Linoleic Acid‐Derived Oxylipins Differentiate Early Stage Alcoholic Hepatitis From Mild Alcohol‐Associated Liver Injury

Abstract

Alcohol‐associated liver disease (ALD) is a spectrum of liver disorders ranging from steatosis to steatohepatitis, fibrosis, and cirrhosis. Alcohol‐associated hepatitis (AH) is an acute and often severe form of ALD with substantial morbidity and mortality. The mechanisms and mediators of ALD progression and severity are not well understood, and effective therapeutic options are limited. Various bioactive lipid mediators have recently emerged as important factors in ALD pathogenesis. The current study aimed to examine alterations in linoleic acid (LA)‐derived lipid metabolites in the plasma of individuals who are heavy drinkers and to evaluate associations between these molecules and markers of liver injury and systemic inflammation. Analysis of plasma LA‐derived metabolites was performed on 66 individuals who were heavy drinkers and 29 socially drinking but otherwise healthy volunteers. Based on plasma alanine aminotransferase (ALT) levels, 15 patients had no liver injury (ALT ≤ 40 U/L), 33 patients had mild liver injury (ALT > 40 U/L), and 18 were diagnosed with moderate AH (mAH) (Model for End‐Stage Liver Disease score <20). Lipoxygenase‐derived LA metabolites (13‐hydroxy‐octadecadienoic acid [13‐HODE] and 13‐oxo‐octadecadienoic acid) were markedly elevated only in patients with mAH. The cytochrome P450‐derived LA epoxides 9,10‐epoxy‐octadecenoic acid (9,10‐EpOME) and 12,13‐EpOME were decreased in all patients regardless of the presence or absence of liver injury. LA‐derived diols 9,10‐dihydroxy‐octadecenoic acid (9,10‐DiHOME) and 12,13‐DiHOME as well as the corresponding diol/epoxide ratio were elevated in the mAH group, specifically compared to patients with mild liver injury. We found that 13‐HODE and 12,13‐EpOME (elevated and decreased, respectively) in combination with elevated interleukin‐1β as independent predictors can effectively predict altered liver function as defined by elevated bilirubin levels. Conclusion: Specific changes in LA metabolites in individuals who are heavy drinkers can distinguish individuals with mAH from those with mild ALD.