Genetics, Genetic Testing, and Management of Hemochromatosis: 15 Years Since Hepcidin
Genetics, Genetic Testing, and Management of Hemochromatosis: 15 Years Since Hepcidin
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DOI：
10.1053/j.gastro.2015.06.045
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发表时间：
2015-10-01
期刊：
影响因子：
29.4
通讯作者：
Pietrangelo, Antonello
中科院分区：
文献类型：
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作者：
Pietrangelo, Antonello
铁调素在2000年的发现和随后在铁领域的研究和发现的前所未有的爆炸，极大地改变了我们对人类铁代谢紊乱的理解。今天，遗传性血色病，典型的铁负荷障碍，被认为是一种内分泌疾病，由于铁调素，由肝脏产生的铁激素的遗传丢失。这种综合征是由于铁在没有增加红细胞生成需求的情况下不受限制地转移到血液中及其在实质器官中的毒性作用。它是由影响任何帮助hepcidin监测血清铁的蛋白质的突变引起的，包括HFE，在罕见的情况下，转铁蛋白受体2和hemojuvelin，或使其受体ferroportin对激素产生抗性。在高加索人中，C282 Y HFE纯合子很多，但他们只倾向于血色素沉着症;由于酗酒或目前正在鉴定的并发遗传修饰剂，少数人会发生完全器官疾病。HFE基因检测可用于诊断有症状患者的血色素沉着症，但需要对肝脏组织学和全基因测序进行分析，以确定患有罕见的非HFE形式疾病的患者。由于铁调素的中心致病作用，预计铁调素丢失的非遗传原因（例如，终末期肝病）可导致获得性血色病。血色素沉着症治疗的支柱仍然是通过静脉切开术去除铁，该方法于20世纪50年代首次引入，但铁调素的鉴定不仅为疾病的发病机制和诊断方法提供了新的线索，而且现在可以预见这些进展的病因学治疗应用。
The discovery of hepcidin in 2000 and the subsequent unprecedented explosion of research and discoveries in the iron field have dramatically changed our understanding of human disorders of iron metabolism. Today, hereditary hemochromatosis, the paradigmatic iron-loading disorder, is recognized as an endocrine disease due to the genetic loss of hepcidin, the iron hormone produced by the liver. This syndrome is due to unchecked transfer of iron into the bloodstream in the absence of increased erythropoietic needs and its toxic effects in parenchymatous organs. It is caused by mutations that affect any of the proteins that help hepcidin to monitor serum iron, including HFE and, in rarer instances, transferrin-receptor 2 and hemojuvelin, or make its receptor ferroportin, resistant to the hormone. In Caucasians, C282Y HFE homozygotes are numerous, but they are only predisposed to hemochromatosis; complete organ disease develops in a minority, due to alcohol abuse or concurrent genetic modifiers that are now being identified. HFE gene testing can be used to diagnose hemochromatosis in symptomatic patients, but analyses of liver histology and full gene sequencing are required to identify patients with rare, non-HFE forms of the disease. Due to the central pathogenic role of hepcidin, it is anticipated that nongenetic causes of hepcidin loss (eg, end-stage liver disease) can cause acquired forms of hemochromatosis. The mainstay of hemochromatosis management is still removal of iron by phlebotomy, first introduced in 1950s, but identification of hepcidin has not only shed new light on the pathogenesis of the disease and the approach to diagnosis, but etiologic therapeutic applications from these advances are now foreseen.