Background: Hepatocellular carcinoma (HCC), the most prevalent form of liver cancer, is difficult to diagnose and
has limited treatment options with a low survival rate. Aside from a few key risk factors, such as hepatitis, high
alcohol consumption, smoking, obesity, and diabetes, there is incomplete etiologic understanding of the disease
and little progress in identification of early risk biomarkers.
Methods: To address these aspects, an untargeted nuclear magnetic resonance metabolomic approach was
applied to pre-diagnostic serum samples obtained from first incident, primary HCC cases (n = 114) and matched
controls (n = 222) identified from amongst the participants of a large European prospective cohort.
Results: A metabolic pattern associated with HCC risk comprised of perturbations in fatty acid oxidation and amino
acid, lipid, and carbohydrate metabolism was observed. Sixteen metabolites of either endogenous or exogenous
origin were found to be significantly associated with HCC risk. The influence of hepatitis infection and potential
liver damage was assessed, and further analyses were made to distinguish patterns of early or later diagnosis.
Conclusion: Our results show clear metabolic alterations from early stages of HCC development with application for
better etiologic understanding, prevention, and early detection of this increasingly common cancer.