Decreased muscle mass in nonalcoholic fatty liver disease: New evidence of a link between growth hormone and fatty liver disease?
Authors: Maureen M.J. Guichelaar, Michael R. Charlton
Journal: Hepatology (2014)

The physiological consequences of chronic overnutrition and obesity present great medical challenges. Some are obvious, such as diabetes, osteoarthritis and cardiovascular diseases. Some are less obvious, such as nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). The physiological relationship between the protean consequences of obesity can be difficult to unravel. We are still not certain, for example, whether NAFLD is a cause or an effect of insulin resistance. Understanding the evolution and relationship of the physiological consequences of obesity is likely to be critical in developing effective prevention and treatment strategies. In this edition of Hepatology, Hong et al.1 report an association of NAFLD with sarcopenia in an ongoing prospective observational cohort study of 452 apparently healthy adults (167 men and 285 women). The liver attenuation index, which is based on computed tomography (CT)-imaging appearance of the liver, was used as an indirect parameter of liver steatosis/NAFLD. Sarcopenia was defined as a skeletal muscle mass index (SMI) of 1 SD below the gender-specific mean value of a reference group, assessed by dual-energy X-ray absorptiometry (DEXA). The main finding is that, in multiple logistic regression analysis, the odds ratio for NAFLD risk was 5.16 (95% confidence interval [CI] = 1.63-16.33) in the lowest quartile of muscle mass compared to the highest after adjusting for potential confounding factors, including insulin resistance. The authors conclude that individuals with lower muscle mass are at increased risk of NAFLD. These results may have important implications for our understanding the pathophysiology of NAFLD and NASH. Similar to bone, muscle mass increases up to a peak around the age of 45-50 years, after which it gradually declines at an estimated rate of 1-2% per year.2 The report by Hong et al. of an increased risk of NAFLD in patients with sarcopenia raises the obvious question of whether sarcopenia plays a pathophysiologic role in NAFLD or whether the physiological changes that produce NAFLD, e.g., insulin resistance and systemic inflammation, also produce sarcopenia. Sarcopenia is known to be associated with obesity and insulin resistance.3, 4 A reflex response to the results of the findings of Hong et al. might be that sarcopenia is a simple reflection of insulin resistance. Although insulin has differential effects on protein synthesis, the primary effect of insulin on protein metabolism is to inhibit proteolysis.5 Insulin deficiency and resistance produce a net loss of protein, particularly structural muscle proteins, including myosin.6 The association of NAFLD with sarcopenia in the report by Hong et al., however, persisted after adjustment for insulin resistance, as measured by homeostatic model assessment-insulin resistance (HOMA-IR). The association of sarcopenia with NAFLD is thus independent of insulin resistance. An independent association of sarcopenia with NAFLD raises the possibility that loss of muscle mass contributes to the development of NAFLD. The potential basis of a potential link between sarcopenia and the development of NAFLD merits detailed consideration. Loss of muscle mass reduces a key cellular target for insulin action, contributing to glucose intolerance and promoting gluconeogenesis, which will, in turn, exacerbate proteolysis and muscle depletion. In addition, insulin resistance results reflexively in lipolysis and generation of free fatty acids, which are taken up by liver and muscle.7, 8 Insulin resistance-mediated decreased muscle mass and the resulting decrease in uptake of free fatty acids by muscle will result in greater exposure to and uptake of free fatty acids by the liver.9 In addition to sarcopenia contributing to the development of NAFLD, it is possible that one or more of the physiological changes that result in NAFLD and NASH simultaneously produce sarcopenia. The catabolic effects of cytokines such as nuclear factor kappa B (NF-κB), interleukin (IL)-6, and tumor necrosis factor alpha (TNF-α), for example, which are increased in NAFLD and NASH, are known to be protein catabolic.10 Although the association of NAFLD with sarcopenia was adjusted for C-reactive protein (CRP) by Hong et al., levels of NF-κB, IL-6, and TNF-α were not measured. A likely potential link between NAFLD and sarcopenia is growth hormone (GH). Evidence for a role of GH in development of NASH is compelling. GH and insulin-like growth factor-1 (IGF-1) are the key effectors of changes in muscle mass. GH deficiency states, including Alstrom's syndrome11 and hypopituitarism,12 are associated with severe NASH with advanced fibrosis. Mice with a single genetic modification resulting in functional GH deficiency (foz/foz) created by a GH receptor defect develop NASH.13 While the physiological basis of GH deficiency in NAFLD is not fully understood, obesity is, in general, associated with low GH levels,14 at least in part due to low circulating levels of ghrelin15 (in response to caloric excess). Ghrelin, in addition to affecting appetite, is a somatotrope.16 GH deficiency, to a degree that meets criteria for adult GH deficiency, was recently shown in a large prospective study to be ubiquitous among patients with histologically progressive NASH.17 In addition to, and perhaps because of, the anabolic effects of GH, NASH can be reversed by exogenous growth hormone supplementation in patients with Alstrom's syndrome.9 Replacement of GH, which has profound effects on the amount and distribution of adipose tissue and fat, is an appealing potential therapeutic approach for NASH and the associated changes in body composition. The study by Hong et al. adds to the rationale for such an approach. The association of NAFLD with sarcopenia has implications beyond potential insights into the pathophysiology of fatty liver disease. NASH is on a trajectory to become the most common indication for liver transplantation in the United States. Preoperative sarcopenia is an important predictor of poor outcomes before (e.g., encephalopathy and infections) and after (patient and graft survival) liver transplantation.18, 19 Awareness and management of sarcopenia among patients with NASH may help to optimize pre- and posttransplant outcomes. A practical implication of the study by Hong et al. pertains the common prescription of exercise as a treatment for NAFLD. While exercise is and should continue to be a core component of our approach to patients with NAFLD,20 sarcopenia will make exercise more difficult. Knowledge of the likely presence of sarcopenia and the well-established ability of exercise to enhance muscle mass may serve to encourage patients to push through the weakness and easy fatigability that characterize sarcopenia and NAFLD. Finally, the study by Hong et al. should serve to remind us that there may be more to a simple observation than meets eye. And when it comes to the muscle mass in patients with NAFLD, there may be less. Maureen M.J. Guichelaar, M.D., Ph.D.1 Michael R. Charlton, MBBS, FRCP2 1Division of Gastroenterology and Hepatology Medical Spectrum Twente Enschede, the Netherlands 2Division of Gastroenterology and Hepatology Intermountain Medical Center Salt Lake City, UT, USA