Iron: Molecular Basis of Hemochromatosis

Abstract Iron can be deleterious in excess because of its ability to generate reactive oxygen species. Consequently, the appropriate maintenance of organismal iron balance is crucial. Disturbances in iron metabolism are the root cause of many prevalent human diseases. Hereditary hemochromatosis is a genetic disorder resulting in a chronic increase of iron uptake from the diet leading to disease. Although first mentioned in the medical literature by Trousseau in 1865, until recently, the genetic and the pathophysiological bases of this disorder were poorly understood. The vast majority of cases are caused by mutations inHFE, the classic hemochromatosis gene. More recently, genetic studies have implicated hemochromatosis disease‐causing mutations in hemojuvelin (HJV), hepcidin (HAMP), transferrin receptor 2 (TFR2), and ferroportin (SLC40A1). Research involving these five genetically distinct causes of hemochromatosis has increased our knowledge of the underlying pathogenic mechanisms of the disease and has led to a better general understanding of iron metabolism. Current thought places hepcidin, a soluble 25‐amino‐acid peptide, as the master regulator of iron homeostasis. Hepcidin acts as a ligand for the iron transporter ferroportin, negatively regulating iron release from red blood cell‐recycling macrophages or dietary iron uptake in the duodenum. Perturbance of the hepcidin–ferroportin regulatory apparatus in hemochromatosis leads to dysregulated dietary iron uptake eventuating in disease. Recent work has augmented our understanding of how iron regulates hepcidin expression. Hemojuvelin, a bone morphogenetic protein (BMP) coreceptor, plays a central role in the regulation of hepcidin expression through aSMAD‐mediated signaling pathway. BothHFEandTFR2are thought to play essential roles in the sensing of total body iron needs, but the mechanism by which these molecules affectHJV/BMP/SMAD‐mediated hepcidin control is not completely elucidated. Recent insights into the molecular basis of hereditary hemochromatosis and iron metabolism will be reviewed in this article.