Comparative prognostic performance of FIB-4, AIP, and TyG for all-cause and cardiovascular mortality in FLI-defined MASLD: a nationally representative NHANES 2011–2018 cohort study

Background Metabolic dysfunction-associated steatotic liver disease (MASLD) is driven by both fibrosis and cardiometabolic dysfunction, but the relative prognostic value of fibrosis- and metabolism-related indices for near-term mortality remains uncertain. Aim To compare the associations and discriminatory performance of the fibrosis-4 index (FIB-4), atherogenic index of plasma (AIP), and triglyceride-glucose (TyG) index for all-cause mortality (ACM) and cardiovascular mortality (CVDM) in adults with FLI-defined MASLD. Methods This prospective cohort analysis included 4,037 adults with FLI-defined MASLD from NHANES 2011–2018. Mortality was ascertained through linkage to the National Death Index through December 31, 2019. Survey-weighted Cox models, restricted cubic splines, and 5-year time-dependent ROC analyses were used to evaluate associations and discrimination. Age-stratified analyses were performed because age is a component of FIB-4. Results During a median follow-up of approximately 4.5 years, 222 all-cause deaths and 66 cardiovascular deaths occurred. In fully adjusted age-stratified models, each 1-SD increase in FIB-4 was associated with higher ACM risk in participants aged < 65 years (HR 1.24, 95% CI 1.09–1.41) and ≥ 65 years (HR 1.34, 95% CI 1.20–1.50). FIB-4 was also associated with CVDM among participants aged ≥ 65 years (HR 1.37, 95% CI 1.19–1.59), whereas AIP and TyG were not significantly associated with CVDM in this age stratum. As standalone markers, FIB-4 showed higher 5-year discrimination than AIP and TyG for ACM (AUC 0.763 vs. 0.494 and 0.522) and CVDM (AUC 0.785 vs. 0.505 and 0.557). In sensitivity analyses using US-FLI-defined MASLD, the association of FIB-4 with ACM remained significant, and additional adjustment for lipid- and glucose-lowering medications did not materially alter the primary estimates. Conclusions In adults with FLI-defined MASLD, FIB-4 showed stronger near-term mortality risk stratification than AIP and TyG as standalone markers. The cardiovascular findings should be interpreted cautiously given the limited number of events and their sensitivity to the operational MASLD definition.