Hepatic cytochrome P450 2E1, steatosis and fibrosis in alcoholic and non-alcoholic steatohepatitis

Abstract

Since alcoholic steatohepatitis (ASH) and non-alcoholic steatohepatitis (NASH) cannot be distinguished by histopathology, similar pathogenetic mechanisms may be involved in the development of steatohepatitis from fatty liver. One of these mechanisms is oxidative stress. Ethanol as well as free fatty acids induce cytochrome P4502E1 (CYP2E1) which generates reactive oxygen species (ROS) leading to lipid peroxidation, fibrosis and DNA lesions (1). Inhibition of CYP2E1 by chlormethiazole also prevents alcoholic liver disease (ALD) in animal experiments (2). To investigate the relation between hepatic CYP2E1, steatosis and fibrosis, liver biopsies were obtained from 60 patients with ASH (40 males and 20 females), and from 39 patients with NASH (19 males and 20 females). To evaluate steatosis, inflammation and fibrosis, a histological scoring system was used (3). CYP2E1 induction was semi-quantitatively assessed (0,1+ (mild), 2+ (moderate) or 3+ (severe)) by immunohistology using a polyclonal rabbit antibody. In ASH 11% had a strong, 57% a moderate, 30% a mild and 1 patient had no CYP2E1 induction. In patients with NASH, 3% had a strong, 41% a moderate, 55% a mild induction and 1 patient did not express CYP2E1 at all. The induction pattern of CYP2E1 was mostly diffuse within the hepatic lobule. Steatosis, inflammation and fibrosis were more pronounced in ASH as compared to NASH. Histologically single cell necrosis, giant mitochondria, Mallory bodies and ballooning of hepatozytes were more often detected in ASH as compared to NASH (p<0.01). The intensity of CYP2E1 induction correlated significantly with steatosis and fibrosis (p<0.0001; r=0.95), but not with the quantity of daily alcohol intake. No correlation between fibrosis and CYP2E1 could be found in NASH. These data show that both in NASH and ASH patients hepatic CYP2E1 is induced, that the intensity of induction is individually variable, and that CYP2E1 induction in ASH seems to be stronger than in NASH. In addition, the extent of hepatic fat seems to correlate positively with CYP2E1, and this is associated with enhanced fibrosis in ASH. Thus, CYP2E1 seems to be an important denominator of the progression in ALD. Supported by a grant of the Dietmar Hopp Foundation.