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We present the magnetic resonance (MR) images of exogenous hemochromatosis in the thyroid gland. On both T1-weighted images and T2-weighted images the thyroid showed low intensity similar to that of the background. Magnetic resonance is of value in imaging the tissue deposition of iron. In assessing thyroid iron accumulation, MR is superior to CT because CT can not differentiate iron deposition from normal iodine concentration.
This case report describes the MR appearance of cardiac iron deposition using spin echo and cine gradient echo imaging (GRE) in a young man with secondary hemochromatosis. The ratio of the signal intensity of left ventricular myocardium to skeletal muscle was abnormally low on both spin echo and GRE compared with normal. The abnormally low myocardial signal was most severe on the cine gradient echo sequence. Cine GRE can be used to establish the diagnosis of cardiac iron deposition.
We report a patient in whom hemochromatosis with high transferrin saturation developed during long-term cimetidine administration. Prior reports have noted impaired iron absorption to be associated with short-term cimetidine use. The effect of chronic cimetidine administration on iron absorption and metabolism has not been studied. We believe this to be the first, and so far the only report of increased iron absorption with long-term cimetidine use.
Yersinia enterocolitica is a rare cause of systemic infections, including spontaneous bacterial peritonitis. Most reported cases have been in patients with iron overload or host defenses compromised by chronic illnesses. We report the case of an alcoholic patient with hemochromatosis who developed spontaneous bacterial peritonitis due to Yersinia enterocolitica.
Although venesection therapy is well established for the initial depletion of iron stores in hereditary hemochromatosis, the frequency of subsequent therapy has not been clearly defined. In this study, 21 homozygotes (16 male, five female; mean age of 58, with a range of 26 to 77 years) who had completed initial venesection therapy were followed without further venesections for a mean of 4.0 years (range of 1 to 10.4 years) with iron reaccumulation assessed by annual serum ferritin concentration. Over the follow-up period, the mean rise in serum ferritin was 99 (micrograms/l)/year (range of 1.2 to 241 micrograms/l). The mean interval for the ferritin to become elevated above the normal range in 10 patients was 3.8 years. Eleven of 21 patients required no further venesection therapy over the follow-up interval. There was no significant correlation between the annual rate of ferritin increase and the age or amount of iron removed by prior venesections. These data demonstrate that monitoring body iron stores annually and the selective use of venesections if iron stores reaccumulate is a safe alternative to lifelong venesections every 2-4 months. Many homozygotes will not require reinitiation of venesection therapy for > 4 years. Annual monitoring of body iron stores with reinstitution of weekly venesection when the serum ferritin exceeds the upper limit of normal was a safe alternative to long-term maintenance venesection.
Hereditary hemochromatosis (HH) is a human leukocyte antigen-linked inherited disease that is characterized by inappropriately high absorption of iron by the gastrointestinal mucosa. The spectrum of disease presentation is changing with more and more patients now being identified before they are symptomatic with complications of iron overload. A candidate gene for HH, called HFE, was identified in 1996, and a test for the gene is commercially available. A review of the recent identification of the gene and its implications for clinical diagnosis and therapy is presented. We also propose an algorithm for evaluation of patients for HH. Early diagnosis and appropriate therapy can prevent significant morbidity and mortality associated with the development of end-organ complications of HH. The understanding of the C282Y and H63D mutations is still evolving, and the algorithm and the contribution of various heterozygous mutations to the diagnosis and management of iron overload need to be confirmed by further clinical and genetic studies.
A 68-year-old man, after having been diagnosed as having hepatic disease at about the age of 41 years, had been hospitalized frequently until his death. Blood sugar, iron, and copper had not increased during his illness. Although the diagnosis of liver cirrhosis had been made and he had been receiving therapy, various neurologic symptoms without disturbances of consciousness appeared six months before his death. Autopsy revealed hemochromatosis, liver cirrhosis, and pancreatic fibrosis. A large amount of iron had accumulated in the liver, the pancreas, and the thyroid gland, while considerable numbers of ceroid and lipofuscin pigment granules had accumulated diffusely in the brain. Abnormal astrocytes of the Alzheimer II type were diffusely distributed in the brain and contained no intranuclear glycogen which stained positive with the carmine stain. No spongy changes were seen in the deeper layers of the cerebral cortex. Chemical analyses for trace metals in the brain, liver, and kidneys revealed a large amount of iron and increased copper in the liver, and considerable quantities of copper, manganese, calcium, and mercury in the brain. Because of changes in the erythrocyte sedimentation rate and marked thymol turbidity seen before and after the occurrence of the neurologic symptoms, this man was suspected of having disorders of the trace-metal binding proteins and/or of their polymers.
We report two sisters with neonatal hemochromatosis (NHC), including the first documented survivor. Characterized by excessive parenchymal iron in liver, pancreas, heart, and other organs, but little iron in the spleen, bone marrow, or other sites of the reticuloendothelial system, NHC is rarely reported and has been uniformly fatal. The first infant (case 1) presented with neonatal hypoglycemia, coagulopathy, and mild hyperbilirubinemia; she rapidly deteriorated and died of multisystem failure. Autopsy showed cirrhosis. Her sister (case 2) presented similarly; liver biopsy showed giant cell hepatitis, which is consistent with idiopathic neonatal hepatitis (INHP). However, iron staining revealed that case 1 had extensive iron deposits in the liver, pancreas, heart, thymus, and bone, but none in bone marrow or spleen. Case 2 had grade 4 liver iron staining, normal bone marrow iron, elevated serum ferritin and transferrin saturation, and HLA-A3 haplotype. At 16 months of age, the growth, development, and serum measures of iron status in case 2 were normal; liver biopsy showed fibrosis, negative iron staining, and normal tissue iron concentration. NHC is compatible with survival, has clinicopathologic features that overlap with INHP, and may frequently be misdiagnosed as INHP. A prospective study is needed to determine the incidence and natural history of NHC--a disorder that may be more common than is currently recognized.
Experience over the last 20 years with 34 patients with idiopathic hemochromatosis is summarized and the literature is reviewed. Methods are now available which are highly effective in the diagnosis of iron overload and virtually all diagnoses are made antemortem. The nature of the disease has changed through the removal of iron by phlebotomy. Early deaths are limited to patients with severe and rapidly progressive heart disease and to those presenting with neoplasm. The major mortality has shifted to a much later period and the incidence of hepatoma is increasing. There is particular interest at the present time in family studies since excessive iron stores are frequently found within the family. The significance of intermediate degrees of iron overload is unclear, but future attention should be given to the recognition of iron overload long before clinical manifestations appear.
PURPOSE: Genetic screening can enable timely detection and treatment of hereditary hemochromatosis (HH). Little is known about patient acceptability of DNA testing as compared to conventional phenotypic testing. METHODS: Within the HEIRS Study, a large primary-care screening study of HH and iron overload, we randomly assigned participants to receive brief information on either HH genotypic or phenotypic testing, and assessed the willingness to accept this test. The study was designed to recruit an equal number of African Americans and Caucasians. RESULTS: A total of 2500 participants were recruited from waiting rooms of primary care practices; 2165 participants who self-identified as African Americans and Caucasians were included in the analyses. Overall, 56% had accepted a genotypic test versus 58% for a phenotypic test. Adjusting for Field Center (FC), age, gender, race, educational attainment, global health rating, and knowledge of the test, the odds ratio of accepting a genotypic versus phenotypic test was 0.85 (95% CI: 0.71, 1.02; P = 0.078). Characteristics associated with test acceptance were age 45-64 years, female gender, Caucasian race, self-rated health less than ''very good'', and knowledge of the test. Test acceptance was associated with interest in knowing more about health (81%) and in helping family members (71%). Refusal reasons included a need to talk with a doctor (44%), concern about privacy (32%), and dislike of blood drawing (29%). CONCLUSION: In this diverse sample of primary care patients, stated acceptance of genotypic testing for HH mutations was similar to phenotypic testing for blood iron. Patient education regarding the nature of test, importance of disease detection, and privacy protection appear to be essential for achieving high rates of screening participation.
An assay is described for high-throughput single nucleotide polymorphism (SNP) genotyping on a microfabricated capillary array electrophoresis (CAE) microchip. The assay targets the three common variants at the HFE locus associated with the genetic disease hereditary hemochromatosis (HHC). The assay employs allele-specific PCR (ASPCR) for the C282Y (845g->a), H63D (187c->g), and S65C (193a->t) variants using fluorescently-labeled energy-transfer (ET) allele-specific primers. Using a 96-channel radial CAE microplate, the labeled ASPCR products generated from 96 samples in a reference Caucasian population are simultaneously separated with single-base-pair resolution and genotyped in under 10 min. Detection is accomplished with a laser-excited rotary four-color fluorescence scanner. The allele-specific amplicons are differentiated on the basis of both their size and the color of the label emission. This study is the first demonstration of the combined use of ASPCR with ET primers and microfabricated radial CAE microplates to perform multiplex SNP analyses in a clinically relevant population.
Juvenile hemochromatosis (JH) is an autosomal recessive condition that leads to significant morbidity due to early onset systemic iron overload. The majority of families with JH link to chromosome 1q and were recently found to have mutations in the HFE2 gene encoding hemojuvelin; however, several JH families have been reported to have mutations in the HAMP gene encoding hepcidin. Here, we report a multiply consanguineous family with a father and daughter showing iron overload consistent with JH. Sequence analysis of HAMP revealed homozygosity for amino acid substitution C78T due to a c.233G > A mutation. This mutation disrupts one of eight highly conserved cysteines that are believed to be critical for the function of the active enzyme. This finding adds support to the importance of the role of these conserved cysteines in the activity of hepcidin.
Several observations indicate that the innate metabolic defect in hereditary hemochromatosis (HH) leads to a defective function of the monocyte-macrophage system. The present study was performed to investigate the possibility that a defect in migration of cells of the monocyte-macrophage system can explain the abnormal location of the submucosal macrophages in HH. Monocytes isolated from 14 patients with HH were investigated with regard to chemotactic responsiveness (MCR). Two different methods were used at two different laboratories. Casein and zymosan-activated serum were used as attractants. No difference in MCR was found between the control group and the group of HH patients. The conclusion can therefore be drawn that the abnormal location of the macrophages of the gut wall in HH cannot be explained by an inborn abnormality of the function of receptors responsible for the chemotactic activity of the monocyte-macrophage system. It is, however, still possible that local factors responsible for the macrophage migration (gut hormones?) may have defective activity in HH patients.
Hereditary hemochromatosis (HH) is a common autosomal recessive disorder that can result in iron overload and a wide range of clinical complications, including hepatic cirrhosis, diabetes mellitus, hypopituitarism, hypogonadism, arthritis, and cardiomyopathy. People with HH can be detected at an asymptomatic stage of the disease by abnormalities in serum iron measures. Early detection is desirable, because periodic phlebotomy provides effective treatment for iron overload and may prevent complications of the disorder. The natural history of HH is poorly understood, however, and the proportion of people detected by screening who will develop serious complications of HH is unknown. The genetics of HH may help to resolve these questions. The gene, HFE, and two mutations, C282Y and H63D, have been identified: the C282Y mutation has a higher penetrance than the H63D mutation, and appears to result in a greater loss of HFE protein function. Most people with HH are C282Y homozygotes, a small proportion are compound heterozygotes or H63D homozygotes, and some have no identifiable HFE mutation or are HFE heterozygotes, suggesting that additional mutations associated with HH are yet to be found. Gender and environmental agents, such as alcohol and dietary iron, influence phenotypic expression of HH. The severity of HH is thus determined by an interaction between genotype and modifying factors. HFE mutations also appear to increase the likelihood of iron overload in inherited anemias and to promote the clinical manifestations of porphyria cutanea tarda. HH is an important paradigm for medical genetics because it offers an opportunity to explore the complexity of gene gene and gene environment interactions.
Education is an essential component of a genetic screening program. Knowledge outcomes were measured after large-scale workplace education and screening for genetic susceptibility to hereditary hemochromatosis. The aim was to assess knowledge of concepts presented, impact of mode of delivery, and knowledge retention. Education in a group setting was delivered via oral or video presentation and knowledge assessed using self-administered questionnaires at baseline, 1 month, and 12 months. Over 60% of 11 679 participants correctly answered all questions at baseline, scoring higher with clinical concepts (disease etiology and treatment) than genetic concepts (penetrance and genetic heterogeneity). Revising the education program significantly increased correct responses for etiology (p < 0.002), whilst modifying the knowledge assessment tool significantly increased correct responses for etiology (p < 0.001) and gene penetrance (p < 0.001). For three of the four concepts assessed, use of video was as effective as oral presentation for knowledge outcomes. A significantly higher proportion of those at increased risk of disease (n = 44) responded correctly at 12 months than did controls (n = 82; p = 0.011 for etiology, p = 0.002 for treatment and p = 0.003 for penetrance). Hence, genetic screening can be successfully offered in a group workplace setting, with participants remembering clinical concepts better than genetic concepts up to 1 year later.
Forty-eight unrelated patients with idiopathic hemochromatosis were found to have a significantly higher frequency of three HLA antigens (A3, B7 and B14) than 591 healthy controls. A significant association between HLA haplotypes and disease segregations was demonstrated in 14 family studies. A recessive inheritance of a strongly A3-linked disease gene responsible for abnormal iron stores in the heterozygote state is postulated. The lod score value (4.415 for theta = 0.025) is compatible with this hypothesis. However, the excess of HLA-identical pairs of affected sibs does not exclude the possibility of a pseudo-recessiveness due to two codominant genes both HLA-linked. For the first time, a means of screening for high risk subjects is available and therefore offers the possibility of a preventive approach.
HLA-A and B antigens were defined in 154 unrelated idiopathic hemochromatosis patients. The study confirmed the highly significant positive association with HLA antigens A3 (corrected P less than 10(-10)) and B14 (corrected P less than 10(-9)). HLA-DR typing showed increased frequency of the specificity DRw6, which was frequently associated with the phenotype A3, B14 and antigen B14, suggesting linkage disequilibrium. This was borne out by PLT data.
The frequency of HLA A3 and B7 antigens was significantly higher in 67 unrelated patients with idiopathic hemochromatosis (IH) than in 700 controls (62.7% vs 22.5%, p less than 10(-8) and 26.9% vs 9.3%, p less than 10(-3), respectively). A3 B7, A3 B35 and A3 B5 were significantly more frequent in 72 haplotypes linked to IH gene than in 278 control haplotypes. The prevalence of B35 and A3 B35 was significantly higher in IH patients from North-Eastern Italy than from other regions (60% vs 21%, p less than .05 and 54.5% vs 8.2%, p less than 0.0001, respectively). All 15 siblings HLA identical to the respective proband were homozygous for IH with variable expression of the disease, whereas minor abnormalities of iron-related indexes were present in 23% of heterozygous relatives. Homozygous-heterozygous mating probably occurred in three of 40 families, accounting for the overt disease in three offspring and in one HLA semi-identical sibling; however, in this last case the possibility of a recombination event cannot be excluded.