ii23 PAPER Gut: first published as 10.1136/gut.52.suppl_2.ii23 on 1 May 2003. Downloaded from Haemochromatosis A Pietrangelo ............................................................................................................................. Gut 2003;52(Suppl II):ii23–ii30 Iron is an important component of the Earth’s crust, but and associated to a mutation in the SLC11A3 its own chemistry greatly limits utilisation and also sets gene,10 coding for a main iron export protein in mammals, ferroportin/IREG/MTP-1. 11–13 the basis for its toxicity. The capacity of readily In the vast majority of cases around the world, exchanging electrons in aerobic conditions makes iron HC is attributable to mutations in the HFE essential for fundamental cell functions, such as DNA gene.14 However, it must be emphasised that while the presence of mutations in the HFE gene synthesis, transport of oxygen and electrons, and cell indicates the existence of the genetic form of HC, respiration. On the other hand, as humans have no the clinical diagnosis of HC is made when iron means to control iron excretion, excess iron, regardless overload is present (see later). Therefore, the identification of any one of the HFE mutations of the route of entry, accumulates in parenchymal (C282Y homozygosity or C282Y/H63D compound organs and threatens cell viability. In fact, a number of hererozigosity) is, by itself, insufficient for the disease states (that is, iron overload diseases) diagnosis of HC. Instead, the identification of the genetic abnormality provides evidence of suscepti- attributable to genetic or acquired factors are bility to developing the phenotype. The diagnosis pathogenetically linked to excess body iron stores and of HC, therefore, must be based on phenotype iron removal therapy is an effective lifesaving strategy in rather then genotype. As mentioned, mutations in other genes have been associated to HC, including such circumstances. SLC11A310 15 and transferrin receptor 2 (TfR2).16 .......................................................................... These mutations may be responsible for heredi- tary iron overload diseases non-HFE or act as modifiers genetic factors in HFE HC heterozy- DEFINITION gotes. All the three forms of HC described so far Haemochromatosis (HC)—synonymous with ge- are characterised by tissue iron overload, organ netic, hereditary, primary iron overload—is the disease and they require iron removal therapy as paradigm of a genetic disorder leading to body http://gut.bmj.com/ treatment. However, the form attributable to HFE, iron overload and multi-organ failure. HC is and apparently that attributable to TfR2 muta- attributable to inappropriately increased iron tions (although the latter has not been exten- absorption in which iron loading of parenchymal sively described clinically, yet) seem to share cells in the liver, pancreas, heart, and other organs common histopathological (predominant paren- impairs the function and damages the structure chymal iron overload) and clinical features. The of these organs.1 This condition is caused by form attributable to the SCL11A3 gene mutations inborn errors of iron metabolism. As shown in (see later) shows peculiar features. In view of on September 30, 2021 by guest. Protected copyright. figure 1, at least three genes may now be these findings the classification of HC has to be associated with a disease phenotype fulfilling this redefined (fig 1). definition, while a distinction should be made between HC and siderosis (that is, excess iron GENETICS, EPIDEMIOLOGY, AND accumulation in tissues) that indirectly results MOLECULAR PATHOGENESIS from other conditions that bring about iron over- HC is the most common inherited autosomal load (acquired iron overload) (fig 1). recessive disorder in the white population, affect- Von Recklinghausen, in 1889, first coined the ing about 1 in 200 of northern European term HC to indicate an iron storage disease with ancestry.14 In the original paper by Feder et al7 2 widespread tissue injury ; he was basically refer- most HC patients were homozygous for a single ring to the clinical syndrome of portal cirrhosis, base transition, resulting in the substitution of a diabetes mellitus, and bronze skin pigmentation, tyrosine for cysteine at position 282 (C282Y) of 3 described by Trousseau 24 years before. After the the unprocessed polypeptide. This mutation pre- identification of the inherited nature of HC by vents correct folding of HFE and, hence, assembly Sheldon,4 Simon and coauthors defined the β β with 2 microglobulin ( 2M) and presentation at incidence and genetic transmission of the disease the cell surface. The distribution of C282Y muta- ....................... that seemed to be linked to the HLA complex on tion coincides with the presence of the disease the short arm of chromosome 6 and mapped in Correspondence to: 56 and is in agreement with the theory of a Celtic or close proximity to the HLA-A locus. A corner- 14 Professor A Pietrangelo, north European origin of the mutation. The Department of Internal stone of HC genetics had been laid in 1996, when Medicine, University of the discovery of a gene candidate for HC was Modena and Reggio published.7 This gene, formerly named HLA-H (H ................................................. Emilia, 41100 Modena, for haemochromatosis), it was then redefined Italy; Abbreviations: HC, haemochromatosis; Tf, transferrin; HFE by the WHO Nomenclature Committee for TfR, transferrin receptor; UIBC, unsaturated iron binding pietrangelo.antonello@ 8 unimo.it Factors of the HLA system. Recently, an auto- capacity; HIC, hepatic iron concentration; HII, hepatic iron ....................... somal dominant form of HC has been described9 index www.gutjnl.com ii24 Pietrangelo 1 Primary iron overload Figure 1 Classification of iron overload diseases. A Haemochromatosis associated to mutations in the HFE gene: Gut: first published as 10.1136/gut.52.suppl_2.ii23 on 1 May 2003. Downloaded from C282Y homozygosity C282Y/H63D compound heterozygosity B Hereditary iron overload associated to mutations in the SLC11A3 gene (Ferroportin/MTP/IREG-1) C Hereditary iron overload associated to mutations in the Transferrin receptor 2 gene D Aceruloplasminaemia E Congenital atransferrinaemia F Others (unidentified genes) 1) Juvenile haemochromatosis 2) Neonatal haemochromatosis 2 Secondary iron overload A Dietary iron overload B Parental iron overload C Iron loading anaemias D Long term haemodialysis E Chronic liver disease Hepatitis C Alcoholic cirrhosis, especially when advanced Non-alcoholic steatohepatitis F Porphyria cutanea tarda G Post-portacaval shunting H Dysmetabolic iron overload syndrome 3 Miscellaneous Iron overload in sub-Sahara Africa percentages of C282Y homozigosity are >90% in the UK and membrane, but is required for HFE to be transported to Tf Brittany with a decreasing gradient northern to southern positive endosomes and for regulation of intracellular iron Europe, with the lowest percentage in Italy (64%) and Greece homeostasis in cultured cells.25 This suggests that the biologi- (30%). Indeed, HC is an example of a founder (the Celtic) cal effect of HFE on TfR may be exerted in the endosomal http://gut.bmj.com/ effect, combined with a strong positive selection of the C282Y compartment where iron is released from TfR-Tf complex and allele, which may confer the ability to absorb more iron and not necessarily at the cell surface. At the tissue level, HFE to survive better in ancient times, when iron deficiency was appears to be preferentially expressed in duodenal crypt cells extremely common. and Kupffer cells of the liver, mainly in the perinuclear A second mutation resulting in the substitution of an compartment.26 27 aspartic acid for histidine at position 63 (H63D) was found in Iron absorption is inappropriate to body iron stores in HC, a number of patients who carried only one copy of the C282Y and steadily increases from birth despite expanding iron on September 30, 2021 by guest. Protected copyright. 7 mutation. The H63D mutation has a worldwide distribution deposits28 (fig2A and B). Typically, in HC subjects there is a 14 with the highest frequency among Basques. This mutation positive iron balance of 1 mg to 2 mg of iron daily that during may have a clinical significance only in cooperation with other childhood and adolescence in men and in menstruated genetic or environmental factors (for example, viral hepatitis, women does not cause marked iron accumulation because of thalassaemia, porphyrias etc). A considerably smaller pro- high growth demands and iron losses, respectively. After- portion of patients are compound heterozygotes for the two wards, iron overload in the liver, pancreas, heart, and joints, mutations (genotype HD/CY). A third substitution of cysteine leads to parenchymal cell damage and organ disease. In view for serine at amino acid position 65 (S65C), has been of the available data, any proposed model of HFE function in implicated in a mild form of HC,17 whereas the role of other iron metabolism has to consider (a) the biochemical evidence rare mutations found in subjects H63D or C282Y heterozy- gotes, is unclear.18 (that is, HFE interacts with TfR1), (b) the pattern of The human HFE protein is closely related to the major his- expression of TfR1 and HFE in vivo, and (c) the phenotype of tocompatibility complex (MHC) class I molecules. The C282Y human HC. α At the biochemical level, data from several tissue culture mutation disrupts a critical disulfide bond in the 3 domain of the HFE