High prevalence of a screening-detected, HFE-unrelated, mild idiopathic iron overload in Northern Italy.
OBJECTIVE
In Italy, typical HFE mutations account for only 64% of the cases with overt hereditary hemochromatosis (HH), and a common HFE-unrelated disease was hypothesized.


METHODS
One thousand and fifty potential blood donors were screened by iron tests, C282Y and H63D HFE mutation analysis in a region in North Italy. Subjects with repeated fasting transferrin saturation of 45% or more and no secondary iron overload were defined as probands with idiopathic iron overload. To assess the inheritance of iron overload, relatives of probands were screened.


RESULTS
The overall frequency of probands with idiopathic iron overload was 3.43% (95% confidence interval, 2.32 to 4.52). Of these, 8.4% had genotypes associated with HH (compound heterozygous for H63D/C282Y or homozygous for H63D HFE mutations), and 91.6% had atypical genotypes: 47.2% were heterozygous for C282Y or H63D HFE mutations, and 44.4% had wild type/wild type genotype. A family history of iron overload was proven in 33.3% of probands with atypical genotypes (1.04% of the overall population). Pedigree analysis excluded linkage of heterozygous HFE mutations with iron overload (cumulative lod score 2.41) and documented a recessive non-HLA-linked locus accounting for iron overload in wild type/wild type genotypes. None of the probands had clinical signs of iron accumulation; in males, serum ferritin positively correlated with age (r=0.63, p<0.01), and the regression model predicted a serum ferritin of 700 ng/mL at the age of 58.


CONCLUSIONS
In Northern Italy an HFE-unrelated, mild idiopathic iron overload is highly prevalent. A recessive locus accounts for iron overload in at least 1.04% of the overall population.
Barosi
Giovanni
G
Laboratorio di Informatica Medica, IRCCS Policlinico S. Matteo, p.le Golgi 3, 27100 Pavia, Italy. barosig@smatteo.pv.it
Salvaneschi
Laura
L
Grasso
Maurizia
M
Martinetti
Miryam
M
Marchetti
Monia
M
Bodini
Umberto
U
Reggiani
Alessandro
A
D'Agostino
Francesco
F
Nalli
Giulio
G
Degiuli
Alberto
A
De Silvestri
Annalisa
A
Arbustini
Eloisa
E
D000293:Adolescent; D000328:Adult; D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D005838:Genotype; D006801:Humans; D007494:Ireland / Q000453:epidemiology; D007501:Iron / Q000097:blood; D019190:Iron Overload / Q000175:diagnosis / Q000453:epidemiology* / Q000209:etiology*; D008297:Male; D008403:Mass Screening; D008875:Middle Aged; D015995:Prevalence
D007501:Iron