Some apoptotic signals in patients with chronic HCV infection

ABSTRACT

Hepatitis C virus [HCV] infects an estimated 3% of the world population and causes an estimated 470,000 death per year caused by complications of the end stage liver disease. Mechanisms leading to liver cell injury, are not fully understood, both immune mediated reactions and more direct cytopathic effects of HCV may be involved. Agoptosis of liver cells may play a significant role in the pathogenesis of hepatitis C. The aim of this study is to evaluate the role of apoptosis in chronic HCV infection by estimating serum levels of Fas, Fas-Ligand [FasL] and hepatocyte expression of Bcl-2 of patients with chronic hepatitis C virus infection, and find out the relationship [if any] between their levels and the degree of hepatic inflammatory activity. Sixty patients having chronic HCV infection [45 males and 15 females; mean age 36h8.6 years] were randomly selected. In addition, 20 apparently healthy subjects [12 males and 8 females; mean age 33.1 +/- 10.4 years] served as a control group. They were anti-HCV and HBsAg negative. Serum soluble Fas and Fas ligand levels were measured and HCV RNA quantitation was done to patients only. Immunohistochemical detection of Bcl-2 expression in the liver tissue was done to all patients. According to the histopathological assessment of hepatic necroinflammatory activity, patients were classified into 3 groups with minimal [n=23, GI], mild [n=23, GII] and moderate and severe [n=14, GIII] activity. Significant positive correlations were found between serum Fas and FasL and the grade of hepatic inflammatory activity. Mean serum levels of Fas in group I, II, and III were [0.7 +/- 0.3, 2.5/1.1 and 5.2 +/- 0.9 nglml] respectively with p<0.01. Mean serum levels of FasL in group GI, GII, and GIII were [0.6 +/- 0.2, 1.7+-0.8and 4 +/- 1.2 nglml] respectively with p<0.01. Bcl-2 expression was more prevalent in liver tissues of patients in GIII where 35.7% of hepatocytes, 57.1% of Kupffer cells and 50% of bile duct cells stained positively. For the three types of cells, it correlated positively with the grade of inflammatory activity [p<0.01 for each]. Percentage of Bci-2 expression in portal infiltrates in GI, GI1 and GI11 were [34.8, 78.3 and 100 respectively with p<0.01]. The results of the current work provide evidence of increased apoptosis in chronic hepatitis of moderate and severe activity and in cirrhosis due to chronic HCV infection suggesting that apoptotic cell death might be involved in the pathways of hepatocellular damage in both conditions. Serum sFas and sFasL levels positively correlated with the degree of necroinflammatory process in chronic HCV patients. Accordingly, serum sFas and sFasL could serve as non-invasive serological indicators of the hepatic inflammatory activity. Furthermore, the increase of serum sFas and sFasL [apoptotic signaling] as well as the increased expression of Bcl-2 [anti-apoptosis] at the same time, suggests that Bcl-2 might play as a protective mechanism against apoptosis. However, apoptosis caused by the activation of Fas/FasL pathway seems to occur by a mechanism that might not be blocked by Bcl-2