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642 Part VI: The Erythrocyte Chapter 43: Iron Deficiency and Overload 643

other hand, are associated with hepatocytes iron overload, as is seen in What has not been taken into account in the studies is that the HFE
classical hemochromatosis. 233,239 gene is in close proximity to (and therefore likely to be coinherited with)
Heart Iron accumulates more slowly in the myocardium than in many immune-response genes on chromosome 6; consequently, it is not
the liver, but the heart is more sensitive to its toxic effects. Myocardial possible to distinguish the minor effects that HFE mutations may have
damage is seen when iron loading is rapid, for example, in β-thalassemic on iron homeostasis from variation in the immune response.
patients dying of transfusional iron overload in their 20s and 30s HAMP (Hepcidin) Mutations Mutations of hepcidin are rare, and
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prior to effective chelation therapy, and in juvenile hemochromatosis are associated with severe juvenile hemochromatosis. 246
patients who usually present with iron-induced cardiomyopathy and SCL40A1 (Ferroportin) Mutations Mutations of the gene encod-
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endocrinopathy rather than liver failure. The myocardium is thick- ing ferroportin cause an autosomal dominant iron storage disease of
ened and the heart is often enlarged; arrhythmias and myocardial fail- two types. Gain-of-function mutations, for example the C326S muta-
ure follows. Accumulation of cardiac iron is the leading cause of death tion, interfere with hepcidin binding to ferroportin or with the resulting
in transfused patients with β-thalassemia major. Patients with transfu- ferroportin endocytosis, so that mutant ferroportin molecules continue
sion-dependent anemias, such as congenital dyserythropoietic anemia exporting iron from enterocytes and macrophages to plasma even in
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and Diamond-Blackfan syndrome, also develop iron overload-induced the face of high hepcidin levels that normally cause ferroportin endo-
cardiomyopathy. In transfused patients with myelodysplastic syn- cytosis and proteolysis. A mouse model of this condition shows that a
dromes, transfusion threshold guidelines of 75 units of blood was sug- heterozygous mutation is sufficient to cause severe iron overload but
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gested as a risk factor of cardiac iron overload but this is not based on that homozygosity for this mutation is even more severe. Loss-of-
firm data. Direct cardiac iron measurement using magnetic resonance function mutations are more common and include ferroportin muta-
imaging predicts cardiac complications and can stratify the risk of sub- tions that do not allow ferroportin protein to localize to the cell surface,
sequent cardiac dysfunction. This technique measures the half-life, or prevent transport of iron. Here storage of iron takes place mostly
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T2*, of cardiac muscle darkening (with respect to echo time) produced in the Kupffer cells and splenic macrophages, and cirrhosis does not
by magnetically active stored cardiac iron. occur. It is not clear why these act in a dominant manner, nor why all of
Marrow The quantity of iron in the marrow of patients with classi- the reported mutations encode amino acid substitutions and none are
cal hereditary hemochromatosis is only modestly increased, if increased completely destructive (frameshift or stop codons). 158,248 An attractive
at all. The iron is characteristically distributed into small, equal-size explanation is that these mutations act in a dominant-negative manner,
granules, and these are located in endothelial lining cells rather than but this mechanism has not yet been supported by convincing biochem-
in macrophages. Indeed, in classical hereditary hemochromatosis, both ical data. A common polymorphism c.744G→T (Gln284His) shows an
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macrophages and intestinal mucosal cells are iron-poor relative to the association with African iron overload, 238,249,250 but is clearly not present
overall iron burden. in all patients who manifest this syndrome.
TfR-2 Mutations Mutations of TfR-2 cause an autosomal recessive
Genetics disorder that is indistinguishable clinically from the common HFE-
Genetic factors play an important role in the etiology of iron storage related form of hereditary hemochromatosis. 230,251–253
disease. This is true not only in the primary forms of the disorder, but Hemojuvelin Mutations Several different mutations of a gene des-
also in secondary hemochromatosis, where genetic disorders of ery- ignated as HFE2 and as HJV cause juvenile hemochromatosis. 231,254–258
thropoiesis are the most common causes. The genetics of these disor- Hemojuvelin belongs to the class of glycosylphosphatidylinositol-
ders, including the thalassemias, dyserythropoietic anemias, and red anchored repulsive-guidance molecules, and may act as a coreceptor for
cell enzymopathies, are described in Chaps. 39, 47, and 48. Mutations of bone morphogenetic proteins (BMPs). BMP receptor is now known to
several genes that play an important role in iron homeostasis have been be a key regulator of hepcidin transcription. 259
found to lead to iron storage disease. 244 DMT-1 Human Mutations DMT-1 human mutations are all asso-
HFE Mutations The most common cause of hereditary hemochro- ciated with hepatic hemosiderosis 207,208,260 and most are associated with
matosis is a mutation of the HFE gene. This HLA-like gene resides on abnormal liver function tests in addition to microcytic hypochromic
chromosome 6. Three polymorphic mutations have been identified. anemia. This is in contrast to mice and rats with DMT-1 mutations, as
These are located at nucleotides 187,193, and 845 of the cDNA (com- these DMT-1–deficient rodents are iron deficient. This is likely because
plementary DNA) and at the protein level encode the H63D, S65C, and humans, unlike rodents, can also absorb heme-containing iron, at least
C282Y mutations, respectively. The phenotypic severity of these muta- to a small degree in a DMT-1 independent manner while the DMT-1
tions on iron homeostasis is manifested in the following order: C282Y dependent iron utilization by erythroblasts is severely impaired in both
> H63D > S65C. Hereditary hemochromatosis is essentially an autoso- humans and rodents.
mal recessive disorder. Approximately two-thirds of homozygotes for
the C282Y and a slightly lower percentage of compound heterozygotes Animal Models
for the C282Y and H63D mutations manifest increased serum transfer- Naturally Occurring Models
rin saturations and serum ferritin levels. Individuals heterozygous for When kept in zoos or other nonnative habitats, a number of animal
either the C282Y or the H63D mutation have, on the average, signifi- species, such as myna birds, the toco toucan, Salers cattle, lemurs, and
cantly higher transferrin saturations and serum ferritin levels than do the browsing rhinoceros, are iron-loaded. Rhinoceroses may represent
wild-type homozygotes. However, the magnitude of this increase is very an interesting paradigm for iron storage in captive species. Although
low. For example, the average transferrin saturation of men with the the browsing rhinoceros species are iron loaded, grazing species are not,
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wild-type genotype is 26.69 percent and heterozygotes for the C282Y even when kept under similar conditions. It seems likely that because
mutation have a transferrin saturation averaging 30.63 percent. The iron is not readily available in the leaves and twigs eaten by the browsing
effect of the H63D mutation is even less, and that of the S65C mutation species, these species have evolved to more efficiently take up iron from
barely perceptible. their diet—more efficiently than needed when fed a zoo diet. Molecular
In spite of the minimal effect of the heterozygous state for HFE comparisons of iron-regulatory genes in browser versus grazer rhinoc-
mutations on iron homeostasis, a number of investigators have pro- eroses identified some promising candidates, but the ultimate cause of
posed that heterozygotes are at increased risk for a variety of disorders. the differences in iron handling has not yet been established. 261

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