PT  - JOURNAL ARTICLE
AU  - Weiss, Emmanuel
AU  - de la Peña-Ramirez, Carlos
AU  - Aguilar, Ferran
AU  - Lozano, Juan-Jose
AU  - Sánchez-Garrido, Cristina
AU  - Sierra, Patricia
AU  - Martin, Pedro Izquierdo-Bueno
AU  - Diaz, Juan Manuel
AU  - Fenaille, François
AU  - Castelli, Florence A
AU  - Gustot, Thierry
AU  - Laleman, Wim
AU  - Albillos, Agustín
AU  - Alessandria, Carlo
AU  - Domenicali, Marco
AU  - Caraceni, Paolo
AU  - Piano, Salvatore
AU  - Saliba, Faouzi
AU  - Zeuzem, Stefan
AU  - Gerbes, Alexander L
AU  - Wendon, Julia A
AU  - Jansen, Christian
AU  - Gu, Wenyi
AU  - Papp, Maria
AU  - Mookerjee, Raj
AU  - Gambino, Carmine Gabriele
AU  - Jiménez, Cesar
AU  - Giovo, Ilaria
AU  - Zaccherini, Giacomo
AU  - Merli, Manuela
AU  - Putignano, Antonella
AU  - Uschner, Frank Erhard
AU  - Berg, Thomas
AU  - Bruns, Tony
AU  - Trautwein, Christian
AU  - Zipprich, Alexander
AU  - Bañares, Rafael
AU  - Presa, José
AU  - Genesca, Joan
AU  - Vargas, Victor
AU  - Fernández, Javier
AU  - Bernardi, Mauro
AU  - Angeli, Paolo
AU  - Jalan, Rajiv
AU  - Claria, Joan
AU  - Junot, Christophe
AU  - Moreau, Richard
AU  - Trebicka, Jonel
AU  - Arroyo, Vicente
TI  - Sympathetic nervous activation, mitochondrial dysfunction and outcome in acutely decompensated cirrhosis: the metabolomic prognostic models (CLIF-C MET)
AID  - 10.1136/gutjnl-2022-328708
DP  - 2023 Aug 01
TA  - Gut
PG  - 1581--1591
VI  - 72
IP  - 8
4099  - http://gut.bmj.com/content/72/8/1581.short
4100  - http://gut.bmj.com/content/72/8/1581.full
SO  - Gut2023 Aug 01; 72
AB  - 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.Data are available upon reasonable request.