Bilirubin-Driven Phenotype Identifies Higher Mortality Risk in Severe Alcohol-Associated Hepatitis.

Background and Aims: Among patients with severe alcohol-associated hepatitis (AH), the prognostic relevance of the dominant component of Maddrey's Discriminant Function (MDF) is unclear. Methods: We conducted a retrospective cohort study of adults with AH treated with corticosteroids at a US academic center (January 2016-December 2024). Using K-means clustering of the bilirubin and prothrombin time (PT) components of MDF, patients were classified into "PT-driven" vs "bilirubin-driven" phenotypes. The primary outcome was 90-day all-cause mortality. Inverse probability of treatment weighting-weighted Cox proportional hazards models were performed under an intention-to-treat framework, in which patients were not censored at liver transplantation. Secondary analyses used Fine-Gray competing risk models with liver transplantation as a competing event. Results: Among 212 patients, 56 (26.4%) died within 90 days. Despite a similar Model for End-Stage Liver Disease, the bilirubin-driven group (n = 100) had significantly lower MDF scores and less hepatic encephalopathy compared to the PT-driven group (n = 112). Nevertheless, in the inverse probability of treatment weighting-weighted Cox proportional hazards model, the bilirubin-driven phenotype was associated with higher 90-day mortality (hazard ratio, 2.06; 95% confidence interval, 1.05-4.04). Findings were consistent in the Fine-Gray competing risks model (subdistribution hazard ratio, 2.11; 95% confidence interval, 1.03-4.35). Conclusion: A bilirubin-dominant phenotype in severe AH was associated with significantly higher 90-day mortality, highlighting disease heterogeneity and suggesting potential value for risk stratification and for guiding future research on individualized care and optimal timing of liver transplant evaluation.