Intrahepatic gene expression in human alcoholic hepatitis☆
Introduction
The incidence and mortality due to alcoholic liver disease (ALD) appears to be rising in the UK [1] and world-wide alcohol is a major cause of liver disease [2], [3]. Morbidities associated with alcoholic liver disease contribute one-third of the inpatient workload of UK gastroenterologists [4]. Presently, there is no satisfactory treatment for this disease. Alcohol has been identified as a direct hepatotoxin and various pathways of pathogenesis have been implicated but their respective contribution to liver injury in humans is not clear [5]. Recent studies suggest that alcohol initiates liver injury via endotoxin [6], oxidative stress [7] and inflammation [5]. The resulting spectrum of alcoholic liver disease (ALD) includes steatosis, alcoholic hepatitis and cirrhosis [8]. Alcoholic steatosis usually is considered a benign lesion with a favorable prognosis on abstinence [9]. The factors that underlie progression to alcoholic hepatitis are not well understood. It involves continuing liver injury, with prominent inflammation and fibrosis.
DNA array analysis has provided novel data regarding pathogenesis of human liver disease in humans with both alcoholic [10], [11] and non-alcoholic liver cirrhosis (autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis and hepatitis C) [12], [13] from our laboratory and have identified several novel genes and pathways in liver disease. Our previous observations of human ALD were restricted to abstinent end-stage (ES) liver transplant patients [10]. The present study was performed to include patients with recent alcohol consumption and focuses on those with alcoholic hepatitis. Findings from this group were compared to alcoholics with minimal liver disease.
Section snippets
Human liver biopsies
Needle liver biopsies were obtained from patients presenting with alcoholic liver disease at various stages of progression (alcoholic steatosis, alcoholic hepatitis, alcoholic cirrhosis; Table 1). AH was defined by the histological features of hepatocellular necrosis, ballooning degeneration, and inflammatory infiltration, with or without Mallory’s hyaline bodies and AC had clinically less severe cirrhosis than ES.
In addition, explant tissues from seven donor livers with normal histopathology
Results
Global intrahepatic transcriptome profiles were generated using DNA microarrays from patients with alcoholic steatosis (AS) and alcoholic hepatitis (AH). Fig. 2 shows plots of ordered t-statistics for quantile normalized intensities for the three comparisons. The two tails depict differentially expressed features with the greatest and least t-statistic, whereas features not differentially expressed clustered around zero. A complete alphabetical listing of differentially expressed genes is
Discussion
Using the DNA microarray approach we compared global intrahepatic transcriptome expression profiles in patients with AS and AH. We were able to successfully distinguish AH from AS by cluster analysis and identify a number of novel differentially expressed genes that may play a role in the pathogenesis of alcoholic hepatitis.
It was interesting to note that Pt 12 that repeatedly clustered with AS was consistent with the dominant histological lesion of AS (Supplemental Figure 2C). There were mild
Acknowledgements
This work was supported by project grants from Department of Veterans’ Affairs, Australia; and National Health and Medical Research Council, Grant # 142607. Dr. Michael Beard provided osteopontin PCR primers and antibody. Mr. Chris Bye assisted with BioConductor software and Dr. Jane Radford with histopathology.
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The authors who have taken part in the research of this paper have no relationship with the manufacturers of the drug involved either in the past or present. The authors state that they did not receive funding from the manufacturers to carry out their research.