Seronegative Autoimmune Hepatitis in Adults Is a Rare Entity Often Obscured by Suboptimal Diagnostic Assessment

Seronegative autoimmune hepatitis (SnAIH) lacks detectable conventional autoantibodies (ANA, SMA, anti-LKM, anti-LC1, and anti-SLA/LP), posing diagnostic challenges. Increasing evidence suggests SnAIH in adults reflects limitations in autoantibody detection rather than a distinct variant. We systematically re-evaluated all biopsy-proven SnAIH cases in a large international multicenter AIH cohort using standardized testing. Among 760 patients with baseline liver biopsy, 52 (6.8%) were initially classified as SnAIH. Forty-three lacked complete autoantibody testing, most commonly anti-SLA/LP. After comprehensive re-evaluation, only 9 patients (1.18%) fulfilled criteria for true SnAIH. All presented acutely with markedly elevated transaminases (median ALT 16.1 × ULN); five had elevated IgG levels. Histology suggestive of autoimmune-like drug-induced liver injury was observed in four cases. All but one relapsed after treatment withdrawal, and 42.9% failed to normalize ALT at six months. In conclusion, SnAIH is rare (~1%), highlighting the importance of standardized, comprehensive autoantibody testing and re-testing according to the guidelines.