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.