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PubMed2004

Expression of the hereditary hemochromatosis protein HFE increases ferritin levels by inhibiting iron export in HT29 cells.

Iron is essential for life in almost all organisms and, in mammals, is absorbed through the villus cells of the duodenum. Using a human colonic carcinoma cell line that has many duodenal characteristics, HT29, we show that genes involved in intestinal iron transport are endogenously expressed. When stably transfected to express the hereditary hemochromatosis protein HFE these cells have increased ferritin levels. We demonstrate that this is not due to an effect on the transferrin (TF)-mediated iron uptake pathway but rather due to inhibition of iron efflux from the cell. The effect of HFE was independent of its interaction with TF receptor 1 as indicated by similar results using both the wild type HFE and the W81A mutant that binds TF receptor 1 with greatly reduced affinity. HFE expression did not affect the mRNA levels of most of the genes involved in iron absorption that were tested; however, it did correspond to a decrease in hephaestin message levels. These results point to a role for HFE in inhibition of iron efflux in HT29 cells. This is a distinct role from that in HeLa and human embryonic kidney 293 cells where HFE has been shown to inhibit TF-mediated iron uptake resulting in decreased ferritin levels. Such a distinction suggests a multifunctional role for HFE that is dependent upon expression levels of proteins involved in iron transport.

Antigens, CD↗
PubMed1986

Hereditary hemochromatosis in a 46-year-old man.

A 46-year-old man experienced weakness, lassitude, and vague, aching abdominal pain in the right upper quadrant. Physical examination was notable for hepatomegaly and slight hyperpigmentation of the hands. Elevated levels were revealed on liver function tests, and massive iron deposition was shown on liver biopsy. The patient was started on a therapeutic regimen of 400-ml phlebotomies. Hereditary hemochromatosis is an iron-storage disease in which total body iron stores can reach incredibly high levels, leading to damage of the liver, heart, pancreas, and pituitary gland. The most specific screening test is measurement of the serum concentration of ferritin, and a transferrin saturation determination is also helpful in diagnosis. Phlebotomy is still the treatment of choice, although new ways of administering chelating agents are being investigated.

Bloodletting↗
PubMed2001

Yersinia enterocolitica infection with multiple liver abscesses uncovering a primary hemochromatosis.

A 60-year-old man, although treated with antibiotics, suffered from a severe pyrexial illness of unknown origin, weight loss and intermittent abdominal pain. There was no history of diarrhea or common infections. Computed tomography and ultrasound imaging showed uncharacteristic multiple small lesions of the entire liver parenchyma. These lesions were histologically pyogenic abscesses. In addition, an unexpected, pronounced accumulation of iron pigment in hepatocytes and second degree fibrotic changes of the liver were detected. Serum iron and serum transferrin were low, but serum ferritin concentration and transferrin saturation were increased to the maximum. The demonstration of the cysteine-282-tyrosine mutation confirmed underlying primary hemochromatosis. Bacteriological cultures of the abscess material yielded Yersinia enterocolitica serotype O:3, while stool and blood cultures were negative. Antibiotic therapy with piperacillin/tazobactam and tobramycin was successful within a few days. A repeat CT scan and ultrasound imaging demonstrated complete regression of the pathologic liver morphology. The patient was discharged and treated with an orally administered fluoroquinolone for an additional 6 months. After this time the patient had no morphological residues of the infection except one enlarged lymph node near the portal vein but still was so weak that he was unable to work again. In conclusion, severe septic forms of yersiniosis are mainly found in patients with iron overload, due to a handicapped iron metabolism of the Yersinia bacteria. Mortality is high despite treatment.

Hemochromatosis↗
PubMed2001

Screening for hemochromatosis: high prevalence and low morbidity in an unselected population of 65,238 persons.

BACKGROUND: Hereditary hemochromatosis (HH) is a common genetic disease leading to accumulation of iron in several organs, most notably the liver. The C282Y/C282Y mutation in the HFE gene is found in most cases. In order to prevent clinical disease and to study the cost and feasibility of screening, a large population was screened. METHODS: In a Norwegian county, all inhabitants 20 years or older were invited to participate in a population-based health survey programme. Screening for HH was one of several subprojects. Blood samples were obtained from 65,238 persons. Subjects with high serum transferrin saturation in two tests and high serum ferritin were clinically evaluated for HH. All subjects with high serum transferrin saturation in two tests were offered genotyping. RESULTS: HH was newly diagnosed in 92 women and 177 men. Phlebotomy treatment was performed in 64 women and 152 men. Severe organ damage (liver cirrhosis) was ascertained in only 4 men. We found no correlation between serum ferritin and age. The estimated cost was US$ 1.6 per subject screened and US$ 390 per newly discovered HH subject. The estimated prevalence of phenotypical HH not previously known was 0.34% in women and 0.68% in men. The prevalence of the C282Y/C282Y mutation was at least 0.68%. CONCLUSION: Large-scale screening for HH can be performed at a relatively low cost if combined with a health survey programme. The yield in terms of newly discovered cases is considerable, but few cases were found seriously ill. Better knowledge of the natural course of HH is necessary if we are to be able to estimate the cost-effectiveness of large-scale screening.

Adult↗
PubMed2002

Benefit of population-based screening for phenotypic hemochromatosis in young men.

BACKGROUND: Hereditary hemochromatosis (HH) is a common genetic disease leading to accumulation of iron in the body, most notably in the liver. More men than women become clinically ill. The prognosis is excellent if phlebotomy treatment is started before liver cirrhosis develops. Screening has been recommended, but the benefit of population-based screening has never been shown in a randomized clinical trial. In this article, we estimate the benefit of screening young men, using a theoretical model. METHODS: A phenotypic screening scenario was modelled using a decision tree. Gain of quality-adjusted life-years was used as a measure of benefit, and estimated using Markov processes. Data on the accuracy of the screening tests, the prevalence of HH and the risk of liver cirrhosis were mainly derived from a cross-sectional study on the prevalence and morbidity of HH in 30509 men. Data on the excess mortality of cirrhosis were taken from relevant literature. Sensitivity analysis was done for important variables. RESULTS: Assuming basal case values for variables, screening a cohort of 1000 men aged 30 years for phenotypic HH would gain about 8 quality-adjusted life-years, compared to awaiting symptomatic disease. Based on actual costs of our cross-sectional study, the screening cost was US$250 per quality-adjusted life-year gained. The prevalence of phenotypic HH, the excess mortality of liver cirrhosis, the quality of life in non-cirrhotic HH patients, and the fractions of patients compliant with treatment were the most important variables in the sensitivity analysis. CONCLUSION: Incorporating screening for phenotypic HH in health survey programmes for young men may be worthwhile.

Adult↗
PubMed1999

High prevalence of the hemochromatosis-associated Cys282Tyr HFE gene mutation in a healthy Norwegian population in the city of Oslo, and its phenotypic expression.

BACKGROUND: Previous studies have shown that 5%-10% of white subjects are heterozygous for the HFE gene C282Y mutation, which is associated with hemochromatosis. The aim of our study was to determine the prevalence of heterozygosity and homozygosity for the C282Y HFE gene mutation and its phenotypic expression in a group of healthy Norwegians. METHODS: Fasting blood samples were obtained from 505 unrelated hospital employees. Serum iron, transferrin, and serum ferritin were measured. Transferrin saturation was calculated. The presence of HFE gene mutation was determined with a polymerase chain reaction-based analysis. RESULTS: Two of the 505 subjects (0.4%) were homozygous and 75 (14.9%) were heterozygous for the C282Y mutation. Median serum ferritin among the heterozygotes was 59 microg/l, compared with 47 microg/l among individuals without the C282Y mutation (P = 0.12). Median transferrin saturation among the heterozygotes was 31%, compared with 24% among individuals without C282Y mutation (P < 0.001). Twenty-three individuals (4.6%) had a serum ferritin level > 200 microg/l. Eight of these (35%) had the C282Y mutation: two homozygotes and six heterozygotes. Transferrin saturation > 50% was observed in 25 individuals (5.0%). Twelve of these (48%) had the C282Y mutation; two were homozygotes and 10 heterozygotes. Only eight individuals (1.6%) had a transferrin saturation > 60%: one homozygote, five heterozygotes, and two individuals without mutation. CONCLUSIONS: Fifteen per cent of a healthy Norwegian population is heterozygous for the HFE gene mutation C282Y. This is among the highest reported prevalence values among healthy individuals. Half of the subjects with transferrin saturation greater than 50% were carriers of the C282Y mutation.

Adult↗
PubMed2000

Genetic hemochromatosis: detection, management, and population screening.

Genetic hemochromatosis (GH) is an inherited disease that results in iron overload, and, if untreated, causes irreversible organ damage. Knowledge and understanding of the early features of the condition, often nonspecific, and of the diagnostic route are necessary to detect iron overload and diagnose GH before irremedial damage has been done. Genetic testing now plays an important role in diagnosis. Management of the patient with established GH centers on venesection to return body iron levels to normal, treatment of the complications of GH, and family screening for GH. Population screening for GH, the ideal strategy to prevent any morbidity from iron overload, has not yet been accepted by public health professionals, largely because of the lack of data on the disease penetrance in genetically susceptible individuals.

Biopsy↗
PubMed2000

Genetic discrimination and screening for hemochromatosis: then and now.

Any two people on earth, save for identical twins, share in common roughly 99.9% of their genetic make-up. That 0.1% difference represents not just what, on a molecular level, distinguishes us from one another, but also has reportedly served as a basis for excluding individuals from insurance, employment, adoption, educational opportunities, family relations, as well as perceived life options. The first federal study of genetic discrimination, discrimination based on genotype as opposed to phenotype, included treated hereditary hemochromatosis (HH) as one of only five genotypes possibly providing a basis for discrimination. HH was selected because if a successfully treated condition that is nonetheless genetic but which, if properly managed, leaves affected individuals at no greater morbidity or mortality risk than the general population, then genotype independent of phenotype apparently provided a basis for exclusions. Since the publication of those results, much more is known about the genotypic and phenotypic variation of affected individuals. This paper discusses what is presently known about HH and genetic discrimination.

Blood Donors↗
PubMed2002

Frequency of hemochromatosis C282Y and H63D mutations in Sardinia.

Hereditary hemochromatosis (HH) is one of the most common autosomal recessive disorders of iron metabolism among Caucasians, and it is associated with C282Y mutation of the HFE gene in populations of Celtic origins. A second mutation, H63D, shows a very high widespread frequency, although its role in iron metabolism is still inconclusive. There are no data on the frequencies of these two mutations in Sardinia, an island in the Mediterranean sea that has not been invaded by Celtic peoples. We examined 836 chromosomes from Sardinian subjects and tested for the mutation by restriction enzyme digestion of PCR products. Among the 836 analyzed chromosomes, we found a C282Y allele frequency of 0.0036 and an H63D allele frequency of 0.173. These data could explain the observed rarity of HH in Sardinia. The high allele frequency of H63D and the rarity of HH in Sardinia is suggestive that this mutation is not a major contributor to this disease.

Gene Frequency↗
PubMed1998

Is the hemochromatosis gene a modifier locus for cystic fibrosis?

The variable clinical manifestations of cystic fibrosis (CF) suggest the influence of modifier genes. For example, meconium ileus is present in approximately 10-15% of neonates with cystic fibrosis; however, the genetic and, or environmental factors that determine whether an individual will develop this complication have not been determined. We propose the HFE gene as a candidate modifier locus for CF based on (1) the suggestion of an association between the HLA loci and CF phenotypes; (2) the location of the HFE gene near the HLA loci and; (3) the similarity between the gastrointestinal manifestations of hereditary hemochromatosis and CF. We have determined the frequency of the C282Y and H63D mutations in a group of 89 CF patients who were homozygous for delta F508 and for whom meconium ileus status was known. The carrier frequency of C282Y among the CF patients with meconium ileus was significantly different from that of our unaffected control group (19.4% versus 7.7%). However, the difference between the meconium ileus and the nonmeconium ileus groups was not significant (19.4% versus 10.3%). There was no difference in the frequency of the H63D among the three groups that were studied. These data are suggestive of a relationship between the development of meconium ileus or other gastrointestinal diseases in CF and the HFE gene. Further study of a larger group of patients is warranted.

Adult↗
PubMed2005

Genotype-based screening for hereditary hemochromatosis: II. Attitudes toward genetic testing and psychosocial impact--a report from a German pilot study.

In collaboration with the German Sickness Fund (Kaufmännische Krankenkasse-KKH), we conducted a pilot study on DNA-based population screening of hereditary hemochromatosis (HH) in Germany. The health insurance organization KKH briefly informed their members about the possibility to participate voluntarily in this pilot project. A total of 5882 KKH members contacted us and received detailed information on the aim of the project and clinical and genetic aspects of HH. Of these individuals, 3961 requested HFE genotyping. After genotype results had been communicated to the participants' general practitioner, we sent a self-administered questionnaire to all homozygous (n = 67) and heterozygous (n = 485) as well as 448 wild-type study participants (sigma = 1000) to assess the psychosocial impact of HFE genotyping. In addition, questionnaires were sent to 8000 randomly selected members of the KKH to investigate their attitude toward genetic testing. Six hundred thirty-one (63.1%) of the test participants and 2141 (26.8%) of the randomly chosen KKH members responded. A total of 59.1% of the members would generally accept predictive genetic testing and 3.7% objected to such tests in principle. Individuals with higher educational status accepted predictive testing significantly more often than individuals with less education. Of the tested individuals, 69.9% thought that participation in the pilot study was probably beneficial for them and 1% (5 heterozygotes and 1 wild-type) thought that it was probably harmful. Of the participants, 94.6% judged their decision to have participated in the pilot study as right and 0.3% (2 heterozygotes) as probably wrong. Only very few of the tested individuals underwent pretest (1 case) or posttest (11 cases) genetic counseling. We conclude that genotype- based screening for HH is generally accepted and was perceived as beneficial. Negative psychosocial consequences are rare and could presumably have been prevented by delivering appropriate pretest and posttest information.

Attitude↗
PubMed1983

Serum marker of type III procollagen in patients with idiopathic hemochromatosis and its relationship to hepatic fibrosis.

A radioimmunoassay for serum procollagen III aminopeptide (sPIIIP) was proposed recently for monitoring hepatic fibroplasia in patients with various inflammatory hepatic lesions. To determine whether sPIIIP also can detect fibroplasia in noninflammatory liver disorders, we measured this index in 16 patients with idiopathic hemochromatosis (IHC) at various stages of the disease and iron overload. Interestingly, we found normal levels of sPIIIP in 12 out of 16 patients examined (75%), despite clear histologic features of fibrosis or cirrhosis. The levels of sPIIIP exhibited no relationship to any of the clinical, laboratory, or histologic parameters of the disease. Thus, unlike other types of cirrhosis, in which sPIIIP is increased, the liver disease in IHC may be a fibrotic process unrelated to type III collagen stimulation. Accordingly, the determination of sPIIIP in these patients is of no value for monitoring the fibrosis associated with the liver disease.

Adult↗
PubMed2003

Association between hemochromatosis (HFE) gene mutation carrier status and the risk of colon cancer.

BACKGROUND: Iron is a pro-oxidant that may promote carcinogenesis. Mutations in the hemochromatosis (HFE) gene are associated with increased total body iron stores in some individuals. We assessed the risk of colon cancer among individuals with and without HFE gene mutations. METHODS: We performed a population-based, case-control study in North Carolina. Case patients with colon cancer and control subjects provided information on multiple environmental exposures, including total iron intake and nonsteroidal anti-inflammatory drug (NSAID) use. They also provided a venous blood sample, from which DNA was extracted, amplified, and subjected to diagnostic restriction enzyme mapping to detect two major HFE gene mutations, C282Y and H63D. Data were analyzed with Fisher's exact test and logistic regression. All statistical tests were two-sided. RESULTS: Thirteen hundred and eight subjects participated (475 case patients, 833 control subjects). The allele frequencies of the H63D and C282Y mutations were greater among case patients (0.11 and 0.046, respectively) than among control subjects (0.09 and 0.044, respectively; P =.14 and P =.85, respectively). When we controlled for age, race, sex, red meat consumption, NSAID use, and total iron intake, subjects with any HFE gene mutation were more likely to have colon cancer than subjects with no HFE gene mutations (adjusted odds ratio [OR] = 1.40, 95% confidence interval [CI] = 1.07 to 1.87). The magnitude of the effect was similar for both the H63D (adjusted OR = 1.44, 95% CI = 1.04 to 1.98) and C282Y mutations (adjusted OR = 1.39, 95% CI = 0.88 to 2.19). The risk of colon cancer associated with an HFE gene mutation was similar for those who did and did not have a family history of colon cancer. Among those with HFE mutations, cancer risk increased with increasing age and total iron intake. CONCLUSIONS: HFE gene mutations are associated with an increased risk of colon cancer. Cancer risk is greatest in mutation carriers who are older or consume high quantities of iron.

Age Factors↗
PubMed2006

Consequences of expressing mutants of the hemochromatosis gene (HFE) into a human neuronal cell line lacking endogenous HFE.

HFE mutations have traditionally been associated with the iron overload disorder known as hemochromatosis. Recently, it has become clear that the two most common mutations in the HFE gene, H63D and C282Y, may be genetic modifiers for risk of neurodegenerative disorders and cancer, respectively. We developed human neuroblastoma stable cell lines that express either wild-type (WT) or mutant HFE to determine the cellular consequences of the mutant forms of HFE. The presence of the C282Y mutation was associated with relatively higher labile iron pool and iron regulatory protein activity than WT or H63D HFE. Targeted gene arrays revealed that the signal transduction pathway was up-regulated in the C282Y cells. H63D cells had higher levels of lipid peroxidation, protein oxidation, and lower mitochondrial membrane potential, suggesting higher baseline stress. This cell line was also more vulnerable to exposure to oxidative stress agents and more responsive to iron chelation than the C282Y cells. These data demonstrate that the different mutations in the HFE gene have unique effects on the cells and provide insights into how the different mutations may have different clinical consequences. The results also raise multiple novel questions for future study about the function of the HFE protein.

Blotting, Western↗
PubMed1991

The immune system in hereditary hemochromatosis: a quantitative and functional assessment of the cellular arm.

The objective of this investigation was to evaluate certain quantitative and functional characteristics of the effector cells of the cellular arm of the immune system in hereditary hemochromatosis (HH) with respect to treatment status. Two observations were consistent with the postulate that the elevated levels of storage iron has in vivo immunoregulatory properties: (1) the absolute number of CD8-positive T cells were significantly elevated in untreated HH patients (n = 7) and reduced in treated patients (n = 7), as compared with controls; and (2) the proliferative response of peripheral blood mononuclear cells from untreated HH patients to mitogens was suboptimal but the response of peripheral blood mononuclear cells (PBM) from treated HH patients was normal. Furthermore, immunoglobulin secretion by PBM from treated HH patients as compared to controls was altered. Finally, one T effector cell abnormality was unrelated to treatment status in that a subset of mature, non-activated T lymphocytes aberrantly formed thermostable erythrocyte-rosettes (TE-R), a lymphoid surface marker usually expressed on thymocytes or activated T cells. Taken together these data define certain immune alterations that are consistent with the interpretation that cellular immunity may be influenced by the high level of storage iron in HH patients.

Antibody Formation↗
PubMed2001

Arthropathy in hereditary hemochromatosis.

Arthropathy is one of the leading clinical manifestations of hereditary hemochromatosis (HH). Although cirrhosis of the liver is crucial for mortality in patients with HH, arthropathy has the greatest impact on the quality of life. Several mutations in the HFE and other genes have recently been identified, and the prevalence of some of these mutations has already been investigated in population studies in greater detail. Even though cofactors other than genetic predisposition may play a role in the establishment of the disease, the new understanding of the genetic background of this iron storage disorder may help in identifying patients before the onset of clinical symptoms. Early initiation of iron depletion therapy, not effective in established arthropathy of HH, might prevent the manifestation of arthropathy or reduce its severity.

Hemochromatosis↗
PubMed1980

Computed tomographic analysis of beta-thalassemic syndromes with hemochromatosis: pathologic findings with clinical and laboratory correlations.

The major clinical problem in patients with thalassemia is iron overloading usually resulting from increased exogenous iron absorption from transfusions. Diseases of various organ systems result, including cirrhosis, cardiomyopathy, diabetes, and other less well appreciated endocrinopathies. Since 1976, we have routinely studied these patients with abdominal computed tomography (CT) and also have scanned other areas of clinical interest. It is the purpose of this report to examine the findings in 35 patients with severe beta-thalassemia and associated hemochromatosis in whom we have tabulated the pertinent CT, clinical and laboratory data.

Adolescent↗