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

Adrian Post,Eline H Van Den Berg,Margery A Connelly,Erwin Garcia,Robin P F Dullaart,Dion Groothof,Berend Daan Westenbrink,Stephan J.L Bakker,Jose L Flores‐Guerrero,Eke G Gruppen

doi:10.1111/eci.13627

Abstract

BackgroundNonalcoholic 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.MethodsPlasma 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.ResultsThe 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).ConclusionCirculating 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.

Highlights

Nonalcoholic fatty liver disease (NAFLD), defined as hepatic steatosis in the absence of excessive alcohol use, is becoming the most common chronic liver disease in the Western world.[1]
In this population-b ased cohort, we have demonstrated to the best our knowledge for the first time that circulating ketone bodies are higher in subjects with suspected NAFLD, using an elevated fatty liver index (FLI) as proxy, as compared to those without an elevated FLI
Mediation analyses suggested that the association of suspected NAFLD with all-cause mortality was in part mediated by higher circulating ketone bodies

Summary

Introduction

Nonalcoholic fatty liver disease (NAFLD), defined as hepatic steatosis in the absence of excessive alcohol use, is becoming the most common chronic liver disease in the Western world.[1]. 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. Higher total ketone bodies were 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

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