Fibrosis correlates with a ductular reaction in hepatitis C: Roles of impaired replication, progenitor cells and steatosis
Fibrosis correlates with a ductular reaction in hepatitis C: Roles of impaired replication, progenitor cells and steatosis
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DOI：
10.1002/hep.20650
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发表时间：
2005-04-01
期刊：
影响因子：
13.5
通讯作者：
Jonsson, JR
中科院分区：
文献类型：
--
作者：
Clouston, AD;Powell, EE;Jonsson, JR
慢性丙型肝炎（HCV）患者中脂肪变性导致进行性纤维化和病情加重的机制仍不清楚。我们假设丙型肝炎病毒感染且有脂肪变性的肝细胞增殖受阻，导致肝祖细胞（HPC）默认激活，肝祖细胞能够分化为胆管细胞和肝细胞谱系，并且由此产生的胆管反应促进门脉纤维化。为了研究这一概念，对115例丙型肝炎患者的肝活检标本进行脂肪变性、炎症和纤维化评分。通过细胞角蛋白7免疫过氧化物酶标记胆管上皮和肝祖细胞，并通过p21和Ki - 67免疫组化评估肝细胞的增殖状态。门脉界面的胆管反应很常见。胆管反应面积与纤维化分期之间存在高度显著的相关性（r = 0.453，P <.0001），在多变量分析后这种相关性仍然独立存在。肝祖细胞数量也与纤维化（r = 0.544，P <.0001）和胆管面积（r = 0.624，P <.0001）相关。此外，脂肪变性与肝祖细胞增殖增加（r = 0.372，P =.0004）和胆管反应（r = 0.374，P <.0001）相关，但不是必需特征。p21表达导致的肝细胞增殖受损与肝祖细胞扩增独立相关（P =.002），且随体重指数（P <.001）和小叶炎症（P =.005）而增加。总之，门脉纤维化与伴有肝祖细胞扩增的门脉周围胆管反应之间的强相关性、脂肪变性的加重作用以及与肝细胞增殖受损的关联表明，再生途径的改变驱动了胆管反应。我们认为这触发了门脉束界面的纤维化。这可能是在其他慢性肝病中具有重要意义的一种刻板反应。
The mechanisms for progressive fibrosis and exacerbation by steatosis in patients with chronic hepatitis C (HCV) are still unknown. We hypothesized that proliferative blockade in HCV-infected and steatotic hepatocytes results in the default activation of hepatic progenitor cells (HPC), capable of differentiating into both biliary and hepatocyte lineages, and that the resultant ductular reaction promotes portal fibrosis. To study this concept, 115 liver biopsy specimens from subjects with HCV were scored for steatosis, inflammation, and fibrosis. Biliary epithelium and HPC were decorated by cytokeratin 7 immunoperoxidase, and the replicative state of hepatocytes was assessed by p21 and Ki-67 immunohistochemistry. A ductular reaction at the portal interface was common. There was a highly significant correlation between the area of ductular reaction and fibrosis stage (r = 0.453, P < .0001), which remained independently associated after multivariate analysis. HPC numbers also correlated with fibrosis (r = 0.544, P < .0001) and the ductular area (r = 0.624, P < .0001). Moreover, steatosis correlated with greater HPC proliferation (r = 0.372, P = .0004) and ductular reaction (r = 0.374, P < .0001) but was not an obligate feature. Impaired hepatocyte replication by p21 expression was independently associated with HPC expansion (P = .002) and increased with the body mass index (P < .001) and lobular inflammation (P = .005). In conclusion, the strong correlation between portal fibrosis and a periportal ductular reaction with HPC expansion, the exacerbation by steatosis, and the associations with impaired hepatocyte replication suggest that an altered regeneration pathway drives the ductular reaction. We believe this triggers fibrosis at the portal tract interface. This may be a stereotyped response of importance in other chronic liver diseases.