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PubMed1997

A genetic defect of an iron pump on chromosome 20 is postulated to cause human hemochromatosis.

Hemochromatosis is postulated to be caused by a heterozygous or homozygous defect of a gene on the short arm of the human chromosome 20 coding for an ubiquitous iron carrier membrane protein responsible for transporting iron ions out of cells. This iron pump would be very important to stabilize the membrane potential and to avoid excessive intracellular storage of iron with the consequence of damage to cells by lipid peroxidation of membranes.

Chromosomes, Human, Pair 20↗
PubMed2000

Bacteremic cellulitis caused by Non-01, Non-0139 Vibrio cholerae: report of a case in a patient with hemochromatosis.

We report a case of bacteremia associated with hemorrhagic bullous skin lesions on the leg caused by non-01, non-0139 Vibrio cholerae in a 66-year-old man with hemochromatosis developed in an inland region. The organism was isolated from blood and bullae fluid. The patient was treated successfully with cefotaxime and doxycycline. This report emphasizes the potential of this organism to produce bacteremic cellulitis in people with underlying illness in the absence of usual epidemiological risk factors.

Aged↗
PubMed2002

Association between increased iron stores and impaired endothelial function in patients with hereditary hemochromatosis.

OBJECTIVES: We studied associations between iron status and early functional and structural vascular abnormalities in patients with hereditary hemochromatosis (HH). BACKGROUND: Iron may be involved in atherogenesis, and patients bearing a genetic mutation associated with HH are possibly at risk of developing coronary heart disease. METHODS: We studied the vascular properties of 41 HH patients who had homozygosity for the C282Y mutation, along with 51 age-matched control subjects, by determination of endothelium-dependent dilation (EDD) of the brachial artery and intima-media thickness (IMT) of the carotid artery. RESULTS: Male HH patients who were not receiving phlebotomy therapy showed a reduced EDD and increased IMT compared with controls and HH patients receiving therapy. In female HH patients, irrespective of treatment status, vascular parameters were not different from those of controls, and none of these patients had severe iron overload. In HH patients, increased iron load was significantly associated with reduced EDD and increased IMT. Moreover, we found a positive correlation between body iron stores and indicators of oxidative stress. When previously untreated male HH patients were re-investigated after intensive phlebotomy therapy, a significant improvement in EDD was observed (2.6 +/- 1.3% before vs. 5.5 +/- 2.1% after treatment, p = 0.0015). CONCLUSIONS: Impaired endothelial function and increased IMT are associated with iron overload, with subsequent induction of oxidative stress, and are not linked to a genetic disability in HH patients. Consequent iron-depletion therapy normalizes endothelial function and may thus reduce the increased risk of cardiovascular events. Female patients may be at a reduced risk, presumably due to continuous iron loss by menstruation.

Adult↗
PubMed1992

Physical and genetic mapping of the telomeric major histocompatibility complex region in man and relevance to the primary hemochromatosis gene (HFE).

We performed pulsed-field gel electrophoresis (PFGE) on genomic DNA from a radiation hybrid (RH) cell line and constructed a high-resolution physical map of the major histocompatibility complex class I region in 6p21.3, where the gene for primary hemochromatosis (HFE) is believed to be located. Due to the intact microsegment of hemizygous human genomic DNA preserved in the RH cell line, simplified and distinct restriction fragment banding patterns were generated. Using the RH cell line, we were able to extend the physical map of the HLA class I region to about 3000 kb, order the known HLA class I genes from centromere to telomere: HLA-B, -C, -E, (-A, -H, -G), and -F, and orient the HLA-F gene along the chromosome. The proximity of HLA-F to HLA-A was confirmed by linkage and linkage disequilibrium analysis. This study shows that RH cell lines can be useful for constructing long-range physical maps in specific regions of the human genome with PFGE. Physical and genetic mapping studies of this region are consistent with a localization of the HFE gene proximal or distal to HLA-A.

Animals↗
PubMed2001

Cardiac transplantation in a patient with hereditary hemochromatosis: role of adjunctive phlebotomy and erythropoietin.

We describe the case of a 36-year-old woman with hereditary hemochromatosis (HH) resulting in end-stage cardiomyopathy and treated successfully with orthotopic cardiac transplantation. Before and after transplantation, the patient underwent aggressive treatment with frequent phlebotomy. We used erythropoietin concomitantly to maintain adequate hematocrit to support continued phlebotomy. We believe that aggressive use of phlebotomy provided the patient hemodynamic benefit and hastened the return of endocrine function post-transplantation. We also believe that the patient's history of high-dose vitamin C usage may have accelerated iron deposition in the heart and other vital organs.

Adult↗
PubMed2000

Hemochromatosis.

The recent cloning of the hemochromatosis gene (HFE) and the demonstration that a single missense mutation is responsible for 90% or more of patients with the disease, have stimulated renewed interest in all aspects of this common disease. The molecular tests for identifying mutations in HFE provide improved means for diagnosis, family screening, and population screening. Moreover, the elucidation of the role of the HFE gene product will provide new insights into the regulation of normal iron absorption and iron metabolism. In addition, it is now apparent that iron, even in the modest tissue concentrations, can act as a co-factor in potentiating cell injury in other liver diseases.

Combined Modality Therapy↗
PubMed1999

Screening for hereditary hemochromatosis: are DNA-based tests the answer?

Universal screening for hereditary hemochromatosis (HH) has been proposed by many experts, with understandable enthusiasm: HH can cause fatal complications, which are preventable with early treatment. The disorder involves excess iron accumulation that can result in tissue iron overload, with secondary cirrhosis, diabetes, heart failure, impotence and arthritis. These complications are preceded by years of iron accumulation, and most are believed to be preventable by removal of excess iron by phlebotomy. Thus, early identification and treatment - the quintessential functions of health screening - seem to make sense for HH. However, the available screening tests are imperfect. While they can identify many persons at increased risk from HH, the proportion that will develop serious clinical manifestations related to iron overload is not known with certainty. DNA-based tests do not provide a simple resolution to these questions.

Genetic Testing↗
PubMed2003

Increased susceptibility to nonalcoholic fatty liver disease in heterozygotes for the mutation responsible for hereditary hemochromatosis.

BACKGROUND: Insulin resistance is a key feature of nonalcoholic fatty liver disease. Patients with hereditary hemochromatosis, a disease characterized by progressive iron overload due, in most cases, to homozygosity for C282Y mutation in the HFE gene, have often decreased insulin sensitivity and release. AIMS: To determine whether increased iron parameters/heterozygosity for the mutations of the HFE gene confer susceptibility to nonalcoholic fatty liver disease. PATIENTS: One hundred and thirty-four consecutive Italian patients with clinical and ultrasonographic diagnosis of nonalcoholic fatty liver disease (82 with hyperferritinemia), half confirmed by liver biopsy. METHODS: Insulin was determined by radioimmunoassay. HFE gene mutations were determined by polymerase chain reaction and restriction fragment length polymorphism analysis. RESULTS: (1) Prevalence of C282Y HFE mutation was significantly higher in patients with nonalcoholic fatty liver disease compared to controls, the difference being more striking in patients with hyperferritinemia than in those without. (2) The presence of mild iron overload was associated with a lower insulin release. (3) Carriers of C282Y mutation developed nonalcoholic fatty liver disease despite lower body mass index and triglycerides. CONCLUSION: The mild iron overload associated with heterozygosity for C282Y HFE mutation confers susceptibility to nonalcoholic fatty liver disease, causing relative insulin deficiency.

Adult↗
PubMed2003

Human platelets express hemochromatosis protein (HFE) and transferrin receptor 2.

OBJECTIVES: While body iron status may influence platelets, little information is available about platelet expression of proteins regulating iron homeostasis. HFE, the protein defective in hereditary hemochromatosis, and transferrin receptor 2 (TfR2) are two novel protein candidates that could be involved in mechanisms of iron transport across the platelet plasma membrane. METHODS: The expression and localization of HFE, TfR1 and TfR2 proteins in human platelets were examined using Western blotting and immunocytochemistry. RESULTS: Human platelets expressed HFE and TfR2, whereas no signal for TfR1 was found. The positive reactions for HFE and TfR2 were mainly confined to the platelet plasma membrane. CONCLUSIONS: Expression of HFE and TfR2 proteins in human platelets may indicate that the mutations in the corresponding genes could influence platelet count, size and/or activation. The presence of TfR2 and absence of TfR1 suggests that HFE may serve a different function in platelets compared with the other HFE-positive cell types, e.g. enterocytes, macrophages and syncytiotrophoblasts.

Blood Platelets↗
PubMed2000

Heterozygosity for the hemochromatosis gene in liver diseases--prevalence and effects on liver histology.

BACKGROUND/AIMS: The effect of heterozygosity for the C282Y mutation in the HFE hemochromatosis gene on iron accumulation and disease progression in liver disease patients is unclear. METHODS: We investigated the prevalence of this mutation in 531 patients and 205 healthy controls. In addition, we assessed the influence of the mutation on liver histology in 34 C282Y heterozygous and 124 age-, sex- and disease-matched controls without the mutation using the modified HAI and Chevallier score. RESULTS: The highest prevalence of the C282Y mutation was observed in patients with autoimmune hepatitis (17.2%, p<0.01) compared to 6.4% in healthy controls. Heterozygotes with hepatitis C and B virus infection showed higher ferritin and hepatic iron concentrations than patients without the mutation. However, we did not detect significant differences in necroinflammatory or fibrosis scores between carriers of the mutation and controls. CONCLUSIONS: There are marked differences in the prevalence of the C282Y mutation in patients with different liver diseases, with the highest prevalence rates in autoimmune hepatitis and PBC. However, the C282Y mutation alone only leads to a mild increase in iron accumulation in the majority of the patients, with the exception of H63D/C282Y compound heterozygotes. We found no evidence for more pronounced fibrosis in C282Y heterozygotes.

Adult↗
PubMed2004

Mechanisms of disease: The role of hepcidin in iron homeostasis--implications for hemochromatosis and other disorders.

The defensin-like circulatory peptide hepcidin is the iron-regulatory hormone that links innate immunity and iron metabolism. In response to inflammatory stimuli, the liver produces hepcidin: this antimicrobial peptide then limits the iron that is vital to invading pathogens, by decreasing iron release/transfer from enterocytes and macrophages and causing secondary hypoferremia. This may lead, however, to reduced iron availability for erythropoiesis and therefore to anemia (and anemia of chronic disease). When iron is scarce, the rate at which it is released into the bloodstream must be enhanced: indeed, iron starvation and hypoxia readily abrogate hepcidin expression. Conversely, if excess iron enters the circulation, hepcidin transcription is turned on and iron release from the intestine and macrophages abrogated. Circumstantial evidence indicates that the effect of circulatory iron on hepcidin requires functional HFE and hemojuvelin, two proteins of unknown function that have recently been linked to human hereditary hemochromatosis. In this disease it is likely that inadequate levels of circulating hepcidin lead to the uncontrolled release of iron from the intestine and macrophages, followed by tissue iron overload and organ damage. Given its role as the iron-regulatory hormone, the modulation of hepcidin activity using agonists or antagonists might offer new treatment opportunities in different human iron-dependent disorders.

Antimicrobial Cationic Peptides↗
PubMed2005

The hemochromatosis C282Y allele: a risk factor for hepatic veno-occlusive disease after hematopoietic stem cell transplantation.

Hepatic veno-occlusive disease (HVOD) is a serious complication of hematopoietic stem cell transplantation (HSCT). Since the liver is a major site of iron deposition in HFE-associated hemochromatosis, and iron has oxidative toxicity, we hypothesized that HFE genotype might influence the risk of HVOD after myeloablative HSCT. We determined HFE genotypes in 166 HSCT recipients who were evaluated prospectively for HVOD. We also tested whether a common variant of the rate-limiting urea cycle enzyme, carbamyl-phosphate synthetase (CPS), previously observed to protect against HVOD in this cohort, modified the effect of HFE genotype. Risk of HVOD was significantly higher in carriers of at least one C282Y allele (RR=3.7, 95% CI 1.2-12.1) and increased progressively with C282Y allelic dose (RR=1.7, 95% CI 0.4-6.8 in heterozygotes; RR=8.6, 95% CI 1.5-48.5 in homozygotes). The CPS A allele, which encodes a more efficient urea cycle enzyme, reduced the risk of HVOD associated with HFE C282Y. We conclude that HFE C282Y is a risk factor for HVOD and that CPS polymorphisms may counteract its adverse effects. Knowledge of these genotypes and monitoring of iron stores may facilitate risk-stratification and testing of strategies to prevent HVOD, such as iron chelation and pharmacologic support of the urea cycle.

Adult↗
PubMed1997

The effect of withdrawal of food iron fortification in Sweden as studied with phlebotomy in subjects with genetic hemochromatosis.

OBJECTIVES: The iron fortification of food in Sweden, the highest in the world, was withdrawn 1st January 1995, because the effect upon target groups was considered to be uncertain. We wanted to study the effect of such a dietary experiment. DESIGN: Comparative cross over study. SETTING: Out patient service and Blood Bank. SUBJECTS: Sixteen men aged 24-73 y on maintenance phlebotomy after treatment for iron overload. One was excluded because of inflammatory disease. INTERVENTIONS: Quantitative phlebotomy with serial measurements of Hb conc., % transferrin saturation and serum ferritin concentration. MAIN OUTCOME MEASURES: Iron absorption was measured by phlebotomy during two periods, with and without iron fortification. 1 g Hb = 3.4 mg Fe. RESULTS: Iron absorption was significantly reduced (P < 0.001) when iron fortification was withdrawn from a mean of 4.27 +/- 1.2 to 3.63 +/- 1.1 mg/d. The difference of 0.65 mg/d (95% c.i. 0.32-0.97) corresponds to the fraction of iron derived from fortification. Intervals between donations had to be extended from 59 +/- 15 to 69 +/- 17 d (P < 0.01) to avoid induction of iron deficiency anemia. The iron content of the fortified diet averaged 15.4 mg/d, of which the fortified fraction constituted 4.1 mg/d (27%). The relative bioavailability of carbonyl iron used as fortificant was 38%. CONCLUSIONS: The relative bioavailability of carbonyl iron used as fortificant was higher than previously reported. Target groups such as menstruating females will probably be affected by a higher prevalence of iron deficiency when food is no longer fortified. People with genetic hemochromatosis will accelerate into clinical disease at a slower rate.

Adult↗
PubMed2003

Juvenile hemochromatosis locus maps to chromosome 1q in a French Canadian population.

Juvenile hemochromatosis (JH) is a rare autosomal recessive disorder that causes iron overload. In the French Canadian region of Saguenay Lac-Saint-Jean the worldwide largest cohort of JH cases has been identified. Here, we report the mapping of this large cohort of cases to the HFE2 locus on chromosome 1q. A maximum multipoint location score of 7.02 was observed with marker D1S2344. A common ancestral haplotype, showing the presence of a founder effect, was identified. The analysis of recombinants allowed us to confirm the JH candidate region.

Adult↗
PubMed1997

Utility of hepatic iron index in American patients with hereditary hemochromatosis: a multicenter study.

BACKGROUND & AIMS: A hepatic iron index (hepatic iron concentration divided by age) of more than 1.9 has been proposed as useful to identify patients with homozygous hereditary hemochromatosis (HHC). There are limited data on the diagnostic use of the hepatic iron index in patients with HHC in the United States. This study evaluated the hepatic iron index in the diagnosis of HHC in a multicenter U.S. study. METHODS: Hepatic iron concentration was measured in 509 patients undergoing liver biopsy. The diagnosis of HHC was made using clinical, biochemical, and histopathologic criteria. RESULTS: Fifty-five patients met criteria for HHC; hepatic iron index was > 1.9 in 51 of 55 (93%) patients with HHC but in none of 454 patients with other liver diseases; hepatic iron concentration was > 71 mumol/g dry weight in 54 of 55 patients with HHC but only 1 of the other 454 patients. CONCLUSIONS: A hepatic iron index of > or = 1.9 can identify most U.S. patients with HHC but is < or = 1.9 in 7%. A "threshold" hepatic iron concentration of 71 mumol/g can almost always distinguish patients with HHC from patients with other liver diseases and may be a useful adjunct to the hepatic iron index in the diagnosis of HHC in the diverse U.S. population.

Adult↗
PubMed2001

Duodenal expression of a putative stimulator of Fe transport and transferrin receptor in anemia and hemochromatosis.

BACKGROUND & AIMS: Stimulator of Fe Transport (SFT) and transferrin receptor (TfR) are proteins involved in iron transport. This study evaluated iron metabolism protein expression in duodenal biopsy specimens from controls and patients with abnormal iron metabolism. METHODS: Twelve controls, 8 patients with iron deficiency anemia, 7 with HFE-related hemochromatosis, and 6 with non-HFE-related iron overload were studied. Immunohistochemistry was performed on duodenal biopsy specimens with anti-TfR and anti-SFT antibodies which recognize a putative stimulator of Fe transport of ~80 kilodaltons. RESULTS: In controls, the putative stimulator of Fe transport was expressed in the middle and distal part of the villi in the subapical cytoplasmatic region. Its expression increased in anemics and, to a lesser degree, in HFE-related hemochromatotics, whereas it was reduced in patients with non-HFE-related iron overload. TfR expression showed a crypt-to-tip gradient in controls, but not in anemics, in whom it was uniformly overexpressed. TfR expression was intermediate in HFE-related hemochromatotics and similar to controls in non-HFE-related iron overload. CONCLUSIONS: Expression of the putative stimulator of Fe transport and TfR increases in iron deficiency. Increased expression of both proteins is present only in HFE-related hemochromatotics suggesting that other factors may be involved in determining non-HFE-related iron overload phenotype.

Adult↗