Anderson Gregory J, Bardou-Jacquet Edouard
Iron Metabolism Laboratory, QIMR Berghofer Medical Research Institute and School of Chemistry and Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
Liver Disease Department, University of Rennes and French Reference Center for Hemochromatosis and Iron Metabolism Disease, Rennes, France.
Ann Transl Med. 2021 Apr;9(8):731. doi: 10.21037/atm-20-5512.
Iron overload disorders represent an important class of human diseases. Of the primary iron overload conditions, by far the most common and best studied is HFE-related hemochromatosis, which results from homozygosity for a mutation leading to the C282Y substitution in the HFE protein. This disease is characterized by reduced expression of the iron-regulatory hormone hepcidin, leading to increased dietary iron absorption and iron deposition in multiple tissues including the liver, pancreas, joints, heart and pituitary. The phenotype of HFE-related hemochromatosis is quite variable, with some individuals showing little or no evidence of increased body iron, yet others showing severe iron loading, tissue damage and clinical sequelae. The majority of genetically predisposed individuals show at least some evidence of iron loading (increased transferrin saturation and serum ferritin), but a minority show clinical symptoms and severe consequences are rare. Thus, the disorder has a high biochemical penetrance, but a low clinical prevalence. Nevertheless, it is such a common condition in Caucasian populations (1:100-200) that it remains an important clinical entity. The phenotypic variability can largely be explained by a range of environmental, genetic and physiological factors. Men are far more likely to manifest significant disease than women, with the latter losing iron through menstrual blood loss and childbirth. Other forms of blood loss, immune system influences, the amount of bioavailable iron in the diet and lifestyle factors such as high alcohol intake can also contribute to iron loading and disease expression. Polymorphisms in a range of genes have been linked to variations in body iron levels, both in the general population and in hemochromatosis. Some of the genes identified play well known roles in iron homeostasis, yet others are novel. Other factors, including both co-morbidities and genetic polymorphisms, do not affect iron levels , but determine the propensity for tissue pathology.
铁过载疾病是人类疾病中的一个重要类别。在原发性铁过载病症中，迄今为止最常见且研究最深入的是与HFE相关的血色素沉着症，它是由一种导致HFE蛋白中C282Y替换的突变纯合子引起的。这种疾病的特征是铁调节激素铁调素的表达减少，导致膳食铁吸收增加以及铁在包括肝脏、胰腺、关节、心脏和垂体在内的多个组织中沉积。与HFE相关的血色素沉着症的表型差异很大，一些个体几乎没有或没有身体铁增加的迹象，而另一些个体则表现出严重的铁负荷、组织损伤和临床后遗症。大多数具有遗传易感性的个体至少有一些铁负荷的迹象（转铁蛋白饱和度和血清铁蛋白增加），但少数个体出现临床症状，严重后果很少见。因此，该疾病具有较高的生化外显率，但临床患病率较低。然而，它在白种人群中是一种常见病症（1:100 - 200），仍然是一个重要的临床实体。表型变异性在很大程度上可以由一系列环境、遗传和生理因素来解释。男性比女性更易表现出明显的疾病，后者通过月经失血和分娩失去铁。其他形式的失血、免疫系统影响、饮食中生物可利用铁的量以及高酒精摄入等生活方式因素也可能导致铁负荷和疾病表现。在一般人群和血色素沉着症患者中，一系列基因的多态性都与体内铁水平的变化有关。一些已确定的基因在铁稳态中发挥着众所周知的作用，而其他一些则是新发现的。其他因素，包括共病和基因多态性，虽不影响铁水平，但决定了组织病理学的倾向。
