Elevated testosterone increases risk of hepatocellular carcinoma in men with chronic hepatitis B and diabetes mellitus

Background and Aim Male sex is a risk factor for hepatocellular carcinoma (HCC). Diabetes mellitus (DM) is associated with a doubled risk of HCC in patients with chronic hepatitis B (CHB). We examined the relationship between serum total testosterone and HCC risk in male CHB patients with DM. Methods We performed a retrospective cohort study of male CHB patients with DM between 2000 and 2017 using a territory-wide electronic health-care database in Hong Kong. DM was defined by use of anti-diabetic medications, hemoglobin A(1c) >= 6.5%, and/or fasting glucose >= 7 mmol/L in two measurements or >= 11.1 mmol/L in one measurement. Results Of 928 male CHB patients with DM, 83 (8.9%) developed HCC at a median (interquartile range) of 10.7 (6.1-14.6) years. Higher testosterone was associated with an elevated risk of HCC (adjusted hazard ratio [aHR] per 1 SD increase 1.23, 95% confidence interval [CI] 1.03-1.46, P = 0.024). The upper tertile of testosterone (aHR 1.86, 95% CI 1.02-3.39, P = 0.043), but not middle tertile (aHR 0.84, 95% CI 0.41-1.69 P = 0.620), was associated with a higher risk of HCC than the lower tertile. The cumulative incidence (95% CI) of HCC at 5, 10, and 15 years was 4.4% (2.5-7.2%), 12.4% (8.7-16.7%), and 19.1% (14.2-24.5%), respectively, in patients in the upper tertile of testosterone. By subgroup analysis, the association between testosterone and HCC was stronger in patients aged >= 50 years and those not receiving antiviral therapy. Conclusion Higher serum testosterone is associated with a higher incidence of HCC in male CHB patients with DM.