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Inadequate hepcidin synthesis leads to iron overload in HFE-related hemochromatosis. We explored the regulation of hepcidin by iron in 88 hemochromatosis patients (61 C282Y/C282Y, 27 C282Y/H63D) and 23 healthy controls by analyzing urinary hepcidin before and 24 hours after a 65-mg oral iron dose. Thirty-four patients were studied at diagnosis and had iron overload, and 54 patients were iron depleted. At diagnosis, hepcidin values in C282Y homozygotes were similar to controls, whereas values in C282Y/ H63D heterozygotes were higher (P ‫؍‬ .02).However, the hepcidin/ferritin ratio was decreased in both homozygotes (P < .001) and heterozygotes (P ‫؍‬ .017), confirming the inadequate hepcidin production for the iron load with both genotypes. In iron-depleted patients of both genotypes studied at a time remote from phlebotomy, basal hepcidin was still lower than in controls (P < .001 for C282Y/C282Y and P ‫؍‬ .002 for heterozygotes). After an iron challenge, mean urinary hepcidin excretion increased in controls (P ‫؍‬ .001) but not patients, irrespective of genotype and iron status. Significant hepcidin increase ( > 10 ng/mg creatinine) was observed in 74% of controls, 15% of homozygotes, and 32% of heterozygotes. The hepcidin response to oral iron is blunted in HFE IntroductionHereditary hemochromatosis (HH) is an autosomal recessive disorder of systemic iron regulation in which dietary iron absorption is inappropriately high. In some patients this may lead to progressive iron loading and damage to the liver and other parenchymal organs. Most patients of Northern European ancestry are homozygous for the C282Y mutation of the HFE gene, and a minority are compound heterozygotes for the C282Y/H63D mutations. Other HFE or other gene mutations are rare 1 . Newly available molecular tests have made it possible to accelerate the diagnosis to a preclinical stage and avoid the need for liver biopsy. In the preclinical stage, most patients display only alterations of iron parameters and/or of liver function tests. 2 Although the C282Y/C282Y genotype is frequent, the clinical disease is relatively uncommon, and its natural history is not well defined. Disease expression may be influenced by age, sex, environmental, and genetic modifiers. [3][4][5] No progression to clinical disease was reported in 2 prospective studies on a small number of C282Y homozygotes followed up for 17 and 25 years, respectively. 6,7 These observations suggest that among subjects with at-risk genotypes, only a subgroup develop enough iron overload to induce clinical complications. Since it is not feasible to predict the outcome of patients based only on blood iron studies, it is common clinical practice that all HFE mutated individuals with altered iron parameters undergo iron depletion by phlebotomy.Iron overload in all genetic types of hemochromatosis, except those due to ferroportin mutations, is explained by the insufficiency of the hepatic peptide hepcidin, 8 the key regulator of systemic iron homeostasis. Hepcidin binds to the iron exporter ferr...

Low plasma PLP concentrations are inversely related to major markers of inflammation and independently associated with increased CAD risk.

Summary. Hereditary hyperferritinaemia±cataract syndrome (HHCS) is an autosomal dominant disease caused by mutations in the iron responsive element (IRE) of the lferritin gene. Despite the elucidation of the genetic basis, the overall clinical spectrum of HHCS has been less well studied as, to date, only individual case reports have been described. Therefore, we studied a total of 62 patients in 14 unrelated families, with nine different mutations. No relevant symptoms other than visual impairment were found to be associated with the syndrome. A marked phenotypic variability was observed, particularly with regard to ocular involvement (i.e. age range at which cataract was diagnosed in 16 subjects with the C39T: 6±40 years). Similarly, serum ferritin levels varied substantially also within subjects sharing the same mutation (i.e. range for the A40G: 700± 2412 mg/l). We followed an HHCS newborn in whom welldefined lens opacities were not detectable either at birth or at 1 year. The lens ferritin content was analysed in two subjects who underwent cataract surgery at different ages, with different cataract morphology. Values were similar and about 1500-fold higher than in controls. These observations suggest that: (i) in HHCS the cataract is not necessarily congenital; (ii) in addition to the IRE genotype, other genetic or environmental factors may modulate the phenotype, especially the severity of the cataract.

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