Screening for hemochromatosis in a population with abnormal iron status.

Iron overload is frequently associated with hereditary or secondary alterations of iron metabolism.1,2 Hereditary hemochromatosis (HH), the most common genetic disease among northern European populations, is an autosomal recessive disorder characterized by an enhanced gastrointestinal absorption of iron that leads to progressive increase of iron stores and, eventually, to multiple organ dysfunction. In 1996 a gene involved in HH pathogenesis, called HFE, was identified on the short arm of chromosome 6. Two missense mutations in the HFE gene, C282Y and H63D, were found to be responsible for most cases of HH.2,3 More recently other HFE and non-HFE mutations were discovered, allowing the number of cases of hemochromatosis defined as idiopathic to be reduced further.4,5 However, the etiology of iron overload is still unclear in many cases.6 In this study we analyzed the prevalence of C282Y and H63D mutations in a population with abnormal iron status. In addition, we evaluated the impact of 10 further mutations in the HFE and TfR2 genes on iron overload. Between October 2000 and December 2002, we tested 339 individuals with increased serum ferritin levels and/or transferrin saturation for HH gene mutations. Of these subjects 237 were male and 102 female; M/F ratio 2.3; their median age was 50.4 years, range 10-85 years; 164 were inpatients and 175 outpatients. Their mean serum ferritin level was 808.1 μg/L (range 9-5250) [normal range: 15–200 μg/L for women and 20-300 μg/L for men]. Their mean transferrin saturation was 48.9% (range 2.899%) [normal range 16-45%]. One hundred and forty-eight subjects (43.7%), analyzed between October 2000 and September 2001, were screened for the C282Y and H63D mutations in the HFE gene only. From October 2001 to December 2002, 191 individuals (56.3%) were tested for the presence of 12 mutations (C282Y, V53M, V59M, H63D, H63H, S65C, Q127H, E168Q, E168X, W169X, Q283P mutations in the HFE gene, and Y250X in the TfR2 gene). Seventy-one subjects were related and members of 23 families, the remaining 268 were unrelated. Regardless of the presence or the type of HH mutations, abnormal iron status was more frequent in men than in women (M/F ratio 2.3) and serum ferritin levels and transferrin saturation were significantly lower in women than in men (669.6 [range 11-3,823 μg/L] vs 862.5 [range 9-5,250 μg/L] μg/L for serum ferritin, p = 0.03 and 44.8 [range 2.8-90%] vs 50.0 % [range 5.8-99%] for transferrin saturation, p = 0.01). One hundred and eighty-eight of the 339 subjects (55.5%) had at least one of the analyzed HH gene mutations. One hundred and three of the 188 cases (57.5%) with a documented HH mutation also had another disease (Table 1). Among the 188 HH positive subjects, 48 (14.2%) were heterozygous for C282Y, 14 (4.1%) homozygous for C282Y, 97 (28.6%) heterozygous for H63D, 14 (4.1%) homozygous for H63D, 11 (3.3%) compound heterozygous for C282Y/H63D, 2 (0.6%) heterozygous for S65C and 2 (0.6%) homozygous for Y250X.