Sections View Full Chapter Figures Tables Videos Annotate Full Chapter Figures Tables Videos Supplementary Content + Download Section PDF Listen ++ For further information, see CMDT Part 16-25: Primary Sclerosing Cholangitis + Key Features Download Section PDF Listen +++ +++ Essentials of Diagnosis ++ Progressive jaundice, itching, and other features of cholestasis Males, aged 20–50 years old Often associated with ulcerative colitis Diagnosis based on characteristic cholangiographic findings At least 10% risk of cholangiocarcinoma +++ General Considerations ++ Characterized by diffuse inflammation of the biliary tract leading to fibrosis and strictures of the biliary system Associated with the histocompatibility antigens HLA-B8 and -DR3 or -DR4 Occasional patients have clinical and histologic features of both sclerosing cholangitis and autoimmune hepatitis A subset of patients with primary sclerosing cholangitis have increased serum IgG4 levels and distinct HLA associations (with a poorer prognosis) but do not meet criteria for IgG4-related sclerosing cholangitis The diagnosis of primary sclerosing cholangitis is difficult to make after biliary surgery or intrahepatic artery chemotherapy, which may result in bile duct injury Primary sclerosing cholangitis must be distinguished from idiopathic adulthood ductopenia, a rare disorder affecting young to middle-aged adults who manifest cholestasis resulting from loss of interlobular and septal bile ducts yet who have a normal cholangiogram +++ Demographics ++ Between 60% and 70% of affected persons are male, usually 20–50 years old (median age 41) Incidence Nearly 3.3 per 100,000 in Asian Americans ~2.8 per 100,000 in Hispanic Americans ~2.1 per 100,000 in African Americans Intermediate incidence in whites (and increasing) Prevalence: 16.2 per 100,000 population, 21 per 100,000 men and 6 per 100,000 women in the United States Closely associated with inflammatory bowel disease (more commonly ulcerative colitis than Crohn colitis), which is present in approximately two-thirds of patients However, clinically significant sclerosing cholangitis develops in only 1–4% of patients with ulcerative colitis As in ulcerative colitis, smoking is associated with a decreased risk of primary sclerosing cholangitis; so is coffee consumption Statin use is associated with improved outcomes in patients with primary sclerosing cholangitis + Clinical Findings Download Section PDF Listen +++ +++ Symptoms and Signs ++ Progressive obstructive jaundice, frequently associated with fatigue, pruritus, anorexia, and indigestion Esophageal varices on initial endoscopy are most likely found in patients with a higher Mayo risk score based on age, serum bilirubin, albumin, and AST and a higher AST/ALT ratio New varices are likely to develop in those with a lower platelet count and higher bilirubin at 2 years In patients with primary sclerosing cholangitis, ulcerative colitis is frequently characterized by rectal sparing and backwash ileitis Associations with cardiovascular disease and diabetes mellitus have been reported Women with primary sclerosing cholangitis may be more likely to have recurrent urinary tract infections +++ Differential Diagnosis ++ Primary biliary cholangitis Choledocholithiasis Cancer of pancreas or biliary tract Biliary stricture Drug-induced cholestasis, eg, chlorpromazine Inflammatory bowel disease complicated by cholestatic liver disease Idiopathic adulthood ductopenia Clonorchis sinensis (Chinese liver fluke) infection Fasciola hepatica (sheep liver fluke) infection Sclerosing cholangitis due to Cytomegalovirus Cryptosporidiosis Microsporidiosis (in AIDS) + Diagnosis Download Section PDF Listen +++ +++ Laboratory Tests ++ Condition may be diagnosed in the presymptomatic phase because of an elevated alkaline phosphatase level Perinuclear ANCA as well as antinuclear, anticardiolipin, antithyroperoxidase, and anti-Saccharomyces cerevisiae antibodies and rheumatoid factor are frequently detected in serum A serum IgG4 level more than 4 times the upper limit of normal or an IgG4:IgG1 ratio of more than 0.24 strongly suggests IgG4-related sclerosing cholangitis, but in up to one-third of cases, the serum IgG4 level is normal +++ Imaging Studies ++ Magnetic resonance cholangiography Shows characteristic segmental fibrosis of the bile ducts with saccular dilatations between strictures Early, as sensitive as ERCP for visualizing the intrahepatic ducts Biliary obstruction by a stone or tumor should be excluded +++ Diagnostic Procedures ++ Liver biopsy is not necessary when cholangiographic findings are characteristic The disease may be confined to small intrahepatic bile ducts, in which case ERCP is normal and the diagnosis is suggested by liver biopsy Liver biopsy may show characteristic periductal fibrosis ("onion-skinning") and is needed for staging, which is based on the degree of fibrosis and which correlates with liver stiffness as measured by elastography + Treatment Download Section PDF Listen +++ +++ Medications ++ Episodes of acute bacterial cholangitis may be treated with ciprofloxacin (750 mg twice daily orally or intravenously) Ursodeoxycholic acid in standard doses, 10–15 mg/kg/day May improve liver chemistry test results However, it does not appear to alter the natural history However, withdrawal of ursodeoxycholic acid may result in worsening of liver chemistry test levels and increased pruritus Ursodeoxycholic acid in intermediate doses (17–23 mg/kg/day) has been reported to be beneficial High-dose ursodeoxycholic acid, 25–30 mg/kg orally daily Has not been shown to reduce cholangiographic progression and liver fibrosis nor to improve survival or prevent cholangiocarcinoma Has been shown to increase the risk of death and need for liver transplantation in patients with a normal serum bilirubin level and an early histologic stage +++ Surgery ++ Cholecystectomy is indicated in patients with primary sclerosing cholangitis and a gallbladder polyp > 8 mm in diameter In patients without cirrhosis, surgical resection of a dominant bile duct stricture may lead to longer survival than endoscopic therapy by decreasing the subsequent risk of cholangiocarcinoma For patients with cirrhosis and clinical decompensation, liver transplantation is the treatment of choice +++ Therapeutic Procedures ++ Careful endoscopic evaluation of the biliary tree may permit balloon dilation of localized strictures If there is a major stricture, short-term placement of a stent (2–3 weeks) may relieve symptoms and improve biochemical abnormalities with sustained improvement after the stent is removed but may not be superior to balloon dilatation alone Repeated balloon dilatation of a recurrent dominant bile duct stricture may improve survival However, long-term stenting may increase the rate of complications such as cholangitis and is not recommended + Outcome Download Section PDF Listen +++ +++ Complications ++ Complications of chronic cholestasis, such as osteoporosis, malabsorption of fat-soluble vitamins, and malnutrition may occur Increased risk of gallstones, cholecystitis, gallbladder polyps, and gallbladder carcinoma in patients with primary sclerosing cholangitis Patients with ulcerative colitis and primary sclerosing cholangitis are at high risk (10-fold higher than ulcerative colitis patients without primary sclerosing cholangitis) for colorectal neoplasia Cholangiocarcinoma Occurs in up to 20% of cases May be difficult to diagnose by cytologic examination or biopsy because of false-negative results A serum CA 19-9 level > 100 units/mL is suggestive but not diagnostic of cholangiocarcinoma Positron emission tomography and peroral cholangioscopy may have roles in early detection +++ Prognosis ++ Survival averages 9–17 years and up to 21 years in population-based studies Adverse prognostic markers Older age Hepatosplenomegaly Higher serum bilirubin and aspartate aminotransferase levels Lower serum albumin levels History of variceal bleeding (also a risk factor for cholangiocarcinoma) Dominant bile duct stricture Extrahepatic duct changes Patients in whom serum alkaline phosphatase levels decline by 40% or more (spontaneously, with ursodeoxycholic acid therapy, or after treatment of a dominant stricture) have longer transplant-free survival times than those in whom the alkaline phosphatase does not decline The Amsterdam-Oxford model has been proposed to predict transplant-free survival; it is based on Disease subtype (large- vs small-duct involvement) Age at diagnosis Serum albumin Platelet count Serum AST Serum alkaline phosphatase Serum bilirubin Transplant-free survival can also be predicted by serum levels of markers of liver fibrosis, for example Hyaluronic acid Tissue inhibitor of metalloproteinase-1 Propeptide of type III procollagen Moreover, improvement in the serum alkaline phosphatase to < 1.5 times the upper limit of normal is associated with a reduced risk of cholangiocarcinoma The risk of progression can be predicted by three findings on MRI and MRCP: Cirrhotic appearance of the liver Portal hypertension Enlarged perihepatic lymph nodes Actuarial survival rates with liver transplantation are as high as 72% at 5 years, but rates are much lower once cholangiocarcinoma has developed Following transplantation, Patients have an increased risk of nonanastomotic biliary strictures In those with ulcerative colitis, an increased risk of colon cancer The disease recurs in 25% Patients who are unable to undergo liver transplantation will ultimately require high-quality palliative care When the disease is confined to small intrahepatic bile ducts, the survival is longer and there is a lower rate of cholangiocarcinoma than with involvement of the large ducts Although maternal primary sclerosing cholangitis is associated with preterm birth and cesarean section delivery, the risk of congenital malformations is not increased +++ Prevention ++ In patients with ulcerative colitis, primary sclerosing cholangitis is an independent risk factor for the development of colorectal dysplasia and cancer, and strict adherence to a colonoscopic surveillance program is recommended + References Download Section PDF Listen +++ + +Alberts R et al. Genetic association analysis identifies variants associated with disease progression in primary sclerosing cholangitis. Gut. 2018 Aug;67(8):1517–24. [PubMed: 28779025] + +Ali AH et al. Surveillance for hepatobiliary cancers in patients with primary sclerosing cholangitis. Hepatology. 2018 Jun;67(6):2338–51. [PubMed: 29244227] + +Bowlus CL et al. AGA Clinical Practice Update on surveillance for hepatobiliary cancers in patients with primary sclerosing cholangitis: expert review. Clin Gastroenterol Hepatol. 2019 Nov;17(12):2416–22. [PubMed: 31306801] + +Chapman MH et al. British Society of Gastroenterology and UK-PSC guidelines for the diagnosis and management of primary sclerosing cholangitis. Gut. 2019 Aug;68(8):1356–78. [PubMed: 31154395] + +de Vries EM et al. A novel prognostic model for transplant-free survival in primary sclerosing cholangitis. Gut. 2018 Oct;67(10):1864–9. [PubMed: 28739581] + +Dyson JK et al. Primary sclerosing cholangitis. Lancet. 2018 Jun 23;391(10139):2547–59. [PubMed: 29452711] + +Fricker ZP et al. Primary sclerosing cholangitis: a concise review of diagnosis and management. Dig Dis Sci. 2019 Mar;64(3):632–42. [PubMed: 30725292] + +Goode EC et al. Factors associated with outcomes of patients with primary sclerosing cholangitis and development and validation of a risk scoring system. Hepatology. 2019 May;69(5):2120–35. [PubMed: 30566748] + +Ponsioen CY et al. No superiority of stents vs balloon dilatation for dominant strictures in patients with primary sclerosing cholangitis. Gastroenterology. 2018 Sep;155(3):752–9. [PubMed: 29803836] + +Stokkeland K et al. Statin use is associated with improved outcomes of patients with primary sclerosing cholangitis. Clin Gastroenterol Hepatol. 2019 Aug;17(9):1860–6. [PubMed: 30448601] + +Torabi Sagvand B et al. Frequency, risk factors, and outcome of gallbladder polyps in patients with primary sclerosing cholangitis: a case-control study. Hepatol Commun. 2018 Nov 13;2(12):1440–5. [PubMed: 30556033] + +Webb GJ et al. Twenty-year comparative analysis of patients with autoimmune liver diseases on transplant waitlists. Clin Gastroenterol Hepatol. 2018 Feb;16(2):278–87. [PubMed: 28993258]