para>Consider PBC in any middle-aged woman with unexplained pruritus or cholestasis.
PHYSICAL EXAM
Exam is normal in most (60%) asymptomatic patients. Physical exam findings usually correlate with disease severity. Abnormal findings include:
- Skin: hyperpigmentation, excoriations secondary to pruritus, xanthomas, jaundice (late finding)
- Abdomen: hepatosplenomegaly (may be present in asymptomatic patients), spider nevi, and other cutaneous stigmata of portal hypertension (late)
- Evidence of decompensated portal hypertension in advanced cirrhosis (ascites, encephalopathy)
- Psychiatric: affective disorders (primarily depression)
DIFFERENTIAL DIAGNOSIS
- Cholestasis secondary to medications or pregnancy; nonalcoholic steatohepatitis; alcoholic liver disease
- Other autoimmune-related hepatobiliary conditions: autoimmune hepatitis, primary sclerosing cholangitis
- Pancreatic and other periampullary carcinomas
- Overlap syndrome exists between PBC and autoimmune hepatitis.
DIAGNOSTIC TESTS & INTERPRETATION
- Based on clinical suspicion or cholestatic pattern of liver enzymes elevation (ALP and/or bilirubin)
- Suspect PBC with ALP elevations in asymptomatic women.
- The American Association for the Study of Liver Disease (AASLD) requires two out of three:
- Serum AMA positive
- Cholestasis based on lab results
- Histologic evidence of bile duct destruction
Initial Tests (lab, imaging)
- Cholestatic liver enzyme profile: disproportionate increase of ALP or GGTP
- Elevated direct > indirect bilirubin (portends poor prognosis; usually late in disease)
- Aminotransaminase elevations, if present, are mild. If they are, causes of cholestatic hepatitis may be considered (e.g., autoimmune hepatitis, drugs, viral hepatitis).
- Antimitochondrial antibodies: positive in 95% (5)[B]
- AMA-positive and -negative patients have similar natural history and response to treatment.
- AMA titers do not correlate with disease progression or with response to treatment.
- Antismooth muscle antibodies: Rule out autoimmune hepatitis or overlap syndrome.
- Lipid levels: mild elevations in low-density lipoprotein (LDL) and very low density lipoprotein (VLDL); marked elevation in high-density lipoprotein (HDL)
- Thrombocytopenia is common in advanced cirrhosis and is a sensitive marker for portal hypertension.
- Hepatobiliary imaging to rule out obstruction:
- Right upper quadrant US (less invasive) or abdominal CT
- Magnetic resonance cholangiopancreatography (MRCP) is preferred to endoscopic retrograde cholangiopancreatography (ERCP) to visualize biliary system because it is noninvasive; ERCP is useful if a therapeutic intervention is likely (stone removal, stent placement, biopsy).
- Esophageal US (EUS)
Follow-Up Tests & Special Considerations
- 5% of biopsy-proven PBC patients are AMA-negative.
- These patients are often antinuclear antibody (ANA)-positive (anti-GB210 and anti-SP100) and/or antismooth muscle antibody (SMA)-positive.
- Medications causing a PBC-like cholestatic picture:
- Phenothiazines, synthetic androgenic steroids, trimethoprim-sulfamethoxazole
- Women of childbearing age should have a pregnancy test because symptoms vary during pregnancy.
Diagnostic Procedures/Other
- Liver biopsy: important if diagnosis is unclear. Without biopsy, staging is unknown.
- MRCP or ERCP if serum AMA is negative or if biliary obstruction is suspected (stricture, stone, bile duct, or pancreatic carcinoma)
Test Interpretation
- Florid bile duct destruction (while uncommon) is the pathognomonic finding for PBC.
- Atypical bile duct hyperplasia with lymphocyte infiltration
TREATMENT
MEDICATION
First Line
- Ursodeoxycholic acid (UDCA) is the only FDA-approved treatment for PBC and is associated with biochemical, histologic, and survival benefits (6,7)[A].
- Combination of UDCA and bezafibrate improves liver biochemistry and the prognosis of PBC but does not improve clinical symptoms or mortality. Adverse events are more common with bezafibrate (8)[A].
- Dosing: 13 to 15 mg/kg/day for patients with abnormal liver enzymes, regardless of histologic stage
ADDITIONAL THERAPIES
- Supplemental treatment for symptomatic relief
- Pruritus (can be severe): Bile acid sequestrants (cholestyramine) is very useful for symptomatic relief. An initial dose of 4 g orally once or twice a day and a maintenance dose of 4 g orally 3 times a day before meals. Dosage should be individualized and based on clinical response and patient tolerance of side effects. Doses range from 8 to 36 g per day in 2 to 4 doses. If refractory, rifampicin 150 to 300 mg/day, opioid antagonist (e.g., naltrexone 50 mg/day), sertraline 75 to 100 mg/day can be tried (9)[A]. Colchicine improves pruritus but otherwise not useful, and its use is controversial.
- Although methotrexate may benefit other outcomes (pruritus score, serum ALP, IgM levels), insufficient evidence supports it for patients with PBC (10)[A].
- Fibrates, rituximab, tetrathiomolybdate therapy show promise, but further studies are needed.
SURGERY/OTHER PROCEDURES
Liver transplantation is the only definitive treatment for patients with progressive or nonresponsive disease and decompensated cirrhosis.
- Posttransplant, 1- and 5-year survival rates are 92% and 85%, respectively (11)[A].
- Posttransplant recurrence risk is 30% after 10 years (12)[B].
- Preventive treatment with UDCA reduces the risk of PBC recurrence after liver transplant (13)[A].
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
- Decrease alcohol intake, optimize weight management, promote tobacco cessation, and avoid hepatotoxic drugs.
- Complications of portal hypertension, such as esophageal varices or ascites, are treated the same as for other cirrhotic patients.
- Pregnant women need closer monitoring.
Patient Monitoring
- Liver tests every 3 to 6 months; monitor cholesterol.
- Thyroid-stimulating hormone (TSH) annually
- Bone mineral density every 2 to 4 years
- Vitamin A, D, and K levels yearly
- If cirrhosis, thrombocytopenia, or Mayo risk score >4.1, periodic endoscopic screening for esophageal varices is recommended.
- Screen periodically for liver cancer in patients with known cirrhosis using US and/or serum α-fetoprotein.
PROGNOSIS
- Varies widely. Prognostic factors include age, histologic stage, UDCA therapy, bilirubin level, thrombocytopenia, hepatic protein synthesis (albumin, prothrombin time).
- Median survival without liver transplantation is 10 to 15 years.
- Antibodies to the nuclear rim pore protein gp210 have shown promise as prognostic markers in PBC.
COMPLICATIONS
- Hepatocellular carcinoma (relative risk = 19)
- Portal hypertension
- Varices, encephalopathy, ascites
- Osteopenia/osteoporosis (in up to 1/3 of patients)
- Intense pruritus, fatigue
- Malabsorption, steatorrhea, diarrhea
REFERENCES
11 Boonstra K, Beuers U, Ponsioen CY. Epidemiology of primary sclerosing cholangitis and primary biliary cirrhosis: a systematic review. J Hepatol. 2012;56(5):1181-1188.22 Hirschfield GM, Gershwin ME. The immunobiology and pathophysiology of primary biliary cirrhosis. Annu Rev Pathol. 2013;8:303-330.33 Mayo MJ. Cholestatic liver disease overlap syndromes. Clin Liver Dis. 2013;17(2):243-253.44 Liang Y, Yang Z, Zhong R. Primary biliary cirrhosis and cancer risk: a systematic review and meta-analysis. Hepatology. 2012;56(4):1409-1417.55 Czaja AJ. Autoantibodies as prognostic markers in autoimmune liver disease. Dig Dis Sci. 2010;55(8):2144-2161.66 Czul F, Peyton A, Levy C. Primary biliary cirrhosis: therapeutic advances. Clin Liver Dis. 2013;17(2):229-242.77 Boberg KM, Wisl ¸ff T, Kj ¸llesdal KS, et al. Cost and health consequences of treatment of primary biliary cirrhosis with ursodeoxycholic acid. Aliment Pharmacol Ther. 2013;38(7):794-803.88 Yin Q, Li J, Xia Y, et al. Systematic review and meta-analysis: bezafibrate in patients with primary biliary cirrhosis. Drug Des Devel Ther. 2015;9:5407-5419.99 Crosignani A, Battezzati PM, Invernizzi P, et al. Clinical features and management of primary biliary cirrhosis. World J Gastroenterol. 2008;14(21):3313-3327.1010 Giljaca V, Poropat G, Stimac D, et al. Methotrexate for primary biliary cirrhosis. Cochrane Database Syst Rev. 2010;(5):CD004385.1111 MacQuillan GC, Neuberger J. Liver transplantation for primary biliary cirrhosis. Clin Liver Dis. 2003;7(4):941-956.1212 Neuberger J. Liver transplantation for primary biliary cirrhosis: indications and risk of recurrence. J Hepatol. 2003;39(2):142-148.1313 Bosch A, Dumortier J, Maucort-Boulch D, et al. Preventive administration of UDCA after liver transplantation for primary biliary cirrhosis is associated with a lower risk of disease recurrence. J Hepatol. 2015;63(6):1449-1458.
ADDITIONAL READING
Selmi C, Bowlus FC, Gershwin ME, et al. Primary biliary cirrhosis. Lancet. 2011;377(9777):1600-1609.
CODES
ICD10
K74.3 Primary biliary cirrhosis
ICD9
571.6 Biliary cirrhosis
SNOMED
Primary biliary cirrhosis (disorder)
CLINICAL PEARLS
- Consider PBC in middle-aged women with unexplained pruritus or asymptomatic elevations of serum ALP.
- Exclude other causes of cholestatic liver disease. Perform imaging (ultrasound, CT scan, or MRCP) to rule out biliary obstruction if diagnosis is uncertain.
- AMA is positive in most cases of PBC (95%). Consider liver biopsy if AMA is negative or AST is >5 times normal.