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The atrium (Latin: ātrium, lit. 'entry hall'; pl.: atria) is one of the two upper chambers in the heart that receives blood from the circulatory system. The blood in the atria is pumped into the heart ventricles through the atrioventricular mitral and tricuspid heart valves.
There are two atria in the human heart – the left atrium receives blood from the pulmonary circulation, and the right atrium receives blood from the venae cavae of the systemic circulation. During the cardiac cycle, the atria receive blood while relaxed in diastole, then contract in systole to move blood to the ventricles. Each atrium is roughly cube-shaped except for an ear-shaped projection called an atrial appendage, previously known as an auricle. All animals with a closed circulatory system have at least one atrium.
The atrium was formerly called the 'auricle'. That term is still used to describe this chamber in some other animals, such as the Mollusca. Auricles in this modern terminology are distinguished by having thicker muscular walls.
== Structure ==
Humans have a four-chambered heart consisting of the right and left atrium, and the right and left ventricle. The atria are the two upper chambers which pump blood to the two lower ventricles.
The right atrium and ventricle are often referred to together as the right heart, and the left atrium and ventricle as the left heart. As the atria do not have valves at their inlets, a venous pulsation is normal, and can be detected in the jugular vein as the jugular venous pressure.
Internally, there are the rough pectinate muscles, and the crista terminalis of His, which act as a boundary inside the atrium and the smooth-walled part of the right atrium, the sinus venarum, which are derived from the sinus venosus. The sinus venarum is the adult remnant of the sinus venosus and it surrounds the openings of the venae cavae and the coronary sinus. Attached to each atrium is an atrial appendage.
=== Right atrium ===
The right atrium receives and holds deoxygenated blood from the superior vena cava, inferior vena cava, anterior cardiac veins, smallest cardiac veins and the coronary sinus, which it then sends down to the right ventricle through the tricuspid valve, which in turn sends it to the pulmonary artery for pulmonary circulation.
==== Right atrial appendage ====
The right atrial appendage (lat: auricula atrii dextra) is located at the front upper surface of the right atrium. Looking from the front, the right atrial appendage appears wedge-shaped or triangular. Its base surrounds the superior vena cava. The right atrial appendage is a pouch-like extension of the right atrium and is covered by a trabecula network of pectinate muscles. The interatrial septum separates the right atrium from the left atrium; this is marked by a depression in the right atrium – the fossa ovalis. The atria are depolarised by calcium.
=== Left atrium ===
The left atrium receives the oxygenated blood from the left and right pulmonary veins, which it pumps to the left ventricle (through the mitral valve (left atrioventricular valve) for pumping out through the aorta for systemic circulation.
==== Left atrial appendage ====
High in the upper part of the left atrium is a muscular ear-shaped pouch – the left atrial appendage (LAA) (lat: auricula atrii sinistra), which has a tubular trabeculated structure. LAA anatomy as seen in a CT scan is characterized as being in one of four groups: chicken wing (48%),
cactus (30%), windsock (19%), and cauliflower(3%). Cauliflower is the morphology most often associated with embolism. The LAA appears to "function as a decompression chamber during left ventricular systole and during other periods when left atrial pressure is high". It also modulates intravascular volume by secreting natriuretic peptides, namely atrial natriuretic peptide (ANP), and brain natriuretic peptide (BNP) into the coronary sinus, where they enter into the blood circulation.
The left atrial appendage can be seen on a standard posteroanterior X-ray, where the lower level of the left hilum becomes concave. It can also be seen clearly using transesophageal echocardiography. The left atrial appendage can serve as an approach for mitral valve surgery.
The body of the left atrial appendage is anterior to the left atrium and parallel to the left pulmonary veins. The left pulmonary artery passes posterosuperiorly and is separated from the atrial appendage by the transverse sinus. In atrial fibrillation, the left atrial appendage fibrillates rather than contracts resulting in blood stasis that predisposes to the formation of blood clots. Because of consequent stroke risk, surgeons may choose to close it during open-heart surgery, using a left atrial appendage occlusion procedure.
=== Conduction system ===
The sinoatrial node (SA node) is located in the posterior aspect of the right atrium, next to the superior vena cava. This is a group of pacemaker cells which spontaneously depolarize to create an action potential. The cardiac action potential then spreads across both atria causing them to contract, forcing the blood they hold into their corresponding ventricles.
The atrioventricular node (AV node) is another node in the cardiac conduction system. This is located between the atria and the ventricles.
=== Blood supply ===
The left atrium is supplied mainly by the left circumflex coronary artery, and its small branches.
The oblique vein of the left atrium is partly responsible for venous drainage; it derives from the embryonic left superior vena cava.
=== Development ===
During embryogenesis at about two weeks, a primitive atrium begins to be formed as one chamber, which over the following two weeks becomes divided by the septum primum into the left atrium and the right atrium. The interatrial septum has an opening in the right atrium, the foramen ovale, which provides access to the left atrium; this connects the two chambers, which is essential for fetal blood circulation. At birth, when the first breath is taken fetal blood flow is reversed to travel through the lungs. The foramen ovale is no longer needed and it closes to leave a depression (the fossa ovalis) in the atrial wall.
In some cases, the foramen ovale fails to close. This abnormality is present in approximately 25% of the general population. This is known as a patent foramen ovale, an atrial septal defect. It is mostly unproblematic, although it can be associated with paradoxical embolization and stroke.
Within the fetal right atrium, blood from the inferior vena cava and the superior vena cava flow in separate streams to different locations in the heart; this has been reported to occur through the Coandă effect.
== Function ==
In human physiology, the atria facilitate circulation primarily by allowing uninterrupted venous flow to the heart during ventricular systole. By being partially empty and distensible, atria prevent the interruption of venous flow to the heart that would occur during ventricular systole if the veins ended at the inlet valves of the heart. In normal physiologic states, the output of the heart is pulsatile, and the venous inflow to the heart is continuous and non-pulsatile. But without functioning atria, venous flow becomes pulsatile, and the overall circulation rate decreases significantly.
Atria have four essential characteristics that cause them to promote continuous venous flow. (1) There are no atrial inlet valves to interrupt blood flow during atrial systole. (2) The atrial systole contractions are incomplete and thus do not contract to the extent that would block flow from the veins through the atria into the ventricles. During atrial systole, blood not only empties from the atria to the ventricles, but blood continues to flow uninterrupted from the veins right through the atria into the ventricles. (3) The atrial contractions must be gentle enough so that the force of contraction does not exert significant back pressure that would impede venous flow. (4) The "let go" of the atria must be timed so that they relax before the start of ventricular contraction, to be able to accept venous flow without interruption.
By preventing the inertia of interrupted venous flow that would otherwise occur at each ventricular systole, atria allow approximately 75% more cardiac output than would otherwise occur. The fact that atrial contraction is 15% of the amount of the succeeding ventricular ejection has led to a misplaced emphasis on their role in pumping up the ventricles (the so-called "atrial kick"), whereas the key benefit of atria is in preventing circulatory inertia and allowing uninterrupted venous flow to the heart.
Also of importance in maintaining the blood flow are the presence of atrial volume receptors. These are low-pressure baroreceptors in the atria, which send signals to the hypothalamus when a drop in atrial pressure (which indicates a drop in blood volume) is detected. This triggers a release of vasopressin.
== Disorders ==
=== Atrial septal defect ===
In an adult, an atrial septal defect results in the flow of blood in the reverse direction – from the left atrium to the right – which reduces cardiac output, potentially causing cardiac failure, and in severe or untreated cases cardiac arrest and sudden death.
=== Left atrial appendage thrombosis ===
In patients with atrial fibrillation, mitral valve disease, and other conditions, blood clots have a tendency to form in the left atrial appendage. The clots may dislodge (forming emboli), which may lead to ischemic damage to the brain, kidneys, or other organs supplied by the systemic circulation.
In those with uncontrollable atrial fibrillation, left atrial appendage occlusion may be performed at the time of any open-heart surgery to prevent future clot formation within the appendage.
=== Functional abnormalities ===
Wolff–Parkinson–White syndrome
Atrial fibrillation
Atrial flutter
Atrial tachycardia
Sinus tachycardia
Multifocal atrial tachycardia – several types
Premature atrial contraction
== Other animals ==
Many other animals, including mammals, also have four-chambered hearts, which have a similar function. Some animals (amphibians and reptiles) have a three-chambered heart, in which the blood from each atrium is mixed in the single ventricle before being pumped to the aorta. In these animals, the left atrium still serves the purpose of collecting blood from the pulmonary veins.
In most fish, the circulatory system is very simple: a two-chambered heart including one atrium and one ventricle. Among sharks, the heart consists of four parts arranged serially: blood flows into the most posterior part, the sinus venosus, and then to the atrium which moves it to the third part, the ventricle, before it reaches the conus anteriosus, which itself is connected to the ventral aorta. This is considered a primitive arrangement, and many vertebrates have condensed the atrium with the sinus venosus and the ventricle with the conus anteriosus.
With the advent of lungs came a partitioning of the atrium into two parts divided by a septum. Among frogs, the oxygenated and deoxygenated blood is mixed in the ventricle before being pumped out to the body's organs; in turtles, the ventricle is almost entirely divided by a septum, but retains an opening through which some mixing of blood occurs. In birds, mammals, and some other reptiles (alligators in particular) the partitioning of both chambers is complete.
== See also ==
Atrial syncytium
Left atrial volume
== References ==
== External links ==
Media related to Heart atria at Wikimedia Commons | Wikipedia/Atrial |
ScienceDirect is a searchable web-based bibliographic database, which provides access to full texts of scientific and medical publications of the Dutch publisher Elsevier as well of several small academic publishers. It hosts over 18 million publications from more than 4,000 academic journals and 30,000 e-books. The access to the full-text requires subscription, while the bibliographic metadata are free to read. ScienceDirect was launched by Elsevier in March 1997.
== Usage ==
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Article abstracts are freely available, and access to their full texts (in PDF and, for newer publications, also HTML) generally requires a subscription or pay-per-view purchase unless the content is freely available in open access.
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ScienceDirect also competes for audience with other large aggregators and hosts of scholarly communication content such as academic social network ResearchGate and open access repository arXiv, as well as with fully open access publishing venues and mega journals like PLOS.
ScienceDirect also carries Cell.
The search and bibliographic export options of ScienceDirect are very limited. For better search capabilities Elsevier provides via internet a paid-access database Scopus.
== See also ==
List of academic databases and search engines
Scopus
== References ==
== Further reading ==
Boukacem-Zeghmouri, Chérifa; Bador, Pascal; Lafouge, Thierry; Prost, Hélène (2016). "Relationships between consumption, publication and impact in French universities in a value perspective: A bibliometric analysis" (PDF). Scientometrics. 106: 263–280. doi:10.1007/s11192-015-1779-z. S2CID 8897085.
Emrani, Ebrahim; Moradi-Salari, A.; Jamali, Hamid R. (2013). "Usage data, e-journal selection and negotiations: Iranian consortium experience". hdl:10760/19670.
Gies, Ted (2018). "The Science Direct accessibility journey: A case study". Learned Publishing. 31: 69–76. doi:10.1002/leap.1142.
== External links ==
Official website | Wikipedia/Elsevier_Science_Direct |
A myxoma is a rare benign tumor of the heart. Myxomata are the most common primary cardiac tumor in adults, and are most commonly found within the left atrium near the valve of the fossa ovalis. Myxoma may also develop in the other heart chambers. The tumor is derived from multipotent mesenchymal cells. Cardiac myxoma can affect adults between 30 and 60 years of age.
== Signs and symptoms ==
Symptoms may occur at any time, but most often they accompany a change of body position. Pedunculated myxomata can have a "wrecking ball effect", as they lead to stasis and may eventually embolize themselves. Symptoms may include:
Shortness of breath with activity
Platypnea – Difficulty breathing in the upright position with relief in the supine position
Paroxysmal nocturnal dyspnea – Breathing difficulty when asleep
Dizziness
Fainting
Palpitations – Sensation of feeling your heart beat
Chest pain or tightness
Sudden Death (In which case the disease is an autopsy finding)
The symptoms and signs of left atrial myxomata often mimic mitral stenosis.
General symptoms may also be present, such as:
Cough
Pulmonary edema – as blood backs up into the pulmonary artery, after increased pressures in the left atrium and atrial dilation
Hemoptysis
Fever
Cachexia – Involuntary weight loss
General discomfort (malaise)
Joint pain
Blue discoloration of the skin, especially the fingers change color upon pressure, cold, or stress (Raynaud's phenomenon)
Clubbing – Curvature of nails accompanied with soft tissue enlargement of the fingers
Swelling – any part of the body
Presystolic heart murmur
These general symptoms may also mimic those of infective endocarditis.
=== Complications ===
Arrhythmias
Pulmonary edema
Peripheral emboli
Spread (metastasis) of the tumor
Blockage of the mitral heart valve
Stroke
Fusiform cerebral aneurysms
== Causes ==
Myxomata are the most common type of adult primary heart tumor. Most myxomata arise sporadically (90%), and only about 10% are thought to arise due to inheritance.
About 10% of myxomata are inherited, as in Carney syndrome. Such tumors are called familial myxomata. They tend to occur in more than one part of the heart at a time, and often cause symptoms at a younger age than other myxomata. Other abnormalities are observed in people with Carney syndrome include skin myxomata, pigmentation, endocrine hyperactivity, schwannomas and epithelioid blue nevi. Myxomata are more common in women than men.
== Diagnosis ==
A doctor will listen to the heart with a stethoscope. A "tumor plop" (a sound related to movement of the tumor), abnormal heart sounds, or a murmur similar to the mid-diastolic rumble of mitral stenosis may be heard. These sounds may change when the patient changes position.
Right atrial myxomata rarely produce symptoms until they have grown to be at least 13 cm (about 5 inches) wide.
Tests may include:
Echocardiogram and Doppler study
Chest x-ray
CT scan of chest
Heart MRI
Left heart angiography
Right heart angiography
ECG—may show atrial fibrillation
Blood tests:
Blood tests: An FBC may show anemia and increased WBCs (white blood cells). The erythrocyte sedimentation rate (ESR) is usually increased.
== Treatment ==
The surgery is treatment of choice, tumor must be surgically removed. Some patients will also need their mitral valve replaced. This can be done during the same surgery. Usually, inadequate excision of the tumor, development from a secondary focus, or intracardiac implantation from the primary tumor are the attributable explanation for recurrence, and it is more likely to occur in the first 10 postoperative years, especially in younger patients.
== Prognosis ==
Although a myxoma is not malignant with risk of metastasis, complications are common. Untreated, a myxoma can lead to an embolism (tumor cells breaking off and traveling with the bloodstream). Myxoma fragments can move to the brain, eye, or limbs.
If the tumor continues to enlarge inside the heart, it can block blood flow through the mitral valve and cause symptoms of mitral stenosis or mitral regurgitation. This may require emergency surgery to prevent sudden death.
== See also ==
Myxoma
Interleukin 6
Papillary fibroelastoma
Rhabdomyomas
Cardiac sarcomas
== References ==
== External links == | Wikipedia/Atrial_myxoma |
The interatrial septum is the wall of tissue that separates the right and left atria of the heart.
== Structure ==
The interatrial septum is a septum that lies between the left atrium and right atrium of the human heart. The interatrial septum lies at angle of 65 degrees from right posterior to left anterior because right atrium is located at the right side of the body while left atrium is located at the left side of the body. The interatrial septum represents the posterior wall of the right atrium.
== Development ==
The interatrial septum forms during the first and second months of fetal development. Formation of the septum occurs in several stages. The first is the development of the septum primum, a crescent-shaped piece of tissue forming the initial divider between the right and left atria. Because of its crescent shape, the septum primum does not fully occlude the space between the left and right atria; the opening that remains is called the ostium primum. During fetal development, this opening allows blood to be shunted from the right atrium to the left.
As the septum primum grows, the ostium primum progressively narrows. Before the ostium primum is completely occluded, a second opening called the ostium secundum begins to form in the septum primum. The ostium secundum allows continued shunting of blood from the right atrium to the left.
To the right of the septum primum, the septum secundum begins to form. This thick, muscular structure initially takes on the same crescent shape as the septum primum, except that it originates anteriorly, whereas the septum primum originates posteriorly. As the septum secundum grows, it leaves a small opening called the foramen ovale. The foramen ovale is continuous with the ostium secundum, again providing for continued shunting of blood.
The ostium secundum progressively enlarges and the size of the septum primum diminishes. Eventually, the septum primum is nothing more than a small flap that covers the foramen ovale on its left side. This flap of tissue is called the valve of the foramen ovale. It opens and closes in response to pressure gradients between the left and right atria. When the pressure is greater in the right atrium, the valve opens; when the pressure is greater in the left atrium, the valve closes. Because the lungs are nonfunctional in fetal life, pressure in the pulmonary circulation is greater than that of the systemic circulation. Consequently, the right atrium is generally under higher pressures than the left atrium, and the valve of the foramen ovale is normally open.
=== At birth ===
At birth, there is a reversal in the pressure gradient between the atria, resulting in functional closure of the valve of the foramen ovale. Permanent anatomical closure of the foramen ovale occurs with time in normal infants. Inappropriate failure of closure of the foramen ovale results in patent foramen ovale.
== Clinical significance ==
An Atrial septal defect is a relatively common heart malformation that occurs when the interatrial septum fails to develop properly.
Persistence of the ostium secundum is the most common atrial septal defect. Additionally, in a subset of the population, the foramen ovale is not overtly patent but the two septa have not fused. In normal physiologic circumstances, the septum primum acts as a one-way valve preventing blood flow as described above; but, if pathologic conditions cause right atrial pressure to exceed left atrial pressure, blood may flow through the foramen ovale from right to left.
Failure of the septum primum to fuse with the endocardial cushion can lead to an ostium primum atrial septal defect. This is the second most common type of atrial septal defect and is commonly seen in Down syndrome. Typically, this defect will cause a shunt to occur from the left atrium to the right atrium. Children born with this defect may be asymptomatic, however, over time pulmonary hypertension and the resulting hypertrophy of the right side of the heart will lead to a reversal of this shunt. This reversal is called Eisenmenger syndrome.
Lipomatous atrial septal hypertrophy (LASH) is the fat deposition in the infoldings of the interatrial septum adjacent to the true atrial septum. It is shaped like a “dumbbell” because the deposition is located at the above and the below the fossa ovalis, sparing the fossa itself. The incidence of LASH increases with older age and obesity. On CT scan, it shows homogeneous, dumbbell mass which is non-enhancing at the interatrial septum. MRI shows extension of the mass into interventricular septum and ventricular wall.
== See also ==
Interventricular septum
== References ==
Gray's Anatomy: The Anatomical Basis of Clinical Practice, 39th ed. (2005). ISBN 0-443-07168-3
"Septum, interatrial." Stedman's Medical Dictionary, 27th ed. (2000). ISBN 0-683-40007-X
== External links ==
Diagram
Animation Archived 2019-09-12 at the Wayback Machine, from Indiana University | Wikipedia/Interatrial_septum |
The atrium (Latin: ātrium, lit. 'entry hall'; pl.: atria) is one of the two upper chambers in the heart that receives blood from the circulatory system. The blood in the atria is pumped into the heart ventricles through the atrioventricular mitral and tricuspid heart valves.
There are two atria in the human heart – the left atrium receives blood from the pulmonary circulation, and the right atrium receives blood from the venae cavae of the systemic circulation. During the cardiac cycle, the atria receive blood while relaxed in diastole, then contract in systole to move blood to the ventricles. Each atrium is roughly cube-shaped except for an ear-shaped projection called an atrial appendage, previously known as an auricle. All animals with a closed circulatory system have at least one atrium.
The atrium was formerly called the 'auricle'. That term is still used to describe this chamber in some other animals, such as the Mollusca. Auricles in this modern terminology are distinguished by having thicker muscular walls.
== Structure ==
Humans have a four-chambered heart consisting of the right and left atrium, and the right and left ventricle. The atria are the two upper chambers which pump blood to the two lower ventricles.
The right atrium and ventricle are often referred to together as the right heart, and the left atrium and ventricle as the left heart. As the atria do not have valves at their inlets, a venous pulsation is normal, and can be detected in the jugular vein as the jugular venous pressure.
Internally, there are the rough pectinate muscles, and the crista terminalis of His, which act as a boundary inside the atrium and the smooth-walled part of the right atrium, the sinus venarum, which are derived from the sinus venosus. The sinus venarum is the adult remnant of the sinus venosus and it surrounds the openings of the venae cavae and the coronary sinus. Attached to each atrium is an atrial appendage.
=== Right atrium ===
The right atrium receives and holds deoxygenated blood from the superior vena cava, inferior vena cava, anterior cardiac veins, smallest cardiac veins and the coronary sinus, which it then sends down to the right ventricle through the tricuspid valve, which in turn sends it to the pulmonary artery for pulmonary circulation.
==== Right atrial appendage ====
The right atrial appendage (lat: auricula atrii dextra) is located at the front upper surface of the right atrium. Looking from the front, the right atrial appendage appears wedge-shaped or triangular. Its base surrounds the superior vena cava. The right atrial appendage is a pouch-like extension of the right atrium and is covered by a trabecula network of pectinate muscles. The interatrial septum separates the right atrium from the left atrium; this is marked by a depression in the right atrium – the fossa ovalis. The atria are depolarised by calcium.
=== Left atrium ===
The left atrium receives the oxygenated blood from the left and right pulmonary veins, which it pumps to the left ventricle (through the mitral valve (left atrioventricular valve) for pumping out through the aorta for systemic circulation.
==== Left atrial appendage ====
High in the upper part of the left atrium is a muscular ear-shaped pouch – the left atrial appendage (LAA) (lat: auricula atrii sinistra), which has a tubular trabeculated structure. LAA anatomy as seen in a CT scan is characterized as being in one of four groups: chicken wing (48%),
cactus (30%), windsock (19%), and cauliflower(3%). Cauliflower is the morphology most often associated with embolism. The LAA appears to "function as a decompression chamber during left ventricular systole and during other periods when left atrial pressure is high". It also modulates intravascular volume by secreting natriuretic peptides, namely atrial natriuretic peptide (ANP), and brain natriuretic peptide (BNP) into the coronary sinus, where they enter into the blood circulation.
The left atrial appendage can be seen on a standard posteroanterior X-ray, where the lower level of the left hilum becomes concave. It can also be seen clearly using transesophageal echocardiography. The left atrial appendage can serve as an approach for mitral valve surgery.
The body of the left atrial appendage is anterior to the left atrium and parallel to the left pulmonary veins. The left pulmonary artery passes posterosuperiorly and is separated from the atrial appendage by the transverse sinus. In atrial fibrillation, the left atrial appendage fibrillates rather than contracts resulting in blood stasis that predisposes to the formation of blood clots. Because of consequent stroke risk, surgeons may choose to close it during open-heart surgery, using a left atrial appendage occlusion procedure.
=== Conduction system ===
The sinoatrial node (SA node) is located in the posterior aspect of the right atrium, next to the superior vena cava. This is a group of pacemaker cells which spontaneously depolarize to create an action potential. The cardiac action potential then spreads across both atria causing them to contract, forcing the blood they hold into their corresponding ventricles.
The atrioventricular node (AV node) is another node in the cardiac conduction system. This is located between the atria and the ventricles.
=== Blood supply ===
The left atrium is supplied mainly by the left circumflex coronary artery, and its small branches.
The oblique vein of the left atrium is partly responsible for venous drainage; it derives from the embryonic left superior vena cava.
=== Development ===
During embryogenesis at about two weeks, a primitive atrium begins to be formed as one chamber, which over the following two weeks becomes divided by the septum primum into the left atrium and the right atrium. The interatrial septum has an opening in the right atrium, the foramen ovale, which provides access to the left atrium; this connects the two chambers, which is essential for fetal blood circulation. At birth, when the first breath is taken fetal blood flow is reversed to travel through the lungs. The foramen ovale is no longer needed and it closes to leave a depression (the fossa ovalis) in the atrial wall.
In some cases, the foramen ovale fails to close. This abnormality is present in approximately 25% of the general population. This is known as a patent foramen ovale, an atrial septal defect. It is mostly unproblematic, although it can be associated with paradoxical embolization and stroke.
Within the fetal right atrium, blood from the inferior vena cava and the superior vena cava flow in separate streams to different locations in the heart; this has been reported to occur through the Coandă effect.
== Function ==
In human physiology, the atria facilitate circulation primarily by allowing uninterrupted venous flow to the heart during ventricular systole. By being partially empty and distensible, atria prevent the interruption of venous flow to the heart that would occur during ventricular systole if the veins ended at the inlet valves of the heart. In normal physiologic states, the output of the heart is pulsatile, and the venous inflow to the heart is continuous and non-pulsatile. But without functioning atria, venous flow becomes pulsatile, and the overall circulation rate decreases significantly.
Atria have four essential characteristics that cause them to promote continuous venous flow. (1) There are no atrial inlet valves to interrupt blood flow during atrial systole. (2) The atrial systole contractions are incomplete and thus do not contract to the extent that would block flow from the veins through the atria into the ventricles. During atrial systole, blood not only empties from the atria to the ventricles, but blood continues to flow uninterrupted from the veins right through the atria into the ventricles. (3) The atrial contractions must be gentle enough so that the force of contraction does not exert significant back pressure that would impede venous flow. (4) The "let go" of the atria must be timed so that they relax before the start of ventricular contraction, to be able to accept venous flow without interruption.
By preventing the inertia of interrupted venous flow that would otherwise occur at each ventricular systole, atria allow approximately 75% more cardiac output than would otherwise occur. The fact that atrial contraction is 15% of the amount of the succeeding ventricular ejection has led to a misplaced emphasis on their role in pumping up the ventricles (the so-called "atrial kick"), whereas the key benefit of atria is in preventing circulatory inertia and allowing uninterrupted venous flow to the heart.
Also of importance in maintaining the blood flow are the presence of atrial volume receptors. These are low-pressure baroreceptors in the atria, which send signals to the hypothalamus when a drop in atrial pressure (which indicates a drop in blood volume) is detected. This triggers a release of vasopressin.
== Disorders ==
=== Atrial septal defect ===
In an adult, an atrial septal defect results in the flow of blood in the reverse direction – from the left atrium to the right – which reduces cardiac output, potentially causing cardiac failure, and in severe or untreated cases cardiac arrest and sudden death.
=== Left atrial appendage thrombosis ===
In patients with atrial fibrillation, mitral valve disease, and other conditions, blood clots have a tendency to form in the left atrial appendage. The clots may dislodge (forming emboli), which may lead to ischemic damage to the brain, kidneys, or other organs supplied by the systemic circulation.
In those with uncontrollable atrial fibrillation, left atrial appendage occlusion may be performed at the time of any open-heart surgery to prevent future clot formation within the appendage.
=== Functional abnormalities ===
Wolff–Parkinson–White syndrome
Atrial fibrillation
Atrial flutter
Atrial tachycardia
Sinus tachycardia
Multifocal atrial tachycardia – several types
Premature atrial contraction
== Other animals ==
Many other animals, including mammals, also have four-chambered hearts, which have a similar function. Some animals (amphibians and reptiles) have a three-chambered heart, in which the blood from each atrium is mixed in the single ventricle before being pumped to the aorta. In these animals, the left atrium still serves the purpose of collecting blood from the pulmonary veins.
In most fish, the circulatory system is very simple: a two-chambered heart including one atrium and one ventricle. Among sharks, the heart consists of four parts arranged serially: blood flows into the most posterior part, the sinus venosus, and then to the atrium which moves it to the third part, the ventricle, before it reaches the conus anteriosus, which itself is connected to the ventral aorta. This is considered a primitive arrangement, and many vertebrates have condensed the atrium with the sinus venosus and the ventricle with the conus anteriosus.
With the advent of lungs came a partitioning of the atrium into two parts divided by a septum. Among frogs, the oxygenated and deoxygenated blood is mixed in the ventricle before being pumped out to the body's organs; in turtles, the ventricle is almost entirely divided by a septum, but retains an opening through which some mixing of blood occurs. In birds, mammals, and some other reptiles (alligators in particular) the partitioning of both chambers is complete.
== See also ==
Atrial syncytium
Left atrial volume
== References ==
== External links ==
Media related to Heart atria at Wikimedia Commons | Wikipedia/Right_atrial_appendage |
The sinoatrial nodal artery, sinoatrial nodal artery or sinoatrial artery is an artery of the heart which supplies the sinoatrial node, the natural pacemaker center of the heart. It is usually a branch of the right coronary artery. It passes between the right atrium, and the opening of the superior vena cava.
== Anatomy ==
=== Origin ===
It arises from the right coronary artery in around 60% of individuals, from the left circumflex coronary artery in about 40% of individuals, and in less than 1% of humans, the artery has an anomalous origin directly from the coronary sinus, descending aorta, or distal right coronary artery.
The origin of the sinoatrial node artery is not related to coronary artery dominance, which means the side (right or left) that provides the circulation to the back of the heart. In contrast, the atrioventricular nodal branch, that is the artery that brings blood to the atrioventricular node, depends on coronary artery dominance.
=== Course ===
In more than 50% of human hearts, the artery actually courses close to the superior posterior aspect of the interatrial septum.
The sinoatrial node surrounds the sinoatrial artery, which can run centrally (in 70% of individuals) or off-center within the node.
=== Variation ===
A left S-shaped sinoatrial artery, originating from the proximal left circumflex or LCx artery, has been described as a common variant in approximately 10% of human hearts. This artery is larger than normal and supplies a good part of the left atrium, but also right-sided structures like part of the sinoatrial node and the atrioventricular nodal areas. In this variant, the artery courses in the sulcus between the left superior pulmonary vein and the left atrial appendage where it could be susceptible to injury during catheter or surgical ablation procedures on the left atrium, especially for atrial fibrillation ablation or open-heart cardiac surgery.
== Additional images ==
== References == | Wikipedia/Sinoatrial_nodal_artery |
The atrium (Latin: ātrium, lit. 'entry hall'; pl.: atria) is one of the two upper chambers in the heart that receives blood from the circulatory system. The blood in the atria is pumped into the heart ventricles through the atrioventricular mitral and tricuspid heart valves.
There are two atria in the human heart – the left atrium receives blood from the pulmonary circulation, and the right atrium receives blood from the venae cavae of the systemic circulation. During the cardiac cycle, the atria receive blood while relaxed in diastole, then contract in systole to move blood to the ventricles. Each atrium is roughly cube-shaped except for an ear-shaped projection called an atrial appendage, previously known as an auricle. All animals with a closed circulatory system have at least one atrium.
The atrium was formerly called the 'auricle'. That term is still used to describe this chamber in some other animals, such as the Mollusca. Auricles in this modern terminology are distinguished by having thicker muscular walls.
== Structure ==
Humans have a four-chambered heart consisting of the right and left atrium, and the right and left ventricle. The atria are the two upper chambers which pump blood to the two lower ventricles.
The right atrium and ventricle are often referred to together as the right heart, and the left atrium and ventricle as the left heart. As the atria do not have valves at their inlets, a venous pulsation is normal, and can be detected in the jugular vein as the jugular venous pressure.
Internally, there are the rough pectinate muscles, and the crista terminalis of His, which act as a boundary inside the atrium and the smooth-walled part of the right atrium, the sinus venarum, which are derived from the sinus venosus. The sinus venarum is the adult remnant of the sinus venosus and it surrounds the openings of the venae cavae and the coronary sinus. Attached to each atrium is an atrial appendage.
=== Right atrium ===
The right atrium receives and holds deoxygenated blood from the superior vena cava, inferior vena cava, anterior cardiac veins, smallest cardiac veins and the coronary sinus, which it then sends down to the right ventricle through the tricuspid valve, which in turn sends it to the pulmonary artery for pulmonary circulation.
==== Right atrial appendage ====
The right atrial appendage (lat: auricula atrii dextra) is located at the front upper surface of the right atrium. Looking from the front, the right atrial appendage appears wedge-shaped or triangular. Its base surrounds the superior vena cava. The right atrial appendage is a pouch-like extension of the right atrium and is covered by a trabecula network of pectinate muscles. The interatrial septum separates the right atrium from the left atrium; this is marked by a depression in the right atrium – the fossa ovalis. The atria are depolarised by calcium.
=== Left atrium ===
The left atrium receives the oxygenated blood from the left and right pulmonary veins, which it pumps to the left ventricle (through the mitral valve (left atrioventricular valve) for pumping out through the aorta for systemic circulation.
==== Left atrial appendage ====
High in the upper part of the left atrium is a muscular ear-shaped pouch – the left atrial appendage (LAA) (lat: auricula atrii sinistra), which has a tubular trabeculated structure. LAA anatomy as seen in a CT scan is characterized as being in one of four groups: chicken wing (48%),
cactus (30%), windsock (19%), and cauliflower(3%). Cauliflower is the morphology most often associated with embolism. The LAA appears to "function as a decompression chamber during left ventricular systole and during other periods when left atrial pressure is high". It also modulates intravascular volume by secreting natriuretic peptides, namely atrial natriuretic peptide (ANP), and brain natriuretic peptide (BNP) into the coronary sinus, where they enter into the blood circulation.
The left atrial appendage can be seen on a standard posteroanterior X-ray, where the lower level of the left hilum becomes concave. It can also be seen clearly using transesophageal echocardiography. The left atrial appendage can serve as an approach for mitral valve surgery.
The body of the left atrial appendage is anterior to the left atrium and parallel to the left pulmonary veins. The left pulmonary artery passes posterosuperiorly and is separated from the atrial appendage by the transverse sinus. In atrial fibrillation, the left atrial appendage fibrillates rather than contracts resulting in blood stasis that predisposes to the formation of blood clots. Because of consequent stroke risk, surgeons may choose to close it during open-heart surgery, using a left atrial appendage occlusion procedure.
=== Conduction system ===
The sinoatrial node (SA node) is located in the posterior aspect of the right atrium, next to the superior vena cava. This is a group of pacemaker cells which spontaneously depolarize to create an action potential. The cardiac action potential then spreads across both atria causing them to contract, forcing the blood they hold into their corresponding ventricles.
The atrioventricular node (AV node) is another node in the cardiac conduction system. This is located between the atria and the ventricles.
=== Blood supply ===
The left atrium is supplied mainly by the left circumflex coronary artery, and its small branches.
The oblique vein of the left atrium is partly responsible for venous drainage; it derives from the embryonic left superior vena cava.
=== Development ===
During embryogenesis at about two weeks, a primitive atrium begins to be formed as one chamber, which over the following two weeks becomes divided by the septum primum into the left atrium and the right atrium. The interatrial septum has an opening in the right atrium, the foramen ovale, which provides access to the left atrium; this connects the two chambers, which is essential for fetal blood circulation. At birth, when the first breath is taken fetal blood flow is reversed to travel through the lungs. The foramen ovale is no longer needed and it closes to leave a depression (the fossa ovalis) in the atrial wall.
In some cases, the foramen ovale fails to close. This abnormality is present in approximately 25% of the general population. This is known as a patent foramen ovale, an atrial septal defect. It is mostly unproblematic, although it can be associated with paradoxical embolization and stroke.
Within the fetal right atrium, blood from the inferior vena cava and the superior vena cava flow in separate streams to different locations in the heart; this has been reported to occur through the Coandă effect.
== Function ==
In human physiology, the atria facilitate circulation primarily by allowing uninterrupted venous flow to the heart during ventricular systole. By being partially empty and distensible, atria prevent the interruption of venous flow to the heart that would occur during ventricular systole if the veins ended at the inlet valves of the heart. In normal physiologic states, the output of the heart is pulsatile, and the venous inflow to the heart is continuous and non-pulsatile. But without functioning atria, venous flow becomes pulsatile, and the overall circulation rate decreases significantly.
Atria have four essential characteristics that cause them to promote continuous venous flow. (1) There are no atrial inlet valves to interrupt blood flow during atrial systole. (2) The atrial systole contractions are incomplete and thus do not contract to the extent that would block flow from the veins through the atria into the ventricles. During atrial systole, blood not only empties from the atria to the ventricles, but blood continues to flow uninterrupted from the veins right through the atria into the ventricles. (3) The atrial contractions must be gentle enough so that the force of contraction does not exert significant back pressure that would impede venous flow. (4) The "let go" of the atria must be timed so that they relax before the start of ventricular contraction, to be able to accept venous flow without interruption.
By preventing the inertia of interrupted venous flow that would otherwise occur at each ventricular systole, atria allow approximately 75% more cardiac output than would otherwise occur. The fact that atrial contraction is 15% of the amount of the succeeding ventricular ejection has led to a misplaced emphasis on their role in pumping up the ventricles (the so-called "atrial kick"), whereas the key benefit of atria is in preventing circulatory inertia and allowing uninterrupted venous flow to the heart.
Also of importance in maintaining the blood flow are the presence of atrial volume receptors. These are low-pressure baroreceptors in the atria, which send signals to the hypothalamus when a drop in atrial pressure (which indicates a drop in blood volume) is detected. This triggers a release of vasopressin.
== Disorders ==
=== Atrial septal defect ===
In an adult, an atrial septal defect results in the flow of blood in the reverse direction – from the left atrium to the right – which reduces cardiac output, potentially causing cardiac failure, and in severe or untreated cases cardiac arrest and sudden death.
=== Left atrial appendage thrombosis ===
In patients with atrial fibrillation, mitral valve disease, and other conditions, blood clots have a tendency to form in the left atrial appendage. The clots may dislodge (forming emboli), which may lead to ischemic damage to the brain, kidneys, or other organs supplied by the systemic circulation.
In those with uncontrollable atrial fibrillation, left atrial appendage occlusion may be performed at the time of any open-heart surgery to prevent future clot formation within the appendage.
=== Functional abnormalities ===
Wolff–Parkinson–White syndrome
Atrial fibrillation
Atrial flutter
Atrial tachycardia
Sinus tachycardia
Multifocal atrial tachycardia – several types
Premature atrial contraction
== Other animals ==
Many other animals, including mammals, also have four-chambered hearts, which have a similar function. Some animals (amphibians and reptiles) have a three-chambered heart, in which the blood from each atrium is mixed in the single ventricle before being pumped to the aorta. In these animals, the left atrium still serves the purpose of collecting blood from the pulmonary veins.
In most fish, the circulatory system is very simple: a two-chambered heart including one atrium and one ventricle. Among sharks, the heart consists of four parts arranged serially: blood flows into the most posterior part, the sinus venosus, and then to the atrium which moves it to the third part, the ventricle, before it reaches the conus anteriosus, which itself is connected to the ventral aorta. This is considered a primitive arrangement, and many vertebrates have condensed the atrium with the sinus venosus and the ventricle with the conus anteriosus.
With the advent of lungs came a partitioning of the atrium into two parts divided by a septum. Among frogs, the oxygenated and deoxygenated blood is mixed in the ventricle before being pumped out to the body's organs; in turtles, the ventricle is almost entirely divided by a septum, but retains an opening through which some mixing of blood occurs. In birds, mammals, and some other reptiles (alligators in particular) the partitioning of both chambers is complete.
== See also ==
Atrial syncytium
Left atrial volume
== References ==
== External links ==
Media related to Heart atria at Wikimedia Commons | Wikipedia/Left_atrial_appendage |
Medical diagnosis (abbreviated Dx, Dx, or Ds) is the process of determining which disease or condition explains a person's symptoms and signs. It is most often referred to as a diagnosis with the medical context being implicit. The information required for a diagnosis is typically collected from a history and physical examination of the person seeking medical care. Often, one or more diagnostic procedures, such as medical tests, are also done during the process. Sometimes the posthumous diagnosis is considered a kind of medical diagnosis.
Diagnosis is often challenging because many signs and symptoms are nonspecific. For example, redness of the skin (erythema), by itself, is a sign of many disorders and thus does not tell the healthcare professional what is wrong. Thus differential diagnosis, in which several possible explanations are compared and contrasted, must be performed. This involves the correlation of various pieces of information followed by the recognition and differentiation of patterns. Occasionally the process is made easy by a sign or symptom (or a group of several) that is pathognomonic.
Diagnosis is a major component of the procedure of a doctor's visit. From the point of view of statistics, the diagnostic procedure involves classification tests.
== Medical uses ==
A diagnosis, in the sense of diagnostic procedure, can be regarded as an attempt at classification of an individual's condition into separate and distinct categories that allow medical decisions about treatment and prognosis to be made. Subsequently, a diagnostic opinion is often described in terms of a disease or other condition. (In the case of a wrong diagnosis, however, the individual's actual disease or condition is not the same as the individual's diagnosis.) A total evaluation of a condition is often termed a diagnostic workup.
A diagnostic procedure may be performed by various healthcare professionals such as a physician, physiotherapist, dentist, podiatrist, optometrist, nurse practitioner, healthcare scientist or physician assistant. This article uses diagnostician as any of these person categories.
A diagnostic procedure (as well as the opinion reached thereby) does not necessarily involve elucidation of the etiology of the diseases or conditions of interest, that is, what caused the disease or condition. Such elucidation can be useful to optimize treatment, further specify the prognosis or prevent recurrence of the disease or condition in the future.
The initial task is to detect a medical indication to perform a diagnostic procedure. Indications include:
Detection of any deviation from what is known to be normal, such as can be described in terms of, for example, anatomy (the structure of the human body), physiology (how the body works), pathology (what can go wrong with the anatomy and physiology), psychology (thought and behavior) and human homeostasis (regarding mechanisms to keep body systems in balance). Knowledge of what is normal and measuring of the patient's current condition against those norms can assist in determining the patient's particular departure from homeostasis and the degree of departure, which in turn can assist in quantifying the indication for further diagnostic processing.
A complaint expressed by a patient.
The fact that a patient has sought a diagnostician can itself be an indication to perform a diagnostic procedure. For example, in a doctor's visit, the physician may already start performing a diagnostic procedure by watching the gait of the patient from the waiting room to the doctor's office even before she or he has started to present any complaints.
Even during an already ongoing diagnostic procedure, there can be an indication to perform another, separate, diagnostic procedure for another, potentially concomitant, disease or condition. This may occur as a result of an incidental finding of a sign unrelated to the parameter of interest, such as can occur in comprehensive tests such as radiological studies like magnetic resonance imaging or blood test panels that also include blood tests that are not relevant for the ongoing diagnosis.
== Procedure ==
General components which are present in a diagnostic procedure in most of the various available methods include:
Complementing the already given information with further data gathering, which may include questions of the medical history (potentially from other people close to the patient as well), physical examination and various diagnostic tests. A diagnostic test is any kind of medical test performed to aid in the diagnosis or detection of disease. Diagnostic tests can also be used to provide prognostic information on people with established disease.
Processing of the answers, findings or other results. Consultations with other providers and specialists in the field may be sought.
There are a number of methods or techniques that can be used in a diagnostic procedure, including performing a differential diagnosis or following medical algorithms.: 198 In reality, a diagnostic procedure may involve components of multiple methods.: 204
=== Differential diagnosis ===
The method of differential diagnosis is based on finding as many candidate diseases or conditions as possible that can possibly cause the signs or symptoms, followed by a process of elimination or at least of rendering the entries more or less probable by further medical tests and other processing, aiming to reach the point where only one candidate disease or condition remains as probable. The result may also remain a list of possible conditions, ranked in order of probability or severity. Such a list is often generated by computer-aided diagnosis systems.
The resultant diagnostic opinion by this method can be regarded more or less as a diagnosis of exclusion. Even if it does not result in a single probable disease or condition, it can at least rule out any imminently life-threatening conditions.
Unless the provider is certain of the condition present, further medical tests, such as medical imaging, are performed or scheduled in part to confirm or disprove the diagnosis but also to document the patient's status and keep the patient's medical history up to date.
If unexpected findings are made during this process, the initial hypothesis may be ruled out and the provider must then consider other hypotheses.
=== Pattern recognition ===
In a pattern recognition method the provider uses experience to recognize a pattern of clinical characteristics.: 198, It is mainly based on certain symptoms or signs being associated with certain diseases or conditions, not necessarily involving the more cognitive processing involved in a differential diagnosis.
This may be the primary method used in cases where diseases are "obvious", or the provider's experience may enable him or her to recognize the condition quickly. Theoretically, a certain pattern of signs or symptoms can be directly associated with a certain therapy, even without a definite decision regarding what is the actual disease, but such a compromise carries a substantial risk of missing a diagnosis which actually has a different therapy so it may be limited to cases where no diagnosis can be made.
=== Diagnostic criteria ===
The term diagnostic criteria designates the specific combination of signs and symptoms, and test results that the clinician uses to attempt to determine the correct diagnosis.
Some examples of diagnostic criteria, also known as clinical case definitions, are:
Amsterdam criteria for hereditary nonpolyposis colorectal cancer
McDonald criteria for multiple sclerosis
ACR criteria for systemic lupus erythematosus
Centor criteria for strep throat
=== Clinical decision support system ===
Clinical decision support systems are interactive computer programs designed to assist health professionals with decision-making tasks. The clinician interacts with the software utilizing both the clinician's knowledge and the software to make a better analysis of the patients data than either human or software could make on their own. Typically the system makes suggestions for the clinician to look through and the clinician picks useful information and removes erroneous suggestions. Some programs attempt to do this by replacing the clinician, such as reading the output of a heart monitor. Such automated processes are usually deemed a "device" by the FDA and require regulatory approval. In contrast, clinical decision support systems that "support" but do not replace the clinician are deemed to be "Augmented Intelligence" if it meets the FDA criteria that (1) it reveals the underlying data, (2) reveals the underlying logic, and (3) leaves the clinician in charge to shape and make the decision.
=== Other diagnostic procedure methods ===
Other methods that can be used in performing a diagnostic procedure include:
Usage of medical algorithms
An "exhaustive method", in which every possible question is asked and all possible data is collected.: 198
== Adverse effects ==
Diagnosis problems are the dominant cause of medical malpractice payments, accounting for 35% of total payments in a study of 25 years of data and 350,000 claims.
=== Overdiagnosis ===
Overdiagnosis is the diagnosis of "disease" that will never cause symptoms or death during a patient's lifetime. It is a problem because it turns people into patients unnecessarily and because it can lead to economic waste (overutilization) and treatments that may cause harm. Overdiagnosis occurs when a disease is diagnosed correctly, but the diagnosis is irrelevant. A correct diagnosis may be irrelevant because treatment for the disease is not available, not needed, or not wanted.
=== Errors ===
Most people will experience at least one diagnostic error in their lifetime, according to a 2015 report by the National Academies of Sciences, Engineering, and Medicine.
Causes and factors of error in diagnosis are:
the manifestation of disease are not sufficiently noticeable
a disease is omitted from consideration
too much significance is given to some aspect of the diagnosis
the condition is a rare disease with symptoms suggestive of many other conditions
the condition has a rare presentation
=== Lag time ===
When making a medical diagnosis, a lag time is a delay in time until a step towards diagnosis of a disease or condition is made. Types of lag times are mainly:
Onset-to-medical encounter lag time, the time from onset of symptoms until visiting a health care provider
Encounter-to-diagnosis lag time, the time from first medical encounter to diagnosis
Lag time due to delays in reading x-rays have been cited as a major challenge in care delivery. The Department of Health and Human Services has reportedly found that interpretation of x-rays is rarely available to emergency room physicians prior to patient discharge.
Long lag times are often called "diagnostic odyssey".
== History ==
The first recorded examples of medical diagnosis are found in the writings of Imhotep (2630–2611 BC) in ancient Egypt (the Edwin Smith Papyrus). A Babylonian medical textbook, the Diagnostic Handbook written by Esagil-kin-apli (fl.1069–1046 BC), introduced the use of empiricism, logic and rationality in the diagnosis of an illness or disease. Traditional Chinese Medicine, as described in the Yellow Emperor's Inner Canon or Huangdi Neijing, specified four diagnostic methods: inspection, auscultation-olfaction, inquiry and palpation. Hippocrates was known to make diagnoses by tasting his patients' urine and smelling their sweat.
== Word ==
Medical diagnosis or the actual process of making a diagnosis is a cognitive process. A clinician uses several sources of data and puts the pieces of the puzzle together to make a diagnostic impression. The initial diagnostic impression can be a broad term describing a category of diseases instead of a specific disease or condition. After the initial diagnostic impression, the clinician obtains follow up tests and procedures to get more data to support or reject the original diagnosis and will attempt to narrow it down to a more specific level. Diagnostic procedures are the specific tools that the clinicians use to narrow the diagnostic possibilities.
The plural of diagnosis is diagnoses. The verb is to diagnose, and a person who diagnoses is called a diagnostician.
=== Etymology ===
The word diagnosis is derived through Latin from the Greek word διάγνωσις (diágnōsis) from διαγιγνώσκειν (diagignṓskein), meaning "to discern, distinguish".
== Society and culture ==
=== Social context ===
Diagnosis can take many forms. It might be a matter of naming the disease, lesion, dysfunction or disability. It might be a management-naming or prognosis-naming exercise. It may indicate either degree of abnormality on a continuum or kind of abnormality in a classification. It is influenced by non-medical factors such as power, ethics and financial incentives for patient or doctor. It can be a brief summation or an extensive formulation, even taking the form of a story or metaphor. It might be a means of communication such as a computer code through which it triggers payment, prescription, notification, information or advice. It might be pathogenic or salutogenic. It is generally uncertain and provisional.
Once a diagnostic opinion has been reached, the provider is able to propose a management plan, which will include treatment as well as plans for follow-up. From this point on, in addition to treating the patient's condition, the provider can educate the patient about the etiology, progression, prognosis, other outcomes, and possible treatments of her or his ailments, as well as providing advice for maintaining health.
A treatment plan is proposed which may include therapy and follow-up consultations and tests to monitor the condition and the progress of the treatment, if needed, usually according to the medical guidelines provided by the medical field on the treatment of the particular illness.
Relevant information should be added to the medical record of the patient.
A failure to respond to treatments that would normally work may indicate a need for review of the diagnosis.
Nancy McWilliams identifies five reasons that determine the necessity for diagnosis:
diagnosis for treatment planning;
information contained in it related to prognosis;
protecting interests of patients;
a diagnosis might help the therapist to empathize with his patient;
might reduce the likelihood that some fearful patients will go-by the treatment.
== Types ==
Sub-types of diagnoses include:
Clinical diagnosis
A diagnosis made on the basis of medical signs and reported symptoms, rather than diagnostic tests
Laboratory diagnosis
A diagnosis based significantly on laboratory reports or test results, rather than the physical examination of the patient. For instance, a proper diagnosis of infectious diseases usually requires both an examination of signs and symptoms, as well as laboratory test results and characteristics of the pathogen involved.
Radiology diagnosis
A diagnosis based primarily on the results from medical imaging studies. Greenstick fractures are common radiological diagnoses.
Electrography diagnosis
A diagnosis based on measurement and recording of electrophysiologic activity.
Endoscopy diagnosis
A diagnosis based on endoscopic inspection and observation of the interior of a hollow organ or cavity of the body.
Tissue diagnosis
A diagnosis based on the macroscopic, microscopic, and molecular examination of tissues such as biopsies or whole organs. For example, a definitive diagnosis of cancer is made via tissue examination by a pathologist.
Principal diagnosis
The single medical diagnosis that is most relevant to the patient's chief complaint or need for treatment. Many patients have additional diagnoses.
Admitting diagnosis
The diagnosis given as the reason why the patient was admitted to the hospital; it may differ from the actual problem or from the discharge diagnoses, which are the diagnoses recorded when the patient is discharged from the hospital.
Differential diagnosis
A process of identifying all of the possible diagnoses that could be connected to the signs, symptoms, and lab findings, and then ruling out diagnoses until a final determination can be made.
Diagnostic criteria
Designates the combination of signs, symptoms, and test results that the clinician uses to attempt to determine the correct diagnosis. They are standards, normally published by international committees, and they are designed to offer the best sensitivity and specificity possible, respect the presence of a condition, with the state-of-the-art technology.
Prenatal diagnosis
Diagnosis work done before birth
Diagnosis of exclusion
A medical condition whose presence cannot be established with complete confidence from history, examination or testing. Diagnosis is therefore by elimination of all other reasonable possibilities.
Dual diagnosis
The diagnosis of two related, but separate, medical conditions or comorbidities. The term almost always referred to a diagnosis of a serious mental illness and a substance use disorder, however, the increasing prevalence of genetic testing has revealed many cases of patients with multiple concomitant genetic disorders.
Self-diagnosis
The diagnosis or identification of a medical conditions in oneself. Self-diagnosis is very common.
Remote diagnosis
A type of telemedicine that diagnoses a patient without being physically in the same room as the patient.
Nursing diagnosis
Rather than focusing on biological processes, a nursing diagnosis identifies people's responses to situations in their lives, such as a readiness to change or a willingness to accept assistance.
Computer-aided diagnosis
Providing symptoms allows the computer to identify the problem and diagnose the user to the best of its ability. Health screening begins by identifying the part of the body where the symptoms are located; the computer cross-references a database for the corresponding disease and presents a diagnosis.
Overdiagnosis
The diagnosis of "disease" that will never cause symptoms, distress, or death during a patient's lifetime
Wastebasket diagnosis
A vague, or even completely fake, medical or psychiatric label given to the patient or to the medical records department for essentially non-medical reasons, such as to reassure the patient by providing an official-sounding label, to make the provider look effective, or to obtain approval for treatment. This term is also used as a derogatory label for disputed, poorly described, overused, or questionably classified diagnoses, such as pouchitis and senility, or to dismiss diagnoses that amount to overmedicalization, such as the labeling of normal responses to physical hunger as reactive hypoglycemia.
Retrospective diagnosis
The labeling of an illness in a historical figure or specific historical event using modern knowledge, methods and disease classifications.
== See also ==
=== Lists ===
List of diagnostic classification and rating scales used in psychiatry
List of diseases
List of disorders
List of medical symptoms
Category:Diseases
== References ==
== External links ==
Media related to Medical diagnosis at Wikimedia Commons | Wikipedia/Clinical_diagnosis |
The United States Preventive Services Task Force (USPSTF) is "an independent panel of experts in primary care and prevention that systematically reviews the evidence of effectiveness and develops recommendations for clinical preventive services". The task force, a volunteer panel of primary care clinicians (including those from internal medicine, pediatrics, family medicine, obstetrics and gynecology, nursing, and psychology) with methodology experience including epidemiology, biostatistics, health services research, decision sciences, and health economics, is funded, staffed, and appointed by the U.S. Department of Health and Human Services' Agency for Healthcare Research and Quality.
== Intent ==
The USPSTF evaluates scientific evidence to determine whether medical screenings, counseling, and preventive medications work for adults and children who have no symptoms.
== Methods ==
The methods of evidence synthesis used by the Task Force have been described in detail. In 2007, their methods were revised.
=== No weight given to cost-effectiveness ===
The USPSTF explicitly does not consider cost as a factor in its recommendations, and it does not perform cost-effectiveness analyses. American health insurance groups are required to cover, at no charge to the patient, any service that the USPSTF recommends, regardless of how much it costs or how small the benefit is.
=== Grade definitions ===
The task force assigns the letter grades A, B, C, D, or I to each of its recommendations, and includes "suggestions for practice" for each grade. The Task Force also defined levels of certainty regarding net benefit.
Levels of certainty vary from high to low according to the evidence.
High: Consistent results from well-designed studies in representative populations that assess the effect of the service on health outcomes.
Moderate: The evidence is sufficient to determine the effects of the service, but confidence is limited. The conclusion might change as more information becomes available.
Low: The evidence is insufficient to assess effects on health outcome.
== Recommended prevention ==
The USPSTF has evaluated many interventions for prevention and found several have an expected net benefit in the general population.
Aspirin in men 45 to 79 and women 55 to 79 for cardiovascular disease
Colon cancer screening by colonoscopy, occult blood testing, or sigmoidoscopy in adults 45 to 75.
Low-dose CT scans for adults 55 to 80 at increased risk of lung cancer
Osteoporosis screening via bone dual-energy X-ray absorptiometry (DEXA) in women over 65
== Breast cancer screening ==
The USPSTF has changed its breast cancer screening recommendations over the years, including at what age women should begin routine screening. In 2009, the task force recommended women at average risk for developing breast cancer should be screened with mammograms every two years beginning at age 50. Previously, they had recommended beginning screening at age 40. The recommendation to begin screening at an older age received significant attention, including proposed congressional intervention. The 2016 recommendations maintained 50 as the age when routine screening should begin.
In April 2024, The USPSTF lowered the recommended age to begin breast cancer screening. Citing rising rates of breast cancer diagnosis and substantially higher rates among Black women in the United States, the task force recommends screening mammograms every two years beginning at age 40. This recommendation applies to all cisgender women and all other people assigned female at birth who are at average risk for breast cancer.
== Prostate cancer screening ==
In the current recommendation published in 2018, the Task Force recommended that prostate-specific antigen (PSA)-based screening for prostate cancer screenings be an individual decision for men between the ages of 55 and 69. In 2018 the Task Force gave PCa screening a C recommendation.
A final statement published in 2018 recommends basing the decision to screen on shared decision making in those 55 to 69 years old. It continues to recommend against screening in those 70 and older.
== History ==
The initial USPSTF was created in 1984 as a 5 year appointment to "develop recommendations for primary care clinicians on the appropriate content of periodic health examinations" and was modelled on the Canadian Task Force on Preventive Health Care, established in 1976. This initial 5 year project concluded in 1989 with the release of their report, the Guide to Clinical Preventive Services. In July 1990, the Department of Health and Human Services reconstituted the Task Force to continue and update these scientific assessments of preventive services.
== References ==
== External links ==
USPSTF on Agency for Healthcare Research and Quality (AHRQ) website
USPSTF website | Wikipedia/U.S._Preventive_Services_Task_Force |
A coronary catheterization is a minimally invasive procedure to access the coronary circulation and blood filled chambers of the heart using a catheter. It is performed for both diagnostic and interventional (treatment) purposes.
Coronary catheterization is one of the several cardiology diagnostic tests and procedures. Specifically, through the injection of a liquid radiocontrast agent and illumination with X-rays, angiocardiography allows the recognition of occlusion, stenosis, restenosis, thrombosis or aneurysmal enlargement of the coronary artery lumens; heart chamber size; heart muscle contraction performance; and some aspects of heart valve function. Important internal heart and lung blood pressures, not measurable from outside the body, can be accurately measured during the test. The relevant problems that the test deals with most commonly occur as a result of advanced atherosclerosis – atheroma activity within the wall of the coronary arteries. Less frequently, valvular, heart muscle, or arrhythmia issues are the primary focus of the test.
Coronary artery luminal narrowing reduces the flow reserve for oxygenated blood to the heart, typically producing intermittent angina. Very advanced luminal occlusion usually produces a heart attack. However, it has been increasingly recognized, since the late 1980s, that coronary catheterization does not allow the recognition of the presence or absence of coronary atherosclerosis itself, only significant luminal changes which have occurred as a result of end stage complications of the atherosclerotic process. See IVUS and atheroma for a better understanding of this issue.
== History ==
The technique of angiography itself was first developed in 1927 by the Portuguese physician Egas Moniz at the University of Lisbon for cerebral angiography, the viewing of brain vasculature by X-ray radiation with the aid of a contrast medium introduced by catheter.
Heart catheterization was first performed in 1929 when the German physician Werner Forssmann inserted a plastic tube in his cubital vein and guided it to the right chamber of the heart. He took an x-ray to prove his success and published it on November 5, 1929, with the title "Über die Sondierung des rechten Herzens" (About probing of the right heart).
In the early 1940s, André Cournand, in collaboration with Dickinson Richards, performed more systematic measurements of the hemodynamics of the heart. For their work in the discovery of cardiac catheterization and hemodynamic measurements, Cournand, Forssmann, and Richards shared the Nobel Prize in Physiology or Medicine in 1956. The first radial access for angiography can be traced back to 1953, where Eduardo Pereira, in Lisbon, Portugal, first cannulated the radial artery to perform a coronary angiogram.
In 1960 F. Mason Sones, a pediatric cardiologist at the Cleveland Clinic, accidentally injected radiocontrast in a coronary artery instead of the left ventricle. Although the patient had a reversible cardiac arrest, Sones and Shirey developed the procedure further, and are credited with the discovery (Connolly 2002); they published a series of 1,000 patents in 1966 (Proudfit et al.).
Since the late 1970s, building on the pioneering work of Charles Dotter in 1964 and especially Andreas Gruentzig starting in 1977, coronary catheterization has been extended to therapeutic uses: (a) the performance of less invasive physical treatment for angina and some of the complications of severe atherosclerosis, (b) treating heart attacks before complete damage has occurred and (c) research for better understanding of the pathology of coronary artery disease and atherosclerosis.
In the early 1960s, cardiac catheterization frequently took several hours and involved significant complications for as many as 2–3% of patients. With multiple incremental improvements over time, simple coronary catheterization examinations are now commonly done more rapidly and with significantly improved outcomes.
== Indications ==
Indications for cardiac catheterization include the following:
Heart Attack (includes ST elevation MI, Non-ST Elevation MI, Unstable Angina)
Abnormal Stress Test
New-onset unexplained heart failure
Survival of sudden cardiac death or dangerous cardiac arrhythmia
Persistent chest pain despite optimal medical therapy
Workup of suspected Prinzmetal angina (coronary vasospasm)
== Patient participation ==
The patient being examined or treated is usually awake during catheterization, ideally with only local anaesthesia such as lidocaine and minimal general sedation, throughout the procedure. Performing the procedure with the patient awake is safer as the patient can immediately report any discomfort or problems and thereby facilitate rapid correction of any undesirable events. Medical monitors fail to give a comprehensive view of the patient's immediate well-being; how the patient feels is often a most reliable indicator of procedural safety.
Death, myocardial infarction, stroke, serious ventricular arrhythmia, and major vascular complications each occur in less than 1% of patients undergoing catheterization. However, though the imaging portion of the examination is often brief, because of setup and safety issues, the patient is often in the lab for 20–45 minutes. Any of multiple technical difficulties, while not endangering the patient (indeed added to protect the patient's interests), can significantly increase the examination time.
== Equipment ==
Coronary catheterization is performed in a catheterization lab, usually located within a hospital. With current designs, the patient must lie relatively flat on a narrow, minimally padded, radiolucent (transparent to X-ray) table. The X-ray source and imaging camera equipment are on opposite sides of the patient's chest and freely move, under motorized control, around the patient's chest so images can be taken quickly from multiple angles. More advanced equipment, termed a bi-plane cath lab, uses two sets of X-ray source and imaging cameras, each free to move independently, which allows two sets of images to be taken with each injection of radiocontrast agent. The equipment and installation setup to perform such testing typically represents a capital expenditure of US$2–5 million (2004), sometimes more, partially repeated every few years.
== Diagnostic procedures ==
During coronary catheterization (often referred to as a "cath" or "cardiac cath" by physicians), blood pressures are recorded and fluoroscopy (X-ray motion picture) shadow-grams of the blood inside the coronary arteries are recorded. In order to create the X-ray pictures, a physician guides a small tube-like device called a catheter, typically ~2.0 mm (6-French) in diameter, through the large arteries of the body until the tip is just within the opening of one of the coronary arteries. By design, the catheter is smaller than the lumen of the artery it is placed in; internal (intra-arterial) blood pressures are monitored through the catheter to verify that the catheter does not block blood flow (as indicated by "dampening" of the blood pressure).
The catheter is itself designed to be radiodense for visibility and it allows a clear, watery, blood compatible radiocontrast agent, commonly called an X-ray dye, to be selectively injected and mixed with the blood flowing within the artery. Typically 3–8 cc of the radiocontrast agent is injected for each image to make the blood flow visible for about 3–5 seconds as the radiocontrast agent is rapidly washed away into the coronary capillaries and then coronary veins. Without the X-ray dye injection, the blood and surrounding heart tissues appear, on X-ray, as only a mildly-shape-changing, otherwise uniform water density mass; no details of the blood and internal organ structure are discernible. The radiocontrast within the blood allows visualization of the blood flow within the arteries or heart chambers, depending on where it is injected.
If atheroma, or clots, are protruding into the lumen, producing narrowing, the narrowing may be seen instead as increased haziness within the X-ray shadow images of the blood/dye column within that portion of the artery; this is as compared to adjacent, presumed healthier, less stenotic areas.
For guidance regarding catheter positions during the examination, the physician mostly relies on detailed knowledge of internal anatomy, guide wire and catheter behavior and intermittently, briefly uses fluoroscopy and a low X-ray dose to visualize when needed. This is done without saving recordings of these brief looks. When the physician is ready to record diagnostic views, which are saved and can be more carefully scrutinized later, he activates the equipment to apply a significantly higher X-ray dose, termed cine, in order to create better quality motion picture images, having sharper radiodensity contrast, typically at 30 frames per second. The physician controls both the contrast injection, fluoroscopy and cine application timing so as to minimize the total amount of radiocontrast injected and times the X-ray to the injection so as to minimize the total amount of X-ray used. Doses of radiocontrast agents and X-ray exposure times are routinely recorded in an effort to maximize safety.
Though not the focus of the test, calcification within the artery walls, located in the outer edges of atheroma within the artery walls, is sometimes recognizable on fluoroscopy (without contrast injection) as radiodense halo rings partially encircling, and separated from the blood filled lumen by the interceding radiolucent atheroma tissue and endothelial lining. Calcification, even though usually present, is usually only visible when quite advanced and calcified sections of the artery wall happen to be viewed on end tangentially through multiple rings of calcification, so as to create enough radiodensity to be visible on fluoroscopy.
=== For congenital malformations ===
Angiocardiography can be used to detect and diagnose congenital defects in the heart and adjacent vessels. In this context, the use of angiocardiography has declined with the introduction of echocardiography. However, angiocardiography is still in use for selected cases as it provides a higher level of anatomical detail than echocardiography.
== Therapeutic procedures ==
By changing the diagnostic catheter to a guiding catheter, physicians can also pass a variety of instruments through the catheter and into the artery to a lesion site. The most commonly used are 0.014-inch-diameter (0.36 mm) guide wires and the balloon dilation catheters.
By injecting radiocontrast agent through a tiny passage extending down the balloon catheter and into the balloon, the balloon is progressively expanded. The hydraulic pressures are chosen and applied by the physician, according to how the balloon within the stenosis (abnormal narrowing in a blood vessel) responds. The radiocontrast filled balloon is watched under fluoroscopy (it typically assumes a "dog bone" shape imposed on the outside of the balloon by the stenosis as the balloon is expanded), as it opens. As much hydraulic brute force is applied as judged needed and visualized to be effective to make the stenosis of the artery lumen visibly enlarge.
Typical normal coronary artery pressures are in the <200 mmHg range (27 kPa). The hydraulic pressures applied within the balloon may extend to as high as 19000 mmHg (2,500 kPa). Prevention of over-enlargement is achieved by choosing balloons manufactured out of high tensile strength clear plastic membranes. The balloon is initially folded around the catheter, near the tip, to create a small cross-sectional profile to facilitate passage through luminal stenotic areas, and is designed to inflate to a specific pre-designed diameter. If over-inflated, the balloon material simply tears and allows the inflating radiocontrast agent to simply escape into the blood.
Additionally, several other devices can be advanced into the artery via a guiding catheter. These include laser catheters, stent catheters, IVUS catheters, Doppler catheter, pressure or temperature measurement catheter and various clot and grinding or removal devices. Most of these devices have turned out to be niche devices, only useful in a small percentage of situations or for research.
Stents, which are specially manufactured expandable stainless steel mesh tubes, mounted on a balloon catheter, are the most commonly used device beyond the balloon catheter. When the stent/balloon device is positioned within the stenosis, the balloon is inflated which, in turn, expands the stent and the artery. The balloon is removed and the stent remains in place, supporting the inner artery walls in the more open, dilated position. Current stents generally cost around $1,000 to 3,000 each (US 2004 dollars), the drug-coated ones being the more expensive.
== Advances in catheter-based physical treatments ==
Interventional procedures have been plagued by restenosis due to the formation of endothelial tissue overgrowth at the lesion site. Restenosis is the body's response to the injury of the vessel wall from angioplasty and to the stent as a foreign body. As assessed in clinical trials during the late 1980 and 1990s, using only balloon angioplasty (POBA, plain old balloon angioplasty), up to 50% of patients developed significant restenosis; but that percentage has dropped to the single to lower two-digit range with the introduction of drug-eluting stents. Sirolimus, paclitaxel, and everolimus are the three drugs used in coatings which are currently FDA approved in the United States. As opposed to bare metal, drug-eluting stents are covered with a medicine that is slowly dispersed with the goal of suppressing the restenosis reaction. The key to the success of drug coating has been (a) choosing effective agents, (b) developing ways of adequately binding the drugs to the stainless surface of the stent struts (the coating must stay bound despite marked handling and stent deformation stresses), and (c) developing coating controlled release mechanisms that release the drug slowly over about 30 days. One of the newest innovations in coronary stents is the development of a dissolving stent. Abbott Laboratories has used a dissolvable material, polylactic acid, that will completely absorb within 2 years of being implanted.
== Alternative approaches ==
CT angiography can act as a less invasive alternative to Catheter angiography. Instead of a catheter being inserted into a vein or artery, CT angiography involves only the injection of a CT-visible dye into the arm or hand via an IV line. CT angiography lowers the risk of arterial perforation and catheter site infection. It provides 3D images that can be studied on computer, and also allows measurement of heart ventricle size. Infarct area and arterial calcium can also be observed (however those require a somewhat higher radiation exposure). That said, one advantage retained by Catheter angiography is the ability of the physician to perform procedure such as balloon angioplasty or insertion of a stent to improve blood flow to the artery.
== Radiation dosage ==
=== Angiography ===
Imaging in coronary angiograms is performed via fluoroscopy using X-rays, which pose a potential for increasing the patient's risk of radiation-induced cancer. The risk increases with the exposure time, consisting of 1) time guiding the probe into and out of the heart and 2) time illuminating the contrast agent to perform the angiogram. Absorbed radiation is also a function of body mass index, with obese patients having twice the dose of normal-weight patients; exposure to the operator was also doubled. Coronary angiograms can be done either transradial (through the wrist) or transfemoral (through the groin). The transradial route results in somewhat greater patient and operator exposure. Overall, patient exposure can range from 2 millisieverts (equivalent of about 20 chest x-ray plates) to 20 millisieverts. For a given patient, exposure can vary within an institution and between institutions by up to 121%.
Radiation exposure to the operator can be reduced by the use of protective equipment. Exposure to the patient can be reduced by minimizing fluoroscopy time.
== See also ==
Angiography
Interventional cardiology
Fractional flow reserve
== References ==
=== Notes ===
=== General ===
Connolly JE. The development of coronary artery surgery: personal recollections. Tex Heart Inst J 2002;29:10-4. PMID 11995842.
Proudfit WL, Shirey EK, Sones FM Jr. Selective cine coronary arteriography. Correlation with clinical findings in 1,000 patients. Circulation 1966;33:901-10. PMID 5942973.
Sones FM, Shirey EK. Cine coronary arteriography. Mod Concepts Cardiovasc Dis 1962;31:735-8. PMID 13915182.
[2] Coronary CT angiography by Eugene Lin
[3] Abbott Dissolving Stent May Be 'Next Revolution' by Michelle Fay Cortez
Selzer, Arthur (1992). Understanding heart disease. University of California Press. p. 43. ISBN 0-520-06560-3. | Wikipedia/Coronary_angiography |
Commonly prescribed drugs are drugs that are frequently provided by doctors in a prescription to treat a certain disease. These drugs are often first-line treatment for the target diseases and are effective in tackling the symptoms. An example of the target disease is ischemic heart disease. Some examples of commonly prescribed drugs for this disease are beta-blockers, calcium-channel blockers and nitrates.
In accordance with the pharmacological effects, commonly prescribed drugs can be divided into different groups. Drugs in the same group exert nearly identical effects, and can be utilized for treating the prevailing disease and sometimes, preventing complications of the existing diseases.
The use of commonly prescribed drugs can be reflected from the number of prescriptions of the drugs. Countries have their own dataset in recording the trend of commonly prescribed drugs. For example, the United States uses the Medical Expenditure Panel Survey (MEPS) and England uses the English Prescribing Dataset to record the prescription data for showing which drugs are commonly prescribed.
Understanding commonly prescribed drugs allows healthcare professionals to react to symptoms quickly and new treatment strategies can be developed. However, the data for commonly prescribed drugs may be outdated due to the time lag between data collection and publication as well as errors in data collection process.
== History ==
Commonly prescribed drugs are prescribed according to guidelines around the world. For instance, for ischemic heart disease, the American College of Cardiology/American Heart Association (ACC/AHA) guideline is used in the United States and the European Society of Cardiology (ESC) guideline is used in Europe. Western guidelines are more commonly used for reference during the development of local practice guidelines due to the large number of western guidelines stored in guideline databases. The data of prescriptions are collected through the government, such as Medical Expenditure Panel Survey (MEPS) in America and the Pharmaceutical Benefit Scheme (PBS) in Australia, providing information on the actual prescription volume of drugs.
=== The United States ===
The Medical Expenditure Panel Survey (MEPS) conducted by the Agency for Healthcare Research and Quality (AHRQ) via the United States government is used to collect prescription data and data for other healthcare services, including home healthcare, children's health and preventive care in America. The survey started in 1996 and was the predecessor of the National Medical Expenditure Survey (NMES) and the National Medical Care Utilization and Expenditure Survey (NMCUES), which were conducted in 1977 (NMES-1), 1980 (NMCUES), and 1987 (NMES-2). The survey is updated every year with the renewed data from the country. The prescription data is published in the Prescribed Medicines File of the MEPS. The collection of data involves two components: Household component and the Medical Provider component. The household component collects self-reported data of the prescribed medicines and the demographic information of the respondents. The Medical Provider component acts as a piece of follow-back information provided by the pharmacy including a computerized printout for all prescription filled for the patient.
=== The United Kingdom ===
The English Prescribing Dataset (EPD) from the NHS Business Services Authority (NHSBSA) provides prescription data in the United Kingdom. The dataset was created in 2014. EPD is a combination of the Detailed Prescribing Information (DPI) and the Practice Level Prescribing in England (PLP). Both DPI and PLP are previous datasets from NHSBSA and NHS Digital respectively and EPD aims to replace them both in the future, but no specific date of replacement is given. EPD collects data from England, Wales, Scotland, Guernsey, Alderney, Jersey and the Isle of Man. EPD provides the item, quantity, net ingredient cost, actual cost, average daily quantity (ADQ), practice name and address details of the prescription.
=== Australia ===
The Pharmaceutical Benefits Scheme (PBS) from the Australian Government Department of Health provides the prescription data of prescriptions under PBS. PBS started in 1948 and the under co-payment prescriptions were added into the dataset from 1 April 2012. It publishes the PBS expenditure and prescriptions report every year recording prescription data in the past 12 months. The examples of data it provides are the top 50 drugs by total prescription volume and the top 50 drugs by government cost.
== Benefits and limitations ==
=== Benefits ===
Understanding commonly prescribed drugs for different diseases can allow healthcare professionals to be more confident and decisive when choosing the most suitable treatment for the patient. This can also help develop new treatment strategies by researchers for more effective treatments. By enriching the knowledge of commonly prescribed drugs, pharmacy students will be more familiar with their mechanism of action, first-line therapy indications and side effects.
=== Limitations ===
Limitations include time lag for the conducted survey. The Medical Expenditure Panel Survey (MEPS) shows data recorded two years before the publishing of the survey. The time lag may lead to a difference in representing the current prescribing practice with the recorded data in the survey. Questionnaires which are self-reported tend to create recall bias. Respondents are likely to underreport the number of prescription drugs they have as those drugs are usually for short-term use and intermittent use, such as analgesics and topical agents.
== Examples of commonly prescribed drugs ==
Two diseases from the top 10 causes of death introduced by the World Health Organization (WHO) in 2019 are used as examples, namely ischemic heart disease (ranked 1st) from cardiovascular diseases and Chronic Obstructive Pulmonary Disease from respiratory diseases (ranked 3rd). Although stroke is ranked 2nd by WHO, drugs used are similar to ischemic heart disease. Moreover, surgical interventions are commonly required, so it will be out of the scope of this article and it will not be introduced.
=== Ischemic Heart Disease ===
Ischemic Heart Disease (IHD) or coronary heart disease is the lack of supply of blood to an area in the heart, often due to plaque formation (atherosclerosis), causing inadequacy of oxygen to heart muscle and eventually leading to myocardial infarction. This disease can be classified into acute and chronic coronary heart disease. This disease caused 8.9 million deaths in 2019 and was ranked 1st in the top 10 causes of death globally by the World Health Organization (WHO).
The treatment of Ischemic Heart Disease can be divided into two directions: risk factor control and symptomatic relief.
Commonly prescribed drugs for Ischemic Heart Disease
=== Chronic Obstructive Pulmonary Disease (COPD) ===
Chronic Obstructive Pulmonary Disease (COPD) is a disease that causes chronic respiratory problems by gradually blocking the respiratory tracts. The continuous exposure to toxic fumes produced by cigarettes, vehicle engines and other human activities leads to inflammation of the respiratory tract, causing the development of COPD. The problem will deteriorate over time if it is not well managed. It will eventually cause respiratory failure and death in the late stage. It is the third deadliest disease reported by WHO in 2019 and it accounted for 6% of total deaths.
There are two types of management plan in COPD, namely regular treatment and acute exacerbation. In acute exacerbation, new medications will be added to the existing prescription and they will be stopped once the exacerbation is managed.
==== Combination inhalers ====
In patients with COPD, multiple inhalers need to be used at a time. There are two major types of inhaler, namely dry-powder inhaler(DPI) and metered-dose inhaler(MDI), and many more subtypes with different techniques for using them. Adherence is also an issue with the use of multiple inhalers. Generally with different types of inhalers, the adherence will be lowered. Proper inhaler technique and adherence are two of the factors that affect the management of COPD. Other factors include smoking cessation and participation in physical activities, to name but a few. With inappropriately applied inhaler technique and low adherence, there will be ineffective management of COPD, thus increasing in the burden on the healthcare sector. As a result, inhalers combining multiple medications are invented to tackle the problem.
== References == | Wikipedia/Commonly_prescribed_drugs |
Tobacco control is a field of international public health science, policy and practice dedicated to addressing tobacco use and thereby reducing the morbidity and mortality it causes. Since most cigarettes and cigars and hookahs contain or use tobacco, tobacco control also addresses these products. Tobacco control is a priority area for the World Health Organization (WHO) as a part of the Framework Convention on Tobacco Control. References to a tobacco control movement may have either positive or negative connotations, depending upon the commentator.
Tobacco control aims to reduce the prevalence of tobacco and nicotine use and this is measured with the "age-standardized prevalence of current tobacco use among persons aged 15 years and older". E-cigarettes do not contain tobacco itself, but often contain nicotine, and are thus often are considered within the context of tobacco control.
== Connotations ==
The tobacco control field comprises the activity of disparate health, policy and legal research and reform advocacy bodies across the world. These took time to coalesce into a sufficiently organised coalition to advance such measures as the World Health Organization Framework Convention on Tobacco Control, and the first article of the first edition of the Tobacco Control journal suggested that developing as a diffusely organised movement was indeed necessary in order to bring about effective action to address the health effects of tobacco use.
The tobacco control movement has also been referred to as an anti-smoking movement by some who disagree with its aims, as documented in internal tobacco industry memoranda.
== Early history ==
The first attempts to respond to the health consequences to tobacco use followed soon after the introduction of tobacco to Europe. Pope Urban VII's thirteen-day papal reign included the world's first known tobacco use restrictions in 1590 when he threatened to excommunicate anyone who "took tobacco in the porchway of or inside a church, whether it be by chewing it, smoking it with a pipe or sniffing it in powdered form through the nose". In this restriction, tobacco was sentenced to excommunication, not so much because it harmed health, but because its use within the Churches was intolerable because it ruined the atmosphere of the masses. Thus, these sentences would not be made against tobacco per se (whose individual consumption was not penalized as long as it was moderate), but rather for its improper use in places considered sacred and public. The condemnation of improper use remains intact in Catholic doctrine today.
The earliest citywide European smoking restrictions were enacted in Bavaria, Kursachsen, and certain parts of Austria in the late 17th century.
In Britain, the still-new habit of smoking met royal opposition in 1604, when King James I wrote A Counterblaste to Tobacco, describing smoking as: "A custome loathsome to the eye, hateful to the nose, harmeful to the brain, dangerous to the lungs, and in the black stinking fume thereof, nearest resembling the horrible Stigian smoke of the pit that is bottomeless." His commentary was accompanied by a doctor of the same period, writing under the pseudonym "Philaretes", who as well as explaining tobacco's harmful effects under the system of the four humours ascribed an infernal motive to its introduction, explaining his dislike of tobacco as grounded upon eight 'principal reasons and arguments' (in their original spelling):
First, that in their use and custom, no method or order is observed. Diversitie and distinction of persons, times and seasons considered.
Secondly, for that it is in qualitie and complexion more hot and drye then may be conveniently used dayly of any man: much lesse of the hot and cholerique constitution.
Thirdly, for that it is experimented and tried to be a most strong and violent purge.
Fourthly, for that it witherete and drieth up naturall moisture in our bodies, thereby causing sterrilitie and barrennesses: In which respect it seemeth an enemy to the continuance and propagacion of mankinde.
Fiftly, for that it decayeth and dissipateh naturall heate, that kindly warmeth in us, and thereby is cause of crudities and rewmes, occasions of infinite maladies.
Sixtly, for that this herb is rather weeed, seemethe not voide of venome and poison, and thereby seemeth an enemy to the lyfe of man.
Seaventhly, for that the first author and finder hereof was the Divell, and the first practisers of the same were the Divells Preiests, and therefore not to be used of us Christians.
Last of all, because it is a great augmentor of all sorts of melancholie in our bodies, a humor fit to prepare our bodies to receave the prestigations and hellih illusions and impressions of the Divell himselfe: in so much that many Phisitions and learned mean doe hold this humour to be the verie seate of the Divell in bodies possessed.
Later in the seventeenth century, Sir Francis Bacon identified the addictive consequences of tobacco use, observing that it "is growing greatly and conquers men with a certain secret pleasure, so that those who have once become accustomed thereto can later hardly be restrained therefrom".
Smoking was forbidden in Berlin in 1723, in Königsberg in 1742, and in Stettin in 1744. These restrictions were repealed in the revolutions of 1848. In 1930s Germany, scientific research for the first time revealed a connection between lung cancer and smoking, so the use of cigarettes and smoking was strongly discouraged by a heavy government sponsored anti-smoking campaign.
== Modern origins ==
After the Second World War, German research was effectively silenced due to perceived associations with Nazism. However, the work of Richard Doll in the UK, who conclusively identified the causal link between smoking and lung cancer in 1952, brought this topic back to public attention. Partial controls and regulatory measures eventually followed in much of the developed world, including partial advertising bans, minimum age of sale requirements, and basic health warnings on tobacco packaging. However, smoking prevalence and associated health issues continued to rise in the developed world in the first three decades following Richard Doll's discovery, with governments sometimes reluctant to curtail a habit seen as socially acceptable, as a result - and increasingly organised disinformation efforts by the tobacco industry and their proxies (covered in more detail below). Realisation dawned gradually that the health effects of smoking and tobacco use were susceptible only to a multi-pronged policy response which combined positive health messages with medical assistance to cease tobacco use and effective marketing restrictions, as initially indicated in a 1962 overview by the British Royal College of Physicians and the 1964 report of the U.S. Surgeon General.
In the United States, the 1964 report of the Advisory Committee to the Surgeon General represented a landmark document that included an objective synthesis of the evidence of the health consequences of smoking according to causal criteria. The report concluded that cigarette smoking was a cause of lung cancer in men and sufficient in scope that "remedial action" was warranted at the societal level. The Surgeon General report process is an enduring example of evidence-based public health in practice.
== Comprehensive tobacco control ==
=== At the global level ===
The concept of multi-pronged and therefore 'comprehensive' tobacco control arose through academic advances (e.g. the dedicated Tobacco Control journal), not-for-profit advocacy groups such as Action on Smoking and Health and government policy initiatives. Progress was initially notable at a state or national level, particularly the pioneering smoke-free public places legislation introduced in New York City in 2002 and the Republic of Ireland in 2004, and the UK efforts to encapsulate the crucial elements of tobacco control activity in the 2004 'six-strand approach' (to deliver upon the joined-up approach set out in the white paper 'Smoking Kills' ) and its local equivalent, the 'seven hexagons of tobacco control'. This broadly organised set of health research and policy development bodies then formed the Framework Convention Alliance to negotiate and support the first international public health treaty, the World Health Organization Framework Convention on Tobacco Control, or FCTC for short.
The FCTC compels signatories to advance activity on the full range of tobacco control fronts, including limiting interactions between legislators and the tobacco industry, imposing taxes upon tobacco products and carrying out demand reduction, protecting people from exposure to second-hand smoke in indoor workplaces and public places through smoking bans, regulating and disclosing the contents and emissions of tobacco products, posting highly visible health warnings upon tobacco packaging, removing deceptive labelling (e.g. 'light' or 'mild'), improving public awareness of the consequences of smoking, prohibiting all tobacco advertising, provision of cessation programmes, effective counter-measures to smuggling of tobacco products, restriction of sales to minors and relevant research and information-sharing among the signatories.
WHO subsequently produced an internationally applicable and now widely recognized summary of the essential elements of tobacco control strategy, publicized as the mnemonic MPOWER tobacco control strategy. The six components are:
Monitor tobacco use and prevention policies
Protect people from tobacco smoke
Offer help to quit tobacco use
Warn about the dangers of tobacco
Enforce bans on tobacco advertising, promotion and sponsorship
Raise taxes on tobacco
One of the targets of the Sustainable Development Goal 3 of the United Nations (to be achieved by 2030) is to "Strengthen the implementation of the World Health Organization Framework Convention on Tobacco Control in all countries, as appropriate." The indicator that is used to measure progress is the "age-standardized prevalence of current tobacco use among persons aged 15 years and older".
In 2003, India passed the Cigarettes and Other Tobacco Products (Prohibition of Advertisement and Regulation of Trade and Commerce, Production, Supply and Distribution) Act, 2003, which restricted advertisement of tobacco products, banned smoking in public places, and placed other regulations on the trade of tobacco products. In 2010, Bhutan, passed the Tobacco Control Act of Bhutan 2010 to regulate tobacco and tobacco products, banning the cultivation, harvesting, production, and sale of tobacco and tobacco products in Bhutan; and the Hindi-language anti-smoking short film Swing is released.
=== Policies ===
==== Age restriction ====
Tobacco policies that limit the sale of cigarettes to minors and restrict smoking in public places are important strategies to deter youth from accessing and consuming cigarettes. Amongst youth in the United States, for example, when compared with students living in states with strict regulations, young adolescents living in states with no or minimal restrictions, particularly high school students, were more likely to be daily smokers. These effects were reduced when logistic regressions were adjusted for sociodemographic characteristics and cigarette price, suggesting that higher cigarette prices may discourage youth to access and consume cigarettes independent of other tobacco control measures.
In December 2022, New Zealand became the first country to pass a bill that effectively raises the minimum age for cigarette consumption annually, in an effort to prohibit their sale to future generations. The bill specifically prohibits the sale of cigarettes to anyone born on or after 1 January 2009. However, the law was later repealed before it could come into effect.
===== Graphic warning labels =====
Some smokers are not fully informed about the risks of smoking. Tobacco packaging warning messages which are graphic, larger, and more comprehensive in content are more effective in communicating health risks and knowledge about smoking. Smokers who noticed the warnings were significantly more likely to endorse health risks, including lung cancer and heart disease. In each instance where labelling policies differed between countries, smokers living in countries with government mandated warnings reported greater health knowledge.
Graphic warning labels on cigarette packs are noticed by the majority of adolescents, increase adolescents' cognitive processing of these messages and have the potential to lower smoking intentions. The introduction of graphic warning labels has greatly reduced smoking among adolescents.
===== Smoke-free public places =====
Smoking in indoor workplaces was first prohibited nationwide by the Republic of Ireland in 2003, with most other leading economies following suit with similar ordinances in subsequent years.
===== Smoking cessation =====
Smoking cessation services borrow from the methodologies of other addiction recovery interventions to assist smokers to quit. As well as reducing morbidity and mortality for individual patients, these have been repeatedly found to reduce the overall cost to health systems of treating smoking-related disease.
== Reception and further international collaboration ==
Now an accepted element of the public health arena, tobacco control policies and activity are seen to have been effective in those administrations which have implemented them in a co-ordinated fashion.
The tobacco control community is internationally organised - as is its main opponent, the tobacco industry (sometimes referred to as 'Big Tobacco'). This allows for sharing of effective practice (both in advocacy and policy) between developed and developing states, for instance through the World Conference on Tobacco or Health held every three years. However, some significant gaps remain, particularly the failure of the US and Switzerland (both bases for international tobacco companies and, in the former case, a tobacco producer) to ratify the FCTC.
=== Journal ===
Tobacco Control is also the name of a journal published by BMJ Group (the publisher of the British Medical Journal) which studies the nature and implications of tobacco use and the effect of tobacco use upon health, the economy, the environment and society. Edited by Ruth Malone, Professor and chair, Department of Social & Behavioral Sciences, University of California, San Francisco, it was first published in 1992.
== Opposition ==
Direct and indirect opposition from the tobacco industry continues, for instance through the tobacco industry's efforts at misinformation via suborned scientists and 'astroturf' counter-advocacy operations such as FOREST.
== See also ==
== Notes and references ==
== Bibliography ==
Chapman, Simon (2007). Public Health Advocacy and Tobacco Control: Making Smoking History. Wiley-Blackwell. ISBN 9781405161633.
Tate, Cassandra. Cigarette wars: the triumph of" the little white slaver" (Oxford University Press, USA, 2000) online.
Young, T. Kue (2005). Population Health: Concepts and Methods. Oxford University Press. ISBN 0-19-515854-7.
== External links ==
Tobacco Control journal
Tobacco Policy | Wikipedia/Tobacco_control |
Obesity is a medical condition, considered by multiple organizations to be a disease, in which excess body fat has accumulated to such an extent that it can potentially have negative effects on health. People are classified as obese when their body mass index (BMI)—a person's weight divided by the square of the person's height—is over 30 kg/m2; the range 25–30 kg/m2 is defined as overweight. Some East Asian countries use lower values to calculate obesity. Obesity is a major cause of disability and is correlated with various diseases and conditions, particularly cardiovascular diseases, type 2 diabetes, obstructive sleep apnea, certain types of cancer, and osteoarthritis.
Obesity has individual, socioeconomic, and environmental causes. Some known causes are diet, low physical activity, automation, urbanization, genetic susceptibility, medications, mental disorders, economic policies, endocrine disorders, and exposure to endocrine-disrupting chemicals.
While many people living with obesity attempt to lose weight and are often successful, maintaining weight loss long-term is rare. Obesity prevention requires a complex approach, including interventions at medical, societal, community, family, and individual levels. Changes to diet as well as exercising are the main treatments recommended by health professionals. Diet quality can be improved by reducing the consumption of energy-dense foods, such as those high in fat or sugars, and by increasing the intake of dietary fiber. The World Health Organization stresses that the disease is a societal responsibility and that these dietary choices should be made the most available, affordable, and accessible options. Medications can be used, along with a suitable diet, to reduce appetite or decrease fat absorption. If diet, exercise, and medication are not effective, a gastric balloon or surgery may be performed to reduce stomach volume or length of the intestines, leading to feeling full earlier, or a reduced ability to absorb nutrients from food. Many do not realize that metabolic surgery is not only about reducing intake, it has also been shown to alter gut hormones for a period of time.
Obesity is a leading preventable cause of death worldwide, with increasing rates in adults and children. In 2022, over 1 billion people lived with obesity worldwide (879 million adults and 159 million children), representing more than a double of adult cases (and four times higher than cases among children) registered in 1990. Obesity is more common in women than in men. Today, obesity is stigmatized in most of the world. Conversely, some cultures, past and present, have a favorable view of obesity, seeing it as a symbol of wealth and fertility. The World Health Organization, the US, Canada, Japan, Portugal, Germany, the European Parliament and medical societies, e.g. the American Medical Association, classify obesity as a disease. Others, such as the UK, do not.
== Classification ==
Obesity is typically defined as a substantial accumulation of body fat that could impact health. Medical organizations tend to classify people living with obesity as based on body mass index (BMI) – a ratio of a person's weight in kilograms to the square of their height in meters. For adults, the World Health Organization (WHO) defines "overweight" as a BMI 25 or higher, and "obesity" as a BMI 30 or higher. The U.S. Centers for Disease Control and Prevention (CDC) further subdivides obesity based on BMI, with a BMI 30 to 35 called class 1 obesity; 35 to 40, class 2 obesity; and 40+, class 3 obesity.
For children, obesity measures take age into consideration along with height and weight. For children aged 5–19, the WHO defines obesity as a BMI two standard deviations above the median for their age (a BMI around 18 for a five-year old; around 30 for a 19-year old). For children under five, the WHO defines obesity as a weight three standard deviations above the median for their height.
Some modifications to the WHO definitions have been made by particular organizations. The surgical literature breaks down class II and III or only class III obesity into further categories whose exact values are still disputed.
Any BMI ≥ 35 or 40 kg/m2 is severe obesity.
A BMI of ≥ 35 kg/m2 and experiencing obesity-related health conditions or ≥ 40 or 45 kg/m2 is morbid obesity.
A BMI of ≥ 45 or 50 kg/m2 is super obesity.
As Asian populations develop negative health consequences at a lower BMI than Caucasians, some nations have redefined obesity; Japan has defined obesity as any BMI greater than 25 kg/m2 while China uses a BMI of greater than 28 kg/m2.
The preferred obesity metric in scholarly circles is the body fat percentage (BF%) – the ratio of the total weight of person's fat to his or her body weight, and BMI is viewed merely as a way to approximate BF%. According to American Society of Bariatric Physicians, levels in excess of 32% for women and 25% for men are generally considered to indicate obesity.
BMI is now viewed as outdated in numerous countries. It ignores variations between individuals in amounts of lean body mass, particularly muscle mass. Individuals involved in heavy physical labor or sports may have high BMI values despite having little fat. For example, more than half of all NFL players are classified as "obese" (BMI ≥ 30), and 1 in 4 are classified as "extremely obese" (BMI ≥ 35), according to the BMI metric. However, their mean body fat percentage, 14%, is well within what is considered a healthy range. Similarly, Sumo wrestlers are typically categorized by BMI as "severely obese" or "very severely obese"; but one study of college-aged Sumo wrestlers found that 40% of them were no longer categorized as obese when body fat percentage (with a cutoff of <25%) was used instead of BMI; this was attributed to their very high lean body mass.
Canada utilises BMI sparingly within their method of defining levels of obesity through use of the Edmonton Scale (for adult obesity). This scale also introduces factors such as Quality of Life, Mental Health & Mobility amongst others. In recent years, Canada chose to allow both Chile & Ireland to adapt their obesity guidelines to suit both countries' health systems. In Ireland, obesity is now defined as "a Complex, Chronic & Relapsing Disease".
== Effects on health ==
Obesity increases a person's risk of developing various metabolic diseases, cardiovascular disease, osteoarthritis, Alzheimer disease, depression, and certain types of cancer. Depending on the degree of obesity and the presence of comorbid disorders, obesity is associated with an estimated 2–20 year shorter life expectancy. High BMI is a marker of risk for, but not a direct cause of, diseases caused by diet and physical activity.
=== Mortality ===
Obesity is one of the leading preventable causes of death worldwide. The mortality risk is lowest at a BMI of 20–25 kg/m2 in non-smokers and at 24–27 kg/m2 in current smokers, with risk increasing along with changes in either direction. This appears to apply in at least four continents. Other research suggests that the association of BMI and waist circumference with mortality is U- or J-shaped, while the association between waist-to-hip ratio and waist-to-height ratio with mortality is more positive. In Asians the risk of negative health effects begins to increase between 22 and 25 kg/m2. In 2021, the World Health Organization estimated that obesity caused at least 2.8 million deaths annually. On average, obesity reduces life expectancy by six to seven years, a BMI of 30–35 kg/m2 reduces life expectancy by two to four years, while severe obesity (BMI ≥ 40 kg/m2) reduces life expectancy by ten years.
=== Morbidity ===
Obesity increases the risk of many physical and mental conditions. These comorbidities are most commonly shown in metabolic syndrome, a combination of medical disorders which includes: diabetes mellitus type 2, high blood pressure, high blood cholesterol, and high triglyceride levels. A study from the RAK Hospital found that obese people are at a greater risk of developing long COVID. The CDC has found that obesity is the single strongest risk factor for severe COVID-19 illness.
Complications may be either directly caused by obesity or indirectly related through mechanisms sharing a common cause such as a poor diet or a sedentary lifestyle. The strength of the link between obesity and specific conditions varies. One of the strongest is the link with type 2 diabetes. Excess body fat underlies 64% of cases of diabetes in men and 77% of cases in women.: 9
Health consequences fall into two broad categories: those attributable to the effects of increased fat mass (such as osteoarthritis, obstructive sleep apnea, social stigmatization) and those due to the increased number of fat cells (diabetes, cancer, cardiovascular disease, non-alcoholic fatty liver disease). Increases in body fat alter the body's response to insulin, potentially leading to insulin resistance. Increased fat also creates a proinflammatory state, and a prothrombotic state.
==== Metrics of health ====
Newer research has focused on methods of identifying healthier obese people by clinicians, and not treating obese people as a monolithic group. Obese people who do not experience medical complications from their obesity are sometimes called (metabolically) healthy obese, but the extent to which this group exists (especially among older people) is in dispute. The number of people considered metabolically healthy depends on the definition used, and there is no universally accepted definition. There are numerous obese people who have relatively few metabolic abnormalities, and a minority of obese people have no medical complications. The guidelines of the American Association of Clinical Endocrinologists call for physicians to use risk stratification with obese patients when considering how to assess their risk of developing type 2 diabetes.: 59–60
In 2014, the BioSHaRE–EU Healthy Obese Project (sponsored by Maelstrom Research, a team under the Research Institute of the McGill University Health Centre) came up with two definitions for healthy obesity, one more strict and one less so:
To come up with these criteria, BioSHaRE controlled for age and tobacco use, researching how both may effect the metabolic syndrome associated with obesity, but not found to exist in the metabolically healthy obese. Other definitions of metabolically healthy obesity exist, including ones based on waist circumference rather than BMI, which is unreliable in certain individuals.
Another identification metric for health in obese people is calf strength, which is positively correlated with physical fitness in obese people. Body composition in general is hypothesized to help explain the existence of metabolically healthy obesity—the metabolically healthy obese are often found to have low amounts of ectopic fat (fat stored in tissues other than adipose tissue) despite having overall fat mass equivalent in weight to obese people with metabolic syndrome.: 1282
=== Survival paradox ===
Although the negative health consequences of obesity in the general population are well supported by the available research evidence, health outcomes in certain subgroups seem to be improved at an increased BMI, a phenomenon known as the obesity survival paradox. The paradox was first described in 1999 in overweight and obese people undergoing hemodialysis and has subsequently been found in those with heart failure and peripheral artery disease (PAD).
In people with heart failure, those with a BMI between 30.0 and 34.9 had lower mortality than those with a normal weight. This has been attributed to the fact that people often lose weight as they become progressively more ill. Similar findings have been made in other types of heart disease. People with class I obesity and heart disease do not have greater rates of further heart problems than people of normal weight who also have heart disease. In people with greater degrees of obesity, however, the risk of further cardiovascular events is increased. Even after cardiac bypass surgery, no increase in mortality is seen in the overweight and obese. One study found that the improved survival could be explained by the more aggressive treatment obese people receive after a cardiac event. Another study found that if one takes into account chronic obstructive pulmonary disease (COPD) in those with PAD, the benefit of obesity no longer exists.
== Causes ==
The "a calorie is a calorie" model of obesity posits a combination of excessive food energy intake and a lack of physical activity as the cause of most cases of obesity. A limited number of cases are due primarily to genetics, medical reasons, or psychiatric illness. The satiety value shows that the feeling of satiety per calorie varies between food types. Increasing rates of obesity at a societal level are felt to be due to an easily accessible and palatable diet, increased reliance on cars, and mechanized manufacturing.
Some other factors have been proposed as causes towards rising rates of obesity worldwide, including insufficient sleep, endocrine disruptors, increased usage of certain medications (such as atypical antipsychotics), increases in ambient temperature, decreased rates of smoking, demographic changes, increasing maternal age of first-time mothers, changes to epigenetic dysregulation from the environment, increased phenotypic variance via assortative mating, social pressure to diet, among others. According to one study, factors like these may play as big of a role as excessive food energy intake and a lack of physical activity; however, the relative magnitudes of the effects of any proposed cause of obesity is varied and uncertain, as there is a general need for randomized controlled trials on humans before definitive statement can be made.
According to the Endocrine Society, there is "growing evidence suggesting that obesity is a disorder of the energy homeostasis system, rather than simply arising from the passive accumulation of excess weight".
=== Diet ===
Excess appetite for palatable, high-calorie food (especially fat, sugar, and certain animal proteins) is seen as the primary factor driving obesity worldwide, likely because of imbalances in neurotransmitters affecting the drive to eat, as well as changes to the duodenum impacting nutrient sensing and signaling. Dietary energy supply per capita varies markedly between different regions and countries. It has also changed significantly over time. From the early 1970s to the late 1990s the average food energy available per person per day (the amount of food bought) increased in all parts of the world except Eastern Europe. The United States had the highest availability with 3,654 calories (15,290 kJ) per person in 1996. This increased further in 2003 to 3,754 calories (15,710 kJ). During the late 1990s, Europeans had 3,394 calories (14,200 kJ) per person, in the developing areas of Asia there were 2,648 calories (11,080 kJ) per person, and in sub-Saharan Africa people had 2,176 calories (9,100 kJ) per person. Total food energy consumption has been found to be related to obesity.
The widespread availability of dietary guidelines has done little to address the problems of overeating and poor dietary choice. From 1971 to 2000, obesity rates in the United States increased from 14.5% to 30.9%. During the same period, an increase occurred in the average amount of food energy consumed. For women, the average increase was 335 calories (1,400 kJ) per day (1,542 calories (6,450 kJ) in 1971 and 1,877 calories (7,850 kJ) in 2004), while for men the average increase was 168 calories (700 kJ) per day (2,450 calories (10,300 kJ) in 1971 and 2,618 calories (10,950 kJ) in 2004). Most of this extra food energy came from an increase in carbohydrate consumption rather than fat consumption. The primary sources of these extra carbohydrates are sweetened beverages, which now account for almost 25 percent of daily food energy in young adults in America, and potato chips. Consumption of sweetened beverages such as soft drinks, fruit drinks, and iced tea is believed to be contributing to the rising rates of obesity and to an increased risk of metabolic syndrome and type 2 diabetes. Vitamin D deficiency is related to diseases associated with obesity.
As societies become increasingly reliant on energy-dense, big-portions, and fast-food meals, the association between fast-food consumption and obesity becomes more concerning. In the United States, consumption of fast-food meals tripled and food energy intake from these meals quadrupled between 1977 and 1995.
Agricultural policy and techniques in the United States and Europe have led to lower food prices. In the United States, subsidization of corn, soy, wheat, and rice through the U.S. farm bill has made the main sources of processed food cheap compared to fruits and vegetables. Calorie count laws and nutrition facts labels attempt to steer people toward making healthier food choices, including awareness of how much food energy is being consumed.
Obese people consistently under-report their food consumption as compared to people of normal weight. This is supported both by tests of people carried out in a calorimeter room and by direct observation.
=== Sedentary lifestyle ===
A sedentary lifestyle may play a significant role in obesity.: 10 Worldwide there has been a large shift towards less physically demanding work, and currently at least 30% of the world's population gets insufficient exercise. This is primarily due to increasing use of mechanized transportation and a greater prevalence of labor-saving technology in the home. In children, there appear to be declines in levels of physical activity (with particularly strong declines in the amount of walking and physical education), likely due to safety concerns, changes in social interaction (such as fewer relationships with neighborhood children), and inadequate urban design (such as too few public spaces for safe physical activity). World trends in active leisure time physical activity are less clear. The World Health Organization indicates people worldwide are taking up less active recreational pursuits, while research from Finland found an increase and research from the United States found leisure-time physical activity has not changed significantly. Physical activity in children may not be a significant contributor.
In both children and adults, there is an association between television viewing time and the risk of obesity. Increased media exposure increases the rate of childhood obesity, with rates increasing proportionally to time spent watching television.
=== Genetics ===
Like many other medical conditions, obesity is the result of an interplay between genetic and environmental factors. Polymorphisms in various genes controlling appetite and metabolism predispose to obesity when sufficient food energy is present. As of 2006, more than 41 of these sites on the human genome have been linked to the development of obesity when a favorable environment is present. People with two copies of the FTO gene (fat mass and obesity associated gene) have been found on average to weigh 3–4 kg more and have a 1.67-fold greater risk of obesity compared with those without the risk allele. The differences in BMI between people that are due to genetics varies depending on the population examined from 6% to 85%.
Obesity is a major feature in several syndromes, such as Prader–Willi syndrome, Bardet–Biedl syndrome, Cohen syndrome, and MOMO syndrome. (The term "non-syndromic obesity" is sometimes used to exclude these conditions.) In people with early-onset severe obesity (defined by an onset before 10 years of age and body mass index over three standard deviations above normal), 7% harbor a single point DNA mutation.
Studies that have focused on inheritance patterns rather than on specific genes have found that 80% of the offspring of two obese parents were also obese, in contrast to less than 10% of the offspring of two parents who were of normal weight. Different people exposed to the same environment have different risks of obesity due to their underlying genetics.
The thrifty gene hypothesis postulates that, due to dietary scarcity during human evolution, people are prone to obesity. Their ability to take advantage of rare periods of abundance by storing energy as fat would be advantageous during times of varying food availability, and individuals with greater adipose reserves would be more likely to survive famine. This tendency to store fat, however, would be maladaptive in societies with stable food supplies. This theory has received various criticisms, and other evolutionarily-based theories such as the drifty gene hypothesis and the thrifty phenotype hypothesis have also been proposed.
=== Other illnesses ===
Certain physical and mental illnesses and the pharmaceutical substances used to treat them can increase risk of obesity. Medical illnesses that increase obesity risk include several rare genetic syndromes (listed above) as well as some congenital or acquired conditions: hypothyroidism, Cushing's syndrome, growth hormone deficiency, and some eating disorders such as binge eating disorder and night eating syndrome. However, obesity is not regarded as a psychiatric disorder, and therefore is not listed in the DSM-IVR as a psychiatric illness. The risk of overweight and obesity is higher in patients with psychiatric disorders than in persons without psychiatric disorders. Obesity and depression influence each other mutually, with obesity increasing the risk of clinical depression, and also depression leading to a higher chance of developing obesity.
=== Drug-induced obesity ===
Certain medications may cause weight gain or changes in body composition; these include insulin, sulfonylureas, thiazolidinediones, atypical antipsychotics, antidepressants, steroids, certain anticonvulsants (phenytoin and valproate), pizotifen, and some forms of hormonal contraception.
=== Social determinants ===
While genetic influences are important to understanding obesity, they cannot completely explain the dramatic increase seen within specific countries or globally. Though it is accepted that energy consumption in excess of energy expenditure leads to increases in body weight on an individual basis, the cause of the shifts in these two factors on the societal scale is much debated. There are a number of theories as to the cause but most believe it is a combination of various factors.
The correlation between social class and BMI varies globally. Research in 1989 found that in developed countries women of a high social class were less likely to be obese. No significant differences were seen among men of different social classes. In the developing world, women, men, and children from high social classes had greater rates of obesity. In 2007 repeating the same research found the same relationships, but they were weaker. The decrease in strength of correlation was felt to be due to the effects of globalization. Among developed countries, levels of adult obesity, and percentage of teenage children who are overweight, are correlated with income inequality. A similar relationship is seen among US states: more adults, even in higher social classes, are obese in more unequal states.
Many explanations have been put forth for associations between BMI and social class. It is thought that in developed countries, the wealthy are able to afford more nutritious food, they are under greater social pressure to remain slim, and have more opportunities along with greater expectations for physical fitness. In undeveloped countries the ability to afford food, high energy expenditure with physical labor, and cultural values favoring a larger body size are believed to contribute to the observed patterns. Attitudes toward body weight held by people in one's life may also play a role in obesity. A correlation in BMI changes over time has been found among friends, siblings, and spouses. Stress and perceived low social status appear to increase risk of obesity.
Smoking has a significant effect on an individual's weight. Those who quit smoking gain an average of 4.4 kilograms (9.7 lb) for men and 5.0 kilograms (11.0 lb) for women over ten years. However, changing rates of smoking have had little effect on the overall rates of obesity.
In the United States, the number of children a person has is related to their risk of obesity. A woman's risk increases by 7% per child, while a man's risk increases by 4% per child. This could be partly explained by the fact that having dependent children decreases physical activity in Western parents.
In the developing world urbanization is playing a role in increasing rate of obesity. In China overall rates of obesity are below 5%; however, in some cities rates of obesity are greater than 20%. In part, this may be because of urban design issues (such as inadequate public spaces for physical activity). Time spent in motor vehicles, as opposed to active transportation options such as cycling or walking, is correlated with increased risk of obesity.
Malnutrition in early life is believed to play a role in the rising rates of obesity in the developing world. Endocrine changes that occur during periods of malnutrition may promote the storage of fat once more food energy becomes available.
=== Gut bacteria ===
The study of the effect of infectious agents on metabolism is still in its early stages. Gut flora has been shown to differ between lean and obese people. There is an indication that gut flora can affect the metabolic potential. This apparent alteration is believed to confer a greater capacity to harvest energy contributing to obesity. Whether these differences are the direct cause or the result of obesity has yet to be determined unequivocally. The use of antibiotics among children has also been associated with obesity later in life.
An association between viruses and obesity has been found in humans and several different animal species. The amount that these associations may have contributed to the rising rate of obesity is yet to be determined.
=== Other factors ===
Not getting enough sleep is also associated with obesity. Whether one causes the other is unclear. Even if short sleep does increase weight gain, it is unclear if this is to a meaningful degree or if increasing sleep would be of benefit.
Some have proposed that chemical compounds called "obesogens" may play a role in obesity.
Certain aspects of personality are associated with being obese. Loneliness, neuroticism, impulsivity, and sensitivity to reward are more common in people who are obese while conscientiousness and self-control are less common in people who are obese. Because most of the studies on this topic are questionnaire-based, it is possible that these findings overestimate the relationships between personality and obesity: people who are obese might be aware of the social stigma of obesity and their questionnaire responses might be biased accordingly. Similarly, the personalities of people who are obese as children might be influenced by obesity stigma, rather than these personality factors acting as risk factors for obesity.
In relation to globalization, it is known that trade liberalization is linked to obesity; research, based on data from 175 countries during 1975–2016, showed that obesity prevalence was positively correlated with trade openness, and the correlation was stronger in developing countries.
== Pathophysiology ==
Two distinct but related processes are considered to be involved in the development of obesity: sustained positive energy balance (energy intake exceeding energy expenditure) and the resetting of the body weight "set point" at an increased value. The second process explains why finding effective obesity treatments has been difficult. While the underlying biology of this process still remains uncertain, research is beginning to clarify the mechanisms.
At a biological level, there are many possible pathophysiological mechanisms involved in the development and maintenance of obesity. This field of research had been almost unapproached until the leptin gene was discovered in 1994 by J. M. Friedman's laboratory. While leptin and ghrelin are produced peripherally, they control appetite through their actions on the central nervous system. In particular, they and other appetite-related hormones act on the hypothalamus, a region of the brain central to the regulation of food intake and energy expenditure. There are several circuits within the hypothalamus that contribute to its role in integrating appetite, the melanocortin pathway being the most well understood. The circuit begins with an area of the hypothalamus, the arcuate nucleus, that has outputs to the lateral hypothalamus (LH) and ventromedial hypothalamus (VMH), the brain's feeding and satiety centers, respectively.
The arcuate nucleus contains two distinct groups of neurons. The first group coexpresses neuropeptide Y (NPY) and agouti-related peptide (AgRP) and has stimulatory inputs to the LH and inhibitory inputs to the VMH. The second group coexpresses pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) and has stimulatory inputs to the VMH and inhibitory inputs to the LH. Consequently, NPY/AgRP neurons stimulate feeding and inhibit satiety, while POMC/CART neurons stimulate satiety and inhibit feeding. Both groups of arcuate nucleus neurons are regulated in part by leptin. Leptin inhibits the NPY/AgRP group while stimulating the POMC/CART group. Thus a deficiency in leptin signaling, either via leptin deficiency or leptin resistance, leads to overfeeding and may account for some genetic and acquired forms of obesity.
== Management ==
The main treatment for obesity consists of weight loss via lifestyle interventions, including prescribed diets and physical exercise. Although it is unclear what diets might support long-term weight loss, and although the effectiveness of low-calorie diets is debated, lifestyle changes that reduce calorie consumption or increase physical exercise over the long term also tend to produce some sustained weight loss, despite slow weight regain over time.
Although 87% of participants in the National Weight Control Registry were able to maintain 10% body weight loss for 10 years, the most appropriate dietary approach for long term weight loss maintenance is still unknown. In the US, intensive behavioral interventions combining both dietary changes and exercise are recommended. Intermittent fasting has no additional benefit of weight loss compared to continuous energy restriction. Adherence is a more important factor in weight loss success than whatever kind of diet an individual undertakes.
Several hypo-caloric diets are effective. In the short-term low carbohydrate diets appear better than low fat diets for weight loss. In the long term, however, all types of low-carbohydrate and low-fat diets appear equally beneficial. Heart disease and diabetes risks associated with different diets appear to be similar.
Promotion of the Mediterranean diets among the obese may lower the risk of heart disease. Decreased intake of sweet drinks is also related to weight-loss. Success rates of long-term weight loss maintenance with lifestyle changes are low, ranging from 2–20%. Dietary and lifestyle changes are effective in limiting excessive weight gain in pregnancy and improve outcomes for both the mother and the child. Intensive behavioral counseling is recommended in those who are both obese and have other risk factors for heart disease.
=== Health policy ===
Obesity is a complex public health and policy problem because of its prevalence, costs, and health effects. As such, managing it requires changes in the wider societal context and effort by communities, local authorities, and governments. Public health efforts seek to understand and correct the environmental factors responsible for the increasing prevalence of obesity in the population. Solutions look at changing the factors that cause excess food energy consumption and inhibit physical activity. Efforts include federally reimbursed meal programs in schools, limiting direct junk food marketing to children, and decreasing access to sugar-sweetened beverages in schools. The World Health Organization recommends the taxing of sugary drinks. When constructing urban environments, efforts have been made to increase access to parks and to develop pedestrian routes. Efforts also exist to address the occurrence of food swamps, or areas with an overabundance of convenient or fast food options, as these has been found to be strongly predictive of obesity rates.
Mass media campaigns seem to have limited effectiveness in changing behaviors that influence obesity, but may increase knowledge and awareness regarding physical activity and diet, which might lead to changes in the long term. Campaigns might also be able to reduce the amount of time spent sitting or lying down and positively affect the intention to be active physically. Nutritional labelling with energy information on menus might be able to help reducing energy intake while dining in restaurants. Some call for policy against ultra-processed foods.
== Medical interventions ==
=== Medication ===
Since the introduction of medicines for the management of obesity in the 1930s, many compounds have been tried. Most of them reduce body weight by small amounts, and several of them are no longer marketed for obesity because of their side effects. Out of 25 anti-obesity medications withdrawn from the market between 1964 and 2009, 23 acted by altering the functions of chemical neurotransmitters in the brain. The most common side effects of these drugs that led to withdrawals were mental disturbances, cardiac side effects, and drug abuse or drug dependence. Deaths were reportedly associated with seven products.
Five medications beneficial for long-term use are: orlistat, lorcaserin, liraglutide, phentermine–topiramate, and naltrexone–bupropion. They result in weight loss after one year ranged from 3.0 to 6.7 kg (6.6-14.8 lbs) over placebo. Orlistat, liraglutide, and naltrexone–bupropion are available in both the United States and Europe, phentermine–topiramate is available only in the United States. European regulatory authorities rejected lorcaserin and phentermine-topiramate, in part because of associations of heart valve problems with lorcaserin and more general heart and blood vessel problems with phentermine–topiramate. Lorcaserin was available in the United States and then removed from the market in 2020 due to its association with cancer. Orlistat use is associated with high rates of gastrointestinal side effects and concerns have been raised about negative effects on the kidneys. There is no information on how these drugs affect longer-term complications of obesity such as cardiovascular disease or death; however, liraglutide, when used for type 2 diabetes, does reduce cardiovascular events.
In 2019 a systematic review compared the effects on weight of various doses of fluoxetine (60 mg/d, 40 mg/d, 20 mg/d, 10 mg/d) in obese adults. When compared to placebo, all dosages of fluoxetine appeared to contribute to weight loss but lead to increased risk of experiencing side effects such as dizziness, drowsiness, fatigue, insomnia and nausea during period of treatment. However, these conclusions were from low certainty evidence. When comparing, in the same review, the effects of fluoxetine on weight of obese adults, to other anti-obesity agents, omega-3 gel and not receiving a treatment, the authors could not reach conclusive results due to poor quality of evidence.
Among antipsychotic drugs for treating schizophrenia clozapine is the most effective, but it also has the highest risk of causing the metabolic syndrome, of which obesity is the main feature. For people who gain weight because of clozapine, taking metformin may reportedly improve three of the five components of the metabolic syndrome: waist circumference, fasting glucose, and fasting triglycerides.
=== Surgery ===
The most effective treatment for obesity is bariatric surgery. The types of procedures include laparoscopic adjustable gastric banding, Roux-en-Y gastric bypass, vertical-sleeve gastrectomy, and biliopancreatic diversion. Surgery for severe obesity is associated with long-term weight loss, improvement in obesity-related conditions, and decreased overall mortality; however, improved metabolic health results from the weight loss, not the surgery. One study found a weight loss of between 14% and 25% (depending on the type of procedure performed) at 10 years, and a 29% reduction in all cause mortality when compared to standard weight loss measures. Complications occur in about 17% of cases and reoperation is needed in 7% of cases.
== Epidemiology ==
In earlier historical periods obesity was rare and achievable only by a small elite, although already recognised as a problem for health. But as prosperity increased in the Early Modern period, it affected increasingly larger groups of the population. Prior to the 1970s, obesity was a relatively rare condition even in the wealthiest of nations, and when it did exist it tended to occur among the wealthy. Then, a confluence of events started to change the human condition. The average BMI of populations in first-world countries started to increase, and consequently there was a rapid increase in the proportion of people overweight and obese.
In 1997, the WHO formally recognized obesity as a global epidemic. As of 2008, the WHO estimates that at least 500 million adults (greater than 10%) are obese, with higher rates among women than men. The global prevalence of obesity more than doubled between 1980 and 2014. In 2014, more than 600 million adults were obese, equal to about 13 percent of the world's adult population, with that figure growing to 16% by 2022, according to the World Health Organisation. The percentage of adults affected in the United States as of 2015–2016 is about 39.6% overall (37.9% of males and 41.1% of females). In 2000, the World Health Organization (WHO) stated that overweight and obesity were replacing more traditional public health concerns such as undernutrition and infectious diseases as one of the most significant cause of poor health.
The rate of obesity also increases with age at least up to 50 or 60 years old: 5 and severe obesity in the United States, Australia, and Canada is increasing faster than the overall rate of obesity. The OECD has projected an increase in obesity rates until at least 2030, especially in the United States, Mexico and England with rates reaching 47%, 39% and 35%, respectively.
Once considered a problem only of high-income countries, obesity rates are rising worldwide and affecting both the developed and developing world. These increases have been felt most dramatically in urban settings. In 2021, nearly half the global adult population - a billion men and 1.11 billion women aged 25 or older - were overweight or obese. It was predicted that if these trends continue about 57.4% of men and 60.3% of women would be overweight or obese by 2050.
Sex- and gender-based differences influence the prevalence of obesity. Globally there are more obese women than men, but the numbers differ depending on how obesity is measured.
== History ==
=== Etymology ===
Obesity is from the Latin obesitas, which means "stout, fat, or plump". Ēsus is the past participle of edere (to eat), with ob (over) added to it. The Oxford English Dictionary documents its first usage in 1611 by Randle Cotgrave.
=== Historical attitudes ===
Ancient Greek medicine recognizes obesity as a medical disorder and records that the Ancient Egyptians saw it in the same way. Hippocrates wrote that "Corpulence is not only a disease itself, but the harbinger of others". The Indian surgeon Sushruta (6th century BCE) related obesity to diabetes and heart disorders. He recommended physical work to help cure it and its side effects. For most of human history, mankind struggled with food scarcity. Obesity has thus historically been viewed as a sign of wealth and prosperity. It was common among high officials in Ancient East Asian civilizations. In the 17th century, English medical author Tobias Venner is credited with being one of the first to refer to the term as a societal disease in a published English language book.
With the onset of the Industrial Revolution, it was realized that the military and economic might of nations were dependent on both the body size and strength of their soldiers and workers. Increasing the average body mass index from what is now considered underweight to what is now the normal range played a significant role in the development of industrialized societies. Height and weight thus both increased through the 19th century in the developed world. During the 20th century, as populations reached their genetic potential for height, weight began increasing much more than height, resulting in obesity. In the 1950s, increasing wealth in the developed world decreased child mortality, but as body weight increased, heart and kidney disease became more common.
During this time period, insurance companies realized the connection between weight and life expectancy and increased premiums for the obese.
Many cultures throughout history have viewed obesity as the result of a character flaw. The obesus or fat character in Ancient Greek comedy was a glutton and figure of mockery. During Christian times, food was viewed as a gateway to the sins of sloth and lust. In modern Western culture, excess weight is often regarded as unattractive, and obesity is commonly associated with various negative stereotypes. People of all ages can face social stigmatization and may be targeted by bullies or shunned by their peers.
Public perceptions in Western society regarding healthy body weight differ from those regarding the weight that is considered ideal – and both have changed since the beginning of the 20th century. The weight that is viewed as an ideal has become lower since the 1920s. This is illustrated by the fact that the average height of Miss America pageant winners increased by 2% from 1922 to 1999, while their average weight decreased by 12%. On the other hand, people's views concerning healthy weight have changed in the opposite direction. In Britain, the weight at which people considered themselves to be overweight was significantly higher in 2007 than in 1999. These changes are believed to be due to increasing rates of adiposity leading to increased acceptance of extra body fat as being normal.
Obesity is still seen as a sign of wealth and well-being in many parts of Africa. This has become particularly common since the HIV epidemic began.
=== The arts ===
The first sculptural representations of the human body 20,000–35,000 years ago depict obese females. Some attribute the Venus figurines to the tendency to emphasize fertility while others feel they represent "fatness" in the people of the time. Corpulence is, however, absent in both Greek and Roman art, probably in keeping with their ideals regarding moderation. This continued through much of Christian European history, with only those of low socioeconomic status being depicted as obese.
During the Renaissance some of the upper class began flaunting their large size, as can be seen in portraits of Henry VIII of England and Alessandro dal Borro. Rubens (1577–1640) regularly depicted heavyset women in his pictures, from which derives the term Rubenesque. These women, however, still maintained the "hourglass" shape with its relationship to fertility. During the 19th century, views on obesity changed in the Western world. After centuries of obesity being synonymous with wealth and social status, slimness began to be seen as the desirable standard. In his 1819 print, The Belle Alliance, or the Female Reformers of Blackburn!!!, artist George Cruikshank criticised the work of female reformers in Blackburn and used fatness as a means to portray them as unfeminine.
== Society and culture ==
=== Economic impact ===
In addition to its health impacts, obesity leads to many problems, including disadvantages in employment: 29 and increased business costs.
In 2005, the medical costs attributable to obesity in the US were an estimated $190.2 billion or 20.6% of all medical expenditures, while the cost of obesity in Canada was estimated at CA$2 billion in 1997 (2.4% of total health costs). The total annual direct cost of overweight and obesity in Australia in 2005 was A$21 billion. Overweight and obese Australians also received A$35.6 billion in government subsidies. The estimated range for annual expenditures on diet products is $40 billion to $100 billion in the US alone.
The Lancet Commission on Obesity in 2019 called for a global treaty—modelled on the WHO Framework Convention on Tobacco Control—committing countries to address obesity and undernutrition, explicitly excluding the food industry from policy development. They estimate the global cost of obesity $2 trillion a year, about or 2.8% of world GDP.
Obesity prevention programs have been found to reduce the cost of treating obesity-related disease. However, the longer people live, the more medical costs they incur. Researchers, therefore, conclude that reducing obesity may improve the public's health, but it is unlikely to reduce overall health spending. Sin taxes such as a sugary drink tax have been implemented in certain countries globally to curb dietary and consumer habits, and as an effort to offset the economic tolls.
Obesity can lead to social stigmatization and disadvantages in employment.: 29 When compared to their ideal weight counterparts, workers with obesity, on average have higher rates of absenteeism from work and take more disability leave, thus increasing costs for employers and decreasing productivity. A study examining Duke University employees found that people with a BMI over 40 kg/m2 filed twice as many workers' compensation claims as those whose BMI was 18.5–24.9 kg/m2. They also had more than 12 times as many lost work days. The most common injuries in this group were due to falls and lifting, thus affecting the lower extremities, wrists or hands, and backs. The Alabama State Employees' Insurance Board approved a controversial plan to charge obese workers $25 a month for health insurance that would otherwise be free unless they take steps to lose weight and improve their health. These measures started in January 2010 and apply to those state workers whose BMI exceeds 35 kg/m2 and who fail to make improvements in their health after one year. This becomes a Catch 22 position as many insurance companies will refuse to pay for treatment methods for workers living with obesity.
Some research shows that people with obesity are less likely to be hired for a job and are less likely to be promoted. People with obesity are also paid less than their counterparts who do not live with obesity for an equivalent job; women with obesity on average make 6% less and men with obesity make 3% less.: 30
Specific industries, such as the airline, healthcare and food industries, have special concerns. Due to rising rates of obesity, airlines face higher fuel costs and pressures to increase seating width. In 2000, the extra weight of passengers with obesity cost airlines US$275 million. The healthcare industry has had to invest in special facilities for handling patients with class III obesity, including special lifting equipment and bariatric ambulances. Costs for restaurants are increased by litigation accusing them of causing obesity. In 2005, the US Congress discussed legislation to prevent civil lawsuits against the food industry in relation to obesity; however, it did not become law.
With the American Medical Association's 2013 classification of obesity as a chronic disease, it is thought that health insurance companies will more likely pay for obesity treatment, counseling and surgery, and the cost of research and development of adipose treatment pills or gene therapy treatments should be more affordable if insurers help to subsidize their cost. The AMA classification is not legally binding, however, so health insurers still have the right to reject coverage for a treatment or procedure.
In 2014, The European Court of Justice ruled that morbid obesity is a disability. The Court said that if an employee's obesity prevents them from "full and effective participation of that person in professional life on an equal basis with other workers", then it shall be considered a disability and that firing someone on such grounds is discriminatory.
In low-income countries, obesity can be a signal of wealth. A 2023 experimental study found that obese individuals in Uganda were more likely to access credit.
=== Size acceptance ===
The principal goal of the fat acceptance movement is to decrease discrimination against people who are overweight and obese. However, some in the movement are also attempting to challenge the established relationship between obesity and negative health outcomes.
A number of organizations exist that promote the acceptance of obesity. They have increased in prominence in the latter half of the 20th century. The US-based National Association to Advance Fat Acceptance (NAAFA) was formed in 1969 and describes itself as a civil rights organization dedicated to ending size discrimination.
The International Size Acceptance Association (ISAA) is a non-governmental organization (NGO) which was founded in 1997. It has more of a global orientation and describes its mission as promoting size acceptance and helping to end weight-based discrimination. These groups often argue for the recognition of obesity as a disability under the US Americans With Disabilities Act (ADA). The American legal system, however, has decided that the potential public health costs exceed the benefits of extending this anti-discrimination law to cover obesity.
=== Industry influence on research ===
In 2015, the New York Times published an article on the Global Energy Balance Network, a nonprofit founded in 2014 that advocated for people to focus on increasing exercise rather than reducing calorie intake to avoid obesity and to be healthy. The organization was founded with at least $1.5M in funding from the Coca-Cola Company, and the company has provided $4M in research funding to the two founding scientists Gregory A. Hand and Steven N. Blair since 2008.
=== Reports ===
Many organizations have published reports pertaining to obesity. In 1998, the first US Federal guidelines were published, titled "Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults: The Evidence Report". In 2006, the Canadian Obesity Network, now known as Obesity Canada published the "Canadian Clinical Practice Guidelines (CPG) on the Management and Prevention of Obesity in Adults and Children". This is a comprehensive evidence-based guideline to address the management and prevention of overweight and obesity in adults and children.
In 2004, the United Kingdom Royal College of Physicians, the Faculty of Public Health and the Royal College of Paediatrics and Child Health released the report "Storing up Problems", which highlighted the growing problem of obesity in the UK. The same year, the House of Commons Health Select Committee published its "most comprehensive inquiry [...] ever undertaken" into the impact of obesity on health and society in the UK and possible approaches to the problem. In 2006, the National Institute for Health and Clinical Excellence (NICE) issued a guideline on the diagnosis and management of obesity, as well as policy implications for non-healthcare organizations such as local councils. A 2007 report produced by Derek Wanless for the King's Fund warned that unless further action was taken, obesity had the capacity to debilitate the National Health Service financially. In 2022 the National Institute for Health and Care Research (NIHR) published a comprehensive review of research on what local authorities can do to reduce obesity.
The Obesity Policy Action (OPA) framework divides measure into upstream policies, midstream policies, and downstream policies. Upstream policies have to do with changing society, while midstream policies try to alter behaviors believed to contribute to obesity at the individual level, while downstream policies treat currently obese people.
== Childhood obesity ==
The healthy BMI range varies with the age and sex of the child. Obesity in children and adolescents is defined as a BMI greater than the 95th percentile. The reference data that these percentiles are based on is from 1963 to 1994 and thus has not been affected by the recent increases in rates of obesity. Childhood obesity has reached epidemic proportions in the 21st century, with rising rates in both the developed and the developing world. Rates of obesity in Canadian boys have increased from 11% in the 1980s to over 30% in the 1990s, while during this same time period rates increased from 4 to 14% in Brazilian children. In the UK, there were 60% more obese children in 2005 compared to 1989. In the US, the percentage of overweight and obese children increased to 16% in 2008, a 300% increase over the prior 30 years.
As with obesity in adults, many factors contribute to the rising rates of childhood obesity. Changing diet and decreasing physical activity are believed to be the two most important causes for the recent increase in the incidence of child obesity. Advertising of unhealthy foods to children also contributes, as it increases their consumption of the product. Antibiotics in the first 6 months of life have been associated with excess weight at age seven to twelve years of age. Because childhood obesity often persists into adulthood and is associated with numerous chronic illnesses, children who are obese are often tested for hypertension, diabetes, hyperlipidemia, and fatty liver disease.
Treatments used in children are primarily lifestyle interventions and behavioral techniques, although efforts to increase activity in children have had little success. In the United States, medications are not FDA approved for use in this age group. Brief weight management interventions in primary care (e.g. delivered by a physician or nurse practitioner) have only a marginal positive effect in reducing childhood overweight or obesity. Multi-component behaviour change interventions that include changes to dietary and physical activity may reduce BMI in the short term in children aged 6 to 11 years, although the benefits are small and quality of evidence is low.
== Other animals ==
Obesity in pets is common in many countries. In the United States, 23–41% of dogs are overweight, and about 5.1% are obese. The rate of obesity in cats was slightly higher at 6.4%. In Australia, the rate of obesity among dogs in a veterinary setting has been found to be 7.6%. The risk of obesity in dogs is related to whether or not their owners are obese; however, there is no similar correlation between cats and their owners.
== See also ==
Portal-visceral hypothesis
Anti-Obesity Day
Health effects of ultra-processed foods
== References ==
=== Citations ===
== Further reading ==
== External links ==
Quotations related to Obesity at Wikiquote
WHO fact sheet on obesity and overweight | Wikipedia/Weight_control |
Positron emission tomography–computed tomography (better known as PET–CT or PET/CT) is a nuclear medicine technique 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. Two- and three-dimensional image reconstruction may be rendered as a function of a common software and control system.
PET–CT has revolutionized medical diagnosis in many fields, by adding precision of anatomic localization to functional imaging, which was previously lacking from pure PET imaging. For example, many diagnostic imaging procedures in oncology, surgical planning, radiation therapy and cancer staging have been changing rapidly under the influence of PET–CT availability, and centers have been gradually abandoning conventional PET devices and substituting them by PET–CTs. Although the combined/hybrid device is considerably more expensive, it has the advantage of providing both functions as stand-alone examinations, being, in fact, two devices in one.
The only other obstacle to the wider use of PET–CT is the difficulty and cost of producing and transporting the radiopharmaceuticals used for PET imaging, which are usually extremely short-lived. For instance, the half-life of radioactive fluorine-18 (18F) used to trace glucose metabolism (using fluorodeoxyglucose, FDG) is only two hours. Its production requires a very expensive cyclotron as well as a production line for the radiopharmaceuticals. At least one PET–CT radiopharmaceutical is made on site from a generator: Ga-68 from a gallium-68 generator.
Benefits of PET–CT
By diagnosing with the help of a PET–CT, the advantages of the two individual methods are combined, and the result considerably exceeds images obtained by the two devices taken separately.
The method allows identification of all cancerous formations in the body, regardless of their size or degree of development.
The diagnosis time is short, the doctor can thus save precious time in the fight with the disease
The substance used, although it is radioactive, presents a very low degree of risk, it is naturally eliminated by the body within a maximum of 24 hours after administration
PET–MRI, like PET–CT, combines modalities to produce co-registered images.
== History ==
The combination of PET and CT scanners was first suggested by R. Raylman in his 1991 Ph.D. thesis. The first PET–CT systems were constructed by David Townsend (at the University of Geneva) and Ronald Nutt (at CPS Innovations in Knoxville, TN) with help from colleagues. The first PET–CT prototype for clinical evaluation was funded by the NCI and installed at the University of Pittsburgh Medical Center in 1998. The first commercial system reached the market by 2001, and by 2004, over 400 systems had been installed worldwide.
== Procedure for FDG imaging ==
An example of how PET–CT works in the work-up of FDG metabolic mapping follows:
Before the exam, the patient fasts for at least 6 hours.
On the day of the exam, the patient rests lying for a minimum of 15 min, in order to quiet down muscular activity, which might be interpreted as abnormal metabolism.
An intravenous bolus injection of a dose of recently produced 2-FDG or 3-FDG is made, usually by arm vein. Dosage ranges from 3.7 to 7.4 megabecquerels (0.1 to 0.2 mCi) per kilogram of body weight.
After one or two hours, the patient is placed into the PET–CT device, usually lying in a supine position with the arms resting at the sides, or brought together above the head, depending on the main region of interest (ROI).
An automatic bed moves head first into the gantry, first obtaining a tomogram, also called a scout view or surview, which is a kind of whole body flat sagittal section, obtained with the X-ray tube fixed into the upper position.
The operator uses the PET–CT computer console to identify the patient and examination, delimit the caudal and rostral limits of the body scan onto the scout view, selects the scanning parameters and starts the image acquisition period, which follows without human intervention.
The patient is automatically moved head first into the CT gantry, and the x-ray tomogram is acquired.
Now the patient is automatically moved through the PET gantry, which is mounted in parallel with the CT gantry, and the PET slices are acquired.
The patient may now leave the device, and the PET–CT software starts reconstructing and aligning the PET and CT images.
A whole body scan, which usually is made from mid-thighs to the top of the head, takes from 5 minutes to 40 minutes depending on the acquisition protocol and technology of the equipment used. FDG imaging protocols acquires slices with a thickness of 2 to 3 mm. Hypermetabolic lesions are shown as false color-coded pixels or voxels onto the gray-value coded CT images. standardized uptake values are calculated by the software for each hypermetabolic region detected in the image. It provides a quantification of size of the lesion, since functional imaging does not provide a precise anatomical estimate of its extent. The CT can be used for that, when the lesion is also visualized in its images (this is not always the case when hypermetabolic lesions are not accompanied by anatomical changes).
FDG doses in quantities sufficient to carry out four to five examinations are delivered daily, twice or more per day, by the provider to the diagnostic imaging center.
For uses in image-guided radiation therapy of cancer, special fiducial markers are placed in the patient's body before acquiring the PET–CT images. The slices thus acquired may be transferred digitally to a linear accelerator which is used to perform precise bombardment of the target areas using high energy photons (radiosurgery).
== See also ==
Single-photon emission computed tomography
Neuroimaging
== References ==
== External links ==
Human Health Campus, The official website of the International Atomic Energy Agency dedicated to Professionals in Radiation Medicine. This site is managed by the Division of Human Health, Department of Nuclear Sciences and Applications
How PET CT works Archived 2008-05-12 at the Wayback Machine – from Harvard Medical School
PET CT for evaluation of Lung Cancer Archived 2008-02-19 at the Wayback Machine – from Harvard Medical School
Benefits of PET–CT - from Medicai | Wikipedia/Positron_emission_tomography_-_computed_tomography |
MPOWER is a policy package intended to assist in the country-level implementation of effective interventions to reduce the demand for tobacco, as ratified by the World Health Organization (WHO) Framework Convention on Tobacco Control. The six evidence-based components of MPOWER are:
Monitor tobacco use and prevention policies
Protect people from tobacco smoke
Offer help to quit tobacco use
Warn about the dangers of tobacco
Enforce bans on tobacco advertising, promotion and sponsorship
Raise taxes on tobacco
Since its launch in New York City by WHO on 7 February 2008, MPOWER has become the internationally-applicable and now widely recognized summary of the essential elements of tobacco control strategy. “MPOWER is the only document of a somewhat strategic nature that is a source of information on the spread of tobacco epidemic, as well as of suggestions concerning specific actions for supporting the fight against this epidemic.”
== History ==
The WHO Report of the Global Tobacco Epidemic: The MPOWER Package was the first in a series of WHO reports to track the status of the tobacco epidemic and the impact of interventions to stop it. The report was launched at a news conference by Margaret Chan, Director-General of WHO with New York City Mayor Michael Bloomberg on 7 February 2008. Bloomberg Philanthropies helped fund the report. According to Bloomberg, “The report released today is revolutionary. For the first time, we have both a rigorous approach to stop the tobacco epidemic and solid data to hold us all accountable.”
Former WHO Advocacy Coordinator Kraig Klaudt developed the MPOWER brand and report's creative concept. He later helped conceptualise the MPOWER policies, which are used today by WHO to promote tobacco control policies worldwide. The report was designed by Ruth Klotzel of Estúdio Infinito in São Paulo, Brazil and the text was edited by Patricia Logullo also in Brazil. According to the International Council of Communication Design Icograda, the “graphic production of the book has a unique feature. It is a rectangular cutout that goes through all the pages and houses a gift for the reader: a box designed purposely to resemble a cigarette box but containing note paper and pens. The pens are printed with the six strategic messages of the MPOWER brand – a means of enhancing message recall.”
The MPOWER report’s unique design caught the attention of journalists covering its launch. According to the Washington Post, “WHO is using marketing techniques reminiscent of the tobacco companies. It has branded the campaign MPOWER – each letter represents one of six strategies – and is eschewing scare tactics in favor of the theme ‘fresh and alive.’ Press materials came with a box that looks like a pack of cigarettes and contains a pad and pens describing the elements of the campaign.” Said Sandra Mullin, a spokeswoman for the World Luigi Foundation, “We're co-opting the tobacco industry's branding strategies to capture the attention of government officials. We want to show that they don't own those mottos – freshness and fun and health.”
As of 2013, Bloomberg Philanthropies had invested US$600 million to support implementation of the MPOWER tobacco control policies. The Philanthropy works through a global network of partners to support countries implementing comprehensive tobacco control policies, including the Campaign for Tobacco-Free Kids, the CDC Foundation, Johns Hopkins Bloomberg School of Public Health, the International Union Against Tuberculosis and Lung Disease, the World Health Organization, and the World Lung Foundation. The Bloomberg's initiative also received an investment from the Bill and Melinda Gates Foundation.
== Impact ==
The findings of a July 2013 WHO report showed that 2.3 billion people – more than a third of the world’s population – are covered by at least one effective MPOWER tobacco control measure, an increase from the 1 billion covered in 2008. In Turkey, the MPOWER strategy had helped lead to 1.2 million fewer adult smokers in the country.
Since the launch of the MPOWER strategy, 18 countries with almost 750 million citizens have passed 100% smoke-free laws including Brazil, Turkey and Pakistan. Several of the world’s largest cities have also gone smoke-free, including Mexico City, Jakarta, and China’s Harbin City. Additionally, 11 countries have passed graphic cigarette pack warning laws and seven countries have passed comprehensive advertising and sponsorship bans that are newly protecting 400 million and 200 million people, respectively.
A 2013 study found that 7 out of 9 recent international human rights treaties contained at least one policy area addressed by the MPOWER strategy, including 30 different articles.
== See also ==
Tobacco control
WHO Framework Convention on Tobacco Control
World Lung Foundation
World No Tobacco Day
== References == | Wikipedia/MPOWER_tobacco_control |
Microangiopathy (also known as microvascular disease, small vessel disease (SVD) or microvascular dysfunction) is a disease of the microvessels, small blood vessels in the microcirculation. It can be contrasted to macroangiopathies such as atherosclerosis, where large and medium-sized arteries (e.g., aorta, carotid and coronary arteries) are primarily affected.
Small vessel diseases (SVDs) affect primarily organs that receive significant portions of cardiac output such as the brain, the kidney, and the retina. Thus, SVDs are a major etiologic cause in debilitating conditions such as renal failure, blindness, lacunar infarcts, and dementia.
== Types ==
Microangiopathies are involved in a variety of different diseases including:
== Pathophysiology ==
The main target of small vessel diseases is the endothelium, which plays a key role in vascular homeostasis. The pathogenesis of SVDs in various organs is characterized by endothelial dysfunction, capillary rarefaction, microthrombi and microvascular remodeling.
Diabetic microangiopathy, which is the most common cause of microangiopathy, is more prevalent in the kidney, retina and vascular endothelium since glucose transport in these sites isn’t regulated by insulin and these tissues cannot stop glucose from entering cells when blood sugar levels are high. Among all biochemical mechanisms involved in diabetic vascular damage such as the polyol pathway and the renin–angiotensin system (RAS), the advanced glycation end products (AGEs) pathway appears to be the most important in the pathogenesis and progression of microvascular complications.
Chronic high blood sugar levels lead to the attachment of sugar molecules to various proteins, including collagen, laminin, and peripheral nerve proteins. This process, called glycosylation, creates advanced glycation end products (AGEs). AGEs formation cross-links these proteins, making them resistant to degradation. This leads to accumulation of AGEs, thickening of the basement membrane, narrowing the blood vessels, reducing blood flow to the tissues and causing ischemic injury.
In addition, oxidative stress, caused by AGEs and the other pathways, causes apoptosis of pericytes and podocytes in the retina and the kidneys respectively leading to capillary wall fragility and increased vascular leakage. This results in local swelling (e.g. macular edema) and impaired tissue function.
=== Microvascular diseases as a multisystem disorder ===
Some researchers have suggested that SVD may be a multisystem disorder, meaning that it can affect multiple organs in the body, including the heart and brain. This is supported by multiple studies stating that cardiac pathologies are more prevalent in patients with pathological evidence of cerebrovascular SVD and vice versa.
Coronary microvascular diseases (CMDs) can be caused by:
On the other hand, Cerebral SVD encompasses a range of vascular pathologies including arteriosclerosis-related CSVD, where lipohyalinosis causes stenosis of the lumen of the arterioles and amyloid-related CSVD, characterized by the build-up of β-amyloid deposits in small- and medium-caliber cerebral vessels.
The vascular anatomy of the heart and brain is similar in that conduit arteries are distributed on the surface of these organs with tissue perfusion achieved through deep penetrating arteries. Both coronary and cerebral microvascular diseases do share some common risk factors such as hypertension. Why some patients with microvascular angina subsequently develop vascular cognitive impairment and others do not is an unanswered question. Potential underpinning mechanisms include premature vascular aging and clustering of vascular risk factors leading to an accelerated cardiovascular risk.
== Diagnosis ==
The diagnosis of microangiopathies can be based on direct visualization of the microcirculation, imaging modalities (e.g. MRI), conventional testings (e.g. ophthalmoscopy for diabetic retinopathy) or other diagnostic measures (e.g. blood smear for schistocytes in thrombotic microangiopathies).
For assessment of the morphological and functional aspects of microcirculation, nailfold videocapillaroscopy (NVC) can be used, in which videocapillaroscopy is performed at the nailfold, where capillaries are arranged with the longitudinal axis parallel to the skin surface, so that they can be examined along their entire length.
NVC has been largely used not only for investigating peripheral microangiopathy, but also as a sort of "window" to systemic microvascular dysfunction. Although its main application is within the connective tissue diseases such as systemic scleroderma and dermatomyositis, it has been employed in non-rheumatic diseases with microvascular involvement such as diabetes mellitus, essential hypertension and COVID-19 infection.
Optical coherence tomography angiography (OCTA) is another imaging modality that offers high-resolution visualization of the retinal capillary network and can be used to evaluate microcirculation in conditions such as diabetic retinopathy.
Many studies have demonstrated that evaluation of the retinal microvascular changes using OCTA or other methods such as fluorescein angiography may reflect the systemic microvascular functions as in patients with coronary microvascular disease, cerebral small vessel diseases or systemic sclerosis (The potential of retinal microvascularopathy as a biomarker for assessing microvascular status of other circulations).
Unlike the retinal microcirculation, the coronary microvasculature cannot be directly imaged. Instead, a number of different tests can be used to measure how much blood is flowing through the coronary microvasculature. These tests can be used to assess how well the coronary microvasculature is functioning and to diagnose coronary microvascular disease. They include non-invasive measures such as cardiac MRI and invasive measures such as intracoronary Doppler wire.
Similarly, CSVD is typically recognized on both brain magnetic resonance imaging (MRI) and computed tomography (CT) scans, but MRI has greater sensitivity and specificity. Neuroimaging of CSVD primarily involves visualizing radiological phenotypes of CSVD such as recent subcortical infarcts or cerebral microbleeds (CMBs).
== Treatment ==
Treatment options of microangiopathies can be directed at:
A better understanding of the mechanisms leading to damage of small blood vessels may be associated with novel therapeutic approaches, the safety and efficacy of some of which will need to be further investigated. Examples include calcium dobesilate and aldose reductase inhibitors in diabetic microangiopathies and endothelin receptor antagonists for pulmonary hypertension.
== References ==
== External links == | Wikipedia/Microvascular_dysfunction |
Cardiovascular disease (CVD) is any disease involving the heart or blood vessels. CVDs constitute a class of diseases that includes: coronary artery diseases (e.g. angina, heart attack), heart failure, hypertensive heart disease, rheumatic heart disease, cardiomyopathy, arrhythmia, congenital heart disease, valvular heart disease, carditis, aortic aneurysms, peripheral artery disease, thromboembolic disease, and venous thrombosis.
The underlying mechanisms vary depending on the disease. It is estimated that dietary risk factors are associated with 53% of CVD deaths. Coronary artery disease, stroke, and peripheral artery disease involve atherosclerosis. This may be caused by high blood pressure, smoking, diabetes mellitus, lack of exercise, obesity, high blood cholesterol, poor diet, excessive alcohol consumption, and poor sleep, among other things. High blood pressure is estimated to account for approximately 13% of CVD deaths, while tobacco accounts for 9%, diabetes 6%, lack of exercise 6%, and obesity 5%. Rheumatic heart disease may follow untreated strep throat.
It is estimated that up to 90% of CVD may be preventable. Prevention of CVD involves improving risk factors through: healthy eating, exercise, avoidance of tobacco smoke and limiting alcohol intake. Treating risk factors, such as high blood pressure, blood lipids and diabetes is also beneficial. Treating people who have strep throat with antibiotics can decrease the risk of rheumatic heart disease. The use of aspirin in people who are otherwise healthy is of unclear benefit.
Cardiovascular diseases are the leading cause of death worldwide except Africa. Together CVD resulted in 17.9 million deaths (32.1%) in 2015, up from 12.3 million (25.8%) in 1990. Deaths, at a given age, from CVD are more common and have been increasing in much of the developing world, while rates have declined in most of the developed world since the 1970s. Coronary artery disease and stroke account for 80% of CVD deaths in males and 75% of CVD deaths in females. Most cardiovascular disease affects older adults. In the United States 11% of people between 20 and 40 have CVD, while 37% between 40 and 60, 71% of people between 60 and 80, and 85% of people over 80 have CVD. The average age of death from coronary artery disease in the developed world is around 80, while it is around 68 in the developing world. CVD is typically diagnosed seven to ten years earlier in men than in women.: 48
== Types ==
There are many cardiovascular diseases involving the blood vessels. They are known as vascular diseases.
Coronary artery disease (coronary heart disease or ischemic heart disease)
Peripheral arterial disease – a disease of blood vessels that supply blood to the arms and legs
Cerebrovascular disease – a disease of blood vessels that supply blood to the brain (includes stroke)
Renal artery stenosis
Aortic aneurysm
There are also many cardiovascular diseases that involve the heart.
Cardiomyopathy – diseases of cardiac muscle
Hypertensive heart disease – diseases of the heart secondary to high blood pressure or hypertension
Heart failure – a clinical syndrome caused by the inability of the heart to supply sufficient blood to the tissues to meet their metabolic requirements
Pulmonary heart disease – a failure at the right side of the heart with respiratory system involvement
Cardiac dysrhythmias – abnormalities of heart rhythm
Inflammatory heart diseases
Endocarditis – inflammation of the inner layer of the heart, the endocardium. The structures most commonly involved are the heart valves.
Inflammatory cardiomegaly
Myocarditis – inflammation of the myocardium, the muscular part of the heart, caused most often by viral infection and less often by bacterial infections, certain medications, toxins, and autoimmune disorders. It is characterized in part by infiltration of the heart by lymphocyte and monocyte types of white blood cells.
Eosinophilic myocarditis – inflammation of the myocardium caused by pathologically activated eosinophilic white blood cells. This disorder differs from myocarditis in its causes and treatments.
Valvular heart disease
Congenital heart disease – heart structure malformations existing at birth
Rheumatic heart disease – heart muscles and valves damage due to rheumatic fever caused by Streptococcus pyogenes a group A streptococcal infection.
== Risk factors ==
There are many risk factors for heart diseases: age, sex, tobacco use, physical inactivity, non-alcoholic fatty liver disease, excessive alcohol consumption, unhealthy diet, obesity, genetic predisposition and family history of cardiovascular disease, raised blood pressure (hypertension), raised blood sugar (diabetes mellitus), raised blood cholesterol (hyperlipidemia), undiagnosed celiac disease, psychosocial factors, poverty and low educational status, air pollution, and poor sleep. While the individual contribution of each risk factor varies between different communities or ethnic groups the overall contribution of these risk factors is very consistent. Some of these risk factors, such as age, sex or family history/genetic predisposition, are immutable; however, many important cardiovascular risk factors are modifiable by lifestyle change, social change, drug treatment (for example prevention of hypertension, hyperlipidemia, and diabetes). People with obesity are at increased risk of atherosclerosis of the coronary arteries.
=== Genetics ===
Cardiovascular disease in a person's parents increases their risk by ~3 fold, and genetics is an important risk factor for cardiovascular diseases. Genetic cardiovascular disease can occur either as
a consequence of single variant (Mendelian) or polygenic influences. There are more than 40 inherited cardiovascular disease that can be traced to a single disease-causing DNA variant, although these conditions are rare. Most common cardiovascular diseases are non-Mendelian and are thought to be due to hundreds or thousands of genetic variants (known as single nucleotide polymorphisms), each associated with a small effect.
=== Age ===
Age is the most important risk factor in developing cardiovascular or heart diseases, with approximately a tripling of risk with each decade of life. Coronary fatty streaks can begin to form in adolescence. It is estimated that 82 percent of people who die of coronary heart disease are 65 and older. Simultaneously, the risk of stroke doubles every decade after age 55.
Multiple explanations are proposed to explain why age increases the risk of cardiovascular/heart diseases. One of them relates to serum cholesterol level. In most populations, the serum total cholesterol level increases as age increases. In men, this increase levels off around age 45 to 50 years. In women, the increase continues sharply until age 60 to 65 years.
Aging is also associated with changes in the mechanical and structural properties of the vascular wall, which leads to the loss of arterial elasticity and reduced arterial compliance and may subsequently lead to coronary artery disease.
=== Sex ===
Men are at greater risk of heart disease than pre-menopausal women. Once past menopause, it has been argued that a woman's risk is similar to a man's although more recent data from the WHO and UN disputes this. If a female has diabetes, she is more likely to develop heart disease than a male with diabetes. 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.
Coronary heart diseases are 2 to 5 times more common among middle-aged men than women. In a study done by the World Health Organization, sex contributes to approximately 40% of the variation in sex ratios of coronary heart disease mortality. Another study reports similar results finding that sex differences explains nearly half the risk associated with cardiovascular diseases One of the proposed explanations for sex differences in cardiovascular diseases is hormonal difference. Among women, estrogen is the predominant sex hormone. Estrogen may have protective effects on glucose metabolism and hemostatic system, and may have direct effect in improving endothelial cell function. The production of estrogen decreases after menopause, and this may change the female lipid metabolism toward a more atherogenic form by decreasing the HDL cholesterol level while increasing LDL and total cholesterol levels.
Among men and women, there are differences in body weight, height, body fat distribution, heart rate, stroke volume, and arterial compliance. In the very elderly, age-related large artery pulsatility and stiffness are more pronounced among women than men. This may be caused by the women's smaller body size and arterial dimensions which are independent of menopause.
=== Tobacco ===
Cigarettes are the major form of smoked tobacco. Risks to health from tobacco use result not only from direct consumption of tobacco, but also from exposure to second-hand smoke. Approximately 10% of cardiovascular disease is attributed to smoking; however, people who quit smoking by age 30 have almost as low a risk of death as never smokers.
=== Physical inactivity ===
Insufficient physical activity (defined as less than 5 x 30 minutes of moderate activity per week, or less than 3 x 20 minutes of vigorous activity per week) is currently the fourth leading risk factor for mortality worldwide. In 2008, 31.3% of adults aged 15 or older (28.2% men and 34.4% women) were insufficiently physically active.
The risk of ischemic heart disease and diabetes mellitus is reduced by almost a third in adults who participate in 150 minutes of moderate physical activity each week (or equivalent). In addition, physical activity assists weight loss and improves blood glucose control, blood pressure, lipid profile and insulin sensitivity. These effects may, at least in part, explain its cardiovascular benefits.
=== Diet ===
High dietary intakes of saturated fat, trans-fats and salt, and low intake of fruits, vegetables and fish are linked to cardiovascular risk, although whether all these associations indicate causes is disputed. The World Health Organization attributes approximately 1.7 million deaths worldwide to low fruit and vegetable consumption. Frequent consumption of high-energy foods, such as processed foods that are high in fats and sugars, promotes obesity and may increase cardiovascular risk. The amount of dietary salt consumed may also be an important determinant of blood pressure levels and overall cardiovascular risk. There is moderate quality evidence that reducing saturated fat intake for at least two years reduces the risk of cardiovascular disease. High trans-fat intake has adverse effects on blood lipids and circulating inflammatory markers, and elimination of trans-fat from diets has been widely advocated. In 2018 the World Health Organization estimated that trans fats were the cause of more than half a million deaths per year. There is evidence that higher consumption of sugar is associated with higher blood pressure and unfavorable blood lipids, and sugar intake also increases the risk of diabetes mellitus. High consumption of processed meats is associated with an increased risk of cardiovascular disease, possibly in part due to increased dietary salt intake.
=== Alcohol ===
The relationship between alcohol consumption and cardiovascular disease is complex, and may depend on the amount of alcohol consumed. There is a direct relationship between high levels of drinking alcohol and cardiovascular disease. Drinking at low levels without episodes of heavy drinking may be associated with a reduced risk of cardiovascular disease, but there is evidence that associations between moderate alcohol consumption and protection from stroke are non-causal. Moderate drinking is defined as one drink per day for women or two drinks a day for men. At the population level, the health risks of drinking alcohol exceed any potential benefits. Exercising regularly can provide the same benefits as potentially consuming small amounts of alcohol and is a much safer alternative. Consuming too much alcohol can cause a high blood pressure, heart failure, and cardiomyopathy. Drinking alcohol can also cause obesity, which can contribute to cardiovascular issues as well.
=== Celiac disease ===
Untreated celiac disease can cause the development of many types of cardiovascular diseases, most of which improve or resolve with a gluten-free diet and intestinal healing. However, delays in recognition and diagnosis of celiac disease can cause irreversible heart damage.
=== Sleep ===
A lack of good sleep, in amount or quality, is documented as increasing cardiovascular risk in both adults and teens. Recommendations suggest that infants typically need 12 or more hours of sleep per day, adolescents at least eight or nine hours, and adults seven or eight. About one-third of adult Americans get less than the recommended seven hours of sleep per night, and in a study of teenagers, just 2.2 percent of those studied got enough sleep, many of whom did not get good quality sleep. Studies have shown that short sleepers getting less than seven hours sleep per night have a 10 percent to 30 percent higher risk of cardiovascular disease.
Sleep disorders such as sleep-disordered breathing and insomnia, are also associated with a higher cardiometabolic risk.
An estimated 50 to 70 million Americans have insomnia, sleep apnea or other chronic sleep disorders.
In addition, sleep research displays differences in race and class. Short sleep and poor sleep tend to be more frequently reported in ethnic minorities than in whites. African-Americans report experiencing short durations of sleep five times more often than whites, possibly as a result of social and environmental factors. Black children and children living in disadvantaged neighborhoods have much higher rates of sleep apnea.
One study found that of adults who are 45 and older, subjects that fell asleep at different times each night and slept inconsistent numbers of hours each night were more likely to develop atherosclerosis. Poor sleep habits, such as too little sleep, too much sleep, or fragmented sleep, were associated with cardiovascular disease, obesity, and high blood pressure. Another study noted that participants whose sleep duration varied by more than two hours within the course of a week were 1.4 times more likely to have elevated levels of coronary artery calcium, a predictor of cardiovascular events.
=== Socioeconomic disadvantage ===
Cardiovascular disease has a greater impact on low- and middle-income countries compared to those with higher income. Although data on the social patterns of cardiovascular disease in low- and middle-income countries is limited, reports from high-income countries consistently demonstrate that low educational status or income are associated with a greater risk of cardiovascular disease. Policies that have resulted in increased socio-economic inequalities have been associated with greater subsequent socio-economic differences in cardiovascular disease implying a cause and effect relationship. Psychosocial factors, environmental exposures, health behaviours, and health-care access and quality contribute to socio-economic differentials in cardiovascular disease. The Commission on Social Determinants of Health recommended that more equal distributions of power, wealth, education, housing, environmental factors, nutrition, and health care were needed to address inequalities in cardiovascular disease and non-communicable diseases.
=== Air pollution ===
Particulate matter has been studied for its short- and long-term exposure effects on cardiovascular disease. Currently, airborne particles under 2.5 micrometers in diameter (PM2.5) are the major focus, in which gradients are used to determine CVD risk. Overall, long-term PM exposure increased rate of atherosclerosis and inflammation. In regards to short-term exposure (2 hours), every 25 μg/m3 of PM2.5 resulted in a 48% increase of CVD mortality risk. In addition, after only 5 days of exposure, a rise in systolic (2.8 mmHg) and diastolic (2.7 mmHg) blood pressure occurred for every 10.5 μg/m3 of PM2.5. Other research has implicated PM2.5 in irregular heart rhythm, reduced heart rate variability (decreased vagal tone), and most notably heart failure. PM2.5 is also linked to carotid artery thickening and increased risk of acute myocardial infarction.
=== Cardiovascular risk assessment ===
Existing cardiovascular disease or a previous cardiovascular event, such as a heart attack or stroke, is the strongest predictor of a future cardiovascular event. Age, sex, smoking, blood pressure, blood lipids and diabetes are important predictors of future cardiovascular disease in people who are not known to have cardiovascular disease. These measures, and sometimes others, may be combined into composite risk scores to estimate an individual's future risk of cardiovascular disease. Numerous risk scores exist although their respective merits are debated. Other diagnostic tests and biomarkers remain under evaluation but currently these lack clear-cut evidence to support their routine use. They include family history, coronary artery calcification score, high sensitivity C-reactive protein (hs-CRP), ankle–brachial pressure index, lipoprotein subclasses and particle concentration, lipoprotein(a), apolipoproteins A-I and B, fibrinogen, white blood cell count, homocysteine, N-terminal pro B-type natriuretic peptide (NT-proBNP), and markers of kidney function. High blood phosphorus is also linked to an increased risk.
=== Psychological stress ===
There is evidence that mental health problems, in particular depression and traumatic stress, is linked to cardiovascular diseases. Whereas mental health problems are known to be associated with risk factors for cardiovascular diseases such as smoking, poor diet, and a sedentary lifestyle, these factors alone do not explain the increased risk of cardiovascular diseases seen in depression, stress, and anxiety. Moreover, posttraumatic stress disorder is independently associated with increased risk for incident coronary heart disease, even after adjusting for depression and other covariates.
Many studies recognize depression and anxiety as two important disorders that can cause an increase in the risk of developing cardiovascular disease. Only half of the instances of cardiovascular disease are explained by factors such as age and gender that cannot be changed. The other half of instances are due to other sources, including psychological stress. Studies have shown that the prevalence of depression in patients with heart failure is higher than 20%.
Another study assessed the link between men and women who had been divorced and instance of cardiovascular disease. The study found that women who had gone through at least two divorces were just as likely to experience cardiovascular disease as a smoker or diabetic. Men, on the other hand, also had a higher risk of cardiovascular disease, however, their health improved upon remarriage while women did not.
This study also found that during a World Cup soccer event in Germany, heart attacks more than doubled during the days when the nation's team was playing. Researchers assume this link is due to the fact that stress can increase inflammation in the body, which can cause high blood pressure and low HDL cholesterol. Chronic stress can also affect sleep, exercise, and food choices.
=== Anxiety ===
Patients who suffer from generalized anxiety disorder are more likely to develop some form of cardiovascular disease. It is hypothesized that anxiety makes one more likely to develop cardiovascular disease due to the fact that it can change the body's stress response through hormonal and physiological reactions. People with anxiety often experience high blood pressure, arrhythmias, and heart attacks. The stress response caused by anxiety can increase inflammation in the body. It was also discovered that patients with anxiety had lower levels of omega-3-fatty acids which is linked to an increased risk of developing cardiovascular disease.
=== Occupational exposure ===
Little is known about the relationship between work and cardiovascular disease, but links have been established between certain toxins, extreme heat and cold, exposure to tobacco smoke, and mental health concerns such as stress and depression.
==== Non-chemical risk factors ====
A 2015 SBU-report looking at non-chemical factors found an association for those:
with mentally stressful work with a lack of control over their working situation — with an effort-reward imbalance
who experience low social support at work; who experience injustice or experience insufficient opportunities for personal development; or those who experience job insecurity
those who work night schedules; or have long working weeks
those who are exposed to noise
Specifically the risk of stroke was also increased by exposure to ionizing radiation. Hypertension develops more often in those who experience job strain and who have shift-work. Differences between women and men in risk are small, however men risk having and dying of heart attacks or stroke twice as often as women during working life.
==== Chemical risk factors ====
A 2017 SBU report found evidence that workplace exposure to silica dust, engine exhaust or welding fumes is associated with heart disease. Associations also exist for exposure to arsenic, benzopyrenes, lead, dynamite, carbon disulphide, carbon monoxide, metalworking fluids and occupational exposure to tobacco smoke. Working with the electrolytic production of aluminium or the production of paper when the sulphate pulping process is used is associated with heart disease. An association was also found between heart disease and exposure to compounds which are no longer permitted in certain work environments, such as phenoxy acids containing TCDD(dioxin) or asbestos.
Workplace exposure to silica dust or asbestos is also associated with pulmonary heart disease. There is evidence that workplace exposure to lead, carbon disulphide, phenoxyacids containing TCDD, as well as working in an environment where aluminum is being electrolytically produced, is associated with stroke.
=== Somatic mutations ===
As of 2017, evidence suggests that certain leukemia-associated mutations in blood cells may also lead to increased risk of cardiovascular disease. Several large-scale research projects looking at human genetic data have found a robust link between the presence of these mutations, a condition known as clonal hematopoiesis, and cardiovascular disease-related incidents and mortality.
=== Radiation therapy ===
Radiation treatments (RT) for cancer can increase the risk of heart disease and death, as observed in breast cancer therapy. Therapeutic radiation increases the risk of a subsequent heart attack or stroke by 1.5 to 4 times; the increase depends on the dose strength, volume, and location. Use of concomitant chemotherapy, e.g. anthracyclines, is an aggravating risk factor. The occurrence rate of RT induced cardiovascular disease is estimated between 10% and 30%.
Side-effects from radiation therapy for cardiovascular diseases have been termed radiation-induced heart disease or radiation-induced cardiovascular disease. Symptoms are dose-dependent and include cardiomyopathy, myocardial fibrosis, valvular heart disease, coronary artery disease, heart arrhythmia and peripheral artery disease. Radiation-induced fibrosis, vascular cell damage and oxidative stress can lead to these and other late side-effect symptoms.
== Pathophysiology ==
Population-based studies show that atherosclerosis, the major precursor of cardiovascular disease, begins in childhood. The Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study demonstrated that intimal lesions appear in all the aortas and more than half of the right coronary arteries of youths aged 7–9 years.
Obesity and diabetes mellitus are linked to cardiovascular disease, as are a history of chronic kidney disease and hypercholesterolaemia. In fact, cardiovascular disease is the most life-threatening of the diabetic complications and diabetics are two- to four-fold more likely to die of cardiovascular-related causes than nondiabetics.
== Screening ==
Screening ECGs (either at rest or with exercise) are not recommended in those without symptoms who are at low risk. This includes those who are young without risk factors. In those at higher risk the evidence for screening with ECGs is inconclusive. Additionally echocardiography, myocardial perfusion imaging, and cardiac stress testing is not recommended in those at low risk who do not have symptoms. Some biomarkers may add to conventional cardiovascular risk factors in predicting the risk of future cardiovascular disease; however, the value of some biomarkers is questionable. Ankle-brachial index (ABI), high-sensitivity C-reactive protein (hsCRP), and coronary artery calcium, are also of unclear benefit in those without symptoms as of 2018.
The NIH recommends lipid testing in children beginning at the age of 2 if there is a family history of heart disease or lipid problems. It is hoped that early testing will improve lifestyle factors in those at risk such as diet and exercise.
Screening and selection for primary prevention interventions has traditionally been done through absolute risk using a variety of scores (ex. Framingham or Reynolds risk scores). This stratification has separated people who receive the lifestyle interventions (generally lower and intermediate risk) from the medication (higher risk). The number and variety of risk scores available for use has multiplied, but their efficacy according to a 2016 review was unclear due to lack of external validation or impact analysis. Risk stratification models often lack sensitivity for population groups and do not account for the large number of negative events among the intermediate and low risk groups. As a result, future preventative screening appears to shift toward applying prevention according to randomized trial results of each intervention rather than large-scale risk assessment.
== Prevention ==
Up to 90% of cardiovascular disease may be preventable if established risk factors are avoided. Currently practised measures to prevent cardiovascular disease include:
Maintaining a healthy diet, such as the Mediterranean diet, a vegetarian, vegan or another plant-based diet.
Replacing saturated fat with healthier choices: Clinical trials show that replacing saturated fat with polyunsaturated vegetable oil reduced CVD by 30%. Prospective observational studies show that in many populations lower intake of saturated fat coupled with higher intake of polyunsaturated and monounsaturated fat is associated with lower rates of CVD.
Decrease body fat if overweight or obese. The effect of weight loss is often difficult to distinguish from dietary change, and evidence on weight reducing diets is limited. In observational studies of people with severe obesity, weight loss following bariatric surgery is associated with a 46% reduction in cardiovascular risk.
Limit alcohol consumption to the recommended daily limits. People who moderately consume alcoholic drinks have a 25–30% lower risk of cardiovascular disease. However, people who are genetically predisposed to consume less alcohol have lower rates of cardiovascular disease suggesting that alcohol itself may not be protective. Excessive alcohol intake increases the risk of cardiovascular disease and consumption of alcohol is associated with increased risk of a cardiovascular event in the day following consumption.
Decrease non-HDL cholesterol. Statin treatment reduces cardiovascular mortality by about 31%.
Stopping smoking and avoidance of second-hand smoke. Stopping smoking reduces risk by about 35%.
At least 150 minutes (2 hours and 30 minutes) of moderate exercise per week.
Lower blood pressure, if elevated. A 10 mmHg reduction in blood pressure reduces risk by about 20%. Lowering blood pressure appears to be effective even at normal blood pressure ranges.
Not enough sleep also raises the risk of high blood pressure. Adults need about 7–9 hours of sleep. Sleep apnea is also a major risk as it causes breathing to stop briefly, which can put stress on the body which can raise the risk of heart disease.
Most guidelines recommend combining preventive strategies. There is some evidence that interventions aiming to reduce more than one cardiovascular risk factor may have beneficial effects on blood pressure, body mass index and waist circumference; however, evidence was limited and the authors were unable to draw firm conclusions on the effects on cardiovascular events and mortality.
There is additional evidence to suggest that providing people with a cardiovascular disease risk score may reduce risk factors by a small amount compared to usual care. However, there was some uncertainty as to whether providing these scores had any effect on cardiovascular disease events. It is unclear whether or not dental care in those with periodontitis affects their risk of cardiovascular disease. According to a 2021 WHO study, working 55+ hours a week raises the risk of stroke by 35% and the risk of dying from heart conditions by 17%, when compared to a 35-40 hours week.
=== Psychological prevention ===
Decrease psychosocial stress. This measure may be complicated by imprecise definitions of what constitute psychosocial interventions. Mental stress–induced myocardial ischemia is associated with an increased risk of heart problems in those with previous heart disease. Severe emotional and physical stress leads to a form of heart dysfunction known as Takotsubo syndrome in some people. Specific relaxation therapies are of unclear benefit. Decreasing psychological stress can be accomplished by receiving access to services and support, recognizing signs and symptoms of mental health disorders, awareness of family history, and understanding which mental health disorders increase the risk of cardiovascular disease. Psychosocial intervention programs have been shown to improve risk of developing cardiovascular disease in the high-risk population.
=== Diet ===
A diet high in fruits and vegetables decreases the risk of cardiovascular disease and death.
A 2021 review found that plant-based diets can provide a risk reduction for CVD if a healthy plant-based diet is consumed. Unhealthy plant-based diets do not provide benefits over diets including meat. A similar meta-analysis and systematic review also looked into dietary patterns and found "that diets lower in animal foods and unhealthy plant foods, and higher in healthy plant foods are beneficial for CVD prevention". A 2018 meta-analysis of observational studies concluded that "In most countries, a vegan diet is associated with a more favourable cardio-metabolic profile compared to an omnivorous diet."
Evidence suggests that the Mediterranean diet may improve cardiovascular outcomes. There is also evidence that a Mediterranean diet may be more effective than a low-fat diet in bringing about long-term changes to cardiovascular risk factors (e.g., lower cholesterol level and blood pressure).
The DASH diet (high in nuts, fish, fruits and vegetables, and low in sweets, red meat and fat) has been shown to reduce blood pressure, lower total and low density lipoprotein cholesterol and improve metabolic syndrome; but the long-term benefits have been questioned. A high-fiber diet is associated with lower risks of cardiovascular disease.
Worldwide, dietary guidelines recommend a reduction in saturated fat, and although the role of dietary fat in cardiovascular disease is complex and controversial there is a long-standing consensus that replacing saturated fat with unsaturated fat in the diet is sound medical advice. Total fat intake has not been found to be associated with cardiovascular risk. A 2020 systematic review found moderate quality evidence that reducing saturated fat intake for at least 2 years caused a reduction in cardiovascular events. A 2015 meta-analysis of observational studies however did not find a convincing association between saturated fat intake and cardiovascular disease. Variation in what is used as a substitute for saturated fat may explain some differences in findings. The benefit from replacement with polyunsaturated fats appears greatest, while replacement of saturated fats with carbohydrates does not appear to have a beneficial effect. A diet high in trans fatty acids is associated with higher rates of cardiovascular disease, and in 2015 the Food and Drug Administration (FDA) determined that there was 'no longer a consensus among qualified experts that partially hydrogenated oils (PHOs), which are the primary dietary source of industrially produced trans fatty acids (IP-TFA), are generally recognized as safe (GRAS) for any use in human food'. There is conflicting evidence concerning whether dietary supplements of omega-3 fatty acids (a type of polyunsaturated essential fatty acid) added to diet improve cardiovascular risk.
The benefits of recommending a low-salt diet in people with high or normal blood pressure are not clear. In those with heart failure, after one study was left out, the rest of the trials show a trend to benefit. Another review of dietary salt concluded that there is strong evidence that high dietary salt intake increases blood pressure and worsens hypertension, and that it increases the number of cardiovascular disease events; both as a result of the increased blood pressure and probably through other mechanisms. Moderate evidence was found that high salt intake increases cardiovascular mortality; and some evidence was found for an increase in overall mortality, strokes, and left ventricular hypertrophy.
==== Intermittent fasting ====
Overall, the current body of scientific evidence is uncertain on whether intermittent fasting could prevent cardiovascular disease. Intermittent fasting may help people lose more weight than regular eating patterns, but was not different from energy restriction diets.
=== Medication ===
Blood pressure medication reduces cardiovascular disease in people at risk, irrespective of age, the baseline level of cardiovascular risk, or baseline blood pressure. The commonly-used drug regimens have similar efficacy in reducing the risk of all major cardiovascular events, although there may be differences between drugs in their ability to prevent specific outcomes. Larger reductions in blood pressure produce larger reductions in risk, and most people with high blood pressure require more than one drug to achieve adequate reduction in blood pressure. Adherence to medications is often poor, and while mobile phone text messaging has been tried to improve adherence, there is insufficient evidence that it alters secondary prevention of cardiovascular disease.
Statins are effective in preventing further cardiovascular disease in people with a history of cardiovascular disease. As the event rate is higher in men than in women, the decrease in events is more easily seen in men than women. In those at risk, but without a history of cardiovascular disease (primary prevention), statins decrease the risk of death and combined fatal and non-fatal cardiovascular disease. The benefit, however, is small. A United States guideline recommends statins in those who have a 12% or greater risk of cardiovascular disease over the next ten years. Niacin, fibrates and CETP Inhibitors, while they may increase HDL cholesterol do not affect the risk of cardiovascular disease in those who are already on statins. Fibrates lower the risk of cardiovascular and coronary events, but there is no evidence to suggest that they reduce all-cause mortality.
Anti-diabetic medication may reduce cardiovascular risk in people with Type 2 diabetes, although evidence is not conclusive. A meta-analysis in 2009 including 27,049 participants and 2,370 major vascular events showed a 15% relative risk reduction in cardiovascular disease with more-intensive glucose lowering over an average follow-up period of 4.4 years, but an increased risk of major hypoglycemia.
Aspirin has been found to be of only modest benefit in those at low risk of heart disease, as the risk of serious bleeding is almost equal to the protection against cardiovascular problems. In those at very low risk, including those over the age of 70, it is not recommended. The United States Preventive Services Task Force recommends against use of aspirin for prevention in women less than 55 and men less than 45 years old; however, it is recommended for some older people.
The use of vasoactive agents for people with pulmonary hypertension with left heart disease or hypoxemic lung diseases may cause harm and unnecessary expense.
Antibiotics for secondary prevention of coronary heart disease
Antibiotics may help patients with coronary disease to reduce the risk of heart attacks and strokes. However, evidence in 2021 suggests that antibiotics for secondary prevention of coronary heart disease are harmful, with increased mortality and occurrence of stroke; the use of antibiotics is not supported for preventing secondary coronary heart disease.
=== Physical activity ===
Exercise-based cardiac rehabilitation following a heart attack reduces the risk of death from cardiovascular disease and leads to less hospitalizations. There have been few high-quality studies of the benefits of exercise training in people with increased cardiovascular risk but no history of cardiovascular disease.
A systematic review estimated that inactivity is responsible for 6% of the burden of disease from coronary heart disease worldwide. The authors estimated that 121,000 deaths from coronary heart disease could have been averted in Europe in 2008 if people had not been physically inactive. Low-quality evidence from a limited number of studies suggest that yoga has beneficial effects on blood pressure and cholesterol. Tentative evidence suggests that home-based exercise programs may be more efficient at improving exercise adherence.
=== Dietary supplements ===
While a healthy diet is beneficial, the effect of antioxidant supplementation (vitamin E, vitamin C, etc.) or vitamins has not been shown to protect against cardiovascular disease and in some cases may possibly result in harm. Mineral supplements have also not been found to be useful. Niacin, a type of vitamin B3, may be an exception with a modest decrease in the risk of cardiovascular events in those at high risk. Magnesium supplementation lowers high blood pressure in a dose-dependent manner. Magnesium therapy is recommended for people with ventricular arrhythmia associated with torsades de pointes who present with long QT syndrome, and for the treatment of people with digoxin intoxication-induced arrhythmias. There is no evidence that omega-3 fatty acid supplementation is beneficial. A 2022 review found that some dietary supplements, including micronutrients, may reduce risk factors for cardiovascular disease.
== Management ==
Cardiovascular disease is treatable with initial treatment primarily focused on diet and lifestyle interventions. Influenza may make heart attacks and strokes more likely and therefore influenza vaccination may decrease the chance of cardiovascular events and death in people with heart disease.
Proper CVD management necessitates a focus on MI and stroke cases due to their combined high mortality rate, keeping in mind the cost-effectiveness of any intervention, especially in developing countries with low or middle-income levels. Regarding MI, strategies using aspirin, atenolol, streptokinase or tissue plasminogen activator have been compared for quality-adjusted life-year (QALY) in regions of low and middle income. The costs for a single QALY for aspirin and atenolol were less than US$25, streptokinase was about $680, and t-PA was $16,000. Aspirin, ACE inhibitors, beta-blockers, and statins used together for secondary CVD prevention in the same regions showed single QALY costs of $350.
There are also surgical or procedural interventions that can save someone's life or prolong it. For heart valve problems, a person could have surgery to replace the valve. For arrhythmias, a pacemaker can be put in place to help reduce abnormal heart rhythms and for a heart attack, there are multiple options two of these are a coronary angioplasty and a coronary artery bypass surgery.
There is probably no additional benefit in terms of mortality and serious adverse events when blood pressure targets were lowered to ≤ 135/85 mmHg from ≤ 140 to 160/90 to 100 mmHg.
== Epidemiology ==
Cardiovascular diseases are the leading cause of death worldwide and in all regions except Africa. In 2008, 30% of all global death was attributed to cardiovascular diseases. Death caused by cardiovascular diseases are also higher in low- and middle-income countries as over 80% of all global deaths caused by cardiovascular diseases occurred in those countries. It is also estimated that by 2030, over 23 million people will die from cardiovascular diseases each year.
It is estimated that 60% of the world's cardiovascular disease burden will occur in the South Asian subcontinent despite only accounting for 20% of the world's population. This may be secondary to a combination of genetic predisposition and environmental factors. Organizations such as the Indian Heart Association are working with the World Heart Federation to raise awareness about this issue.
== Research ==
There is evidence that cardiovascular disease existed in pre-history, and research into cardiovascular disease dates from at least the 18th century. The causes, prevention, and/or treatment of all forms of cardiovascular disease remain active fields of biomedical research, with hundreds of scientific studies being published on a weekly basis.
Recent areas of research include the link between inflammation and atherosclerosis the potential for novel therapeutic interventions, and the genetics of coronary heart disease.
== References ==
== External links ==
WHO fact sheet on cardiovascular diseases
2021 ESC Guidelines on cardiovascular disease prevention in clinical practice
Heart Disease MedicineNet Slides, photos, descriptions
Risk calculator
Interactive CV Risk Calculator | Wikipedia/Diet_and_heart_disease |
Nicotine replacement therapy (NRT) is a medically approved way to treat people with tobacco use disorder by taking nicotine through means other than tobacco. It is used to help with quitting smoking or stopping chewing tobacco. It increases the chance of quitting tobacco smoking by about 55%. Often it is used along with other behavioral techniques. NRT has also been used to treat ulcerative colitis. Types of NRT include the adhesive patch, chewing gum, lozenges, nose spray, and inhaler. The use of multiple types of NRT at a time may increase effectiveness.
Common side effects depend on the formulation of nicotine. Common side effects with the gum include nausea, hiccups, and irritation of the mouth. Common side effects with the patch include skin irritation and a dry mouth while the inhaler commonly results in a cough, runny nose, or headaches. Serious risks include nicotine poisoning and continued addiction. They do not appear to increase the risk of heart attacks. There are possible harms to the baby if used during pregnancy. Nicotine replacement therapy works by reducing cravings caused by nicotine addiction.
They were first approved for use in 1984, in the United States. Nicotine replacement products are on the World Health Organization's List of Essential Medicines. They are available as generic medications.
== Medical uses ==
Nicotine replacement therapy, in the form of gum, patches, nasal spray, inhaler and lozenges all improve the ability of people trying to quit tobacco products. Nicotine replacement therapy is as effective as medications, such as bupropion, in helping people quit smoking for at least six months. All forms of nicotine replacement therapy, including nicotine gum, patches, nasal spray, inhalers, and lozenges, have similar success rates in terms of helping people stop smoking. However, the likelihood that someone will stick to a certain treatment varies, with compliance being the highest with nicotine patches, followed by nicotine gum, inhalers, and nasal sprays. Using a few different nicotine replacement methods in combination may improve success rates in stopping tobacco use. Additionally, using nicotine replacement with counseling has been proven to improve tobacco abstinence rates. These other strategies include: creating a plan to quit and utilizing quit programs, a quit phone line, or app that provides tips and inspiration to help quit.
Using nicotine replacement therapy to quit smoking should be considered for people who are severely dependent on nicotine. People who are severely dependent include those who smoke: more than one pack per day, within five minutes of awakening, while ill, when they wake up in the middle of the night, to ease withdrawal signs and symptoms.
Nicotine replacement products are most beneficial for heavy smokers who smoke more than 15 cigarettes per day. There are not enough studies to show whether NRT helps those who smoke fewer than 10 cigarettes per day.
=== Effectiveness ===
Evaluation of NRT in real-world studies produces more modest outcomes than efficacy studies conducted by industry-funded trials. The National Health Service (NHS) in England has a smoking cessation service based on pharmacotherapy in combination with counseling support. An Action on Smoking and Health (UK) (ASH) report claims that the average cost per life-year gained for every smoker successfully treated by these services is less than £1,000 (below the NICE guidelines of £20,000 per QALY (quality-adjusted life year). However, the investment in NHS stop smoking services is relatively low. A comparison with treatment costs for illicit drug users shows that £585 million is committed for 350,000 problem drug users compared to £56 million for 9 million users of tobacco. This is £6.20 for each smoker, compared to £1,670 per illegal drug user.
The claims for high efficacy and cost-effectiveness of NRT have not been substantiated in real-world effectiveness studies. Pierce and Gilpin (2002) stated their conclusion as follows: "Since becoming available over the counter, NRT appears no longer effective in increasing long-term successful cessation" (p. 1260). Efficacy studies, which are conducted using randomized controlled trials, do not transfer very well to real-world effectiveness. Bauld, Bell, McCullough, Richardson and Greaves (2009) reviewed 20 studies on the effectiveness of intensive NHS treatments for smoking cessation published between 1990 and 2007. Quit rates showed a dramatic decrease between 4-weeks and one year. A quit rate of 53% at four weeks fell to only 15% at one year. Younger smokers, females, pregnant smokers and more deprived smokers had lower quit rates than other groups.
The efficacy for each of the formulations alone (lozenges, nasal spray, gum, and transdermal patch) to aid in smoking cessation is equal. Efficacy increases 15% to 36% with combining treatments such as gum and lozenges. Higher doses increase the chance of stopping smoking for a period of six months and more. For patches, the most efficient doses were 25 mg worn over 16 hours or 21 mg worn over 24 hours. The evidence suggests that 4 mg nicotine gum leads to higher quit rates compared with 2 mg in heavy smokers.
== Toxicity ==
N-Nitrosonornicotine, a strong carcinogen present in unburned tobacco and cigarette smoke, has been found in the urine of some users of oral NRT products. Nicotine patches is an alternative.
== Side effects ==
Some side effects are caused by the nicotine, and are common to NRT products. Other common side effects depend on the formulation of nicotine. Common side effects with the gum include nausea, hiccups, and irritation of the mouth. Common side effects with the patch include skin irritation and a dry mouth while the inhaler commonly results in a cough, runny nose, or headaches. To minimize local skin reactions from the patch, the application site should be moved daily. The nicotine patch can also cause strange dreams if worn while asleep. Nasal sprays commonly cause nasal irritation, watering eyes, and coughing.
Serious risks include nicotine poisoning, which includes symptoms like visual disturbances, hyper-salivation, nausea, and vomiting; and continued addiction to nicotine products. Avoiding smoking and other products with nicotine are recommended since it may lead to nicotine overdose. Although overdose is rare, it can be problematic, especially in children and pets. The symptoms of nicotine overdose include headache, pale skin and mouth, belly pain, weakness, diarrhea, tremors or seizures, agitation, confusion, restlessness, high or low blood pressure, fast or irregular heartbeat, fast breathing, and cold sweats.
Limited evidence exists regarding long-term NRT use.
== Safety ==
=== Pregnancy ===
Nicotine is not safe to use in any amount during pregnancy. Nicotine crosses the placenta and is found in the breast milk of mothers who smoke as well as mothers who inhale passive smoke. There are possible harms to the baby if NRT is used during pregnancy. Thus, pregnant women and those who are breastfeeding should also consult a physician before initiating NRT. The gum, lozenge, and nasal spray are pregnancy category C. The transdermal patch is pregnancy category D. The transdermal patch is considered less safe for the fetus because it delivers continuous nicotine exposure, as opposed to the gum or lozenge, which delivers intermittent and thus lower nicotine exposure.
Strong evidence suggests that nicotine cannot be regarded as a safe substance of cigarette use. Nicotine itself could be at least partly responsible for many of the adverse after birth health results related to cigarette use while the mother was pregnant. There is evidence that nicotine negatively affects fetal brain development and pregnancy outcomes. There is also risk of stillbirth and pre-term birth. Nicotine use will probably harm fetal neurological development. Risks to the child later in life from nicotine exposure during pregnancy include type 2 diabetes, obesity, hypertension, neurobehavioral defects, respiratory dysfunction, and infertility. Nicotine exposure during pregnancy can result in attention deficit hyperactivity disorder (ADHD) and learning disabilities in the child. It also puts the child at increased risk for nicotine addiction in the future.
Pregnant women should consider behavioral therapy before NRT is considered.
=== Youth ===
In people under the age of eighteen, a physician is often consulted before starting NRT. The evidence suggests that exposure to nicotine between the ages of 10 and 25 years causes lasting harm to the brain and cognitive ability. Evidence is unclear whether adolescents gain benefit from cognitive-behavioral therapy or smoking cessation over the long-term as of 2017. Most tobacco users are under-eighteens when they start, and almost no-one over the age of 25 starts using.
=== Cardiovascular conditions ===
While there is no evidence that NRT can increase the risk of heart attacks, individuals with pre-existing cardiovascular conditions or recent heart attacks should consult a physician before initiating NRT.
Smoking is known to cause cardiovascular diseases such as coronary heart disease, hypertension, heart attack, stroke, and peripheral artery disease. Cigarette smoking is the cause of 20% of all cardiovascular deaths in the United States, which is the leading cause of mortality.
=== Other conditions ===
Nicotine replacement therapies should be used cautiously in individuals with the following conditions: severe reactive airway diseases (for nasal spray), chronic nasal disorders such as sinusitis, polyps, rhinitis, or allergy (for nasal spray), diabetes (insulin-dependent), gastrointestinal diseases such as esophagitis, active gastric or peptic ulcer disease, liver problems, hyperthyroidism, pheochromocytoma, phenylketonuria (for lozenges), renal problems, and skin conditions such as psoriasis or dermatitis (for the transdermal patch).
== Mechanism of action ==
Nicotine replacement therapy works by reducing cravings due to nicotine addiction. Smoking cigarettes releases high doses of nicotine to the brain in a matter of seconds as opposed to low doses released over a period of minutes to hours by the various forms of nicotine replacement therapy. Nicotine from NRT does not reach as high a concentration in the blood as does nicotine from smoke inhalation due to different absorption methods. NRT relies on systemic venous absorption, whereas nicotine from cigarettes reaches the arterial system. Nicotine replacement products vary in the time it takes for the nicotine to enter the body and the total time nicotine stays in the body. The more quickly a dose of nicotine is delivered and absorbed, the higher the addiction risk. It is possible to become dependent on some NRTs.
Nicotine patches are applied to the skin and continuously administer a stable dose of nicotine slowly over 16–24 hours. Nicotine gum, nicotine sprays, nicotine toothpicks, nicotine sublingual tablets, and nicotine lozenges administer nicotine orally with quicker nicotine uptake into the body but lasting a shorter amount of time. Nicotine inhalers are metered-dose inhalers that administer nicotine through the lungs and mucous membranes of the throat quickly, lasting for a short amount of time. For example, blood nicotine levels are the highest 5–10 minutes after using the nicotine nasal spray, 20 minutes after using a nicotine inhaler or chewing nicotine gum, and 2–4 hours after using a nicotine patch.
== Society and culture ==
NRT products were first approved for use in the United States in 1984. Nicotine replacement products are on the World Health Organization's List of Essential Medicines. They are available as generic medication.
=== Formulations ===
The nicotine patch is a once-daily, longer-acting form of NRT. An advantage of the nicotine patch is its simple compliance; it does not require active use throughout the day. The gum, lozenge, sublingual tablet, oral inhaler, oral spray, and nasal spray are acutely dosed products, providing the user with the benefit and ability of self-titrating based on cravings.
Brand names include Commit Lozenge, Nicoderm, Nicogum, Nicorette, Nicotex, Nicotinell, and Thrive. NRT products contain similar pharmaceutical grade nicotine as is used in e-cigarettes.
=== Medicines ===
In 2015, the United States Public Health Service listed seven agents for the stopping of tobacco, which included five nicotine replacement treatments (nicotine patches, gum, lozenges, inhalers, and nasal sprays) and two oral medications (bupropion and varenicline). Other NRT options are available, including nicotine mouth sprays and sublingual tablets.
=== Dosing ===
The dose of nicotine replacement therapy products is generally based on if the user is considered a heavy, average, or light smoker.
A cigarette delivers an average of 1 mg to 3 mg of the nicotine contained in it. NRT products typically aim to parallel this, but the amount of nicotine absorbed by the user is less than the original dose.
Nicotine nasal sprays are formulated in doses of lowest strength, available in 0.5 mg and 1 mg strengths.
Nicotine lozenges deliver doses as low as 1 mg up to 4 mg. It is not chewed as the gum would be, and dissolves in approximately 30 minutes. This formulation may be preferred by those individuals who do not find gum chewing to be acceptable.
Nicotine gum is available in doses of 2 mg and 4 mg. Using 4 mg nicotine gum versus 2 mg gum increases the likelihood of successful smoking cessation. When using the gum, acidic beverages like soda, coffee, or beer should be avoided fifteen minutes prior and during use because they can impede proper absorption of nicotine.
Nicotine inhalers come in 10 mg and 15 mg cartridge strengths and typically deliver around 4 mg in one dose. The inhaler may be preferred in individuals who want to satisfy the hand-to-mouth ritual that smoking provides.
Transdermal patches deliver between 5 mg and 52.5 mg of nicotine, which results in plasma levels similar to that of heavy smokers. Combining nicotine patch treatment with a faster nicotine-delivery means, like nicotine gum or spray, improves the likelihood of successful treatment.
=== Not approved as NRTs ===
Some smokeless consumer products available can function as alternative nicotine delivery systems (ANDS) but they have not received FDA approval as smoking-cessation therapy aids that are safe and effective.
Snus and nasal snuff also allow for nicotine administration outside of tobacco smoking. Nicotine pouches are described as similar to or a tobacco-free variant of snus. They are pre-portioned and are held in the user's lip or cheek allowing for sublingual or buccal delivery of flavors and high doses of nicotine. The small pouches are not like chewing tobacco, as the user does not need to spit since the contents of the pouches stay inside during use. Swedish pouches have been available on the American consumer market since at least 2016 but their popularity and controversy surged in 2019 and 2020. In the US and UK concerns have been raised that nicotine pouches are seemingly too similar to banned snus products, is aimed at teenagers, further complicating the youth vaping trend, falling into the hands of adolescents easily, and are discrete enough to easily pass for regular gums or lozenges.
Nicotine infused toothpicks are another product that has been available in the United States since at least 2013. They can have a total nicotine delivery that is comparable to that of nicotine gum. Nicotine toothpicks generally are infused with food-grade flavorings and 1–3 mg of nicotine, which is similar to that of other oral-delivery nicotine products and some cigarettes. In spite of these similarities, as of 2018 they have been a subject of controversy. Online retailers have been under scrutiny for allowing their products to be too easily purchased by youth. Various news outlets and school districts have expressed the concern that these products have a high appeal to minors wanting to experiment with nicotine due to; the multitude of sweet flavors offered, ease & speed of use, seeming innocuous, and having a discreet nature. In 2015, NRT sales fell for the first time since 2008 while sales for e-cigarettes or electronic nicotine delivery systems (ENDS) continued to increase at a substantial rate. The evidence is that UK smokers are trying to quit with e-cigarettes rather than NRT methods.
E-cigarettes are often, although not always, designed to look and feel like cigarettes. They have been marketed as less harmful alternatives to cigarettes, but very few are as yet approved as NRTs in any jurisdiction. Some electronic cigarettes have coarsely adjustable nicotine levels. Some healthcare groups have hesitated to recommend e-cigarettes for quitting smoking, because of limited evidence of effectiveness and safety. However, more recent review show the opposite, possibly because of newer types of e‐cigarettes have better nicotine delivery than older one.
The U.S. Food and Drug Administration (FDA) has a list of additional tobacco products they are seeking to regulate, including electronic cigarettes. Most approved NRT products have been approved for over 20 years, however the FDA has also approved nicotine inhalers as a form of NRT.
Future approaches of NRT could include nicotine preloading, a true pulmonary inhaler, and nicotine vaccines. Nicotine preloading, otherwise known as pre-cessation or pre-quitting NRT, has found that using the patch for a few weeks before the quit date produces significantly higher quit rates than if it was started on the quit day. The true pulmonary inhaler would deliver nicotine to the lungs in a manner that more resembles cigarette smoking, which would provide better relief of background cravings as well as acute cravings. Nicotine vaccines are under investigation as a method to treat tobacco dependence through priming the body to mount an immune response against nicotine.
== References ==
== External links ==
"Nicotine". Drug Information Portal. U.S. National Library of Medicine.
University of Wisconsin Center for Tobacco Research and Intervention
Recommendations for special populations
"Nicotine Lozenges". MedlinePlus. 2018-08-15.
"Nicotine Nasal Spray". MedlinePlus. 2016-07-15.
"Nicotine Oral Inhalation". MedlinePlus. 2016-07-15.
"Nicotine Gum". MedlinePlus. 2017-10-15.
"Quit Smoking Therapy". 2baconil. 2020-07-12. | Wikipedia/Nicotine_replacement_therapy |
A cardiac stress test is a cardiological examination that evaluates the cardiovascular system's response to external stress within a controlled clinical setting. This stress response can be induced through physical exercise (usually a treadmill) or intravenous pharmacological stimulation of heart rate.
As the heart works progressively harder (stressed) it is monitored using an electrocardiogram (ECG) monitor. This measures the heart's electrical rhythms and broader electrophysiology. Pulse rate, blood pressure and symptoms such as chest discomfort or fatigue are simultaneously monitored by attending clinical staff. Clinical staff will question the patient throughout the procedure asking questions that relate to pain and perceived discomfort. Abnormalities in blood pressure, heart rate, ECG or worsening physical symptoms could be indicative of coronary artery disease.
Stress testing does not accurately diagnose all cases of coronary artery disease, and can often indicate that it exists in people who do not have the condition. The test can also detect heart abnormalities such as arrhythmias, and conditions affecting electrical conduction within the heart such as various types of fascicular blocks.
A "normal" stress test does not offer any substantial reassurance that a future unstable coronary plaque will not rupture and block an artery, inducing a heart attack. As with all medical diagnostic procedures, data is only from a moment in time. A primary reason stress testing is not perceived as a robust method of CAD detection — is that stress testing generally only detects arteries that are severely narrowed (~70% or more).
== Stress testing and echocardiography ==
A stress test may be accompanied by echocardiography. The echocardiography is performed both before and after the exercise so that structural differences can be compared.
A resting echocardiogram is obtained prior to stress. The ultrasound images obtained are similar to the ones obtained during a full surface echocardiogram, commonly referred to as transthoracic echocardiogram. The patient is subjected to stress in the form of exercise or chemically (often dobutamine). After the target heart rate is achieved, 'stress' echocardiogram images are obtained. The two echocardiogram images are then compared to assess for any abnormalities in wall motion of the heart. This is used to detect obstructive coronary artery disease.
== Cardiopulmonary exercise stress testing ==
While also measuring breathing gases (e.g., oxygen saturation, maximal oxygen consumption), the test is often referred to as a cardiopulmonary exercise test. Common indications for a cardiopulmonary exercise test include evaluation of shortness of breath, workup before heart transplantation, and prognosis and risk assessment of heart failure patients.
The test is also common in sport science for measuring athletes' maximal oxygen consumption, V̇O2 max. In 2016, the American Heart Association published an official scientific statement advocating that cardiorespiratory fitness, quantifiable as V̇O2 max and measured during a cardiopulmonary exercise test, be categorized as a clinical vital sign and should be routinely assessed as part of clinical practice.
The CPX test can be done on a treadmill or cycle ergometer. In untrained subjects, V̇O2 max is 10% to 20% lower when using a cycle ergometer compared with a treadmill.
== Stress testing using injected nuclear markers ==
A nuclear stress test uses a gamma camera to image radioisotopes injected into the bloodstream. The best known example is myocardial perfusion imaging. Typically, a radiotracer (Tc-99 sestamibi, Myoview or thallous chloride 201) may be injected during the test. After a suitable waiting period to ensure proper distribution of the radiotracer, scans are acquired with a gamma camera to capture images of the blood flow. Scans acquired before and after exercise are examined to assess the state of the coronary arteries of the patient. By showing the relative amounts of radioisotope within the heart muscle, the nuclear stress tests more accurately identify regional areas of reduced blood flow.
Stress and potential cardiac damage from exercise during the test is a problem in patients with ECG abnormalities at rest or in patients with severe motor disability. Pharmacological stimulation from vasodilators such as dipyridamole or adenosine, or positive chronotropic agents such as dobutamine can be used. Testing personnel can include a cardiac radiologist, a nuclear medicine physician, a nuclear medicine technologist, a cardiology technologist, a cardiologist, and/or a nurse. The typical dose of radiation received during this procedure can range from 9.4 to 40.7 millisieverts.
== Recommended utility of this procedure ==
The American Heart Association recommends ECG treadmill testing as the first choice for patients with medium risk of coronary heart disease according to risk factors of smoking, family history of coronary artery stenosis, hypertension, diabetes and high cholesterol. In 2013, in its "Exercise Standards for Testing and Training", the AHA indicated that high frequency QRS analysis during ECG treadmill test have useful test performance for detection of coronary heart disease.
Perfusion stress test (with 99mTc labelled sestamibi) is appropriate for select patients, especially those with an abnormal resting electrocardiogram.
Intracoronary ultrasound or angiogram can provide more information but is invasive and carries the risk of complications associated with cardiac catheterization procedures.
== Diagnostic value ==
The common approach for stress testing recommended by the American College of Cardiology and the American Heart Association involves several methods to assess cardiac health. These methods provide information for diagnosing and managing heart-related conditions. Two primary stress tests utilized are a treadmill test using ECG/electrophysiology metrics and nuclear testing, each have unique sensitivity and specificity values.
The treadmill test, employing the modified Bruce protocol, demonstrates a sensitivity range of around 73-90% and a specificity range of around 50-74%. Sensitivity refers to the percentage of individuals with the condition correctly identified by the test, while specificity denotes the percentage of individuals without the condition correctly identified as not having it. The nuclear stress test exhibits a sensitivity of 81% and a specificity ranging from 85 to 95%.
To arrive at the patient's post test likelihood of disease, the interpretation of the stress test result necessitates the integration of the patient's pretest likelihood with the test's sensitivity and specificity. This method, initially introduced by Diamond and Forrester in the 1970s, provides an estimate of the patient's post-test likelihood of disease. Stress tests have limitations in assessing the significance and nature of cardiac problems, they should be seen in context - as an initial assessment that can lead to a number of other diagnostic approaches in the broader management of cardiac diseases.
According to data from the US Centers for Disease Control and Prevention (CDC) common first systems of coronary artery disease is a heart attack. According to the American Heart Association, a significant percentage of individuals, approximately 65% of men and 47% of women, present with a heart attack or sudden cardiac arrest as their first symptom of cardiovascular disease. Consequently, stress tests performed shortly before these events may not be highly relevant for predicting infarction in the majority of individuals tested.
== Contraindications and termination conditions ==
Stress cardiac imaging is not recommended for asymptomatic, low-risk patients as part of their routine care. Some estimates show that such screening accounts for 45% of cardiac stress imaging, and evidence does not show that this results in better outcomes for patients. Unless high-risk markers are present, such as diabetes in patients aged over 40, peripheral arterial disease, or a risk of coronary heart disease greater than 2 percent yearly, most health societies do not recommend the test as a routine procedure.
Absolute contraindications to cardiac stress test include:
Acute myocardial infarction within 48 hours
Unstable angina not yet stabilized with medical therapy
Uncontrolled cardiac arrhythmia, which may have significant hemodynamic responses (e.g. ventricular tachycardia)
Severe symptomatic aortic stenosis, aortic dissection, pulmonary embolism, and pericarditis
Multivessel coronary artery diseases that have a high risk of producing an acute myocardial infarction
Decompensated or inadequately controlled congestive heart failure
Uncontrolled hypertension (blood pressure > 200/110 mmHg)
Severe pulmonary hypertension
Acute aortic dissection
Acutely ill for any reason
Indications for termination:
A cardiac stress test should be terminated before completion under the following circumstances:
Absolute indications for termination include:
Systolic blood pressure decreases by more than 10 mmHg with increase in work rate, or drops below baseline in the same position, with other evidence of ischemia.
Increase in nervous system symptoms: Dizziness, ataxia or near syncope
Moderate to severe anginal pain (above 3 on standard 4-point scale)
Signs of poor perfusion, e.g. cyanosis or pallor
Request of the test subject
Technical difficulties (e.g. difficulties in measuring blood pressure or EGC)
ST Segment elevation of more than 1 mm in aVR, V1 or non-Q wave leads
Sustained ventricular tachycardia
Relative indications for termination include:
Systolic blood pressure decreases by more than 10 mmHg with increase in work rate, or drops below baseline in the same position, without other evidence of ischemia.
ST or QRS segment changes, e.g. more than 2 mm horizontal or downsloping ST segment depression in non-Q wave leads, or marked axis shift
Arrhythmias other than sustained ventricular tachycardia e.g. Premature ventricular contractions, both multifocal or triplet; heart block; supraventricular tachycardia or bradyarrhythmias
Intraventricular conduction delay or bundle branch block or that cannot be distinguished from ventricular tachycardia
Increasing chest pain
Fatigue, shortness of breath, wheezing, claudication or leg cramps
Hypertensive response (systolic blood pressure > 250 mmHg or diastolic blood pressure > 115 mmHg)
== Adverse effects ==
Side effects from cardiac stress testing may include
Palpitations, chest pain, myocardial infarction, shortness of breath, headache, nausea or fatigue.
Adenosine and dipyridamole can cause mild hypotension.
As the radioactive tracers used for this test are chemically carcinogenic, frequent use of these tests carries a small risk of cancer.
== Use of pharmacological agents to stress the heart ==
Pharmacologic stress testing relies on coronary steal. Vasodilators are used to dilate coronary vessels, which causes increased blood velocity and flow rate in normal vessels and less of a response in stenotic vessels. This difference in response leads to a steal of flow and perfusion defects appear in cardiac nuclear scans or as ST-segment changes.
The choice of pharmacologic stress agents used in the test depends on factors such as potential drug interactions with other treatments and concomitant diseases.
Pharmacologic agents such as adenosine, regadenoson (Lexiscan), or dipyridamole is generally used when a patient cannot achieve adequate work level with treadmill exercise, or has poorly controlled hypertension or left bundle branch block. However, an exercise stress test may provide more information about exercise tolerance than a pharmacologic stress test.
Commonly used agents include:
Vasodilators acting as adenosine receptor agonists, such as adenosine itself, and dipyridamole (Persantine), which acts indirectly at the receptor.
Regadenoson (Lexiscan), which acts specifically at the adenosine A2A receptor, thus affecting the heart more than the lung.
Dobutamine – The effects of beta-agonists such as dobutamine can be reversed by administering beta-blockers such as propranolol.
Regadenoson or dobutamine is often used in patients with severe reactive airway disease (asthma or COPD) as adenosine and dipyridamole can cause acute exacerbation of these conditions. If the patient's asthma is treated with an inhaler then it should be used as a pre-treatment prior to the injection of the pharmacologic stress agent. In addition, if the patient is actively wheezing then the physician should determine the benefits versus the risk to the patient of performing a stress test especially outside of a hospital setting. Caffeine is usually held 24 hours prior to an adenosine stress test, as it is a competitive antagonist of the A2A adenosine receptor and can attenuate the vasodilatory effects adenosine.
Aminophylline may be used to attenuate severe and/or persistent adverse reactions to adenosine and regadenoson.
== History ==
Cardiac stress testing, used since the 1960s, has a history rooted in the diagnostic and prognostic assessment of patients with suspected coronary artery disease. It has evolved to evaluate inducible myocardial ischemia as an indicator of adverse outcomes. The factors influencing mortality risk have changed over time due to decreasing angina symptoms, increasing prevalence of conditions like diabetes and obesity, and the rise in pharmacologic testing for patients unable to exercise during stress tests.
== See also ==
Cardiac steal syndrome
Duke Treadmill Score
Harvard step test
Metabolic equivalent
Robert A. Bruce
Wasserman 9-Panel Plot
== References ==
== External links ==
Preparing for the exercise stress test Archived 2021-02-28 at the Wayback Machine
"A Simple Exercise Tolerance Test for Circulatory Efficiency with Standard Tables for Normal Individuals," American Journal of the Medical Sciences
"Optimal Medical Therapy with or without PCI for Stable Coronary Disease," New England Journal of Medicine
Stress test information from the American Heart Association
Nuclear stress test information at NIH MedLine | Wikipedia/Stress_echocardiography |
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/Bentham_Science_Publishers |
An anticoagulant, commonly known as a blood thinner, is a chemical substance that prevents or reduces the coagulation of blood, prolonging the clotting time. Some occur naturally in blood-eating animals, such as leeches and mosquitoes, which help keep the bite area unclotted long enough for the animal to obtain blood.
As a class of medications, anticoagulants are used in therapy for thrombotic disorders. Oral anticoagulants (OACs) are taken by many people in pill or tablet form, and various intravenous anticoagulant dosage forms are used in hospitals. Some anticoagulants are used in medical equipment, such as sample tubes, blood transfusion bags, heart–lung machines, and dialysis equipment. One of the first anticoagulants, warfarin, was initially approved as a rodenticide.
Anticoagulants are closely related to antiplatelet drugs and thrombolytic drugs by manipulating the various pathways of blood coagulation. Specifically, antiplatelet drugs inhibit platelet aggregation (clumping together), whereas anticoagulants inhibit specific pathways of the coagulation cascade, which happens after the initial platelet aggregation but before the formation of fibrin and stable aggregated platelet products.
Common anticoagulants include warfarin and heparin.
== Medical uses ==
The use of anticoagulants is a decision based on the risks and benefits of anticoagulation. The biggest risk of anticoagulation therapy is the increased risk of bleeding. In otherwise healthy people, the increased risk of bleeding is minimal, but those who have had recent surgery, cerebral aneurysms, and other conditions may have too great a risk of bleeding. Generally, the benefit of anticoagulation is preventing or reducing the progression of a thromboembolic disease. Some indications for anticoagulant therapy that are known to have benefit from therapy include:
Atrial fibrillation – commonly forms an atrial appendage clot
Coronary artery disease
Deep vein thrombosis – can lead to pulmonary embolism
Ischemic stroke
Hypercoagulable states (e.g., Factor V Leiden) – can lead to deep vein thrombosis
Mechanical heart valves
Myocardial infarction
Pulmonary embolism
Restenosis from stents
Cardiopulmonary bypass (or any other surgeries requiring temporary aortic occlusion)
Heart failure
In these cases, anticoagulation therapy prevents the formation or growth of dangerous clots.
The decision to begin therapeutic anticoagulation often involves the use of multiple bleeding risk predictable outcome tools as non-invasive pre-test stratifications due to the potential for bleeding while on blood thinning agents. Among these tools are HAS-BLED, ATRIA, HEMORR2HAGES, and CHA2DS2-VASc. The risk of bleeding using the risk assessment tools above must then be weighed against thrombotic risk to formally determine the patient's overall benefit in starting anticoagulation therapy.
There is no evidence to indicate that adding anticoagulant therapy to standard treatment has a benefit for people with cerebral small vessel disease but not dementia, and there is an increased risk of a person with this disease experiencing a bleed with this approach.
== Adverse effects ==
The most serious and common adverse side effects associated with anticoagulants are increased risk of bleeding, both nonmajor and major bleeding events. The bleeding risk depends on the class of anticoagulant agent used, the patient's age, and pre-existing health conditions. Warfarin has an estimated incidence of bleeding of 15–20% per year and a life-threatening bleeding rate of 1–3% per year. Newer non-vitamin K antagonist oral anticoagulants appear to have fewer life-threatening bleeding events than warfarin. Additionally, patients aged 80 years or more may be especially susceptible to bleeding complications, with a rate of 13 bleeds per 100 person-years. Bleeding risk is especially important to consider in patients with renal impairment and NOAC therapy because all NOACs, to some extent, are excreted by the kidneys. Thus, patients with renal impairment may be at higher risk of increased bleeding.
In people with cancer, a systematic review has found warfarin had no effect on death rate or the risk of blood clots. However, it did increase the risk of major bleeding in 107 more people per 1000 population and minor bleeding in 167 more people per 1000 population. Apixaban had no effect on mortality, recurrence of blood clots in blood vessels, or major or minor bleeding. However, this finding comes only from one study.
Nonhemorrhagic adverse events are less common than hemorrhagic adverse events but should still be monitored closely. Nonhemorrhagic adverse events of warfarin include skin necrosis, limb gangrene, and purple toe syndrome. Skin necrosis and limb gangrene are most commonly observed on the third to eighth day of therapy. The exact pathogenesis of skin necrosis and limb gangrene is not completely understood but it is believed to be associated with warfarin's effect on inhibiting the production of protein C and protein S. Purple toe syndrome typically develops three to eight weeks after initiation of warfarin therapy. Other adverse effects of warfarin are associated with depletion of vitamin K, which can lead to inhibition of G1a proteins and growth arrest-specific gene 6, which can lead to increased risk of arterial calcification and heart valve, especially if too much Vitamin D is present. Warfarin's interference with G1a proteins has also been linked to abnormalities in fetal bone development in mothers who were treated with warfarin during pregnancy. Long-term warfarin and heparin usage have also been linked to osteoporosis.
Another potentially severe complication associated with heparin use is called heparin-induced thrombocytopenia (HIT). There are two distinct types: HIT 1) immune-mediated and 2) non-immune-mediated. Immune-mediated HIT most commonly arises five to ten days after exposure to heparin. Pathogenesis of immune-mediated HIT is believed to be caused by heparin-dependent immunoglobulin antibodies binding to platelet factor 4/heparin complexes on platelets, leading to widespread platelet activation.
== Interactions ==
Foods and food supplements with blood-thinning effects include nattokinase, lumbrokinase, beer, bilberry, celery, cranberries, fish oil, garlic, ginger, ginkgo, ginseng, green tea, horse chestnut, licorice, niacin, onion, papaya, pomegranate, red clover, soybean, St. John's wort, turmeric, wheatgrass, and willow bark. Many herbal supplements have blood-thinning properties, such as danshen and feverfew. Multivitamins that do not interact with clotting are available for patients on anticoagulants.
However, some foods and supplements encourage clotting. These include alfalfa, avocado, cat's claw, coenzyme Q10, and dark leafy greens such as spinach. Excessive intake of the food mentioned above should be avoided while taking anticoagulants, or if coagulability is being monitored, their intake should be kept approximately constant so that anticoagulant dosage can be maintained at a level high enough to counteract this effect without fluctuations in coagulability.
Grapefruit interferes with some anticoagulant drugs, increasing the time it takes for them to be metabolized out of the body, and should be eaten with caution when on anticoagulant drugs.
Anticoagulants are often used to treat acute deep-vein thrombosis. People using anticoagulants to treat this condition should avoid using bed rest as a complementary treatment because there are clinical benefits to continuing to walk and remaining mobile while using anticoagulants in this way. Bed rest while using anticoagulants can harm patients in circumstances in which it is not medically necessary.
== Types ==
Several anticoagulants are available. Warfarin, other coumarins, and heparins have long been used. Since the 2000s, several agents have been introduced that are collectively referred to as direct oral anticoagulants (DOACs), previously named novel oral anticoagulants (NOACs) or non-vitamin K antagonist oral anticoagulants. These agents include direct thrombin inhibitor (dabigatran) and factor Xa inhibitor (rivaroxaban, apixaban, betrixaban and edoxaban), and they have been shown to be as good or possibly better than the coumarins with less serious side effects. The newer anticoagulants (NOACs/DOACs) are more expensive than the traditional ones and should be used in caring for patients with kidney problems.
=== Coumarins (vitamin K antagonists) ===
These oral anticoagulants are derived from coumarin found in many plants. A prominent member of this class, warfarin (Coumadin), was found to be the anticoagulant most prescribed in a large multispecialty practice. The anticoagulant effect takes at least 48 to 72 hours to develop. Where an immediate effect is required, heparin is given concomitantly. These anticoagulants are used to treat patients with deep-vein thrombosis (DVT) and pulmonary embolism (PE) and to prevent emboli in patients with atrial fibrillation (AF), and mechanical prosthetic heart valves. Other examples are acenocoumarol, phenprocoumon, atromentin, and phenindione.
The coumarins brodifacoum and difenacoum are used as mammalicides (particularly as rodenticides) but are not used medically.
=== Heparin and derivative substances ===
Heparin is the most widely used intravenous clinical anticoagulant worldwide. Heparin is a naturally occurring glycosaminoglycan. There are three major categories of heparin: unfractionated heparin (UFH), low molecular weight heparin (LMWH), and ultra-low-molecular weight heparin (ULMWH). Unfractionated heparin is usually derived from pig intestines and bovine lungs. UFH binds to the enzyme inhibitor antithrombin III (AT), causing a conformational change that results in its activation. The activated AT then inactivates factor Xa, thrombin, and other coagulation factors. Heparin can be used in vivo (by injection), and also in vitro to prevent blood or plasma clotting in or on medical devices. In venipuncture, Vacutainer brand blood collecting tubes containing heparin usually have a green cap.
==== Low molecular weight heparin (LMWH) ====
Low molecular weight heparin (LMWH) is produced through a controlled depolymerization of unfractionated heparin. LMWH exhibits a higher anti-Xa/anti-IIa activity ratio and is useful as it does not require monitoring of the APTT coagulation parameter and has fewer side effects.
=== Synthetic pentasaccharide inhibitors of factor Xa ===
Fondaparinux is a synthetic sugar composed of the five sugars (pentasaccharides) in heparin that bind to antithrombin. It is a smaller molecule than low molecular-weight heparin.
Idraparinux
Idrabiotaparinux
=== Direct oral ===
The direct oral anticoagulants (DOACs) were introduced in and after 2008. There are five DOACs currently on the market: dabigatran, rivaroxaban, apixaban, edoxaban and betrixaban. They were also previously referred to as "new/novel" and "non-vitamin K antagonist" oral anticoagulants (NOACs).
Compared to warfarin, DOACs have a rapid onset action and relatively short half-lives; hence, they carry out their function more rapidly and effectively, allowing drugs to reduce their anticoagulation effects quickly. Routine monitoring and dose adjustments of DOACs are less important than for warfarin, as they have better predictable anticoagulation activity. DOAC monitoring, including laboratory monitoring and a complete medication review, should generally be conducted before initiation of a DOAC, 1–3 months after initiation, and then every 6–12 months afterwards.
Both DOACs and warfarin are equivalently effective, but compared to warfarin, DOACs have fewer drug interactions, no known dietary interactions, a wider therapeutic index, and have conventional dosing that does not require dose adjustments with constant monitoring. However, there is no countermeasure for most DOACs, unlike for warfarin; nonetheless, the short half-lives of DOACs will allow their effects to recede swiftly. A reversal agent for dabigatran, idarucizumab, is currently available and approved for use by the FDA. Rates of adherence to DOACs are only modestly higher than adherence to warfarin among patients prescribed these drugs. Thus, adherence to anticoagulation is often poor despite hopes that DOACs would lead to higher adherence rates.
DOACs are significantly more expensive than warfarin, but the patients on DOACs may experience reduced lab costs as they do not need to monitor their INR.
==== Direct factor Xa inhibitors ====
Drugs such as rivaroxaban, apixaban and edoxaban work by inhibiting factor Xa directly (unlike heparins and fondaparinux, which work via antithrombin activation).
Also included in this category are betrixaban from Portola Pharmaceuticals, the discontinued darexaban (YM150) from Astellas, and, more recently, the discontinued letaxaban (TAK-442) from Takeda and eribaxaban (PD0348292) from Pfizer.
Betrixaban is significant as it was in 2018, the only oral factor Xa inhibitor approved by the FDA for use in acutely medically ill patients. Darexaban development was discontinued in September 2011; in a trial for prevention of recurrences of myocardial infarction in addition to dual antiplatelet therapy (DAPT), the drug did not demonstrate effectiveness, and the risk of bleeding was increased by approximately 300%. The development of letaxaban for acute coronary syndrome was discontinued in May 2011 following negative results from a Phase II study.
==== Direct thrombin inhibitors ====
Another type of anticoagulant is the direct thrombin inhibitor. Current members of this class include the bivalent drugs hirudin, lepirudin, and bivalirudin and the monovalent drugs argatroban and dabigatran. An oral direct thrombin inhibitor, ximelagatran (Exanta), was denied approval by the Food and Drug Administration (FDA) in September 2004 and was pulled from the market entirely in February 2006 after reports of severe liver damage and heart attacks. In November 2010, dabigatran etexilate was approved by the FDA to prevent thrombosis in atrial fibrillation.
==== Relevance to dental treatments ====
As in any invasive procedure, patients on anticoagulation therapy have an increased risk for bleeding, and caution should be used along with local hemostatic methods to minimize bleeding risk during the operation as well as postoperatively. However, with regards to DOACs and invasive dental treatments, there has not been enough clinical evidence and experience to prove any reliable adverse effects, relevance or interaction between these two. Further clinical prospective studies on DOACs are required to investigate the bleeding risk and hemostasis associated with surgical and dental procedures.
Recommendations of modifications to the usage/dosage of DOACs before dental treatments are made based on the balance of the bleeding risk of each procedure and also the individual's own bleeding risks and renal functionality. With low-bleeding-risk dental procedures, it is recommended that DOACs be continued by the patient to avoid any increase in the risk of a thromboembolic event. For dental procedures with a higher risk of bleeding complications (i.e. complex extractions, adjacent extractions leading to a large wound, or more than three extractions), the recommended practice is for the patient to miss or delay a dose of their DOAC before such procedures to minimize the effect on bleeding risk.
=== Antithrombin protein therapeutics ===
The antithrombin protein is used as a protein therapeutic that can be purified from human plasma or produced recombinantly (for example, Atryn, produced in the milk of genetically modified goats).
The FDA approves Antithrombin as an anticoagulant for preventing clots before, during, or after surgery or birthing in patients with hereditary antithrombin deficiency.
=== Other ===
Many other anticoagulants exist in research and development, diagnostics, or as drug candidates.
Batroxobin, a toxin from snake venom, clots platelet-rich plasma without affecting platelet functions (cleaves fibrinogen).
Hementin is an anticoagulant protease from the salivary glands of the giant Amazon leech, Haementeria ghilianii.
Vitamin E
Alcoholic beverage
== Reversal agents ==
With the growing number of patients taking oral anticoagulation therapy, studies into reversal agents are gaining increasing interest due to major bleeding events and the need for urgent anticoagulant reversal therapy. Reversal agents for warfarin are more widely studied, and established guidelines for reversal exist due to a longer history of use of warfarin and the ability to get a more accurate measurement of anticoagulation effect in a patient via measuring the INR (International Normalized Ratio). In general, vitamin K is most commonly used to reverse the effect of warfarin in non-urgent settings. However, in urgent settings or settings with extremely high INR (INR >20), hemostatic reversal agents such as fresh frozen plasma (FFP), recombinant factor VIIa, and prothrombin complex concentrate (PCC) have been utilized with proven efficacy. Specifically with warfarin, four-factor PCC (4F-PCC) has been shown to have superior safety and mortality benefits compared to FPP in lowering INR levels.
Although specific antidotes and reversal agents for DOACs are not as widely studied, idarucizumab (for dabigatran) and andexanet alfa (for factor Xa inhibitor) have been used in clinical settings with varying efficacy. Idarucizumab is a monoclonal antibody, approved by the US FDA in 2015, that reverses the effect of dabigatran by binding to both free and thrombin-bound dabigatran. Andexanet alfa is a recombinant modified human factor Xa decoy that reverses the effect of factor Xa inhibitors by binding at the active sites of factor Xa inhibitor and making it catalytically inactive. Andexanet alfa was approved by the US FDA in 2018. Another drug called ciraparantag, a potential reversal agent for direct factor Xa inhibitors, is still under investigation. Additionally, hemostatic reversal agents have also been used with varying efficacy to reverse the effects of DOACs.
== Coagulation inhibitor measurement ==
A Bethesda unit (BU) is a measure of blood coagulation inhibitor activity. It is the amount of inhibitor that will inactivate half of a coagulant during the incubation period. It is the standard measure used in the United States and is so named because it was adopted as a standard at a conference in Bethesda, Maryland.
== Laboratory use ==
If blood is allowed to clot, laboratory instruments, blood transfusion bags, and medical and surgical equipment will get clogged up and non-operational. In addition, test tubes used for laboratory blood tests will have chemicals added to stop blood clotting. Besides heparin, most of these chemicals bind calcium ions, preventing the coagulation proteins from using them.
Ethylenediaminetetraacetic acid (EDTA) strongly and irreversibly chelates (binds) calcium ions, preventing blood from clotting.
Citrate is in liquid form in the tube and is used for coagulation tests and blood transfusion bags. It binds calcium but not as strongly as EDTA. The correct proportion of this anticoagulant to blood is crucial because of the dilution, which can be reversed with the addition of calcium. Formulations include plain sodium citrate, acid-citrate-dextrose, and more.
Oxalate has a mechanism similar to that of citrate. It is the anticoagulant used in fluoride/oxalate tubes to determine glucose and lactate levels. The fluoride inhibits glycolysis, which can throw off blood sugar measurements. Citrate/fluoride/EDTA tubes work better in this regard.
== Dental considerations for long-term users ==
Dental practitioners play an important role in the early detection of anticoagulant overdose through oral manifestations, as the patient does not show any symptoms. Dental treatment of patients taking anticoagulant or antiplatelet medication raises safety concerns in terms of the potential risk of bleeding complications following invasive dental procedures. Therefore, certain guidelines for the dental care of patients taking these drugs are needed.
Detecting overdose
An overdose of anticoagulants usually occurs in people who have heart problems and need to take anticoagulants in the long term to reduce the risk of stroke from their high blood pressure.
An International Normalised Ratio (INR) test would be recommended to confirm the overdose so that the dosage can be adjusted to an acceptable standard. The INR test measures the time it takes for a clot to form in a blood sample relative to a standard.
An INR value of 1 indicates a level of coagulation equivalent to that of an average patient not taking warfarin, and values greater than 1 indicate a longer clotting time and, thus, a longer bleeding time.
Assessing bleeding risk
There are two main parts to the assessment of bleeding risk:
Assessment of the likely risk of bleeding associated with the required dental procedure
Assessment of the patient's individual-level bleeding risk
Managing bleeding risk
A patient who is on anticoagulants or antiplatelet medications may undergo dental treatments which are unlikely to cause bleeding, such as local anesthesia injection, basic gum charting, removal of plaque, calculus and stain above the gum level, direct or indirect fillings which are above the gingiva, root canal treatment, taking impression for denture or crown and fitting or adjustment of orthodontic appliances. For all these procedures, it is recommended that the dentist treat the patient following the normal standard procedure and taking care to avoid any bleeding.
For a patient who needs to undergo dental treatments which are more likely to cause bleeding, such as simple tooth extractions (1-3 teeth with small wound size), drainage of swelling inside the mouth, periodontal charting, root planing, direct or indirect filling which extends below the gingiva, complex filling, flap raising procedure, gingival recontouring and biopsies, the dentist needs to take extra precautions apart from the standard procedure. The recommendations are as follows:
if the patient has another medical condition or is taking other medication that may increase bleeding risk, consult the patient's general medical practitioner or specialist
if the patient is on a short course of anticoagulant or antiplatelet therapy, delay the non-urgent, invasive procedure until the medication has been discontinued
plan treatment for early in the day and week, where possible, to allow time for the management of prolonged bleeding or re-bleeding if it occurs
perform the procedure as traumatically as possible, use appropriate local measures and only discharge the patient once hemostasis has been confirmed
if travel time to emergency care is a concern, place particular emphasis at the time of the initial treatment on the use of measures to avoid complications
advise the patient to take paracetamol, unless contraindicated, for pain relief rather than NSAIDs such as aspirin, ibuprofen, diclofenac or naproxen
provide the patient with written post-treatment advice and emergency contact details
follow the specific recommendations and advice given for the management of patients taking different anticoagulants or antiplatelet drugs
There is general agreement that in most cases, treatment regimens with older anticoagulants (e.g., warfarin) and antiplatelet agents (e.g., clopidogrel, ticlopidine, prasugrel, ticagrelor, and/or aspirin) should not be altered before dental procedures. The risks of stopping or reducing these medication regimens (i.e., thromboembolism, stroke, myocardial infarction) far outweigh the consequences of prolonged bleeding, which can be controlled with local measures. In patients with other existing medical conditions that can increase the risk of prolonged bleeding after dental treatment or receiving other therapy that can increase bleeding risk, dental practitioners may wish to consult the patient's physician to determine whether care can safely be delivered in a primary care office. Any suggested modification to the medication regimen before dental surgery should be done in consultation and on the advice of the patient's physician.
Based on limited evidence, the consensus appears to be that in most patients who are receiving the newer direct-acting oral anticoagulants (i.e., dabigatran, rivaroxaban, apixaban, or edoxaban) and undergoing dental treatment (in conjunction with usual local measures to control bleeding), no change to the anticoagulant regimen is required. In patients deemed to be at higher risk of bleeding (e.g., patients with other medical conditions or undergoing more extensive procedures associated with higher bleeding risk), consideration may be given, in consultation with and on advice of the patient's physician, to postponing the timing of the daily dose of the anticoagulant until after the procedure; timing the dental intervention as late as possible after last dose of anticoagulant; or temporarily interrupting drug therapy for 24 to 48 hours.
== Research ==
A substantial number of compounds are being investigated for use as anticoagulants. The most promising ones act on the contact activation system (factor XIIa and factor XIa); it is anticipated that this may provide agents that prevent thrombosis without conferring a risk of bleeding.
As of November 2021, the direct factor XIa inhibitor milvexian is in Phase II clinical trials for the prevention of an embolism after surgery.
=== Utilization ===
Research has been conducted on changes in anticoagulant drug supply for hospitals in the US during the COVID-19 pandemic from 2018–2022. According to researchers, "there was a 43.4% decline in the total volume of anticoagulants and antiplatelets at US hospitals in March 2020, driven by a decrease in heparin volume." Furthermore, it has been found that "Therapeutic AC [Anticoagulation] use declined from 32% in 2020 to 12% in 2022, especially after December 2021" and the introduction of the Omicron variant.
== See also ==
CHADS2 score
Direct factor Xa inhibitors
Hypercoagulability in pregnancy
== References ==
== External links ==
Staying Active and Healthy with Blood Thinners by the Agency for Healthcare Research and Quality | Wikipedia/Anticoagulation_therapy |
Drug eluting implants encompass a wide range of bioactive implants that can be placed in or near a tissue to provide a controlled, sustained or on demand release of drug while overcoming barriers associated with traditional oral and intravenous drug administration, such as limited bioavailability, metabolism, and toxicity. These implants can be used to treat location-specific and surrounding illness and commonly use 3D printing technologies to achieve individualized implants for patients.
The production of drug eluting implants has grown significantly in the last decade and continues to be an area of research due to their flexible nature that can be utilised for the treatment of a multitude of medical conditions. These implants can be loaded with a variety of different drug types such as antibiotics, antivirals, chemotherapy, growth factors and anti-inflammatory drugs.
Drug eluting implants can provide a versatile method of drug delivery that can be personalized and targeted to treat a variety of medical conditions and overcome issues such as drug bioavailability, metabolism and dosage associated with traditional drug delivery systems.
== Applications ==
Drug eluting implants can be used in the management and treatment of a variety of medical conditions. Traditional drug delivery methods have potential disadvantages that have led to the development of different drug delivery techniques across most body systems, many of which can improve treatment efficacy.
=== Cardiovascular ===
Drug-eluting stents and balloons are a common therapeutic method in the management and treatment of cardiovascular disease that to open and maintain arteries while delivering drug locally to an area of a vessel.
=== Gynecology ===
Common gynecological implants that elute contraceptive medication can be inserted subcutaneously or into the uterus. Non-invasive drug eluting ring implants that can be inserted into the vagina and release therapeutic doses of contraceptive, anti-inflammatory and antibiotic drugs to increase compliance of contraceptive therapeutics are under development.
=== Orthopedics ===
The treatment of orthopedic conditions has proved to be a large target area for drug eluting implants. Current uses for this method drug delivery include bone and joint implants that can release drugs at the joint replacement sites to prevent infection and anti-inflammatory responses.
Other potential treatments using this method of drug delivery in orthopedic medicine include drug eluting implants that aid in the regeneration of bone at implantation sites while reducing microbial growth.
=== Oncology ===
Current treatment for oncological conditions include chemotherapy, radiation and surgery. Drug eluting implants have shown potential in the treatment of cancer through adjuvant chemotherapy that has shown to suppress tumor formation locally, overcoming side effects associated with systemic chemotherapy treatment and reduce the need for surgical resection of cancerous tumors.
=== Ophthalmology ===
Intravitreal administration of therapeutic drug doses is commonly done via injection or implant. Drug eluting contact lenses and implants can deliver targeted and extended doses of drug to the retina without the need for injection.
=== Dermatology ===
Drug eluting sutures can produce a prolonged local release of anaesthetic as well as heal wounds. This has the potential to limit the need for postoperative opioid analgesics that can cause addiction.
== Design ==
Drug eluting implants are designed to be implanted into location specific tissues and release drug locally. These implants are made using biocompatible materials that will not elicit an immune response.
The structure of the implant is individualized and designed to conform to the shape of the tissue that is being treated. The implant contains a reservoir that elutes a drug dependent on the mechanism of release. This mechanism be in the form of a matrix coating of the implant or a reservoir within the implant. Designs aim to provide therapeutic dosage to the target tissue while reducing negative side effects and maximizing efficacy.
== Development and Manufacturing ==
There are a variety of methods used in the manufacturing of drug eluting implants, most of which utilize 3D printing technology. Techniques are dependent on factors such as the condition being managed, the drug being released and the individual patient being treated.
=== 3D Printing ===
3D printing involves the production of a 3-dimensional object through the layering of material. There are a variety of 3D printing techniques, all of which come with their own advantages and disadvantages which should be considered when creating an individualized implant. The production of these drug eluting implants through 3D printing is currently being investigated to determine drug delivery properties and efficacy to improve individualized medicinal devices.
Traditional bio-printing technologies used in the field of biomedical engineering include inkjet-based systems, extrusion-based systems, and laser-assisted systems that can be used to create highly specific and individual implants for patients.
== Materials ==
The most common materials used to create drug eluting implants include highly versatile polymers, ceramics, and metals, all with varying kinetics that can be manipulated to produce the desired drug delivery effect.
=== Polymers ===
Polymers and polymer networks are among the most widely used materials in drug eluting implants. These implants are classified as either degradable and able to be broken down and metabolized by the body, or non-degradable which eventually require removal.
Common degradable polymer materials used in drug eluting implants include poly e-caprolactone (PCL), polylactic-co-glycolic acid (PLGA) and poly-L-lactic acid (PLLA), while non-degradable polymer materials include silicones commonly used in plastic surgery, urethanes and acrylates, and are more likely to be used in the treatment of chronic conditions in which long term implantation is to be expected.
Polymers can be used to create monolithic drug delivery systems in which a drug is released in a rate-controlled polymer matrix, reservoir drug delivery systems containing a drug-filled core that releases drug in a manner dependent on the surrounding polymer, and hydrogels that can release drugs controlled by a variety of stimuli including ultrasound, temperature, and pH changes.
=== Ceramics ===
In relation to biomedical implant manufacturing, the term 'ceramic' can be used to encompass a wide variety of non-metallic substances that can be utilised in drug eluting implants due to their biocompatible properties such as resistance to corrosion and shear, low electrical conductance ability, and high melting temperatures.
Ceramic implants can be classified as bio-inert and include materials such as aluminum, zirconia, and certain carbon and silicon derivatives which are not biodegradable. Bioactive ceramic implants are biodegradable substances that include calcium phosphates, and a variety of oxidised minerals that mimic natural bone properties. Ceramic drug eluting implants are therefore commonly used in hard tissue replacement surgeries such as bone.
=== Metals ===
Metals such as titanium are highly biocompatible and therefore commonly used in osteopathic medicine in the manufacturing of artificial joints. These joints are often coated in polymeric, or ceramic material embedded with drugs for prevention of infection and rejection, and to reduce inflammatory responses that are common among joint implants.
Metals however are susceptible to erosion and infection and lack biological activity. When metals are used as an implant as opposed to a permanent mechanical fixture, problems can arise when contacting associated bone and releasing drug to target tissues such as static stresses that can lead to bone loss at the site of implantation.
== Drug Loading ==
The idea of a drug eluting implant is to overcome many of the obstacles associated with traditional drug therapies, as well as reducing the need for potentially invasive procedures, including those involved in the removal of embedded drug eluting implants.
The loading of a drug onto a matrix can be either incorporated into the drug at the time of manufacture or performed after the printing of an implant is complete. Drugs integrated at the point of manufacture through blending with polymeric materials are generally able to withstand preparation conditions which can exclude many sensitive drugs from this mechanism. Therefore, loading after manufacture is considered to be an easier method.
Normally, once drug is loaded into a delivery system, there is no non-invasive way to refill once drug levels in the system are depleted. Developments in drug delivery refilling have shown potential through chemically modified drug-loaded hydrogels that, once in the body, are able to translocate to a specific local drug delivery depot as a non-invasive means of refilling.
== Advantages ==
Drug eluting implants aim to improve efficacy of drug delivery by overcoming issues commonly associated with traditional systemic administration of drugs such as metabolism, toxicity, and an inability to maintain a certain concentration of drug in the circulation. To overcome these issues, patients are usually administered higher doses of drugs in a controlled and clinical setting.
The introduction of a drug eluting implant to a local tissue can provide targeted and sustained dosing of drug and prevent systemic metabolism, a common obstacle seen in orally delivered medications. This can reduce dosage which can in turn reduce treatment cost. Lower drug concentrations delivered via local depots can therefore lower the risk of toxicity as well as increasing compliance and reducing physician/patient burden to manage appropriate drug concentrations.
Drug eluting implants also provide an effective mechanism for bypassing the blood-brain barrier, and this method of drug delivery is primarily used in the treatment of glial tumors.
== Limitations ==
There are issues that can arise with the local and targeted method of drug eluting implants. One of the largest obstacles that the field of drug eluting implants faces is the mechanism of drug loading and reloading of non-biodegradable implants. The development of drugs that can travel from systemic circulation to a specific depot could prove a useful way to overcome the need for invasive refilling and re-implantation.
Foreign bodies implanted into the body can elicit immune responses. Medically implanted drug eluting devices can induce an inflammatory response as well as being rejected by the body which can cause chronic inflammation. Anti-inflammatory drugs can be administered alongside the implantation of a drug eluting device to prevent chronic inflammation and systemic immune side effects that this may induce.
== Future of drug eluting implants ==
The field of drug eluting implants is expanding to encompass treatment and management methods for a variety of treatments. In the future, possibilities exist to manufacture 'smart' drug eluting implants fitted with sensors that can provide feedback-controlled drug delivery in patients suffering from abnormalities such as diabetes, or for patients that experience seizures and require prophylactic treatment.
The development of novel drug eluting implant materials and mechanisms has the potential for improving patient safety, comfort, compliance and thus acting on global health challenges such as chronic diseases, infectious and non-infectious diseases, and contraception.
== References == | Wikipedia/Drug-eluting_implant |
Pharmacotherapy, also known as pharmacological therapy or drug therapy, is defined as medical treatment that utilizes one or more pharmaceutical drugs to improve ongoing symptoms (symptomatic relief), treat the underlying condition, or act as a prevention for other diseases (prophylaxis).
It can be distinguished from therapy using surgery (surgical therapy), radiation (radiation therapy), movement (physical therapy), or other modes. Among physicians, sometimes the term medical therapy refers specifically to pharmacotherapy as opposed to surgical or other therapy; for example, in oncology, medical oncology is thus distinguished from surgical oncology.
Today's pharmacological therapy has evolved from a long history of medication use, and it has changed most rapidly in the last century due to advancements in drug discovery. The therapy is administered and adjusted by healthcare professionals according to the evidence-based guidelines and the patient's health condition. Personalized medicine also plays a crucial role in pharmacological therapy. Personalized medicine, or precision medicine, takes account of the patient's genetic variation, liver function, kidney function, etc, to provide a tailor-made treatment for a patient. In pharmacological therapy, pharmacists will also consider medication compliance. Medication compliance, or medication adherence, is defined as the degree to which the patient follows the therapy that is recommended by the healthcare professionals.
== History ==
=== From natural compounds to pharmaceutical drugs ===
The use of medicinal substances can be traced back to 4000 BC in the Sumer civilization. Healers at the time (called apothecaries), for example, understood the application of opium for pain relief. The history of natural remedies can also be found in other cultures, including traditional Chinese medicine in China and Ayurvedic medicine in India, which are still in use nowadays. Dioscorides, a 1st -century Greek surgeon, described more than six hundred animals, plants, and their derivatives in his medical botany, which remained the most influential pharmacopeia for fourteen hundred years. Besides substances derived from living organisms, metals, including copper, mercury, and antimony, were also used as medical therapies. They were said to cure various diseases during the late Renaissance. In 1657, tartar emetic, which is an antimony compound, was credited with curing Louis XIV of typhoid fever. The drug was also administered intravenously for the treatment of schistosomiasis in the 20th century. However, due to the concern over acute and chronic antimony poisoning, the role of tartar emetic as an antischistosomal agent was gradually replaced after the advent of praziquantel.
Other than using natural products, humans also learned to compound medicine by themselves. The first pharmaceutical text was found on clay tablets from the Mesopotamians, who lived around 2100 BC. Later in the 2nd century AD, compounding was formally introduced by Galen as “a process of mixing two or more medicines to meet the individual needs of a patient”. Initially, compounding was only done by individual pharmacists, but in the post-World War II period, pharmaceutical manufacturers surged in number and took over the role of making medicine. Meanwhile, there was a marked increase in pharmaceutical research, which led to a growing number of new drugs. Most drug discovery milestones were made in the last hundred years, from antibiotics to biologics, contributing to the foundation of current pharmacological therapy.
=== Drug discovery ===
Most drugs were discovered by empirical means, including observation, accident, and trial and error. One famous example is the discovery of penicillin, the first antibiotic in the world. The substance was discovered by Alexander Fleming in 1928 after a combination of unanticipated events occurred in his laboratory during his summer vacation. The Penicillium mold on the petri dish was believed to secrete a substance (later named "penicillin") that inhibited bacterial growth. Large pharmaceutical companies then started to establish their microbiological departments and search for new antibiotics. The screening program for antimicrobial compounds also led to the discovery of drugs with other pharmacological properties, such as immunosuppressants like Cyclosporin A.The discovery of penicillin was a serendipitous (i.e. chance) discovery. Another, more advanced approach to drug discovery is rational drug design. The method is underpinned by an understanding of the biological targets of the drugs, including enzymes, receptors, and other proteins. In the late 19th century, Paul Ehrlich observed the selective affinity of dyes for different tissues and proposed the existence of chemoreceptors in our bodies. Receptors were believed to be the specific binding sites for drugs. The drug-receptor recognition was described as a key-and-lock interplay by Emil Fischer in the early 1890s. It was later found that the receptors can either be stimulated or inhibited by chemotherapeutic agents to attain the desired physiological response. Once the ligand interacting with the target macromolecule is identified, drug candidates can be designed and optimized based on the structure-activity relationship. Nowadays, artificial intelligence is employed in drug design to predict drug-protein interactions, drug activity, the 3D configuration of proteins, etc.
== Evidence-based medicine ==
Evidence-based medicine is defined as deploying the best current scientific evidence that is available to give the best treatment and make the best decision effectively and efficiently. Clinical guidelines are developed based on scientific evidence; for example, the ACC/AHA guidelines (for cardiovascular diseases), the GOLD guidelines (for chronic obstructive pulmonary disease), the GINA guidelines (for asthma), etc. They convert and classify the evidence using a systematic method, aiming to provide care with quality. The guidelines cannot substitute clinical judgment, as they cannot meet all the circumstances. Healthcare professionals can use the clinical guidelines as references or evidence to support their clinical judgement when prescribing therapy to patients.
Example: Clinical Guideline for controlling blood pressure (hypertension)
If there is an Asian male patient who is 40 years old and has recently been diagnosed with high blood pressure (with a blood pressure of 140/90) and without any other chronic diseases (comorbidities), such as type-2 diabetes, gout, benign prostatic hyperplasia, etc. His estimated 10-year risk of cardiovascular disease is 15%.
According to the NICE 2019 Hypertension guideline, the healthcare professional can consider starting anti-hypertensive therapy after a discussion with the patient. The first-line therapy will be either an Angiotensin Converting Enzyme Inhibitor (ACEi) or an Angiotensin receptor blocker (ARB) (if the patient cannot tolerate ACEi). If the blood pressure of the patient is not well controlled, the healthcare professionals can consider adding a calcium channel blocker (CCB) or a Thiazide-like diuretic to the previous therapy, i,e, ACEi or ARBs with a CCB or a thiazide-like diuretic.
== Personalized medicine ==
Every patient has their own body condition, for example, kidney function, liver function, genetic variations, medical history, etc. These are all the factors that should be considered by healthcare professionals before giving any pharmacological therapy. Most importantly, the advancing technology in genetics guides us to have more insight into the linkage between health and genes. In pharmacological therapy, two areas of study are evolving: pharmacogenetics and pharmacogenomics. Age will affect the pharmacokinetics and pharmacodynamics of drugs, and hence the efficacy of the therapy. The effect of age causes deterioration of organ function, like liver function and kidney function. Pharmacokinetics is the study of drugs' effects on absorption, distribution, metabolism, and elimination. Pharmacodynamics is the study of drugs' effects on our body and their mechanisms.
=== Pharmacogenetics and pharmacogenomics ===
Pharmacogenetics is defined as the study of inherited genes causing different drug metabolisms that vary from each other, such as the rate of metabolism and metabolites. Pharmacogenomics is defined as the study of associating the drug response with one's gene. Both terms are similar in nature, so they are used interchangeably.
Multiple alleles can contribute together to a change in response to a drug by expressing a different form of an enzyme that responds differently than the normal ones. The different forms of enzymes (phenotypes) include ultra-rapid metabolizers, moderate metabolizers, no-enzyme activity, etc. The genetic variations can also be used to match the particular adverse drug reaction in order to prevent the patient from suffering the unfavorable outcomes. The genetic make-up can affect the pharmacokinetics.
=== Example: Azathioprine Therapy ===
Azathioprine is an immunomodulator for inflammatory bowel disease, for instance. Its metabolite relies on two different enzymes (TPMT and NUDT15) to eliminate its effect on our body during its metabolism. If the patient has the phenotype of the enzymes that metabolize it poorly, i.e., the poor metabolizer, more toxic metabolites are accumulated in the body. Thus, the patient has a greater risk of the related side-effect. The side effect causes the adjustment of dosage or switching to another drug.
=== Example: Omalizumab Therapy ===
Omalizumab is a humanized monoclonal antibody for the treatment of various allergic diseases, including asthma, urticaria, and allergic rhinitis. It targets the immunoglobulin E (IgE) in human body, which plays an important role in allergic reactions. The efficacy of omalizumab may vary among patients. To identify responders to omalizumab, the level of several biomarkers can be measured, including serum eosinophils, fractional exhaled nitric oxide, and serum IgE. For instance, patients with higher baseline eosinophil counts are likely to respond better to omalizumab therapy.
== Medication compliance ==
Medication compliance is defined as the degree to which the patient follows the therapy that is recommended by healthcare professionals. There are direct and indirect methods to evaluate compliance. Direct method refers to the measurement that the healthcare professionals observed or measure the patient's drug-taking behavior. Indirect method refers to the healthcare professionals do not observe or measure the drug-taking behavior of the patient but use the other source of information to evaluate the compliance.
The direct method includes measurement of drug (or the corresponding metabolite) concentration, while the indirect method includes pill counting and the self-report from the patient. The direct method is more time-consuming, more expensive, more invasive, but it is more accurate. The indirect method has a lower accuracy but is easier to administer to the patient. If the patient fails to comply with treatment, for example, by not taking the medication according to the instructions, it leads to risk and a poor treatment outcome.
=== Example: Tuberculosis treatment ===
For tuberculosis patients, directly observed therapy is still part of the treatment. This is to increase medication compliance. This is to prevent treatment failure, relapse, and transmission in the community. Apart from the traditional direct observed therapy (DOT), there is another method proposed to try increasing medication compliance. Video-observed therapy (VOT) is one of the methods. It has some advantages and disadvantages. It reduces the cost of healthcare and the travel costs for the patient. The downside of the intervention is the need for quality control training as it would be hard to confirm the patient's adherence.
== Role of Pharmacists ==
Pharmacists are experts in pharmacotherapy and are responsible for ensuring the safe, appropriate, and economical use of pharmaceutical drugs. The skills required to function as a pharmacist require knowledge, training and experience in biomedical, pharmaceutical and clinical sciences. Pharmacology is the science that aims to continually improve pharmacotherapy. The pharmaceutical industry and academia use basic science, applied science, and translational science to create new pharmaceutical drugs.
As pharmacotherapy specialists and pharmacists have responsibility for direct patient care, often functioning as a member of a multidisciplinary team, and acting as the primary source of drug-related information for other healthcare professionals. A pharmacotherapy specialist is an individual who is specialized in administering and prescribing medication, and requires extensive academic knowledge in pharmacotherapy.
In the US, a pharmacist can gain Board Certification in the area of pharmacotherapy upon fulfilling eligibility requirements and passing a certification examination. While pharmacists provide valuable information about medications for patients and healthcare professionals, they are not typically considered covered pharmacotherapy providers by insurance companies.
== See also ==
== References == | Wikipedia/Pharmacological_therapy |
Minimally invasive direct coronary artery bypass (MIDCAB) is a surgical treatment for coronary heart disease that is a less invasive method of coronary artery bypass surgery (CABG). MIDCAB gains surgical access to the heart with a smaller incision than other types of CABG. MIDCAB is sometimes referred to as "keyhole" heart surgery because the operation is analogous to operating through a keyhole.
MIDCAB is a form of off-pump coronary artery bypass surgery (OPCAB), performed "off-pump" – without the use of cardiopulmonary bypass (the heart-lung machine). MIDCAB differs from OPCAB in the type of incision used for the surgery; with traditional CABG and OPCAB a median sternotomy (dividing the breastbone) provides access to the heart; with MIDCAB, the surgeon enters the chest cavity through a mini-thoracotomy (a 2-to-3 inch incision between the ribs).
MIDCAB surgery is no longer reserved for only anteriorly placed single- or double-vessel diseases, because such lesions are usually managed with angioplasty. The surgery has recently begun to be used in multi-vessel coronary disease.
== MIDCAB in hybrid revascularization ==
People with multi-vessel coronary disease, who desire a minimally invasive approach to surgery may be eligible for hybrid bypass. A hybrid approach combines coronary bypass (using the MIDCAB approach) and coronary stenting.
== See also ==
Cardiac surgeon
Cardiac surgery
Totally endoscopic coronary artery bypass surgery
== References == | Wikipedia/Minimally_invasive_direct_coronary_artery_bypass_surgery |
Totally endoscopic coronary artery bypass surgery (TECAB) is an entirely endoscopic robotic surgery used to treat coronary heart disease, developed in the late 1990s. It is an advanced form of minimally invasive direct coronary artery bypass surgery, which allows bypass surgery to be conducted off-pump without opening the ribcage. The technique involves three or four small holes in the chest cavity through which two robotic arms, and one camera are inserted.
== TECAB technology ==
TECAB surgery uses the da Vinci tele-robotic stereoscopic 3-D imaging system. The system consists of a robotic "slave" system at the bedside. The robot relays its information to an external surgical control unit, where a cardiac surgeon has a three-dimensional view of the chest cavity, and twin controllers for the robotic arms. The procedure frequently involves grafting of the internal mammary artery to the diseased coronary artery, and therefore does not require external harvesting of blood vessels.
== References == | Wikipedia/Totally_endoscopic_coronary_artery_bypass_surgery |
Cardiovascular disease (CVD) is any disease involving the heart or blood vessels. CVDs constitute a class of diseases that includes: coronary artery diseases (e.g. angina, heart attack), heart failure, hypertensive heart disease, rheumatic heart disease, cardiomyopathy, arrhythmia, congenital heart disease, valvular heart disease, carditis, aortic aneurysms, peripheral artery disease, thromboembolic disease, and venous thrombosis.
The underlying mechanisms vary depending on the disease. It is estimated that dietary risk factors are associated with 53% of CVD deaths. Coronary artery disease, stroke, and peripheral artery disease involve atherosclerosis. This may be caused by high blood pressure, smoking, diabetes mellitus, lack of exercise, obesity, high blood cholesterol, poor diet, excessive alcohol consumption, and poor sleep, among other things. High blood pressure is estimated to account for approximately 13% of CVD deaths, while tobacco accounts for 9%, diabetes 6%, lack of exercise 6%, and obesity 5%. Rheumatic heart disease may follow untreated strep throat.
It is estimated that up to 90% of CVD may be preventable. Prevention of CVD involves improving risk factors through: healthy eating, exercise, avoidance of tobacco smoke and limiting alcohol intake. Treating risk factors, such as high blood pressure, blood lipids and diabetes is also beneficial. Treating people who have strep throat with antibiotics can decrease the risk of rheumatic heart disease. The use of aspirin in people who are otherwise healthy is of unclear benefit.
Cardiovascular diseases are the leading cause of death worldwide except Africa. Together CVD resulted in 17.9 million deaths (32.1%) in 2015, up from 12.3 million (25.8%) in 1990. Deaths, at a given age, from CVD are more common and have been increasing in much of the developing world, while rates have declined in most of the developed world since the 1970s. Coronary artery disease and stroke account for 80% of CVD deaths in males and 75% of CVD deaths in females. Most cardiovascular disease affects older adults. In the United States 11% of people between 20 and 40 have CVD, while 37% between 40 and 60, 71% of people between 60 and 80, and 85% of people over 80 have CVD. The average age of death from coronary artery disease in the developed world is around 80, while it is around 68 in the developing world. CVD is typically diagnosed seven to ten years earlier in men than in women.: 48
== Types ==
There are many cardiovascular diseases involving the blood vessels. They are known as vascular diseases.
Coronary artery disease (coronary heart disease or ischemic heart disease)
Peripheral arterial disease – a disease of blood vessels that supply blood to the arms and legs
Cerebrovascular disease – a disease of blood vessels that supply blood to the brain (includes stroke)
Renal artery stenosis
Aortic aneurysm
There are also many cardiovascular diseases that involve the heart.
Cardiomyopathy – diseases of cardiac muscle
Hypertensive heart disease – diseases of the heart secondary to high blood pressure or hypertension
Heart failure – a clinical syndrome caused by the inability of the heart to supply sufficient blood to the tissues to meet their metabolic requirements
Pulmonary heart disease – a failure at the right side of the heart with respiratory system involvement
Cardiac dysrhythmias – abnormalities of heart rhythm
Inflammatory heart diseases
Endocarditis – inflammation of the inner layer of the heart, the endocardium. The structures most commonly involved are the heart valves.
Inflammatory cardiomegaly
Myocarditis – inflammation of the myocardium, the muscular part of the heart, caused most often by viral infection and less often by bacterial infections, certain medications, toxins, and autoimmune disorders. It is characterized in part by infiltration of the heart by lymphocyte and monocyte types of white blood cells.
Eosinophilic myocarditis – inflammation of the myocardium caused by pathologically activated eosinophilic white blood cells. This disorder differs from myocarditis in its causes and treatments.
Valvular heart disease
Congenital heart disease – heart structure malformations existing at birth
Rheumatic heart disease – heart muscles and valves damage due to rheumatic fever caused by Streptococcus pyogenes a group A streptococcal infection.
== Risk factors ==
There are many risk factors for heart diseases: age, sex, tobacco use, physical inactivity, non-alcoholic fatty liver disease, excessive alcohol consumption, unhealthy diet, obesity, genetic predisposition and family history of cardiovascular disease, raised blood pressure (hypertension), raised blood sugar (diabetes mellitus), raised blood cholesterol (hyperlipidemia), undiagnosed celiac disease, psychosocial factors, poverty and low educational status, air pollution, and poor sleep. While the individual contribution of each risk factor varies between different communities or ethnic groups the overall contribution of these risk factors is very consistent. Some of these risk factors, such as age, sex or family history/genetic predisposition, are immutable; however, many important cardiovascular risk factors are modifiable by lifestyle change, social change, drug treatment (for example prevention of hypertension, hyperlipidemia, and diabetes). People with obesity are at increased risk of atherosclerosis of the coronary arteries.
=== Genetics ===
Cardiovascular disease in a person's parents increases their risk by ~3 fold, and genetics is an important risk factor for cardiovascular diseases. Genetic cardiovascular disease can occur either as
a consequence of single variant (Mendelian) or polygenic influences. There are more than 40 inherited cardiovascular disease that can be traced to a single disease-causing DNA variant, although these conditions are rare. Most common cardiovascular diseases are non-Mendelian and are thought to be due to hundreds or thousands of genetic variants (known as single nucleotide polymorphisms), each associated with a small effect.
=== Age ===
Age is the most important risk factor in developing cardiovascular or heart diseases, with approximately a tripling of risk with each decade of life. Coronary fatty streaks can begin to form in adolescence. It is estimated that 82 percent of people who die of coronary heart disease are 65 and older. Simultaneously, the risk of stroke doubles every decade after age 55.
Multiple explanations are proposed to explain why age increases the risk of cardiovascular/heart diseases. One of them relates to serum cholesterol level. In most populations, the serum total cholesterol level increases as age increases. In men, this increase levels off around age 45 to 50 years. In women, the increase continues sharply until age 60 to 65 years.
Aging is also associated with changes in the mechanical and structural properties of the vascular wall, which leads to the loss of arterial elasticity and reduced arterial compliance and may subsequently lead to coronary artery disease.
=== Sex ===
Men are at greater risk of heart disease than pre-menopausal women. Once past menopause, it has been argued that a woman's risk is similar to a man's although more recent data from the WHO and UN disputes this. If a female has diabetes, she is more likely to develop heart disease than a male with diabetes. 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.
Coronary heart diseases are 2 to 5 times more common among middle-aged men than women. In a study done by the World Health Organization, sex contributes to approximately 40% of the variation in sex ratios of coronary heart disease mortality. Another study reports similar results finding that sex differences explains nearly half the risk associated with cardiovascular diseases One of the proposed explanations for sex differences in cardiovascular diseases is hormonal difference. Among women, estrogen is the predominant sex hormone. Estrogen may have protective effects on glucose metabolism and hemostatic system, and may have direct effect in improving endothelial cell function. The production of estrogen decreases after menopause, and this may change the female lipid metabolism toward a more atherogenic form by decreasing the HDL cholesterol level while increasing LDL and total cholesterol levels.
Among men and women, there are differences in body weight, height, body fat distribution, heart rate, stroke volume, and arterial compliance. In the very elderly, age-related large artery pulsatility and stiffness are more pronounced among women than men. This may be caused by the women's smaller body size and arterial dimensions which are independent of menopause.
=== Tobacco ===
Cigarettes are the major form of smoked tobacco. Risks to health from tobacco use result not only from direct consumption of tobacco, but also from exposure to second-hand smoke. Approximately 10% of cardiovascular disease is attributed to smoking; however, people who quit smoking by age 30 have almost as low a risk of death as never smokers.
=== Physical inactivity ===
Insufficient physical activity (defined as less than 5 x 30 minutes of moderate activity per week, or less than 3 x 20 minutes of vigorous activity per week) is currently the fourth leading risk factor for mortality worldwide. In 2008, 31.3% of adults aged 15 or older (28.2% men and 34.4% women) were insufficiently physically active.
The risk of ischemic heart disease and diabetes mellitus is reduced by almost a third in adults who participate in 150 minutes of moderate physical activity each week (or equivalent). In addition, physical activity assists weight loss and improves blood glucose control, blood pressure, lipid profile and insulin sensitivity. These effects may, at least in part, explain its cardiovascular benefits.
=== Diet ===
High dietary intakes of saturated fat, trans-fats and salt, and low intake of fruits, vegetables and fish are linked to cardiovascular risk, although whether all these associations indicate causes is disputed. The World Health Organization attributes approximately 1.7 million deaths worldwide to low fruit and vegetable consumption. Frequent consumption of high-energy foods, such as processed foods that are high in fats and sugars, promotes obesity and may increase cardiovascular risk. The amount of dietary salt consumed may also be an important determinant of blood pressure levels and overall cardiovascular risk. There is moderate quality evidence that reducing saturated fat intake for at least two years reduces the risk of cardiovascular disease. High trans-fat intake has adverse effects on blood lipids and circulating inflammatory markers, and elimination of trans-fat from diets has been widely advocated. In 2018 the World Health Organization estimated that trans fats were the cause of more than half a million deaths per year. There is evidence that higher consumption of sugar is associated with higher blood pressure and unfavorable blood lipids, and sugar intake also increases the risk of diabetes mellitus. High consumption of processed meats is associated with an increased risk of cardiovascular disease, possibly in part due to increased dietary salt intake.
=== Alcohol ===
The relationship between alcohol consumption and cardiovascular disease is complex, and may depend on the amount of alcohol consumed. There is a direct relationship between high levels of drinking alcohol and cardiovascular disease. Drinking at low levels without episodes of heavy drinking may be associated with a reduced risk of cardiovascular disease, but there is evidence that associations between moderate alcohol consumption and protection from stroke are non-causal. Moderate drinking is defined as one drink per day for women or two drinks a day for men. At the population level, the health risks of drinking alcohol exceed any potential benefits. Exercising regularly can provide the same benefits as potentially consuming small amounts of alcohol and is a much safer alternative. Consuming too much alcohol can cause a high blood pressure, heart failure, and cardiomyopathy. Drinking alcohol can also cause obesity, which can contribute to cardiovascular issues as well.
=== Celiac disease ===
Untreated celiac disease can cause the development of many types of cardiovascular diseases, most of which improve or resolve with a gluten-free diet and intestinal healing. However, delays in recognition and diagnosis of celiac disease can cause irreversible heart damage.
=== Sleep ===
A lack of good sleep, in amount or quality, is documented as increasing cardiovascular risk in both adults and teens. Recommendations suggest that infants typically need 12 or more hours of sleep per day, adolescents at least eight or nine hours, and adults seven or eight. About one-third of adult Americans get less than the recommended seven hours of sleep per night, and in a study of teenagers, just 2.2 percent of those studied got enough sleep, many of whom did not get good quality sleep. Studies have shown that short sleepers getting less than seven hours sleep per night have a 10 percent to 30 percent higher risk of cardiovascular disease.
Sleep disorders such as sleep-disordered breathing and insomnia, are also associated with a higher cardiometabolic risk.
An estimated 50 to 70 million Americans have insomnia, sleep apnea or other chronic sleep disorders.
In addition, sleep research displays differences in race and class. Short sleep and poor sleep tend to be more frequently reported in ethnic minorities than in whites. African-Americans report experiencing short durations of sleep five times more often than whites, possibly as a result of social and environmental factors. Black children and children living in disadvantaged neighborhoods have much higher rates of sleep apnea.
One study found that of adults who are 45 and older, subjects that fell asleep at different times each night and slept inconsistent numbers of hours each night were more likely to develop atherosclerosis. Poor sleep habits, such as too little sleep, too much sleep, or fragmented sleep, were associated with cardiovascular disease, obesity, and high blood pressure. Another study noted that participants whose sleep duration varied by more than two hours within the course of a week were 1.4 times more likely to have elevated levels of coronary artery calcium, a predictor of cardiovascular events.
=== Socioeconomic disadvantage ===
Cardiovascular disease has a greater impact on low- and middle-income countries compared to those with higher income. Although data on the social patterns of cardiovascular disease in low- and middle-income countries is limited, reports from high-income countries consistently demonstrate that low educational status or income are associated with a greater risk of cardiovascular disease. Policies that have resulted in increased socio-economic inequalities have been associated with greater subsequent socio-economic differences in cardiovascular disease implying a cause and effect relationship. Psychosocial factors, environmental exposures, health behaviours, and health-care access and quality contribute to socio-economic differentials in cardiovascular disease. The Commission on Social Determinants of Health recommended that more equal distributions of power, wealth, education, housing, environmental factors, nutrition, and health care were needed to address inequalities in cardiovascular disease and non-communicable diseases.
=== Air pollution ===
Particulate matter has been studied for its short- and long-term exposure effects on cardiovascular disease. Currently, airborne particles under 2.5 micrometers in diameter (PM2.5) are the major focus, in which gradients are used to determine CVD risk. Overall, long-term PM exposure increased rate of atherosclerosis and inflammation. In regards to short-term exposure (2 hours), every 25 μg/m3 of PM2.5 resulted in a 48% increase of CVD mortality risk. In addition, after only 5 days of exposure, a rise in systolic (2.8 mmHg) and diastolic (2.7 mmHg) blood pressure occurred for every 10.5 μg/m3 of PM2.5. Other research has implicated PM2.5 in irregular heart rhythm, reduced heart rate variability (decreased vagal tone), and most notably heart failure. PM2.5 is also linked to carotid artery thickening and increased risk of acute myocardial infarction.
=== Cardiovascular risk assessment ===
Existing cardiovascular disease or a previous cardiovascular event, such as a heart attack or stroke, is the strongest predictor of a future cardiovascular event. Age, sex, smoking, blood pressure, blood lipids and diabetes are important predictors of future cardiovascular disease in people who are not known to have cardiovascular disease. These measures, and sometimes others, may be combined into composite risk scores to estimate an individual's future risk of cardiovascular disease. Numerous risk scores exist although their respective merits are debated. Other diagnostic tests and biomarkers remain under evaluation but currently these lack clear-cut evidence to support their routine use. They include family history, coronary artery calcification score, high sensitivity C-reactive protein (hs-CRP), ankle–brachial pressure index, lipoprotein subclasses and particle concentration, lipoprotein(a), apolipoproteins A-I and B, fibrinogen, white blood cell count, homocysteine, N-terminal pro B-type natriuretic peptide (NT-proBNP), and markers of kidney function. High blood phosphorus is also linked to an increased risk.
=== Psychological stress ===
There is evidence that mental health problems, in particular depression and traumatic stress, is linked to cardiovascular diseases. Whereas mental health problems are known to be associated with risk factors for cardiovascular diseases such as smoking, poor diet, and a sedentary lifestyle, these factors alone do not explain the increased risk of cardiovascular diseases seen in depression, stress, and anxiety. Moreover, posttraumatic stress disorder is independently associated with increased risk for incident coronary heart disease, even after adjusting for depression and other covariates.
Many studies recognize depression and anxiety as two important disorders that can cause an increase in the risk of developing cardiovascular disease. Only half of the instances of cardiovascular disease are explained by factors such as age and gender that cannot be changed. The other half of instances are due to other sources, including psychological stress. Studies have shown that the prevalence of depression in patients with heart failure is higher than 20%.
Another study assessed the link between men and women who had been divorced and instance of cardiovascular disease. The study found that women who had gone through at least two divorces were just as likely to experience cardiovascular disease as a smoker or diabetic. Men, on the other hand, also had a higher risk of cardiovascular disease, however, their health improved upon remarriage while women did not.
This study also found that during a World Cup soccer event in Germany, heart attacks more than doubled during the days when the nation's team was playing. Researchers assume this link is due to the fact that stress can increase inflammation in the body, which can cause high blood pressure and low HDL cholesterol. Chronic stress can also affect sleep, exercise, and food choices.
=== Anxiety ===
Patients who suffer from generalized anxiety disorder are more likely to develop some form of cardiovascular disease. It is hypothesized that anxiety makes one more likely to develop cardiovascular disease due to the fact that it can change the body's stress response through hormonal and physiological reactions. People with anxiety often experience high blood pressure, arrhythmias, and heart attacks. The stress response caused by anxiety can increase inflammation in the body. It was also discovered that patients with anxiety had lower levels of omega-3-fatty acids which is linked to an increased risk of developing cardiovascular disease.
=== Occupational exposure ===
Little is known about the relationship between work and cardiovascular disease, but links have been established between certain toxins, extreme heat and cold, exposure to tobacco smoke, and mental health concerns such as stress and depression.
==== Non-chemical risk factors ====
A 2015 SBU-report looking at non-chemical factors found an association for those:
with mentally stressful work with a lack of control over their working situation — with an effort-reward imbalance
who experience low social support at work; who experience injustice or experience insufficient opportunities for personal development; or those who experience job insecurity
those who work night schedules; or have long working weeks
those who are exposed to noise
Specifically the risk of stroke was also increased by exposure to ionizing radiation. Hypertension develops more often in those who experience job strain and who have shift-work. Differences between women and men in risk are small, however men risk having and dying of heart attacks or stroke twice as often as women during working life.
==== Chemical risk factors ====
A 2017 SBU report found evidence that workplace exposure to silica dust, engine exhaust or welding fumes is associated with heart disease. Associations also exist for exposure to arsenic, benzopyrenes, lead, dynamite, carbon disulphide, carbon monoxide, metalworking fluids and occupational exposure to tobacco smoke. Working with the electrolytic production of aluminium or the production of paper when the sulphate pulping process is used is associated with heart disease. An association was also found between heart disease and exposure to compounds which are no longer permitted in certain work environments, such as phenoxy acids containing TCDD(dioxin) or asbestos.
Workplace exposure to silica dust or asbestos is also associated with pulmonary heart disease. There is evidence that workplace exposure to lead, carbon disulphide, phenoxyacids containing TCDD, as well as working in an environment where aluminum is being electrolytically produced, is associated with stroke.
=== Somatic mutations ===
As of 2017, evidence suggests that certain leukemia-associated mutations in blood cells may also lead to increased risk of cardiovascular disease. Several large-scale research projects looking at human genetic data have found a robust link between the presence of these mutations, a condition known as clonal hematopoiesis, and cardiovascular disease-related incidents and mortality.
=== Radiation therapy ===
Radiation treatments (RT) for cancer can increase the risk of heart disease and death, as observed in breast cancer therapy. Therapeutic radiation increases the risk of a subsequent heart attack or stroke by 1.5 to 4 times; the increase depends on the dose strength, volume, and location. Use of concomitant chemotherapy, e.g. anthracyclines, is an aggravating risk factor. The occurrence rate of RT induced cardiovascular disease is estimated between 10% and 30%.
Side-effects from radiation therapy for cardiovascular diseases have been termed radiation-induced heart disease or radiation-induced cardiovascular disease. Symptoms are dose-dependent and include cardiomyopathy, myocardial fibrosis, valvular heart disease, coronary artery disease, heart arrhythmia and peripheral artery disease. Radiation-induced fibrosis, vascular cell damage and oxidative stress can lead to these and other late side-effect symptoms.
== Pathophysiology ==
Population-based studies show that atherosclerosis, the major precursor of cardiovascular disease, begins in childhood. The Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study demonstrated that intimal lesions appear in all the aortas and more than half of the right coronary arteries of youths aged 7–9 years.
Obesity and diabetes mellitus are linked to cardiovascular disease, as are a history of chronic kidney disease and hypercholesterolaemia. In fact, cardiovascular disease is the most life-threatening of the diabetic complications and diabetics are two- to four-fold more likely to die of cardiovascular-related causes than nondiabetics.
== Screening ==
Screening ECGs (either at rest or with exercise) are not recommended in those without symptoms who are at low risk. This includes those who are young without risk factors. In those at higher risk the evidence for screening with ECGs is inconclusive. Additionally echocardiography, myocardial perfusion imaging, and cardiac stress testing is not recommended in those at low risk who do not have symptoms. Some biomarkers may add to conventional cardiovascular risk factors in predicting the risk of future cardiovascular disease; however, the value of some biomarkers is questionable. Ankle-brachial index (ABI), high-sensitivity C-reactive protein (hsCRP), and coronary artery calcium, are also of unclear benefit in those without symptoms as of 2018.
The NIH recommends lipid testing in children beginning at the age of 2 if there is a family history of heart disease or lipid problems. It is hoped that early testing will improve lifestyle factors in those at risk such as diet and exercise.
Screening and selection for primary prevention interventions has traditionally been done through absolute risk using a variety of scores (ex. Framingham or Reynolds risk scores). This stratification has separated people who receive the lifestyle interventions (generally lower and intermediate risk) from the medication (higher risk). The number and variety of risk scores available for use has multiplied, but their efficacy according to a 2016 review was unclear due to lack of external validation or impact analysis. Risk stratification models often lack sensitivity for population groups and do not account for the large number of negative events among the intermediate and low risk groups. As a result, future preventative screening appears to shift toward applying prevention according to randomized trial results of each intervention rather than large-scale risk assessment.
== Prevention ==
Up to 90% of cardiovascular disease may be preventable if established risk factors are avoided. Currently practised measures to prevent cardiovascular disease include:
Maintaining a healthy diet, such as the Mediterranean diet, a vegetarian, vegan or another plant-based diet.
Replacing saturated fat with healthier choices: Clinical trials show that replacing saturated fat with polyunsaturated vegetable oil reduced CVD by 30%. Prospective observational studies show that in many populations lower intake of saturated fat coupled with higher intake of polyunsaturated and monounsaturated fat is associated with lower rates of CVD.
Decrease body fat if overweight or obese. The effect of weight loss is often difficult to distinguish from dietary change, and evidence on weight reducing diets is limited. In observational studies of people with severe obesity, weight loss following bariatric surgery is associated with a 46% reduction in cardiovascular risk.
Limit alcohol consumption to the recommended daily limits. People who moderately consume alcoholic drinks have a 25–30% lower risk of cardiovascular disease. However, people who are genetically predisposed to consume less alcohol have lower rates of cardiovascular disease suggesting that alcohol itself may not be protective. Excessive alcohol intake increases the risk of cardiovascular disease and consumption of alcohol is associated with increased risk of a cardiovascular event in the day following consumption.
Decrease non-HDL cholesterol. Statin treatment reduces cardiovascular mortality by about 31%.
Stopping smoking and avoidance of second-hand smoke. Stopping smoking reduces risk by about 35%.
At least 150 minutes (2 hours and 30 minutes) of moderate exercise per week.
Lower blood pressure, if elevated. A 10 mmHg reduction in blood pressure reduces risk by about 20%. Lowering blood pressure appears to be effective even at normal blood pressure ranges.
Not enough sleep also raises the risk of high blood pressure. Adults need about 7–9 hours of sleep. Sleep apnea is also a major risk as it causes breathing to stop briefly, which can put stress on the body which can raise the risk of heart disease.
Most guidelines recommend combining preventive strategies. There is some evidence that interventions aiming to reduce more than one cardiovascular risk factor may have beneficial effects on blood pressure, body mass index and waist circumference; however, evidence was limited and the authors were unable to draw firm conclusions on the effects on cardiovascular events and mortality.
There is additional evidence to suggest that providing people with a cardiovascular disease risk score may reduce risk factors by a small amount compared to usual care. However, there was some uncertainty as to whether providing these scores had any effect on cardiovascular disease events. It is unclear whether or not dental care in those with periodontitis affects their risk of cardiovascular disease. According to a 2021 WHO study, working 55+ hours a week raises the risk of stroke by 35% and the risk of dying from heart conditions by 17%, when compared to a 35-40 hours week.
=== Psychological prevention ===
Decrease psychosocial stress. This measure may be complicated by imprecise definitions of what constitute psychosocial interventions. Mental stress–induced myocardial ischemia is associated with an increased risk of heart problems in those with previous heart disease. Severe emotional and physical stress leads to a form of heart dysfunction known as Takotsubo syndrome in some people. Specific relaxation therapies are of unclear benefit. Decreasing psychological stress can be accomplished by receiving access to services and support, recognizing signs and symptoms of mental health disorders, awareness of family history, and understanding which mental health disorders increase the risk of cardiovascular disease. Psychosocial intervention programs have been shown to improve risk of developing cardiovascular disease in the high-risk population.
=== Diet ===
A diet high in fruits and vegetables decreases the risk of cardiovascular disease and death.
A 2021 review found that plant-based diets can provide a risk reduction for CVD if a healthy plant-based diet is consumed. Unhealthy plant-based diets do not provide benefits over diets including meat. A similar meta-analysis and systematic review also looked into dietary patterns and found "that diets lower in animal foods and unhealthy plant foods, and higher in healthy plant foods are beneficial for CVD prevention". A 2018 meta-analysis of observational studies concluded that "In most countries, a vegan diet is associated with a more favourable cardio-metabolic profile compared to an omnivorous diet."
Evidence suggests that the Mediterranean diet may improve cardiovascular outcomes. There is also evidence that a Mediterranean diet may be more effective than a low-fat diet in bringing about long-term changes to cardiovascular risk factors (e.g., lower cholesterol level and blood pressure).
The DASH diet (high in nuts, fish, fruits and vegetables, and low in sweets, red meat and fat) has been shown to reduce blood pressure, lower total and low density lipoprotein cholesterol and improve metabolic syndrome; but the long-term benefits have been questioned. A high-fiber diet is associated with lower risks of cardiovascular disease.
Worldwide, dietary guidelines recommend a reduction in saturated fat, and although the role of dietary fat in cardiovascular disease is complex and controversial there is a long-standing consensus that replacing saturated fat with unsaturated fat in the diet is sound medical advice. Total fat intake has not been found to be associated with cardiovascular risk. A 2020 systematic review found moderate quality evidence that reducing saturated fat intake for at least 2 years caused a reduction in cardiovascular events. A 2015 meta-analysis of observational studies however did not find a convincing association between saturated fat intake and cardiovascular disease. Variation in what is used as a substitute for saturated fat may explain some differences in findings. The benefit from replacement with polyunsaturated fats appears greatest, while replacement of saturated fats with carbohydrates does not appear to have a beneficial effect. A diet high in trans fatty acids is associated with higher rates of cardiovascular disease, and in 2015 the Food and Drug Administration (FDA) determined that there was 'no longer a consensus among qualified experts that partially hydrogenated oils (PHOs), which are the primary dietary source of industrially produced trans fatty acids (IP-TFA), are generally recognized as safe (GRAS) for any use in human food'. There is conflicting evidence concerning whether dietary supplements of omega-3 fatty acids (a type of polyunsaturated essential fatty acid) added to diet improve cardiovascular risk.
The benefits of recommending a low-salt diet in people with high or normal blood pressure are not clear. In those with heart failure, after one study was left out, the rest of the trials show a trend to benefit. Another review of dietary salt concluded that there is strong evidence that high dietary salt intake increases blood pressure and worsens hypertension, and that it increases the number of cardiovascular disease events; both as a result of the increased blood pressure and probably through other mechanisms. Moderate evidence was found that high salt intake increases cardiovascular mortality; and some evidence was found for an increase in overall mortality, strokes, and left ventricular hypertrophy.
==== Intermittent fasting ====
Overall, the current body of scientific evidence is uncertain on whether intermittent fasting could prevent cardiovascular disease. Intermittent fasting may help people lose more weight than regular eating patterns, but was not different from energy restriction diets.
=== Medication ===
Blood pressure medication reduces cardiovascular disease in people at risk, irrespective of age, the baseline level of cardiovascular risk, or baseline blood pressure. The commonly-used drug regimens have similar efficacy in reducing the risk of all major cardiovascular events, although there may be differences between drugs in their ability to prevent specific outcomes. Larger reductions in blood pressure produce larger reductions in risk, and most people with high blood pressure require more than one drug to achieve adequate reduction in blood pressure. Adherence to medications is often poor, and while mobile phone text messaging has been tried to improve adherence, there is insufficient evidence that it alters secondary prevention of cardiovascular disease.
Statins are effective in preventing further cardiovascular disease in people with a history of cardiovascular disease. As the event rate is higher in men than in women, the decrease in events is more easily seen in men than women. In those at risk, but without a history of cardiovascular disease (primary prevention), statins decrease the risk of death and combined fatal and non-fatal cardiovascular disease. The benefit, however, is small. A United States guideline recommends statins in those who have a 12% or greater risk of cardiovascular disease over the next ten years. Niacin, fibrates and CETP Inhibitors, while they may increase HDL cholesterol do not affect the risk of cardiovascular disease in those who are already on statins. Fibrates lower the risk of cardiovascular and coronary events, but there is no evidence to suggest that they reduce all-cause mortality.
Anti-diabetic medication may reduce cardiovascular risk in people with Type 2 diabetes, although evidence is not conclusive. A meta-analysis in 2009 including 27,049 participants and 2,370 major vascular events showed a 15% relative risk reduction in cardiovascular disease with more-intensive glucose lowering over an average follow-up period of 4.4 years, but an increased risk of major hypoglycemia.
Aspirin has been found to be of only modest benefit in those at low risk of heart disease, as the risk of serious bleeding is almost equal to the protection against cardiovascular problems. In those at very low risk, including those over the age of 70, it is not recommended. The United States Preventive Services Task Force recommends against use of aspirin for prevention in women less than 55 and men less than 45 years old; however, it is recommended for some older people.
The use of vasoactive agents for people with pulmonary hypertension with left heart disease or hypoxemic lung diseases may cause harm and unnecessary expense.
Antibiotics for secondary prevention of coronary heart disease
Antibiotics may help patients with coronary disease to reduce the risk of heart attacks and strokes. However, evidence in 2021 suggests that antibiotics for secondary prevention of coronary heart disease are harmful, with increased mortality and occurrence of stroke; the use of antibiotics is not supported for preventing secondary coronary heart disease.
=== Physical activity ===
Exercise-based cardiac rehabilitation following a heart attack reduces the risk of death from cardiovascular disease and leads to less hospitalizations. There have been few high-quality studies of the benefits of exercise training in people with increased cardiovascular risk but no history of cardiovascular disease.
A systematic review estimated that inactivity is responsible for 6% of the burden of disease from coronary heart disease worldwide. The authors estimated that 121,000 deaths from coronary heart disease could have been averted in Europe in 2008 if people had not been physically inactive. Low-quality evidence from a limited number of studies suggest that yoga has beneficial effects on blood pressure and cholesterol. Tentative evidence suggests that home-based exercise programs may be more efficient at improving exercise adherence.
=== Dietary supplements ===
While a healthy diet is beneficial, the effect of antioxidant supplementation (vitamin E, vitamin C, etc.) or vitamins has not been shown to protect against cardiovascular disease and in some cases may possibly result in harm. Mineral supplements have also not been found to be useful. Niacin, a type of vitamin B3, may be an exception with a modest decrease in the risk of cardiovascular events in those at high risk. Magnesium supplementation lowers high blood pressure in a dose-dependent manner. Magnesium therapy is recommended for people with ventricular arrhythmia associated with torsades de pointes who present with long QT syndrome, and for the treatment of people with digoxin intoxication-induced arrhythmias. There is no evidence that omega-3 fatty acid supplementation is beneficial. A 2022 review found that some dietary supplements, including micronutrients, may reduce risk factors for cardiovascular disease.
== Management ==
Cardiovascular disease is treatable with initial treatment primarily focused on diet and lifestyle interventions. Influenza may make heart attacks and strokes more likely and therefore influenza vaccination may decrease the chance of cardiovascular events and death in people with heart disease.
Proper CVD management necessitates a focus on MI and stroke cases due to their combined high mortality rate, keeping in mind the cost-effectiveness of any intervention, especially in developing countries with low or middle-income levels. Regarding MI, strategies using aspirin, atenolol, streptokinase or tissue plasminogen activator have been compared for quality-adjusted life-year (QALY) in regions of low and middle income. The costs for a single QALY for aspirin and atenolol were less than US$25, streptokinase was about $680, and t-PA was $16,000. Aspirin, ACE inhibitors, beta-blockers, and statins used together for secondary CVD prevention in the same regions showed single QALY costs of $350.
There are also surgical or procedural interventions that can save someone's life or prolong it. For heart valve problems, a person could have surgery to replace the valve. For arrhythmias, a pacemaker can be put in place to help reduce abnormal heart rhythms and for a heart attack, there are multiple options two of these are a coronary angioplasty and a coronary artery bypass surgery.
There is probably no additional benefit in terms of mortality and serious adverse events when blood pressure targets were lowered to ≤ 135/85 mmHg from ≤ 140 to 160/90 to 100 mmHg.
== Epidemiology ==
Cardiovascular diseases are the leading cause of death worldwide and in all regions except Africa. In 2008, 30% of all global death was attributed to cardiovascular diseases. Death caused by cardiovascular diseases are also higher in low- and middle-income countries as over 80% of all global deaths caused by cardiovascular diseases occurred in those countries. It is also estimated that by 2030, over 23 million people will die from cardiovascular diseases each year.
It is estimated that 60% of the world's cardiovascular disease burden will occur in the South Asian subcontinent despite only accounting for 20% of the world's population. This may be secondary to a combination of genetic predisposition and environmental factors. Organizations such as the Indian Heart Association are working with the World Heart Federation to raise awareness about this issue.
== Research ==
There is evidence that cardiovascular disease existed in pre-history, and research into cardiovascular disease dates from at least the 18th century. The causes, prevention, and/or treatment of all forms of cardiovascular disease remain active fields of biomedical research, with hundreds of scientific studies being published on a weekly basis.
Recent areas of research include the link between inflammation and atherosclerosis the potential for novel therapeutic interventions, and the genetics of coronary heart disease.
== References ==
== External links ==
WHO fact sheet on cardiovascular diseases
2021 ESC Guidelines on cardiovascular disease prevention in clinical practice
Heart Disease MedicineNet Slides, photos, descriptions
Risk calculator
Interactive CV Risk Calculator | Wikipedia/Left_main_disease |
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_factor |
A transesophageal echocardiogram (TEE; also spelled transoesophageal echocardiogram; TOE in British English) is an alternative way to perform an echocardiogram. A specialized probe containing an ultrasound transducer at its tip is passed into the patient's esophagus. This allows image and Doppler evaluation which can be recorded. It is commonly used during cardiac surgery and is an excellent modality for assessing the aorta, although there are some limitations.
It has several advantages and some disadvantages compared with a transthoracic echocardiogram (TTE).
== Details ==
TEE is a semi-invasive procedure in that the probe must enter the body but does not require surgical (i.e., invasive) cutting for this procedure.
Before inserting the probe, mild to moderate sedation is induced in the patient to ease the discomfort and to decrease the gag reflex.
Usually a local anesthetic spray (e.g., lidocaine, benzocaine, xylocaine) is used for the back of the throat or as a jelly/lubricant anesthetic for the esophagus.
Sedation and anesthesia are required to make the procedure tolerable and safer, as biting the probe, coughing, vomiting, and patient movement would drastically reduce the value of the procedure.
Mild or moderate sedation can be induced with medications such as midazolam (a benzodiazepine with sedating, amnesiac qualities), fentanyl (an opioid), or propofol (a sedative/general anesthetic, depending on dosage).
Children are anesthetized. Adults are sometimes anesthetized as well if moderate sedation is unsuccessful.
Due to the procedure being invasive, sonographers do not perform this procedure unlike transthoracic echo.
Once adequate sedation and anesthesia are achieved, the probe is passed through the mouth and into the esophagus.
From here, the protocol used for the procedure is highly variable.
As the study could be terminated any second (e.g., respiratory compromise, hypotension, intolerance to the probe) the structures of particular interest could be visualized first. For example, if the TEE is ordered to look for
mitral regurgitation then the mitral valve may be fully inspected first. At the completion of the study, the probe is removed and patient is monitored for recovery from sedation.
=== Advantages ===
The advantage of TEE over TTE is usually clearer images, especially of structures that are difficult to view transthoracically (through the chest wall). This difficulty with TTE is exemplified with obesity and COPD, as both of these can drastically limit both the window available and the quality of the images obtained through those windows. This reduces the attenuation (weakening) of the ultrasound signal, generating a stronger return signal, ultimately enhancing image and Doppler quality. Comparatively, transthoracic ultrasound must first traverse skin, fat, ribs and lungs before reflecting off the heart and back to the probe before an image can be created. All these structures, along with the increased distance the beam must travel, weaken the ultrasound signal thus degrading the image and Doppler quality.
In adults, several structures can be evaluated and imaged better with the TEE, including the aorta, pulmonary artery, valves of the heart, both atria, atrial septum, left atrial appendage, and coronary arteries.
TEE has a very high sensitivity for locating a blood clot inside the left atrium.
TEE is also frequently used concurrently with cardiac surgery to provide immediate visualization, inspection, and monitoring of the patient throughout the procedure. Its intraoperative utility includes real-time hemodynamic monitoring by the cardiac anesthesiologist, evaluation of relevant cardiac pathologies before and after surgical repair, and immediate assessment of the success of surgical interventions after cardiopulmonary bypass. TEE can also evaluate for unintended complications from surgery, for example unintended injury to cardiac valves, the aorta, or other structures during the procedure.
=== Disadvantages ===
TEE has several disadvantages, although they should be weighed against its significant benefits. The patient must follow the ASA NPO guidelines (usually not eat anything for eight hours and not drink anything for two hours prior to the procedure). Rather than one sonographer, a TEE needs a team of medical personnel of at least one nurse to monitor/administer sedation and a physician to perform the procedure (a third physician/sonographer can be used to push buttons on the ultrasound machine). It takes longer to perform a TEE than a TTE. It may be uncomfortable for the patient, who may require general anesthesia at the extreme to perform a TEE safely. Due to being an invasive procedure often involving sedation, it is more technically difficult to perform and requires experience to do it well while maintaining safety.
TEE is limited to available anatomy. For example, if the patient has esophageal varices, esophageal stricture, Barrett's esophagus, or other esophageal or stomach problems then this can increase the risk of a TEE significantly.
Performing an esophagogastroduodenoscopy (EGD) beforehand may be necessary to visualize the anatomy for safety, which exposes the patient to a second procedure.
The anatomy may result in prohibitive risk.
With transthoracic echo, numerous measurements are taken to aid in diagnosis and grading of diseases.
These normal ranges are not as well defined for TEE and so there is less accepted standards (e.g., left atrial enlargement).
Some risks are associated with the procedure, such as esophageal perforation around 1 in 10,000, and adverse reactions to the medication.
Specialty medicine professional organizations recommend against using transesophageal echocardiography to detect cardiac sources of embolization after a patient's health care provider has identified a source of embolization and if that person would not change a patient's management as a result of getting more information. Such organizations further recommend that doctors and patients should avoid seeking transesophageal echocardiography only for the sake of protocol-driven testing and to agree to the test only if it is right for the individual patient.
== Clinical uses ==
In addition to use by cardiologists in outpatient and inpatient settings, TEE can be performed by a cardiac anesthesiologist to evaluate, diagnose, and treat patients in the perioperative period. Most commonly used during open heart procedures, if the patient's status warrants it, TEE can be used in the setting of any operation.
TEE is very useful during many cardiac surgical procedures (e.g., mitral valve repair). It is actually an essential monitoring tool during this procedure. It helps to detect and quantify the disease preoperatively as well as to assess the results of surgery immediately after the procedure. If the repair is found to be inadequate, showing significant residual regurgitation, the surgeon can decide whether to go back to cardiopulmonary bypass to try to correct the defect.
Aortic dissections are another important condition where TEE is very helpful.
TEE can also help the surgeon during the insertion of a catheter for retrograde cardioplegia.
== Probes ==
TEE probes are similar in style to those used for esophagogastroduodenoscopy except the probe contains an ultrasound crystal rather than a visual camera.
The ultrasound crystal images radially to the probe rather than axially (along the probe length) as the heart is not inline with the esophagus, but rather adjacent (anterior) to it.
=== Angle ===
Most TEE probes contain a two-dimensional ultrasound crystal.
This permits rotation of the 2-D echo plane without physical movement of the probe.
This is often referred to the "angle" and varies between 0° and 180° (flipped image of 0°).
For any given position of the probe in the body, different angles permit viewing structures more optimally.
The angle can be adjusted with buttons or a dial, and this varies with the specific probe and ultrasound machine.
=== Movement ===
The probes often have one or two degrees of freedom:
Flexion or retroflexion can point the crystal superiorly or inferiorly, respectively
Left and right flexion tilts the probe left and right
These two degrees are typically adjusted using dials on the handle of the probe.
A third degree is axial rotation of the probe (clockwise or counter-clockwise) and is present regardless of the other two degrees of freedom.
A fourth degree is the translation of the probe long its axis to permit passing through the mouth, into the esophagus, and into the stomach.
The combination of these four degrees of freedom permit 2-D, color, and Doppler echo of practically every structure in the heart.
== Positions ==
Transthoracic echo is far more commonly used than TEE and transthoracic echo is limited to by the available windows through the chest wall to visualize the heart.
TEE does not have such discrete locations and can visualize the heart anywhere along the esophagus to the stomach.
With that said, there are commonly accepted positions along this path that are used when performing a standard TEE.
=== Midesophageal ===
The midesophageal view is positioned posterior from the left atrium and at 0° this provides for a long-axis four chamber view.
At 0°, the long-axis four chamber view can be obtained with slight retroflexion of the probe. However, slight rotation and insertion may be needed to better visualize the right heart and tricuspid valve.
At 45°, the short-axis view of the aortic valve can be obtained.
At this angle, a short-axis view of the right ventricle can be seen to visualize the right atrium, tricuspid valve, right ventricle, and pulmonary valve in a single view.
At 90°, the probe can be rotated clockwise to obtain the "bicaval view" in which the right atrial and both the inferior and superior vena cava can be viewed.
At 135°, the long-axis view of the aortic valve can be obtained.
The left atrial appendage, with proper probe positioning, can be visualized at all angles and often visualized at 0*, 45°, 90°, and 135° to adequately rule out a thrombus.
=== Transgastric ===
Pushing the TEE probe past the gastroesophageal junction into the stomach and flexing the probe (pointing it toward the superior) yields a short-axis view of the heart.
At 0°, the short-axis of the left ventricle can be obtained to see wall motion in the basal, mid, and distal sections.
If the probe is rotated clockwise, then the right heart and tricuspid valve can be visualized.
It is in the transgastric position that is best used to quantify the aortic valve with pulse- and continuous-wave Doppler as this is the best view to be best coaxial with the valve.
=== Upper esophagus ===
Pulling back of the TEE probe higher into the esophagus reveals the aortic arch. Typically, in the midesophageal view the probe is rotated until the descending aorta is visualized. Pulling back the probe permits visualization of the aorta and any atheromatous plaques within the aorta. Short axis visualization at 0° allows for descending aorta size measurements. Further pulling back will eventually reach the aorta arch and clockwise rotation will bring the arch into view. Continuous visualization of the aorta to the arch level can visualize coarctation of the aorta.
== History ==
The transesophageal echocardiogram was first invented by Dr. Leon Frazin in 1974 while working at the Loyola University Stritch School of Medicine, Maywood, and Veterans Administration Hospital, Hines, Illinois. His early findings were published in 1976 in Circulation.
== Diseases ==
While TEE can be used to answer many questions that a transthoracic echo can answer, the TEE is used for some diseases in particular.
Infective endocarditis to get better quality images of the affected valve and better plan surgery, or need for surgery
Aortic root abscess, which generally is not visible on transthoracic echo
Eccentric mitral regurgitation can be better appreciated on TEE due to Coandă effect
Left atrial appendage thrombus and evaluation, follow up, and insertion of a left atrial appendage occlusion device
Evaluation for patent foramen ovale and atrial septal defect after a stroke, and insertion of a PFO/ASD plug
Monitoring during a procedure to cross the interatrial septum safely without poking the needle through an undesired structure
During cardiothoracic surgery for numerous procedures including immediately before and after replacement of a valve
== References ==
== External links ==
Virtual TEE – online interactive learning resource
TEE online simulator, interactive | Wikipedia/Transesophageal_echocardiography |
Central core disease (CCD), also known as central core myopathy, is an autosomal dominant inherited muscle disorder present from birth that negatively affects the skeletal muscles. It was first described by Shy and Magee in 1956. It is characterized by the appearance of the myofibril under the microscope.
== Signs and symptoms ==
The symptoms of CCD are variable, but usually involve hypotonia (decreased muscle tone) at birth, mild delay in child development (highly variable between cases), weakness of the facial muscles, and skeletal malformations such as scoliosis and hip dislocation.
CCD is usually diagnosed in infancy or childhood, but some patients remain asymptomatic until adulthood to middle age.
== Pathophysiology ==
Central core disease is inherited in an autosomal dominant fashion. Most cases have demonstrable mutations in the ryanodine receptor type 1 (RYR1) gene, which are often de novo (newly developed). People with CCD are at increased risk for developing malignant hyperthermia (MH) when receiving general anesthesia.
== Diagnosis ==
The diagnosis is made based on the combination of typical symptoms and the appearance on biopsy (tissue sample) from muscle. The name derives from the typical appearance of the biopsy on light microscopy, where the muscle cells have cores that are devoid of mitochondria and specific enzymes.
Respiratory insufficiency develops in a small proportion of cases. Creatine kinase tend to be normal and electromyography (EMG) shows short duration, short amplitude motor unit action potentials.
== Treatment ==
There is no specific treatment for central core disease. Certain triggering anesthetics must be avoided, and relatives should be screened for RYR1 mutations that cause malignant hyperthermia.
Research has shown that some patients may benefit from treatment with oral salbutamol.
== References ==
== External links == | Wikipedia/Central_core_disease |
Myotonia congenita is a congenital neuromuscular channelopathy that affects skeletal muscles (muscles used for movement). It is a genetic disorder. The hallmark of the disease is the failure of initiated contraction to terminate, often referred to as delayed relaxation of the muscles (myotonia) and rigidity. Symptoms include delayed relaxation of the muscles after voluntary contraction (myotonia), and may also include stiffness, hypertrophy (enlargement), transient weakness in some forms of the disorder (from certain genetic mutations), severe masseter spasm, and cramping. The condition is sometimes referred to as fainting goat syndrome, as it is responsible for the eponymous 'fainting' seen in fainting goats when presented with a sudden stimulus. Of note, myotonia congenita has no association with malignant hyperthermia (MH).
== Symptoms and signs ==
The prolonged muscle contractions, which occur most commonly in the leg muscles in recessive mutations, and more commonly in the hands, face, and eyelids in dominant mutations, are often enhanced by inactivity, and in some forms are relieved by repetitive movement known as "the warm-up effect". This effect often diminishes quickly with rest. Some individuals with myotonia congenita are prone to falling as a result of hasty movements or an inability to stabilize themselves after a loss of balance. During a fall, a person with myotonia congenita may experience partial or complete rigid paralysis that will quickly resolve once the event is over. However, a fall into cold water may render the person unable to move for the duration of submergence. As with myotonic goats, children are more prone to falling than adults, due to their impulsivity.
The two major types of myotonia congenita are distinguished by the severity of their symptoms and their patterns of inheritance. Becker disease usually appears later in childhood than Thomsen disease, and causes more severe myotonia, muscle stiffness and transient weakness. Although myotonia in itself is not normally associated with pain, cramps or myalgia may develop. People with Becker disease often experience temporary attacks of muscle weakness, particularly in the arms and hands, brought on by movement after periods of rest. They may also develop mild, permanent muscle weakness over time. This muscle weakness is not observed in people with Thomsen disease. However, in recent times, as more of the individual mutations that cause myotonia congenita are identified, these limited disease classifications are becoming less widely used.
Early symptoms in a child may include:
Difficulty swallowing
Gagging
Stiff movements that improve when they are repeated
Frequent falling
Difficulties opening eyelids after strenuous contraction or crying (von Graefe's sign)
Possible complications may include:
Aspiration pneumonia (caused by swallowing difficulties)
Frequent choking or gagging in infants (also caused by swallowing difficulties)
Abdominal muscle weakness
Chronic joint problems
Injury due to falls
=== Phenotypic variability ===
Both Thomsen and Becker myotonia have high phenotype variability. Severity of symptoms can vary greatly between individuals and throughout the lives of the individuals themselves. This may be partly because there are over 130 currently known different mutations that can cause the disorder, each with their own specifics, and also because myotonia congenita is an ion channel disorder, and ion channels are sensitive to internal and external environmental factors. It has been shown that pregnancy and the use of diuretics aggravate myotonia, and both these conditions are linked to the loss of divalent cations such as magnesium and calcium. It has further been shown that in chemically-induced myotonia in isolated rat muscle, myotonia could be dampened by increasing the magnesium and calcium content of the extracellular medium. This has also been shown for isolated human muscle.
Adrenaline/epinephrine is well known to make myotonia worse in most individuals with the disorder, and a person with myotonia congenita may experience a sudden increase in difficulty with mobility in a particularly stressful situation during which adrenaline is released.
Due to the invisible nature of the disorder, the fact that those with myotonia congenita often appear very fit and able bodied, the general lack of knowledge about the disorder by the general and medical community, and often by the individual themselves, and the potential for inconsistency with the symptoms, many people with myotonia congenita have experienced a degree of social persecution at one time or another because of the effects of their disorder.
=== The warm-up phenomenon ===
This phenomenon was described along with the disease by Thomsen in 1876 but its etiology remains unclear.
Patients report that myotonia congenita may present itself in the following ways (this is from first hand experience). If the person is sedentary and then decides to walk up a set of stairs, by the third or fourth step their leg muscles begin to stiffen significantly, requiring them to slow down almost to a complete stop. But as the muscles loosen up, a few steps later, they can once again begin to climb the steps at a normal pace. If this person plays any kind of a sport, a good warm-up is mandatory. Otherwise if they need to quickly and intensively use their muscles, such as in a sprint race or a basketball game, their muscles will freeze up, causing them to slow down or almost come to a complete stop. But once the muscles are warmed up, they can once again function normally. This can happen in various muscles, even in muscles such as the tongue. For example, if a person has not spoken for awhile and then wants to speak, their tongue may be stiff at first causing the words to come out a little garbled, but after a few seconds of trying to speak, the tongue muscle will loosen up and then they can speak normally for the remainder of the time that they are conversing.
Patients report that repeated contraction of muscle alleviates present myotonia with each contraction, such that myotonia is almost absent after a few contractions of the same muscle. The effect lasts about five minutes. There have been several proposed mechanisms for this phenomenon, but none have been demonstrated conclusively; one hypothesis is that the Na+/K+-ATPase is stimulated during the myotonic activity by increased intracellular Na+ in the cytosol of the muscle cell, increasing the activity of the Na+/K+-ATPase. However, in experiments with patients where the Na+/K+-ATPase had been blocked in the underarm by infusion of the Na+/K+-ATPase-blocker Ouabain, no effect on warm-up was observed. Another hypothesis states that the few remaining functional chloride channels in muscle may become more active with increased muscle activity.
It has been proposed that inactivation of sodium channel protein type 4 subunit alpha, residing in skeletal muscle, could play an important role in the warm-up phenomenon. In particular, slow inactivation of the channel is believed to have a spatial and temporal extent that is correlated to warm-up and therefore may provide a plausible cause.
== Causes ==
The disorder is caused by mutations in part of a gene (CLCN1) encoding the ClC-1 chloride channel, resulting in muscle fiber membranes having an unusually exaggerated response to stimulation (hyperexcitability).
Three cases have been reported who were diagnosed with Thomsen's myotonia and proved on genetic testing not to have mutations in the chloride gene but rather in the alpha-subunit of the voltage gated sodium channel (SCN4A). Like chloride channel mutations, patients with sodium channel mutations may have a very varied phenotype, making a diagnosis more difficult.
== Mechanisms ==
Myotonia congenita is caused in humans by loss-of-function mutations in the gene CLCN1. This is the gene encoding the protein CLCN1, that forms the ClC-1 chloride channel, critical for the normal function of skeletal muscle cells. This gene is also associated with the condition in horses, goats, and dogs. In short, in lack of sufficient functional chloride channels, the muscle fiber membrane becomes hyper-excitable and continues to be electrically active (firing action potentials) when stimulated, for longer periods of time, than a normal muscle fiber. This results in prolonged contraction/delayed relaxation of the muscle.
The dysfunctional Cl− channels are located in the muscle fiber membrane and do not affect the motor nerve innervating the muscle. However, many studies have shown that denervation of muscle fibers alter the resting membrane conductance, but whether this affects myotonia in the muscle has been subject to heavy debate, and results from experiments are inconclusive.
In skeletal muscle fibers, a large transverse tubule system with a high surface-area to volume ratio exists. The onset of skeletal muscle activity is associated with the initiation and propagation of action potentials again associated with an efflux of K+ to the extracellular fluid and transverse tubule system. When many action potentials are elicited subsequently more K+ is expelled from the cell into the transverse tubular system. As K+ accumulates in the transverse tubular system the equilibrium potential for K+ (EK+) normally around -80 mV, becomes more depolarized (depolarization), according to the Nernst equation. In skeletal muscle fibers the equilibrium potential for Cl− is around -80 mV, equal to that of K+ at rest. Cl− moves towards its equilibrium potential around -80 mV, while potassium moves towards its equilibrium potential more depolarized than -80 mV during activity. This results in a slightly more depolarized membrane potential of the fiber during repeated action potentials, see Goldman equation. The Na+ conductance is only elevated shortly compared to the K+ conductance during each action potential, which is why K+ largely determines the membrane potential (Cl− is passively distributed during rest).
In the case of myotonia congenita, the chloride channels that allow Cl− to move across the membrane towards its equilibrium potential are defective, thus K+ is the only ion determining the membrane potential, and as more and more K+ accumulates in the transverse tubular system with each subsequent action potential the fiber depolarizes until the membrane potential comes close enough to the action potential threshold for spontaneous activity to ensue
Spontaneous action potentials can arise for several seconds, leading to the delayed relaxation that is the hallmark of myotonia. Cessation of spontaneous activity is associated with sodium channel inactivation (Nav1.4).
== Diagnosis ==
=== Types ===
Two types of myotonia congenita exist, an autosomal dominant form and an autosomal recessive form. Autosomal dominant myotonia congenita (OMIM #160800) is also called Thomsen disease, after Danish/German physician Asmus Julius Thomas Thomsen (1815–1896), who himself had the disease and who wrote the first description of it in the medical literature (in 1876). Autosomal recessive myotonia congenita (OMIM #255700) is also called generalized myotonia, recessive generalized myotonia (RGM), Becker disease, and Becker myotonia, after the German professor Peter Emil Becker, who discovered its recessive nature.
The term congenital in its sense of "clinically apparent from birth" applies only to Thomsen disease, as the clinical onset of Becker myotonia may be delayed up to the age of 4 to 6 years. But in either form of myotonia congenita, the term's strictest sense reflects that the disease is genetically present from birth, although the clinical onset may be delayed.
With the advent of genetic testing, it has recently been found that some typically recessive mutations may occur in a dominant fashion in some individuals. The reason for this is not known.
Because several CLCN1 mutations can cause either Becker disease or Thomsen disease, doctors usually rely on characteristic signs and symptoms to distinguish the two forms of myotonia congenita. However, myotonia caused by CLCN1 mutations can occasionally be clinically indistinguishable from myotonia caused by sodium channel mutations (SCN4A mutations) resulting in the similar disease paramyotonia congenita.
A so-called Finnish heritage disease, congenital myotonia is more common in Finland and among ethnic Finns. A molecular study of the CLCN1 gene in 24 families in northern Finland, including 46 affected individuals, showed that although the inheritance appeared to be dominant (Thomsen type), in fact it is recessive (Becker type).
=== Differential diagnosis ===
Sodium channel myotonias (SCN4A)
Potassium-aggravated myotonia (acetazolamide responsive myotonia)
Paramyotonia congenita
Hyperkalemic periodic paralysis
Dystrophies
Myotonic dystrophy (myotonic muscular dystrophy: Type 1 and Type 2)
Potassium channel disorders (KCNJ2)
Andersen-Tawil syndrome
Other disorders
Thyroid disorders
Neuromyotonia (Isaacs Syndrome)
Schwartz–Jampel syndrome
Stiff person syndrome
Brody myopathy (Brody Disease, Brody's Disease, Brody's Myopathy)
== Treatment ==
Some cases of myotonia congenita do not require treatment, or it is determined that the risks of the medication outweigh the benefits. If necessary, however, symptoms of the disorder may be relieved with quinine, ranolazine, procainamide, flecainide, phenytoin, carbamazepine, mexiletine and other anticonvulsant drugs. Physical therapy and other rehabilitative measures may also be used to help muscle function. Genetic counseling is available.
== Epidemiology ==
In northern Scandinavia, the prevalence of myotonia congenita has been estimated at 1:10,000.
Myotonia congenita is estimated to affect 1 in 100,000 people worldwide.
== Research ==
The name Thomsen's disease refers to the Danish physician Julius Thomsen (1815–1896) who described the condition in himself and his family.
Myotonia can be achieved in preparations of intact isolated muscle by the administration of 9-Anthracenecarboxylic acid, a blocker of chloride channels. It is also possible to achieve myotonia in preparations of intact isolated muscle by greatly lowering or removing the extracellular content of chloride in the bathing medium.
During the 1970s several murine models of myotonia appeared. One in particular has been used widely, the adr mouse or "arrested development of righting response". This model is often used in scientific work with muscular dystrophy, and displays myotonia due to lack of functional chloride channels.
== See also ==
Fainting goat
Tonic immobility
New Forest pony
== References ==
== External links ==
GeneReview/NCBI/NIH/UW entry on myotonia congenita
NINDS: Myotonia congenita Archived 2016-12-15 at the Wayback Machine
National Library of Medicine: Myotonia congenita | Wikipedia/Thomsen_disease |
Gap junction alpha-1 protein (GJA1), also known as connexin 43 (Cx43), is a protein that in humans is encoded by the GJA1 gene on chromosome 6. As a connexin, GJA1 is a component of gap junctions, which allow for gap junction intercellular communication (GJIC) between cells to regulate cell death, proliferation, and differentiation. As a result of its function, GJA1 is implicated in many biological processes, including muscle contraction, embryonic development, inflammation, and spermatogenesis, as well as diseases, including oculodentodigital dysplasia (ODDD), heart malformations, and cancers.
== Structure ==
GJA1 is a 43.0 kDa protein composed of 382 amino acids. GJA1 contains a long C-terminal tail, an N-terminal domain, and multiple transmembrane domains. The protein passes through the phospholipid bilayer four times, leaving its C- and N-terminals exposed to the cytoplasm. The C-terminal tail is composed of 50 amino acids and includes post-translational modification sites, as well as binding sites for transcription factors, cytoskeleton elements, and other proteins. As a result, the C-terminal tail is central to functions such as regulating pH gating and channel assembly. Notably, the DNA region of the GJA1 gene encoding this tail is highly conserved, indicating that it is either resistant to mutations or becomes lethal when mutated. Meanwhile, the N-terminal domain is involved in channel gating and oligomerization and, thus, may control the switch between the channel's open and closed states. The transmembrane domains form the gap junction channel while the extracellular loops facilitate proper channel docking. Moreover, two extracellular loops form disulfide bonds that interact with two hexamers to form a complete gap junction channel.
The connexin-43 internal ribosome entry site is an RNA element present in the 5' UTR of the mRNA of GJA1. This internal ribosome entry site (IRES) allows cap independent translation during conditions such as heat shock and stress.
== Function ==
As a member of the connexin family, GJA1 is a component of gap junctions, which are intercellular channels that connect adjacent cells to permit the exchange of low molecular weight molecules, such as small ions and secondary messengers, to maintain homeostasis.
GJA1 is the most ubiquitously expressed connexin and is detected in most cell types.
It is the major protein in heart gap junctions and is purported to play a crucial role in the synchronized contraction of the heart. Despite its key role in the heart and other vital organs, GJA1 has a short half-life (only two to four hours), indicating that the protein undergoes daily turnover in the heart and may be highly abundant or compensated with other connexins.
GJA1 is also largely involved in embryonic development. For instance, transforming growth factor-beta 1 (TGF-β1) was observed to induce GJA1 expression via the Smad and ERK1/2 signaling pathways, resulting in trophoblast cell differentiation into the placenta.
Furthermore, GJA1 is expressed in many immune cells, such as eosinophils and T cells, where its gap junction function promotes the maturation and activation of these cells and, by extension, the cross-communication necessary to mount an inflammatory response. It has also been shown that uterine macrophage directly physically couple with uterine myocytes through GJA1, transferring Ca²⁺, to promote uterine muscle contraction and excitation during human labor onset.
In addition, GJA1 can be found in the Leydig cells and seminiferous tubules between Sertoli cells and spermatogonia or primary spermatocytes, where it plays a key role in spermatogenesis and testis development through controlling the tight junction proteins in the blood-testis barrier.
While it is a channel protein, GJA1 can also perform channel-independent functions. In the cytoplasm, the protein regulates the microtubule network and, by extension, cell migration and polarity. This function has been observed in brain and heart development, as well as wound-healing in endothelial cells. GJA1 has also been observed to localize to the mitochondria, where it promotes cell survival by downregulating the intrinsic apoptotic pathway during conditions of oxidative stress.
== Clinical significance ==
Mutations in this gene have been associated with ODDD; craniometaphyseal dysplasia; sudden infant death syndrome, which is linked to cardiac arrhythmia; Hallermann–Streiff syndrome; and heart malformations, such as viscero-atrial heterotaxia. There have also been a few cases of reported hearing loss and skin disorders unrelated to ODDD. Ultimately, GJA1 has low tolerance for deviations from its original sequence, with mutations resulting in loss- or gain-of-channel function that lead to disease phenotypes. It is paradoxical, however, that patients with an array of somatic mutations in GJA1 most often do not present with cardiac arrhythmias, even though connexin-43 is the most abundant protein forming gap junctional pores in cardiomyocytes and are essential for normal action potential propagation.
Notably, GJA1 expression has been associated with a wide variety of cancers, including nasopharyngeal carcinoma, meningioma, hemangiopericytoma, liver tumor, colon cancer, esophageal cancer, breast cancer, mesothelioma, glioblastoma, lung cancer, adrenocortical tumors, renal cell cancer, cervical carcinoma, ovarian carcinoma, endometrial carcinoma, prostate cancer, thyroid carcinoma, and testicular cancer. Its role in controlling cell motility and polarity was thought to contribute to cancer development and metastasis, though its role as a gap junction protein may also be involved. Moreover, the cytoprotective effects of this protein can promote tumor cell survival in radiotherapy treatments, while silencing its gene increases radiosensitivity. As a result, GJA1 may serve as a target for improving the success of radiotherapeutic treatment of cancer. As a biomarker, GJA1 could also be used to screen young males for risk of testis cancer.
The thyroid hormone triiodothyronine (T3) downregulates the expression of GJA1. This is assumed to be a key mechanism why the conduction velocity in myocardial tissue is reduced in thyrotoxicosis, thereby promoting cardiac arrhythmia.
Currently, only rotigaptide, an antiarrhythmic peptide-based drug, and its derivatives, such as danegaptide, have reached clinical trials for treating cardiac pathologies by enhancing GJA1 expression. Alternatively, drugs could target complementary connexins, such as Cx40, which function similarly to GJA1. However, both approaches still require a system to target the diseased tissue to avoid inducing developmental abnormalities elsewhere. Thus, a more effective approach entails designing a miRNA through antisense oligonucleotides, transfection, or infection to knock down only mutant GJA1 mRNA, thus allowing the expression of wildtype GJA1 and retaining normal phenotype.
== Interactions ==
Gap junction protein, alpha 1 has been shown to interact with:
Cx37,
Cx40,
Cx45,
MAPK7,
Caveolin 1,
Tight junction protein 1
CSNK1D, and
PTPmu (PTPRM).
== See also ==
Connexin
Hypoplastic left heart syndrome
== References ==
== Further reading ==
== External links ==
Page for Connexin-43 internal ribosome entry site (IRES) at Rfam | Wikipedia/Gap_junction_protein,_alpha_1 |
The New York Heart Association (NYHA) Functional Classification provides a simple way of classifying the extent of heart failure. It places patients in one of four categories based on how much they are limited during physical activity; the limitations/symptoms are in regard to normal breathing and varying degrees in shortness of breath and/or angina.
It originated in 1928, when no measurements of cardiac function were possible, to provide a common language for physicians to communicate. Despite difficulties in applying it, such as the challenge of consistently classifying patients in class II or III, because functional capacity is such a powerful determinant of outcome, it remains arguably the most important prognostic marker in routine clinical use in heart failure today. With time the classification system evolved and updated multiple times. Presently, the ninth edition of the NYHA classification is being used in the clinical practice released in the year 1994 by the Criteria Committee of the American Heart Association, New York City Affiliate.
Another frequently used functional classification of cardiovascular disease is the Canadian Cardiovascular Society grading of angina pectoris.
== See also ==
Canadian Cardiovascular Society grading of angina pectoris
European Heart Rhythm Association score of atrial fibrillation
== References == | Wikipedia/New_York_Heart_Association_Functional_Classification |
Fetal echocardiography, or Fetal echocardiogram, is the name of the test used to diagnose cardiac conditions in the fetal stage. Cardiac defects are amongst the most common birth defects.
Their diagnosis is important in the fetal stage as it might help provide an opportunity to plan and manage the baby as and when the baby is born.
Not all pregnancies need to undergo fetal echo.
== Patient criteria ==
Specific maternal and fetal conditions would indicate the need for this test. these conditions are as listed below:
Maternal:
Diabetes
Anticonvulsant intake
Prev child with CHD
Infections: Parvovirus, Rubella, Coxsackie
AutoImmune Disease: Anti Rho/La positive
Fetal:
Increased Nuchal thickness
Abnormal ductus venosus
Abnormal fetal cardiac screening
Major extracardiac abnormality
Abnormal Fetal karyotype
Hydrops
Fetal dysrthythhmia
Fetal Echo is usually performed by a Pediatric Cardiologist but may also be performed by a Sonologist.
To date, no detrimental effects in humans have been demonstrated.
The performance of a fetal echocardiogram requires experience and a systematic approach. Guidelines for training have been formulated, and only qualified individuals should perform this highly specialized examination. A brief description of the examination is presented here for interest only. The first step is to determine the position and orientation of the fetus within the uterus. Within the thorax, the heart, because of its motion, is usually the easiest and most recognizable structure to examine.
The four-chamber view is most important and should be recorded first. For orientation, the left atrium is identified by the presence of the septum primum and the pulmonary veins. Cardiac situs can be determined by identifying the systemic veins and the position of the atria relative to the liver and spleen. Next, the atrioventricular valves are identified, with the tricuspid valve slightly more apical than the mitral valve. The outlet portions of the heart are then evaluated. Cardiac measurements can be made and compared with normal values that have been defined for all gestational ages.
Doppler techniques can be used to visualize blood flow through the heart, great vessels, and umbilical vessels. Assessment of fetal arrhythmias is best accomplished by using a combination of M-mode and Doppler recordings. When these arrhythmias are present, a careful search for structural heart disease is mandatory. With this approach, a wealth of diagnostic information is available. Knowledge of complex congenital heart disease before delivery allows therapeutic interventions to begin immediately after birth and can be life saving for such patients. In both of these examples, knowledge about the presence and severity of congenital cardiac defects facilitated management of labor and delivery and allowed perinatal care to be optimized.
The critical role of echocardiography in prenatal diagnosis is evident, and both the accuracy and safety of the test are now well established. The structures in these images are small, however, and random movements of the fetus make for a challenging and time-consuming examination. Despite these factors, fetal echocardiography has provided clinicians with earlier diagnosis of heart disease and a better understanding of fetal hemodynamics.
Today, a dedicated fetal echocardiogram can detect nearly 100% of serious congenital heart disease. Yet most pregnant women do not have a fetal echocardiogram but rather undergo a general obstetric ultrasound that may detect only around a third of fetal heart disease. To improve detection, some propose universal fetal echocardiography. But others cite cost and lack of specialized personnel as barriers that prevent echocardiography for every fetus.
Fetal Echocardiogram is done in select patients. The best way to improve pickup in majority if the patients is by training sonologists to perform a more thorough evaluation. It has been traditionally taught that a four chamber visualisation is enough but current experiences suggest that may not be enough. A better evaluation would include a 4 chamber, a 5 chamber and a 3 vessel evaluation(3).
== References ==
Carvalho JS (Apr 2001). "Early prenatal diagnosis of major congenital heart defects". Curr Opin Obstet Gynecol. 13 (2): 155–9. doi:10.1097/00001703-200104000-00010. PMID 11315870. S2CID 29109972.
Davey BT, Seubert DE, Phoon CK (Jun 2009). "Indications for fetal echocardiography high referral, low yield?". Obstet Gynecol Surv. 64 (6): 405–15. doi:10.1097/OGX.0b013e31819f9d7b. PMID 19445814. S2CID 33615449.{{cite journal}}: CS1 maint: multiple names: authors list (link)
Fetal Echocardiography Task Force; American Institute of Ultrasound in Medicine Clinical Standards Committee; American College of Obstetricians Gynecologists; Society for Maternal-Fetal Medicine (Jan 2011). "AIUM practice guideline for the performance of fetal echocardiography". J. Ultrasound Med. 30 (1): 127–36. doi:10.7863/jum.2011.30.1.127. PMID 21193716.
Lee W, Allan L, Carvalho JS; et al. (August 2008). "ISUOG consensus statement: what constitutes a fetal echocardiogram?". Ultrasound Obstet Gynecol. 32 (2): 239–42. doi:10.1002/uog.6115. PMID 18663769.{{cite journal}}: CS1 maint: multiple names: authors list (link) | Wikipedia/Fetal_echocardiography |
Strain rate imaging is a method in echocardiography (medical ultrasound) for measuring regional or global deformation of the myocardium (heart muscle). The term "deformation" refers to the myocardium changing shape and dimensions during the cardiac cycle. If there is myocardial ischemia, or there has been a myocardial infarction, in part of the heart muscle, this part is weakened and shows reduced and altered systolic function. Also in regional asynchrony, as in bundle branch block, there is regional heterogeneity of systolic function. By strain rate imaging, the simultaneous function of different regions can be displayed and measured. The method was first based on colour tissue Doppler. by using the longitudinal myocardial velocity gradient, already in use transmurally. Later, the regional deformation has also been available by speckle tracking echocardiography, both methods having some, but different methodological weaknesses. Both methods, however, will acquire the same data (measurements may differ somewhat, however, being method dependent), and also can be displayed by the same type of display.
The point of deformation imaging, is that a passive segment in the myocardium for instance after an infarct, may move due to the action of an adjacent segment (tethering). Thus the displacement or velocity of a segment do not tell about the function of that segment. Deformation imaging, on the other hand, measures the differences of motion and velocity within the segment, which is equivalent to the deformation.
== Basic concepts ==
Strain means Deformation, and is defined as relative change in length. The Lagrangian formula εL = (L-L0)/L0 = ΔL/L0, where L0 is baseline length and L is the resulting length, defines strain in relation to the original length as a dimensionless measure, where shortening will be negative, and lengthening will be positive. It is usually expressed in percent. An alternative definition, Eulerian strain defines the strain in relation to the instantaneous length: εE = ΔL/L. For a change over time, the Lagrangian strain will be: εL = Σ ΔL/L0, and Eulerian Strain εE = Σ (ΔL/L). The term was first used by Mirsky and Parmley in describing regional differences in deformation between normal and ischemic myocardium
Strain rate is the rate of deformation. In ultrasound it is usually measured from the velocity gradient SR = (v2 - v1)/L where v2and v1 are the myocardial velocities at two different points, and L is the instantaneous distance between them. This is thus equivalent to the velocity difference per length unit (the spatial derivative of velocity) and has the unit s−1. Strain is then integrated from strain rate. This method, however, yields the Eulerian strain rate and strain. It has become traditional to use the Velocity gradient, but in integrating strain rate it is converted to Lagrangian strain by the formula εL = eεE - 1.
Strain in three dimensions: Basically, any object or body is three dimensional, and can be deformed in different directions simultaneously. Strain can be described as a tensor with three principal strains (εx, εy and εz in a Cartesian coordinate system), and six shear strains components. In the heart, it has been customary to describe the three principal strain components as longitudinal (in the direction of the long axis of the ventricles), circumferential (in the direction of the ventricular circumference), and transmural (the deformation across the wall. Transmural deformation has also been called "radial", but this is unfortunate as in ultrasound in general the term radial describes "in the direction of the ultrasound beam"). However, as the heart muscle is incompressible, the three principal strain must balance; ((εx+1)(εy+1)(εz+1) = 1). As the ventricle contracts in systole, there is longitudinal shortening (negative strain), circumferential shortening (negative strain) and transmural (wall) thickening (positive strain). Due to this, and the fact that the left ventricle in normal conditions contract with a relatively invariant outer contour, the longitudinal strain contains the main information, while transmural strain (wall thickening) is a function of wall shortening, wall thickness and chamber diameter, while circumferential shortening is mainly a function of wall thickening. It has been shown clinically that longitudinal strain rate and wall thickening are diagnostically equivalent.
== Methods ==
Strain rate imaging can be done by two principally different methods.
=== Tissue Doppler ===
The Tissue Doppler method is based on the colour Doppler, giving a velocity field with velocity vectors along the ultrasound beam over the whole sector. It measures the velocity gradient between two points along the ultrasound beam with a set distance. It gives the same result as the velocity gradient. This method has been validated experimentally in a mechanical model, in an animal model, and in patients against echocardiography, coronary angiography and MR
The method is limited to one direction; along the ultrasound beam, can thus mainly be used from the apical window, and for longitudinal strain and strain rate measurements only. It is sensitive to angle deviation between the velocity vector (direction of motion) and the ultrasound beam, and is sensitive to noise, especially clutter noise. It has a high temporal resolution, at the cost of a relatively low lateral spatial resolution.
=== Speckle tracking ===
Speckle tracking echocardiography is based on grey scale echocardiography (B-mode), and the fact that the reflected echo from the myocardium shows a speckle pattern that is a mixture of small scatters and interference patterns. The pattern being random, each region of the myocardium (called a "kernel"), has a unique speckle pattern, and that this speckle pattern is relatively stable, at least from one frame to next. By this, the movement of a kernel from one frame to the next, can be tracked by a "best match" search algorithm. The most commonly used is the "sum of absolute differences", shown to be similarly accurate as Cross-correlation. The method thus tracks a kernels motion from one frame to the next. From the frame rate, the velocity vector can be calculated, both in magnitude and direction. From this, a velocity field again can be generated over the whole sector, as with tissue Doppler, and strain rate can be derived, and then strain can be integrated. Alternatively strain can be measured directly from the change in distance between speckles. (resulting in Lagrangian strain directly), and strain rate derived temporally (it then has to be converted to Eulerian strain rate). The speckle tracking methods varies with non-commercial and commercial systems. Speckle tracking has been shown to be comparable to tissue Doppler derived strain, and has been validated against MR
The method tracks independently of the beam directions, and can thus track in two dimensions. It is also said to be independent of the angle error inherent in the Doppler algorithm. However, as the radial resolution (along the beam) is far better than the lateral resolution which also decreases with depth, both the angle independence and the tracking ability across the sector is lower. Also, instead of angle independency, the resulting strain values are dependent on the ROI (Region Of Interest) size and shape. Finally, in order to achieve tracking quality, the values are in most commercial applications smoothed by a spline smoothing function along the ROI, so the regional measurements are not pure regional, but rather to a degree, spline functions of the global average. In addition, the method has a lower sampling rate due to the limited frame rate of B-mode, which reduces tracking validity, especially at high heart rates.
== Display ==
Both methods measures the same physiological phenomena (deformation), and results can in principle be displayed the same way.
=== Curves ===
The most common way is by displaying curves of the strain and strain rate, typically the time course during one heart cycle. Each curve will then represent the deformation in one region of the myocardium, but acquisition of a full sector allows display of multiple curves simultaneously in the same image for comparison.
=== Colour display ===
Strain and strain rate values can be reduced to colour coded images, where strain or strain rate are shown as colours in semi-quantitative parametric imaging. This makes the method more robust, but numerical values are not available. On the other hand, this may result in a better spatial resolution. The displays most commonly used, are Bull's eye (reconstructed from multiple apical planes), which displays all parts of the left ventricle simultaneously, but only at one point in time. This is useful for either mid systolic strain rate or end systolic strain. Inhomogeneous strain rate or strain, representing regions with reduced contractility are often very evident visually.
Curved anatomical M-mode from either one wall, or both walls simultaneously, gives a space-time diagram of the deformation, showing both spatial or temporal inhomogeneities in deformation. It is most useful when applied to strain rate, due to the rapid shifts in phase visible as seen by the figure. The strain rate values are reduced to semi quantitative visual display, but this mode allows measurement of timing, as well as depth, and is best suited to space-time relation measurement
== Clinical use ==
It is a major point that strain rate imaging is just a part of an integrated echocardiographic examination. Like all other measures, deformation measurements have limited accuracy, and should be considered together with the rest of findings. Also, a knowledge of the pitfalls and artefacts of the specific methods, is an advantage. However, the methods offer unique ways of imaging regional dysfunction, that may strengthen the conclusion.
=== Regional function ===
Normal values for strain and strain rate has been established by the HUNT study.
==== Myocardial infarction ====
In myocardial infarction, a limited region of the heart muscle has reduced or totally absent function. It has been shown to be at least as accurate as B-mode echocardiography. Deformation imaging has also been shown to be useful in following recovery of an infarcted myocardial area, to ascertain the amount of Myocardial stunning vs. necrosis.
==== Myocardial ischemia ====
In stress echocardiography (see Cardiac stress test), the regional dysfunction due to ischemia will become evident when the myocardial oxygen demand surpasses the Coronary flow reserve of a stenosed coronary artery. Strain rate imaging during stress has been shown to give incremental value over ordinary echocardiography, both diagnostic and prognostic. In stress echo, the increased heart rate has speckle tracking at a disadvantage, due to the limited frame rate that affects tracking at higher heart rates.
==== Ventricular dyssynchrony ====
In Left bundle branch block (LBBB), the asynchronous activation of the left ventricle gives asynchronous contraction as well. This asynchrony can be visualised by ordinary echocardiography. It can also be demonstrated by tissue velocities, but strain rate imaging will in addition demonstrate the distribution of the asynchrony, and the demonstration of the amount of inefficient work done by the asynchronous ventricle. Disappointingly, large scale studies have not been able to establish additional echo criteria for selection of Heart failure patients with LBBB who may respond to Cardiac resynchronization therapy, although smaller studies are promising
=== Global function ===
In later years, Global strain by speckle tracking has achieved popularity as the global functional measure. It has an advantage over Ejection fraction (EF), it shows reduced cardiac function also in hypertrophic hearts with small ventricles and normal ejection fraction (HFNEF), which is often seen in Hypertensive heart disease, Hypertrophic cardiomyopathy and Aortic stenosis. The EF is not a pure functional measure, as it is also dependent on wall thickness It has also been shown to be more sensitive than EF. However, the incremental diagnostic and prognostic value of measuring LV shortening was already shown for the absolute measure
Global strain is basically LV shortening/LV end diastolic length, which means that this is a normalisation of LV shortening for LV heart size. It remains to be proven that this actually confers additional information.
== References ==
== Further reading ==
Sutherland; Hatle; Claus; D'hooge;Bijnens (2006) Doppler Myocardial Imaging. BSWK, Belgium. ISBN 978-90-810592-1-3
Marwick; Yu; Sun (2007) Myocardial Imaging: Tissue Doppler and Speckle Tracking. Wiley-Blackwell. ISBN 978-1-4051-6113-8 | Wikipedia/Strain_rate_imaging |
Coronary artery disease (CAD), also called coronary heart disease (CHD), or ischemic heart disease (IHD), is a type of heart disease involving the reduction of blood flow to the cardiac muscle due to a build-up of atheromatous plaque in the arteries of the heart. It is the most common of the cardiovascular diseases. CAD can cause stable angina, unstable angina, myocardial ischemia, and myocardial infarction.
A common symptom is angina, which is chest pain or discomfort that may travel into the shoulder, arm, back, neck, or jaw. Occasionally it may feel like heartburn. In stable angina, symptoms occur with exercise or emotional stress, last less than a few minutes, and improve with rest. Shortness of breath may also occur and sometimes no symptoms are present. In many cases, the first sign is a heart attack. Other complications include heart failure or an abnormal heartbeat.
Risk factors include high blood pressure, smoking, diabetes mellitus, lack of exercise, obesity, high blood cholesterol, poor diet, depression, and excessive alcohol consumption. A number of tests may help with diagnosis including electrocardiogram, cardiac stress testing, coronary computed tomographic angiography, biomarkers (high-sensitivity cardiac troponins) and coronary angiogram, among others.
Ways to reduce CAD risk include eating a healthy diet, regularly exercising, maintaining a healthy weight, and not smoking. Medications for diabetes, high cholesterol, or high blood pressure are sometimes 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 improves life expectancy or decreases heart attack risk.
In 2015, CAD affected 110 million people and resulted in 8.9 million deaths. It makes up 15.6% of all deaths, making it the most common cause of death globally. The risk of death from CAD for a given age decreased between 1980 and 2010, especially in developed countries. The number of cases of CAD for a given age also decreased between 1990 and 2010. In the United States 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 were higher among males than females of a given age.
== Signs and symptoms ==
The most common symptom is chest pain or discomfort that occurs regularly with activity, after eating, or at other predictable times; this phenomenon is termed stable angina and is associated with narrowing of the arteries of the heart. Angina also includes chest tightness, heaviness, pressure, numbness, fullness, or squeezing. Angina that changes in intensity, character, or frequency is termed unstable. Unstable angina may precede myocardial infarction. In adults who go to the emergency department with an unclear cause of pain, about 30% have pain due to coronary artery disease. Angina, shortness of breath, sweating, nausea or vomiting, and lightheadedness are signs of a heart attack or myocardial infarction, and immediate emergency medical services are crucial.
With advanced disease, the narrowing of coronary arteries reduces the supply of oxygen-rich blood flowing to the heart, which becomes more pronounced during strenuous activities during which the heart beats faster and has an increased oxygen demand. For some, this causes severe symptoms, while others experience no symptoms at all.
=== Symptoms in females ===
Symptoms in females can differ from those in males, and the most common symptom reported by females of all races is shortness of breath. Other symptoms more commonly reported by females than males are extreme fatigue, sleep disturbances, indigestion, and anxiety. However, some females experience irregular heartbeat, dizziness, sweating, and nausea. Burning, pain, or pressure in the chest or upper abdomen that can travel to the arm or jaw can also be experienced in females, but females less commonly report it than males. Generally, females experience symptoms 10 years later than males. Females are less likely to recognize symptoms and seek treatment.
== Risk factors ==
Coronary artery disease is characterized by heart problems that result from atherosclerosis. Atherosclerosis is a type of arteriosclerosis which is the "chronic inflammation of the arteries which causes them to harden and accumulate cholesterol plaques (atheromatous plaques) on the artery walls". CAD has several well-determined risk factors contributing to atherosclerosis. These risk factors for CAD include "smoking, diabetes, high blood pressure (hypertension), abnormal (high) amounts of cholesterol and other fat in the blood (dyslipidemia), type 2 diabetes and being overweight or obese (having excess body fat)" due to lack of exercise and a poor diet. Some other risk factors include high blood pressure, smoking, diabetes, lack of exercise, obesity, high blood cholesterol, poor diet, depression, family history, psychological stress and excessive alcohol. About half of cases are linked to genetics. Apart from these classical risk factors, several unconventional risk factors have also been studied including high serum fibrinogen, high c-reactive protein (CRP), chronic inflammatory conditions, hypovitaminosis D, high lipoprotein A levels, serum homocysteine etc. Smoking and obesity are associated with about 36% and 20% of cases, respectively. Smoking just one cigarette per day about doubles the risk of CAD. Lack of exercise has been linked to 7–12% of cases. Exposure to the herbicide Agent Orange may increase risk. Rheumatologic diseases such as rheumatoid arthritis, systemic lupus erythematosus, psoriasis, and psoriatic arthritis are independent risk factors as well.
Job stress appears to play a minor role accounting for about 3% of cases. In one study, females who were free of stress from work life saw an increase in the diameter of their blood vessels, leading to decreased progression of atherosclerosis. In contrast, females who had high levels of work-related stress experienced a decrease in the diameter of their blood vessels and significantly increased disease progression.
=== Air pollution ===
Air pollution, both indoor and outdoor, is responsible for roughly 28% of deaths from CAD. This varies by region: In highly developed areas, this is approximately 10%, whereas in Southern, East and West Africa, and South Asia, approximately 40% of deaths from CAD can be attributed to unhealthy air. In particular, fine particle pollution (PM2.5), which comes mostly from the burning of fossil fuels, is a key risk factor for CAD.
=== Blood fats ===
The consumption of different types of fats including trans fat (trans unsaturated), and saturated fat, in a diet "influences the level of cholesterol that is present in the bloodstream". Unsaturated fats originate from plant sources (such as oils). There are two types of unsaturated fats, cis and trans isomers. Cis unsaturated fats are bent in molecular structure and trans are linear. Saturated fats originate from animal sources (such as animal fats) and are also molecularly linear in structure. The linear configurations of unsaturated trans and saturated fats allow them to easily accumulate and stack at the arterial walls when consumed in high amounts (and other positive measures towards physical health are not met).
Fats and cholesterol are insoluble in blood and thus are amalgamated with proteins to form lipoproteins for transport. Low-density lipoproteins (LDL) transport cholesterol from the liver to the rest of the body and raise blood cholesterol levels. The consumption of "saturated fats increases LDL levels within the body, thus raising blood cholesterol levels".
High-density lipoproteins (HDL) are considered 'good' lipoproteins as they search for excess cholesterol in the body and transport it back to the liver for disposal. Trans fats also "increase LDL levels whilst decreasing HDL levels within the body, significantly raising blood cholesterol levels".
High levels of cholesterol in the bloodstream lead to atherosclerosis. With increased levels of LDL in the bloodstream, "LDL particles will form deposits and accumulate within the arterial walls, which will lead to the development of plaques, restricting blood flow". The resultant reduction in the heart's blood supply due to atherosclerosis in coronary arteries "causes shortness of breath, angina pectoris (chest pains that are usually relieved by rest), and potentially fatal heart attacks (myocardial infarctions)".
=== Genetics ===
The heritability of coronary artery disease has been estimated between 40% and 60%. Genome-wide association studies have identified over 160 genetic susceptibility loci for coronary artery disease.
=== Transcriptome ===
Several RNA Transcripts associated with CAD - FoxP1, ICOSLG, IKZF4/Eos, SMYD3, TRIM28, and TCF3/E2A are likely markers of regulatory T cells (Tregs), consistent with known reductions in Tregs in CAD.
The RNA changes are mostly related to ciliary and endocytic transcripts, which in the circulating immune system would be related to the immune synapse. One of the most differentially expressed genes, fibromodulin (FMOD), which is increased 2.8-fold in CAD, is found mainly in connective tissue and is a modulator of the TGF-beta signaling pathway. However, not all RNA changes may be related to the immune synapse. For example, Nebulette, the most down-regulated transcript (2.4-fold), is found in cardiac muscle; it is a 'cytolinker' that connects actin and desmin to facilitate cytoskeletal function and vesicular movement. The endocytic pathway is further modulated by changes in tubulin, a key microtubule protein, and fidgetin, a tubulin-severing enzyme that is a marker for cardiovascular risk identified by genome-wide association study. Protein recycling would be modulated by changes in the proteasomal regulator SIAH3, and the ubiquitin ligase MARCHF10. On the ciliary aspect of the immune synapse, several of the modulated transcripts are related to ciliary length and function. Stereocilin is a partner to mesothelin, a related super-helical protein, whose transcript is also modulated in CAD. DCDC2, a double-cortin protein, modulates ciliary length. In the signaling pathways of the immune synapse, numerous transcripts are directly related to T-cell function and the control of differentiation. Butyrophilin is a co-regulator for T cell activation. Fibromodulin modulates the TGF-beta signaling pathway, a primary determinant of Tre differentiation. Further impact on the TGF-beta pathway is reflected in concurrent changes in the BMP receptor 1B RNA (BMPR1B), because the bone morphogenic proteins are members of the TGF-beta superfamily, and likewise impact Treg differentiation. Several of the transcripts (TMEM98, NRCAM, SFRP5, SHISA2) are elements of the Wnt signaling pathway, which is a major determinant of Treg differentiation.
=== Other ===
Endometriosis in females under the age of 40.
Depression and hostility appear to be risks.
The number of categories of adverse childhood experiences (psychological, physical, or sexual abuse; violence against mother; or living with household members who used substances, mentally ill, suicidal, or incarcerated) showed a graded correlation with the presence of adult diseases including coronary artery (ischemic heart) disease.
Hemostatic factors: High levels of fibrinogen and coagulation factor VII are associated with an increased risk of CAD.
Low hemoglobin.
In the Asian population, the b fibrinogen gene G-455A polymorphism was associated with the risk of CAD.
Patient-specific vessel ageing or remodelling determines endothelial cell behaviour and thus disease growth and progression. Such 'hemodynamic markers' are patient-specific risk surrogates.
HIV is a known risk factor for developing atherosclerosis and coronary artery disease.
== Pathophysiology ==
Limitation of blood flow to the heart causes ischemia (cell starvation secondary to a lack of oxygen) of the heart's muscle cells. The heart's muscle cells may die from lack of oxygen and this is called a myocardial infarction (commonly referred to as a heart attack). It leads to damage, death, and eventual scarring of the heart muscle without regrowth of heart muscle cells. Chronic high-grade narrowing of the coronary arteries can induce transient ischemia which leads to the induction of a ventricular arrhythmia, which may terminate into a dangerous heart rhythm known as ventricular fibrillation, which often leads to death.
Typically, coronary artery disease occurs when part of the smooth, elastic lining inside a coronary artery (the arteries that supply blood to the heart muscle) develops atherosclerosis. With atherosclerosis, the artery's lining becomes hardened, stiffened, and accumulates deposits of calcium, fatty lipids, and abnormal inflammatory cells – to form a plaque. Calcium phosphate (hydroxyapatite) deposits in the muscular layer of the blood vessels appear to play a significant role in stiffening the arteries and inducing the early phase of coronary arteriosclerosis. This can be seen in a so-called metastatic mechanism of calciphylaxis as it occurs in chronic kidney disease and hemodialysis. Although these people have kidney dysfunction, almost fifty percent of them die due to coronary artery disease. Plaques can be thought of as large "pimples" that protrude into the channel of an artery, causing partial obstruction to blood flow. People with coronary artery disease might have just one or two plaques or might have dozens distributed throughout their coronary arteries. A more severe form is chronic total occlusion (CTO) when a coronary artery is completely obstructed for more than 3 months.
Microvascular angina is a type of angina pectoris in which chest pain and chest discomfort occur without signs of blockages in the larger coronary arteries of their hearts when an angiogram (coronary angiogram) is being performed.
The exact cause of microvascular angina is unknown. Explanations include microvascular dysfunction or epicardial atherosclerosis. For reasons that are not well understood, females are more likely than males to have it; however, hormones and other risk factors unique to females may play a role.
== Diagnosis ==
The diagnosis of CAD depends largely on the nature of the symptoms and imaging. The first investigation when CAD is suspected is an electrocardiogram (ECG/EKG), both for stable angina and acute coronary syndrome. An X-ray of the chest, blood tests and resting echocardiography may be performed.
For stable symptomatic patients, several non-invasive tests can diagnose CAD depending on pre-assessment of the risk profile. Noninvasive imaging options include; Computed tomography angiography (CTA) (anatomical imaging, best test in patients with low-risk profile to "rule out" the disease), positron emission tomography (PET), single-photon emission computed tomography (SPECT)/nuclear stress test/myocardial scintigraphy and stress echocardiography (the three latter can be summarized as functional noninvasive methods and are typically better to "rule in"). Exercise ECG or stress test is inferior to non-invasive imaging methods due to the risk of false negative and false positive test results. The use of non-invasive imaging is not recommended on individuals who are exhibiting no symptoms and are otherwise at low risk for developing coronary disease. Invasive testing with coronary angiography (ICA) can be used when non-invasive testing is inconclusive or show a high event risk.
The diagnosis of microvascular angina (previously known as cardiac syndrome X – the rare coronary artery disease that is more common in females, as mentioned, is a diagnosis of exclusion. Therefore, usually, the same tests are used as in any person suspected of having coronary artery disease:
Intravascular ultrasound
Magnetic resonance imaging (MRI)
=== Stable angina ===
Stable angina is the most common manifestation of ischemic heart disease, and is associated with reduced quality of life and increased mortality. It is caused by epicardial coronary stenosis which results in reduced blood flow and oxygen supply to the myocardium.
Stable angina is short-term chest pain during physical exertion caused by an imbalance between myocardial oxygen supply and metabolic oxygen demand. Various forms of cardiac stress tests may be used to induce both symptoms and detect changes by way of electrocardiography (using an ECG), echocardiography (using ultrasound of the heart) or scintigraphy (using uptake of radionuclide by the heart muscle). If part of the heart seems to receive an insufficient blood supply, coronary angiography may be used to identify stenosis of the coronary arteries and suitability for angioplasty or bypass surgery.
In minor to moderate cases, nitroglycerine may be used to alleviate acute symptoms of stable angina or may be used immediately before exertion to prevent the onset of angina. Sublingual nitroglycerine is most commonly used to provide rapid relief for acute angina attacks and as a complement to anti-anginal treatments in patients with refractory and recurrent angina. When nitroglycerine enters the bloodstream, it forms free radical nitric oxide, or NO, which activates guanylate cyclase and in turn stimulates the release of cyclic GMP. This molecular signaling stimulates smooth muscle relaxation, resulting in vasodilation and consequently improved blood flow to heart regions affected by atherosclerotic plaque.
Stable coronary artery disease (SCAD) is also often called stable ischemic heart disease (SIHD). A 2015 monograph explains that "Regardless of the nomenclature, stable angina is the chief manifestation of SIHD or SCAD." There are U.S. and European clinical practice guidelines for SIHD/SCAD. 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).
=== Acute coronary syndrome ===
Diagnosis of acute coronary syndrome generally takes place in the emergency department, where ECGs may be performed sequentially to identify "evolving changes" (indicating ongoing damage to the heart muscle). Diagnosis is clear-cut if ECGs show elevation of the "ST segment", which in the context of severe typical chest pain is strongly indicative of an acute myocardial infarction (MI); this is termed a STEMI (ST-elevation MI) and is treated as an emergency with either urgent coronary angiography and percutaneous coronary intervention (angioplasty with or without stent insertion) or with thrombolysis ("clot buster" medication), whichever is available. In the absence of ST-segment elevation, heart damage is detected by cardiac markers (blood tests that identify heart muscle damage). If there is evidence of damage (infarction), the chest pain is attributed to a "non-ST elevation MI" (NSTEMI). If there is no evidence of damage, the term "unstable angina" is used. This process usually necessitates hospital admission and close observation on a coronary care unit for possible complications (such as cardiac arrhythmias – irregularities in the heart rate). Depending on the risk assessment, stress testing or angiography may be used to identify and treat coronary artery disease in patients who have had an NSTEMI or unstable angina.
=== Risk assessment ===
There are various risk assessment systems for determining the risk of coronary artery disease, with various emphasis on the different variables above. A notable example is Framingham Score, used in the Framingham Heart Study. It is mainly based on age, gender, diabetes, total cholesterol, HDL cholesterol, tobacco smoking, and systolic blood pressure. When predicting risk in younger adults (18–39 years old), the Framingham Risk Score remains below 10–12% for all deciles of baseline-predicted risk.
Polygenic score is another way of risk assessment. In one study the relative risk of incident coronary events was 91% higher among participants at high genetic risk than among those at low genetic risk.
== Prevention ==
Up to 90% of cardiovascular disease may be preventable if established risk factors are avoided. Prevention involves adequate physical exercise, decreasing obesity, treating high blood pressure, eating a healthy diet, decreasing cholesterol levels, and stopping smoking. Medications and exercise are roughly equally effective. High levels of physical activity reduce the risk of coronary artery disease by about 25%. Life's Essential 8 are the key measures for improving and maintaining cardiovascular health, as defined by the American Heart Association. AHA added sleep as a factor influencing heart health in 2022.
Most guidelines recommend combining these preventive strategies. A 2015 Cochrane Review found some evidence that counseling and education to bring about behavioral change might help in high-risk groups. However, there was insufficient evidence to show an effect on mortality or actual cardiovascular events.
In diabetes mellitus, there is little evidence that very tight blood sugar control improves cardiac risk although improved sugar control appears to decrease other problems such as kidney failure and blindness.
A 2024 study published in The Lancet Diabetes & Endocrinology found that the oral glucose tolerance test (OGTT) is more effective than hemoglobin A1c (HbA1c) for detecting dysglycemia in patients with coronary artery disease. The study highlighted that 2-hour post-load glucose levels of at least 9 mmol/L were strong predictors of cardiovascular outcomes, while HbA1c levels of at least 5.9% were also significant but not independently associated when combined with OGTT results.
=== Diet ===
A diet high in fruits and vegetables decreases the risk of cardiovascular disease and death. Vegetarians have a lower risk of heart disease, possibly due to their greater consumption of fruits and vegetables. Evidence also suggests that the Mediterranean diet and a high fiber diet lower the risk.
The consumption of trans fat (commonly found in hydrogenated products such as margarine) has been shown to cause a precursor to atherosclerosis and increase the risk of coronary artery disease.
Evidence does not support a beneficial role for omega-3 fatty acid supplementation in preventing cardiovascular disease (including myocardial infarction and sudden cardiac death).
=== Secondary prevention ===
Secondary prevention is preventing further sequelae of already established disease. Effective lifestyle changes include:
Weight control
Smoking cessation
Avoiding the consumption of trans fats (in partially hydrogenated oils)
Decreasing psychosocial stress
Exercise
Aerobic exercise, like walking, jogging, or swimming, can reduce the risk of mortality from coronary artery disease. Aerobic exercise can help decrease blood pressure and the amount of blood cholesterol (LDL) over time. It also increases HDL cholesterol.
Although exercise is beneficial, it is unclear whether doctors should spend time counseling patients to exercise. The U.S. Preventive Services Task Force found "insufficient evidence" to recommend that doctors counsel patients on exercise but "it did not review the evidence for the effectiveness of physical activity to reduce chronic disease, morbidity, and mortality", only the effectiveness of counseling itself. The American Heart Association, based on a non-systematic review, recommends that doctors counsel patients on exercise.
Psychological symptoms are common in people with CHD. Many psychological treatments may be offered following cardiac events. There is no evidence that they change mortality, the risk of revascularization procedures, or the rate of non-fatal myocardial infarction.
Antibiotics for secondary prevention of coronary heart disease
Early studies suggested that antibiotics might help patients with coronary disease to reduce the risk of heart attacks and strokes. However, a 2021 Cochrane meta-analysis found that antibiotics given for secondary prevention of coronary heart disease are harmful to people with increased mortality and occurrence of stroke. So, antibiotic use is not currently supported for preventing secondary coronary heart disease.
=== Neuropsychological assessment ===
A thorough systematic review found that indeed there is a link between a CHD condition and brain dysfunction in females. Consequently, since research is showing that cardiovascular diseases, like CHD, can play a role as a precursor for dementia, like Alzheimer's disease, individuals with CHD should have a neuropsychological assessment.
== Treatment ==
There are a number of treatment options for coronary artery disease:
Lifestyle changes
Medical treatment – commonly prescribed drugs (e.g., cholesterol lowering medications, beta-blockers, nitroglycerin, calcium channel blockers, etc.);
Coronary interventions as angioplasty and coronary stent;
Coronary artery bypass grafting (CABG)
=== Medications ===
Statins, which reduce cholesterol, reduce the risk of coronary artery disease
Nitroglycerin
Calcium channel blockers and/or beta-blockers
Antiplatelet drugs such as aspirin
It is recommended that blood pressure typically be reduced to less than 140/90 mmHg. The diastolic blood pressure should not be below 60 mmHg. Beta-blockers are recommended first line for this use.
==== Aspirin ====
In those with no previous history of heart disease, aspirin decreases the risk of a myocardial infarction but does not change the overall risk of death. Aspirin therapy to prevent heart disease is thus recommended only in adults who are at increased risk for cardiovascular events, which may include postmenopausal females, males above 40, and younger people with risk factors for coronary heart disease, including high blood pressure, a family history of heart disease, or diabetes. The benefits outweigh the harms most favorably in people at high risk for a cardiovascular event, where high risk is defined as at least a 3% chance over five years, but others with lower risk may still find the potential benefits worth the associated risks.
==== Anti-platelet therapy ====
Clopidogrel plus aspirin (dual anti-platelet therapy) reduces cardiovascular events more than aspirin alone in those with a STEMI. In others at high risk but not having an acute event, the evidence is weak. Specifically, its use does not change the risk of death in this group. In those who have had a stent, more than 12 months of clopidogrel plus aspirin does not affect the risk of death.
=== Surgery ===
Revascularization for acute coronary syndrome has a mortality benefit. Percutaneous revascularization for stable ischaemic heart disease does not appear to have benefits over medical therapy alone. In those with disease in more than one artery, coronary artery bypass grafts appear better than percutaneous coronary interventions. Newer "anaortic" or no-touch off-pump coronary artery revascularization techniques have shown reduced postoperative stroke rates comparable to percutaneous coronary intervention. Hybrid coronary revascularization has also been shown to be a safe and feasible procedure that may offer some advantages over conventional CABG though it is more expensive.
== Epidemiology ==
As of 2010, CAD was the leading cause of death globally resulting in over 7 million deaths. This increased from 5.2 million deaths from CAD worldwide in 1990. It may affect individuals at any age but becomes dramatically more common at progressively older ages, with approximately a tripling with each decade of life. Males are affected more often than females.
The World Health Organization reported that: "The world's biggest killer is ischemic heart disease, responsible for 13% of the world's total deaths. Since 2000, the largest increase in deaths has been for this disease, rising by 2.7 million to 9.1 million deaths in 2021."
It is estimated that 60% of the world's cardiovascular disease burden will occur in the South Asian subcontinent despite only accounting for 20% of the world's population. This may be secondary to a combination of genetic predisposition and environmental factors. Organizations such as the Indian Heart Association are working with the World Heart Federation to raise awareness about this issue.
Coronary artery disease is the leading cause of death for both males and females and accounts for approximately 600,000 deaths in the United States every year. According to present trends in the United States, half of healthy 40-year-old males will develop CAD in the future, and one in three healthy 40-year-old females. It is the most common reason for death of males and females over 20 years of age in the United States.
After analysing data from 2 111 882 patients, the recent meta-analysis revealed that the incidence of coronary artery diseases in breast cancer survivors was 4.29 (95% CI 3.09–5.94) per 1000 person-years.
== Society and culture ==
=== Names ===
Other terms sometimes used for this condition are "hardening of the arteries" and "narrowing of the arteries". In Latin it is known as morbus ischaemicus cordis (MIC).
=== Support groups ===
The Infarct Combat Project (ICP) is an international nonprofit organization founded in 1998 which tries to decrease ischemic heart diseases through education and research.
=== Industry influence on research ===
In 2016 research into the internal documents of the Sugar Research Foundation, the trade association for the sugar industry in the US, had sponsored an influential literature review published in 1965 in the New England Journal of Medicine that downplayed early findings about the role of a diet heavy in sugar in the development of CAD and emphasized the role of fat; that review influenced decades of research funding and guidance on healthy eating.
== Research ==
Research efforts are focused on new angiogenic treatment modalities and various (adult) stem-cell therapies. A region on chromosome 17 was confined to families with multiple cases of myocardial infarction. Other genome-wide studies have identified a firm risk variant on chromosome 9 (9p21.3). However, these and other loci are found in intergenic segments and need further research in understanding how the phenotype is affected.
A more controversial link is that between Chlamydophila pneumoniae infection and atherosclerosis. While this intracellular organism has been demonstrated in atherosclerotic plaques, evidence is inconclusive regarding whether it can be considered a causative factor. Treatment with antibiotics in patients with proven atherosclerosis has not demonstrated a decreased risk of heart attacks or other coronary vascular diseases.
Myeloperoxidase has been proposed as a biomarker.
Plant-based nutrition has been suggested as a way to reverse coronary artery disease, but strong evidence is still lacking for claims of potential benefits.
Several immunosuppressive drugs targeting the chronic inflammation in coronary artery disease have been tested.
== See also ==
Mental stress-induced myocardial ischemia
== References ==
== External links ==
Risk Assessment of having a heart attack or dying of coronary artery disease, from the American Heart Association.
"Coronary Artery Disease". MedlinePlus. U.S. National Library of Medicine.
Norman J (7 October 2019). "Managing Diabetes with Blood Glucose Control". Endocrineweb. | Wikipedia/Ischemic_Heart_Disease |
Tissue Doppler echocardiography (TDE) is a medical ultrasound technology, specifically a form of echocardiography that measures the velocity of the heart muscle (myocardium) through the phases of one or more heartbeats by the Doppler effect (frequency shift) of the reflected ultrasound. The technique is the same as for flow Doppler echocardiography measuring flow velocities. Tissue signals, however, have higher amplitude and lower velocities, and the signals are extracted by using different filter and gain settings. The terms tissue Doppler imaging (TDI) and tissue velocity imaging (TVI) are usually synonymous with TDE because echocardiography is the main use of tissue Doppler.
Like Doppler flow, tissue Doppler can be acquired both by spectral analysis (spectral density estimation) as pulsed Doppler and by the autocorrelation technique as colour tissue Doppler (duplex ultrasonography). While pulsed Doppler only acquires the velocity at one point at a time, colour Doppler can acquire simultaneous pixel velocity values across the whole imaging field. Pulsed Doppler on the other hand, is more robust against noise, as peak values are measured on top of the spectrum, and are unaffected of the presence of clutter (stationary reverberation noise).
== Pulsed tissue Doppler echocardiography ==
This has become a major echocardiographic tool for assessment of both systolic and diastolic ventricular function. However, as this is a spectral technique, it is important to realise that measurement of peak values is dependent on the width of the spectrum, which again is a function of gain setting.
=== Clinical use ===
Pulsed wave spectral tissue Doppler has become a universal tool that is part of the general echocardiographic examination. Like any other echocardiographic measurement, measures by tissue Doppler should be interpreted in the context of the whole examination. The velocity curves are in general taken from the base of the mitral annulus at the insertion of the mitral leaflets, in the septal and lateral points of the four chamber view, and eventually the anterior and inferior points of the two-chamber views. For the right ventricle it is customary to use the lateral point of the tricuspid annulus only. Averaging peak velocities from the septal and lateral point has become common, although it has been shown that averaging all four points mentioned above, gives significantly less variability
The method measures annular velocities to and from the probe during the heart cycle.
Annular velocities summarize the longitudinal contraction of the ventricle during systole, and elongation during diastole. Peak velocities are commonly used.
==== Systolic function ====
Peak systolic annular velocity (S') of the left ventricle is as close to a contractility measure as you can get by imaging (bearing in mind that any imaging method only measures the result of fibre shortening, without measuring myocyte tension). S' has become a reliable measure of global function It shares the advantage of annular displacement, that it is reduced also in hypertrophic hearts with small ventricles and normal ejection fraction (HFNEF), which is often seen in Hypertensive heart disease, Hypertrophic cardiomyopathy and Aortic stenosis.
Likewise, peak tricuspid annular systolic velocity has become a measure of the right ventricular systolic function
==== Diastolic function ====
As the ventricle relaxes, the annulus moves towards the base of the heart, signifying the volume expansion of the ventricle. The peak mitral annular velocity during early filling, e' is a measure of left ventricular diastolic function, and has been shown to be relatively independent of left ventricular filling pressure. If there is impaired relaxation (Diastolic dysfunction), the e' velocity decreases. After the early relaxation, the ventricular myocardium is passive, the late velocity peak a' is a function of atrial contraction. The ratio between e' and a' is also a measure of diastolic function, in addition to the absolute values.
During the two filling phases, there is early (E) and late (A) blood flow from the atrium to the ventricle, corresponding to the annular velocity phases. The flow, is driven by the pressure difference between atrium and ventricle, this pressure difference is both a function of the pressure drop during early relaxation and the initial atrial pressure. In light diastolic dysfunction, the peak early mitral flow velocity E is reduced in proportion to the e', but if relaxation is so reduced that it causes increase in atrial pressure, E will increase again, while e', being less load dependent, remains low. Thus, the ratio E/e' is related to the atrial pressure, and can show increased filling pressure although with several reservations. In the right ventricle this is not an important principle, as the right atrial pressure is the same as central venous pressure which can easily be assessed from venous congestion.
==== Heart failure with preserved ejection fraction (HFPEF) ====
One of the main advantages of tissue Doppler is that diastolic and systolic function can be measured by the same tool. Before the advent of tissue Doppler, systolic function was usually assessed with ejection fraction (EF), and diastolic function by mitral flow. This led to the concept of pure "diastolic heart failure". However, In hypertrophic left ventricles with small cavity size, the systolic function is reduced although EF is not, as the EF is dependent on the relative wall thickness. This has led to the concept of "pure diastolic heart failure" being discarded. The preferred term is now heart failure with normal ejection fraction (HFNEF) or heart failure with preserved ejection fraction (HFPEF). This is common and is often seen in hypertensive heart disease, hypertrophic cardiomyopathy and aortic stenosis, and may comprise as much as 50% of the total heart failure population. The prognosis of HFPEF is the same as for heart failure with dilated hearts.
==== Mitral valve prolapse (MVP) ====
Pulsed-wave tissue Doppler can be used as a way to evaluate the severeness of arrhythmic mitral valve prolapse, by looking at the peak in the middle of the systole, which looks similar to Prussian Pickelhaube helmet, hence the name Pickelhaube spike. This is one of the risk markers for malignant arrhythmias in patients with myxomatous mitral valve disease (MMVD) and bileaflet mitral valve prolapse (BMVP). It's significant when exceeds 16 cm/s. The sudden systolic overload of which Pickelhaube spike is an expression can act as a trigger for the onset of ventricular arrhythmias.
=== Normal values and physiology ===
Normal gender and age related reference values For both S', e' and a' have been established in the large HUNT study, comprising 1266 subjects free of heart disease, hypertension and diabetes.
This study also shows that both S' and e' values decline with age, while a' increases (fig). There is also a significant correlation between S' and e', also in healthy subjects, showing the connection between systolic and diastolic function. The e'/a' ratio becomes <1 about 60 years of age, which is similar to the E/A ratio of mitral flow. Women has slightly higher S' and e' velocities than men, although the difference disappears with age. The study also did show that velocities were highest in the lateral wall, and lowest in the septum. The E/e' was thus dependent on the site of e' measurement. The ratio was also age dependent.
== Colour tissue Doppler ==
Unlike spectral Doppler, colour tissue Doppler samples velocities from all points of the sector, by shooting two pulses successively, and calculating the velocity from the phase shift between them by autocorrelation. The calculation is slightly different from the true Doppler effect, but the result becomes identical. This results in a single velocity value per sample volume. The result is a velocity field of (nearly) simultaneous velocity vectors towards the probe. The advantage of colour Doppler over spectral Doppler is that all velocities can be sampled simultaneously. The disadvantage is that if there is clutter noise (stationary reverberations), the stationary echoes will be integrated in the velocity calculation, resulting in an under estimate. As pulsed wave Doppler are displayed as a spectrum, the colour Doppler values will correspond to the mean of the spectrum (in the absence of clutter), giving slightly lower values. In the HUNT study, the difference in peak systolic values were about 1.5 cm/s.
The local velocities are not the result of the local function, as segments are moved by the action of neighbouring segments. Thus the velocity differences velocity gradient are the main measure of regional contraction, and has become the most important employment of colour tissue Doppler, in the method of strain rate imaging.
== Objections ==
There are philosophical, methodological and applicational flaws in tissue Doppler. Doppler methodology and mensuration are suitable for flow but unsuitable for tissue application. In contrast to the regular Doppler which is High Velocity Flow Doppler (HVFD) it is better to call tissue Doppler as Low Velocity Flow Doppler (LVFD).
Thus, in tissue Doppler, velocity measurements are unscientific due to flaws in application of measurement and Doppler methodology. There is no diagnostic directional information which is vital in Doppler studies. It has poor spatial resolution and is very sensitive - resulting in false positive data. The audio output is useless. Tissue Doppler has no particular advantage in the current form but may be used to study low flow thrombogenic states like spontaneous echo contrasts.
== References ==
== Further reading == | Wikipedia/Tissue_Doppler_echocardiography |
In the fields of cardiology and medical imaging, speckle tracking echocardiography (STE) is an echocardiographic imaging technique. It analyzes the motion of tissues in the heart by using the naturally occurring speckle pattern in the myocardium (or motion of blood when imaged by ultrasound).
This method of documentation of myocardial motion is a noninvasive method of definition for both vectors and velocity. When compared to other technologies seeking noninvasive definition of ischemia, speckle tracking seems a valuable endeavor. The speckle pattern is a mixture of interference patterns and natural acoustic reflections. These reflections are also described as speckles or markers.
The pattern being random, each region of the myocardium has a unique speckle pattern (also called patterns, features, or fingerprints) that allows the region to be tracked. The speckle pattern is relatively stable, at least from one frame to the next. In post processing this can be tracked consecutively frame to frame and ultimately resolved into angle-independent two-dimensional (2D) and three-dimensional strain-based sequences (3D). These sequences provide both quantitative and qualitative information regarding tissue deformation and motion.
== Basic principles ==
As the speckle pattern is random, any region of the myocardium has a unique speckle pattern: Within the picture, a defined area "kernel" can be defined, and as this speckle pattern is relatively stable, the kernel can be recognised in the next frame, within a larger search area, by a "best match" search algorithm. There are different search algorithms, the most commonly used is "sum of absolute differences", shown to be similarly accurate as cross-correlation, which is an alternative. The movement of the kernel across the image can thus be tracked, in principle independent of the beam angle, as opposed to tissue Doppler. Speckle tracking can thus track in two dimensions. However, as the axial (in the direction of the beam) resolution of the ultrasound is far better than the transverse, the tracking ability is less in the transverse direction. Also, the transverse resolution (and hence, tracking ability) decreases with depth, in a sector scan where ultrasound beams diverge.
Different commercial and non commercial operators then use different approaches to derive motion and deformation parameters. The motion of a single kernel can be resolved into displacement curves, and the distance between two kernels into strain (deformation). Strain rate will then be time derivative of strain. In some commercial applications, the acoustic markers are tracked more individually, calculating the velocity from the motion and the sampling interval (inverse of frame rate) generating a velocity field. Unlike tissue Doppler, this velocity field in not limited to the beam direction. Strain rate and strain are then calculated from the velocities. Speckle tracking has been shown to be comparable to tissue Doppler derived strain, and has been validated against MR.
== Strain ==
Strain is defined as the fractional or percentage change in an objects dimension in comparison to the object’s original dimension. Similarly, strain rate can be defined as the speed at which deformation occurs. Mathematically, three components of normal strain (εx, εy, and εz) and three components of shear strain (εxy, εxz, and εyz) are recognized. Congruently, when applied to the left ventricle, left ventricular deformation is defined by the three normal strains (longitudinal, circumferential, and radial) and three shear strains (circumferential-longitudinal, circumferential-radial, and longitudinal-radial). The principal benefit of LV shear strains is amplification of the 15% shortening of myocytes into 40% radial LV wall thickening, which ultimately translates into a >60% change in LV ejection fraction. Left ventricular shearing increases towards the subendocardium, resulting in a subepicardial to subendocardial thickening strain gradient. Similar to MRI, STE utilizes "Lagrangian strain" which defines motion around a particular point in tissue as it revolves through time and space. Throughout the cardiac cycle, the end-diastolic tissue dimension represents the unstressed initial material length. Speckle tracking is one of two methods for Strain rate imaging, the other being Tissue Doppler.
Twist or torsional deformation define the base-to-apex gradient and is the result of myocardial shearing in the circumferential-longitudinal planes such that, when viewed from the apex, the base rotates in a counterclockwise direction. Likewise the LV apex concomitantly rotates in a clockwise direction. During ejection, LV torsion results in the storage of potential energy into the deformed myofibers. This stored energy is released with the onset of relaxation similar to a spring uncoiling and results in suction forces. These forces are then used for rapid early diastolic restoration.
== Applications and limitations ==
The utilities of STE are increasingly recognized. Strain results derived from STE have been validated using sonomicrometry and tagged MRI and results correlate significantly with Tissue Doppler–derived measurements. Tissue Doppler technology, the alternative method for strain rate imaging to speckle tracking technology, requires achieving sufficient parallel orientation between the direction of motion and the ultrasound beam. Its use has remained limited due to angle dependency, substantial intraobserver and interobserver variability and noise interference. Speckle tracking technology has to a certain degree overcome these limitations.
In order to achieve sufficient tracking quality when single markers are used, however commercial algorithms very often resort to varieties of spline smoothing using available information from the strongest echoes, very oft the mitral annulus, so the regional measurements are not pure regional, but rather to a degree, spline functions of the global average. AS the method uses B-mode, frame rate of speckle tracking is limited to the relatively low frame rate of B-mode. If the frame rate is too low, the tracking quality becomes reduced, due to frame-to-frame decorrelation. This may also be a problem if the heart rate is high, (which in fact is a relative decrease in frame rate - fewer frames per heart cycle).
Increasing frame rate in B-mode is done by reducing line density, i.e. lateral resolution, and thus making the method more angle dependent. Finally, the method on some applications is dependent on the ROI (Region Of Interest) size and shape. In principle Speckle tracking is available for deformation measurement in all directions, however, due to the limitation of lateral resolution in apical images, measuring circumferential and transmural deformation needs parasternal cross sectional views. On the other hand, compared to Tissue Doppler, that method is mainly only available for longitudinal measures from the apical position.
In the study by Cho et al, both TVI derived and speckle tracking derived longitudinal strain showed modest correlation with MRI derived strain. The ROC analysis showed significantly higher AUC for speckle tracking for detecting dysfunctional segments. However, this study only included patients with coronary disease. The lower frame rate has been seen to be a problem in stress echo, as the peak stress shows a fairly high frame rate.
The main problem with speckle tracking, however, is increasingly recognised: The lack of standardisation. Each vendor of ultrasound equipment, or analysis software, has different algorithms, that will perform differently during analysis. In head to head comparisons, biases between analysis may be substantial, especially when compared to an external reference. Thus, measurements, normal limits and cut off values are only vendor specific. Due to industrial secrecy, the details of the different algorithms may also be largely unavailable, so a detailed investigation in modelling is difficult.
Clinical Applications of Speckle Tracking Technology:
Coronary Artery Disease
Myocardial Infarctions
Stress Echocardiography
Revascularization
Valvular Disease
Left Ventricular Hypertrophy
Hypertensive Heart Disease
Hypertrophic Cardiomyopathy
Dilated Cardiomyopathy
Stress Cardiomyopathy
Pericardial Disease/Restrictive Cardiomyopathy
Diastolic Heart Disease
Left Ventricular dyssynchrony
Congenital Heart Disease
Drug-Induced Cardiotoxicity
== See also ==
Echocardiography terminology
Strain rate imaging
== References ==
== Further reading ==
Sutherland; Hatle; Claus; D'hooge;Bijnens (2006) Doppler Myocardial Imaging. BSWK, Belgium. ISBN 978-90-810592-1-3
Marwick; Yu; Sun (2007) Myocardial Imaging: Tissue Doppler and Speckle Tracking. Wiley-Blackwell. ISBN 978-1-4051-6113-8
== External links ==
Asbjorn Stoylen: Website; Strain rate Imaging. Myocardial deformation imaging by ultrasound. | Wikipedia/Speckle_tracking_echocardiography |
Migraine surgery is a surgical operation undertaken with the goal of reducing or preventing migraines. Migraine surgery most often refers to surgical nerve decompression of one or several nerves in the head and neck which have been shown to trigger migraine symptoms in many migraine sufferers. Following the development of nerve decompression techniques for the relief of migraine pain in the year 2000, these procedures have been extensively studied and shown to be effective in appropriate candidates. The nerves that are most often addressed in migraine surgery are found outside of the skull, in the face and neck, and include the supra-orbital and supra-trochlear nerves in the forehead, the zygomaticotemporal nerve and auriculotemporal nerves in the temple region, and the greater occipital, lesser occipital, and third occipital nerves in the back of the neck. Nerve impingement in the nasal cavity has additionally been shown to be a trigger of migraine symptoms.
== Indications and patient selection ==
Migraine surgery is usually reserved for migraine patients who fail more conservative therapy or who cannot tolerate the side effects of drugs used to treat their migraines. Appropriate patients are screened using injections of local anesthesia to provide a temporary nerve block. In some cases, Botox may be used to provide temporary decompression of the nerve. Patients who respond to nerve blocks often see an immediate though temporary reduction in their pain by "shutting off" the nerve that is triggering the migraine, while pain relief following Botox injections is provided by relaxation of nearby muscle tissue that may be compressing the nerve. Patients who respond well to these screening procedures are felt to be excellent candidates for migraine surgery.
== Surgical procedures ==
Migraine surgery is an outpatient procedure which addresses peripheral nerves through limited incisions. Depending on the symptoms of the patient and the screening results following nerve blocks or Botox, different areas of the head and neck may be addressed to treat the nerves found to be the migraine trigger in a given patient. Migraine surgery is always individualized to each patient's symptoms and anatomy.
=== Anterior nerves ===
Nerves found in the forehead (supra-orbital and supra-trochlear nerves) are either addressed using endoscopic surgery or by using an incision in the crease of the upper eyelid. Structures that are found pressing on the nerves here are released and may include bone at the upper orbit, fascia, blood vessels, or muscle tissue. The supra-orbital and supra-trochlear nerves travel through the corrugator supercilii muscle which enables frowning of the brow. These nerves are released from these muscles so they may lie free of pressure from these muscle structures. Small blood vessels which travel with these nerves may be divided to prevent pressure as well. In the bony notch where these nerves exit the eye socket, small pieces of bone or connective tissue may be removed so undue pressure is not placed on the nerves in this region.
=== Nerves of the temple region ===
The zygomaticotemporal nerve and auriculotemporal nerves are found in areas between the top of the ear and the lateral portion of the eye, in different areas of the temple. These nerves can also be addressed by endoscopic techniques, or well hidden small incisions. Blood vessels next to or crossing these nerves are often found to be the source of compression, and these blood vessels may be divided to prevent irritation of these nerves. Associated temporal muscle release in the region of these nerves may also be indicated. Because these nerves are very small and provide feeling to small regions of the scalp, they are often cut or avulsed, allowing the ends to retract into muscle tissue to prevent neuroma formation.
=== Posterior nerves ===
Chronic irritation of the occipital nerves is called occipital neuralgia and is frequently the cause of migraine symptoms. The greater occipital and third occipital nerves are addressed through an incision at the base of the scalp in the upper neck by either a vertical or transverse incision. Incisions are usually placed within the hairline. The greater occipital nerve travels through several muscle layers (including the trapezius muscle and splenius capitis muscle) where it is often compressed, and therefore surgery for this nerve involves releasing it from tight muscle and fascia in the upper neck. Blood vessels found crossing the nerve such as the occipital artery may be divided in order to avoid chronic pressure and irritation of the greater occipital nerve. The third occipital nerve is a small nerve that travels near the greater occipital nerve and may treated similarly in order to alleviate chronic irritation.
The lesser occipital nerve is a small nerve that has additionally been found to be associated with migraine pain. This nerve is found near the sternocleidomastoid muscle and may be decompressed or divided here through a small incision. As this small nerve provides feeling for a small region of the scalp, the minimal numbness resulting from the division of this nerve often goes un-noticed.Neurostimulation surgery, in which electrical stimulators are implemented over the occipital and/or superorbital nerves, has also been used to treat migraines, although there is scarce evidence for the effectiveness of this procedure.
=== Nerves of the nose ===
The nerves of the nasal lining may be impinged by structures in the nose such as the nasal septum and turbinates. Nasal surgery to decompress these regions may include septoplasty, turbinectomy, or other rhinoplasty procedures.
== Surgical outcomes ==
Though initially thought to be experimental surgery, the benefits of migraine surgery have now been well documented. Followup data has shown that 88% of migraine surgery patients experienced a positive response to the procedure after 5 years. 29% of patients have been shown to achieve complete elimination of their migraine disease, while an additional 59% of patients reported a significant decrease in their pain and symptoms 5 years following their migraine surgery. 12% of patients undergoing migraine surgery reported no change in their symptoms after 5 years.
Migraine surgery has additionally been studied in a socioeconomic context and has been shown to reduce both direct and indirect costs associated with migraine disease. Such costs after migraine surgery have been shown to be reduced by a median of $3,949 per patient per year.
=== Surgery ===
Chronic daily headache is a major worldwide health problem that affects 3–5% of the population and results in substantial disability. Advances in the medical management of headache disorders have meant that a substantial proportion of patients can be effectively treated with medical treatments. However, a significant proportion of these patients are intractable to drug treatment. The successful use of surgical procedures for the treatment of migraine is becoming more frequently reported in the medical literature, particularly for those patients who do not respond to medication. There is resistance in some quarters the concept of surgery for migraine, on the grounds that it is unnecessarily invasive. On the contrary, others argue that to undergo a relatively minor and minimally invasive once-off surgical procedure is not as invasive as having to permanently take chronic medication, which in many people has unpleasant or intolerable side effects, or is ineffective. The answer to this conundrum lies however in informed consent - the patient must be advised of all the possibilities, and of all the pros and cons of each option, so that an informed choice can be made. In some instances, patients opt for the drug route, and only take the surgical option when the medication has not had the desired effect. For others, the thought of being on chronic medication is anathema.
==== Arterial pain ====
In many migraine sufferers, the pain originates in painfully dilated extracranial terminal branches of the external carotid artery. That vasodilatation is an important factor in migraine is further confirmed by the fact that the most widely used migraine rescue medications, the ergots, the triptans, and the promising newer drugs, the gepants, possess one significant common denominator: they all potently constrict abnormally dilated extracranial arteries while simultaneously reducing or eliminating migraine pain. Furthermore, to date all migraine-provoking agents have had vasodilating properties.
===== Arterial surgery =====
In patients where the pain has been positively diagnosed to originate from the scalp arteries (the terminal branches of the external carotid artery), the preventive treatment of choice is surgical cauterization of the responsible arteries – known as the Shevel Procedure.
In order to pinpoint the position of the relevant arteries, a three-dimensional CT scan is done, which allows accurate visualization of the course of each artery. This is necessary, as the course of the arteries varies from person to person, and even from side to side in the same individual. During surgery, the position of the artery is further verified by means of a Doppler Flowmeter, with which one can hear the blood flowing through the vessel. Use of the three-dimensional CT scan and the Doppler Flowmeter allows the surgeon to make use of the smallest possible incision, so the procedure is minimally invasive. The most common vessels involved in the pain of migraine are the terminal branches of the external carotid artery, and in particular, the superficial temporal artery and its frontal branch, and the occipital artery, but the maxillary, posterior auricular, supra-orbital, and supra-trochlear branches may also be involved. These vessels are subcutaneous (just under the skin) and the small incisions required to access them and the minimally invasive nature of the procedure means that the surgery can be done in a day facility. As these vessels have no connection with the arterial supply to the brain, the Shevel Procedure is exceedingly safe with no unpleasant side effects. The cosmetic effect is excellent as most of the incisions are within the hairline.
Arterial surgery is only indicated once there is positive confirmation that the arteries are indeed the source of pain. Some migraine sufferers have a visibly distended artery on the temple during an attack, which confirms that the arteries are involved. The distention usually subsides as the pain is controlled by vasoconstrictor drugs (ergots or triptans). In some, this artery is always visible, but it is only when it becomes distended during an attack that it becomes important for diagnosis. Patients who take triptans or ergots for relief of migraine pain are also prime candidates for arterial surgery. The reason for this is that the action of these drugs is to constrict the painfully dilated branches of the external carotid artery - the same arteries that are targeted by the surgery. The purpose of the surgery is to provide a permanent 'triptan or ergot effect'. Most of these arteries are in the scalp and are readily accessible to minimally invasive surgery. This treatment modality is of particular value in: 1) patients who have not responded to preventive drug therapy, 2) patients who are unable to use drug therapy because they experience unacceptable side effects, 3) patients who have to make too frequent use of abortive drugs such as the triptans or ergots, and 4) patients who would prefer not to be on permanent medication. Included in this category are those with Chronic Daily Headache (headache on more than 15 days per month) and patients with what is known as "refractory headache" - headache that has not benefited from any other form of treatment. Elliot Shevel, a South African surgeon, showed that patients with chronic migraine experienced a significant reduction in pain levels and significant improvement in their quality of life following the surgery.
==== Muscle surgery - trigger site release ====
Trigger site release was first described by a plastic surgeon, Dr Bahaman Guyuron. The theory is that trigger sites (TSs) exist where sensory nerves are being compressed by a surrounding muscle. The nerve becomes inflamed, and a cascade of events is initiated, triggering migraine headaches. Thus far, three muscle trigger areas where the nerve passes through a muscle have been identified as surgical candidates – where the a) greater occipital nerve pierces through the semispinalis capitis muscle, b) the zygomaticotemporal nerve passes through the temporalis muscle, and c) the supraorbital/supratrochlear nerves pass through the glabellar muscle group (the corrugator supercilii, depressor supercilii, and procerus muscles). Several large series of studies have been conducted to evaluate the efficacy of surgical obliteration of trigger points. Almost all demonstrated more than 90% response in a carefully selected group of patients who have a positive response to Botox therapy, with at least 50% improvement to complete resolution of migraine pain.
===== Details of the procedures =====
Patients have to be screened preoperatively with a full neurological examination, and subsequent Botox injection. A positive response to Botox has been an accurate predictor of a successful outcome. Single or multiple TSs may be treated. Migraine headaches can start in one area depending on their corresponding trigger site and spread to the rest of the head. It is important to identify the initial trigger sites rather than address all the areas of pain, after the inflammation involves the entire trigeminal tree.
Forehead migraine headaches: In the glabellar area the supra-orbital and supra-trochlear nerves are skeletonized by resecting the corrugator and depressor supercilii muscle using an endoscopic approach similar that of used for cosmetic forehead lift.
Temporal migraine headaches: The temporal area, where the zygomaticotemporal branch of trigeminal nerve passes through the temporalis muscle, is addressed using a similar endoscopic approach but involves removing a segment of the nerve rather than transecting the muscle. This results in a slight sensory defect over temporal skin area, but cross-innervation from other sensory nerves helps to limit the damage.
Occipital migraine headaches: The posterior neck area where the greater occipital nerve passes through the semispinalis capitis muscle is addressed with an open surgical approach with resection of a small segment of the semispinalis muscle and shielding the nerves with a subcutaneous adipose flap.
A further trigger point, not involving muscles, has been identified in the nose of patients who have significant nasal septum deviation with enlargement of the turbinates. The nasal trigger points where enlarged turbinates are in contact with the nasal septum are addressed with a septoplasty and a turbinectomy.
==== Patent foramen ovale closure ====
There is evidence that a link exists between migraine with aura and the presence of a patent foramen ovale (PFO), a hole between the upper chambers (the atria) of the heart. It is estimated that 20-25% of the general population in the United States has a PFO. Medical research studies have shown that migraineurs are twice as likely as the general population to have a PFO, that over 50% of sufferers of migraine with aura have a PFO, that patients with a PFO are 5.1 times more likely to suffer from migraines and 3.2 times more likely to have migraines with aura than the general population, and that patients with migraine with aura are much more likely to have a large opening than the general PFO population. There is however some controversy, as some have shown a link, while others have failed to demonstrate a link.
===== Details of the procedure =====
A catheter is advanced up to the hole in the heart after it is inserted in a vein in the leg. Through the catheter, a device is then placed which blocks the hole between the left and right atria of the heart. There are a number of different devices being used or tested, the Coherex FlatStent PFO Closure System, the CardioSEAL, and the AMPLATZER PFO Occluder device.
Migraine frequency and severity has been shown to be reduced if the hole (PFO) is patched surgically. It has been suggested that there is an advantage to non-pharmacological migraine relief - "in contrast to drugs, PFO closure appears highly effective against migraines and usually has no side effects". Because PFO closure continues to prove successful, new devices are being produced to make the surgery easier to perform and less invasive. Some studies, however, have emphasized caution in relating PFO closure surgeries to migraines, stating that the favorable studies have been poorly designed retrospective studies and that insufficient evidence exists to justify the dangerous procedure. There have however been reports of short-term increases in migraine frequency and intensity following the surgery.
==== Nerve stimulation ====
===== Occipital nerve stimulation =====
Published reports from open-label studies have demonstrated possible efficacy of ONS in a variety of primary headache disorders, including chronic migraine. ONS for the treatment of medically intractable headaches was introduced by Weiner and Reed ONS is typically performed with the equipment normally used for spinal cord stimulation (SCS), which includes electrodes and their leads, anchors to fasten the leads to connective tissue, and the implantable pulse generator (IPG).
===== Details of the procedure =====
Electrodes are placed subcutaneously (under the skin) superficial to the cervical muscle fascia, transverse to the affected occipital nerve trunk at the level of C1, usually using fluoroscopic guidance. The standard procedure is typically performed in two stages. The first stage, carried out under local anesthesia with sedation, is used to test the stimulation and determine optimal placement of electrodes. The second part, which involves insertion of the rest of the ONS system, is carried out under general anesthesia. However, a recent report of a small case series described successful placement of ONS systems entirely under general anesthesia while still achieving the desired occipital region stimulation.
===== When is ONS indicated? =====
A stimulation trial can be performed before the permanent implantation, with the view to improving selection of the candidates for a permanent stimulation. The procedure involves inserting percutaneous (through the skin) leads into the epidural space and externally powering them for 5–7 days. If the trial is successful in terms of significant pain improvement, the patient is offered a permanent implantation. However, in primary headache syndromes, unlike in neuropathic pain, there can be a considerable delay of several weeks to months before the response emerges and therefore the utility of a stimulation trial in selecting patients for permanent implantation remains questionable for now.
=== Procedures ===
==== Muscle relaxation ====
The involvement of the pericranial muscles in migraine has been well documented, and muscle relaxation techniques have been used successfully to prevent migraine.
===== Intra-oral appliances =====
Intra-oral appliance are designed to relax the pericranial muscles, which have been reported to be tender in 100% of migraine sufferers during an attack. There are a number of different designs, which have been reported to be effective in many migraine sufferers.
===== Biofeedback =====
Biofeedback is the process of gaining greater awareness of many physiological functions primarily using instruments that provide information on the activity of those same systems, with a goal of being able to manipulate them at will. Some of the processes that can be controlled include brainwaves, muscle tone, skin conductance, heart rate and pain perception. Biofeedback to induce muscle relaxation is widely used in migraine prevention.
===== Botulinum Toxin (Botox) =====
OnabotulinumtoxinA (trade name Botox) received FDA approval for treatment of chronic migraines (occurring more than 15 days per month) in 2010. The toxin is injected into the muscles of head and neck. Approval followed evidence presented to the agency from two studies funded by Allergan, Inc. showing an improvement in incidence of chronic migraines for migraine sufferers undergoing the Botox treatment. Since then, several randomized control trials have shown Botulinum Toxin Type A to improve headache symptoms and quality of life when used prophylactically for patients with chronic migraine
=== Arterial surgery ===
Surgical cauterization of the superficial blood vessels of the scalp (the terminal branches of the external carotid artery) is only carried out if it has been established with certainty that these vessels are indeed the source of pain. It is a safe and relatively atraumatic procedure which can be performed in a day facility.
=== Nerve decompression ===
Migraine surgery which involves decompression of certain nerves around the head and neck may be an option in certain people who do not improve with medications. It is only effective in those who respond well to Botox injections in specific areas.
=== Closure of patent foramen ovale ===
There also appears to be a causal link between the presence of a patent foramen ovale (PFO) and migraine. There is evidence that the correction of the congenital heart defect, PFO, reduces migraine frequency and severity. Recent studies have advised caution, though, in relation to PFO closure for migraine, as insufficient evidence exists to justify this dangerous procedure.
== See also ==
Management of migraine
== References ==
81. Sultaneh A. Migraine: new surgical treatment. In: Congress of Neurological Surgeons, San Diego, CA, 29 September–4 October 2001, Abstract no. 173. | Wikipedia/Migraine_surgery |
Chronic kidney disease (CKD) is a type of long-term kidney disease, defined by the sustained presence of abnormal kidney function and/or abnormal kidney structure. To meet criteria for CKD, the abnormalities must be present for at least three months. Early in the course of CKD, patients are usually asymptomatic, but later symptoms may include leg swelling, feeling tired, vomiting, loss of appetite, and confusion. Complications can relate to hormonal dysfunction of the kidneys and include (in chronological order) high blood pressure (often related to activation of the renin–angiotensin system), bone disease, and anemia. Additionally CKD patients have markedly increased cardiovascular complications with increased risks of death and hospitalization. CKD can lead to end-stage kidney failure requiring kidney dialysis or kidney transplantation.
Causes of chronic kidney disease include diabetes, high blood pressure, glomerulonephritis, and polycystic kidney disease. Risk factors include a family history of chronic kidney disease. Diagnosis is by blood tests to measure the estimated glomerular filtration rate (eGFR), and a urine test to measure albumin. Ultrasound or kidney biopsy may be performed to determine the underlying cause. Several severity-based staging systems are in use.
Testing people with risk factors (case-finding) is recommended. Initial treatments may include medications to lower blood pressure, blood sugar, and cholesterol. Angiotensin converting enzyme inhibitors (ACEIs) or angiotensin II receptor antagonists (ARBs) are generally first-line agents for blood pressure control, as they slow progression of the kidney disease and the risk of heart disease. Loop diuretics may be used to control edema and, if needed, to further lower blood pressure. NSAIDs should be avoided. Other recommended measures include staying active, and "to adopt healthy and diverse diets with a higher consumption of plant-based foods compared to animal-based foods and a lower consumption of ultraprocessed foods." Plant-based diets are feasible and are associated with improved intermediate outcomes and biomarkers. An example of a general, healthy diet, suitable for people with CKD who do not require restrictions, is the Canada Food Guide Diet. People with CKD who require dietary restrictions or who have other specific nutritional problems should be referred to a dietitian. Treatments for anemia and bone disease may also be required. Severe disease requires hemodialysis, peritoneal dialysis, or a kidney transplant for survival.
Chronic kidney disease affected 753 million people globally in 2016 (417 million females and 336 million males.) In 2015, it caused 1.2 million deaths, up from 409,000 in 1990. The causes that contribute to the greatest number of deaths are high blood pressure at 550,000, followed by diabetes at 418,000, and glomerulonephritis at 238,000.
== Signs and symptoms ==
CKD is initially without symptoms and is usually detected on routine screening blood work by either an increase in serum creatinine, or protein in the urine. As the kidney function decreases, more unpleasant symptoms may emerge:
Blood pressure is increased due to fluid overload and the production of vasoactive hormones created by the kidney via the renin-angiotensin system, increasing the risk of developing hypertension and heart failure. People with CKD are more likely than the general population to develop atherosclerosis with consequent cardiovascular disease, an effect that may be at least partly mediated by uremic toxins. People with both CKD and cardiovascular disease have significantly worse prognoses than those with only cardiovascular disease.
Urea accumulates, leading to azotemia and ultimately uremia (symptoms ranging from lethargy to pericarditis and encephalopathy). Due to its high systemic concentration, urea is excreted in eccrine sweat at high concentrations and crystallizes on the skin as the sweat evaporates ("uremic frost").
Potassium accumulates in the blood (hyperkalemia with a range of symptoms including malaise and potentially fatal cardiac arrhythmias). Hyperkalemia usually does not develop until the glomerular filtration rate falls to less than 20–25 mL/min/1.73 m2, when the kidneys have decreased ability to excrete potassium. Hyperkalemia in CKD can be exacerbated by acidemia (triggering the cells to release potassium into the bloodstream to neutralize the acid) and from lack of insulin.
Fluid overload symptoms may range from mild edema to life-threatening pulmonary edema.
Hyperphosphatemia results from poor phosphate elimination in the kidney, and contributes to increased cardiovascular risk by causing vascular calcification. Circulating concentrations of fibroblast growth factor-23 (FGF-23) increase progressively as the kidney capacity for phosphate excretion declines, which may contribute to left ventricular hypertrophy and increased mortality in people with CKD .
Hypocalcemia results from 1,25 dihydroxyvitamin D3 deficiency (caused by high FGF-23 and reduced kidney mass) and the skeletal resistance to the calcemic action of parathyroid hormone. Osteocytes are responsible for the increased production of FGF-23, which is a potent inhibitor of the enzyme 1-alpha-hydroxylase (responsible for the conversion of 25-hydroxycholecalciferol into 1,25 dihydroxyvitamin D3). Later, this progresses to secondary hyperparathyroidism, kidney osteodystrophy, and vascular calcification that further impairs cardiac function. An extreme consequence is the occurrence of the rare condition named calciphylaxis.
Changes in mineral and bone metabolism that may cause 1) abnormalities of calcium, phosphorus (phosphate), parathyroid hormone, or vitamin D metabolism; 2) abnormalities in bone turnover, mineralization, volume, linear growth, or strength (kidney osteodystrophy); and 3) vascular or other soft-tissue calcification. CKD–mineral and bone disorders have been associated with poor outcomes.
Metabolic acidosis may result from decreased capacity to generate enough ammonia from the cells of the proximal tubule. Acidemia affects the function of enzymes and increases the excitability of cardiac and neuronal membranes by the promotion of hyperkalemia.
Anemia is common and is especially prevalent in those requiring hemodialysis. It is multifactorial in cause but includes increased inflammation, reduction in erythropoietin, and hyperuricemia leading to bone marrow suppression. Hypoproliferative anemia occurs due to inadequate production of erythropoietin by the kidneys.
In later stages, cachexia may develop, leading to unintentional weight loss, muscle wasting, weakness, and anorexia.
Cognitive decline in patients experiencing CKD is an emerging symptom revealed in research literature. Research suggests that patients with CKD face a 35–40% higher likelihood of cognitive decline and or dementia. This relation is dependent on the severity of CKD in each patient; although emerging literature indicates that patients at all stages of CKD will have a higher risk of developing these cognitive issues.
Sexual dysfunction is very common in both men and women with CKD. A majority of men have a reduced sex drive, difficulty obtaining an erection, and reaching orgasm, and the problems get worse with age. Most women have trouble with sexual arousal, and painful menstruation and problems with performing and enjoying sex are common.
== Causes ==
The most common causes of CKD are diabetes mellitus, hypertension, and glomerulonephritis. About one of five adults with hypertension and one of three adults with diabetes have CKD. If the cause is unknown, it is called idiopathic.
=== By anatomical location ===
Vascular disease includes large-vessel disease such as bilateral kidney artery stenosis and small-vessel disease such as ischemic nephropathy, hemolytic–uremic syndrome, and vasculitis.
Glomerular disease comprises a diverse group and is classified into:
Primary glomerular disease such as focal segmental glomerulosclerosis and IgA nephropathy (or nephritis)
Secondary glomerular disease such as diabetic nephropathy and lupus nephritis
Tubulointerstitial disease includes drug- and toxin-induced chronic tubulointerstitial nephritis, and reflux nephropathy
Obstructive nephropathy, as exemplified by bilateral kidney stones and benign prostatic hyperplasia of the prostate gland; rarely, pinworms infecting the kidney can cause obstructive nephropathy.
=== Other ===
Genetic congenital disease such as polycystic kidney disease or 17q12 microdeletion syndrome.
Mesoamerican nephropathy, is "a new form of kidney disease that could be called agricultural nephropathy". A high and so-far unexplained number of new cases of CKD, referred to as the Mesoamerican nephropathy, has been noted among male workers in Central America, mainly in sugarcane fields in the lowlands of El Salvador and Nicaragua. Heat stress from long hours of piece-rate work at high average temperatures of about 36 °C (96 °F) is suspected, as are agricultural chemicals
Chronic lead exposure
== Diagnosis ==
Diagnosis of CKD is largely based on history, examination, and urine dipstick combined with the measurement of the serum creatinine level. Differentiating CKD from acute kidney injury (AKI) is important because AKI can be reversible. One diagnostic clue that helps differentiate CKD from AKI is a gradual rise in serum creatinine (over several months or years) as opposed to a sudden increase in the serum creatinine (several days to weeks). In many people with CKD, previous kidney disease or other underlying diseases are already known. A significant number present with CKD of unknown cause.
=== Screening ===
Screening those who have neither symptoms nor risk factors for CKD is not recommended. Those who should be screened include: those with hypertension or history of cardiovascular disease, those with diabetes or marked obesity, those aged > 60 years, subjects with African American ancestry, those with a history of kidney disease in the past, and subjects who have relatives who had kidney disease requiring dialysis.
Screening should include calculation of the estimated GFR (eGFR) from the serum creatinine level, and measurement of urine albumin-to-creatinine ratio (ACR) in a first-morning urine specimen (this reflects the amount of a protein called albumin in the urine), as well as a urine dipstick screen for hematuria.
The GFR is derived from the serum creatinine and is proportional to 1/creatinine, i.e. it is a reciprocal relationship; the higher the creatinine, the lower the GFR. It reflects one aspect of kidney function, how efficiently the glomeruli – the filtering units – work. The normal GFR is >90 ml/min. The units of creatinine vary from country to country, but since the glomeruli comprise <5% of the mass of the kidney, the GFR does not indicate all aspects of kidney health and function. This can be done by combining the GFR level with the clinical assessment of the person, including fluid status, and measuring the levels of hemoglobin, potassium, phosphate, and parathyroid hormone.
=== Ultrasound ===
Kidney ultrasonography is useful for diagnostic and prognostic purposes in chronic kidney disease. Whether the underlying pathologic change is glomerular sclerosis, tubular atrophy, interstitial fibrosis, or inflammation, the result is often increased echogenicity of the cortex. The echogenicity of the kidney should be related to the echogenicity of the liver or the spleen. Moreover, decreased kidney size and cortical thinning are often seen especially when the disease progresses. However, kidney size correlates to height, and short persons tend to have small kidneys; thus, kidney size as the only parameter is unreliable.
=== Additional imaging ===
Additional tests may include nuclear medicine MAG3 scan to confirm blood flow and establish the differential function between the two kidneys. Dimercaptosuccinic acid (DMSA) scans are also used in kidney imaging; with both MAG3 and DMSA being used chelated with the radioactive element technetium-99.
=== Stages ===
A glomerular filtration rate (GFR) ≥ 60 mL/min/1.73 m2 is considered normal without chronic kidney disease if there is no kidney damage present.
Kidney damage is defined as signs of damage seen in blood, urine, or imaging studies which include lab albumin/creatinine ratio (ACR) ≥ 30. All people with a GFR <60 mL/min/1.73 m2 for 3 months are defined as having chronic kidney disease.
Protein in the urine is regarded as an independent marker for the worsening of kidney function and cardiovascular disease. Hence, British guidelines append the letter "P" to the stage of chronic kidney disease if protein loss is significant.
Stage 1: Slightly diminished function; kidney damage with normal or relatively high GFR (≥90 mL/min/1.73 m2) and persistent albuminuria. Kidney damage is defined as pathological abnormalities or markers of damage, including abnormalities in blood or urine tests or imaging studies.
Stage 2: Mild reduction in GFR (60–89 mL/min/1.73 m2) with kidney damage. Kidney damage is defined as pathological abnormalities or markers of damage, including abnormalities in blood or urine tests or imaging studies.
Stage 3: Moderate reduction in GFR (30–59 mL/min/1.73 m2):. British guidelines distinguish between stage 3A (GFR 45–59) and stage 3B (GFR 30–44) for purposes of screening and referral.
Stage 4: Severe reduction in GFR (15–29 mL/min/1.73 m2) Preparation for kidney replacement therapy.
Stage 5: Established kidney failure (GFR <15 mL/min/1.73 m2), permanent kidney replacement therapy, or end-stage kidney disease.
The term "non-dialysis-dependent chronic kidney disease" (NDD-CKD) is a designation used to encompass the status of those persons with an established CKD who do not yet require the life-supporting treatments for kidney failure known as kidney replacement therapy (RRT, including maintenance dialysis or kidney transplantation). The condition of individuals with CKD, who require either of the two types of kidney replacement therapy (dialysis or transplant), is referred to as end-stage kidney disease (ESKD). Hence, the start of the ESKD is practically the irreversible conclusion of the NDD-CKD. Even though the NDD-CKD status refers to the status of persons with earlier stages of CKD (stages 1 to 4), people with advanced stages of CKD (stage 5), who have not yet started kidney replacement therapy, are also referred to as NDD-CKD.
== Management ==
Chronic kidney disease (CKD) is a serious condition often linked to diabetes and high blood pressure. There is no cure, but a combination of lifestyle changes and medications can help slow its progression. This might include a plant-dominant diet with less protein and salt, medications to control blood pressure and sugar, and potentially newer anti-inflammatory drugs. Doctors may also focus on managing heart disease risk, preventing infections, and avoiding further kidney damage. While dialysis may eventually be needed, a gradual transition can help preserve remaining kidney function. More research is ongoing to improve CKD management and patient outcomes.
=== Blood pressure ===
Angiotensin converting enzyme inhibitors (ACEIs) or angiotensin II receptor antagonists (ARBs) are recommended as first-line agents since they have been found to slow the decline of kidney function, relative to a more rapid decline in those not on one of these agents. They have also been found to reduce the risk of major cardiovascular events such as myocardial infarction, stroke, heart failure, and death from cardiovascular disease when compared to placebo in individuals with CKD. ACEIs may be superior to ARBs for protection against progression to kidney failure and death from any cause in those with CKD. Aggressive blood pressure lowering decreases people's risk of death.
=== Other measures ===
Aggressive treatment of high blood lipids is recommended.
A low-protein, low-salt diet may result in slower progression of CKD and reduction in proteinuria as well as controlling symptoms of advanced CKD to delay dialysis start. A tailored low-protein diet, designed for low acidity, may help prevent damage to kidneys for people with CKD. Additionally, controlling salt ingestion helps to decrease the incidence of coronary heart disease, lowering blood pressure and reducing albuminuria.
Anemia – A target hemoglobin level of 100–120 g/L is recommended; raising hemoglobin levels to the normal range has not been found to be of benefit.
Guidelines recommend treatment with parenteral iron prior to treatment with erythropoietin.
Replacement of erythropoietin is often necessary in people with advanced disease.
It is unclear if androgens improve anemia.
Calcitriol is recommended for vitamin D deficiency and control of metabolic bone disease.
Phosphate binders are used to control the serum phosphate levels, which are usually elevated in advanced chronic kidney disease.
Phosphodiesterase-5 inhibitors and zinc may improve sexual dysfunction in men.
=== Lifestyle interventions ===
==== Weight loss ====
Obesity may have a negative impact in CKD, increasing the risk of disease progression to ESKD or kidney failure compared to controls with healthy weight, and when in advanced stages also may hinder people's eligibility to kidney transplantation. For example, the consumption of high calorie and high fructose beverages can make an individual "60% more likely to develop CKD".
Weight management interventions in overweight and obese adults with CKD include lifestyle interventions (dietary changes, physical activity/exercise, or behavioural strategies), pharmacological (used to reduce absorption or suppress appetite) and surgical interventions. Any of these can help people with CKD lose weight, however, it is not known if they can also prevent death or cardiovascular events like heart complications or stroke. It is recommended that weight management interventions should be individualised, according to a thorough patients' assessment regarding clinical condition, motivations, and preferences.
==== Dietary salt intake ====
High dietary sodium intake may increase the risk of hypertension and cardiovascular disease. The effect of dietary restriction of salt in foods has been investigated in people with chronic kidney disease. For people with CKD, including those on dialysis, reduced salt intake may help to lower both systolic and diastolic blood pressure, as well as albuminuria. Some people may experience low blood pressure and associated symptoms, such as dizziness, with lower salt intake. The effect of salt restriction on extracellular fluid, oedema, and total body weight reduction is unknown.
EHealth interventions may improve dietary sodium intake and fluid management for people with CKD.
==== Omega-3 supplementation ====
In people with CKD who require hemodialysis, there is a risk that vascular blockage due to clotting, may prevent dialysis therapy from being possible. Even though Omega-3 fatty acids contribute to the production of eicosanoid molecules that reduce clotting, it does not have any impact on the prevention of vascular blockage in people with CKD.
==== Protein supplementation ====
Regular consumption of oral protein-based nutritional supplements may increase serum albumin levels slightly in people with CKD, especially among those requiring hemodialysis or who are malnourished. Prealbumin level and mid-arm muscle circumference may also be increased following supplementation. Despite possible improvement in these indicators of nutritional status, it is not certain that protein supplements affect the quality of life, life expectancy, inflammation, or body composition.
==== Iron supplementation ====
Intravenous (IV) iron therapy may help more than oral iron supplements in reaching target hemoglobin levels. However, allergic reactions may also be more likely following IV-iron therapy.
=== Sleep ===
Individuals with CKD have an increased prevalence of sleep apnea compared to the general population (both obstructive sleep apnea and central sleep apnea). The presence of sleep apnea in CKD has been associated with an increased risk of cardiovascular events and mortality.
People with CKD also experience sleep disorders, thus unable to get quality sleep. There are several strategies that could help, such as relaxation techniques, exercise, and medication. Exercise may be helpful with sleep regulation and may decrease fatigue and depression in people with CKD. However, none of these options have been proven to be effective in the treatment of sleep disorders. This means that it is unknown what is the best guidance to improve sleep quality in this population.
=== Referral to a nephrologist ===
Guidelines for referral to a nephrologist vary between countries. Most agree that nephrology referral is required by Stage 4 CKD (when eGFR/1.73m2 is less than 30 mL/min; or decreasing by more than 3 mL/min/year).
It may also be useful at an earlier stage (e.g. CKD3) when urine albumin-to-creatinine ratio is more than 30 mg/mmol, when blood pressure is difficult to control, or when hematuria or other findings suggest either a primarily glomerular disorder or secondary disease amenable to a specific treatment. Other benefits of early nephrology referral include proper education regarding options for kidney replacement therapy as well as pre-emptive transplantation, and timely workup and placement of an arteriovenous fistula in those people with chronic kidney disease opting for future hemodialysis.
=== Renal replacement therapy ===
At stage 5 CKD, kidney replacement therapy is usually required, in the form of either dialysis or a kidney transplant.
In CKD numerous uremic toxins accumulate in the blood. Even when ESKD (largely synonymous with CKD5) is treated with dialysis, the toxin levels do not go back to normal as dialysis is not that efficient. Similarly, after a kidney transplant, the levels may not go back to normal as the transplanted kidney may not work 100%. If it does, the creatinine level is often normal. The toxins show various cytotoxic activities in the serum and have different molecular weights, and some of them are bound to other proteins, primarily to albumin. Uremic toxins are classified into three groups as small water-soluble solutes, middle molecular-weight solutes, and protein-bound solutes. Hemodialysis with high-flux dialysis membrane, long or frequent treatment, and increased blood/dialysate flow has improved removal of water-soluble small molecular weight uremic toxins. Middle molecular weight molecules are removed more effectively with hemodialysis using a high-flux membrane, hemodiafiltration, and hemofiltration. However, conventional dialysis treatment is limited in its ability to remove protein-bound uremic toxins.
== Prognosis ==
CKD increases the risk of cardiovascular disease, and people with CKD often have other risk factors for heart disease, such as high blood lipids. The most common cause of death in people with CKD is cardiovascular disease rather than kidney failure.
Chronic kidney disease results in worse all-cause mortality (the overall death rate) which increases as kidney function decreases. The leading cause of death in chronic kidney disease is cardiovascular disease, regardless of whether there is progression to stage 5.
While kidney replacement therapies can maintain people indefinitely and prolong life, the quality of life is negatively affected. Kidney transplantation increases the survival of people with stage 5 CKD when compared to other options; however, it is associated with an increased short-term mortality due to complications of the surgery. Transplantation aside, high-intensity home hemodialysis appears to be associated with improved survival and a greater quality of life, when compared to the conventional three-times-a-week hemodialysis and peritoneal dialysis.
People with ESKD are at increased overall risk for cancer. This risk is particularly high in younger people and gradually diminishes with age. Medical specialty professional organizations recommend that physicians do not perform routine cancer screening in people with limited life expectancies due to ESKD because the evidence does not show that such tests lead to improved outcomes.
In children, growth failure is a common complication of CKD. Children with CKD will be shorter than 97% of children the same age and sex. This can be treated with additional nutritional support or medication such as growth hormone.
=== Survival without dialysis ===
Survival rates of CKD are generally longer with dialysis than without (having only conservative kidney management). However, from the age of 80 and in elderly patients with comorbidities there is no difference in survival between the two groups. Quality of life might be better for people without dialysis.
People who had decided against dialysis treatment when reaching end-stage chronic kidney disease could survive several years and experience improvements in their mental well-being in addition to sustained physical well-being and overall quality of life until late in their illness course. However, use of acute care services in these cases is common, and the intensity of end-of-life care is highly variable among people opting out of dialysis.
== High prevalence of CKD in some areas ==
High Prevalence of Chronic Kidney Disease in Certain Regions
Overview
Chronic kidney disease (CKD) is a growing global health problem, affecting over 10% of the world's population—more than 800 million people. While CKD is prevalent worldwide, certain regions and communities experience exceptionally high rates, often due to a combination of traditional and unique risk factors.
Regional Hotspots and Prevalence
In India, the Uddanam region of Andhra Pradesh has reported a CKD prevalence of 18.2%, which is 3–4 times higher than most other areas in India and comparable to global hotspots like Sri Lanka and Central America. Notably, a significant proportion of CKD cases here are of unknown cause (CKDu), not linked to common risk factors like diabetes or hypertension.
In Thailand, the overall CKD prevalence was found to be 17.5%, with certain rural areas reaching as high as 22.2%.
Globally, the estimated prevalence of CKD is about 13.4%.
Risk Factors and Contributing Causes
Traditional risk factors include diabetes, hypertension, obesity, and aging, which are rapidly increasing in low- and middle-income countries (LMICs).
Environmental and occupational exposures, such as toxins, heat stress, and possibly contaminated water, are suspected contributors in CKD hotspots like Uddanam, Sri Lanka, and Central America, though the exact causes often remain unclear.
Limited access to healthcare, high poverty rates, and underfunded health systems exacerbate the problem, leading to late diagnosis and high mortality.
Public Health Impact
CKD is a leading cause of morbidity and mortality, particularly in regions with high prevalence and limited treatment options.
The financial burden of CKD is substantial, especially where access to dialysis and transplantation is limited.
Dr Y.Sreehari created new word 'CKDum'. That means Chronic Kidney Disease Un Conclusive etiology and Mystery Un Conclusive:
A. Un conclusive etiology means, No BP or Diabetis, no any other risk factors.
B. Mystery Un Conclusive means:
1.No causes of Environmental (Toxins,Heavy Metals: Exposure to cadmium, arsenic, lead, and fluoride through drinking water or soil).
2.No Pesticides and Herbicides,No Chronic exposure to glyphosate, organophosphates and other agrochemicals used in farming.
3.No Heat Stress and Dehydration.
4.No Prolonged physical labor in hot, humid climates.
5.No Contaminated Water Sources
6.No Hard water with high fluoride, silica, and sodium content.
7.No Groundwater contamination.
8.No Poor nutrition.
9.No Use of NSAIDs (Painkillers)
2. Dr Y. Sreehari is a physician, and belongs to Visakhapatnam, chairman of Dr Sreehari hospitals.
3. The world has a crores of Villages. 'X' is a world average prevalence CKD . So as per probability, chance, like lottery chances,have some villages may be more than world average prevalence 'X'
5. If we count the top 10 villages with high CKDum prevalence , any 10 villages must be in top position.
6.Probability Theory and CKDum:
Probability theory governs the likelihood of events in large populations. In the context of CKDum, we can model its prevalence using a binomial distribution, which describes the number of occurrences of an event (e.g., CKDum cases) in a fixed number of trials (e.g., individuals in a village). Let’s denote:
p = the global average prevalence of CKDum (a subset of X, estimated to be lower, e.g., 1–2% in high-risk rural populations []).
n = the population of a village.
k = the number of CKDum cases in the village.
The probability of observing k cases in a village of size n is given by the binomial probability formula:
P(k)=(nk)pk(1−p)n−kP(k) = \binom{n}{k} p^k (1-p)^{n-k}P(k)=(kn)pk(1−p)n−k
where (nk)\binom{n}{k}(kn) is the binomial coefficient, representing the number of ways to choose k cases from n individuals.
In a world with millions of villages, the law of large numbers suggests that most villages will have CKDum prevalence close to p. However, the central limit theorem implies that, due to random variation, some villages will exhibit prevalence significantly higher or lower than p. This is analogous to a lottery, where a small number of tickets (villages) win the "prize" of unusually high prevalence by chance alone.
7.The Top 10 Villages: A Statistical Inevitability:Dr. Sreehari posits that if we rank villages worldwide by CKDum prevalence, the top 10 will inevitably show rates far above the global average, purely due to statistical chance.
This can be understood through extreme value theory, which studies the behavior of the tails of probability distributions. In a large sample (e.g., millions of villages), the maximum values of CKDum prevalence are expected to be significantly higher than the mean.
For example, suppose p = 0.02 (2% prevalence) and a village has n = 1000 residents. The expected number of CKDum cases is n⋅p=20n \cdot p = 20n⋅p=20. However, the standard deviation of the binomial distribution is:
σ=n⋅p⋅(1−p)=1000⋅0.02⋅0.98≈4.43\sigma = \sqrt{n \cdot p \cdot (1-p)} = \sqrt{1000 \cdot 0.02 \cdot 0.98} \approx 4.43σ=n⋅p⋅(1−p)=1000⋅0.02⋅0.98≈4.43
Using a normal approximation, the probability of observing, say, 50 or more cases (5% prevalence, 2.5 times the expected value) can be calculated using the z-score:
z=50−204.43≈6.77z = \frac{50 - 20}{4.43} \approx 6.77z=4.4350−20≈6.77
The probability of z≥6.77z \geq 6.77z≥6.77 is extremely small (on the order of 10−1110^{-11}10−11), but with millions of villages globally, the expected number of such outliers becomes non-negligible. For instance, with 10 million villages worldwide, we expect:
10,000,000⋅P(z≥6.77)≈a small but positive number of villages10,000,000 \cdot P(z \geq 6.77) \approx \text{a small but positive number of villages}10,000,000⋅P(z≥6.77)≈a small but positive number of villages
Thus, it is statistically inevitable that some villages will have CKDum prevalence far exceeding the global average, even without specific causal factors.
Global Applicability: With millions of villages worldwide, Dr. Sreehari’s framework applies universally. Whether in Sri Lanka, India, or Central America, the lottery-like distribution of CKDum explains why certain communities are disproportionately affected.
Conclusion: The CKDum Mystery Solved
Dr. Y. Sreehari’s innovative application of probability theory offers a compelling resolution to the CKDum mystery.
...
== Epidemiology ==
About one in ten people have chronic kidney disease. In Canada 1.9 to 2.3 million people were estimated to have CKD in 2008. CKD affected an estimated 13.9% of U.S. adults aged 18 years and older in the period from 2017 to 2020. In 2007 8.8% of the population of Great Britain and Northern Ireland had symptomatic CKD.
Chronic kidney disease was the cause of 956,000 deaths globally in 2013, up from 409,000 deaths in 1990.
=== Chronic kidney disease of unknown aetiology ===
The cause of chronic kidney disease is sometimes unknown; it is referred to as chronic kidney disease of unknown aetiology (CKDu). As of 2020 a rapidly progressive chronic kidney disease, unexplained by diabetes and hypertension, had increased dramatically in prevalence over a few decades in several regions in Central America and Mexico, a CKDu referred to as the Mesoamerican nephropathy (MeN). It was estimated in 2013 that at least 20,000 men had died prematurely, some in their 20s and 30s; a figure of 40,000 per year was estimated in 2020. In some affected areas CKD mortality was five times the national rate. MeN primarily affects men working as sugarcane labourers. The cause is unknown, but in 2020 the science found a clearer connection between heavy labour in high temperatures and incidence of CKDu; improvements such as regular access to water, rest and shade, can significantly decrease the potential CKDu incidence. CKDu also affects people in Sri Lanka where it is the eighth largest cause of in-hospital mortality.
=== Race ===
African, Hispanic, and South Asian (particularly those from Pakistan, Sri Lanka, Bangladesh, and India) populations are at high risk of developing CKD. Africans are at greater risk due to the number of people affected with hypertension among them. As an example, 37% of ESKD cases in African Americans can be attributed to high blood pressure, compared with 19% among Caucasians. Treatment efficacy also differs between racial groups. Administration of antihypertensive drugs generally halts disease progression in white populations but has little effect in slowing kidney disease among black people, and additional treatment such as bicarbonate therapy is often required. While lower socioeconomic status contributes to the number of people affected with CKD, differences in the number of people affected by CKD are still evident between Africans and Whites when controlling for environmental factors.
Although CKD of unknown etiology was first documented among sugar cane workers in Costa Rica in the 1970s, it may well have affected plantation laborers since the introduction of sugar cane farming to the Caribbean in the 1600s. In colonial times the death records of slaves on sugar plantations were much higher than for slaves forced into other labor.
==== Denial of care ====
Denial of care in chronic kidney disease treatment and management is a significant issue for minority populations. This can be due to healthcare provider prejudice, structural barriers, and health insurance coverage disparities. Healthcare provider biases can lead to under-treatment, misdiagnosis, or delayed diagnosis. Structural barriers, such as lack of insurance and limited healthcare facilities, hinder access to timely care. Furthermore, health insurance coverage disparities, with minority populations lacking adequate coverage, contribute to these disparities. Denial of care worsens health outcomes and perpetuates existing health inequities.
==== Race-based kidney function metric ====
Race-based kidney function metrics, particularly normalizing creatinine, pose ethical challenges in diagnosing and managing chronic kidney disease (CKD). While certain racial and ethnic groups are at higher risk, using race as a reference range may reinforce stereotypes and perpetuate health disparities. This approach fails to account for the complex interplay of genetic, environmental, and social factors influencing kidney function. Depending solely on race-based metrics may lead to misdiagnosis or underdiagnosis in minority populations. Alternative approaches that consider socioeconomic status, environmental exposures, and genetic vulnerability, are needed to accurately assess kidney function and address CKD care disparities.
== Society and culture ==
=== Organisations ===
The International Society of Nephrology is an international body representing specialists in kidney diseases.
==== United States ====
The National Kidney Foundation is a national organization representing people with chronic kidney diseases and professionals who treat kidney diseases.
The American Kidney Fund is a national nonprofit organization providing treatment-related financial assistance to one of every five people undergoing dialysis each year.
The Renal Support Network is a nonprofit, patient-focused, patient-run organization that provides non-medical services to those affected by CKD.
The American Association of Kidney Patients is a nonprofit, patient-centric group focused on improving the health and well-being of CKD and people undergoing dialysis .
The Renal Physicians Association is an association representing nephrology professionals.
==== United Kingdom ====
It was said to be costing the National Health Service about £1.5 billion a year in 2020.
Kidney Care UK and The UK National Kidney Federation represent people with chronic kidney disease. The Renal Association represents Kidney physicians and works closely with the National Service Framework for kidney disease.
==== Australia ====
Kidney Health Australia serves that country.
== Other animals ==
=== Dogs ===
The incidence rate of CKD in dogs was 15.8 cases per 10,000 dog years at risk. The mortality rate of CKD was 9.7 deaths per 10,000 dog years at risk. (Rates developed from a population of 600,000 insured Swedish dogs; one dog year at risk is one dog at risk for one year). The breeds with the highest rates were the Bernese mountain dog, miniature schnauzer, and boxer. The Swedish elkhound, Siberian husky and Finnish spitz were the breeds with the lowest rates.
=== Cats ===
Cats with chronic kidney disease may have a buildup of waste products usually removed by the kidneys. They may appear lethargic, unkempt, and lose weight, and may have hypertension. The disease can prevent appropriate concentration of urine, causing cats to urinate in greater volumes and drink more water to compensate. Loss of important proteins and vitamins through urine may cause abnormal metabolism and loss of appetite. The buildup of acids within the blood can result in acidosis, which can lead to anemia (which can sometimes be indicated by pink or whitish gums, but by no means does the presence of normal colored gums guarantee that anemia is not present or developing), and lethargy.
== Research ==
As of 2019 several compounds are in development for the treatment of CKD. These include the angiotensin receptor blocker (ARB) olmesartan medoxomil; and sulodexide, a mixture of low molecular weight heparin and dermatan sulfate.
== References ==
== External links ==
Dialysis Complications of Chronic Renal Failure at eMedicine
Chronic Renal Failure Information Archived 2013-03-15 at the Wayback Machine from Great Ormond Street Hospital
Note also the External resources links in the table below. | Wikipedia/End-stage_kidney_disease |
Coronary artery disease (CAD), also called coronary heart disease (CHD), or ischemic heart disease (IHD), is a type of heart disease involving the reduction of blood flow to the cardiac muscle due to a build-up of atheromatous plaque in the arteries of the heart. It is the most common of the cardiovascular diseases. CAD can cause stable angina, unstable angina, myocardial ischemia, and myocardial infarction.
A common symptom is angina, which is chest pain or discomfort that may travel into the shoulder, arm, back, neck, or jaw. Occasionally it may feel like heartburn. In stable angina, symptoms occur with exercise or emotional stress, last less than a few minutes, and improve with rest. Shortness of breath may also occur and sometimes no symptoms are present. In many cases, the first sign is a heart attack. Other complications include heart failure or an abnormal heartbeat.
Risk factors include high blood pressure, smoking, diabetes mellitus, lack of exercise, obesity, high blood cholesterol, poor diet, depression, and excessive alcohol consumption. A number of tests may help with diagnosis including electrocardiogram, cardiac stress testing, coronary computed tomographic angiography, biomarkers (high-sensitivity cardiac troponins) and coronary angiogram, among others.
Ways to reduce CAD risk include eating a healthy diet, regularly exercising, maintaining a healthy weight, and not smoking. Medications for diabetes, high cholesterol, or high blood pressure are sometimes 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 improves life expectancy or decreases heart attack risk.
In 2015, CAD affected 110 million people and resulted in 8.9 million deaths. It makes up 15.6% of all deaths, making it the most common cause of death globally. The risk of death from CAD for a given age decreased between 1980 and 2010, especially in developed countries. The number of cases of CAD for a given age also decreased between 1990 and 2010. In the United States 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 were higher among males than females of a given age.
== Signs and symptoms ==
The most common symptom is chest pain or discomfort that occurs regularly with activity, after eating, or at other predictable times; this phenomenon is termed stable angina and is associated with narrowing of the arteries of the heart. Angina also includes chest tightness, heaviness, pressure, numbness, fullness, or squeezing. Angina that changes in intensity, character, or frequency is termed unstable. Unstable angina may precede myocardial infarction. In adults who go to the emergency department with an unclear cause of pain, about 30% have pain due to coronary artery disease. Angina, shortness of breath, sweating, nausea or vomiting, and lightheadedness are signs of a heart attack or myocardial infarction, and immediate emergency medical services are crucial.
With advanced disease, the narrowing of coronary arteries reduces the supply of oxygen-rich blood flowing to the heart, which becomes more pronounced during strenuous activities during which the heart beats faster and has an increased oxygen demand. For some, this causes severe symptoms, while others experience no symptoms at all.
=== Symptoms in females ===
Symptoms in females can differ from those in males, and the most common symptom reported by females of all races is shortness of breath. Other symptoms more commonly reported by females than males are extreme fatigue, sleep disturbances, indigestion, and anxiety. However, some females experience irregular heartbeat, dizziness, sweating, and nausea. Burning, pain, or pressure in the chest or upper abdomen that can travel to the arm or jaw can also be experienced in females, but females less commonly report it than males. Generally, females experience symptoms 10 years later than males. Females are less likely to recognize symptoms and seek treatment.
== Risk factors ==
Coronary artery disease is characterized by heart problems that result from atherosclerosis. Atherosclerosis is a type of arteriosclerosis which is the "chronic inflammation of the arteries which causes them to harden and accumulate cholesterol plaques (atheromatous plaques) on the artery walls". CAD has several well-determined risk factors contributing to atherosclerosis. These risk factors for CAD include "smoking, diabetes, high blood pressure (hypertension), abnormal (high) amounts of cholesterol and other fat in the blood (dyslipidemia), type 2 diabetes and being overweight or obese (having excess body fat)" due to lack of exercise and a poor diet. Some other risk factors include high blood pressure, smoking, diabetes, lack of exercise, obesity, high blood cholesterol, poor diet, depression, family history, psychological stress and excessive alcohol. About half of cases are linked to genetics. Apart from these classical risk factors, several unconventional risk factors have also been studied including high serum fibrinogen, high c-reactive protein (CRP), chronic inflammatory conditions, hypovitaminosis D, high lipoprotein A levels, serum homocysteine etc. Smoking and obesity are associated with about 36% and 20% of cases, respectively. Smoking just one cigarette per day about doubles the risk of CAD. Lack of exercise has been linked to 7–12% of cases. Exposure to the herbicide Agent Orange may increase risk. Rheumatologic diseases such as rheumatoid arthritis, systemic lupus erythematosus, psoriasis, and psoriatic arthritis are independent risk factors as well.
Job stress appears to play a minor role accounting for about 3% of cases. In one study, females who were free of stress from work life saw an increase in the diameter of their blood vessels, leading to decreased progression of atherosclerosis. In contrast, females who had high levels of work-related stress experienced a decrease in the diameter of their blood vessels and significantly increased disease progression.
=== Air pollution ===
Air pollution, both indoor and outdoor, is responsible for roughly 28% of deaths from CAD. This varies by region: In highly developed areas, this is approximately 10%, whereas in Southern, East and West Africa, and South Asia, approximately 40% of deaths from CAD can be attributed to unhealthy air. In particular, fine particle pollution (PM2.5), which comes mostly from the burning of fossil fuels, is a key risk factor for CAD.
=== Blood fats ===
The consumption of different types of fats including trans fat (trans unsaturated), and saturated fat, in a diet "influences the level of cholesterol that is present in the bloodstream". Unsaturated fats originate from plant sources (such as oils). There are two types of unsaturated fats, cis and trans isomers. Cis unsaturated fats are bent in molecular structure and trans are linear. Saturated fats originate from animal sources (such as animal fats) and are also molecularly linear in structure. The linear configurations of unsaturated trans and saturated fats allow them to easily accumulate and stack at the arterial walls when consumed in high amounts (and other positive measures towards physical health are not met).
Fats and cholesterol are insoluble in blood and thus are amalgamated with proteins to form lipoproteins for transport. Low-density lipoproteins (LDL) transport cholesterol from the liver to the rest of the body and raise blood cholesterol levels. The consumption of "saturated fats increases LDL levels within the body, thus raising blood cholesterol levels".
High-density lipoproteins (HDL) are considered 'good' lipoproteins as they search for excess cholesterol in the body and transport it back to the liver for disposal. Trans fats also "increase LDL levels whilst decreasing HDL levels within the body, significantly raising blood cholesterol levels".
High levels of cholesterol in the bloodstream lead to atherosclerosis. With increased levels of LDL in the bloodstream, "LDL particles will form deposits and accumulate within the arterial walls, which will lead to the development of plaques, restricting blood flow". The resultant reduction in the heart's blood supply due to atherosclerosis in coronary arteries "causes shortness of breath, angina pectoris (chest pains that are usually relieved by rest), and potentially fatal heart attacks (myocardial infarctions)".
=== Genetics ===
The heritability of coronary artery disease has been estimated between 40% and 60%. Genome-wide association studies have identified over 160 genetic susceptibility loci for coronary artery disease.
=== Transcriptome ===
Several RNA Transcripts associated with CAD - FoxP1, ICOSLG, IKZF4/Eos, SMYD3, TRIM28, and TCF3/E2A are likely markers of regulatory T cells (Tregs), consistent with known reductions in Tregs in CAD.
The RNA changes are mostly related to ciliary and endocytic transcripts, which in the circulating immune system would be related to the immune synapse. One of the most differentially expressed genes, fibromodulin (FMOD), which is increased 2.8-fold in CAD, is found mainly in connective tissue and is a modulator of the TGF-beta signaling pathway. However, not all RNA changes may be related to the immune synapse. For example, Nebulette, the most down-regulated transcript (2.4-fold), is found in cardiac muscle; it is a 'cytolinker' that connects actin and desmin to facilitate cytoskeletal function and vesicular movement. The endocytic pathway is further modulated by changes in tubulin, a key microtubule protein, and fidgetin, a tubulin-severing enzyme that is a marker for cardiovascular risk identified by genome-wide association study. Protein recycling would be modulated by changes in the proteasomal regulator SIAH3, and the ubiquitin ligase MARCHF10. On the ciliary aspect of the immune synapse, several of the modulated transcripts are related to ciliary length and function. Stereocilin is a partner to mesothelin, a related super-helical protein, whose transcript is also modulated in CAD. DCDC2, a double-cortin protein, modulates ciliary length. In the signaling pathways of the immune synapse, numerous transcripts are directly related to T-cell function and the control of differentiation. Butyrophilin is a co-regulator for T cell activation. Fibromodulin modulates the TGF-beta signaling pathway, a primary determinant of Tre differentiation. Further impact on the TGF-beta pathway is reflected in concurrent changes in the BMP receptor 1B RNA (BMPR1B), because the bone morphogenic proteins are members of the TGF-beta superfamily, and likewise impact Treg differentiation. Several of the transcripts (TMEM98, NRCAM, SFRP5, SHISA2) are elements of the Wnt signaling pathway, which is a major determinant of Treg differentiation.
=== Other ===
Endometriosis in females under the age of 40.
Depression and hostility appear to be risks.
The number of categories of adverse childhood experiences (psychological, physical, or sexual abuse; violence against mother; or living with household members who used substances, mentally ill, suicidal, or incarcerated) showed a graded correlation with the presence of adult diseases including coronary artery (ischemic heart) disease.
Hemostatic factors: High levels of fibrinogen and coagulation factor VII are associated with an increased risk of CAD.
Low hemoglobin.
In the Asian population, the b fibrinogen gene G-455A polymorphism was associated with the risk of CAD.
Patient-specific vessel ageing or remodelling determines endothelial cell behaviour and thus disease growth and progression. Such 'hemodynamic markers' are patient-specific risk surrogates.
HIV is a known risk factor for developing atherosclerosis and coronary artery disease.
== Pathophysiology ==
Limitation of blood flow to the heart causes ischemia (cell starvation secondary to a lack of oxygen) of the heart's muscle cells. The heart's muscle cells may die from lack of oxygen and this is called a myocardial infarction (commonly referred to as a heart attack). It leads to damage, death, and eventual scarring of the heart muscle without regrowth of heart muscle cells. Chronic high-grade narrowing of the coronary arteries can induce transient ischemia which leads to the induction of a ventricular arrhythmia, which may terminate into a dangerous heart rhythm known as ventricular fibrillation, which often leads to death.
Typically, coronary artery disease occurs when part of the smooth, elastic lining inside a coronary artery (the arteries that supply blood to the heart muscle) develops atherosclerosis. With atherosclerosis, the artery's lining becomes hardened, stiffened, and accumulates deposits of calcium, fatty lipids, and abnormal inflammatory cells – to form a plaque. Calcium phosphate (hydroxyapatite) deposits in the muscular layer of the blood vessels appear to play a significant role in stiffening the arteries and inducing the early phase of coronary arteriosclerosis. This can be seen in a so-called metastatic mechanism of calciphylaxis as it occurs in chronic kidney disease and hemodialysis. Although these people have kidney dysfunction, almost fifty percent of them die due to coronary artery disease. Plaques can be thought of as large "pimples" that protrude into the channel of an artery, causing partial obstruction to blood flow. People with coronary artery disease might have just one or two plaques or might have dozens distributed throughout their coronary arteries. A more severe form is chronic total occlusion (CTO) when a coronary artery is completely obstructed for more than 3 months.
Microvascular angina is a type of angina pectoris in which chest pain and chest discomfort occur without signs of blockages in the larger coronary arteries of their hearts when an angiogram (coronary angiogram) is being performed.
The exact cause of microvascular angina is unknown. Explanations include microvascular dysfunction or epicardial atherosclerosis. For reasons that are not well understood, females are more likely than males to have it; however, hormones and other risk factors unique to females may play a role.
== Diagnosis ==
The diagnosis of CAD depends largely on the nature of the symptoms and imaging. The first investigation when CAD is suspected is an electrocardiogram (ECG/EKG), both for stable angina and acute coronary syndrome. An X-ray of the chest, blood tests and resting echocardiography may be performed.
For stable symptomatic patients, several non-invasive tests can diagnose CAD depending on pre-assessment of the risk profile. Noninvasive imaging options include; Computed tomography angiography (CTA) (anatomical imaging, best test in patients with low-risk profile to "rule out" the disease), positron emission tomography (PET), single-photon emission computed tomography (SPECT)/nuclear stress test/myocardial scintigraphy and stress echocardiography (the three latter can be summarized as functional noninvasive methods and are typically better to "rule in"). Exercise ECG or stress test is inferior to non-invasive imaging methods due to the risk of false negative and false positive test results. The use of non-invasive imaging is not recommended on individuals who are exhibiting no symptoms and are otherwise at low risk for developing coronary disease. Invasive testing with coronary angiography (ICA) can be used when non-invasive testing is inconclusive or show a high event risk.
The diagnosis of microvascular angina (previously known as cardiac syndrome X – the rare coronary artery disease that is more common in females, as mentioned, is a diagnosis of exclusion. Therefore, usually, the same tests are used as in any person suspected of having coronary artery disease:
Intravascular ultrasound
Magnetic resonance imaging (MRI)
=== Stable angina ===
Stable angina is the most common manifestation of ischemic heart disease, and is associated with reduced quality of life and increased mortality. It is caused by epicardial coronary stenosis which results in reduced blood flow and oxygen supply to the myocardium.
Stable angina is short-term chest pain during physical exertion caused by an imbalance between myocardial oxygen supply and metabolic oxygen demand. Various forms of cardiac stress tests may be used to induce both symptoms and detect changes by way of electrocardiography (using an ECG), echocardiography (using ultrasound of the heart) or scintigraphy (using uptake of radionuclide by the heart muscle). If part of the heart seems to receive an insufficient blood supply, coronary angiography may be used to identify stenosis of the coronary arteries and suitability for angioplasty or bypass surgery.
In minor to moderate cases, nitroglycerine may be used to alleviate acute symptoms of stable angina or may be used immediately before exertion to prevent the onset of angina. Sublingual nitroglycerine is most commonly used to provide rapid relief for acute angina attacks and as a complement to anti-anginal treatments in patients with refractory and recurrent angina. When nitroglycerine enters the bloodstream, it forms free radical nitric oxide, or NO, which activates guanylate cyclase and in turn stimulates the release of cyclic GMP. This molecular signaling stimulates smooth muscle relaxation, resulting in vasodilation and consequently improved blood flow to heart regions affected by atherosclerotic plaque.
Stable coronary artery disease (SCAD) is also often called stable ischemic heart disease (SIHD). A 2015 monograph explains that "Regardless of the nomenclature, stable angina is the chief manifestation of SIHD or SCAD." There are U.S. and European clinical practice guidelines for SIHD/SCAD. 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).
=== Acute coronary syndrome ===
Diagnosis of acute coronary syndrome generally takes place in the emergency department, where ECGs may be performed sequentially to identify "evolving changes" (indicating ongoing damage to the heart muscle). Diagnosis is clear-cut if ECGs show elevation of the "ST segment", which in the context of severe typical chest pain is strongly indicative of an acute myocardial infarction (MI); this is termed a STEMI (ST-elevation MI) and is treated as an emergency with either urgent coronary angiography and percutaneous coronary intervention (angioplasty with or without stent insertion) or with thrombolysis ("clot buster" medication), whichever is available. In the absence of ST-segment elevation, heart damage is detected by cardiac markers (blood tests that identify heart muscle damage). If there is evidence of damage (infarction), the chest pain is attributed to a "non-ST elevation MI" (NSTEMI). If there is no evidence of damage, the term "unstable angina" is used. This process usually necessitates hospital admission and close observation on a coronary care unit for possible complications (such as cardiac arrhythmias – irregularities in the heart rate). Depending on the risk assessment, stress testing or angiography may be used to identify and treat coronary artery disease in patients who have had an NSTEMI or unstable angina.
=== Risk assessment ===
There are various risk assessment systems for determining the risk of coronary artery disease, with various emphasis on the different variables above. A notable example is Framingham Score, used in the Framingham Heart Study. It is mainly based on age, gender, diabetes, total cholesterol, HDL cholesterol, tobacco smoking, and systolic blood pressure. When predicting risk in younger adults (18–39 years old), the Framingham Risk Score remains below 10–12% for all deciles of baseline-predicted risk.
Polygenic score is another way of risk assessment. In one study the relative risk of incident coronary events was 91% higher among participants at high genetic risk than among those at low genetic risk.
== Prevention ==
Up to 90% of cardiovascular disease may be preventable if established risk factors are avoided. Prevention involves adequate physical exercise, decreasing obesity, treating high blood pressure, eating a healthy diet, decreasing cholesterol levels, and stopping smoking. Medications and exercise are roughly equally effective. High levels of physical activity reduce the risk of coronary artery disease by about 25%. Life's Essential 8 are the key measures for improving and maintaining cardiovascular health, as defined by the American Heart Association. AHA added sleep as a factor influencing heart health in 2022.
Most guidelines recommend combining these preventive strategies. A 2015 Cochrane Review found some evidence that counseling and education to bring about behavioral change might help in high-risk groups. However, there was insufficient evidence to show an effect on mortality or actual cardiovascular events.
In diabetes mellitus, there is little evidence that very tight blood sugar control improves cardiac risk although improved sugar control appears to decrease other problems such as kidney failure and blindness.
A 2024 study published in The Lancet Diabetes & Endocrinology found that the oral glucose tolerance test (OGTT) is more effective than hemoglobin A1c (HbA1c) for detecting dysglycemia in patients with coronary artery disease. The study highlighted that 2-hour post-load glucose levels of at least 9 mmol/L were strong predictors of cardiovascular outcomes, while HbA1c levels of at least 5.9% were also significant but not independently associated when combined with OGTT results.
=== Diet ===
A diet high in fruits and vegetables decreases the risk of cardiovascular disease and death. Vegetarians have a lower risk of heart disease, possibly due to their greater consumption of fruits and vegetables. Evidence also suggests that the Mediterranean diet and a high fiber diet lower the risk.
The consumption of trans fat (commonly found in hydrogenated products such as margarine) has been shown to cause a precursor to atherosclerosis and increase the risk of coronary artery disease.
Evidence does not support a beneficial role for omega-3 fatty acid supplementation in preventing cardiovascular disease (including myocardial infarction and sudden cardiac death).
=== Secondary prevention ===
Secondary prevention is preventing further sequelae of already established disease. Effective lifestyle changes include:
Weight control
Smoking cessation
Avoiding the consumption of trans fats (in partially hydrogenated oils)
Decreasing psychosocial stress
Exercise
Aerobic exercise, like walking, jogging, or swimming, can reduce the risk of mortality from coronary artery disease. Aerobic exercise can help decrease blood pressure and the amount of blood cholesterol (LDL) over time. It also increases HDL cholesterol.
Although exercise is beneficial, it is unclear whether doctors should spend time counseling patients to exercise. The U.S. Preventive Services Task Force found "insufficient evidence" to recommend that doctors counsel patients on exercise but "it did not review the evidence for the effectiveness of physical activity to reduce chronic disease, morbidity, and mortality", only the effectiveness of counseling itself. The American Heart Association, based on a non-systematic review, recommends that doctors counsel patients on exercise.
Psychological symptoms are common in people with CHD. Many psychological treatments may be offered following cardiac events. There is no evidence that they change mortality, the risk of revascularization procedures, or the rate of non-fatal myocardial infarction.
Antibiotics for secondary prevention of coronary heart disease
Early studies suggested that antibiotics might help patients with coronary disease to reduce the risk of heart attacks and strokes. However, a 2021 Cochrane meta-analysis found that antibiotics given for secondary prevention of coronary heart disease are harmful to people with increased mortality and occurrence of stroke. So, antibiotic use is not currently supported for preventing secondary coronary heart disease.
=== Neuropsychological assessment ===
A thorough systematic review found that indeed there is a link between a CHD condition and brain dysfunction in females. Consequently, since research is showing that cardiovascular diseases, like CHD, can play a role as a precursor for dementia, like Alzheimer's disease, individuals with CHD should have a neuropsychological assessment.
== Treatment ==
There are a number of treatment options for coronary artery disease:
Lifestyle changes
Medical treatment – commonly prescribed drugs (e.g., cholesterol lowering medications, beta-blockers, nitroglycerin, calcium channel blockers, etc.);
Coronary interventions as angioplasty and coronary stent;
Coronary artery bypass grafting (CABG)
=== Medications ===
Statins, which reduce cholesterol, reduce the risk of coronary artery disease
Nitroglycerin
Calcium channel blockers and/or beta-blockers
Antiplatelet drugs such as aspirin
It is recommended that blood pressure typically be reduced to less than 140/90 mmHg. The diastolic blood pressure should not be below 60 mmHg. Beta-blockers are recommended first line for this use.
==== Aspirin ====
In those with no previous history of heart disease, aspirin decreases the risk of a myocardial infarction but does not change the overall risk of death. Aspirin therapy to prevent heart disease is thus recommended only in adults who are at increased risk for cardiovascular events, which may include postmenopausal females, males above 40, and younger people with risk factors for coronary heart disease, including high blood pressure, a family history of heart disease, or diabetes. The benefits outweigh the harms most favorably in people at high risk for a cardiovascular event, where high risk is defined as at least a 3% chance over five years, but others with lower risk may still find the potential benefits worth the associated risks.
==== Anti-platelet therapy ====
Clopidogrel plus aspirin (dual anti-platelet therapy) reduces cardiovascular events more than aspirin alone in those with a STEMI. In others at high risk but not having an acute event, the evidence is weak. Specifically, its use does not change the risk of death in this group. In those who have had a stent, more than 12 months of clopidogrel plus aspirin does not affect the risk of death.
=== Surgery ===
Revascularization for acute coronary syndrome has a mortality benefit. Percutaneous revascularization for stable ischaemic heart disease does not appear to have benefits over medical therapy alone. In those with disease in more than one artery, coronary artery bypass grafts appear better than percutaneous coronary interventions. Newer "anaortic" or no-touch off-pump coronary artery revascularization techniques have shown reduced postoperative stroke rates comparable to percutaneous coronary intervention. Hybrid coronary revascularization has also been shown to be a safe and feasible procedure that may offer some advantages over conventional CABG though it is more expensive.
== Epidemiology ==
As of 2010, CAD was the leading cause of death globally resulting in over 7 million deaths. This increased from 5.2 million deaths from CAD worldwide in 1990. It may affect individuals at any age but becomes dramatically more common at progressively older ages, with approximately a tripling with each decade of life. Males are affected more often than females.
The World Health Organization reported that: "The world's biggest killer is ischemic heart disease, responsible for 13% of the world's total deaths. Since 2000, the largest increase in deaths has been for this disease, rising by 2.7 million to 9.1 million deaths in 2021."
It is estimated that 60% of the world's cardiovascular disease burden will occur in the South Asian subcontinent despite only accounting for 20% of the world's population. This may be secondary to a combination of genetic predisposition and environmental factors. Organizations such as the Indian Heart Association are working with the World Heart Federation to raise awareness about this issue.
Coronary artery disease is the leading cause of death for both males and females and accounts for approximately 600,000 deaths in the United States every year. According to present trends in the United States, half of healthy 40-year-old males will develop CAD in the future, and one in three healthy 40-year-old females. It is the most common reason for death of males and females over 20 years of age in the United States.
After analysing data from 2 111 882 patients, the recent meta-analysis revealed that the incidence of coronary artery diseases in breast cancer survivors was 4.29 (95% CI 3.09–5.94) per 1000 person-years.
== Society and culture ==
=== Names ===
Other terms sometimes used for this condition are "hardening of the arteries" and "narrowing of the arteries". In Latin it is known as morbus ischaemicus cordis (MIC).
=== Support groups ===
The Infarct Combat Project (ICP) is an international nonprofit organization founded in 1998 which tries to decrease ischemic heart diseases through education and research.
=== Industry influence on research ===
In 2016 research into the internal documents of the Sugar Research Foundation, the trade association for the sugar industry in the US, had sponsored an influential literature review published in 1965 in the New England Journal of Medicine that downplayed early findings about the role of a diet heavy in sugar in the development of CAD and emphasized the role of fat; that review influenced decades of research funding and guidance on healthy eating.
== Research ==
Research efforts are focused on new angiogenic treatment modalities and various (adult) stem-cell therapies. A region on chromosome 17 was confined to families with multiple cases of myocardial infarction. Other genome-wide studies have identified a firm risk variant on chromosome 9 (9p21.3). However, these and other loci are found in intergenic segments and need further research in understanding how the phenotype is affected.
A more controversial link is that between Chlamydophila pneumoniae infection and atherosclerosis. While this intracellular organism has been demonstrated in atherosclerotic plaques, evidence is inconclusive regarding whether it can be considered a causative factor. Treatment with antibiotics in patients with proven atherosclerosis has not demonstrated a decreased risk of heart attacks or other coronary vascular diseases.
Myeloperoxidase has been proposed as a biomarker.
Plant-based nutrition has been suggested as a way to reverse coronary artery disease, but strong evidence is still lacking for claims of potential benefits.
Several immunosuppressive drugs targeting the chronic inflammation in coronary artery disease have been tested.
== See also ==
Mental stress-induced myocardial ischemia
== References ==
== External links ==
Risk Assessment of having a heart attack or dying of coronary artery disease, from the American Heart Association.
"Coronary Artery Disease". MedlinePlus. U.S. National Library of Medicine.
Norman J (7 October 2019). "Managing Diabetes with Blood Glucose Control". Endocrineweb. | Wikipedia/Coronary_disease |
Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems with language, disorientation (including easily getting lost), mood swings, loss of motivation, self-neglect, and behavioral issues. As a person's condition declines, they often withdraw from family and society. Gradually, bodily functions are lost, ultimately leading to death. Although the speed of progression can vary, the average life expectancy following diagnosis is three to twelve years.
The causes of Alzheimer's disease remain poorly understood. There are many environmental and genetic risk factors associated with its development. The strongest genetic risk factor is from an allele of apolipoprotein E. Other risk factors include a history of head injury, clinical depression, and high blood pressure. The progression of the disease is largely characterised by the accumulation of malformed protein deposits in the cerebral cortex, called amyloid plaques and neurofibrillary tangles. These misfolded protein aggregates interfere with normal cell function, and over time lead to irreversible degeneration of neurons and loss of synaptic connections in the brain. A probable diagnosis is based on the history of the illness and cognitive testing, with medical imaging and blood tests to rule out other possible causes. Initial symptoms are often mistaken for normal brain aging. Examination of brain tissue is needed for a definite diagnosis, but this can only take place after death.
No treatments can stop or reverse its progression, though some may temporarily improve symptoms. A healthy diet, physical activity, and social engagement are generally beneficial in aging, and may help in reducing the risk of cognitive decline and Alzheimer's. Affected people become increasingly reliant on others for assistance, often placing a burden on caregivers. The pressures can include social, psychological, physical, and economic elements. Exercise programs may be beneficial with respect to activities of daily living and can potentially improve outcomes. Behavioral problems or psychosis due to dementia are sometimes treated with antipsychotics, but this has an increased risk of early death.
As of 2020, there were approximately 50 million people worldwide with Alzheimer's disease. It most often begins in people over 65 years of age, although up to 10% of cases are early-onset impacting those in their 30s to mid-60s. It affects about 6% of people 65 years and older, and women more often than men. The disease is named after German psychiatrist and pathologist Alois Alzheimer, who first described it in 1906. Alzheimer's financial burden on society is large, with an estimated global annual cost of US$1 trillion. It is ranked as the seventh leading cause of death worldwide.
Given the widespread impacts of Alzheimer's disease, both basic-science and health funders in many countries support Alzheimer's research at large scales. For example, the US National Institutes of Health program for Alzheimer's research, the National Plan to Address Alzheimer's Disease, has a budget of US$3.98 billion for fiscal year 2026. In the European Union, the 2020 Horizon Europe research programme awarded over €570 million for dementia-related projects.
== Signs and symptoms ==
The course of Alzheimer's is generally described in three stages, with a progressive pattern of cognitive and functional impairment. The three stages are described as early or mild, middle or moderate, and late or severe. The disease is known to target the hippocampus which is associated with memory, and this is responsible for the first symptoms of memory impairment. As the disease progresses so does the degree of memory impairment.
=== First symptoms ===
The first symptoms are often mistakenly attributed to aging or stress. Detailed neuropsychological testing can reveal mild cognitive difficulties up to eight years before a person fulfills the clinical criteria for diagnosis of Alzheimer's disease. These early symptoms can affect the most complex activities of daily living. The most noticeable deficit is short term memory loss, which shows up as difficulty in remembering recently learned facts and inability to acquire new information.
Subtle problems with the executive functions of attentiveness, planning, flexibility, and abstract thinking, or impairments in semantic memory (memory of meanings, and concept relationships) can also be symptomatic of the early stages of Alzheimer's disease. Apathy and depression can be seen at this stage, with apathy remaining as the most persistent symptom throughout the course of the disease. People with objective signs of cognitive impairment, but not more severe symptoms, may be diagnosed with mild cognitive impairment (MCI). If memory loss is the predominant symptom of MCI, it is termed amnestic MCI and is frequently seen as a prodromal or early stage of Alzheimer's disease. Amnestic MCI has a greater than 90% likelihood of being associated with Alzheimer's.
=== Early stage ===
In people with Alzheimer's disease, the increasing impairment of learning and memory eventually leads to a definitive diagnosis. In a small percentage, difficulties with language, executive functions, perception (agnosia), or execution of movements (apraxia) are more prominent than memory problems. Alzheimer's disease does not affect all memory capacities equally. Older memories of the person's life (episodic memory), facts learned (semantic memory), and implicit memory (the memory of the body on how to do things, such as using a fork to eat or how to drink from a glass) are affected to a lesser degree than new facts or memories.
Language problems are mainly characterised by a shrinking vocabulary and decreased word fluency, leading to a general impoverishment of oral and written language. In this stage, the person with Alzheimer's is usually capable of communicating basic ideas adequately. While performing fine motor tasks such as writing, drawing, or dressing, certain movement coordination and planning difficulties (apraxia) may be present; however, they are commonly unnoticed. As the disease progresses, people with Alzheimer's disease can often continue to perform many tasks independently; however, they may need assistance or supervision with the most cognitively demanding activities.
=== Middle stage ===
Progressive deterioration eventually hinders independence, with subjects being unable to perform most common activities of daily living. Speech difficulties become evident due to an inability to recall vocabulary, which leads to frequent incorrect word substitutions (paraphasias). Reading and writing skills are also progressively lost. Complex motor sequences become less coordinated as time passes and Alzheimer's disease progresses, so the risk of falling increases. During this phase, memory problems worsen, and the person may fail to recognise close relatives. Long-term memory, which was previously intact, becomes impaired.
Behavioral and neuropsychiatric changes become more prevalent. Common manifestations are wandering, irritability and emotional lability, leading to crying, outbursts of unpremeditated aggression, or resistance to caregiving. Sundowning can also appear. Approximately 30% of people with Alzheimer's disease develop illusionary misidentifications and other delusional symptoms. Subjects also lose insight of their disease process and limitations (anosognosia). Urinary incontinence can develop. These symptoms create stress for relatives and caregivers, which can be reduced by moving the person from home care to other long-term care facilities.
=== Late stage ===
During the final stage, known as the late-stage or severe stage, there is complete dependence on caregivers. Language is reduced to simple phrases or even single words, eventually leading to complete loss of speech. Despite the loss of verbal language abilities, people can often understand and return emotional signals. Although aggressiveness can still be present, extreme apathy and exhaustion are much more common symptoms. People with Alzheimer's disease will ultimately not be able to perform even the simplest tasks independently; muscle mass and mobility deteriorates to the point where they are bedridden and unable to feed themselves. The cause of death is usually an external factor, such as infection of pressure ulcers or pneumonia, not the disease itself. In some cases, there is a paradoxical lucidity immediately before death, where there is an unexpected recovery of mental clarity.
== Causes ==
Alzheimer's disease is believed to occur when abnormal amounts of amyloid beta (Aβ), accumulating extracellularly as amyloid plaques and tau proteins, or intracellularly as neurofibrillary tangles, form in the brain, affecting neuronal functioning and connectivity, resulting in a progressive loss of brain function. This altered protein clearance ability is age-related, regulated by brain cholesterol, and associated with other neurodegenerative diseases.
The cause for most Alzheimer's cases is still mostly unknown, except for 1–2% of cases where deterministic genetic differences have been identified. Several competing hypotheses attempt to explain the underlying cause; the most predominant hypothesis is the amyloid beta (Aβ) hypothesis.
In the 1970s, the cholinergic hypothesis proposed that Alzheimer's disease is caused by reduced synthesis of the neurotransmitter acetylcholine. The loss of cholinergic neurons noted in the limbic system and cerebral cortex, is a key feature in the progression of Alzheimer's. The 1991 amyloid hypothesis postulated that extracellular amyloid beta (Aβ) deposits are the fundamental cause of the disease. Support for this postulate comes from the location of the gene for the amyloid precursor protein (APP) on chromosome 21, together with the fact that people with trisomy 21 (Down syndrome) who have an extra gene copy almost universally exhibit at least the earliest symptoms of Alzheimer's disease by 40 years of age. A specific isoform of apolipoprotein, APOE4, is a major genetic risk factor for Alzheimer's disease. While apolipoproteins enhance the breakdown of amyloid beta, some isoforms are not very effective at this task (such as APOE4), leading to excess amyloid buildup in the brain.
=== Genetic ===
==== Late onset ====
Late-onset Alzheimer's is about 70% heritable. Most cases of Alzheimer's are not familial, and so they are termed sporadic Alzheimer's disease. Of the cases of sporadic Alzheimer's disease, most are classified as late onset where they are developed after the age of 65 years.
The strongest genetic risk factor for sporadic Alzheimer's disease is APOEε4. APOEε4 is one of four alleles of apolipoprotein E (APOE). APOE plays a major role in lipid-binding proteins in lipoprotein particles and the ε4 allele disrupts this function. Between 40% and 80% of people with Alzheimer's disease possess at least one APOEε4 allele. The APOEε4 allele increases the risk of the disease by three times in heterozygotes and by 15 times in homozygotes. Like many human diseases, environmental effects and genetic modifiers result in incomplete penetrance. For example, Nigerian Yoruba people do not show the relationship between dose of APOEε4 and incidence or age-of-onset for Alzheimer's disease seen in other human populations.
==== Early onset ====
Only 1–2% of Alzheimer's cases are inherited due to autosomal dominant effects, as Alzheimer's is highly polygenic. When the disease is caused by autosomal dominant variants, it is known as early onset familial Alzheimer's disease, which is rarer and has a faster rate of progression. Less than 5% of sporadic Alzheimer's disease have an earlier onset, and early-onset Alzheimer's is about 90% heritable. Familial Alzheimer's disease usually implies two or more persons affected in one or more generations.
Early onset familial Alzheimer's disease can be attributed to mutations in one of three genes: those encoding amyloid-beta precursor protein (APP) and presenilins PSEN1 and PSEN2. Most mutations in the APP and presenilin genes increase the production of a small protein called amyloid beta (Aβ)42, which is the main component of amyloid plaques. Some of the mutations merely alter the ratio between Aβ42 and the other major forms—particularly Aβ40—without increasing Aβ42 levels in the brain. Two other genes associated with autosomal dominant Alzheimer's disease are ABCA7 and SORL1.
Alleles in the TREM2 gene have been associated with a three to five times higher risk of developing Alzheimer's disease.
A Japanese pedigree of familial Alzheimer's disease was found to be associated with a deletion mutation of codon 693 of APP. This mutation and its association with Alzheimer's disease was first reported in 2008, and is known as the Osaka mutation. Only homozygotes with this mutation have an increased risk of developing Alzheimer's disease. This mutation accelerates Aβ oligomerization but the proteins do not form the amyloid fibrils that aggregate into amyloid plaques, suggesting that it is the Aβ oligomerization rather than the fibrils that may be the cause of this disease. Mice expressing this mutation have all the usual pathologies of Alzheimer's disease.
=== Hypotheses ===
==== Amyloid beta and tau protein ====
The tau hypothesis proposes that tau protein abnormalities initiate the disease cascade. In this model, hyperphosphorylated tau begins to pair with other threads of tau as paired helical filaments. Eventually, they form neurofibrillary tangles inside neurons. When this occurs, the microtubules disintegrate, destroying the structure of the cell's cytoskeleton which collapses the neuron's transport system.
A number of studies connect the misfolded amyloid beta and tau proteins associated with the pathology of Alzheimer's disease, as bringing about oxidative stress that leads to neuroinflammation. This chronic inflammation is also a feature of other neurodegenerative diseases including Parkinson's disease, and ALS. Spirochete infections have also been linked to dementia. DNA damages accumulate in Alzheimer's diseased brains; reactive oxygen species may be the major source of this DNA damage.
==== Sleep ====
Sleep disturbances are seen as a possible risk factor for inflammation in Alzheimer's disease. Sleep disruption was previously only seen as a consequence of Alzheimer's disease, but as of 2020, accumulating evidence suggests that this relationship may be bidirectional.
==== Metal toxicity, smoking, neuroinflammation and air pollution ====
The cellular homeostasis of biometals such as ionic copper, iron, and zinc is disrupted in Alzheimer's disease, though it remains unclear whether this is produced by or causes the changes in proteins. Smoking is a significant Alzheimer's disease risk factor. Systemic markers of the innate immune system are risk factors for late-onset Alzheimer's disease. Exposure to air pollution may be a contributing factor to the development of Alzheimer's disease.
==== Age-related myelin decline ====
Retrogenesis is a medical hypothesis that just as the fetus goes through a process of neurodevelopment beginning with neurulation and ending with myelination, the brains of people with Alzheimer's disease go through a reverse neurodegeneration process starting with demyelination and death of axons (white matter) and ending with the death of grey matter. Likewise the hypothesis is, that as infants go through states of cognitive development, people with Alzheimer's disease go through the reverse process of progressive cognitive impairment.
According to one theory, dysfunction of oligodendrocytes and their associated myelin during aging contributes to axon damage, which in turn generates in amyloid production and tau hyperphosphorylation. Comorbidities between the demyelinating disease, multiple sclerosis, and Alzheimer's disease have been reported.
==== Other hypotheses ====
The association with celiac disease is unclear, with a 2019 study finding no increase in dementia overall in those with celiac disease while a 2018 review found an association with several types of dementia including Alzheimer's disease.
Studies have shown a potential link between infection with certain viruses and developing Alzheimer's disease later in life. Notably, a large scale study conducted on 6,245,282 patients has shown an increased risk of developing Alzheimer's disease following COVID-19 infection in cognitively normal individuals over 65.
Some evidence suggests that some viral infections such as Herpes simplex virus 1 (HSV-1) may be associated with dementia, but there are conflicting results and the association with Alzheimer's is unclear as of 2024.
Some researchers have proposed that Alzheimer's disease is Type 3 diabetes because of a number of correspondences with both Type 1 and Type 2 diabetes.
== Pathophysiology ==
=== Neuropathology ===
Alzheimer's disease is characterised by loss of neurons and synapses in the cerebral cortex and certain subcortical regions. This loss results in gross atrophy of the affected regions, including degeneration in the temporal lobe and parietal lobe, and parts of the frontal cortex and cingulate gyrus. Degeneration is also present in brainstem nuclei particularly the locus coeruleus in the pons. Studies using MRI and PET have documented reductions in the size of specific brain regions in people with Alzheimer's disease as they progressed from mild cognitive impairment to Alzheimer's disease, and in comparison with similar images from healthy older adults.
Both Aβ plaques and neurofibrillary tangles are clearly visible by microscopy in brains of those with Alzheimer's disease, especially in the hippocampus. However, Alzheimer's disease may occur without neurofibrillary tangles in the neocortex. Plaques are dense, mostly insoluble deposits of amyloid beta peptide and cellular material outside and around neurons. Neurofibrillary tangles are aggregates of the microtubule-associated protein tau which has become hyperphosphorylated and accumulate inside the cells themselves. Although many older individuals develop some plaques and tangles as a consequence of aging, the brains of people with Alzheimer's disease have a greater number of them in specific brain regions such as the temporal lobe. Lewy bodies are not rare in the brains of people with Alzheimer's disease.
=== Biochemistry ===
==== Amyloid beta ====
Alzheimer's disease has been identified as a protein misfolding disease, a proteopathy, caused by the accumulation of abnormally folded amyloid beta protein into amyloid plaques, and tau protein into neurofibrillary tangles in the brain. Plaques are made up of small peptides, 39–43 amino acids in length, called amyloid beta. Amyloid beta is a fragment from the larger amyloid-beta precursor protein (APP) a transmembrane protein that penetrates the cell's membrane. APP is critical to neuron growth, survival, and post-injury repair. In Alzheimer's disease, gamma secretase and beta secretase act together in a proteolytic process which causes APP to be divided into smaller fragments. Although commonly researched as neuronal proteins, APP and its processing enzymes are abundantly expressed by other brain cells. One of these fragments gives rise to fibrils of amyloid beta, which then form clumps that deposit outside neurons in dense formations known as amyloid plaques. Excitatory neurons are known to be the major producers of amyloid beta that contribute to major extracellular plaque deposition.
==== Phosphorylated tau ====
Alzheimer's disease is also considered a tauopathy due to abnormal aggregation of the tau protein. Every neuron has a cytoskeleton, an internal support structure partly made up of structures called microtubules. These microtubules act like tracks, guiding nutrients and molecules from the body of the cell to the ends of the axon and back. A protein called tau stabilises the microtubules when phosphorylated, and is therefore called a microtubule-associated protein. In Alzheimer's disease, tau undergoes chemical changes, becoming hyperphosphorylated; it then begins to pair with other threads, creating neurofibrillary tangles and disintegrating the neuron's transport system. Pathogenic tau can also cause neuronal death through transposable element dysregulation. Necroptosis has also been reported as a mechanism of cell death in brain cells affected with tau tangles.
=== Disease mechanism ===
Exactly how disturbances of production and aggregation of the beta-amyloid peptide give rise to the pathology of Alzheimer's disease is not known. The amyloid hypothesis traditionally points to the accumulation of beta-amyloid peptides as the central event triggering neuron degeneration. Accumulation of aggregated amyloid fibrils, which are believed to be the toxic form of the protein responsible for disrupting the cell's calcium ion homeostasis, induces programmed cell death (apoptosis). It is also known that Aβ selectively builds up in the mitochondria in the cells of Alzheimer's-affected brains, and it also inhibits certain enzyme functions and the utilisation of glucose by neurons.
Evidence supports Aβ as playing a central role in the pathogenesis of AD, but it does not completely explain the condition, as individuals may have normal cognition and very high Aβ burden in their brains at an advanced age, and the beneficial effect of therapeutics (such as monoclonal antibodies) promoting Aβ clearance has ranged from nonexistent to modest.
Iron dyshomeostasis is linked to disease progression, an iron-dependent form of regulated cell death called ferroptosis could be involved. Products of lipid peroxidation are also elevated in AD brain compared with controls.
Various inflammatory processes and cytokines may also have a role in the pathology of Alzheimer's disease. Inflammation is a general marker of tissue damage in any disease, and may be either secondary to tissue damage in Alzheimer's disease or a marker of an immunological response. There is increasing evidence of a strong interaction between the neurons and the immunological mechanisms in the brain. Obesity and systemic inflammation may interfere with immunological processes which promote disease progression.
Alterations in the distribution of different neurotrophic factors and in the expression of their receptors such as the brain-derived neurotrophic factor (BDNF) have been described in Alzheimer's disease.
Evidence has accrued for microglia as central actors in the mechanism of AD. Microglia are topographically associated with pTau and Aβ within the brain, even when each pathologic component occurs in distinct brain regions, and microglial activation has been documented in those with mild cognitive impairment, despite a lack of tracer uptake, suggesting that microglial dysfunction may precede plaque deposition as an inciting event in AD. Microglia are the principal immunological cells of the central nervous system, serving as the tissue-resident macrophages of the brain; they are capable of recognizing and taking up Aβ through multiple pattern recognition receptors, making them central to amyloid clearance within the brain. However, microglia can also be a major source of pro-inflammatory mediators which can be deleterious to neurological function.
== Diagnosis ==
Alzheimer's disease (AD) can only be definitively diagnosed with autopsy findings; in the absence of autopsy, clinical diagnoses of AD are "possible" or "probable", based on other findings. Up to 23% of those clinically diagnosed with AD may be misdiagnosed and may have pathology suggestive of another condition with symptoms that mimic those of AD.
AD is usually clinically diagnosed based on a person's medical history, observations from friends or relatives, and behavioral changes. The presence of characteristic neuropsychological changes with impairments in at least two cognitive domains that are severe enough to affect a person's functional abilities are required for the diagnosis. Domains that may be impaired include memory (most commonly impaired), language, executive function, visuospatial functioning, or other areas of cognition. The neurocognitive changes must be a decline from a prior level of function and the diagnosis requires ruling out other common causes of neurocognitive decline. Advanced medical imaging with computed tomography (CT) or magnetic resonance imaging (MRI), and with single-photon emission computed tomography (SPECT) or positron emission tomography (PET), can be used to help exclude other cerebral pathology or subtypes of dementia. On MRI or CT, Alzheimer's disease usually shows a generalised or focal cortical atrophy, which may be asymmetric. Atrophy of the hippocampus is also commonly seen. Brain imaging commonly also shows cerebrovascular disease, most commonly previous strokes (small or large territory strokes), and this is thought to be a contributing cause of many cases of dementia (up to 46% cases of dementia also have cerebrovascular disease on imaging). FDG-PET scan is not required for the diagnosis but it is sometimes used when standard testing is unclear. FDG-PET shows a bilateral, asymmetric, temporal and parietal reduced activity. Advanced imaging may predict conversion from prodromal stages (mild cognitive impairment) to Alzheimer's disease. FDA-approved radiopharmaceutical diagnostic agents used in PET for Alzheimer's disease are florbetapir (2012), flutemetamol (2013), florbetaben (2014), and flortaucipir (2020). Because many insurance companies in the United States do not cover this procedure, its use in clinical practice is largely limited to clinical trials as of 2018.
Assessment of intellectual functioning including memory testing can further characterise the state of the disease. Medical organizations have created diagnostic criteria to ease and standardise the diagnostic process for practising physicians. Definitive diagnosis can only be confirmed with post-mortem evaluations when brain material is available and can be examined histologically for senile plaques and neurofibrillary tangles.
=== Criteria ===
There are three sets of criteria for the clinical diagnoses of the spectrum of Alzheimer's disease: the 2013 fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5); the National Institute on Aging-Alzheimer's Association (NIA-AA) definition as revised in 2011; and the International Working Group criteria as revised in 2010.
Eight intellectual domains are most commonly impaired in AD—memory, language, perceptual skills, attention, motor skills, orientation, problem solving and executive functional abilities, as listed in the fourth text revision of the DSM (DSM-IV-TR).
The DSM-5 defines criteria for probable or possible AD for both major and mild neurocognitive disorder. Major or mild neurocognitive disorder must be present along with at least one cognitive deficit for a diagnosis of either probable or possible AD. For major neurocognitive disorder due to AD, probable Alzheimer's disease can be diagnosed if the individual has genetic evidence of AD or if two or more acquired cognitive deficits, and a functional disability that is not from another disorder, are present. Otherwise, possible AD can be diagnosed as the diagnosis follows an atypical route. For mild neurocognitive disorder due to AD, probable Alzheimer's disease can be diagnosed if there is genetic evidence, whereas possible AD can be met if all of the following are present: no genetic evidence, decline in both learning and memory, two or more cognitive deficits, and a functional disability not from another disorder.
The NIA-AA criteria are used mainly in research rather than in clinical assessments. They define AD through three major stages: preclinical, mild cognitive impairment (MCI), and Alzheimer's dementia. Diagnosis in the preclinical stage is complex and focuses on asymptomatic individuals; the latter two stages describe individuals experiencing symptoms, along with biomarkers, predominantly those for neuronal injury (mainly tau-related) and amyloid beta deposition. The core clinical criteria itself rests on the presence of cognitive impairment without the presence of comorbidities. The third stage is divided into probable and possible AD dementia. In probable AD dementia there is steady impairment of cognition over time and a memory-related or non-memory-related cognitive dysfunction. In possible AD dementia, another causal disease such as cerebrovascular disease is present.
=== Techniques ===
Neuropsychological tests including cognitive tests such as the mini–mental state examination (MMSE), the Montreal Cognitive Assessment (MoCA) and the Mini-Cog are widely used to aid in diagnosis of the cognitive impairments in AD. These tests may not always be accurate, as they lack sensitivity to mild cognitive impairment, and can be biased by language or attention problems; more comprehensive test arrays are necessary for high reliability of results, particularly in the earliest stages of the disease.
Further neurological examinations are crucial in the differential diagnosis of Alzheimer's disease and other diseases. Interviews with family members are used in assessment; caregivers can supply important information on daily living abilities and on the decrease in the person's mental function. A caregiver's viewpoint is particularly important, since a person with Alzheimer's disease is commonly unaware of their deficits. Many times, families have difficulties in the detection of initial dementia symptoms and may not communicate accurate information to a physician.
Supplemental testing can rule out other potentially treatable diagnoses and help avoid misdiagnoses. Common supplemental tests include blood tests, thyroid function tests, as well as tests to assess vitamin B12 levels, rule out neurosyphilis and rule out metabolic problems (including tests for kidney function, electrolyte levels and for diabetes). MRI or CT scans might also be used to rule out other potential causes of the symptoms – including tumors or strokes. Delirium and depression can be common among individuals and are important to rule out.
Psychological tests for depression are used, since depression can either be concurrent with AD (see Depression of Alzheimer disease), an early sign of cognitive impairment, or even the cause.
Due to low accuracy, the C-PIB-PET scan is not recommended as an early diagnostic tool or for predicting the development of AD when people show signs of mild cognitive impairment (MCI). The use of 18F-FDG PET scans, as a single test, to identify people who may develop Alzheimer's disease is not supported by evidence.
In May 2025, the US FDA approved a blood test by Fujirebio Diagnostics’ Lumipulse G pTau217/ß-Amyloid 1-42 Plasma Ratio diagnostic device for the early detection of amyloid plaques associated with AD in adults aged 55 years and older who are exhibiting signs and symptoms of the disease.
== Prevention ==
There are no disease-modifying treatments available to cure Alzheimer's disease and because of this, AD research has focused on interventions to prevent the onset and progression. There is no evidence that supports any particular measure in preventing AD, and studies of measures to prevent the onset or progression have produced inconsistent results. Epidemiological studies have proposed relationships between an individual's likelihood of developing AD and modifiable factors, such as medications, lifestyle, and diet. There are some challenges in determining whether interventions for AD act as a primary prevention method, preventing the disease itself, or a secondary prevention method, identifying the early stages of the disease. These challenges include duration of intervention, different stages of disease at which intervention begins, and lack of standardization of inclusion criteria regarding biomarkers specific for AD. Further research is needed to determine factors that can help prevent AD.
=== Medication ===
Cardiovascular risk factors, such as hypercholesterolaemia, hypertension, diabetes, and smoking, are associated with a higher risk of onset and worsened course of AD. The use of statins to lower cholesterol may be of benefit in AD. Antihypertensive and antidiabetic medications in individuals without overt cognitive impairment may decrease the risk of dementia by influencing cerebrovascular pathology. More research is needed to examine the relationship with AD specifically; clarification of the direct role medications play versus other concurrent lifestyle changes (diet, exercise, smoking) is needed.
Depression is associated with an increased risk for AD; management with antidepressant medications may provide a preventative measure.
Historically, long-term usage of non-steroidal anti-inflammatory drugs (NSAIDs) were thought to be associated with a reduced likelihood of developing AD as it reduces inflammation, but NSAIDs do not appear to be useful as a treatment. Additionally, because women have a higher incidence of AD than men, it was once thought that estrogen deficiency during menopause was a risk factor, but there is a lack of evidence to show that hormone replacement therapy (HRT) in menopause decreases risk of cognitive decline.
=== Lifestyle ===
Certain lifestyle activities, such as physical and cognitive exercises, higher education and occupational attainment, cigarette smoking, stress, sleep, and the management of other comorbidities, including diabetes and hypertension, may affect the risk of developing AD.
Physical exercise is associated with a decreased rate of dementia, and is effective in reducing symptom severity in those with AD. Memory and cognitive functions can be improved with aerobic exercises including brisk walking three times weekly for forty minutes. It may also induce neuroplasticity of the brain. Participating in mental exercises, such as reading, crossword puzzles, and chess have shown potential to be preventive. Meeting the WHO recommendations for physical activity is associated with a lower risk of AD.
Higher education and occupational attainment, and participation in leisure activities, contribute to a reduced risk of developing AD, or of delaying the onset of symptoms. This is compatible with the cognitive reserve theory, which states that some life experiences result in more efficient neural functioning providing the individual a cognitive reserve that delays the onset of dementia manifestations. Education delays the onset of Alzheimer's disease syndrome without changing the duration of the disease.
Cessation in smoking may reduce risk of developing AD, specifically in those who carry the APOE ɛ4 allele. The increased oxidative stress caused by smoking results in downstream inflammatory or neurodegenerative processes that may increase risk of developing AD. Avoidance of smoking, counseling and pharmacotherapies to quit smoking are used, and avoidance of environmental tobacco smoke is recommended.
Alzheimer's disease is associated with sleep disorders but the precise relationship is unclear. It was once thought that as people get older, the risk of developing sleep disorders and AD independently increase, but research suggests sleep disorders may be a risk factor for AD. One theory is that the mechanisms to increase clearance of toxic substances, including Aβ, are active during sleep. With decreased sleep, a person is increasing Aβ production and decreasing Aβ clearance, resulting in Aβ accumulation. Receiving adequate sleep (approximately 7–8 hours) every night has become a potential lifestyle intervention to prevent the development of AD.
Stress is a risk factor for the development of AD. The mechanism by which stress predisposes someone to development of AD is unclear, but it is suggested that lifetime stressors may affect a person's epigenome, leading to an overexpression or under expression of specific genes. Although the relationship of stress and AD is unclear, strategies to reduce stress and relax the mind may be helpful strategies in preventing the progression or Alzheimer's disease. Meditation, for instance, is a helpful lifestyle change to support cognition and well-being, though further research is needed to assess long-term effects.
== Management ==
There is no cure for AD; available treatments offer relatively small symptomatic benefits but remain palliative in nature. Treatments can be divided into pharmaceutical, psychosocial, and caregiving.
=== Pharmaceutical ===
Medications used to treat the cognitive symptoms of AD rather than the underlying cause include: four acetylcholinesterase inhibitors (tacrine, rivastigmine, galantamine, and donepezil) and memantine, an NMDA receptor antagonist. The acetylcholinesterase inhibitors are intended for those with mild to severe AD, whereas memantine is intended for those with moderate or severe Alzheimer's disease. The benefit from their use is small.
Reduction in the activity of the cholinergic neurons is a well-known feature of AD. Acetylcholinesterase inhibitors are employed to reduce the rate at which acetylcholine (ACh) is broken down, thereby increasing the concentration of ACh in the brain and combating the loss of ACh caused by the death of cholinergic neurons. There is evidence for the efficacy of these medications in mild to moderate AD, and some evidence for their use in the advanced stage. The use of these drugs in mild cognitive impairment has not shown any effect in a delay of the onset of Alzheimer's disease. The most common side effects are nausea and vomiting, both of which are linked to cholinergic excess. These side effects arise in approximately 10–20% of users, are mild to moderate in severity, and can be managed by slowly adjusting medication doses. Less common secondary effects include muscle cramps, decreased heart rate (bradycardia), decreased appetite and weight, and increased gastric acid production.
Glutamate is an excitatory neurotransmitter of the nervous system, although excessive amounts in the brain can lead to cell death through a process called excitotoxicity which consists of the overstimulation of glutamate receptors. Excitotoxicity occurs not only in AD, but also in other neurological diseases such as Parkinson's disease and multiple sclerosis. Memantine is a noncompetitive NMDA receptor antagonist first used as an anti-influenza agent. It acts on the glutamatergic system by blocking NMDA receptors and inhibiting their overstimulation by glutamate. Memantine has been shown to have a small benefit in the treatment of moderate to severe AD. Reported adverse events with memantine are infrequent and mild, including hallucinations, confusion, dizziness, headache and fatigue. The combination of memantine and donepezil has been shown to be "of statistically significant but clinically marginal effectiveness".
An extract of Ginkgo biloba known as EGb 761 has been used for treating AD and other neuropsychiatric disorders. Its use is approved throughout Europe. The World Federation of Biological Psychiatry guidelines lists EGb 761 with the same weight of evidence (level B) given to acetylcholinesterase inhibitors and memantine. EGb 761 is the only one that showed improvement of symptoms in both AD and vascular dementia. EGb 761 may have a role either on its own or as an add-on if other therapies prove ineffective. A 2016 review concluded that the quality of evidence from clinical trials on Ginkgo biloba has been insufficient to warrant its use for treating AD.
Atypical antipsychotics are modestly useful in reducing aggression and psychosis in people with AD, but their advantages are offset by serious adverse effects, such as stroke, movement difficulties or cognitive decline. When used in the long-term, they have been shown to associate with increased mortality. They are recommended in dementia only after first line therapies such as behavior modification have failed, and due to the risk of adverse effects, they should be used for the shortest amount of time possible. Stopping antipsychotic use in this group of people appears to be safe.
=== Psychosocial ===
Psychosocial interventions are used as an adjunct to pharmaceutical treatment and can be classified within behavior-, emotion-, cognition- or stimulation-oriented approaches.
Behavioral interventions attempt to identify and reduce the antecedents and consequences of problem behaviors. This approach has not shown success in improving overall functioning, but can help to reduce some specific problem behaviors, such as incontinence. There is a lack of high quality data on the effectiveness of these techniques in other behavior problems such as wandering. Music therapy is effective in reducing behavioral and psychological symptoms.
Emotion-oriented interventions include reminiscence therapy, validation therapy, supportive psychotherapy, sensory integration, also called snoezelen, and simulated presence therapy. A Cochrane review has found no evidence that this is effective. Reminiscence therapy (RT) involves the discussion of past experiences individually or in group, many times with the aid of photographs, household items, music and sound recordings, or other familiar items from the past. A 2018 review of the effectiveness of RT found that effects were inconsistent, small in size and of doubtful clinical significance, and varied by setting. Simulated presence therapy (SPT) is based on attachment theories and involves playing a recording with voices of the closest relatives of the person with AD. There is partial evidence indicating that SPT may reduce challenging behaviors.
The aim of cognition-oriented treatments, which include reality orientation and cognitive retraining, is the reduction of cognitive deficits. Reality orientation consists of the presentation of information about time, place, or person to ease the understanding of the person about its surroundings and his or her place in them. On the other hand, cognitive retraining tries to improve impaired capacities by exercising mental abilities. Both have shown some efficacy improving cognitive capacities.
Stimulation-oriented treatments include art, music and pet therapies, exercise, and any other kind of recreational activities. Stimulation has modest support for improving behavior, mood, and, to a lesser extent, function. Nevertheless, as important as these effects are, the main support for the use of stimulation therapies is the change in the person's routine.
=== Caregiving ===
Since AD has no cure and it gradually renders people incapable of tending to their own needs, caregiving is essentially the treatment and must be carefully managed over the course of the disease.
During the early and moderate stages, modifications to the living environment and lifestyle can increase safety and reduce caretaker burden. Examples of such modifications are the adherence to simplified routines, the placing of safety locks, the labeling of household items to cue the person with the disease or the use of modified daily life objects. If eating becomes problematic, food will need to be prepared in smaller pieces or even puréed. When swallowing difficulties arise, the use of feeding tubes may be required. In such cases, the medical efficacy and ethics of continuing feeding is an important consideration of the caregivers and family members. The use of physical restraints is rarely indicated in any stage of the disease, although there are situations when they are necessary to prevent harm to the person with Alzheimer's disease or their caregivers.
During the final stages of the disease, treatment is centred on relieving discomfort until death, often with the help of hospice.
=== Diet ===
Diet may be a modifiable risk factor for the development of Alzheimer's disease but more research needs to be conducted. The Mediterranean diet, and the DASH diet are both associated with less cognitive decline. A different approach has been to incorporate elements of both of these diets into one known as the MIND diet.
Results from large-scale epidemiological studies and clinical trials have not demonstrated an independent role for most individual dietary components.
== Prognosis ==
The early stages of AD are difficult to diagnose. A definitive diagnosis is usually made once cognitive impairment compromises daily living activities, although the person may still be living independently. The symptoms will progress from mild cognitive problems, such as memory loss through increasing stages of cognitive and non-cognitive disturbances, eliminating any possibility of independent living, especially in the late stages of the disease.
Life expectancy of people with AD is reduced. The normal life expectancy for 60 to 70 years old is 23 to 15 years; for 90 years old it is 4.5 years. Following AD diagnosis it ranges from 7 to 10 years for those in their 60s and early 70s (a loss of 13 to 8 years), to only about 3 years or less (a loss of 1.5 years) for those in their 90s.
Fewer than 3% of people live more than fourteen years after diagnosis. Disease features significantly associated with reduced survival are an increased severity of cognitive impairment, decreased functional level, disturbances in the neurological examination, history of falls, malnutrition, dehydration and weight loss. Other coincident diseases such as heart problems, diabetes, or history of alcohol abuse are also related with shortened survival. While the earlier the age at onset the higher the total survival years, life expectancy is particularly reduced when compared to the healthy population among those who are younger. Men have a less favourable survival prognosis than women.
Aspiration pneumonia is the most frequent immediate cause of death brought by AD. While the reasons behind the lower prevalence of cancer in AD patients remain unclear, some researchers hypothesize that biological mechanisms shared by both diseases might play a role. However, this requires further investigation.
== Epidemiology ==
Two main measures are used in epidemiological studies: incidence and prevalence. Incidence is the number of new cases per unit of person-time at risk (usually number of new cases per thousand person-years); while prevalence is the total number of cases of the disease in the population at any given time.
Regarding incidence, cohort longitudinal studies (studies where a disease-free population is followed over the years) provide rates between 10 and 15 per thousand person-years for all dementias and 5–8 for AD, which means that half of new dementia cases each year are Alzheimer's disease. Advancing age is a primary risk factor for the disease and incidence rates are not equal for all ages: every 5 years after the age of 65, the risk of acquiring the disease approximately doubles, increasing from 3 to as much as 69 per thousand person years. Females with AD are more common than males, but this difference is likely due to women's longer life spans. When adjusted for age, both sexes are affected by Alzheimer's at equal rates. In the United States, the risk of dying from AD in 2010 was 26% higher among the non-Hispanic white population than among the non-Hispanic black population, and the Hispanic population had a 30% lower risk than the non-Hispanic white population. However, much AD research remains to be done in minority groups, such as the African American, East Asian and Hispanic/Latino populations. Studies have shown that these groups are underrepresented in clinical trials and do not have the same risk of developing AD when carrying certain genetic risk factors (i.e. APOE4), compared to their caucasian counterparts.
The prevalence of AD in populations is dependent upon factors including incidence and survival. Since the incidence of AD increases with age, prevalence depends on the mean age of the population for which prevalence is given. In the United States in 2020, AD dementia prevalence was estimated to be 5.3% for those in the 60–74 age group, with the rate increasing to 13.8% in the 74–84 group and to 34.6% in those greater than 85. Prevalence rates in some less developed regions around the globe are lower. Both the prevalence and incidence rates of AD are steadily increasing, and the prevalence rate is estimated to triple by 2050 reaching 152 million, compared to the 50 million people with AD globally in 2020.
== History ==
The ancient Greek and Roman philosophers and physicians associated old age with increasing dementia. It was not until 1901 that German psychiatrist Alois Alzheimer identified the first case of what became known as Alzheimer's disease, named after him, in a fifty-year-old woman he called Auguste D. He followed her case until she died in 1906 when he first reported publicly on it. During the next five years, eleven similar cases were reported in the medical literature, some of them already using the term Alzheimer's disease. The disease was first described as a distinctive disease by Emil Kraepelin after suppressing some of the clinical (delusions and hallucinations) and pathological features (arteriosclerotic changes) contained in the original report of Auguste D. He included Alzheimer's disease, also named presenile dementia by Kraepelin, as a subtype of senile dementia in the eighth edition of his Textbook of Psychiatry, published on 15 July 1910.
For most of the 20th century, the diagnosis of Alzheimer's disease was reserved for individuals between the ages of 45 and 65 who developed symptoms of dementia. The terminology changed after 1977 when a conference on Alzheimer's disease concluded that the clinical and pathological manifestations of presenile and senile dementia were almost identical, although the authors also added that this did not rule out the possibility that they had different causes. This eventually led to the diagnosis of Alzheimer's disease independent of age. The term senile dementia of the Alzheimer type (SDAT) was used for a time to describe the condition in those over 65, with classical Alzheimer's disease being used to describe those who were younger. Eventually, the term Alzheimer's disease was formally adopted in medical nomenclature to describe individuals of all ages with a characteristic common symptom pattern, disease course, and neuropathology.
The National Institute of Neurological and Communicative Disorders and Stroke (NINCDS) and the Alzheimer's Disease and Related Disorders Association (ADRDA, now known as the Alzheimer's Association) established the most commonly used NINCDS-ADRDA Alzheimer's Criteria for diagnosis in 1984, extensively updated in 2007. These criteria require that the presence of cognitive impairment, and a suspected dementia syndrome, be confirmed by neuropsychological testing for a clinical diagnosis of possible or probable Alzheimer's disease. A histopathologic confirmation including a microscopic examination of brain tissue is required for a definitive diagnosis. Good statistical reliability and validity have been shown between the diagnostic criteria and definitive histopathological confirmation.
== Society and culture ==
=== Social costs ===
Dementia, and specifically Alzheimer's disease, may be among the most costly diseases for societies worldwide. As populations age, these costs will probably increase and become an important social problem and economic burden. Costs associated with AD include direct and indirect medical costs, which vary between countries depending on social care for a person with AD. Direct costs include doctor visits, hospital care, medical treatments, nursing home care, specialised equipment, and household expenses. Indirect costs include the cost of informal care and the loss in productivity of informal caregivers.
In the United States as of 2019, informal (family) care is estimated to constitute nearly three-fourths of caregiving for people with AD at a cost of US$234 billion per year and approximately 18.5 billion hours of care. The cost to society worldwide to care for individuals with AD is projected to increase nearly ten-fold, and reach about US$9.1 trillion by 2050.
Costs for those with more severe dementia or behavioral disturbances are higher and are related to the additional caregiving time to provide physical care.
=== Caregiving burden ===
Individuals with Alzheimer's will require assistance in their lifetime, and care will most likely come in the form of a full-time caregiver which is often a role that is taken on by the spouse or a close relative. Caregiving tends to include physical and emotional burdens as well as time and financial strain at times on the person administering the aid. Alzheimer's disease is known for placing a great burden on caregivers which includes social, psychological, physical, or economic aspects. Home care is usually preferred by both those people with Alzheimer's disease as well as their families. This option also delays or eliminates the need for more professional and costly levels of care. Nevertheless, two-thirds of nursing home residents have dementias.
Dementia caregivers are subject to high rates of physical and mental disorders. Factors associated with greater psychosocial problems of the primary caregivers include having an affected person at home, the caregiver being a spouse, demanding behaviors of the cared person such as depression, behavioral disturbances, hallucinations, sleep problems or walking disruptions and social isolation. In the United States, the yearly cost of caring for a person with dementia ranges from $28,078-$56,022 per year for formal medical care and $36,667-$92,689 for informal care provided by a relative or friend (assuming market value replacement costs for the care provided by the informal caregiver) and $15,792-$71,813 in lost wages.
Cognitive behavioral therapy and the teaching of coping strategies either individually or in group have demonstrated their efficacy in improving caregivers' psychological health.
=== Media ===
Alzheimer's disease has been portrayed in films such as: Iris (2001), based on John Bayley's memoir of his wife Iris Murdoch; The Notebook (2004), based on Nicholas Sparks's 1996 novel of the same name; A Moment to Remember (2004); Thanmathra (2005); Memories of Tomorrow (Ashita no Kioku) (2006), based on Hiroshi Ogiwara's novel of the same name; Away from Her (2006), based on Alice Munro's short story The Bear Came over the Mountain; Still Alice (2014), about a Columbia University professor who has early onset Alzheimer's disease, based on Lisa Genova's 2007 novel of the same name and featuring Julianne Moore in the title role. Documentaries on Alzheimer's disease include Malcolm and Barbara: A Love Story (1999) and Malcolm and Barbara: Love's Farewell (2007), both featuring Malcolm Pointon.
Alzheimer's disease has also been portrayed in music by English musician the Caretaker in releases such as Persistent Repetition of Phrases (2008), An Empty Bliss Beyond This World (2011), and Everywhere at the End of Time (2016–2019). Paintings depicting the disorder include the late works by American artist William Utermohlen, who drew self-portraits from 1995 to 2000 as an experiment of showing his disease through art.
== Research directions ==
Antibodies may have the ability to alter the disease course by targeting amyloid beta with immunotherapy medications such as donanemab and lecanemab.
Lecanemab was approved via the FDA accelerated approval process, and was converted to traditional approval in July 2023, after further testing, along with the addition of a boxed warning about amyloid-related imaging abnormalities. As of early August 2024, lecanemab was approved for sale in Japan, South Korea, China, Hong Kong and Israel although it was recommended against approval by an advisory body of the European Union on July 26, citing its side effects.
Donanemab was approved by the FDA in July 2024. Anti-amyloid drugs also cause brain shrinkage. The cholinesterase inhibitor benzgalantamine was approved by the FDA in July 2024.
Specific medications that may reduce the risk or progression of Alzheimer's disease have been studied. The research trials investigating medications generally impact Aβ plaques, inflammation, APOE, neurotransmitter receptors, neurogenesis, growth factors or hormones.
Machine learning algorithms with electronic health records are being studied as a way to predict Alzheimer's disease earlier.
== References ==
== External links ==
"Alzheimer's Disease Research Timeline – Alzforum". www.alzforum.org.
"Alzheimer's Disease Brain Cell Atlas- brain-map.org". portal.brain-map.org. | Wikipedia/Alzheimer_disease |
In cardiology, ventricular remodeling (or cardiac remodeling) refers to changes in the size, shape, structure, and function of the heart. This can happen as a result of exercise (physiological remodeling) or after injury to the heart muscle (pathological remodeling). The injury is typically due to acute myocardial infarction (usually transmural or ST segment elevation infarction), but may be from a number of causes that result in increased pressure or volume, causing pressure overload or volume overload (forms of strain) on the heart. Chronic hypertension, congenital heart disease with intracardiac shunting, and valvular heart disease may also lead to remodeling. After the insult occurs, a series of histopathological and structural changes occur in the left ventricular myocardium that lead to progressive decline in left ventricular performance. Ultimately, ventricular remodeling may result in diminished contractile (systolic) function and reduced stroke volume.
Physiological remodeling is reversible while pathological remodeling is mostly irreversible. Remodeling of the ventricles under left/right pressure demand make mismatches inevitable. Pathologic pressure mismatches between the pulmonary and systemic circulation guide compensatory remodeling of the left and right ventricles. The term "reverse remodeling" in cardiology implies an improvement in ventricular mechanics and function following a remote injury or pathological process.
Ventricular remodeling may include ventricular hypertrophy, ventricular dilation, cardiomegaly, and other changes. It is an aspect of cardiomyopathy, of which there are many types. Concentric hypertrophy is due to pressure overload, while eccentric hypertrophy is due to volume overload.
== Pathophysiology ==
The cardiac myocyte is the major cell involved in remodeling. Fibroblasts, collagen, the interstitium, and the coronary vessels to a lesser extent, also play a role. A common scenario for remodeling is after myocardial infarction. There is myocardial necrosis (cell death) and disproportionate thinning of the heart. This thin, weakened area is unable to withstand the pressure and volume load on the heart in the same manner as the other healthy tissue. As a result, there is dilatation of the chamber arising from the infarct region. The initial remodeling phase after a myocardial infarction results in repair of the necrotic area and myocardial scarring that may, to some extent, be considered beneficial since there is an improvement in or maintenance of LV function and cardiac output. Over time, however, as the heart undergoes ongoing remodeling, it becomes less elliptical and more spherical. Ventricular mass and volume increase, which together adversely affect cardiac function. Eventually, diastolic function, or the heart's ability to relax between contractions may become impaired, further causing decline.
After a myocardial infarction (MI), cardiac myocyte death can be triggered by necrosis, apoptosis, or autophagy, leading to thinning of the cardiac wall. The surviving cardiac myocytes either arrange in parallel or in series to each other, contributing to ventricular dilatation or ventricular hypertrophy, depending on the loading stress on the ventricular wall. Besides, reduced expression of V1 myosin and L-type calcium channels on cardiac myocytes are also thought to cause cardiac remodeling. Under normal body conditions, fatty acid accounts for 60 to 90% of the energy supply of the heart. Post MI, as fatty acid oxidation decreases, it leads to reduced energy supply for the cardiac myocytes, accumulation of fatty acids to toxic levels, and dysfunction of mitochondria. These consequences also led to the increase in oxidative stress on the heart, causing the proliferation of fibroblasts, activation of metalloproteinases, and induction of apoptosis, which would be explained below. Besides, inflammatory immune response after MI also contributes to the above changes.
Besides, the cardiac interstitium which consisted of largely Type I and Type III collagen fibres are also involved in cardiac remodeling. Cardiac collagen is synthesized by fibroblasts and degraded by metalloproteinases. Fibroblasts are activated post MI, leading to increased collagen synthesis and fibrosis of the heart. Increase expression of MMP1 and MMP9 led to degradation of collagen fibres, and subsequently dilatation of the heart. Several signal pathways such as Angiotensin II, Transforming growth factor beta (TGF-beta), and Endothelin 1 are known to trigger synthesis and degradation of collagen fibres in the heart.
Other factors such as high blood pressure, activation of sympathetic system which releases norepinephrine, activation of renin–angiotensin system which releases renin and anti-diuretic hormones are important contributors of cardiac remodelling. However, atrial natriuretic peptide is thought to be cardio-protective.
== Evaluation ==
Remodeling of the heart is evaluated by performing an echocardiogram. The size and function of the atria and ventricles can be characterized using this test.
== Treatment ==
Many factors influence the time course and extent of remodeling, including the severity of the injury, secondary events (recurrent ischemia or infarction), neurohormonal activation, genetic factors and gene expression, and treatment. Medications may attenuate remodeling. Angiotensin-converting enzyme (ACE) inhibitors have been consistently shown to decrease remodeling in animal models or transmural infarction and chronic pressure overload. Clinical trials have shown that ACE inhibitor therapy after myocardial infarction leads to improved myocardial performance, improved ejection fraction, and decreased mortality compared to patients treated with placebo. Likewise, inhibition of aldosterone, either directly or indirectly, leads to improvement in remodeling. Carvedilol, a 3rd generation beta blocker, may actually reverse the remodeling process by reducing left ventricular volumes and improving systolic function. Cardiac resynchronization therapy (CRT) has shown the ability to reverse left ventricular remodeling in some patients. Early correction of congenital heart defects, if appropriate, may prevent remodeling, as will treatment of chronic hypertension or valvular heart disease. Often, reverse remodeling, or improvement in left ventricular function, will also be seen.
== See also ==
Dor procedure
Athlete's heart
== References ==
== Further reading ==
"Left Ventricular Remodeling in Heart Failure: Current Concepts in Clinical Significance and Assessment". imaging.onlinejacc.org. Retrieved 2016-02-12. | Wikipedia/Cardiac_remodeling |
Gap junction proteins
Gap junction α (GJA) proteins
GJA1, Cx43, gap junction alpha-1 protein
GJA2, Cx38, gap junction alpha-2 protein
GJA3, Cx46, gap junction alpha-3 protein
GJA4, Cx37, gap junction alpha-4 protein
GJA5, Cx40, gap junction alpha-5 protein
GJA6, Cx33 gap junction alpha-6 protein
GJA7, Cx44.3-45.6, gap junction alpha-7 protein
GJA8, Cx50, gap junction alpha-8 protein
GJA9, Cx58, gap junction alpha-9 protein
GJA10, Cx62, gap junction alpha-10 protein
GJA11, Cx59, gap junction alpha-11 protein
GJA12, Cx46.6, gap junction alpha-12 protein
Gap junction β (GJB) proteins
GJB1, Cx32, gap junction beta-1 protein
GJB2, Cx26, gap junction beta-2 protein
GJB3, Cx31, gap junction beta-3 protein
GJB4, Cx30.3, gap junction beta-4 protein
GJB5, Cx31.1, gap junction beta-5 protein
GJB6, Cx30, gap junction beta-6 protein
GJB7, Cx25, gap junction beta-7 protein
Gap junction γ (GJC) proteins
GJC1, Cx45.6, gap junction gamma-1 protein
GJC2, Cx47, gap junction gamma-2 protein
GJC3, Cx29, gap junction gamma-3 protein
Gap junction δ (GJD) proteins
GJD1, Cx29, gap junction delta-1 protein
GJD2, Cx36, gap junction delta-2 protein
GJD3, Cx31.9, gap junction delta-3 protein
GJD4, Cx40.1, gap junction delta-4 protein
Gap junction ε (GJE) proteins
GJE1, Cx23, gap junction epsilon-1 protein
== See also ==
Tight junction protein | Wikipedia/Gap_junction_protein |
Hyperthyroidism is a endocrine disease in which the thyroid gland produces excessive amounts of thyroid hormones. Thyrotoxicosis is a condition that occurs due to elevated levels of thyroid hormones of any cause and therefore includes hyperthyroidism. Some, however, use the terms interchangeably. Signs and symptoms vary between people and may include irritability, muscle weakness, sleeping problems, a fast heartbeat, heat intolerance, diarrhea, enlargement of the thyroid, hand tremor, and weight loss. Symptoms are typically less severe in the elderly and during pregnancy. An uncommon but life-threatening complication is thyroid storm in which an event such as an infection results in worsening symptoms such as confusion and a high temperature; this often results in death. The opposite is hypothyroidism, when the thyroid gland does not make enough thyroid hormone.
Graves' disease is the cause of about 50% to 80% of the cases of hyperthyroidism in the United States. Other causes include multinodular goiter, toxic adenoma, inflammation of the thyroid, eating too much iodine, and too much synthetic thyroid hormone. A less common cause is a pituitary adenoma. The diagnosis may be suspected based on signs and symptoms and then confirmed with blood tests. Typically blood tests show a low thyroid stimulating hormone (TSH) and raised T3 or T4. Radioiodine uptake by the thyroid, thyroid scan, and measurement of antithyroid autoantibodies (thyroidal thyrotropin receptor antibodies are positive in Graves disease) may help determine the cause.
Treatment depends partly on the cause and severity of disease. There are three main treatment options: radioiodine therapy, medications, and thyroid surgery. Radioiodine therapy involves taking iodine-131 by mouth which is then concentrated in and destroys the thyroid over weeks to months. The resulting hypothyroidism is treated with synthetic thyroid hormone. Medications such as beta blockers may control the symptoms, and anti-thyroid medications such as methimazole may temporarily help people while other treatments are having an effect. Surgery to remove the thyroid is another option. This may be used in those with very large thyroids or when cancer is a concern. In the United States hyperthyroidism affects about 1.2% of the population. Worldwide, hyperthyroidism affects 2.5% of adults. It occurs between two and ten times more often in women. Onset is commonly between 20 and 50 years of age. Overall the disease is more common in those over the age of 60 years.
== Signs and symptoms ==
Hyperthyroidism may be asymptomatic or present with significant symptoms. Some of the symptoms of hyperthyroidism include nervousness, irritability, increased perspiration, heart racing, hand tremors, anxiety, trouble sleeping, thinning of the skin, fine brittle hair, and muscular weakness—especially in the upper arms and thighs. More frequent bowel movements may occur, and diarrhea is common. Weight loss, sometimes significant, may occur despite a good appetite (though 10% of people with a hyperactive thyroid experience weight gain), vomiting may occur, and, for women, menstrual flow may lighten and menstrual periods may occur less often, or with longer cycles than usual.
Thyroid hormone is critical to normal function of cells. In excess, it both overstimulates metabolism and disrupts the normal functioning of sympathetic nervous system, causing "speeding up" of various body systems and symptoms resembling an overdose of epinephrine (adrenaline). These include fast heartbeat and symptoms of palpitations, nervous system tremor such as of the hands and anxiety symptoms, digestive system hypermotility, unintended weight loss, and, in lipid panel blood tests, a lower and sometimes unusually low serum cholesterol.
Major clinical signs of hyperthyroidism include weight loss (often accompanied by an increased appetite), anxiety, heat intolerance, hair loss (especially of the outer third of the eyebrows), muscle aches, weakness, fatigue, hyperactivity, irritability, high blood sugar, excessive urination, excessive thirst, delirium, tremor, pretibial myxedema (in Graves' disease), emotional lability, and sweating. Panic attacks, inability to concentrate, and memory problems may also occur. Psychosis and paranoia, common during thyroid storm, are rare with milder hyperthyroidism. Many persons will experience complete remission of symptoms 1 to 2 months after a euthyroid state is obtained, with a marked reduction in anxiety, sense of exhaustion, irritability, and depression. Some individuals may have an increased rate of anxiety or persistence of affective and cognitive symptoms for several months to up to 10 years after a euthyroid state is established. In addition, those with hyperthyroidism may present with a variety of physical symptoms such as palpitations and abnormal heart rhythms (the notable ones being atrial fibrillation), shortness of breath (dyspnea), loss of libido, amenorrhea, nausea, vomiting, diarrhea, gynecomastia and feminization. Long term untreated hyperthyroidism can lead to osteoporosis. These classical symptoms may not be present often in the elderly.
Bone loss, which is associated with overt but not subclinical hyperthyroidism, may occur in 10 to 20% of patients. This may be due to an increase in bone remodelling and a decrease in bone density, and increases fracture risk. It is more common in postmenopausal women; less so in younger women, and men. Bone disease related to hyperthyroidism was first described by Frederick von Recklinghausen, in 1891; he described the bones of a woman who died of hyperthyroidism as appearing "worm-eaten".
Neurological manifestations can include tremors, chorea, myopathy, and in some susceptible individuals (in particular of Asian descent) periodic paralysis. An association between thyroid disease and myasthenia gravis has been recognized. Thyroid disease, in this condition, is autoimmune in nature and approximately 5% of people with myasthenia gravis also have hyperthyroidism. Myasthenia gravis rarely improves after thyroid treatment and the relationship between the two entities is becoming better understood over the past 15 years.In Graves' disease, ophthalmopathy may cause the eyes to look enlarged because the eye muscles swell and push the eye forward. Sometimes, one or both eyes may bulge. Some have swelling of the front of the neck from an enlarged thyroid gland (a goiter).
Minor ocular (eye) signs, which may be present in any type of hyperthyroidism, are eyelid retraction ("stare"), extraocular muscle weakness, and lid-lag. In hyperthyroid stare (Dalrymple sign) the eyelids are retracted upward more than normal (the normal position is at the superior corneoscleral limbus, where the "white" of the eye begins at the upper border of the iris). Extraocular muscle weakness may present with double vision. In lid-lag (von Graefe's sign), when the person tracks an object downward with their eyes, the eyelid fails to follow the downward moving iris, and the same type of upper globe exposure which is seen with lid retraction occurs, temporarily. These signs disappear with treatment of the hyperthyroidism.
Neither of these ocular signs should be confused with exophthalmos (protrusion of the eyeball), which occurs specifically and uniquely in hyperthyroidism caused by Graves' disease (note that not all exophthalmos is caused by Graves' disease, but when present with hyperthyroidism is diagnostic of Graves' disease). This forward protrusion of the eyes is due to immune-mediated inflammation in the retro-orbital (eye socket) fat. Exophthalmos, when present, may exacerbate hyperthyroid lid-lag and stare.
=== Thyroid storm ===
Thyroid storm is a severe form of thyrotoxicosis characterized by rapid and often irregular heart beat, high temperature, vomiting, diarrhea, and mental agitation. Symptoms may not be typical in the young, old, or pregnant. It usually occurs due to untreated hyperthyroidism and can be provoked by infections. It is a medical emergency and requires hospital care to control the symptoms rapidly. The mortality rate in thyroid storm is 3.6-17%, usually due to multi-organ system failure.
=== Hypothyroidism ===
Hyperthyroidism due to certain types of thyroiditis can eventually lead to hypothyroidism (a lack of thyroid hormone), as the thyroid gland is damaged. Also, radioiodine treatment of Graves' disease often eventually leads to hypothyroidism. Such hypothyroidism may be diagnosed with thyroid hormone testing and treated by oral thyroid hormone supplementation.
== Causes ==
There are several causes of hyperthyroidism. Most often, the entire gland is overproducing thyroid hormone. Less commonly, a single nodule is responsible for the excess hormone secretion, called a "hot" nodule. Thyroiditis (inflammation of the thyroid) can also cause hyperthyroidism. Functional thyroid tissue producing an excess of thyroid hormone occurs in a number of clinical conditions.
The major causes in humans are:
Graves' disease. An autoimmune disease (usually, the most common cause with 50–80% worldwide, although this varies substantially with location- i.e., 47% in Switzerland (Horst et al., 1987) to 90% in the USA (Hamburger et al. 1981)). Thought to be due to varying levels of iodine in the diet. It is eight times more common in females than males and often occurs in young females, around 20 to 40 years of age.
Toxic thyroid adenoma (the most common cause in Switzerland, 53%, thought to be atypical due to a low level of dietary iodine in this country)
Toxic multinodular goiter
High blood levels of thyroid hormones (most accurately termed hyperthyroxinemia) can occur for a number of other reasons:
Inflammation of the thyroid is called thyroiditis. There are several different kinds of thyroiditis including Hashimoto's thyroiditis (Hypothyroidism immune-mediated), and subacute thyroiditis (de Quervain's). These may be initially associated with secretion of excess thyroid hormone but usually progress to gland dysfunction and, thus, to hormone deficiency and hypothyroidism.
Oral consumption of excess thyroid hormone tablets is possible (surreptitious use of thyroid hormone), as is the rare event of eating ground beef or pork contaminated with thyroid tissue, and thus thyroid hormones (termed hamburger thyrotoxicosis or alimentary thyrotoxicosis). Pharmacy compounding errors may also be a cause.
Amiodarone, an antiarrhythmic drug, is structurally similar to thyroxine and may cause either under-or overactivity of the thyroid.
Postpartum thyroiditis (PPT) occurs in about 7% of women during the year after they give birth. PPT typically has several phases, the first of which is hyperthyroidism. This form of hyperthyroidism usually corrects itself within weeks or months without the need for treatment.
A struma ovarii is a rare form of monodermal teratoma that contains mostly thyroid tissue, which leads to hyperthyroidism.
Excess iodine consumption notably from algae such as kelp.
Thyrotoxicosis can also occur after taking too much thyroid hormone in the form of supplements, such as levothyroxine (a phenomenon known as exogenous thyrotoxicosis, alimentary thyrotoxicosis, or occult factitial thyrotoxicosis).
Hypersecretion of thyroid stimulating hormone (TSH), which in turn is almost always caused by a pituitary adenoma, accounts for much less than 1 percent of hyperthyroidism cases.
== Diagnosis ==
Measuring the level of thyroid-stimulating hormone (TSH), produced by the pituitary gland (which in turn is also regulated by the hypothalamus's TSH Releasing Hormone) in the blood is typically the initial test for suspected hyperthyroidism. A low TSH level typically indicates that the pituitary gland is being inhibited or "instructed" by the brain to cut back on stimulating the thyroid gland, having sensed increased levels of T4 and/or T3 in the blood. In rare circumstances, a low TSH indicates primary failure of the pituitary, or temporary inhibition of the pituitary due to another illness (euthyroid sick syndrome) and so checking the T4 and T3 is still clinically useful.
Measuring specific antibodies, such as anti-TSH-receptor antibodies in Graves' disease, or anti-thyroid peroxidase in Hashimoto's thyroiditis—a common cause of hypothyroidism—may also contribute to the diagnosis. The diagnosis of hyperthyroidism is confirmed by blood tests that show a decreased thyroid-stimulating hormone (TSH) level and elevated T4 and T3 levels. TSH is a hormone made by the pituitary gland in the brain that tells the thyroid gland how much hormone to make. When there is too much thyroid hormone, the TSH will be low. A radioactive iodine uptake test and thyroid scan together characterizes or enables radiologists and doctors to determine the cause of hyperthyroidism. The uptake test uses radioactive iodine injected or taken orally on an empty stomach to measure the amount of iodine absorbed by the thyroid gland. Persons with hyperthyroidism absorb much more iodine than healthy persons which includes radioactive iodine which is easy to measure. A thyroid scan producing images is typically conducted in connection with the uptake test to allow visual examination of the over-functioning gland.
Thyroid scintigraphy is a useful test to characterize (distinguish between causes of) hyperthyroidism, and this entity from thyroiditis. This test procedure typically involves two tests performed in connection with each other: an iodine uptake test and a scan (imaging) with a gamma camera. The uptake test involves administering a dose of radioactive iodine (radioiodine), traditionally iodine-131 (131I), and more recently iodine-123 (123I). Iodine-123 may be the preferred radionuclide in some clinics due to its more favorable radiation dosimetry (i.e. less radiation dose to the person per unit administered radioactivity) and a gamma photon energy more amenable to imaging with the gamma camera. For the imaging scan, I-123 is considered an almost ideal isotope of iodine for imaging thyroid tissue and thyroid cancer metastasis. Thyroid scintigraphy should not be performed in those who are pregnant, a thyroid ultrasound with color flow doppler may be obtained as an alternative in these circumstances.
Typical administration involves a pill or liquid containing sodium iodide (NaI) taken orally, which contains a small amount of iodine-131, amounting to perhaps less than a grain of salt. A 2-hour fast of no food prior to and for 1 hour after ingesting the pill is required. This low dose of radioiodine is typically tolerated by individuals otherwise allergic to iodine (such as those unable to tolerate contrast mediums containing larger doses of iodine such as used in CT scan, intravenous pyelogram (IVP), and similar imaging diagnostic procedures). Excess radioiodine that does not get absorbed into the thyroid gland is eliminated by the body in urine. Some people with hyperthyroidism may experience a slight allergic reaction to the diagnostic radioiodine and may be given an antihistamine.
The person returns 24 hours later to have the level of radioiodine "uptake" (absorbed by the thyroid gland) measured by a device with a metal bar placed against the neck, which measures the radioactivity emitting from the thyroid. This test takes about 4 minutes while the uptake % (i.e., percentage) is accumulated (calculated) by the machine software. A scan is also performed, wherein images (typically a center, left and right angle) are taken of the contrasted thyroid gland with a gamma camera; a radiologist will read and prepare a report indicating the uptake % and comments after examining the images. People with hyperthyroid will typically "take up" higher than normal levels of radioiodine. Normal ranges for RAI uptake are from 10 to 30%.
In addition to testing the TSH levels, many doctors test for T3, Free T3, T4, and/or Free T4 for more detailed results. Free T4 is unbound to any protein in the blood. Adult limits for these hormones are: TSH (units): 0.45 – 4.50 uIU/mL; T4 Free/Direct (nanograms): 0.82 – 1.77 ng/dl; and T3 (nanograms): 71 – 180 ng/dl. Persons with hyperthyroidism can easily exhibit levels many times these upper limits for T4 and/or T3. See a complete table of normal range limits for thyroid function at the thyroid gland article.
In hyperthyroidism CK-MB (Creatine kinase) is usually elevated.
=== Subclinical ===
In overt primary hyperthyroidism, TSH levels are low and T4 and T3 levels are high. Subclinical hyperthyroidism is a milder form of hyperthyroidism characterized by low or undetectable serum TSH level, but with a normal serum free thyroxine level. Although the evidence for doing so is not definitive, treatment of elderly persons having subclinical hyperthyroidism could reduce the number of cases of atrial fibrillation. There is also an increased risk of bone fractures (by 42%) in people with subclinical hyperthyroidism; there is insufficient evidence to say whether treatment with antithyroid medications would reduce that risk.
A 2022 meta-analysis found subclinical hyperthyroidism to be associated with cardiovascular death.
=== Screening ===
In those without symptoms who are not pregnant there is little evidence for or against screening.
== Treatment ==
=== Antithyroid drugs ===
Thyrostatics (antithyroid drugs) are drugs that inhibit the production of thyroid hormones, such as carbimazole (used in the UK) and methimazole (used in the US, Germany and Russia), and propylthiouracil. Thyrostatics are believed to work by inhibiting the iodination of thyroglobulin by thyroperoxidase and, thus, the formation of tetraiodothyronine (T4). Propylthiouracil also works outside the thyroid gland, preventing the conversion of (mostly inactive) T4 to the active form T3. Because thyroid tissue usually contains a substantial reserve of thyroid hormone, thyrostatics can take weeks to become effective and the dose often needs to be carefully titrated over a period of months, with regular doctor visits and blood tests to monitor results.
=== Beta-blockers ===
Many of the common symptoms of hyperthyroidism such as palpitations, trembling, and anxiety are mediated by increases in beta-adrenergic receptors on cell surfaces. Beta blockers, typically used to treat high blood pressure, are a class of drugs that offset this effect, reducing rapid pulse associated with the sensation of palpitations, and decreasing tremor and anxiety. Thus, a person with hyperthyroidism can often obtain immediate temporary relief until the hyperthyroidism can be characterized with the Radioiodine test noted above and more permanent treatment take place. Note that these drugs do not treat hyperthyroidism or any of its long-term effects if left untreated, but, rather, they treat or reduce only symptoms of the condition.
Some minimal effect on thyroid hormone production however also comes with propranolol—which has two roles in the treatment of hyperthyroidism, determined by the different isomers of propranolol. L-propranolol causes beta-blockade, thus treating the symptoms associated with hyperthyroidism such as tremor, palpitations, anxiety, and heat intolerance. D-propranolol inhibits thyroxine deiodinase, thereby blocking the conversion of T4 to T3, providing some though minimal therapeutic effect. Other beta-blockers are used to treat only the symptoms associated with hyperthyroidism. Propranolol in the UK, and metoprolol in the US, are most frequently used to augment treatment for people with hyperthyroid .
=== Diet ===
People with autoimmune hyperthyroidism (such as in Grave's disease) should not eat foods high in iodine, such as edible seaweed and seafood.
From a public health perspective, the general introduction of iodized salt in the United States in 1924 resulted in lower disease, goiters, as well as improving the lives of children whose mothers would not have eaten enough iodine during pregnancy which would have lowered the IQs of their children.
=== Surgery ===
Surgery (thyroidectomy to remove the whole thyroid or a part of it) is not extensively used because most common forms of hyperthyroidism are quite effectively treated by the radioactive iodine method, and because there is a risk of also removing the parathyroid glands, and of cutting the recurrent laryngeal nerve, making swallowing difficult, and even simply generalized staphylococcal infection as with any major surgery. Some people with Graves' may opt for surgical intervention. This includes those that cannot tolerate medicines for one reason or another, people that are allergic to iodine, or people that refuse radioiodine.
A 2019 systematic review concluded that the available evidence shows no difference between visually identifying the nerve or utilizing intraoperative neuroimaging during surgery, when trying to prevent injury to recurrent laryngeal nerve during thyroid surgery.
If people have toxic nodules treatments typically include either removal or injection of the nodule with alcohol.
=== Radioiodine ===
In iodine-131 (radioiodine) radioisotope therapy, which was first pioneered by Dr. Saul Hertz, radioactive iodine-131 is given orally (either by pill or liquid) on a one-time basis, to severely restrict, or altogether destroy the function of a hyperactive thyroid gland. This isotope of radioactive iodine used for ablative treatment is more potent than diagnostic radioiodine (usually iodine-123 or a very low amount of iodine-131), which has a biological half-life from 8–13 hours. Iodine-131, which also emits beta particles that are far more damaging to tissues at short range, has a half-life of approximately 8 days. People not responding sufficiently to the first dose are sometimes given an additional radioiodine treatment, at a larger dose. Iodine-131 in this treatment is picked up by the active cells in the thyroid and destroys them, rendering the thyroid gland mostly or completely inactive.
Since iodine is picked up more readily (though not exclusively) by thyroid cells, and (more important) is picked up even more readily by over-active thyroid cells, the destruction is local, and there are no widespread side effects with this therapy. Radioiodine ablation has been used for over 50 years, and the only major reasons for not using it are pregnancy and breastfeeding (breast tissue also picks up and concentrates iodine). Once the thyroid function is reduced, replacement hormone therapy (levothyroxine) taken orally each day replaces the thyroid hormone that is normally produced by the body.
There is extensive experience, over many years, of the use of radioiodine in the treatment of thyroid overactivity and this experience does not indicate any increased risk of thyroid cancer following treatment. However, a study from 2007 has reported an increased number of cancer cases after radioiodine treatment for hyperthyroidism.
The principal advantage of radioiodine treatment for hyperthyroidism is that it tends to have a much higher success rate than medications. Depending on the dose of radioiodine chosen, and the disease under treatment (Graves' vs. toxic goiter, vs. hot nodule etc.), the success rate in achieving definitive resolution of the hyperthyroidism may vary from 75 to 100%. A major expected side-effect of radioiodine in people with Graves' disease is the development of lifelong hypothyroidism, requiring daily treatment with thyroid hormone. On occasion, some people may require more than one radioactive treatment, depending on the type of disease present, the size of the thyroid, and the initial dose administered.
People with Graves' disease manifesting moderate or severe Graves' ophthalmopathy are cautioned against radioactive iodine-131 treatment, since it has been shown to exacerbate existing thyroid eye disease. People with mild or no ophthalmic symptoms can mitigate their risk with a concurrent six-week course of prednisone. The mechanisms proposed for this side effect involve a TSH receptor common to both thyrocytes and retro-orbital tissue.
As radioactive iodine treatment results in the destruction of thyroid tissue, there is often a transient period of several days to weeks when the symptoms of hyperthyroidism may actually worsen following radioactive iodine therapy. In general, this happens as a result of thyroid hormones being released into the blood following the radioactive iodine-mediated destruction of thyroid cells that contain thyroid hormone. In some people, treatment with medications such as beta blockers (propranolol, atenolol, etc.) may be useful during this period of time. Most people do not experience any difficulty after the radioactive iodine treatment, usually given as a small pill. On occasion, neck tenderness or a sore throat may become apparent after a few days, if moderate inflammation in the thyroid develops and produces discomfort in the neck or throat area. This is usually transient, and not associated with a fever, etc.
It is recommended that breastfeeding be stopped at least six weeks before radioactive iodine treatment and that it not be resumed, although it can be done in future pregnancies. It also shouldn't be done during pregnancy, and pregnancy should be put off until at least 6–12 months after treatment.
A common outcome following radioiodine is a swing from hyperthyroidism to the easily treatable hypothyroidism, which occurs in 78% of those treated for Graves' thyrotoxicosis and in 40% of those with toxic multinodular goiter or solitary toxic adenoma. Use of higher doses of radioiodine reduces the number of cases of treatment failure, with penalty for higher response to treatment consisting mostly of higher rates of eventual hypothyroidism which requires hormone treatment for life.
There is increased sensitivity to radioiodine therapy in thyroids appearing on ultrasound scans as more uniform (hypoechogenic), due to densely packed large cells, with 81% later becoming hypothyroid, compared to just 37% in those with more normal scan appearances (normoechogenic).
=== Thyroid storm ===
Thyroid storm presents with extreme symptoms of hyperthyroidism. It is treated aggressively with resuscitation measures along with a combination of the above modalities including: intravenous beta blockers such as propranolol, followed by a thioamide such as methimazole, an iodinated radiocontrast agent or an iodine solution if the radiocontrast agent is not available, and an intravenous steroid such as hydrocortisone. Propylthiouracil is the preferred thioamide in thyroid storm as it can prevent the conversion of T4 to the more active T3 in the peripheral tissues in addition to inhibiting thyroid hormone production.
=== Alternative medicine ===
In countries such as China, herbs used alone or with antithyroid medications are used to treat hyperthyroidism. Very low quality evidence suggests that traditional Chinese herbal medications may be beneficial when taken along with routine hyperthyroid medications, however, there is no reliable evidence to determine the effectiveness of Chinese herbal medications for treating hyperthyroidism.
== Epidemiology ==
In the United States hyperthyroidism affects about 1.2% of the population. About half of these cases have obvious symptoms while the other half do not. It occurs between two and ten times more often in women. The disease is more common in those over the age of 60 years.
Subclinical hyperthyroidism modestly increases the risk of cognitive impairment and dementia.
== History ==
Caleb Hillier Parry first made the association between the goiter and protrusion of the eyes in 1786, however, did not publish his findings until 1825. In 1835, Irish doctor Robert James Graves discovered a link between the protrusion of the eyes and goiter, giving his name to the autoimmune disease now known as Graves' Disease.
== Pregnancy ==
Recognizing and evaluating hyperthyroidism in pregnancy is a diagnostic challenge. Thyroid hormones are commonly elevated during the first trimester of pregnancy as the pregnancy hormone human chorionic gonadotropin (hCG) stimulates thyroid hormone production, in a condition known as gestational transient thyrotoxicosis. Gestational transient thyrotoxicosis generally abates in the second trimester as hCG levels decline and thyroid function normalizes. Hyperthyroidism can increase the risk of complications for mother and child. Such risks include pregnancy-related hypertension, pregnancy loss, low-birth weight, pre-eclampsia, preterm delivery, still birth and behavioral disorders later in the child's life. Nonetheless, high maternal FT4 levels during pregnancy have been associated with impaired brain developmental outcomes of the offspring and this was independent of hCG levels.
Propylthiouracil is the preferred antithyroid medication in the 1st trimester of pregnancy as it is less teratogenic than methimazole.
== Other animals ==
=== Cats ===
Hyperthyroidism is one of the most common endocrine conditions affecting older domesticated housecats. In the United States, up to 10% of cats over ten years old have hyperthyroidism. The disease has become significantly more common since the first reports of feline hyperthyroidism in the 1970s. The most common cause of hyperthyroidism in cats is the presence of benign tumors called adenomas. 98% of cases are caused by the presence of an adenoma, but the reason these cats develop such tumors continues to be studied.
The most common presenting symptoms are: rapid weight loss, tachycardia (rapid heart rate), vomiting, diarrhea, increased consumption of fluids (polydipsia), increased appetite (polyphagia), and increased urine production (polyuria). Other symptoms include hyperactivity, possible aggression, an unkempt appearance, and large, thick claws. Heart murmurs and a gallop rhythm can develop due to secondary hypertrophic cardiomyopathy. About 70% of affected cats also have enlarged thyroid glands (goiter). 10% of cats exhibit "apathetic hyperthyroidism", which is characterized by anorexia and lethargy.
The same three treatments used with humans are also options in treating feline hyperthyroidism (surgery, radioiodine treatment, and anti-thyroid drugs). There is also a special low iodine diet available that will control the symptoms providing no other food is fed; Hill's y/d formula, when given exclusively, decreases T4 production by limiting the amount of iodine needed for thyroid hormone production. It is the only available commercial diet that focuses on managing feline hyperthyroidism. Medical and dietary management using methimazole and Hill's y/d cat food will give hyperthyroid cats an average of 2 years before dying due to secondary conditions such as heart and kidney failure. Drugs used to help manage the symptoms of hyperthyroidism are methimazole and carbimazole. Drug therapy is the least expensive option, even though the drug must be administered daily for the remainder of the cat's life. Carbimazole is only available as a once daily tablet. Methimazole is available as an oral solution, a tablet, and compounded as a topical gel that is applied using a finger cot to the hairless skin inside a cat's ear. Many cat owners find this gel a good option for cats that don't like being given pills.
Radioiodine treatment, however, is not available in all areas, as this treatment requires nuclear radiological expertise and facilities that not only board the cat, but are specially equipped to manage the cat's urine, sweat, saliva, and stool, which are radioactive for several days after the treatment, usually for a total of 3 weeks (the cat spends the first week in total isolation and the next two weeks in close confinement). In the United States, the guidelines for radiation levels vary from state to state; some states such as Massachusetts allow hospitalization for as little as two days before the animal is sent home with care instructions.
=== Dogs ===
Hyperthyroidism is much less common in dogs compared to cats. Hyperthyroidism may be caused by a thyroid tumor. This may be a thyroid carcinoma. About 90% of carcinomas are very aggressive; they invade the surrounding tissues and metastasize (spread) to other tissues, particularly the lungs. This has a poor prognosis. Surgery to remove the tumor is often very difficult due to metastasis into arteries, the esophagus, or the windpipe. It may be possible to reduce the size of the tumor, thus relieving symptoms and allowing time for other treatments to work. About 10% of thyroid tumors are benign; these often cause few symptoms.
In dogs treated for hypothyroidism (lack of thyroid hormone), iatrogenic hyperthyroidism may occur as a result of an overdose of the thyroid hormone replacement medication, levothyroxine; in this case, treatment involves reducing the dose of levothyroxine. Dogs which display coprophagy, the consumption of feces, and also live in a household with a dog receiving levothyroxine treatment, may develop hyperthyroidism if they frequently eat the feces from the dog receiving levothyroxine treatment.
Hyperthyroidism may occur if a dog eats an excessive amount of thyroid gland tissue. This has occurred in dogs fed commercial dog food.
== See also ==
High-output cardiac failure
Jod-Basedow phenomenon
Hashitoxicosis
== References ==
== Further reading ==
== External links ==
Merck Manual article about hyperthyroidism
Hyperthyroidism at MedlinePlus | Wikipedia/Subclinical_hyperthyroidism |
Heart rate is the frequency of the heartbeat measured by the number of contractions of the heart per minute (beats per minute, or bpm). The heart rate varies according to the body's physical needs, including the need to absorb oxygen and excrete carbon dioxide. It is also modulated by numerous factors, including (but not limited to) genetics, physical fitness, stress or psychological status, diet, drugs, hormonal status, environment, and disease/illness, as well as the interaction between these factors. It is usually equal or close to the pulse rate measured at any peripheral point.
The American Heart Association states the normal resting adult human heart rate is 60–100 bpm. An ultra-trained athlete would have a resting heart rate of 37–38 bpm. Tachycardia is a high heart rate, defined as above 100 bpm at rest. Bradycardia is a low heart rate, defined as below 60 bpm at rest. When a human sleeps, a heartbeat with rates around 40–50 bpm is common and considered normal. When the heart is not beating in a regular pattern, this is referred to as an arrhythmia. Abnormalities of heart rate sometimes indicate disease.
== Physiology ==
While heart rhythm is regulated entirely by the sinoatrial node under normal conditions, heart rate is regulated by sympathetic and parasympathetic input to the sinoatrial node. The accelerans nerve provides sympathetic input to the heart by releasing norepinephrine onto the cells of the sinoatrial node (SA node), and the vagus nerve provides parasympathetic input to the heart by releasing acetylcholine onto sinoatrial node cells. Therefore, stimulation of the accelerans nerve increases heart rate, while stimulation of the vagus nerve decreases it.
As water and blood are incompressible fluids, one of the physiological ways to deliver more blood to an organ is to increase heart rate. Normal resting heart rates range from 60 to 100 bpm. Bradycardia is defined as a resting heart rate below 60 bpm. However, heart rates from 50 to 60 bpm are common among healthy people and do not necessarily require special attention. Tachycardia is defined as a resting heart rate above 100 bpm, though persistent rest rates between 80 and 100 bpm, mainly if they are present during sleep, may be signs of hyperthyroidism or anemia (see below).
Central nervous system stimulants such as substituted amphetamines increase heart rate.
Central nervous system depressants or sedatives decrease the heart rate (apart from some particularly strange ones with equally strange effects, such as ketamine which can cause – amongst many other things – stimulant-like effects such as tachycardia).
There are many ways in which the heart rate speeds up or slows down. Most involve stimulant-like endorphins and hormones being released in the brain, some of which are those that are 'forced'/'enticed' out by the ingestion and processing of drugs such as cocaine or atropine.
This section discusses target heart rates for healthy persons, which would be inappropriately high for most persons with coronary artery disease.
=== Influences from the central nervous system ===
==== Cardiovascular centres ====
The heart rate is rhythmically generated by the sinoatrial node. It is also influenced by central factors through sympathetic and parasympathetic nerves. Nervous influence over the heart rate is centralized within the two paired cardiovascular centres of the medulla oblongata. The cardioaccelerator regions stimulate activity via sympathetic stimulation of the cardioaccelerator nerves, and the cardioinhibitory centers decrease heart activity via parasympathetic stimulation as one component of the vagus nerve. During rest, both centers provide slight stimulation to the heart, contributing to autonomic tone. This is a similar concept to tone in skeletal muscles. Normally, vagal stimulation predominates as, left unregulated, the SA node would initiate a sinus rhythm of approximately 100 bpm.
Both sympathetic and parasympathetic stimuli flow through the paired cardiac plexus near the base of the heart. The cardioaccelerator center also sends additional fibers, forming the cardiac nerves via sympathetic ganglia (the cervical ganglia plus superior thoracic ganglia T1–T4) to both the SA and AV nodes, plus additional fibers to the atria and ventricles. The ventricles are more richly innervated by sympathetic fibers than parasympathetic fibers. Sympathetic stimulation causes the release of the neurotransmitter norepinephrine (also known as noradrenaline) at the neuromuscular junction of the cardiac nerves. This shortens the repolarization period, thus speeding the rate of depolarization and contraction, which results in an increased heartrate. It opens chemical or ligand-gated sodium and calcium ion channels, allowing an influx of positively charged ions.
Norepinephrine binds to the beta–1 receptor. High blood pressure medications are used to block these receptors and so reduce the heart rate.
Parasympathetic stimulation originates from the cardioinhibitory region of the brain with impulses traveling via the vagus nerve (cranial nerve X). The vagus nerve sends branches to both the SA and AV nodes, and to portions of both the atria and ventricles. Parasympathetic stimulation releases the neurotransmitter acetylcholine (ACh) at the neuromuscular junction. ACh slows HR by opening chemical- or ligand-gated potassium ion channels to slow the rate of spontaneous depolarization, which extends repolarization and increases the time before the next spontaneous depolarization occurs. Without any nervous stimulation, the SA node would establish a sinus rhythm of approximately 100 bpm. Since resting rates are considerably less than this, it becomes evident that parasympathetic stimulation normally slows HR. This is similar to an individual driving a car with one foot on the brake pedal. To speed up, one need merely remove one's foot from the brake and let the engine increase speed. In the case of the heart, decreasing parasympathetic stimulation decreases the release of ACh, which allows HR to increase up to approximately 100 bpm. Any increases beyond this rate would require sympathetic stimulation.
==== Input to the cardiovascular centres ====
The cardiovascular centre receive input from a series of visceral receptors with impulses traveling through visceral sensory fibers within the vagus and sympathetic nerves via the cardiac plexus. Among these receptors are various proprioreceptors, baroreceptors, and chemoreceptors, plus stimuli from the limbic system which normally enable the precise regulation of heart function, via cardiac reflexes. Increased physical activity results in increased rates of firing by various proprioreceptors located in muscles, joint capsules, and tendons. The cardiovascular centres monitor these increased rates of firing, suppressing parasympathetic stimulation or increasing sympathetic stimulation as needed in order to increase blood flow.
Similarly, baroreceptors are stretch receptors located in the aortic sinus, carotid bodies, the venae cavae, and other locations, including pulmonary vessels and the right side of the heart itself. Rates of firing from the baroreceptors represent blood pressure, level of physical activity, and the relative distribution of blood. The cardiac centers monitor baroreceptor firing to maintain cardiac homeostasis, a mechanism called the baroreceptor reflex. With increased pressure and stretch, the rate of baroreceptor firing increases, and the cardiac centers decrease sympathetic stimulation and increase parasympathetic stimulation. As pressure and stretch decrease, the rate of baroreceptor firing decreases, and the cardiac centers increase sympathetic stimulation and decrease parasympathetic stimulation.
There is a similar reflex, called the atrial reflex or Bainbridge reflex, associated with varying rates of blood flow to the atria. Increased venous return stretches the walls of the atria where specialized baroreceptors are located. However, as the atrial baroreceptors increase their rate of firing and as they stretch due to the increased blood pressure, the cardiac center responds by increasing sympathetic stimulation and inhibiting parasympathetic stimulation to increase HR. The opposite is also true.
Increased metabolic byproducts associated with increased activity, such as carbon dioxide, hydrogen ions, and lactic acid, plus falling oxygen levels, are detected by a suite of chemoreceptors innervated by the glossopharyngeal and vagus nerves. These chemoreceptors provide feedback to the cardiovascular centers about the need for increased or decreased blood flow, based on the relative levels of these substances.
The limbic system can also significantly impact HR related to emotional state. During periods of stress, it is not unusual to identify higher than normal HRs, often accompanied by a surge in the stress hormone cortisol. Individuals experiencing extreme anxiety may manifest panic attacks with symptoms that resemble those of heart attacks. These events are typically transient and treatable. Meditation techniques have been developed to ease anxiety and have been shown to lower HR effectively. Doing simple deep and slow breathing exercises with one's eyes closed can also significantly reduce this anxiety and HR.
=== Factors influencing heart rate ===
Using a combination of autorhythmicity and innervation, the cardiovascular center is able to provide relatively precise control over the heart rate, but other factors can impact on this. These include hormones, notably epinephrine, norepinephrine, and thyroid hormones; levels of various ions including calcium, potassium, and sodium; body temperature; hypoxia; and pH balance.
==== Epinephrine and norepinephrine ====
The catecholamines, epinephrine and norepinephrine, secreted by the adrenal medulla form one component of the extended fight-or-flight mechanism. The other component is sympathetic stimulation. Epinephrine and norepinephrine have similar effects: binding to the beta-1 adrenergic receptors, and opening sodium and calcium ion chemical- or ligand-gated channels. The rate of depolarization is increased by this additional influx of positively charged ions, so the threshold is reached more quickly and the period of repolarization is shortened. However, massive releases of these hormones coupled with sympathetic stimulation may actually lead to arrhythmias. There is no parasympathetic stimulation to the adrenal medulla.
==== Thyroid hormones ====
In general, increased levels of the thyroid hormones (thyroxine(T4) and triiodothyronine (T3)), increase the heart rate; excessive levels can trigger tachycardia. The impact of thyroid hormones is typically of a much longer duration than that of the catecholamines. The physiologically active form of triiodothyronine, has been shown to directly enter cardiomyocytes and alter activity at the level of the genome. It also impacts the beta-adrenergic response similar to epinephrine and norepinephrine.
==== Calcium ====
Calcium ion levels have a great impact on heart rate and myocardial contractility: increased calcium levels cause an increase in both. High levels of calcium ions result in hypercalcemia and excessive levels can induce cardiac arrest. Drugs known as calcium channel blockers slow HR by binding to these channels and blocking or slowing the inward movement of calcium ions.
==== Caffeine and nicotine ====
Caffeine and nicotine are both stimulants of the nervous system and of the cardiac centres causing an increased heart rate. Caffeine works by increasing the rates of depolarization at the SA node, whereas nicotine stimulates the activity of the sympathetic neurons that deliver impulses to the heart.
==== Effects of stress ====
Both surprise and stress induce physiological response: elevate heart rate substantially. In a study conducted on 8 female and male student actors ages 18 to 25, their reaction to an unforeseen occurrence (the cause of stress) during a performance was observed in terms of heart rate. In the data collected, there was a noticeable trend between the location of actors (onstage and offstage) and their elevation in heart rate in response to stress; the actors present offstage reacted to the stressor immediately, demonstrated by their immediate elevation in heart rate the minute the unexpected event occurred, but the actors present onstage at the time of the stressor reacted in the following 5 minute period (demonstrated by their increasingly elevated heart rate). This trend regarding stress and heart rate is supported by previous studies; negative emotion/stimulus has a prolonged effect on heart rate in individuals who are directly impacted.
In regard to the characters present onstage, a reduced startle response has been associated with a passive defense, and the diminished initial heart rate response has been predicted to have a greater tendency to dissociation. Current evidence suggests that heart rate variability can be used as an accurate measure of psychological stress and may be used for an objective measurement of psychological stress.
==== Factors decreasing heart rate ====
The heart rate can be slowed by altered sodium and potassium levels, hypoxia, acidosis, alkalosis, and hypothermia. The relationship between electrolytes and HR is complex, but maintaining electrolyte balance is critical to the normal wave of depolarization. Of the two ions, potassium has the greater clinical significance. Initially, both hyponatremia (low sodium levels) and hypernatremia (high sodium levels) may lead to tachycardia. Severely high hypernatremia may lead to fibrillation, which may cause cardiac output to cease. Severe hyponatremia leads to both bradycardia and other arrhythmias. Hypokalemia (low potassium levels) also leads to arrhythmias, whereas hyperkalemia (high potassium levels) causes the heart to become weak and flaccid, and ultimately to fail.
Heart muscle relies exclusively on aerobic metabolism for energy. Severe myocardial infarction (commonly called a heart attack) can lead to a decreasing heart rate, since metabolic reactions fueling heart contraction are restricted.
Acidosis is a condition in which excess hydrogen ions are present, and the patient's blood expresses a low pH value. Alkalosis is a condition in which there are too few hydrogen ions, and the patient's blood has an elevated pH. Normal blood pH falls in the range of 7.35–7.45, so a number lower than this range represents acidosis and a higher number represents alkalosis. Enzymes, being the regulators or catalysts of virtually all biochemical reactions – are sensitive to pH and will change shape slightly with values outside their normal range. These variations in pH and accompanying slight physical changes to the active site on the enzyme decrease the rate of formation of the enzyme-substrate complex, subsequently decreasing the rate of many enzymatic reactions, which can have complex effects on HR. Severe changes in pH will lead to denaturation of the enzyme.
The last variable is body temperature. Elevated body temperature is called hyperthermia, and suppressed body temperature is called hypothermia. Slight hyperthermia results in increasing HR and strength of contraction. Hypothermia slows the rate and strength of heart contractions. This distinct slowing of the heart is one component of the larger diving reflex that diverts blood to essential organs while submerged. If sufficiently chilled, the heart will stop beating, a technique that may be employed during open heart surgery. In this case, the patient's blood is normally diverted to an artificial heart-lung machine to maintain the body's blood supply and gas exchange until the surgery is complete, and sinus rhythm can be restored. Excessive hyperthermia and hypothermia will both result in death, as enzymes drive the body systems to cease normal function, beginning with the central nervous system.
==== Physiological control over heart rate ====
A study shows that bottlenose dolphins can learn – apparently via instrumental conditioning – to rapidly and selectively slow down their heart rate during diving for conserving oxygen depending on external signals. In humans regulating heart rate by methods such as listening to music, meditation or a vagal maneuver takes longer and only lowers the rate to a much smaller extent.
== In different circumstances ==
Heart rate is not a stable value and it increases or decreases in response to the body's need in a way to maintain an equilibrium (basal metabolic rate) between requirement and delivery of oxygen and nutrients. The normal SA node firing rate is affected by autonomic nervous system activity: sympathetic stimulation increases and parasympathetic stimulation decreases the firing rate.
=== Resting heart rate ===
Normal pulse rates at rest, in beats per minute (BPM):
The basal or resting heart rate (HRrest) is defined as the heart rate when a person is awake, in a neutrally temperate environment, and has not been subject to any recent exertion or stimulation, such as stress or surprise. The normal resting heart rate is based on the at-rest firing rate of the heart's sinoatrial node, where the faster pacemaker cells driving the self-generated rhythmic firing and responsible for the heart's autorhythmicity are located.
In one 1993 study, 98% of cardiologists suggested that as a desirable target range, 50 to 90 beats per minute is more appropriate than 60 to 100. The available evidence indicates that the normal range for resting heart rate is 50–90 beats per minute (bpm). In a study of over 35,000 American men and women over age 40 during the 1999–2008 period, 71 bpm was the average for men, and 73 bpm was the average for women.
Resting heart rate is often correlated with mortality. In the Copenhagen City Heart Study a heart rate of 65 bpm rather than 80 bpm was associated with 4.6 years longer life expectancy in men and 3.6 years in women. Other studies have shown all-cause mortality is increased by 1.22 (hazard ratio) when heart rate exceeds 90 beats per minute. ECG of 46,129 individuals with low risk for cardiovascular disease revealed that 96% had resting heart rates ranging from 48 to 98 beats per minute. The mortality rate of patients with myocardial infarction increased from 15% to 41% if their admission heart rate was greater than 90 beats per minute. For endurance athletes at the elite level, it is not unusual to have a resting heart rate between 33 and 50 bpm.
=== Maximum heart rate ===
The maximum heart rate (HRmax) is the age-related highest number of beats per minute of the heart when reaching a point of exhaustion without severe problems through exercise stress.
In general it is loosely estimated as 220 minus one's age.
It generally decreases with age. Since HRmax varies by individual, the most accurate way of measuring any single person's HRmax is via a cardiac stress test. In this test, a person is subjected to controlled physiologic stress (generally by treadmill or bicycle ergometer) while being monitored by an electrocardiogram (ECG). The intensity of exercise is periodically increased until certain changes in heart function are detected on the ECG monitor, at which point the subject is directed to stop. Typical duration of the test ranges ten to twenty minutes. Adults who are beginning a new exercise regimen are often advised to perform this test only in the presence of medical staff due to risks associated with high heart rates.
The theoretical maximum heart rate of a human is 300 bpm; however, there have been multiple cases where this theoretical upper limit has been exceeded. The fastest human ventricular conduction rate recorded to this day is a conducted tachyarrhythmia with ventricular rate of 600 beats per minute, which is comparable to the heart rate of a mouse.
For general purposes, a number of formulas are used to estimate HRmax. However, these predictive formulas have been criticized as inaccurate because they only produce generalized population-averages and may deviate significantly from the actual value. (See § Limitations.)
==== Haskell & Fox (1970) ====
Notwithstanding later research, the most widely cited formula for HRmax is still:
HRmax = 220 − age
Although attributed to various sources, it is widely thought to have been devised in 1970 by Dr. William Haskell and Dr. Samuel Fox. They did not develop this formula from original research, but rather by plotting data from approximately 11 references consisting of published research or unpublished scientific compilations. It gained widespread use through being used by Polar Electro in its heart rate monitors, which Dr. Haskell has "laughed about", as the formula "was never supposed to be an absolute guide to rule people's training."
While this formula is commonly used (and easy to remember and calculate), research has consistently found that it is subject to bias, particularly in older adults. Compared to the age-specific average HRmax, the Haskell and Fox formula overestimates HRmax in young adults, agrees with it at age 40, and underestimates HRmax in older adults. For example, in one study, the average HRmax at age 76 was about 10bpm higher than the Haskell and Fox equation. Consequently, the formula cannot be recommended for use in exercise physiology and related fields.
==== Other formulas ====
HRmax is strongly correlated to age, and most formulas are solely based on this. Studies have been mixed on the effect of gender, with some finding that gender is statistically significant, although small when considering overall equation error, while others finding negligible effect. The inclusion of physical activity status, maximal oxygen uptake, smoking, body mass index, body weight, or resting heart rate did not significantly improve accuracy. Nonlinear models are slightly more accurate predictors of average age-specific HRmax, particularly above 60 years of age, but are harder to apply, and provide statistically negligible improvement over linear models. The Wingate formula is the most recent, had the largest data set, and performed best on a fresh data set when compared with other formulas, although it had only a small amount of data for ages 60 and older so those estimates should be viewed with caution. In addition, most formulas are developed for adults and are not applicable to children and adolescents.
==== Limitations ====
Maximum heart rates vary significantly between individuals. Age explains only about half of HRmax variance. For a given age, the standard deviation of HRmax from the age-specific population mean is about 12bpm, and a 95% interval for the prediction error is about 24bpm. For example, Dr. Fritz Hagerman observed that the maximum heart rates of men in their 20s on Olympic rowing teams vary from 160 to 220. Such a variation would equate to an age range of -16 to 68 using the Wingate formula. The formulas are quite accurate at predicting the average heart rate of a group of similarly-aged individuals, but relatively poor for a given individual.
Robergs and Landwehr opine that for VO2 max, prediction errors in HRmax need to be less than ±3 bpm. No current formula meets this accuracy. For prescribing exercise training heart rate ranges, the errors in the more accurate formulas may be acceptable, but again it is likely that, for a significant fraction of the population, current equations used to estimate HRmax are not accurate enough. Froelicher and Myers describe maximum heart formulas as "largely useless". Measurement via a maximal test is preferable whenever possible, which can be as accurate as ±2bpm.
=== Heart rate reserve ===
Heart rate reserve (HRreserve) is the difference between a person's measured or predicted maximum heart rate and resting heart rate. Some methods of measurement of exercise intensity measure percentage of heart rate reserve. Additionally, as a person increases their cardiovascular fitness, their HRrest will drop, and the heart rate reserve will increase. Percentage of HRreserve is statistically indistinguishable from percentage of VO2 reserve.
HRreserve = HRmax − HRrest
This is often used to gauge exercise intensity (first used in 1957 by Karvonen).
Karvonen's study findings have been questioned, due to the following:
The study did not use VO2 data to develop the equation.
Only six subjects were used.
Karvonen incorrectly reported that the percentages of HRreserve and VO2 max correspond to each other, but newer evidence shows that it correlated much better with VO2 reserve as described above.
=== Target heart rate ===
For healthy people, the Target Heart Rate (THR) or Training Heart Rate Range (THRR) is a desired range of heart rate reached during aerobic exercise which enables one's heart and lungs to receive the most benefit from a workout. This theoretical range varies based mostly on age; however, a person's physical condition, sex, and previous training also are used in the calculation.
==== By percent, Fox–Haskell-based ====
The THR can be calculated as a range of 65–85% intensity, with intensity defined simply as percentage of HRmax. However, it is crucial to derive an accurate HRmax to ensure these calculations are meaningful.
Example for someone with a HRmax of 180 (age 40, estimating HRmax As 220 − age):
65% Intensity: (220 − (age = 40)) × 0.65 → 117 bpm
85% Intensity: (220 − (age = 40)) × 0.85 → 154 bpm
==== Karvonen method ====
The Karvonen method factors in resting heart rate (HRrest) to calculate target heart rate (THR), using a range of 50–85% intensity:
THR = ((HRmax − HRrest) × % intensity) + HRrest
Equivalently,
THR = (HRreserve × % intensity) + HRrest
Example for someone with a HRmax of 180 and a HRrest of 70 (and therefore a HRreserve of 110):
50% Intensity: ((180 − 70) × 0.50) + 70 = 125 bpm
85% Intensity: ((180 − 70) × 0.85) + 70 = 163 bpm
==== Zoladz method ====
An alternative to the Karvonen method is the Zoladz method, which is used to test an athlete's capabilities at specific heart rates. These are not intended to be used as exercise zones, although they are often used as such. The Zoladz test zones are derived by subtracting values from HRmax:
THR = HRmax − Adjuster ± 5 bpm
Zone 1 Adjuster = 50 bpm
Zone 2 Adjuster = 40 bpm
Zone 3 Adjuster = 30 bpm
Zone 4 Adjuster = 20 bpm
Zone 5 Adjuster = 10 bpm
Example for someone with a HRmax of 180:
Zone 1 (easy exercise): 180 − 50 ± 5 → 125 − 135 bpm
Zone 4 (tough exercise): 180 − 20 ± 5 → 155 − 165 bpm
=== Heart rate recovery ===
Heart rate recovery (HRR) is the reduction in heart rate at peak exercise and the rate as measured after a cool-down period of fixed duration. A greater reduction in heart rate after exercise during the reference period is associated with a higher level of cardiac fitness.
Heart rates assessed during treadmill stress test that do not drop by more than 12 bpm one minute after stopping exercise (if cool-down period after exercise) or by more than 18 bpm one minute after stopping exercise (if no cool-down period and supine position as soon as possible) are associated with an increased risk of death. People with an abnormal HRR defined as a decrease of 42 beats per minutes or less at two minutes post-exercise had a mortality rate 2.5 times greater than patients with a normal recovery. Another study reported a four-fold increase in mortality in subjects with an abnormal HRR defined as ≤12 bpm reduction one minute after the cessation of exercise. A study reported that a HRR of ≤22 bpm after two minutes "best identified high-risk patients". They also found that while HRR had significant prognostic value it had no diagnostic value.
=== Heart rate prediction ===
Heart rate prediction using machine learning has gained significant attention in health monitoring and sports performance research. Namazi et.al., 2025 study evaluated various models including Long Short-Term Memory (LSTM), Physics-Informed Neural Networks (PINNs), and 1D Convolutional Neural Networks (1D CNNs), using physiological data such as heart rate (HR), breathing rate (BR), and RR intervals collected from wearable sensors during sports activities. The study introduced a hybrid approach combining Singular Spectrum Analysis (SSA) with these models to enhance predictive performance. Among the tested models, the SSA-LSTM method yielded the lowest prediction error, particularly when multivariate inputs (HR + BR + RR) were used. These findings support the use of AI-driven, multivariate prediction models for real-time cardiovascular monitoring in athletic and healthcare settings.
=== Development ===
The human heart beats more than 2.8 billion times in an average lifetime.
The heartbeat of a human embryo begins at approximately 21 days after conception, or five weeks after the last normal menstrual period (LMP), which is the date normally used to date pregnancy in the medical community. The electrical depolarizations that trigger cardiac myocytes to contract arise spontaneously within the myocyte itself. The heartbeat is initiated in the pacemaker regions and spreads to the rest of the heart through a conduction pathway. Pacemaker cells develop in the primitive atrium and the sinus venosus to form the sinoatrial node and the atrioventricular node respectively. Conductive cells develop the bundle of His and carry the depolarization into the lower heart.
The human heart begins beating at a rate near the mother's, about 75–80 beats per minute (bpm). The embryonic heart rate then accelerates linearly for the first month of beating, peaking at 165–185 bpm during the early 7th week, (early 9th week after the LMP). This acceleration is approximately 3.3 bpm per day, or about 10 bpm every three days, an increase of 100 bpm in the first month.
After peaking at about 9.2 weeks after the LMP, it decelerates to about 150 bpm (+/-25 bpm) during the 15th week after the LMP. After the 15th week the deceleration slows reaching an average rate of about 145 (+/-25 bpm) bpm at term. The regression formula which describes this acceleration before the embryo reaches 25 mm in crown-rump length or 9.2 LMP weeks is:
A
g
e
i
n
d
a
y
s
=
E
H
R
(
0.3
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+
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{\displaystyle \mathrm {Age\ in\ days} =\ \mathrm {EHR} (0.3)+6}
== Clinical significance ==
=== Manual measurement ===
Heart rate is measured by finding the pulse of the heart. This pulse rate can be found at any point on the body where the artery's pulsation is transmitted to the surface by pressuring it with the index and middle fingers; often it is compressed against an underlying structure like bone. The thumb should not be used for measuring another person's heart rate, as its strong pulse may interfere with the correct perception of the target pulse.
The radial artery is the easiest to use to check the heart rate. However, in emergency situations the most reliable arteries to measure heart rate are carotid arteries. This is important mainly in patients with atrial fibrillation, in whom heart beats are irregular and stroke volume is largely different from one beat to another. In those beats following a shorter diastolic interval left ventricle does not fill properly, stroke volume is lower and pulse wave is not strong enough to be detected by palpation on a distal artery like the radial artery. It can be detected, however, by doppler.
Possible points for measuring the heart rate are:
The ventral aspect of the wrist on the side of the thumb (radial artery).
The ulnar artery.
The inside of the elbow, or under the biceps muscle (brachial artery).
The groin (femoral artery).
Behind the medial malleolus on the feet (posterior tibial artery).
Middle of dorsum of the foot (dorsalis pedis).
Behind the knee (popliteal artery).
Over the abdomen (abdominal aorta).
The chest (apex of the heart), which can be felt with one's hand or fingers. It is also possible to auscultate the heart using a stethoscope.
In the neck, lateral of the larynx (carotid artery)
The temple (superficial temporal artery).
The lateral edge of the mandible (facial artery).
The side of the head near the ear (posterior auricular artery).
=== Electronic measurement ===
A more precise method of determining heart rate involves the use of an electrocardiograph, or ECG (also abbreviated EKG). An ECG generates a pattern based on electrical activity of the heart, which closely follows heart function. Continuous ECG monitoring is routinely done in many clinical settings, especially in critical care medicine. On the ECG, instantaneous heart rate is calculated using the R wave-to-R wave (RR) interval and multiplying/dividing in order to derive heart rate in heartbeats/min. Multiple methods exist:
HR = 1000 · 60/(RR interval in milliseconds)
HR = 60/(RR interval in seconds)
HR = 300/number of "large" squares between successive R waves.
HR= 1,500 number of large blocks
Heart rate monitors allow measurements to be taken continuously and can be used during exercise when manual measurement would be difficult or impossible (such as when the hands are being used). Various commercial heart rate monitors are also available. Some monitors, used during sport, consist of a chest strap with electrodes. The signal is transmitted to a wrist receiver for display.
Alternative methods of measurement include seismocardiography.
=== Optical measurements ===
Pulse oximetry of the finger and laser Doppler imaging of the eye fundus are often used in the clinics. Those techniques can assess the heart rate by measuring the delay between pulses.
=== Tachycardia ===
Tachycardia is a resting heart rate more than 100 beats per minute. This number can vary as smaller people and children have faster heart rates than average adults.
Physiological conditions where tachycardia occurs:
Pregnancy
Emotional conditions such as anxiety or stress.
Exercise
Pathological conditions where tachycardia occurs:
Sepsis
Fever
Anemia
Hypoxia
Hyperthyroidism
Hypersecretion of catecholamines
Cardiomyopathy
Valvular heart diseases
Acute Radiation Syndrome
Dehydration
Metabolic myopathies (At rest, tachycardia is commonly seen in fatty acid oxidation disorders. An inappropriate rapid heart rate response to exercise is seen in muscle glycogenoses and mitochondrial myopathies, where the tachycardia is faster than would be expected during exercise).
=== Bradycardia ===
Bradycardia was defined as a heart rate less than 60 beats per minute when textbooks asserted that the normal range for heart rates was 60–100 bpm. The normal range has since been revised in textbooks to 50–90 bpm for a human at total rest. Setting a lower threshold for bradycardia prevents misclassification of fit individuals as having a pathologic heart rate. The normal heart rate number can vary as children and adolescents tend to have faster heart rates than average adults. Bradycardia may be associated with medical conditions such as hypothyroidism, heart disease, or inflammatory disease. At rest, although tachycardia is more commonly seen in fatty acid oxidation disorders, more rarely acute bradycardia can occur.
Trained athletes tend to have slow resting heart rates, and resting bradycardia in athletes should not be considered abnormal if the individual has no symptoms associated with it. For example, Miguel Indurain, a Spanish cyclist and five time Tour de France winner, had a resting heart rate of 28 beats per minute, one of the lowest ever recorded in a healthy human. Daniel Green achieved the world record for the slowest heartbeat in a healthy human with a heart rate of just 26 bpm in 2014.
=== Arrhythmia ===
Arrhythmias are abnormalities of the heart rate and rhythm (sometimes felt as palpitations). They can be divided into two broad categories: fast and slow heart rates. Some cause few or minimal symptoms. Others produce more serious symptoms of lightheadedness, dizziness and fainting.
=== Hypertension ===
Elevated heart rate is a powerful predictor of morbidity and mortality in patients with hypertension. Atherosclerosis and dysautonomia are major contributors to the pathogenesis.
=== Correlation with cardiovascular mortality risk ===
A number of investigations indicate that faster resting heart rate has emerged as a new risk factor for mortality in homeothermic mammals, particularly cardiovascular mortality in human beings. High heart rate is associated with endothelial dysfunction and increased atheromatous plaque formation leading to atherosclerosis. Faster heart rate may accompany increased production of inflammation molecules and increased production of reactive oxygen species in cardiovascular system, in addition to increased mechanical stress to the heart. There is a correlation between increased resting rate and cardiovascular risk. This is not seen to be "using an allotment of heart beats" but rather an increased risk to the system from the increased rate.
An Australian-led international study of patients with cardiovascular disease has shown that heart beat rate is a key indicator for the risk of heart attack. The study, published in The Lancet (September 2008) studied 11,000 people, across 33 countries, who were being treated for heart problems. Those patients whose heart rate was above 70 beats per minute had significantly higher incidence of heart attacks, hospital admissions and the need for surgery. Higher heart rate is thought to be correlated with an increase in heart attack and about a 46 percent increase in hospitalizations for non-fatal or fatal heart attack.
Other studies have shown that a high resting heart rate is associated with an increase in cardiovascular and all-cause mortality in the general population and in patients with chronic diseases. A faster resting heart rate is associated with shorter life expectancy and is considered a strong risk factor for heart disease and heart failure, independent of level of physical fitness. Specifically, a resting heart rate above 65 beats per minute has been shown to have a strong independent effect on premature mortality; every 10 beats per minute increase in resting heart rate has been shown to be associated with a 10–20% increase in risk of death. In one study, men with no evidence of heart disease and a resting heart rate of more than 90 beats per minute had a five times higher risk of sudden cardiac death. Similarly, another study found that men with resting heart rates of over 90 beats per minute had an almost two-fold increase in risk for cardiovascular disease mortality; in women it was associated with a three-fold increase. In patients having heart rates of 70 beats/minute or above, each additional beat/minute was associated with increased rate of cardiovascular death and heart failure hospitalization.
Given these data, heart rate should be considered in the assessment of cardiovascular risk, even in apparently healthy individuals. Heart rate has many advantages as a clinical parameter: It is inexpensive and quick to measure and is easily understandable. Although the accepted limits of heart rate are between 60 and 100 beats per minute, this was based for convenience on the scale of the squares on electrocardiogram paper; a better definition of normal sinus heart rate may be between 50 and 90 beats per minute.
Standard textbooks of physiology and medicine mention that heart rate (HR) is readily calculated from the ECG as follows: HR = 1000*60/RR interval in milliseconds, HR = 60/RR interval in seconds, or HR = 300/number of large squares between successive R waves. In each case, the authors are actually referring to instantaneous HR, which is the number of times the heart would beat if successive RR intervals were constant.
Lifestyle and pharmacological regimens may be beneficial to those with high resting heart rates. Exercise is one possible measure to take when an individual's heart rate is higher than 80 beats per minute. Diet has also been found to be beneficial in lowering resting heart rate: In studies of resting heart rate and risk of death and cardiac complications on patients with type 2 diabetes, legumes were found to lower resting heart rate. This is thought to occur because in addition to the direct beneficial effects of legumes, they also displace animal proteins in the diet, which are higher in saturated fat and cholesterol. Another nutrient is omega-3 long chain polyunsaturated fatty acids (omega-3 fatty acid or LC-PUFA). In a meta-analysis with a total of 51 randomized controlled trials (RCTs) involving 3,000 participants, the supplement mildly but significantly reduced heart rate (-2.23 bpm; 95% CI: -3.07, -1.40 bpm). When docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) were compared, modest heart rate reduction was observed in trials that supplemented with DHA (-2.47 bpm; 95% CI: -3.47, -1.46 bpm), but not in those received EPA.
A very slow heart rate (bradycardia) may be associated with heart block. It may also arise from autonomous nervous system impairment.
== See also ==
Heart rate monitor
Cardiac cycle
Electrocardiography
Sinus rhythm
Second wind (heart rate is measured during 12 Minute Walk Test)
Bainbridge reflex
== Notes ==
== References ==
This article incorporates text from the CC BY book: OpenStax College, Anatomy & Physiology. OpenStax CNX. 30 July 2014.
== Bibliography ==
== External links ==
Online Heart Beats Per Minute Calculator Tap along with your heart rate
An application (open-source) for contactless real time heart rate measurements by means of an ordinary web cam | Wikipedia/Target_heart_rate |
Tissue remodeling is the reorganization or renovation of existing tissues. Tissue remodeling can be either physiological or pathological. The process can either change the characteristics of a tissue such as in blood vessel remodeling, or result in the dynamic equilibrium of a tissue such as in bone remodeling. Macrophages repair wounds and remodel tissue by producing extracellular matrix and proteases to modify that specific matrix.
A myocardial infarction induces tissue remodeling of the heart in a three-phase process: inflammation, proliferation, and maturation. Inflammation is characterized by massive necrosis in the infarcted area. Inflammatory cells clear the dead cells. In the proliferation phase, inflammatory cells die by apoptosis, being replaced by myofibroblasts which produce large amounts of collagen. In the maturation phase, myofibroblast numbers are reduced by apoptosis, allowing for infiltration by endothelial cells (for blood vessels) and cardiomyocytes (heart tissue cells). Usually, however, much of the tissue remodeling is pathological, resulting in a large amount of fibrous tissue. By contrast, aerobic exercise can produce beneficial cardiac tissue remodeling in those suffering from left ventricular hypertrophy.
Programmed cellular senescence contributes to beneficial tissue remodeling during embryonic development of the fetus.
In a brain stroke the penumbra area surrounding the ischemic event initially undergoes a damaging remodeling, but later transitions to a tissue remodeling characterized by repair.
Vascular remodeling refers to a compensatory change in blood vessel walls due to plaque growth. Vascular expansion is called positive remodeling, whereas vascular constriction is called negative remodeling.
Tissue remodeling occurs in adipose tissue with increased body fat. In obese subjects, this remodeling is often pathological, characterized by excessive inflammation and fibrosis.
== See also ==
Collagen hybridizing peptide, a molecular marker to directly image tissue remodeling
== References == | Wikipedia/Tissue_remodeling |
Cardiac surgery, or cardiovascular surgery, is a surgery on the heart or great vessels performed by cardiac surgeons. It is often used to treat complications of ischemic heart disease (for example, with coronary artery bypass grafting); to correct congenital heart disease; or to treat valvular heart disease from various causes, including endocarditis, rheumatic heart disease, and atherosclerosis. It also includes heart transplantation.
== History ==
=== 19th century ===
The earliest operations on the pericardium (the sac that surrounds the heart) took place in the 19th century and were performed by Francisco Romero (1801) in the city of Almería (Spain), Dominique Jean Larrey (1810), Henry Dalton (1891), and Daniel Hale Williams (1893). The first surgery on the heart itself was performed by Axel Cappelen on 4 September 1895 at Rikshospitalet in Kristiania, now Oslo. Cappelen ligated a bleeding coronary artery in a 24-year-old man who had been stabbed in the left axilla and was in deep shock upon arrival. Access was through a left thoracotomy. The patient awoke and seemed fine for 24 hours but became ill with a fever and died three days after the surgery from mediastinitis.
=== 20th century ===
Surgery on the great vessels (e.g., aortic coarctation repair, Blalock–Thomas–Taussig shunt creation, closure of patent ductus arteriosus) became common after the turn of the century. However, operations on the heart valves were unknown until, in 1925, Henry Souttar operated successfully on a young woman with mitral valve stenosis. He made an opening in the appendage of the left atrium and inserted a finger in order to palpate and explore the damaged mitral valve. The patient survived for several years, but Souttar's colleagues considered the procedure unjustified, and he could not continue.
Alfred Blalock, Helen Taussig, and Vivien Thomas performed the first successful palliative pediatric cardiac operation at Johns Hopkins Hospital on 29 November 1944, in a one-year-old girl with Tetralogy of Fallot. Their work on patient Eileen Saxon was dramatically portrayed by HBO in the 2004 television film Something The Lord Made as the birth of modern cardiac surgery.
Cardiac surgery changed significantly after World War II. In 1947, Thomas Sellors of Middlesex Hospital in London operated on a Tetralogy of Fallot patient with pulmonary stenosis and successfully divided the stenosed pulmonary valve. In 1948, Russell Brock, probably unaware of Sellors's work, used a specially designed dilator in three cases of pulmonary stenosis. Later that year, he designed a punch to resect a stenosed infundibulum, which is often associated with Tetralogy of Fallot. Many thousands of these "blind" operations were performed until the introduction of cardiopulmonary bypass made direct surgery on valves possible.
Also in 1948, four surgeons carried out successful operations for mitral valve stenosis resulting from rheumatic fever. Horace Smithy of Charlotte used a valvulotome to remove a portion of a patient's mitral valve, while three other doctors—Charles Bailey of Hahnemann University Hospital in Philadelphia; Dwight Harken in Boston; and Russell Brock of Guy's Hospital in London—adopted Souttar's method. All four men began their work independently of one another within a period of a few months. This time, Souttar's technique was widely adopted, with some modifications.
The first successful intracardiac correction of a congenital heart defect using hypothermia was performed by lead surgeon Dr. F. John Lewis (Dr. C. Walton Lillehei assisted) at the University of Minnesota on 2 September 1952. In 1953, Alexander Alexandrovich Vishnevsky conducted the first cardiac surgery under local anesthesia. In 1956, Dr. John Carter Callaghan performed the first documented open-heart surgery in Canada.
== Types of cardiac surgery ==
=== Open-heart surgery ===
Open-heart surgery is any kind of surgery in which a surgeon makes a large incision (cut) in the chest to open the rib cage and operate on the heart. "Open" refers to the chest, not the heart. Depending on the type of surgery, the surgeon also may open the heart.
Dr. Wilfred G. Bigelow of the University of Toronto found that procedures involving opening the patient's heart could be performed better in a bloodless and motionless environment. Therefore, during such surgery, the heart is temporarily stopped, and the patient is placed on cardiopulmonary bypass, meaning a machine pumps their blood and oxygen. Because the machine cannot function the same way as the heart, surgeons try to minimize the time a patient spends on it.
Cardiopulmonary bypass was developed after surgeons realized the limitations of hypothermia in cardiac surgery: Complex intracardiac repairs take time, and the patient needs blood flow to the body (particularly to the brain), as well as heart and lung function. In July 1952, Forest Dodrill was the first to use a mechanical pump in a human to bypass the left side of the heart whilst allowing the patient's lungs to oxygenate the blood, in order to operate on the mitral valve. In 1953, Dr. John Heysham Gibbon of Jefferson Medical School in Philadelphia reported the first successful use of extracorporeal circulation by means of an oxygenator, but he abandoned the method after subsequent failures. In 1954, Dr. Lillehei performed a series of successful operations with the controlled cross-circulation technique, in which the patient's mother or father was used as a "heart-lung machine". Dr. John W. Kirklin at the Mayo Clinic was the first to use a Gibbon-type pump-oxygenator. Russell M. Nelson became the first surgeon to perform an open heart surgery in Utah in 1955.
Nazih Zuhdi performed the first total intentional hemodilution open-heart surgery on Terry Gene Nix, age 7, on 25 February 1960 at Mercy Hospital in Oklahoma City. The operation was a success; however, Nix died three years later. In March 1961, Zuhdi, Carey, and Greer performed open-heart surgery on a child, aged 3+1⁄2, using the total intentional hemodilution machine.
==== Modern beating-heart surgery ====
In the early 1990s, surgeons began to perform off-pump coronary artery bypass, done without cardiopulmonary bypass. In these operations, the heart continues beating during surgery, but is stabilized to provide an almost still work area in which to connect a conduit vessel that bypasses a blockage. The conduit vessel that is often used is the saphenous vein. This vein is harvested using a technique known as endoscopic vein harvesting (EVH).
=== Heart transplant ===
In 1945, the Soviet pathologist Nikolai Sinitsyn successfully transplanted a heart from one frog to another frog and from one dog to another dog.
Norman Shumway is widely regarded as the father of human heart transplantation, although the world's first adult heart transplant was performed by a South African cardiac surgeon, Christiaan Barnard, using techniques developed by Shumway and Richard Lower. Barnard performed the first transplant on Louis Washkansky on 3 December 1967 at Groote Schuur Hospital in Cape Town. Adrian Kantrowitz performed the first pediatric heart transplant on 6 December 1967 at Maimonides Hospital (now Maimonides Medical Center) in Brooklyn, New York, barely three days later. Shumway performed the first adult heart transplant in the United States on 6 January 1968 at Stanford University Hospital.
=== Coronary artery bypass grafting ===
Coronary artery bypass grafting (CABG), also called revascularization, is a common surgical procedure to create an alternative path to deliver blood supply to the heart and body, with the goal of preventing clot formation. This can be done in many ways, and the arteries used can be taken from several areas of the body. Arteries are typically harvested from the chest, arm, or wrist and then attached to a portion of the coronary artery, relieving pressure and limiting clotting factors in that area of the heart.
The procedure is typically performed because of coronary artery disease (CAD), in which a plaque-like substance builds up in the coronary artery, the main pathway carrying oxygen-rich blood to the heart. This can cause a blockage and/or a rupture, which can lead to a heart attack.
=== Minimally invasive surgery ===
As an alternative to open-heart surgery, which involves a five- to eight-inch incision in the chest wall, a surgeon may perform an endoscopic procedure by making very small incisions through which a camera and specialized tools are inserted.
In robot-assisted heart surgery, a machine controlled by a cardiac surgeon is used to perform a procedure. The main advantage to this is the size of the incision required: three small port holes instead of an incision big enough for the surgeon's hands. The use of robotics in heart surgery continues to be evaluated, but early research has shown it to be a safe alternative to traditional techniques.
== Post-surgical procedures ==
As with any surgical procedure, cardiac surgery requires postoperative precautions to avoid complications. Incision care is needed to avoid infection and minimize scarring. Swelling and loss of appetite are common.
Recovery from open-heart surgery begins with about 48 hours in an intensive care unit, where heart rate, blood pressure, and oxygen levels are closely monitored. Chest tubes are inserted to drain blood around the heart and lungs. After discharge from the hospital, compression socks may be recommended in order to regulate blood flow.
== Risks ==
The advancement of cardiac surgery and cardiopulmonary bypass techniques has greatly reduced the mortality rates of these procedures. For instance, repairs of congenital heart defects are currently estimated to have 4–6% mortality rates.
A major concern with cardiac surgery is neurological damage. Stroke occurs in 2–3% of all people undergoing cardiac surgery, and the rate is higher in patients with other risk factors for stroke. A more subtle complication attributed to cardiopulmonary bypass is postperfusion syndrome, sometimes called "pumphead". The neurocognitive symptoms of postperfusion syndrome were initially thought to be permanent, but turned out to be transient, with no permanent neurological impairment.
In order to assess the performance of surgical units and individual surgeons, a popular risk model has been created called the EuroSCORE. It takes a number of health factors from a patient and, using precalculated logistic regression coefficients, attempts to quantify the probability that they will survive to discharge. Within the United Kingdom, the EuroSCORE was used to give a breakdown of all cardiothoracic surgery centres and to indicate whether the units and their individuals surgeons performed within an acceptable range. The results are available on the Care Quality Commission website.
Another important source of complications are the neuropsychological and psychopathologic changes following open-heart surgery. One example is Skumin syndrome, described by Victor Skumin in 1978, which is a "cardioprosthetic psychopathological syndrome" associated with mechanical heart valve implants and characterized by irrational fear, anxiety, depression, sleep disorder, and weakness.
=== Risk reduction ===
Pharmacological and non-pharmacological prevention approaches may reduce the risk of atrial fibrillation after an operation and reduce the length of hospital stays, however there is no evidence that this improves mortality.
==== Non-pharmacologic approaches ====
Preoperative physical therapy may reduce postoperative pulmonary complications, such as pneumonia and atelectasis, in patients undergoing elective cardiac surgery and may decrease the length of hospital stay by more than three days on average. There is evidence that quitting smoking at least four weeks before surgery may reduce the risk of postoperative complications.
==== Pharmacological approaches ====
Beta-blocking medication is sometimes prescribed during cardiac surgery. There is some low certainty evidence that this perioperative blockade of beta-adrenergic receptors may reduce the incidence of atrial fibrillation and ventricular arrhythmias in patients undergoing cardiac surgery.
== See also ==
Frank Gerbode (surgeon)
== References ==
== Further reading ==
Cohn, Lawrence H.; Edmunds, L. Henry Jr., eds. (2003). Cardiac surgery in the adult. New York: McGraw-Hill, Medical Pub. Division. ISBN 978-0-07-139129-0. Archived from the original on 14 June 2016.
== External links ==
Media related to Cardiac surgery at Wikimedia Commons | Wikipedia/Heart_surgery |
Angiology is a peer-reviewed academic journal that publishes papers in the field of Vascular disease. The journal's editor is Dimitri P. Mikhailidis. It has been in publication since 1950 and is currently published by SAGE Publications.
== Scope ==
Angiology aims to publish papers and case reports relative to all phases of all vascular diseases. The journal covers areas such as diagnostic methods, therapeutic approaches, and clinical and laboratory research and also publishes special issues and supplements relating to specific topics of current interest to surgeons and internists.
== Abstracting and indexing ==
Angiology is abstracted and indexed in, among other databases: SCOPUS, and the Social Sciences Citation Index. According to the Journal Citation Reports, its 2010 impact factor is 0.992, ranking it 56 out of 66 journals in the category ‘Peripheral Vascular Disease’.
== References ==
== External links ==
Official website | Wikipedia/Vascular_Diseases_(journal) |
Atrial fibrillation (AF, AFib or A-fib) is an abnormal heart rhythm (arrhythmia) characterized by rapid and irregular beating of the atrial chambers of the heart. It often begins as short periods of abnormal beating, which become longer or continuous over time. It may also start as other forms of arrhythmia such as atrial flutter that then transform into AF.
Episodes can be asymptomatic. Symptomatic episodes may involve heart palpitations, fainting, lightheadedness, loss of consciousness, or shortness of breath. Atrial fibrillation is associated with an increased risk of heart failure, dementia, and stroke. It is a type of supraventricular tachycardia.
Atrial fibrillation frequently results from bursts of tachycardia that originate in muscle bundles extending from the atrium to the pulmonary veins. Pulmonary vein isolation by transcatheter ablation can restore sinus rhythm. The ganglionated plexi (autonomic ganglia of the heart atrium and ventricles) can also be a source of atrial fibrillation, and are sometimes also ablated for that reason. Not only the pulmonary vein, but the left atrial appendage and ligament of Marshall can be a source of atrial fibrillation and are also ablated for that reason. As atrial fibrillation becomes more persistent, the junction between the pulmonary veins and the left atrium becomes less of an initiator and the left atrium becomes an independent source of arrhythmias.
High blood pressure and valvular heart disease are the most common modifiable risk factors for AF. Other heart-related risk factors include heart failure, coronary artery disease, cardiomyopathy, and congenital heart disease. In low- and middle-income countries, valvular heart disease is often attributable to rheumatic fever. Lung-related risk factors include COPD, obesity, and sleep apnea. Cortisol and other stress biomarkers, as well as emotional stress, may play a role in the pathogenesis of atrial fibrillation.
Other risk factors include excess alcohol intake, tobacco smoking, diabetes mellitus, subclinical hypothyroidism, and thyrotoxicosis. However, about half of cases are not associated with any of these aforementioned risks. Healthcare professionals might suspect AF after feeling the pulse and confirm the diagnosis by interpreting an electrocardiogram (ECG). A typical ECG in AF shows irregularly spaced QRS complexes without P waves.
Healthy lifestyle changes, such as weight loss in people with obesity, increased physical activity, and drinking less alcohol, can lower the risk for AF and reduce its burden if it occurs. AF is often treated with medications to slow the heart rate to a near-normal range (known as rate control) or to convert the rhythm to normal sinus rhythm (known as rhythm control). Electrical cardioversion can convert AF to normal heart rhythm and is often necessary for emergency use if the person is unstable. Ablation may prevent recurrence in some people. For those at low risk of stroke, AF does not necessarily require blood-thinning though some healthcare providers may prescribe an anti-clotting medication. Most people with AF are at higher risk of stroke. For those at more than low risk, experts generally recommend an anti-clotting medication. Anti-clotting medications include warfarin and direct oral anticoagulants. While these medications reduce stroke risk, they increase rates of major bleeding.
Atrial fibrillation is the most common serious abnormal heart rhythm and, as of 2020, affects more than 33 million people worldwide. As of 2014, it affected about 2 to 3% of the population of Europe and North America. The incidence and prevalence of AF increases. In the developing world, about 0.6% of males and 0.4% of females are affected. The percentage of people with AF increases with age with 0.1% under 50 years old, 4% between 60 and 70 years old, and 14% over 80 years old being affected. The first known report of an irregular pulse was by Jean-Baptiste de Sénac in 1749. Thomas Lewis was the first doctor to document this by ECG in 1909.
== Signs and symptoms ==
Atrial fibrillation is usually accompanied by symptoms related to a rapid heart rate. Rapid and irregular heart rates may be perceived as the sensation of the heart beating too fast, irregularly, or skipping beats (palpitations) or exercise intolerance.
Other possible symptoms include congestive heart failure symptoms such as fatigue, shortness of breath, or swelling. Loss of consciousness can also occur on atrial fibrillations due to lack of oxygen and blood to the brain. The abnormal heart rhythm (arrhythmia) is sometimes only identified with the onset of a stroke or a transient ischemic attack (TIA). It is not uncommon for a person to first become aware of AF from a routine physical examination or electrocardiogram, as it often does not cause symptoms.
Since most cases of AF are secondary to other medical problems, the presence of chest pain or angina, signs and symptoms of hyperthyroidism (an overactive thyroid gland) such as weight loss and diarrhea, and symptoms suggestive of lung disease can indicate an underlying cause. A history of stroke or TIA, as well as high blood pressure, diabetes, heart failure, or rheumatic fever, may indicate whether someone with AF is at a higher risk of complications.
=== Rapid heart rate ===
Presentation is similar to other forms of rapid heart rate and may be asymptomatic. Palpitations and chest discomfort are common complaints. The rapid uncoordinated heart rate may result in reduced output of blood pumped by the heart (cardiac output), resulting in inadequate blood flow, and therefore oxygen delivery to the rest of the body. Common symptoms of uncontrolled atrial fibrillation may include shortness of breath, shortness of breath when lying flat, dizziness, and sudden onset of shortness of breath during the night. This may progress to swelling of the lower extremities, a manifestation of congestive heart failure. Due to inadequate cardiac output, individuals with AF may also complain of lightheadedness.
AF can cause respiratory distress due to congestion in the lungs. By definition, the heart rate will be greater than 100 beats per minute. Blood pressure may be variable, and often difficult to measure as the beat-by-beat variability causes problems for most digital (oscillometric) non-invasive blood pressure monitors. For this reason, when determining the heart rate in AF, direct cardiac auscultation is recommended. Low blood pressure is most concerning, and a sign that immediate treatment is required. Many of the symptoms associated with uncontrolled atrial fibrillation are a manifestation of congestive heart failure due to the reduced cardiac output. The affected person's respiratory rate often increases in the presence of respiratory distress. Pulse oximetry may confirm the presence of too little oxygen reaching the body's tissues, related to any precipitating factors such as pneumonia. Examination of the jugular veins may reveal elevated pressure (jugular venous distention). Examination of the lungs may reveal crackles, which are suggestive of pulmonary edema. Examination of the heart will reveal a rapid irregular rhythm.
== Causes ==
AF is linked to several forms of cardiovascular disease but may occur in otherwise normal hearts. Cardiovascular factors known to be associated with the development of AF include high blood pressure, coronary artery disease, mitral valve stenosis (e.g., due to rheumatic heart disease or mitral valve prolapse), mitral regurgitation, left atrial enlargement, hypertrophic cardiomyopathy, pericarditis, congenital heart disease, and previous heart surgery. People with congenital heart disease tend to develop atrial fibrillation at a younger age, that is more likely to be of right atrial origin (atypical) than of left origin, and have a greater risk of progressing to permanent atrial fibrillation.
Additionally, lung diseases (such as pneumonia, lung cancer, pulmonary embolism, and sarcoidosis) may play a role in certain people. Sepsis also increases the risk of developing new-onset atrial fibrillation. Disorders of breathing during sleep, such as obstructive sleep apnea (OSA), are also associated with AF. OSA, specifically, was found to be a very strong predictor of atrial fibrillation. Patients with OSA were shown to have an increased incidence of atrial fibrillation and a study done by Gami et al. demonstrated that increased nocturnal oxygen desaturation from OSA severity was correlated with higher incidences of atrial fibrillation. Obesity is a risk factor for AF. Hyperthyroidism and subclinical hyperthyroidism are associated with AF development.
Caffeine consumption does not appear to be associated with AF; excessive alcohol consumption ("binge drinking" or "holiday heart syndrome") is linked to AF. Low-to-moderate alcohol consumption also appears to be associated with an increased risk of developing atrial fibrillation, although the increase in risk associated with drinking less than two drinks daily appears to be small. Tobacco smoking and secondhand tobacco smoke exposure are associated with an increased risk of developing atrial fibrillation. Long-term endurance exercise that far exceeds the recommended amount of exercise (e.g., long-distance cycling or marathon running) appears to be associated with a modest increase in the risk of atrial fibrillation in middle-aged and elderly people.
Major stress biomarkers (including cortisol and heat shock proteins) indicate that stress plays a significant role in causing atrial fibrillation. There is some evidence that night shift working may be linked to a diagnosis of AF.
Atrial fibrillation is associated with elevated levels of inflammatory markers and clotting factors. Mendelian randomization indicates a causal relationship of inflammation leading to atrial fibrillation.
=== Genetics ===
Family history in a first degree relative is associated with a 40% increase in risk of AF. This finding led to the mapping of different loci such as 10q22-24, 6q14-16 and 11p15-5.3 and discover mutations associated with the loci. Mutations have been found in the genes of K+ channels and Na+ channels which affect the processes of polarization-depolarization of the myocardium, cellular hyper-excitability, shortening of effective refractory period favoring re-entries.
Using genome-wide association study (GWAS), which screen the entire genome for single nucleotide polymorphism (SNP), three susceptibility loci have been found for AF (4q25, 1q21 and 16q22). In these loci there are SNPs associated with a 30% increase in risk of recurrent atrial tachycardia after ablation. There are also SNPs associated with loss of function of the Pitx2c gene (involved in cellular development of pulmonary valves), responsible for re-entries. There are also SNPs close to ZFHX3 genes involved in the regulation of Ca2+. A 2018 meta-analysis of GWAS studies identified 97 locis associated with AF, of which 70 were newly identified associations: they are associated with genes that encode transcription factors, such as TBX3 and TBX5, NKX2-5 or PITX2, involved in the regulation of cardiac conduction, modulation of ion channels and in cardiac development.
=== Sedentary lifestyle ===
A sedentary lifestyle increases the risk factors associated with AF, such as obesity, hypertension, or diabetes mellitus. This favors remodeling processes of the atrium due to inflammation or alterations in the depolarization of cardiomyocytes by elevation of sympathetic nervous system activity. A sedentary lifestyle is associated with an increased risk of AF compared to physical activity. In both men and women, the practice of moderate exercise reduces the risk of AF progressively; intense sports may increase the risk of developing AF, as seen in athletes. It is due to a remodeling of cardiac tissue, and an increase in vagal tone, which shortens the effective refractory period (ERP) favoring re-entries from the pulmonary veins.
=== Tobacco ===
The rate of AF in smokers is 1.4 times higher than in non-smokers. Snus consumption, which delivers nicotine at a dose equivalent to that of cigarettes, is not correlated with AF.
=== Alcohol ===
Acute alcohol consumption can directly trigger an episode of atrial fibrillation. Regular alcohol consumption also increases the risk of atrial fibrillation in several ways. The long-term use of alcohol alters the physical structure and electrical properties of the atria. Alcohol consumption does this by repeatedly stimulating the sympathetic nervous system, increasing inflammation in the atria, raising blood pressure, lowering the levels of potassium and magnesium in the blood, worsening obstructive sleep apnea, and by promoting harmful structural changes (remodeling) in the atria and ventricles of the heart. This remodeling leads to abnormally increased pressure in the left atrium, inappropriately dilates it, and increases scarring (fibrosis) in the left atrium. The aforementioned structural changes increase the risk of developing atrial fibrillation when paired with the harmful changes in how the left atrium conducts electricity.
=== Hypertension ===
Hypertension is reportedly present in 49% to 90% of patients with atrial fibrillation. According to the CHARGE Consortium, both systolic and diastolic blood pressure are predictors of the risk of AF. Systolic blood pressure values close to normal limit the increase in the risk associated with AF. Diastolic dysfunction is also associated with AF, which increases left atrial pressure, left atrial volume, size, and left ventricular hypertrophy, characteristic of chronic hypertension. All atrial remodeling is related to heterogeneous conduction and the formation of re-entrant electric conduction from the pulmonary veins.
=== Other diseases ===
There is a relationship between risk factors such as obesity and hypertension, with the appearance of diseases such as diabetes mellitus and sleep apnea-hypopnea syndrome, specifically, obstructive sleep apnea (OSA). These diseases are associated with an increased risk of AF due to their remodeling effects on the left atrium.
=== Medications ===
Several medications are associated with an increased risk of developing atrial fibrillation. Few studies have examined this phenomenon, and the exact incidence of medication-induced atrial fibrillation is unknown. Medications that are commonly associated with an increased risk of developing atrial fibrillation include dobutamine and the chemotherapy agent cisplatin. Agents associated with a moderately increased risk include nonsteroidal anti-inflammatory drugs (e.g., ibuprofen), bisphosphonates, and other chemotherapeutic agents such as melphalan, interleukin 2, and anthracyclines. Other medications that rarely increase the risk of developing atrial fibrillation include adenosine, aminophylline, corticosteroids, ivabradine, ondansetron, and antipsychotics. This form of atrial fibrillation occurs in people of all ages but is most common in the elderly, in those with other atrial fibrillation risk factors, and after heart surgery.
== Pathophysiology ==
The normal electrical conduction system of the heart allows electrical impulses generated by the heart's own pacemaker (the sinoatrial node) to spread to and stimulate the muscular layer of the heart (myocardium) in both the atria and the ventricles. When the myocardium is stimulated it contracts, and if this occurs in an orderly manner allows blood to be pumped to the body. In AF, the normal regular electrical impulses generated by the sinoatrial node are overwhelmed by disorganized electrical waves, usually originating from the roots of the pulmonary veins. These disorganized waves conduct intermittently through the atrioventricular node, leading to irregular activation of the ventricles that generate the heartbeat.
=== Pathology ===
The primary pathologic change seen in atrial fibrillation is the progressive fibrosis of the atria. This fibrosis is due primarily to atrial dilation; however, genetic causes and inflammation may be factors in some individuals. Dilation of the atria can be due to almost any structural abnormality of the heart that can cause a rise in the pressure within the heart. This includes valvular heart disease (such as mitral stenosis, mitral regurgitation, and tricuspid regurgitation), hypertension, and congestive heart failure. Any inflammatory state that affects the heart can cause fibrosis of the atria.
Once dilation of the atria has occurred, this begins a chain of events that leads to the activation of the renin–angiotensin–aldosterone system (RAAS) and subsequent increase in the matrix metalloproteinases and disintegrin, which leads to atrial remodeling and fibrosis, with loss of atrial muscle mass. This process occurs gradually, and experimental studies have revealed patchy atrial fibrosis may precede the occurrence of atrial fibrillation and may progress with prolonged durations of atrial fibrillation.
Fibrosis is not limited to the muscle mass of the atria and may occur in the sinus node (SA node) and atrioventricular node (AV node), correlating with sick sinus syndrome. Prolonged episodes of atrial fibrillation have been shown to correlate with prolongation of the sinus node recovery time; this suggests that dysfunction of the SA node is progressive with prolonged episodes of atrial fibrillation.
Along with fibrosis, alterations in the atria that predispose to atrial fibrillation affect their electrical properties, as well as their responsiveness to the autonomic nervous system. The atrial remodeling that includes the pathologic changes described above has been referred to as atrial myopathy.
=== Electrophysiology ===
There are multiple theories about the cause of atrial fibrillation. An important theory is that the regular impulses produced by the sinus node for a normal heartbeat are overwhelmed by rapid electrical discharges produced in the atria and adjacent parts of the pulmonary veins. Non-pulmonary vein sources of triggers for atrial fibrillation have been identified in 10% to 33% of patients. These triggers include the coronary sinus, the posterior wall of the left atrium, the ligament of Marshall, and the left atrial appendage.
Sources of these disturbances are either automatic foci, often localized at one of the pulmonary veins, or a small number of localized sources in the form of either a re-entrant leading circle or electrical spiral waves (rotors); these localized sources may be in the left atrium near the pulmonary veins or in a variety of other locations through both the left or right atrium. Three fundamental components favor the establishment of a leading circle or a rotor: slow conduction velocity of the cardiac action potential, a short refractory period, and a small wavelength. Meanwhile, the wavelength is the product of velocity and refractory period. If the action potential has fast conduction, with a long refractory period and/or conduction pathway shorter than the wavelength, an AF focus would not be established. In multiple wavelet theory, a wavefront will break into smaller daughter wavelets when encountering an obstacle, through a process called vortex shedding. But, under the proper conditions, such wavelets can reform and spin around a center, forming an AF focus.
In a heart with AF, the increased calcium release from the sarcoplasmic reticulum and increased calcium sensitivity can lead to an accumulation of intracellular calcium and causes downregulation of L-type calcium channels. This reduces the duration of action potential and the refractory period, thus favoring the conduction of re-entrant waves. Increased expression of inward-rectifier potassium ion channels can cause a reduced atrial refractory period and wavelength. The abnormal distribution of gap junction proteins such as GJA1 (also known as connexin 43), and GJA5 (connexin 40) causes non-uniformity of electrical conduction, thus causing the arrhythmia.
AF can be distinguished from atrial flutter (AFL), which appears as an organized electrical circuit usually in the right atrium. AFL produces characteristic saw-toothed F-waves of constant amplitude and frequency on an ECG, whereas AF does not. In AFL, the discharges circulate rapidly at a rate of 300 beats per minute (bpm) around the atrium. In AF, there is no such regularity, except at the sources where the local activation rate can exceed 500 bpm. Although AF and atrial flutter are distinct arrhythmias, atrial flutter may degenerate into AF, and an individual may experience both arrhythmias at different times.
Although the electrical impulses of AF occur at a high rate, most of them do not result in a heartbeat. A heartbeat results when an electrical impulse from the atria passes through the atrioventricular (AV) node to the ventricles and causes them to contract. During AF, if all of the impulses from the atria passed through the AV node, there would be severe ventricular tachycardia, resulting in a severe reduction of cardiac output. This dangerous situation is prevented by the AV node since its limited conduction velocity reduces the rate at which impulses reach the ventricles during AF.
== Diagnosis ==
Atrial fibrillation is diagnosed on an electrocardiogram (ECG/EKG). The evaluation of atrial fibrillation involves a determination of the cause of the arrhythmia, and classification of the arrhythmia. Diagnostic investigation of AF typically includes a complete medical history and physical examination, ECG, transthoracic echocardiogram and blood tests.
=== Screening ===
Numerous guidelines recommend opportunistic screening for atrial fibrillation in those 65 years and older. These organizations include the: European Society of Cardiology,
National Heart Foundation of Australia and the Cardiac Society of Australia and New Zealand,
European Heart Rhythm Society,
AF-SCREEN International Collaboration,
Royal College of Physicians of Edinburgh
European Primary Care Cardiovascular Society, and Irish Health Information and Quality Authority.
Single timepoint screening detects undiagnosed AF, which is often asymptomatic, in approximately 1.4% of people in people aged 65 years and older. In 2022, the United States Preventive Services Task Force found insufficient evidence to determine the usefulness of routine screening.
Some smartwatches may detect AF.
==== Bloodwork ====
Blood tests such as complete blood count, kidney function, electrolytes, glucose or HbA1c, and thyroid function is often determined in new-onset atrial fibrillation, to provide risk stratification and exclude certain etiology.
==== Electrocardiogram ====
Atrial fibrillation is diagnosed on an electrocardiogram (ECG), an investigation performed routinely whenever an irregular heartbeat is suspected. Characteristic findings are the absence of P waves, with disorganized electrical activity in their place, and irregular R–R intervals due to irregular conduction of impulses to the ventricles. At very fast heart rates, atrial fibrillation may look more regular, which may make it more difficult to separate from other supraventricular tachycardias or ventricular tachycardia.
QRS complexes should be narrow, signifying that they are initiated by normal conduction of atrial electrical activity through the intraventricular conduction system. Wide QRS complexes are worrisome for ventricular tachycardia, although, in cases where there is a disease of the conduction system, wide complexes may be present in A-fib with a rapid ventricular response.
If paroxysmal AF is suspected, but an ECG during an office visit shows only a regular rhythm, AF episodes may be detected and documented with the use of ambulatory Holter monitoring (e.g., for a day). If the episodes are too infrequent to be detected by Holter monitoring with reasonable probability, then the person can be monitored for longer periods (e.g., a month) with an ambulatory event monitor.
==== Echocardiography ====
In general, a non-invasive transthoracic echocardiogram (TTE) is performed in newly diagnosed AF, as well as if there is a major change in the person's clinical state. This ultrasound-based scan of the heart may help identify valvular heart disease (which may greatly increase the risk of stroke and alter recommendations for the appropriate type of anticoagulation), left and right atrial size (which predicts the likelihood that AF may become permanent), left ventricular size and function, peak right ventricular pressure (pulmonary hypertension), presence of left atrial thrombus (low sensitivity), presence of left ventricular hypertrophy and pericardial disease.
Significant enlargement of both the left and right atria is associated with long-standing atrial fibrillation and, if noted at the initial presentation of atrial fibrillation, suggests that the atrial fibrillation is likely to be of a longer duration than the individual's symptoms.
==== Transesophageal echocardiogram ====
A regular echocardiogram (transthoracic echocardiogram; TTE) has a low sensitivity for identifying blood clots in the heart. If this is suspected (e.g. when planning urgent electrical cardioversion), a transesophageal echocardiogram (TEE, or TOE where British spelling is used) is preferred.
The TEE has much better visualization of the left atrial appendage than transthoracic echocardiography. This structure, located in the left atrium, is the place where a blood clot forms in more than 90% of cases in non-valvular (or non-rheumatic) atrial fibrillation. TEE has a high sensitivity for locating thrombi in this area and can also detect sluggish blood flow in this area that is suggestive of blood clot formation. If a blood clot is seen on TEE, then cardioversion is contraindicated due to the risk of stroke, and anticoagulation is recommended.
==== Ambulatory Holter monitoring ====
A Holter monitor is a wearable ambulatory heart monitor that continuously monitors the heart rate and heart rhythm for a short duration, typically 24 hours. In individuals with symptoms of significant shortness of breath with exertion or palpitations regularly, a Holter monitor may be of benefit to determine whether rapid heart rates (or unusually slow heart rates) during atrial fibrillation are the cause of the symptoms.
=== Classification ===
The American College of Cardiology (ACC), American Heart Association (AHA), and the European Society of Cardiology (ESC) recommend in their guidelines the following classification system based on simplicity and clinical relevance.
All people with AF are initially in the category called first detected AF. These people may or may not have had previous undetected episodes. If a first detected episode stops on its own in less than seven days and then another episode begins, later on, the category changes to paroxysmal AF. Although people in this category have episodes lasting up to seven days, in most cases of paroxysmal AF, the episodes will stop in less than 24 hours. If the episode lasts for more than seven days, it is unlikely to stop on its own and is then known as persistent AF. In this case, cardioversion can be attempted to restore a normal rhythm. If an episode continues for a year or more, the rhythm is then known as long-standing persistent AF. If a decision is made by the person and their medical team to accept persistent AF and not attempt restoration of a normal sinus rhythm but instead manage the AF by simply controlling the person's ventricular rate then the rhythm is referred to as permanent AF. As a further subtype, AF that is detected only by an implanted or wearable cardiac monitor is known as subclinical AF.
Episodes that last less than 30 seconds are not considered in this classification system. Also, this system does not apply to cases where the AF is a secondary condition that occurs in the setting of a primary condition that may be the cause of the AF.
About half of people with AF have permanent AF, while a quarter have paroxysmal AF, and a quarter have persistent AF.
In addition to the above AF categories, which are mainly defined by episode timing and termination, the ACC/AHA and ESC guidelines describe additional outdated AF categories in terms of other characteristics of the person. Valvular AF refers to AF attributable to moderate to severe mitral valve stenosis or atrial fibrillation in the presence of a mechanical artificial heart valve. This distinction may be useful as it has implications on appropriate treatment, including differing recommendations for anticoagulation, but the term is discouraged as it may be confusing. Other historically used definitions include lone AF – AF occurring in those aged under 60 in the absence of other cardiovascular or respiratory diseases. This description is also discouraged since it offers no clinical value. Secondary AF refers to AF that occurs in the setting of another condition that have caused the AF, such as acute myocardial infarction, cardiac surgery, pericarditis, myocarditis, hyperthyroidism, pulmonary embolism, pneumonia, or another acute pulmonary disease.
== Prevention ==
Prevention of atrial fibrillation focuses primarily on preventing or controlling its risk factors. Many of its risk factors, such as obesity, smoking, lack of physical activity, and excessive alcohol consumption, are modifiable and preventable with lifestyle modification or can be managed by a healthcare professional.
=== Lifestyle modification ===
Several healthy lifestyle behaviors are associated with a lower likelihood of developing atrial fibrillation. Accordingly, consensus guidelines recommend abstaining from alcohol and recreational drugs, stopping tobacco use, maintaining a healthy weight, and regularly participating in moderate-intensity physical activities. Consistent moderate-intensity aerobic exercise, defined as achieving 3.0–5.9 METs of intensity, for at least 150 minutes per week may reduce the risk of developing new-onset atrial fibrillation. Few studies have examined the role of specific dietary changes and how it relates to the prevention of atrial fibrillation.
== Management ==
The main goals of treatment are to prevent circulatory instability and stroke. Rate or rhythm control is used to achieve the former, whereas anticoagulation is used to decrease the risk of the latter. If cardiovascularly unstable due to uncontrolled tachycardia, immediate cardioversion is indicated. Many antiarrhythmics, when used long term, increase the risk of death without any meaningful benefit. An integrated management approach, which includes stroke prevention, symptoms control and management of associated comorbidities has been associated with better outcomes in patients with atrial fibrillation.
This holistic or integrated care approach is summed up as the ABC (Atrial fibrillation Better Care) pathway, as follows:
A: Avoid stroke with Anticoagulation, where the default is stroke prevention unless the patient is at low risk. Stroke prevention means use of oral anticoagulation (OAC), whether with well managed vitamin K antagonists (VKA), with time in therapeutic range >70%, or more commonly, label-adherent dosed direct oral anticoagulant (DOAC).
B: Better symptom and atrial fibrillation management with patient-centred, symptom directed decisions on rate control or rhythm control. In some selected patients, use early rhythm control may be beneficial.
C: Cardiovascular risk factor and comorbidity management, including attention to lifestyle factors and psychological morbidity.
=== Lifestyle modification ===
Regular aerobic exercise improves atrial fibrillation symptoms and AF-related quality of life. The effect of high-intensity interval training on reducing atrial fibrillation burden is unclear. Weight loss of at least 10% is associated with reduced atrial fibrillation burden in people who are overweight or obese.
=== Comorbidity treatment ===
For people who have both atrial fibrillation and obstructive sleep apnea, observational studies suggest that continuous positive airway pressure (CPAP) treatment appears to lower the risk of atrial fibrillation recurrence after undergoing ablation. Randomized controlled trials examining the role of obstructive sleep apnea treatment on atrial fibrillation incidence and burden are lacking. Guideline-recommended lifestyle and medical interventions are recommended for people with atrial fibrillation and coexisting conditions such as hyperlipidemia, diabetes mellitus, or hypertension without specific blood sugar or blood pressure targets for people with atrial fibrillation.
Bariatric surgery may reduce the risk of new-onset atrial fibrillation in people with obesity without AF and may reduce the risk of a recurrence of AF after an ablation procedure in people with coexisting obesity and atrial fibrillation. It is important for all people with atrial fibrillation to optimize the control of all coexisting medical conditions that can worsen their atrial fibrillation, such as hyperthyroidism, diabetes, congestive heart failure, high blood pressure, chronic obstructive pulmonary disease, stimulant use (e.g., methamphetamine dependence), and excessive alcohol consumption.
=== Anticoagulants ===
Anticoagulation medication can be used to reduce the risk of stroke from AF. Anticoagulation medication is recommended in most people with increased risk of stroke, which can be estimated using the CHA2DS2-VASc score.
The risk of falls and consequent bleeding in frail elderly people should not be considered a barrier to initiating or continuing anticoagulation since the risk of fall-related brain bleeding is low and the benefit of stroke prevention often outweighs the risk of bleeding. The presence or absence of AF symptoms does not determine whether a person warrants anticoagulation and is not an indicator of stroke risk.
Direct oral anticoagulant (DOAC) are recommended over warfarin in atrial fibrillation. In atrial fibrillation with presence of moderate to severe mitral stenosis or mechanical heart valve, warfarin is recommended over other therapies. DOACs carry a lower risk of bleeding in the brain compared to warfarin, although dabigatran is associated with a higher risk of intestinal bleeding.
Direct oral anticoagulant (DOAC), previously called "new", "novel", or "non-vitamin K antagonist" oral anticoagulant (NOAC), are medications taken orally that have another mechanism of action on the coagulation cascade than warfarin. DOACs recommended in atrial fibrillation include apixaban, dabigatran, edoxaban and rivaroxaban.
Antiplatelet drugs alone, such as aspirin or dual antiplatelet therapy with aspirin and clopidogrel, is not recommended as stroke prophylaxis in atrial fibrillation. In those who are also on aspirin, DOACs appear to be better than warfarin.
The optimal approach to anticoagulation in people with AF and who simultaneously have other diseases (e.g., cirrhosis and end-stage kidney disease on dialysis) that predispose a person to both bleeding and clotting complications is unclear.
For vitamin K antagonists (VKA) such as warfarin, time in therapeutic range (TTR) and INR variability are commonly used to assess the quality of VKA treatment. Patients who are unable to maintain a therapeutic INR on VKA, as indicated by low TTR and/or high INR variability, are at an increased risk of thromboembolic and bleeding events. In these patients, treatment with a DOAC is recommended. While there are no significant changes in adherence, persistence or clinical outcomes in patients switched from a VKA to a DOAC, an increase in therapy satisfaction has been reported.
=== Rate versus rhythm control ===
There are two ways to approach atrial fibrillation using medications: rate control and rhythm control. Both methods have similar outcomes. Rate control lowers the heart rate closer to normal, usually 60 to 100 bpm, without trying to convert to a regular rhythm. Rhythm control tries to restore a normal heart rhythm in a process called cardioversion and maintains the normal rhythm with medications. Studies suggest that rhythm control is more important in the acute setting AF, whereas rate control is more important in the long-term.
The risk of stroke appears to be lower with rate control versus attempted rhythm control, at least in those with heart failure. AF is associated with a reduced quality of life, and, while some studies indicate that rhythm control leads to a higher quality of life, some did not find a difference. Neither rate nor rhythm control is superior in people with heart failure when they are compared in various clinical trials. However, rate control is recommended as the first-line treatment regimen for people with heart failure. On the other hand, rhythm control is only recommended when people experience persistent symptoms despite adequate rate control therapy.
In those with a fast ventricular response, intravenous magnesium significantly increases the chances of achieving successful rate and rhythm control in the urgent setting without major side-effects. A person with poor vital signs, mental status changes, preexcitation, or chest pain often will go to immediate treatment with synchronized direct current cardioversion. Otherwise, the decision of rate control versus rhythm control using medications is made. This is based on several criteria that include whether or not symptoms persist with rate control.
=== Rate control ===
Rate control to a target heart rate of fewer than 110 beats per minute is recommended in most people. Lower heart rates may be recommended in those with left ventricular hypertrophy or reduced left ventricular function. Rate control is achieved with medications that work by increasing the degree of the block at the level of the AV node, decreasing the number of impulses that conduct into the ventricles. This can be done with:
Beta blockers (preferably the "cardioselective" beta blockers such as metoprolol, bisoprolol, or nebivolol)
Non-dihydropyridine calcium channel blockers (e.g., diltiazem or verapamil)
Cardiac glycosides (e.g., digoxin) – have less use, apart from in older people who are sedentary. They are not as effective as either beta-blockers or calcium channel blockers.
In addition to these agents, amiodarone has some AV node blocking effects (in particular when administered intravenously) and can be used in individuals when other agents are contraindicated or ineffective (particularly due to hypotension).
=== Cardioversion ===
Cardioversion is the attempt to switch an irregular heartbeat to a normal heartbeat using electrical or chemical means.
Electrical cardioversion involves the restoration of normal heart rhythm through the application of a direct current electrical shock. The exact placement of the pads does not appear to be important.
Chemical cardioversion is performed with medications, such as amiodarone, dronedarone, procainamide (especially in pre-excited atrial fibrillation), dofetilide, ibutilide, propafenone, or flecainide.
After successful cardioversion, the heart may be stunned, which means that there is a normal rhythm, but the restoration of normal atrial contraction has not yet occurred.
=== Surgery ===
==== Ablation ====
Catheter ablation (CA) is a procedure performed by an electrophysiologist, a cardiologist who specializes in heart rhythm problems, to restore the heart's normal rhythm by destroying, or electrically isolating, specific parts of the atria. A group of cardiologists led by Dr Haïssaguerre from Bordeaux University Hospital noted in 1998 that the pulmonary veins are an important source of ectopic beats, initiating frequent paroxysms of atrial fibrillation, with these foci responding to treatment with radio-frequency ablation. Most commonly, CA electrically isolates the left atrium from the pulmonary veins, where most of the abnormal electrical activity promoting atrial fibrillation originates. CA is a form of rhythm control that restores normal sinus rhythm and reduces AF-associated symptoms more reliably than antiarrhythmic medications.
Electrophysiologists generally use three forms of catheter ablation: radiofrequency (RF) ablation, cryoablation ("cryo"), or pulsed field (PF). In young people with little-to-no structural heart disease where rhythm control is desired and cannot be maintained by medication or cardioversion, ablation may be attempted and may be preferred over several years of medical therapy. Although radiofrequency ablation has become an accepted intervention in selected younger people and may be more effective than medication at improving symptoms and quality of life, there is no evidence that ablation reduces all-cause mortality, stroke, or heart failure. Some evidence indicates CA may be particularly helpful for people with AF who also have heart failure. AF may recur in people who have undergone CA and nearly half of people who undergo it will require a repeat procedure to achieve long-term control of their AF.
In general, CA is more successful at preventing AF recurrence if AF is paroxysmal as opposed to persistent. As CA does not reduce the risk of stroke, many are advised to continue their anticoagulation. Possible complications include common, minor complications such as the formation of a collection of blood at the site where the catheter goes into the vein (access site hematoma), but also more dangerous complications including bleeding around the heart (cardiac tamponade), stroke, damage to the esophagus (atrio-esophageal fistula), or even death. Use of pulsed field ablation as a non-thermal method of inducing electroporation avoids damage to the phrenic nerve, esophagus, and blood vessels, while being at least as effective as thermal ablation methods.
A hybrid convergent procedure has been developed which combines endocardial ablation with epicardial ablation, which can reduce AF recurrence to less than 5% for over one year. The epicardial ablation is performed first, with a minimally invasive surgical approach.
==== Maze procedure ====
An alternative to catheter ablation is surgical ablation. The maze procedure, first performed in 1987, is an effective invasive surgical treatment that is designed to create electrical blocks or barriers in the atria of the heart. The idea is to force abnormal electrical signals to move along one, uniform path to the lower chambers of the heart (ventricles), thus restoring the normal heart rhythm. People with AF often undergo cardiac surgery for other underlying reasons and are frequently offered concomitant AF surgery to reduce the frequency of short- and long-term AF. Concomitant AF surgery is more likely to lead to the person being free from atrial fibrillation and off medications long-term after surgery and Cox-Maze IV procedure is the gold standard treatment. There is a slightly increased risk of needing a pacemaker following the procedure. Less invasive modifications of the maze procedure have been developed, designated as minimaze procedures.
==== Left atrial appendage occlusion ====
There is growing evidence that left atrial appendage occlusion therapy may reduce the risk of stroke in people with non-valvular AF as much as warfarin. The addition of left atrial appendage isolation to catheter ablation has reduced AF recurrence by 80% in patients with persistent AF.
==== After surgery ====
After catheter ablation, people are moved to a cardiac recovery unit, intensive care unit, or cardiovascular intensive care unit where they are not allowed to move for 4–6 hours. Minimizing movement helps prevent bleeding from the site of the catheter insertion. The length of time people stay in the hospital varies from hours to days. This depends on the problem, the length of the operation, and whether or not general anesthetic was used. Additionally, people should not engage in strenuous physical activity – to maintain a low heart rate and low blood pressure – for around six weeks.
AF often occurs after cardiac surgery and is usually self-limiting. It is strongly associated with age, preoperative hypertension, and the number of vessels grafted. Measures should be taken to control hypertension preoperatively to reduce the risk of AF. Also, people with a higher risk of AF, e.g., people with pre-operative hypertension, more than three vessels grafted, or greater than 70 years of age, should be considered for prophylactic treatment. Postoperative pericardial effusion is also suspected to be the cause of atrial fibrillation. Prophylaxis may include prophylactic postoperative rate and rhythm management. Some authors perform posterior pericardiotomy to reduce the incidence of postoperative AF. When AF occurs, management should primarily be rate and rhythm control. However, cardioversion may be used if the patient is hemodynamically unstable, highly symptomatic, or AF persists for six weeks after discharge. In persistent cases, anticoagulation should be used.
== Prognosis ==
Atrial fibrillation can progress from infrequent occurrences to more frequent occurrences, ultimately becoming permanent. Some cases do not progress, especially among patients with a healthy lifestyle.
Many mechanisms contribute to cardiac remodeling leading to a worsening of atrial fibrillation, including fibrosis, fatty infiltration, amyloidosis, and ion channel modifications. Fatty infiltration helps explain why obesity is a risk factor for atrial fibrillation in one fifth of patients.
Atrial fibrillation increases the risk of heart failure by 11 per 1000, kidney problems by 6 per 1000, death by 4 per 1000, stroke by 3 per 1000, and coronary heart disease by 1 per 1000. Women have a worse outcome overall than men. Evidence increasingly suggests that atrial fibrillation is independently associated with a higher risk of developing dementia.
=== Blood clots ===
==== Prediction of embolism ====
Determining the risk of an embolism causing a stroke is important for guiding the use of anticoagulants. The most accurate clinical prediction rules is the CHA2DS2-VASc score. The addition of blood based biomarkers such as NT-proBNP and neurofilament light chain improves risk prediction significantly. A CHA2DS2-VASc score of zero is considered very low risk.
==== Mechanism of thrombus formation ====
In atrial fibrillation, the lack of an organized atrial contraction can result in some stagnant blood in the left atrium (LA) or left atrial appendage (LAA). This lack of movement of blood can lead to thrombus formation (blood clotting). If the clot becomes mobile and is carried away by the blood circulation, it is called an embolus. An embolus proceeds through smaller and smaller arteries until it plugs one of them and prevents blood from flowing through the artery. This process results in end organ damage due to the loss of nutrients, oxygen, and the removal of cellular waste products. Emboli in the brain may result in an ischemic stroke or a transient ischemic attack (TIA).
More than 90% of cases of thrombi associated with non-valvular atrial fibrillation evolve in the left atrial appendage. However, the LAA lies in close relation to the free wall of the left ventricle, and thus the LAA's emptying and filling, which determines its degree of blood stagnation, may be helped by the motion of the wall of the left ventricle if there is good ventricular function.
=== Dementia ===
Atrial fibrillation has been independently associated with a higher risk of developing cognitive impairment, vascular dementia, and Alzheimer disease and with elevated levels of neurofilament light chain in blood, a biomarker indicating neuroaxonal injury. Several mechanisms for this association have been proposed, including silent small blood clots (subclinical microthrombi) traveling to the brain resulting in small ischemic strokes without symptoms, altered blood flow to the brain, inflammation, clinically silent small bleeds in the brain, and genetic factors. Tentative evidence suggests that effective anticoagulation with direct oral anticoagulants or warfarin may be somewhat protective against AF-associated dementia and evidence of silent ischemic strokes on MRI but this remains an active area of investigation.
== Epidemiology ==
Atrial fibrillation is the most common arrhythmia and affects more than 33 million people worldwide. In Europe and North America, as of 2014, it affects about 2% to 3% of the population. In the developing world, rates are about 0.6% for males and 0.4% for females. The number of people diagnosed with AF has increased due to better detection of silent AF, increasing age and increase of conditions that predispose to it such as obesity and increasing survival from other forms of cardiovascular disease.
The rate of hospital admissions for AF has risen. AF is the cause for 20% of all ischemic strokes. After a transient ischemic attack or stroke, about 11% are found to have a new diagnosis of atrial fibrillation. 3% to 11% of patients with AF have structurally normal hearts.
The number of new cases each year of AF increases with age. In younger people the prevalence is estimated to be 0.05% and is associated with congenital heart disease or structural heart disease in this demographic. As of 2001, it was anticipated that in developed countries, the number of people with atrial fibrillation was likely to increase during the following 50 years, due to the growing proportion of elderly people.
=== Gender ===
Atrial fibrillation is more common in men than in women when reviewed in European and North American populations. In developed and developing countries, there is also a higher rate in men than in women. The risk factors associated with AF are also distributed differently according to gender. In men, coronary disease is more frequent, while in women, high systolic blood pressure and valvular heart disease are more prevalent.
=== Ethnicity ===
Rates of AF are lower in populations of African descent than in populations of European descent. African descent is associated with a protective effect for AF, due to the lower presence of SNPs with guanine alleles. European ancestry has more frequent mutations. The variant rs4611994 for the gene PITX2 is associated with risk of AF in African and European populations. Hispanic and Asian populations have a lower risk of AF than European populations. The risk of AF in non-European populations is associated with characteristic risk factors of these populations, such as hypertension.
=== Young people ===
Atrial fibrillation is an uncommon condition in children but sometimes occurs in association with certain inherited and acquired conditions. Congenital heart disease and rheumatic fever are the most common causes of atrial fibrillation in children. Other inherited heart conditions associated with the development of atrial fibrillation in children include Brugada syndrome, short QT syndrome, Wolff Parkinson White syndrome, and other forms of supraventricular tachycardia (e.g., AV nodal reentrant tachycardia). Adults who survived congenital heart disease have an increased risk of developing AF. In particular, people who had atrial septal defects, Tetralogy of Fallot, or Ebstein's anomaly, and those who underwent the Fontan procedure, are at higher risk with prevalence rates of up to 30% depending on the heart's anatomy and the person's age.
== History ==
Because the diagnosis of atrial fibrillation requires measurement of the electrical activity of the heart, atrial fibrillation was not truly described until 1874, when Edmé Félix Alfred Vulpian observed the irregular atrial electrical behavior that he termed "fremissement fibrillaire" in dog hearts. In the mid-18th century, Jean-Baptiste de Sénac made note of dilated, irritated atria in people with mitral stenosis. The irregular pulse associated with AF was first recorded in 1876 by Carl Wilhelm Hermann Nothnagel and termed "delirium cordis", stating that "[I]n this form of arrhythmia the heartbeats follow each other in complete irregularity. At the same time, the height and tension of the individual pulse waves are continuously changing". Correlation of delirium cordis with the loss of atrial contraction, as reflected in the loss of a waves in the jugular venous pulse, was made by Sir James MacKenzie in 1904. Willem Einthoven published the first ECG showing AF in 1906. The connection between the anatomic and electrical manifestations of AF and the irregular pulse of delirium cordis was made in 1909 by Carl Julius Rothberger, Heinrich Winterberg, and Sir Thomas Lewis.
== Other animals ==
Atrial fibrillation occurs in other animals, including cats, dogs, and horses. Unlike humans, dogs rarely develop the complications that stem from blood clots breaking off from inside the heart and traveling through the arteries to distant sites (thromboembolic complications). Cats rarely develop atrial fibrillation but appear to have a higher risk of thromboembolic complications than dogs.
Cats and dogs with atrial fibrillation often have underlying structural heart disease that predisposes them to the condition. The medications used in animals for atrial fibrillation are largely similar to those used in humans. Electrical cardioversion is occasionally performed in these animals, but the need for general anesthesia limits its use. Standardbred horses appear to be genetically susceptible to developing atrial fibrillation. Horses that develop atrial fibrillation often have minimal or no underlying heart disease, and the presence of atrial fibrillation in horses can adversely affect physical performance.
== References ==
== Further reading ==
Van Gelder IC, Rienstra M, Bunting KV, Casado-Arroyo R, Caso V, Crijns HJ, et al. (30 August 2024). "2024 ESC Guidelines for the management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS)". European Heart Journal. 45 (36): 3314–3414. doi:10.1093/eurheartj/ehae176. hdl:11392/2573658. ISSN 0195-668X. PMID 39210723.
Joglar JA, Chung MK, Armbruster AL, Benjamin EJ, Chyou JY, Cronin EM, et al. (30 November 2023). "2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines". Circulation. 149 (1): e1 – e156. doi:10.1161/CIR.0000000000001193. PMC 11095842. PMID 38033089.
== External links ==
"Atrial Fibrillation". CVD Roadmaps. World Heart Federation.
Media related to Atrial fibrillation at Wikimedia Commons | Wikipedia/Management_of_atrial_fibrillation |
Thyroid disease in pregnancy can affect the health of the mother as well as the child before and after delivery. Thyroid disorders are prevalent in women of childbearing age and for this reason commonly present as a pre-existing disease in pregnancy, or after childbirth. Uncorrected thyroid dysfunction in pregnancy has 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. Due to an increase in thyroxine-binding globulin, an increase in placental type 3 deiodinase, and the placental transfer of maternal thyroxine to the fetus, the demand for thyroid hormones is increased during pregnancy. The necessary increase in thyroid hormone production is facilitated by high human chorionic gonadotropin (hCG) concentrations, which bind the TSH receptor and stimulate the maternal thyroid to increase maternal thyroid hormone concentrations by roughly 50%. If the necessary increase in thyroid function cannot be met, this may cause a previously unnoticed (mild) thyroid disorder to worsen and become evident as gestational thyroid disease. Currently, there is not enough evidence to suggest that screening for thyroid dysfunction is beneficial, especially since treatment with thyroid hormone supplementation may come with a risk of overtreatment. After women give birth, about 5% develop postpartum thyroiditis, which can occur up to nine months afterward. This is characterized by a short period of hyperthyroidism followed by a period of hypothyroidism; 20–40% remain permanently hypothyroid.
== The thyroid in pregnancy ==
Fetal thyroxine is wholly obtained from maternal sources in early pregnancy since the fetal thyroid gland only becomes functional in the second trimester of gestation. As thyroxine is essential for fetal neurodevelopment, maternal delivery of thyroxine to the fetus must be ensured early in gestation. In pregnancy, iodide losses through the urine and the feto-placental unit contribute to a state of relative iodine deficiency. Thus, pregnant women require additional iodine intake. A daily iodine intake of 250 μg is recommended in pregnancy, but this is not always achieved even in iodine-sufficient parts of the world.
Thyroid hormone concentrations in blood are increased in pregnancy, partly due to the high levels of estrogen and due to the weak thyroid-stimulating effects of human chorionic gonadotropin (hCG) that acts like TSH. Thyroxine (T4) levels rise from about 6–12 weeks and peak by mid-gestation; reverse changes are seen with TSH. Gestation-specific reference ranges for thyroid function tests are not widely in use, although many centres are now preparing them.
== Hypothyroidism ==
=== Clinical evaluation ===
Hypothyroidism is common in pregnancy with an estimated prevalence of 2-3% and 0.3-0.5% for subclinical and overt hypothyroidism, respectively. Endemic iodine deficiency accounts for most hypothyroidism in pregnant women worldwide while chronic autoimmune thyroiditis is the most common cause of hypothyroidism in iodine sufficient parts of the world. The presentation of hypothyroidism in pregnancy is not always classical and may sometimes be difficult to distinguish from the symptoms of normal pregnancy. A high index of suspicion is therefore required, especially in women at risk of thyroid disease, e.g. women with a personal or family history of thyroid disease, goitre, or co-existing primary autoimmune disorder like type 1 diabetes.
=== Risks of hypothyroidism on fetal and maternal well-being ===
Hypothyroidism is diagnosed by noting a high TSH associated with a subnormal T4 concentration. Subclinical hypothyroidism (SCH) is present when the TSH is high but the T4 level is in the normal range, but usually low normal. SCH is the most common form of hypothyroidism in pregnancy and is usually due to progressive thyroid destruction due to autoimmune thyroid disease.
Several studies, mostly retrospective, have shown an association between overt hypothyroidism and adverse fetal and obstetric outcomes (e.g., Glinoer 1991). Maternal complications such as miscarriages, anaemia in pregnancy, pre-eclampsia, abruptio placenta and postpartum haemorrhage can occur in pregnant women with overt hypothyroidism. Also, the offspring of these mothers can have complications such as premature birth, low birth weight and increased neonatal respiratory distress. Similar complications have been reported in mothers with subclinical hypothyroidism. A three-fold risk of placental abruption and a two-fold risk of pre-term delivery were reported in mothers with subclinical hypothyroidism. Another study showed a higher prevalence of subclinical hypothyroidism in women with pre-term delivery (before 32 weeks) compared to matched controls delivering at term. An association with adverse obstetric outcomes has also been demonstrated in pregnant women with thyroid autoimmunity independent of thyroid function. Treatment of hypothyroidism reduces the risks of these adverse obstetric and fetal outcomes; a retrospective study of 150 pregnancies showed that treatment of hypothyroidism led to reduced rates of abortion and premature delivery. Also, a prospective intervention trial study showed that treatment of euthyroid antibody-positive pregnant women led to lower rates of miscarriage than untreated controls.
It has long been known that cretinism (i.e., gross reduction in IQ) occurs in areas of severe iodine deficiency because the mother is unable to make T4 for transport to the fetus, particularly in the first trimester. This neurointellectual impairment (on a more modest scale) has now been shown in an iodine-sufficient area (USA) where a study showed that the IQ scores of 7- to 9-year-old children, born to mothers with undiagnosed and untreated hypothyroidism in pregnancy, were seven points lower than those of children of matched control women with normal thyroid function in pregnancy. Another study showed that persistent hypothyroxinaemia at 12 weeks gestation was associated with an 8-10 point deficit in mental and motor function scores in infant offspring compared to children of mothers with normal thyroid function. Even maternal thyroid peroxidase antibodies were shown to be associated with impaired intellectual development in the offspring of mothers with normal thyroid function. It has been shown that it is only the maternal FT4 levels that are associated with child IQ and brain morphological outcomes, as opposed to maternal TSH levels.
=== Management of hypothyroidism in pregnancy ===
Medications to treat hypothyroidism are safe during pregnancy. Levothyroxine is the treatment of choice for hypothyroidism in pregnancy. Thyroid function should be normalised before conception in women with pre-existing thyroid disease. Once pregnancy is confirmed, the thyroxine dose should be increased by about 30-50%, and subsequent titrations should be guided by thyroid function tests (FT4 and TSH) that should be monitored 4-6 weekly until euthyroidism is achieved. It is recommended that TSH levels are maintained below 2.5 mU/L in the first trimester of pregnancy and below 3 mU/L in later pregnancy. The recommended maintenance dose of thyroxine in pregnancy is about 2.0-2.4 μg/kg daily. Thyroxine requirements may increase in late gestation and return to pre-pregnancy levels in the majority of women on delivery. Pregnant patients with subclinical hypothyroidism (normal FT4 and elevated TSH) should be treated as well, since supplementation with levothyroxine in such cases results in a significantly higher delivery rate, with a pooled relative chance of 2.76.
== Hyperthyroidism ==
=== Clinical evaluation ===
Hyperthyroidism occurs in about 0.2-0.4% of all pregnancies. Most cases are due to Graves' disease, although less common causes (e.g. toxic nodules and thyroiditis) may be seen. Clinical assessment alone may occasionally be inadequate in differentiating hyperthyroidism from the hyperdynamic state of pregnancy. Distinctive clinical features of Graves' disease include the presence of ophthalmopathy, diffuse goitre, and pretibial myxoedema. Also, hyperthyroidism must be distinguished from gestational transient thyrotoxicosis, a self-limiting hyperthyroid state due to the thyroid stimulatory effects of beta-hCG. This distinction is important since the latter condition is typically mild and will not usually require specific antithyroid treatment. Red cell zinc may also be useful in differentiating the two. Hyperthyroidism due to Graves' disease may worsen in the first trimester of pregnancy, remit in later pregnancy, and subsequently relapse in the postpartum.
=== Risks of hyperthyroidism on fetal and maternal well-being ===
Uncontrolled hyperthyroidism in pregnancy is associated with an increased risk of severe pre-eclampsia and up to a fourfold increased risk of low birth weight deliveries. Some of these unfavourable outcomes are more marked in women who are diagnosed for the first time in pregnancy. A recent study has also shown that already high normal maternal FT4 levels are associated with a decrease in child IQ and gray matter and cortex volumes, similar to the effects of hypothyroidism.
Uncontrolled and inadequately treated maternal hyperthyroidism may also result in fetal and neonatal hyperthyroidism due to the transplacental transfer of stimulatory TSH receptor antibodies. Clinical neonatal hyperthyroidism occurs in about 1% of infants born to mothers with Graves' disease. Rarely, neonatal hypothyroidism may also be observed in the infants of mothers with Graves' hyperthyroidism. This may result from transplacental transfer of circulating maternal anti-thyroid drugs, pituitary-thyroid axis suppression from transfer of maternal thyroxine.
=== Management of hyperthyroidism in pregnancy ===
Ideally, a woman who is known to have hyperthyroidism should seek pre-pregnancy advice, although as yet there is no evidence for its benefit. Appropriate education should allay fears that are commonly present in these women. She should be referred for specialist care for frequent checking of her thyroid status, thyroid antibody evaluation and close monitoring of her medication needs. Medical therapy with anti-thyroid medications is the treatment of choice for hyperthyroidism in pregnancy. Methimazole and propylthiouracil are effective in preventing pregnancy complications by hyperthyroidism. Surgery is considered for patients who have severe adverse reactions to anti-thyroid drugs and this is best performed in the second trimester of pregnancy. Radioactive iodine is absolutely contraindicated in pregnancy and the puerperium. If a woman is already receiving carbimazole, a change to propylthiouracil is recommended, but this should be changed back to carbimazole after the first trimester. On occasion, Carbimazole is associated with skin and midline defects in the fetus, but propylthiouracil long-term can cause liver side effects in the adult. Carbimazole and propylthiouracil are both secreted in breast milk, but evidence suggests that antithyroid drugs are safe during lactation. There are no adverse effects on IQ or psychomotor development in children whose mothers have received antithyroid drugs in pregnancy. Current guidelines suggest that a pregnant patient should be on propylthiouracil during the first trimester of pregnancy due to lower teratogenic effects and then be switched to methimazole during the second and third trimesters due to lower liver dysfunction side effects.
== Postpartum thyroiditis ==
Postpartum thyroid dysfunction is a syndrome of thyroid dysfunction occurring within the first 12 months of delivery as a consequence of the postpartum immunological rebound that follows the immune-tolerant state of pregnancy. Postpartum thyroid dysfunction is destructive thyroiditis with similar pathogenetic features to Hashimoto's thyroiditis.
The disease is very common, with a prevalence of 5-9% of unselected postpartum women. Typically, there is a transient hyperthyroid phase that is followed by a phase of hypothyroidism. Permanent hypothyroidism occurs in as much as 30% of cases after 3 years and in 50% at 7–10 years. The hyperthyroid phase will not usually require treatment, but, rarely, propranolol may be used for symptom control in severe cases. The hypothyroid phase should be treated with thyroxine if patients are symptomatic, planning to get pregnant, or if TSH levels are above 10 mU/L. Long-term follow-up is necessary due to the risk of permanent hypothyroidism.
Nearly all the women with Postpartum thyroid dysfunction have anti-thyroid peroxidase antibodies. This marker can be a useful screening test in early pregnancy, as 50% of women with antibodies will develop thyroid dysfunction postpartum. In addition, some but not all studies have shown an association between Postpartum thyroid dysfunction and depression, so thyroid function should be checked postpartum in women with mood changes.
== References == | Wikipedia/Thyroid_disease_in_pregnancy |
The Bradley method of natural childbirth (also known as "husband-coached childbirth") is a method of natural childbirth developed in 1947 by Robert A. Bradley, M.D. (1917–1998) and popularized by his book Husband-Coached Childbirth, first published in 1965. The Bradley method emphasizes that birth is a natural process: mothers are encouraged to trust their body and focus on diet and exercise throughout pregnancy; and it teaches couples to manage labor through deep breathing and the support of a partner or labor coach.
== Principles ==
Teachers of the Bradley method believe that—with adequate preparation, education and help from a loving, supportive coach—most women can give birth naturally, without drugs or surgery. The Bradley method emphasizes measures that can be taken to help keep women healthy and lower their risk for complications that may lead to medical intervention.
The primary goal of the Bradley method is healthy mothers and healthy babies. The method holds that, in most circumstances, a natural (drug-free) childbirth is the best way to achieve that goal. Proponents of the Bradley Method claim that 86 percent of mothers who follow the method have vaginal births without drugs.
Classes teach nutrition, relaxation and natural breathing as pain management techniques, along with active participation of the husband as coach. Parents-to-be are taught to be knowledgeable consumers of birth services and to take responsibility in making informed decisions regarding procedures, attendants and the birthplace.
The method itself is an application of what Dr. Bradley termed "the six needs of the laboring woman": deep and complete relaxation and abdominal breathing; quiet, darkness and solitude; physical comfort; and closed eyes and the appearance of sleep. The method relies heavily on training fathers to be labor "coaches" or partners. Bradley method teachers usually supplement these primary techniques with training in different labor positions and comfort measures. In order to master the ability to relax completely as a pain relief tool, couples are taught several different relaxation techniques and encouraged to practice relaxation daily, so that the mother can rely on a conditioned relaxation response to her partner's voice and touch.
== History ==
Robert Bradley entered the field of obstetrics in 1947, at a time when mothers were restrained in hospital beds and unable to freely move throughout labor due to the medication they were administered. Terming this practice as "knock-em-out, drag-em-out obstetrics", when "twilight sleep" and general anesthesia were common in hospital deliveries, Bradley decided to develop his own method. Having been raised on a farm and witnessed many animal births as a part of farm life, Bradley believed that women, like the non-human animals he had observed growing up, could give birth without drugs or distress. Based on observations of mammals during labor and birth, he developed a childbirth method to teach women to do the things that animal mothers do instinctively.
Soon after starting to implement his new childbirth method with pregnant nurses as a trial, Dr. Bradley began to believe that the presence and support of the father during labor and birth was important to the mother's success in achieving a natural birth. He became a pioneer in including fathers in the birth process and eventually expanded his childbirth method to include extensive instruction of the father as labor coach.
Bradley Method instructors are certified by the American Academy of Husband-Coached Childbirth (AAHCC).
== References ==
== Sources ==
Bradley, Robert A. (1996). Husband-Coached Childbirth (4th ed.). New York: Bantam Books. ISBN 0-553-37556-3.
Hathaway, Marjie; Hathaway, Jay; Bek, Susan Hathaway; Hathaway, James (2002). The Bradley Method Student Workbook. Sherman Oaks, CA: American Academy of Husband-Coached Childbirth. ISBN 0-931560-01-2.
== External links ==
Official website | Wikipedia/Bradley_method_of_natural_childbirth |
Obstetrical forceps are a medical instrument used in childbirth. Their use can serve as an alternative to the ventouse (vacuum extraction) method.
== Medical uses ==
Forceps births, like all assisted births, should be undertaken only to help promote the health of the mother or baby. In general, a forceps birth is likely to be safer for both the mother and baby than the alternatives – either a ventouse birth or a caesarean section – although caveats such as operator skill apply.
Advantages of forceps use include avoidance of caesarean section (and the short and long-term complications that accompany this), reduction of delivery time, and general applicability with cephalic presentation (head presentation). Common complications include the possibility of bruising the baby and causing more severe vaginal tears (perineal laceration) than would otherwise be the case. Severe and rare complications (occurring less frequently than 1 in 200) include nerve damage, Descemet's membrane rupture, skull fractures, and cervical cord injury.
Maternal factors for use of forceps:
Maternal exhaustion.
Prolonged second stage of labour.
Maternal illness such as heart disease, hypertension, glaucoma, aneurysm, or other conditions that make pushing difficult or dangerous.
Hemorrhaging.
Analgesic drug-related inhibition of maternal effort (especially with epidural/spinal anaesthesia).
Fetal factors for use of forceps:
Non-reassuring fetal heart tracing.
Fetal distress.
After-coming head in breech delivery.
== Complications ==
=== Baby ===
Cuts and bruises.
Increased risk of facial nerve injury (usually temporary).
Increased risk of clavicle fracture (rare).
Increased risk of intracranial hemorrhage - sometimes leading to death: 4/10,000.
Increased risk of damage to cranial nerve VI, resulting in strabismus.
=== Mother ===
Increased risk of perineal lacerations, pelvic organ prolapse, and incontinence.
Increased risk of injury to vagina and cervix.
Increased postnatal recovery time and pain.
Increased difficulty evacuating during recovery time.
== Structure ==
Obstetric forceps consist of two branches (blades) that are positioned around the head of the fetus. These branches are defined as left and right depending on which side of the mother's pelvis they will be applied. The branches usually, but not always, cross at a midpoint, which is called the articulation. Most forceps have a locking mechanism at the articulation, but a few have a sliding mechanism instead that allows the two branches to slide along each other. Forceps with a fixed lock mechanism are used for deliveries where little or no rotation is required, as when the fetal head is in line with the mother's pelvis. Forceps with a sliding lock mechanism are used for deliveries requiring more rotation.
The blade of each forceps branch is the curved portion that is used to grasp the fetal head. The forceps should surround the fetal head firmly, but not tightly. The blade characteristically has two curves, the cephalic and the pelvic curves. The cephalic curve is shaped to conform to the fetal head. The cephalic curve can be rounded or rather elongated depending on the shape of the fetal head. The pelvic curve is shaped to conform to the birth canal and helps direct the force of the traction under the pubic bone. Forceps used for rotation of the fetal head should have almost no pelvic curve.
The handles are connected to the blades by shanks of variable lengths. Forceps with longer shanks are used if rotation is being considered.
=== Anglo-American types ===
All American forceps are derived from French forceps (long forceps) or English forceps (short forceps). Short forceps are applied on the fetal head already descended significantly in the maternal pelvis (i.e., proximal to the vagina). Long forceps are able to reach a fetal head still in the middle or even in the upper part of the maternal pelvis. At present practice, it is uncommon to use forceps to access a fetal head in the upper pelvis. So, short forceps are preferred in the UK and USA. Long forceps are still in use elsewhere.
Simpson forceps (1848) are the most commonly used among the types of forceps and has an elongated cephalic curve. These are used when there is substantial molding, that is, temporary elongation of the fetal head as it moves through the birth canal.
Elliot forceps (1860) are similar to Simpson forceps but with an adjustable pin in the end of the handles which can be drawn out as a means of regulating the lateral pressure on the handles when the instrument is positioned for use. They are used most often with women who have had at least one previous vaginal delivery because the muscles and ligaments of the birth canal provide less resistance during second and subsequent deliveries. In these cases, the fetal head may remain rounder.
Kielland forceps (1915, Norwegian) are distinguished by having no angle between the shanks and the blades and a sliding lock. The pelvic curve of the blades is identical to all other forceps. The common misperception that there is no pelvic curve has become so entrenched in the obstetric literature that it may never be able to be overcome, but it can be proved by holding a blade of Kielland's against any other forceps of one's choice. Kielland forceps are probably the most common forceps used for rotation. The sliding mechanism at the articulation can be helpful in asynclitic births (when the fetal head is tilted to the side) since it is no longer in line with the birth canal. Because the handles, shanks, and blades are all in the same plane the forceps can be applied in any position to affect rotation. Because the shanks and handles are not angled, the forceps cannot be applied to a high station as readily as those with the angle since the shanks impinge on the perineum.
Wrigley's forceps, named after Arthur Joseph Wrigley, are used in low or outlet deliveries (see explanations below), when the maximum diameter is about 2.5 cm (0.98 in) above the vulva. Wrigley's forceps were designed for use by general practitioner obstetricians, having the safety feature of an inability to reach high into the pelvis. Obstetricians now use these forceps most commonly in cesarean section delivery where manual traction is proving difficult. The short length results in a lower chance of uterine rupture.
Piper's forceps has a perineal curve to allow application to the after-coming head in breech delivery.
== Technique ==
The cervix must be fully dilated and retracted and the membranes ruptured. The urinary bladder should be empty, perhaps with the use of a catheter. High forceps are never indicated in the modern era. Mid forceps can occasionally be indicated but require operator skill and caution. The station of the head must be at the level of the ischial spines. The woman is placed on her back, usually with the aid of stirrups or assistants to support her legs. A regional anaesthetic (usually either a spinal, epidural or pudendal block) is used to help the mother remain comfortable during the birth. Ascertaining the precise position of the fetal head is paramount, and though historically was accomplished by feeling the fetal skull suture lines and fontanelles, in the modern era, confirmation with ultrasound is essentially mandatory. At this point, the two blades of the forceps are individually inserted, the left blade first for the commonest occipito-anterior position; posterior blade first if a transverse position, then locked. The position on the baby's head is checked. The fetal head is then rotated to the occiput anterior position if it is not already in that position. An episiotomy may be performed if necessary. The baby is then delivered with gentle (maximum 30 lbf or 130 Newton) traction in the axis of the pelvis.
=== Outlet, low, mid or high ===
The accepted clinical standard classification system for forceps deliveries according to station and rotation was developed by the American College of Obstetricians and Gynecologists and consists of:
Outlet forceps delivery, where the forceps are applied when the fetal head has reached the perineal floor and its scalp is visible between contractions. This type of assisted delivery is performed only when the fetal head is in a straight forward or backward vertex position or in slight rotation (less than 45 degrees to the right or left) from one of these positions.
Low forceps delivery, when the baby's head is at +2 station or lower. There is no restriction on rotation for this type of delivery.
Midforceps delivery, when the baby's head is above +2 station. There must be head engagement before it can be carried out.
High forceps delivery is not performed in modern obstetrics practice. It would be a forceps-assisted vaginal delivery performed when the baby's head is not yet engaged.
== History ==
Abu al-Qasim al-Zahrawi, known in the West as Albucasis, was a pioneering 10th-century physician and surgeon from Al-Andalus. In his comprehensive medical encyclopedia, Al-Tasrif, he introduced over 200 surgical instruments, many of which he designed himself. Notably, al-Zahrawi devised surgical scissors, grasping forceps, and obstetrical forceps.
The obstetric forceps were introduced into the European parctice by the eldest son of the Chamberlen family of surgeons. The Chamberlens were French Huguenots from Normandy who worked in Paris before they migrated to England in 1569 to escape the religious violence in France. William Chamberlen, the patriarch of the family, was most likely a surgeon; he had two sons, both named Pierre, who became maverick surgeons and specialists in midwifery. William and the eldest son practiced in Southampton and then settled in London. The inventor was probably the eldest Peter Chamberlen the elder, who became obstetrician-surgeon of Queen Henriette, wife of King Charles I of England and daughter of Henry IV, King of France. He was succeeded by his nephew, Dr. Peter Chamberlen (barbers-surgeons were not doctors in the sense of physician), as royal obstetrician. The success of this dynasty of obstetricians with the royal family and high nobles was related in part to the use of this "secret" instrument allowing delivery of a live child in difficult cases.
In fact, the instrument was kept secret for 150 years by the Chamberlen family. Hugh Chamberlen the elder, grandnephew of Peter the eldest, tried to sell the instrument in Paris in 1670, but the demonstration he performed in front of François Mauriceau, responsible for Paris Hotel-Dieu maternity, was a failure which resulted in the death of mother and child. The secret may have been sold by Hugh Chamberlen to Dutch obstetricians at the start of the 18th century in Amsterdam, but there are doubts about the authenticity of what was actually provided to buyers.
The forceps were used most notably in difficult childbirths. The forceps could avoid some infant deaths when previous approaches (involving hooks and other instruments) extracted them in parts. In the interest of secrecy, the forceps were carried into the birthing room in a lined box and would only be used once everyone was out of the room and the mother blindfolded.
Models derived from the Chamberlen instrument finally appeared gradually in England and Scotland in 1735. About 100 years after the invention of the forceps by Peter Chamberlen Sr. a surgeon by the name of Jan Palfijn presented his obstetric forceps to the Paris Academy of Sciences in 1723. They contained parallel blades and were called the Hands of Palfijn.
These "hands" were possibly the instruments described and used in Paris by Gregoire father and son, Dussée, and Jacques Mesnard.
In 1813, Peter Chamberlen's midwifery tools were discovered at Woodham Mortimer Hall near Maldon (UK) in the attic of the house. The instruments were found along with gloves, old coins and trinkets. The tools discovered also contained a pair of forceps that were assumed to have been invented by the father of Peter Chamberlen because of the nature of the design.
The Chamberlen family's forceps were based on the idea of separating the two branches of "sugar clamp" (as those used to remove "stones" from bladder), which were put in place one after another in the birth canal. This was not possible with conventional tweezers previously tested. However, they could only succeed in a maternal pelvis of normal dimensions and on fetal heads already well engaged (i.e. well lowered into maternal pelvis). Abnormalities of pelvis were much more common in the past than today, which complicated the use of Chamberlen forceps. The absence of pelvic curvature of the branches (vertical curvature to accommodate the anatomical curvature of maternal sacrum) prohibited blades from reaching the upper-part of the pelvis and exercising traction in the natural axis of pelvic excavation.
In 1747, French obstetrician Andre Levret, published Observations sur les causes et accidents de plusieurs accouchements laborieux (Observations on the Causes and Accidents of Several difficult Deliveries), in which he described his modification of the instrument to follow the curvature of the maternal pelvis, this "pelvic curve" allowing a grip on a fetal head still high in the pelvic excavation, which could assist in more difficult cases.
This improvement was published in 1751 in England by William Smellie in the book A Treatise on the theory and practice of midwifery. After this fundamental improvement, the forceps would become a common obstetrical instrument for more than two centuries.
The last improvement of the instrument was added in 1877 by a French obstetrician, Stephan Tarnier in "descriptions of two new forceps." This instrument featured a traction system misaligned with the instrument itself, sometimes called the "third curvature of the forceps". This particularly ingenious traction system, allowed the forceps to exercise traction on the head of the child following the axis of the maternal pelvic excavation, which had never been possible before.
Tarnier's idea was to "split" mechanically the grabbing of the fetal head (between the forceps blades) on which the operator does not intervene after their correct positioning, from a mechanical accessory set on the forceps itself, the "tractor" on which the operator exercises traction needed to pull down the fetal head in the correct axis of the pelvic excavation. Tarnier forceps (and its multiple derivatives under other names) remained the most widely used system in the world until the development of the cesarean section.
Forceps had a profound influence on obstetrics as it allowed for the speedy delivery of the baby in cases of difficult or obstructed labour. Over the course of the 19th century, many practitioners attempted to redesign the forceps, so much so that the Royal College of Obstetrics and Gynecologists' collection has several hundred examples. In the last decades, however, with the ability to perform a cesarean section relatively safely, and the introduction of the ventouse or vacuum extractor, the use of forceps and training in the technique of its use has sharply declined.
=== Historical role in the medicalisation of childbirth ===
The introduction of the obstetrical forceps provided huge advances in the medicalisation of childbirth. Before the 18th century, childbirth was thought of as a medical phase that could be overseen by a female relative. Usually, if a doctor had to get involved that meant something had gone wrong. Around this era in the 18th century, there were no female doctors. Since males were exclusively called in under extreme circumstances, the act of childbirth was thought to be better known to a midwife or female relative than a male doctor. Usually the male doctor's job was to save the mother's life if, for example, the baby had become stuck on his or her way exiting the mother.
Before the obstetrical forceps, this had to be done by cutting the baby out piece by piece. In other cases, if the baby was deemed undeliverable, then the doctor would use a tool called a crochet. This was used to crush the baby's skull, allowing the baby to be pulled out of the mother's womb. Still in other cases, a caesarean section (c section) could be performed, but this would almost always result in the mother's death. "In addition, women who had forceps deliveries had shorter after-childbirth complications than those who had caesarean sections performed." These procedures came with various risks to the mother's health, along with the death of the baby.
However, with the introduction of the obstetrical forceps, the male doctor had a more important role. In many cases, they could actually save the baby's life if called early enough. Although the use of the forceps in childbirth came with its own set of risks, the positives included a significant decrease in risk to the mother, a decrease in child morbidity, and a decreased risk to the baby. Since the forceps in childbirth were made public around 1720, they gave male doctors a way to assist and even oversee childbirths.
Around this time, in large cities such as London and Paris, some men would become devoted to obstetrical practices. It became stylish among wealthy women of the era to have their childbirth overseen by male midwives. A notable male midwife was William Hunter. He popularised obstetrics. "In 1762, he was appointed as obstetrician to Queen Charlotte." In addition, with the use of forceps, male doctors invented lying in hospitals to provide safe, somewhat advanced obstetrical care because of the use of the obstetrical forceps.
=== Historical complications ===
Child birth was not considered a medical practice before the 18th century. It was mostly overseen by a midwife, mother, stepmother, neighbor, or any female relative. Around the 19th and 20th centuries, childbirth was considered dangerous for women. With the introduction of obstetrical forceps, this allowed non-medical professionals, such as the aforementioned individuals, to continue to oversee childbirths. In addition, this gave some of the public more comfort in trusting childbirth oversight to common people. However, the introduction of obstetrical forceps also had a negative effect, because there was no medical oversight of childbirth by any kind of medical professional, this exposed the practice to unnecessary risks and complications for the fetus and mother. These risks could range from minimal effects to lifetime consequences for both individuals. The baby could develop cuts and bruises in various body parts due to the forcible squeezing of his or her body through the mother's vagina. In addition, there could be bruising on the baby's face if the forceps' handler were to squeeze too tight. In some extreme cases, this could cause temporary or permanent facial nerve injury. Furthermore, if the forceps' handler were to twist his or her wrist while the grip was on the baby's head, this would twist the baby's neck and cause damage to a cranial nerve, resulting in strabismus. In rare cases, a clavicle fracture to the baby could occur. The addition of obstetrical forceps came with complication to the mother during and after childbirth. The use of the forceps gave rise to an increased risk in cuts and lacerations along the vaginal wall. This, in turn, would cause an increase in post-operative recovery time and increase the pain experienced by the mother. In addition, the use of forceps could cause more difficulty evacuating during the recovery time as compared to a mother who did not use the forceps. While some of these risks and complications were very common, in general, many people overlooked them and continued to use them.
== See also ==
Instruments used in general surgery
== References ==
== External links ==
GLOWM video demonstrating forceps delivery technique | Wikipedia/Obstetrical_forceps |
Hypertensive disease of pregnancy, also known as maternal hypertensive disorder, is a group of high blood pressure disorders that include preeclampsia, preeclampsia superimposed on chronic hypertension, gestational hypertension, and chronic hypertension.
Maternal hypertensive disorders occurred in about 20.7 million women in 2013. About 10% of pregnancies globally are complicated by hypertensive diseases. In the United States, hypertensive disease of pregnancy affects about 8% to 13% of pregnancies. Rates have increased in the developing world. They resulted in 29,000 deaths in 2013 down from 37,000 deaths in 1990. They are one of the three major causes of death in pregnancy (16%) along with post partum bleeding (13%) and puerperal infections (2%).
Hypertensive disorders during pregnancy, such as gestational hypertension, preeclampsia, and eclampsia, are a major contributor to maternal and fetal illness and death on a worldwide scale. Around 5-10% of pregnancies are affected by these conditions, with preeclampsia being responsible for up to 14% of maternal deaths globally. The effects of HDP are significant, but there is still a limited understanding of its root causes. Studies show an interconnection of genetic, immunological, and environmental elements. Accurately pinpointing particular risk factors has stifled researchers because of the varied nature of Hypertensive disorders of pregnancy. All types of HDP can be due to a various number of factors as mentioned above and can be brought upon in irregular manners.
== Signs and symptoms ==
Although many pregnant women with high blood pressure have healthy babies without serious problems, high blood pressure can be dangerous for both the mother and baby. Women with pre-existing, or chronic, high blood pressure are more likely to have certain complications during pregnancy than those with normal blood pressure. However, some women develop high blood pressure while they are pregnant (often called gestational hypertension).
Chronic poorly-controlled high blood pressure before and during pregnancy puts a pregnant woman and her baby at risk for problems. It is associated with an increased risk for maternal complications such as preeclampsia, placental abruption (when the placenta separates from the wall of the uterus), and gestational diabetes. These women also face a higher risk for poor birth outcomes such as preterm delivery, having an infant small for his/her gestational age, and infant death.
== Risk factors ==
Some women have a greater risk of developing hypertension during pregnancy. These are:
Women with chronic hypertension (high blood pressure before becoming pregnant).
Women who developed high blood pressure or preeclampsia during a previous pregnancy, especially if these conditions occurred early in the pregnancy.
Women who are obese before pregnancy.
Pregnant women under the age of 15 or over the age of 30.
Women who are pregnant with more than one baby.
Women with diabetes, kidney disease, rheumatoid arthritis, lupus, or scleroderma.
== Diagnosis ==
There is no single test to predict or diagnose preeclampsia. Key signs are increased blood pressure and protein in the urine (proteinuria). Other symptoms that seem to occur with preeclampsia include persistent headaches, blurred vision or sensitivity to light, and abdominal pain.
All of these sensations can be caused by other disorders; they can also occur in healthy pregnancies. Regular visits are scheduled to track blood pressure and level of protein in urine, to order and analyze blood tests that detect signs of preeclampsia, and to monitor fetal development more closely.
=== Classification ===
A classification of hypertensive disorders of pregnancy uses 4 categories as recommended by the U.S. National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy:
Chronic hypertension;
Preeclampsia-eclampsia;
Preeclampsia superimposed on chronic hypertension;
Gestational hypertension (transient hypertension of pregnancy or chronic hypertension identified in the latter half of pregnancy).
This terminology is preferred over the older but widely used term pregnancy-induced hypertension (PIH) because it is more precise. The newer terminology reflects simply relation of pregnancy with either the onset or first detection of hypertension; the question of causation, while pathogenetically interesting, is not the important point for most health care purposes. This classification treats HELLP syndrome as a type of preeclampsia rather than a parallel entity.
=== Chronic hypertension ===
Chronic hypertension is a type of high blood pressure in a pregnant woman that is pre-existing before conception, diagnosed early in pregnancy, or persists significantly after the end of pregnancy. It affects about 5% of all pregnancies and can be a primary disorder of essential hypertension or secondary to another condition; it is not caused by pregnancy itself.
The diagnostic criteria for chronic hypertension are typically considered to be at least two separate blood pressure readings taken at least four hours apart with systolic blood pressure ≥ 140mmHg, diastolic blood pressure ≥90 mmHg, or both, identified before pregnancy, before 20 weeks gestation, or persisting at least 12 weeks after giving birth. However, there is some controversy over the utility of adopting lower thresholds for the diagnosis of chronic hypertension, which is more consistent with recent recommendations from the American College of Cardiology and the American Heart Association for the diagnosis of hypertension in adults. Chronic hypertension in pregnancy is now considered mild if blood pressures do not exceed 159 mmHg systolic and 109 mmHg diastolic and severe if pressures are ≥ 160 mmHg systolic or 110 mmHg diastolic, although controversy also exists as to the most appropriate cutoffs for this definition.
Because chronic hypertension can progress to more severe forms of disease, it is important to accurately diagnose the condition early, ideally before pregnancy, and initiate management to control parental blood pressure. This is often difficult, as many reproductive individuals may not regularly visit the doctor and, when pregnant, may initially present for prenatal care in the second trimester.
=== Pre-eclampsia and eclampsia ===
Preeclampsia is a medical condition which usually develops after 20 weeks of gestation and traditionally involves both newly increased blood pressure (blood pressure > 140/90 mmHg) and proteinuria.
Preeclampsia is a leading cause of fetal complications, which include low birth weight, preterm birth, and stillbirth. Women with preeclampsia are encouraged to deliver the child after 37 weeks of gestation to minimize the risks of severe complications.
Preeclampsia, the most severe type of HDP, has been a major subject of research for scientists. Preeclampsia is usually characterized by elevated blood pressure and frequently protein in the urine after the 20th week of pregnancy, believed to be caused by abnormal placental growth leading to endothelial dysfunction and inflammation. Nevertheless, the order of these occurrences is still debated, making targeted treatment strategies more challenging. Furthermore, preventive measures are postponed since current criteria only show evidence in the second or third trimester.
Recent studies have found important biomarkers linked to HDP, like placental growth factor. Unusual levels of this angiogenic factor and others have displayed potential in forecasting preeclampsia, which could enable earlier intervention and monitoring methods. Furthermore, scientists are studying lifestyle elements such as diet and physical activity to evaluate their possible impact on decreasing HDP risk, even though definite conclusions have not been made.
Preeclampsia can also be diagnosed if a woman has both increased blood pressure and 1 or more signs of significant organ damage. Signs of significant organ damage include:
Severely elevated blood pressure (blood pressure > 160/110)
Thrombocytopenia
Increased or rapidly elevating levels of creatinine in the blood
Increased liver enzymes
Pulmonary edema
New or persistent headaches that do not respond to pain medication
Blurred or altered vision
If a woman with preeclampsia has any of these signs of significant organ damage, then her condition is classified as preeclampsia with severe features. This diagnosis can be made even if the patient does not have proteinuria. Women with preeclampsia with severe features are encouraged to deliver the child after 34 weeks of gestation to minimize the risks of severe complications.
Preeclampsia can also present with seizures in the pregnant mother. In this case, the patient would be diagnosed with eclampsia.
There is no proven way to prevent preeclampsia/eclampsia. Most women who develop signs of preeclampsia, however, are closely monitored to lessen or avoid related problems. The only way to "cure" preeclampsia/eclampsia is to deliver or abort the baby.
==== Eclampsia ====
Eclampsia is one particularly concerning form of preeclampsia in which a pregnant woman who previously presented with signs of newly increased blood pressure begins to experience new generalized seizures or coma. Up to 70% of patients with eclampsia experience complications associated with pregnancy. These complications can include HELLP syndrome, acute kidney injury, and disseminated intravascular coagulation among others.
==== HELLP Syndrome ====
HELLP Syndrome is a type of preeclampsia with severe features that involve increased hemolysis, increased liver enzymes, and low platelet levels. While most women with HELLP syndrome have high blood pressure and proteinuria, up to 20% of HELLP syndrome cases do not present with these classical signs of preeclampsia. However, like pre-eclampsia, HELLP syndrome can also lead to low birth weight and premature birth of the fetus/neonate. HELLP syndrome has a fetal/neonatal mortality rate of 7-20%.
=== Preeclampsia superimposed on chronic hypertension ===
Preeclampsia superimposed on chronic hypertension occurs when a pregnant woman with chronic hypertension develops signs of pre-eclampsia, typically defined as new onset of proteinuria ≥30 mg/dL (1+ in the dipstick) in at least 2 random urine specimens that were collected ≥4 h apart (but within a 7-day interval) or 0.3 g in a 24-h period. Like ordinary pre-eclampsia, superimposed pre-eclampsia can also occur with severe features, which are defined as: systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥110 mmHg despite escalation of antihypertensive therapy; thrombocytopenia (platelet count <100,000/microL); impaired liver function; new-onset or worsening renal insufficiency; pulmonary edema; or persistent cerebral or visual disturbances. As a result, superimposed pre-eclampsia can be diagnosed without proteinuria when a sudden increase in previously well-controlled blood pressure is accompanied by severe features of pre-eclampsia.
=== Gestational hypertension ===
Gestational hypertension is a provisional diagnosis that involves newly increased blood pressure in a pregnant woman that usually develops after 20 weeks of gestation but does not currently show any signs of proteinuria or other features associated with preeclampsia. Up to 50% of gestational hypertension patients go on to develop some form of preeclampsia.
Gestational hypertension will normally resolve by 12 weeks postpartum. In this case, the diagnosis of gestational hypertension will be updated to be transient hypertension of pregnancy. If the increased blood pressure does not resolve by 12 weeks postpartum, then the diagnosis of gestational hypertension will be updated to be chronic hypertension. At home blood pressure measurements have been documented to be a possible way to improve rates of early detection of hypertension in postpartum patients.
== Prevention ==
Blood pressure control can be accomplished before pregnancy. Medications can control blood pressure. Certain medications may not be ideal for blood pressure control during pregnancy, such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin II (AII) receptor antagonists. Controlling weight gain during pregnancy can help reduce the risk of hypertension during pregnancy.
There is limited evidence to suggest that calcium supplementation may reduce the risk of pre-eclampsia or stillbirth but it is unclear if it has other benefits.
Current research is focused on enhancing early identification, exploring genetic and environmental factors, and creating novel therapies. Improving maternal and fetal health outcomes globally could be greatly enhanced by addressing these disparities in HDP.
== Management ==
The only way to definitively treat a hypertensive disease of pregnancy (i.e., preeclampsia/eclampsia, gestational hypertension, etc. ) is to deliver the fetus. This prevents further development of complications related to the disorder in both the mother and the fetus. Therefore, the first-line approach to management of these conditions is to consider induction of preterm labor. The exact timing of when to induce labor is dependent on the severity of symptoms related to the hypertensive disease, as well as the medical condition of both the mother and the fetus. Generally, in mothers with preeclampsia, labor is induced once the gestational age is >37 weeks. In patients with preeclampsia with severe features or eclampsia, labor is induced once the gestational age is >34 weeks. In patients with gestational hypertension and no other signs of severe disease, labor is generally induced at term.
In cases where the fetus has not yet reached a safe gestational age to be delivered, management is focused on managing symptoms to give the fetus more time to mature. In women with gestational hypertension, some studies have found that usage of baby aspirin can prevent the progression of the condition to preeclampsia/eclampsia and reduce the risk of complications associated with hypertensive disorders of pregnancy.
Pregnant women with chronic hypertension diagnosed before or early in pregnancy should be evaluated to identify the underlying cause of hypertension as well as possible existing end-organ damage caused by hypertension, such as cardiac and kidney injury. Although most cases of chronic hypertension are primary, and thus classified as essential hypertension, secondary causes such as renal, vascular, and endocrine disorders must also be considered, especially in patients with chronic hypertension presenting abnormally, for instance at a young age or refractory to first-line treatment. If end-organ damage or an underlying cause of hypertension is identified, these conditions must also be treated. Women with chronic hypertension in pregnancy must be closely monitored because they are five times as likely as those with normal blood pressure to develop pre-eclampsia, which is a much more severe condition with serious risks for the mother and fetus.
For all hypertensive disorders of pregnancy, a major component of care is management of the associated hypertension. This involves the use of antihypertensive medication as well as restricting activity to lower blood pressure to reduce the risk of stroke. In women with preeclampsia or eclampsia, magnesium sulfate is often prescribed to prevent the occurrence of seizures in the gestational parent. Shorter duration of treatment with magnesium sulfate has high significance of evidence of reducing duration of urinary catheterization and time to ambulation, but there is insufficient evidence to show that reducing length of treatment impacts risk of seizures, maternal, or infant morbidities. Lower dose magnesium sulfate regimens may reduce rates of overdose but there is low significance of evidence that it increases risk of seizures of patients with eclampsia or mortality of patients with eclampsia.
Treatment should be continued from the time of diagnosis to several weeks postpartum, given the increased risk of medical complications immediately following delivery of the fetus. A recent systematic review found that postpartum home blood pressure monitoring likely improves the determination of blood pressure measures and overall patient of these conditions. Additionally, home blood pressure monitoring lessens physical and financial barriers to blood pressure surveillance, likely decreasing health disparities between black and non-black patients.
While there is no known cure for hypertensive disorders in pregnant women other than to deliver the baby, there are studies with treatments that have shown to manage hypertension in pregnant women because delivering a baby too early can lead to other complications. According to an article from the New England Journal of Medicine, antihypertensive therapies have been shown to reduce the risk of severe hypertension while pregnant and to reduce the number of other potential outcomes that can happen as a result of severe gestational hypertension. The goal of the treatment from this experiment was for the group receiving the treatment to reach a blood pressure below 140/90 mm Hg. This experiment showed that the group receiving the treatment had lower blood pressure and better pregnancy outcomes compared to the group that was not receiving no treatment.
Low-dose calcium supplementation has shown some evidence that it could reduce the risk of outcomes that can come from gestational hypertension. Specifically, it has been shown to reduce the risk of death, severe preeclampsia, and eclampsia. Calcium supplementation can especially benefit women who are not getting enough calcium in their daily diet.
A study looked at the effect of the three most common oral antihypertensive drugs, including Nifedipine, Labetalol, and Methyldopa. The outcome of this study is that most women showed reduced blood pressure and had no adverse effects in all three groups. However, Nifedipine should the greatest results in 6 hours but also had the greatest rate for admissions to the ICU. More research is needed on these oral antihypertensive drugs to determine which one is the best for most pregnant women. Additionally, a study done in 2023 demonstrated that treatment of patients with oral diuretic furosemide, a loop diuretic, may decrease the length of hypertension postpartum.
== Prognosis ==
The effects of high blood pressure during pregnancy vary depending on the disorder and other factors. Preeclampsia does not, in general, increase a woman's risk for developing chronic hypertension or other heart-related problems. Women with normal blood pressure who develop preeclampsia after the 20th week of their first pregnancy have short-term complications, including increased blood pressure, which usually go away within about six weeks after delivery.
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.
Even though high blood pressure and related disorders during pregnancy can be serious, most women with high blood pressure and those who develop preeclampsia have successful pregnancies. Obtaining early and regular prenatal care for pregnant women is important to identify and treat blood pressure disorders. Monitoring blood pressure can help catch postpartum hypertension early and might even help with racial disparities in follow up care.
== Epidemiology ==
High blood pressure problems occur in six percent to eight percent of all pregnancies in the U.S., about 70 percent of which are first-time pregnancies. In 1998, more than 146,320 cases of preeclampsia alone were diagnosed.
Although the proportion of pregnancies with gestational hypertension and eclampsia has remained about the same in the U.S. over the past decade, the rate of preeclampsia has increased by nearly one-third. This increase is due in part to a rise in the numbers of older mothers and of multiple births, where preeclampsia occurs more frequently. For example, in 1998, birth rates among women ages 30 to 44 and the number of births to women ages 45 and older were at the highest levels in three decades, according to the National Center for Health Statistics. Furthermore, between 1980 and 1998, rates of twin births increased about 50 percent overall and 1,000 percent among women ages 45 to 49; rates of triplet and other higher-order multiple births jumped more than 400 percent overall, and 1,000 percent among women in their 40s.
== References == | Wikipedia/Hypertensive_disease_of_pregnancy |
Endocrinology (from endocrine + -ology) is a branch of biology and medicine dealing with the endocrine system, its diseases, and its specific secretions known as hormones. It is also concerned with the integration of developmental events proliferation, growth, and differentiation, and the psychological or behavioral activities of metabolism, growth and development, tissue function, sleep, digestion, respiration, excretion, mood, stress, lactation, movement, reproduction, and sensory perception caused by hormones. Specializations include behavioral endocrinology and comparative endocrinology.
The endocrine system consists of several glands, all in different parts of the body, that secrete hormones directly into the blood rather than into a duct system. Therefore, endocrine glands are regarded as ductless glands. Hormones have many different functions and modes of action; one hormone may have several effects on different target organs, and, conversely, one target organ may be affected by more than one hormone.
== The endocrine system ==
Endocrinology is the study of the endocrine system in the human body. This is a system of glands which secrete hormones. Hormones are chemicals that affect the actions of different organ systems in the body. Examples include thyroid hormone, growth hormone, and insulin. The endocrine system involves a number of feedback mechanisms, so that often one hormone (such as thyroid stimulating hormone) will control the action or release of another secondary hormone (such as thyroid hormone). If there is too much of the secondary hormone, it may provide negative feedback to the primary hormone, maintaining homeostasis.
In the original 1902 definition by Bayliss and Starling (see below), they specified that, to be classified as a hormone, a chemical must be produced by an organ, be released (in small amounts) into the blood, and be transported by the blood to a distant organ to exert its specific function. This definition holds for most "classical" hormones, but there are also paracrine mechanisms (chemical communication between cells within a tissue or organ), autocrine signals (a chemical that acts on the same cell), and intracrine signals (a chemical that acts within the same cell). A neuroendocrine signal is a "classical" hormone that is released into the blood by a neurosecretory neuron (see article on neuroendocrinology).
=== Hormones ===
Griffin and Ojeda identify three different classes of hormones based on their chemical composition:
==== Amines ====
Amines, such as norepinephrine, epinephrine, and dopamine (catecholamines), are derived from single amino acids, in this case tyrosine. Thyroid hormones such as 3,5,3'-triiodothyronine (T3) and 3,5,3',5'-tetraiodothyronine (thyroxine, T4) make up a subset of this class because they derive from the combination of two iodinated tyrosine amino acid residues.
==== Peptide and protein ====
Peptide hormones and protein hormones consist of three (in the case of thyrotropin-releasing hormone) to more than 200 (in the case of follicle-stimulating hormone) amino acid residues and can have a molecular mass as large as 31,000 grams per mole. All hormones secreted by the pituitary gland are peptide hormones, as are leptin from adipocytes, ghrelin from the stomach, and insulin from the pancreas.
==== Steroid ====
Steroid hormones are converted from their parent compound, cholesterol. Mammalian steroid hormones can be grouped into five groups by the receptors to which they bind: glucocorticoids, mineralocorticoids, androgens, estrogens, and progestogens. Some forms of vitamin D, such as calcitriol, are steroid-like and bind to homologous receptors, but lack the characteristic fused ring structure of true steroids.
== As a profession ==
Although every organ system secretes and responds to hormones (including the brain, lungs, heart, intestine, skin, and the kidneys), the clinical specialty of endocrinology focuses primarily on the endocrine organs, meaning the organs whose primary function is hormone secretion. These organs include the pituitary, thyroid, adrenals, ovaries, testes, and pancreas.
An endocrinologist is a physician who specializes in treating disorders of the endocrine system, such as diabetes, hyperthyroidism, and many others (see list of diseases).
=== Work ===
The medical specialty of endocrinology involves the diagnostic evaluation of a wide variety of symptoms and variations and the long-term management of disorders of deficiency or excess of one or more hormones.
The diagnosis and treatment of endocrine diseases are guided by laboratory tests to a greater extent than for most specialties. Many diseases are investigated through excitation/stimulation or inhibition/suppression testing. This might involve injection with a stimulating agent to test the function of an endocrine organ. Blood is then sampled to assess the changes of the relevant hormones or metabolites. An endocrinologist needs extensive knowledge of clinical chemistry and biochemistry to understand the uses and limitations of the investigations.
A second important aspect of the practice of endocrinology is distinguishing human variation from disease. Atypical patterns of physical development and abnormal test results must be assessed as indicative of disease or not. Diagnostic imaging of endocrine organs may reveal incidental findings called incidentalomas, which may or may not represent disease.
Endocrinology involves caring for the person as well as the disease. Most endocrine disorders are chronic diseases that need lifelong care. Some of the most common endocrine diseases include diabetes mellitus, hypothyroidism and the metabolic syndrome. Care of diabetes, obesity and other chronic diseases necessitates understanding the patient at the personal and social level as well as the molecular, and the physician–patient relationship can be an important therapeutic process.
Apart from treating patients, many endocrinologists are involved in clinical science and medical research, teaching, and hospital management.
=== Training ===
Endocrinologists are specialists of internal medicine or pediatrics. Reproductive endocrinologists deal primarily with problems of fertility and menstrual function—often training first in obstetrics. Most qualify as an internist, pediatrician, or gynecologist for a few years before specializing, depending on the local training system. In the U.S. and Canada, training for board certification in internal medicine, pediatrics, or gynecology after medical school is called residency. Further formal training to subspecialize in adult, pediatric, or reproductive endocrinology is called a fellowship. Typical training for a North American endocrinologist involves 4 years of college, 4 years of medical school, 3 years of residency, and 2 years of fellowship. In the US, adult endocrinologists are board certified by the American Board of Internal Medicine (ABIM) or the American Osteopathic Board of Internal Medicine (AOBIM) in Endocrinology, Diabetes and Metabolism.
== Diseases treated by endocrinologists ==
Diabetes mellitus: This is a chronic condition that affects how your body regulates blood sugar. There are two main types: type 1 diabetes, which is an autoimmune disease that occurs when the body attacks the cells that produce insulin, and type 2 diabetes, which is a condition in which the body either doesn't produce enough insulin or doesn't use it effectively.
Thyroid disorders: These are conditions that affect the thyroid gland, a butterfly-shaped gland located in the front of your neck. The thyroid gland produces hormones that regulate your metabolism, heart rate, and body temperature. Common thyroid disorders include hyperthyroidism (overactive thyroid) and hypothyroidism (underactive thyroid).
Adrenal disorders: The adrenal glands are located on top of your kidneys. They produce hormones that help regulate blood pressure, blood sugar, and the body's response to stress. Common adrenal disorders include Cushing syndrome (excess cortisol production) and Addison's disease (adrenal insufficiency).
Pituitary disorders: The pituitary gland is a pea-sized gland located at the base of the brain. It produces hormones that control many other hormone-producing glands in the body. Common pituitary disorders include acromegaly (excess growth hormone production) and Cushing's disease (excess ACTH production).
Metabolic disorders: These are conditions that affect how your body processes food into energy. Common metabolic disorders include obesity, high cholesterol, and gout.
Calcium and bone disorders: Endocrinologists also treat conditions that affect calcium levels in the blood, such as hyperparathyroidism (too much parathyroid hormone) and osteoporosis (weak bones).
Sexual and reproductive disorders: Endocrinologists can also help diagnose and treat hormonal problems that affect sexual development and function, such as polycystic ovary syndrome (PCOS) and erectile dysfunction.
Endocrine cancers: These are cancers that develop in the endocrine glands. Endocrinologists can help diagnose and treat these cancers.
== Diseases and medicine ==
=== Diseases ===
See main article at Endocrine diseases
Endocrinology also involves the study of the diseases of the endocrine system. These diseases may relate to too little or too much secretion of a hormone, too little or too much action of a hormone, or problems with receiving the hormone.
=== Societies and Organizations ===
Because endocrinology encompasses so many conditions and diseases, there are many organizations that provide education to patients and the public. The Hormone Foundation is the public education affiliate of The Endocrine Society and provides information on all endocrine-related conditions. Other educational organizations that focus on one or more endocrine-related conditions include the American Diabetes Association, Human Growth Foundation, American Menopause Foundation, Inc., and American Thyroid Association.
In North America the principal professional organizations of endocrinologists include The Endocrine Society, the American Association of Clinical Endocrinologists, the American Diabetes Association, the Lawson Wilkins Pediatric Endocrine Society, and the American Thyroid Association.
In Europe, the European Society of Endocrinology (ESE) and the European Society for Paediatric Endocrinology (ESPE) are the main organisations representing professionals in the fields of adult and paediatric endocrinology, respectively.
In the United Kingdom, the Society for Endocrinology and the British Society for Paediatric Endocrinology and Diabetes are the main professional organisations.
The European Society for Paediatric Endocrinology is the largest international professional association dedicated solely to paediatric endocrinology. There are numerous similar associations around the world.
== History ==
The earliest study of endocrinology began in China. The Chinese were isolating sex and pituitary hormones from human urine and using them for medicinal purposes by 200 BC. They used many complex methods, such as sublimation of steroid hormones. Another method specified by Chinese texts—the earliest dating to 1110—specified the use of saponin (from the beans of Gleditsia sinensis) to extract hormones, but gypsum (containing calcium sulfate) was also known to have been used.
Although most of the relevant tissues and endocrine glands had been identified by early anatomists, a more humoral approach to understanding biological function and disease was favoured by the ancient Greek and Roman thinkers such as Aristotle, Hippocrates, Lucretius, Celsus, and Galen, according to Freeman et al., and these theories held sway until the advent of germ theory, physiology, and organ basis of pathology in the 19th century.
In 1849, Arnold Berthold noted that castrated cockerels did not develop combs and wattles or exhibit overtly male behaviour. He found that replacement of testes back into the abdominal cavity of the same bird or another castrated bird resulted in normal behavioural and morphological development, and he concluded (erroneously) that the testes secreted a substance that "conditioned" the blood that, in turn, acted on the body of the cockerel. In fact, one of two other things could have been true: that the testes modified or activated a constituent of the blood or that the testes removed an inhibitory factor from the blood. It was not proven that the testes released a substance that engenders male characteristics until it was shown that the extract of testes could replace their function in castrated animals. Pure, crystalline testosterone was isolated in 1935.
Graves' disease was named after Irish doctor Robert James Graves, who described a case of goiter with exophthalmos in 1835. The German Karl Adolph von Basedow also independently reported the same constellation of symptoms in 1840, while earlier reports of the disease were also published by the Italians Giuseppe Flajani and Antonio Giuseppe Testa, in 1802 and 1810 respectively, and by the English physician Caleb Hillier Parry (a friend of Edward Jenner) in the late 18th century. Thomas Addison was first to describe Addison's disease in 1849.
In 1902 William Bayliss and Ernest Starling performed an experiment in which they observed that acid instilled into the duodenum caused the pancreas to begin secretion, even after they had removed all nervous connections between the two. The same response could be produced by injecting extract of jejunum mucosa into the jugular vein, showing that some factor in the mucosa was responsible. They named this substance "secretin" and coined the term hormone for chemicals that act in this way.
Joseph von Mering and Oskar Minkowski made the observation in 1889 that removing the pancreas surgically led to an increase in blood sugar, followed by a coma and eventual death—symptoms of diabetes mellitus. In 1922, Banting and Best realized that homogenizing the pancreas and injecting the derived extract reversed this condition.
Neurohormones were first identified by Otto Loewi in 1921. He incubated a frog's heart (innervated with its vagus nerve attached) in a saline bath, and left in the solution for some time. The solution was then used to bathe a non-innervated second heart. If the vagus nerve on the first heart was stimulated, negative inotropic (beat amplitude) and chronotropic (beat rate) activity were seen in both hearts. This did not occur in either heart if the vagus nerve was not stimulated. The vagus nerve was adding something to the saline solution. The effect could be blocked using atropine, a known inhibitor to heart vagal nerve stimulation. Clearly, something was being secreted by the vagus nerve and affecting the heart. The "vagusstuff" (as Loewi called it) causing the myotropic (muscle enhancing) effects was later identified to be acetylcholine and norepinephrine. Loewi won the Nobel Prize for his discovery.
Recent work in endocrinology focuses on the molecular mechanisms responsible for triggering the effects of hormones. The first example of such work being done was in 1962 by Earl Sutherland. Sutherland investigated whether hormones enter cells to evoke action, or stayed outside of cells. He studied norepinephrine, which acts on the liver to convert glycogen into glucose via the activation of the phosphorylase enzyme. He homogenized the liver into a membrane fraction and soluble fraction (phosphorylase is soluble), added norepinephrine to the membrane fraction, extracted its soluble products, and added them to the first soluble fraction. Phosphorylase activated, indicating that norepinephrine's target receptor was on the cell membrane, not located intracellularly. He later identified the compound as cyclic AMP (cAMP) and with his discovery created the concept of second-messenger-mediated pathways. He, like Loewi, won the Nobel Prize for his groundbreaking work in endocrinology.
== See also ==
Comparative endocrinology
Endocrine disease
Hormone
Hormone replacement therapy
Neuroendocrinology
Pediatric endocrinology
Reproductive endocrinology and infertility
Wildlife endocrinology
List of instruments used in endocrinology
== References == | Wikipedia/endocrinology |
Hypolipoproteinemia, hypolipidemia, or hypolipidaemia (British English) is a form of dyslipidemia that is defined by abnormally lowered levels of any or all lipids and/or lipoproteins in the blood. It occurs in genetic disorders (e.g. hypoalphalipoproteinemia, hypobetalipoproteinemia), malnutrition, malabsorption, wasting disease, cancer, hyperthyroidism, and liver disease.
== Presentation ==
== Causes ==
Causes of hypolipidemia include:
Hypobetalipoproteinemia (low levels of LDL cholesterol or apolipoprotein B)
Malnutrition
Malabsorption
Wasting disease
Certain cancers
Hyperthyroidism (overactive thyroid)
Liver disorders
== Diagnosis ==
It can be diagnosed via blood study that identifies fat particles. The patient must fast overnight to prevent interference from fat in the blood due to food intake. The criteria for this (without the involvement of cholesterol-lowering drugs) are total cholesterol levels below 120 mg/dL and LDL cholesterol levels under 50 mg/dL.
=== Critical illness ===
In the setting of critical illness, low cholesterol levels are predictive of clinical deterioration, and are correlated with altered cytokine levels.
In humans with genetic loss-of-function variants in one copy of the ANGPTL3 gene, the serum LDL-C levels are reduced. In those with loss-of-function variants in both copies of ANGPTL3, low LDL-C, low HDL-C, and low triglycerides are seen ("familial combined hypolipidemia").
Hooft disease is a rare condition evidenced by low blood lipid level, red rash and mental and physical retardation.
== Treatment ==
Vitamin E supplements have shown to help children with the deficiency.
== See also ==
== References ==
== External links == | Wikipedia/Hypolipoproteinemia |
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/Familial_apoprotein_CII_deficiency |
Hypobetalipoproteinemia is a disorder consisting of low levels of LDL cholesterol or apolipoprotein B, below the 5th percentile. The patient can have hypobetalipoproteinemia and simultaneously have high levels of HDL cholesterol.
Notably, in people who do not have the genetic disorder hypobetalipoproteinemia, a very low cholesterol level (less than 100 mg/dl) may be a marker for poor nutrition, wasting disease, cancer, hyperthyroidism, and liver disease. In 1997 a study showed that Japanese Centenarians had tenfold increase of hypobetalipoproteinemia compared with controls.
== Presentation ==
== Causes ==
One form is thought to be caused by mutated apolipoprotein B.
Another form is associated with microsomal triglyceride transfer protein which causes abetalipoproteinemia.
A third form, chylomicron retention disease (CRD), is associated with SARA2.
== Diagnosis ==
Typically in hypobetalipoproteinemia, plasma cholesterol levels will be around 80–120 mg/dL, LDL cholesterol will be around 50–80 mg/dL.
== Treatment ==
Early high doses of vitamin E in infants and children has shown to be effective.
== References ==
== External links == | Wikipedia/Hypobetalipoproteinemia |
Familial dysbetalipoproteinemia or type III hyperlipoproteinemia is a condition characterized by increased total cholesterol and triglyceride levels, and decreased HDL levels.
== Signs and symptoms ==
Signs of familial dysbetaproteinemia include xanthoma striatum palmare (orange or yellow discoloration of the palms) and tuberoeruptive xanthomas over the elbows and knees. The disease leads to premature atherosclerosis and therefore a possible early onset of coronary artery disease and peripheral vascular disease leading to a heart attack, i.e. myocardial infarction, chest pain on exercise, i.e. angina pectoris or stroke in young adults or middle aged patients.
== Causes ==
This condition is more likely when a mutation in apolipoprotein E (ApoE) is present. ApoE serves as a ligand for the liver receptor for chylomicrons, IDL and VLDL, also known as very-low-density-lipoprotein receptor. Individuals with two copies of the ApoE2 gene have substantially elevated risk of this condition. This defect prevents the normal metabolism of chylomicrons, IDL and VLDL, otherwise known as remnants, and therefore leads to accumulation of cholesterol within scavenger cells (macrophages) to enhance development and acceleration of atherosclerosis.
== Diagnosis ==
== Treatment ==
First line of management is fibrates.
== See also ==
Primary hyperlipoproteinemia
Apolipoprotein B deficiency
List of cutaneous conditions
== References ==
== External links == | Wikipedia/Familial_dysbetalipoproteinemia |
Thyroid function tests (TFTs) is a collective term for blood tests used to check the function of the thyroid.
TFTs may be requested if a patient is thought to suffer from hyperthyroidism (overactive thyroid) or hypothyroidism (underactive thyroid), or to monitor the effectiveness of either thyroid-suppression or hormone replacement therapy. It is also requested routinely in conditions linked to thyroid disease, such as atrial fibrillation and anxiety disorder.
A TFT panel typically includes thyroid hormones such as thyroid-stimulating hormone (TSH, thyrotropin) and thyroxine (T4), and triiodothyronine (T3) depending on local laboratory policy.
== Thyroid-stimulating hormone ==
Thyroid-stimulating hormone (TSH, thyrotropin) is generally increased in hypothyroidism and decreased in hyperthyroidism, making it the most important test for early detection of both of these conditions. The result of this assay is suggestive of the presence and cause of thyroid disease, since a measurement of elevated TSH generally indicates hypothyroidism, while a measurement of low TSH generally indicates hyperthyroidism. However, when TSH is measured by itself, it can yield misleading results, so additional thyroid function tests must be compared with the result of this test for accurate diagnosis.
TSH is produced in the pituitary gland. The production of TSH is controlled by thyrotropin-releasing hormone (TRH), which is produced in the hypothalamus. TSH levels may be suppressed by excess free T3 (fT3) or free T4 (fT4) in the blood.
=== History ===
First-generation TSH assays were done by radioimmunoassay and were introduced in 1965. There were variations and improvements upon TSH radioimmunoassay, but their use declined as a new immunometric assay technique became available in the middle of the 1980s. The new techniques were more accurate, leading to the second, third, and even fourth generations of TSH assay, with each generation possessing ten times greater functional sensitivity than the last. Third generation immunometric assay methods are typically automated. Fourth generation TSH immunometric assay has been developed for use in research.
=== Modern standard ===
Third generation TSH assay is the requirement for modern standards of care. TSH testing in the United States is typically carried out with automated platforms using advanced forms of immunometric assay. Nonetheless, there is no international standard for measurement of thyroid-stimulating hormone.
=== Interpretation ===
Accurate interpretation takes a variety of factors into account, such as the thyroid hormones i.e. thyroxine (T4) and triiodothyronine (T3), current medical status (such as pregnancy), certain medications like propylthiouracil, temporal effects including circadian rhythm and hysteresis, and other past medical history.
== Thyroid hormones ==
=== Total thyroxine ===
Total thyroxine is rarely measured, having been largely superseded by free thyroxine tests. Total thyroxine (Total T4) is generally elevated in hyperthyroidism and decreased in hypothyroidism. It is usually slightly elevated in pregnancy secondary to increased levels of thyroid binding globulin (TBG).
Total T4 is measured to see the bound and unbound levels of T4. The total T4 is less useful in cases where there could be protein abnormalities. The total T4 is less accurate due to the large amount of T4 that is bound. The total T3 is measured in clinical practice since the T3 has decreased amount that is bound as compared to T4.
Reference ranges depend on the method of analysis. Results should always be interpreted using the range from the laboratory that performed the test. Example values are:
=== Free thyroxine ===
Free thyroxine (fT4 or free T4) is generally elevated in hyperthyroidism and decreased in hypothyroidism.
Reference ranges depend on the method of analysis. Results should always be interpreted using the range from the laboratory that performed the test. Example values are:
=== Total triiodothyronine ===
Total triiodothyronine (Total T3) is rarely measured, having been largely superseded by free T3 tests. Total T3 is generally elevated in hyperthyroidism and decreased in hypothyroidism.
Reference ranges depend on the method of analysis. Results should always be interpreted using the range from the laboratory that performed the test. Example values are:
=== Free triiodothyronine ===
Free triiodothyronine (fT3 or free T3) is generally elevated in hyperthyroidism and decreased in hypothyroidism.
Reference ranges depend on the method of analysis. Results should always be interpreted using the range from the laboratory that performed the test. Example values are:
== Carrier proteins ==
=== Thyroxine-binding globulin ===
An increased thyroxine-binding globulin results in an increased total thyroxine and total triiodothyronine without an actual increase in hormonal activity of thyroid hormones.
Reference ranges:
== Thyroglobulin ==
Reference ranges:
=== Other binding hormones ===
Transthyretin (prealbumin)
Albumin
== Protein binding function ==
=== Thyroid hormone uptake ===
Thyroid hormone uptake (Tuptake or T3 uptake) is a measure of the unbound thyroxine binding globulins in the blood, that is, the TBG that is unsaturated with thyroid hormone. Unsaturated TBG increases with decreased levels of thyroid hormones. It is not directly related to triiodothyronine, despite the name T3 uptake.
Reference ranges:
=== Other protein binding tests ===
Thyroid Hormone Binding Ratio (THBR)
Thyroxine-binding index (TBI)
== Mixed parameters ==
=== Free thyroxine index ===
The Free Thyroxine Index (FTI or T7) is obtained by multiplying the total T4 with T3 uptake. FTI is considered to be a more reliable indicator of thyroid status in the presence of abnormalities in plasma protein binding. This test is rarely used now that reliable free thyroxine and free triiodothyronine assays are routinely available.
FTI is elevated in hyperthyroidism and decreased in hypothyroidism.
== Calculated and structure parameters ==
Derived structure parameters that describe constant properties of the overall feedback control system may add useful information for special purposes, e.g. in diagnosis of nonthyroidal illness syndrome or central hypothyroidism.
=== Secretory capacity (GT) ===
Thyroid's secretory capacity (GT, also referred to as SPINA-GT) is the maximum stimulated amount of thyroxine the thyroid can produce in one second. GT is elevated in hyperthyroidism and reduced in hypothyroidism.
GT is calculated with
G
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{\displaystyle {\hat {G}}_{T}={{\beta _{T}(D_{T}+[TSH])(1+K_{41}[TBG]+K_{42}[TBPA])[FT_{4}]} \over {\alpha _{T}[TSH]}}}
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{\displaystyle {\hat {G}}_{T}={{\beta _{T}(D_{T}+[TSH])[TT_{4}]} \over {\alpha _{T}[TSH]}}}
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{\displaystyle \alpha _{T}}
: Dilution factor for T4 (reciprocal of apparent volume of distribution, 0.1 l−1)
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{\displaystyle \beta _{T}}
: Clearance exponent for T4 (1.1e-6 sec−1)
K41: Dissociation constant T4-TBG (2e10 L/mol)
K42: Dissociation constant T4-TBPA (2e8 L/mol)
DT: EC50 for TSH (2.75 mU/L)
=== Sum activity of peripheral deiodinases (GD) ===
The sum activity of peripheral deiodinases (GD, also referred to as SPINA-GD) is reduced in nonthyroidal illness with hypodeiodination.
GD is obtained with
G
^
D
=
β
31
(
K
M
1
+
[
F
T
4
]
)
(
1
+
K
30
[
T
B
G
]
)
[
F
T
3
]
α
31
[
F
T
4
]
{\displaystyle {\hat {G}}_{D}={{\beta _{31}(K_{M1}+[FT_{4}])(1+K_{30}[TBG])[FT_{3}]} \over {\alpha _{31}[FT_{4}]}}}
or
G
^
D
=
β
31
(
K
M
1
+
[
F
T
4
]
)
[
T
T
3
]
α
31
[
F
T
4
]
{\displaystyle {\hat {G}}_{D}={{\beta _{31}(K_{M1}+[FT_{4}])[TT_{3}]} \over {\alpha _{31}[FT_{4}]}}}
α
31
{\displaystyle \alpha _{31}}
: Dilution factor for T3 (reciprocal of apparent volume of distribution, 0.026 L−1)
β
31
{\displaystyle \beta _{31}}
: Clearance exponent for T3 (8e-6 sec−1)
KM1: Dissociation constant of type-1-deiodinase (5e-7 mol/L)
K30: Dissociation constant T3-TBG (2e9 L/mol)
=== TSH index ===
Jostel's TSH index (JTI or TSHI) helps to determine thyrotropic function of anterior pituitary on a quantitative level. It is reduced in thyrotropic insufficiency and in certain cases of non-thyroidal illness syndrome.
It is calculated with
T
S
H
I
=
L
N
(
T
S
H
)
+
0.1345
∗
F
T
4
{\displaystyle TSHI=LN(TSH)+0.1345*FT4}
.
Additionally, a standardized form of TSH index may be calculated with
s
T
S
H
I
=
(
T
S
H
I
−
2.7
)
/
0.676
{\displaystyle sTSHI=(TSHI-2.7)/0.676}
.
=== TTSI ===
The Thyrotroph Thyroid Hormone Sensitivity Index (TTSI, also referred to as Thyrotroph T4 Resistance Index or TT4RI) was developed to enable fast screening for resistance to thyroid hormone. Somewhat similar to the TSH Index it is calculated from equilibrium values for TSH and FT4, however with a different equation.
=== TFQI ===
The Thyroid Feedback Quantile-based Index (TFQI) is another parameter for thyrotropic pituitary function. It was defined to be more robust to distorted data than JTI and TTSI. It is calculated with
T
F
Q
I
=
F
F
T
4
(
F
T
4
)
−
(
1
−
F
T
S
H
(
T
S
H
)
)
{\displaystyle TFQI=F_{FT4}(FT4)-(1-F_{TSH}(TSH))}
from quantiles of FT4 and TSH concentration (as determined based on cumulative distribution functions). Per definition the TFQI has a mean of 0 and a standard deviation of 0.37 in a reference population. Higher values of TFQI are associated with obesity, metabolic syndrome, impaired renal function, diabetes, and diabetes-related mortality. TFQI results are also elevated in takotsubo syndrome, potentially reflecting type 2 allostatic load in the situation of psychosocial stress. Reductions have been observed in subjects with schizophrenia after initiation of therapy with oxcarbazepine, potentially reflecting declining allostatic load.
=== Reconstructed set point ===
In healthy persons, the intra-individual variation of TSH and thyroid hormones is considerably smaller than the inter-individual variation. This results from a personal set point of thyroid homeostasis. In hypothyroidism, it is impossible to directly access the set point, but it can be reconstructed with methods of systems theory.
A computerised algorithm, called Thyroid-SPOT, which is based on this mathematical theory, has been implemented in software applications. In patients undergoing thyroidectomy it could be demonstrated that this algorithm can be used to reconstruct the personal set point with sufficient precision.
== Effects of drugs ==
Drugs can profoundly affect thyroid function tests. Listed below is a selection of important effects.
↓: reduced serum concentration or structure parameter; ↑: increased serum concentration or structure parameter; ↔: no change; TSH: Thyroid-stimulating hormone; T3: Total triiodothyronine; T4: Total thyroxine; fT4: Free thyroxine; fT3: Free triiodothyronine; rT3: Reverse triiodothyronine
== See also ==
Reference ranges for thyroid hormones
Long-acting thyroid stimulator (LATS)
== References ==
== Further reading ==
American Thyroid Association: Thyroid Function Tests. Posted on June 4, 2012, seen on January 9, 2013.
Thyroid function panel - Lab Tests Online
== External links ==
SPINA Thyr: Open source software for calculating GT and GD
Interpretation of thyroid function tests by Dayan, Colin M. 2001. The Lancet, Vol. 357.
=== CDC laboratory procedure manuals ===
The Centers for Disease Control and Prevention has published the following laboratory procedure manuals for measuring thyroid-stimulating hormone:
Thyroid Stimulating Hormone (TSH) (University of Washington Medical Center). September 2011. Method: Access 2 (Beckman Coulter).
Thyroid Stimulating Hormone (TSH) (Collaborative Laboratory Services). September 2011. Method: Access 2 (Beckman Coulter).
Thyroid Stimulating Hormone (TSH). September 2009. Method: Access 2 (Beckman Coulter).
Lab 18 Thyroid Stimulating Hormone. 2001-2002. Method: Microparticle Enzyme Immunoassay.
Lab 18 TSH - Thyroid Stimulating Hormone. 1999-2000. Method: Microparticle Enzyme Immunoassay. | Wikipedia/Thyroid_function_tests |
Many conditions are associated with disorders of the function of the parathyroid gland. Some disorders may be purely anatomical resulting in an enlarged gland which will raise concern. Such benign disorders, such as parathyroid cyst, are not discussed here. Parathyroid diseases can be divided into those causing hyperparathyroidism, and those causing hypoparathyroidism.
== Comparison ==
== Hyperparathyroidism and related conditions ==
The single major disease of parathyroid glands is overactivity of one or more of the parathyroid lobes, which make too much parathyroid hormone, causing a potentially serious calcium imbalance. This is called hyperparathyroidism; it leads to hypercalcemia, kidney stones, osteoporosis, and various other symptoms. Hyperparathyroidism was first described in 1925 and the symptoms have collectively become known as "moans, groans, stones, and bones." By far, the most common symptom is fatigue, but depression, memory loss, and bone aches are also very common. Primary hyperparathyroidism is relatively more common in postmenopausal women. Continuous ambulatory peritoneal dialysis(CAPD) In CAPD, the lining of the abdomen acts as a natural filter, and dialysis fluid is introduced into and removed from the abdominal cavity through a catheter. While kidney dialysis technicians are not directly involved in the day-to-day administration of CAPD continuous ambulatory peritoneal dialysis (CAPD), they play an important role in supporting and educating patients, ensuring they have the knowledge and resources needed to manage their treatment effectively. The primary treatment for this disease is the surgical removal of the faulty gland.
If a patient has elevated calcium, several different types of tests can be used to locate the abnormal glands. The most common and most accurate test to find a parathyroid tumor is the Sestamibi scan. The Sestamibi scan does not have high resolution. Neck ultrasound has higher resolution, but requires some expertise to perform. Ultrasound's shortcomings include: it cannot determine glandular function (normal vs. hyperfunctioning) or visualize unusual locations such as retropharyngeal or mediastinal. Thin cut computed tomography of the neck can reveal glands in locations that the ultrasound cannot evaluate well; e.g. retropharyngeal, mediastinal. These tests are ordered by an endocrinologist or a surgeon that specializes in parathyroid surgery. Often, these "localizing" tests used to "find" the bad parathyroid gland are not successful in locating which parathyroid gland has become a tumor. This often causes confusion for the patient and doctor, since the tumor was not located. This simply means that the tumor was not found using these tests; it does not mean the tumor does not exist. The use of ultrasound-guided FNA, and parathyroid hormone washings can confirm the abnormal glands. For decades, it has been known that the best way to find a parathyroid tumor is through a very experienced parathyroid surgeon.
Even if a patient has a non-localizing Sestamibi scan (a negative sestamibi scan), he/she should almost always have a neck exploration to remove the tumor if he/she has high calcium levels, among other symptoms. Minimally-invasive parathyroid surgery is becoming more available, but, depending on the expertise of the surgeon, the patient may need to have a positive sestamibi scan before a minimally-invasive operation is attempted. Some of the most experienced surgeons perform mini-parathyroid surgery on all patients, but this is available only at highly specialized centers. Some patients will need both sides of their necks explored to find the dysfunctional gland(s).
Another related condition is called secondary hyperparathyroidism (HPT for short), which is common in patients with chronic kidney disease on dialysis. In secondary HPT, the parathyroid glands make too much parathyroid hormone (PTH) because the kidneys have failed, and the calcium and phosphorus are out of balance. Even though one may not have any symptoms, treating secondary HPT is important. Cinacalcet (Sensipar) is a medicine that can help treat such dialysis patients and is available by prescription only. Most experts believe that Sensipar should not be used for patients with primary hyperparathyroidism (patients that have a high calcium and are not on kidney dialysis).
Parathyroid surgery is usually performed when there is hyperparathyroidism. This condition causes many diseases related with calcium reabsorption, because the principal function of the parathyroid hormone is to regulate it. Parathyroid surgery could be performed in two different ways: first is a complete parathyroidectomy, and second is the auto transplantation of the removed parathyroid glands. There are various conditions that can indicate the need for the removal or transplant of the parathyroid glands. Hyperparathyroidism is a condition caused by overproduction of PTH, and can be divided into three types.
Primary hyperparathyroidism happens when the normal mechanism of regulation by negative feedback of calcium is interrupted, or in other words the amount of blood calcium would ordinarily signal less production of PTH. Most of the time this is caused by adenomas, hyperplasia or carcinomas.
Secondary hyperparathyroidism normally occurs in patients that suffer chronic kidney disease. Poor kidney function leads to a mineral disequilibrium that causes the glands hypertrophy in order to synthesize and release more PTH.
Tertiary hyperparathyroidism develops when the hyperplastic gland of secondary hyperparathyroidism constantly releases PTH, independent of the regulation systems.
Another condition is hypercalcemia, which refers to a calcium level above 10.5 mg/dL. Consequences of this are heart rhythm diseases, and extra production of gastrin that causes peptic ulcers.
Parathyroid transplant is recommended if the parathyroid glands are removed accidentally during a thyroidectomy. They are autotransplanted to the nearby sternocleidomastoid muscle, or to the forearm so that another intervention would be less risky. A biopsy is recommended to be sure that the transplanted tissue is parathyroid and not a lymph node with metastatic disease. During parathyroid surgery if there is an adenoma the transplantation is not recommended; instead it is cryopreserved for research an if there is a recurrent hypoparathyroidism.
The surgery is indicated for all patients that are diagnosed with hyperparathyroidism with or without symptoms, especially in younger patients. In some cases the surgery works as therapy for nephrolithiasis, bone changes, and neuromuscular symptoms.
=== Procedure ===
Parathyroidectomy, or the removal of the parathyroids, requires general anesthesia. The patient is intubated and placed in a supine position with the chin at fifteen degrees by elevating the shoulders to permit the extension of the neck. Then a transverse cut is made above the sternal notch. The transversal thyroid lobe is reached and is rotated up to discover and ligate the thyroid vein to separate the thyroid artery. Exploration must be done meticulously to search for adenomas. If an adenoma is identified, exploration must be continued because it is common that more than one neoplasia appears. Before the procedure, the glands are marked to make them more visible during the procedure. If one of them cannot be found, the procedure is to remove a complete thyroid lobe on the side where the gland is not found to avoid an intrathyroid parathyroid gland. After exploration, if there is one, two or even three parathyroid glands affected, they are removed and the other one left in situ. If all four glands are affected then three and a half are removed. The remaining half is marked with a suture and the surgeon must be sure that the blood supply will not be compromised. A total parathyroidectomy or auto transplantation to the forearm of the remaining half gland, may also be recommended.
=== Parathyroid auto transplantation ===
Parathyroid auto transplantation is part of the treatment when a patient has hyperparathyroidism and three or four parathyroid glands were already removed, but during the surgery one of the glands (in the case of the removal of three) is relocated at another part of the body to make, the procedure less risky another procedure. In the case of complete parathyroidectomy, a half gland is cryopreserved. In case the patient suffers hypoparathyroidism. If this happens the extracted parathyroid is relocated to another place of the body for example the forearm. Parathyroid auto transplantation begins with parathyroid tissue extraction, which must be preserved into a cold isotonic solution until the patient needs it. Research has shown that parathyroid tissue can function at subcutaneous level until the transplantation. If this is not possible, the most common procedure is to create a small pocket of muscle, tissue at least 2 cm deep by separating the muscular fibers. Then the parathyroid tissue is placed into and closed by suturing the area. After the extraction the tissue might be processed at the laboratory, as soon as possible. Once at the laboratory the tissue sample is placed at a frozen petri dish where it is cut into small pieces (approximately 1–2 mm). The small pieces are placed into test tubes and filled with a solution in three parts one at 20% of autologous serum (about 0.6 ml) and the other part of isotonic solution at 20% (about 0.6 ml) then a solution of 2 ml of polypropylene and mixed gently. Then is placed into a container at -70 °C for a night then finally the container passes through the phase of liquid or vapor nitrogen immersion and is kept there until needed. When it is needed the sample is taken out of the nitrogen and placed into a bath of water at 37 °C until the ice is melted almost completely except for the samples core. Then 0.5 ml of the melted solution is removed and replaced for fresh isotonic solution.
== Related conditions ==
Hypoparathyroidism
Pseudohypoparathyroidism
Pseudopseudohypoparathyroidism
Disorders of the parathyroid hormone receptor have been associated with Jansen's metaphyseal chondroplasia and Blomstrand's chondroplasia
Parathyroid carcinoma
== References == | Wikipedia/Parathyroid_disease |
Abetalipoproteinemia (also known as: Bassen–Kornzweig syndrome, microsomal triglyceride transfer protein deficiency disease, MTP deficiency, and betalipoprotein deficiency syndrome) is a disorder characterized by abnormal absorption of fat and fat-soluble vitamins from food. It is caused by a mutation in microsomal triglyceride transfer protein resulting in deficiencies in the apolipoproteins B-48 and B-100, which are used in the synthesis and exportation of chylomicrons and VLDL respectively. It is not to be confused with familial dysbetalipoproteinemia.
It is a rare autosomal recessive disorder.
== Presentation ==
=== Symptoms ===
Initial symptoms usually appear in infancy, including:
Failure to thrive (i.e. failure to grow in infancy)
Steatorrhea (i.e. fatty, pale stools)
Frothy stools
Foul smelling stools
Protruding abdomen
The rate of occurrence of additional symptoms later in life varies and increases with age. These may include:
Intellectual disability/developmental delay
Ataxia (problems with balance and movement)
Muscle weakness
Slurred speech (dysarthria)
Lordosis (curved lower back) and kyphoscoliosis (curved upper back)
Progressive decreased vision
Reflex and proprioception problems
=== Signs ===
Acanthocytosis
Retinitis pigmentosa
Low blood cholesterol
=== Features ===
Abetalipoproteinemia affects the absorption of dietary fats, cholesterol, and certain vitamins. People affected by this disorder are not able to make certain lipoproteins, which are molecules that consist of proteins combined with cholesterol and particular fats called triglycerides. This leads to a multiple vitamin deficiency, affecting the fat-soluble vitamin A, vitamin D, vitamin E, and vitamin K. However, many of the observed effects are due to vitamin E deficiency in particular.
Signs and symptoms vary and present differently from person to person. In general, 80–99% of individuals exhibit malabsorption of fats and fat-soluble vitamins. Approximately 30–79% of people with the disease display symptoms related to abnormality of the retinal pigmentation, ataxia, muscular hypotonia or reduced tendon reflexes.
The signs and symptoms of abetalipoproteinemia appear in the first few months of life (because pancreatic lipase is not active in this period). They can include failure to gain weight and grow at the expected rate (failure to thrive); diarrhea; abnormal spiny red blood cells (acanthocytosis); and fatty, foul-smelling stools (steatorrhea). The stool may contain large chunks of fat and/or blood. Infants often present with gastrointestinal problems caused by the poor fat absorption, which also contributes to steatorrhea. Other features of this disorder may develop later in childhood and often impair the function of the nervous system. They can include poor muscle coordination, difficulty with balance and movement (ataxia), and progressive degeneration of the retina (the light-sensitive layer in the posterior eye) that can progress to near-blindness (due to deficiency of vitamin A, retinol). Adults in their thirties or forties may have increasing difficulty with balance and walking. Many of the signs and symptoms of abetalipoproteinemia result from a severe vitamin deficiency, especially vitamin E deficiency, which typically results in eye problems with degeneration of the spinocerebellar and dorsal column tracts.
== Genetics ==
Mutations in the microsomal triglyceride transfer protein gene (MTTP) have been associated with this condition (apolipoprotein B deficiency, a related condition, is associated with deficiencies of apolipoprotein B).
The MTTP gene provides instructions for making a protein called microsomal triglyceride transfer protein, which is essential for creating beta-lipoproteins. These lipoproteins are both necessary for the absorption of fats, cholesterol, and fat-soluble vitamins from the diet and necessary for the efficient transport of these substances in the bloodstream. Most of the mutations in this gene lead to the production of an abnormally short microsomal triglyceride transfer protein, which prevents the normal creation of beta-lipoproteins in the body. MTTP-associated mutations are inherited in an autosomal recessive pattern, which means both copies of the gene must be faulty to produce the disease.
The disease is extremely rare with approximately 100 reported cases worldwide since it was first identified by doctors Bassen and Kornzweig in 1950.
== Mechanism ==
Abetalipoproteinemia effects multiple physiological systems, the two most common being the nervous and the skeletal. Disruption of nervous function includes loss of reflexes, speech impairments, tremors or involuntary motor tics, or peripheral neuropathy (damage to the nerves outside of the brain and spinal cord). Peripheral neuropathy causes loss of sensation, weakness or numbness and pain in the extremities through stabbing, burning, or tingling sensations. Skeletal system developments often include lordosis, kyphoscoliosis, or pes cavus. Individuals often have abnormal bleeding due to the difficulty of forming clots.
Additional complications of the diseases if not properly treated include blindness, mental deterioration, ataxia, loss of peripheral nerve function.
== Diagnosis ==
The initial workup of Abetalipoproteinemia typically consists of stool sampling, a peripheral blood smear, and a fasting lipid panel, though these tests are not confirmatory. As the disease is rare, though a genetics test is necessary for diagnosis, it is generally not done initially. However, prenatal testing may be available for pregnancies identified to be at an increased risk (if both parents are unaffected carrier or one parent is affected and the other in a carrier).{}
Acanthocytes are seen on blood smear. Since there is no or little assimilation of chylomicrons, their levels in plasma remains low.
The inability to absorb fat in the ileum will result in steatorrhea, or fat in the stool. As a result, this can be clinically diagnosed when foul-smelling stool is encountered. Low levels of plasma chylomicron are also characteristic.
There is an absence of apolipoprotein B. On intestinal biopsy, vacuoles containing lipids are seen in enterocytes. This disorder may also result in fat accumulation in the liver (hepatic steatosis). Because the epithelial cells of the bowel lack the ability to place fats into chylomicrons, lipids accumulate at the surface of the cell, crowding the functions that are necessary for proper absorption.
Multiple related disorders present with similar symptoms as abetalipoproteinemia that can provide a useful diagnosis through comparisons. Some of those disorders are:
== Treatment ==
Treatment normally consists of rigorous dieting, involving massive amounts of vitamin E. High-dose Vitamin E therapy helps the body restore and produce lipoproteins, which people with abetalipoproteinemia usually lack. Vitamin E also helps keep skin and eyes healthy; studies show that many affected males will have vision problems later on in life. Common additional supplementation includes medium chain fatty acids and linoleic acid. Treatments also aim to slow the progression of nervous system abnormalities. Developmental coordination disorder and muscle weakness are usually treated with physiotherapy or occupational therapy. Dietary restriction of triglycerides has also been useful. Nutritionists often work with medical professionals to design appropriate dietary treatments for their patients.
== Prognosis ==
Prognosis can vary heavily based on the severity of the neurological dysfunction. If treatment is initiated early in disease the neurologic sequelae may be reversed and further deterioration can be prevented. Long-term outlook is reasonably good for most people when diagnosed and treated early. A case study presented a female patient diagnosed at the age of 11. Despite the relatively late diagnosis, the patient married and at the age of 34, gave birth to a full-term healthy infant. Her medication included vitamin K 10 mg twice a week, beta-carotene 40,000 IU daily, vitamin A 10,000 IU daily, vitamin E 400 IU daily, vitamins B6 and B12, calcium, magnesium and eye drops.
Prolonged vitamin deficiencies can further compromise health. Specifically, a prolonged vitamin E deficiency can lead to the development of limiting ataxia and gait disturbances. Some individuals may develop retinal degeneration and blindness. If left untreated, the condition may lead to death.'
== Current research ==
A primary goal of abetalipoproteinemia research is to supply the fat-soluble vitamins the body lacks in the disease. Previous research considered the short-term use of intravenous infusion of vitamins A and E. The goal was to determine whether these infusions would delay or counteract the symptoms in patients. No results were posted.
More recent research has focused on different ways to supply the patient with vitamin E. In 2018, the Journal of Lipid Research published a study testing alternative forms of vitamin E absorption. Currently, vitamin E is most often supplemented in the fat-soluble form vitamin E acetate. Due to fat malabsorption, the intended supplementation is considerably compromised. Two different forms were tested: vitamin E tocofersolan and α-tocopherol acetate. The study concluded that plasma bioavailabilities were extremely low (2.8% and 3.1%, respectively). Additionally, plasma concentrations of tocopherol were not significantly different in patients.
This study provides new insight in vitamin E supplementation and suggests further research is needed with different forms of vitamin E as possible treatment options to abetalipoproteinemia.
Currently, there is a clinical study recruiting abetalipoproteinemia patients to study inherited retinal degenerative disease. There is also a second clinical study, currently under recruitment, to investigate the consequences of deficiencies in lipophilic nutrients in this disease, such as lutein and carotenes, on retinal macular function.
== References ==
== External links ==
Abetalipoproteinemia at NLM Genetics Home Reference | Wikipedia/Abetalipoproteinemia |
Pancreatic beta cell function (synonyms Gβ or, if calculated from fasting concentrations of insulin and glucose, HOMA-Beta or SPINA-GBeta) is one of the preconditions of euglycaemia, i.e. normal blood sugar regulation. It is defined as insulin secretory capacity, i.e. the maximum amount of insulin to be produced by beta cells in a given unit of time.
== Physiology and pathophysiology ==
Beta cells play a paramount role in glucose homeostasis. Progressive loss of insulin secretory capacity is a key defect associated with the transition from a healthy glycaemic state to hyperglycaemia, characteristic of untreated diabetes mellitus. In type 1 diabetes mellitus and pancreatogenic diabetes beta cell destruction is a primary event from the perspective of the feedback loop. In type 2 diabetes beta cell dysfunction is an essential constituent as well, but subsequent to the development of insulin resistance. Other mechanisms, including lipotoxicity, amyloid deposition, oxidative stress, mitochondrial dysfunction, ER stress and inflammation may be involved as well. The beta cell loss in type 2 diabetes is mainly caused by reduced beta cell number rather than size. Hyperglycaemia becomes clinically significant once insulin over-secretion can no longer compensate for the degree of insulin resistance.
It remains an unsolved question if impaired pancreatic beta cell function or hypersecretion of insulin represent the primary event in the pathogenesis of type 2 diabetes. Both scenarios may be cause and consequence, and it has been postulated that the direction of causality depends on the respective subtype of diabetes. Therefore, they may be part of a complex feedback loop involving glucose toxicity leading to a biphasic response, thereby preventing neoplastic effects of dynamical compensation by mutant takeover.
== Assessing beta cell function ==
Measuring beta-cell function is a challenge, since insulin secretory capacity cannot be readily assessed. Therefore, indirect methods of measurement have been developed. They include dynamic and static function tests.
=== Single-point measurements ===
One-time measurements of certain hormones or metabolites provide some limited information. Examples are:
Fasting glucose concentration
Fasting or random C-peptide concentration
Although single-point measurements have the benefit of being convenient and inexpensive, they are generally not regareded as sufficiently informative for early diagnosis of impaired glucose homeostasis or early-stage type 1 diabetes.
=== Dynamic function tests ===
Dynamic function tests for beta-cell function include:
Oral glucose tolerance testing (OGTT)
Intravenous glucose tolerance tests (IVGTT)
Meal tolerance tests
Hyperglycaemic clamp
=== Static function tests ===
Static function tests for the assessment of beta-cell function comprise:
Insulin-glucose ratio
Amended insulin-glucose ratio
HOMA-Beta
SPINA-GBeta
== Challenges and limits ==
Measuring beta-cell function requires the rate of secretion to be interpreted in relation to the prevailing glucose concentration. Therefore, a mathematical model is needed that links the time courses of insulin secretion and glucose concentration as a mechanistic causal relationship.
Additionally, beta-cell function has to be interpreted in light of the prevailing insulin sensitivity. This is necessary since the beta cell mass is adjusted as required by dynamical compensation, giving rise to a hyperbolic relationship between insulin sensitivity and beta cell function. In the state of insulin resistance beta cells proliferate and their secretory capacity subsequently rises. One possibility to address this relation is to resort to a normalization of beta cell function based on a disposition metric. The disposition index, calculated as product of insulin sensitivity and beta cell function, is assumed to be a constant during the development of insulin resistance. It is generally assumed that the glucose tolerance of an individual is related to the disposition index. In this model, different values of glucose tolerance are represented by different hyperbolas, so that within one hyperbola the product of insulin sensitivity and beta cell function remains a constant.
In summary, to provide a meaningful mechanistic explanation of insulin-glucose homeostasis, beta cell function and insulin sensitivity have to be assessed simultaneously and it is necessary to interpret all observations in the context of insulin sensitivity or resistance.
== See also ==
== References == | Wikipedia/Pancreatic_beta_cell_function |
A pituitary disease is a disorder primarily affecting the pituitary gland.
== Table ==
The main disorders involving the pituitary gland are:
Overproduction or underproduction of a pituitary hormone will affect the respective end-organ. For example, insufficient production (hyposecretion) of thyroid stimulating hormone (TSH) in the pituitary gland will cause hypothyroidism, while overproduction (hypersecretion) of TSH will cause hyperthyroidism. Thyroidisms caused by the pituitary gland are less common though, accounting for less than 10% of all hypothyroidism cases and much less than 1% of hyperthyroidism cases.
== See also ==
Hypophysitis, inflammation of the pituitary gland.
Autoimmune hypophysitis (or lymphocytic hypophysitis), inflammation of the pituitary gland due to autoimmunity.
Nelson's syndrome, may occur after surgical removal of both adrenal glands, an out-dated method of treating Cushing's disease.
Pituitary tumour, a tumor of the pituitary gland.
Pituitary adenoma, a noncancerous tumor of the pituitary gland.
Pituicytoma, a rare brain tumor.
Pituitary apoplexy, bleeding into or impaired blood supply of the pituitary gland.
== References ==
== External links == | Wikipedia/Pituitary_disease |
Ovarian diseases refer to diseases or disorders of the ovary.
These can be classified as endocrine disorders or as a disorders of the reproductive system.
If the egg fails to release from the follicle in the ovary an ovarian cyst may form. Small ovarian cysts are common in healthy women. Some women have more follicles than usual (polycystic ovary syndrome), which inhibits the follicles to grow normally and this will cause cycle irregularities.
Various types of ovarian diseases exist. Some of the ovarian diseases or disorders include: endometriosis, ovarian cysts, ovarian epithelial cancer, ovarian germ cell tumors, ovarian low malignant potential tumors, and polycystic ovary syndrome (PCOS).
== Endometriosis ==
Endometriosis is a condition in which tissues lining the uterus (endometrial stroma and gland) grows abnormally beyond the uterus that may become quite painful. In simpler terms, it means that the tissue lining the uterus develops in different parts outside of it. It can be either at ovary, fallopian tubes, or peritoneal spaces.
There is no single cause of endometriosis.
Symptoms:
Menstrual cramps, heavy menstrual bleeding, bowel or urinary problems, nausea, vomiting, blood with stools, painful intercourse, fatigues, spotting or bleeding between periods.
Treatment:
Surgery at extreme situations
Hormonal treatments using birth controls.
Healthier lifestyle.
== Ovarian cysts ==
It is common for many women to develop a cyst in their lifetime. At times, these can go unnoticed without pain or visible symptoms. A cyst may develop in either of the ovaries that are responsible for producing hormones and carrying eggs. Ovarian cysts can be of various types, such as dermoid cysts, endometrioma cysts, and the functional cyst.
Symptoms:
Abdominal bloating or swelling.
Painful bowel movement.
Pelvic pain before or after the menstrual cycle.
Painful intercourse.
Pain in the lower back or thighs.
Breast tenderness.
Nausea and vomiting.
Fever.
Rapid breathing.
Faintness or dizziness.
Sharp pelvic pain.
Treatment:
Taking of oral contraceptives or birth control pills as prescribed by the doctor.
Laparoscopy: Surgery to remove the cyst.
Hysterectomy in case the cyst is cancerous.
== Ovarian epithelial cancer ==
It is one of the common ovarian cancers that affect women worldwide. It develops outside the ovaries and ultimately spreads outside and can affect other organs.
Causes:
It may happen if there is a family medical history of breast cancer, colon cancer, rectal cancer or uterine cancer, or Lynch syndrome. If someone is under Estrogen Replacement Therapy for a long time. Smoking habits may also lead to the same. [1]
Treatment:
Surgery to remove the uterus.
Chemotherapy.
== Ovarian germ cell tumors ==
Ovarian germ cell tumors are common among teenagers and young women. It is a growth in the ovaries. [2]
Causes:
Though the exact causes are not known, it may happen owing to certain birth defects affecting the genitals, nervous system or the urinary tract. There may be genetic conditions affecting the sex chromosomes that result in this kind of tumors as well.
Symptoms
Belly swelling.
Pain or pressure in the belly.
Swollen abdomen.
Vaginal bleeding after menopause.
Treatment:
Surgery to remove the tumor, or the Fallopian tubes or one or more ovaries.
Hysterectomy.
Chemotherapy in case the tumor is cancerous.
Radiation therapy to prevent the cancerous cells from developing.
== Ovarian low malignant potential tumors ==
The tumor forms in the ovaries and gradually spreads to the outside of ovary. This mostly affects younger women and also hinders the reproductive system.
Causes:
Causes are debatable and these may occur to both pregnant women and women who do not opt for pregnancy
Symptoms:
Abdominal pain or swelling.
Bowel problems or constipation.
Treatment:
Depending on the size of the tumor, choice of pregnancy, the spreading of the tumor, age and choices, removing the affected ovary is the most common treatment. In rare situations, the tumor is taken out of the ovary. Also, hysterectomy can be an option.
== Polycystic ovary syndrome ==
This is a hormonal imbalance, where androgens (also called male hormones) are elevated.
The increased level of androgens may result in irregular menstrual cycle and diabetes and heart problem in the long run. It also affects the body in various ways like problem getting pregnant, sleep apnea, depression and anxiety, can enhance the risk of endometrial cancer.
Symptoms:
Irregular periods.
Heavy bleeding during periods.
Excess hair growth on face and other parts of the body like chest, back, belly.
Acne.
Weight gain.
Darkening of skin.
Headaches.
Treatment:
Oral contraceptives to promote regular periods
Healthier lifestyle.
Other conditions include:
Ovarian cancer
Luteoma
Hypogonadism
Hyperthecosis
== References ==
== External links == | Wikipedia/Ovarian_disease |
Tangier disease or hypoalphalipoproteinemia is an extremely rare inherited disorder characterized by a severe reduction in the amount of high density lipoprotein (HDL), often referred to as "good cholesterol", in the bloodstream. Worldwide, approximately 100 cases have even been identified.
The disorder was originally discovered on Tangier Island off the coast of Virginia, but has now been identified in people from many countries.
== Signs and symptoms ==
Individuals that are homozygotes for Tangier's disease develop various cholesterol ester depositions. These are especially visible in the tonsils, as they may appear yellow/orange. The cholesterol esters may also be found in lymph nodes, bone marrow, the liver and spleen.
Due to the cholesterol ester depositions the tonsils may be enlarged. Hepatosplenomegaly (enlarged liver and spleen) is common.
Neuropathy and cardiovascular disease are the most devastating developments caused by Tangier's disease.
== Genetics ==
Mutations to chromosome 9q31 lead to a defective ABCA1 transporter. These mutations prevent the ABCA1 protein from effectively transporting cholesterol and phospholipids out of cells for pickup by ApoA1 in the bloodstream. This inability to transport cholesterol out of cells leads to a deficiency of high-density lipoproteins in the circulation, which is a risk factor for coronary artery disease. Additionally, the buildup of cholesterol in cells can be toxic, causing cell death or impaired function. These combined factors lead to the signs and symptoms of Tangier disease.
This condition is inherited in an autosomal recessive pattern, meaning that for the phenotype to appear, two copies of the gene must be present in the genotype. Most often, the parents of an individual with an autosomal recessive disorder are carriers of one copy of the altered gene but do not show signs and symptoms of the disorder.
== Diagnosis ==
Tangier disease results in familial high-density lipoprotein deficiency. High-density lipoproteins are created when a protein in the bloodstream, Apolipoprotein A1 (apoA1), combines with cholesterol and phospholipids. The cholesterol and phospholipids used to form HDL originate from inside cells but are transported out of the cell into the blood via the ABCA1 transporter. People with Tangier disease have defective ABCA1 transporters resulting in a greatly reduced ability to transport cholesterol out of their cells, which leads to an accumulation of cholesterol and phospholipids in many body tissues, which can cause them to increase in size. Reduced blood levels of high-density lipoproteins is sometimes described as hypoalphalipoproteinemia.
People affected by this condition also have slightly elevated amounts of fat in the blood (mild hypertriglyceridemia) and disturbances in nerve function (neuropathy). The tonsils are visibly affected by this disorder; they frequently appear orange or yellow and are extremely enlarged. Affected people often develop premature atherosclerosis, which is characterized by fatty deposits and scar-like tissue lining the arteries. Other signs of this condition may include an enlarged spleen (splenomegaly), an enlarged liver (hepatomegaly), clouding of the cornea, and early-onset cardiovascular disease.
== Treatment ==
There are drugs that can increase serum HDL such as niacin or gemfibrozil. While these drugs are useful for patients with hyperlipidemia, Tangier's disease patients do not benefit from these pharmaceutical interventions.
Therefore, the only current treatment modality for Tangier's disease is diet modification. A low-fat diet can reduce some of the symptoms, especially those involving neuropathies.
== History ==
In 1959, a five-year-old patient named Teddy Laird from Tangier Island, Virginia, presented with strikingly large and yellow-orange tonsils which were removed by armed forces physicians. After initial diagnosis with Niemann-Pick he was transferred to Dr. Louis Avioli at the National Cancer Institute. Donald Fredrickson, then head of the Molecular Disease Branch, became aware of the case and had a hunch that the original diagnosis was incorrect. In 1960, he traveled with Dr. Avioli to Tangier Island for further investigation. After finding the same symptom in Teddy's sister, an investigation revealed an extremely high number of foam cells (cholesterol ester-laden macrophages) in not only the tonsils, but also in a wide range of tissues, including the bone marrow and spleen. During a second trip to the island, they found that the family had very low levels of HDL cholesterol, suggesting a genetic basis of the disease.
== References ==
== External links ==
Tangier disease at NLM Genetics Home Reference | Wikipedia/Tangier_disease |
Chylomicron retention disease is a disorder of fat absorption. It is associated with SAR1B. Mutations in SAR1B prevent the release of chylomicrons in the circulation which leads to nutritional and developmental problems. It is a rare autosomal recessive disorder with around 40 cases reported worldwide. Since the disease allele is recessive, parents usually do not show symptoms.
Without functional chylomicrons, certain fat-soluble vitamins such as vitamin D and vitamin E cannot be absorbed. Chylomicrons have a crucial role in fat absorption and transport, thus a deficiency in chylomicron functioning reduces available levels of dietary fats and fat-soluble vitamins.
== Signs and symptoms ==
Physical symptoms of CMRD involving the development and function of the gastrointestinal tract and nervous system typically manifest between infancy and adolescence. The symptoms of CmRD are similar to the physical symptoms of malnutrition, as the disease arises due to the poor absorption of lipids and fat-soluble nutrients such as vitamin E. For this reason, the disease is likely to be underdiagnosed by physicians. Fat-soluble nutrients are essential for growth, development, and normal bodily function. Vitamin E deficiency is especially serious, as the vitamin is necessary for proper neurological function and development. Without Vitamin E, neurons cannot operate correctly and signals from the brain are weakened. This leads to reduced muscle development and reduced muscle contraction.
Symptoms that manifest in the GI tract are likely to be a consequence of both reduced absorption of fats and physiological stress imposed on enterocytes that can not shuttle fats into circulation. Additional symptoms that occur throughout the body can be attributed to the lack of sufficient lipid sources.
Chronic Malabsorptive Diarrhea- Diarrhea that results from the poor absorption of fats
Steatorrhea- Abnormal stools, often foul smelling, due to the increased presence of undigested fats
Vomiting
Vitamin E deficiency- Low levels of Vitamin E due to the malabsorption of fats in the diet, causes poor brain, muscle, and eye development.
Cardiomyopathy- A class of diseases that affects heart muscle, causing shortness of breath, tiredness, and swelling of the legs
Slowed Growth
Failure to thrive- Insufficient weight gain, or drastic levels of weight loss in children
Hypocholesterolemia- Low blood cholesterol levels
Hepatic Steatosis (Fatty Liver)- Excessive fat buildup in the liver, a result of the abnormal lipid panels of CMRD patients
Hyporeflexia- Absent or low levels of muscle reflexes
Amyotrophy- Muscle tissue "wasting," the loss of muscle tissue
== Genetics ==
The Sar1B GTPase is an enzyme located in epithelial cells of the gastrointestinal tract. These proteins are critical for release of chylomicrons in the body.
Chylomicron retention disease is an autosomal homozygous recessive disorder arising from mutations in the gene encoding the Sar1B GTPase. The Sar1B gene is located at position 5q31.1 in the fifth chromosome and is composed of eight exons. Alternative splicing of the second exon results into two different splice isoforms for the Sar1B transcript RNA. In CMRD, a mutation of this genomic sequence affects the Sar1B enzyme's ability to interact with Guanine Exchange Factors (GEFs) and GTP-Activating Proteins (GAPs). The mutation of exon 6 of the sequence can eliminate the critical chain that is responsible for recognizing guanine. This strips the GTPase of its capability to hydrolyze GTP, its hallmark trait. This overall affects the ability of Sar1B GTPase to control chylomicron release. A third mutant allele containing a missense mutation has also been reported to cause CMRD. All three of these alleles display recessive inheritance, suggesting that they loss-of-function mutations cause the symptoms of CMRD.
== Physiology ==
During digestion, fats, or triglycerides(TGs), are enzymatically catabolized by lipases into two fatty acids and a monoglyceride molecule. Those components are then transported across the enterocyte membrane as micelles and reformed into triglycerides once across the membrane.
Once transported to the ER the triglycerides are incorporated into pre-chylomicrons which are made up of TGs, cholesterol, and phospholipids. The pre-chylomicrons are then packaged into PCTV to be transported to the Golgi apparatus for additional maturation prior to exocytosis into the lymphatic system. From the lymphatic system, they enter general circulation, where they are produced in various forms that can be absorbed by bodily tissues and metabolized or stored by adipose tissue.
Before the PCTV leaves the ER, it is incorporated into a COPII coatomer of five proteins.
The PCTV undergoes a similar mechanism for budding as normal COPII transport vesicles. Though PCTV does not require COPII coatomer proteins for budding from the ER, association with the coatomer is necessary for docking and fusion with the cis-golgi network. In chylomicron retention disease, the PCTV vesicles are competent for budding from the ER membrane but are defective for fusion with the cis-golgi body.
Sar1B is a GTPase and one of the five proteins of the COPll coatomer. A mutation in the sar1B gene and subsequently the sar1B protein are the common genetic origins of chylomicron retention disorder. Without the fully functional sar1B protein, the COPll coatomer proteins engulf pre-chylomicrons exiting the ER but are unable to disassemble upon arrival at the cis-Golgi, preventing membrane fusion with this organelle.
== Diagnosis ==
There is no medical consensus on methodology of diagnosis for CMRD itself. There are, however, protocols used to diagnose the family of genetic disorders to which CMRD belongs. Assessment of hypobetalipoproteinemia relies chiefly on blood lipid analysis following a 12-hr fasting period. Lipids analyzed are LDL (low-density lipoproteins), triglyceride, and apolipoprotein B levels. A patient could be diagnosed with CMRD should they lack sufficient apolipoprotein B levels in the blood. Furthermore, a minimally invasive endoscopic procedure can be used to examine the bowel. A pale intestine can also be indicative of CMRD.
Because patient outcomes rely on early diagnosis, it is recommended that candidates for the disorder should receive lipid panel testing prior to 6 months of age. In patients with only CMRD, lipid panels are expected to display normal triglyceride levels, but LDL and HDL levels may >50% below normal range. The test should also reveal low levels of Vitamin E and heightened levels of creatine kinase in the blood.
== Treatment ==
It is recommended that patients with CMRD follow a strict low-fat diet in addition to fat-soluble vitamin supplementation. The fat soluble vitamins are A, D, E, and K. A combination of vitamin A and vitamin E are effective for combating ophthalmologic complications. When vitamin D is administered early, it aids in preventing osteopenia. People with CMRD are at an increased risk for essential fatty acid deficiency, so dietary counseling is required to maintain the low-fat diet, while attaining sufficient caloric intake and essential fatty acid intake.
=== Proposed Treatment Plan ===
Early diagnosis is important for improving patient outcomes. Patients with delayed diagnoses experienced decreased growth compared to those diagnosed earlier in life. Long-term treatment plans center around dietary management, but because long term results have not been documented due to a lack of thorough research, careful monitoring of the disease is required. Yearly check-ups are recommended to track the growth of children affected by the disease.
Evaluations tracking liver function that involve the use of ultrasounds to monitor liver growth, are recommended to be administered every three years. At about ten years of age (pre-puberty), neurological and ophthalmological exams may be required every three years to track muscle and eye activity/strength. In adulthood, past eighteen years of age, echocardiograms are recommended to track heart activity. Thorough and vigorous testing warrant themselves to the treatment of a disease of which we know so little.
== Prognosis ==
As of March 2020, only 50 cases of CMRD have been documented in the medical literature. This small number speaks to the rarity of the disease as well as the lack of thorough research and documentation. As a result, the full course of the disease, life expectancy, and mortality are also poorly documented.
Clinical manifestation of CMRD symptoms begin during infancy and early childhood but may go undetected due to the non-specific symptoms associated with the disease. Many of these symptoms can be attributed to malnutrition and nonspecific postnatal diarrhea, confounding early diagnosis. Careful regulation of diet and nutrition are required for management of CMRD since the disease results from the poor absorption of nutrients from food.
== History ==
Charlotte Anderson first published a description of the disorder in 1961, where she observed a seven month old girl who developed intestinal mucosa filled with fat droplets. In 2003, Jones and colleagues identified mutations in the SAR1B gene, which transcripts the SAR1B protein involved in COPII transport and proposed this was the molecular defect of the disorder. To present day, 16 mutations of the SAR1B gene have been discovered. This disease is rare, with only 55 cases diagnosed worldwide.
== References == | Wikipedia/Chylomicron_retention_disease |
Hypothalamic disease is a disorder presenting primarily in the hypothalamus, which may be caused by damage resulting from malnutrition, including anorexia and bulimia eating disorders, genetic disorders, radiation, surgery, head trauma, lesion, tumour or other physical injury to the hypothalamus. The hypothalamus is the control center for several endocrine functions. Endocrine systems controlled by the hypothalamus are regulated by antidiuretic hormone (ADH), corticotropin-releasing hormone, gonadotropin-releasing hormone, growth hormone-releasing hormone, oxytocin, all of which are secreted by the hypothalamus. Damage to the hypothalamus may impact any of these hormones and the related endocrine systems. Many of these hypothalamic hormones act on the pituitary gland. Hypothalamic disease therefore affects the functioning of the pituitary and the target organs controlled by the pituitary, including the adrenal glands, ovaries and testes, and the thyroid gland.
Numerous dysfunctions manifest as a result of hypothalamic disease. Damage to the hypothalamus may cause disruptions in body temperature regulation, growth, weight, sodium and water balance, milk production, emotions, and sleep cycles. Hypopituitarism, neurogenic diabetes insipidus, tertiary hypothyroidism, and developmental disorders are examples of precipitating conditions caused by hypothalamic disease.
== Hypopituitarism ==
The hypothalamus and pituitary gland are tightly integrated. Damage to the hypothalamus will impact the responsiveness and normal functioning of the pituitary. Hypothalamic disease may cause insufficient or inhibited signalling to the pituitary leading to deficiencies of one or more of the following hormones: thyroid-stimulating hormone, adrenocorticotropic hormone, beta-endorphin, luteinizing hormone, follicle-stimulating hormone, and melanocyte–stimulating hormones. Treatment for hypopituitarism involves hormone replacement therapy.
== Neurogenic diabetes insipidus ==
Neurogenic diabetes insipidus may occur due to low levels of ADH production from the hypothalamus. Insufficient levels of ADH result in increased thirst and urine output, and prolonged excessive urine excretion increases the risk of dehydration.
== Tertiary hypothyroidism ==
The thyroid gland is an auxiliary organ to the hypothalamus-pituitary system. Thyrotropin-releasing hormone (TRH) produced by the hypothalamus signals to the pituitary to release thyroid-stimulating hormone (TSH), which then stimulates the thyroid to secrete T4 and T3 thyroid hormones. Secondary hypothyroidism occurs when TSH secretion from the pituitary is impaired, whereas tertiary hypothyroidism is the deficiency or inhibition of TRH.
Thyroid hormones are responsible for metabolic activity. Insufficient production of the thyroid hormones result in suppressed metabolic activity and weight gain. Hypothalamic disease may therefore have implications for obesity.
== Developmental disorders ==
Growth hormone-releasing hormone (GHRH) is another releasing factor secreted by the hypothalamus. GHRH stimulates the pituitary gland to secrete growth hormone (GH), which has various effects on body growth and sexual development. Insufficient GH production may cause poor somatic growth, precocious puberty or gonadotropin deficiency, failure to initiate or complete puberty, and is often associated with rapid weight gain, low T4, and low levels of sex hormones.
== Sleep disorders ==
Non-24-hour sleep-wake syndrome, a disabling condition in which one's sleep/wake cycle is longer, or rarely, shorter, than the standard 24 hours, is thought to involve or be caused by, at least in some cases, an abnormal functioning of the suprachiasmatic nucleus (SCN) in the hypothalamus.
== References ==
== External links == | Wikipedia/Hypothalamic_disease |
Urbach–Wiethe disease is a very rare recessive genetic disorder, with approximately 400 reported cases since its discovery. It was first officially reported in 1929 by Erich Urbach and Camillo Wiethe, although cases may be recognized dating back as early as 1908.
The symptoms of the disease vary greatly from individual to individual. They may include a hoarse voice, lesions and scarring on the skin, easily damaged skin with poor wound healing, dry, wrinkly skin, and beading of the papules around the eyelids. All of these are results of a general thickening of the skin and mucous membranes. In some cases there is also a hardening of brain tissue in the medial temporal lobes, which can lead to epilepsy and neuropsychiatric abnormalities. The disease is typically not life-threatening and patients do not show a decreased life span.
Because Urbach–Wiethe disease is an autosomal recessive condition individuals can be carriers of the disease but show no symptoms. The disease is caused by loss-of-function mutations to chromosome 1 at 1q21, the extracellular matrix protein 1 (ECM1) gene. The dermatological symptoms are caused by a buildup of a hyaline material in the dermis and the thickening of the basement membranes in the skin. Urbach–Wiethe disease is typically diagnosed by its clinical dermatological manifestations, particularly the beaded papules on the eyelids. The discovery of the mutations within the ECM1 gene has allowed the use of genetic testing to confirm an initial clinical diagnosis. Periodic acid-Schiff (PAS) and immunohistochemical staining may also be used for diagnosis.
Currently, there is no cure for Urbach–Wiethe disease although there are ways to individually treat many of its symptoms. The discovery of the mutations of the ECM1 gene has opened the possibility of gene therapy or a recombinant ECM1 protein for Urbach–Wiethe disease treatment, but neither of these options are currently available. Some researchers are examining patients with Urbach–Wiethe disease to learn more about other conditions that exhibit similar neurological symptoms, such as autism.
== Symptoms and signs ==
Urbach–Wiethe disease is characterized by both neurological and dermatological symptoms.
=== Dermatological ===
Although symptoms can vary greatly between affected individuals, even those within the same family, symptoms normally begin in infancy and are typically a result of thickening skin and mucous membranes. The first symptom is often a weak cry or a hoarse voice due to a thickening of the vocal cords. The hoarse voice can be one of the most striking clinical manifestations of the disease. Lesions and scars also appear on the skin, usually the face and the distal parts of the limbs. This is often the result of poor wound healing and the scarring continues to increase as the patient ages, leaving the skin with a waxy appearance. Skin may be easily damaged as a result of only a minor trauma or injury, leaving many blisters and additional scars. The skin is also usually very dry and wrinkly. White or yellow infiltrates form on the lips, buccal mucosa, tonsils, uvula, epiglottis and frenulum of the tongue. This can lead to upper respiratory tract infection and sometimes requires tracheostomy to relieve the symptom. Too much thickening of the frenulum can restrict tongue movement and may result in speech impediments. Beading of the papules around the eyelids is a very common symptom and is often used as part of a diagnosis of the disease. Some other dermatological symptoms that are sometimes seen but less common include hair loss, parotitis and other dental abnormalities, corneal ulceration, and focal degeneration of the macula.
=== Neurological ===
Although the dermatological changes are the most obvious symptoms of Urbach–Wiethe disease, many patients also have neurological symptoms. About 50–75% of the diagnosed cases of Urbach–Wiethe disease also show bilateral symmetrical calcifications on the medial temporal lobes. These calcifications often affect the amygdala and the periamygdaloid gyri. The amygdala is thought to be involved in processing biologically relevant stimuli and in emotional long-term memory, particularly those associated with fear, and both PET and MRI scans have shown a correlation between amygdala activation and episodic memory for strongly emotional stimuli. Therefore, Urbach–Wiethe disease patients with calcifications and lesions in these regions may suffer impairments in these systems. These calcifications are the result of a buildup of calcium deposits in the blood vessels within this brain region. Over time, these vessels harden and the tissue they are a part of dies, causing lesions. The amount of calcification is often related to disease duration. The true prevalence of these calcifications is difficult to accurately state as not all patients undergo brain imaging. Some patients also exhibit epilepsy and neuropsychiatric abnormalities. Epilepsy symptoms could begin with light anxiety attacks and can be controlled with anti-epileptic medications. Other patients present with symptoms similar to schizophrenia while some suffer from mood, anxiety, and psychotic disorders.
== Causes ==
Researchers have mapped Urbach–Wiethe disease to chromosome 1 at 1q21 and specifically identified the extracellular matrix protein 1 (ECM1) gene as the gene containing mutations that can lead to the development of the condition. At this point, 41 different mutations within ECM1 have been reported to lead to Urbach–Wiethe disease. These were all homozygous loss-of-function mutations (i.e. nonsense, frameshift or internal deletions). It is an autosomal recessive condition, requiring two mutated copies of the ECM1 gene to cause the disease.
ECM1 codes for a glycoprotein of previously unknown origin. The discovery that the loss of ECM1 expression leads to the symptoms associated with Urbach–Wiethe disease suggests that ECM1 may contribute to skin adhesion, epidermal differentiation, and wound healing and scarring. It is also thought to play a role in endochondral bone formation, tumor biology, endothelial cell proliferation and blood vessel formation.
The dermatological symptoms are caused by a buildup of a hyaline material in the dermis and the thickening of the basement membranes in the skin. The nature of this material is unknown, but researchers have suggested that it may be a glycoprotein, a glycolipid, an acid mucopolysaccharide, altered collagen or elastic tissue.
== Diagnosis ==
Urbach–Wiethe disease is typically diagnosed by its clinical dermatological manifestations, particularly the beaded papules on the eyelids. Doctors can also test the hyaline material with a periodic acid-Schiff (PAS) staining, as the material colors strongly for this stain.
Immunohistochemical skin labeling for antibodies for the ECM1 protein as labeling has been shown to be reduced in the skin of those affected by Urbach–Wiethe disease. Staining with anti-type IV collagen antibodies or anti-type VII collagen antibodies reveals bright, thick bands at the dermoepidermal junction.
Non-contrast CT scans can image calcifications, but this is not typically used as a means of diagnosing the disease. This is partly due to the fact that not all Urbach-Wiethe patients exhibit calcifications, but also because similar lesions can be formed from other diseases such as herpes simplex and encephalitis. The discovery of mutations within the ECM1 gene has allowed the use of genetic testing to confirm initial clinical diagnoses of Urbach–Wiethe disease. It also allows doctors to better distinguish between Urbach–Wiethe disease and other similar diseases not caused by mutations in ECM1.
== Treatment ==
Currently, there is no cure for Urbach–Wiethe disease although there are some ways to individually treat many of its symptoms. There has been some success with oral dimethyl sulfoxide (DMSO) and intralesional heparin, but this is not true in all cases. D-penicillamine has also shown promise, but has yet to have been used extensively. There are also some reports of patients being treated with etretinate, a drug typically prescribed to treat psoriasis. In some cases, calcifications in the brain can lead to abnormal electrical activity among neurons. Some patients are given anti-seizure medication to help deal with these abnormalities. Tracheostomy is often used to relieve upper respiratory tract infections. Carbon dioxide laser surgery of thickened vocal cords and beaded eyelid papules have improved these symptoms for patients. The discovery of the mutations of the ECM1 gene has opened the possibility of gene therapy or a recombinant EMC1 protein for Urbach–Wiethe disease treatment, but neither of these two options are currently available.
== Prognosis ==
Urbach–Wiethe disease is typically not a life-threatening condition. The life expectancy of these patients is normal as long as the potential side effects of thickening mucosa, such as respiratory obstruction, are properly addressed. Although this may require a tracheostomy or carbon dioxide laser surgery, such steps can help ensure that individuals with Urbach–Wiethe disease are able to live a full life. Oral dimethyl sulfoxide (DMSO) has been shown to reduce skin lesions, helping to minimize discomfort for these individuals.
== Incidence ==
Urbach–Wiethe disease is very rare; there are fewer than 300 reported cases in medical literature. Although Urbach–Wiethe disease can be found worldwide, almost a quarter of reported diagnoses are in South Africa. Many of these are in patients of Dutch, German, and Khoisan ancestry. This high frequency is thought to be due to the founder effect. Due to its recessive genetic cause and the ability to be a carrier of the disease without symptoms, Urbach–Wiethe disease often runs in families. In some regions of South Africa, up to one in 12 individuals may be carriers of the disease. Most of the case studies involving Urbach–Wiethe disease patients involve only one to three cases and these cases are often in the same family. Due to its low incidence, it is difficult to find a large enough number of cases to adequately study the disease.
== History ==
In 1908, what appears to be the first case of Urbach–Wiethe disease was reported by Friedrich Siebenmann, a professor of otolaryngology in Basel, Switzerland. In 1925, Friedrich Miescher, a Swiss dermatologist, reported on three similar patients. An official report of Urbach–Wiethe disease was first described in 1929 by a Viennese dermatologist and otorhinolaryngologist, Urbach and Wiethe. Its original name of 'lipoidosis cutis et mucosae' was changed to 'lipoid proteinosis cutis et mucosae' due to Urbach's belief that the condition was due to abnormal lipid and protein deposits within the tissues. Some have debated as to whether or not the disease is actually a form of mucopolysaccharidosis, amyloidosis, or even porphyria. The discovery of the Urbach–Wiethe disease causing mutation to the ECM1 gene has now provided a definitive way to differentiate Urbach–Wiethe disease from these other conditions.
== See also ==
Klüver–Bucy syndrome
S.M. (patient)
List of cutaneous conditions
List of radiographic findings associated with cutaneous conditions
== References ==
== External links == | Wikipedia/Urbach–Wiethe_disease |
Protein–energy undernutrition (PEU), once called protein–energy malnutrition (PEM), is a form of malnutrition that is defined as a range of conditions arising from coincident lack of dietary protein and/or energy (calories) in varying proportions. The condition has mild, moderate, and severe degrees.
Types include:
Kwashiorkor (protein malnutrition predominant)
Marasmus (deficiency in calorie intake)
Marasmic kwashiorkor (marked protein deficiency and marked calorie insufficiency signs present, sometimes referred to as the most severe form of malnutrition)
PEU is fairly common worldwide in both children and adults and accounts for about 250,000 deaths annually. In the industrialized world, PEM is predominantly seen in hospitals, is associated with disease, or is often found in the elderly.
Note that PEU may be secondary to other conditions such as chronic renal disease or cancer cachexia in which protein energy wasting (PEW) may occur.
Protein–energy undernutrition affects children the most because they have less protein intake. The few rare cases found in the developed world are almost entirely found in small children as a result of fad diets, or ignorance of the nutritional needs of children, particularly in cases of milk allergy.
== Prenatal protein undernutrition ==
Protein undernutrition is detrimental at any point in life, but protein undernutrition prenatally has been shown to have significant lifelong effects. Diets that consist of less than 6% protein in utero have been linked with many deficits, including decreased brain weight, increased obesity, and impaired communication within the brain in some animals. Even diets of mild protein undernutrition (7.2%) have been shown to have lasting and significant effects in rats. The following are some studies in which prenatal protein deficiency has been shown to have unfavorable consequences.
Decreased brain size: Protein deficiency has been shown to affect the size and composition of brains in rhesus monkeys. Monkeys whose mother had eaten a diet with an adequate amount of protein were shown to have no deficit in brain size or composition, even when their body weight amounted to less than one-half of that of the controls, whereas monkeys whose mothers had eaten low-protein diets were shown to have smaller brains regardless of the diet given after birth.
Impaired neocortical long-term potentiation: Mild protein deficiency (in which 7.2% of the diet consists of protein) in rats has been shown to impair entorhinal cortex plasticity (visuospatial memory), noradrenergic function in the neocortex, and neocortical long-term potentiation.
Altered fat distribution: Protein undernutrition can have varying effects depending on the period of fetal life during which the malnutrition occurred. Although there were not significant differences in the food intake, there were increased amounts of perirenal fat in rats that were protein-deprived during early (gestation days 0–7) and mid (gestation days 8–14) pregnancy, and throughout pregnancy, whereas rats that were protein-deprived only late in gestation (gestation days 15–22) were shown to have increased gonadal fat.
Increased obesity: Mice exposed to a low-protein diet prenatally weighed 40% less than the control group at birth (intrauterine growth retardation). When fed a high-fat diet after birth, the prenatally undernourished mice were shown to have increased body weight and adiposity (body fat), while those who were adequately nourished prenatally did not show an increase in body weight or adiposity when fed the same high-fat diet after birth.
Decreased birth weight, and gestation duration: Supplementation of protein and energy can lead to increased duration of gestation and higher birth weight. When fed a supplement containing protein, energy, and micronutrients, pregnant women showed more successful results during birth, including high birth weights, longer gestations, and fewer pre-term births, than women who had consumed a supplement with micronutrients and low energy but no protein (although this finding may be due to the increase of energy in the supplements, not the increase of protein).
Increased stress sensitivity: Male offspring of pregnant rats fed low-protein diets have been shown to exhibit blood pressure that is hyperresponsive to stress and salt.
Decreased sperm quality: A low-protein diet during gestation in rats has been shown to affect the sperm quality of the male offspring in adulthood. The protein deficiency appeared to reduce sertoli cell number, sperm motility, and sperm count.
Altered cardiac energy metabolism: Prenatal nutrition, specifically protein nutrition, may affect the regulation of cardiac energy metabolism through changes in specific genes.
Increased passive stiffness: Intrauterine undernutrition was shown to increase passive stiffness in skeletal muscles in rats.
From these studies it is possible to conclude that prenatal protein nutrition is vital to the development of the fetus, especially the brain, the susceptibility to diseases in adulthood, and even gene expression. When pregnant females of various species were given low-protein diets, the offspring were shown to have many deficits. These findings highlight the great significance of adequate protein in the prenatal diet.
== Epidemiology ==
Although protein energy malnutrition is more common in low-income countries, children from higher-income countries are also affected, including children from large urban areas in low socioeconomic neighborhoods. This may also occur in children with chronic diseases, and children who are institutionalized or hospitalized for a different diagnosis. Risk factors include a primary diagnosis of intellectual disability, cystic fibrosis, malignancy, cardiovascular disease, end stage renal disease, oncologic disease, genetic disease, neurological disease, multiple diagnoses, or prolonged hospitalization. In these conditions, the challenging nutritional management may get overlooked and underestimated, resulting in an impairment of the chances for recovery and the worsening of the situation.
PEM is fairly common worldwide in both children and adults and accounts for 250,000 deaths annually. In the industrialized world, PEM is predominantly seen in hospitals, is associated with disease, or is often found in the elderly.
== Co-morbidity ==
A large percentage of children that suffer from PEM also have other co-morbid conditions. The most common co-morbidities are diarrhea (72.2% of a sample of 66 subjects) and malaria (43.3%). However, a variety of other conditions have been observed with PEM, including sepsis, severe anaemia, bronchopneumonia, HIV, tuberculosis, scabies, chronic suppurative otitis media, rickets, and keratomalacia. These co-morbidities, according to Agozie Ubesie and other paediatricians, tax already malnourished children and may prolong hospital stays initially for PEM and may increase the likelihood of death.
The general explanation of increased infectious comorbidity in malnourished people is that (1) the immune system is what prevents such diseases from being more widespread in healthy, well-nourished people and (2) malnutrition stresses and diminishes immune function. In other words, malnutrition tends to cause (mild or moderate) immunodeficiency, eroding the barriers that normally keep infectious diseases at bay. For example, this reversal is well established regarding the variable natural history of tuberculosis in the pre–TB drug era. Epidemiologically, there are also associations between malnutrition and other health risks via the common underlying factor of poverty. For example, condoms can reduce spread of HIV, but impoverished people often may not have money to buy condoms or a nearby place to buy them. Also, once a poor person has any particular infection, they may not have access to optimal treatment of it, which allows it to get worse, present more chances of transmission, and so on. Even when a developing country nominally/officially has national health insurance with universal health care, the poorest quarter of its population may face a de facto reality of poor health care access.
== References ==
== Further reading ==
== External links == | Wikipedia/Protein–energy_malnutrition |
Keshan disease is a congestive cardiomyopathy caused by a combination of dietary deficiency of selenium and the presence of a mutated strain of Coxsackievirus, named after Keshan County of Heilongjiang province, Northeast China, where symptoms were first noted. These symptoms were later found prevalent in a wide belt extending from northeast to southwest China, all due to selenium-deficient soil. The disease peaked in 1960–1970, killing thousands of people.
Often fatal, the disease affects children and women of child-bearing age, characterized by heart failure and pulmonary edema. Over decades, supplementation with selenium reduced this condition.
It had been linked to the coxsackie B virus. Current research suggests that the lack of selenium results in a more virulent strain of the coxsackievirus becoming the dominant viral species present in the population of virus, but the mechanism of this selection event is unclear.
Keshan disease can also lead to higher rates of cancer, cardiovascular disease, hypertension, and strokes. In addition, an individual can experience eczema, psoriasis, arthritis, cataracts, alcoholism, and infections.
== Signs and symptoms ==
There are four main types of Keshan disease: acute, subacute, chronic, and latent.
Some signs and symptoms of acute Keshan disease include dizziness, malaise, nausea, chills, loss of appetite, projectile vomiting, pallor, low arterial blood pressure (less than 80/60 mmHg), dyspnea, precardiac (anterior to the heart) or substernal (behind or below the sternum) discomfort, cardiogenic shock, and constricted veins in one's extremities.
Some signs and symptoms of subacute Keshan disease include malaise, restlessness, gallop rhythm, facial edema, heart dilation, and cardiac shock.
Some signs and symptoms of chronic Keshan disease include palpitations, dyspnea, cough (with blood), pain in one's right upper quadrant, edema, oliguria, enlargement of the heart, systolic murmur, gallop rhythm, and hepatomegaly.
Some signs and symptoms of latent Keshan disease include dizziness, fatigue, palpitations, and mild enlargement of the heart.
== Treatments ==
The treatment for Keshan disease is selenium supplementation. The recommended amounts are fifty-five micrograms of selenium per day for adult men and women, sixty micrograms a day for women during pregnancy and seventy micrograms per day for women after pregnancy. A doctor may insist that if a man is sexually active, he may have to take up to seventy micrograms of selenium per day. A doctor may also recommend that the individual take vitamin E; selenium and vitamin E are medically linked and seem to work together. An individual will also be advised to have a diet that includes seafood, meats such as kidney, and liver, and some grains and seeds; all of these are high in selenium. Brewer's yeast and wheat germ both contain high levels of selenium. Garlic, onions, mushroom, broccoli, tomatoes, radishes, and Swiss chard may be good sources of selenium if the soil in which they are grown contains it. An individual will have to be monitored once they begin to take the selenium supplements, due to the fact that too much of it can cause balding, intestinal distress, weakness, and slow mental functioning. Individuals in China with the disease treat it with a herb called Astragalus, which accumulates selenium from the soil.
=== Living with Keshan disease ===
An individual will most likely be prescribed selenium supplements (in the form of selenomethionine) or have injections of this mineral. Other recommendations for managing Keshan disease are to increase consumption of foods rich in selenium in addition to supplements, avoid alcohol, monitor side effects to medications, and increase sleep. Cardiac surgery (implants, stents or full heart transplant) may be advised.
== See also ==
Selenium deficiency
Kashin–Beck disease
== References ==
== External links == | Wikipedia/Keshan_disease |
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/Primary_hyperlipoproteinemia |
In medicine, wasting, also known as wasting syndrome, refers to the process by which a debilitating disease causes muscle and fat tissue to "waste" away. Wasting is sometimes referred to as "acute malnutrition" because it is believed that episodes of wasting have a short duration, in contrast to stunting, which is regarded as chronic malnutrition. An estimated 45 million children under 5 years of age (or 6.7%) were wasted in 2021.: 4 Wasting prevalence declined from 7.5 % in 2012 to 6.8% in 2022, with 6.2% of children under five years old projected to be wasted in 2030, more than double the 3% Sustainable Development Goals target. Prevalence is highest in Southern Asia, followed by Oceania (excluding Australia and New Zealand) and South-eastern Asia.: 14
== Causes ==
Wasting can be caused by an extremely low energy intake (e.g., caused by famine), nutrient losses due to infection, or a combination of low intake and high loss. Infections and conditions associated with wasting include tuberculosis, chronic diarrhea, AIDS, and superior mesenteric artery syndrome. The mechanism may involve cachectin – also called tumor necrosis factor, a macrophage-secreted cytokine. Caretakers and health providers can sometimes contribute to wasting if the patient is placed on an improper diet. Voluntary weight loss and eating disorders are excluded as causes of wasting.
== Diagnosis ==
=== Classification ===
Children: Weight-for-height (WFH). In infants under 24 months, recumbent (supine) length is used. WFH as % of median reference value is calculated this way:
W
F
H
=
weight of a given child
median weight for a given child of that height
×
100
{\displaystyle \mathrm {WFH} ={\frac {\mbox{weight of a given child}}{\mbox{median weight for a given child of that height}}}\times 100}
Cutoff points may vary, but <80% (close to −2 Z-score) is often used.
Adults:
Body Mass Index (BMI) is the quotient between weight and height squared (kg/m2). An individual with a BMI < 18.5 is regarded as a case of wasting.
Percent of body weight lost (At Tufts, an unintentional loss of 6% or more in 6 months is regarded as wasting)
== Treatment ==
Antiretrovirals and anabolic steroids have been used to treat HIV wasting syndrome. Additionally, an increase in protein-rich foods such as peanut butter and legumes (dried beans and peas) can assist in controlling the loss of muscle mass.
== See also ==
Anorexia
Atrophy
Cachexia
Superior mesenteric artery syndrome
Weight loss
== Sources ==
This article incorporates text from a free content work. Licensed under CC BY 4.0. Text taken from The State of Food Security and Nutrition in the World 2024, FAO, IFAD, UNICEF, WFP and WHO, FAO.
== References ==
== External links ==
Chronic Wasting Disease and Potential Transmission to Humans, Center for Disease Control and Prevention
Unintentional Weight Loss/Wasting, Tufts University Nutrition/Infection Unit | Wikipedia/Wasting_disease |
Apolipoprotein B (ApoB) is a protein that in humans is encoded by the APOB gene. Its measurement is commonly used to detect the risk of atherosclerotic cardiovascular disease.
== Isoforms ==
The protein occurs in the plasma in two main isoforms, ApoB48 and ApoB100. The first is synthesized exclusively by the small intestine, the second by the liver. ApoB-100 is the largest of the apoB group of proteins, consisting of 4563 amino acids, including a 27-amino acid signal peptide and a 4536-amino acid mature protein. Both isoforms are coded by APOB and by a single mRNA transcript larger than 16 kb. ApoB48 is generated when a stop codon (UAA) at residue 2153 is created by RNA editing. There appears to be a trans-acting tissue-specific splicing gene that determines which isoform is ultimately produced. Alternatively, there is some evidence that a cis-acting element several thousand bp upstream determines which isoform is produced.
As a result of the RNA editing, ApoB48 and ApoB100 share a common N-terminal sequence, but ApoB48 lacks ApoB100's C-terminal LDL receptor binding region. ApoB48 is named because it constitutes 48% of the sequence for ApoB100. ApoB48 is a unique protein in chylomicrons from the small intestine. After most of the lipids in the chylomicron have been absorbed, ApoB48 returns to the liver as part of the chylomicron remnant, where it is endocytosed and degraded.
== Function ==
Apolipoprotein B is the primary apolipoprotein of chylomicrons, VLDL, Lp(a), IDL, and LDL particles (LDL—commonly known as "bad cholesterol" when in reference to both heart disease and vascular disease in general), which is responsible for carrying fat molecules (lipids), including cholesterol, around the body to all cells within all tissues. While all the functional roles of ApoB within the LDL (and all larger) particles remain somewhat unclear, it is the primary organizing protein (of the entire complex shell enclosing/carrying fat molecules within) component of the particles and is absolutely required for the formation of these particles. What is also clear is that the ApoB on the LDL particle acts as a ligand for LDL receptors in various cells throughout the body (i.e., less formally, ApoB indicates fat-carrying particles are ready to enter any cells with ApoB receptors and deliver fats carried within into the cells).
=== Role in innate immune system ===
Very low-density lipoproteins and low-density lipoproteins interfere with the quorum sensing system that upregulates genes required for invasive Staphylococcus aureus infection. The mechanism of antagonism entails binding ApoB to a S. aureus autoinducer pheromone, preventing signaling through its receptor. Mice deficient in ApoB are more susceptible to invasive bacterial infection.
== Clinical significance ==
Through mechanisms only partially understood, high levels of ApoB, especially associated with the higher LDL particle concentrations, are the primary driver of plaques that cause vascular disease (atherosclerosis), commonly first becoming obviously symptomatic as heart disease, stroke and many other body wide complications after decades of progression. There is considerable evidence that concentrations of ApoB and especially the NMR assay (specific for LDL-particle concentrations) are superior indicators of vascular/heart disease driving physiology than either total cholesterol or LDL-cholesterol (as long promoted by the NIH starting in the early 1970s). However, primarily for historic cost/complexity reasons, cholesterol, and estimated LDL-cholesterol by calculation, remains the most commonly promoted lipid test for the risk factor of atherosclerosis. ApoB is routinely measured using immunoassays such as ELISA or nephelometry. Refined and automated NMR methods allow measurement distinctions between the many different ApoB particles.
=== Genetic disorders ===
High levels of ApoB are related to heart disease.
Hypobetalipoproteinemia is a genetic disorder that can be caused by a mutation in the ApoB gene, APOB. Abetalipoproteinaemia is caused by a mutation in the microsomal triglyceride transfer protein gene, MTTP.
Mutations in gene APOB100 can also cause familial hypercholesterolemia, a hereditary (autosomal dominant) form of metabolic disorder hypercholesterolemia.
=== Role in insulin resistance ===
Overproduction of apolipoprotein B can result in lipid-induced endoplasmic reticulum stress and insulin resistance in the liver.
=== Role in lipoproteins and atherosclerosis ===
ApoB100 is found in lipoproteins originating from the liver (VLDL, IDL, LDL). Importantly, there is one ApoB100 molecule per hepatic-derived lipoprotein. Hence, using that fact, one can quantify the number of lipoprotein particles by noting the total ApoB100 concentration in the circulation. Since there is one and only one ApoB100 per particle, the number of particles is reflected by the ApoB100 concentration. The same technique can be applied to individual lipoprotein classes (e.g., LDL) and thereby enable one to count them as well.
It is well established that ApoB100 levels are associated with coronary heart disease, they are a far better predictor of it than are LDL-C concentrations. Reason: LDL-C does not reflect actual particle concentrations and cholesterol cannot dissolve or move (in water) without particles to carry it. A simple way to understand this observation is the fact that ApoB100, one per particle, reflects actual lipoprotein particle concentration (independent of their cholesterol or other lipid content). In this way, one can understand that the number of ApoB100-containing lipoprotein particles which can carry lipids into the artery walls is a key determinant, driver of atherosclerosis and heart disease.
One way to explain the above is to consider that large numbers of lipoprotein particles, and, in particular, large numbers of LDL particles, lead to competition at the ApoB100 receptor (i.e., LDL receptor) of peripheral cells. Since such competition will prolong the residence time of LDL particles in the circulation, it may lead to greater opportunity for them to undergo oxidation and/or other chemical modifications. Such modifications may lessen the particles' ability to be cleared by the classic LDL receptor and/or increase their ability to interact with so-called "scavenger" receptors. The net result is the shunting of LDL particles to these scavenger receptors. Scavenger receptors are typically found on macrophages, with cholesterol-laden macrophages being better known as "foam cells". Foam cells characterize atherosclerotic lesions. In addition to this possible mechanism of foam cell generation, an increase in the levels of chemically modified LDL particles may also lead to an increase in endothelial damage. This occurs as a result of modified-LDL's toxic effect on vascular endothelium as well as its ability both to recruit immune effector cells and to promote platelet activation.
The INTERHEART study found that the ApoB100 / ApoA1 ratio is more effective at predicting heart attack risk in patients who had had an acute myocardial infarction than either the ApoB100 or ApoA1 measure alone. (ApoA1 is the major HDL protein.) In the general population this remains unclear although in a recent study ApoB was the strongest risk marker for cardiovascular events.
A Mediterranean diet is recommended as a means of lowering Apolipoprotein B.
== Mouse studies ==
Mice have been used as model organisms in ApoB study as they express an equivalent protein known as mouse ApoB (mApoB). Mice overexpressing mApoB have increased levels of LDL and decreased levels of HDL. Mice containing only one functional copy of the mApoB gene show the opposite effect, being resistant to hypercholesterolemia. Mice containing no functional copies of the gene are not viable.
== Interactions ==
ApoB has been shown to interact with apo(a), PPIB, Calcitonin receptor and HSP90B1. Interaction of ApoB with proteoglycans, collagen, and fibronectin is believed to cause atherosclerosis.
== Interactive pathway map ==
Click on genes, proteins and metabolites below to link to respective articles.
== Regulation ==
The expression of APOB is regulated by cis-regulatory elements in the APOB 5′ UTR and 3′ UTR.
== RNA editing ==
The mRNA encoding this protein is subject to cytidine to uridine (C to U) site-specific RNA editing. ApoB100 and ApoB48 are encoded by the same gene, however, the differences in the translated proteins are not due to alternative splicing but are due to the tissue-specific RNA editing event.
ApoB mRNA editing was the first example of editing observed in vertebrates. Editing of ApoB mRNA occurs in all placental mammals. Editing occurs post transcriptionally as the nascent polynucleotides do not contain edited nucleosides.
=== Type ===
C to U editing of ApoB mRNA requires an editing complex or holoenzyme (editosome) consisting of the C to U-editing enzyme Apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 (ApoBEC-1) as well as other auxiliary factors. ApoBEC-1 is a protein that in humans is encoded by the APOBEC1 gene.[1]It is a member of the cytidine deaminase family. ApoBEC-1 alone is not sufficient for the editing of ApoB mRNA and requires at least one of these auxiliary factors, APOBEC1 complementation factor (A1CF) for editing to occur. A1CF contains 3 non-identical repeats. It acts as the RNA-binding subunit and directs ApoBEC-1 to the ApoB mRNA downstream of the edited cytidine. Other auxiliary factors are known to be part of the holoenzyme. Some of these proteins have been identified. these are CUG binding protein 2 (CUGBP2), SYNCRIP (glycine-arginine-tyrosine-rich RNA binding protein, GRY-RBP), heterogeneous nuclear ribonucleoprotein (hnRNP)-C1 (HNRNPC), ApoBEC-1 binding protein ABBP1 (HNRNPAB), ABBP2, KH-type splicing regulatory binding protein (KHSRP), Bcl-2-associated athanogene 4 (BAG4), and auxiliary factor (AUX)240. All these proteins have been identified using detection assays and have all been demonstrated to interact with either ApoBEC-1, A1CF, or ApoB RNA. The function of these auxiliary proteins in the editing complex is unknown. As well as editing ApoB mRNA, the ApoBEC-1 editsome also edits the mRNA of NF1. mRNA editing of ApoB mRNA is the best-defined example of this type of C to U RNA editing in humans.
=== Location ===
Despite being a 14,000-residue-long transcript, a single cytidine is targeted for editing. Within the ApoB mRNA, a sequence consisting of 26 nucleotides necessary for editing is found. This is known as the editing motif. These nucleotides (6662–6687) were determined to be essential by site-specific mutagenesis experiments. An 11 nucleotide portion of this sequence 4–5 nucleotides downstream from the editing site is an important region known as the mooring sequence. A region called the spacer element is found 2–8 nucleotides between the edited nucleoside and this mooring sequence. There is also a regulatory sequence 3′ to the editing site. The active site of ApoBEC-1, the catalytic component of the editing holoenzyme, is thought to bind to an AU-rich region of the mooring sequence with the aid of ACF in binding the complex to the mRNA.
The edited cytidine residue is located at nucleotide 6666 located in exon 26 of the gene. Editing at this site results in a codon change from a Glutamine codon (CAA) to an in-frame stop codon (UAA). Computer modelling has detected that for editing to occur, the edited Cytidine is located in a loop. The selection of the edited cytidine is also highly dependent on this secondary structure of the surrounding RNA. There are also some indications that this loop region is formed between the mooring sequence and the 3′ regulatory region of the ApoB mRNA. The predicted secondary structure formed by ApoB mRNA is thought to allow for contact between the residue to be edited and the active site of APOBEC1, as well as for binding of ACF and other auxiliary factors associated with the editosome.
=== Regulation ===
Editing of ApoB mRNA in humans is tissue-regulated, with ApoB48 being the main ApoB protein of the small intestine in humans. It occurs in lesser amounts in the colon, kidney, and stomach, along with the non-edited version.
Editing is also developmentally regulated, with the non-edited version only being translated early in development, but the edited form increases during development in the tissues where editing can occur.
Editing levels of ApoB mRNA have been shown to vary in response to changes in diet. exposure to alcohol and hormone levels.
=== Conservation ===
ApoB mRNA editing also occurs in mice and rats. In contrast to humans editing occurs in liver in mice and rats up to a frequency of 65%. It has not been observed in birds or lesser species.
=== Consequences ===
==== Structure ====
Editing results in a codon change creating an in-frame stop codon, leading to translation of a truncated protein, ApoB48. This stop codon results in the translation of a protein that lacks the carboxyl terminus, which contains the protein's LDLR binding domain. The full protein ApoB100, which has nearly 4500 amino acids, is present in VLDL and LDL. Since many parts of ApoB100 are in an amphipathic condition, the structure of some of its domains is dependent on underlying lipid conditions. However, it is known to have the same overall folding as LDL, having five main domains. Recently the first structure of LDL at human body temperature in native condition has been found using cryo-electron microscopy at a resolution of 16 Angstrom. The overall folding of ApoB-100 has been confirmed, and some heterogeneity in the local structure of its domains has been mapped.
==== Function ====
Editing is restricted to those transcripts expressed in the small intestine. This shorter version of the protein has a function specific to the small intestine. The main function of the full-length liver expressed ApoB100 is as a ligand for activation of the LDL-R. However, editing results in a protein lacking this LDL-R binding region of the protein. This alters the function of the protein and the shorter ApoB48 protein, as specific functions relative to the small intestine.
ApoB48 is identical to the amino-terminal 48% of ApoB100. The function of this isoform is in fat absorption of the small intestine and is involved in the synthesis, assembly and secretion of chylomicrons. These chylomicrons transport dietary lipids to tissues, while the remaining chylomicrons, along with associated residual lipids, are in 2–3 hours taken up by the liver via the interaction of apolipoprotein E (ApoE) with lipoprotein receptors. It is the dominant ApoB protein in the small intestine of most mammals. It is a key protein in the exogenous pathway of lipoprotein metabolism. Intestinal proteins containing ApoB48 are metabolized to chylomicron remnant particles, which are taken up by remnant receptors.
== See also ==
Apolipoprotein A1
ACAT2
Cardiovascular disease
Lipid metabolism
== References ==
== Further reading ==
== External links ==
Database of RNA editing (DARNED).
Applied Research on Apolipoprotein-B
Human APOB genome location and APOB gene details page in the UCSC Genome Browser. | Wikipedia/Apolipoprotein_B |
The steroidogenic acute regulatory protein, commonly referred to as StAR (STARD1), is a transport protein that regulates cholesterol transfer within the mitochondria, which is the rate-limiting step in the production of steroid hormones. It is primarily present in steroid-producing cells, including theca cells and luteal cells in the ovary, Leydig cells in the testis and cell types in the adrenal cortex.
== Function ==
Cholesterol needs to be transferred from the outer mitochondrial membrane to the inner membrane where cytochrome P450scc enzyme (CYP11A1) cleaves the cholesterol side chain, which is the first enzymatic step in all steroid synthesis. The aqueous phase between these two membranes cannot be crossed by the lipophilic cholesterol, unless certain proteins assist in this process. A number of proteins have historically been proposed to facilitate this transfer including: sterol carrier protein 2 (SCP2), steroidogenic activator polypeptide (SAP), peripheral benzodiazepine receptor (PBR or translocator protein, TSPO), and StAR. It is now clear that this process is primarily mediated by the action of StAR.
The mechanism by which StAR causes cholesterol movement remains unclear as it appears to act from the outside of the mitochondria and its entry into the mitochondria ends its function. Various hypotheses have been advanced. Some involve StAR transferring cholesterol itself like a shuttle. While StAR may bind cholesterol itself, the exorbitant number of cholesterol molecules that the protein transfers would indicate that it would have to act as a cholesterol channel instead of a shuttle. Another notion is that it causes cholesterol to be kicked out of the outer membrane to the inner (cholesterol desorption). StAR may also promote the formation of contact sites between the outer and inner mitochondrial membranes to allow cholesterol influx. Another suggests that StAR acts in conjunction with PBR, causing the movement of Cl− out of the mitochondria to facilitate contact site formation. However, evidence for an interaction between StAR and PBR remains elusive.
== Structure ==
In humans, the gene for StAR is located on chromosome 8p11.23 and the protein has 285 amino acids. The signal sequence of StAR that targets it to the mitochondria is clipped off in two steps with import into the mitochondria. Phosphorylation at the serine at position 195 increases its activity.
The domain of StAR important for promoting cholesterol transfer is the StAR-related transfer domain (START domain). StAR is the prototypic member of the START domain family of proteins and is thus also known as STARD1 for "START domain-containing protein 1". It is hypothesized that the START domain forms a pocket in StAR that binds single cholesterol molecules for delivery to P450scc.
The closest homolog to StAR is MLN64 (STARD3). Together they comprise the StarD1/D3 subfamily of START domain-containing proteins.
== Production ==
StAR is a mitochondrial protein that is rapidly synthesized in response to stimulation of the cell to produce steroid. Hormones that stimulate its production depend on the cell type and include luteinizing hormone (LH), ACTH and angiotensin II.
At the cellular level, StAR is synthesized typically in response to activation of the cAMP second messenger system, although other systems can be involved even independently of cAMP.
StAR has thus far been found in all tissues that can produce steroids, including the adrenal cortex, the gonads, the brain and the nonhuman placenta. One known exception is the human placenta.
Substances that suppress StAR activity, like those listed below, can cause endocrine disrupting effects, including altered steroid hormone levels and fertility.
Alcohol
DEHP and DBP
Permethrin and cypermethrin
DES and arsenite
BPA
== Pathology ==
Mutations in the gene for StAR cause lipoid congenital adrenal hyperplasia (lipoid CAH), in which patients produce little steroid and can die shortly after birth. Mutations that less severely affect the function of StAR result in nonclassic lipoid CAH or familial glucocorticoid deficiency type 3.
All known mutations disrupt StAR function by altering its START domain. In the case of StAR mutation, the phenotype does not present until birth since human placental steroidogenesis is independent of StAR.
At the cellular level, the lack of StAR results in a pathologic accumulation of lipid within cells, especially noticeable in the adrenal cortex as seen in the mouse model. The testes are undescended and the resident steroidogenic Leydig cells are modestly affected. Early in life, the ovary is spared as it does not express StAR until puberty. After puberty, lipid accumulations and hallmarks of ovarian failure are noted.
== StAR-independent steroidogenesis ==
While loss of functional StAR in the human and the mouse catastrophically reduces steroid production, it does not eliminate all of it, indicating the existence of StAR-independent pathways for steroid generation. Aside from the human placenta, these pathways are considered minor for endocrine production.
It is unclear what factors catalyze StAR-independent steroidogenesis. Candidates include oxysterols which can be freely converted to steroid and the ubiquitous MLN64.
== New roles ==
Recent findings suggest that StAR may also traffic cholesterol to a second mitochondrial enzyme, sterol 27-hydroxylase. This enzyme converts cholesterol to 27-hydroxycholesterol. In this way it may be important for the first step in one of the two pathways for the production of bile acids by the liver (the alternative pathway).
Evidence also shows that the presence of StAR in a type of immune cell, the macrophage, where it can stimulate the production of 27-hydroxycholesterol. In this case, 27-hydroxycholesterol may by itself be helpful against the production of inflammatory factors associated with cardiovascular disease. It is important to note that no study has yet found a link between the loss of StAR and problems in bile acid production or increased risk for cardiovascular disease.
Recently StAR was found to be expressed in cardiac fibroblasts in response to ischemic injury due to myocardial infarction. In these cells it has no apparent de novo steroidogenic activity, as evidenced by the lack of the key steroidogenic enzymes cytochrome P450 side chain cleavage (CYP11A1) and 3 beta hydroxysteroid dehydrogenase (3βHSD). StAR was found to have an anti-apoptotic effect on the fibroblasts, which may allow them to survive the initial stress of the infarct, differentiate and function in tissue repair at the infarction site.
== History ==
The StAR protein was first identified, characterized and named by Douglas Stocco at Texas Tech University Health Sciences Center in 1994. The role of this protein in lipoid CAH was confirmed the following year in collaboration with Walter Miller at the University of California, San Francisco. All of this work follows the initial observations of the appearance of this protein and its phosphorylated form coincident with factors that caused steroid production by Nanette Orme-Johnson while at Tufts University.
== See also ==
Steroidogenic enzyme
== References ==
== External links ==
steroidogenic+acute+regulatory+protein at the U.S. National Library of Medicine Medical Subject Headings (MeSH) | Wikipedia/Steroidogenic_acute_regulatory_protein |
Lipoprotein(a) is a low-density lipoprotein variant containing a protein called apolipoprotein(a). Genetic and epidemiological studies have identified lipoprotein(a) as a risk factor for atherosclerosis and related diseases, such as coronary heart disease and stroke.
Lipoprotein(a) was discovered in 1963 by Kåre Berg. The human gene encoding apolipoprotein(a) was successfully cloned in 1987.
== Structure ==
Lipoprotein(a) [Lp(a)] consists of an LDL-like particle and the specific apolipoprotein(a), which is bound covalently to the apoB contained in the outer shell of the particle. Lp(a) plasma concentrations are highly heritable and mainly controlled by the LPA gene located on chromosome 6q25.3–q26. Apo(a) proteins vary in size due to a size polymorphism [KIV-2 VNTR], which is caused by a variable number of kringle IV repeats in the LPA gene. This size variation at the gene level is expressed on the protein level as well, resulting in apo(a) proteins with 10 to more than 50 kringle IV repeats (each of the variable kringle IV consists of 114 amino acids). These variable apo(a) sizes are known as "apo(a) isoforms".
There is a general inverse correlation between the size of the apo(a) isoform and the Lp(a) plasma concentration. One theory explaining this correlation involves different rates of protein synthesis. Specifically, the larger the isoform, the more apo(a) precursor protein accumulates intracellularly in the endoplasmic reticulum. Lp(a) is not fully synthesised until the precursor protein is released from the cell, so the slower production rate for the larger isoforms limits the plasma concentration.
=== Populations ===
Lp(a) concentrations can vary by more than one thousand between individuals, from <0.2 to >200 mg/dL. Scientists have found that this range of concentrations has been observed in all populations studied. The mean and median concentrations differ among world populations. Most prominently, there is a two to threefold higher mean Lp(a) plasma concentration in populations of African descent compared to Asian, Oceanic, or European populations. The general inverse correlation between apo(a) isoform size and Lp(a) plasma concentration is observed in all populations. However, it was also discovered that mean Lp(a) associated with certain apo(a) isoforms varies between populations.
In addition to size effects, mutations in the LPA promoter may lead to a decreased apo(a) production.
The Atherosclerosis Risk in Communities (ARIC) Study is a community-based cohort from 4 geographically diverse US communities. The ARIC Study found that the proportion of Atherosclerotic Cardiovascular Disease cases potentially attributable to elevated Lp(a) was 10.2% among Black adults compared with 4.7% among white adults. The population-attributable fraction ratio for Black adults compared with white adults was 2.30.
Because the hazard ratios for ASCVD associated with higher Lp(a) did not significantly differ between races, the ARIC study concluded that these differences appeared to be driven largely by racial differences in the distribution of Lp(a) levels.
== Function and pathology ==
Lp(a) is assembled at the hepatocyte cell membrane surface, which is similar to typical LDL particles. However, there are other possible locations of assembly. The particles mainly exist in plasma.
Lp(a) contributes to the process of atherogenesis. The structure of apolipoprotein(a) is similar to plasminogen and tPA (tissue plasminogen activator), and it competes with plasminogen for its binding site, leading to reduced fibrinolysis. Also, because Lp(a) stimulates secretion of PAI-1, it leads to thrombogenesis. It also may enhance coagulation by inhibiting the function of tissue factor pathway inhibitor.
Moreover, Lp(a) carries atherosclerosis-causing cholesterol and binds atherogenic pro-inflammatory oxidised phospholipids as a preferential carrier of oxidised phospholipids in human plasma, which attracts inflammatory cells to vessel walls and leads to smooth muscle cell proliferation. Moreover, Lp(a) also is hypothesised to be involved in wound healing and tissue repair by interacting with components of the vascular wall and extracellular matrix. Apo(a), a distinct feature of the Lp(a) particle, binds to immobilized fibronectin and endows Lp(a) with the serine-proteinase-type proteolytic activity.
Nonetheless, individuals without Lp(a) or with very low Lp(a) levels seem to be healthy. Thus, plasma Lp(a) is not vital, at least under normal environmental conditions. Since apo(a)/Lp(a) appeared rather recently in mammalian evolution — only old world monkeys and humans have been shown to harbour Lp(a) — its function might not be vital, but just evolutionarily advantageous under certain environmental conditions, e.g., in case of exposure to certain infectious diseases.
Another possibility, suggested by Linus Pauling, is that Lp(a) is a primate adaptation to L-gulonolactone oxidase (GULO) deficiency, found only in certain lines of mammals. GULO is required for converting glucose to ascorbic acid (vitamin C), which is needed to repair arteries; following the loss of GULO, those primates who adopted diets less abundant in vitamin C may have used Lp(a) as an ascorbic-acid surrogate to repair arterial walls.
== Catabolism and clearance ==
The half-life of Lp(a) in circulation is approximately three to four days. The mechanism and sites of Lp(a) catabolism are largely unknown. The LDL receptor has been reported as a receptor for Lp(a) clearance, but is not a major pathway of Lp(a) metabolism under normal or hypercholesterolemic conditions. The kidney has been identified as playing a role in Lp(a) clearance from plasma.
== Disease ==
High Lp(a) in blood correlates with coronary heart disease (CHD), cardiovascular disease (CVD), atherosclerosis, thrombosis, and stroke. However, the association between Lp(a) levels and stroke is not as strong as that between Lp(a) and cardiovascular disease. Lp(a) concentrations may be affected by disease states (for example, kidney failure), but are only slightly affected by diet, exercise, and other environmental factors.
Most commonly prescribed lipid-reducing drugs have little or no effect on Lp(a) concentration. Results using statin medications have been mixed in most trials, although a meta-analysis published in 2012 suggests that atorvastatin may be of benefit.
Niacin (Vitamin B3) has been shown to reduce the levels of Lp(a) significantly in individuals with high levels of low-molecular weight Lp(a).
High Lp(a) correlates with early atherosclerosis independently of other cardiac risk factors, including LDL. In patients with advanced cardiovascular disease, Lp(a) indicates a coagulant risk of plaque thrombosis. Apo(a) contains domains very similar to plasminogen (PLG). Lp(a) accumulates in the vessel wall and inhibits the binding of PLG to the cell surface, reducing plasmin generation, which increases clotting. This inhibition of PLG by Lp(a) also promotes the proliferation of smooth muscle cells. These unique features of Lp(a) suggest that Lp(a) causes generation of clots and atherosclerosis.
In a homogeneous tribal population in Tanzania, vegetarians have higher levels of Lp(a) than fish eaters, raising the possibility that pharmacologic amounts of fish oil supplements may help lower the levels of Lp(a). Researchers in studies in 1995 and 1998 concluded that regular consumption of moderate amounts of alcohol led to a significant decline in plasma levels of Lp(a). Other studies did not report this.
== Diagnostic testing ==
Numerous studies confirming a strong correlation between elevated Lp(a) and heart disease have led to the consensus that Lp(a) is an important independent predictor of cardiovascular disease. Animal studies have shown that Lp(a) may directly contribute to atherosclerotic damage by increasing plaque size, inflammation, instability, and smooth muscle cell growth. Genetic data also support the theory that Lp(a) causes cardiovascular disease.
The European Atherosclerosis Society recommends that patients with a moderate or high risk of cardiovascular disease should have their Lp(a) levels checked. Any patient with one of the following risk factors should be screened:
premature cardiovascular disease
Familial hypercholesterolaemia
family history of premature cardiovascular disease
family history of elevated Lp(a)
recurrent cardiovascular disease despite statin treatment
≥3% ten-year risk of fatal cardiovascular disease according to the European guidelines
≥10% ten-year risk of fatal and/or non-fatal cardiovascular disease according to the U.S. guidelines
If the level is elevated, treatment should be initiated to bring the level below 50 mg/dL. In addition, the patient's other cardiovascular risk factors (including LDL levels) should be managed optimally. Apart from the total Lp(a) plasma concentration, the apo(a) isoform might be an important risk parameter as well.
Prior studies of the relationship between Lp(a) and ethnicity have shown inconsistent results. Lp(a) levels seem to differ in different populations. For example, in some African populations, Lp(a) levels are higher on average than in other groups, so that using a risk threshold of 30 mg/dl could classify over 50% of the individuals as higher risk. Some part of this complexity may be related to the different genetic factors involved in determining Lp(a) levels. One recent study showed that in different ethnic groups, different genetic alterations were associated with increased Lp(a) levels.
More recent data suggest that prior studies were underpowered. The Atherosclerosis Risk in Communities (ARIC) Study followed 3467 African Americans and 9851 whites for 20 years. The researchers found that an elevated Lp(a) conferred the same risk in each group. African Americans had roughly three times the level of Lp(a); however, Lp(a) also predicted an increased risk of stroke.
Approximate levels of risk are indicated by the results below, although at present, there are various methods by which to measure Lp(a). A standardized international reference material has been developed and is accepted by the WHO Expert Committee on Biological Standardization and the International Federation of Clinical Chemistry and Laboratory Medicine. Although further standardization is still needed, the development of a reference material is an important step toward standardizing results.
Lipoprotein(a) — Lp(a)
Desirable: <14 mg/dL (<35 nmol/L)
Borderline risk: 14–30 mg/dL (35–75 nmol/L)
High risk: 31–50 mg/dL (75–125 nmol/L)
Very high risk: >50 mg/dL (>125 nmol/L)
Lp(a) appears with different isoforms (per kringle repeats) of apolipoprotein; 40% of the variation in Lp(a) levels when measured in mg/dl can be attributed to different isoforms. Lighter Lp(a) are also associated with disease. Thus, a test with simple quantitative results may not provide a complete assessment of risk.
The US FDA has given the Tina-quant® lipoprotein Lp(a) RxDx assay from Roche a Breakthrough Device Designation. The assay is designed to identify patients who may benefit from therapies aimed at decreasing Lp(a) levels.
== Treatment ==
The current simplest treatment for elevated Lp(a) is to take 1–3 grams of niacin daily, typically in an extended-release form. Niacin therapy may reduce Lp(a) levels by 20–30%. However more recent research suggests that the inflammatory effects of the breakdown products of excess niacin lead to an increase in risk of major adverse cardiovascular event.
A meta-analysis suggested that atorvastatin may lower Lp(a) levels. In severe cases, such as familial hypercholesterolemia or treatment-resistant hypercholesterolemia, LDL apheresis may dramatically reduce Lp(a). The goal of the treatment is to reduce levels to below 50 mg/dL. Cost is prohibitively high.
A meta-analysis of six clinical trials confirmed that flaxseed supplementation modestly lowers Lp(a) levels.
Testosterone is known to reduce Lp(a) levels. Testosterone replacement therapy also appears to be associated with lower Lp(a) levels. Estrogen replacement therapy in post-menopausal women will reduce Lp(a). Raloxifene has not been shown to reduce Lp(a), while tamoxifen has.
L-carnitine may also reduce Lp(a) levels. A systematic review and meta-analysis found a significant reduction with oral but not intravenous carnitine. Other medications that are in various stages of development include thyromimetics, cholesterol-ester-transfer protein (CETP inhibitors), anti-sense oligonucleopeptides (such as Pelacarsen and Olpasiran), and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors.
The American Academy of Pediatrics now recommends that all children between the ages of nine and eleven years old be screened for hyperlipidemia. Lp(a) levels should be considered in children with a family history of early heart disease or high blood cholesterol levels. However, there have not been enough studies to determine which therapies might be beneficial.
In March 2025, Eli Lilly announced that an experimental drug, lepodisiran, showed promising results in significantly lowering Lp(a) levels for months with a single injection.
== Interactions ==
Lp(a) has been shown to interact with calnexin, fibronectin, and fibrinogen beta chain.
== See also ==
== References ==
== External links ==
Lipoprotein(a) at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
Overview of all the structural information available in the PDB for UniProt: P08519 (Apolipoprotein(a)) at the PDBe-KB. | Wikipedia/Lipoprotein_a |
The unified Parkinson's disease rating scale (UPDRS) is used to follow the longitudinal course of Parkinson's disease. The UPD rating scale is the most commonly used scale in the clinical study of Parkinson's disease.
The UPDRS is made up of these sections:
Part I: evaluation of mentation, behavior, and mood
Part II: self-evaluation of the activities of daily life (ADLs) including speech, swallowing, handwriting, dressing, hygiene, falling, salivating, turning in bed, walking, and cutting food
Part III: clinician-scored monitored motor evaluation
Part IV: complications of therapy
Part V: Hoehn and Yahr staging of severity of Parkinson's disease
Part VI: Schwab and England ADL scale
These are evaluated by interview and clinical observation. Some sections require multiple grades assigned to each extremity.
Clinicians and researchers alike use the UPDRS and the motor section in particular to follow the progression of a person's Parkinson's disease. Scientific researchers use it to measure benefits from a given therapy in a more unified and accepted rating system. Neurologists also use it in clinical practice to follow the progression of their patients' symptoms in a more objective manner.
Following the UPDRS scores over time provides insight into the patient's disease progression. For instance Michael J. Fox's symptoms started with a slight tremor, so his motor score would have been less than 10. For most patients, the "mentation, behavior and mood" scores increase later in the disease, but a subset exists for whom those symptoms develop early on.
== Similar rating scales ==
Other rating scales for Parkinson's disease are the Hoehn and Yahr scale and Schwab and England activities of daily living scale, although both of these measures are currently included within the UPDRS in modified format.
== MDS-UPDRS ==
In 2007, the Movement Disorder Society (MDS) published a revision of the UPDRS, known as the MDS-UPDRS. The revision became desirable after an MDS-sponsored Task Force on Rating Scales for Parkinson's Disease highlighted the limitations of the original UPDRS. Two major limitations include the lack of consistent anchor among subscales and the low emphasis on the nonmotor features of PD. The modified UPDRS retains the four-scale structure with a reorganization of the various subscales. Score ranges from 0 to 260, with 0 indicating no disability and 260 indicating total disability. The scales are:
Part I: Nonmotor experiences of daily living: 13 items. Score range: 0–52, 10 and below is mild, 22 and above is severe.
Part II: Motor experiences of daily living: 13 items. Score range: 0–52, 12 and below is mild, 30 and above is severe.
Part III: Motor examination: 18 items. Score range: 0–132, 32 and below is mild, 59 and above is severe.
Part IV: Motor complications: 6 items. Score range: 0–24, 4 and below is mild, 13 and above is severe.
Each item has 0–4 ratings: 0 (normal), 1 (slight), 2 (mild), 3 (moderate), and 4 (severe).
== References ==
== External links ==
Unified Parkinson's Disease Rating Scale on National Parkinson Foundation site
Unified Parkinson's Disease Rating Scale on Movement Disorders Virtual University site
Free online UPDRS calculator
UPDRS online calculator Archived 2018-02-27 at the Wayback Machine | Wikipedia/Unified_Parkinson's_disease_rating_scale |
The Drug Quality and Security Act (H.R. 3204) is a law that amended the Federal Food, Drug, and Cosmetic Act to grant the Food and Drug Administration more authority to regulate and monitor the manufacturing of compounded drugs. The bill was written in response to the New England Compounding Center meningitis outbreak that took place in 2012, which killed 64 people. The bill was signed by President Obama on November 27, 2013.
Title I of the DQSA comprises the Compounding Quality Act (CQA), which amends regulations concerning compounding drugs. Title II, the Drug Supply Chain Security Act (DSCSA), established requirements to facilitate the tracing of prescription drug products through the pharmaceutical supply distribution chain. These requirements included a ten-year timeline culminating in the building of "an electronic, interoperable system to identify and trace certain prescription drugs as they are distributed in the United States."
== Background ==
The bill was introduced by Rep. Upton in response to the New England Compounding Center meningitis outbreak that took place in 2012. 64 people were killed and 750 were infected by fungal meningitis. Rep. Upton's district had 3 deaths and there were 19 total in Michigan.
Compounding is the creation of a particular pharmaceutical product to fit the unique need of a patient. To do this, compounding pharmacists combine or process appropriate ingredients using various tools. This may be done for medically necessary reasons, such as to change the form of the medication from a solid tablet to a liquid, to avoid a non-essential ingredient that the patient is allergic to, or to obtain the exact dose(s) needed or deemed best of particular active pharmaceutical ingredient(s). It may also be done for more optional reasons, such as adding flavors to a medication or otherwise altering taste or texture.
== Parts ==
Title I of the law amended the Federal Food, Drug, and Cosmetic Act to grant the Food and Drug Administration more authority to regulate and monitor the manufacturing of compounded drugs. The act also prohibited reselling drugs that are labeled "not for resale." Title II of the DQSA was passed with the intent to "make it easier to trace drugs throughout the U.S. supply chain" in part by outlining the steps "to build an electronic, interoperable system to identify and trace certain prescription drugs as they are distributed in the United States" by 2023.
The below summary is based largely on the summary provided by the Congressional Research Service, a public domain source.
=== Title I: Compounding Quality Act (CQA) ===
Title I of the Drug Quality and Security Act, the Compounding Quality Act, amends the Federal Food, Drug, and Cosmetic Act (FFDCA) with respect to the regulation of compounding drugs. The act exempts compounded drugs from new drug requirements, labeling requirements, and track-and-trace requirements of the DCSCA if the drug is compounded by or under the direct supervision of a licensed pharmacist in a pharmacy or in a registered outsourcing facility and meets applicable requirements. The act also created a new category of regulated entity: human drug compounding outsourcing facilities.
A typical community pharmacy (503A), or specialty pharmacy (503A) may compound only under specific conditions as noted in section 503A of the FD&C Act. A significant portion of the provision that allows this states the compounded product is subject to a prescription requirements for an individual. This is the subject of an official guidance document with the FDA.
Compounding may occur either extemporaneously upon the presentation of a valid prescription or order, or by anticipatory compounding, which would be compounding before the existence of a prescription order. Compounding may be completed only pursuant to a valid patient order and may not be completed for 'office use' or prescriber general use. In the case of office use, a prescriber may utilize compounded products from a 503B outsourcing facility registered with the FDA according to the act. Alternatively a physician may administer or order compounded products from a 503A pharmacy for certain reasons including acute care and inpatient status patients, but subject to the valid order clauses.
In the case of extemporaneous compounding, a pharmacy may compound on the presentation of a valid patient order according to provisions in the FD&C Act.
For anticipatory compounding a pharmacy may compound: “limited quantities before the receipt of a valid prescription order for such individual patient” if: 1. The compounding is based on a history of the licensed pharmacist or licensed physician receiving valid prescription orders for the compounding of the human drug product; and 2. The orders have been generated solely within an established relationship between the licensed pharmacist or licensed physician and either such patient for whom the prescription order will be provided or the physician or other licensed practitioner who will write such prescription order.
Under section 503B of the FD&C Act, a human drug compounder can elect to register with the Food and Drug Administration (FDA) as an outsourcing facility. An outsourcing facility is defined as “a facility at one geographic location or address that (i) is engaged in the compounding of sterile drugs; (ii) has elected to register as an outsourcing facility; (iii) and complies with all of the requirements of this section.”
(Section 503B(d)(4) of the FD&C Act.)
CQA authorizes FDA to assess and collect fees from entities that register with FDA as outsourcing facilities. FDA spends fee revenues to hire, support, and maintain personnel for the oversight of these outsourcing facilities.
Outsourcing facilities are subject to current good manufacturing practice (CGMP) requirements under section 501(a)(2)(B) of the FD&C Act and will be inspected by FDA on a risk-based schedule (see sections 503B(a) and 503B(b)(4)). Drug products compounded by or under the direct supervision of a licensed pharmacist at an outsourcing facility may be able to qualify for exemptions from the following three sections of the FD&C Act: (1) section 505 (concerning FDA approval of drugs); (2) section 502(f)(1) (concerning the labeling of drug products with adequate directions for use); and section 582 (concerning the drug supply chain security requirements). An outsourcing facility is not required to be a licensed pharmacy and may or may not obtain patient-specific prescriptions.
To qualify for the exemptions, certain conditions must be met. For example, outsourcing facilities must report the drugs that they compound, as well as certain adverse events, to FDA. They must not compound drugs that are essentially copies of one or more approved drugs, and the compounded drugs must not be sold or transferred by an entity other than the outsourcing facility that compounded them. CQA lists the conditions under which drugs compounded by outsourcing facilities can qualify for the exemptions in section 503B and is available on FDA's website.
Under CQA, outsourcing facility fees shall be used to supplement and not supplant any other federal funds available to carry out the activities relating to outsourcing facility oversight (section 744K(d) and section 744K(e)). Therefore, the fees are used to augment appropriations that FDA uses for oversight of outsourcing facilities. CQA requires FDA to submit an annual report to Congress no later than 120 days after each fiscal year (section 744K(h) of the FD&C Act). As required by statute, this report presents: 1) a description of fees assessed; 2) a description of fees collected; 3) a summary description of entities paying the fees; 4) a description of the hiring and placement of new staff; 5) a description of the use of fee resources to support inspecting outsourcing facilities; and 6) the number of inspections and reinspections of facilities performed each year.
The act also revised compounding pharmacy requirements to repeal prohibitions on advertising and promotion of compounded drugs by compounding pharmacies and repealed the requirement that prescriptions filled by a compounding pharmacy be unsolicited.
The act requires the Comptroller General (GAO) to report on pharmacy compounding and the adequacy of state and federal efforts to assure the safety of compounded drugs.
=== Title II: Drug Supply Chain Security Act (DSCSA) ===
Title II of the act, the Drug Supply Chain Security Act (DSCSA), established requirements to facilitate the tracing of prescription drug products through the pharmaceutical supply distribution chain.
Under DSCSA, the Secretary is required to establish standards for the exchange of transaction documentation, including transaction information, transaction history, and transaction statements. The Secretary must also establish processes to: (1) provide waivers of requirements, including for undue economic hardship or emergency medical reasons; (2) provide exceptions to requirements relating to product identifiers if a product is packaged without sufficient space to bear the information; and (3) determine other products or transactions that should be exempt from the requirements of the act.
==== Requirements ====
The act established requirements for drug manufacturers, wholesalers, dispensers, and repackagers:
Manufacturers, wholesalers, dispensers, and repackagers are required to ensure that all prior transaction information is provided at each transfer of ownership.
In the event of a recall or for the purpose of investigating a suspect product or an illegitimate product, manufacturers, wholesale distributors, dispensers, and repackagers are required to provide within a reasonable time the applicable transaction documentation upon request by the Secretary or other appropriate federal or state official.
Manufacturers and repackagers are required to affix or imprint a product identifier on each package and homogeneous case intended to be introduced in a transaction into commerce except for products that are required to have a standardized numerical identifier.
Manufacturers, wholesale distributors, dispensers, and repackagers are all required to ensure that each of their trading partners are authorized.
Manufacturers, wholesale distributors, dispensers, and repackagers are required to implement systems to: (1) investigate suspect products; and (2) handle illegitimate products, including through quarantine, disposal, and appropriate notice to the Secretary and, as necessary, trading partners.
Manufacturers, wholesale distributors, and repackagers are required to verify returned products before further distribution.
The act contains a provision that allows a dispenser to enter into a written agreement with a third party, including an authorized wholesale distributor, that requires the third party to maintain confidentially any information and statements required to be maintained. The Secretary is required to provide for alternative methods of compliance with such additional drug distribution security requirements.
The act preempts state and local requirements related to tracing drugs through the distribution system, and licensure of wholesale distributors and third party logistics providers.
==== 2023 timeline ====
Section 203 of the act prescribes additional requirements related to the tracing of products at the package level (enhanced drug distribution security) to enter into effect by November 27, 2023.
Under this section, the Secretary is required to: (1) establish one or more pilot projects and hold public meetings to enhance the safety and security of the pharmaceutical distribution supply chain, (2) issue a final guidance document that outlines and makes recommendations with respect to the system attributes necessary to enable secure tracing at the package level, and (3) identify and make recommendations with respect to the standards necessary for adoption in order to support the secure interoperable electronic data exchange among the pharmaceutical distribution supply chain that comply with a form and format developed by a widely recognized international standards development organization. The act also requires the Secretary to establish standards for the licensing of wholesale distributors and third party logistics providers.
In November 2019, the regulatory milestone requiring wholesalers to verify the authenticity of product returns was delayed by the FDA for one year.
==== FDA pilot project program ====
In 2016, public meetings were held to discuss proposed design objectives of pilot projects. In 2019, the FDA announced a DSCSA Pilot Project Program and selected 20 participants. These included standards organizations and industry associations, manufacturers, wholesale distributors, logistics providers, and dispensers. At least six of the pilots involved the use of blockchain technologies. In 2020, 16 of the pilots released their findings to the public.
== Procedural history ==
The Drug Quality and Security Act was introduced in the United States House of Representatives on September 27, 2013, by Rep. Fred Upton (R, MI-6). It was referred to the United States House Committee on Energy and Commerce. The House voted on September 28, 2013, to pass the bill in a voice vote.
The Drug Quality and Security Act was received in the Senate on September 30, 2013. The Senate began working on the bill on November 12, 2013. They voted 97–1 to begin working on the bill; Senator Vitter was the only "no" vote. The Senate passed the bill without amendments on November 18, 2013.
The bill was presented to President Obama on November 21, 2013, and signed into law on November 27.
== Debate and discussion ==
The Hill reported that the bill had "broad bipartisan support" in both the House and the Senate.
=== Vitter filibuster ===
Senator David Vitter (R-LA) filibustered the bill, using that tactic to try to get the Senate to vote on the Show Your Exemption Act. That bill would require Senators and Representatives to "disclose which of their staff they have exempted from enrolling in insurance through the ObamaCare health exchange." Majority Leader Harry Reid criticized this move, insisting that the Drug Quality and Security Act was more important to finish. Reid also vowed not to "let one senator dictate what goes on here in the Senate."
== See also ==
List of bills in the 113th United States Congress
Drugs in the United States
New England Compounding Center meningitis outbreak
Drug distribution
== Notes/References ==
== External links ==
Library of Congress - Thomas H.R. 3204
beta.congress.gov H.R. 3204
GovTrack.us H.R. 3204
OpenCongress.org H.R. 3204
WashingtonWatch.com H.R. 3204
Congressional Budget Office report on H.R. 3204
Scant Oversight of Drug Maker in Fatal Meningitis Outbreak - New York Times, October 6, 2012
This article incorporates public domain material from websites or documents of the United States government. | Wikipedia/Drug_Quality_and_Security_Act |
Estradiol benzoate butyrate (EBB), sold under the brand names Neolutin N, Redimen, Soluna, and Unijab and formerly known under the developmental code name Unimens, is an estrogen medication which is used in hormonal birth control for women. It is formulated in combination with dihydroxyprogesterone acetophenide (DHPA; algestone acetophenide), a progestin, and is used specifically as a combined injectable contraceptive. EBB is not available for medical use alone. The medication, in combination with DHPA, is given by injection into muscle once a month.
Side effects of EBB include breast tenderness, breast enlargement, nausea, headache, and fluid retention. EBB 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.
EBB was first described in 1938. It was developed for use as a form of birth control in the 1970s and was introduced for medical use for this indication by the 1980s. The medication is used in combination with DHPA as a combined injectable contraceptive in Peru and Singapore.
== Medical uses ==
EBB is used in combination with DHPA as a once-a-month combined injectable contraceptive to prevent pregnancy in women.
=== Available forms ===
The combination of EBB and DHPA contains 10 mg estradiol benzoate butyrate (EBB), an estrogen, and 150 mg algestone acetophenide (dihydroxyprogesterone acetophenide; DHPA), a progestin.
== Side effects ==
The combination of EBB and DHPA is said to be associated with poor control of menstrual bleeding when used as a once-a-month combined injectable contraceptive.
== Pharmacology ==
=== Pharmacodynamics ===
EBB is an estradiol ester, or a prodrug of estradiol. As such, it is an estrogen, or an agonist of the estrogen receptors. EBB is of about 64% higher molecular weight than estradiol due to the presence of its C3 benzoate and C17β butyrate esters. Because EBB is a prodrug of estradiol, it is considered to be a natural and bioidentical form of estrogen.
The estrogenic potency of oral ethinylestradiol is approximately 30-fold higher than that of parenteral EBB. In accordance, 50 μg/day oral ethinylestradiol has been reported to be about 3 times stronger in estrogenic effect than once-a-month injections of 10 mg EBB.
=== Pharmacokinetics ===
A single 10 mg intramuscular injection of EBB has a duration of approximately 3 weeks. Its duration is shorter than that of estradiol enantate. A preliminary study of the duration of EBB relative to other estradiol esters was conducted in 1952.
== Chemistry ==
EBB is a synthetic estrane steroid and the C3 benzoate (benzenecarboxylate) and C17β butyrate (butanoate) diester of estradiol. It is also known as estradiol 3-benzoate 17β-n-butyrate or as estra-1,3,5(10)-triene-3,17β-diol 3-benzoate 17β-n-butyrate.
The experimental octanol/water partition coefficient (logP) of EBB is 6.3.
== History ==
EBB, along with a variety of other estradiol esters, was first described in 1938 by Karl Miescher and colleagues of Ciba in Basel, Switzerland. It was developed in combination with DHPA as a combined injectable contraceptive in the 1970s. The combination was marketed for use as a combined injectable contraceptive in Peru by 1987.
== Society and culture ==
=== Brand names ===
EBB is marketed in combination with DHPA under the brand names Neolutin N, Redimen, Soluna, and Unijab. It was originally developed under the tentative brand name Unimens, but ultimately was not marketed under this particular brand name.
=== Availability ===
The combination of EBB and DHPA is available only in Peru and Singapore.
== See also ==
Estradiol benzoate butyrate/dihydroxyprogesterone acetophenide
== References == | Wikipedia/Estradiol_benzoate_butyrate |
Low-density lipoprotein (LDL) is one of the five major groups of lipoprotein that transport all fat molecules around the body in extracellular water. These groups, from least dense to most dense, are chylomicrons (aka ULDL by the overall density naming convention), very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL) and high-density lipoprotein (HDL). LDL delivers fat molecules to cells. LDL has been associated with the progression of atherosclerosis.
== Overview ==
Lipoproteins transfer lipids (fats) around the body in the extracellular fluid, making fats available to body cells for receptor-mediated endocytosis. Lipoproteins are complex particles composed of multiple proteins, typically 80–100 proteins per particle (organized by a single apolipoprotein B for LDL and the larger particles). A single LDL particle is about 22–27.5 nanometers in diameter, typically transporting 3,000 to 6,000 fat molecules per particle and varying in size according to the number and mix of fat molecules contained within. The lipids carried include all fat molecules with cholesterol, phospholipids, and triglycerides dominant; amounts of each vary considerably.
A good clinical interpretation of blood lipid levels is that high LDL, in combination with a low amount of HDL, is associated with an increased risk of cardiovascular diseases.
== Biochemistry ==
=== Structure ===
Each native LDL particle enables emulsification, i.e. surrounding the fatty acids being carried, enabling these fats to move around the body within the water outside cells. Each particle contains a single apolipoprotein B-100 molecule (Apo B-100, a protein that has 4536 amino acid residues and a mass of 514 kDa), along with 80 to 100 additional ancillary proteins. Each LDL has a highly hydrophobic core consisting of polyunsaturated fatty acid known as linoleate and hundreds to thousands (about 1500 commonly cited as an average) of esterified and unesterified cholesterol molecules. This core also carries varying numbers of triglycerides and other fats and is surrounded by a shell of phospholipids and unesterified cholesterol, as well as the single copy of Apo B-100. LDL particles are approximately 22 nm (0.00000087 in.) to 27.5 nm in diameter and have a mass of about 3 million daltons. Since LDL particles contain a variable and changing number of fatty acid molecules, there is a distribution of LDL particle mass and size. Determining the structure of LDL has been difficult for biochemists because of its heterogeneous structure. However, the structure of LDL at human body temperature in native condition, with a resolution of about 16 Angstroms using cryogenic electron microscopy, has been described in 2011.
== Physiology ==
LDL particles are formed when triglycerides are removed from VLDL by the lipoprotein lipase enzyme (LPL), and they become smaller and denser (i.e., fewer fat molecules with the same protein transport shell), containing a higher proportion of cholesterol esters.
=== Transport into the cell ===
When a cell requires more cholesterol than its HMG-CoA pathway can produce, it synthesizes the necessary LDL receptors as well as PCSK9, a proprotein convertase that marks the LDL receptor for degradation. LDL receptors are inserted into the plasma membrane and diffuse freely until they associate with clathrin-coated pits. When LDL receptors bind LDL particles in the bloodstream, the clathrin-coated pits are endocytosed into the cell.
Vesicles containing LDL receptors bound to LDL are delivered to the endosome. In the presence of low pH, such as that found in the endosome, LDL receptors undergo a conformation change, releasing LDL. LDL is then shipped to the lysosome, where cholesterol esters in the LDL are hydrolysed. LDL receptors are typically returned to the plasma membrane, where they repeat this cycle. If LDL receptors bind to PCSK9, however, transport of LDL receptors is redirected to the lysosome, where they are degraded.
=== Role in the innate immune system ===
LDL interferes with the quorum sensing system that upregulates genes required for invasive Staphylococcus aureus infection. The mechanism of antagonism entails binding apolipoprotein B to a S. aureus autoinducer pheromone, preventing signaling through its receptor. Mice deficient in apolipoprotein B are more susceptible to invasive bacterial infection.
=== LDL size patterns ===
LDL can be grouped based on its size: large low-density LDL particles are described as pattern A, and small high-density ("small dense") LDL particles are pattern B. Pattern B has been associated by some with a higher risk for Coronary artery disease.: 1–10 This is thought to be because the smaller particles are more easily able to penetrate the endothelium of arterial walls. Pattern I, or intermediate, indicates that most LDL particles are very close in size to the normal gaps in the endothelium (26 nm). According to one study, sizes 19.0–20.5 nm were designated as pattern B and LDL sizes 20.6–22 nm were designated as pattern A.
Some evidence suggests the correlation between pattern B and coronary artery disease is stronger than the correspondence between the LDL number measured in the standard lipid profile test. Tests to measure these LDL subtype patterns have been more expensive and not widely available, so the standard lipid profile test is used more often.
There has also been noted a correspondence between higher triglyceride levels and higher levels of smaller, denser LDL particles and alternately lower triglyceride levels and higher levels of the larger, less dense ("buoyant") LDL.
With continued research, decreasing cost, greater availability, and wider acceptance of other lipoprotein subclass analysis assay methods, including NMR spectroscopy, research studies have shown a stronger correlation between clinically evident human cardiovascular events and quantitatively measured particle concentrations.
=== Oxidized LDL ===
Oxidized LDL (oxLDL) is a general term for LDL particles with oxidatively modified structural components. As a result, from free radical attack, both lipid and protein parts of LDL can be oxidized in the vascular wall. Besides the oxidative reactions in the vascular wall, oxidized lipids in LDL can also be derived from oxidized dietary lipids. Oxidized LDL is known to associate with the development of atherosclerosis, and it is therefore widely studied as a potential risk factor of cardiovascular diseases. Atherogenicity of oxidized LDL has been explained by lack of recognition of oxidation-modified LDL structures by the LDL receptors, preventing the normal metabolism of LDL particles and leading eventually to the development of atherosclerotic plaques. Of the lipid material contained in LDL, various lipid oxidation products are known as the ultimate atherogenic species. Acting as a transporter of these injurious molecules is another mechanism by which LDL can increase the risk of atherosclerosis.
The LOX-1 scavenge receptor does take up oxLDL, but the liver does not naturally express it. It is instead expressed by endothelial cells, platelets, macrophages, smooth muscle cells, and cardiomyocytes as an innate immune scavenge receptor. When activated, pro-inflammatory signals are generated in the cell, and damaging compounds are released as well. As a result, these cells are most sensitive to the effects of oxLDL. SR-BI and CD36, two class B scavenge receptors, also take up oxLDL into the macrophage.
Despite lower recognition efficacy by the LDLR, the liver does remove oxLDLs from the circulation. This is achieved by Kupffer cells and liver sinusoidal endothelial cells (LSECs). In LSECs, stabilin-1 and stabilin-2 mediate most of the uptake. Uptake of oxLDLs causes visible disruption to the structure of the LSEC in rats. Doing the same also damages human LSEC cultures.
=== Acetyl LDL ===
Acetyl LDL (acLDL) is a construct generated in vitro. When scientists produced such a modified version of LDL, they found that a class of scavenge receptors, now called SR-A, can recognize them and take them up. Because scavenge receptors work much faster than the downregulated native LDL receptor of a macrophage, oxLDL and acLDL can both fill up a macrophage quickly, turning it into a foam cell.
== Testing ==
Blood tests commonly report LDL-C: the amount of cholesterol that is estimated to be contained with LDL particles, on average, using a formula, the Friedewald equation. In a clinical context, mathematically calculated estimates of LDL-C are commonly used to estimate how much low-density lipoproteins drive the progression of atherosclerosis. The problem with this approach is that LDL-C values are commonly discordant with both direct measurements of LDL particles and actual rates of atherosclerosis progression.
Direct LDL measurements are also available and better reveal individual issues but are less often promoted or done due to slightly higher costs and are available from only a couple of laboratories in the United States. In 2008, the ADA and ACC recognized direct LDL particle measurement by NMR as superior for assessing individual risk of cardiovascular events.
=== Estimation of LDL particles via cholesterol content ===
Chemical measures of lipid concentration have long been the most-used clinical measurement, not because they have the best correlation with individual outcomes but because these lab methods are less expensive and more widely available.
The lipid profile does not measure LDL particles. It only estimates them using the Friedewald equation
by subtracting the amount of cholesterol associated with other particles, such as HDL and VLDL, assuming a prolonged fasting state, etc.:
L
≈
C
−
H
−
k
T
{\displaystyle L\approx C-H-kT}
where H is HDL cholesterol, L is LDL cholesterol, C is total cholesterol, T is triglycerides, and k is 0.20 if the quantities are measured in mg/dL and 0.45 in mmol/L.
There are limitations to this method, most notably that samples must be obtained after a 12 to 14 h fast and that LDL-C cannot be calculated if plasma triglyceride is >4.52 mmol/L (400 mg/dL). Even at triglyceride levels of 2.5 to 4.5 mmol/L, this formula is considered inaccurate. If both total cholesterol and triglyceride levels are elevated then a modified formula, with quantities in mg/dL, may be used
L
=
C
−
H
−
0.16
T
{\displaystyle L=C-H-0.16T}
This formula provides an approximation with fair accuracy for most people, assuming the blood was drawn after fasting for about 14 hours or longer, but does not reveal the actual LDL particle concentration because the percentage of fat molecules within the LDL particles, which are cholesterol, varies as much as 8:1 variation. There are several formulas published addressing the inaccuracy in LDL-C estimation. The inaccuracy is based on the assumption that VLDL-C (Very low density lipoprotein cholesterol) is always one-fifth of the triglyceride concentration. Other formulae address this issue by using an adjustable factor or using a regression equation. There are few studies which have compared the LDL-C values derived from this formula and values obtained by direct enzymatic method. Direct enzymatic methods are found to be accurate and must be the test of choice in clinical situations. In resource-poor settings, the option to use the formula has to be considered.
However, the concentration of LDL particles, and to a lesser extent, their size, has a stronger and consistent correlation with individual clinical outcomes than the amount of cholesterol within LDL particles, even if the LDL-C estimation is approximately correct. There is increasing evidence and recognition of the value of more targeted and accurate measurements of LDL particles. Specifically, LDL particle number (concentration) and, to a lesser extent, size have shown slightly stronger correlations with atherosclerotic progression and cardiovascular events than obtained using chemical measures of the amount of cholesterol carried by the LDL particles. It is possible that the LDL cholesterol concentration can be low, yet LDL particle number high and cardiovascular events rates are high. Correspondingly, it is possible that LDL cholesterol concentration can be relatively high, yet LDL particle number is low, and cardiovascular events are also low.
==== Normal ranges ====
In the US, the American Heart Association, NIH, and NCEP provide a set of guidelines for fasting LDL-Cholesterol levels, estimated or measured, and risk for heart disease. As of about 2005, these guidelines were:
Over time, with more clinical research, these recommended levels keep being reduced because LDL reduction, including to abnormally low levels, was the most effective strategy for reducing cardiovascular death rates in one large double blind, randomized clinical trial of men with hypercholesterolemia; far more effective than coronary angioplasty/stenting or bypass surgery.
The 2004 updated American Heart Association, NIH, and NCEP recommendations for people with known atherosclerosis diseases are for lowering LDL levels to less than 70 mg/dL. This low level of less than 70 mg/dL was recommended for primary prevention of 'very-high risk patients' and secondary prevention as a 'reasonable further reduction'. This position was disputed. Statin drugs involved in such clinical trials have numerous physiological effects beyond simply the reduction of LDL levels.
From longitudinal population studies following the progression of atherosclerosis-related behaviors from early childhood into adulthood, the usual LDL in childhood, before the development of fatty streaks, is about 35 mg/dL. However, all the above values refer to chemical measures of lipid/cholesterol concentration within LDL, not measured low-density lipoprotein concentrations, which is the accurate approach.
A study was conducted measuring the effects of guideline changes on LDL cholesterol reporting and control for diabetes visits in the US from 1995 to 2004. It was found that although LDL cholesterol reporting and control for diabetes and coronary heart disease visits improved continuously between 1995 and 2004, neither the 1998 ADA guidelines nor the 2001 ATP III guidelines increased LDL cholesterol control for diabetes relative to coronary heart disease.
=== Direct measurement of LDL particle concentrations ===
There are several competing methods for measuring lipoprotein particle concentrations and size. The evidence is that the NMR methodology (developed, automated & significantly reduced in costs while improving accuracy as pioneered by Jim Otvos and associates) results in a 22-25% reduction in cardiovascular events within one year, contrary to the longstanding claims by many in the medical industry that the superiority over existing methods was weak, even by statements of some proponents.
Since the later 1990s, because of the development of NMR measurements, it has been possible to clinically measure lipoprotein particles at lower cost [under $80 US (including shipping) & is decreasing versus the previous costs of >$400 to >$5,000] and higher accuracy. There are two other assays for LDL particles; however, most estimate only LDL particle concentrations like LDL-C.
The ADA and ACC mentioned direct LDL particle measurement by NMR in a 28 March 2008 joint consensus statement, as having advantages for predicting individual risk of atherosclerosis disease events, but the statement noted that the test is less widely available, is more expensive [about $13.00 US (2015 without insurance coverage) from some labs which use the Vantera Analyzer]. Debate continues that it is "...unclear whether LDL particle size measurements add value to the measurement of LDL-particle concentration", though outcomes have continuously tracked LDL particle, not LDL-C, concentrations.
Using NMR, the total LDL particle concentrations in nmol/L plasma are typically subdivided by percentiles referenced to the 5,382 men and women participating in the MESA trial who are not on any lipid medications.
LDL particle concentration can also be measured by measuring the concentration of the protein ApoB, based on the generally accepted principle that each LDL or VLDL particle carries one ApoB molecule.
==== Optimal ranges ====
The LDL particle concentrations are typically categorized by percentiles, <20%, 20–50%, 50th–80th%, 80th–95%, and >95% groups of the people participating and being tracked in the MESA trial, a medical research study sponsored by the United States National Heart, Lung, and Blood Institute.
Over time, the lowest incidence of atherosclerotic events occurs within the <20% group, with increased rates for the higher groups. Multiple other measures, including particle sizes, small LDL particle concentrations, large total and HDL particle concentrations, along with estimations of insulin resistance pattern and standard cholesterol lipid measurements (for comparison of the plasma data with the estimation methods discussed above) are also routinely provided.
== Lowering LDL-cholesterol ==
The mevalonate pathway serves as the basis for the biosynthesis of many molecules, including cholesterol. The enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG CoA reductase) is an essential component and performs the first of 37 steps within the cholesterol production pathway, and is present in every animal cell. Statins block this first step.
LDL-C is not a count of actual LDL particles. LDL-C represents how much cholesterol is being transported by all LDL particles, which is either a smaller concentration of large particles or a high concentration of small particles. LDL-C itself can be estimated by subtraction (Friedewald's method) or directly measured; see the section #Testing above to see how it's measured. LDL particles carry many lipid molecules (typically 3,000 to 6,000 lipid molecules per LDL particle); this includes cholesterol, triglycerides, phospholipids and others. An LDL-C measurement cannot account for differences in size and composition between types of LDL.
=== Pharmaceutical ===
PCSK9 inhibitors, in clinical trials, by several companies, are more effective for LDL reduction than the statins, including statins alone at high dose (though not necessarily the combination of statins plus ezetimibe). They have been approved and are recommended in patients not receiving enough reduction from their maximally tolerated dose of statins + ezetimibe.
Statins reduce high levels of LDL particles by inhibiting the enzyme HMG-CoA reductase in cells, the rate-limiting step of cholesterol synthesis. To compensate for the decreased cholesterol availability, synthesis of LDL receptors (including hepatic) is increased, resulting in an increased clearance of LDL particles from the extracellular water, including of the blood.
Ezetimibe reduces intestinal absorption of cholesterol, thus can reduce LDL particle concentrations when combined with statins.
Niacin (nicotinic acid), lowers LDL by selectively inhibiting hepatic diacylglycerol acyltransferase 2, reducing triglyceride synthesis and VLDL secretion through a receptor HM74 and HM74A or GPR109A. Introduced in 1955.
Clofibrate is effective at lowering cholesterol levels, but has been associated with significantly increased cancer and stroke mortality, despite lowered cholesterol levels. Other developed and tested fibrates, e.g. fenofibric acid have had a better track record and are primarily promoted for lowering VLDL particles (triglycerides), not LDL particles, yet can help some in combination with other strategies.
Probucol, introduced in the 1970s. Now known to work through, among other ways, changing the shape and size of the LDL particle so they can be taken up by the liver without involving the LDL receptor. It has been discontinued in the west due to HDL-C decreases that were not explainable at the time. It's now known that it enhances the reverse cholesterol transport and antioxidant functions of HDL despite decreasing HDL-C.
==== Not approved as drugs ====
Several CETP inhibitors have been researched to improve HDL concentrations, but so far, despite dramatically increasing HDL-C, have not had a consistent track record in reducing atherosclerosis disease events. Some have increased mortality rates compared with placebo.
Some tocotrienols, especially delta- and gamma-tocotrienols, are being promoted as statin alternative non-prescription agents to treat high cholesterol, having been shown in vitro to have an effect. In particular, gamma-tocotrienol appears to be another HMG-CoA reductase inhibitor, and can reduce cholesterol production. As with statins, this decrease in intra-hepatic (liver) LDL levels may induce hepatic LDL receptor up-regulation, also decreasing plasma LDL levels. As always, a key issue is how benefits and complications of such agents compare with statins—molecular tools that have been analyzed in large numbers of human research and clinical trials since the mid-1970s.
Phytosterols are widely recognized as having a proven LDL cholesterol lowering efficacy' A 2018 review found a dose-response relationship for phytosterols, with intakes of 1.5 to 3 g/day lowering LDL-C by 7.5% to 12%, but reviews as of 2017 had found no data indicating that the consumption of phytosterols may reduce the risk of CVD. Current supplemental guidelines for reducing LDL recommend doses of phytosterols in the 1.6-3.0 grams per day range (Health Canada, EFSA, ATP III, FDA) with a 2009 meta-analysis demonstrating an 8.8% reduction in LDL-cholesterol at a mean dose of 2.15 gram per day.
=== Lifestyle ===
LDL cholesterol can be lowered through dietary intervention by limiting foods with saturated fat and avoiding foods with trans fat. Saturated fats are found in meat products (including poultry), full-fat dairy, eggs, and refined tropical oils like coconut and palm. Added trans fat (in the form of partially hydrogenated oils) has been banned in the US since 2021. However, trans fat can still be found in red meat and dairy products as it is produced in small amounts by ruminants such as sheep and cows. LDL cholesterol can also be lowered by increasing consumption of soluble fiber and plant-based foods.
Another lifestyle approach to reduce LDL cholesterol has been minimizing total body fat, in particular fat stored inside the abdominal cavity (visceral body fat). Visceral fat, which is more metabolically active than subcutaneous fat, has been found to produce many enzymatic signals, e.g. resistin, which increase insulin resistance and circulating VLDL particle concentrations, thus both increasing LDL particle concentrations and accelerating the development of diabetes mellitus.
== Research ==
Some studies dispute the benefits of low LDL in elderly people, but not in other age groups.
=== Gene editing ===
In 2021, scientists demonstrated that CRISPR gene editing can decrease blood levels of LDL cholesterol in Macaca fascicularis monkeys for months by 60% via knockout of PCSK9 in the liver.
== See also ==
== Notes and references ==
== External links ==
Fat (LDL) Degradation: PMAP The Proteolysis Map-animation
Adult Treatment Panel III Full Report
ATP III Update 2004
O'Keefe JH, Cordain L, Harris WH, Moe RM, Vogel R (June 2004). "Optimal low-density lipoprotein is 50 to 70 mg/dL: lower is better and physiologically normal". Journal of the American College of Cardiology. 43 (11): 2142–6. doi:10.1016/j.jacc.2004.03.046. PMID 15172426. | Wikipedia/Low_density_lipoprotein |
Chorea, or (rarely) choreia, () is an abnormal involuntary movement disorder, characterized by quick movements of the hands or feet. It is one of a group of neurological disorders called dyskinesias. The term chorea is derived from Ancient Greek χορεία (choreia) 'dance', as the movements of the body is comparable to dancing.
The term hemichorea refers to chorea of one side of the body, such as chorea of one arm but not both (analogous to hemiballismus).
== Presentation ==
Chorea is characterized by brief, semi-directed, irregular movements that are not repetitive or rhythmic, but appear to flow from one muscle to the next. These 'dance-like' movements of chorea often occur with athetosis, which adds twisting and writhing movements. Walking may become difficult and include odd postures and leg movements. Unlike ataxia, which affects the quality of voluntary movements, or Parkinsonism, which is a hindrance of voluntary movements, the movements of chorea and ballism occur on their own, without conscious effort. Thus, chorea is said to be a hyperkinetic movement disorder. When chorea is serious, slight movements will become thrashing motions; this form of severe chorea is referred to as ballism, or ballismus.
== Causes ==
=== Huntington's disease ===
Huntington's disease is a neurodegenerative disease and most common inherited cause of chorea. The condition was formerly called Huntington's chorea but was renamed because of the important non-choreic features including cognitive decline and behavioural change.
=== Other genetic causes ===
Other genetic causes of chorea are rare. They include the classical Huntington's disease 'mimic' or phenocopy syndromes, called Huntington's disease-like syndrome types 1, 2 and 3; inherited prion disease, the spinocerebellar ataxias type 1, 3 and 17, neuroacanthocytosis, dentatorubral-pallidoluysian atrophy (DRPLA), brain iron accumulation disorders, Wilson's disease, benign hereditary chorea, Friedreich's ataxia, mitochondrial disease and Rett syndrome.
=== Acquired causes ===
The most common acquired causes of chorea are cerebrovascular disease and, in the developing world, HIV infection—usually through its association with cryptococcal disease.
Sydenham's chorea occurs as a complication of streptococcal infection. Twenty percent (20%) of children and adolescents with rheumatic fever develop Sydenham's chorea as a complication. It is increasingly rare, which may be partially due to penicillin, improved social conditions, and/or a natural reduction in the bacteria (Streptococcus) it has stemmed from. Psychological symptoms may precede or accompany this acquired chorea and may be relapsing and remitting. The broader spectrum of paediatric autoimmune neuropsychiatric disorders associated with streptococcal infection can cause chorea and are collectively referred to as PANDAS.
Chorea gravidarum refers to choreic symptoms that occur during pregnancy. If left untreated, the disease resolves in 30% of patients before delivery but, in the other 70%, it persists. The symptoms then progressively disappear in the next few days following the delivery.
Chorea may also be caused by drugs (commonly levodopa, anti-convulsants and anti-psychotics).
Other acquired causes include CSF leak, systemic lupus erythematosus, antiphospholipid syndrome, thyrotoxicosis, polycythaemia rubra vera, transmissible spongiform encephalopathies, coeliac disease and gluten ataxia.
== Treatment ==
There is no standard course of treatment for chorea. Treatment depends on the type of chorea and the associated disease. Although there are many drugs that can control it, no cure has yet been identified.
== History ==
Historically, choreas like Huntington disease and Sydenham's chorea were called Saint Vitus' dance, related to a series of social phenomena of the same name.
== See also ==
Choreoathetosis
Dancing mania
Stimming
Tic
== References ==
== External links ==
Chorea Gravidarum~clinical at eMedicine | Wikipedia/Chorea_(disease) |
Bioidentical hormone replacement therapy (BHRT), also known as bioidentical hormone therapy (BHT) or natural hormone therapy, is the use of hormones that are identical on a molecular level with endogenous hormones in hormone replacement therapy. It may also be combined with blood and saliva testing of hormone levels, and the use of pharmacy compounding to obtain hormones in an effort to reach a targeted level of hormones in the body. A number of claims by some proponents of BHT have not been confirmed through scientific testing. Specific hormones used in BHT include estrone, estradiol, progesterone, testosterone, dehydroepiandrosterone (DHEA), and estriol.
Custom-compounded BHT is a practice almost wholly restricted to the United States and is a form of alternative medicine. It has been promoted as a panacea for many diseases and for relieving the symptoms of menopause beyond the medical objective of reducing the risk of osteoporosis. There is little evidence to support these incremental claims; the hormones are expected to have the same risks and benefits as comparable approved drugs for which there is evidence based on extensive research and regulation, except for progesterone, which may have an improved safety profile than artificial progestogens, though direct comparisons with progestins have not been made. Risks associated with the less-controlled process of compounding bioidentical hormones are not clearly understood. In addition, the accuracy and efficacy of saliva testing have not been definitively proven, and the long-term effects of using blood testing to reach target levels of hormones have not been researched.
The International Menopause Society, American Congress of Obstetricians and Gynecologists, Society of Obstetricians and Gynaecologists of Canada, The Endocrine Society, the North American Menopause Society (NAMS), United States Food and Drug Administration, American Association of Clinical Endocrinologists, American Medical Association, American Cancer Society, and the Mayo Clinic have released statements that there is a lack of evidence that the benefits and risks of bioidentical hormones differ from well-studied non-bioidentical counterparts; until such evidence is produced the risks should be treated as if they are similar; and that compounded hormone products may have additional risks related to compounding. A major safety concern in compounded BHT is that there is no requirement to include package inserts, despite the potential for serious adverse effects (including life-threatening adverse effects) associated with HRT, which can harm consumers as they are misled into believing that any hormone-related problems and dangers are exclusively related to non-bioidentical hormones, and that compounded BHT is safe and has no side effects. In reality, the risks of bioidentical hormones have not been studied to the extent of non-bioidentical hormones, so the risks are not well-understood. Regulatory bodies require pharmacies to include important safety information with conventional hormone replacement therapy (CHRT) via package inserts.
== History ==
Bioidentical hormones were first used for menopausal symptom relief in the 1930s, after Canadian researcher James Collip developed a method to extract an orally active estrogen from the urine of pregnant women and marketed it as the active agent in a product called Emmenin. It was supplanted on the market when its manufacturer, Ayerst (later Wyeth Pharmaceuticals), began producing the more-easily manufactured conjugated equine estrogens in 1941 under the brand name Premarin; by 1992, Premarin was the most widely prescribed drug in the United States.
In the 1970s, research and reports indicating risks from synthetic conjugated estrogens began to appear. Investigations determined that the addition of a progestogen to estrogen treatment reduced the risks. As early as 1980, the British Medical Journal (now The BMJ) recommended oral bioidentical progesterone as an option when side effects from synthetic progestogens otherwise mandated discontinuing treatment. In May 1998 the FDA approved Prometrium, an oral bioidentical progesterone product produced by Solvay Pharmaceutical.
Physicians John R. Lee and Jonathan Wright were pioneers in the field of BHT. Lee authored several popular books on BHT and promoted custom-compounded BHT, with the goal of achieving what he called a "natural hormone balance". He based this goal on the clinical testing of saliva to establish where "deficiencies" existed, though agencies such as the FDA and the American Congress of Obstetricians and Gynecologists state that blood and saliva testing is unreliable and biologically meaningless. Lee also believed that progesterone acted as a panacea and general health tonic for many health conditions, basing his claims on anecdotal data rather than peer-reviewed research, which has not been supported by any clinical trials. Wright also authored a popular book on BHT. Compared to previous bioidentical formulas that only used estradiol, he promoted a triple-estrogen formula called Triest, which combined three estrogens found in human females: estriol, estradiol and estrone. It was based on an unpublished study whose conclusions did account for how estrogens are processed and excreted in the body—particularly how the liver processes oral estrogens, converting most of them to estrone. No follow-up was performed by Wright to replicate these observations. Wright may have been the first proponent of BHT to use the term bioidentical—the word he coined to describe unpatentable, plant-derived molecules he believed were identical to human hormones. However, no structural crystallographic evidence has been used to support the idea that these molecules are identical to endogenous human hormones. When the Women's Health Initiative's reports on the unappreciated risks of equine estrogens were released, many prescribers of BHT used Wright's assertions (and his terminology) to proclaim the superiority of bioidentical molecules despite a lack of scientifically supported evidence. Following the publication of a popular book written by Suzanne Somers in 2006, the term bioidentical gained more prominence in popular consciousness as a "poorly understood new adjective" regarding hormone replacement therapy.
== Terminology ==
There is no single definition for the term bioidentical hormone replacement therapy; it is generally used to refer to 17β-estradiol, but other uses include plant-based or compounded estrogen products that blend estradiol with estriol and sometimes with estrone. A bioidentical hormone is defined as a molecule identical to a hormone produced by the human body (though not all allegedly bioidentical hormones sold by custom-compounding pharmacies are necessarily molecularly identical to endogenous humans). The FDA considers BHT as currently used by BHT advocates to be a marketing term, not a scientific term, and does not recognize its use. The meaning of plant-derived has also been attached to the term bioidentical, and it may also mean that the hormones are "natural"; throughout the 1990s plant-derived, compounded hormones were referred to as "natural hormone therapy". However, the term natural can be applied to all products where the principal ingredient originates from an animal, plant, or mineral source, and both bioidentical and non-bioidentical hormones can be produced from the same plant sources.
BHT is often used to refer to a set of diagnostic, prescribing, preparation and marketing practices including compounding, saliva testing, and an emphasis on countering the effects of aging rather than relieving the symptoms of menopause. This compounded BHT package has been promoted by Somers, Oprah Winfrey, and other proponents as safer and more effective than CHRT, though there is no evidence to support these claims. Compounded BHT has been marketed on the internet by pharmacies that make unfounded claims for its safety and its effectiveness for a variety of conditions.
There are a variety of FDA-approved products, made using bioidentical estrogens and micronized progesterone, used to treat the symptoms of menopause:
The term synthetic is also used incorrectly in two ways: to refer to the process used to manufacture all estrogens, including bioidentical estrogens, and to compounds that interact with estrogen receptors similarly to estrogen molecules but are not found in nature. Examples of the latter two include diethylstilbestrol and ethinylestradiol.
== Uses ==
BHT is used to reduce the symptoms of menopause. It is also promoted by some practitioners for anti-aging purposes providing benefits beyond menopausal symptom relief, such as improving quality of life, though there is little evidence to support these claims.
== Components and compounding ==
Compounded preparations of bioidentical hormones usually include estriol, estrone, estradiol, testosterone, progesterone, and sometimes dehydroepiandrosterone (DHEA), either individually or combined. They are promoted as natural, safer and (in some cases) more efficacious than CHT; however, there are no scientific studies to support claims of superiority of BHT over CHRT. Estimates from sales of bulk hormones for compounding suggest that more than one million women may be using compounded BHT in the United States. Bioidentical hormones are expected to have the same risks as conventional hormones made with the same categories of hormones.
=== Estrogens ===
In premenopausal women the majority of estrogen produced by the body is estradiol (produced primarily in the ovaries), while in postmenopausal women estrone (produced in fat cells) is the type of primary estrogen present; however, the body is able to convert one type of estrogen into another to a certain extent. Because of the limited research into potency, delivery methods, and conversion of the various estrogens, a valid scientific understanding of compounded estrogen products has not been achieved. Synthetic estradiol, taken orally, decomposes when absorbed in the gastrointestinal tract and delivers bioidentical estradiol to the bloodstream.
The hormone estriol, produced during pregnancy, is frequently compounded into bioidentical preparations in the United States. While some think it to be a weaker estrogen, with a more limited period of effectiveness than estradiol, it has been demonstrated to be a stronger estrogen in certain ways. Though initial research in the 1970s suggested possible use, follow-up studies have failed to confirm this potential. Estriol is not found in any FDA-approved drug, and its safety and effectiveness as a hormone supplement is unknown.
Estriol was part of the United States Pharmacopeia before FDA approval was needed for its use. Its approval was grandfathered in by the FDA until 2008 when the agency banned its use, stating that manufacturers of estriol would have to create a new application and estriol would be treated as a new drug. Its use is not approved by Health Canada; estriol is not available as a pharmaceutical preparation in Canada or the United States, but is a commonly prescribed conventional treatment in other countries and is available as a cream or vaginal suppository in the United Kingdom and the European Union. Estradiol is available as brand-name products in both oral and transdermal forms.
=== Progesterone ===
Progesterone is used both orally and transdermally. Oral progesterone is micronized (ground) to increase availability and is approved by the FDA to treat endometrial hyperplasia when used in opposition to estrogen. It has also been approved to relieve menopausal symptoms, either alone or in combination with estrogen. It is more reliable in treating menopausal sleep disorders than synthetic progestins. Transdermal progesterone is often used as a component of compounded BHT but has not been clinically proven to prevent endometrial hyperplasia, as oral progesterone has. The editors-in-chief of the scientific journal Climacteric state that the greatest difference in function between bioidentical and synthetic hormones may be found in progesterone's behavior compared with progestin. Laboratory studies have suggested that bioidentical progesterone binds primarily to progesterone receptors, while synthetic progestins activate other receptors with a variety of effects. The editors suggested that progesterone may have neutral to positive effects on the cardiovascular system, and induce apoptosis in breast epithelial cells. These compounds have not been directly compared with each other in appropriate scientific tests, though as of 2010 trials had begun. Progesterone is approved for use by both the FDA and Health Canada as a brand-name oral preparation. The French epidemiological study "Etude Epidemiologique aupres de femmes de l'Education Nationale" suggested micronized progesterone may offer a reduced risk of breast cancer compared to other progestins, though large-scale clinical trials have not been conducted. A 2012 practice advisory published by Canadian Family Physician concluded "there is no convincing evidence that bioidentical hormones are safer or more effective than synthetic HRT".
=== Other hormones ===
Testosterone supplementation can improve libido in postmenopausal women, but can also reduce levels of high-density lipoproteins. Commercial sources for testosterone for women in the United States are limited and include the estrogen-testosterone mixture Estratest; compounding pharmacies are the main source of testosterone-only preparations for women. A testosterone patch has been approved for use in the United Kingdom and European Union, but in Canada and the United States there is no long-term safety data on it.
DHEA is an androgen precursor that lacks FDA and Health Canada approval for use in women, and is not available in Canada as a pharmaceutical preparation; it is sold as an over-the-counter drug or incorporated into compounded preparations in the United States. In the body, it can be converted into testosterone then estrogen; there are no consistent scientific findings or safety information supporting its use. High levels of DHEA have been linked to breast cancer.
=== Compounding ===
Compounding pharmacies use commercially available bulk drugs to create new formulations which differ in form or dosage from those manufactured on a large scale by pharmaceutical companies. Custom-compounded BHT is almost wholly restricted to the United States, where pharmacy compounding is governed at the state level while the FDA has regulatory authority over the compounded product. Some internet-based compounding pharmacies understate harm and claim benefits of compounded BHT beyond what can be proven by evidence-based medicine, and many of their claims exceed those made by other BHT practitioners.
== Adverse effects ==
BHT benefits and adverse effects are expected to be the same for bioidentical and synthetic hormones. Dosages used in BHT can be as high as ten times the oral dose provided by comparable HRT regimens; the hormones used are known to adversely impact biological markers of cardiovascular disease and may produce a substantially higher risk of heart attack or stroke. There are potentially serious adverse effects and important safety information that is required to be given with FDA approved HRT as package inserts; however, they are typically not given (or required) with compounded bioidentical preparations, which has caused consumers to falsely assume that bioidenticals are safer than FDA-approved hormones or lack any adverse effects—one of the concerns expressed about the hormones. BHT has also been associated with endometrial cancer.
=== Estrogens ===
Less common (but serious) side effects of all post-menopausal estrogens include increased risk or severity of breast, ovarian or uterine cancer; stroke; heart attack; blood clots; dementia; gallbladder disease; high blood pressure, liver problems; high blood sugar, fluid retention, enlargement of benign tumors (fibroids) of the uterus; a spotty darkening of the skin, especially on the face (melasma); and vaginal yeast infection.
==== Estradiol ====
Estradiol only recommended for use for the shortest period of time and at the lowest effective dose due to its adverse-effects profile. There is the potential for a range of adverse effects in breasts, skin, eyes, cardiovascular, gastrointestinal, genitourinary or central nervous systems.
=== Progesterone ===
Progesterone can cause the emergence (or significant worsening) of abdominal pain, constipation, yeast infections, breast cancer, cystitis, acne, conjunctivitis, thrombotic disorders resulting in pulmonary embolus, strokes or heart attacks, epilepsy, migraine, asthma, and cardiac or renal dysfunction. Psychiatric reactions can include emotional instability, depression, aggression, decreased libido, and drowsiness. Adverse effects can also occur in the urinary, central or peripheral nervous, or musculoskeletal systems. A review of clinical trials studying bioidentical progesterone use found that it was ineffective in managing vasomotor symptoms of menopause, but had mild and self-limiting side effects.
== Administration ==
Hormones can be administered in a variety of ways, including percutaneous skin and vaginal creams, oral pills, topical gels, vaginal rings and tablets, and transdermal patches. Although all preparations of a given type of estrogen may be molecularly identical before their introduction into the human body, estrogens administered orally are modified by the liver before entering the bloodstream and most of it is converted to estrone; estrogen bypassing the digestive tract and liver via the skin is not converted to a new form before entering the bloodstream. Creams and gels applied to the skin also enter the blood directly and without modification but absorption of the gels, creams, and patches can vary from application to application, depending on the temperature and condition of the skin.
== Criticisms ==
Advocates for BHT have claimed that commonly compounded BHT preparations are not commercially available, but there are many FDA-approved hormone preparations containing bioidentical molecules available both as proprietary or generic brands. The exception is estriol, used in the compounded bioidentical preparations Triest and Biest—in 2008, the FDA banned estriol until a New Drug Application was completed; these preparations are not approved by the FDA or Health Canada. Some advocates of compounding have also claimed that customized compounding provides customized results, but the claim is weak since compounding is aimed at producing a single hormone profile with absolute blood or saliva levels—which has not been demonstrated to be better than CHRT—and does not consider the rate at which individuals will differ in the activity, metabolism and excretion of the hormones. There have been no clinical trials directly comparing the effectiveness or efficacy of bioidentical versus non-bioidentical compounds.
A 2010 article published in The Medical Letter on Drugs and Therapeutics concluded that "[t]here is no acceptable evidence that 'bioidentical' hormones are safe or effective. Patients should be discouraged from taking them."
=== Salivary testing and compounding ===
BHT is frequently associated with the testing of saliva to establish a baseline hormone level and compounding of the substances by pharmacists (according to a doctor's advice) to produce preparations (and blood levels) of hormones that are specific to each patient. There is no research demonstrating any benefit to either of these practices. Although promoters of BHT claim that saliva testing can be used to customize hormone levels for individuals, and tests are used to determine which hormones are supposed to be deficient and require supplementation, there is no scientific basis to support the use of saliva testing. Estrogens are secreted in pulses within and over days, resulting in varying levels in saliva. Certain compounding formulations also attempt to use a single profile for all women, with no evidence that a specific profile is beneficial in all cases and no recognition that women differ in their sensitivity to hormones and metabolic rate. Testing-based customizing also does not account for much of the effects, and synthesis of hormones occurs within tissues rather than in the blood, so blood or saliva hormone levels may not necessarily reflect the actual biological activity. Other concerns include lack of evidence that samples are stable during storage and transportation, poor replication of results and considerable variation among assays. There are also no studies that link symptoms with blood or saliva hormone levels. The FDA recommends adjusting hormone therapy to the symptoms of the patient, and that there is no reason to adjust the dosing or monitor patients receiving BHT. BHT skeptics have also pointed out that there is no certainty regarding hormone levels in the body. The North American Menopause Society has supported warnings about the potential harm BHT could cause, as it unnecessarily compounds drugs that are already FDA-approved in ways that lack an evidence base of safety or harm. The warnings are supported by the Society of Obstetricians and Gynaecologists of Canada.
Although promoted as a way of customizing treatment, hormone therapy does not require customization; the use of testing to determine the number of hormones administered could result in the dose being higher than the minimum recommended level to alleviate symptoms, or the administration of unnecessary hormones to asymptomatic women may result in greater risks to the patient. Analysis of the material used to promote BHT suggests that rather than basing hormone doses on saliva results, practitioners are adjusting dosage based on symptoms. Different bioidentical preparations result in mixtures with different strengths, and practitioners using compounded formulations may be unaware of the total dose of hormones their patients receive. In a 2001 test of compounded bioidentical hormone products, the FDA found that 10 out of 29 products failed their quality tests; nine out of ten failed potency tests (comparable rates for drug manufacturers were less than 2% and 0.13%, respectively). A 2006 test found potency levels ranging from 67.5% to 268.4% of the potency specified on the label; some samples were mixtures of different hormones with some being above, and others below, the specified potency. The failure of potency testing could be problematic and dangerous for progesterone products, where specific levels of progesterone are required to protect the endometrium against precancerous hyperplasia.
Boothby, Doering, and Kipersztok summarize the issue as being a poor effort to apply principles of pharmacokinetics to achieve individualized dosing for drugs that do not require it.
Saliva testing has not been shown to accurately measure blood-bound hormone levels. The FDA recommends the lowest dose of hormones that effectively relieve symptoms and does not recommend custom compounding, blood or saliva testing.
=== Lack of evidence for claims ===
Bioidentical hormones have been advertised, marketed and promoted as a risk-free panacea that is safer than standard HRT. Literature reviews by private practitioners who sell bioidentical preparations suggest benefits and advantages of BHT over its conventional counterpart, but there is skepticism over claims made about BHT; there is no peer-reviewed evidence that compounded bioidentical hormones are safer or more effective than FDA-approved formulations or that they carry less risk. The hormones are expected to carry the same risks as their conventional counterparts, while the risks of including estriol—a hormone normally produced in large amounts only in pregnant women—have not been studied. The United States FDA warned that claims about compounded BHT products are unsupported by medical evidence. Bioidentical hormones have been described as a form of marketing; the chief medical editor of Endocrine Today called compounded BHT a "marketing concept" with no scientific backing, and the FDA warned that pharmacies use these terms to imply that the drugs are natural and have the same effects as endogenous hormones. Other claims include compounded BHT's ability to prevent or treat conditions such as heart disease, stroke, Alzheimer's disease, endometrial and breast cancer; fewer side effects; and custom blending to uniquely address individuals. There is no credible evidence to support these claims. Bioidentical hormones and compounded BHT are expected to have the same risks and benefits as CHRT; the latter benefits from years of study and regulation, while compounded BHT has no scientific data to support claims of superior safety or efficacy. The following specific claims have been made for the efficacy of bioidentical hormones and compounded BHT, with varying evidence to support or contradict them:
In 2006, Somers released the book Ageless: The Naked Truth About Bioidentical Hormones endorsing the use of bioidentical hormones. The book was criticized by a group of doctors who (though generally supportive of BHT) state that more research is required, and object to protocols mentioned in the book—because of their potential danger and the promoters' lack of qualifications. Somers' book may have increased awareness of the existence of BHT for a growing number of menopausal women, but also may have caused confusion by making unsubstantiated claims for BHT and referring to bioidentical hormones as non-drug products with fewer risks. Bioidentical hormones have also been discussed on The Oprah Winfrey Show, with Somers as a guest.
Michael Cirigliano and Judi Chervenak have stated in reviews of the literature on BHT that large-scale, peer-reviewed studies should be used to establish the safety, efficacy and beliefs about the use of bioidentical hormones. Two 2008 studies conducted in France found that estradiol plus micronized progesterone did not increase the incidence of breast cancer, while a comparison of estradiol plus different types of progestins found a reduced risk of invasive breast cancer with micronized progesterone. Christine Derzko stated that the evidence supported the use of bioidentical estrogen plus progesterone, but since the trial was an observational cohort study rather than a randomized controlled trial that compared different types of hormones head-to-head, more data was required before concluding bioidentical hormones were safer and preferred. Derzko concluded that there was weak (but promising) preliminary evidence that bioidentical hormones may present equal (or possibly lower) risks than conventional HRT; however, there was no data supporting the use of compounding. Derzko recommended following evidence-based medicine and cited concerns over BHT by numerous medical organizations—requirements for oversight over compounding, black box warnings for all bioidentical products, and the establishment of mandatory adverse-events registry.
M. Sarah Rosenthal, Director of the University of Kentucky Program for Bioethics and Patients' Rights, has stated that she believes BHT is an experimental therapy that is often prescribed by practitioners who sell the products, and are thus in an unethical position of conflict of interest. Rosenthal has also described problematic issues with BHT including patients receiving information from popular books while lacking the scientific literacy to separate rhetoric from evidence about hormone replacement, illegitimate claims of a "big pharma" conspiracy to suppress bioidentical prescribing, the extra and unnecessary cost of the products that are often not covered by insurance plans, and the inaccurate depiction of bioidentical prescribing as "cutting edge science" rather than unproven alternative medicine.
=== "Natural" claims ===
Bioidentical hormones are frequently marketed as being "natural", or more natural than conventional HRT. The term natural can be used to suggest or emphasize a variety of different ideas—similarity with endogenous hormones, extraction from a plant-based source, and that the hormones are not manufactured or synthesized.
Endogeny: this meaning of natural implies that the hormones are molecularly identical to those found within the body. However, BHT is unnatural as it opposes the biologically determined declining levels of fertility hormones in aging women and medicalizes a stage of human life that is probably normal. Most of the conjugated equine estrogens extracted from pregnant horse urine (such as Premarin) are converted to human estrogens once they enter the body. However, not all are converted, and BHT advocates allege that the small amount that is not converted may have some harmful effects. This is still being studied.
Plant-derived: Women who purchase compounded BHT are more likely to associate natural with the idea that the hormones are derived from plant sources. However, both bioidentical and non-bioidentical hormones are sourced from the same plants, generally soy beans or yams.
Manufacturing: both bioidentical and non-bioidentical hormones are synthesized using the same chemical precursors; diosgenin is extracted from soy or yam plants, converted into progesterone and used as a hormone chemical precursor to create the final product. "Natural" is also used to promote the idea of being unmodified, and containing the "goodness" of a pure substance. However, this argument simultaneously draws upon a scientific discourse and methodology; even hormones called "bioidentical" have been heavily processed and converted in a pharmaceutical lab. Premarin (conjugated estrogens extracted from the urine of pregnant horses) contains the only truly "natural" hormones—natural in the sense of being completely unmodified beyond blending the estrogens to achieve a specific ratio.
The monthly newsletter Harvard Women's Health Watch, published by Harvard Medical School, states that natural does not automatically mean safe, and that it can be used to indicate any product with an animal, plant, or mineral source—including hormones that are not bioidentical (such as Premarin), as well as the molecules extracted from soybean and yam sources used in many bioidentical and non-bioidentical commercial preparations.
=== Cost ===
Compounded BHT may be more expensive than conventional, FDA-approved HRT, and is often not covered by health insurance.
== Safety ==
Bioidentical hormones are expected to carry the same risks and benefits as their non-bioidentical counterparts, but there have been no studies that directly compare compounded bioidentical hormones with their non-bioidentical counterparts. Hormones—as used in CHRT—have been studied for years and their risk, benefit, and effectiveness profiles are known and demonstrated through considerable research.
In 2002, the Women's Health Initiative study (WHI) that was designed to demonstrate additional benefits of conventional hormone therapy (study participants were given Prempro or a placebo) was terminated prematurely after preliminary data indicated small increases in the risks of breast cancer, heart attack and stroke in older women using Prempro. Its early termination and the subsequent publicity about these previously unappreciated risks led to a decline in prescriptions for CHRT. The results from the study were used by BHT prescribers to promote bioidentical hormones as safer than the FDA-regulated preparations despite a lack of evidence; according to the FDA, the results found by the study apply to all estrogens. BHT has since been strongly promoted as a natural alternative with fewer risks than CHRT, though there is no evidence to support this claim. BHT practitioners recommend compounded products due to their claim that they more closely mimic the composition and ratio of circulating hormones in a woman's body than do commercially manufactured products.
The Endocrine Society issued a position statement that bioidentical hormones carry essentially the same risks and benefits as non-bioidentical molecules. In February 2009 the American Congress of Obstetricians and Gynecologists reiterated its position (from November 2005) that there are no proven benefits in regard to the safety or efficacy of compounded bioidentical hormones, nor are there any benefits in salivary testing of hormone levels or customized dosing of hormones. The Mayo Clinic states that there is no evidence that pharmacy-compounded BHT is safer or more effective than conventional hormone replacement, and that some bioidentical hormones are already available in certain FDA-approved products. The American Cancer Society also stated that "natural" and "bioidentical" hormones present the same risks as synthetic hormone replacement therapy such as heart disease, blood clots, strokes and an increased risk of breast cancer with long-term use.
The U.S. Food and Drug Administration has warned several pharmacies about making unsubstantiated claims about the safety and effectiveness of compounded hormone products. The North American Menopause Society has stated that compounded bioidentical hormones have not been approved by the FDA; there is no guarantee of purity, potency, efficacy or safety, and they may contain unknown contaminants. The Australian Menopause Society has similarly stated that there is no evidence that bioidentical hormones administered using lozenges are any safer than their approved counterparts. The International Menopause Society has stated "There are no medical or scientific reasons to recommend unregistered 'bioidentical hormones'. The measurement of hormone levels in the saliva is not clinically useful. These 'customized' hormonal preparations have not been tested in studies and their purity and risks are unknown."
In November 2006, the American Medical Association adopted a policy requesting that the FDA better monitor and regulate bioidentical hormones, releasing an editorial stating that compounded bioidentical molecules were expected to have the same risks as conventional hormones until proven otherwise.
Deborah Moskowitz published an article suggesting that some forms of bioidentical hormones may be safer than non-bioidentical hormones in safety and effectiveness, though this review was criticized for "[attempting] to demonstrate that BHT has a good safety profile, but the data presented only serve to demonstrate similar risks to conventional HRT."
Quackwatch recommends against the use of bioidentical hormones due to lack of quality control over compounding, posing the same risks as conventional hormones, the use of unnecessary saliva testing, and including the non-FDA-approved hormone estriol. Stephen Barrett, the site's owner, concludes his review with: "The bottom line for consumers is very simple: Steer clear of anyone who prescribes "bioidentical" hormones or recommends saliva testing as the basis for evaluating hormone status."
== Regulatory status in the United States ==
Compounded BHT is used almost exclusively in the United States, and many FDA-approved formulations that are wholly or partially made of bioidentical hormones are available. Topical hormone preparations such as progesterone, estrogen and DHEA creams can be purchased in stores or over the internet and are not regulated by the FDA, as they are generally considered cosmetic.
When prescribed by a licensed practitioner, the compounding of bioidentical hormones is controlled by the state pharmacy boards rather than the FDA, and pharmacists are permitted to adjust dose and delivery method according to the prescription. However, the FDA does have authority over the compounded product. In 2001 the FDA surveyed a limited number of compounded preparations, including eight hormone compounds. All three estradiol products passed every test; however, two out of five progesterone products failed at least one test of potency, content or uniformity.
In October 2005 Wyeth Pharmaceuticals, a manufacturer of both FDA-approved bioidentical and non-bioidentical HRT preparations, filed a citizen petition with the FDA asking for enforcement action against compounding pharmacies that dispensed BHT and to investigate labelling and advertising guidelines. Soon after, the FDA took a number of enforcement actions against several (primarily Internet-based) pharmacies that were producing compounded BHT and in 2008, banned the use of estriol in the US. The FDA stated that it did not take these regulatory actions against compounded bioidentical hormones in response to Wyeth's request, since that is not the purpose of a citizen petition. They said that they had an ongoing investigation when they received the petition. The FDA ordered pharmacies to discontinue use of estriol. The agency's Assistant Director of the Office of Compliance stated that the use of estriol would require a permit for research and a new drug application. The FDA also stated that it has not approved any drug containing estriol and that no information had been submitted to the FDA regarding its safety and effectiveness. The FDA's concerns over the marketing and use of bioidentical hormones were supported by the American Association of Clinical Endocrinologists. In response to the FDA's actions, the International Academy of Compounding Pharmacists began a letter-writing campaign to the FDA to reverse this action, citing Wyeth's attempt as a "self-serving, and at times duplicitous, campaign to restrict patients' access to alternatives to its own products".
In November 2006, the American Medical Association adopted a policy urging the FDA to survey compounded BHT products for purity and dosage; to maintain a registry and require mandatory adverse event reporting by manufacturers and compounding pharmacies related to bioidentical hormones; to mandate the inclusion of uniform patient information, including warnings and precautions regarding bioidentical products; and to prohibit the use of the term bioidentical hormones unless the agency has approved the preparation.
On July 18, 2008, a US Appeals Court issued a ruling stating that new drug approval processes should not be applied to compounded drugs that complied with established guidelines, and also that provisions of the regulations relevant to the use of estriol were still in effect, preventing the FDA from taking action against pharmacies using estriol in compounded products.
== Wiley Protocol ==
The Wiley Protocol is a version of compounded BHT endorsed by T. S. Wiley. Its goal is to produce serum levels of estradiol and progesterone that are identical to those of a young woman with a normal menstrual cycle. It has been criticized for a variety of reasons. Wiley has no academic credentials.
== See also ==
European Menopause and Andropause Society
Women's health
== References ==
== External links ==
Senate Hearings on Bioidentical Hormones: Sound Science or Bad Medicine? by the United States Senate Special Committee on Aging
Interview regarding bioidentical hormones with Arlene Weintraub on the Canadian Broadcasting Corporation radio program The Current, November 8, 2010 | Wikipedia/Bioidentical_hormone_therapy |
High-density lipoprotein (HDL) is one of the five major groups of lipoproteins. Lipoproteins are complex particles composed of multiple proteins which transport all fat molecules (lipids) around the body within the water outside cells. They are typically composed of 80–100 proteins per particle (organized by one, two or three ApoA). HDL particles enlarge while circulating in the blood, aggregating more fat molecules and transporting up to hundreds of fat molecules per particle.
HDL particles are commonly referred to as "good cholesterol", because they transport fat molecules out of artery walls, reduce macrophage accumulation, and thus help prevent or even regress atherosclerosis.
== Overview ==
Lipoproteins are divided into five subgroups, by density/size (an inverse relationship), which also correlates with function and incidence of cardiovascular events. Unlike the larger lipoprotein particles, which deliver fat molecules to cells, HDL particles remove fat molecules from cells. The lipids carried include cholesterol, phospholipids, and triglycerides, amounts of each are variable.
HDL particles remove fats and cholesterol from cells, including within artery wall atheroma, and transport it back to the liver for excretion or re-use. Increasing concentrations of HDL particles in the blood are associated with decreasing accumulation of atherosclerosis within the walls of arteries, reducing the risk of sudden plaque ruptures, cardiovascular disease, stroke and other vascular diseases. People with higher levels of HDL-C tend to have fewer problems with cardiovascular diseases, while those with low HDL-C cholesterol levels (especially less than 40 mg/dL or about 1 mmol/L) have increased rates for heart disease. Higher native HDL levels are correlated with lowered risk of cardiovascular disease in healthy people.
However, a higher blood level of HDL is not necessarily protective against cardiovascular disease and may even be harmful in extremely high quantities, with an increased cardiovascular risk, especially in hypertensive patients.
== Testing ==
Because of the high cost of directly measuring HDL particles, blood tests commonly measure a surrogate value, HDL-cholesterol (HDL-C), i.e. the cholesterol associated with HDL particles.
HDL-C is often contrasted with the amount of cholesterol estimated to be carried within low-density lipoprotein particles, known as LDL-C, with HDL-C being nicknamed "good cholesterol" and LDL-C "bad cholesterol".
In healthy individuals, about 30% of blood cholesterol, along with other fats, is carried by HDL. This is often contrasted with the amount of cholesterol estimated to be carried within low-density lipoprotein particles, LDL, and called LDL-C. HDL particles remove fats and cholesterol from cells, including within artery wall atheroma, and transport it back to the liver for excretion or re-utilization; thus the cholesterol carried within HDL particles (HDL-C) is sometimes called "good cholesterol". Those with higher levels of HDL-C tend to have fewer problems with cardiovascular diseases, while those with low HDL-C cholesterol levels (especially less than 40 mg/dL or about 1 mmol/L) have increased rates for heart disease. Higher native HDL levels are correlated with lowered risk of cardiovascular disease in healthy people.
The remainder of the serum cholesterol after subtracting the HDL is the non-HDL cholesterol. The concentration of these other components, which may cause atheroma, is known as the non-HDL-C. This is now preferred to LDL-C as a secondary marker as it has been shown to be a better predictor and it is more easily calculated.
== Structure and function ==
With a size ranging from 5 to 17 nm, HDL is the smallest of the lipoprotein particles. It is the densest because it contains the highest proportion of protein to lipids. Its most abundant apolipoproteins are apo A-I and apo A-II. A rare genetic variant, ApoA-1 Milano, has been documented to be far more effective in both protecting against and regressing arterial disease, atherosclerosis.
The liver synthesizes these lipoproteins as complexes of apolipoproteins and phospholipid, which resemble cholesterol-free flattened spherical lipoprotein particles, whose NMR structure was published; the complexes are capable of picking up cholesterol, carried internally, from cells by interaction with the ATP-binding cassette transporter A1 (ABCA1). A plasma enzyme called lecithin-cholesterol acyltransferase (LCAT) converts the free cholesterol into cholesteryl ester (a more hydrophobic form of cholesterol), which is then sequestered into the core of the lipoprotein particle, eventually causing the newly synthesized HDL to assume a spherical shape. HDL particles increase in size as they circulate through the blood and incorporate more cholesterol and phospholipid molecules from cells and other lipoproteins, such as by interaction with the ABCG1 transporter and the phospholipid transport protein (PLTP).
HDL transports cholesterol mostly to the liver or steroidogenic organs such as adrenals, ovary, and testes by both direct and indirect pathways. HDL is removed by HDL receptors such as scavenger receptor BI (SR-BI), which mediate the selective uptake of cholesterol from HDL. In humans, probably the most relevant pathway is the indirect one, which is mediated by cholesteryl ester transfer protein (CETP). This protein exchanges triglycerides of VLDL against cholesteryl esters of HDL. As the result, VLDLs are processed to LDL, which are removed from the circulation by the LDL receptor pathway. The triglycerides are not stable in HDL, but are degraded by hepatic lipase so that, finally, small HDL particles are left, which restart the uptake of cholesterol from cells.
The cholesterol delivered to the liver is excreted into the bile and, hence, intestine either directly or indirectly after conversion into bile acids. Delivery of HDL cholesterol to adrenals, ovaries, and testes is important for the synthesis of steroid hormones.
Several steps in the metabolism of HDL can participate in the transport of cholesterol from lipid-laden macrophages of atherosclerotic arteries, termed foam cells, to the liver for secretion into the bile. This pathway has been termed reverse cholesterol transport and is considered as the classical protective function of HDL toward atherosclerosis.
HDL carries many lipid and protein species, several of which have very low concentrations but are biologically very active. For example, HDL and its protein and lipid constituents help to inhibit oxidation, inflammation, activation of the endothelium, coagulation, and platelet aggregation. All these properties may contribute to the ability of HDL to protect from atherosclerosis, and it is not yet known which are the most important. In addition, a small subfraction of HDL lends protection against the protozoan parasite Trypanosoma brucei brucei. This HDL subfraction, termed trypanosome lytic factor (TLF), contains specialized proteins that, while very active, are unique to the TLF molecule.
In the stress response, serum amyloid A, which is one of the acute-phase proteins and an apolipoprotein, is under the stimulation of cytokines (interleukin 1, interleukin 6), and cortisol produced in the adrenal cortex and carried to the damaged tissue incorporated into HDL particles. At the inflammation site, it attracts and activates leukocytes. In chronic inflammations, its deposition in the tissues manifests itself as amyloidosis.
It has been postulated that the concentration of large HDL particles more accurately reflects protective action, as opposed to the concentration of total HDL particles. This ratio of large HDL to total HDL particles varies widely and is measured only by more sophisticated lipoprotein assays using either electrophoresis (the original method developed in the 1970s) or newer NMR spectroscopy methods (See also nuclear magnetic resonance and spectroscopy), developed in the 1990s.
=== Subfractions ===
Five subfractions of HDL have been identified. From largest (and most effective in cholesterol removal) to smallest (and least effective), the types are 2a, 2b, 3a, 3b, and 3c.
== Epidemiology ==
Men tend to have noticeably lower HDL concentrations, with smaller size and lower cholesterol content, than women. Men also have a greater incidence of atherosclerotic heart disease. Studies confirm the fact that HDL has a buffering role in balancing the effects of the hypercoagulable state in type 2 diabetics and decreases the high risk of cardiovascular complications in these patients. Also, the results obtained in this study revealed that there was a significant negative correlation between HDL and activated partial thromboplastin time (APTT).
Epidemiological studies have shown that high concentrations of HDL (over 60 mg/dL) have protective value against cardiovascular diseases such as ischemic stroke and myocardial infarction. Low concentrations of HDL (below 40 mg/dL for men, below 50 mg/dL for women) increase the risk for atherosclerotic diseases.
Data from the landmark Framingham Heart Study showed that, for a given level of LDL, the risk of heart disease increases 10-fold as the HDL varies from high to low. On the converse, however, for a fixed level of HDL, the risk increases 3-fold as LDL varies from low to high.
Even people with very low LDL levels achieved by statin treatment are exposed to increased risk if their HDL levels are not high enough.
Very high HDL-C levels (≥80 mg/dL in men, ≥100 mg/dL in women) appears to be detrimental to cardiovascular outcomes. Several genetic conditions cause abnormally low or high HDL-C levels, often without the expected change in cardiovascular disease rates. In fact, when many known correlates of CVD risks are controlled for, HDL-C does not have any correlation with cardiovascular event risks. In this way, HDL-C only seems to serve as an imperfect, but easy-to-measure, proxy for a healthy lifestyle. What does correlate well with CVD risks even when these factors are controlled for is a direct measure of the capability for reverse cholesterol transport in a person's blood serum, the cholesterol efflux capacity (CEC).
== Estimating HDL via associated cholesterol ==
Clinical laboratories formerly measured HDL cholesterol by separating other lipoprotein fractions using either ultracentrifugation or chemical precipitation with divalent ions such as Mg2+, then coupling the products of a cholesterol oxidase reaction to an indicator reaction. The reference method still uses a combination of these techniques. Most laboratories now use automated homogeneous analytical methods in which lipoproteins containing apo B are blocked using antibodies to apo B, then a colorimetric enzyme reaction measures cholesterol in the non-blocked HDL particles. HPLC can also be used. Subfractions (HDL-2C, HDL-3C) can be measured, but clinical significance of these subfractions has not been determined. The measurement of apo-A reactive capacity can be used to measure HDL cholesterol but is thought to be less accurate.
=== Recommended ranges ===
The American Heart Association, NIH and NCEP provide a set of guidelines for fasting HDL levels and risk for heart disease.
High LDL with low HDL level is an additional risk factor for cardiovascular disease.
== Measuring HDL concentration and sizes ==
As technology has reduced costs and clinical trials have continued to demonstrate the importance of HDL, methods for directly measuring HDL concentrations and size (which indicates function) at lower costs have become more widely available and increasingly regarded as important for assessing individual risk for progressive arterial disease and treatment methods.
=== Electrophoresis measurements ===
Since the HDL particles have a net negative charge and vary by density & size, ultracentrifugation combined with electrophoresis have been utilized since before 1950 to enumerate the concentration of HDL particles and sort them by size with a specific volume of blood plasma. Larger HDL particles are carrying more cholesterol.
=== NMR measurements ===
Concentration and sizes of lipoprotein particles can be estimated using nuclear magnetic resonance fingerprinting.
==== Optimal total and large HDL concentrations ====
The HDL particle concentrations are typically categorized by event rate percentiles based on the people participating and being tracked in the MESA trial, a medical research study sponsored by the United States National Heart, Lung, and Blood Institute.
The lowest incidence of atherosclerotic events over time occurs within those with both the highest concentrations of total HDL particles (the top quarter, >75%) and the highest concentrations of large HDL particles. Multiple additional measures, including LDL particle concentrations, small LDL particle concentrations, VLDL concentrations, estimations of insulin resistance and standard cholesterol lipid measurements (for comparison of the plasma data with the estimation methods discussed above) are routinely provided in clinical testing.
== Increasing HDL levels ==
While higher HDL levels are correlated with lower risk of cardiovascular diseases, no medication used to increase HDL has been proven to improve health. As of 2017, numerous lifestyle changes and drugs to increase HDL levels were under study.
HDL lipoprotein particles that bear apolipoprotein C3 are associated with increased, rather than decreased, risk for coronary heart disease.
=== Diet and exercise ===
Certain changes in diet and exercise may have a positive impact on raising HDL levels:
Decreased intake of simple carbohydrates.
Aerobic exercise
Weight loss
Avocado consumption
Magnesium supplements raise HDL-C.
Addition of soluble fiber to diet
Consumption of omega-3 fatty acids such as fish oil or flax oil
Increased intake of unsaturated fats
Removal of trans fatty acids from the diet
Most saturated fats increase HDL cholesterol to varying degrees but also raise total and LDL cholesterol.
=== Recreational drugs ===
HDL levels can be increased by smoking cessation, or mild to moderate alcohol intake.
Cannabis in unadjusted analyses, past and current cannabis use was not associated with higher HDL-C levels. A study performed in 4635 patients demonstrated no effect on the HDL-C levels (P=0.78) [the mean (standard error) HDL-C values in control subjects (never used), past users and current users were 53.4 (0.4), 53.9 (0.6) and 53.9 (0.7) mg/dL, respectively].
Exogenous anabolic androgenic steroids, particularly 17α-alkylated anabolic steroids and others administered orally, can reduce HDL-C by 50 percent or more. Other androgen receptor agonists such as selective androgen receptor modulators can also lower HDL. As there is some evidence that the HDL reduction is caused by increased reverse cholesterol transport, it is unknown if AR agonists' HDL-lowering effect is pro- or anti-atherogenic.
=== Pharmaceutical drugs and niacin ===
Pharmacological therapy to increase the level of HDL cholesterol includes use of fibrates and niacin. Fibrates have not been proven to have an effect on overall deaths from all causes, despite their effects on lipids.
Niacin (nicotinic acid, a form of vitamin B3) increases HDL by selectively inhibiting hepatic diacylglycerol acyltransferase 2, reducing triglyceride synthesis and VLDL secretion through a receptor HM74 otherwise known as niacin receptor 2 and HM74A / GPR109A, niacin receptor 1.
Pharmacologic (1- to 3-gram/day) niacin doses increase HDL levels by 10–30%, making it the most powerful agent to increase HDL-cholesterol. A randomized clinical trial demonstrated that treatment with niacin can significantly reduce atherosclerosis progression and cardiovascular events. Niacin products sold as "no-flush", i.e. not having side-effects such as "niacin flush", do not, however, contain free nicotinic acid and are therefore ineffective at raising HDL, while products sold as "sustained-release" may contain free nicotinic acid, but "some brands are hepatotoxic"; therefore the recommended form of niacin for raising HDL is the cheapest, immediate-release preparation. Both fibrates and niacin increase artery toxic homocysteine, an effect that can be counteracted by also consuming a multivitamin with relatively high amounts of the B-vitamins, but multiple European trials of the most popular B-vitamin cocktails, trial showing 30% average reduction in homocysteine, while not showing problems have also not shown any benefit in reducing cardiovascular event rates. A 2011 extended-release niacin (Niaspan) study was halted early because patients adding niacin to their statin treatment showed no increase in heart health, but did experience an increase in the risk of stroke.
In contrast, while the use of statins is effective against high levels of LDL cholesterol, most have little or no effect in raising HDL cholesterol. Rosuvastatin and pitavastatin, however, have been demonstrated to significantly raise HDL levels.
Lovaza has been shown to increase HDL-C. However, the best evidence to date suggests it has no benefit for primary or secondary prevention of cardiovascular disease.
The PPAR modulator GW501516 has shown a positive effect on HDL-C and an antiatherogenic where LDL is an issue. However, research on the drug has been discontinued after it was discovered to cause rapid cancer development in several organs in rats.
== See also ==
Asymmetric dimethylarginine
Cardiovascular disease
Cholesteryl ester storage disease
Endothelium
Lipid profile
Lysosomal acid lipase deficiency
== References == | Wikipedia/High_density_lipoprotein |
The pharmacology of estradiol, an estrogen medication and naturally occurring steroid hormone, concerns its pharmacodynamics, pharmacokinetics, and various routes of administration.
Estradiol is a naturally occurring and bioidentical estrogen, or an agonist of the estrogen receptor, the biological target of estrogens like endogenous estradiol. Due to its estrogenic activity, estradiol has antigonadotropic effects and can inhibit fertility and suppress sex hormone production in both women and men. Estradiol differs from non-bioidentical estrogens like conjugated estrogens and ethinylestradiol in various ways, with implications for tolerability and safety.
Estradiol can be taken by mouth, held under the tongue, as a gel or patch that is applied to the skin, in through the vagina, by injection into muscle or fat, or through the use of an implant that is placed into fat, among other routes.
== Mechanism of action ==
Estradiol is an estrogen, or an agonist of the nuclear estrogen receptors (ERs), the estrogen receptor alpha (ERα) and the estrogen receptor beta (ERβ). In one study, the EC50Tooltip half-maximal effective concentration value of estradiol for the human ERα was 50 pM (0.05 nM) and for the human ERβ was 200 pM (0.2 nM). Estradiol is also an agonist of the membrane estrogen receptors (mERs), including the G protein-coupled estrogen receptor (GPER) (3–6 nM), Gq-coupled membrane estrogen receptor (Gq-mER), ER-X, and ERx. It is far more potent as an estrogen than are other natural and bioidentical estrogens like estrone and estriol. Given by subcutaneous injection in mice, estradiol is about 10-fold more potent than estrone and about 100-fold more potent than estriol. In addition, much of the estrogenic potency of estrone in vivo is actually due to conversion into estradiol.
Estradiol has little to no affinity for other steroid hormone receptors, including the androgen, progesterone, glucocorticoid, and mineralocorticoid receptors. It has weak affinity for the androgen receptor, with about 8% of relative binding affinity of testosterone according to one study, and shows agonistic activity at this receptor. However, estrogens circulate in the picomolar (10−12 M) range while androgens circulate in the nanomolar (10−9 M) to micromolar (10−6 M) range, and in accordance with this, estradiol is active as an estrogen in target tissues at approximately 1,000-fold lower concentrations than is testosterone. In addition, while estradiol did show activation of the androgen receptor in vitro at very high concentrations, its efficacy as an androgen receptor agonist was of such low potency that it was not possible to calculate an EC50Tooltip half-maximal effective concentration value for the activity. As such, the weak activity of estradiol at the androgen receptor is unlikely to be of biological significance at normal physiological concentrations.
The affinities of estradiol for the ERs are high (around 0.1 nM), and there is a relatively low quantity of about 10,000 to 20,000 ERs in the cytoplasm per cell in estrogen target tissues. Estradiol stays bound to the ERs for about 24 hours, which is longer than that of other estrogens such as estriol (6 hours). A prolonged duration of binding to the ERs (e.g., 9 to 12 hours for endometrial effects), as with estradiol, is necessary for full estrogenic responses in various tissues. The ERs downregulate with exposure to estradiol, and in accordance, the expression of the ERs is dependent on estradiol concentrations. Constant levels of estradiol may result in downregulation of the ERs and relatively diminished responses to estradiol, although this has not been assessed clinically. Once bound to estradiol, the ERs are ubiquitinated and degraded by proteasomes, which is a major mechanism of ER downregulation. The unbound ERα has an intracellular half-life of up to 5 days, but this shortens to 3–4 hours once bound to a ligand such as estradiol. Estrogen deprivation can easily increase sensitivity to estrogens like estradiol by 10,000-fold or more, demonstrating a profound capacity of the ERs for upregulation and downregulation. This increase in sensitivity is mediated by a 100-fold increase in ERs, as well as other mechanisms such as changes in coactivator sensitivity and degree of phosphorylation of transactivation factors. Progestogens like progesterone and androgens like testosterone downregulate the ERs in certain tissues such as the endometrium and breasts, among others. While progestogens may reduce the expression of ERs and progesterone receptors (PR) in the breasts of primates, the estrogen-induced proliferation of the mammary epithelium is not inhibited, but rather enhanced by progestogens.
Estradiol is a steroid and a lipophilic compound. As a result, it readily enters cells via simple passive diffusion through the lipid bilayer of the cell membrane. This is in contrast to hydrophilic estrogen conjugates such as estrone sulfate and estradiol glucuronide, which require active transport via specific membrane transport proteins to enter cells. The ERs are nuclear receptors that are mostly present in the cell nucleus. Upon binding of estradiol to an ER, the receptor dimerizes (combines) with another estradiol-bound ER. These ER dimers can be ERα–ERα or ERβ–ERβ homodimers or ERα–ERβ heterodimers. Once in the dimerized state, the estradiol-bound ER–ER complex binds to short estrogen response elements (EREs) (of the minimal nucleotide sequence 5'-GGTCANNNTGACC-3', where N is any nucleotide) in the promoter regions of estrogen-responsive genes on chromosomes, in turn modulating their expression. Some prominent examples ERE-containing and hence estrogen-modulated genes in humans include the genes encoding the proteins oxytocin, c-fos, c-myc, and transforming growth factor alpha (TGFα).
== Effects in the body and brain ==
The ERs are expressed widely throughout the body, including in the breasts, uterus, vagina, prostate gland, fat, skin, bone, liver, pituitary gland, hypothalamus, and elsewhere throughout the brain. Through activation of the ERs (as well as the mERs), estradiol has many effects, including the following:
Promotes growth, function, and maintenance of the breasts, uterus, and vagina during puberty and thereafter
Mediates deposition of subcutaneous fat in a feminine pattern, especially in the breasts, hips, buttocks, and thighs
Maintains skin health, integrity, appearance, and hydration and slows the rate of aging of the skin
Produces the growth spurt and epiphyseal closure in both sexes during puberty, mediates widening of the hips in females during puberty, and maintains bone mineral density in both sexes throughout life
Modulates hepatic protein synthesis, such as the production of sex hormone-binding globulin (SHBG) and numerous other proteins, with consequent effects on the cardiovascular system and various other systems
Exerts negative feedback on the hypothalamic–pituitary–gonadal axis (HPG axis) by suppressing the secretion of the gonadotropins FSH and LH from the pituitary gland, thereby inhibiting gonadal sex hormone production as well as ovulation and fertility
Regulates the vasomotor system and body temperature via the hypothalamus, thereby preventing hot flashes
Modulates brain function, with effects on mood, emotionality, and sexuality, as well as cognition and memory
Influences the risk and/or progression of hormone-sensitive cancers including breast cancer, prostate cancer, and endometrial cancer
Estrogen has also been found to increase the secretion of oxytocin and to increase the expression of its receptor, the oxytocin receptor, in the brain. In women, a single dose of estradiol has been found to be sufficient to increase circulating oxytocin concentrations.
=== Effects on sex-hormone levels ===
==== Antigonadotropic effects ====
Estrogens are powerful antigonadotropins at sufficiently high concentrations. By exerting negative feedback on the hypothalamic–pituitary–gonadal axis (HPG axis), they are able to suppress the secretion of the gonadotropins, LH and FSH, and thereby inhibit gonadal sex hormone production and circulating sex hormone levels as well as fertility (ovulation in women and spermatogenesis in men). Clinical studies have found that in men treated with them, estrogens can maximally suppress testosterone levels by about 95% or well into the castrate/female range (<50 ng/dL). This is equivalent to the reduction in testosterone levels achieved by orchiectomy and gonadotropin-releasing hormone analogue (GnRH analogue) therapy, corresponding to a complete shutdown of gonadal testosterone production. In addition, it is greater than that achieved with high-dose progestogens like cyproterone acetate and gestonorone caproate, which can maximally suppress testosterone levels in men by about 75%.
Inhibition of ovulation by estradiol monotherapy in women has been studied and demonstrated for oral estradiol, transdermal estradiol patches, subcutaneous estradiol implants, and intramuscular estradiol undecylate injections. A study of ovulation inhibition in women found that oral non-micronized estradiol was 55% effective at 1 mg/day, 61% effective at 2 mg/day, and 88% effective at 5 mg/day.
Suppression of testosterone levels by estradiol to within the castrate/female range (<50 ng/dL) in men requires relatively high levels of estradiol and has been associated with circulating levels of 200 to 300 pg/mL and above. However, although the castrate range in men has been defined as testosterone concentrations of less than 50 ng/dL, mean levels of testosterone with surgical castration are actually about 15 ng/dL. To achieve such levels of testosterone with estradiol therapy, higher concentrations of estradiol of about 500 pg/mL have been necessary to produce the requisite maximal suppression of testosterone production. Injected estradiol esters like polyestradiol phosphate, estradiol valerate, and estradiol undecylate, as well as high-dose estradiol transdermal patches, are used as a form of high-dose estrogen therapy to suppress testosterone levels into the castrate range in men with prostate cancer. High dosages of estradiol in various forms and routes are also used to suppress testosterone levels in transgender women. The suppression of testosterone levels by estradiol in men is rapid. A single intramuscular injection of 2 mg aqueous estradiol suppressed testosterone levels in young men from 760 ng/dL at baseline to 295 ng/dL (60% reduction) after 24 hours and to a maximum of 123 ng/dL (85% reduction) after 36 hours.
Lower dosages and concentrations of estradiol can also significantly suppress gonadotropin secretion and testosterone levels in men and transgender women. A retrospective study of oral estradiol monotherapy in transgender women found that dosages of 1 to 8 mg/day increased mean estradiol levels to about 50 to 150 pg/mL and suppressed mean testosterone levels to about 10 to 120 ng/dL. However, there was high interindividual variability in the estradiol and testosterone levels achieved, and testosterone levels were insufficiently suppressed in many even at 8 mg/day. In another study, a dosage of 1 mg/day oral micronized estradiol in healthy older men, which increased circulating estradiol levels by a relatively high amount of 6-fold (to 159 pg/mL), estrone levels by 15-fold (to 386 pg/mL), and SHBG levels by 17%, was found to suppress total testosterone levels by 27% (to 436 ng/dL) and free testosterone levels by 34% (to 11.8 ng/dL). A pharmacodynamic study of testosterone suppression by polyestradiol phosphate in men with prostate cancer found that estradiol levels of about 135 pg/mL (500 pmol/L) would decrease testosterone levels by 50% (from 430 ng/dL to 215 ng/dL), while estradiol levels of about 410 to 545 pg/mL (1500–2000 pmol/L) would decrease testosterone levels well into the castrate range to about 6 to 12 ng/dL (0.2–0.4 nmol/L).
Oral conjugated estrogens at a dosage of 7.5 mg/day has been found to suppress total testosterone levels in men to an equivalent extent as 3 mg/day oral diethylstilbestrol, which is the minimum dosage of diethylstilbestrol required to consistently suppress total testosterone levels into the castrate range (<50 ng/dL). The equivalent dosage in the case of oral estradiol has not been reported. However, on the basis of the results of one study, it appears to be greater than 8 mg/day. In addition, oral estradiol is known to have similar or slightly lower antigonadotropic potency than oral conjugated estrogens; the potencies of oral conjugated estrogens in terms of suppression of LH and FSH levels are 1.0 and 1.1–1.3 relative to oral estradiol, respectively.
In addition to their antigonadotropic effects, high doses of estrogens appear to have direct toxic effects in the testes. Following long-term therapy (>3 years) with high-dose estrogen therapy, testosterone levels fail to return to normal upon discontinuation of treatment in men with prostate cancer. Long-lasting suppression of pituitary gland function, persisting after estrogen discontinuation, may also be involved. With shorter-term estrogen therapy, testicular morphology has been reported to return to normal within 18 to 24 months following estrogen discontinuation.
==== Progonadotropic effects ====
Generally, estrogens are antigonadotropic and inhibit gonadotropin secretion. However, in women, a sharp increase in estradiol levels to about 200 to 500 pg/mL occurs at the end of the follicular phase (mid-cycle) during the normal menstrual cycle and paradoxically triggers a surge in LH and FSH secretion. This occurs when estradiol concentrations reach levels of about 250 to 300 pg/mL. During the mid-cycle surge, LH levels increase by 3- to 12-fold and FSH levels increase by 2- to 4-fold. The surge lasts about 24 to 36 hours and triggers ovulation, the rupture of the dominant ovarian follicle and the release of the egg from the ovary into the oviduct. This estrogen-mediated gonadotropin surge effect has also been found to occur with exogenous estrogen, including in transgender women on hormone therapy and pre-hormone therapy transgender men acutely challenged with a high dose of an estrogen, but does not occur in men, pre-hormone therapy transgender women, or transgender men on hormone therapy, hence indicating a hormonally-based sex difference. Progestogens have antiestrogenic actions on the progonadotropic effects of estrogens and a sufficient amount of progesterone (corresponding to levels greater than 2 ng/mL) or a progestin prevents the mid-cycle estradiol-induced surge in gonadotropin levels in women. This is how progestins prevent ovulation and in part mediate their contraceptive effects in women.
==== Effects on adrenal androgen levels ====
In addition to their antigonadotropic effects, estrogens at high concentrations can significantly decrease androgen production by the adrenal glands. A study found that treatment with a high dosage of ethinylestradiol (100 μg/day) reduced circulating adrenal androgen levels by 27 to 48% in transgender women. Another study found similar effects in men with prostate cancer, with levels of the adrenal androgens dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenedione (A4) all decreasing significantly more with high-dose estrogen therapy (oral ethinylestradiol plus intramuscular polyestradiol phosphate) than with orchiectomy (by 33–39% and 10–26%, respectively).
However, studies have found that these effects occur with high-dose oral and synthetic estrogens such as ethinylestradiol and estramustine phosphate but minimally with the parenteral bioidentical estrogens polyestradiol phosphate and estradiol undecylate, suggesting that decreases in adrenal androgen levels are secondary to changes in liver protein synthesis rather than due to a direct action in the adrenal cortex, and that such changes will only occur in the context of strong hepatic impact. Cortisol levels were unchanged in the other groups (e.g., orchiectomy, GnRH agonist therapy, and parenteral estrogen therapy) in this study, but increased by 300 to 400% in the oral and synthetic estrogen groups, likely secondary to increases in hepatic corticosteroid-binding globulin (CBG) production and compensatory upregulation of adrenal corticosteroid synthesis.
Changes in levels of weak adrenal androgens are of relevance as these androgens serve as circulating reservoir of precursors that are transformed in tissues into potent androgens like testosterone and dihydrotestosterone and into estrogens.
=== Effects on liver protein synthesis ===
Estradiol and other estrogens modulate liver protein synthesis via activation of hepatic ERs. Estradiol increases the production and by extension circulating levels of sex hormone-binding globulin (SHBG), corticosteroid-binding globulin (CBG), angiotensinogen (AGT), pregnancy zone protein (PZP), coagulation factors, and numerous other hepatic proteins. Conversely, estradiol decreases hepatic synthesis and by extension circulating levels of insulin-like growth factor 1 (IGF-1). The effects of estradiol on liver protein synthesis are moderated by route of administration, with oral administration having 4- or 5-fold stronger effects on liver protein synthesis than doses by the transdermal route with equivalent general/systemic estrogenic potency. The influences of estradiol on liver protein synthesis have a variety of effects in the body, with implications for the bioavailability of androgens and the cardiovascular system.
The influence of 2 mg/day oral estradiol on levels of hepatic proteins such as SHBG, CBG, and AGT is much lower than that with 10 μg/day oral ethinylestradiol. Vaginal micronized estradiol at 0.25 mg/day increased SHBG levels by about 10% after 2 weeks of therapy in women. Estradiol-containing birth control pills, which contain 1 to 3 mg/day estradiol or estradiol valerate, have been found to increase SHBG levels by 1.5-fold. Both oral estradiol valerate at 6 mg/day and intramuscular estradiol valerate at 10 mg every 10 days have 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. High-dose polyestradiol phosphate by intramuscular injection has been found to increase SHBG levels by about 1.5-fold.
Estradiol valerate in oil solution by intramuscular injection has been studied in the treatment of prostate cancer. Although parenteral estradiol has diminished effects on liver protein synthesis and by extension coagulation and cardiovascular risk compared to oral estradiol and non-bioidentical estrogens, a property attributable to its absence of disproportionate effects on the liver, sufficient doses of parenteral estradiol can nonetheless result in high estradiol concentrations in the liver and may increase coagulation and cardiovascular risk similarly. Estradiol valerate at a dose of 10 to 40 mg by intramuscular injection once every 2 weeks in men with prostate cancer has been found to increase markers of coagulation and plasminogen system activation such as levels of thrombin–antithrombin complex and quantitative D-dimers. Administration of daily prophylactic anticoagulation in the form of low molecular-weight heparin was able to successfully return these hemostasis markers to baseline. Doses of estradiol valerate of 10 to 40 mg by intramuscular injection have also been used to limit bleeding in women with hemorrhage due to dysfunctional uterine bleeding, although this is due primarily to stimulation of uterine growth.: 318 : 60
=== Other effects ===
Estrogens have been reported to downregulate androgen receptor expression in adipose tissue, and may thereby inhibit the effects of androgens on fat distribution.
== Differences from other estrogens ==
Estradiol has relatively low oral bioavailability of about 5%. In addition, there is considerable interindividual variability in levels of estradiol achieved with oral estradiol. In contrast to estradiol, the synthetic estrogen ethinylestradiol has about 45% oral bioavailability, around 80- to 200-fold greater systemic oral estrogenic potency, roughly 500- to 1,500-fold greater hepatic oral estrogenic potency, and less interindividual variability in circulating estrogen levels achieved. An oral dose of ethinylestradiol that is approximately 100-fold lower than that of estradiol achieves similar maximal circulating estrogen concentrations (e.g., 50 pg/mL ethinylestradiol with a single 20 μg dose of ethinylestradiol relative to 40 pg/mL estradiol with a single 2 mg dose of micronized estradiol or estradiol valerate). These differences are due to the introduction of an ethynyl group at the C17α position in ethinylestradiol (also known as 17α-ethynylestradiol), which results in steric hindrance and greatly diminishes the first-pass metabolism of ethinylestradiol relative to estradiol with oral administration. Estradiol and ethinylestradiol have similar affinities for and efficacies as agonists of the ERs, and the systemic estrogenic potency of estradiol and ethinylestradiol is similar when they are administered by the intravenous route.
Synthetic estrogens like ethinylestradiol and diethylstilbestrol and the natural but animal-derived conjugated estrogens have disproportionate effects on liver protein synthesis relative to their effects in other tissues when compared to estradiol. At doses via the oral route with comparable systemic estrogenic potency, conjugated estrogens have about 1.3 to 4.5 times the hepatotropic potency (i.e., potency in modulating liver protein synthesis) of estradiol, ethinylestradiol has about 2.9 to 5.0 times the hepatotropic potency of estradiol, and diethylstilbestrol shows about 5.7 to 7.5 times the hepatotropic potency of estradiol (all measured via a small selection of estrogen-modulated hepatic proteins that included HDL cholesterol, SHBGTooltip sex hormone-binding globulin, CBGTooltip corticosteroid-binding globulin, and angiotensinogen). The greater hepatotropic potency of these estrogens relative to estradiol is related to susceptibility to hepatic metabolism. Whereas estradiol is metabolized and thereby inactivated rapidly upon entry into the liver, other estrogens like ethinylestradiol and diethylstilbestrol are resistant to hepatic metabolism and persist in the liver for a longer amount of time. This is reflected in the biological half-lives of these estrogens; the blood half-life of estradiol is about 1 to 2 hours, while the half-lives of ethinylestradiol and diethylstilbestrol are approximately 20 hours and 24 hours, respectively. In accordance with its long half-life, ethinylestradiol passes through the liver many times prior to its elimination. Because humans are not adapted to efficiently metabolize conjugated estrogens (which are equine (horse) estrogens) and synthetic estrogens like ethinylestradiol and diethylstilbestrol, these estrogens are not properly inactivated in the liver, with markedly disproportionate hepatic estrogenic effects resulting.
In addition to differences in hepatotropic potency between estradiol and other estrogens, there are differences in hepatotropic potency between different routes of administration of estradiol. Due to the first pass through the liver, oral estradiol results in disproportionate and unphysiological hepatic estradiol levels that are 4- to 5-fold higher than in the circulation. Conversely, parenteral routes of estradiol, such as transdermal, vaginal, and injection, bypass the first pass through the liver and produce levels of estradiol in the circulation and liver that are comparable. As an example of the reduced hepatic impact of parenteral estradiol relative to oral estradiol, a study found that 1 mg/day oral estradiol significantly increased SHBG levels by 45%, while 50 μg/day transdermal estradiol increased SHBG levels non-significantly by only 12% (with these dosages being roughly equivalent in systemic estrogenic potency). As such, not only do oral non-bioidentical estrogens like ethinylestradiol and conjugated estrogens have substantially greater potency in the liver than does oral estradiol, oral estradiol has considerably greater potency in the liver than does parenteral estradiol. Thus, the hepatotropic effects of oral non-bioidentical estrogens like ethinylestradiol are massive in comparison to parenteral estradiol (see the graph above/to the right), which in contrast to these estrogens has very weak or even absent effects on liver protein synthesis at normal therapeutic dosages. Whereas high-dosage 320 mg/month intramuscular polyestradiol phosphate increased SHBG levels to 166% in men with prostate cancer, the combination of 80 mg/month intramuscular polyestradiol phosphate and high-dosage 150 μg/day oral ethinylestradiol increased levels of SHBG to 617%, an almost 8-fold difference in increase and almost 4-fold difference in absolute levels between the two treatment regimens.
The effects of estrogens on liver protein synthesis, such as on the synthesis of coagulation factors, lipoproteins, and triglycerides, can cause an increased risk of thromboembolic and cardiovascular complications, which in turn can result in increased mortality. The risk of thromboembolic and cardiovascular complications is significantly increased in postmenopausal women taking oral conjugated estrogens as a component of menopausal hormone therapy. Both oral estradiol and oral esterified estrogens have been found to have a significantly lower risk of thromboembolic and cardiovascular complications than oral conjugated estrogens, and transdermal estradiol appears to have no such risks at all. Widely employed in the past, oral synthetic estrogens like ethinylestradiol and diethylstilbestrol are no longer used in menopausal hormone therapy due to their high risks of thromboembolic and cardiovascular complications. Studies have found a markedly increased 5-year risk of cardiovascular mortality of 14 to 26% in men treated with high-dosage oral synthetic estrogens like ethinylestradiol and diethylstilbestrol for prostate cancer. With diethylstilbestrol, there is an up to 35% incidence of cardiovascular toxicity and an up to 15% incidence of venous thromboembolism. In a small study comparing high-dosage 320 mg/month intramuscular polyestradiol phosphate versus the combination of 80 mg/month polyestradiol phosphate with high-dosage 150 μg/day oral ethinylestradiol for prostate cancer, there was a 25% incidence of cardiovascular complications over the course of a year in the group that was also treated with ethinylestradiol, whereas there were no cardiovascular complications in the polyestradiol phosphate-only group. In accordance, another study found no change in levels of coagulation factor VII, a protein of particular importance in the cardiovascular side effects of estrogens, with 240 mg/month intramuscular polyestradiol phosphate. In spite of the markedly reduced impact of parenteral estradiol on the liver compared to other estrogens however, high dosages of parenteral estradiol, producing high levels of circulating estradiol, can still result in important and undesirable changes in liver protein synthesis as with other estrogens. A high dosage of 320 mg/month polyestradiol phosphate has been found to result in significantly increased cardiovascular morbidity (due to non-fatal ischemic heart events and heart decompensation) in men with prostate cancer in two large studies, though cardiovascular mortality was notably not increased.
In addition to the liver, ethinylestradiol shows disproportionate estrogenic effects in the uterus. This is due to its inability to be inactivated by uterine 17β-hydroxysteroid dehydrogenase (17β-HSD). Because of its disproportionate effects in the uterus, ethinylestradiol is associated with a significantly lower incidence of vaginal bleeding and spotting than is estradiol, particularly in combination with progestogens (which induce 17β-HSD expression and hence estradiol metabolism in the uterus), and is an important contributing factor in why ethinylestradiol, among other reasons and in spite of its inferior safety profile, has been widely used in oral contraceptives instead of estradiol. Although ethinylestradiol has increased effects in the uterus relative to estradiol, it is similarly not associated with an increase in the risk of endometrial hyperplasia and endometrial cancer when used in combination with a progestogen, but instead with a significant decrease.
== See also ==
Pharmacokinetics of estradiol
Pharmacodynamics of progesterone
Pharmacokinetics of progesterone
== References ==
== Further reading ==
Alfred S. Wolf; H.P.G. Schneider (1989). Östrogene in Diagnostik und Therapie [Estrogens in Diagnostics and Therapy]. Springer-Verlag. pp. 1–. ISBN 978-3-642-75101-1.
Kuhl H (September 1990). "Pharmacokinetics of oestrogens and progestogens". Maturitas. 12 (3): 171–97. doi:10.1016/0378-5122(90)90003-O. PMID 2170822.
Lobo RA, Cassidenti DL (January 1992). "Pharmacokinetics of oral 17 beta-estradiol". J Reprod Med. 37 (1): 77–84. PMID 1548642.
O'Connell MB (September 1995). "Pharmacokinetic and pharmacologic variation between different estrogen products". J Clin Pharmacol. 35 (9S): 18S – 24S. doi:10.1002/j.1552-4604.1995.tb04143.x. PMID 8530713. S2CID 10159196.
Michael Oettel; Ekkehard Schillinger (1999). Estrogens and Antiestrogens I: Physiology and Mechanisms of Action of Estrogens and Antiestrogens. Springer Science & Business Media. ISBN 978-3-642-58616-3.
Michael Oettel; Ekkehard Schillinger (1999). Estrogens and Antiestrogens II: Pharmacology and Clinical Application of Estrogens and Antiestrogen. Springer Science & Business Media. ISBN 978-3-642-60107-1.
Ruggiero RJ, Likis FE (2002). "Estrogen: physiology, pharmacology, and formulations for replacement therapy". J Midwifery Womens Health. 47 (3): 130–8. doi:10.1016/S1526-9523(02)00233-7. PMID 12071379.
Kuhl H (2005). "Pharmacology of estrogens and progestogens: influence of different routes of administration" (PDF). Climacteric. 8 (Suppl 1): 3–63. doi:10.1080/13697130500148875. PMID 16112947. S2CID 24616324.
Barnes, Randall B.; Levrant, Seth G. (2007). Treatment of the Postmenopausal Woman. pp. 767–777. doi:10.1016/B978-012369443-0/50066-1. ISBN 9780123694430.
Fruzzetti F, Trémollieres F, Bitzer J (2012). "An overview of the development of combined oral contraceptives containing estradiol: focus on estradiol valerate/dienogest". Gynecol. Endocrinol. 28 (5): 400–8. doi:10.3109/09513590.2012.662547. PMC 3399636. PMID 22468839.
Stanczyk FZ, Archer DF, Bhavnani BR (2013). "Ethinyl estradiol and 17β-estradiol in combined oral contraceptives: pharmacokinetics, pharmacodynamics and risk assessment". Contraception. 87 (6): 706–27. doi:10.1016/j.contraception.2012.12.011. PMID 23375353. | Wikipedia/Pharmacodynamics_of_estradiol |
Combined birth control pills that contain natural estradiol or an estradiol ester (e.g., estradiol valerate) include:
Estradiol valerate and cyproterone acetate (brand name Femilar) – introduced in Finland (only) in 1993
Estradiol valerate and dienogest (brand names Qlaira, Natazia) – introduced in Europe in 2009 and the U.S.Tooltip United States in 2010
Estradiol and nomegestrol acetate (brand name Zoely) – introduced in Europe in 2011
Estradiol, mainly as esters including estradiol valerate, estradiol cypionate, and estradiol enanthate, is also the exclusive estrogen used in combined injectable contraceptives.
As of 2021, more than 95% of prescriptions are for combined hormonal birth control forms containing the synthetic estrogen ethinylestradiol (EE). Hence, estradiol-based birth control pills are still not widely used.
== Side effects ==
Birth control pills containing estradiol have less impact on liver protein synthesis than ethinylestradiol-containing birth control pills, and it is thought that for this reason, they may pose less of a risk of venous thromboembolism (VTE). In accordance, although birth control pills containing estradiol valerate/dienogest are associated with a significantly increased risk of VTE, they are associated with a significantly lower risk of venous thromboembolism than birth control pills containing ethinylestradiol and a progestin. The risk of VTE with estradiol/nomegestrol acetate birth control pills is under study.
Incidence of irregular vaginal bleeding may be higher with estradiol-containing birth control pills in relation to the fact that estradiol is a weaker estrogen than ethinylestradiol in the endometrium.
== Pharmacology ==
The pharmacodynamics and pharmacokinetics of estradiol in the context of use in birth control pills have been studied and reviewed.
== Research ==
Experimental estradiol-containing birth control pills that were studied but never marketed include:
Estradiol/norethisterone (Netagen, Netagen 403)
Estradiol/estriol/norethisterone (Netagen 423)
Estradiol/estriol/norethisterone acetate
Estradiol/desogestrel
Estradiol cyclooctyl acetate/desogestrel
Estradiol/ethinylestradiol/dienogest
A large randomized controlled trial of a birth control pill containing ethinylestradiol/norethisterone acetate versus a birth control pill containing estradiol/estriol/norethisterone acetate has been conducted.
== See also ==
Birth control pill formulations
Estetrol/drospirenone
== References == | Wikipedia/Estradiol-containing_birth_control_pill |
Gender-affirming hormone therapy (GAHT), also called hormone replacement therapy (HRT) or transgender hormone therapy, is a form of hormone therapy in which sex hormones and other hormonal medications are administered to transgender or gender nonconforming individuals for the purpose of more closely aligning their secondary sexual characteristics with their gender identity. This form of hormone therapy is given as one of two types, based on whether the goal of treatment is masculinization or feminization:
Masculinizing hormone therapy – for transgender men or transmasculine people; consists of androgens and occasionally antiestrogens.
Feminizing hormone therapy – for transgender women or transfeminine people; consists of estrogens with or without antiandrogens.
Eligibility for GAHT may require an assessment for gender dysphoria or persistent gender incongruence; Many medical institutions now use an informed consent model, which ensures patients are informed of the procedure process, including possible benefits and risks, while removing many of the historical barriers needed to start hormone therapy. Treatment guidelines for therapy have been developed by several medical associations.
Non-binary people may also engage in hormone therapy in order to achieve a desired balance of sex hormones or to help align their bodies with their gender identities. Many transgender people obtain hormone replacement therapy from a licensed health care provider, while others obtain and self-administer hormones.
== History ==
== Requirements ==
The formal requirements to begin gender-affirming hormone therapy vary widely depending on geographic location and specific institution. Gender-affirming hormones can be prescribed by a wide range of medical providers including, but not limited to, primary care physicians, endocrinologists, and gynecologists. Requirements to be prescribed these hormones generally include a minimum age: According to the Endocrine Society, there has been little research on taking cross-sex hormones before the age of about 14.
Historically, many health centers required a psychiatric evaluation and/or a letter from a therapist before beginning hormone replacement therapy. Many centers now use an informed consent model that does not require any routine formal psychiatric evaluation, but rather focuses on reducing barriers to care while ensuring a person can understand the risks and benefits of treatment. Some LGBT health organizations, including Chicago's Howard Brown Health Center and Planned Parenthood, advocate for this type of informed consent model.
The World Professional Association for Transgender Health (WPATH) Standards of Care, 7th edition, note that both of these approaches to care are appropriate.
=== Gender dysphoria ===
Many international guidelines and institutions require persistent, well-documented gender dysphoria as a pre-requisite to starting gender-affirmation therapy. Gender dysphoria refers to the psychological discomfort or distress that an individual can experience if their sex assigned at birth is incongruent with that person's gender identity. Signs of gender dysphoria can include comorbid mental health stressors such as depression, anxiety, low self-esteem, and social isolation. Not all gender nonconforming individuals experience gender dysphoria, and measuring a person's gender dysphoria is critical when considering medical intervention for gender nonconformity.
== Treatment options ==
=== Guidelines ===
For transgender youth, the Dutch protocol existed as among the earlier guidelines for hormone therapy by delaying puberty until age 16. The World Professional Association for Transgender Health (WPATH) and the Endocrine Society later formulated guidelines that created a foundation for health care providers to care for transgender patients. UCSF guidelines are also sometimes used. There is no generally agreed-upon set of guidelines, however.
=== Delaying puberty in adolescents ===
Adolescents experiencing gender dysphoria may opt to undergo puberty-suppressing hormone therapy at the onset of puberty. The Standards of Care set forth by WPATH recommend individuals pursuing puberty-suppressing hormone therapy wait until at least experiencing Tanner Stage 2 pubertal development. Tanner Stage 2 is defined by the appearance of scant pubic hair, breast bud development, and/or slight testicular growth. WPATH classifies puberty-suppressing hormone therapy as a "fully reversible" intervention. Delaying puberty allows individuals more time to explore their gender identity before deciding on more permanent interventions and prevents the physical changes associated with puberty.
The preferred puberty-suppressing agent for both individuals assigned male at birth and individuals assigned female at birth is a GnRH Analogue. This approach temporarily shuts down the Hypothalamic-Pituitary-Gonadal (HPG) Axis, which is responsible for the production of hormones (estrogen, testosterone) that cause the development of secondary sexual characteristics in puberty.
According to a study by JAMA Pediatrics published in January of 2025, less than 0.1% of adolescents covered by private medical insurance in the US take gender-affirming medication to treat gender dysphoria.
=== Feminizing hormone therapy ===
Feminizing hormone therapy is typically used by transgender women, who desire the development of feminine secondary sex characteristics. Individuals who identify as non-binary may also opt-in for feminizing hormone treatment to better align their body with their desired gender expression. Feminizing hormone therapy usually includes medication to suppress testosterone production and induce feminization. Types of medications include estrogens, antiandrogens (testosterone blockers), and progestogens. Most commonly, an estrogen is combined with an antiandrogen to suppress and block testosterone. This allows for demasculinization and promotion of feminization and breast development. Estrogens are administered in various modalities including injection, transdermal patch, and oral tablets.
The desired effects of feminizing hormone therapy focus on the development of feminine secondary sex characteristics. These desired effects include: breast tissue development, redistribution of body fat, decreased body hair, reduction of muscle mass, and more. The table below summarizes some of the effects of feminizing hormone therapy in transgender women:
=== Masculinizing hormone therapy ===
Masculinizing hormone therapy is typically used by transgender men, who desire the development of masculine secondary sex characteristics. Masculinizing hormone therapy usually includes testosterone to produce masculinization and suppress the production of estrogen. Treatment options include oral, subcutaneous injections or implant, and transdermal (patches, gels). Dosing is patient-specific, depending on the patient's rate of metabolism, and is discussed with the physician. The most commonly prescribed methods are intramuscular and subcutaneous injections. This dosing can be daily, weekly or biweekly depending on the route of administration and the individual patient.
Unlike feminizing hormone therapy, individuals undergoing masculinizing hormone therapy do not usually require additional hormone suppression such as estrogen suppression. Therapeutic doses of testosterone are usually sufficient to inhibit the production of estrogen to desired physiologic levels.
The desired effects of masculinizing hormone therapy focus on the development of masculine secondary sex characteristics. These desired effects include: increased muscle mass, increased bone turnover, development of facial hair, voice deepening, increase and thickening of body hair, and more.
== Safety ==
Hormone therapy for transgender individuals has been shown in medical literature to be generally safe, when supervised by a qualified medical professional. There are potential risks with hormone treatment that will be monitored through screenings and lab tests such as blood count (hemoglobin), kidney and liver function, blood sugar, potassium, and cholesterol. Taking more medication than directed may lead to health problems such as increased risk of cancer, heart attack from thickening of the blood, blood clots, and elevated cholesterol. Hormone therapy has been shown to improve the psychosocial well-being among transgender individuals. It's been seen to lower levels of distress in transgender individuals.
=== Feminizing hormone therapy ===
The Standards of Care published by the World Professional Association for Transgender Health (WPATH) summarize many of the risks associated with feminizing hormone therapy (outlined below). For more in-depth information on the safety profile of estrogen-based feminizing hormone therapy visit the feminizing hormone therapy page.
=== Masculinizing hormone therapy ===
The Standards of Care published by the World Professional Association for Transgender Health (WPATH) summarize many of the risks associated with masculinizing hormone therapy (outlined below). For more in-depth information on the safety profile of testosterone-based masculinizing hormone therapy visit the masculinizing hormone therapy page.
=== Fertility consideration ===
GAHT may limit fertility potential. Should a transgender individual choose to undergo gender-affirming surgery, their fertility potential is lost completely. Before starting any treatment, individuals may consider fertility issues and fertility preservation. Options include semen cryopreservation, oocyte cryopreservation, and ovarian tissue cryopreservation.
A study presented at ENDO 2019 (the Endocrine Society's conference) shows that even after one year of treatment with testosterone, a transgender man can preserve his fertility potential.
=== Counterfeit products ===
Some online scammers have been targeting trans consumers with products that do not contain any hormones or contain ones that are opposite of what is advertised. This can happen when legislations outlaw or restrict access to treatments by legitimate medical professionals.
== Treatment eligibility ==
Many providers use informed consent, whereby someone seeking hormone therapy can sign a statement of informed consent and begin treatment without much gatekeeping. For other providers, eligibility is determined using major diagnostic tools such as ICD-11 or the Diagnostic and Statistical Manual of Mental Disorders (DSM) to classify a patient with gender dysphoria. The Endocrine Society requires physicians that diagnose gender dysphoria and gender incongruence to be trained in psychiatric disorders with competency in ICD-11 and DSM-5. The healthcare provider should also obtain a thorough assessment of the patient's mental health and identify potential psychosocial factors that can affect therapy.
=== WPATH Standards of Care ===
The WPATH Standards of Care, most recently published in 2022, outlines a series of guidelines which should be met before a patient should be allowed gender-affirming hormone therapy:
Gender incongruence is marked and sustained
Patient meets diagnostic criteria for gender incongruence prior to gender-affirming hormone treatment in regions where a diagnosis is necessary to access health care
Patient has capacity to consent to hormone therapy treatment
Other possible causes of apparent gender incongruence have been identified and excluded
Mental health and physical conditions that could negatively impact the outcome of treatment have been assessed
Understands the effect of gender-affirming hormone treatment on reproduction and they have explored reproductive options
The WPATH standards of care distinguish between gender-affirming hormone therapy, and hormone replacement therapy, with the latter referring to the replacement of endogenous hormones after a gonadectomy to prevent cardiovascular and musculoskeletal issues.
=== Readiness ===
Some organizations—but fewer than in the past—require that patients spend a certain period of time living in their desired gender role before starting hormone therapy. This period is sometimes called real-life experience (RLE).
In Sweden, for instance, patients seeking to access gender affirming healthcare must first undergo extended evaluations with psychiatric professionals, during which they must—without any form of medical transition—successfully live for one full year as their desired gender in all professional, social, and personal matters. Gender clinics are recommended to provide patients with wigs and breast prostheses for the endeavor. The evaluation additionally involves, if possible, meetings with family members and/or other individuals close to the patient. Patients may be denied care for any number of "psychosocial dimensions", including their choice of job or their marital status.
Transgender and gender non-conforming activists, such as Kate Bornstein, have asserted that RLE is psychologically harmful and is a form of "gatekeeping", effectively barring individuals from transitioning for as long as possible, if not permanently.
In September 2022, the World Professional Association for Transgender Health (WPATH) Standards of Care for the Health of Transgender and Gender Diverse People (SOC) Version 8 were released and removed the requirement of RLE for all gender-affirming treatments, including gender-affirming surgery.
== Accessibility ==
Some transgender people choose to self-administer hormone replacement medications, often because doctors have too little experience in this area, or because no doctor is available. Others self-administer because their doctor will not prescribe hormones without an approval letter from a psychotherapist. Many therapists require extended periods of continuous psychotherapy and/or real-life experience before they will write such a letter. Because many individuals must pay for evaluation and care out-of-pocket, costs can be prohibitive.
Access to medication can be poor even where health care is provided free. In a patient survey conducted by the United Kingdom's National Health Service in 2008, 5% of respondents acknowledged resorting to self-medication, and 46% were dissatisfied with the amount of time it took to receive hormone therapy. The report concluded in part: "The NHS must provide a service that is easy to access so that vulnerable patients do not feel forced to turn to DIY remedies such as buying drugs online with all the risks that entails. Patients must be able to access professional help and advice so that they can make informed decisions about their care, whether they wish to take the NHS or private route without putting their health and indeed their lives in danger." Self-administration of cross-gender hormones without medical supervision may have untoward health effects and risks.
A number of private companies have attempted to increase accessibility for hormone replacement medications and help transgender people navigate the complexities of access to treatment.
== See also ==
Hormone therapy
Gender-affirming surgery
Real-life experience (transgender)
Hormone replacement therapy
Feminizing hormone therapy
== References == | Wikipedia/Gender-affirming_hormone_therapy |
Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems with language, disorientation (including easily getting lost), mood swings, loss of motivation, self-neglect, and behavioral issues. As a person's condition declines, they often withdraw from family and society. Gradually, bodily functions are lost, ultimately leading to death. Although the speed of progression can vary, the average life expectancy following diagnosis is three to twelve years.
The causes of Alzheimer's disease remain poorly understood. There are many environmental and genetic risk factors associated with its development. The strongest genetic risk factor is from an allele of apolipoprotein E. Other risk factors include a history of head injury, clinical depression, and high blood pressure. The progression of the disease is largely characterised by the accumulation of malformed protein deposits in the cerebral cortex, called amyloid plaques and neurofibrillary tangles. These misfolded protein aggregates interfere with normal cell function, and over time lead to irreversible degeneration of neurons and loss of synaptic connections in the brain. A probable diagnosis is based on the history of the illness and cognitive testing, with medical imaging and blood tests to rule out other possible causes. Initial symptoms are often mistaken for normal brain aging. Examination of brain tissue is needed for a definite diagnosis, but this can only take place after death.
No treatments can stop or reverse its progression, though some may temporarily improve symptoms. A healthy diet, physical activity, and social engagement are generally beneficial in aging, and may help in reducing the risk of cognitive decline and Alzheimer's. Affected people become increasingly reliant on others for assistance, often placing a burden on caregivers. The pressures can include social, psychological, physical, and economic elements. Exercise programs may be beneficial with respect to activities of daily living and can potentially improve outcomes. Behavioral problems or psychosis due to dementia are sometimes treated with antipsychotics, but this has an increased risk of early death.
As of 2020, there were approximately 50 million people worldwide with Alzheimer's disease. It most often begins in people over 65 years of age, although up to 10% of cases are early-onset impacting those in their 30s to mid-60s. It affects about 6% of people 65 years and older, and women more often than men. The disease is named after German psychiatrist and pathologist Alois Alzheimer, who first described it in 1906. Alzheimer's financial burden on society is large, with an estimated global annual cost of US$1 trillion. It is ranked as the seventh leading cause of death worldwide.
Given the widespread impacts of Alzheimer's disease, both basic-science and health funders in many countries support Alzheimer's research at large scales. For example, the US National Institutes of Health program for Alzheimer's research, the National Plan to Address Alzheimer's Disease, has a budget of US$3.98 billion for fiscal year 2026. In the European Union, the 2020 Horizon Europe research programme awarded over €570 million for dementia-related projects.
== Signs and symptoms ==
The course of Alzheimer's is generally described in three stages, with a progressive pattern of cognitive and functional impairment. The three stages are described as early or mild, middle or moderate, and late or severe. The disease is known to target the hippocampus which is associated with memory, and this is responsible for the first symptoms of memory impairment. As the disease progresses so does the degree of memory impairment.
=== First symptoms ===
The first symptoms are often mistakenly attributed to aging or stress. Detailed neuropsychological testing can reveal mild cognitive difficulties up to eight years before a person fulfills the clinical criteria for diagnosis of Alzheimer's disease. These early symptoms can affect the most complex activities of daily living. The most noticeable deficit is short term memory loss, which shows up as difficulty in remembering recently learned facts and inability to acquire new information.
Subtle problems with the executive functions of attentiveness, planning, flexibility, and abstract thinking, or impairments in semantic memory (memory of meanings, and concept relationships) can also be symptomatic of the early stages of Alzheimer's disease. Apathy and depression can be seen at this stage, with apathy remaining as the most persistent symptom throughout the course of the disease. People with objective signs of cognitive impairment, but not more severe symptoms, may be diagnosed with mild cognitive impairment (MCI). If memory loss is the predominant symptom of MCI, it is termed amnestic MCI and is frequently seen as a prodromal or early stage of Alzheimer's disease. Amnestic MCI has a greater than 90% likelihood of being associated with Alzheimer's.
=== Early stage ===
In people with Alzheimer's disease, the increasing impairment of learning and memory eventually leads to a definitive diagnosis. In a small percentage, difficulties with language, executive functions, perception (agnosia), or execution of movements (apraxia) are more prominent than memory problems. Alzheimer's disease does not affect all memory capacities equally. Older memories of the person's life (episodic memory), facts learned (semantic memory), and implicit memory (the memory of the body on how to do things, such as using a fork to eat or how to drink from a glass) are affected to a lesser degree than new facts or memories.
Language problems are mainly characterised by a shrinking vocabulary and decreased word fluency, leading to a general impoverishment of oral and written language. In this stage, the person with Alzheimer's is usually capable of communicating basic ideas adequately. While performing fine motor tasks such as writing, drawing, or dressing, certain movement coordination and planning difficulties (apraxia) may be present; however, they are commonly unnoticed. As the disease progresses, people with Alzheimer's disease can often continue to perform many tasks independently; however, they may need assistance or supervision with the most cognitively demanding activities.
=== Middle stage ===
Progressive deterioration eventually hinders independence, with subjects being unable to perform most common activities of daily living. Speech difficulties become evident due to an inability to recall vocabulary, which leads to frequent incorrect word substitutions (paraphasias). Reading and writing skills are also progressively lost. Complex motor sequences become less coordinated as time passes and Alzheimer's disease progresses, so the risk of falling increases. During this phase, memory problems worsen, and the person may fail to recognise close relatives. Long-term memory, which was previously intact, becomes impaired.
Behavioral and neuropsychiatric changes become more prevalent. Common manifestations are wandering, irritability and emotional lability, leading to crying, outbursts of unpremeditated aggression, or resistance to caregiving. Sundowning can also appear. Approximately 30% of people with Alzheimer's disease develop illusionary misidentifications and other delusional symptoms. Subjects also lose insight of their disease process and limitations (anosognosia). Urinary incontinence can develop. These symptoms create stress for relatives and caregivers, which can be reduced by moving the person from home care to other long-term care facilities.
=== Late stage ===
During the final stage, known as the late-stage or severe stage, there is complete dependence on caregivers. Language is reduced to simple phrases or even single words, eventually leading to complete loss of speech. Despite the loss of verbal language abilities, people can often understand and return emotional signals. Although aggressiveness can still be present, extreme apathy and exhaustion are much more common symptoms. People with Alzheimer's disease will ultimately not be able to perform even the simplest tasks independently; muscle mass and mobility deteriorates to the point where they are bedridden and unable to feed themselves. The cause of death is usually an external factor, such as infection of pressure ulcers or pneumonia, not the disease itself. In some cases, there is a paradoxical lucidity immediately before death, where there is an unexpected recovery of mental clarity.
== Causes ==
Alzheimer's disease is believed to occur when abnormal amounts of amyloid beta (Aβ), accumulating extracellularly as amyloid plaques and tau proteins, or intracellularly as neurofibrillary tangles, form in the brain, affecting neuronal functioning and connectivity, resulting in a progressive loss of brain function. This altered protein clearance ability is age-related, regulated by brain cholesterol, and associated with other neurodegenerative diseases.
The cause for most Alzheimer's cases is still mostly unknown, except for 1–2% of cases where deterministic genetic differences have been identified. Several competing hypotheses attempt to explain the underlying cause; the most predominant hypothesis is the amyloid beta (Aβ) hypothesis.
In the 1970s, the cholinergic hypothesis proposed that Alzheimer's disease is caused by reduced synthesis of the neurotransmitter acetylcholine. The loss of cholinergic neurons noted in the limbic system and cerebral cortex, is a key feature in the progression of Alzheimer's. The 1991 amyloid hypothesis postulated that extracellular amyloid beta (Aβ) deposits are the fundamental cause of the disease. Support for this postulate comes from the location of the gene for the amyloid precursor protein (APP) on chromosome 21, together with the fact that people with trisomy 21 (Down syndrome) who have an extra gene copy almost universally exhibit at least the earliest symptoms of Alzheimer's disease by 40 years of age. A specific isoform of apolipoprotein, APOE4, is a major genetic risk factor for Alzheimer's disease. While apolipoproteins enhance the breakdown of amyloid beta, some isoforms are not very effective at this task (such as APOE4), leading to excess amyloid buildup in the brain.
=== Genetic ===
==== Late onset ====
Late-onset Alzheimer's is about 70% heritable. Most cases of Alzheimer's are not familial, and so they are termed sporadic Alzheimer's disease. Of the cases of sporadic Alzheimer's disease, most are classified as late onset where they are developed after the age of 65 years.
The strongest genetic risk factor for sporadic Alzheimer's disease is APOEε4. APOEε4 is one of four alleles of apolipoprotein E (APOE). APOE plays a major role in lipid-binding proteins in lipoprotein particles and the ε4 allele disrupts this function. Between 40% and 80% of people with Alzheimer's disease possess at least one APOEε4 allele. The APOEε4 allele increases the risk of the disease by three times in heterozygotes and by 15 times in homozygotes. Like many human diseases, environmental effects and genetic modifiers result in incomplete penetrance. For example, Nigerian Yoruba people do not show the relationship between dose of APOEε4 and incidence or age-of-onset for Alzheimer's disease seen in other human populations.
==== Early onset ====
Only 1–2% of Alzheimer's cases are inherited due to autosomal dominant effects, as Alzheimer's is highly polygenic. When the disease is caused by autosomal dominant variants, it is known as early onset familial Alzheimer's disease, which is rarer and has a faster rate of progression. Less than 5% of sporadic Alzheimer's disease have an earlier onset, and early-onset Alzheimer's is about 90% heritable. Familial Alzheimer's disease usually implies two or more persons affected in one or more generations.
Early onset familial Alzheimer's disease can be attributed to mutations in one of three genes: those encoding amyloid-beta precursor protein (APP) and presenilins PSEN1 and PSEN2. Most mutations in the APP and presenilin genes increase the production of a small protein called amyloid beta (Aβ)42, which is the main component of amyloid plaques. Some of the mutations merely alter the ratio between Aβ42 and the other major forms—particularly Aβ40—without increasing Aβ42 levels in the brain. Two other genes associated with autosomal dominant Alzheimer's disease are ABCA7 and SORL1.
Alleles in the TREM2 gene have been associated with a three to five times higher risk of developing Alzheimer's disease.
A Japanese pedigree of familial Alzheimer's disease was found to be associated with a deletion mutation of codon 693 of APP. This mutation and its association with Alzheimer's disease was first reported in 2008, and is known as the Osaka mutation. Only homozygotes with this mutation have an increased risk of developing Alzheimer's disease. This mutation accelerates Aβ oligomerization but the proteins do not form the amyloid fibrils that aggregate into amyloid plaques, suggesting that it is the Aβ oligomerization rather than the fibrils that may be the cause of this disease. Mice expressing this mutation have all the usual pathologies of Alzheimer's disease.
=== Hypotheses ===
==== Amyloid beta and tau protein ====
The tau hypothesis proposes that tau protein abnormalities initiate the disease cascade. In this model, hyperphosphorylated tau begins to pair with other threads of tau as paired helical filaments. Eventually, they form neurofibrillary tangles inside neurons. When this occurs, the microtubules disintegrate, destroying the structure of the cell's cytoskeleton which collapses the neuron's transport system.
A number of studies connect the misfolded amyloid beta and tau proteins associated with the pathology of Alzheimer's disease, as bringing about oxidative stress that leads to neuroinflammation. This chronic inflammation is also a feature of other neurodegenerative diseases including Parkinson's disease, and ALS. Spirochete infections have also been linked to dementia. DNA damages accumulate in Alzheimer's diseased brains; reactive oxygen species may be the major source of this DNA damage.
==== Sleep ====
Sleep disturbances are seen as a possible risk factor for inflammation in Alzheimer's disease. Sleep disruption was previously only seen as a consequence of Alzheimer's disease, but as of 2020, accumulating evidence suggests that this relationship may be bidirectional.
==== Metal toxicity, smoking, neuroinflammation and air pollution ====
The cellular homeostasis of biometals such as ionic copper, iron, and zinc is disrupted in Alzheimer's disease, though it remains unclear whether this is produced by or causes the changes in proteins. Smoking is a significant Alzheimer's disease risk factor. Systemic markers of the innate immune system are risk factors for late-onset Alzheimer's disease. Exposure to air pollution may be a contributing factor to the development of Alzheimer's disease.
==== Age-related myelin decline ====
Retrogenesis is a medical hypothesis that just as the fetus goes through a process of neurodevelopment beginning with neurulation and ending with myelination, the brains of people with Alzheimer's disease go through a reverse neurodegeneration process starting with demyelination and death of axons (white matter) and ending with the death of grey matter. Likewise the hypothesis is, that as infants go through states of cognitive development, people with Alzheimer's disease go through the reverse process of progressive cognitive impairment.
According to one theory, dysfunction of oligodendrocytes and their associated myelin during aging contributes to axon damage, which in turn generates in amyloid production and tau hyperphosphorylation. Comorbidities between the demyelinating disease, multiple sclerosis, and Alzheimer's disease have been reported.
==== Other hypotheses ====
The association with celiac disease is unclear, with a 2019 study finding no increase in dementia overall in those with celiac disease while a 2018 review found an association with several types of dementia including Alzheimer's disease.
Studies have shown a potential link between infection with certain viruses and developing Alzheimer's disease later in life. Notably, a large scale study conducted on 6,245,282 patients has shown an increased risk of developing Alzheimer's disease following COVID-19 infection in cognitively normal individuals over 65.
Some evidence suggests that some viral infections such as Herpes simplex virus 1 (HSV-1) may be associated with dementia, but there are conflicting results and the association with Alzheimer's is unclear as of 2024.
Some researchers have proposed that Alzheimer's disease is Type 3 diabetes because of a number of correspondences with both Type 1 and Type 2 diabetes.
== Pathophysiology ==
=== Neuropathology ===
Alzheimer's disease is characterised by loss of neurons and synapses in the cerebral cortex and certain subcortical regions. This loss results in gross atrophy of the affected regions, including degeneration in the temporal lobe and parietal lobe, and parts of the frontal cortex and cingulate gyrus. Degeneration is also present in brainstem nuclei particularly the locus coeruleus in the pons. Studies using MRI and PET have documented reductions in the size of specific brain regions in people with Alzheimer's disease as they progressed from mild cognitive impairment to Alzheimer's disease, and in comparison with similar images from healthy older adults.
Both Aβ plaques and neurofibrillary tangles are clearly visible by microscopy in brains of those with Alzheimer's disease, especially in the hippocampus. However, Alzheimer's disease may occur without neurofibrillary tangles in the neocortex. Plaques are dense, mostly insoluble deposits of amyloid beta peptide and cellular material outside and around neurons. Neurofibrillary tangles are aggregates of the microtubule-associated protein tau which has become hyperphosphorylated and accumulate inside the cells themselves. Although many older individuals develop some plaques and tangles as a consequence of aging, the brains of people with Alzheimer's disease have a greater number of them in specific brain regions such as the temporal lobe. Lewy bodies are not rare in the brains of people with Alzheimer's disease.
=== Biochemistry ===
==== Amyloid beta ====
Alzheimer's disease has been identified as a protein misfolding disease, a proteopathy, caused by the accumulation of abnormally folded amyloid beta protein into amyloid plaques, and tau protein into neurofibrillary tangles in the brain. Plaques are made up of small peptides, 39–43 amino acids in length, called amyloid beta. Amyloid beta is a fragment from the larger amyloid-beta precursor protein (APP) a transmembrane protein that penetrates the cell's membrane. APP is critical to neuron growth, survival, and post-injury repair. In Alzheimer's disease, gamma secretase and beta secretase act together in a proteolytic process which causes APP to be divided into smaller fragments. Although commonly researched as neuronal proteins, APP and its processing enzymes are abundantly expressed by other brain cells. One of these fragments gives rise to fibrils of amyloid beta, which then form clumps that deposit outside neurons in dense formations known as amyloid plaques. Excitatory neurons are known to be the major producers of amyloid beta that contribute to major extracellular plaque deposition.
==== Phosphorylated tau ====
Alzheimer's disease is also considered a tauopathy due to abnormal aggregation of the tau protein. Every neuron has a cytoskeleton, an internal support structure partly made up of structures called microtubules. These microtubules act like tracks, guiding nutrients and molecules from the body of the cell to the ends of the axon and back. A protein called tau stabilises the microtubules when phosphorylated, and is therefore called a microtubule-associated protein. In Alzheimer's disease, tau undergoes chemical changes, becoming hyperphosphorylated; it then begins to pair with other threads, creating neurofibrillary tangles and disintegrating the neuron's transport system. Pathogenic tau can also cause neuronal death through transposable element dysregulation. Necroptosis has also been reported as a mechanism of cell death in brain cells affected with tau tangles.
=== Disease mechanism ===
Exactly how disturbances of production and aggregation of the beta-amyloid peptide give rise to the pathology of Alzheimer's disease is not known. The amyloid hypothesis traditionally points to the accumulation of beta-amyloid peptides as the central event triggering neuron degeneration. Accumulation of aggregated amyloid fibrils, which are believed to be the toxic form of the protein responsible for disrupting the cell's calcium ion homeostasis, induces programmed cell death (apoptosis). It is also known that Aβ selectively builds up in the mitochondria in the cells of Alzheimer's-affected brains, and it also inhibits certain enzyme functions and the utilisation of glucose by neurons.
Evidence supports Aβ as playing a central role in the pathogenesis of AD, but it does not completely explain the condition, as individuals may have normal cognition and very high Aβ burden in their brains at an advanced age, and the beneficial effect of therapeutics (such as monoclonal antibodies) promoting Aβ clearance has ranged from nonexistent to modest.
Iron dyshomeostasis is linked to disease progression, an iron-dependent form of regulated cell death called ferroptosis could be involved. Products of lipid peroxidation are also elevated in AD brain compared with controls.
Various inflammatory processes and cytokines may also have a role in the pathology of Alzheimer's disease. Inflammation is a general marker of tissue damage in any disease, and may be either secondary to tissue damage in Alzheimer's disease or a marker of an immunological response. There is increasing evidence of a strong interaction between the neurons and the immunological mechanisms in the brain. Obesity and systemic inflammation may interfere with immunological processes which promote disease progression.
Alterations in the distribution of different neurotrophic factors and in the expression of their receptors such as the brain-derived neurotrophic factor (BDNF) have been described in Alzheimer's disease.
Evidence has accrued for microglia as central actors in the mechanism of AD. Microglia are topographically associated with pTau and Aβ within the brain, even when each pathologic component occurs in distinct brain regions, and microglial activation has been documented in those with mild cognitive impairment, despite a lack of tracer uptake, suggesting that microglial dysfunction may precede plaque deposition as an inciting event in AD. Microglia are the principal immunological cells of the central nervous system, serving as the tissue-resident macrophages of the brain; they are capable of recognizing and taking up Aβ through multiple pattern recognition receptors, making them central to amyloid clearance within the brain. However, microglia can also be a major source of pro-inflammatory mediators which can be deleterious to neurological function.
== Diagnosis ==
Alzheimer's disease (AD) can only be definitively diagnosed with autopsy findings; in the absence of autopsy, clinical diagnoses of AD are "possible" or "probable", based on other findings. Up to 23% of those clinically diagnosed with AD may be misdiagnosed and may have pathology suggestive of another condition with symptoms that mimic those of AD.
AD is usually clinically diagnosed based on a person's medical history, observations from friends or relatives, and behavioral changes. The presence of characteristic neuropsychological changes with impairments in at least two cognitive domains that are severe enough to affect a person's functional abilities are required for the diagnosis. Domains that may be impaired include memory (most commonly impaired), language, executive function, visuospatial functioning, or other areas of cognition. The neurocognitive changes must be a decline from a prior level of function and the diagnosis requires ruling out other common causes of neurocognitive decline. Advanced medical imaging with computed tomography (CT) or magnetic resonance imaging (MRI), and with single-photon emission computed tomography (SPECT) or positron emission tomography (PET), can be used to help exclude other cerebral pathology or subtypes of dementia. On MRI or CT, Alzheimer's disease usually shows a generalised or focal cortical atrophy, which may be asymmetric. Atrophy of the hippocampus is also commonly seen. Brain imaging commonly also shows cerebrovascular disease, most commonly previous strokes (small or large territory strokes), and this is thought to be a contributing cause of many cases of dementia (up to 46% cases of dementia also have cerebrovascular disease on imaging). FDG-PET scan is not required for the diagnosis but it is sometimes used when standard testing is unclear. FDG-PET shows a bilateral, asymmetric, temporal and parietal reduced activity. Advanced imaging may predict conversion from prodromal stages (mild cognitive impairment) to Alzheimer's disease. FDA-approved radiopharmaceutical diagnostic agents used in PET for Alzheimer's disease are florbetapir (2012), flutemetamol (2013), florbetaben (2014), and flortaucipir (2020). Because many insurance companies in the United States do not cover this procedure, its use in clinical practice is largely limited to clinical trials as of 2018.
Assessment of intellectual functioning including memory testing can further characterise the state of the disease. Medical organizations have created diagnostic criteria to ease and standardise the diagnostic process for practising physicians. Definitive diagnosis can only be confirmed with post-mortem evaluations when brain material is available and can be examined histologically for senile plaques and neurofibrillary tangles.
=== Criteria ===
There are three sets of criteria for the clinical diagnoses of the spectrum of Alzheimer's disease: the 2013 fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5); the National Institute on Aging-Alzheimer's Association (NIA-AA) definition as revised in 2011; and the International Working Group criteria as revised in 2010.
Eight intellectual domains are most commonly impaired in AD—memory, language, perceptual skills, attention, motor skills, orientation, problem solving and executive functional abilities, as listed in the fourth text revision of the DSM (DSM-IV-TR).
The DSM-5 defines criteria for probable or possible AD for both major and mild neurocognitive disorder. Major or mild neurocognitive disorder must be present along with at least one cognitive deficit for a diagnosis of either probable or possible AD. For major neurocognitive disorder due to AD, probable Alzheimer's disease can be diagnosed if the individual has genetic evidence of AD or if two or more acquired cognitive deficits, and a functional disability that is not from another disorder, are present. Otherwise, possible AD can be diagnosed as the diagnosis follows an atypical route. For mild neurocognitive disorder due to AD, probable Alzheimer's disease can be diagnosed if there is genetic evidence, whereas possible AD can be met if all of the following are present: no genetic evidence, decline in both learning and memory, two or more cognitive deficits, and a functional disability not from another disorder.
The NIA-AA criteria are used mainly in research rather than in clinical assessments. They define AD through three major stages: preclinical, mild cognitive impairment (MCI), and Alzheimer's dementia. Diagnosis in the preclinical stage is complex and focuses on asymptomatic individuals; the latter two stages describe individuals experiencing symptoms, along with biomarkers, predominantly those for neuronal injury (mainly tau-related) and amyloid beta deposition. The core clinical criteria itself rests on the presence of cognitive impairment without the presence of comorbidities. The third stage is divided into probable and possible AD dementia. In probable AD dementia there is steady impairment of cognition over time and a memory-related or non-memory-related cognitive dysfunction. In possible AD dementia, another causal disease such as cerebrovascular disease is present.
=== Techniques ===
Neuropsychological tests including cognitive tests such as the mini–mental state examination (MMSE), the Montreal Cognitive Assessment (MoCA) and the Mini-Cog are widely used to aid in diagnosis of the cognitive impairments in AD. These tests may not always be accurate, as they lack sensitivity to mild cognitive impairment, and can be biased by language or attention problems; more comprehensive test arrays are necessary for high reliability of results, particularly in the earliest stages of the disease.
Further neurological examinations are crucial in the differential diagnosis of Alzheimer's disease and other diseases. Interviews with family members are used in assessment; caregivers can supply important information on daily living abilities and on the decrease in the person's mental function. A caregiver's viewpoint is particularly important, since a person with Alzheimer's disease is commonly unaware of their deficits. Many times, families have difficulties in the detection of initial dementia symptoms and may not communicate accurate information to a physician.
Supplemental testing can rule out other potentially treatable diagnoses and help avoid misdiagnoses. Common supplemental tests include blood tests, thyroid function tests, as well as tests to assess vitamin B12 levels, rule out neurosyphilis and rule out metabolic problems (including tests for kidney function, electrolyte levels and for diabetes). MRI or CT scans might also be used to rule out other potential causes of the symptoms – including tumors or strokes. Delirium and depression can be common among individuals and are important to rule out.
Psychological tests for depression are used, since depression can either be concurrent with AD (see Depression of Alzheimer disease), an early sign of cognitive impairment, or even the cause.
Due to low accuracy, the C-PIB-PET scan is not recommended as an early diagnostic tool or for predicting the development of AD when people show signs of mild cognitive impairment (MCI). The use of 18F-FDG PET scans, as a single test, to identify people who may develop Alzheimer's disease is not supported by evidence.
In May 2025, the US FDA approved a blood test by Fujirebio Diagnostics’ Lumipulse G pTau217/ß-Amyloid 1-42 Plasma Ratio diagnostic device for the early detection of amyloid plaques associated with AD in adults aged 55 years and older who are exhibiting signs and symptoms of the disease.
== Prevention ==
There are no disease-modifying treatments available to cure Alzheimer's disease and because of this, AD research has focused on interventions to prevent the onset and progression. There is no evidence that supports any particular measure in preventing AD, and studies of measures to prevent the onset or progression have produced inconsistent results. Epidemiological studies have proposed relationships between an individual's likelihood of developing AD and modifiable factors, such as medications, lifestyle, and diet. There are some challenges in determining whether interventions for AD act as a primary prevention method, preventing the disease itself, or a secondary prevention method, identifying the early stages of the disease. These challenges include duration of intervention, different stages of disease at which intervention begins, and lack of standardization of inclusion criteria regarding biomarkers specific for AD. Further research is needed to determine factors that can help prevent AD.
=== Medication ===
Cardiovascular risk factors, such as hypercholesterolaemia, hypertension, diabetes, and smoking, are associated with a higher risk of onset and worsened course of AD. The use of statins to lower cholesterol may be of benefit in AD. Antihypertensive and antidiabetic medications in individuals without overt cognitive impairment may decrease the risk of dementia by influencing cerebrovascular pathology. More research is needed to examine the relationship with AD specifically; clarification of the direct role medications play versus other concurrent lifestyle changes (diet, exercise, smoking) is needed.
Depression is associated with an increased risk for AD; management with antidepressant medications may provide a preventative measure.
Historically, long-term usage of non-steroidal anti-inflammatory drugs (NSAIDs) were thought to be associated with a reduced likelihood of developing AD as it reduces inflammation, but NSAIDs do not appear to be useful as a treatment. Additionally, because women have a higher incidence of AD than men, it was once thought that estrogen deficiency during menopause was a risk factor, but there is a lack of evidence to show that hormone replacement therapy (HRT) in menopause decreases risk of cognitive decline.
=== Lifestyle ===
Certain lifestyle activities, such as physical and cognitive exercises, higher education and occupational attainment, cigarette smoking, stress, sleep, and the management of other comorbidities, including diabetes and hypertension, may affect the risk of developing AD.
Physical exercise is associated with a decreased rate of dementia, and is effective in reducing symptom severity in those with AD. Memory and cognitive functions can be improved with aerobic exercises including brisk walking three times weekly for forty minutes. It may also induce neuroplasticity of the brain. Participating in mental exercises, such as reading, crossword puzzles, and chess have shown potential to be preventive. Meeting the WHO recommendations for physical activity is associated with a lower risk of AD.
Higher education and occupational attainment, and participation in leisure activities, contribute to a reduced risk of developing AD, or of delaying the onset of symptoms. This is compatible with the cognitive reserve theory, which states that some life experiences result in more efficient neural functioning providing the individual a cognitive reserve that delays the onset of dementia manifestations. Education delays the onset of Alzheimer's disease syndrome without changing the duration of the disease.
Cessation in smoking may reduce risk of developing AD, specifically in those who carry the APOE ɛ4 allele. The increased oxidative stress caused by smoking results in downstream inflammatory or neurodegenerative processes that may increase risk of developing AD. Avoidance of smoking, counseling and pharmacotherapies to quit smoking are used, and avoidance of environmental tobacco smoke is recommended.
Alzheimer's disease is associated with sleep disorders but the precise relationship is unclear. It was once thought that as people get older, the risk of developing sleep disorders and AD independently increase, but research suggests sleep disorders may be a risk factor for AD. One theory is that the mechanisms to increase clearance of toxic substances, including Aβ, are active during sleep. With decreased sleep, a person is increasing Aβ production and decreasing Aβ clearance, resulting in Aβ accumulation. Receiving adequate sleep (approximately 7–8 hours) every night has become a potential lifestyle intervention to prevent the development of AD.
Stress is a risk factor for the development of AD. The mechanism by which stress predisposes someone to development of AD is unclear, but it is suggested that lifetime stressors may affect a person's epigenome, leading to an overexpression or under expression of specific genes. Although the relationship of stress and AD is unclear, strategies to reduce stress and relax the mind may be helpful strategies in preventing the progression or Alzheimer's disease. Meditation, for instance, is a helpful lifestyle change to support cognition and well-being, though further research is needed to assess long-term effects.
== Management ==
There is no cure for AD; available treatments offer relatively small symptomatic benefits but remain palliative in nature. Treatments can be divided into pharmaceutical, psychosocial, and caregiving.
=== Pharmaceutical ===
Medications used to treat the cognitive symptoms of AD rather than the underlying cause include: four acetylcholinesterase inhibitors (tacrine, rivastigmine, galantamine, and donepezil) and memantine, an NMDA receptor antagonist. The acetylcholinesterase inhibitors are intended for those with mild to severe AD, whereas memantine is intended for those with moderate or severe Alzheimer's disease. The benefit from their use is small.
Reduction in the activity of the cholinergic neurons is a well-known feature of AD. Acetylcholinesterase inhibitors are employed to reduce the rate at which acetylcholine (ACh) is broken down, thereby increasing the concentration of ACh in the brain and combating the loss of ACh caused by the death of cholinergic neurons. There is evidence for the efficacy of these medications in mild to moderate AD, and some evidence for their use in the advanced stage. The use of these drugs in mild cognitive impairment has not shown any effect in a delay of the onset of Alzheimer's disease. The most common side effects are nausea and vomiting, both of which are linked to cholinergic excess. These side effects arise in approximately 10–20% of users, are mild to moderate in severity, and can be managed by slowly adjusting medication doses. Less common secondary effects include muscle cramps, decreased heart rate (bradycardia), decreased appetite and weight, and increased gastric acid production.
Glutamate is an excitatory neurotransmitter of the nervous system, although excessive amounts in the brain can lead to cell death through a process called excitotoxicity which consists of the overstimulation of glutamate receptors. Excitotoxicity occurs not only in AD, but also in other neurological diseases such as Parkinson's disease and multiple sclerosis. Memantine is a noncompetitive NMDA receptor antagonist first used as an anti-influenza agent. It acts on the glutamatergic system by blocking NMDA receptors and inhibiting their overstimulation by glutamate. Memantine has been shown to have a small benefit in the treatment of moderate to severe AD. Reported adverse events with memantine are infrequent and mild, including hallucinations, confusion, dizziness, headache and fatigue. The combination of memantine and donepezil has been shown to be "of statistically significant but clinically marginal effectiveness".
An extract of Ginkgo biloba known as EGb 761 has been used for treating AD and other neuropsychiatric disorders. Its use is approved throughout Europe. The World Federation of Biological Psychiatry guidelines lists EGb 761 with the same weight of evidence (level B) given to acetylcholinesterase inhibitors and memantine. EGb 761 is the only one that showed improvement of symptoms in both AD and vascular dementia. EGb 761 may have a role either on its own or as an add-on if other therapies prove ineffective. A 2016 review concluded that the quality of evidence from clinical trials on Ginkgo biloba has been insufficient to warrant its use for treating AD.
Atypical antipsychotics are modestly useful in reducing aggression and psychosis in people with AD, but their advantages are offset by serious adverse effects, such as stroke, movement difficulties or cognitive decline. When used in the long-term, they have been shown to associate with increased mortality. They are recommended in dementia only after first line therapies such as behavior modification have failed, and due to the risk of adverse effects, they should be used for the shortest amount of time possible. Stopping antipsychotic use in this group of people appears to be safe.
=== Psychosocial ===
Psychosocial interventions are used as an adjunct to pharmaceutical treatment and can be classified within behavior-, emotion-, cognition- or stimulation-oriented approaches.
Behavioral interventions attempt to identify and reduce the antecedents and consequences of problem behaviors. This approach has not shown success in improving overall functioning, but can help to reduce some specific problem behaviors, such as incontinence. There is a lack of high quality data on the effectiveness of these techniques in other behavior problems such as wandering. Music therapy is effective in reducing behavioral and psychological symptoms.
Emotion-oriented interventions include reminiscence therapy, validation therapy, supportive psychotherapy, sensory integration, also called snoezelen, and simulated presence therapy. A Cochrane review has found no evidence that this is effective. Reminiscence therapy (RT) involves the discussion of past experiences individually or in group, many times with the aid of photographs, household items, music and sound recordings, or other familiar items from the past. A 2018 review of the effectiveness of RT found that effects were inconsistent, small in size and of doubtful clinical significance, and varied by setting. Simulated presence therapy (SPT) is based on attachment theories and involves playing a recording with voices of the closest relatives of the person with AD. There is partial evidence indicating that SPT may reduce challenging behaviors.
The aim of cognition-oriented treatments, which include reality orientation and cognitive retraining, is the reduction of cognitive deficits. Reality orientation consists of the presentation of information about time, place, or person to ease the understanding of the person about its surroundings and his or her place in them. On the other hand, cognitive retraining tries to improve impaired capacities by exercising mental abilities. Both have shown some efficacy improving cognitive capacities.
Stimulation-oriented treatments include art, music and pet therapies, exercise, and any other kind of recreational activities. Stimulation has modest support for improving behavior, mood, and, to a lesser extent, function. Nevertheless, as important as these effects are, the main support for the use of stimulation therapies is the change in the person's routine.
=== Caregiving ===
Since AD has no cure and it gradually renders people incapable of tending to their own needs, caregiving is essentially the treatment and must be carefully managed over the course of the disease.
During the early and moderate stages, modifications to the living environment and lifestyle can increase safety and reduce caretaker burden. Examples of such modifications are the adherence to simplified routines, the placing of safety locks, the labeling of household items to cue the person with the disease or the use of modified daily life objects. If eating becomes problematic, food will need to be prepared in smaller pieces or even puréed. When swallowing difficulties arise, the use of feeding tubes may be required. In such cases, the medical efficacy and ethics of continuing feeding is an important consideration of the caregivers and family members. The use of physical restraints is rarely indicated in any stage of the disease, although there are situations when they are necessary to prevent harm to the person with Alzheimer's disease or their caregivers.
During the final stages of the disease, treatment is centred on relieving discomfort until death, often with the help of hospice.
=== Diet ===
Diet may be a modifiable risk factor for the development of Alzheimer's disease but more research needs to be conducted. The Mediterranean diet, and the DASH diet are both associated with less cognitive decline. A different approach has been to incorporate elements of both of these diets into one known as the MIND diet.
Results from large-scale epidemiological studies and clinical trials have not demonstrated an independent role for most individual dietary components.
== Prognosis ==
The early stages of AD are difficult to diagnose. A definitive diagnosis is usually made once cognitive impairment compromises daily living activities, although the person may still be living independently. The symptoms will progress from mild cognitive problems, such as memory loss through increasing stages of cognitive and non-cognitive disturbances, eliminating any possibility of independent living, especially in the late stages of the disease.
Life expectancy of people with AD is reduced. The normal life expectancy for 60 to 70 years old is 23 to 15 years; for 90 years old it is 4.5 years. Following AD diagnosis it ranges from 7 to 10 years for those in their 60s and early 70s (a loss of 13 to 8 years), to only about 3 years or less (a loss of 1.5 years) for those in their 90s.
Fewer than 3% of people live more than fourteen years after diagnosis. Disease features significantly associated with reduced survival are an increased severity of cognitive impairment, decreased functional level, disturbances in the neurological examination, history of falls, malnutrition, dehydration and weight loss. Other coincident diseases such as heart problems, diabetes, or history of alcohol abuse are also related with shortened survival. While the earlier the age at onset the higher the total survival years, life expectancy is particularly reduced when compared to the healthy population among those who are younger. Men have a less favourable survival prognosis than women.
Aspiration pneumonia is the most frequent immediate cause of death brought by AD. While the reasons behind the lower prevalence of cancer in AD patients remain unclear, some researchers hypothesize that biological mechanisms shared by both diseases might play a role. However, this requires further investigation.
== Epidemiology ==
Two main measures are used in epidemiological studies: incidence and prevalence. Incidence is the number of new cases per unit of person-time at risk (usually number of new cases per thousand person-years); while prevalence is the total number of cases of the disease in the population at any given time.
Regarding incidence, cohort longitudinal studies (studies where a disease-free population is followed over the years) provide rates between 10 and 15 per thousand person-years for all dementias and 5–8 for AD, which means that half of new dementia cases each year are Alzheimer's disease. Advancing age is a primary risk factor for the disease and incidence rates are not equal for all ages: every 5 years after the age of 65, the risk of acquiring the disease approximately doubles, increasing from 3 to as much as 69 per thousand person years. Females with AD are more common than males, but this difference is likely due to women's longer life spans. When adjusted for age, both sexes are affected by Alzheimer's at equal rates. In the United States, the risk of dying from AD in 2010 was 26% higher among the non-Hispanic white population than among the non-Hispanic black population, and the Hispanic population had a 30% lower risk than the non-Hispanic white population. However, much AD research remains to be done in minority groups, such as the African American, East Asian and Hispanic/Latino populations. Studies have shown that these groups are underrepresented in clinical trials and do not have the same risk of developing AD when carrying certain genetic risk factors (i.e. APOE4), compared to their caucasian counterparts.
The prevalence of AD in populations is dependent upon factors including incidence and survival. Since the incidence of AD increases with age, prevalence depends on the mean age of the population for which prevalence is given. In the United States in 2020, AD dementia prevalence was estimated to be 5.3% for those in the 60–74 age group, with the rate increasing to 13.8% in the 74–84 group and to 34.6% in those greater than 85. Prevalence rates in some less developed regions around the globe are lower. Both the prevalence and incidence rates of AD are steadily increasing, and the prevalence rate is estimated to triple by 2050 reaching 152 million, compared to the 50 million people with AD globally in 2020.
== History ==
The ancient Greek and Roman philosophers and physicians associated old age with increasing dementia. It was not until 1901 that German psychiatrist Alois Alzheimer identified the first case of what became known as Alzheimer's disease, named after him, in a fifty-year-old woman he called Auguste D. He followed her case until she died in 1906 when he first reported publicly on it. During the next five years, eleven similar cases were reported in the medical literature, some of them already using the term Alzheimer's disease. The disease was first described as a distinctive disease by Emil Kraepelin after suppressing some of the clinical (delusions and hallucinations) and pathological features (arteriosclerotic changes) contained in the original report of Auguste D. He included Alzheimer's disease, also named presenile dementia by Kraepelin, as a subtype of senile dementia in the eighth edition of his Textbook of Psychiatry, published on 15 July 1910.
For most of the 20th century, the diagnosis of Alzheimer's disease was reserved for individuals between the ages of 45 and 65 who developed symptoms of dementia. The terminology changed after 1977 when a conference on Alzheimer's disease concluded that the clinical and pathological manifestations of presenile and senile dementia were almost identical, although the authors also added that this did not rule out the possibility that they had different causes. This eventually led to the diagnosis of Alzheimer's disease independent of age. The term senile dementia of the Alzheimer type (SDAT) was used for a time to describe the condition in those over 65, with classical Alzheimer's disease being used to describe those who were younger. Eventually, the term Alzheimer's disease was formally adopted in medical nomenclature to describe individuals of all ages with a characteristic common symptom pattern, disease course, and neuropathology.
The National Institute of Neurological and Communicative Disorders and Stroke (NINCDS) and the Alzheimer's Disease and Related Disorders Association (ADRDA, now known as the Alzheimer's Association) established the most commonly used NINCDS-ADRDA Alzheimer's Criteria for diagnosis in 1984, extensively updated in 2007. These criteria require that the presence of cognitive impairment, and a suspected dementia syndrome, be confirmed by neuropsychological testing for a clinical diagnosis of possible or probable Alzheimer's disease. A histopathologic confirmation including a microscopic examination of brain tissue is required for a definitive diagnosis. Good statistical reliability and validity have been shown between the diagnostic criteria and definitive histopathological confirmation.
== Society and culture ==
=== Social costs ===
Dementia, and specifically Alzheimer's disease, may be among the most costly diseases for societies worldwide. As populations age, these costs will probably increase and become an important social problem and economic burden. Costs associated with AD include direct and indirect medical costs, which vary between countries depending on social care for a person with AD. Direct costs include doctor visits, hospital care, medical treatments, nursing home care, specialised equipment, and household expenses. Indirect costs include the cost of informal care and the loss in productivity of informal caregivers.
In the United States as of 2019, informal (family) care is estimated to constitute nearly three-fourths of caregiving for people with AD at a cost of US$234 billion per year and approximately 18.5 billion hours of care. The cost to society worldwide to care for individuals with AD is projected to increase nearly ten-fold, and reach about US$9.1 trillion by 2050.
Costs for those with more severe dementia or behavioral disturbances are higher and are related to the additional caregiving time to provide physical care.
=== Caregiving burden ===
Individuals with Alzheimer's will require assistance in their lifetime, and care will most likely come in the form of a full-time caregiver which is often a role that is taken on by the spouse or a close relative. Caregiving tends to include physical and emotional burdens as well as time and financial strain at times on the person administering the aid. Alzheimer's disease is known for placing a great burden on caregivers which includes social, psychological, physical, or economic aspects. Home care is usually preferred by both those people with Alzheimer's disease as well as their families. This option also delays or eliminates the need for more professional and costly levels of care. Nevertheless, two-thirds of nursing home residents have dementias.
Dementia caregivers are subject to high rates of physical and mental disorders. Factors associated with greater psychosocial problems of the primary caregivers include having an affected person at home, the caregiver being a spouse, demanding behaviors of the cared person such as depression, behavioral disturbances, hallucinations, sleep problems or walking disruptions and social isolation. In the United States, the yearly cost of caring for a person with dementia ranges from $28,078-$56,022 per year for formal medical care and $36,667-$92,689 for informal care provided by a relative or friend (assuming market value replacement costs for the care provided by the informal caregiver) and $15,792-$71,813 in lost wages.
Cognitive behavioral therapy and the teaching of coping strategies either individually or in group have demonstrated their efficacy in improving caregivers' psychological health.
=== Media ===
Alzheimer's disease has been portrayed in films such as: Iris (2001), based on John Bayley's memoir of his wife Iris Murdoch; The Notebook (2004), based on Nicholas Sparks's 1996 novel of the same name; A Moment to Remember (2004); Thanmathra (2005); Memories of Tomorrow (Ashita no Kioku) (2006), based on Hiroshi Ogiwara's novel of the same name; Away from Her (2006), based on Alice Munro's short story The Bear Came over the Mountain; Still Alice (2014), about a Columbia University professor who has early onset Alzheimer's disease, based on Lisa Genova's 2007 novel of the same name and featuring Julianne Moore in the title role. Documentaries on Alzheimer's disease include Malcolm and Barbara: A Love Story (1999) and Malcolm and Barbara: Love's Farewell (2007), both featuring Malcolm Pointon.
Alzheimer's disease has also been portrayed in music by English musician the Caretaker in releases such as Persistent Repetition of Phrases (2008), An Empty Bliss Beyond This World (2011), and Everywhere at the End of Time (2016–2019). Paintings depicting the disorder include the late works by American artist William Utermohlen, who drew self-portraits from 1995 to 2000 as an experiment of showing his disease through art.
== Research directions ==
Antibodies may have the ability to alter the disease course by targeting amyloid beta with immunotherapy medications such as donanemab and lecanemab.
Lecanemab was approved via the FDA accelerated approval process, and was converted to traditional approval in July 2023, after further testing, along with the addition of a boxed warning about amyloid-related imaging abnormalities. As of early August 2024, lecanemab was approved for sale in Japan, South Korea, China, Hong Kong and Israel although it was recommended against approval by an advisory body of the European Union on July 26, citing its side effects.
Donanemab was approved by the FDA in July 2024. Anti-amyloid drugs also cause brain shrinkage. The cholinesterase inhibitor benzgalantamine was approved by the FDA in July 2024.
Specific medications that may reduce the risk or progression of Alzheimer's disease have been studied. The research trials investigating medications generally impact Aβ plaques, inflammation, APOE, neurotransmitter receptors, neurogenesis, growth factors or hormones.
Machine learning algorithms with electronic health records are being studied as a way to predict Alzheimer's disease earlier.
== References ==
== External links ==
"Alzheimer's Disease Research Timeline – Alzforum". www.alzforum.org.
"Alzheimer's Disease Brain Cell Atlas- brain-map.org". portal.brain-map.org. | Wikipedia/Alzheimer's_Disease |
Combined injectable contraceptives (CICs) are a form of hormonal birth control for women. They consist of monthly injections of combined formulations containing an estrogen and a progestin to prevent pregnancy.
CICs are different from progestogen-only injectable contraceptives (POICs), such as depot medroxyprogesterone acetate (DMPA; brand names Depo-Provera, Depo-SubQ Provera 104) and norethisterone enantate (NETE; brand name Noristerat), which are not combined with an estrogen and are given once every two to three months instead of once a month.
Hormonal contraception works primarily by preventing ovulation, but it may also thicken the cervical mucus inhibiting sperm penetration. Hormonal contraceptives also have effects on the endometrium, that theoretically could affect implantation.
== Medical uses ==
CICs are administered by intramuscular injection into the deltoid, gluteus maximus, or anterior thigh. They are ideally administered every 28 to 30 days, though they have been demonstrated to be effective up to 33 days.
Some CICs have been said to be used by transgender women as a means of feminizing hormone therapy as well.
=== Available forms ===
A variety of different CICs, generally containing a short-acting natural estradiol ester and a long-acting progestin ester, are available for clinical use. Estrogens that are used include estradiol valerate, estradiol cypionate, estradiol enantate, estradiol benzoate butyrate, and estradiol, while progestins that are used include norethisterone enantate, medroxyprogesterone acetate, algestone acetophenide (dihydroxyprogesterone acetophenide), hydroxyprogesterone caproate, and megestrol acetate. Estradiol benzoate has a duration that is too short for once-monthly CICs, and is not used in them. Conversely, estradiol enantate is said to have a duration that is too long for once-monthly CICs, but is nonetheless used in them.
== Side effects ==
Side effects of CICs, besides menstrual bleeding changes, are minimal. The most prominent side effects of CICs are menstrual irregularities during the first 3 to 6 months of use. Dysmenorrhea has been reported in 30 to 65% of women. Other side effects include breast tenderness/pain, headache, and libido changes. Some fluid retention can occur, but weight gain is minimal. Local injection site reactions have also been reported in 15 to 35% of women.
Effects of CICs on coagulation and fibrinolysis are minimal and are not thought to be clinically relevant. Conversely, combined oral contraceptive pills containing ethinylestradiol have considerable effects on coagulation and fibrinolysis. The differences can be attributed to the lack of the first-pass effect with parenteral administration as well as structural and pharmacological differences between estradiol and ethinylestradiol.
== Pharmacology ==
CICs contain an estrogen and a progestin. The estrogen is generally a short-acting estradiol ester, which acts as a prodrug of estradiol. Esters of estradiol are natural and bioidentical estrogens, and are believed to have more favorable effects on lipid metabolism, cardiovascular health, and hemostasis than synthetic estrogens such as ethinylestradiol. The progestin is a long-acting progestogen ester, which may or may not act as a prodrug. Progesterone derivatives including medroxyprogesterone acetate, algestone acetophenide (dihydroxyprogesterone acetophenide), hydroxyprogesterone caproate, and megestrol acetate are active themselves and are not prodrugs, whereas the testosterone derivative norethisterone enantate is a prodrug of norethisterone. Regardless of whether they are prodrugs or not, steroid esters form a depot and have an extended duration of action due to a depot effect when administered by intramuscular or subcutaneous injection.
Because CICs are administered parenterally, they bypass the first-pass effect in the liver and intestines that occurs with oral administration of estrogens. However, is estimated that about 20% of an administered dose does still eventually pass through the liver. Hence, these preparations are not completely liver-neutral. Nonetheless, they have dramatically reduced hepatic effects relative to oral ethinylestradiol. In addition, parenteral estradiol in general has about 4- or 5-fold reduced potency in the liver than oral estradiol.
CICs have antigonadotropic effects via their estrogenic and progestogenic activity and inhibit fertility and suppress sex hormone levels. A single intramuscular injection of estradiol valerate/norethisterone enanthate (5 mg/50 mg) (Mesigyna) has been found to strongly suppress testosterone levels in men. Testosterone levels decreased from a baseline of ~503 ng/dL to a trough of ~30 ng/dL (a 94% decrease) which occurred at day 7 post-injection.
== History ==
The first CIC to be studied was estradiol valerate/hydroxyprogesterone caproate (EV/OHPC) in 1963, and the second CIC to be studied was estradiol enantate/algestone acetophenide (E2-EN/DHPA) in 1964. In 1967, E2-EN/DHPA was in the late stages of clinical development. By 1969, the medication was available for medical use under the brand name Perlutal. Within a few years, it was marketed under other brand names such as Topasel and Ova-Repos as well. In addition, several other CICs had been introduced for medical use by 1972. By 1976, two major CICs were in use: E2-EN/DHPA (brand names Perlutan, Topasel) in Spain and Latin America, and EV/OHPC (brand name Injectable No. 1) in China. These CICs have been described as first-generation CICs. Two second-generation CICs, estradiol cypionate/medroxyprogesterone acetate (EC/MPA; brand names Cyclofem and later Lunelle) and estradiol valerate/norethisterone enantate (EV/NETE; brand name Mesigyna), were introduced for clinical use in 1993. On 5 October 2000, Pharmacia received FDA approval for Lunelle Monthly Contraceptive Injection. In April 2003, Pharmacia was acquired by Pfizer (makers of depot medroxyprogesterone acetate). In October 2003, Lunelle was discontinued in the United States.
== Society and culture ==
=== Availability ===
CICs are available in many countries throughout the world, including widely throughout Central and South America, in Mexico and the Caribbean, in China, in several Southeast Asian and African countries, and in Turkey. They were also previously available in the United States, Portugal, and Spain, but have been discontinued in these countries.
== Research ==
Many other CICs have been studied but have not been approved or marketed for clinical use.
The following are marketed CICs at different doses than those that are approved:
Estradiol valerate 2.5 to 5 mg + norethisterone enantate 50 to 80 mg in an oil solution
Estradiol valerate 10 mg + hydroxyprogesterone caproate 500 mg in an oil solution
Estradiol cypionate 2.5 to 10 mg + medroxyprogesterone acetate 12.5 to 50 mg in a microcrystalline aqueous suspension
Estradiol enantate 5 to 50 mg + algestone acetophenide 75 to 200 mg in an oil solution
The half-progestin-dose formulation of estradiol valerate/norethisterone enantate (5 mg / 25 mg) is also known as HRP-103 and the half-progestin-dose formulation of estradiol cypionate/medroxyprogesterone acetate (5 mg / 12.5 mg) is also known as HRP-113.
The following are CICs that have never been marketed:
Estradiol valerate 20 mg + medroxyprogesterone acetate 100 mg in a microcrystalline aqueous suspension
Estradiol undecylate 5 to 10 mg + norethisterone enantate 50 to 70 mg in an oil solution
Estradiol cypionate + norethisterone enantate
Estradiol valerate 10 mg + methenmadinone caproate 60 mg (Lutofollin)
Estradiol hexahydrobenzoate 5 mg (oil solution) + norgestrel 25 mg (aqueous suspension)
Estradiol cypionate 3.5 to 5 mg + megestrol acetate 25 mg in a microcrystalline aqueous suspension (marketed in China?)
Estradiol valerate 3 to 5 mg + chlormadinone caproate 80 mg in an oil solution
Estradiol valerate 5 mg + megestrol acetate 15 mg in an aqueous suspension of gelatin microspheres (50–80 μm)
Estradiol 5 mg + levonorgestrel 7 mg in an aqueous suspension of monolithic microspheres (80 μm) or in a macrocrystalline suspension (15 μm)
Estradiol cypionate 5 mg + levonorgestrel butanoate 7 mg in an aqueous suspension
Estradiol benzoate 5 to 10 mg + norethisterone enanthate 50 to 100 mg
Mestranol 1.0–1.2 mg + norethisterone 10–12 mg in a microcrystalline aqueous suspension of defined particle sizes (125–177 μm)
Ethinylestradiol + norethisterone
Estradiol 5 mg and progesterone 100 to 300 mg in an aqueous suspension of monolithic microspheres or in a macrocrystalline suspension
Polyestradiol phosphate 40 mg + medroxyprogesterone acetate 150 mg
== See also ==
Special Programme on Human Reproduction
Concept Foundation
Extended cycle combined hormonal contraceptive
Reproductive Health Supplies Coalition
Estradiol-containing oral contraceptive
== References ==
== Further reading ==
Garza-Flores J (April 1994). "Pharmacokinetics of once-a-month injectable contraceptives". Contraception. 49 (4): 347–59. doi:10.1016/0010-7824(94)90032-9. PMID 8013219.
Sang GW (April 1994). "Pharmacodynamic effects of once-a-month combined injectable contraceptives". Contraception. 49 (4): 361–85. doi:10.1016/0010-7824(94)90033-7. PMID 8013220. | Wikipedia/Combined_injectable_birth_control |
Estradiol stearate (E2-17-St), also known as estradiol octadecanoate and sold under the brand name Depofollan, is a naturally occurring estrogen and an estrogen ester – specifically, the C17β stearate ester of estradiol. It occurs in the body as a very long-lasting metabolite and prohormone of estradiol. The compound is one of the components that collectively constitute lipoidal estradiol, another of which is estradiol palmitate. It is extremely lipophilic and hydrophobic. Estradiol stearate has no affinity for the estrogen receptor, requiring transformation into estradiol via esterases for its estrogenic activity. The compound does not bind to sex hormone-binding globulin or α-fetoprotein, instead being transported by lipoproteins such as high-density lipoprotein and low-density lipoprotein.
Estradiol stearate has a prolonged duration of action relative to estradiol regardless of whether it is given by intravenous injection or subcutaneous injection. This is in contrast to short-chain fatty acid esters of estradiol, such as estradiol benzoate, which do not show a prolonged duration with intravenous injection. When administered by intravenous injection in rodents, estradiol stearate has a greatly increased terminal half-life relative to estradiol (6 hours vs. 2 minutes). Estradiol stearate also had a half-life that was 60% longer than that of estradiol arachidonate, despite similar ester chain lengths. In contrast to the long-chain esters, the half-lives of short-chain estradiol esters such as estradiol acetate and estradiol hexanoate were the same as that of estradiol. As such, whereas short-chain estradiol esters are rapidly hydrolyzed, long-chain estradiol esters like estradiol stearate are resistant to metabolism. Thus, the prolongation of effect of short-chain estradiol esters is purely due to their increased lipophilicity and slow release from the injected depot, whereas the prolonged duration of long-chain estradiol esters is due both to this property and to their resistance to metabolism. Estradiol stearate is susceptible to first-pass metabolism in the liver, and hence has much greater potency by subcutaneous injection than by oral administration.
In addition to its endogenous role, estradiol stearate was previously available as a pharmaceutical drug for use via depot intramuscular injection. The medication was introduced between 1938 and 1941 under the brand name Depofollan. It has been used to treat prostate cancer. Estradiol stearate is a long-acting estrogen and is said to have been the first long-acting estrogen used in medicine, although it was never widely employed. It was reported to have a duration of more than one month. The medication was provided as an oil solution in ampoules containing 15 mg estradiol stearate. It was manufactured by Chinoin, a Hungarian pharmaceutical company. The compound was studied by Karl Miescher in 1938 and was patented by Miescher and Chinoin in 1939 and 1941, respectively. A similar clinically used long-acting estradiol ester is estradiol undecylate, which has 11 carbon atoms instead of the 18 carbon atoms in estradiol stearate.
== See also ==
List of estrogen esters § Estradiol esters
== References == | Wikipedia/Estradiol_stearate |
Intermediate-density lipoproteins (IDLs) belong to the lipoprotein particle family and are formed from the degradation of very low-density lipoproteins as well as high-density lipoproteins. IDL is one of the five major groups of lipoproteins (chylomicrons, VLDL, IDL, LDL, HDL) that enable fats and cholesterol to move within the water-based solution of the bloodstream. Each native IDL particle consists of protein that encircles various lipids, enabling, as a water-soluble particle, these lipids to travel in the aqueous blood environment as part of the fat transport system within the body. Their size is, in general, 25 to 35 nm in diameter, and they contain primarily a range of triglycerides and cholesterol esters. They are cleared from the plasma into the liver by receptor-mediated endocytosis, or further degraded by hepatic lipase to form LDL particles.
Although one might intuitively assume that "intermediate-density" refers to a density between that of high-density and low-density lipoproteins, it in fact refers to a density between that of low-density and very-low-density lipoproteins.
In general, IDL, somewhat similar to low-density lipoprotein (LDL), transports a variety of triglyceride fats and cholesterol and, like LDL, can also promote the growth of atheroma.
VLDL is a large, triglyceride-rich lipoprotein secreted by the liver that transports triglyceride to adipose tissue and muscle. The triglycerides in VLDL are removed in capillaries by the enzyme lipoprotein lipase, and the VLDL returns to the circulation as a smaller particle with a new name, intermediate-density lipoprotein (IDL). The IDL particles have lost most of their triglyceride, but they retain cholesteryl esters. Some of the IDL particles are rapidly taken up by the liver; others remain in circulation, where they undergo further triglyceride hydrolysis by hepatic lipase and are converted to LDL. A distinguishing feature of the IDL particle is their content of multiple copies of the receptor ligand ApoE in addition to a single copy of ApoB-100. The multiple copies of ApoE allow IDL to bind to the LDL receptor with a very high affinity. When IDL is converted to LDL, the ApoE leaves the particle and only the ApoB-100 remains. Thereafter, the affinity for the LDL receptor is much reduced.
== References == | Wikipedia/Intermediate-density_lipoprotein |
Radiocontrast agents are substances used to enhance the visibility of internal structures in X-ray-based imaging techniques such as computed tomography (contrast CT), projectional radiography, and fluoroscopy. Radiocontrast agents are typically iodine, or more rarely barium sulfate. The contrast agents absorb external X-rays, resulting in decreased exposure on the X-ray detector. This is different from radiopharmaceuticals used in nuclear medicine which emit radiation.
Magnetic resonance imaging (MRI) functions through different principles and thus MRI contrast agents have a different mode of action. These compounds work by altering the magnetic properties of nearby hydrogen nuclei.
== Types and uses ==
Radiocontrast agents used in X-ray examinations can be grouped in positive (iodinated agents, barium sulfate), and negative agents (air, carbon dioxide, methylcellulose).
=== Iodine (circulatory system) ===
Iodinated contrast contains iodine. It is the main type of radiocontrast used for intravenous administration. Iodine has a particular advantage as a contrast agent for radiography because its innermost electron ("k-shell") binding energy is 33.2 keV, similar to the average energy of x-rays used in diagnostic radiography. When the incident x-ray energy is closer to the k-edge of the atom it encounters, photoelectric absorption is more likely to occur. Its uses include:
Contrast CTs
Angiography (arterial investigations)
Venography (venous investigations)
VCUG (voiding cystourethrography)
HSG (hysterosalpingogram)
IVU (intravenous urography)
Organic iodine molecules used for contrast include iohexol, iodixanol and ioversol.
=== Barium sulfate (digestive system) ===
Barium sulfate is mainly used in the imaging of the digestive system. The substance exists as a water-insoluble white powder that is made into a slurry with water and administered directly into the gastrointestinal tract.
Upper gastrointestinal series
Barium enema (large bowel investigation) and DCBE (double contrast barium enema).
Barium swallow (oesophageal investigation)
Barium meal (stomach investigation) and double contrast barium meal
Barium follow through (stomach and small bowel investigation)
CT pneumocolon / virtual colonoscopy
Barium sulfate, an insoluble white powder, is typically used for enhancing contrast in the GI tract. Depending on how it is to be administered the compound is mixed with water, thickeners, de-clumping agents, and flavourings to make the contrast agent. As the barium sulfate does not dissolve, this type of contrast agent is an opaque white mixture. It is only used in the digestive tract; it is usually swallowed as a barium sulfate suspension or administered as an enema. After the examination, it leaves the body with the feces.
=== Air ===
Air can be used as a contrast material because it is less radio-opaque than the tissues it is defining. A double contrast barium enema, or DCBE, uses both air and barium together. In an air arthrogram, where air alone is used as a contrast medium, the injection of air into a joint cavity allows the cartilage covering the ends of the bones to be visualized.
Before the advent of modern neuroimaging techniques, air or other gases were used as contrast agents employed to displace the cerebrospinal fluid in the brain while performing a pneumoencephalography. Sometimes called an "air study", this once common yet highly-unpleasant procedure was used to enhance the outline of structures in the brain, looking for shape distortions caused by the presence of lesions.
=== Carbon dioxide ===
Carbon dioxide also has a role in angioplasty. It is low-risk as it is a natural product with no risk of allergic potential. However, it can be used only below the diaphragm as there is a risk of embolism in neurovascular procedures. It must be used carefully to avoid contamination with room air when injected. It is a negative contrast agent in that it displaces blood when injected intravascularly.
=== Discontinued agents ===
==== Thorotrast ====
Thorotrast was a contrast agent based on thorium dioxide, which is radioactive. It was first introduced in 1929. While it provided good image enhancement, its use was abandoned in the late 1950s since it turned out to be carcinogenic. Given that the substance remained in the bodies of those to whom it was administered, it gave a continuous radiation exposure and was associated with a risk of cancers of the liver, bile ducts and bones, as well as higher rates of hematological malignancy (leukemia and lymphoma). Thorotrast may have been administered to millions of patients prior to being disused.
==== Nonsoluble substances ====
In the past, some non water-soluble contrast agents were used. One such substance was iofendylate (trade names: Pantopaque, Myodil) which was an iodinated oil-based substance that was commonly used in myelography. Due to it being oil-based, it was recommended that the physician remove it from the patient at the end of the procedure. This was a painful and difficult step and because complete removal could not always be achieved, iofendylate's persistence in the body might sometimes lead to arachnoiditis, a potentially painful and debilitating lifelong disorder of the spine. Iofendylate's use ceased when water-soluble agents (such as metrizamide) became available in the late 1970s. Also, with the advent of MRI, myelography became much less-commonly performed.
== Adverse effects ==
Modern iodinated contrast agents – especially non-ionic compounds – are generally well tolerated. The adverse effects of radiocontrast can be subdivided into type A reactions (e.g. thyrotoxicosis), and type B reactions (hypersensitivity reactions: allergy and non-allergy reactions [formerly called anaphylactoid reactions]).
Patients receiving contrast via IV typically experience a hot feeling around the throat, and this hot sensation gradually moves down to the pelvic area.
The documentation of adverse drug reactions to contrast media should be documented precisely so that the patient receives adequate prophylaxis if contrast medium is administered again.
=== Contrast induced nephropathy ===
Iodinated contrast may be toxic to the kidneys, especially when given via the arteries prior to studies such as catheter coronary angiography. Non-ionic contrast agents, which are almost exclusively used in computed tomography studies, have not been shown to cause CIN when given intravenously at doses needed for CT studies.
=== Thyroid dysfunction ===
Iodinated radiocontrast can induce overactivity (hyperthyroidism) and underactivity (hypothyroidism) of the thyroid gland. The risk of either condition developing after a single examination is 2–3 times that of those who have not undergone a scan with iodinated contrast. Thyroid underactivity is mediated by two phenomena called the Plummer and Wolff–Chaikoff effect, where iodine suppresses the production of thyroid hormones; this is usually temporary but there is an association with longer-term thyroid underactivity. Some other people show the opposite effect, called Jod-Basedow phenomenon, where the iodine induces overproduction of thyroid hormone; this may be the result of underlying thyroid disease (such as nodules or Graves' disease) or previous iodine deficiency. Children exposed to iodinated contrast during pregnancy may develop hypothyroidism after birth and monitoring of the thyroid function is recommended.
== See also ==
Contrast agent – Substance used in medical imaging to enhance the contrast of structures or fluids within the body
Medical imaging – Technique and process of creating visual representations of the interior of a body
Radiology – Medical specialty for imaging procedures
== References ==
== External links ==
Media related to Radiocontrast agents at Wikimedia Commons | Wikipedia/Radiographic_contrast_agents |
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/Renal_function |
Serum total protein, also known as total protein, is a clinical chemistry parameter representing the concentration of protein in serum.
Serum contains many proteins including serum albumin, a variety of globulins, and many others. While it is possible to analyze these proteins individually, total protein is a relatively quick and inexpensive analysis that does not discriminate by protein type.
The traditional method for measuring total protein uses the biuret reagent, but other chemical methods such as dye-binding and refractometry are now available. The measurement is usually performed on automated analysers along with other laboratory tests.
== Interpretation ==
The reference range for total protein is typically 60-80g/L. (It is also sometimes reported as "6.0-8.0g/dl"), but this may vary depending on the method of analysis.
Concentrations below the reference range usually reflect low albumin concentration, for instance in liver disease or acute infection. Rarely, low total protein may be a sign of immunodeficiency.
Concentrations above the reference range are found in paraproteinaemia, Hodgkin's lymphoma, leukaemia or any condition causing an increase in immunoglobulins. Total protein is also commonly elevated in dehydration and C677T gene mutation.
== References ==
== External links ==
Total protein and A/G ratio at Lab Tests Online
Total protein: analyte monograph - The Association for Clinical Biochemistry and Laboratory Medicine | Wikipedia/Serum_total_protein |
Liver function tests (LFTs or LFs), also referred to as a hepatic panel or liver panel, are groups of blood tests that provide information about the state of a patient's liver. These tests include prothrombin time (PT/INR), activated partial thromboplastin time (aPTT), albumin, bilirubin (direct and indirect), and others. The liver transaminases aspartate transaminase (AST or SGOT) and alanine transaminase (ALT or SGPT) are useful biomarkers of liver injury in a patient with some degree of intact liver function.
Most liver diseases cause only mild symptoms initially, but these diseases must be detected early. Hepatic (liver) involvement in some diseases can be of crucial importance. This testing is performed on a patient's blood sample. Some tests are associated with functionality (e.g., albumin), some with cellular integrity (e.g., transaminase), and some with conditions linked to the biliary tract (gamma-glutamyl transferase and alkaline phosphatase). Because some of these tests do not measure function, it is more accurate to call these liver chemistries or liver tests rather than liver function tests.
Several biochemical tests are useful in the evaluation and management of patients with hepatic dysfunction. These tests can be used to detect the presence of liver disease. They can help distinguish among different types of liver disorders, gauge the extent of known liver damage, and monitor the response to treatment. Some or all of these measurements are also carried out (usually about twice a year for routine cases) on individuals taking certain medications, such as anticonvulsants, to ensure that these medications are not adversely impacting the person's liver.
== Standard liver panel ==
Standard liver tests for assessing liver damage include alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP). Bilirubin may be used to estimate the excretory function of the liver and coagulation tests and albumin can be used to evaluate the metabolic activity of the liver.
Although example reference ranges are given, these will vary depending on method of analysis used at the administering laboratory, as well as age, gender, ethnicity, and potentially unrelated health factors. Individual results should always be interpreted using the reference range provided by the laboratory that performed the test.
=== Total bilirubin ===
Measurement of total bilirubin includes both unconjugated (indirect) and conjugated (direct) bilirubin. Unconjugated bilirubin is a breakdown product of heme (a part of hemoglobin in red blood cells). The liver is responsible for clearing the blood of unconjugated bilirubin, by 'conjugating' it (modified to make it water-soluble) through an enzyme named UDP-glucuronyl-transferase. When the total bilirubin level exceeds 17 μmol/L, it indicates liver disease. When total bilirubin levels exceed 40 μmol/L, bilirubin deposition at the sclera, skin, and mucous membranes will give these areas a yellow colour, thus it is called jaundice.
The increase in predominantly unconjugated bilirubin is due to overproduction, reduced hepatic uptake of the unconjugated bilirubin and reduced conjugation of bilirubin. Overproduction can be due to the reabsorption of a haematoma and ineffective erythropoiesis leading to increased red blood cell destruction. Gilbert's syndrome and Crigler–Najjar syndrome have defects in the UDP-glucuronyl-transferase enzyme, affecting bilirubin conjugation.
The degree of rise in conjugated bilirubin is directly proportional to the degree of hepatocyte injury. Viral hepatitis can also cause the rise in conjugated bilirubin. In parenchymal liver disease and incomplete extrahepatic obstruction, the rise in conjugated bilirubin is less than the complete common bile duct obstruction due to malignant causes. In Dubin–Johnson syndrome, a mutation in multiple drug-resistance protein 2 (MRP2) causes a rise in conjugated bilirubin.
In acute appendicitis, total bilirubin can rise from 20.52 μmol/L to 143 μmol/L. In pregnant women, the total bilirubin level is low in all three trimesters.
The measurement of bilirubin levels in the newborns is done through the use of bilimeter or transcutanoeus bilirubinometer instead of performing LFTs. When the total serum bilirubin increases over 95th percentile for age during the first week of life for high risk babies, it is known as hyperbilirubinemia of the newborn (neonatal jaundice) and requires light therapy to reduce the amount of bilirubin in the blood. Pathological jaundice in newborns should be suspected when the serum bilirubin level rises by more than 5 mg/dL per day, serum bilirubin more than the physiological range, clinical jaundice more than 2 weeks, and conjugated bilirubin (dark urine staining clothes). Haemolytic jaundice is the commonest cause of pathological jaundice. Those babies with Rh hemolytic disease, ABO incompatibility with the mother, Glucose-6-phosphate dehydrogenase (G-6-PD) deficiency and minor blood group incompatibility are at increased risk of getting haemolytic jaundice.
=== Alanine transaminase (ALT) ===
Apart from being found in high concentrations in the liver, ALT is found in the kidneys, heart, and muscles. It catalyses the transamination reaction, and only exists in a cytoplasmic form. Any kind of liver injury can cause a rise in ALT. A rise of up to 300 IU/L is not specific to the liver, but can be due to the damage of other organs such as the kidneys or muscles. When ALT rises to more than 500 IU/L, causes are usually from the liver. It can be due to hepatitis, ischemic liver injury, and toxins that causes liver damage. The ALT levels in hepatitis C rises more than in hepatitis A and B. Persistent ALT elevation more than 6 months is known as chronic hepatitis. Alcoholic liver disease, non-alcoholic fatty liver disease (NAFLD), fat accumulation in liver during childhood obesity, steatohepatitis (inflammation of fatty liver disease) are associated with a rise in ALT. Rise in ALT is also associated with reduced insulin response, reduced glucose tolerance, and increased free fatty acids and triglycerides. Bright liver syndrome (bright liver on ultrasound suggestive of fatty liver) with raised ALT is suggestive of metabolic syndrome.
In pregnancy, ALT levels would rise during the second trimester. In one of the studies, measured ALT levels in pregnancy-related conditions such as hyperemesis gravidarum was 103.5 IU/L, pre-eclampsia was 115, HELLP syndrome was 149. ALT levels would reduce by greater than 50% in three days after child delivery. Another study also shows that caffeine consumption can reduce the risk of ALT elevation in those who consume alcohol, overweight people, impaired glucose metabolism, and viral hepatitis.
=== Aspartate transaminase (AST) ===
AST exists in two isoenzymes namely mitochondrial form and cytoplasmic form. It is found in highest concentration in the liver, followed by heart, muscle, kidney, brain, pancreas, and lungs. This wide range of AST containing organs makes it a relatively less specific indicator of liver damage compared to ALT. An increase of mitochondrial AST in bloods is highly suggestive of tissue necrosis in myocardial infarction and chronic liver disease. More than 80% of the liver AST activity are contributed by mitochondrial form of the isoenzymes, while the circulating AST in blood are contributed by cytoplasmic form of AST. AST is especially markedly raised in those with liver cirrhosis. AST can be released from a variety of other tissues and if the elevation is less than two times the normal AST, no further workup needs to be performed if a patient is proceeding to surgery.
In certain pregnancy related conditions such as hyperemesis gravidarum, AST can reach as high as 73 IU/L, 66 IU/L in pre-eclampsia, and 81 IU/L in HELLP syndrome.
=== AST/ALT ratio ===
The AST/ALT ratio increases in liver functional impairment. In alcoholic liver disease, the mean ratio is 1.45, and mean ratio is 1.33 in post necrotic liver cirrhosis. Ratio is greater than 1.17 in viral cirrhosis, greater than 2.0 in alcoholic hepatitis, and 0.9 in non-alcoholic hepatitis. Ratio is greater than 4.5 in Wilson disease or hyperthyroidism.
=== Alkaline phosphatase (ALP) ===
Alkaline phosphatase (ALP) is an enzyme in the cells lining the biliary ducts of the liver. It can also be found on the mucosal epithelium of the small intestine, proximal convoluted tubule of the kidneys, bone, liver, and placenta. It plays an important role in lipid transposition in small intestines and calcification of bones. 50% of all the serum ALP activities in blood are contributed by bone. Acute viral hepatitis usually has normal or increased ALP. For example, hepatitis A has increased ALP due to cholestasis (impaired bile formation or bile flow obstruction) and would have the feature of prolonged itching. Other causes include: infiltrative liver diseases, granulomatous liver disease, abscess, amyloidosis of the liver and peripheral arterial disease. Mild elevation of ALP can be seen in liver cirrhosis, hepatitis, and congestive cardiac failure. Transient hyperphosphataemia is a benign condition in infants, and can reach normal level in 4 months. In contrast, low levels of ALP is found in hypothyroidism, pernicious anemia, zinc deficiency, and hypophosphatasia.
ALP activity is significantly increased in the third trimester of pregnancy. This is due to increased synthesis from the placenta as well as increased synthesis in the liver induced by large amounts of estrogens. Levels in the third trimester can be as much as 2-fold greater than in non-pregnant women. As a result, ALP is not a reliable marker of hepatic function in pregnant women. In contrast to ALP, levels of ALT, AST, GGT, and lactate dehydrogenase are only slightly changed or largely unchanged during pregnancy. Bilirubin levels are significantly decreased in pregnancy.
In pregnancy conditions such as hyperemesis gravdirum, ALP levels can reach 215 IU/L, meanwhile, in pre-eclampsia, ALP can reach 14 IU/L, and in HELLP syndrome ALP levels can reach 15 IU/L.
=== Gamma-glutamyltransferase (GGT) ===
GGT is a microsomal enzyme found in hepatocytes, biliary epithelial cells, renal tubules, pancreas, and intestines. It helps in glutathione metabolism by transporting peptides across the cell membrane. Much like ALP, GGT measurements are usually elevated if cholestasis is present. In acute viral hepatitis, the GGT levels can peak at 2nd and 3rd week of illness, and remained elevated at 6 weeks of illness. GGT is also elevated in 30% of the hepatitis C patients. GGT can increase by 10 times in alcoholism. GGT can increase by 2 to 3 times in 50% of the patients with non-alcoholic liver disease. When GGT levels is elevated, the triglyceride level is elevated also. With insulin treatment, the GGT level can reduce. Other causes of elevated GGT are: diabetes mellitus, acute pancreatitis, myocardial infarction, anorexia nervosa, Guillain–Barré syndrome, hyperthyroidism, obesity and myotonic dystrophy.
In pregnancy conditions GGT activity is reduced in 2nd and 3rd trimesters. In hyperemesis gravidarum, GGT level value can reach 45 IU/L, 17 IU/L in pre-eclampsia, and 35 IU/L in HELPP syndrome.
=== Albumin ===
Albumin is a protein made specifically by the liver, and can be measured cheaply and easily. It is the main constituent of total protein (the remaining constituents are primarily globulins). Albumin levels are decreased in chronic liver disease, such as cirrhosis. It is also decreased in nephrotic syndrome, where it is lost through the urine. The consequence of low albumin can be edema since the intravascular oncotic pressure becomes lower than the extravascular space. An alternative to albumin measurement is prealbumin, which is better at detecting acute changes (half-life of albumin and prealbumin is about 2 weeks and about 2 days, respectively).
== Other tests ==
Other tests are requested alongside LFT to rule out specific causes.
=== 5' Nucleotidase ===
5' Nucleotidase (5NT) is a glycoprotein found throughout the body, in the cytoplasmic membrane, catalyzing the conversion to inorganic phosphates from nucleoside-5-phosphate. Its level is raised in conditions such as obstructive jaundice, parenchymal liver disease, liver metastases, and bone disease.
Serum NT levels are higher during 2nd and 3rd trimesters in pregnancy.
=== Ceruloplasmin ===
Ceruloplasmin is an acute phase protein synthesized in the liver. It is the carrier of the copper ion. Its level is increased in infections, rheumatoid arthritis, pregnancy, non-Wilson liver disease and obstructive jaundice. In Wilson disease, the ceruloplasmin level is depressed which lead to copper accumulation in body tissues.
=== Alpha-fetoprotein ===
Alpha-fetoprotein (AFP) is significantly expressed in foetal liver. However, the mechanism that led to the suppression of AFP synthesis in adults is not fully known. Exposure of the liver to cancer-causing agents and arrest of liver maturation in childhood can lead to the rise in AFP. AFP can reach until 400–500 μg/L in hepatocellular carcinoma. AFP concentration of more than 400 μg/L is associated with greater tumour size, involvement of both lobes of liver, portal vein invasion and a lower median survival rate.
=== Coagulation test ===
The liver is responsible for the production of the vast majority of coagulation factors. In patients with liver disease, international normalized ratio (INR) can be used as a marker of liver synthetic function as it includes factor VII, which has the shortest half life (2–6 hours) of all coagulation factors measured in INR. An elevated INR in patients with liver disease, however, does not necessarily mean the patient has a tendency to bleed, as it only measures procoagulants and not anticoagulants. In liver disease the synthesis of both are decreased and some patients are even found to be hypercoagulable (increased tendency to clot) despite an elevated INR. In liver patients, coagulation is better determined by more modern tests such as thromboelastogram (TEG) or thomboelastrometry (ROTEM).
Prothrombin time (PT) and its derived measures of prothrombin ratio (PR) and INR are measures of the extrinsic pathway of coagulation. This test is also called "ProTime INR" and "INR PT". They are used to determine the clotting tendency of blood, in the measure of warfarin dosage, liver damage, and vitamin K status.
=== Serum glucose ===
The serum glucose test, abbreviated as "BG" or "Glu", measures the liver's ability to produce glucose (gluconeogenesis); it is usually the last function to be lost in the setting of fulminant liver failure.
=== Lactate dehydrogenase ===
Lactate dehydrogenase (LDH) is found in many body tissues, including the liver. Elevated levels of LDH may indicate liver damage. LDH isotype-1 (or cardiac) is used for estimating damage to cardiac tissue, although troponin and creatine kinase tests are preferred.
== See also ==
Reference ranges for blood tests
Elevated transaminases
Liver disorders
Child–Pugh score
== References ==
== External links ==
Liver Function Tests at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
Liver Function Tests at Lab Tests Online
Overview at Mayo Clinic
Abnormal Liver Function Tests Archived 11 April 2012 at the Wayback Machine
Overview of liver enzymes
Abnormal Liver Tests Curriculum at AASLD
Further workup of abnormal liver tests: "etiology panel" | Wikipedia/Liver_function_tests |
Elevated alpha-fetoprotein refers to a state where alpha-fetoprotein levels are outside of the reference range.
There are two categories of AFP tests: tests performed on serum (blood plasma), and tests performed on amniotic fluid. Tests performed on serum are further categorized by the reason for performing the test: maternal serum, adult tumor marker, and pediatric tumor marker.
== Serum ==
The standard is a quantitative test, reporting a measured concentration of AFP in the sample, but there is also a less expensive qualitative test, reporting only that the concentration is normal or high. The qualitative test is appropriate only in some circumstances.
The resulting test report should specify the assay method and equipment used, and the report of a quantitative test should also provide a reference range for the test result. Many laboratories report reference ranges that are based on all other samples tested in that laboratory, necessarily including samples with abnormal AFP concentrations due to disease. Superior reference ranges are produced by research on healthy subjects.
AFP test results often are reported as either ng/ml or MoM (multiple of the median, where the median is calculated for an appropriate reference population).
=== Maternal testing for fetal screening ===
Abnormally elevated AFP in the serum of a pregnant woman can have one or more of these sources:
a problem with the fetus
a problem with the placenta
a tumor or liver disease in the woman
a normally elevated AFP in the fetus or woman (some people naturally have very high AFP)
Usual follow-up steps include (1) a prenatal ultrasound exam to look for fetal abnormalities and/or (2) measurement of AFP in amniotic fluid obtained via amniocentesis.
Maternal serum AFP (MSAFP) varies by orders of magnitude during the course of a normal pregnancy. MSAFP increases rapidly until about 32 weeks gestation, then decreases gradually. After the pregnancy ends it decreases rapidly, with a half-life of about 5 days.
Typically, MSAFP is measured in the beginning of the second trimester (14–16 weeks). It may be measured alone or as part of a package of routine prenatal screening tests, such as a triple test or quad test.
Because MSAFP test results must be interpreted according to the gestational age, they often are reported in terms of multiple of the median (MoM). Because the median is calculated from tests of other women's pregnancies at the same gestational age, in effect MoM is independent of gestational age, but depend on accurate gestational dating. A typical normal range is 0.5 to 2.0 or 2.5 MoM.
MSAFP above normal is seen in multiple gestation, when there is placental abruption, as well as in a number of fetal abnormalities, such as neural tube defects including spina bifida and anencephaly, and abdominal wall defects. Other possibility is error in the date of the gestation. Mothers with Methylenetetrahydrofolate reductase genetic variant also have more frequent elevated MSAFP. Rarely, high MSAFP is due to endodermal sinus tumor (EST) or another germ cell tumor containing EST. These tumors can occur in the pregnant woman (often as an ovarian tumor) or in the fetus.
MSAFP below normal is associated with a smaller number of conditions, including Down syndrome and Trisomy 18. Diabetic patients also have lower levels.
Patients with abnormal MSAFP need to undergo detailed obstetric ultrasonography. The information is then used to decide whether to proceed with amniocentesis. Genetic counseling usually is offered when the screening test result is positive.
If a woman is already getting a Quad test for Down Syndrome screening, then the AFP-marker that is part of this test provides the screen result for neural-tube and abdominal wall defects. However, if a woman received a 1st Trimester Combined screen for Down Syndrome, which does not include AFP, then some physicians will specifically order an AFP-only test in the 2nd trimester to screen for neural tube/abdominal wall defects. However, because AFP-based screening only has an 80-85% sensitivity for neural tube and abdominal wall defects, many maternal-fetal medicine specialists and some obstetricians do not bother ordering an AFP test and instead perform detailed "Level-II" ultrasounds on all of their patients, which, in competent hands, results in a 97% sensitivity for these defects. In fact, these physicians might disregard the AFP-related information on neural tube/abdominal wall defects and do the detailed ultrasound to look for these defects even if the patient has a "normal" AFP reading.
=== Tumor marker ===
Principal tumors that secrete AFP are endodermal sinus tumor (yolk sac carcinoma), hepatoblastoma, and hepatocellular carcinoma. In patients with AFP-secreting tumors, serum levels of AFP often correlate with tumor size. Resection is usually associated with a fall in serum levels. Serum levels are useful in assessing response to treatment.
Like any elevated tumor marker, elevated AFP by itself is not diagnostic, only suggestive. Tumor markers are used primarily to monitor the result of a treatment (e.g. chemotherapy). If levels of AFP go down after treatment, the tumor is not growing. In the case of babies, after treatment AFP should go down faster than it would normally. A temporary increase in AFP immediately following chemotherapy may indicate not that the tumor is growing but rather that it is shrinking (and releasing AFP as the tumor cells die).
==== Nonseminomatous germ cell tumor ====
In the context of evidence-based medicine, AFP is validated at the highest level as a tumor marker for use in patients with nonseminomatous germ cell tumors.
There are case reports of elevated AFP associated with teratoma. However, some of these case reports involve infants but do not correct for the normal elevation of AFP in infants, while others ignore the likelihood that teratoma (and other germ cell tumors) may in fact be mixed tumors containing elements of endodermal sinus tumor.
AFP is normally elevated in infants, and because teratoma is the single most common kind of tumor in infants, several studies have provided reference ranges for AFP in normal infants.
Perhaps the most useful is this equation: log Y = 7.397 - 2.622.log (X + 10), where X = age in days and Y = AFP level in nanograms per milliliter. When neonatal AFP is above normal (after adjustment for age), a low fraction of AFP-L3 is reassuring.
==== Hepatocellular carcinoma ====
For hepatocellular carcinoma (HCC), AFP cannot be considered to be specifically diagnostic of HCC, levels of AFP may be elevated in serum from patients with chronic disease; for example, research has indicated that AFP is not useful for screening in patients with cirrhosis or Hepatitis C and therefore elevated AFP in these patients may not be indicative, or be only suggestive, of HCC. AFP is considered a useful marker for post-treatment monitoring of HCC patients (e.g. for treatment efficacy or tumor recurrence). The value of such tests may be improved by parallel monitoring of other markers.
AFP-L3, an isoform of AFP which binds Lens culinaris agglutinin, can be particularly useful in early identification of aggressive tumors associated with HCC.
==== Other tumor ====
Rare AFP-secreting tumor types include carcinoma in a mixed Müllerian tumor. The Sertoli-Leydig cell tumor, which itself is rare, rarely secretes AFP.
In Wilms tumor AFP is rarely elevated, but when it is elevated it may serve as a marker of disease progression or recurrence.
=== Other ===
Increased serum levels in adults are also seen in acute hepatitis, colitis and ataxia telangiectasia. Increased serum levels of alpha-fetoprotein are sometimes found in citrullinemia and argininosuccinate synthetase deficiency.
== Amniotic fluid ==
AFP in amniotic fluid has one or two sources. The fetus normally excretes AFP into its urine, hence into the amniotic fluid. A fetus with one of three broad categories of defects also releases AFP by other means. These categories are open neural tube defect, open abdominal wall defect, and skin disease or other failure of the interior or exterior body surface.
Abnormally elevated AFP in amniotic fluid can have one or more of many different causes:
normal elevation. 75% of AF AFP test results in the range 2.0 to 4.9 MoM are false positives: the baby is normal.
open neural tube defect
open abdominal wall defect
congenital nephrosis
others
== CSF ==
In normal infants, AFP in CSF is:
median 61 kIU/L (5th-95th centile: 2-889 kIU/L) in infants -69 to 31 days old
median 1.2 kIU/L (5th-95th centile: 0.1-12.5 kIU/L) in infants 32 to 110 days old
Levels of AFP in CSF decline with gestational age in proportion to levels of AFP in serum
== References ==
== External links == | Wikipedia/Elevated_alpha-fetoprotein |
Hyperproteinemia is the state of having overly high levels of protein in the blood. This can occur due to monoclonal gammopathies such as multiple myeloma and after intravenous immunoglobulin has been given. It can result in a falsely low appearing sodium level (hyponatremia).
== Causes ==
Increases in certain proteins that are typically present in relatively low concentrations, such as acute phase reactants and polyclonal immunoglobulins caused by inflammation, late-stage liver disease, and infections, can result in mild hyperproteinemia. Normal total protein levels are not sufficient to rule out multiple myeloma or other malignant paraproteinemias, but they may also be the cause of moderate-to-marked hyperproteinemia. To determine the reason behind the elevated serum total protein, a serum protein electrophoresis should be carried out.
The plasma protein level may increase due to dehydration from blood loss of fluids (severe vomiting and diarrhea).
1. Physiological causes:
Standing position
Vigorous exercise
Excessive stasis while withdrawing blood
2. Pathological causes:
Infective disease like tuberculosis
Multiple myeloma
Reduced production (hypogammaglobulinemia), as well as increased protein loss (nephrotic syndrome, protein-losing enteropathy), can cause hypoproteinemia. To determine the reason behind the lower serum total protein, a serum protein electrophoresis ought to be carried out. Urine protein electrophoresis needs to be carried out if a nephrotic pattern is found.
== See also ==
Hypoproteinemia
Plasma protein
== References ==
== Further reading ==
Wang, Guang; Wang, Yong-Feng; Li, Jiang-Lan; Peng, Ru-Ji; Liang, Xin-Yin; Chen, Xue-Dong; Jiang, Gui-Hua; Shi, Jin-Fang; Si-Ma, Yang-Hu; Xu, Shi-Qing (May 5, 2022). "Mechanism of hyperproteinemia-induced blood cell homeostasis imbalance in an animal model". Zoological Research. 43 (3). Editorial Office of Zoological Research, Kunming Institute of Zoology, The Chinese Academy of Sciences: 301–318. doi:10.24272/j.issn.2095-8137.2021.397. PMC 9113973. PMID 35312240.
Leonard, Cardon; Donald H, Atlas (1943). "Incidence and causes of hyperproteinemia a study of 4,390 cases". Arch Intern Med. 71 (3): 377–390. doi:10.1001/archinte.1943.00210030078007. Retrieved 28 December 2023.
== External links ==
Cleveland Clinic
Mayo Clinic | Wikipedia/Hyperproteinemia |
Hypoproteinemia is a condition where there is an abnormally low level of protein in the blood. There are several causes that all result in edema once serum protein levels fall below a certain threshold.
== Signs and symptoms ==
The severity of symptoms can vary, but may include:
fatigue and weakness
recurrent infections
brittle nails and dry skin
thinning and breaking hair
mood changes and irritability
== Causes ==
Nutritional hypoproteinemia is due to severe limitation of protein intake in the diet. An example of nutritional hypoproteinemia is Kwashiorkor, a type of protein energy malnutrition affecting young children.
Malabsorption, often caused by celiac disease or inflammatory bowel disease
Liver disease can also cause hypoproteinemia by decreasing synthesis of plasma proteins like albumin.
Renal disease like nephrotic syndrome can also result in hypoproteinemia because plasma proteins are lost in the urine.
Sepsis (whole body infection) – macrophages activated in the liver and spleen secrete TNF-alpha into the bloodstream resulting in hypoproteinemia.
== Pathophysiology ==
== Diagnosis ==
Hypoproteinemia is often confirmed by testing for serum albumin and total protein levels.
== References ==
== External links == | Wikipedia/Hypoproteinemia |
Apolipoprotein C-II (Apo-CII, or Apoc-II), or apolipoprotein C2 is a protein that in humans is encoded by the APOC2 gene.
The protein encoded by this gene is secreted in plasma, where it is a component of very low density lipoproteins and chylomicrons. This protein activates the enzyme lipoprotein lipase in capillaries, which hydrolyzes triglycerides and thus provides free fatty acids and glycerols for cells. Mutations in this gene cause hyperlipoproteinemia type IB, characterized by xanthomas, pancreatitis, and hepatosplenomegaly, but no increased risk for atherosclerosis. Lab tests will show elevated blood levels of triglycerides, cholesterol, and chylomicrons
== Interactive pathway map ==
Click on genes, proteins and metabolites below to link to respective articles.
== See also ==
Apolipoprotein C
== References ==
== External links ==
Human APOC2 genome location and APOC2 gene details page in the UCSC Genome Browser. | Wikipedia/Apolipoprotein_C2 |
Graves' disease, also known as toxic diffuse goiter or Basedow’s disease, is an autoimmune disease that affects the thyroid. It frequently results in and is the most common cause of hyperthyroidism. It also often results in an enlarged thyroid. Signs and symptoms of hyperthyroidism may include irritability, muscle weakness, sleeping problems, a fast heartbeat, poor tolerance of heat, diarrhea and unintentional weight loss. Other symptoms may include thickening of the skin on the shins, known as pretibial myxedema, and eye bulging, a condition caused by Graves' ophthalmopathy. About 25 to 30% of people with the condition develop eye problems.
The exact cause of the disease is unclear, but symptoms are a result of antibodies binding to receptors on the thyroid causing over-expression of thyroid hormone. Persons are more likely to be affected if they have a family member with the disease. If one monozygotic twin is affected, a 30% chance exists that the other twin will also have the disease. The onset of disease may be triggered by physical or emotional stress, infection, or giving birth. Those with other autoimmune diseases, such as type 1 diabetes and rheumatoid arthritis, are more likely to be affected. Smoking increases the risk of disease and may worsen eye problems. The disorder results from an antibody, called thyroid-stimulating immunoglobulin (TSI), that has a similar effect to thyroid stimulating hormone (TSH). These TSI antibodies cause the thyroid gland to produce excess thyroid hormones. The diagnosis may be suspected based on symptoms and confirmed with blood tests and radioiodine uptake. Typically, blood tests show a raised T3 and T4, low TSH, increased radioiodine uptake in all areas of the thyroid, and TSI antibodies.
The three treatment options are radioiodine therapy, medications, and thyroid surgery. Radioiodine therapy involves taking iodine-131 by mouth, which is then concentrated in the thyroid and destroys it over weeks to months. The resulting hypothyroidism is treated with synthetic thyroid hormones. Medications such as beta blockers may control some of the symptoms, and antithyroid medications such as methimazole may temporarily help people, while other treatments are having effect. Surgery to remove the thyroid is another option. Eye problems may require additional treatments.
Graves disease develops in about 0.5% of males and 3.0% of females. It occurs about 7.5 times more often in women than in men. Often, it starts between the ages of 40 and 60, but can begin at any age. It is the most common cause of hyperthyroidism in the United States (about 50 to 80% of cases). The condition is named after Irish surgeon Robert Graves, who described it in 1835. A number of prior descriptions also exist.
== Signs and symptoms ==
The signs and symptoms of Graves disease virtually all result from the direct and indirect effects of hyperthyroidism, with main exceptions being Graves ophthalmopathy, goiter, and pretibial myxedema (which are caused by the autoimmune processes of the disease). Symptoms of the resultant hyperthyroidism are mainly insomnia, hand tremor, hyperactivity, hair loss, excessive sweating, oligomenorrhea, itching, heat intolerance, weight loss despite increased appetite, diarrhea, frequent defecation, palpitations, periodic partial muscle weakness or paralysis in those especially of Asian descent, and skin warmth and moistness. Further signs that may be seen on physical examination are most commonly a diffusely enlarged (usually symmetric), nontender thyroid, lid lag, excessive lacrimation due to Graves' ophthalmopathy, arrhythmias of the heart, such as sinus tachycardia, atrial fibrillation, and premature ventricular contractions, and hypertension.
== Cause ==
The exact cause is unclear, but it is believed to involve a combination of genetic and environmental factors. While a theoretical mechanism occurs by which exposure to severe stressors and high levels of subsequent distress such as post-traumatic stress disorder could increase the risk of immune disease and cause an aggravation of the autoimmune response that leads to Graves disease, more robust clinical data are needed for a firm conclusion.
=== Genetics ===
A genetic predisposition for Graves' disease is seen, with some people more prone to develop TSH receptor-activating antibodies due to a genetic cause. Human leukocyte antigen DR (especially DR3) appears to play a role. To date, no clear genetic defect has been found to point to a single-gene cause.
Genes believed to be involved include those for thyroglobulin, thyrotropin receptor, protein tyrosine phosphatase nonreceptor type 22 (PTPN22), and cytotoxic T-lymphocyte–associated antigen 4, among others.
=== Infectious trigger ===
Since Graves disease is an autoimmune disease that appears suddenly, often later in life, a viral or bacterial infection may trigger antibodies, which cross-react with the human TSH receptor, a phenomenon known as antigenic mimicry.
The bacterium Yersinia enterocolitica bears structural similarity with the human thyrotropin receptor and was hypothesized to contribute to the development of thyroid autoimmunity arising for other reasons in genetically susceptible individuals.
In the 1990s, Y. enterocolitica was suggested to be possibly associated with Graves' disease.
More recently, the role for Y. enterocolitica has been disputed.
Epstein–Barr virus is another potential trigger.
== Mechanism ==
Thyroid-stimulating immunoglobulins recognize and bind to the TSH receptor, which stimulates the secretion of thyroxine (T4) and triiodothyronine (T3). Thyroxine receptors in the pituitary gland are activated by the surplus hormone, suppressing additional release of TSH in a negative feedback loop. The result is very high levels of circulating thyroid hormones and a low TSH level.
=== Pathophysiology ===
Graves' disease is an autoimmune disorder, in which the body produces antibodies that are specific to a self-protein - the receptor for thyroid-stimulating hormone. (Antibodies to thyroglobulin and to the thyroid hormones T3 and T4 may also be produced.)
These antibodies cause hyperthyroidism because they bind to the TSHr and chronically stimulate it. The TSHr is expressed on the thyroid follicular cells of the thyroid gland (the cells that produce thyroid hormone), and the result of chronic stimulation is an abnormally high production of T3 and T4. This, in turn, causes the clinical symptoms of hyperthyroidism, and the enlargement of the thyroid gland visible as goiter.
The infiltrative exophthalmos frequently encountered has been explained by postulating that the thyroid gland and the extraocular muscles share a common antigen, which is recognized by the antibodies. Antibodies binding to the extraocular muscles would cause swelling behind the eyeball.
The "orange peel" skin has been explained by the infiltration of antibodies under the skin, causing an inflammatory reaction and subsequent fibrous plaques.
The three types of autoantibodies to the TSH receptor are:
Thyroid stimulating immunoglobulins: these antibodies (mainly IgG) act as long-acting thyroid stimulants (LATS), activating the cells through a slower and more drawn out process compared to TSH, leading to an elevated production of thyroid hormone.
Thyroid growth immunoglobulins: these antibodies bind directly to the TSH receptor and have been implicated in the growth of thyroid follicles.
Thyrotrophin binding-inhibiting immunoglobulins: these antibodies inhibit the normal union of TSH with its receptor.
Some actually act as if TSH itself is binding to its receptor, thus inducing thyroid function.
Other types may not stimulate the thyroid gland, but prevent TSI and TSH from binding to and stimulating the receptor.
Another effect of hyperthyroidism is bone loss from osteoporosis, caused by an increased excretion of calcium and phosphorus in the urine and stool. The effects can be minimized if the hyperthyroidism is treated early. Thyrotoxicosis can also augment calcium levels in the blood by as much as 25%. This can cause stomach upset, excessive urination, and impaired kidney function.
== Diagnosis ==
Graves disease may present clinically with one or more of these characteristic signs:
Rapid heartbeat (80%)
Diffuse palpable goiter with audible bruit (70%)
Tremor (40%)
Exophthalmos (protuberance of one or both eyes), periorbital edema (25%)
Fatigue (70%), weight loss (60%) with increased appetite in young people and poor appetite in the elderly, and other symptoms of hyperthyroidism/thyrotoxicosis
Heat intolerance (55%)
Tremulousness (55%)
Palpitations (50%)
Two signs are truly diagnostic of Graves' disease (i.e., not seen in other hyperthyroid conditions): exophthalmos and non-pitting edema (pretibial myxedema). Goiter is an enlarged thyroid gland and is of the diffuse type (i.e., spread throughout the gland). Diffuse goiter may be seen with other causes of hyperthyroidism, although Graves' disease is the most common cause of diffuse goiter. A large goiter will be visible to the naked eye, but a small one (mild enlargement of the gland) may be detectable only by physical examination. Occasionally, goiter is not clinically detectable, but may be seen only with computed tomography or ultrasound examination of the thyroid. Another sign of Graves' disease is hyperthyroidism, that is, overproduction of the thyroid hormones T3 and T4. Normal thyroid levels are also seen, and occasionally also hypothyroidism, which may assist in causing goiter (though it is not the cause of the Graves' disease). Hyperthyroidism in Graves' disease is confirmed, as with any other cause of hyperthyroidism, by measuring elevated blood levels of free (unbound) T4.
Other useful laboratory measurements in Graves disease include thyroid-stimulating hormone (TSH, usually undetectable in Graves' disease due to negative feedback from the elevated T3 and T4), and protein-bound iodine (elevated). Serologically detected thyroid-stimulating antibodies, radioactive iodine uptake, or thyroid ultrasound with Doppler all can independently confirm a diagnosis of Graves' disease.
Biopsy to obtain histiological testing is not normally required, but may be obtained if thyroidectomy is performed.
The goiter in Graves' disease is often not nodular, but thyroid nodules are also common. Differentiating common forms of hyperthyroidism such as Graves' disease, single thyroid adenoma, and toxic multinodular goiter is important to determine proper treatment. The differentiation among these entities has advanced, as imaging and biochemical tests have improved. Measuring TSH-receptor antibodies with the h-TBII assay has been proven efficient and was the most practical approach found in one study.
=== Eye disease ===
Thyroid-associated ophthalmopathy (TAO), or thyroid eye disease (TED), is the most common extrathyroidal manifestation of Graves' disease. It is a form of idiopathic lymphocytic orbital inflammation, and although its pathogenesis is not completely understood, autoimmune activation of orbital fibroblasts, which in TAO express the TSH receptor, is thought to play a central role.
Hypertrophy of the extraocular muscles, adipogenesis, and deposition of nonsulfated glycosaminoglycans and hyaluronate, causes expansion of the orbital fat and muscle compartments, which within the confines of the bony orbit may lead to dysthyroid optic neuropathy, increased intraocular pressures, proptosis, venous congestion leading to chemosis and periorbital edema, and progressive remodeling of the orbital walls. Other distinctive features of TAO include lid retraction, restrictive myopathy, superior limbic keratoconjunctivitis, and exposure keratopathy.
Severity of eye disease may be classified by the mnemonic: "NO SPECS":
Class 0: No signs or symptoms
Class 1: Only signs (limited to upper lid retraction and stare, with or without lid lag)
Class 2: Soft tissue involvement (oedema of conjunctivae and lids, conjunctival injection, etc.)
Class 3: Proptosis
Class 4: Extraocular muscle involvement (usually with diplopia)
Class 5: Corneal involvement (primarily due to lagophthalmos)
Class 6: Sight loss (due to optic nerve involvement)
Typically, the natural history of TAO follows Rundle's curve, which describes a rapid worsening during an initial phase, up to a peak of maximum severity, and then improvement to a static plateau without, however, resolving back to a normal condition.
== Management ==
Treatment of Graves disease includes antithyroid drugs that reduce the production of thyroid hormone, radioiodine (radioactive iodine I-131) and thyroidectomy (surgical excision of the gland). As operating on a hyperthyroid patient is dangerous, prior to thyroidectomy, preoperative treatment with antithyroid drugs is given to render the patient euthyroid. Each of these treatments has advantages and disadvantages, and no single treatment approach is considered the best for everyone.
Treatment with antithyroid medications must be administered for six months to two years to be effective. Even then, upon cessation of the drugs, the hyperthyroid state may recur. The risk of recurrence is about 40–50%, and lifelong treatment with antithyroid drugs carries some side effects such as agranulocytosis and liver disease. Side effects of the antithyroid medications include a potentially fatal reduction in the level of white blood cells. Therapy with radioiodine is the most common treatment in the United States, while antithyroid drugs and/or thyroidectomy are used more often in Europe, Japan, and most of the rest of the world.
β-Blockers (such as propranolol) may be used to inhibit the sympathetic nervous system symptoms of tachycardia and nausea until antithyroid treatments start to take effect. Pure β-blockers do not inhibit lid retraction in the eyes, which is mediated by alpha adrenergic receptors.
=== Antithyroid drugs ===
The main antithyroid drugs are carbimazole (in the UK), methimazole (in the US), and propylthiouracil/PTU. These drugs block the binding of iodine and coupling of iodotyrosines. The most dangerous side effect is agranulocytosis (1/250, more in PTU). Others include granulocytopenia (dose-dependent, which improves on cessation of the drug) and aplastic anemia. Patients on these medications should see a doctor if they develop sore throat or fever. The most common side effects are rash and peripheral neuritis. These drugs also cross the placenta and are secreted in breast milk. Lugol's iodine may be used to block hormone synthesis before surgery.
A randomized control trial testing single-dose treatment for Graves found methimazole achieved euthyroid state more effectively after 12 weeks than did propylthyouracil (77.1% on methimazole 15 mg vs 19.4% in the propylthiouracil 150 mg groups).
No difference in outcome was shown for adding thyroxine to antithyroid medication and continuing thyroxine versus placebo after antithyroid medication withdrawal. However, two markers were found that can help predict the risk of recurrence. These two markers are a positive TSHr antibody (TSHR-Ab) and smoking. A positive TSHR-Ab at the end of antithyroid drug treatment increases the risk of recurrence to 90% (sensitivity 39%, specificity 98%), and a negative TSHR-Ab at the end of antithyroid drug treatment is associated with a 78% chance of remaining in remission. Smoking was shown to have an impact independent to a positive TSHR-Ab.
=== Radioiodine ===
Radioiodine (radioactive iodine-131) was developed in the early 1940s at the Mallinckrodt General Clinical Research Center. This modality is suitable for most patients, although some prefer to use it mainly for older patients. Indications for radioiodine are failed medical therapy or surgery and where medical or surgical therapy are contraindicated. Hypothyroidism may be a complication of this therapy, but may be treated with thyroid hormones if it appears. The rationale for radioactive iodine is that it accumulates in the thyroid and irradiates the gland with its beta and gamma radiations, about 90% of the total radiation being emitted by the beta (electron) particles. The most common method of iodine-131 treatment is to administer a specified amount in microcuries per gram of thyroid gland based on palpation or radiodiagnostic imaging of the gland over 24 hours. Patients who receive the therapy must be monitored regularly with thyroid blood tests to ensure they are treated with thyroid hormone before they become symptomatically hypothyroid.
Contraindications to RAI are pregnancy (absolute), ophthalmopathy (relative; it can aggravate thyroid eye disease), or solitary nodules.
Disadvantages of this treatment are a high incidence of hypothyroidism (up to 80%) requiring eventual thyroid hormone supplementation in the form of a daily pill(s). The radioiodine treatment acts slowly (over months to years) to destroy the thyroid gland, and Graves' disease–associated hyperthyroidism is not cured in all persons by radioiodine, but has a relapse rate that depends on the dose of radioiodine which is administered. In rare cases, radiation induced thyroiditis has been linked to this treatment.
=== Surgery ===
This modality is suitable for young people and pregnant females. Indications for thyroidectomy can be separated into absolute indications or relative indications. These indications aid in deciding which people would benefit most from surgery. The absolute indications are a large goiter (especially when compressing the trachea), suspicious nodules or suspected cancer (to pathologically examine the thyroid), and people with ophthalmopathy and additionally if it is the person's preferred method of treatment or if refusing to undergo radioactive iodine treatment. Pregnancy is advised to be delayed for six months after radioactive iodine treatment.
Both bilateral subtotal thyroidectomy and the Hartley-Dunhill procedure (hemithyroidectomy on one side and partial lobectomy on other side) are possible.
Advantages are immediate cure and potential removal of carcinoma. Its risks are injury of the recurrent laryngeal nerve, hypoparathyroidism (due to removal of the parathyroid glands), hematoma (which can be life-threatening if it compresses the trachea), relapse following medical treatment, infections (less common), and scarring. The increase in the risk of nerve injury can be due to the increased vascularity of the thyroid parenchyma and the development of links between the thyroid capsule and the surrounding tissues. Reportedly, a 1% incidence exists of permanent recurrent laryngeal nerve paralysis after complete thyroidectomy. Risks related to anesthesia are many, thus coordination with the anesthesiologist and patient optimization for surgery preoperatively are essential. Removal of the gland enables complete biopsy to be performed to have definite evidence of cancer anywhere in the thyroid. (Needle biopsies are not so accurate at predicting a benign state of the thyroid). No further treatment of the thyroid is required, unless cancer is detected. Radioiodine uptake study may be done after surgery, to ensure all remaining (potentially cancerous) thyroid cells (i.e., near the nerves to the vocal cords) are destroyed. Besides this, the only remaining treatment will be levothyroxine, or thyroid replacement pills to be taken for the rest of the patient's life.
A 2013 review article concludes that surgery appears to be the most successful in the management of Graves' disease, with total thyroidectomy being the preferred surgical option.
=== Eyes ===
Mild cases are treated with lubricant eye drops or nonsteroidal anti-inflammatory drops. Severe cases threatening vision (corneal exposure or optic nerve compression) are treated with steroids or orbital decompression. In all cases, cessation of smoking is essential. Double vision can be corrected with prism glasses and surgery (the latter only when the process has been stable for a while).
Difficulty closing eyes can be treated with lubricant gel at night, or with tape on the eyes to enable full, deep sleep.
Orbital decompression can be performed to enable bulging eyes to retreat back into the head. Bone is removed from the skull behind the eyes, and space is made for the muscles and fatty tissue to fall back into the skull.
For management of clinically active Graves disease, orbitopathy (clinical activity score >2) with at least mild to moderate severity, intravenous glucocorticoids are the treatment of choice, usually administered in the form of pulse intravenous methylprednisolone. Studies have consistently shown that pulse intravenous methylprednisolone is superior to oral glucocorticoids both in terms of efficacy and decreased side effects for managing Graves' orbitopathy.
== Prognosis ==
If left untreated, more serious complications could result, including birth defects in pregnancy, increased risk of a miscarriage, bone mineral loss and, in extreme cases, death (e.g. indirectly through complications, or through a thyroid storm event). Graves' disease is often accompanied by an increase in heart rate, which may lead to further heart complications, including loss of the normal heart rhythm (atrial fibrillation), which may lead to stroke. If the eyes are proptotic (bulging) enough that the lids do not close completely at night, dryness will occur – with the risk of a secondary corneal infection, which could lead to blindness. Pressure on the optic nerve behind the globe can lead to visual field defects and vision loss, as well. Prolonged untreated hyperthyroidism can lead to bone loss, which may resolve when treated.
== Epidemiology ==
Graves' disease occurs in about 0.5% of people. Graves' disease data has shown that the lifetime risk for women is around 3% and 0.5% for men. It occurs about 7.5 times more often in women than in men and often starts between the ages of 40 and 60. It is the most common cause of hyperthyroidism in the United States (about 50 to 80% of cases).
== History ==
Graves disease owes its name to the Anglo-Irish doctor Robert James Graves, who described a case of goiter with exophthalmos in 1835. (Medical eponyms are often styled nonpossessively; thus Graves' disease and Graves disease are variant stylings of the same term.)
The German Karl Adolph von Basedow independently reported the same constellation of symptoms in 1840. As a result, on the European continent, the terms "Basedow syndrome", "Basedow disease", or "Morbus Basedow" are more common than "Graves' disease".
Graves disease has also been called exophthalmic goiter.
Less commonly, it has been known as Parry disease, Begbie disease, Flajan disease, Flajani–Basedow syndrome, and Marsh disease. These names for the disease were derived from Caleb Hillier Parry, James Begbie, Giuseppe Flajani, and Henry Marsh. Early reports, not widely circulated, of cases of goiter with exophthalmos were published by the Italians Giuseppe Flajani and Antonio Giuseppe Testa, in 1802 and 1810, respectively. Prior to these, Caleb Hillier Parry, a notable provincial physician in England of the late 18th century (and a friend of Edward Miller-Gallus), described a case in 1786. This case was not published until 1825 - ten years ahead of Graves.
However, fair credit for the first description of Graves disease goes to the 12th-century Persian physician Sayyid Ismail al-Jurjani, who noted the association of goiter and exophthalmos in his Thesaurus of the Shah of Khwarazm, the major medical dictionary of its time.
== Society and culture ==
=== Notable cases ===
Ayaka, Japanese singer, was diagnosed with Graves disease in 2007. After going public with her diagnosis in 2009, she took a two-year hiatus from music to focus on treatment.
Susan Elizabeth Blow, American educator and founder of the first publicly funded kindergarten in the United States, was forced to retire and seek treatment for Graves disease in 1884.
George H. W. Bush, former U.S. president, developed new atrial fibrillation and was diagnosed in 1991 with hyperthyroidism due to the disease and treated with radioactive iodine. The president's wife, Barbara Bush, also developed the disease around the same time, which, in her case, produced severe infiltrative exophthalmos.
Rodney Dangerfield, American comedian and actor
Gail Devers, American sprinter: A doctor considered amputating her feet after she developed blistering and swelling following radiation treatment for Graves' disease, but she went on to recover and win Olympic medals.
Missy Elliott, American hip-hop artist
Marty Feldman, British comedy writer, comedian and actor
Sia, Australian singer and songwriter
Sammy Gravano, Italian-American former underboss of the Gambino crime family
Jim Hamilton, Scottish rugby player, discovered he had Graves' disease shortly after retiring from the sport in 2017.
Heino, German folk singer, whose dark sunglasses (worn to hide his symptoms) became part of his trademark look
Herbert Howells, British composer; the first person to be treated with radium injections
Vybz Kartel, Jamaican dancehall musician; contracted disease while incarcerated
Yayoi Kusama, Japanese artist
Nadezhda Krupskaya, Russian Communist and wife of Vladimir Lenin
Umm Kulthum was an Egyptian singer, songwriter, and film actress active from the 1920s to the 1970s.
Barbara Leigh, an American former actress and fashion model, now spokeswoman for the National Graves' Disease Foundation
Keiko Masuda, Japanese singer and one-half of the duo Pink Lady.
Yūko Miyamura, Japanese voice actress
Lord Monckton, former UKIP and Conservative politician; notorious promoter of climate change denial
Sophia Parnok, Russian poet
Sir Cecil Spring Rice, British ambassador to the United States during World War I, died suddenly of the disease in 1918.
Daisy Ridley, British actress
Christina Rossetti, English Victorian-era poet
Dame Maggie Smith, British actress
Mary Webb, British novelist and poet
Wendy Williams, American TV show host
Act Yasukawa, Japanese professional wrestler
=== Literature ===
In Italo Svevo's novel Zeno's Conscience, character Ada develops the disease.
Ern Malley was an acclaimed Australian poet whose work was not published until after his death from Graves' disease in 1943. However, Malley's existence and entire biography was actually later revealed to be a literary hoax.
== Research ==
Agents that act as antagonists at thyroid stimulating hormone receptors are under investigation as a possible treatment for Graves' disease.
== References ==
== External links ==
"Graves' disease". Genetics Home Reference. U.S. National Library of Medicine.
Graves disease on ncbi | Wikipedia/Graves-Basedow_disease |
Cushing's disease is one cause of Cushing's syndrome characterised by increased secretion of adrenocorticotropic hormone (ACTH) from the anterior pituitary (secondary hypercortisolism). This is most often as a result of a pituitary adenoma (specifically pituitary basophilism) or due to excess production of hypothalamus CRH (corticotropin releasing hormone) (tertiary hypercortisolism/hypercorticism) that stimulates the synthesis of cortisol by the adrenal glands. Pituitary adenomas are responsible for 80% of endogenous Cushing's syndrome, when excluding Cushing's syndrome from exogenously administered corticosteroids. The equine version of this disease is Pituitary pars intermedia dysfunction.
This should not be confused with ectopic Cushing syndrome or exogenous steroid use.
== Signs and symptoms ==
The symptoms of Cushing's disease are similar to those seen in other causes of Cushing's syndrome. Patients with Cushing's disease usually present with one or more signs and symptoms secondary to the presence of excess cortisol or ACTH. Although uncommon, some patients with Cushing's disease have large pituitary tumors (macroadenomas). In addition to the severe hormonal effects related to increased blood cortisol levels, the large tumor can compress adjacent structures. These tumors can compress the nerves that carry information from the eyes, causing a decrease in peripheral vision. Glaucoma and cataracts also may occur in Cushing's syndrome. In children, the two main symptoms are obesity and decreased linear growth.
The clinical diagnosis must be based on the presence of one or more of the symptoms listed below because the syndrome itself has no true pathognomonic signs or symptoms.
The most common symptoms seen in male patients are purple striae, muscle atrophy, osteoporosis, and kidney stones.
=== Common ===
Common signs and symptoms of Cushing's disease include the following:
=== Less common ===
The less-common signs and symptoms of Cushing's disease include the following:
== Diagnosis ==
Diagnosis is made first by diagnosing Cushing's syndrome (hypercortisolism), which can be difficult to do clinically since the most characteristic symptoms only occur in a minority of patients. Some of the biochemical diagnostic tests used include salivary and blood serum cortisol testing, 24-hour urinary free cortisol (UFC) testing, the dexamethasone suppression test (DST). No single test is perfect and multiple tests should always be used to achieve a proper diagnosis. Diagnosing Cushing's disease is a multidisciplinary process involving doctors, endocrinologists, radiologists, surgeons, and chemical pathologists. Often, it is hard to differentiate true Cushing's from pseudo-Cushing's (non-neoplastic hypercortisolism).
=== ACTH blood test ===
Once Cushing's syndrome has been diagnosed, the first step towards finding the cause is measuring plasma adrenocorticotropic hormone (ACTH) concentration. A concentration consistently below 1.1 pmol/L is classified as corticotropin-independent and does not lead to a diagnosis of Cushing's disease. In such cases, the next step is adrenal imaging with CT.
If plasma corticotropin concentrations are consistently above 3.3 pmol/L, then corticotropin-dependent Cushing's syndrome is most likely. Any intermediate values need to be cautiously interpreted and a corticotropin-releasing hormone (CRH) test is advised in order to confirm corticotropin dependency. If corticotropin-dependent Cushing's syndrome is determined then the next step is to distinguish between Cushing's disease and ectopic corticotropin syndrome. This is done via a combination of techniques including CRH, high-dose DST, pituitary MRI and bilateral inferior petrosal sinus sampling (IPSS).
=== Dexamethasone suppression test ===
Two dexamethasone suppression tests (DSTs) are generally used, the overnight test and the 48 hour test. For both tests, a plasma cortisol level above 50 nmol/L is indicative of Cushing's disease. However, 3–8% of patients with Cushing's disease will test negative due to a retention of dexamethasone suppression abilities. For non-Cushing or healthy patients, the false-positive rate is 30%. The 48-h DST is advantageous since it is more specific and can be done by outpatients upon proper instruction. In the high-dose 48-h DST, 2 mg of dexamethasone is given every 6 hours for 48 hours or a single dose of 8 mg is given. This test is not needed if the 48-h low-dose DST has shown suppression of cortisol by over 30%. These tests are based on the glucocorticoid sensitivity of pituitary adenomas compared to non-pituitary tumors.
=== ACTH stimulation test ===
An ACTH stimulation test involving administration of corticotropin-releasing hormone (CRH) or another agent can differentiate this condition from ectopic ACTH secretion. In a patient with Cushing's disease, the tumor cells will be stimulated to release corticotropin and elevated plasma corticotropin levels will be detected. This rarely occurs with ectopic corticotropin syndrome and thus is quite useful for distinguishing between the two conditions. If ectopic, the plasma ACTH and cortisol levels should remain unchanged; if this is pituitary related, levels of both would rise. The CRH test uses recombinant human or bovine-sequence CRH, which is administered via a 100μg intravenous bolus dose. The sensitivity of the CRH test for detecting Cushing's disease is 93% when plasma levels are measured after fifteen and thirty minutes. However, this test is used only as a last resort due to its high cost and complexity.
=== Imaging ===
A CT or MRI of the pituitary may also show the ACTH-secreting tumor if present. However, in 40% of Cushing's disease patients MRI is unable to detect a tumor. In one study of 261 patients with confirmed pituitary Cushing's disease, only 48% of pituitary lesions were identified using MRI prior to surgery. The average size of tumor, both those that were identified on MRI and those that were only discovered during surgery, was 6 mm.
=== Inferior petrosal sinus sampling ===
IPSS (inferior petrosal sinus sampling) or BIPSS (bilateral IPSS) is a more accurate but invasive test used to differentiate pituitary from ectopic or adrenal Cushing's syndrome. A corticotropin gradient sample via BIPSS is required to confirm diagnosis when pituitary MRI imaging and biochemical diagnostic tests have been inconclusive. A basal central:peripheral ratio of over 2:1, or a ratio over 3:1 when CRH is administered, is indicative of Cushing's disease. This test has been the gold standard for distinguishing between Cushing's disease and ectopic corticotropin syndrome, with a sensitivity and specificity of 94% for Cushing's disease, and a very low rate of complications.
=== Urinary free cortisol test ===
Another diagnostic test used is the urinary free cortisol (UFC) test, which measures the excess cortisol excreted by the kidneys into the urine. Results of 4x higher cortisol levels than normal are likely to be Cushing's disease. This test should be repeated three times in order to exclude any normally occurring periods of hypercortisolism. The UFC test has a specificity of 81% and thus has a high rate of false-positives that are due to pseudo-Cushing states, sleep apnea, polycystic ovary syndrome, familial glucocorticoid resistance, and hyperthyroidism.
=== Late night (midnight) salivary cortisol test ===
The late-night or midnight salivary cortisol test has been gaining support due to its ease of collection and stability at room temperature, therefore it can be assigned to outpatients. The test measures free circulating cortisol and have both a sensitivity and specificity of 95–98%. This test is especially useful for diagnosing children.
== Treatment ==
The first-line treatment of Cushing's disease is surgical resection of ACTH-secreting pituitary adenoma; this surgery involves removal of the tumor via transsphenoidal surgery (TSS).
There are two possible options for access to the sphenoidal sinus, including of endonasal approach (through the nostril) or sublabial approach (through an incision under the upper lip); many factors such as the size of nostril, the size of the lesion, and the preferences of the surgeon cause the selection of one access route over the other. Some tumors do not contain a discrete border between the tumor and pituitary gland; therefore, careful sectioning through the pituitary gland may be required to identify the location of the tumor. The probability of successful resection is higher in patients where the tumor was identified at initial surgery in comparison to patients where no tumor was found initially; the overall remission rates in patients with microadenomas undergoing TSS are in range of 65%–90%, and the remission rate in patients with macroadenomas are lower than 65%. Patients with persistent disease after initial surgery are treated with repeated pituitary surgery as soon as the active persistent disease is evident; however, reoperation has a lower success rate and increases the risk of pituitary insufficiency.
Pituitary radiation therapy is another option for treatment of postoperative persisting hypercortisolemia following unsuccessful transsphenoidal surgery. External-beam pituitary RT is more effective treatment for pediatric CD in children with cure rates of 80–88%. Hypopituitarism specifically growth hormone deficiency has been reported as the only most common late morbidity of this treatment; GHD has been reported in 36% and 68% of the patients undergoing post-pituitary RT for Cushing's disease.
Bilateral adrenalectomy is another treatment that provides immediate reduction of cortisol level and control of hypercortisolism. However, it requires education of patients, because lifelong glucocorticoid and mineralocorticoid replacement therapy is needed for these patients. One of the major complications of this treatment is progression of Nelson's syndrome which is caused by enhance level of tumor growth and ACTH secretion post adrenalectomy in 8–29% of patients with CD.
During post-surgical recovery, patients collect a 24-hour urine sample and blood sample for detecting the level of cortisol with the purpose of cure test; level of cortisol near the detection limit assay corresponds to cure. Hormonal replacement such as steroid is given to patients because of steroid withdrawal. After the completion of collecting urine and blood samples, patients are asked to switch to glucocorticoid such as prednisone to decrease symptoms associated with adrenal withdrawal. Mitotane is also used
A study of 3,525 cases of TSS for Cushing's disease in the nationally representative sample of US hospitals between 1993 and 2002 was conducted and revealed the following results: the in-hospital mortality rate was 0.7%; the complication rate was 42.1%. Diabetes insipidus (15%), fluid and electrolyte abnormalities (12.5%), and neurological deficits (5.6%) were the most common complications reported. The analyses of the study show that complications were more likely in patients with pre-operative comorbidities. Patients older than 64 years were more likely to have an adverse outcome and prolonged hospital stay. Women were 0.3 times less likely to have adverse outcomes in comparison to men.
== Epidemiology ==
Cases of Cushing's disease are rare, and little epidemiological data is available on the disease. An 18-year study conducted on the population of Vizcaya, Spain reported a 0.004% prevalence of Cushing's disease. The average incidence of newly diagnosed cases was 2.4 cases per million inhabitants per year. The disease is often diagnosed 3–6 years after the onset of illness. Several studies have shown that Cushing's disease is more prevalent in women than men at a ratio of 3–6:1, respectively. Moreover, most women affected were between the ages of 50 and 60 years. The prevalence of hypertension, and abnormalities in glucose metabolism are major predictors of mortality and morbidity in untreated cases of the disease. The mortality rate of Cushing's disease was reported to be 10–11%, with the majority of deaths due to vascular disease. Women aged 45–70 years have a significantly higher mortality rate than men. Moreover, the disease shows a progressive increase with time. Reasons for the trend are unknown, but better diagnostic tools and a higher incidence rate are two possible explanations.
== History ==
The disease associated with this increased secretion of cortisol was described by the American neurosurgeon Harvey Cushing in 1912 after he was presented with a unique case of the disease in 1910 a 23-year-old woman called Minnie G. whose symptoms included painful obesity, amenorrhea, hypertrichosis (abnormal hair growth), underdevelopment of secondary sexual characteristics, hydrocephalus and cerebral tension. This combination of symptoms was not yet described by any medical disorder at the time. However, Cushing was confident that Minnie's symptoms were due to dysfunction of the pituitary gland and resembled those associated with an adrenal tumor. Given this conviction, and his knowledge of the three anterior pituitary cell types, Cushing hypothesized that if acidophil hyperpituitarism (excess secretion from the acidophil cells) caused acromegaly, then an excess of basophil cells must be involved in another pituitary disorder that involves sexual dysfunction (amenorrhea in females and erectile dysfunction in males) and could explain Minnie's symptoms. Experimental evidence and case reports by Cushing led to his publication in 1932 on pituitary basophilism as the cause of Cushing's disease. In this publication, the clinical symptoms of the disease, named after Cushing, were described. Out of the 12 cases with hypercortisolism described in Cushing's monograph on the pituitary body, 67% died within a few years after symptom presentation, whereas Minnie G. survived for more than 40 years after symptom presentation, despite the fact that she did not receive any treatments for a pituitary tumor. The prolonged survival made Minnie's case unique at the time. The reason behind this survival remains a mystery since an autopsy of Minnie was refused after her death. However, the most likely explanation, proposed by J. Aidan Carney and based on statistical evidence, was that the basophil adenoma Minnie might have harbored underwent partial infarction, leading to symptom regression. The other hypothesis was that Minnie might have had Primary Pigmented Nodular Adrenocortical Disease (PPNAD), which when associated with Cushing's syndrome (Carney complex) can infrequently cause spontaneous symptom regression of the latter.
In 1924, the Soviet neurologist Nikolai Itsenko reported two patients with pituitary adenoma. The resulting excessive adrenocorticotropic hormone secretion led to the production of large amounts of cortisol by the adrenal glands. Considering this impact, the name of Itsenko was added to the title in some East European and Asian countries, and the disease is called Itsenko-Kushing disease.
== References ==
== Further reading ==
Consensus on Diagnosis and Management of Cushing's Disease: A Guideline Update (2021)
== External links ==
The difference between Cushing's disease and other forms of Cushing's syndrome
"The burden of Cushing's disease (CD): clinical and health-related quality of life aspects" (RA Feelders, SJ Pulgar, A Kempel, and AM Pereira) | Wikipedia/Cushing's_disease |
Caroli disease (communicating cavernous ectasia, or congenital cystic dilatation of the intrahepatic biliary tree) is a rare inherited disorder characterized by cystic dilatation (or ectasia) of the bile ducts within the liver. There are two patterns of Caroli disease: focal or simple Caroli disease consists of abnormally widened bile ducts affecting an isolated portion of liver. The second form is more diffuse, and when associated with portal hypertension and congenital hepatic fibrosis, is often referred to as "Caroli syndrome". The underlying differences between the two types are not well understood. Caroli disease is also associated with liver failure and polycystic kidney disease. The disease affects about one in 1,000,000 people, with more reported cases of Caroli syndrome than of Caroli disease.
Caroli disease is distinct from other diseases that cause ductal dilatation caused by obstruction, in that it is not one of the many choledochal cyst derivatives.
== Signs and symptoms ==
The first symptoms typically include fever, intermittent abdominal pain, and an enlarged liver. Occasionally, yellow discoloration of the skin occurs. Caroli disease usually occurs in the presence of other diseases, such as autosomal recessive polycystic kidney disease, cholangitis, gallstones, biliary abscess, sepsis, liver cirrhosis, kidney failure, and cholangiocarcinoma (7% affected). People with Caroli disease are 100 times more at risk for cholangiocarcinoma than the general population. After recognizing symptoms of related diseases, Caroli disease can be diagnosed.
Morbidity is common and is caused by complications of cholangitis, sepsis, choledocholithiasis, and cholangiocarcinoma. These morbid conditions often prompt the diagnosis. Portal hypertension may be present, resulting in other conditions including enlarged spleen, hematemesis, and melena. These problems can severely affect the patient's quality of life. In a 10-year period between 1995 and 2005, only 10 patients were surgically treated for Caroli disease, with an average patient age of 45.8 years.
After reviewing 46 cases of Caroli disease before 1990, 21.7% of the cases were the result of an intrahepatic cyst or nonobstructive biliary tree dilation, 34.7% were linked with congenital hepatic fibrosis, 13% were isolated choledochal cystic dilation, and the remaining 24.6% had a combination of all three.
== Causes ==
The cause appears to be genetic; the simple form is an autosomal dominant trait, while the complex form is an autosomal recessive trait. Females are more prone to Caroli disease than males. Family history may include kidney and liver disease due to the link between Caroli disease and ARPKD. PKHD1, the gene linked to ARPKD, has been found mutated in patients with Caroli syndrome. PKHD1 is expressed primarily in the kidneys with lower levels in the liver, pancreas, and lungs, a pattern consistent with phenotype of the disease, which primarily affects the liver and kidneys. The genetic basis for the difference between Caroli disease and Caroli syndrome has not been defined.
== Diagnosis ==
Modern imaging techniques allow the diagnosis to be made more easily and without invasive imaging of the biliary tree. Commonly, the disease is limited to the left lobe of the liver. Images taken by CT scan, X-ray, or MRI show enlarged intrahepatic (in the liver) bile ducts due to ectasia. Using an ultrasound, tubular dilation of the bile ducts can be seen. On a CT scan, Caroli disease can be observed by noting the many fluid-filled, tubular structures extending to the liver. A high-contrast CT must be used to distinguish the difference between stones and widened ducts. Bowel gas and digestive habits make it difficult to obtain a clear sonogram, so a CT scan is a good substitution. When the intrahepatic bile duct wall has protrusions, it is clearly seen as central dots or a linear streak. Caroli disease is commonly diagnosed after this “central dot sign” is detected on a CT scan or ultrasound. However, cholangiography is the best, and final, approach to show the enlarged bile ducts as a result of Caroli disease.
== Treatment ==
The treatment depends on clinical features and the location of the biliary abnormality. When the disease is localized to one hepatic lobe, hepatectomy relieves symptoms and appears to remove the risk of malignancy. Good evidence suggests that malignancy complicates Caroli disease in roughly 7% of cases.
Antibiotics are used to treat the inflammation of the bile duct, and ursodeoxycholic acid is used for hepatolithiasis. Ursodiol is given to treat cholelithiasis. In diffuse cases of Caroli disease, treatment options include conservative or endoscopic therapy, internal biliary bypass procedures, and liver transplantation in carefully selected cases. Surgical resection has been used successfully in patients with monolobar disease. An orthotopic liver transplant is another option, used only when antibiotics have no effect, in combination with recurring cholangitis. With a liver transplant, cholangiocarcinoma is usually avoided in the long run.
Family studies are necessary to determine if Caroli disease is due to inheritable causes. Regular follow-ups, including ultrasounds and liver biopsies, are performed.
== Prognosis ==
Mortality is indirect and caused by complications. After cholangitis occurs, patients typically die within 5–10 years.
== Epidemiology ==
Caroli disease is typically found in Asia, and diagnosed in persons under the age of 22. Cases have also been found in infants and adults. As medical imaging technology improves, diagnostic age decreases.
== History ==
Jacques Caroli, a gastroenterologist, first described a rare congenital condition in 1958 in Paris, France.
He described it as "nonobstructive saccular or fusiform multifocal segmental dilatation of the intrahepatic bile ducts"; basically, he observed cavernous ectasia in the biliary tree causing a chronic, often life-threatening hepatobiliary disease.
Caroli, born in France in 1902, learned and practiced medicine in Angers. After World War II, he was chief of service for 30 years at Saint-Antoine in Paris. Before dying in 1979, he was honored with the rank of commander in the Legion of Honour in 1976.
== References ==
== External links == | Wikipedia/Caroli_disease |
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