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PubMed1990

Hepatic mitochondrial malondialdehyde metabolism in rats with chronic iron overload.

Peroxidative decomposition of mitochondrial membrane phospholipids with subsequent mitochondrial dysfunction is a postulated mechanism of liver cell injury in parenchymal iron overload. Malondialdehyde is formed when polyunsaturated fatty acids of membrane phospholipids undergo peroxidative decomposition, and it is metabolized by aldehyde dehydrogenase. We studied mitochondrial metabolism of malondialdehyde in rats with chronic dietary iron overload. Hepatic malondialdehyde concentrations were significantly increased in iron-loaded livers, and mitochondrial respiratory control ratios using glutamate as a substrate were decreased by 47% largely owing to reductions in state 3 respiration. When exogenous malondialdehyde was added to mitochondrial fractions, there was significantly less metabolism of malondialdehyde in mitochondria of iron-loaded livers as compared with controls. In addition, there was a 28% decrease in mitochondrial aldehyde dehydrogenase in iron-loaded livers but no change in cytosolic aldehyde dehydrogenase. Increased hepatic malondialdehyde in chronic iron overload may result from a combination of increased production and decreased metabolism of malondialdehyde, both of which may be due to iron-induced mitochondrial lipid peroxidation.

Aldehyde Dehydrogenase↗
PubMed1999

Iron overload upregulates haem oxygenase 1 in the lung more rapidly than in other tissues.

Haem oxygenase-1 is upregulated by numerous insults, including oxidative stress, and under such circumstances it is considered to be a protective stratagem. We have measured the haem oxygenase-1 expression in heart, lung and liver tissues of control and iron-overloaded rats. Lung tissue from iron-overloaded rats displayed a significant increase in the haem oxygenase-1 protein but no changes in haem oxygenase-1 mRNA. Conversely, heart tissue showed a significant increase in haem oxygenase-1 mRNA but no changes in haem oxygenase-1 protein. We conclude that during oxidative stress caused by iron overload, lung tissue responds with a rapid upregulation of haem oxygenase-1 levels.

Animals↗
PubMed1992

Inhibition of iron overload toxicity in rat hepatocyte cultures by pyoverdin Pf, the siderophore of Pseudomonas fluorescens.

The effect of the pyoverdin Pf (an iron chelating agent isolated and purified from Pseudomonas fluorescens CCM 2798) was studied on iron overloaded rat hepatocyte cultures. Iron overload was obtained by addition of 5-80 microM ferric nitrilotriacetate to the culture medium. Twenty-four hours after iron treatment, a significant increase in aspartate aminotransferase and lactate dehydrogenase in the culture medium was observed. This corresponded to intracellular decrease in the activity of these two enzymes and correlated with a decrease in albumin secretion and an increase in total free malondialdehyde production. The iron toxicity was inhibited by desferrioxamine B. Pyoverdin Pf added to the hepatocyte cultures served as an effective agent to prevent iron toxicity induced in overload. The observed effect of the pyoverdin Pf was as potent as that of desferrioxamine B.

Amino Acid Sequence↗
PubMed2005

Experimental renal failure and iron overload: a histomorphometric study in rat tibia.

Renal failure (RF) is a serious disease of relatively high incidence, known to cause bone alterations. RF patients frequently suffer anemia, which is usually treated with iron. Given that iron overload inhibits bone formation, the aim of the present study was to evaluate the effect of iron on the subchondral bone of rat tibiae, using a model of renal failure. Male Wistar rats were subjected to experimental nephrectomy in order to induce renal failure and to iron overload by daily intraperitoneal injections of 88 mg/kg body weight of iron-dextran for 16 days. Tetracyclines were injected intraperitoneally to evaluate dynamic parameters of bone. Undecalcified histological sections of the tibiae were obtained. Serum urea, creatinine, and paratohormone (PTH) levels were evaluated 30 days after the onset of the experiment. Static and dynamic histomorphometric measurements were performed. Iron overload modified the response of the animals with renal failure: a reduction in bone forming activity compatible with adynamic bone disease and a decrease in peritrabecular fibrosis were observed. Our results suggest that iron is yet one more factor involved in the imbalance in bone metabolism typically found in renal failure patients treated with iron, rendering diagnosis and treatment of bone disease in these patients more complex.

Animals↗
PubMed1991

Chronic dietary iron overload in rats results in impaired calcium sequestration by hepatic mitochondria and microsomes [corrected].

The purpose of these experiments was to determine whether chronic dietary iron overload causes impairment of hepatic mitochondrial and/or microsomal calcium sequestration. Experimental iron overload was produced by feeding three groups of rats a chow diet supplemented with 3.0% (wt/wt) carbonyl iron for up to 8 weeks achieving graded increases in hepatic iron concentrations ranging from 1360 to 3170 micrograms/g. At low levels of iron overload, there were no changes in mitochondrial oxidative metabolism or calcium sequestration, whereas at moderate and high degrees of iron loading, both of these parameters were significantly reduced. In contrast, there were significant decreases in microsomal cytochrome P450 levels and microsomal calcium sequestration at all three levels of iron loading. These abnormalities occurred at hepatic iron concentrations at which the authors have previously found evidence of hepatic organelle lipid peroxidation. These alterations in organelle calcium sequestration may impair intracellular calcium homeostasis in the liver and contribute to subsequent cellular injury.

Animals↗
PubMed1999

Low dose desferrioxamine can improve erythropoiesis in iron-overload hemodialysis patients without side effects.

OBJECTIVE: Multiple blood transfusions were often required to treat anemia in uremia patients before the era of recombinant human erythropoietin (r-HuEPO). Iron overload thus frequently occurred in chronic hemodialysis patients. Desferrioxamine (DFO) is an effective chelating agent, which can remove excessive iron and can enhance erythropoiesis. Large dose DFO treatment is a therapy associated with the development of severe complications. In this study, a low dose DFO regime was used to treat iron overloaded hemodialysis patients. The efficacy and side effects of this regiment were evaluated. MATERIALS AND METHODS: Eight iron overloaded chronic hemodialysis patients were enrolled in this study. All patients received DFO 500 mg intravenously twice-a-week for eight months. Serum aluminum, transferrin saturation (TFS) and r-HuEPO requirement were recorded before and after DFO treatment. Serum ferritin and hematocrit (Hct) were measured before, during, and after the DFO withdrawal period. All patients were evaluated and followed closely during treatment. RESULTS: Changes in aluminum, TFS and r-HuEPO dosage were unremarkable (p > 0.05). Hct increased significantly after eight months of DFO treatment (from 25.3% to 27.0%, p < 0.05). Ferritin level was reduced by 43.2% at the end of treatment and an evident decline of ferritin was achieved after four months of treatment (2102 ng/mL to 1166 ng/mL, p < 0.05). All patients tolerated the treatment well and no complications were found. CONCLUSION: Low dose DFO can chelate iron effectively in chronic hemodialysis patients. This treatment can enhance erythropoiesis without adverse effects.

Anemia↗
PubMed1999

Derangement of Kupffer cell functioning and hepatotoxicity in hyperthyroid rats subjected to acute iron overload.

Liver oxidative stress, Kupffer cell functioning, and cell injury were studied in control rats and in animals subjected to L-3,3',5-tri-iodothyronine (T3) and/or acute iron overload. Thyroid calorigenesis with increased rates of hepatic O2 uptake was not altered by iron treatment, whereas iron enhanced serum and liver iron levels independently of T3. Liver thiobarbituric acid reactants formation increased by 5.8-, 5.7-, or 11.0-fold by T3, iron, or their combined treatment, respectively. Iron enhanced the content of protein carbonyls independently of T3 administration, whereas glutathione levels decreased in T3- and iron-treated rats (54%) and in T3Fe-treated animals (71%). Colloidal carbon infusion into perfused livers elicited a 109% and 68% increase in O2 uptake in T3 and iron-treated rats over controls. This parameter was decreased (78%) by the joint T3Fe administration and abolished by gadolinium chloride (GdCl3) pretreatment in all experimental groups. Hyperthyroidism and iron overload did not modify the sinusoidal efflux of lactate dehydrogenase, whereas T3Fe-treated rats exhibited a 35-fold increase over control values, with a 54% reduction by GdCl3 pretreatment. Histological studies showed a slight increase in the number or size of Kupffer cells in hyperthyroid rats or in iron overloaded animals, respectively. Kupffer cell hypertrophy and hyperplasia with presence of inflammatory cells and increased hepatic myeloperoxidase activity were found in T3Fe-treated rats. It is concluded that hyperthyroidism increases the susceptibility of the liver to the toxic effects of iron, which seems to be related to the development of a severe oxidative stress status in the tissue, thus contributing to the concomitant liver injury and impairment of Kupffer cell phagocytosis and particle-induced respiratory burst activity.

Animals↗
PubMed2005

Screening for HFE and iron overload.

Type 1 hereditary hemochromatosis is a common disorder of iron overload occurring in individuals homozygous for the C282Y HFE gene mutation. It can be a progressive and fatal condition. Early detection and phlebotomy prior to the onset of cirrhosis can reduce morbidity and normalize life expectancy. It is readily identified through biochemical testing for iron overload using serum transferrin saturation and genetic testing for C282Y homozygosity. General population screening has been waived in preference to targeting high-risk groups such as first-degree relatives of affected individuals and those with clinical features suggestive of iron loading. This screening strategy is likely to continue until uncertainties regarding the natural history of the disease, age-related penetrance, and management of asymptomatic individuals are clarified. Potential ethical, legal, and psychosocial issues arising through application of genetic screening programs also must be resolved prior to implementation of general population screening programs.

Genetic Markers↗
PubMed2001

Secondary iron overload.

Transfusion therapy for inherited anemias and acquired refractory anemias both improves the quality of life and prolongs survival. A consequence of chronic transfusion therapy is secondary iron overload, which adversely affects the function of the heart, the liver and other organs. This session will review the use of iron chelating agents in the management of transfusion-induced secondary iron overload. In Section I Dr. John Porter describes techniques for the administration of deferoxamine that exploit the pharmacokinetic properties of the drug and minimize potential toxic side effects. The experience with chelation therapy in patients with thalassemia and sickle cell disease will be reviewed and guidelines will be suggested for chelation therapy of chronically transfused adults with refractory anemias. In Section II Dr. Nancy Olivieri examines the clinical consequences of transfusion-induced secondary iron overload and suggests criteria useful in determining the optimal timing of the initiation of chelation therapy. Finally, Dr. Olivieri discusses the clinical trials evaluating orally administered iron chelators.

Anemia, Sickle Cell↗
PubMed1985

Ferritin in erythrocytes and plasma of patients with iron overload.

Erythrocyte and plasma ferritin was followed in 13 patients with iron overload undergoing phlebotomies for at least 6 months in comparison with untreated patients and normal males. Plasma ferritin was widely scattered with an average of only twice the normal, whereas erythrocyte ferritin was highly elevated to about twelve times the normal (p less than 0.0001). - The time course of plasma and erythrocyte ferritin during phlebotomy therapy was analyzed in 3 patients with idiopathic hemochromatosis. Three stages were established: 1. plasma ferritin dropped gradually into the normal range while erythrocyte ferritin remained high, 2. appropriate phlebotomies maintained normal plasma ferritin and high erythrocyte ferritin, and indicated a monthly uptake of dietary iron of 150-200 mg at a steady state, 3. at low plasma ferritin levels, erythrocyte ferritin was rapidly decreased by further intensive phlebotomy therapy. Based on the presumed net removal of iron, 1 microgram/l plasma ferritin was equivalent to 3-6 mg of body iron and 1 microgram/l erythrocyte ferritin to somewhat less than 1 mg of body iron. - An elevated erythrocyte ferritin during phlebotomy therapy in iron overload not only depends on body iron stores like plasma ferritin but may also be regulated by the activity of erythropoiesis.

Adult↗
PubMed1995

Proposed role for a combination of citric acid and ascorbic acid in the production of dietary iron overload: a fundamental cause of disease.

This paper presents a review of the significant body of literature liking dietary iron overload, not only to heart disease, but also to cancer, diabetes, osteoporosis, arthritis, and possibly other disorders. Following an analysis of our understanding of the mechanistic role iron plays in oxidative damage, an interpretation of the fact that plasma concentrations of several antioxidants are decreased in the presence of disease is offered. Evaluation of (1) age-related dietary trends over time and (2) factors involved in iron absorption leads to the hypothesis that the combination of citric acid and ascorbic acid (a synergistic pair of strong enhancers) is instrumental in causing a deleterious increase in iron load in aging populations. Iron overload may be the most important common etiologic factor in the development of the diseases mentioned; therefore, the synergistic combination of citric and ascorbic acids may play a major role in our worsening disease statistics. Evidence to support this hypothesis and possible experiments to test it are included. This combination needs further study, particularly because the iron overload produced may be correctable.

Aging↗
PubMed2004

Labile plasma iron (LPI) as an indicator of chelatable plasma redox activity in iron-overloaded beta-thalassemia/HbE patients treated with an oral chelator.

Persistent levels of plasma nontransferrin bound iron (NTBI) have been associated with tissue iron overload and toxicity. We characterized NTBI's susceptibility to deferoxamine (directly chelatable iron [DCI]) and redox activity (labile plasma iron [LPI]) during the course of long-term, continuous L1 (deferiprone) treatment of patients with hemoglobin E disease and beta-thalassemia (n = 17). In 97% of serum samples (n = 267), the LPI levels were more than 0.4 microM (mean +/- SEM, 3.1 +/- 0.2 microM) and the percent transferrin (Tf) saturation more than 85 (111 +/- 6), whereas only in 4% of sera were the LPI levels more than 0.4 microM for Tf saturation less than 85%. Daily administration of L1 (50 mg/kg) for 13 to 17 months caused both LPI and DCI to decrease from respective initial 5.1 +/- 0.5 and 5.4 +/- 0.6 microM to steady mean levels of 2.18 +/- 0.24 and 2.81 +/- 0.14 microM. The steady lowest levels of LPI and DCI were attained after 6 to 8 months, with a half time (t(1/2)) of 2 to 3 months. Serum ferritin and red cell membrane-associated iron followed a similar course but attained steady basal levels only after 10 to 12 months of continuous treatment, with a t(1/2) of 5 to 7 months. These studies indicate that LPI and DCI can serve as early indicators of iron overload and as measures for the effectiveness of iron chelation in reducing potentially toxic iron in the plasma.

Biomarkers↗
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↗
PubMed2002

Experimental renal failure and iron overload: a histomorphometric study in the alveolar bone of rats.

Renal failure is a serious disease of a relatively high incidence, which among other lesions, causes bone alterations. These patients frequently suffer from anemia that is generally treated with iron. Given that iron overload inhibits bone formation, our aim was to evaluate the effect of iron on the interradicular bone of animals with experimental renal failure. Acute renal failure was induced in male rats by 5/6 nephrectomy. The animals were subjected to iron overload in the form of daily intraperitoneal injections of 88 mg/kg body weight of iron-dextran over a period of 16 days. Tetracyclines were injected intraperitoneally 14 days apart to evaluate dynamic parameters of bone. Serum urea and creatinine levels were evaluated immediately before the animals were killed on day 30. Static and dynamic histomorphometric measurements were performed. The data indicate that the iron overload modified the response of the renal failure animals which showed decreased interradicular bone volume and adynamic bone disease, characterized by reduced cell activity. These results should be taken into account when renal failure patients treated with iron must undergo dental treatments that depend on bone forming activity for their success.

Acute Kidney Injury↗
PubMed2006

Deferasirox--an oral agent for chronic iron overload.

OBJECTIVE: To review the available literature on the pharmacology, pharmacokinetics, efficacy, toxicology, adverse effects, drug interactions, and dosage guidelines for deferasirox, an oral iron chelator, in Phase III trials. DATA SOURCES: Reviewers searched the following databases for English-language studies: MEDLINE (1966-April 2006), International Pharmaceutical Abstracts (1970-April 2006), and the Cochrane Library Database. Key search terms included iron chelation, chelation, iron overload, deferasirox, and ICL670. STUDY SELECTION AND DATA EXTRACTION: Data on efficacy, toxicology, adverse effects, and pharmacokinetics for deferasirox were obtained from randomized, open-label, blinded clinical trials. Other information was obtained from the manufacturer, including unpublished studies in abstract form as well as available data on deferasirox. DATA SYNTHESIS: Deferasirox is an orally active iron chelator. In clinical trials, deferasirox demonstrated efficacy at dosages of 20 and 30 mg/kg/day in treating iron overload in patients with beta-thalassemia. Deferasirox has been studied in patients older than 2 years and appears to be safe, with the most common adverse effects reported being mild, transient nausea, gastrointestinal disturbances, and rash. There were no reports of serious adverse effects in trials to date. CONCLUSIONS: Deferasirox represents a new approach to the management of chronic iron overload in patients with chronic anemias who require blood transfusions. The available literature suggests that deferasirox is safe and as effective as the current standard of therapy at dosages of 20-30 mg/kg/day for beta-thalassemia. Further studies are needed to confirm its efficacy in other chronic transfusion-requiring diseases.

Benzoates↗
PubMed1990

Differential expression of transferrin receptor in duodenal mucosa in iron overload. Evidence for a site-specific defect in genetic hemochromatosis.

In genetic hemochromatosis, metabolic studies have demonstrated inappropriately increased iron absorption by cells of the duodenal mucosa. It is not clear whether this reflects an intrinsic abnormality of iron homeostasis at this site or is a consequence of a more generalized defect in cellular iron metabolism particularly involving the liver. We have previously used the expression of iron-related proteins as markers of iron homeostasis and have demonstrated normal regulation of the transferrin receptor and ferritin in the liver in this condition. In the present study we used immunohistochemical techniques to study transferrin-receptor expression in the gastrointestinal epithelium in normal subjects and patients with iron overload. In untreated genetic hemochromatosis and normal subjects, villus epithelial cells expressed receptor in the basolateral, subnuclear region. In contrast, in patients with secondary iron overload, receptor staining was absent in villus epithelial cells. The cells in the duodenal crypts showed intense staining for the transferrin receptor in all subjects investigated, a finding consistent with the known behavior of this receptor in proliferating cells. Given that body iron stores in both types of iron overload were comparable, these findings indicating a failure of down-regulation of the villus enterocyte transferrin receptor in genetic hemochromatosis may reflect the presence of a regulatory defect associated with the inability to control iron absorption in this condition.

Adult↗
PubMed1996

Hemochromatosis: association of severity of iron overload with genetic markers.

We postulated that the severity of iron overload in homozygous hemochromatosis probands is related to the expression of HLA-A3 or D6S105 allele 8. Therefore, we used these markers to characterize Alabama hemochromatosis probands and normal control subjects. We then quantified the blood removed by phlebotomy to exhaust body iron stores and maintain normal serum ferritin concentrations in our hemochromatosis probands. Induction and maintenance phlebotomy requirements were significantly greater in presumed HLA-A3 homozygotes or in D6S105 allele 8 homozygotes than in homozygous probands lacking these markers. Intermediate values were observed in probands who were HLA-A3 or allele 8 heterozygotes, respectively. We also analyzed data from males and females separately. Among subjects of the same sex, the induction and maintenance phlebotomy requirements in subjects presumed to be HLA-A3 homozygotes or in allele 8 homozygotes were greater than those of other groups. Our results support the hypothesis that the severity of iron overload in hemochromatosis is determined predominantly by genetic factors, and provide evidence that two or more mutations for hemochromatosis exist. However, the design of our study does not permit a distinction to be made between allelic and locus heterogeneity for the hemochromatosis gene(s).

Alleles↗
PubMed2001

A mutation, in the iron-responsive element of H ferritin mRNA, causing autosomal dominant iron overload.

Ferritin, which is composed of H and L subunits, plays an important role in iron storage and in the control of intracellular iron distribution. Synthesis of both ferritin subunits is controlled by a common cytosolic protein, iron regulatory protein (IRP), which binds to the iron-responsive element (IRE) in the 5'-UTR of the H- and L-ferritin mRNAs. In the present study, we have identified a single point mutation (A49U) in the IRE motif of H-ferritin mRNA, in four of seven members of a Japanese family affected by dominantly inherited iron overload. Gel-shift mobility assay and Scatchard-plot analysis revealed that a mutated IRE probe had a higher binding affinity to IRP than did the wild-type probe. When mutated H subunit was overexpressed in COS-1 cells, suppression of H-subunit synthesis and of the increment of radiolabeled iron uptake were observed. These data suggest that the A49U mutation in the IRE of H-subunit is responsible for tissue iron deposition and is a novel cause of hereditary iron overload, most likely related to impairment of the ferroxidase activity generated by H subunit.

Aged↗