Dataset Information

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

ABSTRACT:

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.

SUBMITTER: Weiss E

PROVIDER: S-EPMC10359524 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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Publications

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

Weiss Emmanuel E de la Peña-Ramirez Carlos C Aguilar Ferran F Lozano Juan-Jose JJ Sánchez-Garrido Cristina C Sierra Patricia P Martin Pedro Izquierdo-Bueno PI Diaz Juan Manuel JM Fenaille François F Castelli Florence A FA Gustot Thierry T Laleman Wim W Albillos Agustín A Alessandria Carlo C Domenicali Marco M Caraceni Paolo P Piano Salvatore S Saliba Faouzi F Zeuzem Stefan S Gerbes Alexander L AL Wendon Julia A JA Jansen Christian C Gu Wenyi W Papp Maria M Mookerjee Raj R Gambino Carmine Gabriele CG Jiménez Cesar C Giovo Ilaria I Zaccherini Giacomo G Merli Manuela M Putignano Antonella A Uschner Frank Erhard FE Berg Thomas T Bruns Tony T Trautwein Christian C Zipprich Alexander A Bañares Rafael R Presa José J Genesca Joan J Vargas Victor V Fernández Javier J Bernardi Mauro M Angeli Paolo P Jalan Rajiv R Claria Joan J Junot Christophe C Moreau Richard R Trebicka Jonel J Arroyo Vicente V

Gut 20230214 8

<h4>Background and aims</h4>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 ...[more]

PMID: 36788015

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Project description:Background: Patients with acutely decompensated cirrhosis (AD) may or may not develop acute-on-chronic liver failure (ACLF). ACLF is characterized by high-grade systemic inflammation, organ failures (OF) and high short-term mortality. Although patients with AD cirrhosis exhibit distinct clinical phenotypes at baseline, they have low short-term mortality, unless ACLF develops during follow-up. Because little is known about the association of profile of systemic inflammation with clinical phenotypes of patients with AD cirrhosis, we aimed to investigate a battery of markers of systemic inflammation in these patients. Methods: Upon hospital admission baseline plasma levels of 15 markers (cytokines, chemokines, and oxidized albumin) were measured in 40 healthy controls, 39 compensated cirrhosis, 342 AD cirrhosis, and 161 ACLF. According to EASL-CLIF criteria, AD cirrhosis was divided into three distinct clinical phenotypes (AD-1: Creatinine<1.5, no HE, no OF; AD-2: creatinine 1.5-2, and or HE grade I/II, no OF; AD-3: Creatinine<1.5, no HE, non-renal OF). Results: Most markers were slightly abnormal in compensated cirrhosis, but markedly increased in AD. Patients with ACLF exhibited the largest number of abnormal markers, indicating "full-blown" systemic inflammation (all markers). AD-patients exhibited distinct systemic inflammation profiles across three different clinical phenotypes. In each phenotype, activation of systemic inflammation was only partial (30% of the markers). Mortality related to each clinical AD-phenotype was significantly lower than mortality associated with ACLF (p < 0.0001 by gray test). Among AD-patients baseline systemic inflammation (especially IL-8, IL-6, IL-1ra, HNA2 independently associated) was more intense in those who had poor 28-day outcomes (ACLF, death) than those who did not experience these outcomes. Conclusions: Although AD-patients exhibit distinct profiles of systemic inflammation depending on their clinical phenotypes, all these patients have only partial activation of systemic inflammation. However, those with the most extended baseline systemic inflammation had the highest the risk of ACLF development and death.

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Dataset Information

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

Background and aims

Methods

Results

Conclusions

Publications

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

Similar Datasets

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