Multi-algorithm consensus classification identifies three distinct acute liver failure subtypes with differential treatment responses: a multi-database cohort study

Acute liver failure (ALF) is a heterogeneous syndrome with high mortality. Current prognostic models fail to capture pathophysiological heterogeneity, necessitating refined patient stratification and personalized therapeutic strategies. We analyzed 2,691 adult patients with ALF from six international critical care databases (MIMIC-IV as discovery cohort, n = 1,227; five validation cohorts: MIMIC-III CareVue, eICU, HiRID, NWICU, and SICdb, n = 1,464). We developed a Multi-algorithm Consensus-based Acute Liver Failure Classification (MCALFC) approach integrating ten clustering algorithms to identify distinct subtypes based on clinical parameters, interventions, comorbidities, and medications. We validated these subtypes across databases, performed survival analyses, conducted SHAP analysis using XGBoost to identify key distinguishing features, and evaluated treatment response heterogeneity. Three robust ALF phenotypes emerged: Subtype 1 (28.3 %) - "critical hemodynamic collapse" with severe cardiovascular instability (MAP 78.9 mmHg, HR 113.5 bpm), highest illness severity (SAPS II: 62.0, SOFA: 12.2), and organ support requirements; Subtype 2 (44.6 %) - "cardiovascular dysfunction" with profound hypotension (MAP 69.1 mmHg) but low heart rate (84.3 bpm); and Subtype 3 (27.0 %) - "hyperacute hepatic necrosis" with preserved hemodynamics (MAP 99.4 mmHg) but severe hepatocellular injury (ALT 1059.8 U/L, AST 1427.3 U/L). Subtypes demonstrated distinct survival trajectories maintained through one-year follow-up (28-day mortality: Subtype 2 HR 0.48, 95 % CI: 0.40-0.59; Subtype 3 HR 0.39, 95 % CI: 0.31-0.50 vs. Subtype 1). Treatment responses varied significantly: epinephrine was harmful in Subtype 1 (OR 1.68) but protective in Subtypes 2 and 3 (OR 0.47, 0.34); dexmedetomidine benefited Subtype 3 (OR 0.26) but harmed Subtype 2 (OR 1.47); renal replacement therapy showed highest risk in Subtype 3 (OR 2.05). ALF comprises three distinct phenotypes with unique pathophysiological features, prognostic trajectories, and treatment responses. This phenotypic classification, validated across multiple international databases, provides a framework for precision medicine in ALF management and challenges the current one-size-fits-all treatment paradigm.