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The most common hereditary cause of iron overload is haemochromatosis. Hypotransferrinemia and aceruloplasminemia are rare disorders of iron transport that can also lead to iron overload.
Hereditary haemochromatosis
Hereditary haemochromatosis (HH) is a genetic disorder of iron metabolism that results in excess iron absorption from the diet (approximately 2-3 times the normal quantity) [1]. The most common form, known as HFE-associated haemochromatosis, is the most common genetic disorder among Caucasians of northern European descent, with approximately 0.3-0.5% being homozygous for the disease [2;3] and 10% being heterozygous [4].
Causes of Hereditary Haemochromatosis
Hereditary haemochromatosis occurs as a result of genetic mutations that effect iron metabolism. In classical hereditary haemochromatosis this 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 [5] and altered folding of the protein [6]. As the HFE protein is believed to regulate synthesis of hepcidin, HH has been linked to the downregulation or absence of hepcidin expression [7]. In normal iron homeostasis, hepcidin systemically regulates iron transport from iron-exporting tissues into plasma via the binding and degradation of ferroportin (found on the surface of enterocytes, hepatocytes and reticuloendothelial cells). The absence of hepcidin allows uncontrolled expression of ferroportin, which in turn leads to increased serum ferritin levels.
Approximately 85% of haemochromatosis is caused by the HFE gene mutation [8]. Other, rarer mutations can result in similar symptoms. These cause non-HFE haemochromatosis and include mutations in the hepcidin antimicrobial peptide (HAMP) gene (which encodes human hepcidin [9]), and in genes that encode the transferrin receptor, hemojuvelin [10] or ferroportin [11;12]. The latter mutation differs from the others as iron accumulates in macrophages rather than in plasma.
Iron overload in hereditary haemochromatosis
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 [3].
The organ damage that occurs in hereditary haemochromatosis 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 hereditary haemochromatosis, however, iron is rapidly exported from the reticuloendothelial system and accumulation occurs primarily in the liver, heart and pancreas.
Hereditary Haemochromatosis Symptoms
Not all individuals genetically predisposed to haemochromatosis develop symptoms. Data varies on the proportion of homozygotic individuals who will develop symptoms of iron overload. For example, one study found that symptoms commonly associated with iron overload were not significantly more prevalent among homozygotic individuals (<1% affected) than among controls [13]. In contrast, a meta-analysis of data from seven studies concluded that clinical manifestations were present in 50% of homozygotic males and 44% of homozygotic females [14].
When symptoms of hereditary haemochromatosis are present, their nature differs between men and women. This is due to the lifelong accumulation of iron in women being offset by factors such as menses and pregnancy. Women typically develop milder, nonspecific symptoms such as fatigue. In men, the initial presentation is often more serious conditions such as diabetes or cirrhosis [15]. Excess iron deposition in the skin may cause a characteristic bronze pigmentation in fair-skinned people, and may progress to an almond hue in people with darker skin.
In advanced hereditary haemochromatosis, clinical findings include diabetes, cardiomyopathy manifested by cardiomegaly, heart failure, and arrhythmias or conduction disturbances [2].Hepatic dysfunction or cirrhosis is common, and hepatocellular carcinoma is more common with hereditary haemochromatosis than with cirrhosis of other etiologies [16]. Pituitary failure is common, and may lead to hypogonadal symptoms such as diminished libido and infertility [17]. Arthropathy, osteoporosis, and severe muscle cramps are common in older patients [17].
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