Hepatic Expression of Candidate Genes in Patients With Alcoholic Hepatitis: Correlation With Disease Severity

Abstract

Alcoholic hepatitis (AH) is a form of acute-on-chronic liver failure for which current therapy is not fully effective. We investigated the hepatic expression of candidate genes in patients with AH to identify new targets for therapy. Hepatic expression of candidate genes (n = 46) was assessed by quantitative polymerase chain reaction in patients with AH (n = 23) and in normal livers (n = 6). Disease severity was assessed by the Maddrey's discriminant function and the occurrence of clinical complications. Histologic analysis included the assessment of myofibroblasts (smooth muscle alpha-actin), collagen deposition (Sirius red), and inflammatory infiltrate (CD43). Portal hypertension was assessed by hepatic venous pressure gradient. Predictive association between gene expression and disease severity was assessed by k-nearest neighbor analysis. Patients with AH showed profound hepatocellular dysfunction advanced fibrosis, and severe portal hypertension. Livers with AH showed up-regulation of genes encoding extracellular matrix proteins (procollagen I), fibrogenesis mediators, inflammatory cytokines, and apoptosis regulators. Key components of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase were markedly up-regulated, whereas cytochrome p450 2E1 and angiotensinogen were down-regulated. The expression of tissue inhibitor of metalloproteinases-1, growth-related oncogene alpha, and several components of NADPH oxidase (dual oxidases 1 and 2) correlated with histologic findings and parameters indicative of disease severity. Genes involved in hepatic fibrogenesis, inflammatory response, and oxidative stress are overexpressed in AH. Some candidate genes correlate with histologic findings and disease severity, suggesting that they may be potential targets for therapy.