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PubMed2001

Mutation analysis of the HFE gene in German hemochromatosis patients and controls using automated SSCP-based capillary electrophoresis and a new PCR-ELISA technique.

BACKGROUND: The diagnosis of hereditary hemochromatosis (HH) before the onset of iron-overload has been difficult in the past. However, a convincing candidate gene for HH: HFE has been described recently. The aims of this study were: 1) To determine the prevalence of the hemochromatosis associated mutations C282Y and H63D of the HFE gene in patients from Southern Germany with hemochromatosis phenotype; and 2) to test two new, time- and cost-saving methods: automated SSCP-based capillary electrophoresis (SSCP-CE) and a PCR-ELISA technique for the analysis of HFE mutations. METHODS: HFE genotype was studied in 36 unrelated HH patients and 126 controls from Southern Germany. In addition, family screening was performed in 76 relatives. The C282Y and H63D mutations were detected using SSCP-CE and restriction length polymorphism (RFLP). The C282Y mutation was additionally analysed by a PCR-ELISA. RESULTS: Twenty-six (72%) HH patients were homozygous for mutation C282Y, and three compound heterozygous for C282Y and H63D. One patient was homozygous for H63D. By performing family screening, six additional patients with the +/+ C282Y mutation were identified. The results of the SSCP-CE and the PCR-ELISA analysis agreed completely with data obtained by RFLP. CONCLUSIONS: SSCP-CE and PCR-ELISA analysis proved to be reliable methods for HFE genotyping and therefore represent cost- and time-effective alternative methods to the widely used restriction analysis allowing large populations to be screened for HH associated with HFE mutations. Surprisingly, only 72% of our HH patients had the C282Y +/+ genotype. This indicates that hemochromatosis in Southern Germany is genetically more heterogeneous than in other regions. A challenge for the future will be to define the genetic or environmental factors responsible for iron-overload in HH patients who do not show typical alterations of the HFE gene.

DNA Mutational Analysis↗
PubMed2001

Psychosocial impact of C282Y mutation testing for hemochromatosis.

The aim of this study was to investigate the psychological effects of genetic testing for hemochromatosis. Study participants included cases discovered through a population screening study in 5211 voluntary blood donors (n = 25) and patients referred for diagnostic evaluation for hemochromatosis (n = 117). Participants completed questionnaires (Spielberger State-Trait Anxiety Index, Medical Outcomes Survey Short Form 36) before and after genetic testing. A subset of participants from the screening study was also interviewed 1 year after testing (Feelings About Test Results Measure). Additional questions included data on insurance applications, time off from work, and family issues. Anxiety significantly decreased in homozygotes and heterozygotes after genetic testing and remained constant in C282Y mutation-negative cases. Vitality and physical composite scores improved after genetic testing. There were no significant deleterious psychological effects of genetic testing on anxiety and on mental and physical health status. There were no negative effects discovered on insurance or time off work. This study has not demonstrated deleterious effects of genetic testing for hemochromatosis on anxiety, mental health and physical health status, insurance, or time off from work. Genetic testing for hemochromatosis is well accepted and should not be discouraged on the basis of potential adverse psychosocial effects.

Absenteeism↗
PubMed2004

Hereditary hemochromatosis genetic testing of at-risk children: what is the appropriate age?

The objective of this study was to consider the objective evidence and ethical arguments for the appropriate age to test children at risk of developing hereditary hemochromatosis. A literature search for information on iron overload in children, onset of disease expression for hemochromatosis, and recommendations for age of cascade screening was undertaken. We examined the objective evidence and arguments for testing in early childhood and those for delaying testing until later teenage years. Cascade testing of offspring of people with hemochromatosis is widely advocated because it is an easily preventable disease. The ideal age to test those offspring is a matter of debate. Some authorities advocate testing at a very young age whereas others recommend delaying testing until late teenage years. To date there has been no published overview of the objective evidence and arguments central to this debate. In children who are C282Y homozygous, iron overload is rare in the first two decades of life and associated morbidity has only been documented in 1 patient. In the cascade setting, genetic testing for hemochromatosis need not be offered until late teenage years.

Adolescent↗
PubMed2004

A previously undescribed frameshift deletion mutation of HFE (c.del277; G93fs) associated with hemochromatosis and iron overload in a C282Y heterozygote.

A 62-year-old white man with a hemochromatosis phenotype was found to be heterozygous for the C282Y mutation of the HFE gene. The H63D and S65C mutations of HFE were not present. As most C282Y heterozygotes do not develop a hemochromatosis phenotype, the coding region of the patient's HFE gene was sequenced and a previously undescribed frameshift mutation was identified in exon 2 (c.del277; G93fs) that resulted in a premature stop-codon. There were no coding region mutations of the ferroportin gene (FPN1). We performed human leukocyte antigen (HLA) typing of the patient and his brother who was heterozygous for the C282Y HFE mutation unassociated with a hemochromatosis phenotype. They shared only C282Y and the HLA haplotype A*03, B*14; hence, the c.del277 mutation was linked to the HLA haplotype A*02, B*44 and therefore not on the same chromosome as the C282Y mutation. Thus, the present patient's only intact HFE protein is C282Y, and this may explain his hemochromatosis phenotype.

Amino Acid Sequence↗
PubMed2000

Can large cell change and high proliferative activity predict hepatocellular carcinoma in patients with hereditary hemochromatosis?

OBJECTIVE: Patients with hereditary hemochromatosis are at high risk of developing hepatocellular carcinoma. This study was undertaken to define whether large cell change and nucleolar organizer regions proliferative index (marker of high proliferative activity) predict hepatocellular carcinoma development in hereditary hemochromatosis. METHODS: Histological staining for large cell change and high proliferative activity were done on baseline liver biopsies of 74 patients with hereditary hemochromatosis (52 with and 22 without cirrhosis), prospectively followed-up for 83 +/- 53 months (range, 1-230 months). RESULTS: Large cell change and high proliferative activity were found only in cirrhotic patients; 16 of 52 patients (31%) had either the large cell change or high proliferative activity. Large cell change was more frequent in patients with hepatitis B surface antigen than in those positive for hepatitis C virus (57% vs 14%, p = 0.04). Hepatocellular carcinoma developed in 7 of 16 (44%) and in 6 of 36 patients (16%) of the patients positive or negative for these morphological variables. The probability of developing hepatocellular carcinoma at 7 yr of follow-up was significantly higher in patients with large cell change or high proliferative activity than in those without. The length of follow-up from baseline histology to hepatocellular carcinoma occurrence was shorter in patients with large cell change or high proliferative activity than in those without these changes (46 +/- 36 and 109 +/- 34 months, p = 0.01). A multivariate analysis indicated that in patients with cirrhosis, large cell change or high proliferative activity (considered as a single variable), and age >55 yr were the only independent variables significantly associated with the risk of developing hepatocellular carcinoma, with a risk ratio of 4.8 (confidence interval 1.2-18.2) and 4.0 (confidence interval 1.1-15.6), respectively. CONCLUSIONS: In hereditary hemochromatosis, the presence of large cell change or high proliferative activity in patients older than 55 yr with cirrhosis should be considered a strong predictor of hepatocellular carcinoma development, especially if hepatitis B virus infection coexists.

Adult↗
PubMed2005

A mouse model of juvenile hemochromatosis.

Hereditary hemochromatosis is an iron-overload disorder resulting from mutations in proteins presumed to be involved in the maintenance of iron homeostasis. Mutations in hemojuvelin (HJV) cause severe, early-onset juvenile hemochromatosis. The normal function of HJV is unknown. Juvenile hemochromatosis patients have decreased urinary levels of hepcidin, a peptide hormone that binds to the cellular iron exporter ferroportin, causing its internalization and degradation. We have disrupted the murine Hjv gene and shown that Hjv-/- mice have markedly increased iron deposition in liver, pancreas, and heart but decreased iron levels in tissue macrophages. Hepcidin mRNA expression was decreased in Hjv-/- mice. Accordingly, ferroportin expression detected by immunohistochemistry was markedly increased in both intestinal epithelial cells and macrophages. We propose that excess, unregulated ferroportin activity in these cell types leads to the increased intestinal iron absorption and plasma iron levels characteristic of the juvenile hemochromatosis phenotype.

Animals↗
PubMed2006

Tumor necrosis factor-alpha -308G>A allelic variant modulates iron accumulation in patients with hereditary hemochromatosis.

BACKGROUND: In vitro and animal studies suggest that tumor necrosis factor alpha (TNF-alpha) modulates intestinal iron transport. We hypothesized that the effect of TNF-alpha might be particularly relevant if iron absorption is not effectively controlled by the HFE gene. METHODS: In patients with homozygous C282Y hemochromatosis, we investigated the influence of TNF-alpha -308G>A allelic variant on total body iron overload, determined in all patients by measuring iron removed during depletion therapy, and hepatic iron index and need for phlebotomy to prevent iron reaccumulation, measured in patient subgroups. RESULTS: Of 86 patients with hereditary hemochromatosis, 16 (19%) were heterozygous carriers and 1 (1%) was a homozygous carrier of the TNF-alpha promoter -308A allele. Mean (SD) total body iron overload was increased 2-fold in TNF-alpha -308A allele carriers [10.9 (7.6) g] compared with homozygous carriers of the G allele [5.6 (5.0) g, P<0.001]. Hepatic iron index differed markedly between TNF-alpha -308A allele carriers [5.6 (3.5) micromol/g/year] and homozygous G allele carriers [3.1 (2.2) micromol/g/year, P=0.040, n=30]. After iron depletion, the need for phlebotomy to prevent iron reaccumulation (maintenance therapy) was substantially higher in TNF-alpha -308A allele carriers than in homozygous G allele carriers (P=0.014, n=73). We used multiple regression analyses to exclude possible confounding effects of sex, age, family screening, body-mass index, and meat or alcohol intake. CONCLUSION: TNF-alpha -308G>A allelic variant modulates iron accumulation in patients with hereditary (homozygous C282Y) hemochromatosis, but the effect of the TNF-alpha -308A allele on clinical manifestations of hemochromatosis was less accentuated than expected from the increased iron load associated with this allele.

Alleles↗
PubMedDate not supplied

Hemochromatosis, HFE C282Y homozygosity, and bariatric surgery: report of three cases.

BACKGROUND: Iron absorption is decreased in some individuals who have undergone bariatric surgery. METHODS: We evaluated measures of iron metabolism and therapeutic phlebotomy in 3 adults with hemochromatosis and HFE C282Y homozygosity who underwent bariatric surgery. RESULTS: 1 male and 1 female had surgery before diagnosis of hemochromatosis (jejuno-ileal bypass and Roux-en-Y gastric bypass, respectively); neither had iron overload. Another man was treated with serial phlebotomy to induce iron depletion; later, he underwent Roux-en-Y gastric bypass. His maintenance phlebotomy requirement for hemochromatosis decreased substantially (on average approximately 1 unit each 71 days before surgery, and approximately 1 unit each 173 days after surgery). None of these patients developed iron deficiency, and none took supplemental iron. CONCLUSIONS: Iron absorption is decreased in some patients with hemochromatosis and HFE C282Y homozygosity after bariatric surgery, but their risk of developing iron deficiency may be diminished.

Adult↗
PubMedDate not supplied

Prevalence of the hemochromatosis gene mutation in patients with nonalcoholic steatohepatitis and correlation with degree of liver fibrosis.

BACKGROUND: Nonalcoholic steatohepatitis is a chronic liver disease with a high prevalence in the general population and a potential to evolve into cirrhosis. It is speculated that iron overload could be associated with liver injury and unfavorable progress in affected patients. AIMS: To evaluate the prevalence of mutation of the hemochromatosis gene (HFE) in patients with nonalcoholic steatohepatitis and to correlate it with histological findings in liver specimens. PATIENTS AND METHODS: Twenty-nine patients with nonalcoholic steatohepatitis were evaluated. The presence of mutation in the hemochromatosis gene (C282Y and H63D) was tested in all patients and its result was evaluated in relation to hepatic inflammatory activity, presence of fibrosis, and iron overload in the liver. The control group was composed of 20 patients with normal liver function tests and 20 patients infected with the hepatitis C virus, with elevated serum levels of aminotransferases and with chronic hepatitis as shown by biopsy. RESULTS: Mutation of the hemochromatosis gene (C282Y and/or H63D) was diagnosed in 16 (55.2%) patients with nonalcoholic steatohepatitis, in 12 (60%) patients with hepatitis C and in 8 (40%) patients with no liver disease. No association was found between the presence of mutation and inflammatory activity, nor with the presence of fibrosis in patients with nonalcoholic steatohepatitis. An association was found between the presence of mutation and the occurrence of iron overload in liver, but there was no association between liver iron and the occurrence of fibrosis. CONCLUSIONS: The findings suggest that iron does not play a major role in the pathogenesis and progression of nonalcoholic steatohepatitis, and routine tests of the hemochromatosis gene mutation in these patients should not be recommended.

Adult↗
PubMed2006

Relationships of serum ferritin, transferrin saturation, and HFE mutations and self-reported diabetes in the Hemochromatosis and Iron Overload Screening (HEIRS) study.

OBJECTIVE: We evaluated the associations of self-reported diabetes with serum ferritin concentration, transferrin saturation (TfSat), and HFE C282Y and H63D mutations in six racial/ethnic groups recruited at five field centers in the Hemochromatosis and Iron Overload Screening (HEIRS) study. RESEARCH DESIGN AND METHODS: Analyses were conducted on 97,470 participants. Participants who reported a previous diagnosis of diabetes and/or hemochromatosis or iron overload were compared with participants who did not report a previous diagnosis. RESULTS: The overall prevalence of diabetes was 13.8%; the highest prevalence was in Pacific Islanders (20.1%). Of all participants with diabetes, 2.0% reported that they also had hemochromatosis or iron overload. The mean serum ferritin concentration was significantly greater in women with diabetes in all racial/ethnic groups and in Native-American men with diabetes than in those without diabetes. The mean serum ferritin concentration was significantly lower in Asian men with diabetes than in those without diabetes. Mean TfSat was lower in participants with diabetes from all racial/ethnic groups except Native-American women than in those without diabetes. There was no significant association of diabetes with HFE genotype. The mean serum ferritin concentration was greater (P < 0.0001) in women with diabetes than in those without diabetes for HFE genotypes except C282Y/C282Y and C282Y/H63D. Log serum ferritin concentration was significantly associated with diabetes in a logistic regression analysis after adjusting for age, sex, racial/ethnic group, HFE genotype, and field center. CONCLUSIONS: Serum ferritin concentration is associated with diabetes, even at levels below those typically associated with hemochromatosis or iron overload.

Adult↗
PubMed2002

Recognition and management of hereditary hemochromatosis.

Hereditary hemochromatosis is the most common inherited single-gene disorder in people of northern European descent. It is characterized by increased intestinal absorption of iron, with deposition of the iron in multiple organs. Previously, the classic description was combined diabetes mellitus, cutaneous hyperpigmentation and cirrhosis. Increasingly, however, hereditary hemochromatosis is being diagnosed at an earlier, less symptomatic stage. The diagnosis is based on a combination of clinical, laboratory and pathologic findings, including elevated serum transferrin saturation. Life expectancy is usually normal if phlebotomy is initiated before the development of cirrhosis or diabetes mellitus. Hereditary hemochromatosis is associated with mutations in the HFE gene. Between 60 and 93 percent of patients with the disorder are homozygous for a mutation designated C282Y. The HFE gene test is useful in confirming the diagnosis of hereditary hemochromatosis, screening adult family members of patients with HFE mutations and resolving ambiguities concerning iron overload.

Adult↗
PubMed2004

Screening selected blood donors with biochemical iron overload for hemochromatosis: a regional experience.

BACKGROUND AND OBJECTIVES: Hemochromatosis is a genetic disorder characterized by progressive iron overload which leads to early abnormalities of iron parameters (increased transferrin saturation =TS and serum ferritin=SF) and late clinical complications. The disease is prevalently due to C282Y and H63D mutations in the HFE gene, but additional molecular defects are present in a minority of patients. DESIGN AND METHODS: From January to December 2002 we screened first time blood donors of Piedmont, a region of North-western Italy, for TS>45%. Individuals with TS>45% underwent a second fasting check, SF assessment and molecular tests, investigating 12 hemochromatosis-associated molecular defects. RESULTS: A total of 13,998 subjects were screened; 868 (6.2%) had TS>45% and were recalled. Four hundred and eight-six underwent molecular testing. In this selected population allele frequencies of C282Y, H63D and S65C were 6.8%, 22.4% and 1.0%, respectively. No rare mutations were detected, except E168Q in HFE. When measured during fasting, TS was significantly higher in C282Y homozygotes and H63D/C282Y heterozygotes (p<0.05) than in wild type subjects, but not in H63D homozygotes. Hyperferritinemia was documented in 32 cases, 9 with wild type genotype. Mean age, body mass index (BMI) and alcohol intake were higher in this group than in individuals with normal SF. INTERPRETATION AND CONCLUSIONS: This study is an example of a large, two-step hemochromatosis screening with moderate effort and low cost, that enriches basal C282Y allele frequency by about three-fold. Screening based on genotyping only subjects found to have a TS>45% is feasible but, in order to be cost effective should be based on the identification of the two prevalent mutations even in an area where several forms of hemochromatosis have been reported.

Adult↗
PubMed2004

Changing the clinical management of hereditary hemochromatosis: translating screening and early case detection strategies into clinical practice.

BACKGROUND: This article describes the effect of an extensive physician educational program on detection and management of hereditary hemochromatosis (HH) before and after a hemochromatosis population screening study. METHODS: We measured the changes in clinical management by medical chart review for newly diagnosed cases before and after the educational program. The effect on detection of HH cases was determined by mail survey to primary care physicians in our health system. RESULTS: The median age at diagnosis of HH was 54 years before the study and 45 years after the study (P =.12). In the same period, among those with diagnosed hemochromatosis, the mean prestudy ferritin level changed from 1848 ng/mL to 606 ng/mL after the study (P =.03). The mean number of units removed by phlebotomy to complete "de-ironing" in diagnosed patients was 40 U before the study and 18 U after the study (P =.06); the number of months required for de-ironing was 15 months before the study and 6 months after the study (P =.02). Before the study, no primary care physician was screening for HH. Two years after completion of the study, 11% (6/54) of primary care physicians indicated they had continued to screen all patients for hemochromatosis. CONCLUSIONS: Early detection and treatment of iron overload may be facilitated by educating health care providers and insurers about an "iron-avid" state, occurring in healthy patients who would benefit from periodic surveillance of their iron status. Continued education of physicians concerning diagnosis and treatment of HH aids progress toward increased early case detection.

Adult↗
PubMed2006

Screening for hemochromatosis in asymptomatic subjects with or without a family history.

BACKGROUND: Hemochromatosis in white subjects is mostly due to homozygosity for the common C282Y substitution in HFE. Although clinical symptoms are preventable by early detection of the genetic predisposition and prophylactic treatment, population screening is not currently advocated because of the discrepancy between the common mutation prevalence and apparently lower frequency of clinical disease. This study compared screening for hemochromatosis in subjects with or without a family history. METHODS: We assessed disease expression by clinical evaluation and liver biopsy in 672 essentially asymptomatic C282Y homozygous subjects identified by either family screening or health checks. We also observed a subgroup of untreated homozygotes with normal serum ferritin levels for up to 24 years. RESULTS: Prevalence of hepatic iron overload and fibrosis were comparable between the 2 groups. Disease-related conditions were more common in male subjects identified by health checks, but they were older. Hepatic iron overload (grades 2-4) was present in 56% and 34.5% of male and female subjects, respectively; hepatic fibrosis (stages 2-4) in 18.4% and 5.4%; and cirrhosis in 5.6% and 1.9%. Hepatic fibrosis and cirrhosis correlated significantly with the hepatic iron concentration, and except in cases of cirrhosis, there was a 7.5-fold reduction in the mean fibrosis score after phlebotomy. All subjects with cirrhosis were asymptomatic. CONCLUSIONS: Screening for hemochromatosis in apparently healthy subjects homozygous for the C282Y mutation with or without a family history reveals comparable levels of hepatic iron overload and disease. Significant hepatic fibrosis is frequently found in asymptomatic subjects with hemochromatosis and, except when cirrhosis is present, is reversed by iron removal.

Adolescent↗
PubMed1994

Hereditary hemochromatosis and red cell aplasia.

A 63-year-old white man with myasthenia gravis and red cell aplasia was found to have hepatic iron overload. The differential diagnosis included hereditary hemochromatosis and secondary iron overload related to red cell aplasia. Family studies of siblings, including HLA typing, initially suggested a diagnosis of secondary iron overload. The investigation of a remote sibling led to the final diagnosis of hereditary hemochromatosis. The case illustrates the importance of complete family investigations in the differentiation between hereditary hemochromatosis and secondary iron overload and the potential hazard of using HLA typing as an indirect genetic test for hereditary hemochromatosis.

Diagnosis, Differential↗
PubMed1994

Serum transferrin receptor in hereditary hemochromatosis and African siderosis.

The present investigation evaluated the serum transferrin receptor concentration in subjects with nontransfusional iron overload who were identified in two separate studies on the basis of a serum ferritin level above 400 micrograms/L. Subjects with preclinical hereditary hemochromatosis were evaluated in the first study and those with the African form of iron overload in the second. In the first study, hereditary hemochromatosis was identified in 14 white men on the basis of a persistent elevation in transferrin saturation above 55%. The serum receptor concentration was elevated above the upper cut-off of 8.5 mg/L in two of the subjects, but the mean receptor of 6.1 +/- 1.4 mg/L (mean +/- 2 SE) did not differ significantly from the normal mean for this assay of 5.6 +/- 0.3 mg/L. In the same study, 60 control subjects with secondary iron overload were identified on the basis of a serum ferritin persistently above 400 micrograms/L, with a normal serum C-reactive protein concentration but with a transferrin saturation < 55%. Three of these subjects had an elevated serum receptor concentration but the mean value of 5.5 +/- 0.4 mg/L did not differ from normals nor from subjects with hemochromatosis. In the second study, 49 black Africans with iron overload were divided into those with or without an elevated transferrin saturation. The mean serum receptor concentration of 5.0 +/- 0.8 mg/L and 4.5 +/- 0.4 mg/L, respectively, did not differ statistically. It was concluded that there is no evidence of generalized dysregulation of the transferrin receptor in hemochromatosis or African siderosis.

Adult↗
PubMed1994

Hereditary hemochromatosis: a prevalent disorder of iron metabolism with an elusive etiology.

Hereditary hemochromatosis is a prevalent inherited disorder with an estimated frequency of homozygosity of 0.2 to 0.45% in Caucasians. The disease is characterized by progressive iron overload until a massive accumulation of body iron occurs. Undetected, the disorder eventually can produce either cirrhosis, diabetes mellitus, cardiac disease, arthritis, or hepatocellular carcinoma or a combination of these manifestations. Early diagnosis and treatment prevents organ damage and normalizes life expectancy. Screening studies to detect hemochromatosis are most effectively accomplished by measurement of the serum iron and total iron binding capacity. Treatment is most effectively performed by frequent phlebotomy until body stores are empty and then 3 to 4 times yearly for life. The basic defect of hemochromatosis appears to increase iron absorption, decrease iron excretion, and produce preferential deposit of iron in hepatic parenchymal cells rather than Kupffer cells. The genetic abnormality of hemochromatosis is located on chromosome 6 in close association with the gene for HLA antigens. Recent speculation postulates that tumor necrosis factor may be involved in the etiology of this disease because of its location on chromosome 6 and its effect upon iron transport.

Family Health↗
PubMed2003

Arthropathy in juvenile hemochromatosis.

OBJECTIVE: To evaluate whether arthropathy is associated with juvenile hemochromatosis and, if so, to assess the relationship between this feature and other clinical features of the disease. METHODS: Clinical, laboratory, and radiologic evidence of arthropathy was studied in 8 Greek patients with genetically proven juvenile hemochromatosis. Osteopenia and osteoporosis were assessed by bone mineral density measurement. RESULTS: Seven of the 8 patients had articular manifestations. The main affected joint was the metacarpophalangeal joint, and the arthritis was progressive independent of phlebotomy therapy. Osteopenia was observed in 2 patients, and osteoporosis in 2 patients. CONCLUSION: Arthropathy may be present in patients with juvenile hemochromatosis, with features similar to those found in patients with hemochromatosis type 1.

Adult↗