Review Article: The Iron Overload Syndromes

A. Siddique; K. V. Kowdley


Aliment Pharmacol Ther. 2012;35(8):876-893. 

In This Article

Abstract and Introduction


Background Iron overload syndromes encompass a wide range of hereditary and acquired conditions. Major developments in the field of genetics and the discovery of hepcidin as a central regulator of iron homeostasis have greatly increased our understanding of the pathophysiology of iron overload syndromes.
Aim To review advances in iron regulation and iron overload syndrome with special emphasis on hereditary haemochromatosis, the prototype iron overload syndrome.
Methods A PubMed search using words such as 'iron overload', 'hemochromatosis', 'HFE', 'Non-HFE', 'secondary iron overload' was undertaken.
Results Iron overload is associated with significant morbidity and mortality. Sensitive diagnostic tests and effective therapy are widely available and can prevent complications associated with iron accumulation in end- organs. Therapeutic phlebotomy remains the cornerstone of therapy for removal of excess body iron, but novel therapeutic agents including oral iron chelators have been developed for iron overload associated with anaemia.
Conclusions Iron overload disorders are common. Inexpensive screening tests as well as confirmatory diagnostic tests are widely available. Increased awareness of the causes and importance of early diagnosis and knowledge of the appropriate use of genetic testing are encouraged. The availability of novel treatments should increase therapeutic options for patients with iron overload disorders.


The term 'iron overload' can be used to describe a condition resulting in increased total body iron stores, with or without organ dysfunction.[1] Iron homeostasis depends on a complex feedback mechanism between body iron requirements and intestinal absorption. Humans lack a physiological mechanism for excretion of excess iron. The hormone hepcidin, a 25-amino acid peptide, is produced mainly in the liver and secreted into the blood and is now recognised as the key regulator of iron homeostasis; dysregulation of hepcidin is a cause of many disorders of iron homeostasis.[2,3]

Haemochromatosis was first described by Armand Trousseau in 1865 as a 'case of bronze diabetes and cirrhosis'.[4] Von Recklinghausen in 1889 named this condition 'hemochromatosis' after discovering that these patients had an iron- containing pigment in the liver cells.[5] In 1935, Sheldon recognised the inherited nature of this disorder and the association with abnormal iron metabolism.[6] However, the specific gene defect was not discovered until 1996 when Feder et al. identified the HFE mutation.[7] Primary iron overload syndromes are now known to be caused by mutations in several iron regulatory genes and characterised by inappropriately low levels of hepcidin resulting in increased dietary iron absorption and iron overload. Iron overload syndromes are broadly divided into two groups: Inherited or Primary iron overload and Secondary iron overload syndromes, as described in Table 1 and Table 2 .

Normal Iron Metabolism (Figure 1)

Figure 1.

Iron regulation by Hepcidin. A model for HFE-mediated signalling to hepcidin in hepatocytes. (a) At low plasma iron concentration, HFE is bound to TfR1 and other proteins involved in signalling to hepcidin remain silent; (b) An increase in plasma iron levels results in displacement of HFE from TfR1, followed by iron uptake. This triggers the assembly of a putative 'iron-sensing' complex, comprising of HFE, TfR2, BMPs (such as BMP-2, BMP-4 and BMP-9) and their receptor BMPR, and Hjv, which mediates signalling to activate hepcidin transcription via Smad proteins. Thus, the hepatocyte integrates signals for regulation of iron metabolism at the cellular and systemic level. Published in World J Gastroenterol 2008; 14: 6893–901.

Dietary iron is present in two forms: heme (10%) and nonheme (90%). Nonheme iron is primarily present in the ferric form (Fe3+). Duodenal cytochrome b (Dcytb), a ferric reductase, which is expressed in the duodenal brush border, plays an important role in dietary iron absorption by reducing ferric to ferrous iron (Fe2+) which is then taken up by divalent metal transporter1 (DMT1).[8,9,10] The DMT1 expression is regulated by body iron requirements. The mechanism for absorption of heme-iron remains unclear. Heme iron is absorbed into the enterocytes by a carrier protein; heme oxygenase in enetrocytes releases the iron bound to heme in the Fe2+ form which then likely enters a common pathway with nonheme iron.[11]

Following uptake by enterocytes, iron is either stored intracellularly as ferritin or is released into the plasma by the iron transport protein ferroportin 1 (FPN).[12] FPN is the only iron exporter identified thus far and plays a critical role in regulating plasma iron concentration.[12,13] FPN is expressed in the duodenal mucosa, macrophages, hepatocytes and syncytial trophoblasts of the placenta.[12] Once in the circulation, iron binds to transferrin (Tf) and is transported to various sites for its utilisation or storage. Prior to its binding to Tf, Fe2+ is oxidised to Fe3+ by the multicopper oxidase hephaestin expressed on the basolateral surface of intestine, and by ceruloplasmin present in the plasma.[14,15] Fe3+ bound to Tf is then delivered to the bone marrow, liver and immune cells where it binds to transferrin receptor 1 (TfR1). Tfr1 is highly expressed in the erythroid precursors to ensure increased iron uptake for erythropoiesis. The interaction of transferrin-bound iron (TBI) with TfR1 results in invagination of the cell membrane and formation of an endosome containing the TBI-TfR1 complex.[16] Acidification of the endosome, likely by a Na+-H+-ATPase, causes conformational changes and iron is released from Tf.[17] The released iron which is present in the Fe3+ form is converted back to Fe2+ by STEAP3, a metalloreductase protein present in the endosome membrane, and is transported from endosome to the cytoplasm by DMT1.[12] Subsequently, Tf is returned to the circulation and TfR1 is recycled back to the cell membrane allowing both molecules to start the cycle again.[17]

Intracellular iron content is tightly controlled by the iron responsive elements (IRE) and the IRE-binding proteins, IRP1 and IRP2.[18,19,20] IREs are components of the mRNA present in the untranslated region of the mRNAs of ferritin and TfR1. Stabilisation or inhibition of mRNA is dependent upon the site of IRP binding to IRE. IRP1 acts as an iron sensor in high oxygen environments whereas IRP2 acts at physiological oxygen tensions.[21] When intracellular iron level is low, IRP binding to IRE at the 3' UTR of TfR1 mRNA causes stabilisation, increased synthesis, and up-regulation of TfR1 levels in the duodenum thereby increasing dietary iron absorption.[22] Conversely, IRP binding to IRE in 5' UTR of ferritin mRNA inhibits translation and blocks synthesis of ferritin. Therefore, in iron depleted states the IRP binding causes increased expression of TfR1 and decreased ferritin. Conversely in iron replete states there is less IRP1 and IRP2 for IRE binding resulting in increased ferritin and decreased TfR1.

The most important regulator of iron homeostasis, however, is the hormone hepcidin. Hepatic hepcidin expression is elegantly regulated by a number of proteins expressed in the hepatocytes, including hereditary haemochromatosis protein HFE, transferrin receptor 2 (TfR2), haemojuvelin (HJV), bone morphogenetic protein 6 (BMP6), matriptase-2 and Tf. Hepcidin serves as the signal from the principal iron storage site (the liver) to the iron absorptive site (the duodenum). The hepcidin gene (HAMP) has been identified on chromosome 19q13.1.[23] The gene product, preprohepcidin, a 84 amino acid protein, is synthesised mainly in the hepatocytes.[3] Hepcidin expression is increased in response to iron overload and inflammation and is decreased in response to iron deficiency, hypoxia and ineffective erythropoiesis. Hepcidin binds to FPN and causes its phosphorylation, internalisation and degradation.[12] This results in reduced iron export from enterocytes and macrophages resulting in decreased serum iron. Conversely, when hepcidin expression is decreased, iron absorption and cellular iron export is up-regulated, resulting in increase in serum iron. The USF2 gene knockout mouse which does not express hepcidin, develops iron overload resembling human HH and Hfe−/− mice.[24]

Hepcidin regulation depends upon signalling through the bone morphogenetic protein (BMP)/Smad pathway.[25] BMPs are cytokines in the TGF-beta superfamily. BMP6, which is highly expressed in the liver, has a predominant role in the activation of the Smad signalling pathway.[26] BMPs bind to type I and type II cell serine/threonine kinase receptors forming a BMP– receptor complex. The activated complex induces phosphorylation of a subset of intracellular Smad proteins (Smad1, Smad5 and Smad8). The receptor activated Smads in turn form a complex with the common mediator Smad4 and these complexes are translocated into the nucleus where they mediate gene transcription.[27] Haemojuvelin (HJV) has also been shown to act as a BMP coreceptor and facilitate the activation of the BMP–receptor complex.[28] Finally, in iron overload states, as the Tf is saturated, the excess iron may also be found as nontransferrin-bound iron (NTBI). NTBI is toxic and is quickly cleared from plasma by the liver.[29] Hfe−/− show increased plasma NTBI and increased hepatocyte NTBI uptake suggesting that NTBI has an important role in hepatocyte iron loading.[30]