Sympathetic nervous activation, mitochondrial dysfunction and outcome in acutely decompensated cirrhosis: the metabolomic prognostic models (CLIF-C MET)

医学 队列 代谢组学 内科学 肝硬化 前瞻性队列研究 胃肠病学 队列研究 内分泌学 生物信息学 生物
作者
Emmanuel Weiss,Carlos de la Peña-Ramirez,Ferrán Aguilar,Juan José Lozano,Cristina Sánchez-Garrido,Patricia Sierra,Pedro Izquierdo-Bueno Martin,Juan Manuel Moreno,François Fenaille,Florence Castelli,Thierry Gustot,Wim Laleman,Agustı́n Albillos,Carlo Alessandria,Marco Domenicali,Paolo Caraceni,Salvatore Piano,Faouzi Saliba,Stefan Zeuzem,Alexander L. Gerbes,Julia Wendon,Christian Jansen,Wen Gu,Mária Papp,Rajeshwar P. Mookerjee,Carmine Gambino,César Jiménez,Ilaria Giovo,Giacomo Zaccherini,Manuela Merli,Antonella Putignano,Frank Erhard Uschner,Thomas Berg,Tony Bruns,Christian Trautwein,Alexander Zipprich,Rafael Bañares,José Presa,Joan Genescà,Vı́ctor Vargas,Javier Fernández,Mauro Bernardi,Paolo Angeli,Rajiv Jalan,J. J. Clariá,Christophe Junot,Richard Moreau,Jonel Trebicka,Vicente Arroyo
出处
期刊:Gut [BMJ]
卷期号:72 (8): 1581-1591 被引量:21
标识
DOI:10.1136/gutjnl-2022-328708
摘要

Background and aims Current prognostic scores of patients with acutely decompensated cirrhosis (AD), particularly those with acute-on-chronic liver failure (ACLF), underestimate the risk of mortality. This is probably because systemic inflammation (SI), the major driver of AD/ACLF, is not reflected in the scores. SI induces metabolic changes, which impair delivery of the necessary energy for the immune reaction. This investigation aimed to identify metabolites associated with short-term (28-day) death and to design metabolomic prognostic models. Methods Two prospective multicentre large cohorts from Europe for investigating ACLF and development of ACLF, CANONIC (discovery, n=831) and PREDICT (validation, n=851), were explored by untargeted serum metabolomics to identify and validate metabolites which could allow improved prognostic modelling. Results Three prognostic metabolites strongly associated with death were selected to build the models. 4-Hydroxy-3-methoxyphenylglycol sulfate is a norepinephrine derivative, which may be derived from the brainstem response to SI. Additionally, galacturonic acid and hexanoylcarnitine are associated with mitochondrial dysfunction. Model 1 included only these three prognostic metabolites and age. Model 2 was built around 4-hydroxy-3-methoxyphenylglycol sulfate, hexanoylcarnitine, bilirubin, international normalised ratio (INR) and age. In the discovery cohort, both models were more accurate in predicting death within 7, 14 and 28 days after admission compared with MELDNa score (C-index: 0.9267, 0.9002 and 0.8424, and 0.9369, 0.9206 and 0.8529, with model 1 and model 2, respectively). Similar results were found in the validation cohort (C-index: 0.940, 0.834 and 0.791, and 0.947, 0.857 and 0.810, with model 1 and model 2, respectively). Also, in ACLF, model 1 and model 2 outperformed MELDNa 7, 14 and 28 days after admission for prediction of mortality. Conclusions Models including metabolites (CLIF-C MET) reflecting SI, mitochondrial dysfunction and sympathetic system activation are better predictors of short-term mortality than scores based only on organ dysfunction (eg, MELDNa), especially in patients with ACLF.
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