Prediagnostic concentrations of circulating bile acids and hepatocellular carcinoma risk: REVEAL-HBV and HCV studies

Hepatocellular carcinoma (HCC) is the dominant histologic type of liver cancer, accounting for 75% of cases. Growing evidence suggests that the cross-talk between the gut microbiome and metabolome (ie, gut-liver axis) are related to the development of hepatic inflammation, and ultimately, HCC. Bile acids are metabolites, derived from cholesterol and synthesized in the liver, which may have a critical role in regulation of the gut-liver axis. We investigated whether prediagnostic circulating bile acids were associated with HCC risk, using the Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer (REVEAL)-Hepatitis B Virus (HBV) and REVEAL-Hepatitis C Virus (HCV) cohorts from Taiwan. Fifteen bile acids were quantitated using liquid chromatography, from 185 cases and 161 matched controls in REVEAL-HBV and 96 cases and 96 matched controls in REVEAL-HCV. Odds ratios (ORs) and 95% confidence intervals (CIs) for associations between bile acid levels and HCC were calculated using multivariable-adjusted logistic regression. Higher levels of glycine and taurine conjugated primary bile acids were associated with a 2- to 8-fold increased risk of HBV- (eg, glycocholic acid OR_Q4vsQ1 = 3.38, 95% CI: 1.48-7.71, P_trend < .003) and HCV-related HCC (eg, OR = 8.16, 95% CI: 2.21-30.18, P_trend < .001). However, higher levels of the secondary bile acid deoxycholic acid were inversely associated with HBV-related HCC risk (OR = 0.41, 95% CI: 0.19-0.88, P_trend = .02). Our study provides evidence that higher concentrations of bile acids-specifically, conjugated primary bile acids-are associated with increased HCC risk. However, our study does not support the hypothesis that higher levels of secondary bile acids increase liver cancer risk; indeed, deoxycholic acid may be associated with a decreased HCC risk.