الفهرس 
Natural history of hepatitis C:Only 14 pages are availabe for public view
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Abstract
Liver fibrosis results from a wound-healing response
to chronic injury, which leads to excessive matrix, or scar
deposition. This scar tissue leading to progressive liver
damage and cirrhosis (the end stage of fibrosis),
complicated by liver failure, portal hypertension and/or
hepatocellular carcinoma (HCC). Genome-wide analysis of
abnormal gene expression showed transcripts deregulation
differences among normal, mild and severe fibrosis during
HCC development with identification of novel serum
markers for its early stage. Recent studies suggest that
genetic markers may be able to define exact stage of liver
fibrosis. In this study, the transcriptional profiling of
fibrosis related genes in HCV-chronically infected patients
with different degrees of liver fibrosis has been examined.
PCR array was used to examine the expression of 84 fibrosis related genes in peripheral blood mononuclear cells
(PBMCs). The RNA from 30 treatment-naïve chronic HCV
patients (17 F0-F2 and 13 F3-F4) and 6 healthy subjects
were enrolled. Validation of the results were performed by
custom real time PCR in 75 treatment-naïve chronic HCV
patients (39 F0-F2 and 36 F3-F4) and 10 controls.
from the first approach data (PCR array data),
selected eleven genes were based on their fold change,
physiological pathway and p value. In the second approach,
custom real time PCR confirmed that expression of
transforming growth factor β (TGF β1) gene at the early
stage of fibrosis is highly regulated compared to control
(fold differential regulation =2.555033, p= 0.035), whereas
the TG- interacting factor (TGIF1) gene which is the
inhibitory of TGF β1 is down regulated (fold differential
regulation =-1.2, p= 0.041). At the late stage of fibrosis,
TGF β1 gene showed no significant changes in fold
regulation when compared with control, while the TGIF1
gene is sharply down regulated (fold differential regulation
=-1.6,p= 0.01).
Whereas the TGFβ2 gene is sharply down
regulated in the late stage without statistically significant.
Also there is increase in Matrix Metalloproteinase 9 (MMP9) fold regulation in the late stage than early stage
when compared with control, but without statistically
significant. Moreover, by custom real time PCR: TIMP1,
TIMP2, IL1B, SP1, PDGFA and THBS1 genes showed no
significant changes in fold regulation in early and late
fibrotic patients when compared with control. While these
results suggest that TGFβ1 and TGIF1 are possible
candidates as biomarkers for the progression of HCVinduced
liver fibrosis and/ or targets for therapeutic
intervention.
Furthermore, the circulating proteins of the extra
cellular matrix (ECM) was evaluated. ELISA has showed
that the level of secreted TIMP2, TIMP1 proteins were
significantly higher in late fibrotic patients (**p=0.000,
*p=0.034) respectively than its conc, in serum of early
fibrotic patients (F0-F2). On the other hand, MMP9 protein
was significantly higher in early fibrotic patients than its
conc, in serum of late fibrotic patients (*p=0.022).
Moreover, the non-parametric Kruskal-Wallis test showed
significant difference for TIMP2, MMP9 proteins levels
among different fibrotic stages p=0.001, 0.042,
respectively, while TIMP1 was not significant p=0.1.Receiver Operating characteristic (ROC) analyses
curve suggested that TGFβ1 mRNA, TIMP2 and
TIMP1proteins (AUC=0.694, 0.777 and 0.659 respectively)
are possible candidates as biomarkers for the progression of
HCV-induced liver fibrosis and/ or adjuvants for
therapeutic intervention to stop failing of the clinical course
of HCV chronic infection in patients.
Keywords:
HCV, gene expression, liver fibrosis, RT-PCR.