New insights into iron homeostasis through the study of non-HFE hereditary haemo-chromatosis. Best Pract Res Clin Haematol
Non-HFE haemochromatosis is a negative definition applied to all those haemochromatosis disorders that are unrelated to HFE mutations. Four genes are responsible for the distinct types of non-HFE haemochromatosis: hepcidin and hemojuvelin are the genes involved in type 2 or juvenile haemochromatosis, transferrin receptor 2 is involved in type 3 haemochromatosis, and ferroportin 1 is mutated in type 4, the atypical dominant form of primary iron overload. Molecular genetic studies of these conditions have greatly contributed to our understanding of the regulation of iron absorption. A milestone was the discovery that hepcidin, the key iron regulator in mice, is the gene mutated in the most severe, juvenile form of haemochromatosis. This finding indicates a fundamental role of hepcidin in inhibiting both iron absorption from duodenal cells and iron release from macrophages, and has opened up a new view of haemochromatosis as a disorder of hepcidin.
Available from: Etheresia Pretorius
- "The genes linked to HH cause disruption of the mechanisms that regulate iron absorption, leading to progressive increase of total body iron and organ damage . Therefore, HH is indicative of disruption of the HFE gene product, as well as commonly (but not inevitably) a persistent elevation of serum ferritin concentration , . Here we also classify hyperferritinemia (HF) as occurring in individuals with high serum ferritin levels (higher than 200 ng/mL−1 for females and 300 ng/mL−1 for males) but not with the genetic mutation in the HFE gene (these individuals were tested for all combinations of the C282Y, H63D as well as S65C mutations, and found to be wild type for these mutations). "
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ABSTRACT: It is well-known that individuals with increased iron levels are more prone to thrombotic diseases, mainly due to the presence of unliganded iron, and thereby the increased production of hydroxyl radicals. It is also known that erythrocytes (RBCs) may play an important role during thrombotic events. Therefore the purpose of the current study was to assess whether RBCs had an altered morphology in individuals with hereditary hemochromatosis (HH), as well as some who displayed hyperferritinemia (HF). Using scanning electron microscopy, we also assessed means by which the RBC and fibrin morphology might be normalized. An important objective was to test the hypothesis that the altered RBC morphology was due to the presence of excess unliganded iron by removing it through chelation. Very striking differences were observed, in that the erythrocytes from HH and HF individuals were distorted and had a much greater axial ratio compared to that accompanying the discoid appearance seen in the normal samples. The response to thrombin, and the appearance of a platelet-rich plasma smear, were also markedly different. These differences could largely be reversed by the iron chelator desferal and to some degree by the iron chelator clioquinol, or by the free radical trapping agents salicylate or selenite (that may themselves also be iron chelators). These findings are consistent with the view that the aberrant morphology of the HH and HF erythrocytes is caused, at least in part, by unliganded ('free') iron, whether derived directly via raised ferritin levels or otherwise, and that lowering it or affecting the consequences of its action may be of therapeutic benefit. The findings also bear on the question of the extent to which accepting blood donations from HH individuals may be desirable or otherwise.
Available from: sciencedirect.com
- "Most JH families have mutations in the recently cloned hemojuvelin (HJV) gene (reviewed in ). For a very small subset of patients, mutations have been identified in hepcidin (HAMP), which encodes a small circulating 25-amino- acid cysteine-rich peptide that constitutes the master regulator of iron homeostasis (reviewed in ). The circulating peptide acts to limit gastrointestinal iron absorption and serum iron by inhibiting dietary intestinal iron absorption and iron recycling by the macrophages . "
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ABSTRACT: Diabetes Mellitus is found with increasing frequency in iron overload patients with hemochromatosis. In these conditions, the pancreas shows predominant iron overload in acini but also islet beta-cells. We assess glucose homeostasis status in iron-overloaded hepcidin-deficient mice. These mice presented with heavy pancreatic iron deposits but only in the acini. The beta-cell function was found unaffected with a normal production and secretion of insulin. The mutant mice were not diabetic, responded as the control group to glucose and insulin challenges, with no alteration of insulin signalling in the muscle and the liver. These results indicate that, beta-cells iron deposits-induced decreased insulin secretory capacity might be of primary importance to trigger diabetes in hemochromatosic patients.
Available from: Elvar Theodorsson
- "A number of recent review articles summarize the biological and possible diagnostic and therapeutic roles of hepcidin, e.g.        . "
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