Development and validation of clinical phenotypes 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 phenotypes. phenotypes were subsequently validated and characterized through XGBoost-based SHAP analysis and survival analysis, which elucidated essential distinguishing features and variability in treatment response. RESULTS: phenotypes 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, phenotypes C and D had higher 30-day mortality rates than phenotype A (HR = 1.44 and 1.32, respectively). There was no significant difference between phenotypes A and B. In SALI, therapeutic responses were specific to phenotypes. Patients with phenotype A experienced advantages from early antibiotic treatment alongside moderate fluid resuscitation. Patients with phenotype B benefited from immediate antibiotics, limited fluids, and low-dose norepinephrine. Patients with phenotype C benefited from a moderate fluid range, low-dose norepinephrine, and relatively lenient antibiotic initiation. Patients with phenotype D benefited from high-volume fluid resuscitation, high-dose norepinephrine administration, and relatively lenient antibiotic timing. CONCLUSIONS: SALI consists of four distinct phenotypes, 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. CLINICAL TIRAL NUMBER: Not applicable.