Piperno Alberto, Pelucchi Sara, Mariani Raffaella
Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.
Centre for Rare Diseases, Disorder of Iron Metabolism, ASST-Monza, S. Gerardo Hospital, Monza, Italy.
Transl Gastroenterol Hepatol. 2020 Apr 5;5:25. doi: 10.21037/tgh.2019.11.15. eCollection 2020.
Hereditary iron overload includes several disorders characterized by iron accumulation in tissues, organs, or even single cells or subcellular compartments. They are determined by mutations in genes directly involved in hepcidin regulation, cellular iron uptake, management and export, iron transport and storage. Systemic forms are characterized by increased serum ferritin with or without high transferrin saturation, and with or without functional iron deficient anemia. Hemochromatosis includes five different genetic forms all characterized by high transferrin saturation and serum ferritin, but with different penetrance and expression. Mutations in HFE, HFE2, HAMP and TFR2 lead to inadequate or severely reduced hepcidin synthesis that, in turn, induces increased intestinal iron absorption and macrophage iron release leading to tissue iron overload. The severity of hepcidin down-regulation defines the severity of iron overload and clinical complications. Hemochromatosis type 4 is caused by dominant gain-of-function mutations of ferroportin preventing hepcidin-ferroportin binding and leading to hepcidin resistance. Ferroportin disease is due to loss-of-function mutation of SLC40A1 that impairs the iron export efficiency of ferroportin, causes iron retention in reticuloendothelial cell and hyperferritinemia with normal transferrin saturation. Aceruloplasminemia is caused by defective iron release from storage and lead to mild microcytic anemia, low serum iron, and iron retention in several organs including the brain, causing severe neurological manifestations. Atransferrinemia and DMT1 deficiency are characterized by iron deficient erythropoiesis, severe microcytic anemia with high transferrin saturation and parenchymal iron overload due to secondary hepcidin suppression. Diagnosis of the different forms of hereditary iron overload disorders involves a sequential strategy that combines clinical, imaging, biochemical, and genetic data. Management of iron overload relies on two main therapies: blood removal and iron chelators. Specific therapeutic options are indicated in patients with atransferrinemia, DMT1 deficiency and aceruloplasminemia.
遗传性铁过载包括几种疾病，其特征是铁在组织、器官甚至单个细胞或亚细胞区室中蓄积。它们由直接参与铁调素调节、细胞铁摄取、管理和输出、铁运输和储存的基因突变所决定。全身性形式的特征是血清铁蛋白升高，伴有或不伴有高转铁蛋白饱和度，伴有或不伴有功能性缺铁性贫血。血色素沉着症包括五种不同的遗传形式，均以高转铁蛋白饱和度和血清铁蛋白为特征，但具有不同的外显率和表达情况。HFE、HFE2、HAMP和TFR2基因的突变导致铁调素合成不足或严重减少，进而诱导肠道铁吸收增加和巨噬细胞铁释放增加，导致组织铁过载。铁调素下调的严重程度决定了铁过载和临床并发症的严重程度。4型血色素沉着症由铁转运蛋白的显性功能获得性突变引起，阻止铁调素与铁转运蛋白结合，导致铁调素抵抗。铁转运蛋白病是由于SLC40A1功能丧失突变，损害了铁转运蛋白的铁输出效率，并导致网状内皮细胞中铁潴留和转铁蛋白饱和度正常的高铁蛋白血症。无铜蓝蛋白血症是由于储存铁释放缺陷所致，导致轻度小细胞贫血、低血清铁以及包括脑在内的多个器官中铁潴留，引起严重的神经学表现。无转铁蛋白血症和二价金属离子转运体1缺乏症的特征是缺铁性红细胞生成、严重小细胞贫血伴高转铁蛋白饱和度以及由于继发性铁调素抑制导致的实质器官铁过载。遗传性铁过载疾病不同形式的诊断需要采用一种综合临床、影像学、生化和基因数据的序贯策略。铁过载的管理依赖于两种主要治疗方法：放血和铁螯合剂。对于无转铁蛋白血症、二价金属离子转运体1缺乏症和无铜蓝蛋白血症患者，有特定的治疗选择。
