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PubMed1998

Heterogeneity of hemochromatosis in Italy.

BACKGROUND & AIMS: Patients with hemochromatosis show variable phenotype expression. We evaluated the frequency of hemochromatosis gene (HFE) mutations and the contribution of HFE genotype, ancestral haplotype, ethnic background, and additional factors (alcohol intake, hepatitis viruses, and beta-thalassemia trait) to the severity of iron overload in a large series of Italian patients with a hemochromatosis phenotype. METHODS: HFE genotype was studied in 188 patients. Phenotype evaluation was available in 153 men and 20 women and was based mainly on iron removed. HFE genotype was determined by a polymerase chain reaction restriction assay and ancestral haplotype through D6S265 and D6S105 microsatellite analysis. RESULTS: The frequency of C282Y homozygotes was 64%, with a decreasing gradient from north to south. C282Y homozygotes showed more severe iron overload than the other HFE genotypes. In the same group, ancestral haplotype was associated with a more severe phenotype. Additional factors may favor the development of a relatively mild hemochromatosis phenotype in patients nonhomozygous for the C282Y mutation. CONCLUSIONS: Hemochromatosis in Italy is a nonhomogenous disorder in which genetic and acquired factors are involved. In patients with a single or no HFE mutation, further studies will enable a differentiation between true genetic disorders and interactions between genetic and acquired factors.

Adult↗
PubMed1997

Evaluation of the hepatic iron index as a diagnostic criterion for genetic hemochromatosis.

The hepatic iron index was originally described as a useful test to discriminate genetic hemochromatosis from alcoholic siderosis. To evaluate the hepatic iron index as a diagnostic criterion, it is essential to evaluate a cohort of hemochromatosis patients in whom the diagnosis has been established with great certainty. The presence of a sibling with identical human leukocyte antigen (HLA) and with iron overload was considered to be the gold standard for the diagnosis. Hepatic iron index was reviewed retrospectively in 55 homozygotes and in 189 patients who did not have hemochromatosis and were referred for hepatic iron analysis. Four of 55 homozygotes (7%) had a hepatic iron index of < or = 1.9. Hepatic iron concentration was increased in all 4 patients, ranging from 36 to 100 micromol/gm dry weight, (normal value <35.5 micromol/gm). Twelve of 189 (6%) patients without hemochromatosis had hepatic iron indexes > 1.9. The positive likelihood ratio for a hepatic iron index of 1.9 was 12.4. Area under the receiver operating characteristic curve was 0.94 (0.9 to 0.99, 95% confidence interval). The hepatic iron index remains a useful tool in the diagnosis of genetic hemochromatosis. However, it should not be an absolute criterion for the diagnosis and should be interpreted in combination with clinical assessment and genetic studies.

Adult↗
PubMed1999

Screening for hemochromatosis. A public health perspective.

CONTEXT: The discovery of the HFE gene in 1996 has introduced DNA testing as a possible tool for screening and diagnosis of hemochromatosis and increased interest in the disorder. Population screening using transferrin saturation has been advocated by experts to permit early detection and treatment with phlebotomy before the onset of clinical disease. METHODS: Based on a literature review, we consider the relative risks and merits of two screening tests as part of a broader look at the evidence required for the recommendation of universal screening for hemochromatosis. RESULTS: Several questions must be answered before universal screening can be recommended. Uncertainties remain about the penetrance and preventable disease burden, laboratory standardization, and optimal strategies to minimize potential risks of screening for hemochromatosis. CONCLUSIONS: As a common genetic disorder with simple, effective therapy, hemochromatosis offers a model for other genetically influenced chronic diseases that some day may have interventions to improve prognosis. Resolution of questions related to prevention of chronic diseases from hemochromatosis, therefore, will have broad usefulness in the future.

Cost of Illness↗
PubMed2000

[Neonatal hemochromatosis].

UNLABELLED: Neonatal hemochromatosis is characterized by abnormal hepatic and extrahepatic iron overload, which spares the reticuloendothelial system. In neonates, hemochromatosis results in an acute and frequently lethal liver failure. CASE REPORTS: We report five cases of neonatal hemochromatosis which demonstrate various aspects of this disorder and underline the complexity of both the diagnosis and treatment. Case 3 had an extremely low arterial pressure, a presentation not yet described. CONCLUSION: Neonatal hemochromatosis should be suspected in the presence of cholestasis with liver failure of perinatal onset and with high blood level ferritin. Abdominal nuclear magnetic resonance and/or liver biopsy can confirm neonatal hemochromatosis. For one of our patients, a medical treatment allowed us to perform a liver transplantation.

Diagnosis, Differential↗
PubMed2004

Hemochromatosis and the enigma of misplaced iron: implications for infectious disease and survival.

The mystery surrounding the apparent lack of iron within the macrophages of individuals with hereditary hemochromatosis, a condition of excessive uptake of dietary iron, has yet to be fully explained. We have suggested that iron deficiency of macrophages in people with hereditary hemochromatosis mutations is associated with increased resistance to infection by Yersinia and other intracellular pathogens, a selection pressure resulting in unusually high current population frequencies of hereditary hemochromatosis mutations. Such selection pressure has been called Epidemic Pathogenic Selection (EPS). In support of the theory of EPS, a considerable number of virulent species of bacteria multiply mainly in iron-rich macrophages of their mammalian hosts. Among these fastidious pathogens are strains of Chlamydia, Coxiella, Francisella, Legionella, Mycobacterium, Salmonella and Yersinia. Iron deficiency of macrophages of persons with hereditary hemochromatosis gene mutations may result in increased resistance to members of these bacterial pathogens. People with genes that result in hereditary hemochromatosis may be protected against coronary artery disease associated with Chlamydia and Coxiella infection in the absence of iron overload. In the clinical setting, when a patient appears to be iron deficient, the reason for this should be carefully evaluated. Iron supplementation may adversely affect the health of individuals who have mounted an acute phase response to infection, injury or stress, or who carry genes predisposing them to iron overload disorders.

Bacterial Infections↗
PubMed2004

Is genetic screening for hemochromatosis worthwhile?

Hereditary hemochromatosis is an iron overload disorder and is the most common recessive disease in Caucasians. About 80% of hemochromatosis patients are homozygous for the C282Y mutation in the HFE gene. Since iron accumulation can be prevented by phlebotomy, there is increasing interest in screening populations for hemochromatosis. Hemochromatosis is a disease that meets all the criteria for screening as set by the World Health Organization (WHO) or the US preventive services task force criteria for a screening program. However, there is no consensus on the value of a screening program for hemochromatosis. Moreover, there is no agreement on whether this screening should be based on the phenotype i.e. biochemical levels of serum iron parameters or on the genotype i.e. based on the presence of mutations in the HFE gene. Other important concerns are the lack of important data in evaluating screening as well as the psychosocial impact of a screening program. The present review analyses the current situation from a genetic-epidemiological perspective. We conclude that general population screening may be helpful to identify high-risk groups or individuals in the early stage of the disease so that treatment can be started. We suggest a two-phase screening program based on the first instance on serum iron levels and then a genetic test to only those with elevated serum iron parameters.

Female↗
PubMed1999

A survey of phlebotomy among persons with hemochromatosis.

BACKGROUND: One in 10 whites in the United States is a carrier for hemochromatosis and an estimated 1 in 200 is clinically affected. Early treatment with therapeutic phlebotomy to remove excess iron can prevent associated chronic diseases. However, little information is available on the amount of blood withdrawn or the rates of withdrawal from hemochromatosis patients. The patterns of therapeutic phlebotomy and the magnitude of charges in persons with hemochromatosis were surveyed. STUDY DESIGN AND METHODS: Surveys were mailed to persons with hemochromatosis identified by health care providers, blood centers, patient advocacy groups, and the Internet. There were 2362 respondents to the survey from the United States. RESULTS: Thirty-seven percent of respondents reported being voluntary blood donors prior to diagnosis. The mean rate of therapeutic phlebotomy for iron depletion was 2.6 units per month (mean duration, 13 months). The mean rate of maintenance phlebotomy was 0.5 units per month. Therapeutic phlebotomy rates varied by sex, age, reason for diagnosis, and severity of symptoms. Seventy-six percent of respondents reported full or partial insurance coverage of therapeutic phlebotomy charges. Seventy-six percent received therapeutic phlebotomy services in a hospital or physician's office and 30 percent in a blood center. Charges for therapeutic phlebotomy varied by site, with a mean cost of $90 in hospitals and $52 in blood centers. Fifty-four percent of respondents attempted to donate blood after their diagnosis but were excluded. CONCLUSION: The amount of blood withdrawn from persons with hemochromatosis is substantial. The location where patients received phlebotomy services appears to be influenced by charges and time since diagnosis.

Adult↗
PubMed2002

Nephrogenic diabetes insipidus associated with hemochromatosis.

Although hemochromatosis is one of the most common genetic disorders in humans, the clinical information on iron-induced renal impairment is limited. We describe the clinical features of nephrogenic diabetes insipidus (NDI) observed in a case of hemochromatosis. A 57-year-old diabetic man was admitted to the hospital with a 6-month history of persistent polyuria, which had been sustained after glycemic optimization with insulin therapy and resulted in hepatic coma. Despite sufficient basal excretion of arginine vasopressin, impaired urinary concentrating capacity was observed, which could not be corrected by supraphysiologic doses of exogenous arginine vasopressin. Histochemical investigations showed widely distributed iron deposition in hepatocytes and moderately increased iron deposits in the tubular epithelium of distal urinary tubules and collecting ducts, suggesting that iron deposition resulting from hemochromatosis leads to NDI. This may be the first case report of NDI associated with hemochromatosis in humans. More attention should be paid to latent NDI as another complication of hemochromatosis.

Diabetes Insipidus, Nephrogenic↗
PubMed2000

Two novel nonsense mutations of HFE gene in five unrelated italian patients with hemochromatosis.

BACKGROUND & AIMS: Most hemochromatosis patients of Northern European descent are homozygous for the C282Y mutation of HFE gene. In Italy, many patients with iron overload are not homozygous for C282Y, and the presence of other mutations or other genetic determinant has been suggested. METHODS: Five unrelated Italian patients heterozygous for C282Y with the classic hemochromatosis phenotype were studied. The entire coding sequence and the exon-intron boundaries of the HFE gene were analyzed. Chromosome 6p haplotypes were defined in each patient by analysis of D6S265, D6S105, and D6S1281 microsatellites. RESULTS: Two novel nonsense HFE mutations were identified in exon 3 in the C282Y negative chromosome. The first one, a G-to-T transition at codon 168, was detected in 3 probands; the second, a G-to-A transition at codon 169, was detected in the others. CONCLUSIONS: The 2 nonsense mutations in the compound heterozygous state with C282Y result in the classic hemochromatosis phenotype in several unrelated Italian patients. This confirms that hemochromatosis in Italy is not as homogeneous as in northern Europe and suggests that other mutations can exist in C282Y or H63D heterozygotes with iron overload. These findings have practical implications for diagnostic and screening strategies for hemochromatosis.

Adult↗
PubMed1977

Idiopathic hemochromatosis. Demonstration of recessive transmission and early detection by family HLA typing.

We studied iron overloading and HLA types in 24 sibships of patients with idiopathic hemochromatosis, of which 15 had at least two subjects with overt forms. HLA types of 84 unrelated patients were also investigated. Among siblings there was a significant association (P less than 0.0001) between the presence of hemochromatosis and the possession of the same two HLA haplotypes. The fact that overt forms of hemochromatosis depend on the presence of two specific homologous chromosomes strongly supports a recessive mode of transmission for the overt disease. The haplotypic equilibrium demonstrated in the unrelated patients group is another supporting argument. The lod-score value (2.239 for theta = 0.005) in six families available for study further supports the conclusion that a hemochromatosis gene is closely linked to the HLA-A locus. HLA typing in families with hemochromatosis could provide a means of early detection of subjects at risk before appearance of any sign of iron overload.

Adult↗
PubMed2005

Early diagnosis of hemochromatosis-related cardiomyopathy with magnetic resonance imaging.

The hallmark of hemochromatosis is the deposition of iron in multiple tissue types, most notably the skin, liver, pancreas, thyroid, and heart. Definitive diagnosis of iron deposition generally requires invasive methods, such as direct tissue biopsy. We describe a 40 year-old woman with end-stage liver disease secondary to hereditary hemochromatosis and alcohol abuse, who was referred to the cardiology service as part of an evaluation for orthotopic liver transplant. The patient had no cardiac history but a dobutamine stress echocardiogram, performed as a portion of the pre-operative cardiac evaluation, could not be completed due to intermittent, supraventricular tachycardia. Additional cardiac testing, including electrocardiography and resting echocardiography, raised suspicion for cardiomyopathy related to hemochromatosis but was non-diagnostic. Cardiac magnetic resonance (MR) of this patient revealed deposition of iron in the myocardium and established the diagnosis of hemachromatosis-related cardiomyopathy. These findings suggest that cardiac MR may be more sensitive than other non-invasive, diagnostic tools in the initial evaluation of hemochromatosis-related cardiomyopathy and may be used as an alternative to myocardial biopsy. We propose that conventional T1- and T2-weighted spin echo MR sequences can be used routinely as non-invasive modalities to assess the presence of iron deposition in the tissues of patients with hemochromatosis.

Adult↗
PubMed2000

Screening for hemochromatosis in routine medical care: an evaluation of mean corpuscular volume and mean corpuscular hemoglobin.

Our aim was to evaluate the potential utility of mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) to detect hemochromatosis. We computed the accuracy of MCV and MCH cut-off points > or = upper reference limits using data from 94 probands and 132 white controls. Our reference ranges are MCV 80.0-97.0 fL and MCH 26.0-32.0 pg. Sensitivity of MCV was 8.6-48.3% for men and 2.8-44.4% for women (cut-off points > or = 105.0 - > or = 97.0 fL, respectively). Sensitivity of MCH was 33.9-70.7% for men and 19.6-50.0% for women (cut-off points > or = 34.0 - > or = 32.0 pg, respectively). Using MCV and a hemochromatosis frequency typical of many western Caucasian populations (0.005), positive predictive values (PV+) were 2.1-100.0% in men and 4.2-100.0% in women. Using MCH, PV+ were 1.7-8.2% in men and 1.8-6.8% in women. We also calculated PV+ using the hemochromatosis frequency 0.015, which could occur in persons receiving medical care. Using MCV cut-off points > or = 101.0 fL, PV+ were 8.9-100.0% in men and 100.0% in women with maximum sensitivities of 24.1% and 25.0%, respectively. Using MCH testing, PV+ was 21.5% in men (cut-off point > or = 34.0 pg) and 18.2% in women (cut-off point > or = 33.0 pg) with sensitivities of 33.9% and 37.0%, respectively. Using MCV or MCH, sensitivity and PV+ for the HFE genotype C282Y/C282Y were generally greater than for "nonclassical" HFE genotypes. All negative predictive values in our study were > or = 98.5%. We conclude that supranormal values of MCV or MCH could be used to detect hemochromatosis in white persons of western European descent who are receiving routine medical care. Comparisons of MCV, MCH, and transferrin saturation testing and other implications of MCV and MCH testing for hemochromatosis in medical care are discussed.

Adult↗
PubMed1986

Hemochromatosis heterozygotes may have significant iron overload when they also have hereditary spherocytosis.

A family is described in which four of six siblings have both hereditary spherocytosis and evidence of abnormal iron metabolism. Three of the four have significant iron overload. HLA typing, which permits the detection of the gene for hemochromatosis, indicates that all family members with hereditary spherocytosis who have abnormal iron metabolism or significant iron overload are heterozygous for the hemochromatosis gene. Family members having hereditary spherocytosis but not the gene for hemochromatosis have normal iron studies as does a family member heterozygous for hemochromatosis but no hereditary spherocytosis. Based on the findings in this kindred, it appears that the combination of chronic hemolysis and the gene for hemochromatosis results in increased iron absorption that may lead to significant iron overload.

Adult↗
PubMed1991

Comparison of stainable liver iron between symptomatic and asymptomatic hemochromatosis homozygotes and their homozygous relatives.

The authors compared the amount of hepatic parenchymal cell stainable iron in 159 hemochromatosis homozygotes. They were separated into four groups. Group 1: 59 symptomatic hemochromatosis probands with hemochromatosis (mean age 49 years) who were identified because of symptoms and signs of iron overload. Group 2: 38 asymptomatic probands with hemochromatosis (mean age 29 years) identified during population screening studies or during routine health maintenance evaluation. Group 3: 47 homozygous relatives (mean age 43 years) of Group 1 probands. Group 4: 15 homozygous relatives (mean age 30 years) of Group 2 probands. The symptomatic probands (Group 1) were 20 years older and had much more stainable hepatic iron (p less than 0.0001) than the asymptomatic probands (Group 2). The homozygous relatives (Group 3) of the symptomatic probands also were older and had much more stainable hepatic iron than the homozygous relatives (Group 4) of asymptomatic probands (p less than 0.0002). The results of this study suggest that population screening studies can result in early identification of individuals with hemochromatosis before massive hepatic iron overload occurs and before symptoms of iron overload develop.

Hemochromatosis↗
PubMedDate not supplied

MR findings of secondary hemochromatosis: transfusional vs erythropoietic.

OBJECTIVE: The aim of this study was to demonstrate the MR characteristics of secondary hemochromatosis (transfusional versus erythropoietic). MATERIALS AND METHODS: Magnetic resonance images of five patients with transfusional (n = 3) or erythropoietic (n = 2) hemochromatosis were reviewed. RESULTS: The liver of all patients had low signal intensity in all pulse sequences. The spleen had low signal intensity in all patients with transfusional iron overload, but normal signal intensity in erythropoietic hemochromatosis, which had similar MR findings to idiopathic hemochromatosis. However, the pancreas had variable signal intensity. CONCLUSION: On MRI the signal intensity of the spleen may allow distinction between transfusional and erythropoietic hemochromatosis.

Adult↗
PubMed2002

Hemochromatosis detection in a health screening program at an Alabama forest products mill.

We analyzed hemochromatosis detection in a 11.5-year multiphasic health screening program at a forest products mill. There were 2199 participants: 2032 Whites (1506 men, 526 women) and 167 African Americans (124 men, 43 women); 85.0% of employees were screened. Iron and transferrin saturation were measured in a serum biochemistry profile on specimens obtained after overnight fasting; ferritin was measured in participants with elevated iron concentrations or transferrin saturation > 48%. Participants with elevated ferritin levels underwent further evaluation. Eight White men were diagnosed to have hemochromatosis (frequency 0.0039 in Whites, 0.0053 in White men). The estimated cost per case detected was $8826. Family members of two participants with hemochromatosis were also diagnosed to have hemochromatosis or iron overload. We conclude that detecting hemochromatosis in a workplace multiphasic health screening program is efficacious and economical.

Adult↗
PubMed1985

Disease risk estimates from marker association data. Application to individuals at risk for hemochromatosis.

The recessive hemochromatosis gene is both linked to the HLA region on chromosome 6 and nonrandomly associated with certain HLA alleles. The use of linked HLA markers to trace known hemochromatosis genes within a family is well known, but using the population associations to detect unsuspected disease genes has not been fully appreciated. Thus, while HLA typing has been utilized to detect asymptomatic affected siblings, it has not been applied to other relatives. We propose a method in which Bayes' rule is used to calculate the probability that designated HLA marker haplotypes, brought into the family by spouses, have attendant hemochromatosis genes. The A3, B14 and A3, B7 haplotypes are such high risk markers. When these haplotypes are inherited from the unaffected parent, the offspring of an individual with hemochromatosis is at marked increased risk for the disease. When A3 and B14 are absent from the HLA marker haplotype, however, the risk of having a hemochromatosis gene is less than that for the general population. This approach should be helpful in identifying family members at a higher risk for developing the disease and who may then undergo appropriate periodic screening.

Bayes Theorem↗
PubMed1999

Screening blood donors for hereditary hemochromatosis: decision analysis model comparing genotyping to phenotyping.

OBJECTIVE: The identification of a gene for hereditary hemochromatosis in 69-100% of typical hemochromatosis patients has resulted in a genotypic test to identify persons with the typical missense mutation. Population screening by genotyping has the potential to reduce screening costs because of a high specificity of the genetic test. METHODS: Decision analysis techniques are used to compare the outcome, utility, and incremental cost savings of a plan to screen voluntary blood donors and their siblings for hemochromatosis using a genotypic test (C282Y mutation) with phenotypic tests (transferrin saturation, serum ferritin). RESULTS: Genotypic screening is less expensive than phenotypic screening only if the cost of the initial genetic test is less than $20. The screening program saves money (dominant strategy) if the cost of the initial genetic test is less than $28. Incremental cost saving declines as the cost of the gene test increases. At a gene test cost of $173, it costs $109,358 to identify a homozygote with potential life-threatening illness. Incremental cost saving also declines as the penetrance of the hemochromatosis gene in the population screened decreases. Phenotypic screening with confirmatory genetic testing results in a cost of $2,711 per homozygote with life-threatening complications. CONCLUSIONS: Population screening programs for hemochromatosis have the potential to save money. Optimal strategies for screening include initial testing for iron overload (phenotyping) with confirmatory genetic testing, or initial genetic testing if the test is less than $28.

Blood Donors↗