Freeman A, Hamid S, Morris L, Vowler S, Rushbrook S, Wight D G D, Coleman N, Alexander G J M
Department of Histopathology, Addenbrooke's Hospital, Cambridge, UK.
J Viral Hepat. 2003 Sep;10(5):345-50. doi: 10.1046/j.1365-2893.2003.00454.x.
To test the hypothesis that hepatitis C virus (HCV) might induce hepatocyte proliferation directly, thereby predisposing HCV carriers to cirrhosis and hepatocellular carcinoma, we have used a new method to identify proliferating hepatocytes, employing a novel monoclonal antibody to minichromosome maintenance (Mcm) proteins, essential components of the pre-replication complex. Antibody to Ki-67, a conventional marker of cell division, was also studied. Eighty-seven patients with chronic HCV infection and a broad spectrum of histological change were studied. Proliferation was observed rarely in hepatocytes from normal liver from healthy controls (always less than 0.01%). However, proliferating hepatocytes were detected in all HCV-infected patients and the proportion of hepatocytes expressing Mcm-2 (3-40%) always exceeded that expressing Ki-67 (1-14%) and correlated positively with increasing stage of fibrosis (P = 0.0001) and viral replication (P = 0.0004). There were weaker but significant associations between the proportion of hepatocytes expressing Mcm-2 and inflammatory indices including interface hepatitis, portal tract inflammation, lobular inflammation and steatosis. There was no association between the proportion of hepatocytes expressing Mcm-2 and age, gender or past alcohol consumption, but there was a weak association with current consumption of alcohol (P = 0.0067). The proportion of Ki-67 hepatocytes did not correlate with any clinical, laboratory or histological parameter. Mcm-2 was also detected in bile duct cells, sinusoidal lining cells and infiltrating lymphocytes, but at low frequency. These data indicate first, that Mcm-2 is a more sensitive marker of hepatocyte proliferation than Ki-67, second that many hepatocytes in chronic HCV infection have entered the cell cycle and third, suggest that interference with the hepatocyte cell cycle might be an alternative approach to therapy.
为了验证丙型肝炎病毒（HCV）可能直接诱导肝细胞增殖，从而使HCV携带者易患肝硬化和肝细胞癌这一假说，我们采用了一种新方法来识别增殖的肝细胞，该方法使用了一种针对微小染色体维持（Mcm）蛋白的新型单克隆抗体，Mcm蛋白是复制前复合体的重要组成部分。我们还研究了针对细胞分裂传统标志物Ki-67的抗体。我们对87例患有慢性HCV感染且具有广泛组织学变化的患者进行了研究。在健康对照者正常肝脏的肝细胞中很少观察到增殖（始终低于0.01%）。然而，在所有HCV感染患者中均检测到增殖的肝细胞，并且表达Mcm-2的肝细胞比例（3%-40%）始终超过表达Ki-67的肝细胞比例（1%-14%），且与纤维化程度增加（P = 0.0001）和病毒复制（P = 0.0004）呈正相关。表达Mcm-2的肝细胞比例与包括界面性肝炎、汇管区炎症、小叶炎症和脂肪变性在内的炎症指标之间存在较弱但显著的关联。表达Mcm-2的肝细胞比例与年龄、性别或既往饮酒量无关，但与当前饮酒量存在较弱的关联（P = 0.0067）。Ki-67阳性肝细胞的比例与任何临床、实验室或组织学参数均无相关性。在胆管细胞、窦状隙衬里细胞和浸润淋巴细胞中也检测到了Mcm-2，但频率较低。这些数据首先表明，Mcm-2是比Ki-67更敏感的肝细胞增殖标志物；其次表明，慢性HCV感染中的许多肝细胞已进入细胞周期；第三表明，干扰肝细胞细胞周期可能是一种替代治疗方法。
