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

Abstract

Background and aimsCurrent 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.MethodsTwo 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.ResultsThree 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.ConclusionsModels 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.

Recent advances in the prevention and treatment of decompensated cirrhosis and acute-on-chronic liver failure (ACLF) and the role of biomarkers

“…Weiss et al showed in two prospective multicentre large cohorts from (CANONIC (discovery, n=831) and PREDICT (validation, n=851)) that models including metabolites (CLIF-C MET)—here the prognostic composite biomarker—reflecting SI, mitochondrial dysfunction and sympathetic system activation were superior to prognostic short-term mortality using established clinical scores (eg, MELDNa). 23 Such prognostic biomarkers are also used in clinical trials as a method to identify patients who might have a higher risk of developing the event of interest, and, as such, enable enrichment of trials and reduce sample size ( figure 1 ).…”

Acute-On-Chronic Liver Failure: Current Interventional Treatment Options and Future Challenges

“…Another recent publication by Weiss et al investigated the role of metabolites reflecting SI, mitochondrial dysfunction, and sympathetic system activation in predicting short term mortality in patients with ACLF, and invented the CLIF-C MET score. However, cost-effectiveness analysis and prospective validation of these markers and scores remains necessary [68].…”

Toward a more precise prognostic stratification in acute decompensation of cirrhosis: The Padua model 2.0

“…On the other hand, patients with unstable decompensated cirrhosis (UDC), who will experience further decompensation without developing ACLF and have an intermediate risk of death, and patients with stable decompensated cirrhosis (SDC), who will not experience any further decompensation and have a lower risk of 1-year mortality. 3 Although our understanding of the pathophysiology of AD-ACLF syndrome has improved in the recent years, 4 leading to the "systemic inflammation hypothesis," 5 prediction of the individual patient's trajectory after AD remains challenging. 6,7 However, better identification of patients with AD at higher risk of progression would improve patient management (i.e., identification of candidates for an expedite evaluation for liver transplantation and/or disease-modifying therapies currently under investigation).…”

“…Although our understanding of the pathophysiology of AD‐ACLF syndrome has improved in the recent years, 4 leading to the “systemic inflammation hypothesis,” 5 prediction of the individual patient's trajectory after AD remains challenging 6,7 . However, better identification of patients with AD at higher risk of progression would improve patient management (i.e., identification of candidates for an expedite evaluation for liver transplantation and/or disease‐modifying therapies currently under investigation) 8–10 …”