Hemochromatosis Genotype

Hereditary hemochromatosis (HH) is a common autosomal recessive iron-storage disorder that affects approximately 1 in every 125 to 333 individuals in the United States, Northern Europe and Australia. Hispanics may also have a high prevalence of hemochromatosis, but African Americans have a much lower prevalence of 1 in 1000 to 3000 individuals. Patients with HH absorb 3 to 4 mg of iron per day compared to the 1 to 2 mg absorbed by normal individuals. Since the body has no means of disposing of excess iron, it ultimately deposits within parenchymal cells of the liver, pancreas, pituitary, synovium, heart and other tissues. After saturating intracellular ferritin stores, free iron catalyzes intracellular redox reactions, generating toxic oxygen radicals that cause cell damage and death. Because this iron buildup occurs slowly, patients usually become symptomatic between the ages of 30 and 50 with one or several clinical features including hepatic dysfunction, diabetes, body hair loss, impotence, arthritis, cardiomyopathy, and fatigue. HH is 10 times more common in men than women. Women have milder symptoms due to loss of iron through menstruation in the reproductive years. Early diagnosis and treatment by phlebotomy are essential to reduce morbidity and mortality.

Iron is absorbed from the GI tract through interaction of iron-bound transferrin with the transferrin receptor expressed on membranes of the small intestinal epithelium. Small intestinal crypt cells possess a transferrin receptor binding protein (called HFE). Normally, HFE binds to the transferrin receptor and decreases its affinity for iron-bound transferrin. HFE is a negative regulator of iron absorption. Mutations in the HFE protein decrease its binding to the transferrin receptor, allowing unregulated and excessive absorption of dietary iron.

The predominant mechanism for loss of HFE function is a single point mutation at amino acid 282 of the HFE protein that converts a cysteine to tyrosine (C282Y). More than 80% of patients with HH are homozygous for this C282Y mutation, but only 0.4% of the general population have this genotype.

Prevalence (%) of HFE Genotypes

HFE Genotype

General Population

Patients with HH

C282Y homozygous



Compound heterozygous



H63D homozygous



C282Y heterozygous



H63D heterozygous



The C282Y HFE mutation occurs much more commonly in heterozygous form, affecting 10 to 15% of Caucasians. Heterozygotes have higher mean transferrin saturation and ferritin values than normal subjects, but rarely develop clinical complications of iron overload.

Although most patients with HH have 2 mutant C282Y alleles, between 10 and 20% do not. Between 3 and 5% of patients with HH have one mutant C282Y allele and an H63D mutation on the other allele. The H63D mutation involves a substitution of aspartic acid for histidine at position 63 of the HFE protein. Patients with two different mutations of a gene are classified as compound heterozygotes. Approximately 2% of the normal population have the compound heterozygous genotype and most of them do not have iron overload. However, this genotype is a risk factor for HH.

The presence of a single H63D mutation is an extremely common polymorphism, occurring in approximately 25% of a healthy population. Individuals with a heterozygous H63D genotype almost never develop HH. Approximately 2% of Caucasians have a homozygous H63D genotype. These individuals appear to have a mildly increased risk of developing HH.

The risk of development of HH for individual HFE mutations has been estimated by calculating the odds ratio using pooled data from United States and European studies. This calculation illustrates that both the compound heterozygous and homozygous H63D genotypes have much lower penetrance than the C282Y homozygous genotype. Penetrance refers to the proportion of individuals with the mutation who develop HH symptoms.

Risk of Developing HH

HFE Genotype

Odds Ratio of HH

C282Y homozygous


Compound heterozygous


H63D homozygous


C282Y heterozygous


H63D heterozygous



Discovery of these mutations has led to an interest in genetic screening for HH. However, little information about the penetrance of the homozygous C282Y mutation has been reported. Until recently, many authorities assumed that most patients with the mutation would eventually become symptomatic. The issue of penetrance was addressed in a recent study (Lancet 2002;359:211-218). The investigators screened 41,038 individuals attending a health appraisal clinic with gene tests for the C282Y and H63D mutations. Of the subjects screened, 152 homozygotes for C282Y and 616 compound heterozygotes for C282Y and H63D were identified. Serum transferrin saturation and ferritin were increased significantly in 75% of men and 50% of women who were homozygous for C282Y. In spite of this, the majority of people with HFE mutations never developed clinical manifestations of HH. Penetrance was less than 1%. A more recent study of 31,000 persons in Melbourne, Australia demonstrated that 28% of male and 1% of female C282Y homozygotes had evidence of iron overload related disease (N Engl J Med 2008;358:221-30). These studies emphasize the fallacy of equating genotype with disease and suggested a limited role for genetic testing in screening for HH.

There is no doubt that it is important to diagnose and treat this disease early since it is preventable. At this time biochemical screening (transferrin saturation) is recommended, with genetic testing reserved for confirmation of the diagnosis in individuals with iron overload, or for screening family members of a HH patient with a known mutation.

The recommended approach to screening for hemochromatosis is measurement of transferrin saturation (see algorithm). Transferrin saturation greater than 50% in men or women on at least two occasions is consistent with the diagnosis and should be followed up with measurement of serum ferritin. If serum ferritin is markedly elevated, liver biopsy is recommended to assess iron overload and determine whether liver fibrosis or cirrhosis is present, and therapeutic phlebotomy is initiated. If serum ferritin is normal, screening tests are repeated at 2-5 year intervals.








Genotype results are reported as:

  • Normal
  • C282Y homozygous
  • C282Y heterozygous
  • H63D homozygous
  • H63D heterozygous
  • C282Y/H63D compound heterozygous


Reference value is normal, meaning that the hemochromatosis gene was not detected.

Specimen requirement is one 5 mL lavender top (EDTA) tube of blood.


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