Causes of Iron Overload

The most common cause of iron overload is thalassemia, particularly in the parts of the world where it is prevalent (see earlier section). Indeed, the cardiac complications of iron overload are among the most common causes of death in I-thalassemia major. Sideroblastic anemias are a group of iron-loading disorders, many of which are of unknown cause. In a hereditary type of this disorder, there is deficiency of erythroid specific 5-aminolevulinic acid synthetase in RBC precursors because of mutations involving the X-linked gene that encodes this enzyme. Iron storage is common in patients with congenital dyserythropoietic anemia and may be found in patients with red cell enzyme deficiencies, particularly pyruvate kinase deficiency. ... 

Most patients who require dialysis have a normocytic normochronic anemia and a hypoproliferative bone marrow. As erythropoiesis decreases with advancing renal disease, iron shifts from circulating red cells to the reticuloendothelial system, leading to high serum ferritin levels. Repeated blood transfusion is also a common cause of iron overload and hyperferritinemia. Clearly the most important cause of the anemia of chronic renal failure is decreased erythropoietin production by the kidneys uremic patients have much lower plasma erythropoietin levels than comparably anemic patients with normal renal function (E8). Less important causes are shortened red cell survival, iron or folate deficiency, aluminum intoxication, and osteitis fibrosa cystica (E8). Uremic retention products such as methylguanidine (G10) and spermidine (R2) may also have an adverse effect on erythropoiesis. 

Hereditary hemochromatosis (HH) is the most common cause of iron overload in humans. Ferroportin-asso-ciated iron overload, erroneously classified as type-4 hemochromatosis in genetic taxonomy, is likely the most common cause of hereditary hyperferritinemia beyond classic HH. The disorder, clinically recognized in 1999, has distinctive genetic, pathological, and clinical features. 

An impressive number of proteins that are involved in iron transport have been identified in recent years (Andrews, 1999 Griffiths et al., 1999). Most of them can either be up-regulated or down-regulated in situations of iron deficiency and different forms of iron overload, in order to maintain a safe iron balance. However, variations in the absolute levels or genetic defects of these proteins may cause iron overload or iron deficiency. In many forms of iron-related pathology detailed information can be obtained using appropriate animal models. 

Evidence of iron overload known hypersensitivity to iron sucrose or any of its inactive components anemia not caused by iron deficiency. 

A second form of storage iron is haemosiderin (Weir et al., 1984). This is deposited in humans as a response to the condition of iron overload. Haemosiderin forms as insoluble granules with electron dense cores surrounded by a protein shell. It exists in two forms primary haemosiderin is the result of iron overload due to excessive adsorption of iron in the gut, whereas the secondary form is caused by the numerous blood transfusions which are used to treat thallassaemia (a form of anaemia). Electron diffraction indicated that the iron core in primary haemosiderin is a 3-line ferrihydrite with magnetic hyperfine splitting only below 4 K and, in the secondary form, consists of poorly ordered goethite. As goethite is less soluble in ammonium oxalate buffer solution (pH 3) it has a lower intrinsic toxicity (Mann et al., 1988). 

Deferasirox is a tridentate chelator with a high affinity for iron and low affinity for other metals, eg, zinc and copper. It is orally active and well absorbed. In the circulation, it binds iron, and the complex is excreted in the bile. Deferasirox was recently approved for the oral treatment of iron overload caused by blood transfusions, a problem in the treatment of thalassemia and myelodysplastic syndrome. 

In erythropoietic protoporphyria, iron can cause a relapse of symptoms (579). An involvement of iron overload in the pathogenesis of some cases of porphyria cutanea tarda has been suggested (580). 

Hereditary hemochromatosis is an autosomal recessive disease of increased intestinal iron absorption and deposition in hepatic, cardiac, and pancreatic tissue. Hepatic iron overload results in the development of fibrosis, hepatic scarring, cirrhosis, and hepatocellular carcinoma. Hemochromatosis can also be caused by repeated blood transfusions, but this mechanism rarely leads to cirrhosis. 

In the beginning of the eighties, the clinical application of DFO expanded to a new type of patient, namely those on maintenance dialysis. As we will see in Chapter 12, some patients suffered from aluminium overload, mostly due to the use of aluminium salts as phosphate binders, while others had obvious transfusional iron overload in the pre-erythropoietin era. DFO was therefore used either to remove aluminium, excess iron or both. Nephrologists established that DFO therapy did not increase the overall incidence of bacterial infections but that it slightly increased the risk of bacteraemia caused by Y. enterocolitica or Y. pseudotuberculosis, as had been previously observed in thalassaemic patients (Boelaert et ah, 1987 Tielemans et ah,... 

An important factor in pathogenesis of chronic hepatitis C is iron overload. Casaril et al. [346] found that even a mild increase in iron content caused additional free radical-mediated... 

Defects of complex III. Like defects of complex I, these can be due to nDNA mutations or to mtDNA mutations. The only nuclear defect described thus far does not affect a complex III subunit, but an ancillary protein needed for proper assembly, BCS1L. Mutations in BCS1L can cause a Leigh s-syndrome-like disorder or a fatal infantile disease called GRACILE (growth retardation, aminoaciduria, cholestasis, iron overload, lactacidosis, and early death). 

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