Higher testosterone levels in men with chronic hepatitis B virus infection and diabetes mellitus were associated with an increased incidence of hepatocellular carcinoma (HCC), according to study results published in the Journal of Gastroenterology and Hepatology.

Male sex is a known risk for HCC, and having diabetes doubles the risk of individuals with hepatitis B virus infection developing HCC. Therefore, investigators performed a retrospective cohort study of men with both chronic hepatitis B virus infection and diabetes between 2000 and 2017 using a territory-wide electronic healthcare database in Hong Kong to examine the relationship between serum total testosterone levels and HCC risk in this population.

Of 928 men with chronic hepatitis B virus infection and diabetes, 8.9% developed HCC at a median of 10.7 years (interquartile range, 6.1-14.6). Higher levels of testosterone were associated with an elevated risk of HCC (adjusted hazard ratio [aHR] per 1 standard deviation increase, 1.23; 95% CI, 1.03-1.46; P=.024). Compared with men with testosterone levels in the lower tertile, those with testosterone levels in the upper tertile were found to be at higher risk of HCC (aHR 1.86; 95% CI, 1.02-3.39; P=.043); this finding was not seen among men with testosterone levels in the middle tertile (aHR 0.84; 95% CI 0.41-1.69; P= .620). Among patients with testosterone levels in the upper tertile, the cumulative incidence of HCC at 5, 10, and 15 years was 4.4% (95% CI, 2.5-7.2), 12.4% (95% CI, 8.7-16.7), and 19.1% (95% CI, 14.2-24.5), respectively. Subgroup analysis revealed a stronger association between testosterone and HCC in men aged ≥50 years and those not on antiviral therapy.

The investigators note that assessment of serum testosterone is not performed routinely. In addition, as the median time difference between baseline and the date of serum testosterone measurement was 3.8 years, testosterone levels may change with the progression of metabolic syndrome or liver fibrosis. Other study limitations include different clinical characteristics among patients who did or did not undergo testosterone assessment. Missing data and irregular intervals of laboratory measurement may also have led to biases. The investigators reported being unable to correctly identify cirrhosis in the study population based on the use of different methods that may affect diagnosis coding in computer databases. Ascertainment bias might also have affected the reliability of the study due to potentially inaccurate entry of the HCC diagnosis code, but the use of the single International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code in the Hong Kong Clinical Data Analysis and Reporting System for the diagnosis of HCC has been previously validated. Finally, duration of diabetes was


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not evaluated as a risk factor, data on other metabolic risk factors were not available, and unmeasured factors such as virus genotype, smoking, or alcohol use may have confounded the study results.

The investigators conclude that this work still demonstrates an association between higher total testosterone levels and higher risk of HCC in men with chronic hepatitis B virus infection and diabetes, an association that is noted to be stronger in patients aged ≥50 years and those not taking antivirals.

Reference

Yip TC-F, Wong GL-H, Chan HL-Y, Lee HW, Wong VW-S. Elevated testosterone increases risk of hepatocellular carcinoma in men with chronic hepatitis B and diabetes mellitus [published online April 28, 2020]. J Gastroenterol Hepatol.  doi:10.1111/jgh.15079