Intrahepatic gene expression profiles and alpha‐smooth muscle actin patterns in hepatitis C virus induced fibrosis

To gain insight into pathogenic mechanisms underlying fibrosis in hepatitis C virus (HCV)-mediated liver injury, we compared intrahepatic gene expression profiles in HCV-infected patients at different stages of fibrosis and alpha-smooth muscle actin (alpha-SMA) staining patterns. We studied 21 liver biopsy specimens: 5 had no fibrosis (Ludwig-Batts stage 0); 10 had early portal or periportal fibrosis (stages 1 and 2); and 6, advanced fibrosis (stages 3 and 4). None of the patients had hepatocellular carcinoma. Transcriptional profiles were determined by high-density oligonucleotide microarrays. ANOVA identified 157 genes for which transcript abundance was associated with fibrosis stage. These defined three distinct hierarchical clusters of patients. Patients with predominantly stage 0 fibrosis had increased abundance of mRNAs linked to glycolipid metabolism. PDGF, a potent stellate cell mitogen, was also increased. Transcripts with increased abundance in stages 1 and 2 fibrosis were associated with oxidative stress, apoptosis, inflammation, proliferation, and matrix degradation, whereas transcripts increased in stages 3 and 4 were associated with fibrogenesis and cellular proliferation. Cells staining for alpha-SMA were detectable at all stages but infrequent in advanced fibrosis without active inflammation. A high frequency of such cells was associated with mRNAs linked to glycolipid metabolism. In conclusion, the presence of alpha-SMA-positive HSCs and expression of PDGF in stage 0 fibrosis suggests that stellate cells are activated early in HCV-mediated injury, possibly in response to oxidative stress resulting from inflammation and lipid metabolism. Increased abundance of transcripts linked to cellular proliferation in advanced fibrosis is consistent with a predisposition to cancer. Supplementary material for this article can be found on the HEPATOLOGY website (http://www.interscience.wiley.com/jpages/0270-9139/suppmat/index/html).