February 20, 2023 Study identifies three prognostic metabolites that could be used to improve care for patients with chronic liver disease Two new prognostic models based on three metabolites reflecting systemic inflammation, mitochondrial dysfunction and sympathetic nervous system activation are found to better predict short-term mortality in acute decompensation of cirrhosis and acute-on-chronic liver failure (ACLF).

BARCELONA—Systemic inflammation is the major driver of acute decompensation of cirrhosis contributing to the development and severity of acute-on-chronic liver failure (ACLF) – a syndrome associated with multiorgan failure and high short-term mortality. About 20% of patients with acute decompensation of cirrhosis develop ACLF within three months of hospitalization. The model for end-stage liver disease (MELD) has been widely used to predict mortality in patients with acute decompensation of cirrhosis and to prioritize patients for liver transplantation. However, MELD and its variations fail to predict early deaths in ACLF patients. The Chronic Liver Failure Consortium acute-on-chronic liver failure (CLIF-C ACLF) score has proven to be superior, yet has limitations in predicting short-term mortality in a significant number of patients. In a previous study, researchers at EF CLIF showed that the presence of a set of metabolites – small molecules that function as intermediate or end products of metabolic reactions that occur throughout the body – correlated with severity of systemic inflammation and ACLF.

In this study, researchers identified three metabolites with the potential to render better prognosis in patients with acute decompensation of cirrhosis and ACLF at high risk of short-term mortality. The study published ahead of print on 14 February 2023 in Gut, describes the design and validation of two metabolomic models (CLIF-C MET): model 1 includes three metabolites independently associated with 28-day mortality in addition to age; whereas model 2, in addition to prognostic metabolites, includes laboratory measurements known to be of prognostic significance (i.e., bilirubin and international normalized ration (INR)), and age.

The retrospective analysis of serum metabolites in more than 1600 patients with acute decompensation of cirrhosis in the CANONIC and PREDICT studies allowed researchers to identify upregulated metabolites in patients who died within 28 days after hospitalization compared to those patients who survived. The metabolomic fingerprints in acute decompensation of cirrhosis and ACLF were found to overlap, suggesting that the pathophysiological mechanisms underlying acute decompensation of cirrhosis and progression to ACLF could both rely on dysfunctional metabolic pathways. Among the top 10 metabolites identified, 4-hydroxy-3-methoxyphenylglycol sulfate, hexanoylcarnitine, and D-galacturonic acid were used together with age and clinically relevant prognostic variables to design two new metabolomic models to better predict the risk of short-term mortality in patients with acute decompensation of cirrhosis and ACLF.

“We aimed to show that systemic inflammatory and metabolic responses may provide adequate biomarkers for prognostication of patients with acute decompensation of cirrhosis and ACLF", said first author in the paper Emmanuel Weiss, former EF CLIF Research Fellow currently at Centre de Recherche sur l’Inflammation, Université Paris Cité, and Hôpital Beaujon France.

The superior performance of the new CLIF-C MET score in predicting short-term mortality in patients with acute decompensation of cirrhosis relies on the detection of increased levels of circulating metabolites that are likely to result from changes in extrahepatic metabolic pathways in response to severe systemic inflammation.

“CLIF-C MET models include from the top-predictive metabolites, those independently associated with short-term mortality. When including standard laboratory measures, such as those included in the MELD and CLIF-C ACLF scores, two of the three selected metabolites were still associated with mortality in our models and still rendered similar results, pointing to the importance metabolites might have in predicting outcome in patients”, explained Carlos de la Peña-Ramirez, Statistician at EF CLIF.

Researchers argued that high levels of 4-hydroxy-3-methoxyphenylglycol sulfate, a sulfated metabolite of a major end product of norepinephrine metabolism, in addition to be associated with vascular dysfunction may be an indirect indication of norepinephrine turnover. Physical activity, danger or stress activate the sympathetic nervous system to trigger the so called “fight-or-flight” response. In the presence of any stressor, release of norepinephrine triggers the rapid mobilization of stored glucose, fatty acids and amino acids to satisfy the energy demand of tissues throughout the body as part of the physiological response to stress. The authors suggested that norepinephrine may help to provide immune cells with the continued supply of energy substrates necessary to maintain the body’s defence against infection and restore tissue homeostasis. The bioenergetic demands of (naïve) immune cells are usually met by complete oxidation of glucose via glycolysis, tricarboxylic acid cycle and mitochondrial oxidative phosphorylation – a series of interconnected, energy-yielding biochemical reactions coupled to the synthesis of adenosine triphosphate. Upon activation, immune cells switch the metabolism of glucose towards the pentose phosphate pathway, a metabolic shunt that parallels glycolysis. Uncoupling between glycolysis and mitochondrial oxidative phosphorylation leads to an increased generation of reactive oxygen species which may contribute to mitochondrial damage. In addition, high levels of D-galacturonic acid, a derivative of glucose, was identified as a good predictor of 28-day mortality in patients with acute decompensation of cirrhosis and ACLF.

Changes in energy substrate utilization and mitochondrial dysfunction are associated with organ dysfunction and poor outcome in patients with sepsis – a life-threatening condition characterized by an acute, excessive immune response to infection. Similarly, mitochondrial dysfunction appears to play a central role in the pathophysiology of acute decompensation of cirrhosis and ACLF. In this context, mitochondrial beta-oxidation of free fatty acids released from adipose tissue provides an additional source of energy both to immune cells and extrahepatic organs. Interestingly, the authors reported an increase in serum hexanoylcarnitine - an acyl ester of carnitine essential for fatty acid oxidation - in patients with ACLF associated with 28-day mortality, suggesting that fatty acid metabolism is dysregulated and mitochondrial function impaired.

“This study nicely demonstrated that vascular dysfunction and systemic inflammation are both related to outcome in patients with acute decompensation”, said corresponding author Jonel Trebicka, Principal Investigator at EF CLIF and Head of the Department of Internal Medicine B, University of Münster, Germany.

“We believe that CLIF-C MET score may be used in clinical practice to individualize outcome prediction in patients with acute decompensation of cirrhosis and to improve organ allocation by prioritizing these patients for liver transplantation", concluded Weiss.

“We still need to demonstrate that we can measure these metabolites at the bed side and show the models keep their predictive ability so they can be used in clinical practice”, added de la Peña-Ramirez.

Emmanuel Weiss was supported by a CellexFoundation grant.

Other authors on the study are Ferran Aguilar, Juan-Jose Lozano, Cristina Sánchez-Garrido, Patricia Sierra, Pedro Izquierdo-Bueno Martin, Juan Manuel Diaz, François Fenaille, Florence A Castelli, Thierry Gustot, Wim Laleman, Agustín Albillos, Carlo Alessandria, Marco Domenicali, Paolo Caraceni, Salvatore Piano, Faouzi Saliba, Stefan Zeuzem, Alexander L Gerbes, Julia A. Wendon, Christian Jansen, Wenyi Gu, Maria Papp, Raj Mookerjee, Carmine Gabriele Gambino, Cesar Jiménez, Ilaria Giovo, Giacomo Zaccherini, Manuela Merli, Antonella Putignano, Frank Erhard Uschner, Thomas Berg, Tony Bruns, Christian Trautwein, Alexander Zipprich, Rafael Bañares, José Presa, Joan Genesca, Victor Vargas, Javier Fernández, Mauro Bernardi, Paolo Angeli, Rajiv Jalan, Joan Claria, Christophe Junot, Richard Moreau, and Vicente Arroyo.

Publication information

Weiss E., de la Peña-Ramirez C., Aguilar F., Lozano J.J., Sánchez-Garrido C., Sierra P., Martin P.I., Diaz J.M., Fenaille F., Castelli F.A., Gustot T., Laleman W., Albillos A., Alessandria C., Domenicali M., Caraceni P., Piano S., Saliba F., Zeuzem S., Gerbes A.L., Wendon J.A., Jansen C., Gu W., Papp M., Mookerjee R., Gambino C.G., Jiménez C., Giovo I., Zaccherini G., Merli M., Putignano A., Uschner F.E., Berg T., Bruns T., Trautwein C., Zipprich A., Bañares R., Presa J., Genesca J., Vargas V., Fernández J., Bernardi M., Angeli P., Jalan R., Claria J., Junot C., Moreau R., Trebicka J., Arroyo V. Sympathetic nervous activation, mitochondrial dysfunction and outcome in acutely decompensated cirrhosis: The metabolomic prognostic models (CLIF-C MET). Gut 2023, 72(8): 1581–1591. DOI: 10.1136/gutjnl-2022-328708

About CANONIC

The CANONIC study, a prospective observational study in 1349 patients with decompensated cirrhosis admitted to 29 European hospitals, aimed to characterize a syndrome that later would be referred to as acute-on-chronic liver failure (ACLF). The CANONIC study has allowed for a comprehensive assessment of the epidemiology, natural history, diagnostic criteria, clinical course, prognosis, prevention and treatment of ACLF.

About PREDICT

The PREDICT study, an observational study conducted in 44 European centers that looked at 1273 patients hospitalized with acute decompensation of cirrhosis in the critical period prior to acute-on-chronic liver failure (ACLF) development aimed to identify the precipitating events of ACLF and further understand the mechanisms of ACLF progression. Results from the PREDICT study have allowed to identify four patterns of acute decompensation of cirrhosis in hospitalized patients with cirrhosis (i.e., stable decompensated cirrhosis, unstable decompensated cirrhosis, pre-ACLF and ACLF) and further defining ACLF based on the number of organ/systems failures.

About EF CLIF

The European Foundation for the Study of Chronic Liver Failure (EF CLIF) is a private non-profit organization connecting biomedical researchers and healthcare professionals with each other, with patients and patient associations, and with society. The fundamental purpose of EF CLIF, reflected in its founding Statements of 2015, is to advance knowledge and promote research and education in liver disease to improve the prognosis of patients living with chronic liver failure.

The Foundation has made pioneering efforts in conducting a series of large, international prospective studies that have been instrumental in reclassifying the trajectory of patients with chronic liver failure and led to the clinical, prognostic and pathophysiological definition of the syndrome referred to as “acute-on-chronic liver failure” characterized by acute decompensation of cirrhosis, severe systemic inflammation, organ failures, and high short-term mortality. We are inspiring best clinical practices for the management of patients with chronic liver failure and promoting a more sustainable and equitable healthcare system.

Within the Foundation, the European Association for the Study of the Liver (EASL) Chair supports research activities through the EASL-CLIF Consortium, a network of 117 tertiary care and university hospitals in 28 European countries. The Grifols Chair promotes translational studies in centers across Europe and North America within the framework of the European Network for Translational Research (ENTR) with 25 centers in 8 countries. Over the last five years, the Foundation has successfully expanded its geographical scope providing the context to support transcontinental collaborative research projects. The Global Projects chapter provides the framework to promote research in cirrhosis across the world with the aim to help to build consensus and ensure health equity worldwide.