Gender Difference in the Association Between Metabolic Factors and Hepatocellular Carcinoma

Background: A gender difference in hepatocellular carcinoma (HCC) that men have higher incidence than women has long been noted and can be explained by the cross-talk between sex hormones and hepatitis B virus/hepatitis C virus (HBV/HCV). Whether metabolic factors yield similar sexual difference in non-HBV/HCV-HCC remains elusive. Methods: There were 74 782 hepatitis B surface antigen (HBsAg)/antibody to hepatitis C virus (anti-HCV) negative residents who participated in the Keelung Community-Based Integrated Screening program and were followed in 2000-2007. Incident HCC was identified by linkage to the Taiwan Cancer Registry. Cox proportional hazards regression models were used to estimate the association between metabolic factors and HCC stratified by sex. All statistical tests were 2-sided. Results: With 320 829 follow-up person-years, 99 residents developed HCC. The adjusted hazard ratios (aHR) were 2.10 (95% confidence interval [CI]=1.07 to 4.13) and 3.71 (95% CI=2.01 to 6.86) for prediabetes and diabetes, respectively, in men. The corresponding adjusted hazard ratios were 1.16 (95% CI=0.48 to 2.83) and 1.47 (95% CI=0.65 to 3.34) in women. Compared with normal weight (body mass index [BMI] = 23-25), underweight (BMI<21, HR=3.56, 95% CI=1.18 to 10.8) and overweight (BMI = 25 to <27.3, HR=3.81, 95% CI=1.43 to 10.2) were associated with an elevated risk in men. The statistically significant gradient relationship per advanced BMI category was noted in women (aHR=1.41, 95% CI = 1.07 to 1.87). The HCC-fasting glucose (P=.046) and HCC-BMI (P=.03) associations were statistically significantly modified by sex. Elevated aspartate aminotransferase, aspartate aminotransferase-to-platelet index and fibrosis index, and habitual alcohol consumption were related to HCC only in men, whereas increased alanine aminotransferase and lower platelet levels predicted HCC risk in women. Conclusions: We found that BMI-HCC associations were U-shape for men and linear for women, and the elevated HCC risk began from glucose impairment in men only. Whether good glycemic and weight control can reduce HCC risk warrants further investigation.