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 16-12: Primary Biliary Cholangitis + Key Features Download Section PDF Listen +++ +++ Essentials of Diagnosis ++ Occurs in middle-aged women Often asymptomatic Elevated serum alkaline phosphatase, IgM, and cholesterol; positive antimitochondrial antibodies (AMA) Characteristic liver biopsy In later stages, can present with fatigue, jaundice, features of cirrhosis, xanthelasma, xanthomata, steatorrhea +++ General Considerations ++ Chronic disease of the liver characterized by autoimmune destruction of small intrahepatic bile ducts and cholestasis The designation "primary biliary cholangitis" has been proposed instead of primary biliary cirrhosis because many patients do not have cirrhosis Insidious in onset Occurs usually in women aged 40–60 Often detected by the chance finding of elevated serum alkaline phosphatase levels It may be associated with Sjögren syndrome Autoimmune thyroid disease Raynaud syndrome Scleroderma Hypothyroidism Gluten enteropathy Infection with Novospingobium aromaticivorans and Chlamydophila pneumoniae may trigger or cause primary biliary cholangitis; other triggers include viruses, lactobacillus vaccination, and xenobiotics Risk factors include History of urinary tract infections Smoking Hormone replacement therapy Use of hair dye Patients with a clinical and histologic picture of primary biliary cholangitis but with no AMA are said to have AMA-negative primary biliary cholangitis ("autoimmune cholangitis"), which has been associated with Lower serum IgM levels Greater frequency of smooth muscle antibodies and antinuclear antibodies +++ Demographics ++ Estimated incidence and prevalence rates in the United States In women: 4.5 and 65.4 per 100,000, respectively In men: 0.7 and 12.1 per 100,000, respectively + Clinical Findings Download Section PDF Listen +++ +++ Symptoms and Signs ++ Many are asymptomatic for years The onset of clinical illness is insidious and is heralded by fatigue and pruritus With progression, physical examination reveals hepatosplenomegaly Xanthomatous lesions may occur in the skin and tendons and around the eyelids Jaundice, steatorrhea, and signs of portal hypertension are late findings, although occasional patients have esophageal varices despite an early histologic stage Autonomic dysfunction, including orthostatic hypotension, associated with fatigue, and cognitive dysfunction appear to be common The risk of low bone density, osteoporosis, and fractures is increased, as in patients with other forms of chronic liver disease +++ Differential Diagnosis ++ Chronic biliary tract obstruction (stone or stricture) Carcinoma of the bile ducts Primary sclerosing cholangitis Sarcoidosis Cholestatic drug toxicity (eg, chlorpromazine) Chronic hepatitis Some patients have overlapping features of primary biliary cholangitis and autoimmune hepatitis + Diagnosis Download Section PDF Listen +++ +++ Laboratory Tests ++ Blood cell counts are normal early in the disease Liver biochemical tests reflect cholestasis with elevation of serum alkaline phosphatase, cholesterol (especially high-density lipoproteins and lipoprotein X), and, in later stages, bilirubin Antimitochondrial antibodies (AMA) Directed against pyruvate dehydrogenase or other 2-oxo-acid enzymes in mitochondria Present in 95% of patients Titer > 1:40 in serum Serum IgM levels are elevated Antinuclear antibodies directed against the nuclear pore complex may be detected in specialized laboratories has high specificity, and predicts progression to liver failure Anti-centromere antibodies predict progression to cirrhosis and portal hypertension +++ Imaging ++ Baseline ultrasonography should be obtained +++ Diagnostic Procedures ++ Liver biopsy Not necessary for diagnosis unless AMAs are absent However, it permits histologic staging Stage I: portal inflammation with granulomas Stage II: bile duct proliferation, periportal inflammation Stage III: interlobular fibrous septa Stage IV: cirrhosis + Treatment Download Section PDF Listen +++ +++ Medications ++ Ursodeoxycholic acid (13–15 mg/kg/day in one or two doses) Preferred medical treatment because it lacks toxicity Can be continued during pregnancy Has been shown to slow the progression of disease (particularly early-stage disease), stabilize histology, improve long-term survival, reduce the risk of developing esophageal varices, and delay (and possibly prevent) the need for liver transplantation even in the absence of liver biochemical test improvement Complete normalization of liver biochemical tests occurs in 20% within 2 years and 40% within 5 years Obeticholic acid Approved for the treatment of primary biliary cholangitis in patients with an incomplete response or intolerance to ursodeoxycholic acid Dosage: Started at 5 mg orally daily and increased to 10 mg daily at 6 months if tolerated, based on the decline in serum alkaline phosphatase and bilirubin levels In patients with Child-Pugh class B or C cirrhosis, the initial dose is 5 mg weekly Pruritus is the principal side effect Expensive; may not be cost-effective Bezafibrate (not available in the United States) and fenofibrate Activate peroxisome proliferator-activated receptors (PPARs) Inhibit bile acid synthesis Have shown promise as second-line agents May improve symptoms, liver biochemical test levels, and fibrosis Colchicine (0.6 mg twice daily) and methotrexate (15 mg/wk) may improve symptoms and levels of serum alkaline phosphatase and bilirubin Methotrexate may also improve liver histology, but overall response rates have been disappointing Penicillamine, corticosteroids, and azathioprine are not beneficial Budesonide may improve liver histology but worsens bone density Mycophenolate mofetil, rituximab, and seladelpar (a peroxisome proliferator-activated receptor delta agonist) are under study For pruritus Cholestyramine (4 g) in water or juice three times daily may be beneficial Rifampin, 150–300 mg twice daily orally, is inconsistently beneficial Opioid antagonists (eg, naloxone, 0.2 mcg/kg/min by intravenous infusion, or naltrexone, starting at 12.5 mg/day orally) may help The 5-HT3 serotonin receptor antagonist ondansetron, 4 mg three times a day as needed orally, and the selective serotonin uptake inhibitor sertraline, 75–100 mg/day orally, may also provide some benefit Plasmapheresis or extracorporeal albumin dialysis may be needed for refractory pruritus Modafinil, 100–200 mg/day orally, may improve daytime somnolence Deficiencies of vitamins A, D, and K may occur if steatorrhea is present and be aggravated when cholestyramine or colestipol is administered Calcium supplementation (500 mg three times daily) may help prevent osteomalacia but is of uncertain benefit in osteoporosis +++ Surgery ++ For patients with advanced disease, liver transplantation is the treatment of choice + Outcome Download Section PDF Listen +++ +++ Prognosis ++ Among asymptomatic patients, at least one-third will become symptomatic within 15 years An increase in liver stiffness of > 2.1 kilopascals per year indicates an adverse prognosis Ursodeoxycholic acid has been shown to Slow the progression of disease Stabilize histology Improve long-term survival Reduce the risk of developing esophageal varices Delay (and possibly prevent) the need for liver transplantation Without liver transplantation, survival averages 7–10 years once symptoms develop In advanced disease, adverse prognosis is indicated by Older age High serum bilirubin Edema Low serum albumin Prolonged prothrombin time Variceal hemorrhage The risk of hepatocellular carcinoma appears to be increased Liver transplantation Should be considered when the MELD-Na score is at least 15, total serum bilirubin at least 6, or Mayo risk score at least 7.8 Associated with a 1-year survival rate of 85–90% The disease recurs in the graft in 20% of patients by 3 years, but this does not seem to affect survival +++ When to Refer ++ For liver biopsy For liver transplant evaluation +++ When to Admit ++ Gastrointestinal bleeding Stage 3–4 hepatic encephalopathy Worsening kidney function Severe hyponatremia Profound hypoxia + References Download Section PDF Listen +++ + +Carey EJ, Levy C (editors). Primary biliary cholangitis. Clin Liver Dis. 2018;22:429–624. [Full issue] [PubMed: 30259845] + +Cheung AC et al; Global PBC Study Group. Effects of age and sex of response to ursodeoxycholic acid and transplant-free survival in patients with primary biliary cholangitis. Clin Gastroenterol Hepatol. 2019 Sep;17(10):2076–84. [PubMed: 30616022] + +Efe C et al. Validation of risk scoring systems in ursodeoxycholic acid-treated patients with primary biliary cholangitis. Am J Gastroenterol. 2019 Jul;114(7):1101–8. [PubMed: 31241547] + +European Association for the Study of the Liver. EASL Clinical Practice Guidelines: the diagnosis and management of patients with primary biliary cholangitis. J Hepatol. 2017 Jul;67(1):145–72. [PubMed: 28427765] + +Hirschfield GM et al. The British Society of Gastroenterology/UK-PBC primary biliary cholangitis treatment and management guidelines. Gut. 2018 Sep;67(9):1568–94. [PubMed: 29593060] + +Kowdley KV et al. A randomized trial of obeticholic acid monotherapy in patients with primary biliary cholangitis. Hepatology. 2018 May;67(5):1890–902. [PubMed: 29023915] + +Levy C. Primary biliary cholangitis guidance update: implications for liver transplantation. Liver Transpl. 2018 Nov;24(11):1508–11. [PubMed: 30091276] + +Lindor KD et al. Primary biliary cholangitis: 2018 practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2019 Jan;69(1):394–419. [PubMed: 30070375] + +Yokoda RT et al. Primary biliary cholangitis and primary sclerosing cholangitis. Am J Gastroenterol. 2019 Oct;114(10):1593–605. [PubMed: 31169523] + +Younossi ZM et al. Diagnosis and management of primary biliary cholangitis. Am J Gastroenterol. 2019 Jan;114(1):48–63. [PubMed: 30429590]