Haptoglobin type neither influences iron accumulation in normal subjects nor predicts clinical presentation in HFE C282Y haemochromatosis: phenotype and genotype analysis

Thorne, Kym; Bowen, Derrick John; McCune, C. Anne; Worwood, Mark

doi:10.1046/j.1365-2141.2003.04436.x

Cited by 34 publications

(27 citation statements)

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“…Considerable effort has been expended, particularly by our laboratory [52][53][54][55][56][57][58] but also by others [59][60][61][62][63][64][65][66][67] to find mutations that interact with HFE mutations to increase or decrease the penetrance. These efforts have been virtually entirely fruitless.…”

Section: Genetic Modifiers Of Hereditary Hemochromatosismentioning

confidence: 99%

Iron storage disease: Facts, fiction and progress

Beutler

2007

Blood Cells, Molecules, and Diseases

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There are many forms of iron storage disease, some hereditary and some acquired. The most common of the hereditary forms is HFE-associated hemochromatosis, and it is this disorder that is the main focus of this presentation. The body iron content is regulated by controlling absorption, and studies in the past decade have clarified, in part, how this regulation functions. A 25 amino acid peptide hepcidin is upregulated by iron and by inflammation, and it inhibits iron absorption and traps iron in macrophages by binding to and causing degradation of the iron transport protein ferroportin. Most forms of hemochromatosis results from dysregulation of hepcidin or defects of hepcidin or ferroportin themselves.Hereditary hemochromatosis was once considered to be very rare, but in the 1970s and 1980s, with the introduction of better diagnostic tests, it became to be considered the most common disease of Europeans. Controlled epidemiologic studies carried out in the last decade have shown, however, the disease itself actually is rare, and it is only the genotype and associated biochemical changes that are common. We do not understand why only a few homozygotes develop severe disease. It now seems unlikely that there are important modifying genes, and although alcohol is known to have some effect, excess drinking probably plays only a modest role in determining the hemochromatosis phenotype.Hereditary hemochromatosis is readily treated by phlebotomy. Secondary forms of the disease require chelation therapy, and the recent introduction of effective oral chelating agents is an important step forward in treating patients with disorders in which iron overload often proves to be fatal, such as thalassemia, myelodysplastic anemias, and dyserythropoietic anemias.While much has been learned about the regulation of iron homeostasis in the past decade, many mysteries remain and represent challenges that will keep us occupied for years to come.It is a great honor for me to present this lecture in memory of my good friend Bracha Ramot. It is because this lecture is in honor of Bracha that I do not feel the least bit uncomfortable speaking about iron storage diseases in a symposium entitled "Genomics and Molecular Biology of Hematopoietic Malignancies". I know that had it been possible to ask her whether this might be appropriate Bracha would have said: "Of course, Ernie. Talk about whatever you want to". That was her way. And, of course, Bracha was no stranger to iron metabolism. She was scientifically broad, a Renaissance hematologist. A MEDLINE search reveals 261 publications by Bracha and eight of those deal with iron --iron in thalassemia, iron in sideroblastic anemia, and iron in iron deficiency anemia.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable...

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Section: Genetic Modifiers Of Hereditary Hemochromatosismentioning

confidence: 99%

Iron storage disease: Facts, fiction and progress

Beutler

2007

Blood Cells, Molecules, and Diseases

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“…28,29 In general, the modifier effect of iron genes has been documented in mice, [30][31][32] and these findings have not been fully confirmed in humans. [33][34][35][36][37] Debate continues over the roles of a fatty liver, a high body mass index, 38,39 and polymorphic changes in oxidative stress-related genes, 40 but there is evidence for a strong association between alcohol and the development of hemochromatosis-related cirrhosis. 41 The existence of nongenetic hepcidin inhibitors (alcohol may be one of many) raises the possibility of purely acquired forms of hemochromatosis (according to the scheme proposed in Fig.…”

Section: Clinical Aspectsmentioning

confidence: 99%

Hemochromatosis: An endocrine liver disease

2007

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This review acknowledges the recent and dramatic advancement in the field of hemochromatosis and highlights the surprising analogies with a prototypic endocrine disease, diabetes. The term hemochromatosis should refer to a unique clinicopathologic subset of ironoverload syndromes that currently includes the disorder related to the C282Y homozygote mutation of the hemochromatosis protein HFE (by far the most common form of hemochromatosis) and the rare disorders more recently attributed to the loss of transferrin receptor 2, HAMP (hepcidin antimicrobial peptide), or hemojuvelin or to certain ferroportin mutations. The defining characteristic of this subset is failure to prevent unneeded iron from entering the circulatory pool as a result of genetic changes compromising the synthesis or activity of hepcidin, the iron hormone. Like diabetes, hemochromatosis results from the complex, nonlinear interaction between genetic and acquired factors. Depending on the underlying mutation, the coinheritance of modifier genes, the presence of nongenetic hepcidin inhibitors, and other host-related factors, the clinical manifestation may vary from simple biochemical abnormalities to severe multiorgan disease. The recognition of the endocrine nature of hemochromatosis suggests intriguing possibilities for new and more effective approaches to diagnosis and treatment. (HEPATOLOGY 2007;46:1291-1301

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“…Other genes may modify the phenotype involved in haemochromatosis. It was found by Langlois et al (200) that men with the 2-2 haplotype for haptoglobin had a higher serum ferritin concentration than those with HP 1-1 or 2-1 but others have not confirmed this finding (201)(202)(203). Until now, no mutations in genes coding for iron transport or storage have been linked to iron deficiency.…”

Section: Genes Modifying Iron Statusmentioning

confidence: 83%