Targeted lipidomics reveals extensive changes in circulating lipid mediators in patients with acutely decompensated cirrhosis

Abstract

Acute-on-chronic liver failure (ACLF) is a newly described syndrome, which develops in patients with acutely decompensated cirrhosis, and is characterized by intense systemic inflammation, multi-organ failure and high short-term mortality. The profile of circulating lipid mediators, which are endogenous signaling molecules generated from polyunsaturated fatty acids released from membrane phospholipids that play a major role in inflammation and immunity, is poorly characterized in ACLF. In the current study, we assessed the profile of lipid mediators by liquid chromatography coupled to tandem mass spectrometry in plasma from patients with acutely decompensated cirrhosis, with (n=119) and without (n=127) ACLF, and from healthy subjects (HS, n=18). Measurements were prospectively repeated in 191 patients with acutely decompensated cirrhosis during a 28-day follow-up period. Fifty-nine lipid mediators (out of 100) were detected in plasma from cirrhotic patients, of which, 16 were significantly associated with the disease status. Among these, 11 lipid mediators distinguished patients at any stage from HS, whereas two lipid mediators (leukotriene [LT] E4 and 12-hydroxyheptadecatrienoic acid, both derived from arachidonic acid) shaped a minimal plasma fingerprint that discriminated patients with ACLF from those without. Levels of LTE4 distinguished ACLF grade 3 from ACLF grades 1 and 2, followed the clinical course of the disease (increased with worsening and decreased with improvement) and positively correlated with markers of inflammation and non-apoptotic cell death. Moreover, LTE4 together with LXA5 (derived from eicosapentaenoic acid) and EKODE (derived from linoleic acid) associated with short-term mortality. Interestingly, LXA5 and EKODE formed a signature profile associated with coagulation and liver failures. Taken together, these findings uncover specific lipid mediator profiles associated with severity and prognosis of patients with acutely decompensated cirrhosis.