Hepatocellular carcinoma: is surveillance cost effective?
Authors: J BRUIX
Journal: Gut (2001)

Is bacterial ash the flash that ignites NASH?As obesity creeps in epidemic proportions through increasingly inert and aZuent "developed" societies, metabolic imbalance has become the commonest cause of liver disease.Fatty liver, although itself benign, predisposes the liver to NASH or non-alcoholic steatohepatitis, a chronic disorder characterised by steatosis, mixed cell type inflammation, focal hepatocyte degeneration, and perivenular or pericellular fibrosis. 1 2NASH is slowly progressive, occasionally resulting in cirrhosis with the potentially fatal complications of portal hypertension, liver failure, and hepatocellular carcinoma. 2 3 Most cases of NASH appear to have a multifactorial aetiopathogenesis.The predisposing factors include obesity, type II diabetes, insulin resistance, hypertriglyceridaemia, and rapid weight loss, each of which can cause hepatic steatosis.The trigger that sets oV injury and inflammation against this background of oxidisable fatty acid excess, and the mechanisms that perpetuate steatohepatitis and fibrogenesis are less clear. 4 A focus of recent experimental studies has been on biochemical processes that reduce oxygen to reactive oxygen species (ROS); these can potentially damage tissues by the process of oxidative stress.Oxidative stress also increases expression of cellular adhesion molecules, and secretion of chemokines and cytokines, thereby initiating the recruitment of an hepatic inflammatory response. 5 6 Weltman and colleagues demonstrated that cytochrome P450 (CYP)2E1 is over expressed in the livers of patients with NASH 7 as well as in a model of steatohepatitis induced by feeding rats a high fat, methionine and choline deficient (MCD) diet. 8Leclercq and colleagues then showed that CYP2E1 catalyses lipid peroxidation in the murine MCD dietary model, 9 contributing to profound oxidative stress.Alternatively, in Cyp2e1 nullizygous mice, CYP4A enzymes are upregulated and function as alternative catalysts of microsomal lipoperoxidation in experimental NASH. 9Other studies have implicated activation of the peroxisome proliferator activated receptor (PPAR ) in a pathway leading to NASH. 10 Activated PPAR is a transcription factor that governs expression of the peroxisomal and microsomal (via CYP4A) pathways of lipid oxidation, with consequent over production of ROS.As opposed to the possible primary role of "biochemical oxidative stress", it is possible that the inflammatory response can be the primary mediator of liver cell injury in steatohepatitis.This is a favoured mechanism in alcoholic hepatitis in which gut derived endotoxin appears to incite necroinflammatory change, 6 even in the absence of CYP2E1. 11Endotoxin is a potent releaser of proinflammatory and cytotoxic cytokines such as tumour necrosis factor (TNF-).The cell types involved include activated macrophages, including KupVer cells, lymphocytes, and neutrophils.In alcoholic hepatitis, 6 and potentially in NASH, such cell types could be recruited to the liver where they not only contribute further to oxidative stress by release of ROS and nitroradicals 12 but also release cytokines that contribute to liver cell injury and hepatic fibrogenesis.