Li Yakun, Chvatal-Medina Mateo, Trillos-Almanza Maria Camila, Bourgonje Arno R, Connelly Margery A, Moshage Han, Bakker Stephan J L, de Meijer Vincent E, Blokzijl Hans, Dullaart Robin P F
Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands.
The Henry D. Janowitz Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Int J Mol Sci. 2024 Nov 28;25(23):12806. doi: 10.3390/ijms252312806.
Circulating citrate may serve as a proxy for mitochondrial dysfunction which plays a role in the progression of end-stage liver disease (ESLD). This study aimed to determine the extent of alterations in circulating citrate in patients with ESLD, and examined its association with all-cause mortality among ESLD patients while on the waiting list for liver transplantation. Plasma citrate levels were measured using nuclear magnetic resonance spectroscopy in 129 ESLD patients (TransplantLines cohort study; NCT03272841) and compared to levels in 4837 participants of the community-dwelling PREVEND cohort. Plasma citrate levels were 40% higher in ESLD patients compared to PREVEND participants ( < 0.001). In a subset of 30 ESLD patients, citrate decreased following liver transplantation ( < 0.001), resulting in levels that were slightly lower than those observed in PREVEND participants. In multivariable analysis, plasma citrate levels were positively associated with Child-Turcotte-Pugh classification and inversely associated with estimated glomerular filtration rate (both < 0.05). Survival was significantly reduced in ESLD patients in the highest citrate tertile (log-rank = 0.037). Elevated citrate levels were associated with an increased risk of all-cause mortality in ESLD patients (HR per 1 Ln SD increment: 1.65 [95% CI: 1.03-2.63], = 0.037). This association was suggested to be particularly present in men (HR: 2.04 [95% CI: 1.08-3.85], = 0.027). In conclusion, plasma citrate levels are elevated in ESLD patients and decrease following liver transplantation. Moreover, elevated plasma citrate levels may be associated with increased all-cause mortality in ESLD patients, likely more pronounced in men.
循环中的柠檬酸盐可能是线粒体功能障碍的一个替代指标，而线粒体功能障碍在终末期肝病（ESLD）的进展中起作用。本研究旨在确定ESLD患者循环中柠檬酸盐的改变程度，并在肝移植等待名单上的ESLD患者中研究其与全因死亡率的关联。在129例ESLD患者中使用核磁共振波谱法测量血浆柠檬酸盐水平（移植队列研究；NCT03272841），并与4837名社区居住的PREVEND队列参与者的水平进行比较。与PREVEND参与者相比，ESLD患者的血浆柠檬酸盐水平高40%（<0.001）。在30例ESLD患者的亚组中，肝移植后柠檬酸盐水平下降（<0.001），导致其水平略低于PREVEND参与者中观察到的水平。在多变量分析中，血浆柠檬酸盐水平与Child-Turcotte-Pugh分类呈正相关，与估计肾小球滤过率呈负相关（均<0.05）。柠檬酸盐水平最高三分位数的ESLD患者生存率显著降低（对数秩=0.037）。ESLD患者中柠檬酸盐水平升高与全因死亡风险增加相关（每增加1个标准差的HR：1.65[95%CI：1.03-2.63]，=0.037）。这种关联在男性中尤为明显（HR：2.04[95%CI：1.08-3.85]，=0.027）。总之，ESLD患者血浆柠檬酸盐水平升高，肝移植后降低。此外，血浆柠檬酸盐水平升高可能与ESLD患者全因死亡率增加相关，在男性中可能更明显。
