Abstract
Sepsis-induced hepatic dysfunction contributes significantly to poor clinical outcomes. Although the Fibrosis-4 (FIB-4) index is established for assessing chronic liver fibrosis, its utility as a prognostic marker for acute sepsis mortality-particularly in patients without pre-existing liver disease-remains unclear. We aimed to evaluate the predictive value of FIB-4 in sepsis using two large, multi-center databases.We conducted a multicenter retrospective study using two large critical care databases: MIMIC-IV (n = 13,983) and eICU (n = 9,976). Sepsis was defined based on established clinical criteria. Missing values were handled using multiple imputation to preserve data integrity. The optimal FIB-4 cutoff points were determined via outcome-based stratification (1.25). Patients were categorized into high and low FIB-4 groups accordingly. We applied restricted cubic spline (RCS) modeling to evaluate nonlinear trends, followed by weighted Cox regression to determine independent associations with in-hospital mortality. Kaplan-Meier survival curves assessed time-to-event differences, while subgroup analyses, ROC curves, and sensitivity analyses explored effect consistency and underlying biological pathways. Across 23,959 sepsis patients from the MIMIC-IV and eICU databases, elevated FIB-4 levels were significantly associated with in-hospital mortality (P < 0.001). An FIB-4 index > 1.25 served as an independent risk factor for mortality (adjusted HRs: 1.38-1.55) and outperformed traditional SOFA and APACHE scores in prognostic discrimination. Kaplan-Meier curves showed significantly reduced survival in the high FIB-4 group. Importantly, sensitivity analyses excluding patients with known liver disease, suspected MASLD, or cardiac admissions confirmed the robustness of these findings. The FIB-4 index serves as a robust, independent prognostic marker for in-hospital mortality in sepsis patients, outperforming traditional scores such as SOFA and APACHE II in predictive accuracy. Crucially, its prognostic value persists even after excluding patients with pre-existing liver disease or acute cardiogenic hepatic congestion, suggesting it reflects broader sepsis-induced physiological derangements rather than solely baseline hepatic fibrosis. Given its simplicity and reliance on routinely available laboratory parameters, FIB-4 offers a practical, accessible tool for early risk stratification in the intensive care setting.