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Cirrhosis, Primary Biliary

- 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).

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 positiveCholestasis based on lab resultsHistologic evidence of bile duct destruction

Initial Tests (lab, imaging)

  • Cholestatic liver enzyme profile: disproportionate increase of ALP or GGTPElevated 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 CTMagnetic 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.