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Iron Overload in Hereditary Hemochromatosis
Hereditary hemochromatosis (HH) is a remarkably common genetic disorder of iron metabolism, resulting in excess iron absorption from the diet (1). Symptoms usually develop after age 40, and may range in severity from fatigue and skin pigmentation to cardiac, hepatic, endocrine, and musculoskeletal complications. By age 20, untreated homozygous hereditary hemochromatosis typically causes excess iron storage associated with an increased risk of cardiac disease and early death (2). In contrast, the heterozygous variant usually produces only moderate iron accumulation through age 50 (2).
Cause of hereditary hemochromatosis
Hereditary hemochromatosis (HH) occurs as a result of genetic mutations that affect iron metabolism. Classical HH is related to a mutation in the HFE gene. Often this is a single point mutation at position 282 that results in the substitution of a tyrosine for a cysteine (3) and altered folding of the protein (4). As the HFE protein is believed to regulate synthesis of hepcidin, HH has been linked to the downregulation or absence of hepcidin expression (5).
Iron overload in hereditary hemochromatosis
The HFE mutation can be either heterozygous or homozygous. Individuals with a heterozygous genotype are known as carriers. They are generally asymptomatic, but may exhibit a slight excess in iron absorption. Individuals who are homozygous to the trait do not necessarily exhibit symptoms due to the incomplete penetrance associated with the alleles (6).
The organ damage that occurs in HH is similar to that seen in transfusional iron overload, although iron accumulation occurs less rapidly and the distribution of iron to reticuloendothelial macrophages is proportionally lower. In conditions of chronic transfusional iron overload, blood transfusions lead to an increase in the erythrocyte population. These are broken down by macrophages, initially leading to an increase in iron levels in the reticuloendothelial system. In HH, however, iron is rapidly exported from the reticuloendothelial system, and accumulation occurs primarily in the liver, heart, and pancreas.
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Disorders of Iron Metabolism
Hereditary Hemochromatosis
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Serum Ferritin
>1000 mcg/L in HH
Iron overload can be confirmed without
liver biopsy in HFE homozygotes if
serum ferritin is
>1000 mcg/L.
References
- (1) 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.
- (2) Olivieri NF, Brittenham GM, Iron-chelating therapy and the treatment of thalassemia. Blood. 1997; 89(3):739-61.
- (3) Feder JN, Gnirke A, Thomas W, et al, A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet. 1996;13(4):399-408.
- (4) Lebron JA, Bennett MJ, Vaughn DE, et al, Crystal structure of the hemochromatosis protein HFE and characterization of its interaction with transferrin receptor. Cell. 1998;93(1):111-23.
- (5) Bridle KR, Frazer DM, Wilkins SJ, Dixon JL, Purdie DM, Crawford DH, Subramaniam VN, Powell LW, Anderson GJ, Ramm GA. Disrupted hepcidin regulation in HFE-associated haemochromatosis and the liver as a regulator of body iron homoeostasis. Lancet 2003; 361(9358):669-73.
- (6) Adams PC, Reboussin DM, Barton JC, McLaren CE, Eckfeldt JH, McLaren GD, Dawkins FW, Acton RT, Harris EL, Gordeuk VR, Leiendecker-Foster C, Speechley M, Snively BM, Holup JL, Thomson E, Sholinsky P. Hemochromatosis and iron-overload screening in a racially diverse population. N Engl J Med 2005; 352(17):1769-78