Circulating Citrate Is Reversibly Elevated in Patients with End-Stage Liver Disease: Association with All-Cause Mortality

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 (p < 0.001). In a subset of 30 ESLD patients, citrate decreased following liver transplantation (p < 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 p < 0.05). Survival was significantly reduced in ESLD patients in the highest citrate tertile (log-rank p = 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], p = 0.037). This association was suggested to be particularly present in men (HR: 2.04 [95% CI: 1.08–3.85], p = 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.