Growth Hormone in Decompensated Liver Cirrhosis

Overview

Globally, cirrhosis and liver cancer carries a huge burden and accounts for about 3.5% (2 million) of all deaths every year. Once decompensated, i.e. development of ascites, variceal bleed, encephalopathy, and jaundice, the life expectancy is markedly reduced to a median of two years. The definitive treatment in this stage, i.e., liver transplantation is limited by cost, lack of donors, and life-long immunosuppression. In addition to complications due to portal hypertension and hepatic insufficiency, decompensated cirrhosis is associated with malnutrition, sarcopenia, immune dysfunction, and impaired regeneration. Patients with cirrhosis are growth hormone (GH) resistant, with reduced insulin-like growth factor, which are linked to malnutrition and poor liver regeneration in cirrhosis. Diverse preclinical and clinical investigations in vitro and in vivo, have shown a benefit of GH in GH deficient, elderly and HIV positive patients. GH therapy in cirrhosis has been shown to improve nitrogen economy and to improve the GH resistance in a small pilot study by Donaghy et al. Also, GH therapy of short duration has shown to increase IGF1 levels, IGFBP-3 levels in patients of cirrhosis. GH therapy has also been shown to improve liver regeneration and protein synthesis after hepatectomy in patients of HCC with cirrhosis. However, there is a scarcity of data on clinical impact of long term administration of GH therapy in patients of cirrhosis. Hence, we undertook the present study to study the effect of growth hormone on clinical outcomes, malnutrition, immune cells and liver regeneration in patients with cirrhosis.

Liver disease accounts for approximately 3.5% all deaths per year around the world, cirrhosis being the 11th most common cause of death globally. Liver cirrhosis is the final stage of all progressive and chronic liver diseases which progresses from asymptomatic compensated stage to decompensated at a rate of 5% to 7% each year. The major complications of liver cirrhosis are portal hypertension, ascites, spontaneous bacterial peritonitis (SBP), variceal bleed, hepatic encephalopathy (HE), hepatocellular carcinoma (HCC). Moreover, complications like protein-calorie malnutrition associated with sarcopenia, cirrhosis associated immune dysfunction (CAID) and impaired regeneration further adds to reduced survival. Liver transplantation is the only effective treatment for these patients but it is limited by resources, costs, expertise, and organ availability. Malnutrition is common in cirrhosis with prevalence ranging from 65 to 100%. Sarcopenia or loss of skeletal muscle mass is the major component of malnutrition in cirrhosis with prevalence of 40- 60%. Independent clinical consequences of sarcopenia in cirrhosis include lower survival, quality of life \& increases risk of complications. Lack of improvement with nutritional supplementation is observed which may be attributed to GH resistance in cirrhotic patients further worsening sarcopenia. CAID is a dynamic phenomenon, comprised of both increased systemic inflammation and immunodeficiency, ultimately leading to 30% mortality. Immunodeficiency in cirrhosis roots from deranged local immunity of liver, compromised immune surveillance of the liver and impairments in systemic immune cells (innate as well as adaptive).The systemic inflammation results from persistent immune cell stimulation due to enhanced gut translocation leading to increased production of various proinflammatory cytokines. Liver regeneration is a complex and unique process. Hepatocytes have a remarkable capacity to meet the replacement demands during cellular loss. However, this regenerative capacity is overwhelmed during the late stage of acute liver injury, compromised in chronic liver injury, and lost in acute-on-chronic liver injury. GH administration have been shown to improve sarcopenia, immune functions \& regeneration in clinical studies and preclinical studies both in vitro and in vivo. Patients with chronic liver diseases are GH resistant i.e. they have high GH levels \& low levels of IGF-1. So, in this study, we will investigate the impact of growth hormone on additional parameters including clinical outcomes, immunological profile and select parameters of liver regeneration in decompensated liver cirrhosis.