Autoimmune Hepatitis and Primary Biliary Cholangitis Overlap Syndrome

Autoimmune hepatitis and primary biliary cholangitis overlap syndrome is a condition in which features of both diseases coexist or follow one another. It affects about 5% to 10% of adults with either condition, more often women.

Diagnosis uses the Paris criteria. For primary biliary cholangitis, at least 2 of: alkaline phosphatase 2 times the upper limit of normal or more (or gamma glutamyl transferase 5 times or more), positive antimitochondrial antibodies, florid bile duct lesions on biopsy. For autoimmune hepatitis, at least 2 of: alanine aminotransferase 5 times the upper limit or more, IgG 2 times the upper limit or more (or positive smooth muscle antibody), moderate or severe interface hepatitis on biopsy.

Progression is faster than in primary biliary cholangitis alone, with higher rates of fibrosis and liver related events.

Pathophysiology.

It reflects a shared autoimmune background with T cell mediated injury to hepatocytes and to small bile ducts. Genetic factors (HLA-DR3, DR4, DR8) and environmental triggers contribute.

Fatigue, pruritus, jaundice, arthralgia and extrahepatic autoimmune disease (thyroid disease, Sjogren syndrome, coeliac disease). Some are asymptomatic and found by abnormal liver tests. Cirrhosis causes portal hypertension features.

Red flags.

• Acute severe hepatitis (jaundice with coagulopathy).
• Variceal bleeding.
• Ascites or encephalopathy.

Liver tests (mixed hepatitic and cholestatic), IgG, antinuclear and smooth muscle antibodies, antimitochondrial antibodies (and anti-gp210 or anti-sp100 when negative). Liver biopsy is essential: interface hepatitis plus florid duct lesions or duct loss. Magnetic resonance cholangiopancreatography excludes large duct disease. Check viral hepatitis, metabolic and drug causes, and elastography for fibrosis.

Differential diagnosis.

• Autoimmune hepatitis alone.
• Primary biliary cholangitis alone.
• Primary sclerosing cholangitis overlap.
• Drug induced liver injury.
• Viral hepatitis.
• Metabolic dysfunction associated steatotic liver disease.

Combine bile acid therapy with immunosuppression when hepatitic activity is present.

• Ursodeoxycholic acid: 13 to 15 mg/kg orally daily in 2 to 3 divided doses; long term; maximum 15 mg/kg daily in this indication; monitor liver tests every 3 months; avoid in complete biliary obstruction; no renal adjustment.
• Prednisolone: 0.5 to 1 mg/kg orally once daily (maximum 60 mg), tapered over 4 to 8 weeks to 5 to 10 mg daily or less; maximum 60 mg daily; monitor glucose, blood pressure, bone density and infection; give calcium and vitamin D, with bone protection if prolonged.
• Azathioprine: 1 to 2 mg/kg orally once daily, started after 2 weeks of prednisolone (maximum 150 mg daily); maintenance for at least 2 to 3 years; monitor blood counts and liver tests every 1 to 2 weeks for 8 weeks, then every 3 months; check thiopurine methyltransferase first; reduce in renal impairment and with allopurinol.
• Budesonide (non-cirrhotic alternative to prednisolone): 9 mg orally once daily for induction, then 6 mg; maximum 9 mg daily; monitor glucose and bone health; avoid in cirrhosis and portal vein thrombosis.

A stepwise approach starting with ursodeoxycholic acid alone for 3 months and adding immunosuppression if aminotransferases remain over 2 times the upper limit is a reasonable alternative. Obeticholic acid or fibrates are used for inadequate biliary response (specialist use). Manage pruritus and bone disease, screen for varices and hepatocellular carcinoma, and refer for transplantation when decompensated.

Monitoring. Liver tests and IgG every 1 to 3 months during treatment; elastography yearly.

Referral and escalation. Hepatology; transplant centre for decompensation.