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.