Hereditary hemochromatosis is a disease of abnormal iron metabolism (iron overload) characterized biochemically by increased transferrin saturation (>40%) and increased level of serum ferritin, and clinically, by early multi-systemic and non specific signs such as weakness, malaise, fatigue, impotence, abdominal pain, joint pain, and late sequelae which includes dark (bronze) skin pigmentation, diabetes mellitus, hepatic cirrhosis, primary

liver cancer, hypogonadotrophic hypogonadism, cardiomyopathy and arthropathy. 

            The mutations in the HFE gene responsible for hemochromatosis (C282Y and H63D) were first reported in 1996 [1-3], and they were shown to be the most prevalent mutations in the Caucasian population. Hereditary hemochromatosis is the most common genetic disease in the Caucasian population, far exceeding the combined incidence of cystic fibrosis, phenylketonuria and muscular dystrophies [4-6]. The relationship between the C282Y mutation and hemochromatosis is considered to be obvious (over 80-90% of the homozygotes have biochemical or clinical signs), whereas that between H63D and hemochromatosis is much more subtle (it has been shown that the prevalence of this mutation among patients with hemochromatosis is no higher than among healthy individuals) [7]. A much rarer mutation in the HFE gene, S65C, is associated with mild forms of hemochromatosis [8].

            The prevalence of the C282Y mutation in the general population in Europe is estimated to be 9.2% (heterozygotes) and 0.4% (homozygotes). It is the highest in northwest Europe, where 1 in 8-10 (10.0-12.5%) are heterozygotes and 1 in 200-400 (0.25-0.5%) are homozygotes [4,6,8]. Heterozygotes are very common in Ireland (28.4%), Denmark (13.7%), Norway (12.8%) and Iceland (10.0%), and less common in southern Europe: Greece (2.6%), Italy (2.2%), Spain (4.5%), Turkey (0%) [9]. In the Slavic populations, prevalence differs in different populations (the former USSR 1.9%, Czech Republic 10.0%). This mutation is absent in populations outside Europe and America [9].

            The prevalence of the H63D mutation is equally high in northwest and southern European populations, where 22.0% are estimated to be heterozygotes and 2.0% are homozygotes, the highest in Spain (32.1%) and lower in Norway and the former USSR (18.0%). Apart from India, where the prevalence is reported to be 15.0%, the H63D mutation is very rare in the populations outside Europe and America [9].

            The S65C mutation is rare in the studied populations: 2.5% in France [8], 1.5% in Denmark [10], and 1.1% in the USA [11].

            The aim of this study was to determine the prevalence of HFE mutations (C282Y, H63D and S65C) in the general population of the Republic of Macedonia.

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Institute of Immunobiology and Human Genetics, Institutes of the Faculty of Medicine, University of Skopje, 1109 Skopje, Republic of Macedonia