Plasma Beta-Hydroxybutyrate and All-Cause Mortality in Patients with Liver Cirrhosis

<b>Background:</b> Liver cirrhosis is often accompanied by metabolic dysfunction. Circulating β-hydroxybutyrate (BHB), the most abundant ketone body, is an emerging metabolic biomarker of mitochondrial dysfunction. <b>Methods:</b> In this prospective observational study, we evaluated plasma BHB concentrations in patients with cirrhosis compared to the general population and investigated their association with all-cause mortality in cirrhosis. Plasma BHB, measured by nuclear magnetic resonance spectroscopy, was compared between 125 patients with cirrhosis on the waiting list for liver transplantation (TransplantLines cohort study; NCT03272841) with 125 propensity-score-matched participants from the population-dwelling PREVEND cohort. Associations of BHB with all-cause mortality were established by tertile-based log-rank tests and Cox regression analyses. A generalized additive model was fitted to assess a potential non-linear association between BHB and mortality. <b>Results:</b> Patients with cirrhosis had lower plasma BHB concentrations than matched PREVEND participants (111.5 µmol/L vs. 138.4 µmol/L, <i>p</i> = 0.02). During 133 (interquartile range 42-375) days of follow up, 27 patients died. All-cause mortality was lowest in the middle BHB tertile and highest in the upper BHB tertile (<i>p</i> < 0.001 by log-rank test). A non-linear, J-shaped association between BHB levels and mortality risk was found with a higher risk of death with the highest and lowest BHB levels. In Cox regression analyses, adjusted for age, sex, MELD score, diabetes, and HDL cholesterol, mortality was highest in the highest BHB tertile (T3 vs. T2 HR: 7.6, 95% CI: 2.3-25.6, <i>p</i> < 0.001). Mortality also tended to be higher in the lowest vs. the middle (T1 vs. T2 HR: 3.5, 95% CI: 0.9-11.7, <i>p</i> = 0.06). Sensitivity analyses, excluding diabetic patients and those with metabolic dysfunction-associated steatotic liver disease, confirmed the robustness of these findings. <b>Conclusion:</b> BHB levels exhibit a J-shaped association with the risk of death in patients with liver cirrhosis. The highest circulating BHB levels are independently associated with increased mortality risk, potentially reflecting underlying metabolic dysregulation. Future studies are necessary to validate the utility of BHB as a prognostic target in cirrhosis.