Abstract
Homozygosity for the C282Y mutation is one of the most common genetic disorders, which predisposes to iron overload related disease known as hereditary hemochromatosis (HH). Severeness of the disease can easily be reduced by using phlebotomies. However, the diagnosis of HH is often drawn only when irreversible organ damage has developed, so screening for HH to prevent disease is desirable. The aim of this thesis was to investigate potential pathophysiological mechanisms of iron overload and to reveal an optimal early management strategy for HH. As the presence of non-transferrin-bound iron (NTBI) was thought to contribute to the HH related diseases, the standardization of the NTBI measurements was investigated, which showed a wide spread of measured mean serum NTBI values. Furthermore, the relation between iron overload and the induction of atherosclerosis was looked into. It revealed an association between excess body iron and increased plasma levels of sICAM-1 but not with markers of in vivo LDL oxidation. As population screening and targeted screening are no optimal strategies for early detection of HH, the family screening strategy was further investigated. It appeared that hemochromatosis related diseases were significantly more present in the HH families compared to the normal population. The amount of accumulated iron in the first-degree family members of C282Y homozygous probands was strongly determined by the HFE-gene profile of the sibling, the severity of iron accumulation in the proband and the age at testing for serum ferritin. Furthermore, C282Y homozygous siblings had a clearly higher penetrance of hemochromatosis related diseases than non-homozygous siblings. Predictive for the disease penetrance were genotype, age and gender. Conclusive, this thesis revealed the usefulness of family screening for the early management of HH. The next step will be to look for additional factors, as e.g. cost-effectiveness, to underline the implementation of family screening for HH.
