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

J Natl Cancer Inst. 2020 Mar 1;112(3):286-294. doi: 10.1093/jnci/djz122.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Aged
  • Alkaloids / blood
  • Case-Control Studies
  • Coffee*
  • Finland / epidemiology
  • Glycochenodeoxycholic Acid / blood
  • Glycocholic Acid / blood
  • Humans
  • Incidence
  • Linear Models
  • Liver Diseases / blood*
  • Liver Diseases / mortality*
  • Liver Neoplasms / blood*
  • Liver Neoplasms / mortality*
  • Male
  • Middle Aged
  • Prospective Studies


  • Alkaloids
  • Coffee
  • trigonelline
  • Glycochenodeoxycholic Acid
  • Glycocholic Acid