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640 Part VI: The Erythrocyte Chapter 43: Iron Deficiency and Overload 641

donor or electron acceptor. The capacity to catalyze oxidation-reduction common in disorders such as β-thalassemia, hereditary dyserythro-
reactions appears to cause iron-mediated cellular and tissue injury. One poietic anemia, and pyruvate kinase deficiency. The amount of body
of the pathways that is considered to be of greatest importance is the iron may greatly exceed the quantity that can be accounted for through
Haber-Weiss reaction: blood transfusion, and iron overload is common even in patients who
.
3+
−
3+
Fe + H O → Fe + OH− + HO O + Fe → O + Fe 2+ are rarely or never transfused.
2+
The iron overload commonly observed in β-thalassemia interme-
2
2
2
2
The sum of these two reactions is the Fenton reaction: dia and major patients likely results, at least in part, from suppression of
the iron-regulatory hormone hepcidin by erythroid factors secreted by
O + H O → O + OH + HO . massively proliferating erythropoietin-stimulated erythroblasts. Candi-
−
−
2
2
2
2
The hydroxyl radical (HO·) has been implicated in producing date erythroid suppressors of hepcidin include growth differentiation
235
234
damage to polysaccharides, DNA, and enzymes, and in causing lipid per- factor 15 (GDF15) and erythroferrone. GDF15 overexpression was
oxidation. Although there is no direct evidence that hydroxyl radical also observed in congenital dyserythropoietic anemia. 236,237
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generation is the main pathway of tissue damage in hemochromatosis, Transfusion or Iron Therapy Iron overload can be iatrogenic in
this common conjecture seems reasonable. Demonstrating a dam- origin. Because erythrocytes contain 1 mg of iron per milliliter, trans-
aging effect of iron alone on experimental animals has been difficult. fusion of 450 mL of whole blood or of 200 mL of red cells adds 200 mg
Although in mouse models of genetic, parenteral, or dietary iron over- of total iron to the body, iron that will not be excreted. Thus, a patient
load subtle biochemical defects have been documented, frank cirrhotic who receives 2 units of blood monthly for an anemia that is not a result
changes have not been found. In gerbils, parenteral iron overload causes of blood loss will accumulate 4.8 g of iron per year. If the need for trans-
hepatic necrosis, fibrosis, and nodular regeneration, as well as cardiac fusion is occasioned by a disorder in which ineffective erythropoiesis
damage. In rats, iron alone does not cause fibrosis, and alcohol alone plays a prominent role, the accumulation of iron is even greater. Thalas-
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causes only minor liver abnormalities. However, administration of both semia is such a circumstance, and iron overload is the most important
excess iron and alcohol results in fibrosis. These findings in rats are cause of death in patients with this disorder (Chap. 48).
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quite consistent with the strong association that has been demonstrated The homeostatic mechanisms of the body are such that the inap-
to exist between alcohol ingestion and cirrhosis in patients with the propriate administration of iron by the oral route is very unlikely to
hemochromatosis genotype. In a number of species, including birds, produce clinically significant iron overload. Of the few cases that have
rhinoceros, tapir, fruit bats, and others, iron overload has been observed been described, all but one were documented before the cloning of the
in zoos or other restricted settings, particularly after a diet other than HFE gene, raising the possibility that the patients had genetic hemo-
the animal’s native diet is fed. chromatosis that was accelerated by excess iron intake. Documented
Iron is stored in ferritin in the cytoplasm of all cells. The multiple iron overload after iron injection is even less common and has not been
isoferritins found in human tissues are composed of variable proportions accompanied by demonstrable tissue damage.
of two subunits: L-ferritin (light) and H-ferritin (heavy). Because free
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iron is potentially harmful to the cell, it is sequestered and detoxified Pathology
to the less-soluble ferric form by ferroxidase activity; H-ferritin exerts Affected tissues and organs exhibit a deep brown color. Histologic
most of its ferroxidase activity in the cytosol. The mitochondrial fer- examination reveals prominent hemosiderin deposition in many tissues
ritin, expressed in the mitochondrial matrix, also has potent ferroxidase and organs.
activity and is markedly upregulated in sideroblastic anemias. Liver The liver is often enlarged. After cirrhosis has developed, the
organ becomes granular or coarsely nodular. In the liver of patients with
Causes of Iron Overload classical hemochromatosis, TfR-2 mutations, and in juvenile hemochro-
Because body iron content is maintained by regulating absorption, matosis, hemosiderin is found primarily in hepatocytes. Kupffer cells are
excess body iron can accumulate only when absorption is increased relatively spared. Prior to the development of cirrhosis, the hemosiderin
above iron requirements, or when iron is injected into the body, either accumulates primarily in periportal hepatocytes and is less toward the
in the form of medicinal iron or as transfused erythrocytes. central veins. The iron of cirrhotic livers is mostly in the periphery of
Excessive Iron Absorption A variety of mutations are known to regenerative nodules. Fibrosis begins periportally, then fibrous septa
cause increased iron absorption in experimental animals and in man traverse the lobules. Usually, the distortion of the architecture is not as
(see Table 43–3 for a summary). Mutations in the genes encoding HFE, severe or as uniform as in alcoholic cirrhosis. The cirrhosis of hemo-
hemojuvelin, TfR-2, ferroportin, and hepcidin are all associated with chromatosis usually has a micronodular appearance. Iron in bile duct
iron overload. The common pathway that causes hyperabsorption of epithelium has sometimes been considered a specific marker for hemo-
iron is deficiency of hepcidin which allows excessive activity of the iron chromatosis, but is not reliable. The amount of iron in the liver is always
exporter ferroportin in the duodenum and in macrophages of the retic- greatly increased. This is apparent on inspection of sections stained for
uloendothelial system. Normally, hepcidin is upregulated when body iron with the Prussian blue reaction, and can be quantitated on liver
iron increases. However, this response is blunted or absent in either biopsy specimens. An iron concentration of more than 300 μmol/g dry
Hfe-, TfR-2–, or Hjv-deficient mice, or in the human disease, 229–231 all weight (or about 50 μmol/g wet weight) is considered strong evidence
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of which exhibit disproportionately low hepcidin levels for the degree for hemochromatosis when factors such as transfusions are eliminated
of iron overload. Although the biochemistry of their interactions is not as the cause.
known, there is increasing evidence that HFE, TfR-2, and hemojuvelin In the original description of African iron overload, the liver
are part of the signaling pathway that regulates hepcidin expression. In pathology was deemed to be indistinguishable from that of classical
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autosomal dominant hereditary hemochromatosis (class 4), ferroportin hemochromatosis, but in newer studies it seems that only some of
mutations interfere with binding of hepcidin to ferroportin 232,233 or with the affected patients manifest iron storage, primarily in the hepatocytes;
the resulting ferroportin endocytosis. some have storage primarily in Kupffer cells. In the case of patients with
Ineffective Erythropoiesis Anemias with ineffective erythropoie- ferroportin mutations that prevent transport of iron, storage of iron
sis commonly cause systemic iron overload with damage to the liver, takes place mostly in the Kupffer cells, and fibrosis seems to be absent;
heart and the endocrine system. Iron storage disease is particularly ferroportin mutations that prevent interaction with hepcidin, on the

Kaushansky_chapter 43_p0627-0650.indd 641 9/17/15 6:27 PM