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

Abstract

Background: 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. Methods: 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. Results: Patients with cirrhosis had lower plasma BHB concentrations than matched PREVEND participants (111.5 µmol/L vs. 138.4 µmol/L, p = 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 (p < 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, p < 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, p = 0.06). Sensitivity analyses, excluding diabetic patients and those with metabolic dysfunction-associated steatotic liver disease, confirmed the robustness of these findings. Conclusion: 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.

Keywords: NMR spectroscopy; Prevention of Renal and Vascular End-stage Disease (PREVEND) cohort study; TransplantLines cohort and biobank study; cirrhosis; ketone bodies; β-hydroxybutyrate.

Figure 1

Ln-transformed β-hydroxybutyrate levels in cirrhosis by etiology of liver disease. The x-axis is in the ln-scale, with markers labeled in absolute values (µmol/L) for reference (i.e., e² ≈ 7, e⁴ ≈ 55, e⁶ ≈ 403). A propensity-matched subset of PREVEND participants is included as a reference group. Statistical comparisons are indicated: *** p < 0.001 vs. the PREVEND subset. ”Other” etiologies refer to cases of autoimmune hepatitis, storage disease, biliary atresia, and vascular disease (portal vein thrombosis, sinusoidal obstruction, Budd–Chiari syndrome).

Figure 2

Kaplan–Meier survival curves for the association between plasma β-hydroxybutyrate concentrations and the risk of all-cause mortality in end-stage liver disease patients on the waiting list for LT. Log-rank test between middle and upper tertile: p < 0.001. Log-rank test between lower and upper tertile: p = 0.009. Log-rank test between lower and middle tertile: p = 0.2.

Figure 3

GAM-smoothed curve (with 95% confidence intervals) showing the relationship between β-hydroxybutyrate and the probability of overall death in patients with cirrhosis. The vertical dashed lines at 82.3 μmol/L and 157.2 μmol/L represent the tertile cutoffs for BHB.