Circulating FGF21 and Ketone Bodies Modify the Risk of MASLD and Mortality: Insights from the PREVEND Cohort Study

Fibroblast growth factor 21 (FGF21) and ketone bodies are markers of metabolic dysregulation, independently associated with metabolic-dysfunction-associated steatotic liver disease (MASLD) and mortality. We studied their interaction with MASLD and all-cause mortality in 6025 participants from the Prevention of Renal and Vascular End-stage Disease (PREVEND) cohort. Plasma FGF21 (immunoassay) and ketone body concentrations (nuclear magnetic resonance spectroscopy) were measured at baseline. A Fatty Liver Index ≥60 was used as a proxy of MASLD. Logistic regression assessed associations with MASLD, and Cox models evaluated all-cause mortality over a median follow-up of 10.3 years. FGF21 and ketone bodies were not correlated (r = 0.02, <i>p</i> = 0.06), but FGF21 (OR: 1.93 [1.81-2.05], <i>p</i> < 0.001) and ketone bodies (OR: 1.29 [1.19-2.05], <i>p</i> < 0.001) were independent of each other associated with MASLD, with a positive interaction (<i>p</i> = 0.004). Higher FGF21 (HR: 1.24, 95% CI: 1.16-1.32, <i>p</i> < 0.001) and ketone bodies (HR: 1.46, 95% CI: 1.34-1.59, <i>p</i> < 0.001) were associated with mortality, as well as with a positive interaction (<i>p</i> = 0.038). After adjustment for potential confounders, only ketone bodies remained independently associated, while the association of FGF21 became dependent on ketone body levels (interaction <i>p</i> = 0.005). These biomarkers may serve as integrated metabolic stress markers, improving risk stratification for MASLD and adverse outcomes.