الفهرس 
Introduction and aim of the workOnly 14 pages are availabe for public view
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Abstract
Hepatitis C virus (HCV) infection is one of the main causes of chronic liver disease worldwide (Lavanchy et al 2007). Egypt has the highest prevalence of adult HCV infection in the world, averaging 15%-25% in rural communities (El-Raziket al., 2007). Combined pegylated interferon and ribavirin therapy are still the most effective therapies in HCV-4 genotype (El-Zayadi et al.,2005), although the rate of sustained virological response (SVR) is around 50% (Kamal et al.,2011). It is of major interest for both patient care and economic approach to predict response to therapy (Asselah.et al., 2010). Combined host factors such as age, gender, liver fibrosis in addition to laboratory investigations were identified as predictors of the therapeutic effects in chronic HCV patients through the application of data mining analysis (Izumi et al., 2010). Cytokines play a key role in the regulation of immune responses. In hepatitis C virus infection, the production of abnormal cytokine levels appears to contribute in the progression of the disease, viral persistence, and affects response to therapy (Pasha et al., 2013). This was a retrospective study, selecting 64 chronic HCV patients who were submitted to pretreatment liver biopsy and received pegylated interferone plus ribivarin for 48 weeks. The patients were divided into responders and non responders.
The aim of this study is to investigate the role of different demographic, laboratory finding, histological parameters and hepatic immunohistochemical expression of interluekin-28, interferon- γ and tumor necrosis factor- α as predictors of response to pegylated interferon plus ribavirin in chronic HCV patients.
Paraffin embedded blocks of pretreatment liver core biopsies were retrieved from Pathology Department, National Liver Institute, Menofiya University. Five micron thick serial liver sections were cut from each paraffin embedded block and mounted on several glass slides. These slides were stained with hematoxylin and eosin stain (H&E) for evaluation the histopathological features associated with chronic HCV (Portal tract inflammation, nature of infiltrate, interface hepatitis , lymphoid aggregates, spotty necrosis, confluent necrosis, HAI grade, fibrosis stage, steatosis, bile duct injury, vascular changes and other sections were cut on charged coated slides on which immunohistochemical staining was performed to detect the following antigens interluekin-28, interferon- γ and tumor necrosis factor- α Age of selected patients ranged between19 and57 years with a median of 34 years. Male gender was predominant (41/64) (64.1%). 56% (36/64) of patients demonstrated elevated ALT (>40U/L) while 39% (25/64) of patients demonstrated elevated AST (>40U/L). All cases showed portal tract inflammation with different grades. HAI score ranged between 2 and 11 with a mean ± SD of 5.4 ± 1.8 and a median of 5. Lobular necrosis and interface hepatitis were present in all cases except one. The inflammatory infiltrate was formed of mononuclear inflammatory cells mostly lymphocytes admixed with plasma cells or esinophils.
The current study demonstrated that young age (p=0.003), female gender (p=0.02) and low serum level of alpha fetoprotein (P= 0.046) are the parameters that favored response to interferon and ribavirin therapy in chronic HCV Egyptian patients. The level of viraemia did not show statistical significant difference between both groups. However, patients with mild viraemia showed more response than those with moderate or high viraemia levels. On the other hand, none of the studied pathological parameters showed any significant difference in relation to response of the therapy.
Thirty five cases out of 64 cases were positive for IL-28 (54%), 17 were responders (10.8%) and 18 cases were non responders (11.52%). The expression was localized to the mononuclear inflammatory cells. Positive IL-28 expression was significantly associated with male gender (p=0.001) and parameters indicating less severe inflammation as low AST level (p=0.005), low HAI score (p= 0.006), absence of confluent necrosis (p=0.05), absence of vascular changes (p=0.05). Steatosis showed significant association with IL-28 expression as presence of steatosis was associated with increased mean percentage of IL-28 expression (P=0.031). The present study demonstrated IFN-γ expression in mononuclear inflammatory cells of 43 cases out of 64 cases (67%), 23 were responders and 20 cases were non responders. There was a tendency of INF- γ expression to be associated with grade I portal inflammation as a predictor of milder degree of inflammation (P=0.085) and with presence of lymphoid aggregate (P=0.062). The present study demonstrated TNF- α expression in inflammatory cells of 29 cases out of 64 cases(45% ), 15 were responders and 14 cases were non responders. Percentage of TNF- α was of higher median value in grade II spotty necrosis compared to grade I (P=0.015) as a predictor of increase severity of inflammation. There was no significant difference between responders and non-responders regarding three markers expression (p>0.05), however mean and median percentage of both IL-28 and IFN-γ were higher in responders in comparison to non- responders. However, median of percentage of TNF- α was higher in non responders in comparison to responders.
Cases that showed positivity for one or two marker (48/64) were associated with grade I portal inflammation (p=0.05) and absence of steatosis (p=0.094) in comparison to group showing positivity for the three markers (10/64).
There was significant association between presence of INF- γ and high percentage of IL-28 expression in responder group (P=0.05) and in all patients (P=0.027). Also, TNF- α expression was associated with high percentage of IL-28 expression only in non-responder group (P=0.017). The cases were subdivided into two groups according to TNF-α expression into those showing TNF-α and those lacking TNF-α. Positive group for TNF-α expression showed association with grade II portal tract inflammation (P=0.025) and absence of steatosis (P=0.07).