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At least 19 recordsLinked to original sources
PubMed1992

Importance of establishing appropriate local reference values for the screening of hemochromatosis: a study of three different control populations and 136 hemochromatosis family members. Hemochromatosis Clinical and Research Group.

Hemochromatosis is a human leukocyte antigen-linked (HLA-linked), potentially lethal disorder of iron metabolism with a high prevalence in white populations albeit an autosomal recessive mode of transmission. The diagnosis and treatment at early stages of the disease are critical to the prevention of the morbidity and mortality caused by the iron overload. After the identification of the first cases of hemochromatosis in Portugal, a screening program was started with a systematic search for the disease among family members of the patients, as well as in subjects from the normal population. In this study we analyze the results obtained with a total of 136 family members from 15 different families and 353 control subjects from three different villages, two in the north and one in the south of Portugal. We establish reference values for the biochemical tests used in the screening for iron overload and analyze the factors that affect those results. Besides sex-related differences, factors that were found to influence biochemical parameters most significantly included age and levels of daily alcohol intake. In addition, differences in iron status were identified between the populations from the regions in the north and the south of the country. We estimate, by HLA typing and family studies, a gene frequency for hemochromatosis of 0.14 that corresponds to a frequency of homozygotes and heterozygotes of 0.019 and 0.24, respectively.

Adolescent↗
PubMedDate not supplied

Is hereditary hemochromatosis a balanced polymorphism: an analysis of family size among hemochromatosis heterozygotes.

BACKGROUND/AIMS: Hereditary hemochromatosis (HH) has a homozygote frequency of 0.5% and a heterozygote frequency of 13%, which suggests that hemochromatosis might be a balanced polymorphism. Evidence for this was sought by assessing reproductive success among hemochromatosis heterozygotes through determining their family size and incidence of miscarriage when compared to nongene carriers. METHODOLOGY: A cohort was defined in which the exposure variable was heterozygosity for hereditary hemochromatosis. Heterozygotes were identified by mailing individuals homozygous for hereditary hemochromatosis questionnaires concerning the number of siblings born alive and the number of miscarriages suffered by their mothers (predominantly heterozygotes, or HHH). Spouses of the hereditary hemochromatosis homozygotes were asked to complete accompanying questionnaires concerning their mothers (CONT). RESULTS: Five hundred and ninety-six responses were received from hereditary hemochromatosis homozygotes and 532 responses from spouses of the hereditary hemochromatosis homozygote respondents. The mothers of the hereditary hemochromatosis homozygote respondents had a mean family size of 3.699. The mothers of the unexposed spouse controls a mean family size of 3.639 (P = 0.66 by ANOVA). One hundred and twenty-three of the HHH mothers suffered a total of 201 miscarriages, whereas 94 of the CONT mothers suffered 147 miscarriages (P = 0.38 by ANOVA). CONCLUSIONS: In this cohort, no evidence among hemochromatosis heterozygotes of reproductive advantage and therefore heterozygous advantage by this mechanism was seen.

Abortion, Spontaneous↗
PubMed1987

A study of 609 HLA haplotypes marking for the hemochromatosis gene: (1) mapping of the gene near the HLA-A locus and characters required to define a heterozygous population and (2) hypothesis concerning the underlying cause of hemochromatosis-HLA association.

We compared 609 haplotypes carrying the idiopathic hemochromatosis allele with 475 control haplotypes. Four haplotypes were more frequent in hemochromatosis: A3, B7 (actually A3, CW., B7, Bfs, DR2); A3, B14 (actually A3, CW., B14, BfF, DRW6); A11, B35; and A11, B5. The linkage disequilibrium for A3, B7 and A3, B14 (and probably also for A11, B5) was undeniably stronger in hemochromatosis than in controls. Two haplotypes--A3, B12 and A3, B15--were more frequent in hemochromatosis, without linkage disequilibrium. Four haplotypes in linkage disequilibrium in hemochromatosis--i.e., A2, B12; A1, B8; A9, B7; and A29, B12--were also found to have the same frequency and strength of linkage in controls. The dual observation (1) that haplotypes carrying A3 without either B7 or B14 were highly significantly more frequent in hemochromatosis than in controls and (2) that haplotypes carrying B7 or B14 but not A3 had the same frequency in hemochromatosis and controls led to the formal conclusion that only A3 is an independent marker for the hemochromatosis allele, B7 and B14 being involved only owing to the haplotypic mode of marking; the hemochromatosis allele can thus be mapped closer to locus A than to locus B. Our findings fit well with the hypothesis that the hemochromatosis mutation was a rare if not unique event that produced an ancestral HLA marking that was subsequently modified by recombinations and geographical scattering due to migrations.

Alleles↗
PubMed2005

Juvenile hemochromatosis associated with pathogenic mutations of adult hemochromatosis genes.

BACKGROUND AND AIMS: Juvenile hemochromatosis is a severe form of hereditary iron overload that has thus far been linked to pathogenic mutations of the gene coding for hemojuvelin (HJV), on chromosome 1, or, more rarely, that coding for hepcidin ( HAMP ), on chromosome 19. A milder adult-onset form is due to pathogenic mutations of HFE or, rarely, serum transferrin receptor 2. METHODS: We studied a pedigree with siblings affected by both juvenile and adult-onset hereditary hemochromatosis. Affected subjects underwent full clinical evaluation, as well as microsatellite and gene sequencing analysis. RESULTS: Two siblings (male and female, aged 24 and 25 years, respectively) were hospitalized for severe endocrinopathy and cardiomyopathy. At age 18 and 17 years, they had presented with impotence and amenorrhea, respectively, and increased serum iron levels. Hypogonadotropic hypogonadism was confirmed in both, and liver biopsy showed marked hepatic iron accumulation and micronodular cirrhosis. Iron levels were normalized after 24 months (female) and 36 months (male) of weekly phlebotomies. Microsatellite analysis showed no linkage with chromosome 1 and 19, and gene sequencing showed no hemojuvelin or hepcidin gene mutations. Instead, combined mutations of HFE (C282Y/H63D compound heterozygosity) and serum transferrin receptor 2 (Q317X homozygosity) were found. A 21-year-old brother with a milder phenotype resembling classic adult-onset hereditary hemochromatosis carried only the Q317X serum transferrin receptor 2 homozygote mutation. CONCLUSIONS: Juvenile hereditary hemochromatosis is not a distinct monogenic disorder invariably due to hemojuvelin or hepcidin mutations: it may be genetically linked to the adult-onset form of hereditary hemochromatosis.

Adult↗
PubMed1999

Hereditary hemochromatosis in adults without pathogenic mutations in the hemochromatosis gene.

BACKGROUND AND METHODS: Hereditary hemochromatosis in adults is usually characterized by mutations in the HFE gene on the short arm of chromosome 6. Most patients have a substitution of tyrosine for cysteine at position 282 (C282Y). We studied a large family from Italy that includes persons who have a hereditary iron-overload condition indistinguishable from hemochromatosis but without apparent pathogenic mutations in the HFE gene. We performed biochemical, histologic, and genetic studies of 53 living members of the family, including microsatellite analysis of chromosome 6 and direct sequencing of the HFE gene. RESULTS: Of the 53 family members, 15 had abnormal serum ferritin levels, values for transferrin saturation that were higher than 50 percent, or both. Thirteen of the 15 had elevated body iron levels, diagnosed on the basis of the clinical evaluation and liver biopsy, and underwent iron-removal therapy. The other two, both children, did not undergo liver biopsy or iron-removal therapy. None of the 15 members had the C282Y mutation of the HFE gene; 5 of the 15 (as well as 5 healthy relatives) had another mutation of this gene, a substitution of aspartate for histidine at position 63, but none were homozygous for it. No other mutations were found after sequencing of the entire HFE gene for all family members. Microsatellite analysis showed no linkage of the hemochromatosis phenotype with the short arm of chromosome 6, the site of the HFE gene. CONCLUSIONS: Hereditary hemochromatosis can occur in adults who do not have pathogenic mutations in the hemochromatosis gene.

Adolescent↗
PubMed1997

Genetic and clinical description of hemochromatosis probands and heterozygotes: evidence that multiple genes linked to the major histocompatibility complex are responsible for hemochromatosis.

We evaluated Alabama hemochromatosis probands (n = 74) and normal control subjects (n = 142) for expression of the hemochromatosis-associated mutations nt 845G-->A (845A; Cys282Tyr) and nt 187C-->G (His63Asp) in a gene linked to the major histocompatibility complex (MHC). We also tabulated parameters of iron metabolism and iron overload in probands and in obligate heterozygote family members of homozygous Cys282Tyr probands. Among probands, 59.4% were Cys282Tyr homozygotes and 20.3% were heterozygotes; 20.3% did not express this mutation. In normal control subjects, 14.7% were heterozygous for the Cys282Tyr mutation; one normal control subject was homozygous for the Cys282Tyr mutation. None (0 of 44) of our Cys282Tyr-homozygous hemochromatosis probands had the His63Asp mutation. Of the Cys282Tyr-heterozygous and -negative probands, the His63Asp mutation occurred in 26.7% (4/15) and 53.3% (8/15), respectively. In normal control subjects, 23.2% were heterozygous for the His63Asp mutation; 2.8% were homozygous. Induction phlebotomy requirements and other manifestations of iron overload were significantly greater in Cys282Tyr homozygotes than among other probands. Cys282Tyr-heterozygous probands had significantly higher values of serum iron parameters than did obligate Cys282Tyr heterozygotes whose values were, on the average, normal. Co-expression of HLA-A3, HLA-B7, and D6S105(8) was significantly more frequent in all subgroups of probands stratified by Cys282Tyr expression than in normal control subjects. These results demonstrate that the severity of iron overload in hemochromatosis is affected significantly by genetic factors. Further, our findings support the hypothesis that one or more MHC-linked genes other than that corresponding to the Cys282Tyr and His63Asp mutations contributes to increased iron absorption and iron overload in hemochromatosis probands.

Adult↗
PubMed2000

The clinical expression of hemochromatosis in Oslo, Norway. Excessive oral iron intake may lead to secondary hemochromatosis even in HFE C282Y mutation negative subjects.

BACKGROUND: The prevalence of hereditary hemochromatosis in Norway is one of the highest reported in the world. However, the clinical presentation in patients with hemochromatosis in Norway seems to be different compared with recent studies elsewhere. The aim of this study was to investigate patients with hemochromatosis in one community hospital in Norway and to study the prevalence of the C282Y mutation. METHODS: One hundred and twenty patients were consecutively admitted to one medical department in Oslo. Serum transferrin and ferritin concentrations were measured in all patients, and a percutaneous liver biopsy was obtained in 108 of 120 (90%) patients. Stainable iron (Perls stain) in hepatocytes was graded from 0 to 4+ and fibrosis from 1 to 4. Genotyping for the C282Y and H63D mutation in the HFE gene was performed by PCR-RFLP. RESULTS: Forty-eight (40%) of the patients suffered from tiredness and astenia and 29 (24%) had typical arthropathy. Only 5 of 105 (4.5%) had biopsy confirmed cirrhosis and 5 had diabetes mellitus. Patients referred from a blood bank had significantly less symptoms and signs compared with other patients. Twenty-one of 120 (17.5%) patients were C282Y mutation negative. Seventeen (81%) of these patients (16 women and 1 man) had a history of extensive oral iron intake lasting from 5 to 50 years. When excluding those with extensive oral iron intake (n = 17), 92 of 103 (89%) were homozygous for the C282Y mutation, 7 (7%) were heterozygous including 3 compound heterozygous and 4 (4%) were mutation negative. CONCLUSIONS: Only a minority of our patients with hemochromatosis had a far advanced disease at the time of diagnosis (less than 5% had cirrhosis) and hemochromatosis in a majority of the C282Y mutation negative patients was associated with excessive oral iron intake for several years.

Adult↗
PubMed1998

Differential diagnosis of hereditary hemochromatosis from other liver disorders by genetic analysis: gene mutation analysis of patients previously diagnosed with hemochromatosis by liver biopsy.

BACKGROUND: Hereditary hemochromatosis, a common autosomal recessive trait caused by mutations in the HLA-H gene, is often diagnosed by the pathologist at the time of histologic examination. Unfortunately, histologic parameters alone do not differentiate between hereditary hemochromatosis and other causes of iron overload. We performed a retrospective study to determine the frequency of familial hemochromatosis in patients diagnosed with he mochromatosis by abnormal liver histology. METHODS AND RESULTS: DNA was isolated from paraffin-embedded tissue sections from 15 patients and used in a polymerase chain reaction-based assay in which we tested for the C282Y and H63D mutations. We found that in this group of patients, 5 (33%) were homozygous for the common C282Y genetic mutation, 3 (20%) were heterozygous, and 7 (47%) were normal. CONCLUSIONS: Our study shows that the molecular assay is the gold standard for the diagnosis of hereditary hemochromatosis. The case study also illustrates that a definitive diagnosis of familial hemochromatosis has significant counseling implications allowing for accurate family studies.

Adult↗
PubMedDate not supplied

Inheritance of two HFE mutations in African Americans: cases with hemochromatosis phenotypes and estimates of hemochromatosis phenotype frequency.

PURPOSE: Two unrelated African Americans had hemochromatosis phenotypes and genotypes. We sought to identify origins of their HFE mutations and estimate frequencies of similar cases. METHODS: HFE and HLA genotyping were performed in index cases and family members. HFE genotypes of 1,373 African American controls in five regions were tabulated. RESULTS: Index cases had C282Y/C282Y and C282Y/H63D, respectively; each corresponding Ch6p was likely of Caucasian origin. In controls, frequencies of hemochromatosis-associated genotypes were as follows: C282Y/C282Y, 0.00011; C282Y/H63D, 0.00067; and H63D/H63D, 0.00101. CONCLUSIONS: Penetrance-adjusted estimates indicate that approximately 9 African Americans per 100,000 have a hemochromatosis phenotype and two common HFE mutations. Hemochromatosis-associated genotype frequencies varied 11.7-fold across regions.

Adult↗
PubMedDate not supplied

[Hemochromatosis arthropathy--an early manifestation of genetic hemochromatosis].

Recent studies have shown a high frequency of genetic hemochromatosis in the Caucasian population. In addition, the well known organ involvement of genetic hemochromatosis was evident; more than 50% of patients develop a typical arthropathy which may result in severe physical disability. Among approximately 5000 patients referred to the rheumatology outpatient clinics of Bad Nauheim and Frankfurt with different rheumatologic diagnoses, 11 patients with typical signs of hemochromatotic arthropathy were identified. In none of those cases had the diagnosis "genetic hemochromatosis" been previously established. These patients had been treated for rheumatoid arthritis and other rheumatologic disorders over several years. All showed severe organ dysfunction due to iron overload, resulting in a reduced life expectancy. This investigation shows that knowledge of the typical signs of hemochromatotic arthropathy could lead to an earlier diagnosis of genetic hemochromatosis which is necessary to prevent the complications of iron overload in those patients.

Adult↗
PubMed1996

Hemochromatosis-like arthropathy in diabetes mellitus without hemochromatosis.

We describe 3 patients with non-insulin-dependent diabetes mellitus who presented with hand pain and swollen joints. All 3 had radiographic changes in the affected joints typical of those associated with hemochromatosis. None of these patients had hemochromatosis. This is the first description of hemochromatosis-like arthropathy in diabetes mellitus without hemochromatosis.

Aged↗
PubMed1999

HFE mutations analysis in 711 hemochromatosis probands: evidence for S65C implication in mild form of hemochromatosis.

Hereditary hemochromatosis (HH) is a common autosomal recessive genetic disorder of iron metabolism. The HFE candidate gene encoding an HLA class I-like protein involved in HH was identified in 1996. Two missense mutations have been described: C282Y, accounting for 80% to 90% of HH chromosomes, and H63D, which is associated with a milder form of the disease representing 40% to 70% of non-C282Y HH chromosomes. We report here on the analysis of C282Y, H63D, and the 193A-->T substitution leading to the S65C missense substitution in a large series of probands and controls. The results confirm that the C282Y substitution was the main mutation involved in hemochromatosis, accounting for 85% of carrier chromosomes, whereas the H63D substitution represented 39% of the HH chromosomes that did not carry the C282Y mutation. In addition, our screening showed that the S65C substitution was significantly enriched in probands with at least one chromosome without an assigned mutation. This substitution accounted for 7.8% of HH chromosomes that were neither C282Y nor H63D. This enrichment of S65C among HH chromosomes suggests that the S65C substitution is associated with the mild form of hemochromatosis.

Amino Acid Substitution↗
PubMed1998

Management of hemochromatosis. Hemochromatosis Management Working Group.

The complications of iron overload in hemochromatosis can be avoided by early diagnosis and appropriate management. Therapeutic phlebotomy is used to remove excess iron and maintain low normal body iron stores, and it should be initiated in men with serum ferritin levels of 300 microg/L or more and in women with serum ferritin levels of 200 microg/L or more, regardless of the presence or absence of symptoms. Typically, therapeutic phlebotomy consists of 1) removal of 1 unit (450 to 500 mL) of blood weekly until the serum ferritin level is 10 to 20 microg/L and 2) maintenance of the serum ferritin level at 50 microg/L or less thereafter by periodic removal of blood. Hyperferritinemia attributable to iron overload is resolved by therapeutic phlebotomy. When applied before iron overload becomes severe, this treatment also prevents complications of iron overload, including hepatic cirrhosis, primary liver cancer, diabetes mellitus, hypogonadotrophic hypogonadism, joint disease, and cardiomyopathy. In patients with established iron overload disease, weakness, fatigue, increased hepatic enzyme concentrations, right upper quadrant pain, and hyperpigmentation are often substantially alleviated by therapeutic phlebotomy. Patients with liver disease, joint disease, diabetes mellitus and other endocrinopathic abnormalities, and cardiac abnormalities often require additional, specific management. Dietary management of hemochromatosis includes avoidance of medicinal iron, mineral supplements, excess vitamin C, and uncooked seafoods. This can reduce the rate of iron reaccumulation; reduce retention of nonferrous metals; and help reduce complications of liver disease, diabetes mellitus, and Vibrio infection. This comprehensive approach to the management of hemochromatosis can decrease the frequency and severity of iron overload, improve quality of life, and increase longevity.

Diet↗
PubMed1996

Quantitative image analysis as an alternative to chemical analysis for follow-up of liver biopsies from a toucan with hemochromatosis. A technique with potential value for the follow-up of hemochromatosis in humans.

OBJECTIVE: To compare the reliability of quantitative image analysis of histologic sections versus chemical analysis for determination of the iron content of serial liver biopsies taken at regular intervals after the onset of treatment, in a case of hemochromatosis in a channel-billed toucan treated with deferoxaminemesilate in combination with a low-iron diet. STUDY DESIGN: Two different image analysis systems were used, one developed for working with black-and-white pictures and another capable of processing colored images. Using Pearson's correlation test, the results with both quantitative image analysis systems were compared to the results obtained by chemical analysis. RESULTS: There was a good correlation between the results of chemical analysis and those obtained with each of the two image analysis systems (0.86 and 0.89, respectively, with a confidence interval of 95%). The results of these serial liver biopsies indicated that the bird responded well to treatment. CONCLUSION: Quantitative image analysis can be used to evaluate follow-up of this disease in toucans as an alternative to chemical determination of the iron content in biopsies of the liver. this technique may have potential value in follow-up of hemochromatosis in humans.

Animals↗
PubMed2001

T-cell receptor repertoire in hereditary hemochromatosis: a study of 32 hemochromatosis patients and 274 healthy subjects.

Low CD8(+) T lymphocyte numbers have contributed to deciphering the genotype/phenotype discrepancies found in hereditary hemochromatosis (HH) patients genotyped for the Hfe mutations, C282Y and H63D. In this study, we extend the analysis of T lymphocytes in HH to the T cell receptor (TcR) repertoire. Thirty-two HH patients (C282Y homozygous) and 274 Hfe genotyped healthy subjects were studied. The following TcR chains were analyzed: Valpha2.3, Vbeta5.1, Vbeta5.2, Vbeta5.3, Vbeta6.7, Vbeta8, and Vbeta12 among the CD4(+) and CD8(+) populations. Lymphopenias and absence of expansions of the Vbeta5.2 and Vbeta12 chains in the CD8(+) pool were seen in controls heterozygous for the C282Y mutation. Expansions in the control group were seen within the CD8(+) pool and were rare/absent within the CD4(+) pool. TcR expansions were found more frequent in patients with iron overload related pathology than in patients without pathology. 9/16 of the patients with pathology have at least one expansion among the CD8(+) pool a number significantly higher compared with patients without pathology (1/16). These findings suggest that Hfe has an effect in the shaping of T-cell populations either directly, as indicated by the lymphopenia seen in the two chains in C282Y heterozygous without iron overload, or indirectly by contributing to iron overload pathology.

Adolescent↗
PubMed2004

Absence of hemochromatosis associated Cys282Tyr HFE gene mutation and low frequency of hemochromatosis phenotype in nonalcoholic chronic liver disease patients in India.

BACKGROUND AND AIM: Hereditary hemochromatosis (HHC) is an autosomal recessive disorder causing primary iron overload syndrome and chronic liver disease (CLD). This genetic disease is commonly associated with C282Y mutation of the HFE gene, commonly seen in the Northern European population. Minor reports on HHC are available from Asia, however, so far no genetic study is available from India. We prospectively studied the prevalence of C282Y mutation in CLD patients and healthy subjects in a tertiary care referral center in India. METHODS: A total of 249 consecutive biopsy proven CLD (HBV = 112, HCV = 72, cryptogenic = 65) patients and 134 age matched healthy controls were included. Cases of secondary iron overload, pregnancy, chronic alcoholism, age < 30 years and hepatocellular carcinoma (HCC) were excluded. A transferrin saturation index (TSI) of >60% was suggestive of a phenotypic presentation of HHC. C282Y mutation was studied by restriction fragment length polymorphism (RFLP) using genomic DNA. The 387 bp fragment obtained after polymerase chain reaction was digested with 10 units of endonuclease Rsa1. The mutation was detected by creation of an additional restriction site, giving rise to fragments of 247 111 and 29 bp. RESULTS: While the mean TSI was comparable, serum ferritin was significantly higher in CLD patients compared to controls (38 +/- 16%vs 28 +/- 13%; p = not significant (NS), and 125 +/- 18 vs 42 +/- 25 ng/mL; p < 0.001). A TSI of >60% was detected in 24 (9.64%) patients. Only one restriction site was found for endonuclease Rsa1, giving rise to two fragments of 247 and 140 bp, suggesting absence of C282Y mutation in the HFE gene in all patients. CONCLUSIONS: Almost 10% of nonalcoholic CLD patients in India have iron overload, but this is independent of C282Y mutation of the HFE gene. Large population based studies are recommended to investigate the prevalence of this rare disorder in India.

Adult↗