Autoimmune Hepatitis and Primary Sclerosing Cholangitis Overlap Syndrome

Autoimmune hepatitis and primary sclerosing cholangitis overlap syndrome is the coexistence of features of autoimmune hepatitis and of primary sclerosing cholangitis. It is seen more often in children, adolescents and young adults, and in men more than in autoimmune hepatitis alone.

It accounts for about 6% to 8% of primary sclerosing cholangitis in adults and a larger share in children. Inflammatory bowel disease, mainly ulcerative colitis, is present in 40% to 80%.

Autoimmune hepatitis features: raised aminotransferases and IgG, positive antinuclear or smooth muscle antibody and interface hepatitis. Sclerosing cholangitis features: typical beading and stricturing on cholangiography, or onion skin fibrosis on biopsy for small duct disease.

Pathophysiology.

Immune injury of hepatocytes and of bile ducts occurs together, with genetic susceptibility (HLA-DRB1) and interaction with the gut microbiome and inflammatory bowel disease.

Fatigue, jaundice, itching, abdominal pain, fever (cholangitis) and weight loss. Many are asymptomatic. Features of inflammatory bowel disease (bloody diarrhoea) coexist. Cirrhosis features appear later.

Red flags.

• Cholangitis (fever with jaundice).
• Dominant stricture with weight loss (cholangiocarcinoma).
• Variceal bleeding.
• Ascites or encephalopathy.

Cholestatic and hepatitic liver tests, IgG, antinuclear and smooth muscle antibodies, and anti-neutrophil cytoplasmic antibodies. Magnetic resonance cholangiopancreatography shows multifocal strictures and dilatation. Liver biopsy shows interface hepatitis with or without periductal fibrosis. Exclude IgG4-related disease (serum IgG4), viral hepatitis, drugs and metabolic causes. Colonoscopy screens for inflammatory bowel disease. Check CA 19-9 and imaging in dominant strictures.

Differential diagnosis.

• Autoimmune hepatitis alone.
• Primary sclerosing cholangitis alone.
• IgG4-related sclerosing cholangitis.
• Secondary sclerosing cholangitis.
• Cholangiocarcinoma.
• Primary biliary cholangitis overlap.

Treat the hepatitic component with immunosuppression and the biliary component with supportive measures.

• Prednisolone: 0.5 to 1 mg/kg orally once daily (maximum 60 mg), tapered over 4 to 8 weeks to the lowest effective dose; maximum 60 mg daily; monitor glucose, blood pressure, bone density and infection; give calcium and vitamin D.
• Azathioprine: 1 to 2 mg/kg orally once daily; maintenance for at least 2 to 3 years; maximum 150 mg daily; 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.
• Ursodeoxycholic acid: 13 to 15 mg/kg orally daily in 2 to 3 divided doses; long term; maximum 15 mg/kg daily; monitor liver tests every 3 months; avoid in complete obstruction. High doses (28 to 30 mg/kg) increase serious events in primary sclerosing cholangitis and are not used.

Endoscopic dilation treats dominant strictures; antibiotics treat cholangitis (piperacillin-tazobactam 4.5 g IV every 6 hours for 4 to 7 days; maximum 18 g daily; monitor renal function and counts; reduce for creatinine clearance under 40 mL/min). Colonoscopy with biopsies yearly in inflammatory bowel disease. Imaging every 6 to 12 months for cholangiocarcinoma and gallbladder polyps. Refer for liver transplantation in decompensated or progressive disease.

Monitoring. Liver tests and IgG every 1 to 3 months during treatment; elastography and imaging at regular intervals.

Referral and escalation. Hepatology and biliary endoscopy; transplant centre.

Special groups. Children need paediatric hepatology and weight based dosing.