• Consider the diagnosis in patients with Northern European ancestry.
• Initial testing is transferrin saturation or unsaturated iron binding capacity and serum ferritin.
• Secondary testing is the C282Y genetic test.
• More than 90% of typical hemochromatosis patients are homozygotes for the C282Y mutation.
• If genetic testing is not typical, reassess the diagnosis and consider secondary iron overload related to cirrhosis, alcoholism, viral hepatitis, or an iron-loading anemia.
• A number of other hemochromatosis genetic mutations are relevant to only a minority of patients.
• Not all patients need a liver biopsy.
• Siblings are at highest risk in a family study.
• Iron overload from hemochromatosis is treated by the weekly removal of 500 mL of blood until the serum ferritin is in the low- normal range of approximately 50 µg/L.
• Some but not all patients require maintenance therapy with three to four phlebotomies per year. In some countries, this can be a voluntary blood donation.
• Excess alcohol, high doses of vitamin C, and iron supplementation should be avoided, but strict dietary restrictions are not recommended.
• Siblings and children of patients should be tested for hemochromatosis with transferrin saturation, ferritin, and genetic testing.
Hemochromatosis is the most common genetic disease in populations of European ancestry. The diagnosis can be elusive because of the nonspecific nature of the symptoms. With the discovery of the hemochromatosis gene (HFE) in 1996 came new insights into the pathogenesis of the disease and new diagnostic strategies.
A fundamental issue that arose after the discovery of the HFE gene is whether the disease hemochromatosis should be defined strictly on phenotypic criteria such as the degree of iron overload (i.e., transferrin saturation, ferritin, liver biopsy, hepatic iron concentration, iron removed by venesection therapy), or whether the condition should be defined as a familial disease in Europeans most commonly associated with the C282Y mutation of the HFE gene and varying degrees of iron overload. Because the genetic test has been increasingly used as a diagnostic tool, most studies now use a combination of phenotypic and genotypic criteria for the diagnosis of hemochromatosis.
Although hemochromatosis is often classified as a liver disease, it should be emphasized that it is a systemic genetic disease with multisystem involvement. The liver is central in both diagnosis and prognosis. Hepatomegaly remains one of the more common physical signs in hemochromatosis, but it is not always present in the young, asymptomatic homozygote. In a study of 717 homozygotes from Australia, 8% of men and 1.7% of women had cirrhosis of the liver at the time of diagnosis. The prevalence of cirrhosis in asymptomatic or screened patients is much lower. It is likely that there are factors other than iron overload that contribute to cirrhosis in hemochromatosis.
These can include the effects of alcohol or comodifying genes. The effect of iron depletion therapy is usually stabilization of the liver disease, and fibrosis improves with repeat liver biopsy after iron depletion. This accounts for the relatively small number of C282Y homozygotes that require liver transplantation. The other common clinical manifestations are arthralgias, pigmentation, congestive heart failure, impotence, and fatigue. Several large population studies failed to demonstrate an increase in diabetes compared with a control population. A population-based study estimated that only 28% of male and 1% of female C282Y homozygotes will develop symptoms of iron overload.
A paradox of genetic hemochromatosis is that the disease is underdiagnosed in the general population and overdiagnosed in patients with secondary iron overload.
Preliminary population studies using genetic testing demonstrate a prevalence of homozygotes of approximately 1:227 among whites. The fact that many physicians consider hemochromatosis to be rare implies either a lack of penetrance of the gene (nonexpressing homozygote) or a large number of patients who remain undiagnosed in the community.
Previous studies had suggested that transferrin saturation would be a good screening test and diagnostic test for hemochromatosis.
The sensitivity of transferrin saturation in population-screening studies designed to detect C282Y homozygotes (genotypic case definition) was only approximately 75%, and transferrin saturation can be in the normal range in young female homozygotes. A large biologic variation in transferrin saturation within an individual patient has also been reported.
The relationship between serum ferritin and total body iron stores was clearly established by strong correlations with hepatic iron concentration and the amount of iron removed by venesection.
However, ferritin can be elevated secondary to chronic inflammation and histiocytic neoplasms. A major diagnostic dilemma in the past was whether the serum ferritin concentration was related to hemochromatosis or to another underlying liver disease, such as alcoholic liver disease, chronic viral hepatitis, or nonalcoholic steatohepatitis. It is likely that most of these difficult cases can now be resolved by genetic testing.
Liver biopsy was previously the gold-standard diagnostic test for hemochromatosis; however, it has shifted from a major diagnostic tool to a method of estimating prognosis and concomitant disease. The need for liver biopsy seems less clear now in the young, asymptomatic C282Y homozygote in whom there is a low clinical suspicion of cirrhosis based on history, physical examination, and liver biochemistry. A large study conducted in France and Canada suggested that C282Y homozygotes with a serum ferritin concentration of less than 1000 µg/L, a normal aspartate transaminase (AST) concentration, and no hepatomegaly have a very low risk of cirrhosis. C282Y homozygotes with a ferritin level greater than 1000 µg/L, an elevated AST, and a platelet count of less than 200,000/mm3 have an 80% chance of having cirrhosis. Hepatic elastography is another noninvasive tool to assess liver fibrosis in hemochromatosis.
Patients with cirrhosis have a 5.5-fold relative risk of death compared with noncirrhotic hemochromatosis patients. Cirrhotic patients are also at increased risk of hepatocellular carcinoma. Liver biopsy is considered in typical C282Y homozygotes with liver dysfunction and in potentially iron-overloaded patients without the typical C282Y mutation. Simple C282Y heterozygotes, compound heterozygotes (C282Y/H63D), H63D homozygotes, and patients with other risk factors (e.g., alcohol abuse, chronic viral hepatitis) who have moderate to severe iron overload (ferritin > 1000 µg/L) may be considered for liver biopsy.
Since the introduction of genetic testing, hepatic iron concentration and hepatic iron index have become less useful in the diagnosis of hemochromatosis.
A major advance stemming from the discovery of the hemochromatosis gene is the use of a diagnostic genetic test. Most studies report that more than 90% of typical hemochromatosis patients were homozygotes for the C282Y mutation. A second minor mutation, H63D, was also described in the original report. Compound heterozygotes (C282Y/H63D) and, less commonly, H63D homozygotes, resemble C282Y homozygotes with mild to moderate iron overload. Genetic mutations involving ferroportin, hemojuvelin, transferrin receptor 2, ceruloplasmin, and hepcidin are associated with iron overload. It is likely that, as more mutations are found, they will be relevant to only a minority of patients. Commercial tests are rarely available for these rare genetic mutations.
Some patients with clinical pictures indistinguishable from genetic hemochromatosis are negative for the C282Y mutation. Most of these cases appear to be isolated, although a few cases of familial iron overload with negative C282Y testing have been reported. A negative C282Y test should alert the physician to question the diagnosis of genetic hemochromatosis and to reconsider secondary iron overload related to cirrhosis, alcoholism, viral hepatitis, or an iron-loading anemia. If no other risk factors are found, the patient should begin phlebotomy treatment, similar to any other hemochromatosis patient.
The interpretation of the genetic test in several settings is shown in Box 1. Genetic discrimination is a concern, given the widespread use of genetic testing, but discrimination has been rarely reported in screening studies. In the case of hemochromatosis, the advantages of early diagnosis of a treatable disease outweigh the disadvantages of genetic discrimination.
|Interpretation of Genetic Testing for Hemochromatosis|
This is the classic genetic pattern seen in more than 90% of typical cases. Expression of disease ranges from no evidence of iron overload to massive iron overload with organ dysfunction. Siblings have a one in four chance of being affected and should have genetic testing. For children to be affected, the other parent must be at least a heterozygote. If iron studies are normal, false-positive genetic testing or a nonexpressing homozygotic state should be considered
“C282Y/H63D Compound Heterozygote”
This patient carries two copies of the minor mutation. Most patients with this genetic pattern have normal iron studies. A small percentage have mild to moderate iron overload. Severe iron overload is usually seen in the setting of another concomitant risk factor (e.g., alcoholism, viral hepatitis)
This patient carries one copy of the major mutation. This pattern is seen in approximately 10% of the white population and is usually associated with normal iron studies. In rare cases, the results of iron studies are high, in the range expected in a homozygote rather than a heterozygote. These patients may carry an unknown hemochromatosis mutation, and liver biopsy is helpful to determine the need for phlebotomy therapy
Most patients with this genotype will have normal iron studies. A small percentage have mild to moderate iron overload. Severe iron overload is usually seen in the setting of another concomitant risk factor (e.g., alcoholism, viral hepatitis)
This patient carries one copy of the minor mutation. This pattern is seen in approximately 20% of the white population and is usually associated with normal iron studies. This pattern is so common in the general population that the presence of iron overload can be related to another risk factor. Liver biopsy is required to determine the cause of the iron overload and the need for treatment in these cases
“No HFE Mutations”
If iron overload is present without any mutations in the hemochromatosis gene (HFE), a careful history for other risk factors must be reviewed, and liver biopsy can be useful to determine the cause of the iron overload and the need for treatment. Most of these are isolated, nonfamilial cases. There are cases described involving genetic mutations in ferroportin, hemojuvelin, transferrin receptor 2, ceruloplasmin, and hepcidin genes. Genetic tests for these mutations are not widely available
Once the proband case is identified and confirmed with the genetic test for the C282Y mutation, family testing is imperative. Siblings have approximately one in four chance of carrying the gene and should be screened with the genetic test (C282Y and H63D mutation), transferrin saturation, and serum ferritin. A cost-effective strategy now possible with genetic testing is to test the spouse for the C282Y mutation to assess the risk in the children. If the spouse is not a C282Y heterozygote or homozygote, the children will be obligate heterozygotes, assuming paternity and excluding another gene or mutation causing hemochromatosis. This strategy is particularly advantageous if the children are geographically separated or in different health care systems.
The treatment of hemochromatosis continues to employ the medieval therapy of periodic bleeding. Blood is removed, with the patient in the reclining position over 15 to 30 minutes. Initial treatment consists of the weekly removal of 500 mL of blood. A hemoglobin test is done before each phlebotomy. If the hemoglobin concentration has decreased to less than 10 g/dL, the phlebotomy schedule is modified to 500 mL every 2 weeks. Phlebotomies are continued until the serum ferritin concentration is approximately 50 mcg/L. Serum ferritin levels are drawn monthly in patients with significant iron overload and increased to weekly as the ferritin decreases to < 200 mcg/L. The concomitant administration of a salt-containing sport beverage (e.g., Gatorade) is a simple method of maintaining plasma volume during the phlebotomy.
Maintenance phlebotomies after iron depletion, consisting of three to four phlebotomies per year, are performed in most patients, although the rate of iron reaccumulation is highly variable.
Maintenance therapy is initiated when the serum ferritin rises from 50 mcg/L to > 300 mcg/L. The transferrin saturation remains elevated in many treated patients and does not normalize unless the patient becomes iron deficient. In some countries, patients with mild iron abnormalities are encouraged to become voluntary blood donors.
Chelation therapy1 is not recommended for hemochromatosis.
Patients are advised to avoid oral iron therapy and alcohol abuse, but there are no dietary restrictions. Patient support groups have been concerned by the practice of iron fortification of foods, but much of this iron is in an inexpensive form with poor bioavailability.
Hemochromatosis is a common and often underdiagnosed disease.
Early diagnosis and treatment result in an excellent long-term prognosis. The development of a diagnostic genetic test has improved the feasibility of the goal of prevention of morbidity and mortality from hemochromatosis.
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1 Not FDA approved for this indication.