Rudnick David A, Perlmutter David H
Department of Pediatics, Washington University School of Medicine, St. Louis, MO, USA.
Hepatology. 2005 Sep;42(3):514-21. doi: 10.1002/hep.20815.
Liver disease in alpha-1-antitrypsin (alpha1AT) deficiency is caused by a gain-of-toxic function mechanism engendered by the accumulation of a mutant glycoprotein in the endoplasmic reticulum (ER). The extraordinary degree of variation in phenotypical expression of this liver disease is believed to be determined by genetic modifiers and/or environmental factors that influence the intracellular disposal of the mutant glycoprotein or the signal transduction pathways that are activated. Recent investigations suggest that a specific repertoire of signaling pathways are involved, including the autophagic response, mitochondrial- and ER-caspase activation, and nuclear factor kappaB (NFkappaB) activation. Whether activation of these signaling pathways, presumably to protect the cell, inadvertently contributes to liver injury or perhaps protects the cell from one injury and, in so doing, predisposes it to another type of injury, such as hepatocarcinogenesis, is not yet known. Recent studies also suggest that hepatocytes with marked accumulation of alpha1ATZ, globule-containing hepatocytes, engender a cancer-prone state by surviving with intrinsic damage and by chronically stimulating in 'trans' adjacent relatively undamaged hepatocytes that have a selective proliferative advantage. Further, this paradigm may apply to other genetic and infectious liver diseases that are predisposed to hepatocellular carcinoma.
α-1抗胰蛋白酶（α1AT）缺乏症中的肝脏疾病是由一种毒性功能获得机制引起的，该机制由内质网（ER）中突变糖蛋白的积累产生。这种肝脏疾病表型表达的显著差异程度被认为是由影响突变糖蛋白细胞内处理的遗传修饰因子和/或环境因素或被激活的信号转导通路所决定的。最近的研究表明，涉及特定的信号通路组合，包括自噬反应、线粒体和内质网半胱天冬酶激活以及核因子κB（NFκB）激活。这些信号通路的激活，大概是为了保护细胞，是否会无意中导致肝损伤，或者是否会保护细胞免受一种损伤，而这样做又使其易患另一种类型的损伤，如肝癌发生，目前尚不清楚。最近的研究还表明，α1ATZ大量积累的肝细胞，即含小球体的肝细胞，通过在内在损伤下存活并通过“反式”慢性刺激相邻相对未受损且具有选择性增殖优势的肝细胞，从而产生易患癌症的状态。此外，这种模式可能适用于其他易患肝细胞癌的遗传性和感染性肝脏疾病。
