Hepatic expression of candidate genes in patients with alcoholic hepatitis: correlation with disease severity.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Colmenero
Jordi
J
Liver Unit, Institut Clínic de Malalties Digestives i Metabòliques, Barcelona, Catalonia, Spain.
Bataller
Ramón
R
Sancho-Bru
Pau
P
Bellot
Pablo
P
Miquel
Rosa
R
Moreno
Montserrat
M
Jares
Pedro
P
Bosch
Jaime
J
Arroyo
Vicente
V
Caballería
Joan
J
Ginès
Pere
P
D000328:Adult; D000368:Aged; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000473:pathology; D005786:Gene Expression Regulation; D006519:Hepatitis, Alcoholic / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D006975:Hypertension, Portal / Q000473:pathology; D007249:Inflammation / Q000473:pathology; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008104:Liver Cirrhosis, Alcoholic / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000235:genetics; D016133:Polymerase Chain Reaction; D011237:Predictive Value of Tests; D011379:Prognosis; D011446:Prospective Studies; D012333:RNA, Messenger / Q000378:metabolism; D012720:Severity of Illness Index; D013030:Spain
D051017:Apoptosis Regulatory Proteins; D016207:Cytokines; D016326:Extracellular Matrix Proteins; D012333:RNA, Messenger; D019255:NADPH Oxidases