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

Erikka Loftfield; Joseph A. Rothwell; Rashmi Sinha; Pekka Keski-Rahkonen; Nivonirina Robinot; Demetrius Albanes; Stephanie J. Weinstein; Andriy Derkach; Joshua Sampson; Augustin Scalbert; Neal D. Freedman


J Natl Cancer Inst. 2020;112(3):286-294. 

In This Article

Abstract and Introduction


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.


Liver cancer is the second-leading cause of cancer death worldwide.[1] Most liver cancers are preceded by chronic liver disease,[2] including cirrhosis, which is also a leading cause of death in the United States, particularly among men.[3] Although liver cancer rates are highest in developing countries, they have increased dramatically in the United States and Europe.[4–7] This increase has been largely attributed to increasing rates of hepatitis C virus (HCV) infection[8,9] but obesity and diabetes are also likely contributors.[10–13] In contrast, coffee drinking has been consistently associated with lower risk of liver cancer, with moderate coffee drinkers experiencing a 40% to 50% lower risk than nondrinkers.[14,15] An earlier analysis in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) cohort estimated that a one-cup-per-day increase in consumption was strongly associated with lower risk of liver cancer and chronic liver disease death.[16] Additionally, coffee consumption has been consistently linked with lower risk of type 2 diabetes[17] and lower rates of liver disease progression in the context of patients with advanced hepatitis C–related liver disease.[18]

The mechanisms linking coffee drinking to liver disease and liver cancer are poorly understood but may involve effects on metabolism and digestion. The liver plays a central role in human metabolism, converting dietary constituents into metabolites that can be used or stored and toxins into substances that are harmless or can be excreted. In addition, the liver produces bile, which is critical for the breakdown and absorption of fats, and it regulates blood glucose by storing and breaking down glycogen as needed. A growing body of research indicates that bile acids play an important role in the pathogenesis of chronic liver disease,[19–21] but their role in the development of liver cancer is unclear.

High-resolution mass spectrometry technologies can simultaneously measure thousands of small molecules in serum and other biospecimens and may improve mechanistic understanding of liver cancer and liver disease etiology as well as the potential protective effects of coffee. The aim of our study was to prospectively evaluate the associations of serum metabolites, particularly those that may provide insight into underlying mechanisms related to coffee drinking, with liver cancer and liver disease mortality in a large cohort of men with low rates of HCV and hepatitis B virus (HBV) infection, a high prevalence of coffee drinking, and baseline serum samples collected up to 27 years prior to diagnosis or death.