Development and Validation of Clinical Subphenotypes in Sepsis-Associated Liver Injury Using Multi-Algorithm Consensus Classification: A Retrospective Cohort Study

Background: Sepsis-associated liver injury (SALI) is a heterogeneous syndrome with high mortality and pathophysiological heterogeneity. Current prognostic models are limited in their ability to capture the heterogeneity in pathophysiology, highlighting the demand for improved stratification of patient subgroups and the development of personalized therapeutic strategies. Methods: We performed a retrospective analysis of ICU patients diagnosed with SALI from 2001 to 2022. The research included 5,755 adult patients obtained from four databases, utilizing the eICU-CRD cohort (n=3,893) for initial exploration and three independent cohorts (NWICU-1.0, MIMIC-III, MIMIC-IV; n=1,862) for subsequent validation. We developed and utilized a novel Multi-algorithm Consensus-based Sepsis-Associated Liver Injury Classification (MCSALIC) method that integrates ten clustering algorithms. This technique identified four distinct SALI subphenotypes. Subphenotypes were subsequently validated and characterized through XGBoost-based SHAP analysis and survival analysis, which elucidated essential distinguishing features and variability in treatment response.. Results: Subphenotypes A (47.9%, liver preservation), B (22.6%, hyperbilirubinemia), C (16.7%, hepatocellular dysfunction), and D (12.8%, cholestasis) were delineated. In the development cohort, subphenotypes C and D had higher 30-day mortality rates than subphenotype A (HR=1.44 and 1.32, respectively). There was no significant difference between subphenotypes A and B. In SALI, therapeutic responses were specific to phenotypes. Patients with subphenotype A experienced advantages from early antibiotic treatment alongside moderate fluid resuscitation. Patients with subphenotype B benefited from immediate antibiotics, limited fluids, and low-dose norepinephrine. Patients with subphenotype C benefited from a moderate fluid range, low-dose norepinephrine, and relatively lenient antibiotic initiation. Patients with subphenotype D benefited from high-volume fluid resuscitation, high-dose norepinephrine administration, and relatively lenient antibiotic timing. Conclusions: SALI consists of four distinct subphenotypes, each characterized by unique pathophysiology, prognostic outcomes, and treatment responses. This stratification, strongly validated across international cohorts, sets the stage for precision medicine and calls into question the current one-size-fits-all approach to treatment.