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classic hemochromatosis


Tuesday 5 August 2008

Definition: Classic hemochromatosis (HFE) (MIM.235200) is an autosomal recessive disorder, caused by mutation in a gene designated HFE on chromosome 6p21.3.


Classic hereditary hemochromatosis is an autosomal recessive iron-overload disorder associated with mutation of the HFE gene, which is located on chromosome 6.


The natural history of classic hereditary hemochromatosis involves a gradual, highly variable, stepwise progression that depends on numerous individual variables.

HFE-related hereditary hemochromatosis develops slowly and is rarely evident before adulthood. Its progression may be accelerated by high dietary iron intake or attenuated by active iron utilization or iron loss.

The "protective effects" of menstruation and pregnancy probably explain why plasma iron loading in girls and young women is more gradual than it is in older women and why the rate of symptomatic organ disease in boys and men is three times the rate in women of reproductive age.

In some cases, disease expression never goes beyond this biochemical phase, but in more than half of all C282Y homozygotes, the plasma iron overload is followed by a second phase, one that involves progressive accumulation of iron in the parenchymal tissues of the liver and other organs, as heralded by rising serum levels of ferritin.

The iron-deposition rate is also influenced by various factors, including the circulating level of hepcidin, the iron-regulatory hormone, and the activity of proteins involved in the metabolism of heme (e.g., hemopexin and haptoglobin) and non-heme iron.

The third phase, which occurs in a limited percentage of cases (bottom panel) and is more common in men than in women, is manifested by markedly elevated levels of serum ferritin along with signs and symptoms of target-organ impairment.

This outcome is related to the toxic effects of redox-active iron but is greatly facilitated by other, concomitant cytotoxic insults and by hypersusceptibility to oxidant damage and fibrogenesis.

Symptomatic organ involvement (when it occurs) generally begins in midlife, often with nonspecific symptoms such as unexplained fatigue or joint pain.

Liver disease (ranging from slightly elevated aminotransferase levels, with or without hepatomegaly, to cirrhosis and even hepatocellular carcinoma) usually predominates, but endocrine disorders (diabetes, hypogonadotropic hypogonadism, impotence, and hypothyroidism), cardiac problems (arrhythmias and heart failure), and joint disease (destructive arthritis) are also found.

Although iron metabolism is abnormal, erythropoiesis is not jeopardized, and hematologic anomalies are not usually seen.


Therapeutic phlebotomy is usually effective in reducing stores of both plasma iron and tissue iron, and even aggressive phlebotomy generally poses no risk of anemia to the patient.

C282Y mutation

In most cases the mutation is a single-base change that results in the substitution of tyrosine for cysteine at position 282 of the HFE protein (C282Y).

C282Y seems to have originated by chance in a single Celtic (or Viking) ancestor in northwestern Europe some 2000 years ago.

The genetic defect, which caused no serious obstacle to reproduction and may even have conferred some advantages (e.g., resistance to dietary iron deficiency and certain infectious diseases), was passed on and spread by population migration.

Homozygosity for the C282Y mutation is now found in approximately 5 of every 1000 persons of northern European descent, a prevalence 10 times that of cystic fibrosis genotypes.

All persons who are homozygous for the C282Y mutation are genetically predisposed to a chain of events that may culminate in severe damage to multiple organs, but it is currently impossible to predict whether, and to what extent, the mutation will be phenotypically expressed.

In a small percentage of C282Y homozygotes, laboratory evidence of altered iron metabolism never develops.

Most persons homozygous for the C282Y mutation have progressive expansion of the plasma iron compartment, as reflected by increasing saturation of transferrin, the plasma iron transporter

Transferrin saturation is calculated as a percentage as follows: 100 x serum iron level (in micrograms per deciliter) รท total iron-binding capacity (in micrograms per deciliter).

Other mutations

Other mutations in HFE, less common than C282Y, have also been described.

The clinical effects of a mutation in which aspartic acid replaces histidine at position 63 (H63D), for example, appear to be limited,11 although 1 to 2 percent of persons with compound heterozygosity for C282Y and H63D seem predisposed to disease expression.

The clinical significance of other, rarer forms of compound heterozygosity, such as heterozygosity for C282Y and a mutation in which cysteine replaces serine at position 65 (S65C) or heterozygosity for H63D and S65C, is still controversial

See also

- primary hemochromatoses