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PubMed2002

Screening for hemochromatosis.

BACKGROUND: Hereditary hemochromatosis is the most common autosomal recessive disorder in populations of northern European descent. ISSUES: Many experts consider hemochromatosis to be an almost ideal disease for population screening because it essentially fulfills almost all the criteria for screening proposed by the WHO. However, others disagree and suggest that more data are required particularly with regard to the natural history and penetrance of the disease. There is also disagreement about the best diagnostic/screening test for the disease and the performance of these tests in the context of screening. Other concerns are the variability and lack of standardization in screening test measurements, the selection of screening threshold values and the identification of false positive cases. The advent of a genetic test for the condition has brought other worries with regard to informed consent and the ethical, legal and social implications of screening particularly in relation to medical and general discrimination. Other important issues include compliance, cost effectiveness and the evidence that screening has lessened the burden of disease in the community. CONCLUSIONS: At the present time, we believe that further data regarding both the exact disease burden and the outcomes of screening studies particularly in the general community are required before widespread population screening is introduced.

Adult↗
PubMed2000

Peripheral blood erythrocyte parameters in hemochromatosis: evidence for increased erythrocyte hemoglobin content.

We studied peripheral blood erythrocyte parameters and HFE genotypes in 94 hemochromatosis probands and 132 white, normal control subjects. Mean red blood cell counts in probands and control subjects were not significantly different. However, mean values of hemoglobin, hematocrit, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC) were significantly higher in C282Y/C282Y probands (n = 60) than in wild-type control subjects (n = 65). Probands with other HFE genotypes also had increased mean erythrocyte parameters (other than red blood cell count). Peripheral blood smears prepared before therapeutic phlebotomy revealed that erythrocytes in many probands had increased diameters and were well filled with hemoglobin. Erythrocyte parameters were similar in C282Y/C282Y probands with and without hepatomegaly, elevated serum concentrations of hepatic enzymes, hepatic cirrhosis, diabetes mellitus, arthropathy, or hypogonadism. Among C282Y/C282Y probands, significantly greater values of MCV (but not other erythrocyte parameters) occurred among those who had transferrin saturation values of 75% or greater or iron overload at diagnosis. After iron depletion, the mean MCV, MCH, and MCHC values of C282Y/C282Y probands decreased but remained significantly greater than values in wild-type control subjects. Mean values of prephlebotomy MCH and MCHC concentrations were lower in HLA-A3-positive than in HLA-A3-negative C282Y/C282Y probands. We conclude that increased values of mean hemoglobin, hematocrit, MCV, MCH, and MCHC in hemochromatosis probands are caused primarily by increased iron uptake and hemoglobin synthesis by immature erythroid cells. Mechanisms of iron uptake by erythrocytes that could explain these results are discussed.

Adult↗
PubMed1999

Cloning of the hereditary hemochromatosis gene: implications for pathogenesis, diagnosis, and screening.

Hereditary hemochromatosis (HH) is one of the most common genetic disorders affecting populations of European ancestry. It is characterized by an inappropriately high iron absorption that leads to iron overload preferentially in the parenchymal organs. Although the severity of the phenotype can be modified by a number of factors, it is clear that most homozygotes will eventually become symptomatic. Clinical manifestations are often nonspecific and easily overlooked. Untreated HH can be associated with substantial morbidity and mortality. Diagnosis in the pre-cirrhotic stage, however, results in normal life expectancy. Early diagnosis and the initiation of phlebotomy therapy are therefore keys to preventing complications related to iron overload. The recent isolation of a strong candidate gene for hemochromatosis has the potential to allow for genetic diagnosis and screening in the near future. This exciting finding is likely not only to change clinical practice but also to yield new insights into the poorly understood pathophysiology of the disease.

Cloning, Molecular↗
PubMed1998

Crystal structure of the hemochromatosis protein HFE and characterization of its interaction with transferrin receptor.

HFE is an MHC-related protein that is mutated in the iron-overload disease hereditary hemochromatosis. HFE binds to transferrin receptor (TfR) and reduces its affinity for iron-loaded transferrin, implicating HFE in iron metabolism. The 2.6 A crystal structure of HFE reveals the locations of hemochromatosis mutations and a patch of histidines that could be involved in pH-dependent interactions. We also demonstrate that soluble TfR and HFE bind tightly at the basic pH of the cell surface, but not at the acidic pH of intracellular vesicles. TfR:HFE stoichiometry (2:1) differs from TfR:transferrin stoichiometry (2:2), implying a different mode of binding for HFE and transferrin to TfR, consistent with our demonstration that HFE, transferrin, and TfR form a ternary complex.

Amino Acid Sequence↗
PubMed2001

Frequency and biochemical expression of C282Y/H63D hemochromatosis (HFE) gene mutations in the healthy adult population in Italy.

BACKGROUND/AIMS: The actual prevalence of the main hemochromatosis (HFE) mutations in the Italian adult population and their phenotypic expression have not yet been established. This information is key to advocate a mass-screening program. METHODS: Two thousand one hundred adults were tested for the C282Y/H63D HFE gene mutations by an automated genotyping assay as well as transferrin saturation (TS) and serum ferritin levels. RESULTS: No homozygotes for the C282Y mutation were found. Heterozygosity for the C282Y mutation was 3.1%, while heterozygosity and homozygosity for the H63D mutation were 21.5% and 2.5%, respectively. TS was significantly higher in C282Y heterozygotes and H63D homozygotes as compared to wild-type individuals (P < 0.01). Interestingly, of the HFE wild-type subjects 5.9% had a TS value above the 45% threshold. CONCLUSIONS: This study shows that (i) the predicted prevalence for C282Y homozygosity in Italy is 1:3900; (ii) the C282Y/H63D wild-type population has an increased baseline of iron parameters possibly due to genetic factors not linked to the C282Y/H63D mutations; (iii) since in the latter population the actual tissue iron burden cannot be assessed, phenotypic (TS) screening in Italy is not recommended until the true prevalence of all mutations in the HFE gene and in other hemochromatosis genes will be established.

Adult↗
PubMed1999

Hepatocellular carcinoma in a patient with hereditary hemochromatosis and noncirrhotic liver. A case report.

A case of a 62-year-old patient with hereditary hemochromatosis is reported, who developed hepatocellular carcinoma (HCC) in the absence of cirrhosis and other potential risk factors for HCC. Occurrence of HCC in patients with genetic hemochromatosis and noncirrhotic liver is a rare event which has previously been described only six times and appears to be limited to male patients.

Carcinoma, Hepatocellular↗
PubMed2000

Clinical aspects of hemochromatosis.

Hemochromatosis is one of the most frequent genetic diseases among the white populations, affecting one in three hundred persons. Its diagnosis has been radically transformed by the discovery of the HFE gene. In a given individual, the diagnosis can, from now on, be ascertained on the sole association of a plasma transferrin saturation (TS) over 45% and homozygosity for the C282Y mutation. Liver biopsy is only required to search for cirrhosis whenever there is hepatomegaly and/or serum ferritin >1000 ng/ml and/or elevated serum AST. Family screening is mandatory, primarily centered on the siblings. The treatment remains based on venesection therapy which improves many features of the disease (one of the most refractory, however, being the joint signs) and permits normal life expectancy provided the diagnosis is established prior to the development of cirrhosis or of insulin-dependent diabetes. In view of the prevalence, the non-invasive diagnosis, the spontaneous severity and the efficacy of a very simple therapy, hemochromatosis should benefit from population screening. This screening could be based, first, on the assessment of transferrin saturation, followed - when elevated - by the search for the C282Y mutation. The discovery of the HFE gene has also paved the road for the individualization of other types of iron overload syndromes which are not HFE-related.

HLA Antigens↗
PubMed2003

Mutations of the hemochromatosis gene in Italian candidate blood donors with increased transferrin saturation.

The aim of this study was to analyze the role of HFE mutations in blood donors with iron parameters suggesting iron overload, taking into account the regional distribution of HFE mutations in Italy. We studied 5880 subjects undergoing evaluation for blood donation eligibility, from different areas of Italy. Abnormal iron parameters were defined as transferrin saturation (TS) >50% or >45% and serum ferritin (SF) >300 or >250 microg/ml in males and females, respectively. Subjects with increased TS and/or SF were re-tested and typed for HFE mutations C282Y and H63D. A total of 548 individuals had increased iron parameters at first testing. In total, 179/548 were available for retesting, and in 109 increased TS and/or SF were confirmed. Increased TS was confirmed in 25 individuals, among whom three were C282Y homozygotes and six were compound heterozygotes for C282Y and H63D. Increased TS was more frequent in northern Italy than in southern regions. In individuals with increased TS and/or SF, the frequency of C282Y and H63D was 0.13 and 0.21 in northern-Italy versus 0.05 and 0.45 in southern Italy (P=0.004 for H63D). Nine out of 10 individuals carrying hemochromatosis-associated genotypes (including compound heterozygosity for C282Y and H63D) originated from northern regions. Among controls, the allelic frequencies of C282Y and H63D were 0.037 and 0.16 in the northern regions and 0.015 and 0.16 in the southern regions. In conclusion, over one-third of individuals with persistently altered TS carried hemochromatosis-associated genotypes, confirming that a diagnostic approach based on TS and genotyping of selected cases may represent a viable screening procedure.

Adolescent↗
PubMed2002

Inactivation of the hemochromatosis gene differentially regulates duodenal expression of iron-related mRNAs between mouse strains.

BACKGROUND & AIMS: Hfe knockout mice, like patients with hereditary hemochromatosis, have augmented duodenal iron absorption and increased iron deposition in hepatic parenchymal cells. The goals of the present study were to gain further insight into the control of iron absorption by comparing the transcript levels of iron-related genes in the duodenum of DBA/2 Hfe-/- mice, susceptible to iron loading, and wild-type controls, and to test whether variations in the duodenal expression of these messengers contribute to the DBA/2 and C57BL/6 strain differences in the severity of hepatic iron loading. METHODS: Expression of the different transcripts was quantified by real-time polymerase chain reaction. RESULTS: The 2 strains differ strikingly, not only in the severity of hepatic iron loading, but also in the duodenal expression of iron-related genes. In DBA/2 Hfe-/- mice, increased intestinal iron absorption results from the concomitant up-regulation of the Dcytb, DMT1, and FPN1 messengers. No increase in the expression of these messengers is seen in C57BL/6 Hfe-/- mice. CONCLUSIONS: The up-regulation of these transcripts suggests that an inappropriate iron-deficiency signal is sensed by the duodenal enterocytes, leading to an enhanced ferric reductase activity and the increase of duodenal iron uptake and transfer to the circulation. The genes modifying the hemochromatosis phenotype probably act by modifying the expression of these 3 messengers.

Animals↗
PubMed2002

The role of hemochromatosis susceptibility gene mutations in protecting against iron deficiency in celiac disease.

BACKGROUND & AIMS: Celiac disease and hereditary hemochromatosis are common HLA-defined conditions in northwestern Europe. We sought to determine whether there is a genetic relationship between the 2 diseases and if hemochromatosis susceptibility gene (HFE) mutations are protective against iron deficiency in celiac disease. METHODS: Polymerase chain reaction amplification using sequence-specific primers capable of identifying the 2 HFE gene mutations (H63D and C282Y) and the HLA class I and II alleles was used to type 145 white patients with celiac disease and 187 matched controls. Hemoglobin and fasting serum iron levels in celiac patients were measured at diagnosis. RESULTS: HFE gene mutations, H63D or C282Y, were identified in 70 celiac patients (48.3%) and 61 controls (32.6%) (P = 0.004). The C282Y mutation was associated with HLA-A*03 and B*07 alleles in controls and with A*01, A*03, B*08, and DRB1*0301 alleles in celiac patients; the H63D mutation was associated with HLA-A*25 and DRB1*03 alleles in controls and A*29 and DRB1*03 alleles in celiac patients. At diagnosis, celiac patients with the C282Y mutation had higher mean hemoglobin and fasting serum iron levels compared with the HFE wild type (P = 0.0002 and 0.006, respectively). This was not observed with the H63D mutation. CONCLUSIONS: In celiac disease, HFE gene mutations are common and are in linkage disequilibrium with different HLA alleles compared with controls. A disease-specific haplotype that carries C282Y and DQB1*02 is suggested. We propose that HFE gene mutations provide a survival advantage by ameliorating the iron deficiency seen in celiac patients.

Adult↗
PubMed2005

Non-HFE hemochromatosis.

The term "non-HFE hemochromatosis" (non-HFE HC) refers to several phenotypically similar but genetically distinct forms of hereditary hemochromatosis affecting individuals without pathogenic mutations of HFE. The involved genes are, sinsu strictu, transferrin receptor 2 (TfR2), hemojuvelin (HJV), and hepcidin (HAMP). Non-HFE HC share common pathogenic and clinical features with HFE HC. However, depending on the role of the affected gene in iron trafficking, the clinical onset may be earlier and phenotypic expressivity more severe than classic HC. Other forms of hereditary iron overload have distinct pathogenesis and phenotype. The most prevalent of these forms is "ferroportin disease," characterized by autosomal dominant trait, predominant reticuloendothelial cell iron overload, and mild organ damage. Non-HFE HC gene products, while responsible for rarer cases of HC as compared with HFE, are much more central than HFE in human iron homeostasis and understanding their function will greatly advance our comprehension of iron trafficking in health and disease.

Antimicrobial Cationic Peptides↗
PubMed2002

Regulation of transferrin-mediated iron uptake by HFE, the protein defective in hereditary hemochromatosis.

The protein defective in hereditary hemochromatosis, called HFE, is similar to MHC class I-type proteins and associates with beta2-microglobulin (beta2M). Its association with beta2M was previously shown to be necessary for its stability, normal intracellular processing, and cell surface expression in transfected COS cells. Here we use stably transfected Chinese hamster ovary cell lines expressing both HFE and beta2M or HFE alone to study the effects of beta2M on the stability and maturation of the HFE protein and on the role of HFE in transferrin receptor 1 (TfR1)-mediated iron uptake. In agreement with prior studies on other cell lines, we found that overexpression of HFE, without overexpressing beta2M, resulted in a decrease in TfR1dependent iron uptake and in lower iron levels in the cells, as evidenced by ferritin and TfR1 levels measured at steady state. However, overexpression of both HFE and beta2M had the reverse effect and resulted in an increase in TfR1-dependent iron uptake and increased iron levels in the cells. The HFE-beta2M complex did not affect the affinity of TfR1 for transferrin or the internalization rate of transferrin-bound TfR1. Instead, HFE-beta2M enhanced the rate of recycling of TfR1 and resulted in an increase in the steady-state level of TfR1 at the cell surface of stably transfected cells. We propose that Chinese hamster ovary cells provide a model to explain the effect of the HFE-beta2M complex in duodenal crypt cells, where the HFE-beta2M complex appears to facilitate the uptake of transferrin-bound iron to sense the level of body iron stores. Impairment of this process in duodenal crypt cells leads them to be iron poor and to signal the differentiating enterocytes to take up iron excessively after they mature into villus cells in the duodenum of hereditary hemochromatosis patients.

Animals↗
PubMed2005

HIV-1 Nef down-regulates the hemochromatosis protein HFE, manipulating cellular iron homeostasis.

The multifunctional Nef protein of HIV-1 is important for the progression to AIDS. One action of Nef is to down-regulate surface MHC I molecules, helping infected cells to evade immunity. We found that Nef also down-regulates the macrophage-expressed MHC 1b protein HFE, which regulates iron homeostasis and is mutated in the iron-overloading disorder hemochromatosis. In model cell lines, Nef reroutes HFE to a perinuclear structure that overlaps the trans-Golgi network, causing a 90% reduction of surface HFE. This activity requires a Src-kinase-binding proline-rich domain of Nef and a conserved tyrosine-based motif in the cytoplasmic tail of HFE. HIV-1 infection of ex vivo macrophages similarly down-regulates naturally expressed surface HFE in a Nef-dependent manner. The effect of Nef expression on cellular iron was explored; iron and ferritin accumulation were increased in HIV-1-infected ex vivo macrophages expressing wild-type HFE, but this effect was lost with Nef-deleted HIV-1 or when infecting macrophages from hemochromatosis patients expressing mutated HFE. The iron accumulation in HIV-1-infected HFE-expressing macrophages was paralleled by an increase in cellular HIV-1-gag expression. We conclude that, through Nef and HFE, HIV-1 directly regulates cellular iron metabolism, possibly benefiting viral growth.

Biological Transport, Active↗
PubMed1998

The hemochromatosis gene product complexes with the transferrin receptor and lowers its affinity for ligand binding.

We recently reported the positional cloning of a candidate gene for hereditary hemochromatosis called HFE. The gene product, a member of the major histocompatibility complex class I-like family, was found to have a mutation, Cys-282 --> Tyr (C282Y), in 85% of patient chromosomes. This mutation eliminates the ability of HFE to associate with beta2-microglobulin (beta2m) and prevents cell-surface expression. A second mutation that has no effect on beta2m association, H63D, was found in eight out of nine patients heterozygous for the C282Y mutant. In this report, we demonstrate in cultured 293 cells overexpressing wild-type or mutant HFE proteins that both the wild-type and H63D HFE proteins form stable complexes with the transferrin receptor (TfR). The C282Y mutation nearly completely prevents the association of the mutant HFE protein with the TfR. Studies on cell-associated transferrin at 37 degrees C suggest that the overexpressed wild-type HFE protein decreases the affinity of the TfR for transferrin. The overexpressed H63D protein does not have this effect, providing the first direct evidence for a functional consequence of the H63D mutation. Addition of soluble wild-type HFE/beta2m heterodimers to cultured cells also decreased the apparent affinity of the TfR for its ligand under steady-state conditions, both in 293 cells and in HeLa cells. Furthermore, at 4 degrees C, the added soluble complex of HFE/beta2m inhibited binding of transferrin to HeLa cell TfR in a concentration-dependent manner. Scatchard plots of these data indicate that the added heterodimer substantially reduced the affinity of TfR for transferrin. These results establish a molecular link between HFE and a key protein involved in iron transport, the TfR, and raise the possibility that alterations in this regulatory mechanism may play a role in the pathogenesis of hereditary hemochromatosis.

Amino Acid Sequence↗
PubMed1999

Transferrin receptor is negatively modulated by the hemochromatosis protein HFE: implications for cellular iron homeostasis.

Hereditary hemochromatosis is a common autosomal recessive disorder of iron metabolism. Recent demonstration of an association between transferrin receptor (TfR) and HFE, a major histocompatibility complex class I-like molecule that has been implicated to play a role in hereditary hemochromatosis, further strengthens the notion that HFE is involved in iron metabolism. Herein we show that TfR is required for and controls the assembly and the intracellular transport and surface expression of HFE. Because surface-expressed HFE and TfR remain firmly associated physically, only the fraction of TfR that is associated with HFE during biosynthesis is affected functionally. Moreover, we show that HFE binding reduces the number of functional transferrin binding sites and impairs TfR internalization, thus reducing the uptake of transferrin-bound iron. Thus, iron homeostasis is indirectly regulated by HFE, a negative modulator of TfR.

Amino Acid Sequence↗
PubMed1999

Experimental hemochromatosis due to MHC class I HFE deficiency: immune status and iron metabolism.

The puzzling linkage between genetic hemochromatosis and histocompatibility loci became even more so when the gene involved, HFE, was identified. Indeed, within the well defined, mainly peptide-binding, MHC class I family of molecules, HFE seems to perform an unusual yet essential function. As yet, our understanding of HFE function in iron homeostasis is only partial; an even more open question is its possible role in the immune system. To advance on both of these avenues, we report the deletion of HFE alpha1 and alpha2 putative ligand binding domains in vivo. HFE-deficient animals were analyzed for a comprehensive set of metabolic and immune parameters. Faithfully mimicking human hemochromatosis, mice homozygous for this deletion develop iron overload, characterized by a higher plasma iron content and a raised transferrin saturation as well as an elevated hepatic iron load. The primary defect could, indeed, be traced to an augmented duodenal iron absorption. In parallel, measurement of the gut mucosal iron content as well as iron regulatory proteins allows a more informed evaluation of various hypotheses regarding the precise role of HFE in iron homeostasis. Finally, an extensive phenotyping of primary and secondary lymphoid organs including the gut provides no compelling evidence for an obvious immune-linked function for HFE.

Animals↗
PubMed2000

Comparison of the interactions of transferrin receptor and transferrin receptor 2 with transferrin and the hereditary hemochromatosis protein HFE.

The transferrin receptor (TfR) interacts with two proteins important for iron metabolism, transferrin (Tf) and HFE, the protein mutated in hereditary hemochromatosis. A second receptor for Tf, TfR2, was recently identified and found to be functional for iron uptake in transfected cells (Kawabata, H., Germain, R. S., Vuong, P. T., Nakamaki, T., Said, J. W., and Koeffler, H. P. (2000) J. Biol. Chem. 275, 16618-16625). TfR2 has a pattern of expression and regulation that is distinct from TfR, and mutations in TfR2 have been recognized as the cause of a non-HFE linked form of hemochromatosis (Camaschella, C., Roetto, A., Cali, A., De Gobbi, M., Garozzo, G., Carella, M., Majorano, N., Totaro, A., and Gasparini, P. (2000) Nat. Genet. 25, 14-15). To investigate the relationship between TfR, TfR2, Tf, and HFE, we performed a series of binding experiments using soluble forms of these proteins. We find no detectable binding between TfR2 and HFE by co-immunoprecipitation or using a surface plasmon resonance-based assay. The affinity of TfR2 for iron-loaded Tf was determined to be 27 nm, 25-fold lower than the affinity of TfR for Tf. These results imply that HFE regulates Tf-mediated iron uptake only from the classical TfR and that TfR2 does not compete for HFE binding in cells expressing both forms of TfR.

Amino Acid Sequence↗
PubMed2002

Hemochromatosis gene in leukemia and lymphoma.

The gene causing hereditary hemochromatosis (HH), HFE is an HLA class I-like gene with no known immunological function but indirectly related to the immune functions because of its role in iron transport. It is located 6.5 Mb telomeric to HLA-A. The most common mutation of HFE, C282Y, has a Celtic origin and most patients with HH are homozygous for it in Northern European populations. While there is an enormously increased risk for hepatocellular cancer in hemochromatosis that is attributed to the toxic effects of iron, the risk for extra-hepatic cancers is also increased slightly. Recent studies have found genetic associations between several cancers and C282Y but only in the presence of a particular allele of the transferrin receptor gene. This suggests that the increased cancer risk is more likely due to the effects of iron. In childhood acute lymphoblastic leukemia (ALL), however, there is a strong association of C282Y with a gender effect in two different Celtic populations. This association does not require homozygosity for C282Y or an interaction with the transferrin receptor gene, and is male-specific. The other HFE mutation H63D does not confer increased risk to childhood ALL. Acute myeloblastic leukemia and Hodgkin's disease in adults do not have an association with HFE. Its male-specificity, occurrence in childhood and the lack of a gene-dosage effect suggest that the C282Y association in childhood ALL may reflect the involvement of another HLA-linked gene in leukemia susceptibility.

Animals↗