Chvatal-Medina Mateo, Li Yakun, Trillos-Almanza María Camila, Post Adrian, Connelly Margery A, Moshage Han, Bakker Stephan J L, Meijer Vincent E de, Blokzijl Hans, Dullaart Robin P F
Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands.
Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, University of Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands.
Biomedicines. 2025 May 6;13(5):1120. doi: 10.3390/biomedicines13051120.
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. 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. Patients with cirrhosis had lower plasma BHB concentrations than matched PREVEND participants (111.5 µmol/L vs. 138.4 µmol/L, = 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 ( < 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, < 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, = 0.06). Sensitivity analyses, excluding diabetic patients and those with metabolic dysfunction-associated steatotic liver disease, confirmed the robustness of these findings. 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.
肝硬化常伴有代谢功能障碍。循环中的β-羟基丁酸（BHB）是最丰富的酮体，是一种新兴的线粒体功能障碍代谢生物标志物。在这项前瞻性观察研究中，我们评估了肝硬化患者与普通人群相比的血浆BHB浓度，并研究了它们与肝硬化全因死亡率的关联。通过核磁共振波谱法测量的血浆BHB，在125例等待肝移植的肝硬化患者（TransplantLines队列研究；NCT03272841）与125例来自人群居住的PREVEND队列中倾向得分匹配的参与者之间进行了比较。通过基于三分位数的对数秩检验和Cox回归分析确定了BHB与全因死亡率的关联。拟合了广义相加模型以评估BHB与死亡率之间潜在的非线性关联。肝硬化患者的血浆BHB浓度低于匹配的PREVEND参与者（111.5µmol/L对138.4µmol/L，P=0.02）。在133天（四分位间距42 - 375天）的随访期间，27例患者死亡。全因死亡率在BHB三分位数的中间组最低，在最高组最高（对数秩检验P<0.001）。发现BHB水平与死亡风险之间呈非线性J形关联，BHB水平最高和最低时死亡风险更高。在Cox回归分析中，校正年龄、性别、终末期肝病模型（MELD）评分、糖尿病和高密度脂蛋白胆固醇后，BHB三分位数最高组的死亡率最高（T3与T2相比，风险比[HR]：7.6，95%置信区间[CI]：2.3 - 25.6，P<0.001）。最低组与中间组相比死亡率也倾向于更高（T1与T2相比，HR：3.
