Abstract Background: Laboratory and emerging epidemiologic data suggest that bile acids (BAs), major regulators of the gut microbiota, play an important role in liver disease and cancer etiology. However, few epidemiologic studies have comprehensively examined associations between BAs and either liver endpoints or biliary cancer.

Methods: In the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study, we designed 1:1 matched nested case-control studies of primary liver cancer (n=247 cases), fatal liver disease (n=261 cases), and primary biliary cancer (n=92 cases). Using baseline serum collected ≤30 years prior to diagnosis or death, we measured concentrations of 15 BAs with liquid chromatography tandem mass spectrometry. We used multivariable conditional logistic regression to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) between BAs and each endpoint, accounting for multiple comparisons.

Results: Comparing the highest to the lowest quartile, ten BAs were positively associated with liver cancer risk, including taurocholic (OR =4.70, 95% CI=2.51-8.78; Q-trend<0.0001), taurochenodeoxycholic (OR =4.61, 95% CI=2.38-8.91; Q-trend<0.0001), and glycocholic acid OR =4.11, 95% CI=2.11-7.99; Q-trend<0.0001), and 11 were positively associated with fatal liver disease risk, including taurochenodeoxycholic acid (OR =9.65, 95% CI=4.41-21.14; Q-trend<0.0001), taurocholic OR =7.45, 95% CI=3.70-14.97; Q-trend<0.0001), taurochenodeoxycholic (OR =9.05, 95% CI=4.04-20.32; Q-trend<0.0001), and glycocholic acid OR=6.12, 95% CI=2.84-13.77; Q-trend<0.0001). No significant associations were observed between BAs and biliary cancer though ORs were consistently >1.

Conclusion: Conjugated BAs were strongly associated with increased risk of liver cancer and fatal liver disease, suggesting mechanistic links between the gut microbiota, BA signaling pathways, and liver cancer or death from liver disease.

Citation Format: Zeinab Farhat, Neal D. Freedman, Joshua N. Sampson, Roni T. Falk, Jill Koshiol, Stephanie J. Weinstein, Demetrius Albanes, Rashmi Sinha, Erikka Loftfield. A prospective investigation of serum bile acids with risk of liver cancer, fatal liver disease, and biliary cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2385.