We read with interest the article by White et al.,1 which concluded that serum total testosterone levels are associated with higher rates of fibrosis and inflammation in hepatitis C virus (HCV)-infected men. The hypothesis was raised that serum testosterone may be implicated in the pathogenesis of HCV-related advanced liver disease in males.
Although this publication investigated the association of total serum testosterone, with fibrosis scores and inflammatory activity, sex hormone binding globulin levels and free testosterone levels were not determined. We therefore believe this raises some concerns regarding the validity of the reported association, given the known derangements seen in the sex hormones in patients with liver disease.
In men, 60% of circulating testosterone is bound to sex hormone-binding globulin (SHBG), 38% is bound to albumin, and only 2% is unbound or free.2 SHBG levels are elevated in patients with cirrhosis due to increased hepatic production, but the pathogenesis of this remains unclear.3, 4 Rising levels of SHBG have been shown to correlate with severity of fibrosis in patients with chronic liver disease.5 Due to the binding of testosterone to SHBG, the total serum testosterone value can remain normal or occasionally be raised in this patient group, despite reduced levels of free (presumed biologically active) testosterone.6
Therefore, total serum testosterone is not an accurate reflection of sex hormone status in cirrhosis, and free testosterone levels should also be determined in this patient group. Regarding the conclusions of this article suggesting testosterone may be implicated in the pathogenesis of cirrhosis, an alternative explanation of the findings is that total testosterone levels are increased simply as a consequence of elevated SHBG levels, whereas free testosterone levels may actually be reduced. Given higher SHBG levels are seen with worsening fibrosis, this may explain the association, but no definitive conclusions can be made without a full hormone profile.