Despite lacking the modern molecular techniques accessible today, he came to accurate conclusions that describe haemochromatosis disease as an inborn error of metabolism where this inherited disorder can increase the absorption of iron and thus cause tissue damage due to iron deposition. Moreover, he rejected theories that alcohol, drug, and other factors contribute to the disorder.The clinical case series from 1935 to 1955 indicated that haemochromatosis was more common than had been acknowledged. During the 1960s, MacDonald, a pathologist at Boston City Hospital, diverted attention away from the true cause of haemochromatosis. He believed that haemochromatosis was a nutritional condition because he observed many drunken patients of Irish ancestry. During this period of time, other investigators reported additional evidence suggesting that a genetic factor could play a central role in the absorption of iron in people with haemochromatosis. However, alcohol consumption is known to increase the risk of liver injury in haemochromatosis. This finding is consistent with the concept that excess iron metabolism is a primary cause of haemochromatosis disease.Finally, in 1976, Marcel Simon and his collaborators confirmed that haemochromatosis is an autosomal recessive disorder that has a link to the human leukocyte antigen (HLA) region of the genome. It took 20 years for researchers at Mercator Genetics to effectively identify and clone the haemochromatosis genes using a positional cloning approach.In 1996, Feder et al. identified HFE, which is a major histocompatibility complex (MHC) gene. They found that 83% of patients have homozygosity for a missense mutation (C282Y) in 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.