Nonalcoholic steatohepatitis Andrea E. Reid  Gastroenterology  Volume 121, Issue 3, Pages 710-723 (September 2001) DOI: 10.1053/gast.2001.27126 Copyright © 2001 American Gastroenterological Association Terms and Conditions

Fig. 1 The pathogenesis of NASH is poorly understood. Obesity, type 2 diabetes mellitus, hyperinsulinemia, increased triglyceride levels, and certain drugs, toxins, and medical conditions can lead to increased serum fatty acids, which are then presented to the liver. Steatosis occurs when the supply of fatty acids in the liver exceeds that needed for triglyceride synthesis, mitochondrial oxidation, and phospholipid and cholesterol ester synthesis. After steatosis occurs, inflammation and fibrosis characteristic of NASH are probably stimulated by multiple factors. Increased expression of CYP2E1 may cause production of free oxygen radicals capable of inducing lipid peroxidation of hepatocyte membrane. Alterations in mitochondrial energy homeostasis may also contribute to hepatocellular injury. Hepatic iron overload, possibly associated with HFE gene mutations in some patients, may contribute to lipid peroxidation. Lipid peroxides damage cellular membranes with subsequent release of inflammatory mediators, including TNF-α. Inflammation ensues, which stimulates the fibrogenic cascade with expansion of the extracellular matrix, leading to fibrosis. The inflammatory response may also be stimulated by Kupffer cells and/or bacterial endotoxin in some cases. The actual interplay between all of these factors may differ, depending on the inciting condition for NASH. Gastroenterology 2001 121, 710-723DOI: (10.1053/gast.2001.27126) Copyright © 2001 American Gastroenterological Association Terms and Conditions