Background: The effects of hepatocellular carcinoma on liver metabolism and circulating metabolites have been subjected to continuing investigation. This study compares the levels of selected metabolites in sera of hepatocellular carcinoma cases versus patients with liver cirrhosis and evaluates the influence of gender, race, and alcoholic cirrhosis on the performance of the metabolites as candidate biomarkers for hepatocellular carcinoma. Methods: Targeted quantitation of 15 metabolites is performed by selected research monitoring in sera from 89 Egyptian subjects (40 hepatocellular carcinoma cases and 49 cirrhotic controls) and 110 U.S. subjects (56 hepatocellular carcinoma cases and 54 cirrhotic controls). Logistic regression models are used to evaluate the ability of these metabolites in distinguishing hepatocellular carcinoma cases from cirrhotic controls. The influences of gender, race, and alcoholic cirrhosis on the performance of the metabolites are analyzed by stratified logistic regression. Results: Two metabolites are selected on the basis of their significance to both cohorts. Although both metabolites discriminate hepatocellular carcinoma cases from cirrhotic controls in males and Caucasians, they are insignificant in females and African Americans. One metabolite is significant in patients with alcoholic cirrhosis and the other in nonalcoholic cirrhosis. Conclusions: The study demonstrates the potential of two metabolites as candidate biomarkers for hepatocellular carcinoma by combining them with a-fetoprotein (AFP) and gender. Stratified statistical analyses reveal that gender, race, and alcoholic cirrhosis affect the relative levels of small molecules in serum. Impact: The findings of this study contribute to a better understanding of the influence of gender, race, and alcoholic cirrhosis in investigating small molecules as biomarkers for hepatocellular carcinoma. Cancer Epidemiol Biomarkers Prev; 23(1); 64-72.
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