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PubMed1991

Clinical presentation of hemochromatosis: a changing scene.

PURPOSE: To investigate the changing modes of clinical presentation and diagnosis in 93 patients with familial hemochromatosis and to compare the results with other reports from 1935 to the present. PATIENTS AND METHODS: The presenting features and the frequency of signs and symptoms were analyzed in 93 homozygotes from 56 families. RESULTS: Hemochromatosis was detected by chance in 40% of the 56 probands. Abdominal pain (16%), joint pains (11%), and weakness (9%) were prominent features that brought the patient to the physician. Although 38% of the male patients had loss of libido and impotence, these were not identified as presenting features. Features of liver disease (84%), arthritis (11%), and diabetes (2%) led the physician to the diagnosis. Impotence and testicular atrophy were notable, by their absence, in alerting physicians to the presence of hemochromatosis. Screening of family members led to the detection of 37 homozygotes, of whom 46% were asymptomatic. Among this group, arthropathy and gonadal failure were the most common symptoms. The classic triad of hepatomegaly, diabetes, and pigmentation was present in only 8% of patients. Clinical features were rare in patients with less than 5 g of exchangeable body iron and invariably present in those with more than 16 g. CONCLUSION: The presenting clinical features of hemochromatosis have changed since the original description of the disease in 1935. Family studies have led to the earlier discovery of more homozygous women and earlier detection with less iron loading and, as a result, fewer signs and symptoms.

Adolescent↗
PubMedDate not supplied

[The value of computerized tomography in the assessment of hepatic iron overload in genetic hemochromatosis].

The aim of the present study was to evaluate the effectiveness of single-energy computed tomography in determining iron overload in idiopathic hemochromatosis, with special reference to slightly overloaded cases. Liver attenuation was determined in 100 patients (46 cases of idiopathic hemochromatosis, 32 cases of chronic liver disease, and 22 normal controls). The iron load was determined for the first two groups by biochemical determination of liver iron concentration (performed in all but 12 subjects in the chronic liver disease group) and hepatic histologic grading. The main results for liver attenuation (upper normal limit, 72 Hounsfield units) showed that despite a high specificity (0.96), this parameter was of low sensitivity (0.63). Although mean liver attenuation in idiopathic hemochromatosis (77 +/- 14) was significantly higher than in chronic liver diseases (53 +/- 17; p less than 10(-4], and normal controls (66 +/- 3; p less than 10(-3], and despite an overall good correlation between liver attenuation and liver iron concentration (r = 0.72; p less than 10(-3], liver attenuation was unable to detect moderate iron overload. Fourteen of 18 patients with a liver iron concentration of less than 150 mumol/g dry liver wt had liver attenuation values of less than 72. Moreover, 3 of 18 subjects with a liver iron concentration of greater than 150 had a liver attenuation of less than 72. Of these 17 false-negatives, only 7 could be attributed to associated steatosis. On the whole, single-energy computed tomography, when used on a routine basis for diagnosing iron overload, is of limited clinical value in idiopathic hemochromatosis due to its poor sensitivity.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1989

Model of reticuloendothelial iron metabolism in humans: abnormal behavior in idiopathic hemochromatosis and in inflammation.

Iron transport in the reticuloendothelial (RE) system plays a central role in iron metabolism, but its regulation has not been characterized physiologically in vivo in humans. In particular, why serum iron is elevated and RE cells are much less iron-loaded than parenchymal cells in idiopathic hemochromatosis is not known. The processing of erythrocyte iron by the RE system was studied after intravenous (IV) injection of 59Fe heat-damaged RBCs (HDRBCs) and 55Fe transferrin in normal subjects and in patients with iron deficiency, idiopathic hemochromatosis, inflammation, marrow aplasia, or hyperplastic erythropoiesis. Early release of 59Fe by the RE system was calculated from the plasma iron turnover and the 59Fe plasma reappearance curve. Late release was calculated from the ratio of 59Fe/55Fe RBC utilization in 2 weeks. The partitioning of iron between the early (release from heme catabolism) and late (release from RE stores) phases depended on the size of RE iron stores, as illustrated by the inverse relationship observed between early release and plasma ferritin (P less than .001). There was a strong correlation between early release and the rate of change of serum iron levels during the first three hours in normal subjects (r = .85, P less than .001). Inflammation produced a blockade of the early release phase, whereas in idiopathic hemochromatosis early release was considerably increased as compared with subjects with similar iron stores. Based on these results, we describe a model of RE iron metabolism in humans. We conclude that the RE system appears to determine the diurnal fluctuations in serum iron levels through variations in the immediate output of heme iron. In idiopathic hemochromatosis, a defect of the RE cell in withholding iron freed from hemoglobin could be responsible for the high serum iron levels and low RE iron stores.

Erythrocytes, Abnormal↗
PubMed1989

[Iron metabolism in hereditary hemochromatosis].

The characteristic features of iron metabolism in hereditary hemochromatosis are described. The patients showed an increase of serum iron, iron saturation of transferrin as well as serum ferritin and erythrocytes. Results of determination of isoferritins of the splenic and cardiac types revealed a biochemical heterogeneity of hereditary hemochromatosis. Methods of differential diagnosis of hereditary hemochromatosis, secondary hemochromatosis and chronic diseases of the liver are described.

Adolescent↗
PubMed1984

Stimulatory activities for human multilineage hemopoietic progenitors (CFU-GEMMT) derived from patients with hemochromatosis and from normal volunteers.

A medium conditioned by leukocytes in the presence of phytohemagglutinin (PHA-LCM) promotes the growth of human multilineage hemopoietic progenitors (CFU-GEMMT) which form mixed hemopoietic colonies in culture containing granulocytes, erythroblasts, megakaryocytes, macrophages, and T-lymphocytes. PHA-LCM derived from six HLA-typed patients with idiopathic hemochromatosis and from six normal individuals were tested for growth-promoting activities for multilineage hemopoietic colony formation. Four out of six conditioned media obtained from patients with hemochromatosis supported mixed hemopoietic colony formation, as did four of six conditioned media from normal HLA-typed volunteers. Active PHA-LCM preparations from patients with hemochromatosis were similar with respect to the number and size of mixed colonies and their cellular composition when compared with conditioned media obtained from volunteers. The study indicates that no link exists between the HLA phenotype of a particular donor and the predictability of obtaining an active PHA-LCM promoting multilineage hemopoietic colony formation. PHA-LCM derived from patients with hemochromatosis had no advantage with respect to stimulatory activity for mixed colony formation when compared with conditioned media obtained from healthy volunteers.

B-Lymphocytes↗
PubMed1984

New diagnostic and therapeutic possibilities in manifest idiopathic hemochromatosis.

Up until recently in clinical practice suspected hemochromatosis with a pathological iron-screening test (plasma iron, percentage transferrin saturation, serum ferritin, desferrioxamine-induced urinary iron excretion) made a liver biopsy necessary. Today, as a first step, the density of the liver parenchyma can be measured by means of computed tomography. Normal findings obviate the need for laparoscopy. Since the late forties weekly or twice weekly phlebotomy has been the sole form of treatment for manifest idiopathic hemochromatosis. In the mid-sixties the hopes placed in chelating substances (desferrioxamine) were not fulfilled, because the plasma half-life (only 7-10 minutes) of this drug was too short. Even with several daily injections only a small amount of iron was removed from the body tissue (10-25 mg daily urinary iron excretion). The introduction of portable infusion pumps in the late seventies offered us a new possibility of administering desferrioxamine by subcutaneous injection (Propper et al., 1976). Until that time such treatment was successfully used only in the field of pediatrics to treat secondary transfusion hemochromatosis in thalassemia. In one case of idiopathic hemochromatosis with severe organic involvement (right heart failure, repeated esophageal hemorrhage and bronzed diabetes) we had to achieve rapid iron elimination, and for this purpose we used continuous long-term desferrioxamine administration by means of a portable infusion pump (Autosyringe) in addition to phlebotomy. Since, particularly in the critical initial phase of treatment when heart failure was always threatening, great care had to be exercised in the use of phlebotomy, iron removal was achieved largely by desferrioxamine administration (daily up to 240 mg iron elimination in urine and stools).(ABSTRACT TRUNCATED AT 250 WORDS)

Bloodletting↗
PubMed1983

Thyroid disease in hemochromatosis. Increased incidence in homozygous men.

The thyroid function of 49 patients homozygous for the hemochromatosis allele was studied by measurement of serum thyroxine and thyrotropin concentrations. Of 34 homozygous men, three were found to be hypothyroid (thyroxine, less than 3.0 micrograms/dL and thyrotropin, greater than 40 ImU/mL) and one was hyperthyroid (thyroxine, 24 micrograms/dL). All 15 homozygous women had normal thyroid function. The hypothyroid patients had elevated titers of antithyroid antibodies. Histologic examination of the thyroid at autopsy of one hypothyroid patient showed notable iron accumulation and fibrosis with modest lymphocytic infiltration. The causative importance of iron deposition in thyroid diseases associated with hemochromatosis was suggested by the reversal of the usual sex ratio of thyroid dysfunction. Men with hemochromatosis had a much greater iron load than women, and they also had a surprisingly higher incidence of thyroid disease. Iron may have caused injury to the thyroid, followed by the development of antithyroid antibodies and hypothyroidism. The frequency of thyroid disorders in men with hemochromatosis is about 80 times that of men in the general population.

Adult↗
PubMed1995

[The role of "hemochromatosis alleles" in the pathogenesis of polyglobulia after renal transplantation].

43 kidney recipients were followed up for 12 months after renal transplantation. In 13 patients treated with cyclosporin A for 6 months polyglobulia was found, which subsided after conversion of immunosuppressive therapy. A highly significant correlation was found between the presence of the antigen A3 and the polyglobulia in kidney recipients treated by cyclosporin A. The serum ferritin level was not elevated in kidney recipients who were carriers of the "hemochromatosis alleles". Results obtained in this study seem to justify the following conclusions: 1. Kidney recipients who are carriers of "hemochromatosis alleles" show a threefold higher risk of posttransplant polyglobulia. 2. Presence of "hemochromatosis alleles" is not an absolute predictor of polyglobulia in patients after kidney transplantation. 3. Both etiology and pathogenesis of posttransplant polyglobulia do not seem to be homogeneous. Cyclosporin A, in contrast to azathioprine, seems to have a promoting effect on the development of posttransplant polyglobulia. Therefore treatment of kidney transplant patients with cyclosporin A, who are carriers of "hemochromatosis alleles", needs careful monitoring.

Adult↗
PubMed1994

[Refractory heart failure in a 26-year-old woman with idiopathic hemochromatosis].

Idiopathic hemochromatosis, the most frequent inherited disease in Caucasians, is frequently undiagnosed. In this disorder, characterized by a continued inappropriated absorption of dietary iron, the clinical manifestations result from damage to those organ systems in which iron has been pathologically deposited, namely, the heart and the liver. Typically, hemochromatosis becomes clinically manifest in later life and in men more frequently than in women. This has been attributed to the extra loss of iron in women through menstruation and pregnancies. Removal of the excess iron by phlebotomy will prevent all of the complications of hemochromatosis of when begun early. In this paper, we report a case of a young woman with a eight years evolution of amenorrhea, cardiac failure, diabetes mellitus and increased pigmentation of the skin, associated with biochemical markers of iron overload. It is emphasized that hemochromatosis most be excluded in all patients with a unexplained cardiac failure.

Adult↗
PubMed1994

Recognizing genetic hemochromatosis.

This article reviews the disease process hemochromatosis, which is now recognized as one of the most common genetic disorders. Hemochromatosis is transmitted as autosomal recessive, and occurs in 3% of persons of Anglo-Saxon descent. It is caused by an inappropriate increase in intestinal iron absorption resulting in deposition of excess iron in tissues. Hemochromatosis usually presents in males in their 40s, and females much later. The most frequent initial symptoms are weakness, lassitude, weight loss, and symptoms related to the onset of diabetes mellitus. The classical triad of cirrhosis, diabetes mellitus, and skin pigmentation occurs late in the disease. There is debate over the value of mass screening for the disorder; however, it is recommended that once a case has been identified family members at risk should be screened. Therapy is directed at removing excess iron by phlebotomy. By instituting early therapy, many of the long-term complications, including cirrhosis and hepatoma, can be prevented. It is imperative that physicians learn to recognize early signs and symptoms of hemochromatosis so that treated patients can expect a normal life span with minimal medical intervention.

Bloodletting↗
PubMed1994

Hepatic cirrhosis and hemochromatosis in three horses.

Hemochromatosis, an iron storage disease, was diagnosed in 3 horses with hepatic cirrhosis. Each horse had bridging portal fibrosis and abundant iron deposits in the cytoplasm of hepatocytes. Serum concentrations of liver-derived enzymes and total bile acids were high. However, serum iron concentration was not high, and iron binding capacity was only 46% saturated in the 1 horse in which it was measured. However, the concentration of iron in the liver of this horse was 20 times the reference limits. Hemochromatosis is common in mynah birds and human beings. There are several types of this iron storage disease. In human beings, there is a familial disease with iron absorption inappropriate for the level of stored iron. Hemochromatosis also occurs secondary to cirrhosis of the liver, and in certain anemia diseases. Another type of hemochromatosis is seen in association with dietary iron overload. These horses were not related, and there was not any evidence of high dietary iron intake.

Animals↗
PubMed1996

-Cardiomyopathy as the cause of death in genetic hemochromatosis-.

Hemochromatosis is an autosomal-recessive disease which causes iron-overload of various organs including liver, pancreas and heart. This report analyzes the course of hemochromatosis in two patients (a 28-year-old man and a 57-year-old woman) in whom hemochromatosis was detected because of severe cardiomyopathy. Initial symptoms were edema, anasarca and dyspnea. Further examinations showed pleural effusion, decreased left-ventricular-function, skin pigmentation, diabetes mellitus and liver cirrhosis. Although phlebotomy treatment and iron-chelation therapy with deferoxamine initially resulted in some improvement, both patients died from cardiomyopathy three months after diagnosis. The reports of these two cases underline that hemochromatosis-associated cardiomyopathy is often irreversible if severe congestive heart failure is present. In cardiac decompensation heart transplantation has to be considered as early as possible.

Adult↗
PubMed1997

Mild liver enzyme abnormalities: eliminating hemochromatosis as cause.

Chronic mild liver enzyme abnormalities are attributable to hereditary hemochromatosis in at least 3% of cases. Hemochromatosis formerly was diagnosed late with diabetes and hepatic and cardiac failure. Only recently have the autosomal recessive inheritance and subtle early presentations been understood. However, patients still wait many years and see many physicians before receiving a correct diagnosis. Increased serum transferrin saturation is currently the best test for detection of those likely to accumulate iron. Serum ferritin identifies those requiring treatment. When liver biopsy (controversial in asymptomatic individuals) is indicated, chemical measurement of liver iron content is helpful and therapeutic phlebotomy is the only effective treatment. Caucasian-type hemochromatosis (prevalence of 0.005) is associated with genetic abnormalities in HLA-H but also occurs in other ethnic groups. Those of African descent may have a different but also heritable iron-loading disease. Caucasian-type and to a lesser extent African iron loading are detectable early by laboratory testing. Early treatment restores normal expectations of length and quality of life in the Caucasian disease. Long-term treatment data are not yet available in African iron loading. Laboratory-initiated screening programs using unsaturated iron-binding capacity can eliminate symptomatic hemochromatosis.

Adult↗
PubMed1998

Hereditary hemochromatosis: etiologic, pathologic, and clinical aspects.

The human leukocyte antigen (HLA)-linked iron-loading gene (HFE) associated with the autosomal recessive disorder known as hereditary hemochromatosis occurs in about 10% of subjects of European descent, most of whom are unaffected heterozygotes. In contrast, the 3 to 5 per 1,000 who are homozygotes are at risk of developing severe and potentially lethal iron overload, with damage to a number of organs, including the liver, pancreas, heart, joints, and the endocrine glands. Although the removal of the excess iron by repeated venesections is simple, effective, and safe therapy, much of the organ damage, once it has occurred, is irreversible. Because symptoms are often nonspecific, it is important for physicians in the relevant specialties to develop a high index of suspicion and to apply widely the appropriate screening tests, including transferrin saturation and serum ferritin concentration. Equally important is the detection of affected family members, who are usually siblings, before they have developed significant iron overload. In addition, screening of populations in which the prevalence of hereditary hemochromatosis is high has become an attractive and cost-effective option, especially now that the molecular structure of the HFE gene has been defined. Using this approach it is now possible to detect individuals homozygous or heterozygous for the gene using a simple polymerase chain reaction-based test. The application of this exciting new tool promises to provide fresh insights into the range of phenotypic expression in hereditary hemochromatosis. A challenge for the future will be to define the genetic or environmental factors responsible for iron overload in up to 20% of patients with clinical hemochromatosis who do not have the HFE gene.

Family Health↗
PubMed2002

HLA-A and -B alleles and haplotypes in hemochromatosis probands with HFE C282Y homozygosity in central Alabama.

BACKGROUND: We wanted to quantify HLA-A and -B allele and haplotype frequencies in Alabama hemochromatosis probands with HFE C282Y homozygosity and controls, and to compare results to those in other populations. METHODS: Alleles were detected using DNA-based typing (probands) and microlymphocytotoxicity (controls). RESULTS: Alleles were determined in 139 probands (1,321 controls) and haplotypes in 118 probands (605 controls). In probands, A*03 positivity was 0.7482 (0.2739 controls; p = or < 0.0001; odds ratio (OR) 7.9); positivity for B*07, B*14, and B*56 was also increased. In probands, haplotypes A*03-B*07 and A*03-B*14 were more frequent (p < 0.0001, respectively; OR = 12.3 and 11.1, respectively). The haplotypes A*01-B*60, A*02-B*39, A*02-B*62, A*03-B*13, A*03-B*15, A*03-B*27, A*03-B*35, A*03-B*44, A*03-B*47, and A*03-B*57 were also significantly more frequent in probands. 37.3% of probands were HLA-haploidentical with other proband(s). CONCLUSIONS: A*03 and A*03-B*07 frequencies are increased in Alabama probands, as in other hemochromatosis cohorts. Increased absolute frequencies of A*03-B*35 have been reported only in the present Alabama probands and in hemochromatosis patients in Italy. Increased absolute frequencies of A*01-B*60, A*02-B*39, A*02-B*62, A*03-B*13, A*03-B*15, A*03-B*27, A*03-B*44, A*03-B*47, and A*03-B*57 in hemochromatosis cohorts have not been reported previously.

Journal Article↗
PubMed2001

Association of mutations in the hemochromatosis gene with shorter life expectancy.

BACKGROUND: To investigate whether the frequency of carriers of mutations in the HFE gene associated with hereditary hemochromatosis diminishes with age as an indication that HFE mutations are associated with increased mortality. It is of value in the debate concerning screening for hereditary hemochromatosis to determine the significance of heterozygosity. METHODS: Genotyping for mutations in exons 2 and 4 of the HFE gene using denaturing gradient gel electrophoresis in 1784 participants aged 45 to 100 years from 4 population-based studies: all 183 centenarians from the Danish Centenarian Study, 601 people aged 92 to 93 years from the Danish 1905 Cohort, 400 aged 70 to 94 years from the Longitudinal Study of Aging Danish Twins, and 600 aged 45 to 67 years from a study of middle-aged Danish twins. RESULTS: All participants (N=1784) were screened for mutations in exon 4, and a trend toward fewer heterozygotes for the C282Y mutation-the mutation most often associated with hereditary hemochromatosis-was found. This was significant for the whole population (P=.005) and for women (P=.004) but not for men (P=.26). A group of 599 participants was screened for mutations in exon 2, and there was no variation in the distribution of mutations in exon 2 in the different age groups. CONCLUSIONS: In a high-carrier frequency population like Denmark, mutations in HFE show an age-related reduction in the frequency of heterozygotes for C282Y, which suggests that carrier status is associated with shorter life expectancy.

Age Distribution↗
PubMed2002

HFE based re-evaluation of heterozygous hemochromatosis.

Homozygosity for the C282Y mutation in the HFE gene is strongly associated with hereditary hemochromatosis. More than one subject out of 10 in the general population is a heterozygote for the C282Y mutation. In this study, we address whether or not conclusions drawn from HLA-based family studies regarding the expression of heterozygous hemochromatosis are applicable to C282Y heterozygotes. The correlation between HLA-inferred and HFE genotypes and the variation of serum iron tests according to HFE genotype and other factors were studied in persons from well-characterized hemochromatosis pedigrees. Subjects were tested for both C282Y and H63D mutations. The following factors were studied: age, sex, alcohol consumption, body mass index, liver function tests, serum lipids and glucose, serum iron, transferrin saturation, and ferritin. HLA-inferred heterozygotes were C282Y heterozygotes in only 70% and compound heterozygotes (i.e., heterozygotes for both C282Y and H63D) in 20%. C282Y heterozygotes did not differ from wild type homozygotes in terms of serum iron tests. Only compound heterozygotes presented with slightly increased transferrin saturation. On the other hand, increased serum ferritin was strongly associated with overweight or lipidic or glucose abnormalities. C282Y heterozygotes selected from family studies do not have greater serum iron tests than wild type homozygotes, except for compound heterozygotes, and therefore should not require special followup. The discovery of abnormal iron tests in a C282Y heterozygote should lead to workup for other causes of iron overload.

Amino Acid Substitution↗
PubMed1998

Heterozygosity for hereditary hemochromatosis is associated with more fibrosis in chronic hepatitis C.

Hepatic iron has been associated with more aggressive liver disease in chronic viral hepatitis. We evaluated whether the recently described C282Y mutation of the hemochromatosis gene, designated HFE (responsible for at least 83% of hereditary hemochromatosis), was associated with more advanced liver disease in chronic hepatitis C. One hundred thirty-seven patients with biopsy-proven chronic hepatitis C were studied and liver biopsies scored for necroinflammation (grade 0-18) and fibrosis (stage 0-6). Genomic DNA was amplified by polymerase chain reaction and the C282Y mutation identified by restriction with RsaI and electrophoretic separation of restriction fragments. Ten (7.3%) patients had the C282Y mutation. No C282Y homozygous patients were identified. Age, sex distribution, and estimated weekly alcohol consumption were not significantly different between those with and without the mutation. Serum ferritin was higher in the heterozygotes (mean, 339 microg/L) compared with homozygous wild types (153 microg/L; P = .0005). In the majority of patients, liver iron was graded 0 out of 4, but hepatocyte iron staining was more commonly present in heterozygotes compared with homozygous normals (30% compared with 4% [P = .02]). Liver disease was more advanced in those with the mutant allele (mean fibrosis stage: 3.6, compared with wild type: 1.5 [P = .01]). Cirrhosis was found more often in those with the mutation (40%) compared with those without (8.7%) (P = .01; odds ratio: 7.6 [1.9-31.2]). There was no significant difference in inflammation scores between heterozygotes and wild type (mean, 5.4 compared with 4.1). Hepatitis C virus (HCV)-RNA titers were measured by branched DNA assay (HCV RNA 2.0-Chiron), and there was no difference between heterozygous and homozygous normal patients. Thus, despite relatively minor increases in iron stores, individuals who are heterozygous for hemochromatosis appear to develop more fibrosis in chronic hepatitis C. Venesection may be useful therapy in this subgroup.

Adult↗