Mutations in the HFE gene directly associated with chronic joint disease

Apr 4 2005

Mutations in the HFE gene, which is involved in iron regulation, seem to be directly associated with chronic joint disease (or haemophilic arthropathy) among haemophilic patients, claim a team of Portuguese scientists in the April issue of the journal Blood.

The results, from a small group of hemophilic patients, if confirmed in a larger population, could have important implications, not only for the treatment of haemophilic arthropathy but potentially also for other arthritic diseases.

Haemophilia is a genetic bleeding disorder that affects an estimated 400,000 people worldwide, although among Caucasians, where is most common, affects approximately 1 person in every 200. The defective gene, which is localised in the X chromosome, is usually carried through generations by women, which transmit it to their children. Queen Victoria of England, probably the most famous female carrier of haemophilia, is accounted for example to have spread the disease throughout the European royal houses. The disease, characterised by chronic bleeding, is caused by a deficiency in blood-clotting factors and its severity correlates with the lack of the clotting factor – individuals with very severe cases can present as little as 1% of the normal levels.

The main cause of disability among haemophilic patients, however, is chronic joint disease – arthropathy - that originates from exposure to an unidentified blood component(s) as result of chronic bleeding into the joints. But although all haemophilia patients suffer from bleeding into the joints only some of them develop arthropathy and even among these there is a wide range of disease severities. Haemophilic patients also have changes in the tissues around the joints, which look very similar to the changes observed in malignant tissues. This has led to the proposal that, as in cancer, these changes are the result of abnormal cell division and inhibition of cellular death. Interestingly, iron can be found accumulated around the joints of these patients and because this metal is known to stimulate cellular proliferation it was suggested that iron might be involved in the alterations in the tissues and consequently in haemophilic arthropathy. And in effect, recent work has shown that iron can increase, in models of this disease, the expression of genes involved in cancer induction and so is probably involved in the tissue changes observed in haemophilic arthropathy patients.

Eugenia Cruz, Manuel Campos, Graça Porto and colleagues from the Hospital Geral de Santo Antonio and the Institute for Molecular and Cell Biology (IBMC) at Porto, Portugal, in an attempt to further understand the connection between iron and haemophilic arthropathy decided to look at a gene involved in iron regulation –HFE - asking if mutations and consequent malfunction of this gene would lead to changes in the disease. HFE regulates the movement of iron into cells and when mutated leads to cellular iron-overload which in time can result in damage to tissues and organs such as the liver. Furthermore, it is known that in HFE-mutated individuals, macrophages - a specialised cell of the immune system that is also present in the joints of haemophilic arthropathy patients - release much higher quantities of iron than macrophages from normal individuals.

Cruz, Campos, Porto and colleagues analysed 34 haemophilic patients and found that patients with a mutated HFE presented a much severer haemophilic arthropathy. The team of scientists proposed that this increase in disease severity was probably the result of a higher quantity of iron in the blood together with an increased release from macrophages directly into the joints of haemophilic HFE-mutated individuals.

This observation is very important as, not only supports the hypothesis that iron is involved in haemophilic arthropathy, but can also help scientists to understand why different haemophilic patients, all with chronic bleeding into the joints, can suffer from such a wide range of disease severities.

Furthermore, the understanding of the connection between iron and arthropathy could be extremely important also for other arthritic illnesses. One such example is rheumatoid arthritis, a debilitating chronic inflammatory disease that affects millions of people around the world - up to 1% of the population in certain regions - and which seems to be also associated with alterations in iron accumulation in the joint.