Clinical spectrum of iron overload, novel uses of iron chelators, and potential treatment of pediatric anemias with erythropoietin. Introduction.
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Anemia↗
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Iron overload after prolonged intramuscular iron therapy.
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Female↗
Studies on the rat liver following iron overload: biochemical studies after iron mobilization.
We have characterized the distribution of iron in different organs of the rat, as well as in subcellular fractions of rat liver during iron loading and during physiologic and induced mobilization of iron. Elimination of iron through the bile was also measured. Iron loading was achieved by giving Jectofer injections, and unloading was obtained by weekly phlebotomizations. To study the fate of iron in the lysosomal compartment we have modified the method for the isolation of iron-loaded lysosomes (residual bodies) using Percoll as gradient medium. Thirty per cent of the stored iron was recovered in the liver, and this compartment gradually decreased during unloading. The spleen stored a minor part initially. This part was, however, increased 2 months after the loading was completed. A high concentration of iron was recovered in isolated liver lysosomes. A substantial portion was also found in the microsomal fraction and the ensuing 100,000 x g supernatant. Ultrastructural investigation showed few ferritin or hemosiderin granules in the microsomal fraction. After unloading, the lysosomes evidently decreased in density both in bled and nonbled animals concomitant with a decrease in iron content. In addition to lysosomes, iron was also mobilized from the microsomal fraction. Biliary iron was increased 100 per cent after iron loading and was further enhanced during unloading, in spite of the lowered concentration of iron in the liver. Enzymatic analysis suggested that in the bled animals iron-loaded lysosomes disappeared more rapidly from Kupffer cells than from the parenchymal cells.
Animals↗
Effects of venesections and restricted diet in patients with the insulin-resistance hepatic iron overload syndrome.
GOAL: We evaluated the effect of venesections and restricted diet on iron and metabolic indices and liver function tests in patients with insulin-resistance hepatic iron overload (IR-HIO). MATERIALS AND METHODS: Patients were divided in three groups: (a) patients without any therapy who were followed-up for 36+28 months; (b) patients venesected; and (c) patients on dietary treatment. In each group baseline and end-point levels of serum iron and metabolic indices, and liver function tests were compared by Student's paired t-test and the relationship between serum ferritin and the other variables during treatment was evaluated by linear regression analysis. FINDINGS AND CONCLUSIONS: In the follow-up group, iron and metabolic indices did not change over time. Serum alanine aminotransferase, gamma-glutamyl transferase, cholesterol and triglycerides significantly decreased after iron depletion. Serum glucose, cholesterol, triglyceride, ferritin and liver function tests significantly decreased after dietary treatment. Transferrin saturation decreased below 20% during phlebotomy treatment in 52% of the patients. In conclusion, our results show that IR-HIO patients had relatively low amount of iron overload that seems not to increase even after a long follow-up period. Both venesections and diet improved iron, metabolic and hepatic indices. Data suggest a relationship between hepatic iron overload and insulin resistance, and a role for both iron overload and insulin resistance in hepatocellular damage. The behaviour of iron indices during venesections suggests an impaired iron release from hepatic cells.
Female↗
Analysis of HFE gene mutations and HLA-A alleles in Brazilian patients with iron overload.
CONTEXT AND OBJECTIVE: Hemochromatosis is a common inherited disorder of iron metabolism and one of the most important causes of iron overload. The objective was to analyze the presence of C282Y, H63D and S65C mutations in the HFE gene and HLA-A alleles for a group of Brazilian patients with iron overload, and to correlate genotype with clinical and laboratory variables. DESIGN AND SETTING: Prospective study, in Discipline of Hematology and Oncology, Faculdade de Ciências Médicas da Santa Casa de Misericórdia de São Paulo. METHODS: We studied 35 patients with iron overload seen at our outpatient unit between January 2001 and December 2003. Fasting levels of serum iron and ferritin, and total iron-binding capacity, were assayed using standard techniques. Determinations of C282Y, H63D and S65C mutations in the HFE gene and of HLA-A alleles were performed by polymerase chain reaction (PCR). RESULTS: Twenty-six out of 35 patients (74%) presented at least one of the HFE gene mutations analyzed. Among these, five (14%) were C282Y/C282Y, four (11%) C282Y/H63D, one (3%) H63D/H63D, six (17%) C282Y/WT and ten (29%) H63D/WT. No patients had the S65C mutation and nine (25%) did not present any of the three HFE mutations. Four out of five patients with C282Y/C282Y genotype (80%) and three out of four patients with C282Y/H63D genotype (75%) were HLA A*03. CONCLUSION: Analysis of HFE gene mutations constitutes an important procedure in identifying patients with hereditary hemochromatosis, particularly for patients with iron overload.
Adult↗
Dietary iron overload as a risk factor for hepatocellular carcinoma in Black Africans.
Although the iron-loading disease, hereditary hemochromatosis, has a strong causal association with hepatocellular carcinoma (HCC), the carcinogenic potential of dietary iron overload in Black Africans is not known. We investigated this potential by evaluating iron status, alcohol consumption, markers for hepatitis B (HBV) and C virus (HCV) infections, and exposure to dietary aflatoxin B1 in 24 rural patients with this tumor, 48 race-, sex-, and age-matched hospital-based controls, and 75 related or unrelated close family members of the cancer patients. Iron overload was defined as a raised serum ferritin concentration in combination with a transferrin saturation > or = 60%, and was confirmed histologically when possible. Among 24 patients and 48 hospital controls, the risk of developing HCC in the iron-loaded subjects was 10.6 (95% confidence limits of 1.5 and 76.8) relative to individuals with normal iron status, after adjusting for alcohol consumption, chronic HBV and HBC infections, and exposure to aflatoxin B1. The risk of HCC in subjects with HBV infection was 33.2 (7.2, 153.4) (odds ratio [95% confidence limits]), HCV infection 6.4 (0.3, 133.5), and alcohol consumption 2.0 (0.5, 8.2). Aflatoxin B1 exposure did not appear to increase the risk of HCC. The population attributable risk of iron overload in the development of HCC was estimated to be 29%. Among 20 cancer patients and 75 family members, the risk of developing HCC with iron overload was 4.1 (0.5, 32.2). We conclude that dietary iron overload may contribute to the development of HCC in Black Africans.
Adolescent↗
Chronic iron overload and toxicity: clinical chemistry perspective.
The content of body iron is regulated primarily by absorption since humans have no physiological mechanism by which excess iron is excreted. This regulation, however, is not absolute. Many factors such as the content of diets, iron doses, life styles, etc. influence iron absorption. In the past, nutrition programs for iron fortification and the ingestion of iron preparations have been widely practiced because of the seriousness of worldwide iron deficiency. Also, we now know that a significant number of asymptomatic people carry the hemochromatosis gene, HFE, indicating that these people have the potential to accumulate excess body iron in their lifetime. Excess body iron can be highly toxic. This toxicity involves many organs leading to a variety of serious diseases such as liver disease, heart disease, diabetes mellitus, hormonal abnormalities, dysfunctional immune system, etc. The tissue damage associated with iron overload is believed to result primarily from free radical reactions mediated by iron. Iron is an effective catalyst in free radical reactions. The diseases associated with iron overload can be managed effectively or prevented. Therefore, early diagnosis of iron overload and appropriate therapy are critical. By providing the necessary laboratory data, clinical chemistry laboratories can play the pivotal role in the management of these health problems.
Animals↗
Iron overload alters innate and T helper cell responses to Candida albicans in mice.
The effect of iron overload on susceptibility of mice to Candida albicans infection and on the type of T helper (Th) immunity elicited was investigated. Iron overload greatly increased susceptibility to disseminated infection with low-virulence C. albicans cells of exogenous origin. The candidacidal activity and the ability to release nitric oxide and bioactive interleukin (IL)-12 were greatly impaired in neutrophils and macrophages from infected mice. CD4 T cells from spleens of iron-overloaded mice were found to produce high levels of IL-4 and IL-10 and low levels of interferon-gamma. Treatment of iron-overloaded mice with the iron chelator, deferoxamine, resulted in the cure of mice from infection, restored the antifungal effector and immunomodulatory functions of the phagocytic cells, and allowed the occurrence of CD4 Th1 protective antifungal responses. These data indicate that iron overload may negatively affect CD4 Th1 development in mice with candidiasis, a function efficiently restored by therapy with deferoxamine.
Animals↗
Enhanced NTPDase and 5'-nucleotidase activities in diabetes mellitus and iron-overload model.
The activity of the enzymes NTPDase and 5'-nucleotidase was studied in both diabetes mellitus and an associated model of iron-overload. Rats were divided in five groups: citrate (CC), saline (S), diabetic (D), iron-overload (IO), and diabetic iron-overload (DIO). Diabetes was induced with alloxan (150 mg/kg), and iron-overload was induced with iron-dextran (10 intramuscular applications of +/-80 mg/kg). The enzymatic activities were evaluated in the platelets. The results demonstrated an increase in the activity of NTPDase with substrates ATP and ADP (60% and 120%, respectively; P<0.001), and 5'-nucleotidase (60%, P<0.001). This increase was more intense in the IO and DIO groups. The results obtained in vitro showed an activation in ATP, ADP, and AMP hydrolysis between 1 microM and 1,000 microM ferric nitrate concentrations, being more pronounced at 100 microM and decreasing at 1,000 microM. We concluded that diabetes mellitus in association with iron-overload increased the hydrolysis of adenine nucleotides in platelets, contributing to the abnormalities found in these pathological conditions.
5'-Nucleotidase↗
Logarithmic quantitation model using serum ferritin to estimate iron overload in secondary haemochromatosis.
Nineteen children and adolescents receiving repeated transfusions and subcutaneous desferrioxamine treatment were investigated in an attempt to quantitate iron overload non-invasively. Before patients were started on desferrioxamine individual relationships were correlated for 12 to 36 months between transfused iron, absorbed iron estimated gastrointestinally, and increasing serum ferritin concentrations. Patients with inflammation, increased liver enzymes, or haemolysis were excluded from analysis. The relationship between the variables could be described by a logarithmic regression curve (y = transfused iron [plus eventually gastrointestinally absorbed iron] = iron overload = a+b log [x = serum ferritin]) for each individual patient. All patients showed close correlation (R2) between x and y (median R2 of 0.909, 0.98, and 0.92 in thalassaemia, aplastic anaemia, and sickle cell anaemia patients, respectively). When started on desferrioxamine, current serum ferritin concentrations were used to derive the iron overload from each individual regression curve. The derived estimated iron overload ranged from 0.6 g to 31 g. Left ventricular dilatation was observed in three patients with beta thalassaemia and in one patient with aplastic anaemia with median iron overload of 20.7 (14.1-31.3) g and 24.0 g respectively. Hypothyroidism was found in four patients with beta thalassaemia and one patient with aplastic anaemia with iron overload between 14.7 (6.8 and 26.1) g and 15.1 g respectively. Human growth hormone deficiency was detected in three patients with beta thalassaemia with an iron overload of 4.2 (3.5-6.8) g; all three patients had excellent desferrioxamine compliance.
Adolescent↗
[Pathogenesis and mechanism of iron overload: ferric nitrilotriacetate, hemosiderin, active oxygen, and carcinogenesis].
Iron overload is found clinically in such conditions as hemochromatosis and sideroblastic anemia, and after long term repeated transfusion in aplastic anemia. An animal model of iron overload was successfully developed in rats and rabbits by repeated intraperitoneal injections of ferric nitrilotriacetate (Fe3+-NTA). This procedure induced a diabetic state with hyperglycemia, ketonemia, glycosuria and ketonuria. Blood venesection on these rats reduced the iron load in the liver and pancreas, and ameliorated the general diabetic symptoms. A single injection of Fe3+-NTA in rats induced a temporary elevation in plasma iron concentration, lipid peroxidation in the perfused liver homogenate expressed by malondialdehyde (MDA) formation, blood GOT, GPT, ALP and gamma-GTP sequentially. Fe3+-NTA uptake in the liver caused membrane lipid peroxidation, and subsequently produced a transit liberation of liver cell enzymes, although the incorporated liver Fe3+-NTA was only 1% of the injected dosage (7.5 mg iron/kg BW) at 3 hr after injection. The direct toxic effect of Fe3+-NTA to living cells was examined using cultured normal rat liver parenchymal cells (RL-34). Marked cytolysis was found in cells exposed to more than 25 micrograms of iron through Fe3+-NTA/ml. At 50 micrograms iron of Fe3+-NTA/ml, most cells were lethally injured and the remaining cells were piled up and aggregated at 15 days. They grew on soft agar culture, and when inoculated subcutaneously to five newly born rats a subcutaneous tumor developed in all animals within three weeks. Lung metastases were found in three of five inoculated rats. A spin trapping technique with electron spin resonance (ESR) on Fe3+-NTA employing 5, 5-dimethyl-l-pyrroline-N-oxide (DMPO) yielded a spin adduct with three doublets (DMPO-Z) which corresponded to singlet oxygen. By ESR in the presence of H2O2, the Fe3+-NTA solution strongly generated hydroxyl radical. The production of active oxygen species by Fe3+-NTA solution may explain the toxicity and carcinogenicity of Fe3+-NTA. The majority of stainable iron in the iron overloaded tissue was hemosiderin (Hs). We tried to purify the Hs from multi-transfused human spleen by the method of Weir et al. The purified Hs did not show a DMPO-OH adducts in the presence of H2O2 and DMPO on ESR measurement. The Hs iron was solubilized with several biological ligands in an acidic state in the presence of a reducing reagent like glutathione. Solubilized Hs iron produced iron chelate complexes which resulted in OH radicals production in the presence of H2O2 in acidic conditions below pH 5.5.(ABSTRACT TRUNCATED AT 400 WORDS)
Acetates↗
African iron overload and hepatocellular carcinoma (HA-7-0-080).
Although HLA-linked hemochromatosis greatly increases the risk for hepatocellular carcinoma in people of European ancestry, iron overload in Africa is not thought to be etiologically related to this malignancy. To determine if African iron overload may be associated with hepatocellular carcinoma, we reviewed 320 consecutive diagnostic liver biopsies processed at the University of Zimbabwe from 1992 to 1994 and we selected for analysis 215 biopsies from adults that were suitable for the histological assessment of hepatocellular iron. Subjects were stratified according to hepatocellular iron grades of 0-2+ (normal levels to mild siderosis; n = 183) and grades of 3+ and 4+ (distinctly elevated levels consistent with iron overload; n = 32). Thirty-six subjects had hepatocellular carcinoma. Logistic regression modeling revealed a significant association between iron overload and hepatocellular carcinoma after adjustment for age, sex and and the presence of portal fibrosis or cirrhosis (p = 0.041). The odds of hepatocellular carcinoma in subjects with iron overload was 3.1 (95% confidence interval of 1.05-9.4) times that of subjects without iron overload. While we could not test for exposure to viral hepatitis or to aflatoxins in this study, our findings suggest that iron overload may be a risk factor for hepatocellular carcinoma in Africa.
Adult↗
Ascorbic acid deficiency, iron overload and alcohol abuse underlie the severe osteoporosis in black African patients with hip fractures--a bone histomorphometric study.
Osteoporosis and femoral neck fractures (FNF) are uncommon in black Africans although osteoporosis accompanying iron overload (from traditional beer brewed in iron containers) associated with ascorbic acid deficiency (oxidative catabolism by iron) has been described from sub-Saharan Africa. This study describes histomorphometric findings of iliac crest bone biopsies and serum biochemical markers of iron overload and of alcohol abuse and ascorbic acid levels in 50 black patients with FNFs (29 M, 21 F), age 62 years (40-95) years (median [min-max]), and in age- and gender-matched black controls. We found evidence of iron overload in 88% of patients and elevated markers of alcohol abuse in 72%. Significant correlations between markers of iron overload and of alcohol abuse reflect a close association between the two toxins. Patients had higher levels of iron markers, i.e., siderin deposits in bone marrow (P < 0.0001), chemical non-heme bone iron (P = 0.012), and serum ferritin (P = 0.017) than controls did. Leukocyte ascorbic acid levels were lower (P = 0.0008) than in controls. The alcohol marker mean red blood cell volume was elevated (P = 0.002) but not liver enzymes or uric acid. Bone volume, trabecular thickness, and trabecular number were lower, and trabecular separation was greater in patients than in controls, all at P < 0.0005; volume, surface, and thickness of osteoid were lower and eroded surface was greater, all at P < 0.0001. There was no osteomalacia. Ascorbic acid deficiency accounted significantly for decrease in bone volume and trabecular number, and increase in trabecular separation, osteoid surface, and eroded surface; iron overload accounted for a reduction in mineral apposition rate. Alcohol markers correlated negatively with osteoblast surface and positively with eroded surface. Relative to reported data in white FNF patients, the osteoporosis was more severe, showed lower osteoid variables and greater eroded surface; FNFs occurred 12 years earlier and were more common among men. We conclude that the osteoporosis underlying FNFs in black Africans is severe, with marked uncoupling of resorption and formation in favor of resorption. All three factors--ascorbic acid deficiency, iron overload, and alcohol abuse--contributed to the osteoporosis, in that order.
Adult↗
Lipid composition and fluidity of liver mitochondria, microsomes and plasma membrane of rats with chronic dietary iron overload.
The effect of chronic dietary iron overload on the lipid composition and physical state of rat liver mitochondria, microsomes and plasma membranes was investigated. After 9 weeks of iron treatment, a significant decrease of polyunsaturated and a parallel increase of saturated fatty acids was observed in mitochondrial and plasma membrane phospholipids. By contrast, no appreciable modification of the fatty acid composition of microsomal membranes was detected. The cholesterol/phospholipid molar ratio as well as the lipid/protein ratio, did not reveal any significant difference in any of the fractions studies. Finally, no change in the molecular order of the various membranes, as assessed by electron spin resonance spectrometry, was observed following iron intoxication. These data indicate that, although in vivo chronic hepatic iron overload induces a modification of fatty acid profile in cellular structures consistent with the in vivo occurrence of lipid peroxidation, these changes do not bring about appreciable modifications of other physico-chemical parameters relevant to membrane integrity and cell viability.
Animals↗
Distribution, excretion and in-vivo metabolism of 14C-hexachlorobenzene and the influence of iron overload in C57BL/10 mice.
Iron overload did not greatly alter the distribution and total excretion of radioactivity from 14C-hexachlorobenzene (HCB) in male C57Bl/10 mice. An increase was observed in the urinary excretion of metabolites but its significance is unclear.
Animals↗
Deferoxamine promotes survival and prevents electrocardiographic abnormalities in the gerbil model of iron-overload cardiomyopathy.
We investigated the time course of electrocardiographic (ECG) changes in the Mongolian gerbil model of iron overload and the effects of the iron chelator deferoxamine (DFO) on these changes. Iron overload was produced with weekly subcutaneous injections of low doses (200 mg/kg/wk) or high doses (800 mg/kg/wk) of iron-dextran. DFO was administered subcutaneously at a dose of 200 mg/kg/day to high-dose animals. Our results show that (1) survival of iron-overloaded gerbils is dose-dependent, with median survival times of 68 and 14 weeks for low- and high-dose animals, respectively; (2) both low and high doses produce prolongation of the PR interval and bradycardia in early stages and prolongation of the QT interval, premature ventricular contractions, variable degrees of atrioventricular block, changes in the ST segment, and T-wave inversion at later stages coinciding with the development of heart failure; (3) DFO prevented death during 20 weeks of high-dose iron-dextran; (4) DFO prevented ECG changes, although delayed prolongation of PR intervals and QRS complexes occurred; and (5) despite marked prolongation of survival and prevention of ECG changes, DFO had modest effects on total cardiac iron content. We speculate that DFO chelates a small iron pool located within the cytoplasm of iron-overloaded cardiomyocytes.
Animals↗
Iron overload augments 7,12-dimethylbenz(a)anthracene-initiated and 12-O-tetradecanoylphorbol-13-acetate-promoted skin tumorigenesis.
Reactive oxygen species and free radicals have been implicated in the multistep cutaneous chemical carcinogenesis. Much of the experimental evidence in this regard is indirect and is based on observations that prooxidant status usually enhances and antioxidant treatments generally inhibit tumor yield. Iron overload is known to enhance peroxidative damage and cause oxidative stress. In this study, we report that iron overload augments 12-O-tetradecanoylphorbol-13-acetate (TPA)-mediated cutaneous tumor promotion. Female Swiss mice were subjected to iron overload by injecting 1 mg iron/ mouse/day consecutively for 2 weeks. Tumors were initiated by applying a single dose of 7,12-dimethylbenz(a)anthracene and promoted with twice weekly applications of TPA for 20 weeks and the appearance of first tumor (latency period), percent incidence and number of tumors per mouse were recorded. It has been observed that the level of iron in involved (tumor-bearing) skin was about fourfold higher as compared to uninvolved (non-tumor) skin of iron overload animals and about tenfold higher as compared to the iron level in the skin of normal animals. When compared to the iron-unloaded control group, the iron overload mice showed an increased incidence of tumors. In iron overload animals, the tumors appeared 3 weeks earlier and also the number of tumors per mouse was significantly higher (2.5-fold). These data indicate that iron overload augments TPA-mediated tumor promotion. We propose that oxidative stress generated by iron overload may be responsible for the augmentation of cutaneous tumorigenesis.
9,10-Dimethyl-1,2-benzanthracene↗
Hemochromatosis mutations in the general population: iron overload progression rate.
The progression rate of iron overload in hereditary hemochromatosis in individuals in the general population is unknown. We therefore examined in the general population iron overload progression rate in C282Y homozygotes. Using a cohort study of the Danish general population, The Copenhagen City Heart Study, we genotyped 9174 individuals. The 23 C282Y homozygotes identified were matched to 2 subjects each of 5 other HFE genotypes with respect to sex, age, and alcohol consumption. As a function of biologic age, transferrin saturation increased from 50% to 70% from 25 to 85 years of age and from 70% to 80% from 35 to 80 years of age in female and male C282Y homozygotes, respectively. Equivalently, ferritin levels increased from 100 to 500 microg/L and decreased from 800 to 400 microg/L in female and male C282Y homozygotes. As a function of 25 years follow-up irrespective of age, transferrin saturation and ferritin levels increased slightly in male and female C282Y homozygotes. None of the C282Y homozygotes developed clinically overt hemochromatosis. In conclusion, individuals in the general population with C282Y homozygosity at most demonstrate modest increases in transferrin saturation and ferritin levels, and clinically overt hemochromatosis is rare. Therefore, C282Y homozygotes identified during population screening, and not because of clinically overt hemochromatosis, at most need to be screened for manifestations of hemochromatosis every 10 to 20 years.
Adult↗