Prospective Investigation of Serum Metabolites, Coffee Drinking, Liver Cancer Incidence, and Liver Disease Mortality

Abstract

Background: Coffee has been consistently associated with lower risk of liver cancer and chronic liver disease, suggesting that coffee affects mechanisms underlying disease development.

Methods: We measured serum metabolites using untargeted metabolomics in 1:1 matched nested case-control studies of liver cancer (n = 221 cases) and fatal liver disease (n = 242 cases) in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention cohort (n = 29 133). Associations between baseline coffee drinking and metabolites were identified using linear regression; conditional logistic regression models were used to identify associations with subsequent outcomes.

Results: Overall, 21 metabolites were associated with coffee drinking and also each subsequent endpoint; nine metabolites and trigonelline, a known coffee biomarker, were identified. Tyrosine and two bile acids, glycochenodeoxycholic acid (GCDCA) and glycocholic acid (GCA), were inversely associated with coffee but positively associated with both outcomes; odds ratios (ORs) comparing the 90th to 10th percentile (modeled on a continuous basis) ranged from 3.93 (95% confidence interval [CI] = 2.00 to 7.74) for tyrosine to 4.95 (95% CI = 2.64 to 9.29) for GCA and from 4.00 (95% CI = 2.42 to 6.62) for GCA to 6.77 (95% CI = 3.62 to 12.65) for GCDCA for liver cancer and fatal liver disease, respectively. The remaining six metabolites and trigonelline were positively associated with coffee drinking but inversely associated with both outcomes; odds ratio ranged from 0.16 to 0.37. Associations persisted following diet adjustment and for outcomes occurring greater than 10 years after blood collection.

Conclusions: A broad range of compounds were associated with coffee drinking, incident liver cancer, and liver disease death over 27 years of follow-up. These associations provide novel insight into chronic liver disease and liver cancer etiology and support a possible hepatoprotective effect of coffee.

Figure 1.

Adjusted receiver operating characteristic curves for metabolites independently associated with liver cancer or liver disease mortality. A) Results for liver cancer (aAUC = 0.78, 95% CI = 0.74 to 0.83) including glycocholic acid, leu-val, hypoxanthine, and lysoPC(18:2). B) Results for liver disease mortality (aAUC = 0.82, 95% CI = 0.78 to 0.85) including glycochenodeoxycholic acid, lysoPC(18:2), serotonin, and trigonelline. aAUC = adjusted area under the curve; CI = confidence interval. The solid line represents the aAUC and the dashed lines represent the upper and lower 95% confidence intervals.