Sympathetic nervous activation, mitochondrial dysfunction and outcome in acutely decompensated cirrhosis: the metabolomic prognostic models (CLIF-C MET)
Authors: Weiss Emmanuel , de la Peña-Ramirez Carlos , Aguilar Ferran , Lozano Juan-Jose , Sánchez-Garrido Cristina , Sierra Patricia , Martin Pedro Izquierdo-Bueno , Diaz Juan Manuel , Fenaille François , Castelli Florence A , Gustot Thierry , Laleman Wim , Albillos Agustín , Alessandria Carlo , Domenicali Marco , Caraceni Paolo , Piano Salvatore , Saliba Faouzi , Zeuzem Stefan , Gerbes Alexander L , Wendon Julia A , Jansen Christian , Gu Wenyi , Papp Maria , Mookerjee Raj , Gambino Carmine Gabriele , Jiménez Cesar , Giovo Ilaria , Zaccherini Giacomo , Merli Manuela , Putignano Antonella , Uschner Frank Erhard , Berg Thomas , Bruns Tony , Trautwein Christian , Zipprich Alexander , Bañares Rafael , Presa José , Genesca Joan , Vargas Victor , Fernández Javier , Bernardi Mauro , Angeli Paolo , Jalan Rajiv , Claria Joan , Junot Christophe , Moreau Richard , Trebicka Jonel , Arroyo Vicente 
Published: February 2023

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.