Normal dietary iron causes organ damage in patients with homozygous Hereditary Hemochromatosis (HH). Heterozygotes (10% of the European population) are at risk for early cardiovascular death. HH patients absorb too much iron and have toxic non-transferrin-bound iron (NTBI) in plasma. This project intends to identify the mechanism of TBI toxicity, and the damage to vascular endothelium (as target for atherosclerosis) and to the liver. An inexpensive method for NTBI measurement will be developed. Oral iron chelators will be developed to inhibit excess absorption of iron and to scavenge NTBI. Iron absorption, as a key pathogenic mechanism, will be analysed at a molecular level. The project is expected to result in less organ damage and in prevention of early death in HH patients.
Iron is an essential nutrient, and its deficiency is worldwide an important cause of anaemia. Food and multivitamin fortification with iron is widely practised. This can have a deleterious effect in patients with hereditary hemochromatosis (HH), a frequent genetic disorder among Europeans. Normal amounts of dietary iron can lead to liver cirrhosis, diabetes, chronic arthritis, cardiomyopathy and liver cancer. Also heterozygotes (10% of all Europeans) are at risk, in particular for early cardio/cerebrovascular death. It is the objective to identify the mechanism of organ and vascular endothelium directed iron toxicity, to develop methods to measure toxic forms of iron in serum, to prevent these deleterious effects by identifying aggravating risk factors and designing iron chelators as safe food additives to scavenge toxic forms of iron.
The results will entail elucidation of:
- dietary, environmental and iron-related genetic risk factors for atherosclerosis and liver damage;
- a rapid, inexpensive method for measurement of toxic iron;
- design of oral iron chelators for prevention of iron damage;
- mechanisms of iron toxicity on liver, heart and endothelium;
- molecular mechanism of iron absorption in HH;
- offer advice to industry and nutritionists for prevention of iron damage in the population at risk.