Untargeted lipidomics uncovers lipid signatures that distinguish severe from moderate forms of acutely decompensated cirrhosis.

Abstract Background and Aim Acutely decompensated of cirrhosis is a heterogeneous clinical entity associated with moderate mortality. In some patients, this condition develops quickly into a more often deadly acute-on-chronic liver failure (ACLF), in which other organs such as the kidneys or brain fail. The aim of this study was to characterize the blood lipidome in a large series of patients with cirrhosis and identify specific signatures associated with acute decompensation and ACLF development. Methods Serum untargeted lipidomics was performed in 561 patients with acutely decompensated (AD) cirrhosis (518 without and 43 with ACLF) (discovery cohort) and in 265 AD patients (128 without and 137 with ACLF) in whom serum samples were available to perform repeated measurements during the 28-day follow-up (validation cohort). Analyses were also performed in 78 AD patients included in a therapeutic albumin trial, 43 patients with compensated cirrhosis and 29 healthy subjects. Results The circulating lipid landscape associated with cirrhosis was characterized by a generalized suppression, which was more manifest during acute decompensation and in non-surviving patients. By computing discriminating accuracy and the variable importance projection score for each of the 223 annotated lipids, we identified a sphingomyelin fingerprint specific for AD cirrhosis and a distinct cholesteryl ester and lysophosphatidylcholine fingerprint for ACLF. Liver dysfunction, mainly, and infections were the principal net contributors to these fingerprints, which were dynamic and interchangeable between AD patients whose condition worsened to ACLF and those who improved. Notably, blood lysophosphatidylcholine levels increased in these patients after albumin therapy. Conclusions Our findings provide insights into the lipid landscape associated with decompensation of cirrhosis and ACLF progression and identify unique noninvasive diagnostic biomarkers of advanced cirrhosis. Lay Summary Analysis of lipids in blood from patients with advanced cirrhosis reveals a general suppression of their levels in the circulation of these patients. A specific group of lipids known as sphingomyelins are useful to distinguish compensated from decompensated patients with cirrhosis. Another group of lipids designated cholesteryl esters further distinguish patients with decompensated patients who are at risk of developing organ failures.