What is the treatment approach for overlap syndrome involving liver diseases, such as primary biliary cholangitis (PBC) and autoimmune hepatitis (AIH)?

Treatment of Overlap Syndrome in Autoimmune Liver Diseases

Treat overlap syndromes by targeting the predominant disease manifestation: combine immunosuppression (corticosteroids with or without azathioprine) for the autoimmune hepatitis component with ursodeoxycholic acid (UDCA) for the cholestatic component. 1

Diagnostic Approach Before Treatment

Before initiating therapy, confirm the overlap syndrome diagnosis by identifying features of both diseases:

• For AIH-PBC overlap: Look for elevated alkaline phosphatase that fails to normalize rapidly with immunosuppression, presence of antimitochondrial antibodies, and histological bile duct injury or loss 1
• For AIH-PSC overlap: Consider MRCP when alkaline phosphatase remains elevated despite treatment, especially if inflammatory bowel disease is present 1
• Liver biopsy is critical when transaminases persistently exceed 100 U/L in suspected PBC patients 1

Treatment Regimens by Overlap Type

AIH-PBC Overlap Syndrome

Primary regimen: Combine prednisolone (or prednisone) with azathioprine PLUS ursodeoxycholic acid 1

• Patients not meeting Paris criteria but with predominant AIH features respond well to conventional immunosuppressive therapy alone 1
• Patients with predominantly PBC features and background AIH may improve with UDCA alone 1
• UDCA dosing: 13-15 mg/kg daily (not exceeding 1.5-2 g daily) 1
• The combination of corticosteroids and low-dose UDCA is endorsed by EASL, though evidence is not strongly based 1

Expected outcomes: Most patients achieve biochemical remission with combined therapy, and serial biopsies show no progression of fibrosis 1

Critical caveat: Despite treatment response, overlap syndrome carries higher risk of variceal bleeding, liver failure, and transplantation compared to PBC or AIH alone 1. This underscores the importance of proactive diagnosis and aggressive treatment of the AIH component 1.

AIH-PSC Overlap Syndrome

Primary regimen: Prednisolone and azathioprine with or without UDCA 1

• In children: UDCA 10 mg/kg twice daily (not exceeding 1.5-2 g daily) combined with prednisone or prednisolone 1
• UDCA combined with immunosuppressive regimen (prednisolone 0.5 mg/kg daily tapered to 10-15 mg/day plus azathioprine 50-75 mg) produces good biochemical response 1

Expected outcomes: Serum transaminases typically fall, but alkaline phosphatase and Mayo risk score remain stable 1. Laboratory resolution is less common than in pure AIH (22% versus 64%), and treatment failure (33% versus 10%) and death/need for transplant (33% versus 8%) are more frequent 1

Prognosis consideration: AIH-PSC overlap has better prognosis than PSC alone but worse than AIH alone 1. Most patients develop cirrhosis despite treatment 1.

Treatment Principles Across All Overlap Syndromes

The International Autoimmune Hepatitis Group advises directing management at the predominant manifestations of the overlap syndrome 1. This principle-based approach recognizes that:

• Regimens targeting a single component can improve liver tests when that phenotype predominates 1
• The management strategy is empiric, as no controlled trials exist for these rare disorders 1, 2
• Treatment is based on the component diseases rather than treating overlap as a distinct entity 1

Monitoring and Transplant Referral

Consider transplant referral when: 1

• Decompensation at presentation or fulminant hepatic failure (strongly recommended)
• MELD score >15 or Child-Pugh score >10
• Clinical decompensation develops (ascites, encephalopathy, hepatorenal syndrome)
• Hepatocellular carcinoma develops
• Signs of impending decompensation appear (variceal bleed, small fibrotic liver on ultrasound, falling albumin, mild ascites or edema)

Common pitfall: Do not rely solely on biochemical improvement. Liver biopsies may show improved inflammation, but cholangiographic appearances may progress and most patients develop cirrhosis 1. The long-term benefits of UDCA in preventing transplantation remain unproven 1.

Key Clinical Pearls

• Overlap syndromes should be suspected when alkaline phosphatase is more than mildly elevated and fails to normalize rapidly with immunosuppression 1
• Sequential presentation is possible—AIH may follow PBC onset (4% of cases) or vice versa (2% of cases) 1
• The Paris criteria identify the most extreme form of AIH-PBC overlap but are useful for objective diagnosis 1
• Treatment evidence is not strongly based, but the combination approach represents consensus expert opinion from multiple international guidelines 1