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Hereditary hemochromatosis (HH) is a group of genetic iron overload disorders that manifest with various symptoms, including hepatic dysfunction, diabetes, and cardiomyopathy. Classic HH type 1, which is common in Caucasians, is caused by bi-allelic mutations of HFE. Severe types of HH are caused by either bi-allelic mutations of HFE2 that encodes hemojuvelin (type 2A) or HAMP that encodes hepcidin (type 2B). HH type 3, which is of intermediate severity, is caused by bi-allelic mutations of TFR2 that encodes transferrin receptor 2. Mutations of SLC40A1 that encodes ferroportin, the only cellular iron exporter, causes either HH type 4A (loss-of-function mutations) or HH type 4B (gain-of-function mutations). Studies on these gene products uncovered a part of the mechanisms of the systemic iron regulation; HFE, hemojuvelin, and TFR2 are involved in iron sensing and stimulating hepcidin expression, and hepcidin downregulates the expression of ferroportin of the target cells. Phlebotomy is the standard treatment for HH, and early initiation of the treatment is essential for preventing irreversible organ damage. However, because of the rarity and difficulty in making the genetic diagnosis, a large proportion of patients with non-HFE HH might have been undiagnosed; therefore, awareness of this disorder is important.

Iron deficiency, with or without anemia, is extremely frequent worldwide, representing a major public health problem. Iron replacement therapy dates back to the seventeenth century, and has progressed relatively slowly until recently. Both oral and intravenous traditional iron formulations are known to be far from ideal, mainly because of tolerability and safety issues, respectively. At the beginning of this century, the discovery of hepcidin/ferroportin axis has represented a turning point in the knowledge of the pathophysiology of iron metabolism disorders, ushering a new era. In the meantime, advances in the pharmaceutical technologies are producing newer iron formulations aimed at minimizing the problems inherent with traditional approaches. The pharmacokinetic of oral and parenteral iron is substantially different, and diversities have become even clearer in light of the hepcidin master role in regulating systemic iron homeostasis. Here we review how iron therapy is changing because of such important advances in both pathophysiology and pharmacology.

Iron is an essential trace metal for nearly all infectious microorganisms, and host defense mechanisms target this dependence to deprive microbes of iron. This review highlights mechanisms that are activated during infections to restrict iron on mucosal surfaces, in plasma and extracellular fluid, and within macrophages. Iron overload disorders, such as hereditary hemochromatosis or β-thalassemia, interfere with iron-restrictive host responses, and thereby cause increased susceptibility to infections with microbes that can exploit this vulnerability. Anemia of inflammation (formerly known as anemia of chronic diseases) is an “off-target” effect of host defense wherein inflammatory cytokines shorten erythrocyte lifespan by activating macrophages, prioritize leukocyte production in the marrow, and induce hepcidin to increase plasma transferrin saturation and the concentration of non-transferrin-bound iron.

Epoetin beta pegol (C.E.R.A.) is a novel, long-acting, erythropoiesis-stimulating agent. We investigated iron utilization associated with erythropoiesis, and how it is affected by the long-term suppression of hepcidin following C.E.R.A. treatment in mice. C57BL/6N mice were administered a single intravenous injection of C.E.R.A. Hemoglobin (Hb) levels were significantly elevated following C.E.R.A. administration, while serum hepcidin levels were continuously suppressed. Expression levels of duodenal iron transporters, ferroportin (FPN) which is internalized by hepcidin binding and divalent metal transporter 1 (DMT1), increased after C.E.R.A. administration. To evaluate the contribution of dietary iron absorption to erythropoiesis following C.E.R.A. treatment, C.E.R.A.-treated mice were fed either an iron-deficient diet to restrict dietary iron absorption or a control diet. The restriction of dietary iron absorption resulted in impaired Hb elevation after C.E.R.A. administration. To investigate the utilization of stored iron for erythropoiesis following C.E.R.A. treatment, iron indices were analyzed in C.E.R.A.-treated mice given an intraperitoneal pre-treatment injection of iron-dextran. Serum hepcidin levels and splenic hemosiderin deposition decreased after C.E.R.A. administration. These results indicate that C.E.R.A. promotes utilization of iron for erythropoiesis both through enhancement of dietary iron absorption and mobilization of iron storage from reticuloendothelial cells.

Hereditary hemochromatosis (HH) is a group of inherited iron-overload disorders associated with pathogenic defects in the genes encoding hemochromatosis (HFE), hemojuvelin (HJV/HFE2), hepcidin (HAMP), transferrin receptor 2 (TfR2), and ferroportin (FPN1/SLC40A1) proteins, and the clinical features are well described. However, there have been only a few detailed reports of HH in Chinese populations. Thus, there is insufficient patient information for population-based analyses in Chinese populations or comparative studies among different ethical groups. In the current work, we describe eight Chinese cases of hereditary hemochromatosis. Gene sequencing results revealed eight mutations (five novel mutations) in HFE, HFE2, TfR2, and SLC40A1 genes in these Chinese HH patients. In addition, we used Polymorphism Phenotyping v2 (Polyphen), Sorting Intolerant From Tolerant (SIFT), and a sequence alignment program to predict the molecular consequences of missense mutations.

Transfusion is believed to be the main cause of iron overload in Japan. A nationwide survey on post-transfusional iron overload subsequently led to the establishment of guidelines for iron chelation therapy in this country. To date, however, detailed clinical information on the entire iron overload population in Japan has not been fully investigated. In the present study, we obtained and studied detailed clinical information on the iron overload patient population in Japan. Of 1109 iron overload cases, 93.1% were considered to have occurred post-transfusion. There were, however, 76 cases of iron overload of unknown origin, which suggest that many clinicians in Japan may encounter some difficulty in correctly diagnosing and treating iron overload. Further clinical data were obtained for 32 cases of iron overload of unknown origin; median of serum ferritin was 1860.5 ng/mL. As occurs in post-transfusional iron overload, liver dysfunction was found to be as high as 95.7% when serum ferritin levels exceeded 1000 ng/mL in these patients. Gene mutation analysis of the iron metabolism-related genes in 27 cases of iron overload with unknown etiology revealed mutations in the gene coding hemojuvelin, transferrin receptor 2, and ferroportin; this indicates that although rare, hereditary hemochromatosis does occur in Japan.

Iron homeostasis in vertebrates requires coordination between cells that export iron into plasma and those that utilize or store plasma iron. The coordination of iron acquisition and utilization is mediated by the interaction of the peptide hormone hepcidin and the iron exporter ferroportin. Hepcidin levels are increased during iron sufficiency and inflammation and are decreased in hypoxia or erythropoiesis. Hepcidin is a negative regulator of iron export. Hepcidin binds to cell surface ferroportin inducing ferroportin degradation and decreasing cellular iron export. Genetic disorders of iron overload of iron-linked anemia can be explained by changes in the level of hepcidin or ferroportin and of the ability of ferroportin to be internalized by hepcidin.