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European research teams, including the Laboratory of Drug Metabolism Studies (LEMM) of the CEA's Joliot Institute, have analyzed the blood lipidome of patients with cirrhosis. They have identified specific biomarkers of the different stages of the disease.
The regenerative capacity of the liver has its limits. The various attacks that it can undergo (alcohol consumption, viral infection...) lead to the accumulation of scar tissue that leads to compensated cirrhosis (CC) or even decompensated cirrhosis (acute decompensation), when the person no longer compensates for the dysfunctions of his/her liver. In the most severe cases (30 to 40% of cases), decompensated cirrhosis evolves into acute-on-chronic liver failure (ACLF), which is characterized by systemic inflammation and the failure of several organs or systems (kidneys, liver, circulatory and respiratory systems).
In their article of July 7, 2021, published in the Journal of Hepatology, researchers from the LEMM (DMTS) have produced the non-targeted lipidomic data necessary to identify, without any a priori, specific biomarkers of the most severe forms of the disease. This is a major advance for developing future diagnoses, which will be faster, more precise and non-invasive. This study completes the work on the blood metabolome of the same patients (Moreau R et al, J Hepatol 2020; Zaccherini G et al, J Hepatol 2021). The results obtained have allowed LEMM to join two European consortia : MICROB-PREDICT and DECISION.
The researchers were interested in the evolution of the levels of different classes of blood lipids (more than 200 lipids measured in total). Their link with the development of ACLF had not yet been established, unlike systemic inflammation and other non-lipid metabolites. As the previous ones, the study is based on the analysis of data from 826 patients with acute decompensation (AD) or ACLF. It also includes healthy patients and patients with compensated cirrhosis (the least advanced stage of the disease).
Using high-resolution mass spectrometry (LC-HRMS) techniques, the researchers were able to assess levels of the principal blood lipid families in different groups of patients. This untargeted analysis of lipidome led them to several results.
In general, they show that there are no or few significant differences between healthy patients and those with CC. Nevertheless, a large, significant and generalized reduction of blood lipids (except fatty acids) is observable in AD patients. This reduction is even more marked in ACLF patients.
HOW TO DISTINGUISH DECOMPENSATED CIRRHOSIS FROM COMPENSATED CIRRHOSIS ?
Analysis of 223 lipids shows that the sphingolipid family allows to unambiguously differentiate decompensated cirrhosis from compensated cirrhosis. Sphingolipids are known for their architectural properties in cells but are also involved in the regulation of immunity and cell survival. Among them, sphingomyelins found in cell membranes are the most specific lipids in the transition from CC to decompensated cirrhosis. Sphingomyelins could be characteristic biomarkers of decompensated cirrhosis, as their blood levels become lower and lower as the disease gets worse.
Analysis of the cluster of 223 lipids revealed a subgroup of 17 lipids highly associated with ACLF. All of the lipids in this subgroup had blood levels that progressively decreased from a healthy patient to an ACLF patient. However, the researchers were able to identify more specific biomarkers such as lysophosphatidylcholines and cholesterol esters. The cholesterol esters were found to be particularly significantly reduced in the transition from decompensated cirrhosis to decompensated cirrhosis with liver failure.
All these observations are a new way to characterize the pathophysiology and biochemical mechanisms of liver cirrhosis. The identification of specific biomarkers would allow the emergence of an innovative medicine that integrates faster, more predictive and personalized diagnoses with the objective of improving the therapeutic management of patients.
J Clària, A Curto, R Moreau, B Colsch, C López-Vicario, J José Lozano, F Aguilar, F A.Castelli, F Fenaille, C Junot, I Zhang, M Vinaixa, O Yanes, P Caraceni, J Trebicka, J Fernández, P Angeli, R Jalan, V Arroyo. Untargeted lipidomics uncovers lipid signatures that distinguish severe from moderate forms of acutely decompensated cirrhosis. Journal of Hepatology 2021 vol. 75
CEA is a French government-funded technological research organisation in four main areas: low-carbon energies, defense and security, information technologies and health technologies. A prominent player in the European Research Area, it is involved in setting up collaborative projects with many partners around the world.