third most common cause of severe HDN. Rh disease is the most common and hemolytic disease of the newborn (anti-Kell) is the second most common cause of severe HDN. It occurs more commonly in women who are Rh D negative.
== Presentation ==
=== Complications ===
High at birth or rapidly rising bilirubin
Prolonged hyperbilirubinemia
Bilirubin Induced Neurological Dysfunction
Cerebral Palsy
Kernicterus
Neutropenia
Thrombocytopenia
Hemolytic Anemia - MUST NOT be treated with iron
Late onset anemia - Must NOT be treated with iron. Can persist up to 12 weeks after birth.
==== Transfusion reactions ====
Once a woman has antibodies, she is at high risk for a transfusion reaction. For this reason, she must carry a medical alert card at all times and inform all doctors of her antibody status.
"Acute hemolytic transfusion reactions may be either immune-mediated or nonimmune-mediated. Immune-mediated hemolytic transfusion reactions caused by immunoglobulin M (IgM) anti-A, anti-B, or anti-A,B typically result in severe, potentially fatal complement-mediated intravascular hemolysis. Immune-mediated hemolytic reactions caused by IgG, Rh, Kell, Duffy, or other non-ABO antibodies typically result in extravascular sequestration, shortened survival of transfused red cells, and relatively mild clinical reactions. Acute hemolytic transfusion reactions due to immune hemolysis may occur in patients who have no antibodies detectable by routine laboratory procedures."
== Causes ==
A Rhc negative mother can become sensitised by red blood cell (RBC) Rhc antigens by her first pregnancy with a Rhc positive fetus. The mother can make IgG anti-Rhc antibodies, which are able to pass through the placenta and enter the fetal circulation. If the fetus is Rhc positive alloimmune hemolysis can occur leading to HDN. This is similar as for Rh disease, which is usually caused when a RhD negative mother is sensitised by her first pregnancy with a RhD positive fetus.
Sensitization to Rhc antigens can also be caused by blood transfusion.
== Diagnosis ==
Testing for HDN involves blood work from both mother and father, and may also include assessment with amniocentesis and Middle Cerebral Artery scans.
Anti-C and anti-c can both show a negative DAT but still have a severely affected infant. An indirect coombs must also be run.
In the case of anti-c, the woman should be checked around 28 weeks to see if she has developed anti-E as well.
=== Mother ===
Blood testing for the mother is called an Indirect Coombs Test (ICT) or an Indirect Agglutination Test (IAT). This test tells whether there are antibodies in the maternal plasma. If positive, the antibody is identified and given a titer. Critical titers are associated with significant risk of fetal anemia and hydrops. Titers of 1:8 or higher is considered critical for Kell. Titers of 1:16 or higher are considered critical for all other antibodies. After critical titer is reached, care is based on MCA scans. If antibodies are low and have a sudden jump later in pregnancy, an MCA scan is warranted. If the titer undergoes a 4 fold increase, it should be considered significant regardless of if the critical value has been reached. Maternal titers are not useful in predicting fetal anemia after the first affected gestation and should not be used for the basis of care. Titers are tested monthly until 24 weeks, after which they are done every 2 weeks.
"In only 2 situations are patients not monitored identically to patients who are Rh sensitized. The first is that of alloimmunization to the c, E, or, C antigens. Some concern exists that hemolysis may occur in these patients with a lower than 1:16 titer. Thus, if the initial titer is 1:4 and stable but increases at 26 weeks' gestation to 1:8, assessment with MCA Doppler velocity at that point is reasonable. However, if the patient presents in the first trimester with a 1:8 titer that remains stable at 1:8 throughout the second trimester, continued serial antibody titers are appropriate.
The second situation in which patients should not be treated identically to patients who are Rh D sensitized is that of Kell isoimmunization because several cases of severe fetal hemolysis with anti-Kell antibodies have occurred in the setting of low titers."
In the case of a positive ICT, the woman must carry a medical alert card or bracelet for life because of the risk of a transfusion reaction.
=== Father ===
Blood is generally drawn from the father to help determine fetal antigen status. If he is homozygous for the antigen, there is a 100% chance of all offspring in the pairing to be positive for the antigen and at risk for HDN. If he is heterozygous, there is a 50% chance of offspring to be positive for the antigen. This test can help with knowledge for the current baby, as well as aid in the decision about future pregnancies. With RhD, the test is called the RhD genotype. With RhCE, and Kell antigen it is called an antigen phenotype.
=== Fetus ===
There are 3 possible ways to test the fetal antigen status. Free Cell DNA, Amniocentesis, and Chorionic Villus Sampling (CVS). Of the three, CVS is no longer used due to risk of worsening the maternal antibody response. Once antigen status has been determined, assessment may be done with MCA scans.
Cell-free DNA can be run on certain antigens. Blood is taken from the mother, and using PCR, can detect the K, C, c, D, and E alleles of fetal DNA. This blood test is non-invasive to the fetus and is an easy way of checking antigen status and risk of HDN. Testing has proven very accurate and is routinely done in the UK at the International Blood Group Reference Laboratory in Bristol. Sanequin laboratory in Amsterdam, Netherlands also performs this test. For US patients, blood may be sent to either of the labs. In the US, Sensigene is done by Sequenome to determine fetal D status. Sequenome does not accept insurance in the US, but US and Canadian patients have had insurance cover the testing done overseas.
Amniocentesis is another recommended method for testing antigen status and risk for HDN. Fetal antigen status can be tested as early as 15 weeks by PCR of fetal cells.
CVS is possible as well to test fetal antigen status but is not recommended. CVS carries a higher risk of fetal maternal hemorrhage and can raise antibody titers, potentially worsening the antibody effect.
MCA scans: Middle cerebral artery - peak systolic velocity is changing the way sensitized pregnancies are managed. This test is done noninvasively with ultrasound. By measuring the peak velocity of blood flow in the middle cerebral artery, a MoM (multiple of the median) score can be calculated. MoM of 1.5 or greater indicates severe anemia and should be treated with IUT.
== Prevention ==
It has been suggested that women of child-bearing age or young girls should not be given a transfusion with Rhc positive blood (or Kell 1 positive blood for similar reasons). This would require a lot of extra work in blood transfusion departments and it is considered not economical to do the blood group screening at the present time.
It is theoretically likely that IgG anti-Rhc antibody injections would prevent sensitization to RBC surface Rhc antigens in a similar way that IgG anti-D antibodies (Rho(D) immune globulin) are used to prevent Rh disease, but the methods for IgG anti-Rhc antibodies have not been developed at the present time.
== Treatment ==
There are several intervention options available in early, mid and late pregnancies.
=== Early pregnancy ===
IVIG - IVIG stands for Intravenous Immunoglobulin. It is used in cases of previous loss, high maternal titers, known aggressive antibodies, and in cases where religion prevents blood transfusion. Ivig can be more effective than IUT alone Fetal mortality was reduced by 36% in the IVIG and IUT group than in the IUT alone group. IVIG and plasmapheresis together can reduce or eliminate the need for an IUT.
Plasmapheresis - Plasmapheresis aims to decrease the maternal titer by direct plasma replacement. Plasmapheresis and IVIG together can even be used on women with previously hydropic fetuses and losses.
=== Mid to late pregnancy ===
IUT - Intrauterine transfusion (IUT) is done either by intraperitoneal transfusion (IPT) or intravenous transfusion (IVT). IVT is preferred over IPT. IUTs are only done until 35 weeks. After that, the risk of an IUT is greater than the risk from post birth transfusion.
Steroids - Steroids are sometimes given to the mother before IUTs and early delivery to mature the fetal lungs.
Phenobarbital - Phenobarbital is sometimes given to the mother to help mature the fetal liver and reduce hyperbilirubinemia.
Early Delivery - Delivery can occur anytime after the age of viability. Emergency delivery due to failed IUT is possible, along with induction of labor at 35–38 weeks.
== After Birth ==
=== Testing ===
Coombs - after birth baby will have a direct coombs test run to confirm antibodies attached to the infant's red blood cells. This test is run from cord blood.
In some cases, the direct coombs will be negative but severe, even fatal HDN can occur. An indirect coombs needs to be run in cases of anti-C, anti-c, and anti-M. Anti-M also recommends antigen testing to rule out the presence of HDN.
Hgb - the infant's hemoglobin should be tested from cord blood.
Reticulocyte count - Reticulocytes are elevated when the infant is producing more blood to combat anemia. A rise in the retic count can mean that an infant may not need additional transfusions. Low retic is observed in infants treated with IUT and in those with HDN from anti-Kell.
Neutrophils - as Neutropenia is one of the complications of HDN, the neutrophil count should be checked.
Thrombocytes - as thrombocytopenia is one of the complications of HDN, the thrombocyte count should be checked.
Bilirubin should be tested from cord blood.
Ferritin - because most infants affected by HDN have iron overload, a ferritin must be run before giving the infant any additional iron.
Newborn Screening Tests - Transfusion with donor blood during pregnancy or shortly after birth can affect the results of the Newborn Screening Tests. It is recommended to wait and retest 10–12 months after last transfusion. In some cases, DNA testing from saliva can be used to rule out certain conditions.
== Treatment ==
Phototherapy - Phototherapy is used for cord bilirubin of 3 or higher. Some doctors use it at lower levels while awaiting lab results.
IVIG - IVIG has been used to successfully treat many cases of HDN. It has been used not only on anti-D, but on anti-E as well. IVIG can be used to reduce the need for exchange transfusion and to shorten the length of phototherapy. The AAP recommends "In isoimmune hemolytic disease, administration of intravenousγ-globulin (0.5-1 g/kg over 2 hours) is recommended if the TSB is rising despite intensive phototherapy or the TSB level is within 2 to 3 mg/dL (34-51 μmol/L) of the exchange level . If necessary, this dose can be repeated in 12 hours (evidence quality B: benefits exceed harms). Intravenous γ-globulin has been shown to reduce the need for exchange transfusions in Rh and ABO hemolytic disease."
Exchange transfusion - Exchange transfusion is used when bilirubin reaches either the high or medium risk lines on the nonogram provided by the American Academy of Pediatrics (Figure 4). Cord bilirubin >4 is also indicative of the need for exchange transfusion.
== History ==
Hemolytic disease of the fetus and newborn (HDN) is a condition where the passage of maternal antibodies results in the hemolysis of fetal/neonatal red cells. The antibodies can be naturally occurring such as anti-A, and anti-B, or immune antibodies developed following a sensitizing event. Isoimmunization occurs when the maternal immune system is sensitized to red blood cell surface antigens. The most common causes of isoimmunization are blood transfusion, and fetal-maternal hemorrhage. The hemolytic process can result in anemia, hyperbilirubinemia, neonatal thrombocytopenia, and neonatal neutropenia. With the use of RhD Immunoprophylaxis, (commonly called Rhogam), the incidence of anti-D has decreased dramatically and other alloantibodies are now a major cause of HDN.
== See also ==
Hemolytic anemia
Hemolytic disease of the newborn
Rh blood group system
== References ==
== Further reading ==
Antenatal & neonatal screening (second edition). Chapter 12: Rhesus and other haemolytic diseases, by E.A. Letsky, I. Leck, J.M. Bowman. 2000. Oxford University Press. ISBN 0-19-262826-7.
Mollison PL, Engelfriet CP and Contreras M. Blood Transfusion in Clinical Medicine. 1997. 10th edition. Blackwell Science, Oxford, UK.
== External links == | Wikipedia/Hemolytic_disease_of_the_newborn_(anti-Rhc) |
C-reactive protein (CRP) is an annular (ring-shaped) pentameric protein found in blood plasma, whose circulating concentrations rise in response to inflammation. It is an acute-phase protein of hepatic origin that increases following interleukin-6 secretion by macrophages and T cells. Its physiological role is to bind to lysophosphatidylcholine expressed on the surface of dead or dying cells (and some types of bacteria) in order to activate the complement system via C1q.
CRP is synthesized by the liver in response to factors released by macrophages, T cells and fat cells (adipocytes). It is a member of the pentraxin family of proteins. It is not related to C-peptide (insulin) or protein C (blood coagulation). C-reactive protein was the first pattern recognition receptor (PRR) to be identified.
== History and etymology ==
Discovered by Tillett and Francis in 1930, it was initially thought that CRP might be a pathogenic secretion since it was elevated in a variety of illnesses, including cancer. The later discovery of hepatic synthesis (made in the liver) demonstrated that it is a native protein. Initially, CRP was measured using the quellung reaction which gave a positive or a negative result. More precise methods nowadays use dynamic light scattering after reaction with CRP-specific antibodies.
CRP was so named because it was first identified as a substance in the serum of patients with acute inflammation that reacted with the cell wall polysaccharide (C-polysaccharide) of pneumococcus.
== Genetics and structure ==
It is a member of the small pentraxins family (also known as short pentraxins). The polypeptide encoded by this gene has 224 amino acids. The full-length polypeptide is not present in the body in significant quantities due to signal peptide, which is removed by signal peptidase before translation is completed. The complete protein, composed of five monomers, has a total mass of approximately 120,000 Da. In serum, it assembles into stable pentameric structure with a discoid shape.
== Function ==
CRP binds to the phosphocholine expressed on the surface of bacterial cells such as pneumococcus bacteria. This activates the complement system, promoting phagocytosis by macrophages, which clears necrotic and apoptotic cells and bacteria. With this mechanism, CRP also binds to ischemic/hypoxic cells, which could regenerate with more time. However, the binding of CRP causes them to be disposed of prematurely. CRP binds to the Fc-gamma receptor IIa, to which IgG isotype antibodies also bind. In addition, CRP activates the classical complement pathway via C1q binding. CRP thus forms immune complexes in the same way as IgG antibodies.
This so-called acute phase response occurs as a result of increasing concentrations of interleukin-6 (IL-6), which is produced by macrophages as well as adipocytes in response to a wide range of acute and chronic inflammatory conditions such as bacterial, viral, or fungal infections; rheumatic and other inflammatory diseases; malignancy; and tissue injury and necrosis. These conditions cause release of IL-6 and other cytokines that trigger the synthesis of CRP and fibrinogen by the liver.
CRP binds to phosphocholine on micro-organisms. It is thought to assist in complement binding to foreign and damaged cells and enhances phagocytosis by macrophages (opsonin-mediated phagocytosis), which express a receptor for CRP. It plays a role in innate immunity as an early defense system against infections.
== Serum levels ==
=== Measurement methods ===
Traditional CRP measurement only detected CRP in the range of 10 to 1,000 mg/L, whereas high sensitivity CRP (hs-CRP) detects CRP in the range of 0.5 to 10 mg/L. hs-CRP can detect cardiovascular disease risk when in excess of 3 mg/L, whereas below 1 mg/L would be low risk. Traditional CRP measurement is faster and less costly than hs-CRP, and can be adequate for some applications, such as monitoring hemodialysis patients. Current immunoassay methods for CRP have similar precision to hsCRP performed by nephelometry and could probably replace hsCRP for cardiovascular risk assessment, however, in the United States this would represent off-label use, making it a laboratory-developed test under FDA regulations.
=== Normal ===
In healthy adults, the normal concentrations of CRP varies between 0.8 mg/L and 3.0 mg/L. However, some healthy adults show elevated CRP at 10 mg/L. CRP concentrations also increase with age, possibly due to subclinical conditions. There are also no seasonal variations of CRP concentrations. Gene polymorphism of interleukin-1 family, interleukin 6, and polymorphic GT repeat of the CRP gene do affect the usual CRP concentrations when a person does not have any medical illnesses.
=== Acute inflammation ===
When there is a stimulus, the CRP level can increase 10,000-fold from less than 50 μg/L to more than 500 mg/L. Its concentration can increase to 5 mg/L by 6 hours and peak at 48 hours. The plasma half-life of CRP is 19 hours, and is constant in all medical conditions. Therefore, the only factor that affects the blood CRP concentration is its production rate, which increases with inflammation, infection, trauma, necrosis, malignancy, and allergic reactions. Other inflammatory mediators that can increase CRP are TGF beta 1, and tumor necrosis factor alpha. In acute inflammation, CRP can increase as much as 50 to 100 mg/L within 4 to 6 hours in mild to moderate inflammation or an insult such as skin infection, cystitis, or bronchitis. It can double every 8 hours and reaches its peak at 36 to 50 hours following injury or inflammation. CRP between 100 and 500 mg/L is considered highly predictive of inflammation due to bacterial infection. Once inflammation subsides, CRP level falls quickly because of its relatively short half-life.
=== Metabolic inflammation ===
CRP concentrations between 2 and 10 mg/L are considered as metabolic inflammation: metabolic pathways that cause arteriosclerosis and type II diabetes mellitus.
== Clinical significance ==
=== Diagnostic use ===
CRP is used mainly as an inflammation marker. Apart from liver failure, there are few known factors that interfere with CRP production. Interferon alpha inhibits CRP production from liver cells which may explain the relatively low levels of CRP found during viral infections compared to bacterial infections
Measuring and charting CRP values can prove useful in determining disease progress or the effectiveness of treatments. ELISA and radial immunodiffusion methods are available for research use, while immunoturbidimetry is used clinically for CRP and nephelometry is typically used for hsCRP. Cutoffs for cardiovascular risk assessment have included:
low: hs-CRP level under 1.0 mg/L
average: between 1.0 and 3.0 mg/L
high: above 3.0 mg/L
Normal levels increase with aging. Higher levels are found in late pregnant women, mild inflammation and viral infections (10–40 mg/L), active inflammation, bacterial infection (40–200 mg/L), severe bacterial infections and burns (>200 mg/L).
CRP cut-off levels indicating bacterial from non-bacterial illness can vary due to co-morbidities such as malaria, HIV and malnutrition and the stage of disease presentation. In patients presenting to the emergency department with suspected sepsis, a CRP/albumin ratio of less than 32 has a negative predictive value of 89% for ruling out sepsis.
CRP is a more sensitive and accurate reflection of the acute phase response than the ESR (erythrocyte sedimentation rate). ESR may be normal while CRP is elevated. CRP returns to normal more quickly than ESR in response to therapy.
=== Cardiovascular disease ===
Recent research suggests that patients with elevated basal levels of CRP are at an increased risk of diabetes, hypertension and cardiovascular disease. A study of over 700 nurses showed that those in the highest quartile of trans fat consumption had blood levels of CRP that were 73% higher than those in the lowest quartile. Although one group of researchers indicated that CRP may be only a moderate risk factor for cardiovascular disease, this study (known as the Reykjavik Study) was found to have some problems for this type of analysis related to the characteristics of the population studied, and there was an extremely long follow-up time, which may have attenuated the association between CRP and future outcomes. Others have shown that CRP can exacerbate ischemic necrosis in a complement-dependent fashion and that CRP inhibition can be a safe and effective therapy for myocardial and cerebral infarcts; this has been demonstrated in animal models and humans.
It has been hypothesized that patients with high CRP levels might benefit from use of statins. This is based on the JUPITER trial that found that elevated CRP levels without hyperlipidemia benefited. Statins were selected because they have been proven to reduce levels of CRP. Studies comparing effect of various statins in hs-CRP revealed similar effects of different statins. A subsequent trial however failed to find that CRP was useful for determining statin benefit.
In a meta-analysis of 20 studies involving 1,466 patients with coronary artery disease, CRP levels were found to be reduced after exercise interventions. Among those studies, higher CRP concentrations or poorer lipid profiles before beginning exercise were associated with greater reductions in CRP.
To clarify whether CRP is a bystander or active participant in atherogenesis, a 2008 study compared people with various genetic CRP variants. Those with a high CRP due to genetic variation had no increased risk of cardiovascular disease compared to those with a normal or low CRP. A study published in 2011 shows that CRP is associated with lipid responses to low-fat and high-polyunsaturated fat diets.
=== Coronary heart disease risk ===
Arterial damage results from white blood cell invasion and inflammation within the wall. CRP is a general marker for inflammation and infection, so it can be used as a very rough proxy for heart disease risk. Since many things can cause elevated CRP, this is not a very specific prognostic indicator. Nevertheless, a level above 2.4 mg/L has been associated with a doubled risk of a coronary event compared to levels below 1 mg/L; however, the study group in this case consisted of patients who had been diagnosed with unstable angina pectoris; whether elevated CRP has any predictive value of acute coronary events in the general population of all age ranges remains unclear. Currently, C-reactive protein is not recommended as a cardiovascular disease screening test for average-risk adults without symptoms.
The American Heart Association and U.S. Centers for Disease Control and Prevention have defined risk groups as follows:
Low Risk: less than 1.0 mg/L
Average risk: 1.0 to 3.0 mg/L
High risk: above 3.0 mg/L
But hs-CRP is not to be used alone and should be combined with elevated levels of cholesterol, LDL-C, triglycerides, and glucose level. Smoking, hypertension and diabetes also increase the risk level of cardiovascular disease.
=== Fibrosis and inflammation ===
Scleroderma, polymyositis, and dermatomyositis elicit little or no CRP response. CRP levels also tend to remain low despite inflammatory activity in systemic lupus erythematosus (SLE) unless serositis or synovitis is present. This may be explained by increased levels of type I IFN in SLE, since type I IFN (i.e IFN alpha) inhibits hepatic CRP production. A polymorphisms of the CRP gene which cause lower CRP levels is also more frequent in SLE patients compared with controls. Elevations of CRP in the absence of clinically significant inflammation can occur in kidney failure. CRP level is an independent risk factor for atherosclerotic disease. Patients with high CRP concentrations are more likely to develop stroke, myocardial infarction, and severe peripheral vascular disease. Elevated level of CRP can also be observed in inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis.
High levels of CRP has been associated to point mutation Cys130Arg in the APOE gene, coding for apolipoprotein E, establishing a link between lipid values and inflammatory markers modulation.
=== Cancer ===
The role of inflammation in cancer is not well understood. Some organs of the body show greater risk of cancer when they are chronically inflamed. While there is an association between increased levels of C-reactive protein and risk of developing cancer, there is no association between genetic polymorphisms influencing circulating levels of CRP and cancer risk.
In a 2004 prospective cohort study on colon cancer risk associated with CRP levels, people with colon cancer had higher average CRP concentrations than people without colon cancer. It can be noted that the average CRP levels in both groups were well within the range of CRP levels usually found in healthy people. However, these findings may suggest that low inflammation level can be associated with a lower risk of colon cancer, concurring with previous studies that indicate anti-inflammatory drugs could lower colon cancer risk.
=== Obstructive sleep apnea ===
C-reactive protein (CRP), a marker of systemic inflammation, is also increased in obstructive sleep apnea (OSA). CRP and interleukin-6 (IL-6) levels were significantly higher in patients with OSA compared to obese control subjects. Patients with OSA have higher plasma CRP concentrations that increased corresponding to the severity of their apnea-hypopnea index score. Treatment of OSA with CPAP (continuous positive airway pressure) significantly alleviated the effect of OSA on CRP and IL-6 levels.
=== Rheumatoid arthritis ===
In the context of rheumatoid arthritis (RA), CRP is one of the acute phase reactants, whose assessment is defined as part of the joint 2010 ACR/EULAR classification criteria for RA with abnormal levels accounting for a single point within the criteria. Higher levels of CRP are associated with more severe disease and a higher likelihood of radiographic progression. Rheumatoid arthritis associated antibodies together with 14-3-3η YWHAH have been reported to complement CRP in predicting clinical and radiographic outcomes in patients with recent onset inflammatory polyarthritis. Elevated levels of CRP appear to be associated with common comorbidities including cardiovascular disease, metabolic syndrome, diabetes and interstitial lung (pulmonary) disease. Mechanistically, CRP also appears to influence osteoclast activity leading to bone resorption and also stimulates RANKL expression in peripheral blood monocytes.
It has previously been speculated that single-nucleotide polymorphisms in the CRP gene may affect clinical decision-making based on CRP in rheumatoid arthritis, e.g. DAS28 (Disease Activity Score 28 joints). A recent study showed that CRP genotype and haplotype were only marginally associated with serum CRP levels and without any association to the DAS28 score. Thus, that DAS28, which is the core parameter for inflammatory activity in RA, can be used for clinical decision-making without adjustment for CRP gene variants.
=== Viral infections ===
Increased blood CRP levels were higher in people with avian flu H7N9 compared to those with H1N1 (more common) influenza, with a review reporting that severe H1N1 influenza had elevated CRP. In 2020, people infected with COVID-19 in Wuhan, China, had elevated CRP.
== Additional images ==
== References ==
== External links ==
MedlinePlus Encyclopedia: C-reactive protein
Inflammation, Heart Disease and Stroke: The Role of C-Reactive Protein (American Heart Association)
C-Reactive+Protein at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
CRP: analyte monograph - The Association for Clinical Biochemistry and Laboratory Medicine
George Vrousgos, N.D. - Southern Cross University Archived 2020-02-18 at the Wayback Machine
Human CRP genome location and CRP gene details page in the UCSC Genome Browser.
Overview of all the structural information available in the PDB for UniProt: P02741 (C-reactive protein) at the PDBe-KB. | Wikipedia/High-sensitivity_C-reactive_protein |
C-reactive protein (CRP) is an annular (ring-shaped) pentameric protein found in blood plasma, whose circulating concentrations rise in response to inflammation. It is an acute-phase protein of hepatic origin that increases following interleukin-6 secretion by macrophages and T cells. Its physiological role is to bind to lysophosphatidylcholine expressed on the surface of dead or dying cells (and some types of bacteria) in order to activate the complement system via C1q.
CRP is synthesized by the liver in response to factors released by macrophages, T cells and fat cells (adipocytes). It is a member of the pentraxin family of proteins. It is not related to C-peptide (insulin) or protein C (blood coagulation). C-reactive protein was the first pattern recognition receptor (PRR) to be identified.
== History and etymology ==
Discovered by Tillett and Francis in 1930, it was initially thought that CRP might be a pathogenic secretion since it was elevated in a variety of illnesses, including cancer. The later discovery of hepatic synthesis (made in the liver) demonstrated that it is a native protein. Initially, CRP was measured using the quellung reaction which gave a positive or a negative result. More precise methods nowadays use dynamic light scattering after reaction with CRP-specific antibodies.
CRP was so named because it was first identified as a substance in the serum of patients with acute inflammation that reacted with the cell wall polysaccharide (C-polysaccharide) of pneumococcus.
== Genetics and structure ==
It is a member of the small pentraxins family (also known as short pentraxins). The polypeptide encoded by this gene has 224 amino acids. The full-length polypeptide is not present in the body in significant quantities due to signal peptide, which is removed by signal peptidase before translation is completed. The complete protein, composed of five monomers, has a total mass of approximately 120,000 Da. In serum, it assembles into stable pentameric structure with a discoid shape.
== Function ==
CRP binds to the phosphocholine expressed on the surface of bacterial cells such as pneumococcus bacteria. This activates the complement system, promoting phagocytosis by macrophages, which clears necrotic and apoptotic cells and bacteria. With this mechanism, CRP also binds to ischemic/hypoxic cells, which could regenerate with more time. However, the binding of CRP causes them to be disposed of prematurely. CRP binds to the Fc-gamma receptor IIa, to which IgG isotype antibodies also bind. In addition, CRP activates the classical complement pathway via C1q binding. CRP thus forms immune complexes in the same way as IgG antibodies.
This so-called acute phase response occurs as a result of increasing concentrations of interleukin-6 (IL-6), which is produced by macrophages as well as adipocytes in response to a wide range of acute and chronic inflammatory conditions such as bacterial, viral, or fungal infections; rheumatic and other inflammatory diseases; malignancy; and tissue injury and necrosis. These conditions cause release of IL-6 and other cytokines that trigger the synthesis of CRP and fibrinogen by the liver.
CRP binds to phosphocholine on micro-organisms. It is thought to assist in complement binding to foreign and damaged cells and enhances phagocytosis by macrophages (opsonin-mediated phagocytosis), which express a receptor for CRP. It plays a role in innate immunity as an early defense system against infections.
== Serum levels ==
=== Measurement methods ===
Traditional CRP measurement only detected CRP in the range of 10 to 1,000 mg/L, whereas high sensitivity CRP (hs-CRP) detects CRP in the range of 0.5 to 10 mg/L. hs-CRP can detect cardiovascular disease risk when in excess of 3 mg/L, whereas below 1 mg/L would be low risk. Traditional CRP measurement is faster and less costly than hs-CRP, and can be adequate for some applications, such as monitoring hemodialysis patients. Current immunoassay methods for CRP have similar precision to hsCRP performed by nephelometry and could probably replace hsCRP for cardiovascular risk assessment, however, in the United States this would represent off-label use, making it a laboratory-developed test under FDA regulations.
=== Normal ===
In healthy adults, the normal concentrations of CRP varies between 0.8 mg/L and 3.0 mg/L. However, some healthy adults show elevated CRP at 10 mg/L. CRP concentrations also increase with age, possibly due to subclinical conditions. There are also no seasonal variations of CRP concentrations. Gene polymorphism of interleukin-1 family, interleukin 6, and polymorphic GT repeat of the CRP gene do affect the usual CRP concentrations when a person does not have any medical illnesses.
=== Acute inflammation ===
When there is a stimulus, the CRP level can increase 10,000-fold from less than 50 μg/L to more than 500 mg/L. Its concentration can increase to 5 mg/L by 6 hours and peak at 48 hours. The plasma half-life of CRP is 19 hours, and is constant in all medical conditions. Therefore, the only factor that affects the blood CRP concentration is its production rate, which increases with inflammation, infection, trauma, necrosis, malignancy, and allergic reactions. Other inflammatory mediators that can increase CRP are TGF beta 1, and tumor necrosis factor alpha. In acute inflammation, CRP can increase as much as 50 to 100 mg/L within 4 to 6 hours in mild to moderate inflammation or an insult such as skin infection, cystitis, or bronchitis. It can double every 8 hours and reaches its peak at 36 to 50 hours following injury or inflammation. CRP between 100 and 500 mg/L is considered highly predictive of inflammation due to bacterial infection. Once inflammation subsides, CRP level falls quickly because of its relatively short half-life.
=== Metabolic inflammation ===
CRP concentrations between 2 and 10 mg/L are considered as metabolic inflammation: metabolic pathways that cause arteriosclerosis and type II diabetes mellitus.
== Clinical significance ==
=== Diagnostic use ===
CRP is used mainly as an inflammation marker. Apart from liver failure, there are few known factors that interfere with CRP production. Interferon alpha inhibits CRP production from liver cells which may explain the relatively low levels of CRP found during viral infections compared to bacterial infections
Measuring and charting CRP values can prove useful in determining disease progress or the effectiveness of treatments. ELISA and radial immunodiffusion methods are available for research use, while immunoturbidimetry is used clinically for CRP and nephelometry is typically used for hsCRP. Cutoffs for cardiovascular risk assessment have included:
low: hs-CRP level under 1.0 mg/L
average: between 1.0 and 3.0 mg/L
high: above 3.0 mg/L
Normal levels increase with aging. Higher levels are found in late pregnant women, mild inflammation and viral infections (10–40 mg/L), active inflammation, bacterial infection (40–200 mg/L), severe bacterial infections and burns (>200 mg/L).
CRP cut-off levels indicating bacterial from non-bacterial illness can vary due to co-morbidities such as malaria, HIV and malnutrition and the stage of disease presentation. In patients presenting to the emergency department with suspected sepsis, a CRP/albumin ratio of less than 32 has a negative predictive value of 89% for ruling out sepsis.
CRP is a more sensitive and accurate reflection of the acute phase response than the ESR (erythrocyte sedimentation rate). ESR may be normal while CRP is elevated. CRP returns to normal more quickly than ESR in response to therapy.
=== Cardiovascular disease ===
Recent research suggests that patients with elevated basal levels of CRP are at an increased risk of diabetes, hypertension and cardiovascular disease. A study of over 700 nurses showed that those in the highest quartile of trans fat consumption had blood levels of CRP that were 73% higher than those in the lowest quartile. Although one group of researchers indicated that CRP may be only a moderate risk factor for cardiovascular disease, this study (known as the Reykjavik Study) was found to have some problems for this type of analysis related to the characteristics of the population studied, and there was an extremely long follow-up time, which may have attenuated the association between CRP and future outcomes. Others have shown that CRP can exacerbate ischemic necrosis in a complement-dependent fashion and that CRP inhibition can be a safe and effective therapy for myocardial and cerebral infarcts; this has been demonstrated in animal models and humans.
It has been hypothesized that patients with high CRP levels might benefit from use of statins. This is based on the JUPITER trial that found that elevated CRP levels without hyperlipidemia benefited. Statins were selected because they have been proven to reduce levels of CRP. Studies comparing effect of various statins in hs-CRP revealed similar effects of different statins. A subsequent trial however failed to find that CRP was useful for determining statin benefit.
In a meta-analysis of 20 studies involving 1,466 patients with coronary artery disease, CRP levels were found to be reduced after exercise interventions. Among those studies, higher CRP concentrations or poorer lipid profiles before beginning exercise were associated with greater reductions in CRP.
To clarify whether CRP is a bystander or active participant in atherogenesis, a 2008 study compared people with various genetic CRP variants. Those with a high CRP due to genetic variation had no increased risk of cardiovascular disease compared to those with a normal or low CRP. A study published in 2011 shows that CRP is associated with lipid responses to low-fat and high-polyunsaturated fat diets.
=== Coronary heart disease risk ===
Arterial damage results from white blood cell invasion and inflammation within the wall. CRP is a general marker for inflammation and infection, so it can be used as a very rough proxy for heart disease risk. Since many things can cause elevated CRP, this is not a very specific prognostic indicator. Nevertheless, a level above 2.4 mg/L has been associated with a doubled risk of a coronary event compared to levels below 1 mg/L; however, the study group in this case consisted of patients who had been diagnosed with unstable angina pectoris; whether elevated CRP has any predictive value of acute coronary events in the general population of all age ranges remains unclear. Currently, C-reactive protein is not recommended as a cardiovascular disease screening test for average-risk adults without symptoms.
The American Heart Association and U.S. Centers for Disease Control and Prevention have defined risk groups as follows:
Low Risk: less than 1.0 mg/L
Average risk: 1.0 to 3.0 mg/L
High risk: above 3.0 mg/L
But hs-CRP is not to be used alone and should be combined with elevated levels of cholesterol, LDL-C, triglycerides, and glucose level. Smoking, hypertension and diabetes also increase the risk level of cardiovascular disease.
=== Fibrosis and inflammation ===
Scleroderma, polymyositis, and dermatomyositis elicit little or no CRP response. CRP levels also tend to remain low despite inflammatory activity in systemic lupus erythematosus (SLE) unless serositis or synovitis is present. This may be explained by increased levels of type I IFN in SLE, since type I IFN (i.e IFN alpha) inhibits hepatic CRP production. A polymorphisms of the CRP gene which cause lower CRP levels is also more frequent in SLE patients compared with controls. Elevations of CRP in the absence of clinically significant inflammation can occur in kidney failure. CRP level is an independent risk factor for atherosclerotic disease. Patients with high CRP concentrations are more likely to develop stroke, myocardial infarction, and severe peripheral vascular disease. Elevated level of CRP can also be observed in inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis.
High levels of CRP has been associated to point mutation Cys130Arg in the APOE gene, coding for apolipoprotein E, establishing a link between lipid values and inflammatory markers modulation.
=== Cancer ===
The role of inflammation in cancer is not well understood. Some organs of the body show greater risk of cancer when they are chronically inflamed. While there is an association between increased levels of C-reactive protein and risk of developing cancer, there is no association between genetic polymorphisms influencing circulating levels of CRP and cancer risk.
In a 2004 prospective cohort study on colon cancer risk associated with CRP levels, people with colon cancer had higher average CRP concentrations than people without colon cancer. It can be noted that the average CRP levels in both groups were well within the range of CRP levels usually found in healthy people. However, these findings may suggest that low inflammation level can be associated with a lower risk of colon cancer, concurring with previous studies that indicate anti-inflammatory drugs could lower colon cancer risk.
=== Obstructive sleep apnea ===
C-reactive protein (CRP), a marker of systemic inflammation, is also increased in obstructive sleep apnea (OSA). CRP and interleukin-6 (IL-6) levels were significantly higher in patients with OSA compared to obese control subjects. Patients with OSA have higher plasma CRP concentrations that increased corresponding to the severity of their apnea-hypopnea index score. Treatment of OSA with CPAP (continuous positive airway pressure) significantly alleviated the effect of OSA on CRP and IL-6 levels.
=== Rheumatoid arthritis ===
In the context of rheumatoid arthritis (RA), CRP is one of the acute phase reactants, whose assessment is defined as part of the joint 2010 ACR/EULAR classification criteria for RA with abnormal levels accounting for a single point within the criteria. Higher levels of CRP are associated with more severe disease and a higher likelihood of radiographic progression. Rheumatoid arthritis associated antibodies together with 14-3-3η YWHAH have been reported to complement CRP in predicting clinical and radiographic outcomes in patients with recent onset inflammatory polyarthritis. Elevated levels of CRP appear to be associated with common comorbidities including cardiovascular disease, metabolic syndrome, diabetes and interstitial lung (pulmonary) disease. Mechanistically, CRP also appears to influence osteoclast activity leading to bone resorption and also stimulates RANKL expression in peripheral blood monocytes.
It has previously been speculated that single-nucleotide polymorphisms in the CRP gene may affect clinical decision-making based on CRP in rheumatoid arthritis, e.g. DAS28 (Disease Activity Score 28 joints). A recent study showed that CRP genotype and haplotype were only marginally associated with serum CRP levels and without any association to the DAS28 score. Thus, that DAS28, which is the core parameter for inflammatory activity in RA, can be used for clinical decision-making without adjustment for CRP gene variants.
=== Viral infections ===
Increased blood CRP levels were higher in people with avian flu H7N9 compared to those with H1N1 (more common) influenza, with a review reporting that severe H1N1 influenza had elevated CRP. In 2020, people infected with COVID-19 in Wuhan, China, had elevated CRP.
== Additional images ==
== References ==
== External links ==
MedlinePlus Encyclopedia: C-reactive protein
Inflammation, Heart Disease and Stroke: The Role of C-Reactive Protein (American Heart Association)
C-Reactive+Protein at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
CRP: analyte monograph - The Association for Clinical Biochemistry and Laboratory Medicine
George Vrousgos, N.D. - Southern Cross University Archived 2020-02-18 at the Wayback Machine
Human CRP genome location and CRP gene details page in the UCSC Genome Browser.
Overview of all the structural information available in the PDB for UniProt: P02741 (C-reactive protein) at the PDBe-KB. | Wikipedia/High_sensitivity_C-reactive_protein |
Degos disease, also known as Köhlmeier-Degos disease or malignant atrophic papulosis, is an extremely rare condition caused by blockage of arteries and veins. Individuals with this condition will develop papules. Those diagnosed with this disease may also develop complications due to impairment of internal organs. The exact underlying mechanism is still unknown, and an effective treatment is still being developed. There are fewer than 50 living patients presently known worldwide, and fewer than 200 reported in medical literature. However, many individuals may go undiagnosed due to rarity of the disease. Most individuals develop symptoms between the ages of 20–50; however, cases outside of this age range have been reported as well.
== Symptoms and signs ==
The characteristic symptom of Degos disease is the development of papules. Initially, individuals may have skin lesions or rashes, but they will proceed to develop distinct bumps, or papules. Papules are circular in shape, have a porcelain-white center and red border. As papules age, the white centers will sink in and only the border will remain raised. Typically, papules range from 0.5 to 1 cm in width. Papules appear on the trunk and upper extremities and are not found on the individual's palms, soles, scalp, or face.
Symptoms vary, depending on whether an individual has the benign variant or malignant variant of the disease. Both the benign and malignant forms have development of the characteristic papules. Individuals with the benign form will have the typical papules persisting anywhere from a few years to throughout their whole lives. In the benign form, no inner organs are affected. If an individual develops the malignant form, it means that not only are the papules present, but inner organs are involved. Most malignant cases involve problems of the gastrointestinal tract leading to small intestine lesions, abdominal pain, diarrhea, and bowel perforation. If the central nervous system is involved, symptoms can include headaches, dizziness, seizures, paralysis of cranial nerves, weakness, stroke, damage to small areas of the brain due to artery blockage (cerebral infarcts, and cerebral hemorrhage). Additional organs commonly impacted include the heart, lungs, and kidneys. Symptoms that may develop from damage to these organs include double vision (diplopia), clouding of lenses of eyes, swelling of the optic disc (papilledema), partial loss of vision, shortness of breath, chest pain, epilepsy, and thickening of pericardium.
Someone with the benign form may suddenly develop symptoms of the malignant form. Symptoms can last anywhere from a few weeks to several years. Onset of symptoms typically begins to manifest between the ages of 20–50. A few cases of this condition in newborns have also been described.
== Causes ==
The papules characteristic for this disease develop due to infarctions, or blockages in small-medium arteries and veins. The underlying cause is unknown for this disease. Though not confirmed, some cases have shown signs of inheritance between first-degree relatives. It has been suggested that the disease has a familial inheritance pattern; it is thought to be an autosomal dominant disorder. In most cases of familial inheritance, the benign variant of the disease has been present.
Due to the lack of knowledge of the pathomechanism for this condition prevention strategies are not known. However, in order to prevent worsening of symptoms, consistent evaluations should be conducted by a physician.
== Mechanism ==
Although this disease has been known for around 70 years, the pathomechanism underlying it is still unknown. Several hypotheses have been developed regarding the underlying mechanism for Degos disease. One theory suggests that inflammation of blood vessels may trigger the condition. Another theory has to do with Degos disease as a coagulopathy. Development of a thrombus and resulting reduction of blood flow is common in this condition. A reduction in blood flow throughout the body can lead to damaged endothelial cells and may perhaps lead to the formation of the characteristic papules. Another hypothesis suggests that abnormal swelling and proliferation of the vascular endothelium can lead to intestinal and central nervous system thrombosis, and ultimately lead to development of symptoms associated with Degos disease. Overall, individuals with Degos disease have abnormal blockages in their arteries and veins; however, the cause of these blockages is unknown.
== Diagnosis ==
Clinical evaluation and identification of characteristics papules may allow a dermatologist to diagnose Degos disease. The papules have a white center and are bordered with a red ring. After lesions begin to appear, the diagnosis for Degos disease can be supported by histological findings. Most cases will show a wedge-shaped connective tissue necrosis in the deep corium. This shape is due to the blockage/occlusion of small arteries.
Individuals may be diagnosed with the benign form if only the papules are present. However, an individual may be diagnosed with the malignant form if involvement of other organs like the lungs, intestine and/or central nervous system occurs. The malignant, or systematic form of this condition may suddenly develop even after having papules present for several years. In order to quickly diagnose this shift to the malignant variant of the disease, it is important for individuals to have consistent follow-up evaluations. In these evaluations, depending on which organs are suspected to be involved, the following procedures and tests may be conducted: skin inspection, brain magnetic resonance tomography, colonoscopy, chest X-ray, and/or abdominal ultrasound.
== Treatment ==
Due to the lack of knowledge around the underlying mechanism of malignant atrophic papulosis, an effective treatment method has not been developed. Treatment for this condition is symptomatic. However, several treatment methods have been tested and are still being developed as more information regarding the condition is found. Fibrinolytic and immunosuppressive therapeutic regimens were tested and found to be mostly unsuccessful as treatment methods.
After treating conditions comorbid with Degos disease, physicians have recently found improvement in symptoms with the use of eculizumab and treprostinil. Discovered by dermatopathologist, Cynthia Magro, response to eculizumab is often immediate and dramatic, but has been of limited duration and is expensive, needing to be infused every 14 days. Treprostinil use has been reported to result in clearing of gastrointestinal and central nervous system findings as well as clearing of cutaneous lesions, but reports are limited. Treprostinil may be more effective than other vasodilators because it may also increase the population of circulating endothelial cells, allowing angiogenesis.
== Recent research ==
A patient diagnosed with the malignant, systemic form of the disease and was severely ill was found to have C5b-9 complexes in the involved vessels of the skin biopsy. Eculizumab was then used for treatment of the thrombotic microangiopathy, a humanized monoclonal antibody drug which is normally used in the treatment of Paroxysmal nocturnal hemoglobinuria. The patient experienced a dramatic improvement in his condition. Physicians at Albany Medical College were later able to treat a pediatric Degos patient with eculizumab.
The team later observed the resolution of Degos skin lesions in an adult patient with an overlap syndrome involving systemic lupus, systemic sclerosis, and Degos disease who was treated with treprostinil for their pulmonary hypertension. They noted the pediatric Degos patient was developing significant complications despite treatment with eculizumab, so treprostinil was incorporated into the treatment. All known long-term survivors of systemic Degos disease are being treated with a combination of eculizumab and treprostinil.
== History ==
In 1941, this disease was first described by Köhlmeier. However, it was not until 1942 that the disease was recognized as a new clinical entity by Robert Degos. Initially the condition was referred to as Degos disease or Köhlmeier-Degos disease. However, Degos himself subsequently suggested the name "papulose atrophiante maligne," translated as malignant atrophic papulosis.
== References ==
=== Notes ===
=== Further reading ===
== External links == | Wikipedia/Degos_disease |
Hemolytic disease of the newborn (anti-RhE) is caused by the anti-RhE antibody of the Rh blood group system. The anti-RhE antibody can be naturally occurring, or arise following immune sensitization after a blood transfusion or pregnancy.
The anti-RhE antibody is quite common especially in the Rh genotype CDe/CDe; it usually only causes a mild hemolytic disease, but can cause a severe condition in the newborn. It can occur with other antibodies, usually the anti-Rhc antibody, which can also cause a severe hemolytic disease.
One study done by Moran et al., found that titers are not reliable for anti-E. Their most severe case of hemolytic disease of the newborn occurred with titers 1:2. Moran states that it would be unwise routinely to dismiss anti-E as being of little clinical consequence.
== Presentation ==
=== Complications ===
High at birth or rapidly rising bilirubin
Prolonged hyperbilirubinemia
Bilirubin-induced neurological dysfunction
Cerebral palsy
Kernicterus
Thrombocytopenia
Hemolytic anemia – must not be treated with iron
Late onset anemia – must not be treated with iron. Can persist up to 12 weeks after birth.
== Mechanism ==
Hemolytic disease of the fetus and newborn (HDN) is a condition where the passage of maternal antibodies results in the hemolysis of fetal/neonatal red cells. The antibodies can be naturally occurring such as anti-A, and anti-B, or immune antibodies developed following a sensitizing event. Isoimmunization occurs when the maternal immune system is sensitized to red blood cell surface antigens. The most common causes of isoimmunization are blood transfusion, and fetal-maternal hemorrhage. The hemolytic process can result in anemia, hyperbilirubinemia, neonatal thrombocytopenia, and neonatal neutropenia. With the use of RhD Immunoprophylaxis, (commonly called Rhogam), the incidence of anti-D has decreased dramatically and other alloantibodies are now a major cause of HDN.
=== Antibody specific ===
One study done by Moran et al., found that titers are not reliable for anti-E. Their most severe case of hemolytic disease of the newborn occurred with titers 1:2. Moran states that it would be unwise routinely to dismiss anti-E as being of little clinical consequence.
In the case of anti-E, the woman should be checked around 28 weeks to see if she has developed anti-c as well.
== Testing ==
Testing for HDN involves blood work from both mother and father, and may also include assessment with amniocentesis and Middle Cerebral Artery scans.
=== Mother ===
Blood testing for the mother is called an indirect Coombs test (ICT) or an indirect agglutination test (IAT). This test tells whether there are antibodies in the maternal plasma. If positive, the antibody is identified and given a titer. Critical titers are associated with significant risk of fetal anemia and hydrops. Titers of 1:8 or higher is considered critical for Kell. Titers of 1:16 or higher are considered critical for all other antibodies. After critical titer is reached, care is based on MCA scans. If antibodies are low and have a sudden jump later in pregnancy, an MCA scan is warranted. If the titer undergoes a 4 fold increase, it should be considered significant regardless of if the critical value has been reached. Maternal titers are not useful in predicting fetal anemia after the first affected gestation and should not be used for the basis of care. Titers are tested monthly until 24 weeks, after which they are done every 2 weeks.
"In only 2 situations are patients not monitored identically to patients who are Rh sensitized. The first is that of alloimmunization to the c, E, or, C antigens. Some concern exists that hemolysis may occur in these patients with a lower than 1:16 titer. Thus, if the initial titer is 1:4 and stable but increases at 26 weeks' gestation to 1:8, assessment with MCA Doppler velocity at that point is reasonable. However, if the patient presents in the first trimester with a 1:8 titer that remains stable at 1:8 throughout the second trimester, continued serial antibody titers are appropriate.
The second situation in which patients should not be treated identically to patients who are Rh D sensitized is that of Kell isoimmunization because several cases of severe fetal hemolysis with anti-Kell antibodies have occurred in the setting of low titers."
In the case of a positive ICT, the woman must carry a medical alert card or bracelet for life because of the risk of a transfusion reaction.
=== Father ===
Blood is generally drawn from the father to help determine fetal antigen status. If he is homozygous for the antigen, there is a 100% chance of all offspring in the pairing to be positive for the antigen and at risk for HDN. If he is heterozygous, there is a 50% chance of offspring to be positive for the antigen. This test can help with knowledge for the current baby, as well as aid in the decision about future pregnancies. With RhD, the test is called the RhD genotype. With RhCE, and Kell antigen it is called an antigen phenotype.
=== Fetus ===
There are three possible ways to test the fetal antigen status. Free cell DNA, amniocentesis, and chorionic villus sampling (CVS). Of the three, CVS is no longer used due to risk of worsening the maternal antibody response. Once antigen status has been determined, assessment may be done with MCA scans.
Cell-free DNA can be run on certain antigens. Blood is taken from the mother, and using PCR, can detect the K, C, c, D, and E alleles of fetal DNA. This blood test is non-invasive to the fetus and is an easy way of checking antigen status and risk of HDN. Testing has proven very accurate and is routinely done in the UK at the International Blood Group Reference Laboratory in Bristol. Sanequin laboratory in Amsterdam, Netherlands also performs this test. For US patients, blood may be sent to either of the labs. In the US, Sensigene is done by Sequenome to determine fetal D status. Sequenome does not accept insurance in the US, but US and Canadian patients have had insurance cover the testing done overseas.
Amniocentesis is another recommended method for testing antigen status and risk for HDN. Fetal antigen status can be tested as early as 15 weeks by PCR of fetal cells.
CVS is possible as well to test fetal antigen status but is not recommended. CVS carries a higher risk of fetal maternal hemorrhage and can raise antibody titers, potentially worsening the antibody effect.
=== MCA scans ===
Middle cerebral artery – peak systolic velocity is changing the way sensitized pregnancies are managed. This test is done noninvasively with ultrasound. By measuring the peak velocity of blood flow in the middle cerebral artery, a MoM (multiple of the median) score can be calculated. MoM of 1.5 or greater indicates severe anemia and should be treated with IUT.
== Intervention ==
There are several intervention options available in early, mid and late pregnancies.
=== Early pregnancy ===
IVIG – IVIG stands for intravenous immunoglobulin. It is used in cases of previous loss, high maternal titers, known aggressive antibodies, and in cases where religion prevents blood transfusion. Ivig can be more effective than IUT alone. Fetal mortality was reduced by 36% in the IVIG and IUT group than in the IUT alone group. IVIG and plasmapheresis together can reduce or eliminate the need for an IUT.
Plasmapheresis – Plasmapheresis aims to decrease the maternal titer by direct plasma replacement. Plasmapheresis and IVIG together can even be used on women with previously hydropic fetuses and losses.
=== Mid to late pregnancy ===
IUT – intrauterine transfusion (IUT) is done either by intraperitoneal transfusion (IPT) or intravenous transfusion (IVT). IVT is preferred over IPT. IUTs are only done until 35 weeks. After that, the risk of an IUT is greater than the risk from post birth transfusion.
Steroids – steroids are sometimes given to the mother before IUTs and early delivery to mature the fetal lungs.
Phenobarbital – Phenobarbital is sometimes given to the mother to help mature the fetal liver and reduce hyperbilirubinemia.
Early delivery – delivery can occur anytime after the age of viability. Emergency delivery due to failed IUT is possible, along with induction of labor at 35–38 weeks.
== After birth ==
=== Testing ===
Coombs – after birth the baby will have a direct Coombs test run to confirm antibodies attached to the infant's red blood cells. This test is run from cord blood.
In some cases, the direct Coombs will be negative but severe, even fatal HDN can occur. An indirect Coombs needs to be run in cases of anti-C, anti-c, and anti-M. Anti-M also recommends antigen testing to rule out the presence of HDN.
Hgb – the infant's hemoglobin should be tested from cord blood.
Reticulocyte count – Reticulocytes are elevated when the infant is producing more blood to combat anemia. A rise in the retic count can mean that an infant may not need additional transfusions. Low retic is observed in infants treated with IUT and in those with HDN from anti-Kell
Neutrophils – as neutropenia is one of the complications of HDN, the neutrophil count should be checked.
Thrombocytes – as thrombocytopenia is one of the complications of HDN, the thrombocyte count should be checked.
Bilirubin should be tested from cord blood.
Ferritin – because most infants affected by HDN have iron overload, a ferritin must be run before giving the infant any additional iron.
Newborn screening tests – transfusion with donor blood during pregnancy or shortly after birth can affect the results of the newborn screening tests. It is recommended to wait and retest 10–12 months after last transfusion. In some cases, DNA testing from saliva can be used to rule out certain conditions.
== Treatment ==
Phototherapy – Phototherapy is used for cord bilirubin of 3 or higher. Some doctors use it at lower levels while awaiting lab results.
IVIG – IVIG has been used to successfully treat many cases of HDN. It has been used not only on anti-D, but on anti-E as well. IVIG can be used to reduce the need for exchange transfusion and to shorten the length of phototherapy. The AAP recommends "In isoimmune hemolytic disease, administration of intravenousγ-globulin (0.5–1 g/kg over 2 hours) is recommended if the TSB is rising despite intensive phototherapy or the TSB level is within 2 to 3 mg/dL (34–51 μmol/L) of the exchange level. If necessary, this dose can be repeated in 12 hours (evidence quality B: benefits exceed harms). Intravenous γ-globulin has been shown to reduce the need for exchange transfusions in Rh and ABO hemolytic disease."
Exchange transfusion – exchange transfusion is used when bilirubin reaches either the high or medium risk lines on the nonogram provided by the American Academy of Pediatrics (Figure 4). Cord bilirubin >4 is also indicative of the need for exchange transfusion.
== Transfusion reactions ==
Once a woman has antibodies, she is at high risk for a transfusion reaction. For this reason, she must carry a medical alert card at all times and inform all doctors of her antibody status.
"Acute hemolytic transfusion reactions may be either immune-mediated or nonimmune-mediated. Immune-mediated hemolytic transfusion reactions caused by immunoglobulin M (IgM) anti-A, anti-B, or anti-A,B typically result in severe, potentially fatal complement-mediated intravascular hemolysis. Immune-mediated hemolytic reactions caused by IgG, Rh, Kell, Duffy, or other non-ABO antibodies typically result in extravascular sequestration, shortened survival of transfused red cells, and relatively mild clinical reactions. Acute hemolytic transfusion reactions due to immune hemolysis may occur in patients who have no antibodies detectable by routine laboratory procedures."
Summary of transfusion reactions in the US:
== See also ==
Coombs test
Hematology
Hemolytic anemia
Hemolytic disease of the newborn
== References ==
== Further reading ==
Antenatal & neonatal screening (second edition). Chapter 12: Rhesus and other haemolytic diseases, by E.A. Letsky, I. Leck, J.M. Bowman. 2000. Oxford University Press. ISBN 0-19-262826-7.
== External links == | Wikipedia/Hemolytic_disease_of_the_newborn_(anti-RhE) |
In medicine, aortoiliac occlusive disease is a form of central artery disease involving the blockage of the abdominal aorta as it transitions into the common iliac arteries.
== Signs and symptoms ==
Classically, it is described in male patients as a triad of the following signs and symptoms:
claudication of the buttocks and thighs
absent or decreased femoral pulses
erectile dysfunction
== Diagnosis ==
The physical examination usually shows weakened femoral pulses and a reduced ankle-brachial index. The diagnosis can be verified by color duplex scanning, which reveals either a peak systolic velocity ratio ≥2.5 at the site of stenosis and/or a monophasic waveform. MRA and multidetector CTA are often used to determine the extent and type of obstruction. Another technique is digital subtraction angiography which allows verification of the diagnosis and endovascular treatment in a single session.
Angiography provides important information regarding the perfusion and patency of distal arteries (e.g. femoral artery). The presence of collateral arteries in the pelvic and groin area is important in maintaining crucial blood flow and lower limb viability. However, angiography should only be used if symptoms warrant surgical intervention.
== Treatment ==
Treatment involves revascularization typically using either angioplasty or a type of vascular bypass
Kissing balloon angioplasty +/- stent, so named because the two common iliac stents touch each other in the distal aorta.
Aorto-iliac bypass graft
Axillary-bi-femoral and femoral-femoral bypass (sometimes abbreviated "ax-fem fem-fem")
== History ==
The condition was first described by Robert Graham in 1813, but the condition with its triad of symptoms was ascribed to René Leriche. Leriche, a French surgeon, linked the pathophysiology with the anatomy of the condition. John Hunter's dissections of atherosclerotic aortic bifurcations from the late 18th century are preserved at the Hunterian Museum, but Leriche was first to publish on the subject based on a patient he treated with the condition at the age of 30. Following treatment the 30-year-old was able to walk without pain and maintain an erection.
== See also ==
Claudication
Peripheral arterial disease
== References ==
== External links == | Wikipedia/Aortoiliac_occlusive_disease |
Cardiovascular disease in women is an integral area of research in the ongoing studies of women's health. Cardiovascular disease (CVD) is an umbrella term for a wide range of diseases affecting the heart and blood vessels, including but not limited to, coronary artery disease, stroke, cardiomyopathy, myocardial infarctions, and aortic aneurysms.
Since the mid-1980s, CVD has been the leading cause of death in women, despite being presumed to be a primarily male disease. Two types of CVDs are shown to be the leading causes of death in women globally according to the World Health Organization: ischemic heart disease and stroke. However, until recently, the gender-specific data available on cardiovascular disease (CVD) has been sparse for numerous reasons. The risks of CVD were unaccounted for in women due to gender biases, under-representation in clinical trials, and lack of research. These factors contributed to an increase in preventable deaths in women due to CVD. Thus, this is now an integral area of research in the ongoing studies of women's health.
Overall, these factors are instrumental in the key differences seen in CVD presentation, which must be accounted for in diagnostic and treatment practices by healthcare providers.
== Diagnostic gap ==
Cardiovascular disease in women may be misdiagnosed or underdiagnosed in women for several reasons. CVD, especially heart attacks, often presents symptoms in women differently than in men due to anatomical and hormonal differences. Research has shown that women may present with symptoms that are classically associated with heart attacks, such as chest pain and shortness of breath, but also with atypical symptoms such as neck, jaw, arm, or shoulder discomfort, nausea or vomiting, heartburn or indigestion, fatigue, headaches, and palpitations. Some healthcare providers may misidentify the causes of these symptoms, attributing them to gastrointestinal or psychological causes instead.
Moreover, although certain factors traditionally associated with developing CVD include age, hypertension, smoking, diabetes mellitus, and dyslipidemia and are similarly influential on women as on men, recent research has found additional risks that should be added to this list as non-traditional or emerging factors. These include pregnancy-associated disorders such as preeclampsia and gestational diabetes, polycystic ovary syndrome, and even depression. This discrepancy is furthered by the under-enrollment of women in research studies establishing a CVD treatment baseline in women for healthcare practitioners.
Furthermore, the anatomical features of the cardiovascular system have some differences in size between men and women. The size of the vessels in women is generally smaller in comparison to men. Thus, a smaller blockage can cause as much damage to women as a regular-sized blockage in men. Women also have a smaller ventricle size than men. This lowers the volume pumped out of the ventricle to the rest of the body, thus requiring their heart to beat faster to ensure a similar amount of blood is pumped out as men. These differences in addition to the cardiovascular functional differences, i.e. a slower fight or flight response, sympathetic activity, and a high rest and digest response, parasympathetic activity, may result in differing presentations of women's illnesses.
== Shifts and trends ==
According to a survey conducted by the AHA in 2000, women are now more aware of CVD as the leading cause of death in women than in 1997. Close to 90% of women are now aware that women experience heart disease symptoms gradually in later years and that the initial hours of treatment are critical to reducing damage to the brain and heart. This is further supported by a study done in Italy in 2022 that found a vast majority of their participants were able to successfully identify CVD as a leading cause of death in women.
However, many women are still unaware of the impact of CVD on women's health. This may be due to infrequent exposure to the concerns a deficit of personalization in education to these groups, and little involvement of women in CVD research until 1986. Numerous studies have noted that many women were unable to identify common risk factors or acknowledge whether they were at possible risk of developing CVD, with quite a few even believing that CVD was a male-exclusive condition.
This lack of awareness seems to also be prominent in the age groups of 25 to 34 years. Nearly 72% of women in this age group consider cancer to be the leading cause of death; however, as age increases, the understanding of heart diseases has also been shown to increase. A national survey conducted by AHA in 2012, suggested increased rates of awareness and consciousness. According to the fifteen-year trend report, some of the significant changes are as follows:
In 2012 the level of awareness increased in women from different ethnicities with percentages rising up to 65% white, 36% black, and 34% Hispanic.
In terms of knowledge of the symptoms of heart attack, 18% of women responded with nausea, while 56% responded with chest pain.
In case of experiencing a heart attack, 10% of Hispanic women were reported to initially take aspirin, compared to 22% black and 18% of white women.
The top 3 health management issues were reported to be exercise (by 49% of women), weight (by 47%), and cholesterol (by 45%).
Analysis of data suggests further improvement in the educational efforts and awareness among women, especially of racial and ethnic minorities, as they face higher mortality rates.
As a follow up, a recent 2019 AHA survey of the awareness of CVD being the leading cause of death in women has been on the decline in the last decade. The greatest differences were seen among Hispanic women, non-Hispanic Black women and the age group of 25 to 34 year old. These trends are similar to those ones found in the 2012 survey done by the American Heart Association. This shift in knowledge demonstrates a great need for cardiovascular health programs targeted to women, to ensure that they are able to successfully access the needed resources to ensure successful CVD treatment and prevention.
Moreover, trends have also demonstrated a difference in CVD risk and treatment amongst women from different ethnicities. In the 1980s, African American women had double the mortality rates compared to other women between the ages of 30 and 39. Although this number has improved, in comparison to white women, the disparity persists. A 2007 study that black and Hispanic women were nearly half as aware (31% and 29% respectively) than their white counterparts (68%). This is alarming as minority groups are at an increased risk of higher cholesterol levels and many other risk factors that cause CVD. Studies have found this may be due to lack of educational intervention being targeted to these groups to ensure equity access to health resources.
Future research is working to establish gender-specific guidelines and ensure that treatments, diagnoses, and overall practices are adjusted to encompass the differences of women with CVD into clinical application.
== Signs and symptoms ==
CVD is the leading cause of death in women worldwide. Studies have shown a recent successful decline in CVD mortality overall. However, there is a strong indication for male-specific reductions being implemented in practice, thus female mortality remains high, despite the incidence of CVD being lower. The number of women surviving and dying from CVD far outweighs the number of men in comparison.
Due to anatomical and biological differences, women with CVD have been shown to present with the expected symptoms, as well as unusual and unexpected symptoms of CVD in comparison to men. The traditional, or common, symptoms seen in both men and women include:
Chest pain or feeling of crushing pain in the chest
Radiating pain in the arms or shoulder
Heartburn
However, some studies have shown that chest pain is not as common a symptom in women. Thus, its absence cannot rule out the likeliness of CVD.
For the atypical symptoms, there are numerous that are commonly vague and seem to be unattached to specific diagnoses. Women generally develop angina and are less likely to present with myocardial infarction at the onset of cardiovascular diseases. The other symptoms to account for include:
Pain or discomfort in the neck, jaw, upper back, or abdomen
Shortness of breath
Nausea/vomiting
Sudden and random sweating
Fatigue
Lightheadedness or dizziness
Overall, these symptoms seem to be more present at rest than any other time of day for women, and at times of emotional distress. Women also tend to report milder symptoms, while also experiencing a combination of more symptoms than men.
To ensure that practitioners can catch all cases and forms presented to them, it is crucial to ensure that women's diagnostic tests are adjusted to include all of these symptoms appropriately.
== Risk factors ==
There are numerous risk factors that have been found to be associated with developing CVD. A number of them are considered traditional, as they are found in men and women with CVD at high rates. However, there are also unique risk factors found only in women that are commonly associated with this group developing CVD. The following list includes the predominant ones found in many cases of CVD in women.
=== Smoking ===
Smoking has been well established as risk factor for plaque formation which can lead to developing different forms of CVD. Previous studies have shown that 4-5 cigarettes per day almost doubled the risk of CVD and 20 cigarettes per day increased the risk of CVD by 6 times. Women who smoke face up to a 25% increased risk of developing CAD compared to their male counterparts, with studies showing that reduction in smoking decreased the incidence of CAD in women by 13%. Furthermore, second-hand smoking may increase the risk of CVD by 25%.
=== Obesity ===
Obesity is associated with several other factors that can cause CVD, such as dyslipidemias. With increasing body mass, the risk of developing various CVDs, such as ischemic stroke and coronary artery disease grows as the unhealthy lifestyle maintained prevents the cardiovascular system from functioning optimally. Women make up about 40% of obese adults over the age of 20. Postmenopausal women are also more likely to experience fat redistribution to the abdomen and develop metabolic syndrome, resulting in increased susceptibility to obesity.
=== Hypertension ===
Chronic high blood pressure (hypertension) alters the structure of vessels over time, such as narrowing or complete blockage of blood flow. This can subsequently lead to CVDs, including stroke. The prevalence of certain disorders such as fibromuscular dysplasia is increased in premenopausal women and can lead to secondary hypertension. These factors, including others such as preeclampsia, have been shown to contribute to the risk of developing hypertension, and thus, consequently, CVDs from the resulting damage. Women who have chronic hypertension have a much higher risk of developing cardiovascular disease compared to women with normal blood pressure.
=== Lipids ===
Cholesterol, is a type of lipid with diverse bodily functions. There are several types of cholesterol but the main two are high-density lipoprotein (HDL) and low-density lipoprotein (LDL). Then levels of these cholesterols can be determined by a blood test. HDL cholesterol is known as "the good cholesterol" and ideally it is recommended to have a high level of this cholesterol. HDL cholesterol works by removing LDL from the bloodstream and returning it to the liver where it can not cause cardiovascular damage.
LDL cholesterol is known as "the bad cholesterol" and it is recommended to have a low level (130 mg/dL or less) anything higher can lead to a higher CVD risk. When there is a high level of LDL cholesterol in the blood it is up-taken by inflammatory cells known as macrophages. The high burden of LDL cholesterol inside macrophages leads to an inflammatory response, which ultimately damages the inner lining of the blood vessels. Due to this damage, macrophages invade the cell walls of the blood vessels and cause plaque formation. A plaque can lead to obstruction of the blood vessel and if this were to occur in a coronary artery it could increase the risk of a myocardial infarction (heart attack).
=== Diabetes mellitus ===
The high blood sugar levels associated with diabetes mellitus is also an important cardiovascular risk factor to consider. Data suggests that women with diabetes are at five times greater risk than those without for developing CVD. Uncontrolled levels of glucose can cause damage to the vessels and nerves alike, increasing the risk of developing other conditions, including CVD. Women with type I diabetes were found to be twice as likely to experience adverse cardiovascular events when compared to men with the same disease, but were less likely to receive aggressive treatment to control modifiable risk factors. Women with Type II diabetes are also at greater risk than men with the same condition despite similar glycemic control.
=== Gestational diabetes mellitus ===
Similar to hypertensive disease of pregnancy, the already prevalent risk factor of diabetes mellitus combined with pregnancy puts women at increased risk of developing CVD. Women diagnosed with gestational diabetes are at a higher risk of developing traditional risk factors for CVD, such as type 2 diabetes mellitus, and hypertension. The irreversible changes made during pregnancy may make these women prone to CVDs in the long term. Additionally, women diagnosed with gestational diabetes remain at higher risk of developing type 2 diabetes mellitus and CVD, despite blood sugar metabolism returning to normal post-pregnancy.
=== Preeclampsia ===
Hypertension can be severely damaging to vessels and the heart and cause CVD to develop. Hypertensive disorders in pregnancy such as pre-eclampsia can be seen in 10% of pregnancies and has been recognized as a risk factor for developing new-onset hypertension after pregnancy.
=== Other pregnancy-associated conditions ===
Pregnancy offers numerous vascular and metabolic changes that, although may seem temporary, result in long-term effects on the cardiovascular system. Women who deliver before 37 weeks gestation are at increased risk of developing CVD, with additional risk depending on the number and timing of preterm births. Data suggests that women with a history of preterm births have two times the risk of CVD-related deaths than women with regular-term births. This may be due to the complications associated with preterm birth and its effect on the mothers. Additionally, intrauterine growth restriction (IUGR), which affects up to 10% of all births, in prior pregnancies is associated with an increase in maternal CVD risk for both the mother and the baby. Finally, prior pregnancy loss, including miscarriage and stillbirth, also contributed to a two-fold increase in risk of maternal CVD. Women who have high blood pressure and had complications in their pregnancy have three times the risk of developing cardiovascular disease compared to women with normal blood pressure who had no complications in pregnancy.
=== Menopause ===
Estrogen has several cardioprotective effects on women, thus during the age of fertility – i.e. puberty to menopause – females are at a lower risk of developing CVD. However, menopause is associated with a decrease in estrogen production. This allows for typical cardiovascular issues to implement their effects with little protection from the women's bodies. In rare cases, early menopause is correlated with increased CVD risk, although the relationship between the two is complex. Premature menopause is defined as menopause before the age of 40. Although the relationship between the two is complex, it seems to be due to the prevalence of atherosclerosis in perimenopause.
=== Physical activity ===
Lower levels of fitness are commonly associated with blockages and obstructed blood flow found in CVDs. As exercise promotes the use of the heart and improves oxygen affinity for muscles, this can help relieve stress from the heart and allow for it to pump at a normal pace while providing more nutrients and oxygen to the body. An observational study found that those with limited physical activity in their day were at 4.7 times increased risk for stroke and other forms of CVD.
=== Ethnicity and race ===
The prevalence of CVD has been shown to vary greatly amongst different ethnic and racial groups. Overall, ethnic minority women exhibit greater risk factors for CVD than white women. Black women are at the highest rate of CVD-related death. The cause for these gaps is still unclear, however, this may be related to genetics, socioeconomic status, education status, or inequitable health resources access.
=== Socioeconomic status ===
Lower socioeconomic status is largely associated with an increased risk of CVD development. This may be due to a combination of psychosocial risk factors affecting those in these groups. Additionally, inequitable access to much-needed resources to appropriately identify and treat these conditions may lead to delayed diagnosis and inability to treat appropriately.
=== Age ===
The risk of CVD development increases as women age. During the fertility age of a woman, the high levels of estrogen provide cardioprotective effects. This, however, curbs significantly after menopause and increases the prevalence of CVD found in women. Research has found that for women 75 years old and higher, the incidence of CVD is significantly higher than for men.
=== Autoimmune diseases ===
Certain autoimmune conditions such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) are significantly more likely to occur in women. Some populations of women are also more likely to be affected than others. For example, SLE is two to four times more prevalent in black women when compared to white women. Studies have also shown that women with SLE are at least nine times more likely to experience a myocardial infarction when compared to the general population, with some estimates showing a 50-fold increase in risk. Similarly, RA increases the risk of death from CVD by 50%. In autoimmune diseases, the immune system reacts to the individual's antigens itself, which can cause local or systemic issues. This is furthered by the microvasculature in women that puts women at increased risk of developing autoimmune diseases themselves.
=== Polycystic ovary syndrome ===
Polycystic ovarian syndrome (PCOS) is an endocrine disorder prevalent in young women that is classically associated with irregular menstruation, androgen excess, and infertility. It is unclear whether PCOS is associated with an increased risk of developing CVD. However, PCOS is associated with multiple traditional risk factors of CVD such as diabetes, obesity, dyslipidemia, and hypertension, which may naturally put the individual at increased risk of developing CVD.
=== Depression ===
Due to biological and sociological causes, women are twice as likely to have depression when compared to men. Studies have shown that women with depression are at greater risk of developing CVD when compared to peers without depression, although this relationship is still unclear. Moreover, depression has also been associated with smoking, a traditional risk factor for CVD.
=== Breast cancer treatment ===
Because of the location of the heart in relation to the breasts, breast cancer treatments have been shown to cause an increased risk, acute or chronic, of CVD. Exposure to radiation and chemotherapy in cancer treatments have shown to cause complications in the heart and its blood vessels, causing scarring or stiffening of heart tissue, which is detrimental to the heart's function.
=== Hormones ===
Estrogen and other associated female sex hormones have been shown to have major cardioprotective effects on women. This may be why it is less common to see women with CVD before menopause, after which estrogen levels decline rapidly. This causal relationship is still yet to be established clearly, as unfortunately hormone replacement therapies have not been successful in controlling this effect and may reflect a larger feedback loop in play to protect females of reproductive age from CVD.
== Diagnosis ==
CVD is an umbrella term to encompass numerous conditions of the cardiovascular system. These can be chronic, i.e. ongoing issues, or acute, i.e. having a sudden onset. There are several different types of CVD, of which the most prevalent are:
=== Arrhythmia ===
Arrhythmia (also known as cardiac arrhythmias, heart arrhythmias, or dysrhythmias) is an irregular heartbeat. The heartbeat is the rate at which the heart beats: too slow (bradycardia) or fast (tachycardia). Although it is normal for the heartbeat to fluctuate at times of activity or rest, chronic consistent irregularity may cause not enough blood to reach all parts of the body, as well as put the individual at an increased risk of blood clotting. This can lead to other forms of CVD that may be life-threatening, such as a stroke, if the blood clot travels to the brain. As women typically have more rapid normal heart rates and receive differing electrocardiogram results than men, is important for practitioners to approach these cases differently than men to make a rapid diagnosis.
=== Coronary artery disease ===
Coronary artery disease (also known as coronary heart disease or ischemic heart disease) is a result of the build-up of substances in the walls of the vessels that provide blood to the heart and parts of the body, the coronary arteries. These substances, which can include cholesterol, cause the vessels to narrow, preventing blood from flowing smoothly through. As the heart compensates for this decrease in blood going out by pumping harder, this can lead to muscle weakness over time, subsequently leading to other life-threatening forms of CVD. The unusual symptoms seen in women with this condition include a sensation of crushing pressure and fatigue – feeling low on energy.
=== Congestive heart failure ===
Congestive heart failure (CHF) is where the heart muscle is unable to pump blood efficiently or at its normal capacity, preventing it from meeting our body's needs. This can cause fluid build-up in various organs, including the lungs and the heart itself, which also makes it life-threatening. Women and men tend to present similarly for CHF, although women frequently report having more of the symptoms, such as shortness of breath. As well, women typically reflect a normal level of amount of blood pumped from the heart, known as the ejection fraction, which makes diagnosis difficult as it is a crucial sign used to identify CHF.
=== Myocardial infarction ===
Heart attack/Myocardial infarction is when the blood flow to parts of the heart is blocked, due to various reasons including plaque build-up, this can cause the heart muscle to die from not being used. This can lead to permanent heart damage, and may even result in death if not treated efficiently. Women can present with different symptoms than men, including jaw pain and nausea/vomiting, thus it is important to be alert for unusual symptoms reported by women.
=== Peripheral arterial disease ===
Peripheral arterial disease: narrowing of the arteries that provide blood to the extremities due to plaque build-up. The lack of oxygen and nutrients can lead to tissue death and subsequent loss of the affected extremities. For this disease, women may or may not show signs, i.e. presenting asymptomatically, which can be a challenge in diagnosing.
=== Stroke ===
Stroke is a result of limiting or blocking the blood supply to a part of the brain, preventing the tissues from receiving the needed oxygen and nutrients to continue to function. This blockage can occur through a blood clot cutting off circulation through an artery (ischemic stroke) or a blood vessel leaking into the brain (hemorrhagic stroke).
=== Valvular heart disease ===
Valvular heart disease is any CVD caused by the valves, the door between the chambers of the heart; aortic, mitral, tricuspid, or pulmonary valve. These can be seen as either valve narrowing, also known as or stenosis, or regurgitation, incomplete closing of the valves which leads to leaking of blood backward through the chambers of the heart. Of these, mitral regurgitation followed by aortic stenosis are the most common forms found in women.
=== Diagnostic tests ===
Various tests are used to diagnose CVDs. These include scans, imaging, blood work, and other laboratory tests. Here are the most frequently used diagnostic tests:
Electrocardiogram (ECG or EKG): An ECG OR EKG monitors the wave representing the activity of the heart. Any discrepancies or changes in the typical patterns indicate a cardiac condition, such as CVD, affecting the individual.
Echocardiogram An echo provides an outline of the heart's function to help assess how well it is operating. This is often combined with a Doppler ultrasound to help track the blood flowing through the heart's chambers and valves.
Holter monitor: The Holter monitor is a portable device worn for a few days to monitor the heart's rhythm and any changes seen throughout the day. This allows for a more in-depth understanding of how well the heart is functioning and whether any irregular patterns are common or infrequent.
Cardiac magnetic resonance imaging (MRI): A cardiac MRI is an imaging machine that uses waves to develop a clear picture of your cardiovascular. It allows for a 3D image of the heart to be produced to allow for more thorough investigations of any issues.
Exercise stress test: This is a physical activity test for healthcare providers to see how an individual's heart functions during physical stress. The results from this test can demonstrate how to guide treatments for different conditions and even the efficacy of the current treatment in affected individuals.
Nuclear stress test: A nuclear stress test involves a trace amount of a radioactive substance put into your blood and is followed as it flows through the heart. The imaging machine uses this as a guide to create a picture of the heart and the flow. By following the flow of the substance, healthcare providers can better understand where the impairment is and in what form.
Cardiac catheterization and angiogram: In this procedure, a thin tube is inserted and threaded into the heart's chambers. This catheter allows for varying instruments to be inserted through it to either measure blood pressure, collect blood samples, or remove a sample of the heart's tissue for further testing.
Cardiac computerized tomography (CT) scan: This cardiac CT scan is an X-ray imaging machine that shows the blood supply to the heart and its arteries. This form of testing offers a non-invasive method to assess for narrowed or blocked vessels.
== Prevention ==
Depending on the risks associated based on age, type of disease, prognosis, pregnancy, or menopausal stages, the following primary preventions can be prescribed to women under the guidance and proper consultation with their healthcare provider.
Nutrition and exercise: Adjusting an individual's lifestyle through diet choices and increased physical activity has been shown to reduce the long-term negatives associated with most risk factors, including plaque buildup and weakening of the heart muscle. Exercise has been shown to strengthen the heart muscle, allowing it to pump greater blood volume at a regular pace, thus preventing overexertion and tissue damage. Additionally, a diet with low trans fat, saturated fat, refined carbohydrates, and sugar-sweetened beverages, and enriched with fruits, vegetables, whole grains, and unsaturated fats have reflected a significant reduction in the risk of developing.
Smoking cessation: The adverse effects associated with smoking have overwhelmingly shown to contribute to numerous risk factors that cause CVDs. These include contributing to atherosclerosis and contributing to blood clot formation. For patients who have a history of smoking, it is important to focus on quitting smoking to prevent additional damage and allow healing to begin.
== Treatment ==
As CVD is the primary result of long-term damage to the cardiovascular system, research has been unable to develop a way to cure it permanently. However, through the available therapies and prevention strategies, there are methods of bettering its effects and making it so the individual's quality of life remains. This can help manage and reduce further risk of developing life-threatening CVDs. The strategies that have been established in routine care include pharmacological therapies, lifestyle changes (including nutrition and exercise), surgery, and smoking cessation.
Pharmacological therapy: Various medications have been shown to mediate the negative symptoms of CVD. These typically work to lower the individual's blood pressure or widen their
Angiotensin II receptor blockers (ARB) & Angiotensin-converting enzyme inhibitors (ACEI): Both types of drugs work to limit the effects of angiotensin II, which raises blood pressure through a feedback loop in the kidneys. They have shown to greatly reduce the mortality associated with CVDs, with ACEIs being more effective than ARBs.
Aspirin: Aspirin, or ASA, promotes platelet function inhibition which reduces the risk of plaque buildup in vessels. This has been shown to alleviate the effects of vessel narrowing and blood flow impairment and prevent numerous CVDs. The Women's Health Study in 2005 also found that Aspirin reduced the risk of developing stroke, as well as myocardial infarction in some age groups, in the long term.
Beta-blockers: Beta-blockers impede the effects of adrenaline, also known as epinephrine, and subsequently slow the heart rate. This type of medication is generally prescribed for hypertension, a major risk factor for many CVDs. However, recent studies have shown that this medication may lead to a higher rate of heart failure than men, thus these medications should be taken with precaution.
Blood thinners: Blood thinners prevent clot formation, which contributes to vessel blockage, and is an effective method of anticoagulation that naturally plays an important role in cardiovascular system conditions. Low dose blood thinners have shown to significantly reduce the risk of developing stroke, heart attacks and even the mortality associated with CVD.
Calcium channel blockers: Calcium channel blockers are vasodilators, i.e. widen our arteries by regulating the calcium entering the cells, which lowers blood pressure. This is effective across all patient groups regardless of age and severity. This is even more effective in combination with other therapies and must be used in moderation to prevent chronic cell damage.
Diuretics: Diuretics assist the kidneys in clearing extra fluid present in the body to help maintain a steady blood volume for the heart to pump around. This helps bring blood pressure down, relieving pressure on the vessels and, consequently, the heart, thus making it a successful treatment for hypertension.
Hormone Replacement Therapy (HRT): HRT is taken by women to replace the declining estrogen levels during times of menopause. This is to control the cardio-protection offered by estrogen as women hit menopause and their levels decline.
Nitroglycerin and Other Nitrogen Oxides: Nitroglycerin and other nitrogen oxide use have been a strong influence on vasodilation, cell permeability, inflammation, and various other cardiovascular processes.
Statin therapy: This therapy aims to reduce levels of fat in the blood, specifically triglycerides and cholesterols. The proposed mechanisms for them are that they stabilize the plaque and reduce blood clots, which prevents most CVDs from developing. As primary prevention, they are significantly effective in patients at reducing the mortality and other life-threatening aspects of CVD.
Surgery: In severe cases of CVD, various forms of surgeries offer a more permanent treatment to replace or remake the affected vasculature to prevent this from reoccurring.
Coronary angioplasty: the insertion of a thin tube with a balloon on the end into the clogged artery which becomes inflated to widen the channel for blood to pass through. In some cases, a stent is left behind to maintain the opening and prevent further relapse of the artery.
Coronary artery bypass graft: using another blood vessel to replace and divert blood around an occluded vessel to maintain regular blood flow of nutrients and oxygen, and prevent tissue death.
Heart transplant: the replacement of an individual's heart that is affected by disease with one of a healthy donor.
== Epidemiology ==
CVD remains the most common cause of death for women, with approximately one-third of deaths worldwide attributed to CVD. In 2015, approximately 8.5 million women died from the disease.
In the United States, approximately 47.8 million women over the age of 20 were diagnosed with CVD between 2011 and 2014, and data from 2015 shows over 400,000 deaths due to CVD in women. While overall deaths from CVD are falling, the decline is slower in women, particular black women. The death rate for women with CVD surpasses that of men from CVD. In Europe, over half of the deaths in women are attributed to CVD. The death rate in some Eastern European countries is high, with over 500 deaths per 100,000 population attributed to CVD. Studies predict that in certain developing countries in Asia and Africa, women will account for a greater percentage of deaths related to CVD by 2040.
Cardiovascular disease is more prevalent in older populations. On average, women develop CVD approximately 10 years after their male counterparts. In the United States, approximately 6% of women over 20 have coronary heart disease. The highest prevalence of CVD is present in adults over the age of 80, and women and men have similar rates of disease after the age of 60.
== History ==
In the last few decades, the greatest changes have been made to acknowledge and focus on sex as an influential factor, thus establishing a great need to incorporate women into research. The events of significance are as follows:
In 1994, the United Nations stated that to establish a policy, there must be more sex-specific research done regarding treatment efficacy, thus encouraging researchers to pursue this line of inquiry.
The Food and Drug Administration (FDA) of the United States established their Office of Women's Health around this time, in 1991, concentrating on the underrepresentation of women in research, especially with CVD.
In 1993, the FDA created a guide for researchers to follow when including women in their studies, with an updated action plan for this published in 2014. It is important to note that the 1993 policy effectively reversed one established in 1977 that called on fertile women to be excluded from clinical trials, which had furthered the lack of women present in research at the time. This was done to address concerns of birth defects among infants and changes in estrogen and progesterone in postmenopausal women. Between 1988 and 1991, only 50% of the data analysis from trials that were not designed for women, accounted for the gender difference. It was assumed that the drugs given to men would work if prescribed to women.
The Institute of Medicine, also from the United States, moved forward with other milestones by publishing papers in 2001 and 2010 that recognized sex and gender for the first time as variables crucial in women's health.
Also in 2010, the Canadian Institutes of Health Research and the Canadian Institute of Gender and Health produced a tool to make incorporating sex and gender as variables easier in research.
This was followed shortly by the World Health Organization, which in 2014, promoted more gender-specific approaches to data analysis and health-inequality monitoring to ensure that a more sustainable approach was taken to this research.
In 2015, the National Institutes of Health and the United Nations both endorsed the necessity for gender-specific reporting or providing a reason for why it was not included in studies to ensure that researchers are held accountable. The United Nations specifically advocated for gender-sensitive strategies to be established by 2030.
Following in North America's footsteps, the League of European Research Universities proposed a list of suggestions for how to undertake gender-specific research for universities, governments, and more.
In 2016, two vital reports from Oxford and the United Nations, "Women's health: a new global agenda" and "Global Strategy for Women's, Children's, and Adolescents' Health (2016–2030)", were published, bringing much-needed attention to this issue.
The European Commission in 2016 provided a published guide for Horizon 2020 to address participation gaps for women in research and strategies to approach this.
These are not the only steps that have been taken to include women in the scientific community. There have been numerous policies and practices already established and continuing to be added to address the growing concern of CVD.
The Centers for Disease Control and Prevention division of heart disease and stroke prevention initiated the Well-Integrated Screening and Evaluation for WOMen Across the Nation (WISEWOMAN) awareness campaign in 1993. It was created to educate women on the risk factors associated with CVD and encourage healthier lifestyles to limit that risk.
In 1999, the AHA created the Guide to Preventive Cardiology for Women guideline to be used by the scientific community. This was the first of its kind in advising CVD management in women.
In 2004, the 1999 guideline was replaced by the Evidence-based guidelines for cardiovascular disease prevention in women by the American Heart Association. These guidelines underlined the importance of including women in research and challenged the notion that men and women are the same for CVD pathogenesis and these differences should encourage research and treatment to be approached accordingly. There were additional updates to this in 2007 and 2011.
The European Society of Cardiology and European Health Network in 2006 started the transnational project for the prevention and management of CVD, where its objective was to "Address the significant burden of CVD in Europe and to determine specific areas of intervention to contribute to preventing avoidable deaths and disability".
The Hellenic Cardiac Society, a European organization, followed this up with a national action plan for CVD projected for 2008 to 2012. Its aim, through the American Heart Association and many other guidelines, was to prevent CVD, primarily heart disease and stroke.
In 2011, the American House of Representatives put forward huge legislation called the "Heart Disease, Education, Analysis, Research, Treatment for Women Act or Heart for Women Act". This is intended to provide healthcare professionals and others with gender-specific information for appropriate medical treatments.
Also in 2011, the European Society of Cardiology released guidelines for the management of cardiovascular diseases during pregnancy: the Task Force on the Management of Cardiovascular Diseases During Pregnancy of the European Society of Cardiology. As pregnancy is a crucial unique factor to consider in women, these guidelines encouraged the scientific community to be able to tailor treatment plans accordingly. There was one update to this made in 2018.
The Journal of American College of Cardiology released a state-of-the-art review in 2017 called "Quality and equitable health care gaps for women: attributions to sex differences in cardiovascular medicine". This discussed the quality and equity of health care received by women.
In that same year, the released survey results that provided insight into the awareness within healthcare providers, and the gaps present in the research and clinical applications thus far.
== Causes ==
As there are a variety of CVDs and causes for CVD, there is no one specific mechanism that can cause CVD. However, there are general components shown to promote CVD development which can be found in a few pathways.
Reactive Oxygen Species (ROS): ROS are produced through numerous processes in our cells, including the induction of oxidative enzymes. The notable species involved in human cells include superoxide anion (O2−), hydroxyl radicals (OH), and hydrogen peroxide (H2O2). Not only does ROS physiologically have a role in controlling the vasculature through tone and endothelial and cardiac function, but it also is a vital player in inflammation, promoting apoptosis, angiogenesis and much more. Additionally, ROS causes oxidative stress within the body which, although may not be the sole proprietor, exacerbates the various factors that contribute to developing CVD, especially hypertension. Finally, ROS also act as signaling molecules to induce the body's inflammatory response to prevent any further damage from happening, which can lead to cell and tissue damage of the vasculature if not moderated appropriately.
Induction of oxidative enzymes: Cytosolic oxidases are another critical component in ROS production. These enzymes transfer electrons to create radicals or superoxide and increase oxidative stress. These enzymes have also shown to be present in various physiological stressful situations, which is associated with hypertension and other traditional risk factors negatively impacting CVD.
Xanthine oxidase (XO): XO, under normal circumstances, is an important enzyme in producing uric acid, released from the kidneys. These are typically located in the liver, however under times of stress from ROS, can increase its activity. This elevates vascular tone and even ROS production in the form of superoxide, thus contributing to higher oxidative stress.
Nitric oxide synthase: Nitric oxide synthases are known for producing nitric oxide, which has numerous functions in the body including vasodilation – i.e. widening of the vessels. Nitric oxide reacts with other forms of ROS to create potent oxidants, consequently causing other pathologic conditions, including heart failure and myocardial infarction. Moreover, this family of enzymes are crucial signaling molecules in regulating vascular tone and multiple other functions. Thus, any disruption in regular functioning impacts the vascular tone regulation.
NADH/NADPH oxidase: These enzymes contribute significantly to the amount of ROS present in the body. If in cardiac distress, an individual may induce excessive production, which may in turn lead to the pathogenesis of varying forms of tissue damage and cellular dysfunction in cardiac muscles.
Uncoupling of Mitochondrial electron transport chain: The mitochondria contribute to the levels of ROS we see within our body. Not only does it produce it, but is also vulnerable to the damage caused by ROS. It also is a key player of cell function in the cardiovascular system. With this damage to the mitochondria, the cell's function may be altered as not enough energy is being produced as needed, thus hindering the cell's ability to function optimally. These events create a disastrous feedback loop where further mitochondrial damage results in increased ROS production, which furthers the damage and contributes to the risk of developing CVD.
Immune cell infiltration and cytokines: A large contributing risk factor to the development of CVD is the production of plaque, also known as atherogenesis or atherosclerosis. This condition is known to involve multiple inflammatory cascades from the immune system responding to varying pathogens. Elevated inflammatory cytokines, including interleukin-6 and tumor necrosis factor-⍺, initiate a cascade conducive to plaque production.
== References ==
== Further reading ==
Go Red for Women
FDA Regulations, Guidance, and Reports related to Women's Health
Coronary heart disease in Western Collaborative Group Study. Final follow-up experience of 8 1/2 years
Women & Cardiovascular Diseases | Wikipedia/Cardiovascular_disease_in_women |
Hemolytic disease of the newborn (anti-Kell1) is the second most common cause of severe hemolytic disease of the newborn (HDN) after Rh disease. Anti-Kell1 is becoming relatively more important as prevention of Rh disease is also becoming more effective.
Hemolytic disease of the newborn (anti-Kell1) is caused by a mismatch between the Kell antigens of the mother and fetus. About 91% of the population are Kell1 negative and about 9% are Kell1 positive. A fraction of a percentage are homozygous for Kell1. Therefore, about 4.5% of babies born to a Kell1 negative mother are Kell1 positive.
The disease results when maternal antibodies to Kell1 are transferred to the fetus across the placental barrier, breaching immune privilege. These antibodies can cause severe anemia by interfering with the early proliferation of red blood cells as well as causing alloimmune hemolysis. Very severe disease can occur as early as 20 weeks gestation. Hydrops fetalis can also occur early. The finding of anti-Kell antibodies in an antenatal screening blood test (indirect Coombs test) is an indication for early referral to a specialist service for assessment, management and treatment.
== Presentation ==
=== Complications ===
High at birth or rapidly rising bilirubin
Prolonged hyperbilirubinemia
Bilirubin Induced Neuorlogical Dysfunction
Cerebral Palsy
Kernicterus
Neutropenia
Thrombocytopenia
Hemolytic Anemia - MUST NOT be treated with iron
Late onset anemia - Must NOT be treated with iron. Can persist up to 12 weeks after birth.
== Cause ==
Mothers who are negative for the Kell1 antigen develop antibodies after being exposed to red blood cells that are positive for Kell1. Over half of the cases of hemolytic disease of the newborn owing the anti-Kell antibodies are caused by multiple blood transfusions, with the remainder due to a previous pregnancy with a Kell1 positive baby.
== Mechanism ==
Hemolytic disease of the fetus and newborn (HDN) is a condition where the passage of maternal antibodies results in the hemolysis of fetal/neonatal red cells. The antibodies can be naturally occurring such as anti-A, and anti-B, or immune antibodies developed following a sensitizing event. Isoimmunization occurs when the maternal immune system is sensitized to red blood cell surface antigens. The most common causes of isoimmunization are blood transfusion, and fetal-maternal hemorrhage. The hemolytic process can result in anemia, hyperbilirubinemia, neonatal thrombocytopenia, and neonatal neutropenia. With the use of RhD Immunoprophylaxis, (commonly called Rhogam), the incidence of anti-D has decreased dramatically and other alloantibodies are now a major cause of HDN.
=== Antibody specific ===
Anti-Kell can cause severe anemia regardless of titer. Anti-Kell suppresses the bone marrow, by inhibiting the erythroid progenitor cells.
anti-Kell2, anti-Kell3 and anti-Kell4 antibodies
Hemolytic disease of the newborn can also be caused by anti-Kell2, anti-Kell3 and anti-Kell4 IgG antibodies. These are rarer and generally the disease is milder.
== Diagnosis ==
Testing for HDN involves blood work from both mother and father, and may also include assessment with amniocentesis and Middle Cerebral Artery scans.
=== Mother ===
Blood testing for the mother is called an Indirect Coombs Test (ICT) or an Indirect Agglutination Test (IAT). This test tells whether there are antibodies in the maternal plasma. If positive, the antibody is identified and given a titer. Titers of 1:4 or higher is considered critical for Kell (compared to 1:16 for most other antibodies) and is considered to confer a high risk of fetal anemia. Such high titers may be managed by weekly follow-up by obstetric ultrasound, assessing the peak systolic velocity of the fetal middle cerebral arterial (MCA), amniotic fluid volume, as well as fetal signs of anemia or hydrops.
=== Father ===
Blood is generally drawn from the father to help determine fetal antigen status. If he is homozygous for the antigen, there is a 100% chance of all offspring in the pairing to be positive for the antigen and at risk for HDN. If he is heterozygous, there is a 50% chance of offspring to be positive for the antigen. This test can help with knowledge for the current baby, as well as aid in the decision about future pregnancies. With RhD, the test is called the RhD genotype. With RhCE, and Kell antigen it is called an antigen phenotype.
=== Fetus ===
There are 3 possible ways to test the fetal antigen status. Cell-free DNA, Amniocentesis, and Chorionic Villus Sampling (CVS). Of the three, CVS is no longer used due to risk of worsening the maternal antibody response. Once antigen status has been determined, assessment may be done with MCA scans.
Cell-free DNA can be used the determine the Rh antigen of the fetus when the mother is Rh negative. Blood is taken from the mother during the pregnancy, and using PCR, can detect the K, C, c, D, and E alleles of fetal DNA. This blood test is non-invasive to the fetus and is an easy way of checking antigen status and risk of HDN. For patients in the United States, BillionToOne, Inc. based in Menlo Park, California offers a non-invasive prenatal test (NIPT) called Unity that can used to determine the fetal Rh antigen for mothers who are Rh negative. Because Unity is the only test in the world that uses next generation sequencing (NGS) to determine the fetal antigen, it is the only test that can screen for the fetal Rh antigen as early as the 10th week of gestation. For patients in the UK testing is offered through the International Blood Group Reference Laboratory in Bristol. Sanequin laboratory in Amsterdam, Netherlands also performs this test. The European tests for fetal Rh antigen utilize qPCR or real-time PCR technology; therefore, testing has to wait until at least the 20th week of gestation. Sensigene used to be offered by Sequenome to determine the fetal Rh antigen. However, this test has been taken off the market.
Amniocentesis is another recommended method for testing antigen status and risk for HDN. Fetal antigen status can be tested as early as 15 weeks by PCR of fetal cells.
CVS is possible as well to test fetal antigen status but is not recommended. CVS carries a higher risk of fetal maternal hemorrhage and can raise antibody titers, potentially worsening the antibody effect.
=== MCA scans ===
Middle cerebral artery - peak systolic velocity is changing the way sensitized pregnancies are managed. This test is done noninvasively with ultrasound. By measuring the peak velocity of blood flow in the middle cerebral artery, a MoM (multiple of the median) score can be calculated. MoM of 1.5 or greater indicates severe anemia and should be treated with intrauterine transfusion (IUT).
== Management ==
There are several intervention options available in early, mid and late pregnancies.
=== Early pregnancy ===
IVIG - IVIG stands for Intravenous Immunoglobulin. It is used in cases of previous loss, high maternal titers, known aggressive antibodies, and in cases where religion prevents blood transfusion. Ivig can be more effective than IUT alone. Fetal mortality was reduced by 36% in the IVIG and IUT group than in the IUT alone group. IVIG and plasmapheresis together can reduce or eliminate the need for an IUT.
Plasmapheresis - Plasmapheresis aims to decrease the maternal titer by direct plasma replacement. Plasmapheresis and IVIG together can even be used on women with previously hydropic fetuses and losses.
=== Mid to late pregnancy ===
IUT - Intrauterine Transfusion (IUT) is done either by intraperitoneal transfusion (IPT) or intravenous transfusion (IVT). IVT is preferred over IPT. IUTs are only done until 35 weeks. After that, the risk of an IUT is greater than the risk from post birth transfusion.
Steroids - Steroids are sometimes given to the mother before IUTs and early delivery to mature the fetal lungs.
Phenobarbital - Phenobarbital is sometimes given to the mother to help mature the fetal liver and reduce hyperbilirubinemia.
Early Delivery - Delivery can occur anytime after the age of viability. Emergency delivery due to failed IUT is possible, along with induction of labor at 35–38 weeks.
== After Birth ==
=== Testing ===
Coombs - after birth baby will have a direct coombs test run to confirm antibodies attached to the infant's red blood cells. This test is run from cord blood.
In some cases, the direct coombs will be negative but severe, even fatal HDN can occur. An indirect coombs needs to be run in cases of anti-C, anti-c, and anti-M. Anti-M also recommends antigen testing to rule out the presence of HDN.
Hgb - the infant's hemoglobin should be tested from cord blood.
Reticulocyte count - Reticulocytes are elevated when the infant is producing more blood to combat anemia. A rise in the retic count can mean that an infant may not need additional transfusions. Low retic is observed in infants treated with IUT and in those with HDN from anti-Kell
Neutrophils - as Neutropenia is one of the complications of HDN, the neutrophil count should be checked.
Thrombocytes - as thrombocytopenia is one of the complications of HDN, the thrombocyte count should be checked.
Bilirubin should be tested from cord blood.
Ferritin - because most infants affected by HDN have iron overload, a ferritin must be run before giving the infant any additional iron.
Newborn Screening Tests - Transfusion with donor blood during pregnancy or shortly after birth can affect the results of the Newborn Screening Tests. It is recommended to wait and retest 10–12 months after last transfusion. In some cases, DNA testing from saliva can be used to rule out certain conditions.
== Prevention ==
Suggestions have been made that women of child-bearing age or young girls should not be given a transfusion with Kell1 positive blood. Donated blood is not currently screened (in the U.S.A.) for the Kell blood group antigens as it is not considered cost effective at this time.
It has been hypothesized that IgG anti-Kell1 antibody injections would prevent sensitization to RBC surface Kell1 antigens in a similar way that IgG anti-D antibodies (Rho(D) Immune Globulin) are used to prevent Rh disease, but the methods for IgG anti-Kell 1 antibodies have not been developed at the present time.
== Treatment ==
Phototherapy - Phototherapy is used for cord bilirubin of 3 or higher. Some doctors use it at lower levels while awaiting lab results.
IVIG - IVIG has been used to successfully treat many cases of HDN. It has been used not only on anti-D, but on anti-E as well. IVIG can be used to reduce the need for exchange transfusion and to shorten the length of phototherapy. The AAP recommends "In isoimmune hemolytic disease, administration of intravenousγ-globulin (0.5-1 g/kg over 2 hours) is recommended if the TSB is rising despite intensive phototherapy or the TSB level is within 2 to 3 mg/dL (34-51 μmol/L) of the exchange level . If necessary, this dose can be repeated in 12 hours (evidence quality B: benefits exceed harms). Intravenous γ-globulin has been shown to reduce the need for exchange transfusions in Rh and ABO hemolytic disease."
Exchange transfusion - Exchange transfusion is used when bilirubin reaches either the high or medium risk lines on the nonogram provided by the American Academy of Pediatrics (Figure 4). Cord bilirubin >4 is also indicative of the need for exchange transfusion.
== Transfusion Reactions ==
Once a woman has antibodies, she is at high risk for a transfusion reaction. For this reason, she must carry a medical alert card at all times and inform all doctors of her antibody status.
"Acute hemolytic transfusion reactions may be either immune-mediated or nonimmune-mediated. Immune-mediated hemolytic transfusion reactions caused by immunoglobulin M (IgM) anti-A, anti-B, or anti-A,B typically result in severe, potentially fatal complement-mediated intravascular hemolysis. Immune-mediated hemolytic reactions caused by IgG, Rh, Kell, Duffy, or other non-ABO antibodies typically result in extravascular sequestration, shortened survival of transfused red cells, and relatively mild clinical reactions. Acute hemolytic transfusion reactions due to immune hemolysis may occur in patients who have no antibodies detectable by routine laboratory procedures"
Summary of transfusion reactions in the US
== See also ==
Coombs test
Hematology
Hemolytic anemia
Kell antigen system
Hemolytic disease of the newborn
== References ==
== Further reading ==
Geifmanholtzman, O; Wojtowycz, M; Kosmas, E; Artal, R (1997). "Female alloimmunization with antibodies known to cause hemolytic disease". Obstetrics & Gynecology. 89 (2): 272–5. doi:10.1016/S0029-7844(96)00434-6. PMID 9015034. S2CID 36953155.
Weiner, Carl P.; Widness, John A. (1996). "Decreased fetal erythropoiesis and hemolysis in Kell hemolytic anemia". American Journal of Obstetrics and Gynecology. 174 (2): 547–51. doi:10.1016/S0002-9378(96)70425-8. PMID 8623782.
== External links == | Wikipedia/Hemolytic_disease_of_the_newborn_(anti-Kell) |
Hypertensive heart disease includes a number of complications of high blood pressure that affect the heart. While there are several definitions of hypertensive heart disease in the medical literature, the term is most widely used in the context of the International Classification of Diseases (ICD) coding categories. The definition includes heart failure and other cardiac complications of hypertension when a causal relationship between the heart disease and hypertension is stated or implied on the death certificate. In 2013 hypertensive heart disease resulted in 1.07 million deaths as compared with 630,000 deaths in 1990.
According to ICD-10, hypertensive heart disease (I11), and its subcategories: hypertensive heart disease with heart failure (I11.0) and hypertensive heart disease without heart failure (I11.9) are distinguished from chronic rheumatic heart diseases (I05-I09), other forms of heart disease (I30-I52) and ischemic heart diseases (I20-I25). However, since high blood pressure is a risk factor for atherosclerosis and ischemic heart disease, death rates from hypertensive heart disease provide an incomplete measure of the burden of disease due to high blood pressure.
== Signs and symptoms ==
The symptoms and signs of hypertensive heart disease will depend on whether or not it is accompanied by heart failure. In the absence of heart failure, hypertension, with or without enlargement of the heart (left ventricular hypertrophy) is usually symptomless.
Symptoms, signs and consequences of congestive heart failure can include:
Fatigue
Irregular pulse or palpitations
Swelling of feet and ankles
Weight gain
Nausea
Shortness of breath
Difficulty sleeping flat in bed (orthopnea)
Bloating and abdominal pain
Greater need to urinate at night
An enlarged heart (cardiomegaly)
Left ventricular hypertrophy and left ventricular remodeling
Diminished coronary flow reserve and silent myocardial ischemia
Coronary heart disease and accelerated atherosclerosis
Heart failure with normal left ventricular ejection fraction (HFNEF), often termed diastolic heart failure
Atrial fibrillation, other cardiac arrhythmias, or sudden cardiac death
Heart failure can develop insidiously over time or patients can present acutely with acute heart failure or acute decompensated heart failure and pulmonary edema due to sudden failure of pump function of the heart. Sudden failure can be precipitated by a variety of causes, including myocardial ischemia, marked increases in blood pressure, or cardiac arrhythmias.
== Diagnosis ==
=== Differential diagnosis ===
Other conditions can share features with hypertensive heart disease and need to be considered in the differential diagnosis. For example:
Coronary artery disease or ischemic heart diseases due to atherosclerosis
Hypertrophic cardiomyopathy
Left ventricular hypertrophy in athletes
Congestive heart failure or heart failure with normal ejection fraction due to other causes
Atrial fibrillation or other disorders of cardiac rhythm due to other causes
Sleep apnea
== Prevention ==
Because there are no symptoms with high blood pressure, people can have the condition without knowing it. Diagnosing high blood pressure early can help prevent heart disease, stroke, eye problems, and chronic kidney disease.
The risk of cardiovascular disease and death can be reduced by lifestyle modifications, including dietary advice, promotion of weight loss and regular aerobic exercise, moderation of alcohol intake and cessation of smoking. Drug treatment may also be needed to control the hypertension and reduce the risk of cardiovascular disease, manage the heart failure, or control cardiac arrhythmias. Patients with hypertensive heart disease should avoid taking over the counter nonsteroidal anti-inflammatory drugs (NSAIDs), or cough suppressants, and decongestants containing sympathomimetics, unless otherwise advised by their physician as these can exacerbate hypertension and heart failure.
=== Blood pressure goals ===
According to JNC 7, BP goals should be as follows:
Less than 140/90mm Hg in patients with uncomplicated hypertension
Less than 130/85mm Hg in patients with diabetes and those with renal disease with less than 1g/24-hour proteinuria
Less than 125/75mm Hg in patients with renal disease and more than 1 g/24-hour proteinuria
== Treatment ==
The medical care of patients with hypertensive heart disease falls under 2 categories—
Treatment of hypertension
Prevention (and, if present, treatment) of heart failure or other cardiovascular disease
== Epidemiology ==
Hypertension or high blood pressure affects at least 26.4% of the world's population. Hypertensive heart disease is only one of several diseases attributable to high blood pressure. Other diseases caused by high blood pressure include ischemic heart disease, cancer, stroke, peripheral arterial disease, aneurysms and kidney disease. Hypertension increases the risk of heart failure by two or three-fold and probably accounts for about 25% of all cases of heart failure. In addition, hypertension precedes heart failure in 90% of cases, and the majority of heart failure in the elderly may be attributable to hypertension. Hypertensive heart disease was estimated to be responsible for 1.0 million deaths worldwide in 2004 (or approximately 1.7% of all deaths globally), and was ranked 13th in the leading global causes of death for all ages. A world map shows the estimated disability-adjusted life years per 100,000 inhabitants lost due to hypertensive heart disease in 2004.
=== Sex differences ===
There are more women than men with hypertension, and, although men develop hypertension earlier in life, hypertension in women is less well controlled. The consequences of high blood pressure in women are a major public health problem and hypertension is a more important contributory factor in heart attacks in women than men. Until recently women have been under-represented in clinical trials in hypertension and heart failure. Nevertheless, there is some evidence that the effectiveness of antihypertensive drugs differs between men and women and that treatment for heart failure may be less effective in women.
=== Ethnic differences ===
Studies in the US indicate that a disproportionate number of African Americans have hypertension compared with non-Hispanic whites and Mexican Americans, and that they have a greater burden of hypertensive heart disease. Heart failure is more common in people of African American ethnicity, mortality from heart failure is also consistently higher than in white patients, and it develops at an earlier age. Recent data suggests that rates of hypertension are increasing more rapidly in African Americans than other ethnic groups. The excess of high blood pressure and its consequences in African Americans is likely to contribute to their shorter life expectancy compared with white Americans.
== References == | Wikipedia/Hypertensive_heart_disease |
In ABO hemolytic disease of the newborn (also known as ABO HDN) maternal IgG antibodies with specificity for the ABO blood group system pass through the placenta to the fetal circulation where they can cause hemolysis of fetal red blood cells which can lead to fetal anemia and HDN. In contrast to Rh disease, about half of the cases of ABO HDN occur in a firstborn baby and ABO HDN does not become more severe after further pregnancies.
The ABO blood group system is the best known surface antigen system, expressed on a wide variety of human cells. For Caucasian populations about one fifth of all pregnancies have ABO incompatibility between the fetus and the mother, but only a very small minority develop symptomatic ABO HDN. The latter typically only occurs in mothers of blood group O, because they can produce enough IgG antibodies to cause hemolysis.
Although very uncommon, cases of ABO HDN have been reported in infants born to mothers with blood groups A and B.
== Presentation ==
=== Complications ===
High at birth or rapidly rising bilirubin
Prolonged hyperbilirubinemia
Bilirubin Induced Neurological Dysfunction
Cerebral Palsy
Kernicterus
Neutropenia
Thrombocytopenia
Hemolytic Anemia - MUST NOT be treated with iron
Late onset anemia - Must NOT be treated with iron. Can persist up to 12 weeks after birth.
== Causes ==
Environmental exposure
Anti-A and anti-B antibodies are usually IgM and do not pass through the placenta, but some mothers "naturally" have IgG anti-A or IgG anti-B antibodies, which can pass through the placenta. Exposure to A-antigens and B-antigens, which are both widespread in nature, usually leads to the production of IgM anti-A and IgM anti-B antibodies but occasionally IgG antibodies are produced.
Fetal-maternal transfusion
Some mothers may be sensitized by fetal-maternal transfusion of ABO incompatible red blood and produce immune IgG antibodies against the antigen they do not have and their baby does. For example, when a mother of genotype OO (blood group O) carries a fetus of genotype AO (blood group A) she may produce IgG anti-A antibodies. The father will either have blood group A, with genotype AA or AO or, more rarely, have blood group AB, with genotype AB.
Blood transfusion
It would be very rare for ABO sensitization to be due to therapeutic blood transfusion as a great deal of effort and checking is done to ensure that blood is ABO compatible between the recipient and the donor.
== Risk factors ==
In about a third of all ABO incompatible pregnancies maternal IgG anti-A or IgG anti-B antibodies pass through the placenta to the fetal circulation leading to a weakly positive direct Coombs test for the neonate's blood. However, ABO HDN is generally mild and short-lived and only occasionally severe because:
IgG anti-A (or IgG anti-B) antibodies that enter the fetal circulation from the mother find A (or B) antigens on many different fetal cell types, leaving fewer antibodies available for binding onto fetal red blood cells.
Fetal RBC surface A and B antigens are not fully developed during gestation and so there are a smaller number of antigenic sites on fetal RBCs.
== Diagnosis ==
Routine antenatal antibody screening blood tests (indirect Coombs test) do not screen for ABO HDN. If IgG anti-A or IgG anti-B antibodies are found in the pregnant woman's blood, they are not reported with the test results, because they do not correlate well with ABO HDN. Diagnosis is usually made by investigation of a newborn baby who has developed jaundice during the first week of life.
Testing
Coombs - after birth, the newborn will have a direct Coombs test run to confirm antibodies attached to the infant's red blood cells. This test is run from cord blood. In some cases, the direct Coombs will be negative but severe, even fatal HDN can occur. An indirect Coombs needs to be run in cases of anti-C, anti-c, or anti-M presence. In case of anti-M detection, it is also recommended to perform antigen testing to rule out the presence of HDN.
Hgb - the infant's hemoglobin should be tested from cord blood.
Reticulocyte count - Reticulocytes are elevated when the infant is producing more blood to combat anemia. A rise in the reticulocyte count can mean that an infant may not need additional transfusions. Low reticulocyte count is observed in infants treated with IUT and in those with HDN from anti-Kell
Neutrophils - as Neutropenia is one of the complications of HDN, the neutrophil count should be checked.
Thrombocytes - as thrombocytopenia is one of the complications of HDN, the thrombocyte count should be checked.
Bilirubin should be tested from cord blood.
Ferritin - because most infants affected by HDN have iron overload, ferritin levels must be measured before giving the infant any additional iron.
Newborn Screening Tests - Transfusion with donor blood during pregnancy or shortly after birth can affect the results of the Newborn Screening Tests. It is recommended to wait and retest 10–12 months after the last transfusion. In some cases, DNA testing from saliva can be used to rule out certain conditions.
== Treatment ==
The antibodies in ABO HDN cause anemia due to destruction of fetal red blood cells and jaundice due to the rise in blood levels of bilirubin a by-product of hemoglobin break down. If the anemia is severe, it can be treated with a blood transfusion, however this is rarely needed. On the other hand, neonates have underdeveloped livers that are unable to process large amounts of bilirubin and a poorly developed blood–brain barrier that is unable to block bilirubin from entering the brain. This can result in kernicterus if left unchecked. If the bilirubin level is sufficiently high as to cause worry, it can be lowered via phototherapy in the first instance or an exchange transfusion if severely elevated.
Phototherapy - Phototherapy is used for cord bilirubin of 3 or higher. Some doctors use it at lower levels while awaiting lab results.
IVIG - Intravenous Immunoglobulin therapy (IVIG) has been used to successfully treat many cases of HDN. It has been used not only on anti-D, but on anti-E as well. IVIG can be used to reduce the need for exchange transfusion and to shorten the length of phototherapy. The AAP recommends "In isoimmune hemolytic disease, administration of intravenous γ-globulin (0.5-1 g/kg over 2 hours) is recommended if the TSB is rising despite intensive phototherapy or the TSB level is within 2 to 3 mg/dL (34-51 μmol/L) of the exchange level . If necessary, this dose can be repeated in 12 hours (evidence quality B: benefits exceed harms). Intravenous γ-globulin has been shown to reduce the need for exchange transfusions in Rh and ABO hemolytic disease."
Exchange transfusion - Exchange transfusion is used when bilirubin reaches either the high or medium risk lines on the normogram provided by the American Academy of Pediatrics (Figure 4). Cord bilirubin >4 is also indicative of the need for exchange transfusion.
== See also ==
Coombs test
Hemolytic anemia
Hematology
== References ==
== External links == | Wikipedia/Hemolytic_disease_of_the_newborn_(ABO) |
Paget–Schroetter disease (which evolved from a venous thoracic outlet syndrome) is a form of upper extremity deep vein thrombosis (DVT), a medical condition in which blood clots form in the deep veins of the arms. These DVTs typically occur in the axillary and/or subclavian veins.
== Signs and symptoms ==
The condition is relatively rare. It usually presents in young and otherwise healthy patients, and also occurs more often in males than females. The syndrome also became known as "effort-induced thrombosis" in the 1960s, as it has been reported to occur after vigorous activity, though it can also occur due to anatomic abnormality such as clavicle impingement or spontaneously. It may develop as a sequela of thoracic outlet syndrome. It is differentiated from secondary causes of upper extremity thrombosis caused by intravascular catheters. Paget–Schroetter syndrome was described once for a viola player who suddenly increased practice time 10-fold, creating enough repetitive pressure against the brachiocephalic and external jugular veins to cause thrombosis.
Symptoms may include sudden onset of pain, warmth, redness, blueness and swelling in the arm. Diagnosis is usually confirmed with an ultrasound. These DVTs have the potential to cause a pulmonary embolism.
== Diagnosis ==
Duplex ultrasonography
MR Venography
== Prevention ==
Prevention of Paget–Schroetter disease can be accomplished by gradual increases in activity and by avoiding strenuous upper extremity activity.
== Treatment ==
The traditional treatment for thrombosis is the same as for a lower extremity DVT, and involves systemic anticoagulation to prevent a pulmonary embolus. Some have also recommended thrombolysis with catheter directed alteplase or mechanical thrombectomy with a large bore catheter and manual aspiration providing definitive intervention with an endovascular approach. If there is thoracic outlet syndrome or other anatomical cause then surgery can be considered to correct the underlying defect.
== History ==
The condition is named after two men. James Paget first proposed the idea of venous thrombosis causing upper extremity pain and swelling, and Leopold von Schrötter later linked the clinical syndrome to thrombosis of the axillary and subclavian veins.
== References ==
== External links == | Wikipedia/Paget–Schroetter_disease |
Electrocardiography is the process of producing an electrocardiogram (ECG or EKG), a recording of the heart's electrical activity through repeated cardiac cycles. It is an electrogram of the heart which is a graph of voltage versus time of the electrical activity of the heart using electrodes placed on the skin. These electrodes detect the small electrical changes that are a consequence of cardiac muscle depolarization followed by repolarization during each cardiac cycle (heartbeat). Changes in the normal ECG pattern occur in numerous cardiac abnormalities, including:
Cardiac rhythm disturbances, such as atrial fibrillation and ventricular tachycardia;
Inadequate coronary artery blood flow, such as myocardial ischemia and myocardial infarction;
and electrolyte disturbances, such as hypokalemia.
Traditionally, "ECG" usually means a 12-lead ECG taken while lying down as discussed below.
However, other devices can record the electrical activity of the heart such as a Holter monitor but also some models of smartwatch are capable of recording an ECG.
ECG signals can be recorded in other contexts with other devices.
In a conventional 12-lead ECG, ten electrodes are placed on the patient's limbs and on the surface of the chest. The overall magnitude of the heart's electrical potential is then measured from twelve different angles ("leads") and is recorded over a period of time (usually ten seconds). In this way, the overall magnitude and direction of the heart's electrical depolarization is captured at each moment throughout the cardiac cycle.
There are three main components to an ECG:
The P wave, which represents depolarization of the atria.
The QRS complex, which represents depolarization of the ventricles.
The T wave, which represents repolarization of the ventricles.
During each heartbeat, a healthy heart has an orderly progression of depolarization that starts with pacemaker cells in the sinoatrial node, spreads throughout the atrium, and passes through the atrioventricular node down into the bundle of His and into the Purkinje fibers, spreading down and to the left throughout the ventricles. This orderly pattern of depolarization gives rise to the characteristic ECG tracing. To the trained clinician, an ECG conveys a large amount of information about the structure of the heart and the function of its electrical conduction system. Among other things, an ECG can be used to measure the rate and rhythm of heartbeats, the size and position of the heart chambers, the presence of any damage to the heart's muscle cells or conduction system, the effects of heart drugs, and the function of implanted pacemakers.
== Medical uses ==
The overall goal of performing an ECG is to obtain information about the electrical functioning of the heart. Medical uses for this information are varied and often need to be combined with knowledge of the structure of the heart and physical examination signs to be interpreted. Some indications for performing an ECG include the following:
Chest pain or suspected myocardial infarction (heart attack), such as ST elevated myocardial infarction (STEMI) or non-ST elevated myocardial infarction (NSTEMI)
Symptoms such as shortness of breath, murmurs, fainting, seizures, funny turns, or arrhythmias including new onset palpitations or monitoring of known cardiac arrhythmias
Medication monitoring (e.g., drug-induced QT prolongation, digoxin toxicity) and management of overdose (e.g., tricyclic overdose)
Electrolyte abnormalities, such as hyperkalemia
Perioperative monitoring in which any form of anesthesia is involved (e.g., monitored anesthesia care, general anesthesia). This includes preoperative assessment and intraoperative and postoperative monitoring.
Cardiac stress testing
Computed tomography angiography (CTA) and magnetic resonance angiography (MRA) of the heart (ECG is used to "gate" the scanning so that the anatomical position of the heart is steady)
Clinical cardiac electrophysiology, in which a catheter is inserted through the femoral vein and can have several electrodes along its length to record the direction of electrical activity from within the heart.
ECGs can be recorded as short intermittent tracings or continuous ECG monitoring. Continuous monitoring is used for critically ill patients, patients undergoing general anesthesia, and patients who have an infrequently occurring cardiac arrhythmia that would unlikely be seen on a conventional ten-second ECG. Continuous monitoring can be conducted by using Holter monitors, internal and external defibrillators and pacemakers, and/or biotelemetry.
=== Screening ===
For adults, evidence does not support the use of ECGs among those without symptoms or at low risk of cardiovascular disease as an effort for prevention. This is because an ECG may falsely indicate the existence of a problem, leading to misdiagnosis, the recommendation of invasive procedures, and overtreatment. However, persons employed in certain critical occupations, such as aircraft pilots, may be required to have an ECG as part of their routine health evaluations. Hypertrophic cardiomyopathy screening may also be considered in adolescents as part of a sports physical out of concern for sudden cardiac death.
== Electrocardiograph machines ==
Mechanical cardiographs (apex cardiogram), developed in the 19th century, recorded heart movements by transmitting heart or chest wall motions to a spring and air chamber system. A writing lever traced these movements onto a smoked rotating cylinder, producing a cardiogram. Their accuracy was limited, as they captured all body movements, introducing errors.
Modern day electrocardiograms are recorded by machines that consist of a set of electrodes connected to a central unit.
In the late 19th century, scientists discovered the heart’s electrical activity, leading to the electrocardiograph’s development. Willem Einthoven’s 1903 string galvanometer enabled precise measurement of these signals, revolutionizing cardiography. He received the 1924 Nobel Prize for this work.
Early ECG machines were constructed with analog electronics, where the signal drove a motor to print out the signal onto paper. Today, electrocardiographs use analog-to-digital converters to convert the electrical activity of the heart to a digital signal. Many ECG machines are now portable and commonly include a screen, keyboard, and printer on a small wheeled cart. Recent advancements in electrocardiography include developing even smaller devices for inclusion in fitness trackers and smart watches. These smaller devices often rely on only two electrodes to deliver a single lead I. Portable twelve-lead devices powered by batteries are also available.
Recording an ECG is a safe and painless procedure. The machines are powered by mains power but they are designed with several safety features including an earthed (ground) lead.
Other features include:
Defibrillation protection: any ECG used in healthcare may be attached to a person who requires defibrillation and the ECG needs to protect itself from this source of energy.
Electrostatic discharge is similar to defibrillation discharge and requires voltage protection up to 18,000 volts.
Additionally, circuitry called the right leg driver can be used to reduce common-mode interference (typically the 50 or 60 Hz mains power).
ECG voltages measured across the body are very small. This low voltage necessitates a low noise circuit, instrumentation amplifiers, and electromagnetic shielding.
Simultaneous lead recordings: earlier designs recorded each lead sequentially, but current models record multiple leads simultaneously.
Most modern ECG machines include automated interpretation algorithms. This analysis calculates features such as the PR interval, QT interval, corrected QT (QTc) interval, PR axis, QRS axis, rhythm and more. The results from these automated algorithms are considered "preliminary" until verified and/or modified by expert interpretation. Despite recent advances, computer misinterpretation remains a significant problem and can result in clinical mismanagement.
=== Cardiac monitors ===
Besides the standard electrocardiograph machine, there are other devices that can record ECG signals. Portable devices have existed since the Holter monitor was introduced in 1962.
Traditionally, these monitors have used electrodes with patches on the skin to record the ECG, but new devices can stick to the chest as a single patch without need for wires, developed by Zio (Zio XT), TZ Medical (Trident), Philips (BioTel) and BardyDx (CAM) among many others.
Implantable devices such as the artificial cardiac pacemaker and implantable cardioverter-defibrillator are capable of measuring a "far field" signal between the leads in the heart and the implanted battery/generator that resembles an ECG signal (technically, the signal recorded in the heart is called an electrogram, which is interpreted differently).
The development of the Holter monitor led to the creation of the implantable loop recorder, which performs the same function but is an implantable device with batteries that last for years.
Additionally, there are available various Arduino kits with ECG sensor modules and smartwatch devices that are capable of recording an ECG signal as well, such as with the 4th generation Apple Watch (2018), Samsung Galaxy Watch 4 (2021) and newer devices.
== Electrodes and leads ==
Electrodes are the actual conductive pads attached to the body surface. Any pair of electrodes can measure the electrical potential difference between the two corresponding locations of attachment. Such a pair forms a lead. However, "leads" can also be formed between a physical electrode and a virtual electrode, which is the average of numerous leads. All clinical ECGs use Wilson's central terminal (WCT) as the virtual electrode from which the precordial leads are measured, whose potential is defined as the average potential measured by the three standard limb leads.
Commonly, 10 electrodes attached to the body are used to form 12 ECG leads, with each lead measuring a specific electrical potential difference.
=== 12-Lead ECG ===
Leads are broken down into three types: limb; augmented limb; and precordial or chest. The 12-lead ECG has a total of three limb leads and three augmented limb leads arranged like spokes of a wheel in the coronal plane (vertical), and six precordial leads or chest leads that lie on the perpendicular transverse plane (horizontal).
Electrodes should be placed in standard positions, with 'left' or 'right' referring to anatomical directions, being the patient's left or right. Exceptions due to emergency or other issues should be recorded to avoid erroneous analysis.
The 12 standard ECG leads and electrodes are listed below. All leads are effectively bipolar, with one positive and one negative electrode; the term "unipolar" is not true, nor useful.
Two types of electrodes in common use are a flat paper-thin sticker and a self-adhesive circular pad.
The former are typically used in a single ECG recording while the latter are for continuous recordings as they stick longer.
Each electrode consists of an electrically conductive electrolyte gel and a silver/silver chloride conductor.
The gel typically contains potassium chloride – sometimes silver chloride as well – to permit electron conduction from the skin to the wire and to the electrocardiogram.
=== Virtual Electrode ===
The virtual electrode is used to obtain useful measurements from the precordial leads, and also allows the creation of the augmented limb leads.
The virtual electrode is known as Wilson's Central Terminal (WCT). For the precordial leads, WCT is formed by averaging the three standard limb leads (I, II, and III):
V
W
=
1
3
(
R
A
+
L
A
+
L
L
)
{\displaystyle V_{W}={\frac {1}{3}}(RA+LA+LL)}
WCT is therefore a virtual electrode which sits slightly posteriorly to the heart. It is a useful point, from which the electrical potential of the precordial leads is measured.
WCT used to be used as a reference for the virtual limb leads, however use in this way produced leads with very small amplitudes. Goldberger's modification is now used to produce each augmented limb lead, aVF, aVR, and aVL, which produces 50% larger amplitude leads than the standard WCT. Goldberger's WCT is formed according to the following:
a
V
R
=
L
A
+
L
L
2
{\displaystyle aVR={\frac {LA+LL}{2}}}
a
V
L
=
R
A
+
L
L
2
{\displaystyle aVL={\frac {RA+LL}{2}}}
a
V
F
=
R
A
+
L
A
2
{\displaystyle aVF={\frac {RA+LA}{2}}}
In a 12-lead ECG, all leads except the limb leads are assumed to be unipolar (aVR, aVL, aVF, V1, V2, V3, V4, V5, and V6).
The measurement of a voltage requires two contacts and so, electrically, the unipolar leads are measured from the common lead (negative) and the unipolar lead (positive).
This averaging for the common lead and the abstract unipolar lead concept makes for a more challenging understanding and is complicated by sloppy usage of "lead" and "electrode".
In fact, instead of being a constant reference, VW has a value that fluctuates throughout the heart cycle. It also does not truly represent the center-of-heart potential due to the body parts the signals travel through. Because voltage is by definition a bipolar measurement between two points, describing an electrocardiographic lead as "unipolar" makes little sense electrically and should be avoided. The American Heart Association states "All leads are effectively 'bipolar,' and the term 'unipolar' in description of the augmented limb leads and the precordial leads lacks precision."
=== Limb leads ===
Leads I, II and III are called the limb leads. The electrodes that form these signals are located on the limbs – one on each arm and one on the left leg. The limb leads form the points of what is known as Einthoven's triangle.
Lead I is the voltage between the (positive) left arm (LA) electrode and right arm (RA) electrode:
I
=
L
A
−
R
A
{\displaystyle I=LA-RA}
Lead II is the voltage between the (positive) left leg (LL) electrode and the right arm (RA) electrode:
I
I
=
L
L
−
R
A
{\displaystyle II=LL-RA}
Lead III is the voltage between the (positive) left leg (LL) electrode and the left arm (LA) electrode:
I
I
I
=
L
L
−
L
A
{\displaystyle III=LL-LA}
=== Augmented limb leads ===
Leads aVR, aVL, and aVF are the augmented limb leads. They are derived from the same three electrodes as leads I, II, and III, but they use Goldberger's central terminal as their negative pole. Goldberger's central terminal is a combination of inputs from two limb electrodes, with a different combination for each augmented lead. It is referred to immediately below as "the negative pole".
Lead augmented vector right (aVR) has the positive electrode on the right arm. The negative pole is a combination of the left arm electrode and the left leg electrode:
a
V
R
=
R
A
−
1
2
(
L
A
+
L
L
)
=
3
2
(
R
A
−
V
W
)
{\displaystyle aVR=RA-{\frac {1}{2}}(LA+LL)={\frac {3}{2}}(RA-V_{W})}
Lead augmented vector left (aVL) has the positive electrode on the left arm. The negative pole is a combination of the right arm electrode and the left leg electrode:
a
V
L
=
L
A
−
1
2
(
R
A
+
L
L
)
=
3
2
(
L
A
−
V
W
)
{\displaystyle aVL=LA-{\frac {1}{2}}(RA+LL)={\frac {3}{2}}(LA-V_{W})}
Lead augmented vector foot (aVF) has the positive electrode on the left leg. The negative pole is a combination of the right arm electrode and the left arm electrode:
a
V
F
=
L
L
−
1
2
(
R
A
+
L
A
)
=
3
2
(
L
L
−
V
W
)
{\displaystyle aVF=LL-{\frac {1}{2}}(RA+LA)={\frac {3}{2}}(LL-V_{W})}
Together with leads I, II, and III, augmented limb leads aVR, aVL, and aVF form the basis of the hexaxial reference system, which is used to calculate the heart's electrical axis in the frontal plane.
Older versions of the nodes (VR, VL, VF) use Wilson's central terminal as the negative pole, but the amplitude is too small for the thick lines of old ECG machines. The Goldberger terminals scale up (augments) the Wilson results by 50%, at the cost of sacrificing physical correctness by not having the same negative pole for all three.
=== Precordial leads ===
The precordial leads lie in the transverse (horizontal) plane, perpendicular to the other six leads. The six precordial electrodes act as the positive poles for the six corresponding precordial leads: (V1, V2, V3, V4, V5, and V6). Wilson's central terminal is used as the negative pole. Recently, unipolar precordial leads have been used to create bipolar precordial leads that explore the right to left axis in the horizontal plane.
=== Specialized leads ===
Additional electrodes may rarely be placed to generate other leads for specific diagnostic purposes. Right-sided precordial leads may be used to better study pathology of the right ventricle or for dextrocardia (and are denoted with an R (e.g., V5R). Posterior leads (V7 to V9) may be used to demonstrate the presence of a posterior myocardial infarction. The Lewis lead or S5-lead (requiring an electrode at the right sternal border in the second intercostal space) can be used to better detect atrial activity in relation to that of the ventricles.
An esophageal lead can be inserted to a part of the esophagus where the distance to the posterior wall of the left atrium is only approximately 5–6 mm (remaining constant in people of different age and weight). An esophageal lead avails for a more accurate differentiation between certain cardiac arrhythmias, particularly atrial flutter, AV nodal reentrant tachycardia and orthodromic atrioventricular reentrant tachycardia. It can also evaluate the risk in people with Wolff-Parkinson-White syndrome, as well as terminate supraventricular tachycardia caused by re-entry.
An intracardiac electrogram (ICEG) is essentially an ECG with some added intracardiac leads (that is, inside the heart). The standard ECG leads (external leads) are I, II, III, aVL, V1, and V6. Two to four intracardiac leads are added via cardiac catheterization. The word "electrogram" (EGM) without further specification usually means an intracardiac electrogram.
=== Lead locations on an ECG report ===
A standard 12-lead ECG report (an electrocardiograph) shows a 2.5 second tracing of each of the twelve leads. The tracings are most commonly arranged in a grid of four columns and three rows. The first column is the limb leads (I, II, and III), the second column is the augmented limb leads (aVR, aVL, and aVF), and the last two columns are the precordial leads (V1 to V6).
Additionally, a rhythm strip may be included as a fourth or fifth row.
The timing across the page is continuous and notes tracings of the 12 leads for the same time period.
In other words, if the output were traced by needles on paper, each row would switch which leads as the paper is pulled under the needle.
For example, the top row would first trace lead I, then switch to lead aVR, then switch to V1, and then switch to V4, and so none of these four tracings of the leads are from the same time period as they are traced in sequence through time.
=== Contiguity of leads ===
Each of the 12 ECG leads records the electrical activity of the heart from a different angle, and therefore align with different anatomical areas of the heart. Two leads that look at neighboring anatomical areas are said to be contiguous.
In addition, any two precordial leads next to one another are considered to be contiguous. For example, though V4 is an anterior lead and V5 is a lateral lead, they are contiguous because they are next to one another.
== Electrophysiology ==
The study of the conduction system of the heart is called cardiac electrophysiology (EP). An EP study is performed via a right-sided cardiac catheterization: a wire with an electrode at its tip is inserted into the right heart chambers from a peripheral vein, and placed in various positions in close proximity to the conduction system so that the electrical activity of that system can be recorded.
Standard catheter positions for an EP study include "high right atrium" or hRA near the sinus node, a "His" across the septal wall of the tricuspid valve to measure bundle of His, a "coronary sinus" into the coronary sinus, and a "right ventricle" in the apex of the right ventricle.
== Interpretation ==
Interpretation of the ECG is fundamentally about understanding the electrical conduction system of the heart.
Normal conduction starts and propagates in a predictable pattern, and deviation from this pattern can be a normal variation or be pathological.
An ECG does not equate with mechanical pumping activity of the heart; for example, pulseless electrical activity produces an ECG that should pump blood but no pulses are felt (and constitutes a medical emergency and CPR should be performed).
Ventricular fibrillation produces an ECG but is too dysfunctional to produce a life-sustaining cardiac output. Certain rhythms are known to have good cardiac output and some are known to have bad cardiac output.
Ultimately, an echocardiogram or other anatomical imaging modality is useful in assessing the mechanical function of the heart.
Like all medical tests, what constitutes "normal" is based on population studies. The heartrate range of between 60 and 100 beats per minute (bpm) is considered normal since data shows this to be the usual resting heart rate.
=== Theory ===
Interpretation of the ECG is ultimately that of pattern recognition.
In order to understand the patterns found, it is helpful to understand the theory of what ECGs represent.
The theory is rooted in electromagnetics and boils down to the four following points:
depolarization of the heart toward the positive electrode produces a positive deflection
depolarization of the heart away from the positive electrode produces a negative deflection
repolarization of the heart toward the positive electrode produces a negative deflection
repolarization of the heart away from the positive electrode produces a positive deflection
Thus, the overall direction of depolarization and repolarization produces positive or negative deflection on each lead's trace.
For example, depolarizing from right to left would produce a positive deflection in lead I because the two vectors point in the same direction.
In contrast, that same depolarization would produce minimal deflection in V1 and V2 because the vectors are perpendicular, and this phenomenon is called isoelectric.
Normal rhythm produces four entities – a P wave, a QRS complex, a T wave, and a U wave – that each have a fairly unique pattern.
The P wave represents atrial depolarization.
The QRS complex represents ventricular depolarization.
The T wave represents ventricular repolarization.
The U wave represents papillary muscle repolarization.
Changes in the structure of the heart and its surroundings (including blood composition) change the patterns of these four entities.
The U wave is not typically seen and its absence is generally ignored. Atrial repolarization is typically hidden in the much more prominent QRS complex and normally cannot be seen without additional, specialized electrodes.
=== Background grid ===
ECGs are normally printed on a grid.
The horizontal axis represents time and the vertical axis represents voltage.
The standard values on this grid are shown in the adjacent image at 25mm/sec (or 40ms per mm):
A small box is 1 mm × 1 mm and represents 0.1 mV × 0.04 seconds.
A large box is 5 mm × 5 mm and represents 0.5 mV × 0.20 seconds.
The "large" box is represented by a heavier line weight than the small boxes.
The standard printing speed in the United States is 25 mm per sec (5 big boxes per second), but in other countries it can be 50 mm per sec.
Faster speeds such as 100 and 200 mm per sec are used during electrophysiology studies.
Not all aspects of an ECG rely on precise recordings or having a known scaling of amplitude or time.
For example, determining if the tracing is a sinus rhythm only requires feature recognition and matching, and not measurement of amplitudes or times (i.e., the scale of the grids are irrelevant).
An example to the contrary, the voltage requirements of left ventricular hypertrophy require knowing the grid scale.
=== Rate and rhythm ===
In a normal heart, the heart rate is the rate at which the sinoatrial node depolarizes since it is the source of depolarization of the heart.
Heart rate, like other vital signs such as blood pressure and respiratory rate, change with age.
In adults, a normal heart rate is between 60 and 100 bpm (normocardic), whereas it is higher in children.
A heart rate below normal is called "bradycardia" (<60 in adults) and above normal is called "tachycardia" (>100 in adults).
A complication of this is when the atria and ventricles are not in synchrony and the "heart rate" must be specified as atrial or ventricular (e.g., the ventricular rate in ventricular fibrillation is 300–600 bpm, whereas the atrial rate can be normal [60–100] or faster [100–150]).
In normal resting hearts, the physiologic rhythm of the heart is normal sinus rhythm (NSR).
Normal sinus rhythm produces the prototypical pattern of P wave, QRS complex, and T wave.
Generally, deviation from normal sinus rhythm is considered a cardiac arrhythmia.
Thus, the first question in interpreting an ECG is whether or not there is a sinus rhythm.
A criterion for sinus rhythm is that P waves and QRS complexes appear 1-to-1, thus implying that the P wave causes the QRS complex.
Once sinus rhythm is established, or not, the second question is the rate.
For a sinus rhythm, this is either the rate of P waves or QRS complexes since they are 1-to-1.
If the rate is too fast, then it is sinus tachycardia, and if it is too slow, then it is sinus bradycardia.
If it is not a sinus rhythm, then determining the rhythm is necessary before proceeding with further interpretation.
Some arrhythmias with characteristic findings:
Absent P waves with "irregularly irregular" QRS complexes are the hallmark of atrial fibrillation.
A "saw tooth" pattern with QRS complexes is the hallmark of atrial flutter.
A sine wave pattern is the hallmark of ventricular flutter.
Absent P waves with wide QRS complexes and a fast heart rate are ventricular tachycardia.
Determination of rate and rhythm is necessary in order to make sense of further interpretation.
=== Axis ===
The heart has several axes, but the most common by far is the axis of the QRS complex (references to "the axis" imply the QRS axis).
Each axis can be computationally determined to result in a number representing degrees of deviation from zero, or it can be categorized into a few types.
The QRS axis is the general direction of the ventricular depolarization wavefront (or mean electrical vector) in the frontal plane.
It is often sufficient to classify the axis as one of three types: normal, left deviated, or right deviated.
Population data shows that a normal QRS axis is from −30° to 105°, with 0° being along lead I and positive being inferior and negative being superior (best understood graphically as the hexaxial reference system).
Beyond +105° is right axis deviation and beyond −30° is left axis deviation (the third quadrant of −90° to −180° is very rare and is an indeterminate axis).
A shortcut for determining if the QRS axis is normal is if the QRS complex is mostly positive in lead I and lead II (or lead I and aVF if +90° is the upper limit of normal).
The normal QRS axis is generally down and to the left, following the anatomical orientation of the heart within the chest. An abnormal axis suggests a change in the physical shape and orientation of the heart or a defect in its conduction system that causes the ventricles to depolarize in an abnormal way.
The extent of a normal axis can be +90° or 105° depending on the source.
=== Amplitudes and intervals ===
All of the waves on an ECG tracing and the intervals between them have a predictable time duration, a range of acceptable amplitudes (voltages), and a typical morphology. Any deviation from the normal tracing is potentially pathological and therefore of clinical significance.
For ease of measuring the amplitudes and intervals, an ECG is printed on graph paper at a standard scale: each 1 mm (one small box on the standard 25mm/s ECG paper) represents 40 milliseconds of time on the x-axis, and 0.1 millivolts on the y-axis.
=== Time-Frequency Analysis in ECG Signal Processing ===
In electrocardiogram (ECG) signal processing, Time-Frequency Analysis (TFA) is an important technique used to reveal how the frequency characteristics of ECG signals change over time, especially in non-stationary signals such as arrhythmias or transient cardiac events.
Common Methods for Time-Frequency Analysis
Steps for Time-Frequency Analysis
Step1: Preprocessing
Signal Denoising: Use wavelet denoising, band-pass filtering (0.5–50 Hz), or Principal Component Analysis (PCA) to remove electromyographic (EMG) noise.
Signal Segmentation: Segment the signal based on heartbeat cycles (e.g., R-wave detection).
Step2: Select an Appropriate TFA Method
Choose methods such as STFT, WT, or HHT based on the application requirements.
Step3: Compute the Time-Frequency Spectrum
Calculate the time-frequency distribution using the selected method to generate a time-frequency representation.
Step4: Feature Extraction
Extract power features from specific frequency bands, such as low-frequency (LF: 0.04–0.15 Hz) and high-frequency (HF: 0.15–0.4 Hz) components.
Step5: Pattern Recognition or Diagnosis
Apply machine learning or deep learning models to detect or classify cardiac events based on the time-frequency features.
Application Scenarios
Heart Rate Variability Analysis (HRV):
Time-frequency analysis helps to separate sympathetic and parasympathetic nervous system activity.
Atrial Fibrillation Detection:
Analyze the time-frequency characteristics of atrial activity.
Ventricular Fibrillation Analysis:
Detect time-frequency changes in high-frequency abnormal components.
=== Limb leads and electrical conduction through the heart ===
The animation shown to the right illustrates how the path of electrical conduction gives rise to the ECG waves in the limb leads.
What is green zone ?
Recall that a positive current (as created by depolarization of cardiac cells) traveling towards the positive electrode and away from the negative electrode creates a positive deflection on the ECG. Likewise, a positive current traveling away from the positive electrode and towards the negative electrode creates a negative deflection on the ECG. The red arrow represents the overall direction of travel of the depolarization. The magnitude of the red arrow is proportional to the amount of tissue being depolarized at that instance. The red arrow is simultaneously shown on the axis of each of the 3 limb leads. Both the direction and the magnitude of the red arrow's projection onto the axis of each limb lead is shown with blue arrows. Then, the direction and magnitude of the blue arrows are what theoretically determine the deflections on the ECG. For example, as a blue arrow on the axis for Lead I moves from the negative electrode, to the right, towards the positive electrode, the ECG line rises, creating an upward wave. As the blue arrow on the axis for Lead I moves to the left, a downward wave is created. The greater the magnitude of the blue arrow, the greater the deflection on the ECG for that particular limb lead.
Frames 1–3 depict the depolarization being generated in and spreading through the sinoatrial node. The SA node is too small for its depolarization to be detected on most ECGs. Frames 4–10 depict the depolarization traveling through the atria, towards the atrioventricular node. During frame 7, the depolarization is traveling through the largest amount of tissue in the atria, which creates the highest point in the P wave. Frames 11–12 depict the depolarization traveling through the AV node. Like the SA node, the AV node is too small for the depolarization of its tissue to be detected on most ECGs. This creates the flat PR segment.
Frame 13 depicts an interesting phenomenon in an over-simplified fashion. It depicts the depolarization as it starts to travel down the interventricular septum, through the bundle of His and bundle branches. After the Bundle of His, the conduction system splits into the left bundle branch and the right bundle branch. Both branches conduct action potentials at about 1 m/s. However, the action potential starts traveling down the left bundle branch about 5 milliseconds before it starts traveling down the right bundle branch, as depicted by frame 13. This causes the depolarization of the interventricular septum tissue to spread from left to right, as depicted by the red arrow in frame 14. In some cases, this gives rise to a negative deflection after the PR interval, creating a Q wave such as the one seen in lead I in the animation to the right. Depending on the mean electrical axis of the heart, this phenomenon can result in a Q wave in lead II as well.
Following depolarization of the interventricular septum, the depolarization travels towards the apex of the heart. This is depicted by frames 15–17 and results in a positive deflection on all three limb leads, which creates the R wave. Frames 18–21 then depict the depolarization as it travels throughout both ventricles from the apex of the heart, following the action potential in the Purkinje fibers. This phenomenon creates a negative deflection in all three limb leads, forming the S wave on the ECG. Repolarization of the atria occurs at the same time as the generation of the QRS complex, but it is not detected by the ECG since the tissue mass of the ventricles is so much larger than that of the atria. Ventricular contraction occurs between ventricular depolarization and repolarization. During this time, there is no movement of charge, so no deflection is created on the ECG. This results in the flat ST segment after the S wave.
Frames 24–28 in the animation depict repolarization of the ventricles. The epicardium is the first layer of the ventricles to repolarize, followed by the myocardium. The endocardium is the last layer to repolarize. The plateau phase of depolarization has been shown to last longer in endocardial cells than in epicardial cells. This causes repolarization to start from the apex of the heart and move upwards. Since repolarization is the spread of negative current as membrane potentials decrease back down to the resting membrane potential, the red arrow in the animation is pointing in the direction opposite of the repolarization. This therefore creates a positive deflection in the ECG, and creates the T wave.
=== Ischemia and infarction ===
Ischemia or non-ST elevation myocardial infarctions (non-STEMIs) may manifest as ST depression or inversion of T waves. It may also affect the high frequency band of the QRS.
ST elevation myocardial infarctions (STEMIs) have different characteristic ECG findings based on the amount of time elapsed since the MI first occurred. The earliest sign is hyperacute T waves, peaked T waves due to local hyperkalemia in ischemic myocardium. This then progresses over a period of minutes to elevations of the ST segment by at least 1 mm. Over a period of hours, a pathologic Q wave may appear and the T wave will invert. Over a period of days the ST elevation will resolve. Pathologic Q waves generally will remain permanently.
The coronary artery that has been occluded can be identified in an STEMI based on the location of ST elevation. The left anterior descending (LAD) artery supplies the anterior wall of the heart, and therefore causes ST elevations in anterior leads (V1 and V2). The LCx supplies the lateral aspect of the heart and therefore causes ST elevations in lateral leads (I, aVL and V6). The right coronary artery (RCA) usually supplies the inferior aspect of the heart, and therefore causes ST elevations in inferior leads (II, III and aVF).
=== Artifacts ===
An ECG tracing is affected by patient motion. Some rhythmic motions (such as shivering or tremors) can create the illusion of cardiac arrhythmia. Artifacts are distorted signals caused by a secondary internal or external sources, such as muscle movement or interference from an electrical device.
Distortion poses significant challenges to healthcare providers, who employ various techniques and strategies to safely recognize these false signals. Accurately separating the ECG artifact from the true ECG signal can have a significant impact on patient outcomes and legal liabilities.
Improper lead placement (for example, reversing two of the limb leads) has been estimated to occur in 0.4% to 4% of all ECG recordings, and has resulted in improper diagnosis and treatment including unnecessary use of thrombolytic therapy.
=== A Method for Interpretation ===
Whitbread, consultant nurse and paramedic, suggests ten rules of the normal ECG, deviation from which is likely to indicate pathology. These have been added to, creating the 15 rules for 12-lead (and 15- or 18-lead) interpretation.
Rule 1: All waves in aVR are negative.
Rule 2: The ST segment (J point) starts on the isoelectric line (except in V1 & V2 where it may be elevated by not greater than 1 mm).
Rule 3: The PR interval should be 0.12–0.2 seconds long.
Rule 4: The QRS complex should not exceed 0.11–0.12 seconds.
Rule 5: The QRS and T waves tend to have the same general direction in the limb leads.
Rule 6: The R wave in the precordial (chest) leads grows from V1 to at least V4 where it may or may not decline again.
Rule 7: The QRS is mainly upright in I and II.
Rule 8: The P wave is upright in I II and V2 to V6.
Rule 9: There is no Q wave or only a small q (<0.04 seconds in width) in I, II and V2 to V6.
Rule 10: The T wave is upright in I II and V2 to V6. The end of the T wave should not drop below the isoelectric baseline.
Rule 11: Does the deepest S wave in V1 plus the tallest R wave in V5 or V6 equal >35 mm?
Rule 12: Is there an Epsilon wave?
Rule 13: Is there an J wave?
Rule 14: Is there a Delta wave?
Rule 15: Are there any patterns representing an occlusive myocardial infarction (OMI)?
== Diagnosis ==
Numerous diagnoses and findings can be made based upon electrocardiography, and many are discussed above. Overall, the diagnoses are made based on the patterns. For example, an "irregularly irregular" QRS complex without P waves is the hallmark of atrial fibrillation; however, other findings can be present as well, such as a bundle branch block that alters the shape of the QRS complexes. ECGs can be interpreted in isolation but should be applied – like all diagnostic tests – in the context of the patient. For example, an observation of peaked T waves is not sufficient to diagnose hyperkalemia; such a diagnosis should be verified by measuring the blood potassium level. Conversely, a discovery of hyperkalemia should be followed by an ECG for manifestations such as peaked T waves, widened QRS complexes, and loss of P waves. The following is an organized list of possible ECG-based diagnoses.
Rhythm disturbances or arrhythmias:
Atrial fibrillation and atrial flutter without rapid ventricular response
Premature atrial contraction (PACs) and premature ventricular contraction (PVCs)
Sinus arrhythmia
Sinus bradycardia and sinus tachycardia
Sinus pause and sinoatrial arrest
Sinus node dysfunction and bradycardia-tachycardia syndrome
Supraventricular tachycardia
Atrial fibrillation with rapid ventricular response
Atrial flutter with rapid ventricular response
AV nodal reentrant tachycardia
Atrioventricular reentrant tachycardia
Junctional ectopic tachycardia
Atrial tachycardia
Ectopic atrial tachycardia (unicentric)
Multifocal atrial tachycardia
Paroxysmal atrial tachycardia
Sinoatrial nodal reentrant tachycardia
Wide complex tachycardia
Ventricular flutter
Ventricular fibrillation
Ventricular tachycardia (monomorphic ventricular tachycardia)
Torsades de pointes (polymorphic ventricular tachycardia)
Pre-excitation syndrome
Lown–Ganong–Levine syndrome
Wolff–Parkinson–White syndrome
J wave (Osborn wave)
Heart block and conduction problems:
Sinoatrial block: first, second, and third-degree
AV node
First-degree AV block
Second-degree AV block (Mobitz [Wenckebach] I and II)
Third-degree AV block or complete AV block
Right bundle
Incomplete right bundle branch block (IRBBB)
Complete right bundle branch block (RBBB)
Left bundle
Incomplete left bundle branch block (ILBBB)
Complete left bundle branch block (LBBB)
Left anterior fascicular block (LAFB)
Left posterior fascicular block (LPFB)
Bifascicular block (LAFB plus LPFB)
Trifascicular block (LAFP plus FPFB plus RBBB)
QT syndromes
Brugada syndrome
Short QT syndrome
Long QT syndromes, genetic and drug-induced
Right and left atrial abnormality
Electrolytes disturbances and intoxication:
Digitalis intoxication
Calcium: hypocalcemia and hypercalcemia
Potassium: hypokalemia and hyperkalemia
Serotonin toxicity
Ischemia and infarction:
Wellens' syndrome (LAD occlusion)
de Winter T waves (LAD occlusion)
ST elevation and ST depression
High frequency QRS changes
Myocardial infarction (heart attack)
Non-Q wave myocardial infarction
NSTEMI
STEMI
Sgarbossa's criteria for ischemia with a LBBB
Structural:
Acute pericarditis
Right and left ventricular hypertrophy
Right ventricular strain or S1Q3T3 (can be seen in pulmonary embolism)
Other phenomena:
Cardiac aberrancy
Ashman phenomenon
Concealed conduction
Electrical alternans
== History ==
In 1872, Alexander Muirhead is reported to have attached wires to the wrist of a patient with fever to obtain an electronic record of their heartbeat.
In 1882, John Burdon-Sanderson working with frogs, was the first to appreciate that the interval between variations in potential was not electrically quiescent and coined the term "isoelectric interval" for this period.
In 1887, Augustus Waller invented an ECG machine consisting of a Lippmann capillary electrometer fixed to a projector. The trace from the heartbeat was projected onto a photographic plate that was itself fixed to a toy train. This allowed a heartbeat to be recorded in real time.
In 1895, Willem Einthoven assigned the letters P, Q, R, S, and T to the deflections in the theoretical waveform he created using equations which corrected the actual waveform obtained by the capillary electrometer to compensate for the imprecision of that instrument. Using letters different from A, B, C, and D (the letters used for the capillary electrometer's waveform) facilitated comparison when the uncorrected and corrected lines were drawn on the same graph. Einthoven probably chose the initial letter P to follow the example set by Descartes in geometry. When a more precise waveform was obtained using the string galvanometer, which matched the corrected capillary electrometer waveform, he continued to use the letters P, Q, R, S, and T, and these letters are still in use today. Einthoven also described the electrocardiographic features of a number of cardiovascular disorders.
In 1897, the string galvanometer was invented by the French engineer Clément Ader.
In 1901, Einthoven, working in Leiden, the Netherlands, used the string galvanometer: the first practical ECG. This device was much more sensitive than the capillary electrometer Waller used.
In 1924, Einthoven was awarded the Nobel Prize in Medicine for his pioneering work in developing the ECG.
By 1927, General Electric had developed a portable apparatus that could produce electrocardiograms without the use of the string galvanometer. This device instead combined amplifier tubes similar to those used in a radio with an internal lamp and a moving mirror that directed the tracing of the electric pulses onto film.
In 1937, Taro Takemi invented a new portable electrocardiograph machine.
In 1942, Emanuel Goldberger increases the voltage of Wilson's unipolar leads by 50% and creates the augmented limb leads aVR, aVL and aVF. When added to Einthoven's three limb leads and the six chest leads we arrive at the 12-lead electrocardiogram that is used today.
In the late 1940s, Rune Elmqvist invented an inkjet printer involving thin jets of ink deflected by electrical potentials from the heart, with good frequency response and direct recording of ECG on paper. The device, called the Mingograf, was sold by Siemens Elema until the 1990s.
=== Etymology ===
The word is derived from the Greek electro, meaning related to electrical activity; kardia, meaning heart; and graph, meaning "to write".
== See also ==
Signal-averaged electrocardiogram
Electrical conduction system of the heart
Electroencephalography
Electrogastrogram
Electropalatography
Electroretinography
Emergency medicine
Forward problem of electrocardiology
Heart rate
Heart rate monitor
Wireless ambulatory ECG
== Notes ==
== References ==
== External links ==
The whole ECG course on 1 A4 paper from ECGpedia, a wiki encyclopedia for a course on interpretation of ECG
Wave Maven – a large database of practice ECG questions provided by Beth Israel Deaconess Medical Center
PysioBank – a free scientific database with physiologic signals (here ecg)
EKG Academy – free EKG lectures, drills and quizzes
ECG Learning Center created by Eccles Health Sciences Library at University of Utah | Wikipedia/Atrial_depolarization |
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