Identification of new molecular targets and the study for the mechanism of bile ducts-and hepatocyte-destruction in primary biliary cirrhosis

抗核抗体（ANA）在原发性胆汁性肝硬化（PBC）的长期预后中的预测作用仍然难以捉摸。本研究的目的是阐明ANA在PBC进展中的意义。使用逐步考克斯比例风险回归和无条件逐步logistic回归模型评估ANA与PBC进展之间的关系，该模型基于276例经活检证实的确诊PBC患者的数据，这些患者已在日本国立医院组织肝病研究组（NHOSLJ）注册。血清抗体的核抗原，包括gp 210，着丝粒，sp100和染色质，通过ELISA法测定从1至292（中位数60.5）个月的观察期。以肝功能衰竭/肝移植（LT）死亡为终点，在所有PBC患者中，抗gp 210抗体阳性（Haza ...更多信息 危险因素包括：早期（Scheuer分期3、4期）（HR=4.285，95% CI：1.682，10.913）和男性（HR=3.266，95% CI：1.321，8.075）。当临床进展至肝衰竭/LT死亡时（即肝功能衰竭型-进展）或食管静脉曲张或肝细胞癌的发展而不发展黄疸（T.胆红素<1.5mg/dl）（即非肝衰竭型-进展）定义为早期终点（Scheuer's stage 1，2）PBC患者中，抗gp 210抗体阳性是肝衰竭型进展的显著危险因素抗着丝粒抗体阳性是非肝功能衰竭型进展的危险因素（OR=4.202，95% CI：1.307，14.763）。组织学上，抗gp 210抗体阳性与更严重的界面肝炎和小叶炎症最显著相关，而抗着丝粒抗体阳性与更严重的导管反应最显著相关。这些结果表明PBC有两种不同的进展类型，肝衰竭型进展和非肝衰竭型进展，其可以分别由阳性抗-GP 210和阳性抗-着丝粒抗体表示。少

The predictive role of anti-nuclear antibodies (ANAs) remains elusive in the long-term outcome of primary biliary cirrhosis (PBC). The aim of this study is to clarify the significance of ANAs in the progression of PBC.The associations between ANAs and the progression of PBC were evaluated using step-wise Cox proportional hazard regression and an unconditional step-wise logistic regression model based on the data of 276 biopsy-proven, definite PBC patients who have been registered to National Hospital Organization Study Group for Liver Disease in Japan (NHOSLJ). Serum antibodies to nuclear antigens including gp210, centromere, sp100 and chromatin were measured by ELISA over periods extending from 1 to 292 (median 60.5) months of observation. A total of 91 PBC liver biopsy specimens were also assessed for histological variables in relation to ANAs.When death of hepatic failure/liver transplantation (LT) was defined as an end-point in all PBC patients, positive anti-gp210 antibodies (Haza … More rd ratio (HR)=6.742, 95% confidence interval (CI) : 2.408, 18.877), the late stage (Scheuer's stage 3, 4) (HR=4.285, 95% CI : 1.682,10.913) and male sex (HR=3.266, 95% CI : 1.321,8.075) were significant risk factors at the time of initial liver biopsy. When clinical progression to death of hepatic failure/LT (i.e. hepatic failure type-progression) or to the development of esophageal varices or hepatocelluar carcinoma without developing jaundice (T.bilirubin<1.5mg/dl) (i.e. non-hepatic failure type-progression) was defined as an end-point in the early stage (Scheuer's stage 1, 2) PBC patients, positive anti-gp210 antibodies was, a significant risk factor for hepatic failure type-progression (odds ratio (OR)=33.777, 95% CI : 5.930, 636.745), whereas positive anti-centromere antibodies was a significant risk factor for non-hepatic failure type-progression (OR=4.202, 95% CI : 1.307, 14.763). Histologically, positive anti-gp210 antibodies was most significantly associated with more severe interface hepatitis and lobular inflammation, while positive anti-centromere antibodies was most significantly associated with more severe ductular reaction These results indicate that there are two different progression-types in PBC, hepatic failure type-and non-hepatic failure type-progression, which may be represented by positive-anti-gp210 and-anti-centromere antibodies, respectively. Less