The most common gene involved in causing Hereditary Hemochromatosis (HH) is the HFE gene. Most patients with hemochromatosis have two copies of the HFE mutation C282Y. A smaller percentage of patients have one copy of C282Y and one copy of another mutation known as H63D. Persons with the C282Y/H63D genotype are called compound heterozygotes.
In persons of northern European extraction approximately 1 in 10 persons carries one copy of C282Y. Carriers of one mutation for C282Y are known as C282Y heterozygotes. Approximately 1 in 200 to 300 persons of northern European extraction carries two copies of C282Y. These persons are known as C282Y homozygotes.
In some northern European populations eg Ireland, Iceland and Brittany the percentage of persons carrying one copy of C282Y is higher and the rate of hemochromatosis is thus higher in these countries. Predictably countries settled by northern Europeans eg Australia, South Africa and Canada have high rates of hemochromatosis.
Hereditary Hemochromatosis fits the criteria set by the World Health Organization for population screening for a disease:
- The homozygous genotype is common and it is potentially fatal if not treated
- The disease has a lengthy latent period with asymptomatic iron accumulation followed by a period of iron overload with reversible organ injury
- Treatment during the latent period and the period with reversible organ injury restores the life expectancy to normal. (Treatment is safe, effective and cost effective)
- HH can be detected by measurement of the transferrin saturation (TS).
It is relatively easy to identify asymptomatic persons in whom iron indices are elevated but HH is not clinically apparent. TS values above 45% for women and 55% for men are suggestive of iron overload. TS levels should be fasting values. Borderline values should be repeated. In patients suspected of having iron overload detected by a high TS value further screening should be a ferritin level and HFE gene testing. It is important to identify potential cases of iron overload. Not all patients with C282Y/C282Y or C282Y/H63D genotypes will load iron. Once potential cases of hemochromatosis are identified they should be followed to see if they accumulate iron and treated accordingly. If the ferritin level exceeds 200 ug/L in men and 300 ug/L in women in identified cases of hemochromatosis they should be deironed to 25 – 75 ug/L and kept in this range.
While most cases of Hereditary Hemochromatosis are C282Y homozygotes or C282Y/H63D compound heterozygotes other variations do occur. Sometimes it is not possible to identify other contributing genetic mutations. There is a lot of current research focused on this area. There are a few laboratories in the world where other mutations are tested for but these are generally not accessible to the general population. Thus sometimes it must be assumed that a patient has an unidentified mutation eg if a patient is a C282Y heterozygote and has a TS value of 90% and a ferritin level of 1,500 ug/L it is probable that this person has hemochromatosis and should be treated accordingly.