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PubMed2002

Hereditary hemochromatosis.

Hereditary hemochromatosis (hh, type 1 hemochromatosis) is an autosomal recessive trait characterized by hyperabsorption of dietary iron. The disease trait occurs in approximately five per thousand Caucasians of northern European descent. The causative gene, designated HFE, was isolated and characterized in 1996; most individuals with hh are homozygous for a mutation resulting in a change from cysteine to tyrosine at residue 282 of the HFE protein (C282Y). Wild-type HFE protein binds to the transferrin receptor, and by an undefined mechanism the enterocyte is "programmed" to absorb an amount of dietary iron precisely matched to the body's needs. The C282Y mutant protein is not expressed on the cell surface and does not bind to the transferrin receptor; the result is an enterocyte programmed to absorb slightly more iron than required. Most individuals with hh display a common laboratory phenotype, an elevated transferrin saturation. Iron stores in excess of normal eventually occur in most men and some women. The prevalence of organ damage due to iron overload, however, remains a controversial issue. Published estimates range from less than 1% to "nearly all." The main reason for this discrepancy has been ascertainment bias. Retrospective studies have been biased in favor of individuals with morbid complications of hh, whereas screening studies of groups such as blood donors generally include only healthy subjects. We focus here on a review of studies that have attempted to avoid ascertainment bias. If biopsy-proven hepatic fibrosis and/or cirrhosis is employed as the single criterion for disease-related morbidity, clinical penetrance of hh occurs in 4% to 25% of homozygotes. This range, although narrower than in biased studies, is still wide and requires clarification. A large-scale population-based study has been sponsored by the National Institutes of Health to address this issue. Until results become available, the pragmatic approach is to continue to screen for hemochromatosis in the primary care setting and to maintain serum ferritin values at approximately 100 micro g/L or lower with phlebotomy therapy.

Family Health↗

PubMed2000

[A 24-year-old patient with decreased libido and erectile dysfunction as initial manifestations of hemochromatosis].

HISTORY AND CLINICAL FINDINGS: A 24 year old yugoslavian father of two children, complained of decreased libido and impotence since seven months. He also described recurrent joint pains in the knees and wrist joints. The urological and internal examination was unremarkable. INVESTIGATIONS: Except for slightly elevated liver enzymes and a mild thrombocytopenia the laboratory tests were normal. Testosteron, follicle stimulating hormone and luteinizing hormone concentrations were markedly decreased. Hepatosplenomegaly was demonstrated by ultrasound. TREATMENT AND COURSE: During testosteron administration for hypogonadotrophic hypogonadism erectile dysfunction improved. 9 months later the patient became diabetic and was referred to our department. Hemochromatosis was confirmed by serum ferritin concentration of 4010 micrograms/l, transferrin saturation of 85% and hepatic iron concentration of 27,900 micrograms/g dry weight. Molecular genetics showed no mutation of the hemochromatosis gene HFE. After venesection the ferritin concentration decreased, the loss of libido and subfertility improved with testosterone administration. CONCLUSION: In subfertility from an endocrine disorder primary hemochromatosis should be considered in the differential diagnosis. Only early diagnosis and prompt iron depletion may improve the prognosis of these patients.

Adult↗

PubMed2006

[Hepatitis C, hemochromatosis and porphyria cutanea tarda].

Porphyria cutanea tarda (PCT) is characterized by decreased activity of the enzyme uroporphyrinogen decarboxylase (URO-D) and the accumulation of uro- and heptaporphyrins in the liver. Apart from increased alcohol exposure and certain drugs, PCT is associated with antibodies to the hepatitis C virus (HCV), with its prevalence increasing from Northern (8-10%) to Southern Europe (71 to 91%). Chronic HCV-infection is thus considered to be a major trigger for PCT and PCT is said to be an important extrahepatic manifestation of HCV-infection in predisposed individuals. Iron overload is common in PCT. Iron is an inhibitory co-factor of URO-D activity in hepatocytes. Accordingly, in support of the critical role of iron, the clinical efficacy of iron removal is coupled to an improvement of hepatic URO-D activities. Up to two thirds of Saxon patients with PCT carry the classical hemochromatosis (HFE) mutations (C282Y and/or H63D). HFE genotyping can help to further classify patients with PCT and associated hemochromatosis. Simple or compound heterozygosity of HFE mutations does not affect the therapeutic response to chloroquine in PCT. Since Patients carrying homozygous mutations (C282Y/C282Y) with hemochromatosis and PCT do not respond to chloroquine, phlebotomy should be first-line treatment to remove toxic iron.

Hemochromatosis↗

PubMed1996

[Ocular side effects of deferoxamine therapy in aplastic anemia with transfusion-induced hemochromatosis].

BACKGROUND: Deferoxamine, an iron chelating agent, has been used for the treatment of hemochromatosis for more than 30 years. Ocular toxicity has begun to be reported only in the last few years. In most cases differentiation of the true etiology, i.e. the underlying disease versus the toxicity of the substance, is not clear. We report a patient with development of severe ocular toxicity during treatment with deferoxamine for transfusional hemochromatosis. HISTORY AND SIGNS: An 8-year-old boy was routinely evaluated in the eye clinic before initiation of treatment with deferoxamine. Over the last three years the boy had developed a transfusional hemochromatosis after multiple blood transfusions for his aplastic anemia. Ophthalmologic examination displayed normal anterior segments with the exception of a unilateral small opacification of the posterior lens cortex, bilateral tortuous vessels, and mottling of the retinal pigment epithelium. After four months the patient developed a decrease in visual acuity, distortion of color vision, visual field defects, alteration of electrophysiological parameters, and severe changes of the retinal pigment epithelium. THERAPY AND OUTCOME: The deferoxamine was discontinued. Over a period of 3 months the patient displayed a normalization of visual acuity and visual fields. The changes of the retinal pigment epithelium and electrophysiological parameters showed further deterioration and did not return to normal. The patient subsequently was restarted on an adequate treatment dose of deferoxamine and maintained an essentially uneventful course with close ophthalmologic followup. CONCLUSION: Deferoxamine can cause severe ocular toxicity with incomplete recovery. Measurement of dark adaptation was especially valuable for follow-up examination.

Anemia, Aplastic↗

PubMedDate not supplied

[Arthropathy in idiopathic hemochromatosis].

Idiopathic hemochromatosis is normally associated with hepatic cirrhosis, myocardial disease and diabetes mellitus. A characteristic arthropathy occurs in approximately 40% of patients with hemochromatosis. The onset may precede other detectable clinical manifestations of the disease. In these cases a early diagnosis and treatment may improve the prognosis. A review of the recent literature is presented. A typical hemochromatosis arthropathy is described in one patient. The significance of a frequent associated chondrocalcinosis is discussed.

Arthritis↗

PubMed1996

Clinical and biochemical abnormalities in people heterozygous for hemochromatosis.

BACKGROUND: Ten percent of whites are heterozygous for the HLA-linked hemochromatosis mutation. We performed a cross-sectional analysis of 1058 genotyped heterozygotes to define the effects of age and sex on the phenotype. METHODS: The heterozygous genotype was assigned to 505 male and 553 female members of 202 pedigrees, each with an HLA-typed homozygous proband. We measured serum iron, transferrin saturation, and ferritin in all heterozygotes and in 321 genetically normal subjects (unaffected family members or spouses of family members). Liver biopsies were performed in a subgroup of heterozygotes. RESULTS: The mean serum iron concentrations and transferrin-saturation values were higher in heterozygotes than in normal subjects and did not increase with age. Initial transferrin-saturation levels exceeding the threshold associated with the homozygous genotype were found in 4 percent of male and 8 percent of female heterozygotes. The geometric mean serum ferritin concentration was higher in heterozygotes than in normal subjects and increased with age. Higher-than-normal values were found in 20 percent of male and 8 percent of female heterozygotes. The clinical and biochemical expression of hemochromatosis was more marked in heterozygotes with paternally transmitted mutations than in those with maternally transmitted mutations. Liver-biopsy abnormalities were generally associated with alcohol abuse, hepatitis, or porphyria cutanea tarda. CONCLUSIONS: The phenotype of persons heterozygous for hemochromatosis differs from that of normal subjects, but complications due to iron overload alone in these heterozygotes are extremely rare.

Adolescent↗

PubMed2002

A nomogram to predict C282Y hemochromatosis.

Genetic testing of hemochromatosis has not been widely used as a diagnostic test because of unawareness of its existence and concerns about genetic discrimination. We developed a nomogram for the prediction of C282Y homozygotes for hemochromatosis from transferrin saturation and ferritin using Bayes theorem. The results of transferrin saturation and C282Y genotyping were available for 8,572 participants (5,042 men, and 3,530 women). The study group included patients in population-screening projects, referred cases, and family members. Likelihood ratios were calculated for transferrin saturation in predicting C282Y homozygotes. Pretest probabilities were estimated on the basis of serum ferritin concentration, and a predictive nomogram for men and women was created with the use of Bayes' theorem. In the highest-risk region of the nomogram in men, the probability of C282Y hemochromatosis was 89.7% (95% confidence interval = 85.1-94.3); in the lowest-risk zone it was 1.1% (0.4-1.9). The corresponding regions in women were 88.9% in the high zone (95% confidence interval = 77.0-100.0) and 6.5% in the lowest (95% confidence interval = 4.9-8.1). This approach allows the clinician to predict the probability of a patient's being a C282Y homozygote over a wide range of ferritin and transferrin saturation values instead of above a particular threshold.

Amino Acid Substitution↗

PubMedDate not supplied

Hereditary hemochromatosis of a young girl: detection of early iron deposition in liver cell lysosomes using transmission electron microscopy and electron energy loss spectroscopy.

A 14-year-old girl demonstrated increased iron concentration and transferrin saturation, suggesting iron overload of unknown origin. Liver biopsy showed no fibrosis or hepatocytic atrophia. Nevertheless, Prussian blue reaction for histochemical detection of iron demonstrated very weak positive granules in a few hepatocytes on the periphery of hepatic lobules in close connection to bile capillaries. This very early stage of hemochromatosis was confirmed by TEM and EELS for iron accumulation inside hepatocytic lysosomes and residual bodies. Such siderosomes were scarce in number and iron content, compared to a case of manifested hemochromatosis and liver cirrhosis (Jonas L, Fulda G, Salemeh T, et al. Ultrastruct Pathol. 2001; 25: 111-118.). Liver iron concentration as measured by inductively coupled plasma-mass spectrometry (ICP-MS) and atomic absorption spectrometry (AAS) yielded 2.005 mg/g tissue dry weight, which was considered not significantly increased. In the absence of known causes for secondary iron overload, the early diagnosis was evidenced by genotyping, revealed homozygosity for the HFE gene C282Y mutation, demonstrating the presence of hereditary hemochromatosis.

Adolescent↗

PubMed1960

The nature of storage iron in idiopathic hemochromatosis and in hemosiderosis. Electron optical, chemical, and serologic studies on isolated hemosiderin granules.

Using three different methods of cells fractionation, hemosiderin granules were isolated from tissues (liver and/or spleen) of three patients. The samples were obtained from a case of idiopathic hemochromatosis, a case of thalassemia major with secondary (transfusional?) hemosiderosis, and a case of transfusional hemosiderosis associated with an unclassified anemia. Iron, nitrogen, and protein content of the hemosiderin granules varied over a wide range. Electron microscopy of sectioned granules revealed aggregates of dense particles of different shapes, with diameters ranging from 10 A to about 75 A. In some of the granules dense particles corresponding to the iron hydroxide micelles of ferritin molecules were abundant. But many of the granules contained very few of these molecules. The presence of ferritin and apoferritin in the samples of hemosiderin granules was demonstrated by means of precipitin tests in agar-gel, using rabbit antiferritin sera with known antibody nitrogen concentrations. At least three antigenic components were detected in highly purified crystalline ferritin prepared from tissues of the three patients; the hemosiderin granules contained the same antigens, but probably in much smaller quantities. Both ferritin and apoferritin molecules were extracted from hemosiderin granules, and were demonstrated in the electron microscope after suitable preparation. The solubility curve of human ferritin in solutions of (NH(4))(2)SO(4) was investigated. The results indicate that substantial quantities of ferritin or apoferritin can be lost in saline, aqueous media during isolation of hemosiderin granules from cells. It was shown by means of electron microdiffraction on selected hemosiderin granules that the dense particles represent forms of partly hydrated alpha-Fe(2)O(3). The conditions necessary for electron microdiffraction in an electron microscope precluded an exact determination of the state of hydration of the alpha-Fe(2)O(3) or of its structural relation to (FeOOH) micelles of pure ferritin in its undenatured state. The findings were considered in the light of evidence on the structure and disposition of hemosiderin in situ in cells, and on the structure of ferritin. Differences between endogenous hemosiderin and hemosiderin derived from injections of colloidal iron compounds were pointed out. The evidence indicates that in hemochromatosis and in secondary hemosiderosis much of the inorganic storage iron in liver and spleen is derived from degraded ferritin. The findings suggest that an abnormal cellular metabolic pathway of ferritin is implicated in the pathogenesis of hemochromatosis and transfusional hemosiderosis.

Anemia↗

PubMed1998

The hemochromatosis 845 G-->A and 187 C-->G mutations: prevalence in non-Caucasian populations.

Hemochromatosis, the inherited disorder of iron metabolism, leads, if untreated, to progressive iron overload and premature death. The hemochromatosis gene, HFE, recently has been identified, and characterization of this gene has shown that it contains two mutations that result in amino acid substitutions-cDNA nucleotides 845 G-->A (C282Y) and 187 C-->G (H63D). Although hemochromatosis is common in Caucasians, affecting >=1/300 individuals of northern European origin, it has not been recognized in other populations. The present study used PCR and restriction-enzyme digestion to analyze the frequency of the 845 G-->A and 187 C-->G mutations in HLA-typed samples from non-Caucasian populations, comprising Australian Aboriginal, Chinese, and Pacific Islanders. Results showed that the 845 G-->A mutation was present in these populations (allele frequency 0.32%), and, furthermore, it was always seen in conjunction with HLA haplotypes common in Caucasians, suggesting that 845 G-->A may have been introduced into these populations by Caucasian admixture. 187 C-->G was present at an allele frequency of 2.68% in the two populations analyzed (Australian Aboriginal and Chinese). In the Australian Aboriginal samples, 187 C-->G was found to be associated with HLA haplotypes common in Caucasians, suggesting that it was introduced by recent admixture. In the Chinese samples analyzed, 187 C-->G was present in association with a wide variety of HLA haplotypes, showing this mutation to be widespread and likely to predate the more genetically restricted 845 G-->A mutation.

Adenine↗

PubMed2001

A rapid PCR-SSP assay for the hemochromatosis-associated Tyr250Stop mutation in the TFR2 gene.

Several genes associated with hemochromatosis and primary iron overload have been identified. Mutations in the HFE gene have been detected in 60-100% of hemochromatosis patients of northern, central, and western European descent, although the frequencies of these mutations vary among racial and ethnic groups. Recently, a mutation in the gene encoding transferrin receptor-2 (exon 6, nucleotide 750 C --> G; Y250X) was detected by a PCR-restriction fragment length polymorphism (RFLP) method in Sicilians with hemochromatosis. We describe a modification of the original assay in which the sequence-specific priming PCR assay does not require the use of restriction endonuclease. The modified assay is robust and cost-efficient, and may be more useful for large-scale population studies because it can be performed rapidly on DNA extracted from buccal swabs.

Adult↗

PubMed2003

Genetic testing for hemochromatosis: attitudes and acceptability among young and older adults.

Hemochromatosis is a genetic disorder of iron overload common in persons of northern European descent. We examined attitudes about testing for hemochromatosis in 118 young adults (YA) (19.7 years +/- 1.9) and 50 older adults (OA) (58.5 years +/- 13.7). Participants read about hemochromatosis and two related tests: transferrin saturation measurement (iron test) and HFE genotyping (HFE test). Interest in each test and attitudes about genetic testing were assessed. More than 80% of all participants were willing to undergo either test, if offered. A majority preferred the iron test because of the information it provides about current health. A majority of participants identified at least one benefit of genetic testing, with improved health through early detection/prevention being most common. YA were more likely to report disadvantages of genetic testing (p < 0.001) and were more concerned about potential negative psychological effects (p < 0.005). OA were more concerned about potential discrimination (p < 0.0001). These findings suggest that young and older adults view genetic testing as beneficial and would accept HFE testing were it offered as part of a screening program.

Adolescent↗

PubMed1975

Hemochromatosis. Pathophysiologic and genetic considerations.

The clinical, genetic, and pathologic findings, and the pertinent case histories in two families with idiopathic hemochromatosis are presented. These studies support the view that idiopathic hemochromatosis is a disease inherited in at least two ways. In one of these families, inheritance appeared to occur in an autosomal recessive manner, whereas in the other, autosomal dominant expression seemed evident. Evidence that an inability of the reticuloendothelial cells to handle iron may play a major role in the pathogenesis of hemochromatosis is presented. The early age of onset and poorer prognosis associated with the recessive inheritance suggest that the defect in reticuloendothelial cell function present in such cases is different from or more severe than those associated with dominant inheritance.

Adolescent↗

PubMed1982

Hereditary hemochromatosis. Analysis of laboratory expression of the disease by genotype in 18 pedigrees.

Tight linkage between the hemochromatosis locus and the HLA region permits determination of genotype in members of hemochromatosis pedigrees. To determine if simple laboratory measures of iron metabolism could predict the affected genotype without the need for HLA typing, we studied seven measures of iron metabolism: serum iron concentration, total iron-binding capacity, per cent saturation of transferrin, serum ferritin concentration, deferoxamine-induced urinary iron excretion and hepatic iron concentration evaluated by both chemical and histological methods. Discriminant analysis showed a per cent saturation of transferrin above 62% to be the best simply-measured indicator of the affected genotype: homozygosity is accurately predicted in 92% of the cases. The logarithmic transform of serum ferritin concentration was only 71% accurate. Pedigree analysis estimated the frequency of the hemochromatosis gene at 0.069 +/- 0.020 with a recombination probability of 0.015 +/- 0.015 with the HLA region. This corresponds to a heterozygote frequency of 0.13 and a disease frequency of 0.005.

Age Factors↗

PubMedDate not supplied

The endocrine manifestations of hemochromatosis.

We have evaluated the endocrine changes in 10 male subjects with hemochromatosis. Two subjects initially had aplastic anemia, and the remainder had idiopathic hemochromatosis. Four of the ten patients had diabetes mellitus. Sexual dysfunction (impotence and/or decreased libido) was observed in 8 subjects. Six patients had subnormal testosterone levels; FSH levels were almost uniformly low, but LH concentrations were more variable. Only three patients had normal testosterone responses to hCG. Hypothyroidism, free T4 less than 0.9 ng/dl, was present in 4 subjects, and the etiology was heterogeneous. Basal prolactin levels were elevated in 2 patients and failed to respond adequately to TRH in 2 other patients. Growth hormone reserve was normal in all but 1 patient, and pituitary-adrenal reserve was normal in all but 1 patient. We conclude that disturbances in both pituitary and end-organ function are observed in hemochromatosis. These central and end-organ defects may exist alone or simultaneously. Hypogonadism is almost universal, and is a consequence of defective function of the hypothalamic-pituitary axis and/or primary Leydig cell disturbance. Other evidence of pituitary disturbance are observed but are rather uncommon.

Endocrine System Diseases↗

PubMed1985

Refractory biventricular heart failure in secondary hemochromatosis.

Cardiac hemochromatosis usually presents with clinical congestive heart failure and an enlarged heart. A woman with secondary hemochromatosis and features of both restrictive and congestive cardiomyopathy with a normal sized heart is described. Despite all interventions she had progressive cardiac impairment and expired eight days following presentation. The clinical and laboratory findings of 49 cases of cardiac hemochromatosis during the last 50 years are reviewed. While the disease usually progresses slowly, a significant minority die within fourteen days of recognition. Not infrequently pericardial tamponade is entertained as a cause for this rapid deterioration; however, both a restrictive and congestive cardiomyopathy appear to be responsible for this catastrophic presentation.

Adult↗

PubMed1990

Southern blood club symposium: an update on selected aspects of hemochromatosis.

Genetic epidemiology studies have indicated that hereditary hemochromatosis (HH) occurs in caucasians with a frequency of 3 to 13 per thousand. Clinical recognition however occurs far less frequently. The disparity is best resolved by defining HH as homozygosity for the HLA-linked hemochromatosis allele, regardless of the total body iron burden. Variability of clinical expression is explained in part by physiologic iron loss in women but variability in males may be due to environmental factors, gene-gene interactions or polymorphisms in mutated hemochromatosis alleles. Although clinical variability is great, the laboratory phenotype of HH is fairly constant and is marked by elevation of the transferrin saturation. The elevated transferrin saturation occurs early in life, before organ iron loading occurs and can be used as a screening tool to detect HH before organ damage occurs. Cloning and characterizing the HH gene, which is located within 1 centimorgan of the HLA-A locus should resolve some of the issues concerning clinical variability.

Adolescent↗

PubMed1999

New developments in hereditary hemochromatosis.

The iron content of the body is normally tightly controlled by regulation of iron absorption. In hereditary hemochromatosis, mutation of an HLA class 1 gene, designated HFE, results in excessive iron absorption. Over many years, accumulating iron produces tissue damage, most notably cirrhosis, cardiomyopathy, diabetes, and arthropathies. Hereditary hemochromatosis is the most common hereditary disease of Northern Europeans with a prevalence of approximately 5 per 1000. The most sensitive screening test for hemochromatosis is saturation of the transferrin with iron; a fasting value greater than 50% is strongly suggestive of the disease. Confirmation of increased iron storage can be achieved most readily by serial phlebotomy. We do not regard liver biopsy to be indicated, except in unusual circumstances. Early diagnosis and treatment by phlebotomy before tissue damage has occurred is essential, because life span seems to be normal in treated patients but markedly shortened in those who are not. Therefore, genetic counseling with evaluation of first-degree relatives is mandatory.

Genetic Counseling↗