Nonalcoholic fatty liver disease, circulating ketone bodies and all‐cause mortality in a general population‐based cohort

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is increasingly prevalent, paralleling the obesity epidemic. Ketone bodies are produced in the liver, but it is currently uncertain whether circulating ketone bodies are increased in the context of NAFLD. We investigated the association between NAFLD and circulating ketone bodies and determined the extent to which NAFLD and circulating ketone bodies are associated with all‐cause mortality. METHODS: Plasma ketone bodies were measured by nuclear magnetic resonance spectroscopy in participants of the general population‐based PREVEND study. A fatty liver index (FLI) ≥60 was regarded as a proxy of NAFLD. Associations of an elevated FLI and ketone bodies with all‐cause mortality were investigated using Cox regression analyses. RESULTS: The study included 6,297 participants aged 54 ± 12 years, of whom 1,970 (31%) had elevated FLI. Participants with elevated FLI had higher total ketone bodies (194 [153‐259] vs 170 [133‐243] µmol/L; P < .001) than participants without elevated FLI. During 7.9 [7.8‐8.9] years of follow‐up, 387 (6%) participants died. An elevated FLI was independently associated with an increased risk of mortality (HR: 1.34 [1.06‐1.70]; P = .02). Higher total ketone bodies were also associated with an increased mortality risk (HR per doubling: 1.29 [1.12‐1.49]; P < .001). Mediation analysis suggested that the association of elevated FLI with all‐cause mortality was in part mediated by ketone bodies (proportion mediated: 10%, P < .001). CONCLUSION: Circulating ketone bodies were increased in participants with suspected NAFLD. Both suspected NAFLD and higher circulating ketone bodies are associated with an increased risk of all‐cause mortality.