When to Consider AIH-PBC Overlap Syndrome in the Pathology Report

Autoimmune hepatitis-primary biliary cholangitis (AIH-PBC) overlap syndrome remains a diagnostic challenge due to the absence of standardized criteria and the limitations of current frameworks, such as the Paris Criteria. In this retrospective study, we reviewed 71 liver biopsies flagged for possible overlap and reclassified them based on clinical diagnosis as AIH (n=21), PBC (n=17), or overlap syndrome (n=33), incorporating 74 clinically and pathologically confirmed AIH (n=42) and PBC (n=32) cases as external controls. Only 46% of flagged cases were confirmed as overlap, indicating a 54% overcall rate. Florid duct lesions and bile duct loss were highly specific for a biliary component but were absent in over half of overlap cases, where lymphocytic cholangitis, although less specific, provided additional support when interpreted with serologic data. AMA positivity and alkaline phosphatase elevation were more specific indicators of PBC involvement than elevated IgM. In suspected overlap, hepatic inflammation characterized by confluent necrosis, interface hepatitis (mHAI A≥2), and lobular inflammation (mHAI C≥3), in conjunction with AST or ALT ≥2×upper limit of normal, more reliably distinguished overlap from isolated PBC. Overlap cases showed milder necroinflammatory activity compared with isolated AIH controls, suggesting under-recognition when relying solely on existing AIH scoring systems. We propose a refined diagnostic approach that integrates key histologic findings and serologic markers, supported by semiquantitative assessment using the modified Hepatic Activity Index (mHAI), to improve diagnostic accuracy and reporting consistency for AIH-PBC overlap syndrome.