Hepatic Fibrosis Group, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; Faculty of Health Sciences, University of Queensland, Brisbane, Queensland, Australia; Department of Gastroenterology and Hepatology, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.
Hepatology. 2014 Mar;59(3):848-57. doi: 10.1002/hep.26706. Epub 2014 Jan 27.
The development of portal fibrosis following the iron loading of hepatocytes is the first stage of fibrogenesis in hereditary hemochromatosis. In other chronic liver diseases it has been shown that a ductular reaction (DR) appears early, correlates with fibrosis progression, and is a consequence of activation of an alternative pathway of hepatocyte replication. This study was designed to investigate the presence of the DR in hemochromatosis and describe its associations. Liver biopsies from 63 C282Y homozygous patients were assessed for hepatic iron concentration (HIC) and graded for iron loading, fibrosis stage, steatosis, and inflammation. Immunostaining allowed quantification of the DR, hepatocyte senescence and proliferation, and analysis incorporated clinical data. Hepatocyte senescence was positively correlated with HIC, serum ferritin, and oxidative stress. A DR was demonstrated and occurred prior to histological fibrosis. HIC, age, hepatocyte senescence and proliferation, portal inflammation, and excessive alcohol consumption all had significant associations with the extent of the DR. In multivariate analysis, iron loading, hepatocyte replicative arrest, and portal inflammation remained independently and significantly associated with the DR. Of factors associated with fibrosis progression, the DR (odds ratio [OR] 10.86 P<0.0001) and the presence of portal inflammation (OR 4.31, P=0.028) remained significant after adjustment for cofactors. The extent of the DR regressed following therapeutic venesection.
Iron loading of hepatocytes leads to impaired replication, stimulating the development of the DR in hemochromatosis and this correlates strongly with hepatic fibrosis. Portal inflammation occurs in hemochromatosis and is independently associated with the DR and fibrosis, and thus its role in this disease should be evaluated further.
肝细胞铁过载后形成门脉纤维化是遗传性血色素沉着症纤维化发生的第一阶段。在其他慢性肝病中已经表明，胆管反应（ductular reaction，DR）很早就会出现，与纤维化进展相关，是肝细胞复制替代途径激活的结果。本研究旨在调查 DR 在血色素沉着症中的存在情况并描述其相关性。对 63 名 C282Y 纯合子患者的肝活检标本进行肝铁浓度（hepatic iron concentration，HIC）评估和铁过载、纤维化分期、脂肪变性和炎症分级。免疫染色允许定量分析 DR、肝细胞衰老和增殖，并将临床数据纳入分析。肝细胞衰老与 HIC、血清铁蛋白和氧化应激呈正相关。证明了 DR 的存在，并发生在组织学纤维化之前。HIC、年龄、肝细胞衰老和增殖、门脉炎症和过量饮酒均与 DR 的严重程度有显著相关性。在多变量分析中，铁过载、肝细胞复制停滞和门脉炎症与 DR 独立且显著相关。在调整协变量后，与纤维化进展相关的因素中，DR（比值比 [odds ratio，OR] 10.86，P<0.0001）和门脉炎症（OR 4.31，P=0.028）仍然具有显著意义。DR 的严重程度在治疗性放血后会消退。
肝细胞铁过载导致复制受损，刺激血色素沉着症中 DR 的发展，且与肝纤维化密切相关。门脉炎症发生在血色素沉着症中，与 DR 和纤维化独立相关，因此应进一步评估其在该疾病中的作用。
