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PubMed1988

Diagnosis and treatment of iron overload in paediatric patients on chronic haemodialysis.

In this study the incidence and contributing factors of iron overload in paediatric patients treated with intermittent haemodialysis were evaluated. Particular attention was given to the diagnostic value of serum ferritin in the assessment of body iron stores in patients with hepatocellular damage. The results of treatment of secondary haemosiderosis with desferrioxamine (DFO) are reported. Serum ferritin levels were measured in 18 children and adolescents undergoing long-term haemodialysis; 8 of these had biochemical evidence of hepatocellular damage. In all patients a good correlation was found between serum ferritin levels and the amount of iron stored in the reticuloendothelial system. Six patients developed iron overload. Patients with secondary haemosiderosis were younger at the start of haemodialysis and received significantly more blood. Although not significant, more patients with haemochromatosis-associated alleles and bilateral nephrectomy had iron overload, and the duration of dialysis was obviously longer for overload patients (40 months versus 26 months). The patients with iron overload were treated with DFO. The data from all patients showed that DFO was ineffective when administered at a dose of 25 mg/kg during dialysis and that in individual patients changes in serum ferritin correlated with changes in the amount of blood transfusions administered.

Adolescent↗
PubMed1995

Resistance to erythropoietin in iron-overloaded haemodialysis patients can be overcome by ascorbic acid administration.

Haemodialysis patients with iron overload sometimes develop resistance to erythropoietin therapy due to 'functional iron deficiency'. It is known that this resistance may be overcome by iron supplementation; however, the latter could worsen haemosiderosis. Therefore, we treated four iron-overloaded haemodialysis patients who had developed relative resistance to erythropoietin (among whom three had features of 'functional iron deficiency') with ascorbic acid (500 mg intravenously after haemodialysis, 1-3 times a week). The erythropoietin doses were voluntarily kept unchanged during the study. After a latency of 2-4 weeks, haematocrit and haemoglobin had increased respectively from 26.5 +/- 0.7 to 32.7 +/- 0.4 vol% and from 8.8 +/- 0.3 to 10.8 +/- 0.2 g/dl (means +/- SEM, P < 0.001). While serum ferritin remained unchanged, transferrin saturation increased from 27 +/- 7 to 54 +/- 12% (P < 0.05), suggesting that ascorbic acid supplementation had allowed mobilization of iron from tissue burdens. In one patient, haematocrit declined after withdrawal of vitamin C and increased again after rechallenge. Also, ascorbate supplementation was continued after the study in two patients and allowed the erythropoietin doses to be decreased, 8 and 11 weeks, respectively, after the start of the trial. When a control group of seven patients with normal iron status and without resistance to erythropoietin were challenged in the same manner with ascorbate, no elevation of haematocrit or transferrin saturation was noted. We conclude that ascorbate supplementation may circumvent resistance to erythropoietin that sometimes occurs in iron-overloaded patients, in particular, in the setting of 'functional iron deficiency'.

Adult↗
PubMedDate not supplied

Iron overload in an African American woman with SS hemoglobinopathy and a promoter mutation in the X-linked erythroid-specific 5-aminolevulinate synthase (ALAS2) gene.

We report the case of an African American woman with sickle cell anemia and iron overload incompletely explained by erythrocyte transfusion who is heterozygous for a promoter mutation in the X-linked erythroid-specific 5-aminolevulinate synthase gene (ALAS2): a C to G transversion at nucleotide -206 from the transcription start site, as defined by primer extension (-258 from the start ATG). This mutation has previously been associated with sideroblastic anemia and iron overload in members of a Welsh kinship. No coding region mutation of HFE, FPN1, TFR2, HAMP, or HJV genes was detected. The mother of the proband has mild, chronic anemia and is also heterozygous for the same proximal promoter region mutation of ALAS2. However, she has no evidence of iron overload. We conclude that an ALAS2 promoter region mutation could partly account for iron overload in the present proband, and that this or other ALAS2 mutations could explain the occurrence of iron overload in other whites or blacks with or without anemia. The occurrence of anemia and iron overload may be discordant in women heterozygous for ALAS2 mutations.

5-Aminolevulinate Synthetase↗
PubMed1995

Human recombinant erythropoietin and phlebotomy in the treatment of iron overload in uremic patients.

Six chronic hemodialysis patients suffering from iron overload (serum ferritin ranged between 2053-15704 mu g/L) were treated with human recombinant erythropoietin (EPO) alone for eighteen months. An initial rapid decrease of serum ferritin was observed in all six patients when the loading dose of EPO was given. Three patients (Cases 4, 5, 6) who suffered from chronic blood loss maintained a continuous decline of serum ferritin in the subsequent stage of maintenance dose EPO therapy, however, the decrease of serum ferritin became sluggish under a maintenance dose in the other three patients (Cases 1, 2 and 3). The serum ferritin eventually decreased to a satisfactory level (975-1761 mu g/L) in Cases 4, 5 and 6, whereas it remained high (4232-8196 mu g/L) in Cases 1, 2, and 3 who had higher basal levels of serum ferritin (5641-15704 mu g/L) and a plateau of response under a maintenance dose of EPO. These three patients were then treated with EPO and phlebotomy. Their serum ferritin decreased quickly from 6752 +/- 1264 mu g/L to 2454 +/- 482 mu g/L after six months of phlebotomy therapy; it was a dramatic improvement in contrast to the stagnant response under a maintenance dose of EPO alone. Our experience indicates that EPO therapy alone has its limitations in treating severe iron overload. Although there is an initial rapid decrease of serum ferritin during the period of the loading dose, the response might become stagnant during the period of maintenance dose. Phlebotomy effectively eliminated the excessive iron stores in these refractory cases. Therefore, we suggest that phlebotomy be considered in severe iron overload if a stagnant response is observed under a maintenance dose EPO therapy.

Adult↗
PubMed1994

TGF-beta and collagen-alpha 1 (I) gene expression are increased in hepatic acinar zone 1 of rats with iron overload.

We have shown that lipid peroxidation stimulates collagen-alpha 1 (I) gene transcription in cultured cells. Because iron is a transitional metal known to induce lipid peroxidation, we investigated whether hepatic lipid peroxidation modulates collagen gene expression in iron-overloaded rats. In this animal model of hemochromatosis, we show colocalization with iron in the hepatic acinar zone 1 of both lipid peroxidation and increased collagen-alpha 1 (I) transcripts, using immunohistochemistry for malondialdehyde-protein adducts and in situ hybridization, respectively. Iron overload stimulated the expression of the cytokine transforming growth factor-beta (TGF-beta) in acinar zone 1, in spite of the minor degree of hepatocellular necrosis and inflammation. The formation of reactive aldehydes and TGF-beta, both inducers of collagen gene expression, may play a role in the stimulation of hepatic collagen production in iron overload. These mechanisms could be a link between iron overload and fibrosis in genetic hemochromatosis.

Animals↗
PubMed2003

Hemochromatosis and Iron Overload Screening (HEIRS) study design for an evaluation of 100,000 primary care-based adults.

BACKGROUND: The HEIRS Study will evaluate the prevalence, genetic and environmental determinants, and potential clinical, personal, and societal impact of hemochromatosis and iron overload in a multiethnic, primary care-based sample of 100,000 adults over a 5-year period. Participants are recruited from 5 Field Centers. Laboratory testing and data management and analysis are performed in a Central Laboratory and Coordinating Center, respectively. METHODS: Participants undergo testing for serum iron measures and common mutations of the hemochromatosis gene ( ) on chromosome 6p and answer questions on demographics, health, and genetic testing attitudes. Participants with elevated values of transferrin saturation and serum ferritin and/or C282Y homozygosity are invited to undergo a comprehensive clinical examination (CCE), as are frequency-matched control subjects. These examinations provide data on personal and family medical history, lifestyle characteristics, physical examination, genetic counseling, and assessment of ethical, legal, and social implications. Primary and secondary causes of iron overload will be distinguished by clinical criteria. Iron overload will be confirmed by quantification of iron stores. Recruiting family members of cases will permit DNA analysis for additional genetic factors that affect iron overload. RESULTS: Of the first 50,520 screened, 51% are white, 24% are African American, 11% are Asian, 11% are Hispanic, and 3% are of other, mixed, or unidentified race; 63% are female and 37% are male. CONCLUSIONS: Information from the HEIRS Study will inform policy regarding the feasibility, optimal approach, and potential individual and public health benefits and risks of primary care-based screening for iron overload and hemochromatosis.

Adult↗
PubMed2003

Novel mutation in ferroportin 1 gene is associated with autosomal dominant iron overload.

We report a family affected with dominant autosomal iron overload related to a new mutation in ferroportin 1, a transmembrane protein involved in the export of iron from duodenal enterocytes and likely from macrophages. The originality of this family is represented by the nature of the mutation consisting in the replacement of glycine 490 with aspartate. Clinicians should be aware of this novel iron overload entity, which corresponds to a particular phenotypic expression (high serum ferritin values contrasting with relatively low transferring saturation, and important Kupffer cell iron deposition as compared to hepatocytic iron excess) with poor tolerance of venesection therapy and a dominant pattern of inheritance. Given this dominant transmission, the mixed Causasian-Asian origin of our Asian proband leaves open the issue of the ethnic origin of the new mutation.

Amino Acid Substitution↗
PubMed1999

Putative hemochromatosis gene mutations and alcoholic liver disease with iron overload in Japan.

It is well known that alcoholic liver disease is associated with iron overload. To study the role of hemochromatosis gene mutations on the pathogenesis of alcoholic liver disease (ALD), we have analyzed C282Y and H63D mutations on the chromosomes obtained from 95 Japanese alcoholics. Patients were divided in two groups [i.e., 64 alcoholic patients with liver damage (group I) and 31 alcoholics without liver damage (group II)]. In group I, biochemical examinations showed that serum levels of iron and ferritin were significantly high, and unsaturated iron binding capacity levels were low, compared with those of group II. An analysis by means of allele-specific polymerase chain reaction demonstrated that C282Y mutation was not observed in both groups I and II. H63D mutation was observed in only two heterozygotes of group I and in one heterozygote of group II. Results could not indicate the relationship between ALD and these mutations. We speculate that other causes of iron overload may exist in ALD with iron overload.

Alcoholism↗
PubMed2004

Total body iron overload in welder's siderosis.

Welder's siderosis occurs as a consequence of the inhalation of iron dust. The iron overload of welder's siderosis is usually considered to be confined to the lungs. Here we present three proven cases of welder's siderosis associated with evidence of increased total systemic iron stores, as evidenced by increased serum ferritin levels. Multiple investigations including molecular genotyping for the common mutations found in genetic haemochromatosis failed to prove this was due to haemochromatosis, nor was there any evidence of any other recognised cause of systemic iron overload. Thus the systemic iron overload described seems likely to be due to either occupational exposure, an uncharacterised genetic haemochromatosis, or a combination of both.

Adult↗
PubMed1998

Serum transferrin receptors are decreased in the presence of iron overload.

To test the hypothesis that the quantities of circulating transferrin receptors are reduced in iron overload, we studied serum transferrin receptors and indirect measures of iron status in 150 subjects from rural Zimbabwe. We found significant inverse correlations between serum concentrations of transferrin receptors and ferritin, the ratio of ferritin to aspartate aminotransferase, and transferrin saturation (r > or = 0.44; P < 0.001). The mean +/- SD concentration of serum transferrin receptors in 23 subjects classified as having iron overload (ferritin > 300 microg/L and transferrin saturation > 60%) was 1.55 +/- 0.61 mg/L, significantly lower than the 2.50 +/- 0.62 mg/L in 75 subjects with normal iron stores (ferritin 20-300 microg/L and transferrin saturation 15-55%; P < 0.0005) and the 2.83 +/- 1.14 mg/L in 8 subjects with iron deficiency (ferritin < 20 microg/L; P = 0.001). In keeping with the regulation of transferrin receptor expression at the cellular level, our findings suggest that serum transferrin receptors are decreased in the presence of iron overload.

Adolescent↗
PubMed1988

DNA repair in lymphocytes from humans and rats with chronic iron overload.

A marked reduction of the proliferative capability after a mitogenic stimulus and a dramatic decrease of the capacity to repair DNA damages were found in lymphocytes from iron overloaded rats. These immunological parameters were not significantly different from controls in peripheral blood lymphocytes from patients with primary iron overload: hereditary hemochromatosis and porphyria cutanea tarda. This discrepancy could be due to the accelerated modality of iron overload in the rat model and to the fact that rat lymphocytes were obtained from an highly iron repleted microenvironment (i.e. spleen). Our data indicate that iron overload can affect the structure and/or the function of cellular DNA thus offering new insights on the close association of iron overload conditions and cancer.

Animals↗
PubMed1990

Iron overload in Chinese patients with hemoglobin H disease.

We examined the iron status of 23 adult patients with hemoglobin H (Hb H) disease. None of them had received multiple blood transfusions or prolonged iron therapy. Studies included serum iron and ferritin concentrations, transferrin saturation, a desferrioxamine test, computed tomography (CT) scan of the liver, and liver biopsy. Iron overload was found in 17 patients (73.9%), especially in males and in patients with splenomegaly (92.9% and 100%, respectively). Four patients with excessive alcohol consumption had clinical manifestations of severe iron overload. Idiopathic hemochromatosis associated HLA antigens, i.e., HLA-A3, -B7, or -B14, were not found in any of the 15 patients tested. These findings indicate that iron overload is common in adult patients with Hb H disease; such patients should abstain from alcohol and be considered for treatment with an iron chelating agent before irreversible organ damage occurs.

Adult↗
PubMed1989

Transfusional iron overload in patients undergoing dialysis: treatment with erythropoietin and phlebotomy.

Five patients undergoing long-term hemodialysis with transfusional iron overload received treatment for 18 weeks with a regimen of recombinant human erythropoietin (150 U/kg) and regular phlebotomy to maintain the hematocrit value at 25% and reduce the total body iron burden. In the 149 phlebotomy sessions performed in these patients, a mean of 228 +/- 8 ml (mean +/- SEM) of whole blood was removed; it had a hematocrit value of 27.7% +/- 0.2%. The iron content of the erythrocytes removed (erythrocyte iron concentration, 787 +/- 11 micrograms/ml in 133 samples) accounted for more than 99% of the total iron removal by phlebotomy. Serum iron (serum iron concentration, 1.57 +/- 0.09 micrograms/ml in 65 samples) accounted for an insignificant fraction of the total iron removed. The iron removed at each phlebotomy session averaged 49.1 +/- 2.0 mg, similar to the amount of iron removed with deferoxamine administration in patients undergoing dialysis who had iron overload, but without the potential for adverse side effects reported with long-term deferoxamine therapy. Total iron removal during the 18 weeks of this study ranged from 732 to 2797 mg. Mean serum ferritin level decreased from 3189 +/- 1076 micrograms/L to 1676 +/- 342 micrograms/L (p less than 0.02, Wilcoxon signed rank test). When compared with a group of five patients without transfusional iron overload who received recombinant human erythropoietin and did not undergo therapeutic phlebotomy, the patients with iron overload had much greater iron losses and a larger decrease in serum ferritin levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2004

Effects of kojic acid on oxidative damage and on iron and trace element level in iron-overloaded mice and rats.

Since members of hydroxypyrone series posses iron chelating properties, kojic acid (KA), 5-hydroxy-2-(hydroxymethyl)-4H-pyran-one, a fungal metabolite of natural origin, has been suggested to might play a role in iron-overload diseases and in oxidative stress conditions involving transition metal. In our experiments in vivo models of iron-overload were used to study iron-chelating properties of KA and its effect on oxidative damage in mice and rats. The treatment of iron-preloaded rats (25 mg Fe x kg(-1) b.w., i.p., daily for five days) with 0.5% KA in drinking water for four weeks did not lower the iron concentration accumulated in the liver, neither diminished the induced hepatic lipid peroxidation in iron-loaded rats. The GSH level decreased in KA-treated group. Similarly, in iron-loaded mice model experiment, the following oral treatment with KA (100 mg x kg(-1)) daily for 7 days did not decrease the level of Fe accumulated in the liver and the lipid peroxidation even enhanced after KA treatment. Though in our experiments in vivo the ability of kojic acid to affect iron kinetics in the organism could not be proved, kojic acid as a molecule of natural origin may serve as a template for the preparation of new biologically active derivatives possessing capability of chelating iron.

Administration, Oral↗
PubMed2000

Mechanism of high susceptibility of iron-overloaded mouse to Vibrio vulnificus infection.

Vibrio vulnificus produces fulminant septicemia in humans with underlying conditions, particularly those with diseases that elevate the iron level. The effect of a high iron level on the virulence of V. vulnificus was therefore investigated in mice treated with iron dextran. The mice loaded with iron became highly susceptible to V. vulnificus infection, the LD50 (50% lethal dose) decreased five logs when infected per peritoneum. However, when infected via the oral route, the LD50 was affected little unless the mouse was treated with an additional drug such as cyclophosphamide or D-galactosamine. Mice with or without iron-overloading died when the bacterial concentration in the blood reached 10(5) cfu/ml or above. Iron increased the growth rate of the bacteria, both inside and outside of the animal, quickly reaching a lethal concentration in the iron-overloaded mouse. V. vulnificus, grown with or without the addition of iron, showed strong cytotoxicity on the isolated cells or within the animal at high bacterial concentration. Iron overload stimulated the production of tumor necrosis factor alpha (TNF-alpha), a major factor of septic shock, in mice upon infection with the bacteria, probably caused by the endotoxin; however, the neutrophils, whose migration is effected by TNF-alpha, appeared to be less active. Taken together, the major virulence factor of V. vulnificus appeared to be the accelerated growth of bacteria to quickly reach the lethal level and the lower activity of immune cells including neutrophil as a result of iron-overloading. These two effects manifest other virulence factors, the host's as well as bacterial. Such factors, other than TNF-alpha stimulated by the endotoxin, enhanced cytotoxicity, which kills the host cells including the host's immune cells.

Animals↗
PubMed2002

Hepatic iron overload does not prevent a sustained virological response to interferon-alpha therapy: a long term follow-up study in hepatitis C-infected patients with beta thalassemia major.

OBJECTIVES: Transfusion-acquired chronic hepatitis C infection and systemic iron overload are common in patients with beta thalassemia major. The magnitude of hepatic iron overload has been associated with a poor response to interferon-based antiviral therapy for hepatitis C. The aim of this study was to evaluate the effect of hepatic iron concentration (HIC) on response to interferon monotherapy in patients with massive hepatic iron overload. METHODS: Twenty-eight patients with beta thalassemia major, transfusion-acquired iron overload, and chronic hepatitis C infection were prospectively treated with interferon for 6 months. HIC was measured by atomic absorption spectroscopy before treatment. Serum iron, ferritin, hepatitis C virus genotype, viral load, and liver histology were analyzed. RESULTS: Eight patients (28%) achieved a sustained virological response that has been durable after a mean of 66 months of follow-up. The median HIC was 2583 microg/g dry weight. There was no difference in HIC between responders and nonresponders to therapy. Serum hepatitis C virus RNA was lower in responders than in nonresponders. Genotype 1 was more frequent in nonresponders, and non-1 genotypes were more frequent in responders, although this did not reach statistical significance because of patient numbers. CONCLUSIONS: A long term response to interferon is unrelated to HIC in this patient group, and a durable response can occur despite massive iron overload. HIC may be a factor in liver cell injury, but it does not reliably predict a response to interferon therapy.

Adult↗
PubMed1996

'Free' iron, as detected by electron paramagnetic resonance spectroscopy, increases unequally in different tissues during dietary iron overload in the rat.

'Free' iron concentration, as determined by electron paramagnetic resonance (EPR) spectroscopy, and lipid peroxidation (LPO), as determined by thiobarbituric acid test, were assessed in the lung, heart, liver, spleen, brain and kidney of rats subjected to experimental iron overload. Two tests, Desferal- and NO-available iron, were used to measure 'free' iron and gave comparable results. The most pronounced accumulation of 'free' iron was observed in liver, kidney and spleen. Differences between control and iron loaded animals increased during the initial 90 days of treatment. Between 90 and 180 days 'free' iron concentration reached a steady state level, or even decreased, as in the case of liver. Lipid peroxidation level, measured in the organs of both treated and matched controls, did not give any significant difference during the initial 90 days of treatment. A significant augmentation was observed in liver, kidney, spleen and heart at 180 days. The results of the present research show that, under conditions of moderate siderosis, the occurrence of LPO is partially related to the level of 'free' iron.

Animals↗
PubMed2000

Iron-overload cardiomyopathy: evidence for a free radical--mediated mechanism of injury and dysfunction in a murine model.

Iron-overload cardiomyopathy is a restrictive cardiomyopathy that manifests itself as systolic or diastolic dysfunction secondary to increased deposition of iron in the heart and occurs with common genetic disorders such as primary hemochromatosis and beta-thalassemia major. Although the exact mechanism of iron-induced heart failure remains to be elucidated, the toxicity of iron in biological systems is believed to be attributed to its ability to catalyze the generation of oxygen-free radicals. In the current investigation, the dose-dependent effects of chronic iron-loading on heart tissue concentrations of iron, glutathione peroxidase (GPx) activity, free-radical production, and cardiac dysfunction were investigated in a murine model of iron-overload cardiomyopathy. It was shown that chronic iron-overload results in dose-dependent (a) increases in myocardial iron burden, (b) decreases in the protective antioxidant enzyme GPx activity, (c) increased free-radical production, and (d) increased mortality. These findings show that the mechanism of iron-induced heart dysfunction involves in part free radical-mediated processes.

Animals↗