Experimental iron overload using ferric nitrilotriacetate (Fe3+-NTA): a proposal model of the diseases in man caused by iron overload.
Explore the source record for details and available documents.
Animals↗
SEARCH · Search PubMed
Results for “Iron Overload”
Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
[Thalassemia minor with iron overload: genetic and clinical study of a family].
A patient with thalassemia minor (TM) is reported who ingested 80 g of alcohol/day and presented an important overload of iron with deposits and a hepatic iron ratio compatible with primary hemochromatosis. The results obtained from the study of histocompatibility antigens, clinical manifestations and family analysis discarded the possibility of two genetic diseases, beta-thalassemia and primary hemochromatosis, being concomitantly present in the same progeny. Thalassemia minor and alcoholic hepatopathy are considered as having acted together and being responsible for the iron overload. The relation between alcohol ingested, TM and iron deposits is discussed.
Adult↗
Enhanced gamma-glutamyl transpeptidase expression and selective loss of CuZn superoxide dismutase in hepatic iron overload.
Liver injury caused by iron overload is presumed to involve lipid peroxidation and the formation of products such as 4-hydroxynonenal (4HNE), which has been implicated in hepatic fibrogenesis. Cellular antioxidants that modulate the formation and detoxification of compounds such as 4HNE may represent important protective mechanisms involved in the response to iron overload. This study examines the relationship between 4HNE, collagen content, and antioxidant defenses in the livers of rats fed carbonyl iron for 10 weeks. Iron-loading resulted in significant increases in iron (8.8-fold), 4HNE (1.7-fold), and hydroxyproline (1.5-fold). Total glutathione content was unchanged by iron, but gamma-glutamyl transpeptidase activity (GGT) increased sixfold and CuZn superoxide dismutase (CuZnSOD) activity decreased >9%. GGT colocalized with iron deposition and was associated with increased GGT mRNA. Decreased CuZnSOD activity was paralleled by a reduction in CuZnSOD protein on Western blot and immunohistochemistry, but no decrease in CuZnSOD mRNA. Glutathione S-transferase (GST) and Mn superoxide dismutase (MnSOD) activities were also significantly increased by iron loading. These results demonstrate that iron overload significantly alters the expression of antioxidant enzymes associated with glutathione (GGT and GST) and superoxide metabolism (CuZnSOD and MnSOD). Furthermore, the localized induction of GGT may enhance detoxification of lipid peroxidation-derived aldehydes via glutathione-dependent pathways in iron-loaded hepatocytes. These alterations in antioxidant defenses may represent an adaptive response, limiting accumulation 4HNE, and thus, stimulation of collagen synthesis, accounting for the mild fibrogenic response seen in this model of iron overload.
Aldehydes↗
A Mössbauer spectroscopic study of the form of iron in iron overload.
There are major differences in the temperature dependence of the Mössbauer spectra of ferritin and haemosiderin extracted from the organs of humans suffering from transfusional iron overload. Iron overload can also occur in animal systems as a result of artificial treatments or dietary factors. None of the animal systems which were investigated in the present study showed evidence in their Mössbauer spectra for the presence of the haemosiderin found in transfusional iron overload in humans. This suggests that the haemosiderin which occurs in the case of human transfusional iron overload may be specific to that situation.
Animals↗
Iron overload among a psychiatric outpatient population.
BACKGROUND: Iron overload has been suggested to be an unrecognized cause of psychiatric morbidity. This study sought to estimate the prevalence of iron overload in a large outpatient psychiatric clinic. METHOD: A retrospective review of screening blood chemistries was conducted on 661 active outpatients at a large, university outpatient psychiatric clinic to identify elevated iron status results (plasma iron, percentage of iron saturation) suggestive of iron overload. Patients with positive profiles were asked to undergo a subsequent blood chemistry to confirm positive results (plasma iron, percentage of iron saturation, plus plasma ferritin). Patients with positive repeated iron chemistry results were considered likely candidates for iron overload. RESULTS: Twenty-one patients (3.2%) were identified as meeting one of the criteria suggestive of iron overload on initial screening reports. Thirty-one percent of those who underwent subsequent, confirmatory testing (5/16) continued to meet one of the criteria. On the basis of these results, we estimated a 1% (3.2 x 0.31) prevalence rate of likely candidates for iron overload. A review of these patients' charts indicated that they carried an unexpectedly high rate of bipolar affective disorder (80%) as a diagnosis and were, without exception, atypical in that they were resistant to conventional psychiatric treatment and lacked a family history for this disorder. The prevalence of positive iron overload profiles on a routine blood chemistry was similar to the prevalence of positive thyroid abnormalities based on TSH results in this population. CONCLUSION: Blood chemistry profiles suggestive of iron overload may be associated with a small portion of treatment-resistant psychiatric patients. Routine screening for iron abnormalities, especially in treatment-resistant patients, should be considered. Further studies are required to determine the causal association, if any, between iron excess and primary psychiatric illnesses.
Adult↗
H ferritin knockout mice: a model of hyperferritinemia in the absence of iron overload.
Ferritin, the iron-storing molecule, is made by the assembly of various proportions of 2 different H and L subunits into a 24-mer protein shell. These heteropolymers have distinct physicochemical properties, owing to the ferroxidase activity of the H subunit, which is necessary for iron uptake by the ferritin molecule, and the ability of the L subunit to facilitate iron core formation inside the protein shell. It has previously been shown that H ferritin is indispensable for normal development, since inactivation of the H ferritin gene by homologous recombination in mice is lethal at an early stage during embryonic development. Here the phenotypic analysis of the mice heterozygous for the H ferritin gene (Fth(+/-) mice) is reported, and differences in gene regulation between the 2 subunits are shown. The heterozygous Fth(+/-) mice were healthy and fertile and did not present any apparent abnormalities. Although they had iron-overloaded spleens at the adult stage, this is identical to what is observed in normal Fth(+/+) mice. However, these heterozygous mice had slightly elevated tissue L ferritin content and 7- to 10-fold more L ferritin in the serum than normal mice, but their serum iron remained unchanged. H ferritin synthesis from the remaining allele was not up-regulated. This probably results from subtle changes in the intracellular labile iron pool, which would stimulate L ferritin but not H ferritin synthesis. These results raise the possibility that reduced H ferritin expression might be responsible for unexplained human cases of hyperferritinemia in the absence of iron overload where the hereditary hyperferritinemia-cataract syndrome has been excluded. (Blood. 2001;98:525-532)
Alleles↗
Effect of iron overload on the benzoyl peroxide-mediated tumor promotion in mouse skin.
In this communication, we report that iron overload augments benzoyl peroxide (BPO)-mediated tumor promotion in 7,12-dimethylbenz[a]anthracene (DMBA)-initiated mouse skin. Female albino Swiss mice were overloaded with iron and tumors were initiated by applying a single topical application of DMBA. A week after the initiation, promoting agent, BPO, was applied three times/week for 46 weeks. The appearance of the first tumor (papilloma) and the number of tumors/mouse were recorded. When compared to the control group, the iron-overloaded mice showed an increased incidence of tumors at various time intervals. In iron-overloaded animals, tumors appeared earlier and also the number of tumors/mouse was significantly higher. These data could be correlated with the iron levels of mouse skin in the two groups. Further, BPO-mediated induction in ornithine decarboxylase (ODC) activity and [3H]thymidine incorporation in cutaneous DNA were higher in the iron overload group. In addition, in iron-overloaded mice, cutaneous lipid peroxidation (LPO) and xanthine oxidase (XOD) activities were higher, whereas catalase activity was reduced. Similar to papilloma induction, a significant increase in carcinoma yield and incidence was observed in iron-overloaded animals. Based on this study, we propose that iron overload significantly increases the tumor promotion and progression potential of BPO. We suggest that oxidative stress generated by iron overload is responsible for the augmentation of BPO-mediated cutaneous tumorigenesis.
9,10-Dimethyl-1,2-benzanthracene↗
Iron overload in Africa. Interaction between a gene and dietary iron content.
BACKGROUND AND METHODS: In contrast to hemochromatosis, which in white populations is inherited through a gene linked to the HLA locus, iron overload in sub-Saharan Africa is believed to result solely from increased dietary iron derived from traditional home-brewed beer. To examine the hypothesis that African iron overload also involves a genetic factor, we used likelihood analysis to test for an interaction between a gene (the hypothesized iron-loading locus) and an environmental factor (increased dietary iron) that determines transferrin saturation and unsaturated iron-binding capacity. We studied 236 members of 36 African families chosen because they contained index subjects with iron overload. Linkage to the HLA region was tested with use of lod scores. RESULTS: In the index subjects, increased iron was present in both hepatocytes and cells of the mononuclear-phagocyte system. Among family members with increased dietary iron due to the consumption of traditional beer, transferrin saturation in serum was distributed bimodally, with 56 normal values (less than 60 percent saturation) and 44 elevated values; the mean serum ferritin concentration was five times higher in the subjects with elevated transferrin saturation (P less than 0.005). The pedigree analysis provided evidence of both a genetic effect (P less than 0.005) and an effect of increased dietary iron (P less than 0.005) on transferrin saturation and unsaturated iron-binding capacity. In the most likely model, increased dietary iron raised the mean transferrin saturation from 30 to 81 percent and lowered the mean unsaturated iron-binding capacity from 38 to 13 mumol per liter in subjects heterozygous for the iron-loading locus. The hypothesis of tight linkage to HLA was rejected. CONCLUSIONS: Iron overload in Africa may be caused by an interaction between the amount of dietary iron and a gene distinct from any HLA-linked gene.
Adult↗
Magnetic resonance imaging of splenic iron overload.
The value of magnetic resonance (MR) imaging in assessing iron overload in the spleen was retrospectively investigated in 40 consecutive patients. MR appearance, measure of signal intensity and T1- and T2-relaxation times were correlated with the histologically determined level of iron in the spleen in each patient. Histologic examination revealed no iron overload in 19 patients, mild iron overload in seven, moderate iron overload in six, and severe iron overload in eight. All 19 patients with no splenic iron overload and 11 of the other 21 patients with splenic iron overload were correctly identified by MR imaging (sensitivity 52%, specificity 100%, accuracy 75%). Splenic iron overload was diagnosed when a decrease of signal intensity of the spleen compared with those of adipose tissue and renal cortex was demonstrated. MR images demonstrated all eight cases of severe, three of the six cases of moderate, and none of the seven cases of mild iron overload. Only spleens with severe iron overload had a significant mean decrease in signal intensity and T1- and T2-relaxation times. Although specific, MR imaging is poorly sensitive to splenic iron overload.
Adolescent↗
Increased release of arachidonic acid and eicosanoids in iron-overloaded cardiomyocytes.
BACKGROUND: Patients with transfusional iron overload may develop a life-limiting cardiomyopathy. The sensitivity of lipid-metabolizing enzymes to peroxidative injury, as well as the reported effects of arachidonic acid (AA) and metabolites on cardiac rhythm, led us to hypothesize that iron-overloaded cardiomyocytes display alterations in the release of AA and prostaglandins. METHODS AND RESULTS: Neonatal rat ventricular myocytes (NRVMs) cultured for 72 hours in the presence of 80 microgram/mL ferric ammonium citrate displayed an increased rate of AA release, both under resting conditions and after stimulation with agonists such as [Sar(1)]Ang II. Although iron treatment did not affect overall incorporation of [(3)H]AA into NRVM phospholipids, it caused a 2-fold increase in the distribution of precursor in phosphatidylcholine species, with a proportional decrease in phosphatidylinositol, phosphatidylserine, and phosphatidylethanolamine. Increased release of AA in iron-overloaded NRVMs was reduced by the diacylglycerol lipase inhibitor RHC80267 but was largely insensitive to inhibitors of phospholipases A(2) and C. Iron-overloaded cardiomyocytes also displayed increased production of eicosanoids and induction of cyclooxygenase-2 after stimulation with interleukin-1alpha. CONCLUSIONS: Iron overload enhances AA release and incorporation of AA into phosphatidylcholine, as well as cyclooxygenase-2 induction and eicosanoid production, in NRVMS: The effects of AA and metabolites on cardiomyocyte rhythmicity suggest a causal connection between these signals and electromechanical alterations in iron-overload-induced cardiomyopathy.
Angiotensin II↗
Pathophysiology of iron overload.
In thalassemia, iron overload is the joint outcome of excessive iron absorption and transfusional siderosis. While iron absorption is limited by a physiologic ceiling of about 3 mg/d, plasma iron turnover in thalassemia may be 10 to 15 times normal, caused by the wasteful, ineffective erythropoiesis of an enormously expanded erythroid marrow. This outpouring of catabolic iron exceeds the iron-binding capacity of transferrin and appears in plasma as non-transferrin-plasma iron (NTPI). The toxicity of NTPI is much higher than of transferrin-iron as judged by its ability to promote hydroxyl radical formation resulting in peroxidative damage to membrane lipids and proteins. In the heart, this results in impaired function of the mitochrondrial respiratory chain and abnormal energy metabolism manifested clinically in fatal hemosiderotic cardiomyopathy. Ascorbate increases the efficacy of iron chelators by expanding the intracellular chelatable iron pool, but, at suboptimal concentrations is a pro-oxidant, enhancing the catalytic effect of iron in free radical formation. NTPI is removed by i.v. DFO in a biphasic manner and reappears rapidly upon cessation of DFO, lending support to the continuous, rather than intermittent, use of chelators. Unlike DFO and other hexadentate chelators, bidentate chelators such as L1 may produce incomplete intermediate iron complexes at suboptimal drug concentrations.
Animals↗
Milk whey protein decreases oxygen free radical production in a murine model of chronic iron-overload cardiomyopathy.
BACKGROUND: Chronic iron overload is a major cause of organ failure worldwide, but its pathogenesis remains to be elucidated. OBJECTIVES: To examine in an experimental murine model of iron-overload cardiomyopathy the relation between milk whey protein and, first, the production of reactive oxygen free radical species and, second, antioxidant reserve status. METHODS: B6D2F1 mice were randomly assigned to four treatment groups (n=8 per treatment group): placebo control; iron only; whey only; and iron with whey. Reactive oxygen free radical species in the heart were quantified by the cytotoxic aldehydes malondialdehyde (MDA), 4-hydroxy-nonenal (HNE) and hexanal, while antioxidant reserve status was quantified by glutathione (GSH) and glutathione peroxidase (GPx) activity in the heart tissue. RESULTS: Significantly decreased concentrations (pmol/100 mg wet weight tissue) of MDA (2468+/-261), HNE (912+/-38) and hexanal (5385+/-927) were observed in the heart tissue of the group receiving iron with whey, in comparison with the iron-only treatment group (MDA 9307+/-387, HNE 1416+/-157, hexanal 14,874+/-2955; P<0.001). Significantly increased GPx (141+/-38 IU/L) and GSH (521+/-136 IU/L) activity were observed in mice receiving iron with whey, in comparison with mice receiving iron only (GPx 100+/-10 IU/L, GSH 446+/-33 IU/L; P<0.001). CONCLUSION: Mice receiving iron treatments with whey supplementation had significantly lower concentrations of cytotoxic aldehydes and significantly higher cardiac levels of GPx and GSH activity than did iron-only treated mice. Additional basic research is warranted to examine the exact mechanisms by which milk whey protein protects the heart.
Aldehydes↗
Iron overload in the rat pancreas following portacaval shunting and dietary iron supplementation.
Reproduction of pancreatic iron overload in an animal model has been difficult to achieve primarily because of the first-pass extraction of iron by the liver. We hypothesized that portacaval shunting would avoid this hepatic phenomenon and increase pancreatic iron deposition. An end-to-side portacaval shunt was surgically created in male Sprague-Dawley rats, and they were subsequently fed a carbonyl iron-supplemented diet for 17 weeks. This resulted in marked iron accumulation in the pancreas (1621 +/- 188 micrograms/g) compared to minimal deposition in sham-operated rats fed the same diet (138 +/- 53 micrograms/g). Iron deposition in the acinar and centroacinar cells was confirmed histologically by Gomori staining, as well as by ultrastructural examination. Iron overloading was associated with enhanced oxidative stress evidenced by a twofold increase in the levels of glutathione disulfide and thiobarbituric acid-reactive substances. Also, adducts of proteins with malondialdehyde and 4-hydroxynonenal were demonstrated in acinar and ductal cells. Other apparent consequences of iron overload were a 50% reduction in pancreatic amylase content and a decrease in pancreatic protein concentration. These hypotrophic changes were associated with a reduced mass of zymogen granules in the acinar cells noted histologically. Our results show that a combination of portacaval shunting and carbonyl iron feeding achieve pancreatic iron overload and support the role of oxidative stress in the pathogenesis of iron-induced damage in the pancreas.
Aldehydes↗
Baroreflex function in conscious rats submitted to iron overload.
Our hypothesis is that iron accumulated in tissue, rather than in serum, may compromise cardiovascular control. Male Fischer 344 rats weighing 180 to 220 g were divided into 2 groups. In the serum iron overload group (SIO, N = 12), 20 mg elemental iron was injected ip daily for 7 days. In the tissue iron overload group (TIO, N = 19), a smaller amount of elemental iron was injected (10 mg, daily) for 5 days followed by a resting period of 7 days. Reflex heart rate responses were elicited by iv injections of either phenylephrine (0.5 to 5.0 microg/kg) or sodium nitroprusside (1.0 to 10.0 microg/kg). Baroreflex curves were determined and fitted to sigmoidal equations and the baroreflex gain coefficient was evaluated. To evaluate the role of other than a direct effect of iron on tissue, acute treatment with the iron chelator deferoxamine (20 mg/kg, iv) was performed on the TIO group and the baroreflex was re-evaluated. At the end of the experiments, evaluation of iron levels in serum confirmed a pronounced overload for the SIO group (30-fold), in contrast to the TIO group (2-fold). Tissue levels of iron, however, were higher in the TIO group. The SIO protocol did not produce significant alterations in the baroreflex curve response, while the TIO protocol produced a nearly 2-fold increase in baroreflex gain (-4.34 +/- 0.74 and -7.93 +/- 1.08 bpm/mmHg, respectively). The TIO protocol animals treated with deferoxamine returned to sham levels of baroreflex gain (-3.7 +/- 0.3 sham vs -3.6 +/- 0.2 bpm/mmHg) 30 min after the injection. Our results indicate an effect of tissue iron overload on the enhancement of baroreflex sensitivity.
Animals↗
Induction of liver cell haem oxygenase in iron-overloaded rats.
Rats were chronically iron-overloaded by intraperitonel injections of iron-dextran. Electron microscopy revealed that the excess iron was deposited in ferritin-like particles packed in lysosomes and scattered in hepatic cytoplasm. No mitochondrial iron deposition or damage was seen. Furthermore, mitochondrial preparations from chronically iron-overloaded animals were found to be contaminated with lysosomes, which could explain previously reported increases in mitochondrial iron by chemical analysis. Mitochondrial function, as measured by cytochromes a-a3, b and c concentrations as well as activity of the rate-limiting enzyme of haem synthesis, delta-aminolaevulinate synthetase, was not diminished by chronic iron-overloading. Microsomal haem was decreased by 30% at the time that haem oxygenase, the rate-limiting enzyme of haem degradation, was increased approx. 3-fold. Animals were given a single intraperitoneal injection of iron-dextran and the activities of delta-aminolaevulinate synthetase and haem oxygenase were measured over 24 h. delta-Aminolaevulinate synthetase activity increased approx. 2-fold in these acutely iron-overloaded rat livers, but at a time after the increase in haem oxygenase. These results suggest that an early consequence of excess iron in liver is acceleration of the rate of haem degradation, possible by haem oxygenase.
5-Aminolevulinate Synthetase↗
Serum ferritin iron in iron overload and liver damage: correlation to body iron stores and diagnostic relevance.
The iron content of serum ferritin has been determined in groups of patients with normal or increased iron stores by using a technique of ferritin immunoprecipitation followed by iron quantitation with atomic absorption spectroscopy. The results were correlated to individual liver iron concentrations, measured non-invasively by superconducting quantum interference device (SQUID) biomagnetometry. A close correlation between serum concentrations of ferritin protein and ferritin iron was found (r = 0.92) in all groups of patients. However, the correlation between ferritin iron concentration and individual liver iron concentration was poor in patients with hemochromatosis (r = 0.63) and patients with beta-thalassemia major (r = 0.57). The degree of ferritin iron saturation was about 5% in iron-loaded patients, which contrasts with results in two recent studies but confirms older observations. In patients with liver cell damage, the ferritin iron saturation in serum was significantly higher than that found in groups with iron overload disease, probably indicating the release of intracellular iron-rich ferritin into the blood. The monitoring of patients undergoing bone marrow transplantation indicated that the release of iron-rich and iron-poor ferritin occurred during phases of hepatocellular damage and inflammation, respectively. We find the benefits of serum ferritin iron measurement to be marginal in patients with iron overload disease.
Adult↗
Evidence that iron-overload promotes 7,12-dimethylbenz(a)anthracene- induced skin tumorigenesis in mice.
Iron overload is known to occur in West European and American populations due to the consumption of an iron-rich diet. There are also genetic disorders which lead to body iron overload. It has been shown that iron overload predisposes humans to an increased risk of cancer. In experimental animals, iron overload is known to enhance intestinal, colon, hepatic, pulmonary and mammary carcinogenesis. However, the mechanism by which iron overload enhances chemically-induced carcinogenesis is not known. In this study, we show that iron overload acts as a mild tumor promoter in mouse skin. Female albino swiss mice were given 1 mg iron/mouse parenterally for 2 weeks to induce iron overload. These animals showed a three-fold increase in cutaneous iron concentration as compared to normal mice. Tumors were initiated by topically applying 7,12-dimethylbenz(a)anthracene (DMBA). Appearance of the first tumor (latency period), percent tumor incidence and number of tumors/mouse were recorded. When compared to the control group, iron overload mice showed an increased incidence of tumors, from 25%-55% by week 20, and tumors appeared 4 weeks earlier. The number of tumors per mouse was four-fold higher in the iron overload group. The induction of cutaneous ornithine decarboxylase (ODC) activity and [3H]thymidine incorporation in cutaneous DNA were higher in iron overload groups as compared to normal control animals. Similar to other oxidant tumor promoters, iron overload enhanced cutaneous lipid peroxidation and xanthine oxidase activity and decreased catalase activity. Our results indicate that iron overload exerts a mild tumor promoting activity in mouse skin. Our data also show that oxidative stress generated by iron overload plays an important role in the augmentation of cutaneous tumorigenesis. These data may also have implications for the enhanced risk of cancer-induction following UVB exposure of human populations with iron overload.
9,10-Dimethyl-1,2-benzanthracene↗
Compound heterozygosity for haemochromatosis gene mutations and hepatic iron overload in allogeneic bone marrow transplant recipients.
Iron overload has been proposed as a cause of liver dysfunction after BMT Factors which could be relevant to iron overload include the number of red cell transfusions and mutations within the haemochromatosis gene (HFE). Two point mutations, Cys282Tyr and His63Asp, have been described within HFE. Cys282Tyr homozygosity is associated with haemochromatosis; the effect of compound heterozygosity, Cys282Tyr/His63Asp, on iron status is variable. We analysed HFE status in 52 allograft patients surviving more than 6 months. Compound heterozygosity was identified in three patients (Cases 1-3). Iron status and liver function were evaluated and, in Cases 1 and 2, liver histology and iron content as well. Case 3 who received 12 units of red cells had a normal ferritin and liver function. Cases 1 and 2 received 29 and 59 units, respectively, and had high serum ferritins and transferrin saturations, abnormal liver function and significant hepatic iron overload on biopsy. Iron overload in Case 1 patient progressed in the context of GVHD and in the absence of further transfusion, suggesting that liver GVHD may increase hepatic iron accumulation. These cases demonstrate the variable phenotypic expression of HFE compound heterozygosity in BMT recipients, which may be only partly explained by transfusional iron loading. Venesection or chelation therapy should be considered in patients with coexistent hepatic GVHD and iron overload.
Adult↗