290 REVIEW Molecular pathogenesis of iron overload Gut: first published as 10.1136/gut.51.2.290 on 1 August 2002. Downloaded from D Trinder, C Fox, G Vautier, J K Olynyk ............................................................................................................................. Gut 2002;51:290–295 Our current understanding of iron absorption under deficiency.34Iron is then stored in the enterocyte normal conditions is presented, together with an or transferred out across the basolateral mem- brane by a membrane bound protein called ferro- overview of the clinical disorders of iron overload and portin (also known as IREG1 and MTP1).5–7 the molecular processes that contribute to increased iron Extracellular ferrous iron is oxidised by the multi deposition in iron overload. Recently, a number of new copper oxidase haephestin and bound by plasma transferrin.8 genes involved in iron metabolism have been identified The mechanism of absorption of haem iron has which is allowing the molecular mechanisms of iron yet to be elucidated. Transfer across the brush absorption to be elucidated. border membrane is probably mediated by an unidentified haem receptor. Once inside, entero- .......................................................................... cyte iron is released from haem by haem oxygen- ase and either stored or transferred out of the ron homeostasis is controlled by the absorption enterocyte by a mechanism that is likely to be of iron from the diet. It occurs mainly in the similar to that for ionic iron (fig 1).9 Iduodenum at a rate of approximately 1–2 mg iron per day. When iron levels in the body or the REGULATION OF IRON ABSORPTION diet are low, the rate of iron absorption is Iron absorption is regulated by a number of increased, and when iron levels are replete there factors, including the level of body iron stores, the is a reduction in the rate of iron absorption and rate of erythropoiesis, and hypoxia. Enterocytes in excess iron is excreted when enterocytes are the crypt region of the duodenal mucosa take up sloughed off every 2–3 days. Recently, a number of iron from plasma in proportion to the body’s iron new genes involved in iron metabolism have been level, and the intracellular iron level in crypt cells identified which is allowing the molecular reflects the body’s iron status.10 Crypt cells express mechanisms of iron absorption to be elucidated. transferrin receptor 1 (TfR1) which mediates the http://gut.bmj.com/ In this review, our current understanding of iron uptake of transferrin bound iron (TBI).11 The absorption under normal conditions is presented haemochromatosis protein (HFE) is also highly followed by an overview of the clinical disorders expressed in crypt cells12 and forms a complex of iron overload and the molecular processes that with β microglobulin and TfR1.13 The role of HFE contribute to increased iron deposition in iron 2 in the regulation of TfR1 mediated uptake of TBI overload. is unclear. A number of studies in isolated cell systems have shown that HFE reduces both the MOLECULAR MECHANISMS OF IRON on September 27, 2021 by guest. Protected copyright. affinity of TfR1 for transferrin and the uptake of ABSORPTION iron, due either to a reduction in the cycling time Iron is found in the diet as ionic (non-haem) iron of the HFE/TfR1-TBI complex through the cell or and haem iron. Absorption of these two forms of a reduced rate of iron release from transferrin iron occurs by different mechanisms. Absorption intracellularly.14–17 Whereas when both HFE and β is a multistep process involving the uptake of iron 2 microglobulin are overexpressed in Chinese Ham- from the intestinal lumen across the apical cell ster Ovary cells, uptake of TBI was enhanced due surface of the villus enterocytes and the transfer to increased recycling of TfR1 through the cell.18 out of the enterocyte across the basolateral mem- A second transferrin receptor (TfR2) has been brane to the plasma. Ionic iron is present in the identified.19 TfR2 mRNA is expressed at very low reduced (ferrous) or oxidised (ferric) state in the levels in the duodenum and does not interact diet and the first step in the uptake of ionic iron with HFE in vitro.20 21 Its role in iron absorption is involves the reduction of iron. Recently, a putative yet to be determined. reductase that is capable of reducing iron from its In iron deficiency, DMT1, ferroportin, and TfR1 ferric to ferrous state has been identified. It is a See end of article for are upregulated while ferritin is downregulated authors’ affiliations membrane bound haem protein called Dcytb that and the converse occurs when iron levels are ....................... is expressed in the brush border of the increased.6 22–24 Expression of ferritin and TfR1 is duodenum.1 Next, ferrous ion is transported Correspondence to: regulated by post-transcriptional mechanisms. Associate Professor J across the lumen cell surface by a transporter Olynyk, University called divalent metal transporter 1 (DMT1) that Department of Medicine, can transport a number of other metal ions ................................................. PO Box 480, Fremantle 2 6959, Western Australia, including copper, cobalt, zinc, and lead. Evidence Abbreviations: DMT1, divalent metal transporter 1; HFE, Australia; for the role of DMT1 in iron absorption is [email protected] supported by studies in mk mice and Belgrade haemochromatosis protein; HH, hereditary haemo- chromatosis; IRE, iron regulatory element; IRP, iron rat. Both of these laboratory animals have a Accepted for publication regulatory protein; NTBI, non-transferrin bound iron; TBI, 4 September 2001 G185R mutation in DMT1 that inhibits iron transferrin bound iron; TfR1, transferrin receptor 1; TfR2, ....................... uptake across the brush border leading to iron transferrin receptor 2. www.gutjnl.com Molecular pathogenesis of iron overload 291 Gut lumen Enterocyte Blood Apical Basolateral Gut: first published as 10.1136/gut.51.2.290 on 1 August 2002. Downloaded from Hephaestin Fe3+ Ferritin DMT1 Transferrin 2+ 2+ 2+ Fe Fe Fe Fe2+ Intracellular Ferroportin iron pool Fe-transferrin Fe3+ Dcytb HFE 2+ Fe-transferrin Fe DMT1 Endocytosis Fe2+ TfR1 Transferrin Fe2+ Haem Haem Haem oxygenase TfR2? Haem receptor Figure 1 A model of the pathways of iron absorption by the enterocyte. The figure shows uptake of ionic iron and haem iron from the gut lumen and transfer of iron to blood. DMT1, divalent metal transporter 1; HFE, haemochromatosis protein, TfR1, transferrin receptor 1; TfR2, transferrin receptor 2. The intracellular iron level controls the interaction of a cytosolic iron regulatory protein (IRP) with an iron regulatory Table 1 Classification of iron overload states element (IRE) in the untranslated region of the mRNA of Familial or hereditary forms of haemochromatosis these genes.25 HFE and TfR2 do not contain IRE and their Hereditary haemochromatosis (HH, HFE1) expression is not iron regulated.19 26 C282Y homozygosity IRP activity is one of the central regulators of iron C282Y, H63D heterozygosity Other HFE gene mutations absorption. IRP activity in crypt cells reflects the body’s iron Juvenile haemochromatosis (HFE2) status. Crypt cells migrate to the villus region of the Transferrin receptor 2 mutation (HFE3) duodenum and differentiate into absorptive cells where the Ferroportin mutation (HFE4) level of IRP binding activity, predetermined in crypts, Acaeruloplasminaemia regulates expression of iron transporters and the rate of iron Atransferrinaemia http://gut.bmj.com/ 27 Neonatal iron overload absorption. Villus cells also respond to a change in iron levels Autosomal dominant haemochromatosis (Solomon Islands) in the diet. An iron gavage reduces IRP activity, DMT1 expres- Acquired iron overload sion, and iron absorption by villus cells within hours.28 Iron loading anaemias Both the rate of erythropoiesis and hypoxia regulate iron Thalassaemia major absorption.29 Expression of ferroportin and Dcytb are upregu- Sideroblastic anaemia Chronic haemolytic anaemias lated in hypoxia and in a hypotransferrinaemic mouse which Dietary iron overload has chronic anaemia due to defective erythropoiesis.16 Chronic liver disease on September 27, 2021 by guest. Protected copyright. Increased expression of these genes is likely to account for the Hepatitis C increase in iron absorption. Alcoholic liver disease Non-alcoholic steatohepatitis Porphyria cutanea tarda CLINICAL SYNDROMES OF IRON OVERLOAD Hereditary haemochromatosis Clinical disorders of iron overload are classified in table 1. In populations of Northern European ancestry, hereditary haemochromatosis (HH) is the most common disorder of pri- 32–34 → mary iron overload. This autosomal recessive disorder usually mutation. A second mutation (His63 Asp; H63D) was results from a homozygous mutation in the HFE gene of also identified but was not associated with the same degree of 26 Anglo-Celtic populations. The clinical features of HH have iron overload as the C282Y mutation. Lower frequencies of been reviewed extensively.30 homozygosity for the C282Y mutation (64%) are found in Southern European patients with HH.35 The C282Y mutation is rare in African, Asian, Polynesian, and indigenous Australian “In populations of Northern European ancestry, 36 hereditary haemochromatosis is the most common chromosomes. disorder of primary iron overload” Other mutations within the HFE gene have been found that are associated with iron overload, usually in combination with C282Y heterozygosity: Mura et al reported enrichment