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.

Trial registration: ClinicalTrials.gov NCT03056612.

Keywords: cirrhosis; liver failure; liver metabolism.

Figure 1

Mortality at 28 days is associated with a general increase in metabolite levels. (A) Volcano plots showing the results of pairwise comparisons of blood metabolites levels of patients from CANONIC (left) and PREDICT (right) study cohorts relative to mortality at 28 days. The vertical dashed lines indicate the threshold for the twofold abundance difference. The horizontal dashed line indicates the p value=0.05 threshold. (B) Cleveland plots. Overview of the fold change of all detected metabolites between patients who died within 28 days after enrolment versus those who survived in each cohort in both CANONIC and PREDICT (red and blue dots, respectively) study cohorts, using CANONIC cohort as reference. Left inset shows the annotation of the top 50 metabolites.

Figure 2

Metabolite abilities to predict mortality at 28 days and their similarities between study cohorts. Hierarchical clustering analysis of C-index values obtained assessing mortality at 28 days with each measured metabolite in the CANONIC (left column) and the PREDICT (right column) study cohort. Vertical green bar and inset identify the cluster formed by the 29 metabolites with the highest C-index in both cohorts.