Adult growth hormone deficiency (GHD) is characterized by metabolic abnormalities associated with visceral obesity, impaired quality of life, and increased mortality. Patients with adult GHD show increased prevalence of non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH), and human growth hormone (HGH) replacement therapy has been shown to improve these conditions. It has also been demonstrated that a decrease in the GH insulin-like growth factor-I (IGF-I) axis is closely associated with the progression of general NAFLD, suggesting a physiological role of these hormones for the maintenance of the liver.
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NASH histologically demonstrates inflammation, necrosis, and fibrosis, in addition to steatosis (and is a serious disease because it can progress to liver cirrhosis and hepatocellular carcinoma in a subset of cases). While fibrosis determines the prognosis of the patient, efficacious treatment for fibrosis is crucial; however, it has not yet been established. Recent studies have clarified the essential roles of GH and IGF-I in the liver. GH profoundly reduces visceral fat, which plays an important role in the development of NAFLD.
Furthermore, GH directly reduces lipogenesis in the hepatocytes. IGF-I induces cellular senescence and inactivates hepatic stellate cells, therefore ameliorating fibrosis. IGF-I treatment has been shown to improve animal models of NASH and cirrhosis, suggesting potential clinical applications of IGF-I in these conditions. In this review, I will focus on the important roles of GH and IGF-I in the liver, their underlying mechanisms, and their potential therapeutic applications.
HGH and Non-Alcoholic Fatty Liver Disease (NAFLD)
Owing to the increasing prevalence of obesity and type 2 diabetes (T2DM), non-alcoholic fatty liver disease (NAFLD) is now recognized as the most common cause of chronic liver disease worldwide. NAFLD consists of non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH), and encompasses liver conditions ranging from simple steatosis to cirrhosis. The diagnosis of NASH is based on a histological examination using liver biopsy . Simple steatosis (NAFL) is characterized by fatty deposits in hepatocytes, while in addition to steatosis, NASH is characterized by inflammatory cell infiltration, hepatocyte ballooning, and fibrosis. Most importantly, NASH can progress to cirrhosis and hepatocellular carcinoma in a subset of cases.
In most cases, NAFLD occurs based on a presence of risk factors, such as metabolic syndrome, obesity, T2DM, mixed hyperlipidemia, hypocholesterolemia (due to familial hypobetalipoproteinemia), and the carriage of risk alleles for selected genetic polymorphisms.
NAFLD is a multifactorial disease resulting from a complex interaction of environmental “hits” and genetic background. Insulin resistance associated with visceral obesity, lipotoxicity and inflammation, and dysbiosis in the gut play an important role in the development of NAFLD. In these conditions, increased reactive oxygen species (ROS), dysregulated cytokine induction, and inflammation lead to the activation of hepatic stellate cells (HSCs) and result in fibrogenesis.
Fibrosis is a histological and biochemical hallmark during the progression to cirrhosis. Recently, fibrosis has been considered as an active biosynthetic process leading to excess deposition of the extracellular matrix (ECM). HSC activation represents a critical event in fibrosis because these cells become the primary source of ECM in the liver upon injury . A large retrospective study demonstrated that liver fibrosis only, with no other histologic features, was associated with long-term outcomes of patients with NAFLD. Therefore, prevention of fibrosis is crucial. Changes in dietary habits and lifestyle have been recommended as standard care for NAFLD, but this behavioural strategy tends to fail in most patients. To date, there have been very few high quality, randomized, blinded, adequately powered, controlled studies of sufficient duration and with adequate histological outcomes. GLP-1 analogue liraglutide, PPARγ agonist pioglitazone, vitamin E, and FXR agonist obeticholic acid have been proven to be efficacious.
In the study of NASH model choline-methionine fed db/db mice, IGF-I administration drastically ameliorated histological changes, along with mice in a DMN-induced cirrhotic model, as well as leading to a biochemical improvement. A limited number of human studies of GH or IGF-I for the treatment of cirrhosis have been conducted without histological examination. It is well known that IGF-I has a strong anabolic action, especially in protein metabolism in muscle tissue, which is generally disturbed in chronic liver disease. Donaghy et al. reported results of a randomized, double-blind, placebo-controlled study of GH treatment in 20 cirrhotic patients. They assessed the GH impact on protein turnover. A relatively high dose of GH (0.25 IU/kg body weight) administration for 7 days significantly increased serum IGF-I levels and improved nitrogen balance in these patients. Interestingly, a prospective randomized study demonstrated that rhGH administration significantly improved the prognosis of the patients with chronic liver failure, suggesting a beneficial effect of GH on a life expectancy. A pilot study showed that IGF-I administration in cirrhotic patients improved serum albumin and energy metabolism after 120 days. Taken together, these data suggest GH or IGF-I may be applicable for the treatment of NASH or cirrhosis with its unique mechanisms, in which especially IGF-I directly inactivates HSCs, concomitant with its anabolic action. It is also suggested that a decrease in IGF-I production in the liver is not only a result of impaired liver function but also plays a key role in the progression of fibrosis.
In conclusion, accumulating evidence demonstrates that GH and IGF-I play an essential role in the liver. NAFLD/NASH is an important complication in patients with adult GHD. Although further additional human studies are necessary, experimental studies suggest that GH or IGF-I may be applicable for the treatment of NASH or cirrhosis.