Medicine (Austin & Northern Health) - Theses
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ItemThe impact of low testosterone and the effect of testosterone therapy in men with advanced liver disease( 2017)Background: Cirrhosis is increasing in prevalence, and disproportionately affects men. Sarcopenia is one of commonest clinical sequelae of cirrhosis, with a reported prevalence of up to 70%. Sarcopenia has been associated with increased mortality across multiple studies, independently of the established prognostic tool the Model for End-stage Liver Disease (MELD). This association appears to be attributable to an increase in infection-related deaths. Serum testosterone is reduced in up to 90% of men with cirrhosis, and has also been independently associated with increased mortality in a single-centre cohort of men waitlisted for liver transplantation. Serum testosterone and muscle mass are closely related in non-liver populations, but the relationship between low testosterone and sarcopenia has not been investigated in cirrhosis. Testosterone therapy increases muscle mass in non-cirrhotic men with hypogonadism, but the impact of testosterone therapy on body composition in cirrhotic men is not known. Aims: This work aims to explore the interaction between low testosterone and sarcopenia and their relative impact on outcome in men with cirrhosis, and prospectively validate the prognostic value of low testosterone. The potential therapeutic application of testosterone as a means of ameliorating sarcopenia in cirrhotic men is assessed in addition to its impact on other outcomes. Methods: A retrospective analysis of 145 patients from a single centre liver transplant database was conducted to correlate muscle mass (as measured by height-adjusted muscle area at the transverse CT scan slice of the 4th lumbar vertebrae) with testosterone levels, and to investigate their respective impact on outcomes including mortality. A prospective cohort study followed 268 consecutive men with cirrhosis reviewed in the hepatology ambulatory care setting for a 12 month period after quantifying baseline circulating testosterone to evaluate the association between testosterone levels and infection, mortality and transplantation. A 12 month, randomised, placebo-controlled trial of testosterone undecanoate in 101 men with cirrhosis with low baseline testosterone levels (total testosterone <12nmol/L or free testosterone <230pmol/L) evaluated the effect of testosterone on body composition (as measured by dual energy x-ray absorptiometry) and other outcomes including mortality, infection, bone density and haematology and biochemistry. Results: In a pre-transplant cohort of cirrhotic men, low testosterone correlates modestly with sarcopenia (tau=0.132, p=0.019) and appeared to be a better predictor of mortality than sarcopenia in a multivariable analysis incorporating the MELD score (HR 1.07, p=0.02 for low testosterone vs HR 1.04, p=0.09 for sarcopenia). In a general hepatology setting, there is an increased risk of mortality or transplantation (OR 2.36, p=0.018) when total testosterone fell below the threshold of 8.3nmol/L, independent of the MELD score. Similarly, the low testosterone group conferred an independent increase in the risk of major infection (HR 3.61, p<0.001). Administration of intramuscular testosterone undecanoate to this population resulted in a significant increase in both appendicular lean mass (mean adjusted difference (MAD) 1.69kg, p=0.021), and total lean mass (MAD 4.74kg, p=0.008) as compared to placebo. In addition, testosteronetreated patients had a reduction in fat mass (MAD -4.34kg, p<0.001) and HbA1c (MAD -0.35%, p=0.024) as well as increased bone mass (MAD 0.08kg, p=0.009) and haemoglobin (MAD 10.2g/L, p=0.041). There was no increase in adverse events in testosterone-treated subjects. Conclusion Low testosterone in men with cirrhosis is associated with increased risk for mortality or transplantation as well as major infection. It may be a better prognostic marker than sarcopenia, which may relate to its non-muscle effects. Testosterone therapy in men with cirrhosis selected for low baseline testosterone levels increases muscle mass as well as increases bone mass and haematocrit, and reduces fat mass and HbA1ct. Testosterone is the first therapy with randomised controlled data to support its use in the treatment of sarcopenia in cirrhosis. Larger-scale studies are required to assess for an effect on clinically meaningful endpoints such as infection risk, hospitalisation and mortality.