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Causes of Iron Overload
Iron is critical for nearly all living cells — required for basic metabolic processes such as oxygen transport, DNA synthesis, cytochrome P-450 enzyme oxidative metabolism, and electron transport. Unlike other nutritional metals, iron is highly conserved, and cannot be actively excreted (1). It is normally removed from the body only passively, via cell shedding from the skin or GI tract, or by menstruation.
Iron overload can result from both primary and secondary causes (2):
- Primary iron overload: results from genetic disorders of iron metabolism that cause excessive absorption of iron from the diet or deficient iron transport within the body.
- Secondary iron overload: results from factors that bypass normal iron metabolic pathways, such as multiple blood transfusions or acute or chronic iron poisoning.
Why iron overload is toxic
The cause of chronic iron toxicity is the same in both primary and secondary iron overload: the body’s limited iron storage or transport capacities have been chronically exceeded, exposing tissues to highly reactive iron complexes.
Iron overload causes the formation of NTBIIron overload causes the formation of NTBI
Saturation of transport proteins (primarily transferrin) leads to formation of non-transferrin-bound iron (NTBI) in the plasma, and iron loading of parenchymal tissues.
Transferrin saturation is most acute in transfusional iron overload (3). Saturation of intracellular storage protein (primarily ferritin) leads to accumulation of labile iron within cells (3). Both processes lead to deposition of NTBI within tissues.
Electron transfer and iron toxicity
The same properties that make iron an essential element for life also make it potentially highly toxic. Electron transfer is the process by which an electron moves from one atom or molecule to another. Iron readily cycles between ferric (Fe3+) and ferrous (Fe2+) forms through the donation or acceptance of an electron:
Iron overload causes the formation of NTBI
This allows unbound iron to catalyze reactions that generate highly reactive free radicals, such as OH- and O2, which in sufficient concentrations cause cellular damage (3):
Iron overload causes the formation of NTBI
Iron overload animations
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Normal iron dstribution
Normal iron distribution
Under normal conditions, dietary uptake provides the exclusive source of iron. After absorption in the duodenum, transferrin molecules (pictured) are the primary means by which iron is transported throughout the body.
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Iron overload
Iron overload
In iron overload, transferrin saturation leads to the accumulation of NTBI complexes that can cause tissue damage.
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Acquired iron storage disorders
Diseases of the liver, such as alcoholic liver disease (4) and chronic hepatitis C and B infections (5) are sometimes associated with increased iron storage, although the mechanisms are unclear.
Transfusional iron overload
Iron overload can develop after as few as 10 transfusions (6,7), and is common among transfusion-dependent patients who do not receive effective iron removal therapy. The rate of iron loading in transfusional iron overload can be much more rapid than in primary iron overload; each unit of red blood cells contains 100 times the normal daily iron intake (6), compared with an excess iron absorption rate of 2 to 3 times normal in homozygous hemochromatosis (8).
Time course of primary and secondary iron overload
Iron overload — and subsequent complications — can develop much more quickly in patients who receive regular blood transfusions than in those who have genetic iron metabolic disorders. Adapted with permission from Olivieri and Brittenham (9).
More about transfusional iron burden
Disorders of iron metabolism
The most common form of genetic iron overload is hereditary hemochromatosis. Other rare inherited diseases cause iron overload because of defects in iron transport.
In hypotransferrinemia/atransferrinemia, transferrin deficiency causes dietary non-transferrin-bound iron (NTBI) to be deposited in the liver via portal circulation (10,11). Besides toxicity to the liver, impaired erythropoiesis is also present because of the unavailability of transferrin to transport iron to erythrocytes. This may lead to anemia.
In aceruloplasminemia, a deficiency in ceruloplasmin prevents adequate oxidization of Fe+2 to Fe+3, thereby disabling the binding of iron to transferrin (12,13). This causes the absorption of NTBI from the diet, exposing vital organs to oxidative stress. The movement of iron from intracellular stores into plasma is also impaired, leading to hemosiderosis.
More about iron metabolic disorders
Acute or chronic iron poisoning
Acute iron intoxication most commonly occurs in children who consume their mothers’ iron tablets. Depending on the amount ingested, circulatory arrest may ensue. Iron poisoning is a leading cause of death from accidental ingestion in children under the age of 5 (14). Treatment for acute iron poisoning includes gastric lavage, induced vomiting, suction and maintenance of a clear airway, iron chelation therapy, control of shock with intravenous fluid and electrolyte replacement, correction of acidosis, and red blood cell transfusion.
Chronic iron poisoning most often results from prolonged exposure to excessive dietary iron, as may happen from cooking with iron implements.
Additional causes of iron overload
In addition to the causes discussed above, iron overload may result from (15):
- Dietary iron overload
- Porphyria cutanea tarda
- Fatty liver disease
- Neonatal iron overload
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Learn moreIn This Section
Iron metabolism
Learn about the cellular and molecular mechanisms by which iron is absorbed, distributed, and stored under normal and pathological conditions.
Disorders of iron metabolism
Learn about hereditary conditions that may lead to primary iron overload, including hereditary hemochromatosis, hypotransferrinemia, and aceruloplasminemia.
Transfusional iron overload
Learn about the pathophysiology of transfusional iron overload, its impact on survival, and the transfusion-dependent anemias that most often underlie it.
References
- (1) Andrews NC, Disorders of iron metabolism. N Engl J Med. 1999;341(26):1986-95.
- (2) Kirking MH, Treatment of chronic iron overload. Clin Pharm. 1991;10(10):775-83.
- (3) Kushner JP, Porter JP, Olivieri NF, Secondary iron overload. Hematology (Am Soc Hematol Educ Program). 2001:47-61.
- (4) Pietrangelo A, Iron-induced oxidant stress in alcoholic liver fibrogenesis. Alcohol. 2003;30(2):121-9.
- (5) Farinati F, Cardin R, De Maria N, et al., Iron storage, lipid peroxidation and glutathione turnover in chronic anti-hcv positive hepatitis. J Hepatol. 1995;22(4):449-56.
- (6) Porter JB, Practical management of iron overload. Br J Haematol. 2001;115(2):239-52.
- (7) Chapter 5: Iron Overload. Cappellini N, Cohen A, Eleftheriou A, Piga A, Porter J, eds. In: Guidelines for the Clinical Management of Thalassaemia: Thalassaemia International Federation;2000:21-35
- (8) Cox TM, Peters TJ, Uptake of iron by duodenal biopsy specimens from patients with iron-deficiency anaemia and primary haemochromatosis. Lancet. 1978;1(8056):123-4.
- (9) Olivieri NF, Brittenham GM, Iron-chelating therapy and the treatment of thalassemia. Blood. 1997;89(3):739-61.
- (10) Ponka P, Rare causes of hereditary iron overload. Semin Hematol. 2002;39(4):249-62.
- (11) Bannerman RM, Genetic defects of iron transport. Fed Proc. 1976;35(11):2281-5.
- (12) Miyajima H, Genetic disorders affecting proteins of iron and copper metabolism: Clinical implications. Intern Med. 2002;41(10):762-9.
- (13) Sheth S, Brittenham GM, Genetic disorders affecting proteins of iron metabolism: Clinical implications. Annu Rev Med. 2000;51:443-64.
- (14) Morris CC, Pediatric iron poisonings in the United States. South Med J. 2000;93(4):352-8.
- (15) Tavil AS, Diagnosis and management of hemochromatosis. AASLD Practice Guidelines. Hepatology; May 2001:1322-28.