A study of 3,011 unrelated white Australians found that 14% were heterozygous carriers of an HFE mutation, 0.5% were homozygous for an HFE mutation, and only 0.25% of the study population had clinically relevant iron overload. Most patients who are homozygous for HFE mutations do not manifest clinically relevant haemochromatosis (see Genetics above). Other populations have a lower prevalence of both the genetic mutation and the clinical disease. It is the most frequent genetic disease in the U.S. with a prevalence of 1:300 in the non-Hispanic white population, It is 2-3 times most common in males.Genetics studies suggest the original haemochromatosis mutation arose in a single person, possibly of Celtic ethnicity, who lived 60–70 generations ago. At that time, when dietary iron may have been scarcer than today, the presence of the mutant allele may have provided an evolutionary advantage by maintaining higher iron levels in the blood.The distribution of the C282Y variant was noted in various countries. Non-HFE associated hemochromatosis, as Haemochromatosis type 2, Haemochromatosis type 3, Haemochromatosis type 4 and Haemochromatosis type 5, were discovered in Mediterranean countries. On the other side, Northern European ancestry is closely linked to hereditary hemochromatosis disease (HFE). In one study, over 93% of Irish patients with HFE C282Y mutation were homozygotic. The G320V mutation in the HJV gene, which produces hemojuvelin protein, is widely distributed in central Europe and Greece. Terminology
The term "haemochromatosis" is used by different sources in many different ways. It is often used to imply an association with the HFE gene.
When transferrin is high, HFE works to increase the intestinal release of iron into the blood. When HFE is mutated, the intestines perpetually interpret a strong transferrin signal as if the body were deficient in iron. This leads to maximal iron absorption from ingested foods and iron overload in the tissues. However, HFE is only part of the story, since many patients with mutated HFE do not manifest clinical iron overload, and some patients with iron overload have a normal HFE genotype. A possible explanation is the fact that HFE normally plays a role in the production of hepcidin in the liver, a function that is impaired in HFE mutations.People with abnormal iron regulatory genes do not reduce their absorption of iron in response to increased iron levels in the body. Thus, the iron stores of the body increase. As they increase, the iron which is initially stored as ferritin is deposited in organs as haemosiderin and this is toxic to tissue, probably at least partially by inducing oxidative stress. Iron is a pro-oxidant. Thus, haemochromatosis shares common symptomology (e.g., cirrhosis and dyskinetic symptoms) with other "pro-oxidant" diseases such as Wilsons disease, chronic manganese poisoning, and hyperuricaemic syndrome in Dalmatian dogs. The latter also experience "bronzing". Diagnosis
The diagnosis of haemochromatosis is often made following the incidental finding on routine blood screening of elevated serum liver enzymes or elevation of the transferrin saturation or elevated serum ferritin.. Arthropathy with stiff joints, diabetes, or fatigue, may be the presenting complaint.