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PubMed1998

Hemochromatosis-associated mortality in the United States from 1979 to 1992: an analysis of Multiple-Cause Mortality Data.

BACKGROUND: Hemochromatosis, which can lead to serious chronic diseases resulting from iron overload, has an estimated prevalence of 50 to 80 cases per 10000 persons. However, little population-based information is available on the impact of hemochromatosis on morbidity and mortality. OBJECTIVE: To evaluate trends over 14 years in deaths and medical conditions associated with hemochromatosis in the United States. DESIGN: We searched Multiple-Cause Mortality Files compiled by the National Center for Health Statistics for the years 1979 to 1992 for all records listing hemochromatosis. We used these data to calculate age-adjusted and age-specific mortality rates, identify medical conditions associated with a known diagnosis of hemochromatosis at death, and calculate proportionate mortality ratios for these medical conditions. RESULTS: The listing of hemochromatosis on death certificates increased 60% from 1979 to 1992. Decedents with hemochromatosis were 23, 13, and 5 times more likely to have liver neoplasms, liver disease, and cardiomyopathy, respectively, than were decedents without hemochromatosis. Conversely, decedents with liver neoplasms, liver disease, and cardiomyopathy were 26, 14, and 5 times more likely, respectively, to have hemochromatosis than were decedents without these conditions. Hemochromatosis was 82 times more likely in persons with the combination of liver neoplasms and diabetes and 43 times more likely in those with the combination of liver disease and diabetes than in those without these conditions. CONCLUSIONS: Comparison of the reported prevalence of hemochromatosis among decedents with estimates of prevalence in the general U.S. population suggests that either the penetrance or the recognition of hemochromatosis, or both, is low. Nevertheless, substantial mortality resulting from liver disease, liver neoplasms, cardiomyopathy, and a combination of liver disease and diabetes in patients with hemochromatosis argues for the improved diagnosis and treatment of hemochromatosis in persons with these conditions.

Age Distribution↗
PubMed2001

Prevalence, donation practices, and risk assessment of blood donors with hemochromatosis.

CONTEXT: Despite changes in eligibility policies, practical barriers limit blood donations from individuals with hemochromatosis. Increased knowledge of hemochromatosis donor characteristics may help foster further changes that will promote more donations. OBJECTIVES: To estimate the prevalence of donors diagnosed as having hemochromatosis and to compare rates of unreported deferrable risks for transfusion-transmissible viral infections (TTVIs), positive screening test results for TTVIs, and donation patterns between hemochromatosis patient donors and donors reporting no medical conditions necessitating phlebotomy (non-health-related donors). DESIGN: An anonymous mail survey conducted in 1998 as part of the ongoing Retrovirus Epidemiology Donor Study. SETTING AND PARTICIPANTS: Among a stratified probability sample of 92 581 blood donors from 8 geographically diverse US blood centers, 52 650 (57%) responded. MAIN OUTCOME MEASURES: Prevalence of hemochromatosis among blood donors; prevalence of unreported deferrable risks and positive screening test results for TTVIs among hemochromatosis patient donors vs non-health-related donors. RESULTS: One hundred ninety-seven respondents (0.4%) identified themselves as hemochromatosis patients and 50 079 (95.1%) as non-health-related donors. An estimated 0.8% of all donations were from hemochromatosis patients, 45.8% of whom reported that they had donated blood to treat their illness. The proportion of repeat donors was higher in hemochromatosis patients than in non-health-related donors (83.5% vs 76.5%; P =.03). Among repeat donors, 68.7% of hemochromatosis patients reported donating at least 3 times in the past year compared with 49.1% of non-health-related donors (P<.001). The prevalence of unreported deferrable risks for TTVIs was similar in hemochromatosis patients (2.0%) and non-health-related donors(3.1%) as was the overall prevalence of positive screening test results (1.3% of hemochromatosis patients vs 1.6% of non-health-related donors). CONCLUSIONS: Although significant numbers of hemochromatosis patients reported donating blood for therapeutic reasons, our findings suggest that this population does not present a greater risk to blood safety than other donors.

Adult↗
PubMed1998

Prevalence of hereditary hemochromatosis in 16031 primary care patients.

BACKGROUND: Despite evidence from screening studies in northern European populations, the prevalence of hemochromatosis in primary care populations in the United States remains speculative. OBJECTIVE: To establish the feasibility of screening for hemochromatosis and to estimate the prevalence of hemochromatosis in a large primary care population. DESIGN: Cross-sectional prevalence study. SETTING: 22 primary care practices in the Rochester, New York, area. PATIENTS: 16031 ambulatory patients without a previous diagnosis of hemochromatosis. INTERVENTION: Serum transferrin saturation screening tests were offered to all adult patients in participating primary care practices. MEASUREMENTS: Patients with a serum transferrin saturation of 45% or more on initial testing had a serum transferrin saturation test done under fasting conditions and had serum ferritin levels measured. Those who had a fasting serum transferrin saturation of 55% or more and a serum ferritin level of 200 microg/L or more with no other apparent cause were presumed to have hemochromatosis and were offered liver biopsy to confirm the diagnosis. RESULTS: 25 patients had biopsy-proven hemochromatosis; 22 patients met the clinical criteria for hemochromatosis but declined liver biopsy and were classified as having clinically proven hemochromatosis; and 23 patients had a serum transferrin saturation of 55% or more with no identifiable cause, indicating probable hemochromatosis. The prevalence of clinically proven and biopsy-proven hemochromatosis combined was 4.5 per 1000 (95% CI, 3.3 to 5.8 per 1000) in the total sample and 5.4 per 1000 (CI, 4.0 to 7.1 per 1000) in white persons. The prevalence was higher in men than in women (ratio, 1.8:1). CONCLUSIONS: Hemochromatosis is relatively common among white persons. Routine screening of white persons for hemochromatosis should be considered by primary care physicians.

Adolescent↗
PubMed1997

Diagnosis of hemochromatosis probands in a community hospital.

PURPOSE: To evaluate factors that lead to the diagnosis of hemochromatosis probands in a community hospital, including education of physicians about hemochromatosis and iron overload, specialty of physicians, diagnostic indicators of hemochromatosis, and clinical manifestations of hemochromatosis probands. PATIENTS AND METHODS: We conducted a hemochromatosis education program for health care personnel associated with a community hospital and the public during 1990 to 1994. Data on physicians who diagnosed probands, diagnostic indicators of hemochromatosis, and manifestations of hemochromatosis and associated illnesses were tabulated. Iron grades of all hospital liver biopsy specimens obtained from Caucasian subjects during 1990 to 1994 were also analyzed. RESULTS: We identified 162 hemochromatosis probands; 66.7% were diagnosed by physicians who participated in our education program. Primary care and internal medicine subspecialty physicians diagnosed 66.7% and 29.6% of probands, respectively, based on elevated serum iron parameters and hepatic enzyme concentrations (51.9% and 36.4% of probands, respectively). Iron overload occurred in 90.7%, and was associated with clinical manifestations in most. Of 844 hospital liver biopsy specimens from Caucasians, 8.5% had increased iron grades; 4.6% represented hemochromatosis. CONCLUSIONS: Physicians with current education readily diagnose hemochromatosis probands during routine health care delivery, but most probands identified in this manner have iron overload. Our results suggest that community physicians and hospitals could contribute substantially to hemochromatosis screening programs, permitting detection of more homozygotes before the development of iron overload.

Adolescent↗
PubMed1981

Coincidental nontransfusional iron overload and thalassemia minor: association with HLA-linked hemochromatosis.

A pedigree was studied in which five individuals with beta-thalassemia minor were found to have nontransfusional hemochromatosis. Three were children under the age of 10 and two were young male adults, ages 28 and 33. A 5-yr-old child without evidence of thalassemia also had hemochromatosis. Since hemochromatosis is transmitted as an HLA-linked autosomal recessive disorder, HLA haplotypes serve as markers of hemochromatosis alleles. In this pedigree, five identifiable HLA haplotypes were associated with hemochromatosis alleles. Only individuals with two hemochromatosis alleles (homozygosity) had heavy iron loads, whether beta-thalassemia minor was present or not. Individuals with beta-thalassemia minor but without a hemochromatosis allele had normal transferrin saturation. A 65-yr-old man with beta-thalassemia minor and a single hemochromatosis allele had only a minimally elevated transferrin saturation (54%). The presence of beta-thalassemia minor did not appear to accentuate the degree of iron loading expected in individuals homozygous or heterozygous for hemochromatosis alleles. Our findings suggest that nontransfusional hemochromatosis found in association with beta-thalassemia minor is due primarily to homozygosity for hemochromatosis.

Adolescent↗
PubMed2003

Hemochromatosis and alcoholic liver disease.

The close association of excessive alcohol consumption and clinical expression of hemochromatosis has been of widespread interest for many years. In most populations of northern European extraction, more than 90% of patients with overt hemochromatosis are homozygous for the C282Y mutation in the HFE gene. Nevertheless, the strong association of heavy alcohol intake with the clinical expression of hemochromatosis remains. We (individually or in association with colleagues from our laboratories) have performed three relevant studies in which this association was explored. In the first, performed in 1975 before the cloning of the HFE gene, the frequency of clinical symptoms and signs was compared in patients with classical hemochromatosis who consumed 100 g or more of alcohol per day versus in nondrinkers or moderate drinkers who consumed less than 100 g of alcohol per day. The results showed no difference between the two groups except for features of complications of alcoholism in the first group, especially jaundice, peripheral neuritis, and hepatic failure. Twenty-five percent of those with heavy alcohol consumption showed histologic features of alcoholic liver disease (including cirrhosis) together with heavy iron overload. It was concluded that these patients had the genetic disease complicated by alcoholic liver disease. In the second study (2002), 206 subjects with classical HFE-associated hemochromatosis in whom liver biopsy had been performed were evaluated to quantify the contribution of excess alcohol consumption to the development of cirrhosis in hemochromatosis. Cirrhosis was approximately nine times more likely to develop in subjects with hemochromatosis who consumed more than 60 g of alcohol per day than in those who drank less than this amount. In the third study (2002), 371 C282Y-homozygous relatives of patients with HFE-associated hemochromatosis were assessed. Eleven subjects had cirrhosis on liver biopsy and four of these drank 60 g or more of alcohol per day. The reason why heavy alcohol consumption accentuates the clinical expression of hemochromatosis is unclear. Increased dietary iron or increased iron absorption is unlikely. The most likely explanation would seem to be the added co-factor effect of iron and alcohol, both of which cause oxidative stress, hepatic stellate cell activation, and hepatic fibrogenesis. In addition, the cumulative effects of other forms of liver injury may result when iron and alcohol are present concurrently. Clearly, the addition of dietary iron in subjects homozygous for hemochromatosis would be unwise.

Alcoholism↗
PubMedDate not supplied

Common variable immunodeficiency and IgG subclass deficiency in central Alabama hemochromatosis probands homozygous for HFE C282Y.

Eight hemochromatosis probands with HFE C282Y homozygosity had frequent, severe, or unusual infections and common variable immunodeficiency (CVID) or immunoglobulin (Ig) G subclass deficiency (IgGSD). Thus, we performed serum Ig isotyping and other characterization of 43 additional unselected probands, 5 human leukocyte antigen (HLA)-identical siblings, and 240 consecutive CVID or IgGSD index patients. C282Y allele frequencies were estimated in 58 CVID or IgGSD index patients without hemochromatosis phenotypes and in 341 controls. HLA-A and -B haplotypes and frequencies were determined in all 51 probands, 186 CVID or IgGSD index patients without hemochromatosis phenotypes, and 751 controls. Thirteen unselected probands (30%) had CVID or IgGSD. Among all 21 hemochromatosis probands with CVID (n = 4) or IgGSD (n = 17), Ig subclass deficiency patterns were IgG(1) (n = 5), IgG(1) and IgG(3) (n = 6), IgG(3) (n = 9), and IgG(1), IgG(3), and IgG(4) (n = 1). IgG(2) or IgA deficiency was not detected; one proband had IgM deficiency. Mean values of total IgG, IgG(1), and IgG(3) were significantly lower in probands with CVID or IgGSD. Mean values of age, transferrin saturation, and ferritin at diagnosis and phlebotomy units required to induce iron depletion were similar in probands with or without CVID or IgGSD; phlebotomy had no apparent effect on IgG levels. C282Y frequencies were similar in CVID or IgGSD index cases without hemochromatosis phenotypes and in controls. There was concordance of Ig and hemochromatosis phenotypes in probands and respective HLA-identical siblings. Eight of 240 CVID or IgGSD index patients had hemochromatosis phenotypes and C282Y homozygosity (3 vs 0.7% and 0.2% controls; P < 0.0001, respectively). The frequency of A*03-B*07 was greater in CVID and IgGSD index cases without hemochromatosis phenotypes than in controls (0.0968 vs 0.0546, respectively; P = 0.0032). HLA-A*03-B*07 was the predominant haplotype in probands grouped by presence or absence of CVID or IgGSD. Some probands in each group were A*03-B*07 homozygotes; group A*03-B*07 frequencies were similar. We conclude that serum IgG abnormalities characteristic of CVID or IgGSD are common in hemochromatosis probands, and that the prevalence of hemochromatosis is increased in CVID and IgGSD index cases. These observations could be explained by the increased frequencies of HLA-A*03-B*07 in C282Y homozygotes and in CVID and IgGSD, and by the common occurrence of putative CVID or IgGSD allele(s) on haplotypes bearing C282Y.

Adult↗
PubMedDate not supplied

Hereditary hemochromatosis.

Genetic (hereditary) hemochromatosis is probably the most common autosomal recessive disorder found in white Americans, of whom about 5/1,000 (0.5 percent) are homozygous for the associated gene. The hemochromatosis gene is probably located close to the HLA-A locus on the short arm of chromosome 6. Homozygous individuals may develop severe and potentially lethal hemochromatosis, especially after age 39. Hereditary hemochromatosis involves an increased rate of iron absorption from the gut with subsequent progressive storage of iron in soft organs of the body. Excess iron storage eventually produces pituitary, pancreatic, cardiac, and liver dysfunction and death may result from cardiac arrhythmias, congestive heart failure, and/or hepatic failure or cancer. Early diagnosis can prevent these excess iron-induced problems. Iron overload owing to HLA-linked hereditary hemochromatosis can be distinguished from other causes of hemochromatosis by liver biopsies and interpretations. Patients at risk for genetic hemochromatosis should be screened, identified, and treated as early as age 20 to prevent or minimize the deadly complications of hemochromatosis. Population screening should include measurements of serum iron concentration, total iron binding capacity (TIBC), percent saturation of transferrin, and serum ferritin concentrations. Family members of hereditary hemochromatosis patients are at increased risk and should be tested. Screening, identification and early treatment (phlebotomies, sometimes in combination with the use of Desferal or other iron-chelating agents) may help prevent or reduce iron-related organ damage and premature deaths. Early diagnosis and treatment will reduce the population of aging individuals with severe, complicated hemochromatosis and dramatically reduce medical costs (billions of U.S. dollars per annum) associated with the management of this disease.

Adult↗
PubMedDate not supplied

Transferrin receptor-2 gene and non-C282Y homozygous patients with hemochromatosis.

More than 80% of the patients affected by hereditary hemochromatosis, a common inherited iron disorder, are homozygotes for the 845G --> A (C282Y) mutation of the HFE gene. However, depending on the population, 10-20% of hereditary hemochromatosis can be linked either to other HFE genotypes, particularly the compound heterozygous state for C282Y and the 187 C --> G (H63D) mutation, or to mutations of new other genes. Recently, Camaschella et al. (Nat. Genet. 25, 14-15, 2000) identified a stop mutation (exon 6 nt 750 C --> T, Y250X) on the transferrin receptor-2 (TFR2) gene in two unrelated Sicilian families with hereditary hemochromatosis. The TFR2 gene is a transferrin receptor gene homologue that seems to be involved in iron metabolism. Moreover, one of the patients described by Camaschella et al. was a H63D homozygote. H63D homozygosity can be associated with various phenotypes from asymptomatic subjects to patients with a typical form of hereditary hemochromatosis. Thus, the Y250X mutation could be the molecular defect responsible for hereditary hemochromatosis in subjects with atypical HFE genotypes. We have searched for the Y250X mutation in 63 unrelated French subjects. Forty-three had a diagnosis of hereditary hemochromatosis based on classical criteria. This group included 12 H63D homozygotes, 3 C282Y heterozygotes, and 3 patients with none of the two most prevalent HFE mutants. These 18 patients had no other HFE sequence change and were subsequently subjected to DNA sequencing of the 15 last exons and flanking sequences of the TFR2 gene. The 25 remaining hereditary hemochromatosis patients who were tested for the Y250X mutant were compound heterozygotes for the C282Y and H63D mutations. Finally, we also tested for this TFR2 mutation 20 H63D homozygotes with milder manifestations of iron overload and no acquired cause of iron overload. None of the 63 tested subjects had the Y250X mutation. Concurrently, none of the 18 hereditary hemochromatosis patients who had their TFR2 gene sequenced had any deleterious mutation. Thus, TFR2 mutations are not responsible for hemochromatosis in non-C282Y homozygous patients of our area.

Adult↗
PubMed2004

Association of porphyria cutanea tarda with hereditary hemochromatosis.

BACKGROUND: An increased frequency of hereditary hemochromatosis gene mutations occurs in patients with porphyria cutanea tarda. Polymerase chain reaction analysis of peripheral blood for hemochromatosis gene (HFE) mutations is available for clinical use. Early detection and treatment of hereditary hemochromatosis limit disease progression and improve life expectancy. OBJECTIVE: We present 8 patients with porphyria cutanea tarda subsequently found to have hereditary hemochromatosis or mutations in the HFE gene. METHODS: Retrospective review of patients in whom both porphyria cutanea tarda and hereditary hemochromatosis or HFE gene mutations were diagnosed between 1976 and 2000. RESULTS: Eight patients with porphyria cutanea tarda (6 males, 2 females; age range, 4-60 years; mean age at diagnosis of porphyria cutanea tarda, 42 years) were subsequently found to have hepatic iron overload or HFE gene mutations. Two patients had liver biopsy findings compatible with homozygous hereditary hemochromatosis. In the other 6 patients, HFE gene analysis revealed 3 homozygous C282Y, 1 compound heterozygous C282Y/H63D, and 2 heterozygous C282Y mutations. Seven patients (88%) had no specific signs or symptoms of hereditary hemochromatosis at diagnosis. In 5 patients (63%), the diagnosis of hereditary hemochromatosis or HFE gene mutation was initially suspected by the dermatologist. CONCLUSION: Porphyria cutanea tarda can be an important cutaneous marker for patients with mutations of the HFE gene. HFE gene analysis should be done in patients who present with porphyria cutanea tarda. The dermatologist may play a key role in the early diagnosis of subclinical hereditary hemochromatosis in patients who present with porphyria cutanea tarda.

Adolescent↗
PubMed2004

Attitudes about and psychosocial outcomes of HFE genotyping for hemochromatosis.

We examined attitudes regarding genetic testing and psychosocial outcomes of HFE genotyping for hemochromatosis. A total of 87 persons with hemochromatosis (patients) (39 women, 48 men), who underwent HFE genotyping, and 50 persons with hypertension (controls) (22 women, 28 men), who had not undergone HFE genotyping, completed a structured interview in which they reported attitudes about benefits and disadvantages of genetic testing and their understanding of genetics and hemochromatosis. Among patients, adherence to treatment for hemochromatosis was assessed. Controls estimated the likelihood of experiencing several potential positive and negative psychosocial outcomes after a positive genetic test. Patients reported their experience pertinent to these outcomes. Patients received information about hemochromatosis when they were diagnosed, and controls read a brief description of hemochromatosis before answering questions. Patients correctly answered 65% of knowledge questions and controls correctly answered 59%. Most participants believed genetic testing is beneficial and described few negative aspects of testing. Controls expected to experience more anxiety, depression, and anger related to a positive genetic test than was reported by patients (p < 0.001). One patient reported discrimination related to the HFE genotype. Most patients were compliant with the iron depletion and maintenance phases of treatment for hemochromatosis. Race, sex, marital status, income, education, barriers to treatment, and knowledge were not significantly associated with adherence to maintenance phlebotomy. We conclude that HFE genotyping appears to be viewed positively and would be generally accepted were it offered as part of a screening program for hemochromatosis. Persons who have not undergone genetic testing may overestimate their emotional responses to a positive test result. In the present hemochromatosis patients, few reported that HFE genotyping was accompanied by negative psychosocial outcomes.

Adult↗
PubMedDate not supplied

Should we screen for hemochromatosis? An examination of evidence of downstream effects on morbidity and mortality.

BACKGROUND: Population-based hemochromatosis screening has been suggested with the rationale that identification and treatment of subclinical disease would decrease morbidity and mortality due to hemochromatosis. OBJECTIVE: To examine the prevalence of elevated serum transferrin saturation levels and the burden of illness of hemochromatosis in terms of ambulatory visits, hospitalizations, and death in the United States. PARTICIPANTS AND METHODS: Four nationally representative data sets were used for the analysis of the prevalence of hemochromatosis as well as ambulatory care, hospitalizations, and deaths related to hemochromatosis. Participants included men and nonpregnant women aged 18 years and older in the Third National Health and Nutrition Examination Survey (1988-1994) and the 1996, 1997, and 1998 National Ambulatory Care Survey, National Hospital Discharge Survey, and Underlying Cause-of-Death Mortality Files. The data sets were based on single measurements of serum transferrin saturation levels, serum ferritin levels, and healthcare provider-recorded diagnoses according to the International Classification of Diseases, Ninth Revision, Clinical Modification, code for hemochromatosis. RESULTS: The prevalence of elevated serum transferrin saturation levels ranged from 1% to 6%. When an elevated serum transferrin saturation level of 55% is combined with an elevated serum ferritin level, the prevalence decreases from 1.9% to 0.65%. The proportion of diagnosed hemochromatosis utilization out of total ambulatory visits, hospitalizations, and deaths is stable across the measures and the 3 years of data ranging from 0.01% to 0.03%. When white men were examined separately, the relationships remained the same as those among the general population of adults. CONCLUSIONS: Although a substantial proportion of adults whose condition is not currently diagnosed would be identified in a population-based screening program for subclinical hemochromatosis, diagnosed morbidity or mortality owing to hemochromatosis is considerably lower than would be expected. Recommendations for screening programs may need to be revisited.

Adolescent↗