Clinical meaning
Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum from simple hepatic steatosis (fat accumulation in more than 5% of hepatocytes without significant inflammation) to non-alcoholic steatohepatitis (NASH, steatosis with lobular inflammation, hepatocyte ballooning, and progressive fibrosis) to cirrhosis and hepatocellular carcinoma. The pathogenesis is explained by the multiple-hit hypothesis: the first hit involves hepatic triglyceride accumulation driven by insulin resistance — hyperinsulinemia increases hepatic de novo lipogenesis via SREBP-1c activation while impairing fatty acid beta-oxidation and VLDL export. Subsequent hits include lipotoxicity from free fatty acids and their metabolites (diacylglycerols, ceramides, lysophosphatidylcholine) that activate hepatocyte endoplasmic reticulum stress, mitochondrial dysfunction, and oxidative stress through reactive oxygen species (ROS) generation. These processes trigger hepatocyte apoptosis and necroptosis, which activate Kupffer cells (resident hepatic macrophages) and hepatic stellate cells. Activated stellate cells transform into myofibroblasts and deposit extracellular matrix (collagen I and III), producing progressive fibrosis that is staged histologically from F0 (no fibrosis) through F4 (cirrhosis). Fibrosis stage is the strongest predictor of liver-related morbidity and mortality, making accurate staging essential. Non-invasive fibrosis assessment uses composite scoring systems (FIB-4 index combining age, AST, ALT, and platelet count; NAFLD Fibrosis Score) and vibration-controlled transient elastography (FibroScan, measuring liver stiffness in kilopascals). Liver biopsy remains the gold standard for distinguishing NASH from simple steatosis and grading activity (NAS score: steatosis, lobular inflammation, and ballooning). Pharmacotherapy targets the underlying metabolic drivers: pioglitazone (thiazolidinedione insulin sensitizer improving adipose tissue insulin sensitivity and reducing hepatic inflammation), vitamin E (antioxidant reducing oxidative stress, recommended for non-diabetic NASH), GLP-1 receptor agonists (semaglutide, liraglutide — promote weight loss, improve insulin sensitivity, and may reverse steatohepatitis), and SGLT2 inhibitors (reduce hepatic fat through caloric loss and improved insulin sensitivity). Resmetirom, a thyroid hormone receptor beta agonist, is the first FDA-approved therapy specifically for NASH with moderate-to-advanced fibrosis.