Genetic hemachromatosis is a condition in which the patient abnormally accumulates iron into organs of the body. Recently, this disorder has become far better understood with the identification and understanding of the genetic defect of hemachromatosis. In 1996, the gene responsible for the development of hemachromatosis was identified. This gene is known as the HFE chromosome 6. Specifically, a mutation in this gene, known as the C282Y mutation, has been considered most important in the development of most hemachromatosis. The frequency of C282Y homozygosity in the general population is approximately 1:200-300 patients. Interestingly, this frequency does not correspond to the frequency of clinical hemachromatosis. As such, patients who have the C282Y homozygosity may not necessarily develop true overt hemachromatosis. Currently, studies attempting to describe disease penetrants are pending.

Patients who have heterozygous C282Y mutation have not been found to be at increased risk for hemachromatosis. There are some patients, though, who will have heterozygous C282Y mutation, who may present with increased iron stores suggestive of hemachromatosis, but it is likely that these patients have other factors such as alcohol consumption or other underlying liver disease, which may explain the increased iron loads within their liver. A second mutation in the HFE protein has been identified as the H63D mutation. The exact significance of an isolated H63D mutation is unclear. Though, interestingly, patients who have heterozygote C282Y gene mutation along with H63D have approximately a 1.5% likelihood of developing significant iron overload.

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Clinical Features

The classic presentation of hemachromatosis is of a middle-aged man with new onset pigmentation, enlarged liver, diminished sexual activity, loss of body hair, joint pains and the onset of diabetes. Though, presentation can vary tremendously. Interestingly, overt clinical hemachromatosis is much more frequent in males than in females, at a ratio of 10:1. Women, who may be homozygous for the C282Y mutation, may not present as early, since women tend to have iron loss with menstruation and pregnancy. Classically, women who do present with hemachromatosis are status post menstruation, in their postmenopausal period, or have had hysterectomies. The majority of cases of hemachromatosis are diagnosed between 40 and 60 yeas of age. Though, with the ability now to genetically test for hemachromatosis, patients are being detected earlier on, prior to presentation of clinical features of the disease. Patients with genetic hemachromatosis tend to have enlarged livers. They may have a dull abdominal pain and in time, their liver will develop into a fibrotic state known as cirrhosis. Primary liver cancer develops in approximately 15 to 30% of patients who have cirrhosis. In patients who have developed advanced disease with genetic hemachromatosis, such that their liver is cirrhotic, approximately 70% of these will have clinical diabetes. Cardiac involvement from iron overload has also been reported, and can present with heart failure. Cardiac complications are thought secondary to iron deposits in the myocardium and conductive system and dysrhythmias have also been noted in this condition. In approximately 50% of patients, they will develop a specific arthropathy of the metacarpophalangeal joints. The arthralgia may or may not improve with subsequent treatment of hemachromatosis, which is principally phlebotomy.

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Diagnosis

Classically, patients who have hemachromatosis will have an elevated ferritin. Interestingly, cirrhosis has not been seen in most patients whose ferritin level is less than 1000. Most patients with hemachromatosis may have normal liver function studies with active clinical disease. Historically, the best way to make the diagnosis of hemachromatosis was by a liver biopsy. Though, with the introduction of the ability to test a patient’s blood for the C282Y homozygote mutation, the utilization of liver biopsy has changed. Specifically, it has been recommended that if the C282Y homozygote gene is present and the patient has a serum ferritin less than 1000, the likelihood that the patient has cirrhosis is low and as such, a liver biopsy may not be required at that point.

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Treatment

The treatment of hemachromatosis is specific to attempting to reduce the amount of iron in the body and this is best accomplished by phlebotomy. Once phlebotomy is initiated, the patient is followed serially with ferritin levels. This is a good means by which to see how the patient is responding to phlebotomy.

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Screening for Early Hemacromatosis

Because of the introduction of the C282Y mutation now, we can take individuals related to knowing patients and test for the likelihood of their developing hemachromatosis. As stated above, if the C282Y mutation is present and is homozygous, the patient is at risk for developing hemachromatosis. Though, the true risk and likelihood is yet to be defined. If the C282Y mutation, which is homozygote, is identified in an asymptomatic patient, they should serially be assessed over time by clinical examination and the additional laboratory studies, such as ferritin, to be drawn. On the other hand, if an individual related to a patient who has had the diagnosis of genetic hemachromatosis has the C282Y mutation, which is heterozygote, the likelihood of them developing genetic hemachromatosis is low, unless they have the added H53D mutation. As already stated above, if they have the combination of those two mutations in a heterozygote state, they may have an approximately 1.5% chance of developing genetic hemachromatosis.

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