Non-Alcoholic Steatohepatitis (NASH)
A form of liver disease characterised by fat accumulation, inflammation, and liver cell damage not caused by alcohol. NASH can progress to cirrhosis and liver failure. GLP-1 receptor agonists are being investigated for NASH treatment based on their effects on weight loss, insulin resistance, and liver inflammation.
Technical Context
NASH is the progressive inflammatory form of non-alcoholic fatty liver disease (NAFLD), characterised histologically by: steatosis (fat accumulation in >5% of hepatocytes) + lobular inflammation + hepatocyte ballooning ± fibrosis. NASH can progress to cirrhosis (approximately 10-20% over 10-20 years) and hepatocellular carcinoma. Prevalence: approximately 3-5% of adults globally. Pathophysiology: insulin resistance drives hepatic lipogenesis → lipotoxicity → oxidative stress and ER stress → hepatocyte injury → inflammation → stellate cell activation → fibrosis. GLP-1 RA relevance: semaglutide Phase II NASH trial showed significant histological improvement (NASH resolution without worsening fibrosis) — the mechanism involves: reduced hepatic lipogenesis (via improved insulin sensitivity and reduced hyperinsulinaemia), weight loss reducing hepatic fat content, and potential direct anti-inflammatory effects through hepatic GLP-1R signalling. Phase III NASH trials for semaglutide are ongoing. Tirzepatide and survodutide (GLP-1/glucagon dual agonist) are also in NASH clinical development.