Proliferation of liver cells chronic liver disease: a study of liver in biopsies using immunohistochemical localization of prolifrating cell nuclear antigen

ABSTRACT

A significant proportion of chronic liver disease [CLD], consisting of chronic hepatitis and liver cirrhosis, results from chronic subclinical infection by hepatitis B and C viruses, HBV and HCV[1]. This chronic hepatitis [CH] is a forerunner of liver cirrhosis [LC] and may further progress to hepatocellular carcinoma[2-3]. The association of cirrhosis with hepatocellular carcinoma [HCC] is also well documented[4]. The exact mechanism of viral hepatocarcinogenesis is yet to be clearly defined[5]. Possibly the persistent liver cell necrosis and the resultant irregular regeneration[6]. The proliferative rate of regenerating hepatocytes may be an important pathogenetic and prognostic factor in chronic liver disease[7]. A number of markers have been used in the assessment of the proliferative status of cells, like bromodeoxyuridine[8], Ki-67[9] and DNA polymerase alpha[10]. Techniques utilizing these markers are complex, however, and require fresh or snap frozen tissue, except for Ki-67, which can be used on paraffin sections. Proliferating cell nuclear antigen [PCNA], an accessory protein of DNA polymerase delta, is one of the best markers for evaluating cell proliferation in studies on retrospective material, since the antigen can be localized in routine formalin-fixed paraffin-embedded tissue[7, 11-14]. Limited reports are available on the proliferation kinetics of normal human livers, though in recent years several studies reported on hepatocytic proliferation rates in acute and chronic liver diseases. Normal hepatocytes are generally quiescent and divide very slowly[15-17] High proliferative rates have been reported in hepatocellular carcinoma, cirrhosis and acute hepatic failure[11, 18-22]. Nakamura et al., [7] have shown that there is no significant difference in PCNA-labeling indices between chronic viral hepatitis types B and C. With increasing knowledge of the biology of hepatitis C virus infection, information on hepatocytic proliferation kinetics is emerging now. In a recent study on the prevalence of HBV- and HCV-associated chronic liver diseases in liver biopsy material over the last decade, we observed a steady rise of HCV-associated diseases and a decline in HBV-associated ones[23]. Chronicity of HCV infection leads to CH and LC much more frequently than chronic infection by other hepatitis viruses[24], and the former infection shows a higher degree of association with hepatocellular carcinoma in several parts of the world[25]. Therefore, we considered it worthwhile to examine for hepatocytic proliferation using PCNA-labeling in our material of chronic liver diseases and to note any differences between hepatitis B- and C-associated diseases