Disordered bile acid metabolism in alcohol-related hepatitis

Background Alcohol-related hepatitis (AH) is characterised by acute cholestasis and liver dysfunction in patients consuming alcohol. Aims To define the bile acid (BA) profile in AH compared to decompensated alcohol-related cirrhosis (DC) and healthy controls (HC). Methods Serum and faecal BAs were measured by UHPLC–MS; FGF19 by ELISA; RNA-sequencing data obtained from liver biopsies; serum cytokines and growth factors quantified by multiplex immunoassay. Hepatocyte growth factor (HGF) was applied to primary human hepatocytes (PHH) and BA transporter expression was assessed by RT-qPCR. Results In two cohorts (Cohort 1: 164 AH, 63 DC, 36 HC; Cohort 2: 94 AH, 175 DC, 72 HC), total serum BAs were highest in AH (median concentration 186.0 μM vs. 64.5 DC vs. 5.0 HC), driven by elevated conjugated primary BAs (182.0 μM vs. 54.0 vs. 2.2). Unconjugated primary BAs were highest in DC. Serum BAs distinguished AH from DC (Cohort 1 AUROC 0.964; Cohort 2 0.922; p < 0.001). Faecal BAs were reduced in AH (0.47 mg/g vs. 1.11 DC vs. 2.64 HC); serum FGF19 elevated (5835 pg/mL AH vs. 865 jaundiced DC [bilirubin > 80 μmol/L]). Serum conjugated BAs correlated negatively with NTCP expression (n = 25, Spearman's rho −0.432, p = 0.031). CYP7A1 was below the limit of detection. HGF was elevated in AH (7899 pg/mL vs. 2607 DC, p < 0.001). HGF treatment reduced PHH BSEP expression. Conclusion Serum conjugated primary BAs accumulate in AH. Elevated HGF may detrimentally affect the hepatoprotective adaptive reduction in NTCP/increase in BSEP seen in cholestasis, contributing to the AH BA profile.