Patients with alcohol-associated hepatitis had significantly elevated levels of conjugated primary bile acids and reduced levels of secondary bile acids, changes that correlated with disease severity, according to a recent study.
The comprehensive review, published in The American Journal of Pathology, examined the mechanistic role of cholestasis in alcohol-associated liver disease (ALD), with an emphasis on alcohol-associated hepatitis (AH), the most severe form of ALD. The researchers, led by Shengmin Yan of Tulane University School of Medicine, New Orleans, evaluated clinical and experimental findings to determine the contribution of impaired bile acid (BA) homeostasis to disease progression and severity.
The review summarized human data from multiple studies that demonstrated elevated circulating levels of conjugated primary BAs—specifically glycocholic acid, taurocholic acid, and taurochenodeoxycholic acid—in patients with AH when compared with both healthy controls and patients with alcohol use disorder. One study reported significantly higher total serum BA levels in patients with AH, with conjugated BAs accounting for most of the increase. In contrast, levels of secondary BAs such as deoxycholic acid and glycodeoxycholic acid were markedly reduced. Using univariate regression analysis, researchers observed that total BA concentrations, absolute conjugated BA levels, and the proportion of conjugated BAs were positively correlated with model for end-stage liver disease scores (r values not specified), while unconjugated BAs demonstrated negative correlations with disease severity.
The researchers also highlighted a second study that analyzed plasma and stool samples from patients with AH, heavy-drinking controls, and healthy patients. In plasma samples, concentrations of glycocholic acid, taurocholic acid, and taurochenodeoxycholic acid were significantly elevated in patients with AH, while levels of deoxycholic acid, taurodeoxycholic acid, and glycodeoxycholic acid were decreased. In stool, a consistent pattern of increased primary BAs and reduced secondary BAs was observed, implicating gut microbiota disruption in disease pathology.
To explore causality, the authors reviewed murine models in which chronic ethanol feeding followed by administration of α-naphthylisothiocyanate—a cholestatic agent—produced hepatic injury resembling human AH. Notably, mice exhibited elevations in alanine aminotransferase and aspartate aminotransferase, increased total serum BA levels, and histological features such as neutrophilic infiltration and bile accumulation. Depletion of neutrophils or treatment with DNase I attenuated liver injury, suggesting a pathogenic role for neutrophil extracellular traps.
The review supports cholestasis as a mechanistic contributor to AH and identifies bile acid signaling pathways—including farnesoid X receptor and gut-liver axis targets—as potential areas for therapeutic investigation. The researchers emphasize the need for further mechanistic and clinical studies to evaluate bile acid–modulating strategies in ALD.
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