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ERROR: type should be string, got "https://profreg.medscape.com/px/getpracticeprofile.do?method=getProfessionalProfile&urlCache=aHR0cHM6Ly9lbWVkaWNpbmUubWVkc2NhcGUuY29tL2FydGljbGUvMTcxMzg2LW92ZXJ2aWV3\nDrugs & Diseases > Gastroenterology\nBiliary Disease\nAuthor: Annie T Chemmanur, MD; Chief Editor: BS Anand, MD more...\nSections Biliary Disease\nGallstone dissolution agents\nFarnesoid X Receptor Agonist\nA diverse spectrum of diseases affects the biliary system, often presenting with similar clinical signs and symptoms. These conditions include gallstones, acute calculus cholecystitis, acute acalculus cholecystitis, Mirizzi syndrome, chronic cholecystitis, cholangitis (recurrent pyogenic, primary sclerosing, primary biliary, autoimmune), biliary tract malignancies, biliary tract cysts, and others.\nSee the images below.\nA normal postcholecystectomy cholangiogram.\nBiliary disease. In a patient with persistent elevation of liver-associated enzymes, the contrast medium entering the biliary ductal system preferentially enters the cystic duct.\nBiliary disease. Even when the catheter is advanced to the proximal common hepatic duct, contrast dye preferentially fills the cystic duct and gallbladder rather than allowing visualization of the intrahepatic ductal system (same patient as in previous image).\nBiliary disease. In this image, the common bile duct is occluded with a balloon-tipped catheter. Contrast material fills the intrahepatic ductal system to reveal diffuse intrahepatic sclerosing cholangitis.\nFor patient education resources, see Digestive Disorders Center and Cholesterol Center, as well as Gallstones, Primary Biliary Cirrhosis (PBC), Cirrhosis (Liver, Symptoms, Stages, and Diet), and Primary Sclerosing Cholangitis.\nBile is produced by the liver and is channeled by the biliary ductal system into the intestinal tract for the emulsification and absorption of fats. Biliary disease is caused by abnormalities in bile composition, biliary anatomy, or function. The liver determines the chemical composition of bile, and this may be modified later by the gallbladder and the biliary epithelium. Cholesterol, ordinarily insoluble in water, comes into solution by forming vesicles with phospholipids (principally lecithin) or mixed micelles with bile salts and phospholipids.\nWhen the ratio of cholesterol, phospholipids, and bile salts is outside an optimum range, cholesterol monohydrate crystals may come out of solution from multilamellar vesicles. Cholesterol supersaturation of bile appears to be a prerequisite for gallstone formation, which involves a variety of factors that affect the activity of low-density lipoprotein (LDL) uptake, hepatic 3-methylglutaryl coenzyme A reductase (HMG CoA), acyl cholesterol-lecithin acyltransferase, and 7-alpha hydroxylase.\nBy itself, cholesterol supersaturation is inadequate for explaining gallstone pathogenesis. Nucleation, the initial step in gallstone formation, is the transition of cholesterol from a soluble state into a solid crystalline form. Within the gallbladder bile, biologic molecules influence the process in a positive or negative fashion.\nFor example, mucus may function to promote nucleation, whereas bile-specific glycoproteins may function to inhibit nucleation. Mucin hypersecretion by the gallbladder mucosa creates a viscoelastic gel that fosters nucleation. Arachidonyl lecithin, which is absorbed from the alimentary tract and secreted into the bile, stimulates prostanoid synthesis by gallbladder mucosa and promotes mucus hypersecretion, while inhibitors of prostaglandin inhibit mucus secretion.\nFinally, gallbladder hypomotility and bile stasis appear to promote gallstone formation and growth, which may be important in diabetes, pregnancy, oral contraceptive use in women, and prolonged fasting in critically ill patients on total parenteral nutrition.\nMore recent research suggests that elevated levels of four circulating interleukins (IL) (IL-6, IL-10, IL-12 [p70], IL-13) are associated with an increased risk of gallstones [1] and/or there may be a genetic predisposition that affects the supersaturation of bile with insoluble compounds (eg, cholesterol) thereby also raising the risk of gallstone disease. [2]\nIn about 80% of patients, gallstones are clinically silent. Approximately 20% of patients develop symptoms over 15-20 years, that is, about 1% per year, and almost all become symptomatic before complications develop. Biliary-type pain, the typical clinical presentation, is due to the obstruction of the bile duct lumen. The predictive value of other complaints (eg, intolerance to fatty food, indigestion) is too low to be clinically helpful. The incidence of gallbladder cancer developing in the setting of cholelithiasis is low, about 0.1% per year. Two main types of gallstones exist.\nCholesterol stones (85%)\nThese are divided into two subtypes—pure (90%-100% cholesterol) or mixed (50%-90% cholesterol).\nPure stones often are solitary, whitish, and larger than 2.5 cm in diameter. Mixed stones usually are smaller, multiple in number, and occur in various shapes and colors. They tend to be arranged in laminated layers of an alternating thicker whitish cholesterol and a thinner dark pigment in a concentric pattern around a pigmented center (similar to the rings visible on the cross section of a tree). These stones tend to occur in residents of Western countries, and they usually are found in the gallbladder.\nThe risk factors associated with the development of cholesterol gallstones include obesity, a high-calorie diet, clofibrate therapy, gastrointestinal disorders involving major malabsorption of bile acids, cystic fibrosis with pancreatic insufficiency, and female sex and the use of oral contraceptives and other estrogenic medications. Coffee and ascorbic acid have been shown to reduce the risk of symptomatic cholesterol gallstones.\nPigment stones (15%)\nPigment stones occur in 2 subtypes—brown and black.\nBrown stones are made up of calcium bilirubinate and calcium-soaps. Bacteria are involved in their formation via secretion of beta glucuronidase and phospholipase. The bacterial glycocalyx aggregates with the bile pigment and precipitates out of solution. These stones are more common in Asia and tend to form within the bile ducts. They frequently are associated with periampullary duodenal diverticula.\nBlack stones typically form in the gallbladder and result when excess bilirubin enters the bile and polymerizes into calcium bilirubinate. These stones are more common in patients with chronic hemolysis, alcoholic cirrhosis, and advanced age.\nAcute calculus cholecystitis\nAcute calculus cholecystitis is an inflammation of the gallbladder that develops in the setting of an obstructed cystic or bile duct. It usually develops after 5 hours of biliary-type pain. The initial inflammation is caused by chemical irritation, and bacterial infection probably is a secondary event. A change in the perception of pain, classically a migration to the right upper quadrant, suggests transmural inflammation of the gallbladder, with involvement of the parietal peritoneum. Nausea and vomiting are common associated symptoms, and most patients are afebrile early in the course of the disease.\nMirizzi syndrome\nMirizzi syndrome refers to common hepatic duct obstruction caused by an extrinsic compression from an impacted stone in the cystic duct. [3] It has been estimated to occur in 0.7-1.4% of all cholecystectomies. It is often not recognized preoperatively, which can lead to significant morbidity and biliary injury, particularly with laparoscopic surgery.\nAcute acalculous cholecystitis\nAcute acalculous cholecystitis is the presence of an inflamed gallbladder in the absence of an obstructed cystic or common bile duct. It typically occurs in the setting of a critically ill patient (eg, severe burns, multiple traumas, lengthy postoperative care, prolonged intensive care) and accounts for 5% of cholecystectomies. Because abdominal pain, fever, and leukocytosis are relatively common in these patients and the signs and symptoms are not specific for acalculous cholecystitis, the physician must have a high index of suspicion to make the diagnosis. The etiology is thought to have an ischemic basis, and a gangrenous gallbladder may result. This condition has an increased rate of complications and mortality. An uncommon subtype known as acute emphysematous cholecystitis generally is caused by infection with clostridial organisms and occlusion of the cystic artery associated with atherosclerotic vascular disease and, often, diabetes.\nChronic cholecystitis\nChronic cholecystitis is a common disorder that frequently is associated with gallstones. The clinical features are nonspecific, and cholescintigraphy initially may suggest the diagnosis. The pathogenesis is poorly understood but may be due to abnormal bile composition leading to chemical injury of the gallbladder mucosa. Histologic evidence of a mononuclear infiltrate, fibrosis, and epithelial metaplasia confirms the diagnosis. A subset of patients develops dystrophic calcifications within the fibrosis, leading to a porcelain gallbladder, which is a risk factor for gallbladder carcinoma.\nCholangitis\nCholangitis is an infection of the biliary system, complicating benign and malignant obstruction of the biliary tract. The clinical presentation is quite variable depending on the nature of the illness, patient age, and condition of the patient. Charcot triad (ie, fever, right upper quadrant pain, jaundice) occurs in only 20%-70% of cases. Hypotension and mental status changes also may accompany severe infection, a pentad described by Reynolds in 1959. [4] The organisms typically identified are enteric in origin, notably Escherichia coli, Streptococcus faecalis, Clostridium species, Klebsiella species, Enterobacter species, Pseudomonas species, and Proteus species. They probably enter the biliary system via portal bacteremia. No correlation exists between the severity of the clinical manifestations and the presence or absence of pus in the biliary system; however, suppurative cholangitis is associated with a higher mortality rate.\nRecurrent pyogenic cholangitis\nRecurrent pyogenic cholangitis, also known as \"oriental cholangiohepatitis,\" is prevalent in several parts of Asia and the Pacific Rim countries. It is limited to Asian immigrants in America, occurs in the second to fourth decades of life, and is associated with a lower socioeconomic class. It is initiated by parasitic infestation of the biliary ducts by Opisthorchis sinensis (formerly Clonorchis sinensis), in which the adult fluke may impair bile flow. In the setting of bile stasis and secondary bacterial infection, pigment stones form around ova and sets the stage for the intermittent obstruction leading to recurrent pyogenic cholangitis. Pathologic changes principally affect the intrahepatic bile ducts (curiously, more often the left duct).\nPrimary sclerosing cholangitis\nPSC is a chronic cholestatic biliary disease characterized by nonsuppurative inflammation and fibrosis of the biliary ductal system. The cause is unknown but is associated with autoimmune inflammatory diseases, such as chronic ulcerative colitis and Crohn colitis (less commonly), and rare conditions, such as Riedel thyroiditis and retroperitoneal fibrosis. Most patients present with fatigue and pruritus and, occasionally, jaundice. The natural history is variable but involves progressive destruction of the bile ducts, leading to cirrhosis and liver failure. The clinical features of cholangitis (ie, fever, right upper quadrant pain, jaundice) are uncommon unless the biliary system has been instrumented.\nPrimary biliary cholangitis\nPrimary biliary cholangitis (PBC), formerly known as primary biliary cirrhosis, is a progressive cholestatic biliary disease that presents with fatigue and itching or asymptomatic elevation of the alkaline phosphatase. The name change reflects the fact that cirrhosis occurs only in the late stage and therefore does not correctly identify patients with early-stage disease. [5] Jaundice develops with progressive destruction of bile ductules that eventually leads to liver cirrhosis and hepatic failure. This autoimmune illness has a familial predisposition, in which even unaffected family members may have immunologic abnormalities, especially an increased serum immunoglobulin M (IgM) and an association with human leucocyte antigen (HLA)-DR8. [6, 7]\nAlthough numerous autoantibodies have been identified, antimitochondrial antibodies (AMA) are present in 95% of patients. AMA is a family of antibodies; those directed against the inner mitochondrial membrane antigen M2 in the 2-oxo-acid dehydrogenase complex are most specific for PBC. [8] Circulating immune complexes also have been identified but are unlikely to play a pathogenic role. Circulating T lymphocyte levels initially are within the reference range and decline as the disease progresses. The histologic appearance of the bile duct destruction resembles hepatic allograft rejection and graft-versus-host disease of the liver and appears to be mediated by cytotoxic T lymphocytes.\nAutoimmune cholangitis\nAutoimmune cholangitis represents a rare, distinct disease entity. While it shares some features with PBC, the results of tests for AMA are negative, the levels of gamma globulin and IgM are lower, and the results of tests for fluorescent antinuclear antibody (FANA) and anti–smooth muscle antibody (ASMA) are positive more commonly.\nNeoplasms of the biliary tract\nCarcinoma of the biliary system manifests with clinical symptoms of weight loss (77%), nausea (60%), anorexia (56%), abdominal pain (56%), fatigue (63%), pruritus (51%), fever (21%), malaise (19%), diarrhea (19%), constipation (16%), and abdominal fullness (16%). Symptomatic patients usually have advanced disease, with spread to hilar lymph nodes before obstructive jaundice occurs. It is associated with a poor prognosis.\nThis uncommon malignancy affects 2.5 individuals per 100,000 population. It represents 54% of biliary tract cancers, and more than 6500 patients die from this disease in the United States each year. Cancer that develops in the infundibulum (neck of the gallbladder) can produce hydrops of the gallbladder that is clinically indistinguishable from an obstructing stone.\nCholangiocarcinoma is an adenocarcinoma of the bile ducts. [9] It may occur without associated risk factors, but it is associated more commonly with chronic cholestatic liver disease such as PSC, choledochal cysts, oriental cholangiohepatitis, and work-related handling of asbestos. Cholangiocarcinoma accounts for 25% of biliary tract cancers. Patients usually present with jaundice, a vague upper or right upper quadrant abdominal pain associated with anorexia, weight loss, and pruritus.\nAmpullary cancer\nAmpullary cancer accounts for 8% of biliary tract cancers. It most commonly presents with painless jaundice or acute pancreatitis.\nBiliary tract cysts\nCystic dilatation of the biliary tree is an uncommon abnormality. About half of the patients present with some combination of jaundice, abdominal pain, and an abdominal mass. The presence of these cysts is often associated with an anomalous union of the pancreatic and biliary ductal system. This suggests that pancreatic juice enters the bile duct, causes a proteolytic and inflammatory injury to the duct wall, and leads to biliary cyst formation. The most commonly used classification scheme was proposed by Todani, which defines 5 cyst types, with groups I and IV having subtypes.\nType I involves a cystic dilatation of the extrahepatic biliary system. In subtype 1a (most common), the entire extrahepatic duct is diffusely involved. In subtype 1b (rare), a localized portion of the common bile duct is segmentally cystic. In subtype 1c (uncommon), the common bile duct is diffusely dilated.\nType II (rare) is a diverticulum of the extrahepatic bile duct.\nType III (uncommon) is a cystic dilatation of the intraduodenal portion of the common bile duct (sometimes referred to as a choledochocele).\nType IV has multiple cysts. Subtype IVa (uncommon) involves both the intrahepatic and extrahepatic biliary system, while subtype IVb (rare) has multiple cysts confined to the extrahepatic system.\nType V (rare) is characterized by single or multiple cysts involving the intrahepatic bile ducts (usually referred to as Caroli disease). Clinical symptoms usually are the result of associated complications such as cholangitis, choledocholithiasis, pancreatitis, hepatic abscess, cirrhosis, and biliary malignancy.\nUnited States statistics\nGallstone disease is one of the most common and costly of all digestive diseases. The third National Health and Nutrition Examination Survey estimated that, in the United States, 6.3 million men and 14.2 million women aged 20-74 years have gallbladder disease.\nThe incidence of gallstones is 1 million new cases per year. The prevalence is 20 million cases among Americans.\nApproximately 2-7 cases per 100,000 population of primary sclerosing cholangitis (PSC) exist. About 5% of patients with chronic ulcerative colitis develop PSC.\nThe incidence of gallbladder cancer is 2.5 cases per 100,000 population.\nThe incidence of primary biliary cholangitis (PBC) is 5.8-15 cases per 1 million population. The incidence of PBC appears to be increasing, but the cause of the increase is unclear. However, the increase is possibly due to better detection and increased awareness rather than a true change in disease incidence.\nAccording to an international multicenter study comprising 4805 patients with primary biliary cholangitis (primary biliary cirrhosis) over 44 years (1970-2014), there was an incremental increase in mean age at diagnosis: 2-3 years per decade from 46.9 ± 10.1 years in the 1970s to 57.0 ± 12.1 years from 2010 onward (P<0.001).<ref>10 </ref>In addition, although there were no significant changes in female predominance (female-male ratio of 9:1) and antimitochondrial antibody positivity (90%), increases in the incidence of mild biochemical disease and mild histologic stage at diagnosis were observed, as well as lower rates of decompensation and higher 10-year transplant-free survival with each decade forward. [10]\nMexican Americans and several American Indian tribes, particularly the Pima Indians in the Southwest, have very high prevalence rates of cholesterol gallstones. Decreased bile acid secretion is believed to be the common denominator in these ethnic groups.\nGallbladder cancer is the most common gastrointestinal malignancy in both Southwestern Native Americans and Mexican Americans. A prominent geographic variability exists in the incidence of gallbladder cancer that correlates with the prevalence of cholelithiasis. High rates of gallbladder cancer are also seen in South American countries, particularly Chile and Bolivia. These populations all share a high prevalence of gallstones and/or Salmonella infection, both recognized risk factors for gallbladder cancer.\nThe prevalence of cholesterol gallstones is higher among females than males (lifetime risk of 35% vs 20%, respectively). This likely is due to endogenous sex hormones, which enhance cholesterol secretion and increase bile cholesterol saturation. Progesterone also may contribute by relaxing gallbladder smooth muscle and impairing gallbladder emptying. Note the following:\nPSC: Males (primarily young to middle-aged [11] ) are affected twice as frequently as females.\nPBC: Females are affected nine times as often as males.\nIncreased age is associated with lithogenic bile and an increased rate of gallstones. Note the following:\nPSC: Mean age of onset is 40 years.\nPBC: Among the autoimmune diseases, PBC is unique in that it never occurs in childhood and is rarely found before age 30 years. The onset is usually between the ages of 30-65 years, but the disease has been reported in women as young as 22 years and as old as 93 years.\nIn primary sclerosing cholangitis (PSC), several factors suggest a high risk of death. These include advancing age, serum bilirubin, serum albumin, presence or absence of inflammatory bowel disease, and histologic stage on liver biopsy.\nMorbidity/mortality\nGallstones are a rare cause of mortality, accounting for 5000 of the 2.2 million deaths annually in the United States.\nPrimary biliary cholangitis (PBC) accounts for 0.6%-2% of deaths from cirrhosis worldwide. The median time of patient survival was 9.3 years from diagnosis. Independent predictors of survival include age and serum levels of alkaline phosphatase, albumin, and bilirubin. Liver failure develops in 26% of patients by 10 years after diagnosis. Neither the presence of antimitochondrial antibodies nor their titer affects disease progression or survival.\nPSC is a leading reason for liver transplantation. Median survival without liver transplantation after diagnosis is approximately 12 years. Variables that appear to predict prognosis in PSC include age, histologic stage, hepatomegaly, splenomegaly, and serum alkaline phosphatase and serum bilirubin levels.\nThe complications common to all of the chronic cholestatic liver diseases, such as PSC and PBC, include fatigue, pruritus, steatorrhea, fat-soluble vitamin deficiencies (A, D, E, and K), metabolic bone disease, hypercholesterolemia, xanthomas, hypothyroidism, and anemia. There is a reported association of PBC with Sjögren syndrome, Raynaud phenomenon, and sicca symptoms.\nApproximately 20% of patients with PSC develop a dominant stricture in the intrahepatic or extrahepatic biliary tree. Medical therapy to treat biliary strictures has been ineffective. Nonsurgical modalities to relieve biliary obstruction, such as endoscopically- or radiologically–guided balloon dilation of strictures or placement of prosthetic stents across strictures, should be attempted initially.\nCholedocholithiasis and cholelithiasis due to cholesterol and/or pigment stones may be present in up to one third of patients with PSC. Bacterial cholangitis can occur in patients with PSC.\nCholangiocarcinoma eventually develops in about 20% of patients with PSC, principally late in the course of long-standing ulcerative colitis and the cirrhotic stage of biliary disease. About half of patients with PSC are diagnosed with cholangiocarcinoma within 2 years of the initial diagnosis, with an associated poor prognosis owing to advanced disease at the time of diagnosis. [12] This complication is difficult to detect, as evidenced by the finding of cholangiocarcinoma in 10% of patients undergoing liver transplantation for PSC. [13]\nThe incidence of hepatocellular carcinoma is increased in patients with PBC who have had stage IV disease for many years. [14]\nPatients with both PSC and ulcerative colitis have an increased risk of colon cancer and progression of neoplastic transformation.\nChaouloff F, Jeanrenaud B. Hyperinsulinemia of the genetically obese (fa/fa) rat is decreased by a low dose of the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). Eur J Pharmacol. 1988 Feb 16. 147(1):111-8. [Medline].\nRebholz C, Krawczyk M, Lammert F. Genetics of gallstone disease. Eur J Clin Invest. 2018 Apr 10. e12935. [Medline].\nYun EJ, Choi CS, Yoon DY, et al. Combination of magnetic resonance cholangiopancreatography and computed tomography for preoperative diagnosis of the Mirizzi syndrome. J Comput Assist Tomogr. 2009 Jul-Aug. 33(4):636-40. [Medline].\nReynolds BM, Dargan EL. Acute obstructive cholangitis; a distinct clinical syndrome. Ann Surg. 1959 Aug. 150(2):299-303. [Medline]. 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[Medline].\nHarnois DM, Lindor KD. Primary sclerosing cholangitis: evolving concepts in diagnosis and treatment. Dig Dis. 1997 Jan-Apr. 15(1-2):23-41. [Medline].\nHendrickse MT, Rigney E, Giaffer MH, et al. Low-dose methotrexate is ineffective in primary biliary cirrhosis: long-term results of a placebo-controlled trial. Gastroenterology. 1999 Aug. 117(2):400-7. [Medline].\nHolzbach RT. Recent progress in understanding cholesterol crystal nucleation as a precursor to human gallstone formation. Hepatology. 1986 Nov-Dec. 6(6):1403-6. [Medline].\nIzumi Y, Teramoto K, Ohshima M. Endoscopic resection of duodenal ampulla with a transparent plastic cap. Surgery. 1998 Jan. 123(1):109-10. [Medline].\nJones DE, Gray JC, Newton J. Perceived fatigue is comparable between different disease groups. QJM. 2009 Sep. 102(9):617-24. [Medline].\nKaplan MM. Primary biliary cirrhosis. N Engl J Med. 1996 Nov 21. 335(21):1570-80. [Medline].\nKrishnamurthy GT, Turner FE. Pharmacokinetics and clinical application of technetium 99m-labeled hepatobiliary agents. Semin Nucl Med. 1990 Apr. 20(2):130-49. [Medline].\nLam SK, Wong KP, Chan PK. Recurrent pyogenic cholangitis: a study by endoscopic retrograde cholangiography. Gastroenterology. 1978 Jun. 74(6):1196-1203. [Medline].\nLevy PF, Smith BF, LaMont JT. Human gallbladder mucin accelerates nucleation of cholesterol in artificial bile. Gastroenterology. 1984 Aug. 87(2):270-5. [Medline].\nLiermann Garcia RF, Evangelista Garcia C, McMaster P. Transplantation for primary biliary cirrhosis: retrospective analysis of 400 patients in a single center. Hepatology. 2001 Jan. 33(1):22-7. [Medline].\nLim JH. Oriental cholangiohepatitis: pathologic, clinical, and radiologic features. Am J Roentgenol. 1991 Jul. 157(1):1-8. [Medline].\nMazer NA, Carey MC. Quasi-elastic light-scattering studies of aqueous biliary lipid systems. Cholesterol solubilization and precipitation in model bile solutions. Biochemistry. 1983 Jan 18. 22(2):426-42. [Medline].\nMoody FG. Pathogenesis and treatment of inflammatory lesions of the papilla of Vater. Jpn J Surg. 1985 Sep. 15(5):341-7. [Medline].\nNijhawan PK, Therneau TM, Dickson ER, Boynton J, Lindor KD. Incidence of cancer in primary biliary cirrhosis: the Mayo experience. Hepatology. 1999 May. 29(5):1396-8. [Medline].\nO'Connor MJ, Schwartz ML, McQuarrie DG, Sumer HW. Acute bacterial cholangitis: an analysis of clinical manifestation. Arch Surg. 1982 Apr. 117(4):437-41. [Medline].\nO'Connor MJ, Sumner HW, Schwartz ML. The clinical and pathologic correlations in mechanical biliary obstruction and acute cholangitis. Ann Surg. 1982 Apr. 195(4):419-23. [Medline].\nPalazzo L, Girollet PP, Salmeron M. Value of endoscopic ultrasonography in the diagnosis of common bile duct stones: comparison with surgical exploration and ERCP. Gastrointest Endosc. 1995 Sep. 42(3):225-31. [Medline].\nPomeranz IS, Shaffer EA. Abnormal gallbladder emptying in a subgroup of patients with gallstones. Gastroenterology. 1985. 88:801. [Medline].\nQuirk DM, Rattner DW, Fernandez-del Castillo C. The use of endoscopic ultrasonography to reduce the cost of treating ampullary tumors. Gastrointest Endosc. 1997 Oct. 46(4):334-7. [Medline].\nRansohoff DF, Gracie WA, Wolfenson LB. Prophylactic cholecystectomy or expectant management for silent gallstones. A decision analysis to assess survival. Ann Intern Med. 1983 Aug. 99(2):199-204. [Medline].\nRos E, Zambon D. Postcholecystectomy symptoms. A prospective study of gall stone patients before and two years after surgery. Gut. 1987 Nov. 28(11):1500-4. [Medline].\nRuffolo TA, Sherman S, Lehman GA. Gallbladder ejection fraction and its relationship to sphincter of Oddi dysfunction. Dig Dis Sci. 1994 Feb. 39(2):289-92. [Medline].\nSampliner RE, Bennett PH, Comess LJ. Gallbladder disease in Pima Indians. Demonstration of high prevalence and early onset by cholecystography. N Engl J Med. 1970 Dec 17. 283(25):1358-64. [Medline].\nSchoenfield LJ, Carey MC, Marks JW. Gallstones: an update. Am J Gastroenterol. 1989 Sep. 84(9):999-1007. [Medline].\nSievers MS, Marquis JR. The Southwest American Indian's burden: biliary disease. JAMA. 1962. 182:570-2.\nStrauch GO. Primary carcinoma of the gall bladder: presentation of seventy cases from the Rhode Island Hospital and a cumulative review of the last ten years of the American literature. Surgery. 1960 Mar. 47:368-83. [Medline].\nStrom BL, Soloway RD, Rios-Dalenz JL, et al. Risk factors for gallbladder cancer. An international collaborative case-control study. Cancer. 1995 Nov 15. 76(10):1747-56. [Medline].\nThistle JL, Cleary PA, Lachin JM, Tyor MP, Hersh T. The natural history of cholelithiasis: the National Cooperative Gallstone Study. Ann Intern Med. 1984 Aug. 101(2):171-5. [Medline].\nWienser RH, Porayko MK, LaRusso NF, et al. In: Schiff L, Schiff ER, eds. Diseases of the Liver. 7th ed. Philadelphia, Pa: JB Lippincott; 1993: 411-26.\nWolfhagen FH, Sternieri E, Hop WC. Oral naltrexone treatment for cholestatic pruritus: a double-blind, placebo-controlled study. Gastroenterology. 1997 Oct. 113(4):1264-9. [Medline].\nYap L, Wycherley AG, Morphett AD. Acalculous biliary pain: cholecystectomy alleviates symptoms in patients with abnormal cholescintigraphy. Gastroenterology. 1991 Sep. 101(3):786-93. [Medline].\nYoshida J, Chijuwa K. Practical classification of the branching types of the biliary tree: an analysis of 1094 consecutive direct cholangiograms. J Am Coll Surg. 1997. 185:274-82. [Medline].\nZeman RK. Cholelithiasis and cholecystitis. In: Gore RM, Levine MS, Laufer I, eds. Text of Gastrointestinal Radiology. Philadelphia, Pa: WB Saunders.; WB Saunders. 1994: 1654-5.\nBiliary disease. Common bile duct stones are among the most frequent problems occurring in the biliary system. In this cholangiogram, the stones line up like peas in a pod.\nBiliary disease. After a biliary sphincterotomy, a balloon-tipped catheter is used to remove the stones one by one.\nBiliary disease. This clearing cholangiogram shows a common bile duct free of filling defects and good flow into the duodenum. The stones are visible as filling defects in the duodenal bulb.\nBiliary disease. A patient with pancreatic cancer developed jaundice during his treatment. The cholangiogram shows a stricture in the distal common bile duct.\nBiliary disease. A patient with pancreatic cancer developed jaundice during his treatment (same patient as in previous image). To palliate the jaundice, the biliary stricture is dilated and stented with a 10F plastic stent. Note the contrast dye flowing down the stent.\nBiliary disease. This computed tomography scan of the abdomen shows a large tumor mass in the head of the pancreas. The brightly colored object within the mass is the biliary stent placed by endoscopic retrograde cholangiopancreatography.\nBiliary disease. This abdominal computed tomography scan shows mild intrahepatic biliary ductal dilatation.\nBiliary disease. Abdominal computed tomography scanning in a patient with jaundice revealed polycystic liver disease.\nBiliary disease. Findings on this endoscopic retrograde cholangiopancreatogram exclude extrahepatic biliary obstruction but demonstrate that the intrahepatic biliary ductal system is splayed by multiple hepatic cysts.\nBiliary disease. This cholangiogram shows a choledochal cyst. Fusiform dilatation of the entire extrahepatic bile duct is present.\nA 92-year-old woman had recurrent abdominal pain and jaundice. A right upper quadrant ultrasonogram showed a dilated biliary duct with no stones. She had a previous Roux-en-Y surgery that made endoscopic retrograde cholangiopancreatography impossible. Critical aortic stenosis increased the risk of most interventions. This percutaneous cholangiogram, performed under conscious sedation in the operating room, revealed a large stone missed by the ultrasonogram. It was removed successfully with percutaneous choledochoscopy and electrohydraulic lithotripsy.\nBiliary disease. This cholangiogram shows a stone too large to deliver through a standard biliary sphincterotomy.\nBiliary disease. Here, a mechanical lithotripter is used to grab a stone too large to deliver through a standard biliary sphincterotomy and crush it into small pieces (same patient as in previous image). The smaller pieces then are removed with a balloon-tipped catheter.\nBiliary disease. A patient had malignant strictures of the biliary system palliated with metal mesh stents. Unfortunately, the tumor grew through the metal mesh to reobstruct the biliary system.\nBiliary disease. A patient had malignant strictures of the biliary system that were palliated with metal mesh stents, but the tumor grew through the metal mesh to reobstruct the biliary system (same patient as in previous image). In this image, after a wire was passed through the lumen, a balloon-dilating catheter was passed into the metal mesh stents and inflated to enlarge the lumen.\nBiliary disease. A patient had malignant strictures of the biliary system that were palliated with metal mesh stents, but the tumor grew through the metal mesh to reobstruct the biliary system (same patient as in previous image). After a wire was passed through the lumen, a balloon-dilating catheter was passed into the metal mesh stents and inflated to enlarge the lumen. In this image, two plastic stents were passed into the intrahepatic ductal system to again palliate the obstruction.\nAnnie T Chemmanur, MD Attending Physician, Metrowest Medical Center and University of Massachusetts Memorial Hospital, Marlborough Campus\nAnnie T Chemmanur, MD is a member of the following medical societies: American College of Physicians-American Society of Internal Medicine, American Gastroenterological Association, American Medical Association, Massachusetts Medical Society\nJeanette G Smith, MD Fellow, Department of Gastroenterology-Hepatology, University of Connecticut School of Medicine\nJeanette G Smith, MD is a member of the following medical societies: American College of Physicians, American Gastroenterological Association, American Public Health Association\nGeorge Y Wu, MD, PhD Professor, Department of Medicine, Director, Hepatology Section, Herman Lopata Chair in Hepatitis Research, University of Connecticut School of Medicine\nGeorge Y Wu, MD, PhD is a member of the following medical societies: American Association for the Study of Liver Diseases, American Gastroenterological Association, American Medical Association, American Society for Clinical Investigation, Association of American Physicians\nBS Anand, MD Professor, Department of Internal Medicine, Division of Gastroenterology, Baylor College of Medicine\nBS Anand, MD is a member of the following medical societies: American Association for the Study of Liver Diseases, American College of Gastroenterology, American Gastroenterological Association, American Society for Gastrointestinal Endoscopy\nRonnie Fass, MD, FACP, FACG Chief of Gastroenterology, Head of Neuroenteric Clinical Research Group, Southern Arizona Veterans Affairs Health Care System; Professor of Medicine, Division of Gastroenterology, University of Arizona School of Medicine\nRonnie Fass, MD, FACP, FACG is a member of the following medical societies: American College of Gastroenterology, American College of Physicians-American Society of Internal Medicine, American Gastroenterological Association, American Neurogastroenterology and Motility Society, American Society for Gastrointestinal Endoscopy, Israeli Medical Association\nDisclosure: Received grant/research funds from Takeda Pharmaceuticals for conducting research; Received consulting fee from Takeda Pharmaceuticals for consulting; Received honoraria from Takeda Pharmaceuticals for speaking and teaching; Received consulting fee from Vecta for consulting; Received consulting fee from XenoPort for consulting; Received honoraria from Eisai for speaking and teaching; Received grant/research funds from Wyeth Pharmaceuticals for conducting research; Received grant/research funds f.\nThe authors and editors of Medscape Drugs & Diseases gratefully acknowledge the contributions of previous author Paul Yakshe, MD, to the development and writing of this article.\nencoded search term (Biliary Disease) and Biliary Disease\nBedside Ultrasonography for Gallbladder Disease\nPediatric Gallbladder Disease Surgery\nLiver Disease and Pregnancy\nPediatric Gallstones (Cholelithiasis)\nAcalculous Cholecystopathy\nAcute Cholecystitis and Biliary Colic\nSurgical Management of Cholecystocholedocholithiasis: 1 or 2 Steps?\nGastroenterology Clinical Practice Guidelines - 2019 Year in Review\nLess Abdominal Surgery Post Sleeve Gastrectomy vs Gastric Bypass\nAppendicitis: Avoiding Pitfalls in Diagnosis\nAccording to Gastroenterologists\n5 Liver-Saving Strategies for the New Year\nFrom Licorice to Slippery Elm: What Works for GI Symptoms?\nWill Smith's Colonoscopy Goes Viral, Sends Message\nInflammatory Bowel Disease Clinical Practice Guidelines (2019)\nProton Pump Inhibitors: Placing Putative Adverse Effects in Proper Perspective\nDiseases & Conditions Biliary Disease\n2010 actigall-urso-forte-ursodiol-342072 Drugs\nDrugs ursodiol\n2001 http://www.medscape.com/resource/gallbladder-biliary-disease\nGallbladder and Biliary Disease\n2002 104439-overview Procedures\nProcedures Bedside Ultrasonography for Gallbladder Disease"

ERROR: type should be string, got "https://profreg.medscape.com/px/getpracticeprofile.do?method=getProfessionalProfile&urlCache=aHR0cHM6Ly9lbWVkaWNpbmUubWVkc2NhcGUuY29tL2FydGljbGUvMjAyMTU4LWd1aWRlbGluZXM=\nDrugs & Diseases > Hematology\nImmune Thrombocytopenia (ITP) Guidelines\nAuthor: Craig M Kessler, MD, MACP; Chief Editor: Srikanth Nagalla, MBBS, MS, FACP more...\nImmune Thrombocytopenia (ITP)\nSections Immune Thrombocytopenia (ITP)\nHistologic Findings\nBone Marrow Examination\nAmerican Society of Hematology Guidelines\nInternational Consensus Report Guidelines - Adults\nInternational Consensus Report Guidelines - Pregnancy and Neonatal\nInternational Consensus Report Guidelines - Pediatric\nImmunosuppressive Antimetabolites\nSynthetic Antineoplastic Drugs\nThrombopoietic Agents\nSYK Inhibitors\nIn 2019, the American Society of Hematology (ASH) published an update to its 2011 evidence-based practice guideline for immune thrombocytopenia (ITP). The 2019 guideline comprises strong recommendations and conditional recommendations/suggestions. Recommendations and suggestions are provided separately for pediatric and adult patients. Some of the 2011 recommendations remain unchanged and were not included in the 2019 review and update. [8] In 2013, ASH issued a clinical practice guide on the treatment of thrombocytopenia in pregnancy, based in part on the 2011 guideline. [18, 42]\nIn 2019, an international group of experts published an International Consensus Report on the investigation and management of primary immune thrombocytopenia, covering adult, pediatric, obstetric, neonatal, and emergency management. The report updates an earlier guideline published in 2010. [40]\nPediatric ITP\nASH recommendations are that bone marrow examination is not necessary in children and adolescents with the typical features of ITP, or in children in whom intravenous immunoglobulin (IVIG) therapy fails. ASH suggests that bone marrow examination is not necessary in similar patients before initiation of treatment with corticosteroids or before splenectomy, and that testing for antinuclear antibodies is not necessary in the evaluation of children and adolescents with suspected ITP. [42]\nASH has moved away from recommending treatment on the basis of the platelet count. The 2019 ASH guidelines recommend that children with no bleeding or mild bleeding (ie, skin manifestations only, such as bruising and petechiae) be managed with observation alone regardless of platelet count. [8]\nASH suggestions include the following for children with non–life-threatening mucosal bleeding and/or diminished health-related quality of life (HRQoL) [8] :\nA short course of corticosteroids over anti-D immunoglobulin or IVIG for first-line treatment\nThrombopoietin receptor agonists (TPO-RAs) over rituximab or splenectomy for second-line treatment\nRituximab over splenectomy for second-line treatment\nAdult ITP\nASH recommends testing adult patients with ITP for hepatitis C virus and HIV. ASH suggests further investigations if the blood count or peripheral blood smear reveals abnormalities other than thrombocytopenia and perhaps findings of iron deficiency. ASH suggests that a bone marrow examination is not necessary irrespective of age in patients presenting with typical ITP. [42]\nThe 2019 ASH guidelines recommend against treatment of patients with a platelet count ≥30×109/L. For newly diagnosed adult patients with a platelet count < 30×109/L, the guidelines suggest treatment with corticosterioids. For adults with a platelet count < 20×109/L who are asymptomatic or have minor mucocutaneous bleeding, the guidelines suggest hospital admission for newly diagnosed patients but outpatient treatment for those with an established diagnosis of ITP. [8]\nFor first-line treatment, the guidelines recommend a short course (≤6 weeks) of steroids over a prolonged course (> 6 weeks, including treatment and taper). Additional first-line treatment suggestions include the following [8] :\nEither prednisone (0.5-2.0 mg/kg per day) or dexamethasone (40 mg per day for 4 days) as the type of corticosteroid\nCorticosteroids alone rather than rituximab and corticosteroids\nThe following 2011 ASH treatment suggestions remain unchanged [42] :\nIVIG may be used with corticosteroids when a more rapid increase in platelet count is required\nEither IVIG or anti-D (in appropriate patients) may be used if corticosteroids are contraindicated\nIf used, IVIG should be administered in a single dose of 1 g/kg; the dose may be repeated if necessary\nFor adults with ITP for ≥3 months who are corticosteroid dependent or unresponsive to corticosteroids, the 2019 second-line treatment suggestions include the following, in order of preference [8] :\nA TPO-RA (either eltrombopag or romiplostim)\nThe 2011 recommendation that for medically suitable patients, laparoscopic and open splenectomy offer similar efficacy, also remains unchanged. [8]\nASH recommends the following tests for thrombocytopenia in pregnant patients [18] :\nViral screening (HIV, HCV, HBV)\nTests to consider if clinically indicated include the following:\nAntinuclear antibody (ANA)\nHelicobacter pylori testing\nDisseminated intravascular coagulation testing—prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen, fibrin split products\nVon Willebrand disease type IIB testing*\nDirect antiglobulin (Coombs) test\nQuantitative immunoglobulin levels\nThe following studies are not recommended:\nAntiplatelet antibody testing\nThrombopoeitin (TPO) levels\nTreatment considerations include the following:\nWomen with no bleeding manifestations and platelet counts ≥30×10 9/L do not require any treatment until 36 weeks’ gestation (sooner if delivery is imminent).\nIf platelet counts are < 30×10 9/L or clinically relevant bleeding is present, first-line therapy is oral corticosteroids or intravenous immunoglobulin (IVIG).\nThe recommended starting dose of IVIG is 1 g/kg.\nPrednisone and prednisolone are preferred to dexamethasone, which crosses the placenta more readily.\nRecommended starting doses of prednisone by different experts vary from 0.25 to 0.5 to 1 mg/kg daily; no evidence exists that a higher starting dose is better.\nMedications should be adjusted to maintain a safe platelet count.\nExpected responses to first-line therapy are as follows:\nOral corticosteroids—initial response 2-14 days, peak response 4-28 days\nIVIG—initial response 1-3 days, peak response 2-7 days\nSecond-line therapy for refractory ITP is with combined corticosteroids and IVIG or, in the second trimester, splenectomy. For third-line therapy, anti-D immunoglobulin and azathioprine are relatively contraindicated. Agents that are not recommended, but whose use in pregnancy has been described, include the following:\nThrombopoietin receptor agonists\nAlemtuzumab\nContraindicated agents include the following:\nVinca alkaloids\nManagement at the time of delivery\nASH recommendations are as follows:\nBecause of the possible need for cesarean delivery, the recommended target platelet count prior to labor and delivery is ≥50×10 9/L.\nA woman whose platelet count is < 8010 9/L but who has not required therapy during pregnancy can be started on oral prednisone (or prednisolone) 10 days prior to anticipated delivery at a dose of 10-20 mg daily and titrated as necessary.\nThe mode of delivery should be determined by obstetric indications.\nAlthough the minimum platelet count for the placement of regional anesthesia is unknown and local practices may differ, many anesthesiologists will place a regional anesthetic if the platelet count is ≥80×10 9/L.\nWhile platelet transfusion alone is generally not effective in ITP, its use in conjunction with IVIG can be considered if an adequate platelet count has not been achieved and delivery is emergent.\nPercutaneous umbilical blood sampling (PUBS) or fetal scalp blood sampling is not recommended, as it is not helpful in predicting neonatal thrombocytopenia and is potentially harmful.\nIn the newborn, the platelet count reaches its nadir 2-5 days after delivery and rises spontaneously by day 7.\nPostpartum thromboprophylaxis should be considered, as women with ITP are at increased risk of venous thromboembolism.\nBasic evaluation in all patients should consist of the following [40] :\nCBC and reticulocyte count\nPeripheral blood film\nQuantitative Ig level measurement\nBlood group (Rh)\nHIV serology - Recommended by the majority of the panel for adult patients in the appropriate geographic setting\nHepatitis C virus serology - Recommended by the majority of the panel for adult patients in the appropriate geographic setting\nHepatitis B virus serology\nTests of potential utility in patients with ITP include the following:\nGlycoprotein-specific antibody (can be used in difficult cases, but has poor sensitivity and is not a primary diagnostic test)\nAntiphospholipid antibodies (including anti-cardiolipin and lupus anticoagulant) if there are clinical features of antiphospholipid syndrome\nAnti-thyroid antibodies and thyroid function\nPregnancy test in women of childbearing potential\nAntinuclear antibodies (ANA) – A positive ANA may be a predictor of chronicity; hydroxychloroquine may be an effective treatment if ANAs are present, especially in young women; ANA testing can be considered before splenectomy because of the increased risk for thrombosis\nPolymerase chain reaction (PCR) testing for Epstein-Barr virus, cytomegalovirus, and parvovirus\nBone marrow examination (may be informative in patients with systemic symptoms, abnormal signs, or with suspicion of a different diagnosis)\nDirect antiglobulin test Helicobacter pylori testing (should be considered in adults with typical ITP, in those with digestive symptoms, and those from areas of high prevalence)\nThe following tests have no proven role in the differential diagnosis of ITP from other thrombocytopenias and do not guide patient management:\nThrombopoietin level\nReticulated platelets/immature platelet fraction\nBleeding time\nSerum complement\nRecommendations for initial treatment of newly diagnosed patients are as follows:\nCorticosteroids are the standard initial treatment for adults with ITP who need treatment and do not have a relative contradiction: prednisone or prednisolone at 1 mg/kg (maximum dose 80 mg, even in patients weighing >80 kg) for 2 weeks, to a maximum of 3 weeks; or dexamethasone 40 mg/d for 4 days, repeated up to 3 times\nIf a response is seen (eg, platelets > 50 × 10 9/L), taper the prednisone/prednisolone, aiming for discontinuation by 6 weeks (maximum 8 weeks), even if the platelet count drops during the taper.\nIf there is no response to the initial dose within 2 weeks, taper the prednisone/prednisolone rapidly over 1 week and discontinue.\nLonger courses of steroids should be avoided, although occasional patients may benefit from continuous low-dose corticosteroids (eg, ≤5 mg/d).\nUse of IVIG (1 g/kg on 1 or 2 consecutive days or 0.4 g/kg per day for 5 days), or IV anti-D (50-75 µg/kg once) where available, may be appropriate in patients with bleeding, at high risk for bleeding, who require a surgical procedure, or who are unresponsive to prednisone/prednisolone. If using anti-D, exercise consideration over potential triggering of disseminated intravascular coagulation (DIC) or hemolysis, and consider steroid premedication to minimize acute infusion reactions (eg, headaches, fever-chills, and/or intravascular hemolysis).\nPatients with contraindications to high-dose corticosteroid therapy (eg, insulin-dependent diabetes, uncontrolled diabetes, psychiatric disorders, active infection) may be managed with only IVIZG or IV anti-D as initial therapy.\nTPO receptor agonists (TPO-RAs) and rituximab are not considered initial therapies.\nFor subsequent therapy, medications with robust evidence of efficacy are as follows:\nTPO-RAs: eltrombopag, avatrombopag, romiplostim\nFostamatinib\nMedical therapies with less robust evidence are as follows:\nSwitching from one TPO-RA to another\n​Consensus-based recommendations for target platelet counts (× 109/L) for dental procedures in adults are as follows:\nDental prophylaxis (descaling, deep cleaning): ≥20 to 30\nSimple extractions: ≥30\nComplex extractions: ≥50\nRegional dental block: ≥30\nConsensus-based recommendations for target platelet counts (× 109/L) for surgery in adults are as follows:\nMinor surgery: ≥50\nMajor surgery: ≥80\nMajor neurosurgery: ≥100\nTreatment of life-threatening bleeding:\nIn emergency situations in which there is an urgent need to increase the platelet count within 24 hours, a combination of initial treatments, including IV corticosteroids and, usually, IVIG, should be used. Platelet transfusions may be helpful and must not be postponed in cases of life-threatening bleeding, especially intracranial hemorrhage (ICH).\nIn the case of life-threatening bleeding and the absence of a significant response to IVIG and platelet transfusion in a patient on corticosteroids, consider use of a TPO-RA.\nAdditional options may include IV anti-D; vincristine or vinblastine; antifibrinolytics in combination with other initial therapies; and, rarely, emergency splenectomy.\nSurgical therapy for persistent and chronic ITP:\nSplenectomy is associated with long-term treatment-free remissions. However, deferring splenectomy for ≥12 to 24 months from diagnosis before performing splenectomy is recommended because of the chance of remission or stabilization of the platelet count at a hemostatic level; up to one third of patients may remit in 1 year, and up to 80% may remit in 5 years.\nWhen available, indium-labeled autologous platelet scanning may be useful prior to splenectomy to confirm that the spleen is the main site of platelet sequestration.\nLaparoscopic splenectomy is as effective as open splenectomy in terms of response and is more comfortable for the patient.\nPostoperative thromboprophylaxis should be considered in patients undergoing splenectomy as long as the platelet count is > 30 to 50 × 10 9/L.\nSplenectomy should be performed by a surgeon experienced in identifying accessory splenic tissue, which is common and should be removed.\nAppropriate vaccination against Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae must be provided ≥2 weeks before splenectomy and maintained according to national guidelines; recent treatment (within 6 months) with rituximab may impair vaccination efficacy.\nPatients should be informed of the long-term risks of splenectomy (ie, increased rates of thrombosis, infection, and cancer) and educated to follow advice aimed at mitigating these complications.\nAntibiotic prophylaxis should be given as per national guidelines.\nApproach when multiple treatments have failed:\nReconsider the diagnosis\nPerform bone marrow examination if not already done\nReassess the need for treatment (consider platelet count/bleeding risk)\nConsider referral to an ITP treatment center\nReassess the adequacy of prior therapies (eg, was the full dose of TPO-RA explored? Did the addition of a small dose of corticosteroid improve response?)\nAssess the risks and benefits of further treatment\nReassess the possibility of splenectomy if not already performed\nConsider other medical therapies if not already attempted (eg, MMF, fostamatinib, rituximab, azathioprine, dapsone, danazol)\nConsider enrollment in a clinical trial\nIn patients who relapse >1 year after responding to splenectomy, an accessory spleen should be searched for and, if found, resected.\nSwitching from one TPO-RA to another and sequential therapy have been shown to have a positive effect on response and adverse effects.\nOther therapies that have been used as last resorts include combination chemotherapy, alemtuzumab, and hematopoietic stem cell transplantation (HSCT). The side effects of these treatment options may be severe, and the data supporting their use are limited.\nAssessment and management of health-related quality of life outcomes\nThe 10-scale ITP-patient assessment questionnaire (ITP-PAQ) is an ITP-specific questionnaire that can be used to measure HRQoL, with estimated minimally important differences (MIDs) aiding interpretation. Additional measures of patient-reported outcomes (PROs) that have been studied in adult patients with ITP include the following:\n36-item Short Form Health Survey (SF-36)\nEuroQol tool (EQ-5D)\nHamilton anxiety and expression rating scales\nMotivation and energy inventory-short form (MEI-SF)\nFatigue subscale of the functional assessment of chronic illness therapy (FACIT-Fatigue)\nFunctional assessment of cancer therapy–thrombocytopenia (FACT-Th6)\nImpaired HRQoL is multifactorial and includes (but is not limited to) issues around actual bleeding, fear of bleeding, reduced energy, depression, treatment side effects, and additive influences of underlying or comorbid diseases. Patients who respond to treatment have improved HRQoL, with those who respond to TPO-RA improving more than those who respond to other therapies; in particular, romiplostim may improve fatigue.\nOther HRQoL recommendations are as follows:\nParticipation in high-risk activities (eg, BMX racing, boxing, American football, ice hockey, lacrosse, motorcycle riding, motocross racing, power lifting, outdoor rock climbing, rodeo, rugby, snowmobiling, trampoline, wrestling) should be discouraged unless the patient has a near-normal platelet count on a consistent and stable basis. Alternatively, treatment should be administered to provide a safe platelet count during the activity.\nIntermittent or continuous treatment may be given to cover activities with appropriate discussion of risks vs benefits of the activity and treatment, with emphasis on psychological well-being and risks for injury, despite treatment.\nChoice of treatment and target platelet count must be carefully evaluated and based on extensive consultation and consideration of the specific activity desired and the bleeding tendency.\nDiagnosis of ITP in pregnancy\nRecommendations for investigation of suspected ITP in pregnancy include the following [40] :\nPatients with a history suggestive of ITP or those with a platelet count < 80 × 10 9/L should be investigated for possible ITP (Grade C recommendation).\nAs in nonpregnant patients, the diagnosis of ITP is one of exclusion using the patient’s history, physical examination, blood counts, and blood smear examination.\nLaboratory evaluation is similar to the nonpregnant patient, but special consideration should be given to rule out hypertensive, microangiopathic, coagulopathic, and hepatic disorders associated with pregnancy. Recommended tests should be based on the clinical features and may include review of the blood smear, reticulocyte count, coagulation screen, liver function, thyroid function, ANAs, and antiphospholipid antibodies.\nBone marrow examination is not recommended unless atypical features are present.\nAnti-platelet antibody testing does not predict the course of maternal or neonatal thrombocytopenia or distinguish ITP from gestational thrombocytopenia and is not recommended.\nTesting of TPO levels is not recommended.\nTreatment of ITP in pregnancy\nRecommendations for the treatment of ITP during pregnancy include the following [40] :\nA platelet count of 20 to 30 × 10 9/L in a nonbleeding patient is safe for most of pregnancy. A platelet count ≥50 × 10 9/L is preferred for delivery.\nInitial treatment is with oral steroids or IVIG.\nIn Rh(D)-positive nonsplenectomized women, IV anti-D appears to be well tolerated and effective; however, it may potentially cause maternal or fetal hemolysis.\nIVIG can provide a rapid, but often very transient, increase in platelet count and can be used to urgently increase platelet counts during bleeding or for delivery.\nCombining therapies (prednisone with IVIg and/or IV anti-D) may elicit a response in patients refractory to single agents alone (Grade C recommendation). High-dose methylprednisolone, in combination with IVIg and/or azathioprine, is suggested for patients refractory to oral corticosteroids or IVIg alone (Grade C recommendation).\nRituximab can be considered in pregnancy for very severe cases, but perinatal and neonatal immunosuppression and subsequent infection are potential complications and require monitoring.\nTPO-RAs may be considered in late pregnancy when other treatments have failed, but published information is limited.\nIn the rare instances when splenectomy is required, it should be performed in the second trimester.\nVinca alkaloids, danazol, and immunosuppressive drugs not listed in these recommendations should be avoided in pregnancy.\nRecommendations for obstetric analgesia and anesthesia\nRecommendations for obstetric analgesia and anesthesia in women with ITP include the following [40] ​:\nAt a platelet count ≥70 × 10 9/L, in the absence of other hemostatic abnormalities, regional axial anesthesia can be safely performed.\nNonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided for postpartum or postoperative analgesia in women with platelet counts < 70 × 10 9/L because of increased hemorrhagic risk.\nA platelet count ≥50 × 10 9/L should be obtained for delivery.\nAll women, despite having ITP, who are at an increased risk for thromboembolism should receive appropriate prophylaxis for venous thromboembolism.\nThe mother with a rapidly falling platelet count should be observed more closely than those with low, but stable, levels.\nRecommendations for management of delivery and newborn infants\nRecommendations for delivery of women with ITP include the following [40] ​:\nCordocentesis and fetal scalp blood sampling should be avoided in the management of the fetus/neonate of a mother with ITP in pregnancy.\nNeonatal alloimmune thrombocytopenia should be excluded by parental testing if the neonate presents with severe thrombocytopenia.\nThe mode of delivery should be determined by obstetric indications, not by anticipation of the neonatal platelet count.\nProcedures during labor that may be associated with increased hemorrhagic risk to the fetus should be avoided, specifically the use of fetal scalp electrodes, fetal blood sampling, ventouse delivery, and rotational forceps.\nPrevious splenectomy has been associated with worsening of maternal ITP in pregnancy and a higher risk for neonatal thrombocytopenia.\nA mother with a previous newborn, thrombocytopenic or not, is likely to have a second baby with a similar platelet count.\nRecommendations for management of neonates born to women with ITP\nRecommendations for the management of neonates born to women with ITP include the following [40] :\nObtain umbilical cord platelet count at the time of delivery or as soon as possible.\nRepeat the platelet count as needed depending on platelet levels, trends in the count, and response to treatment (if any). If cord platelet count is < 100 × 10 9/L, repeat the platelet count daily until stable. The incidence of pseudothrombocytopenia is high in neonates because of the difficulties encountered in obtaining unclotted blood with blood draws.\nIf platelet count is < 50 × 10 9/L at birth, perform a cranial ultrasound. A magnetic resonance imaging for confirmation or clarification can be performed without anesthesia using the sleep and swaddle approach 30 to 60 minutes prior.\nIn the case of ICH, give IVIG and limited steroids to maintain platelet count >100 × 10 9/L for 1 week if possible and >50 × 10 9/L for another week. The use of platelet transfusion may increase neonatal risk.\nIf there is symptomatic bleeding or if platelet count is < 30 × 10 9/L, with or without platelet transfusion, give IVIG.\nIf severe thrombocytopenia continues for >1 week in a breast-fed infant, consider pausing breastfeeding for a few days to see whether platelet count increases.\nWomen who had a splenectomy may have a thrombocytopenic newborn, even if their platelet count is normal.\nThe only currently reliable predictor of whether a baby will be thrombocytopenic is if a previous sibling was thrombocytopenic.\nRecommendations for initial investigation of suspected childhood ITP are as follows [40] :\nPerform a complete history, physical examination, full blood count, and expert analysis of the peripheral blood smear at initial diagnosis.\nA direct anti-globulin test (DAT) is recommended to exclude coexistent autoimmune hemolytic anemia, especially prior to therapy.\nBaseline Ig levels, to exclude coexisting immunodeficiency, is recommended prior to therapy.\nWhen a child's CBC shows isolated thrombocytopenia, the peripheral blood smear shows no abnormal features beyond thrombocytopenia, and signs of bleeding are present on physical examination, a bone marrow aspiration/biopsy is not required, even prior to steroid therapy.\nChildren with newly diagnosed ITP, especially with atypical features, should be referred to, or their case discussed with, a hematologist experienced in assessment and treatment of children with ITP.\nBone marrow aspiration, biopsy, and cytogenetics should be performed if abnormal or potentially malignant cells are visualized on smear and carefully considered if there are other abnormalities of the hemoglobin and/or white cell count (with the exception of microcytic anemia) or if there is hepatosplenomegaly and/or adenopathy. In addition, failure to acutely respond to ITP therapy merits a bone marrow examination.\nAdditional investigations are based on clinical assessment and may include tests insuch as molecular genetics, autoantibody screening, liver-spleen imaging, and other laboratory testing\nRecommendations for subsequent investigation of children with persistent or chronic ITP are as follows:\nPerform a repeat history, physical examination, full blood count, and expert analysis of the peripheral blood smear to reassess the diagnosis.\nPerform bone marrow aspiration, biopsy, and cytogenetics if no spontaneous platelet increase and no response to treatment has occurred after 3 to 6 months, or earlier if there is no response to treatment within the expected timeframe. Consider next-generation sequencing or targeted sequencing, if available.\nA bone marrow biopsy is not indicated prior to further therapy (eg, with TPO), but should be included in reevaluation of the diagnosis in the setting of increasingly difficult-to-treat persistent or chronic ITP.\nAdditional evaluation could include testing for the following:\nLupus and other markers of autoimmune diseases that might require specific treatment (eg, test for APLAs, ANAs, anti-cardiolipin antibody, lupus anticoagulant, and serum Igs)\nChronic infections (hepatitis, cytomegalovirus, HIV, and/or H pylori in at-risk populations or when there is no other explanation)\nComplex immunodeficiency diseases\nGenetic screening for inherited thrombocytopenia and bone marrow failure syndromes\nA bleeding scale for pediatric patients with ITP is shown in Table 1, below.\nTable 1. Bleeding scale for pediatric patients with ITP (Open Table in a new window)\nManagement approach\nGrade 1 (minor)\nMinor bleeding, few petechiae (≤100 total) and/or ≤5 small bruises (≤3 cm in diameter), no mucosal bleeding\nConsent for observation\nGrade 2 (mild)\nMild bleeding, many petechiae (>100 total) and/or >5 large bruises (>3 cm in diameter), no mucosal bleeding\nGrade 3 (moderate)\nModerate bleeding, overt mucosal bleeding, troublesome lifestyle\nIntervention to reach grade 1 or 2\nGrade 4 (severe)\nSevere bleeding, mucosal bleeding leading to decrease in Hb > 2 g/dL or suspected internal hemorrhage\nWatch-and-wait\nRecommendations for a watch-and-wait policy, based on clinical classification, are as follows:\nAt diagnosis, children and adolescents with ITP and mild or even moderate bleeding on a pediatric bleeding assessment tool (grade 1-3) may be managed expectantly with supportive advice and a 24-hour contact point, irrespective of platelet count\nThose with grade 3 bleeding are more likely to require therapy because of the higher rates of serious bleeding requiring hospital admission and emergency treatment.\nAll patients need regular reevaluation to monitor for worsening, including health-related quality of life (HRQoL) and evolution to a serious bone marrow disorder or a secondary form of ITP. The frequency of clinical and laboratory monitoring should be based on bleeding, HRQoL, trend in platelet counts, and impression of family reliability.\nThe same monitoring and 24-hour access are needed with persistent and chronic ITP, depending upon the factors listed above, but at less frequent intervals in a stable patient. Observation or watch-and-wait is less validated in patients with persistent and chronic ITP because it is based on the expectation of spontaneous future improvement.\nRecommendations for when to start initial treatment in children newly diagnosed with ITP are as follows:\nAny severe (grade 4) bleeding requires immediate hospital admission and treatment to increase platelet levels until bleeding has decreased.\nAny moderate (grade 3) bleeding requires hospital review and consideration for admission and therapy.\nAdminister treatment and strongly consider hospitalization in the following cases:\nWorsening bleeding or significant comorbidities\nRisk of ICH (eg, head trauma or unexplained headaches); patients at higher risk for ICH include those with a history of moderate or severe bleed in the preceding 28 days, recent administration (within 8 hours) of NSAIDs, and another clinically significant coagulopathy (eg, von Willebrand disease). In the case of head trauma, treatment should precede a head computed tomography scan.\nA change in behavior or mood consistent with significant depression or irritability\nParents are anxious about bleeding and do not believe that they can control (young child) or restrict (older child) their child’s activity.\nParents cannot be relied upon to bring the child back readily if there is an emergency (eg, they live too far away, they cannot afford to return, there are additional social concerns).\nChild has not spontaneously improved and must be overly restricted in activities.\nChild needs to take an anticoagulant or antiplatelet agent.\nHigher risk of bleeding due to another medical or psychological issue\nInitial treatment regimens:\nIf the patient has moderate or severe bleeding, IVIG and anti-D can often increase the platelet count to hemostatic levels (>50 × 10 9/L) within 24 to 48 hours. IVIGg is effective when given as a single dose of 0.8 to 1.0 g/kg. Anti-D has similar efficacy to IVIG when given as a single dose of 75 µg/kg and is rarely associated with severe hemolysis. High-dose steroid premedication is recommended for IV anti-D and is useful for IVIG.\nA second dose of IVIg or anti-D may be administered if there is a suboptimal initial response and/or ongoing bleeding.\nGive prednisone/prednisolone at 4 mg/kg per day in 3 or 4 divided doses for 4 days with no taper, with a maximum daily dose of 200 mg or at 1 to 2 mg/kg, with an 80-mg maximum daily dose, even in patients weighing >80 kg, for 1 to 2 weeks. If a response is seen (eg, platelets > 50 × 10 9/L), taper the prednisone/prednisolone, aiming to stop it by 3 weeks, even if the platelet count drops during the taper.\nIf there is no response to the initial dose within 2 weeks, taper the prednisone/prednisolone rapidly over 1 week and stop it.\nIn general, corticosteroids are used for grade 1 or 2 bleeding or for patients not responsive to IVIG.\nIV anti-D can be used if the patient is Rh positive, not splenectomized, does not have a positive direct Coombs test (DAT), and has hemoglobin ≥9 g/dL.\nEmergency treatment:\nCombination therapy, including platelet transfusions, IV corticosteroids, and IVIG, with or without anti-D, is recommended. Administer platelet transfusions as a bolus, followed by continuous infusion in combination with IV high-dose steroids (eg, IV methylprednisone/prednisolone, 30 mg/kg per day). For ICH or other life-threatening or serious bleeding, give IVIG (0.8-1.0 g/kg per day, with or without single-dose IV anti-D (75 µg/kg). A second dose of IVIG and IV steroids may be required if a platelet response is not seen within 24 hours of the initial dose.\nIVIG, steroids, and IV anti-D (if available) can be used to attempt to ensure the most likely and fastest platelet increase. Antifibrinolytics may be given if bleeding continues despite therapy.\nIn patients with an ICH, emergency splenectomy and/or neurosurgical control of bleeding should be considered in conjunction with emergency platelet-raising therapy, but medical treatment should never be delayed because of surgical or radiologic intervention if at all possible.\nTPO-RAs should be considered, as they may aid the acute response in patients and prevent a decrease in platelet count if initial response to emergency therapy is lost.\nTreatment of persistent or chronic ITP:\nMost children with persistent or chronic ITP can be managed with watchful waiting. If an acute bleeding episode occurs, rescue therapy with corticosteroids, IVIG, and/or IV anti-D can be used.\nChildren who are having frequent or severe bleeding episodes or impaired HRQoL (including reduction in important activities) require referral to a hematologist experienced in treating pediatric ITP.\nTPO-RAs often produce a good response and reduction in bleeding frequency, with an absence of adverse effects in the majority of patients. If the patient does not respond to a TPO-RA or loses response, switch to an alternative TPO-RA and/or consider combining with MMF or another immunosuppressant.\nConsider rituximab and dexamethasone for patients, especially adolescent girls, in whom TPO-RAs fail.\nSplenectomy:\nSplenectomy is very rarely indicated in childhood ITP, and should be undertaken in consultation with a hematologist experienced in the management of children with ITP. It should only be considered in children who have failed all available medical therapies, are having thrombocytopenia-related bleeding, and whose life is at risk or whose HRQoL is substantially impaired.\nSplenectomy should be avoided if at all possible before 5 years of age and within 1 year of disease onset.\nBefore considering splenectomy, reassess the diagnosis of ITP by excluding alternative diagnoses, including inherited thrombocytopenia, bone marrow failure, drug-induced thrombocytopenia, subclinical viral infections, immunodeficiency syndromes (eg, common variable immune deficiency [CVID], autoimmune lymphoproliferative syndrome), and myelodysplastic syndrome.\nPrior to splenectomy, ensure that vaccinations are up to date according to national policy. Vaccination, as a minimum, should include pneumococcal 13-valent conjugate vaccine, followed by pneumococcal 23-valent vaccine 4 weeks later; H influenzae type B; and both meningococcal vaccines to cover all 5 species subtypes.\nIf there is any concern for an immunodeficiency-related ITP, even if undocumented, reducing the risk for postsplenectomy sepsis by assessing response to pneumococcal vaccines preprocedure is advisable.\nHealth-related quality of life considerations:\nHRQoL should be reported using the Kid’s ITP Tool (KIT) or another validated scale before and after treatment, to assess the effect of treatment beyond the platelet count.\nCorticosteroids may worsen HRQoL in children with ITP; TPO-RAs may improve their HRQoL, and romiplostim especially appears to improve parental burden.\nSchool and participation in sporting activities:\nChildren and adolescents 5 to 18 years old need ≥60 minutes of physical activity per day, ≥3 d/wk. 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[Full Text].\nPeripheral blood smear from a patient with immune thrombocytopenia (ITP) shows a decreased number of platelets, a normal-appearing neutrophil, and normal-appearing erythrocytes. ITP is diagnosed by excluding other diseases; therefore, the absence of other findings from the peripheral smear is at least as important as the observed findings. This smear demonstrates the absence of immature leukocytes (as in leukemia) and fragmented erythrocytes (as in thrombotic thrombocytopenic purpura) and no clumps of platelets (as in pseudothrombocytopenia).\nTable 1. Bleeding scale for pediatric patients with ITP\nCraig M Kessler, MD, MACP Professor, Department of Medicine and Pathology, Division of Hematology/Oncology, Georgetown University School of Medicine; Director, Clinical Coagulation Laboratory, Lombardi Comprehensive Cancer Center, Georgetown University Hospital\nDisclosure: Received honoraria from NovoNordisk for consulting; Received grant/research funds from NovoNordisk for other; Received honoraria from Baxter-Immuno for consulting; Received honoraria from Octapharma for speaking and teaching; Received grant/research funds from Octapharma for none; Received consulting fee from Amgen for consulting; Received honoraria from Bayer for review panel membership.\nHira Latif, MBBS Fellow in Hematology and Medical Oncology, Washington Cancer Institute, MedStar Georgetown University Hospital-Washington Hospital Center\nHira Latif, MBBS is a member of the following medical societies: American College of Physicians, American Society of Clinical Oncology, American Society of Hematology, International Association for the Study of Lung Cancer, Pakistan Medical and Dental Council\nJulia M Cunningham, MD Assistant Professor of Medicine, Division of Hematology and Oncology, Attending Physician in Hematology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center\nJulia M Cunningham, MD is a member of the following medical societies: American Medical Association, American Society of Clinical Oncology, American Society of Hematology, Hemostasis and Thrombosis Research Society\nRonald A Sacher, MBBCh, FRCPC, DTM&H Professor of Internal Medicine and Pathology, Director, Hoxworth Blood Center, University of Cincinnati Academic Health Center\nRonald A Sacher, MBBCh, FRCPC, DTM&H is a member of the following medical societies: American Association for the Advancement of Science, American Association of Blood Banks, American Clinical and Climatological Association, American Society for Clinical Pathology, American Society of Hematology, College of American Pathologists, International Society of Blood Transfusion, International Society on Thrombosis and Haemostasis, Royal College of Physicians and Surgeons of Canada\nSrikanth Nagalla, MBBS, MS, FACP Associate Professor of Medicine, Division of Hematology and Oncology, UT Southwestern Medical Center\nSrikanth Nagalla, MBBS, MS, FACP is a member of the following medical societies: American Society of Hematology, Association of Specialty Professors\nDisclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Alexion; Alnylam.\nencoded search term (Immune Thrombocytopenia (ITP)) and Immune Thrombocytopenia (ITP)\nThrombocytopenia in Pregnancy\nAnemia and Thrombocytopenia in Pregnancy\nImmune Thrombocytopenia and Pregnancy\nHeparin-Induced Thrombocytopenia\nThrombocytopenia-Absent Radius Syndrome\nIntravenous Immunoglobulin\nChildren With ITP: Navigating an Unpredictable Course\nBelantamab Mafodotin Elicits Responses in R/R Multiple Myeloma\nOvarian Cancer Drug Olaparib Approved in Scotland\n11 Common-to-Rare Infant Skin Conditions\nDiseases & Conditions Thrombocytopenia in Pregnancy\nDiseases & Conditions Immune Thrombocytopenia (ITP)\nDiseases & Conditions Thrombocytopenia-Absent Radius Syndrome\nDiseases & Conditions Heparin-Induced Thrombocytopenia"