A prospective investigation of serum bile acids with risk of liver cancer, fatal liver disease, and biliary tract cancer

Bile acids (BAs), major regulators of the gut microbiota, may play an important role in hepatobiliary cancer etiology. However, few epidemiologic studies have comprehensively examined associations between BAs and liver or biliary tract cancer. In the Alpha‐Tocopherol, Beta‐Carotene Cancer Prevention (ATBC) study, we designed 1:1 matched, nested, case–control studies of primary liver cancer (n = 201 cases), fatal liver disease (n = 261 cases), and primary biliary tract cancer (n = 138 cases). Using baseline serum collected ≤30 years before diagnosis or death, we measured concentrations of 15 BAs with liquid chromatography–tandem mass spectrometry. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) using multivariable conditional logistic regression models, adjusted for age, education, diabetes status, smoking, alcohol intake, and body mass index. We accounted for multiple comparisons using a false discovery rate (FDR) correction. Comparing the highest to the lowest quartile, seven BAs were positively associated with liver cancer risk, including taurocholic acid (TCA) (OR, 5.62; 95% CI, 2.74–11.52; Q trend < 0.0001), taurochenodeoxycholic acid (TCDCA) (OR, 4.77; 95% CI, 2.26–10.08; Q trend < 0.0001), and glycocholic acid (GCA) OR, 5.30; 95% CI, 2.41–11.66; Q trend < 0.0001), and 11 were positively associated with fatal liver disease risk, including TCDCA (OR, 9.65; 95% CI, 4.41–21.14; Q trend < 0.0001), TCA (OR, 7.45; 95% CI, 3.70–14.97; Q trend < 0.0001), and GCA (OR, 6.98; 95% CI, 3.32–14.68; Q trend < 0.0001). For biliary tract cancer, associations were generally >1 but not significant after FDR correction. Conjugated BAs were strongly associated with increased risk of liver cancer and fatal liver disease, suggesting mechanistic links between BA metabolism and liver cancer or death from liver disease.