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Scientific research is an important part of our mission to promote public awareness about hereditary hemochromatosis and to provide valuable information to patients and physicians. Patients can access research on the diagnosis and treatment of hemochromatosis. Physicians, scientists or other professionals can access a wealth of in-depth resources in our research section.

Select the Full Text link below to view research published in respected medical journals on hemochromatosis and related conditions. These articles are intended to help you understand the latest research. The information provided is not a substitute for advice from your doctor or other health care provider and the Hemochromatosis Information Society is not responsible for any content contained in or available through these documents.

Hemochromatosis Patients as Voluntary Blood Donors
  Canadian Journal of Gastroenterology
Volume 18 (2004), Issue 6, Pages 393-396
  Abstract Full Text
The present study was designed to investigate hemochromatosis patients’ suitability as blood donors as well as their perceptions and experience with the current public donation system. Participants were gathered from a list of current hemochromatosis patients (n=120) and members of the Canadian Hemochromatosis Society (n=1000). Of the 1120 surveys mailed out to these groups, 801 surveys were returned completed. The sample respondents had a mean age of 57.44 years (SD=12.73; range 19 to 87 years), and 57% were men. It was found that 20% (160) of the respondents have donated blood since their diagnosis; however, only 12% of the respondents indicated that they use voluntary blood donation as a means of maintaining their iron levels. Forty per cent of the respondents indicated that they had been refused from voluntary donation. Despite the fact that in May 2001 the Canadian Blood Services, in collaboration with the Canadian Hemochromatosis Society, began a promotion campaign to encourage hemochromatosis patients to become voluntary blood donors, the present study found that 15% of the respondents reported having been refused from the voluntary blood donation service due to the diagnosis of hemochromatosis. With respect to quality of life, it was found that individuals who donate blood were generally healthier with respect to physical functioning and bodily pain, however, these findings may indicate that hemochromatosis patients who are healthier are better able to donate at public blood banks, rather than that voluntary blood donation has an effect on the donors’ physical functioning over phlebotomy clinic users. These study findings suggest that although there may be other medical factors limiting individuals from donating, hemochromatosis patients are interested in being voluntary blood donors and this potential resource is currently under-used.
Citation Tara E Power and Paul C Adams, “Hemochromatosis Patients as Voluntary Blood Donors,” Canadian Journal of Gastroenterology, vol. 18, no. 6, pp. 393-396, 2004. doi:10.1155/2004/767529
A Multi-Scale Model of Hepcidin Promoter Regulation Reveals Factors Controlling Systemic Iron Homeostasis
  PLoS Computational Biology
Volume 10 (2014), Issue 1, e1003421
  Abstract Full Text
Systemic iron homeostasis involves a negative feedback circuit in which the expression level of the peptide hormone hepcidin depends on and controls the iron blood levels. Hepcidin expression is regulated by the BMP6/SMAD and IL6/STAT signaling cascades. Deregulation of either pathway causes iron-related diseases such as hemochromatosis or anemia of inflammation. We quantitatively analyzed how BMP6 and IL6 control hepcidin expression. Transcription factor (TF) phosphorylation and reporter gene expression were measured under co-stimulation conditions, and the promoter was perturbed by mutagenesis. Using mathematical modeling, we systematically analyzed potential mechanisms of cooperative and competitive promoter regulation by the transcription factors, and experimentally validated the model predictions. Our results reveal that hepcidin cross-regulation primarily occurs by combinatorial transcription factor binding to the promoter, whereas signaling crosstalk is insignificant. We find that the presence of two BMP-responsive elements enhances the steepness of the promoter response towards the iron-sensing BMP signaling axis, which promotes iron homeostasis in vivo. IL6 co-stimulation reduces the promoter sensitivity towards the BMP signal, because the SMAD and STAT transcription factors compete for recruiting RNA polymerase to the transcription start site. This may explain why inflammatory signals disturb iron homeostasis in anemia of inflammation. Taken together, our results reveal why the iron homeostasis circuit is sensitive to perturbations implicated in disease.
Citation Casanovas, Guillem, et al. “A Multi-Scale Model of Hepcidin Promoter Regulation Reveals Factors Controlling Systemic Iron Homeostasis.” PLoS Computational Biology, vol. 10, no. 1, Feb. 2014, doi:10.1371/journal.pcbi.1003421.
Autoimmune Conditions in 235 Hemochromatosis Probands with HFE C282Y Homozygosity and Their First-Degree Relatives
  Journal of Immunology Research
Volume 2015 (2015), Article ID 453046, 11 pages
  Abstract Full Text
We performed a retrospective study of autoimmune conditions (ACs) in 235 hemochromatosis probands at diagnosis by analyzing age, sex, ACs, history of first-degree family members with ACs (FH), diabetes, heavy ethanol consumption, elevated serum ALT/AST, nonalcoholic fatty liver disease, viral hepatitis, cirrhosis, iron removed to achieve iron depletion (QFe), and positivity for human leukocyte antigen (HLA) haplotypes A∗01, B∗08; A∗02, B∗44; A∗03, B∗07; A∗03, B∗14; and A∗29, B∗44. There were 138 men (58.7%). Median follow-up was 19.6 y. One or more of 19 ACs were diagnosed in each of 35 probands (14.9%). Prevalences of Hashimoto’s thyroiditis, rheumatoid arthritis, and ankylosing spondylitis were 8.1% (95% CI: [5.1, 12.5]), 1.7% [0.6, 4.6], and 0.0085 [0.0015, 0.0337], respectively. Eighteen probands (7.7%) had a FH. Eight probands with ACs had 9 family members with ACs. In a logistic regression, ACs were less likely in men (odds ratio (OR) 0.3 [0.1, 0.6]) and more likely in probands with a FH (OR 4.1 [1.4, 11.8]). Overall ACs risk was not significantly associated with QFe or HLA haplotypes. Estimated survival of probands with and without ACs did not differ significantly. We conclude that ACs are common in hemochromatosis probands, especially women and probands with a FH.
Citation James C. Barton and J. Clayborn Barton, “Autoimmune Conditions in 235 Hemochromatosis Probands with HFE C282Y Homozygosity and Their First-Degree Relatives,” Journal of Immunology Research, vol. 2015, Article ID 453046, 11 pages, 2015. doi:10.1155/2015/453046
Hemochromatosis (HFE) gene mutations in Brazilian chronic hemodialysis patients
  Brazilian Journal of Medical and Biological Research
Volume 38 (2015), Issue 9, Pages 1321-1324
  Abstract Full Text
Patients with chronic renal insufficiency (CRI) have reduced hemoglobin levels, mostly as a result of decreased kidney production of erythropoietin, but the relation between renal insufficiency and the magnitude of hemoglobin reduction has not been well defined. Hereditary hemochromatosis is an inherited disorder of iron metabolism. The importance of the association of hemochromatosis with treatment for anemia among patients with CRI has not been well described. We analyzed the frequency of the C282Y and H63D mutations in the HFE gene in 201 Brazilian individuals with CRI undergoing hemodialysis. The analysis of the effects of HFE mutations on iron metabolism and anemia with biochemical parameters was possible in 118 patients of this study (hemoglobin, hematocrit, ferritin levels, transferrin saturation, and serum iron). A C282Y heterozygous mutation was found in 7/201 (3.4%) and H63D homozygous and heterozygous mutation were found in 2/201 (1.0%) and 46/201 (22.9%), respectively. The allelic frequencies of the HFE mutations (0.017 for C282Y mutation and 0.124 for H63D mutation) did not differ between patients with CRI and healthy controls. Regarding the biochemical parameters, no differences were observed between HFE heterozygous and mutation-negative patients, although ferritin levels were not higher among patients with the H63D mutation (P = 0.08). From what we observed in our study, C282Y/H63D HFE gene mutations are not related to degrees of anemia or iron stores in CRI patients receiving intravenous iron supplementation (P > 0.10). Nevertheless, the present data suggest that the H63D mutation may have an important function as a modulating factor of iron overload in these patients.
Citation Perícole, F.V., Alves, M.A.V.R., Saad, S.T.O., & Costa, F.F.. (2005). Hemochromatosis (HFE) gene mutations in Brazilian chronic hemodialysis patients. Brazilian Journal of Medical and Biological Research, 38(9), 1321-1324.
A novel immunological assay for hepcidin quantification in human serum
Volume 4 (2009), Issue 2, e4581
  Abstract Full Text
Hepcidin is a 25-aminoacid cysteine-rich iron regulating peptide. Increased hepcidin concentrations lead to iron sequestration in macrophages, contributing to the pathogenesis of anaemia of chronic disease whereas decreased hepcidin is observed in iron deficiency and primary iron overload diseases such as hereditary hemochromatosis. Hepcidin quantification in human blood or urine may provide further insights for the pathogenesis of disorders of iron homeostasis and might prove a valuable tool for clinicians for the differential diagnosis of anaemia. This study describes a specific and non-operator demanding immunoassay for hepcidin quantification in human sera.
Citation Koliaraki V, Marinou M, Vassilakopoulos TP, Vavourakis E, Tsochatzis E, et al. (2009) A Novel Immunological Assay for Hepcidin Quantification in Human Serum. PLOS ONE 4(2): e4581.
The role of hepatic transferrin receptor 2 in the regulation of iron homeostasis in the body
  Frontiers in Pharmacology
Volume 5 (2014), Article 34, 8 pages
  Abstract Full Text
Fine-tuning of body iron is required to prevent diseases such as iron-overload and anemia. The putative iron sensor, transferrin receptor 2 (TfR2), is expressed in the liver and mutations in this protein result in the iron-overload disease Type III hereditary hemochromatosis (HH). With the loss of functional TfR2, the liver produces about 2-fold less of the peptide hormone hepcidin, which is responsible for negatively regulating iron uptake from the diet. This reduction in hepcidin expression leads to the slow accumulation of iron in the liver, heart, joints, and pancreas and subsequent cirrhosis, heart disease, arthritis, and diabetes. TfR2 can bind iron-loaded transferrin (Tf) in the bloodstream, and hepatocytes treated with Tf respond with a 2-fold increase in hepcidin expression through stimulation of the bone morphogenetic protein (BMP)-signaling pathway. Loss of functional TfR2 or its binding partner, the original HH protein, results in a loss of this transferrin-sensitivity. While much is known about the trafficking and regulation of TfR2, the mechanism of its transferrin-sensitivity through the BMP-signaling pathway is still not known.
Citation Worthen, Christal A., and Caroline A. Enns. “The Role of Hepatic Transferrin Receptor 2 in the Regulation of Iron Homeostasis in the Body.” Frontiers in Pharmacology, vol. 5, June 2014, doi:10.3389/fphar.2014.00034.
Dietary Iron Intake and Serum Ferritin Concentration in 213 Patients Homozygous for the HFEC282Y Hemochromatosis Mutation
  Canadian Journal of Gastroenterology
Volume 26 (2012), Issue 6, Pages 345-349
  Abstract Full Text
BACKGROUND: HFEC282Y homozygotes have an increased risk for developing increased iron stores and related disorders. It is controversial whether dietary iron restrictions should be recommended to such individuals.OBJECTIVE: To determine whether dietary iron content influences iron stores in HFEC282Y homozygotes as assessed by serum ferritin concentration.DESIGN: Serum ferritin concentration was measured and a dietary iron questionnaire was completed as part of the evaluation of 213 HFEC282Y homozygotes who were identified through screening of >100,000 primary care patients at five Hemochromatosis and Iron Overload Screening (HEIRS) Study Field Centers in the United States and Canada.

RESULTS: No significant relationships between serum ferritin concentration and dietary heme iron content, dietary nonheme iron content or reports of supplemental iron use were found.

CONCLUSION: These results do not support recommending dietary heme or nonheme iron restrictions for HFEC282Y homozygotes diagnosed through screening in North America.

Citation Victor R Gordeuk, Laura Lovato, James C Barton, et al., “Dietary Iron Intake and Serum Ferritin Concentration in 213 Patients Homozygous for the HFEC282Y Hemochromatosis Mutation,” Canadian Journal of Gastroenterology, vol. 26, no. 6, pp. 345-349, 2012. doi:10.1155/2012/676824
Effects of highly conserved major histocompatibility complex (MHC) extended haplotypes on iron and low CD8+ T lymphocyte phenotypes in HFE C282Y homozygous hemochromatosis patients from three geographically distant areas.
Volume 8 (2013), Issue 11, e79990
  Abstract Full Text
Hereditary Hemochromatosis (HH) is a recessively inherited disorder of iron overload occurring commonly in subjects homozygous for the C282Y mutation in HFE gene localized on chromosome 6p21.3 in linkage disequilibrium with the human leukocyte antigen (HLA)-A locus. Although its genetic homogeneity, the phenotypic expression is variable suggesting the presence of modifying factors. One such genetic factor, a SNP microhaplotype named A-A-T, was recently found to be associated with a more severe phenotype and also with low CD8(+)T-lymphocyte numbers. The present study aimed to test whether the predictive value of the A-A-T microhaplotype remained in other population settings. In this study of 304 HH patients from 3 geographically distant populations (Porto, Portugal 65; Alabama, USA 57; Nord-Trøndelag, Norway 182), the extended haplotypes involving A-A-T were studied in 608 chromosomes and the CD8(+) T-lymphocyte numbers were determined in all subjects. Patients from Porto had a more severe phenotype than those from other settings. Patients with A-A-T seemed on average to have greater iron stores (p = 0.021), but significant differences were not confirmed in the 3 separate populations. Low CD8(+) T-lymphocytes were associated with HLA-A*03-A-A-T in Porto and Alabama patients but not in the greater series from Nord-Trøndelag. Although A-A-T may signal a more severe iron phenotype, this study was unable to prove such an association in all population settings, precluding its use as a universal predictive marker of iron overload in HH. Interestingly, the association between A-A-T and CD8(+) T-lymphocytes, which was confirmed in Porto and Alabama patients, was not observed in Nord-Trøndelag patients, showing that common HLA haplotypes like A*01-B*08 or A*03-B*07 segregating with HFE/C282Y in the three populations may carry different messages. These findings further strengthen the relevance of HH as a good disease model to search for novel candidate loci associated with the genetic transmission of CD8(+) T-lymphocyte numbers.
Citation Costa M, Cruz E, Barton JC, Thorstensen K, Morais S, et al. (2013) Effects of Highly Conserved Major Histocompatibility Complex (MHC) Extended Haplotypes on Iron and Low CD8+ T Lymphocyte Phenotypes in HFE C282Y Homozygous Hemochromatosis Patients from Three Geographically Distant Areas. PLOS ONE 8(11): e79990.






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