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PubMed2005

Deferiprone therapy for transfusional iron overload.

Iron chelation is needed to prevent damage to the heart, liver and endocrine glands from iron overload in patients with refractory anaemias who receive regular blood transfusions. Desferrioxamine is still the first-line drug, but because of its expense in many countries, and lack of compliance because of difficulty with administration, there is a major need for an orally active (and cheaper) chelating drug. Seventeen years after the first clinical trials deferiprone, which is orally active, has emerged as suitable for patients for whom desferrioxamine is, for one reason or another, inadequate. Many patients are successfully chelated at a dose of deferiprone 75 mg/kg/day. Some patients may need higher doses (up to 100 mg/kg), or combination therapy of deferiprone every day and desferrioxamine on several days each week. Recent data suggest that deferiprone may be superior to desferrioxamine at protecting the heart from iron overload. The side-effects of deferiprone--agranulocytosis, neutropenia, gastrointestinal symptoms, arthropathy, transient changes in liver enzymes, and zinc deficiency--are now well recognized; they result in discontinuation of the drug in only 5-10% of patients. Deferiprone is now licensed in 43 countries for thalassaemia major patients for whom desferrioxamine is inadequate. If results of current trials confirm its superiority at reducing cardiac damage, it may well become the first-line drug for many patients.

Chelation Therapy↗
PubMed2001

The effects of cardiac myocytes on interstitial fibroblasts in toxic iron overload.

Iron deposits preferentially in myocytes in mixed cultures of cardiac myocytes and nonmyocytic fibroblasts. In vivo, iron overload is associated with cardiac fibrosis. Therefore, we examined whether iron loading of cardiac myocytes in culture could trigger a response in nonmyocytes characteristic of a fibrogenic phenotype. We found that the nonmyocytes adopted a myofibroblast phenotype in culture. The rate of DNA synthesis (measured by [3H]thymidine incorporation) by the nonmyocytes was decreased by the myocyte-conditioned medium, compared to that of the unconditioned medium, and this activity was retained in <10-kDa fractions. The rate was partially restored when the medium was obtained from iron-loaded myocytes, and in this medium, the <10-kDa fraction was even more effective in reversing the suppression of proliferation. This suppression suggests a decreased secretion of a growth inhibitory substance in the iron-loaded myocytes, and this effect was partially reversed when the iron-loaded cells were treated with the iron chelator, deferoxamine. This indicates that cardiac myocytes may play a paracrine role in suppressing the proliferation of myofibroblasts that is partially overcome when the myocytes are iron overloaded. The myocyte-conditioned medium also affects the myofibroblast phenotype, increasing the cells' fibronectin mRNA content and decreasing alpha-smooth-muscle actin mRNA. The myocyte-conditioned medium increases transforming growth factor-beta (TGF-beta) secretion by myofibroblasts, but the TGF-beta content of the conditioned medium was found to play, at most, a minor role in determining the response of the myofibroblast.

Animals↗
PubMed1995

Resistance to oxidation of native lipoproteins and erythrocyte membrane lipids in rats with iron overload.

Iron plays a promoting role in lipid oxidation through several mechanisms. Therefore, hepatic iron deposits in the rat may lead to peroxidative damage and to alterations in the lipoprotein formation. In this report we observed that an iron overload in rats strongly reduced the hepatic lipoprotein secretion but did not affect oxidation resistance of native lipoproteins and erythrocyte lipids in spite of tocopherol and ascorbate deficiencies. Since oxidation resistance depends on the substrate to antioxidant vitamin molar ratio, our results show that an iron overload probably alters the lipoprotein lipid fatty acid composition in rats.

Animals↗
PubMed2000

Iron metabolism: iron deficiency and iron overload.

Iron is an essential cofactor in a variety of cellular processes. Except for a few unusual bacterial species, iron is indispensable for living organisms. However, free iron is toxic because of its propensity to induce the formation of dangerous free radicals. Consequently, iron balance is tightly regulated. Disorders of iron homeostasis are among the most common afflictions of humans. This review discusses inherited iron deficiency and iron overload disorders and recent insights into their pathophysiology.

Anemia, Iron-Deficiency↗
PubMed1995

[Iron overload and iron deficiency regulate ED1 and ED2 expression in spleen macrophages of rats].

Monoclonal antibodies ED1 and ED2 can recognize epitopes on the spleen macrophage related with its antigen presenting activity. Immunohistochemical and histochemical methods were used to show the influence of iron overload and iron deficiency on the expression of ED1, ED2 and phagocytic functions of the macrophages in the spleen. We found that iron overloaded rats had large amounts of hemosiderin deposits in the macrophages of red and white pulp with reduced expression of ED1, ED2 and phagocytic function. It is suggested that iron concentration can regulate the expression of ED1, ED2 and phagocytic activity of the macrophage, which may in turn influence its antigen presentation and anti-infection functions.

Animals↗
PubMed1982

Comparative study between biochemical and histological methods and image analysis in liver iron overload.

Iron overload has been measured in 100 hepatic biopsies by three different methods: (i) biochemical assay of the liver iron concentration (LIC), (ii) histological grading (HISTO) and (iii) automated image analysis with a Leitz Texture Analysis System by estimating two parameters, (a) the total iron area (TIA) and (b) the first grey level step (FGLS) at which the iron is detected. Image analysis appears as a specific, sensitive, quick, reproducible and valid method.

Autoanalysis↗
PubMed1997

Effect of iron overload and iron deficiency on atherosclerosis in the hypercholesterolemic rabbit.

It has been suggested that iron plays an important role in the pathogenesis of atherosclerosis, primarily by acting as a catalyst for the atherogenic modification of LDL. Although some epidemiological data suggest that high stored iron levels are an independent risk factor for coronary artery disease and that iron has been detected in both early and advanced atherosclerotic lesions, the evidence is often contradictory and inconclusive. We used the New Zealand White rabbit to investigate the effects of iron overload (FeO) and iron deficiency (FeD) on atherosclerosis. Groups of 7 rabbits were either iron loaded by injections of iron dextran (FeO group), iron depleted by phlebotomy (FeD group), or given injections of saline (control group) for a total of 9 weeks. All rabbits were fed a chow diet containing 1% (wt/wt) cholesterol for the last 6 weeks of the study. Iron and antioxidant status and cholesterol levels were assayed in plasma before cholesterol feeding (week 3) and at the time that the rabbits were killed (week 9). In addition, the susceptibility of LDL to oxidation was measured and pathological examination of the aortic arch and thoracic aorta performed at the end of the study. FeD significantly decreased the levels of blood hemoglobin, serum iron, and transferrin saturation compared with controls. Conversely, FeO significantly increased transferrin Fe saturation. FeO but not FeD decreased plasma cholesterol levels compared with control animals both before (P < .05) and after (P = .055) cholesterol feeding. Neither FeO nor FeD had a significant effect on the levels of antioxidants and lipid peroxidation products in plasma and aortic tissue or on the susceptibility of LDL to ex-vivo oxidation. FeO significantly decreased aortic arch lesion formation by 56% compared with controls (P < .05), whereas FeD had no significant effect. These results indicate that in this animal model, FeO decreases rather than increases atherosclerosis, likely because iron dextran exerts a hypocholesterolemic effect. Our data do not support the hypotheses that elevation of Fe stores increases or that a reduction of Fe stores by phlebotomy decreases the risk of coronary artery disease.

Animals↗
PubMed2006

New chelation therapies and emerging chelating drugs for the treatment of iron overload.

Iron chelation therapy using deferoxamine or deferiprone (L1) is effective for the treatment of most transfused iron-loaded patients. The combination administration of deferiprone in the daytime and deferoxamine in the night appears to be universally effective in rapidly achieving negative iron balance. The cardiac iron removal effect of deferiprone increases the prospects of longer survival in beta-thalassaemia patients. New chelators have reached the stage of clinical development such as deferitrin, 1-allyl-2-methyl-3-hydroxypyrid-4-one (L1NAll) and the starch deferoxamine polymers. Deferasirox has received a conditional approval in the US under the FDA-accelerated approval regulations, but needs further verification of its efficacy and safety. Future iron chelation therapies are likely to be based on combinations of chelating drugs.

Carboxylic Acids↗
PubMed1986

Serum ferritin in the assessment of liver iron overload and iron removal therapy in porphyria cutanea tarda.

Serum ferritin, an index of iron stores, was studied in 60 patients with porphyria cutanea tarda (PCT), in 21 patients who had other liver diseases without siderosis (cirrhosis [LC] and chronic active hepatitis [CAH]), and in 32 patients with associated liver siderosis (alcoholic LC, LC and CAH in minor thalassemia). Ferritin levels were higher in patients with porphyria than in healthy controls and patients without liver siderosis (P less than 0.001), whereas no statistical difference was observed between patients with porphyria and those with liver siderosis. Because iron removal is considered the treatment of choice for PCT, some patients with PCT underwent phlebotomy and others received chelating therapy with subcutaneous infusion of deferoxamine. Follow-up of the patients showed a correlation between serum ferritin level and urinary porphyrin excretion; when the clinical and biochemical syndrome became normal, serum iron and ferritin had fallen to normal values (t test pair data analysis before and after: P less than 0.001 in each group). No appreciable difference was found between controls and patients with PCT whose conditions had been normalized, irrespective of the chronic liver damage always present in PCT. Our results suggest that serum ferritin increase in PCT is related more to liver iron overload than to liver damage, and ferritin follow-up is recommended to indicate the exhaustion of hepatic iron stores during iron depletion therapy, as well as to detect an early replenishment after remission.

Adult↗
PubMed1982

Pyridoxal complexes as potential chelating agents for oral therapy in transfusional iron overload.

Iron chelation therapy for patients maintained on a regular transfusion regime is at present best carried out by means of daily infusions of desferrioxamine (Hussain et al 1977; Pippard et al 1978) but this is onerous for the patient and has social and economic disadvantages. Many recent attempts to provide more effective drugs for iron chelation have been summarized by Jacobs (1979) and increasing attention is now being paid to the possibility of oral iron chelation therapy. Hoy et al (1979) showed that when isonicotinic acid hydrazide (INH) and pyridoxal are mixed in equimolar amounts a hydrazone is formed which chelates iron, and oral administration of this compound to rats results in an eightfold increase in faecal iron excretion. It is effective on repeated administration (Cikrt et al 1980), the main route of iron excretion being through the bile. Long term studies in the rat have not been successful in reducing the iron load of test animals and this appears to be related both to their high dietary iron content and instability of the hydrazone. Its effective shelf life at room temperature is no longer than one month and this is a considerable disadvantage from a therapeutic point of view. Pyridoxal is known to form a Schiff base with many amino acids and its reactivity has led us to examine complexes of pyridoxal with a number of substances in an attempt to find an alternative iron chelator of greater stability than the INH complex and of comparable effectiveness on oral administration. The screening procedures used were the effects on Chang cell iron metabolism (White et al 1976) and on iron excretion in the rat (Hoy et al 1979).

Animals↗
PubMed2002

HBED ligand: preclinical studies of a potential alternative to deferoxamine for treatment of chronic iron overload and acute iron poisoning.

We have continued the preclinical evaluation of the efficacy and safety of the hexadentate phenolic aminocarboxylate iron chelator N, N'-bis(2-hydroxybenzyl) ethylenediamine-N, N'-diacetic acid monosodium salt (NaHBED) for the treatment of both chronic transfusional iron overload and acute iron poisoning. We examined the effect of route of administration by giving equimolar amounts of NaHBED and deferoxamine (DFO) to Cebus apella monkeys as either a subcutaneous (SC) bolus or a 20-minute intravenous (IV) infusion. By both routes, NaHBED was consistently about twice as efficient as DFO in producing iron excretion. For both chelators at a dose of 150 micromol/kg, SC was more efficient than IV administration. The biochemical and histopathologic effects of NaHBED administration were assessed. No systemic toxicity was found after either IV administration once daily for 14 days to iron-loaded dogs or after SC administration every other day for 14 days to dogs without iron overload. Evidence of local irritation was found at some SC injection sites. When the NaHBED concentration was reduced to 15% or less in a volume comparable to a clinically useful one, no local irritation was found with SC administration in rats. Because treatment of acute iron poisoning may require rapid chelator infusion, we compared the effects of IV bolus administration of the compounds to normotensive rats. Administration of DFO produced a prompt, prolonged drop in blood pressure and acceleration of heart rate; NaHBED had little effect. NaHBED may provide an alternative to DFO for the treatment of both chronic transfusional iron overload and of acute iron poisoning.

Acute Disease↗
PubMed2006

Three kinships with ALAS2 P520L (c. 1559 C --> T) mutation, two in association with severe iron overload, and one with sideroblastic anemia and severe iron overload.

Mutations in aminolevulinate synthase 2 (ALAS2) are usually associated with sideroblastic anemia and iron overload. The objective of this study was to determine if "mild" mutations in ALAS2 might increase the severity of primary iron overload. Direct sequencing of the ALAS2 gene was performed on 24 subjects with primary hemochromatosis and one subject with sideroblastic anemia with severe iron overload. We identified a novel mutation P520L (c. 1559 C --> T) in ALAS2 in three subjects. Two had severe iron overload and no anemia: one also had HFE C282Y homozygosity, and the other was wildtype for HFE and other iron-related genes. The third subject had sideroblastic anemia with iron overload, and was hemizygous for both P520L and R560H (c. 1679 G --> A) mutations in ALAS2. The P520L mutation was found at a frequency of 0.0013 (741 alleles) in white control subjects, but was not found in 158 alleles from black control subjects. The proline in this position is highly conserved across species from humans to zebrafish. However, genotype/phenotype studies of the families demonstrate that the P520L mutation alone has no iron-associated phenotype, but it may act as a modifier of iron overload in the presence of mutations in HFE or other uncharacterized hemochromatosis genes. Thus, ALAS2 mutations might contribute to more severe iron loading in persons with primary hemochromatosis.

5-Aminolevulinate Synthetase↗
PubMed2002

Lipid peroxidation and protein modification in a mouse model of chronic iron overload.

Iron-storage diseases are believed to cause organ damage through generation of reactive oxygen species. Using a murine model of iron overload, we found that hepatic iron stores increased logarithmically during 3 weeks of chronic intraperitoneal administration of iron dextran, while hepatic glutathione peroxidase activity declined linearly by approximately 50% during the same period. Plasma concentrations of aliphatic aldehydes increased by 2- to 3-fold, and plasma malondialdehyde (MDA) by 6-fold. Modification of total liver protein by products of lipid peroxidation, including MDA-lysine, 4-hydroxynonenal-lysine, and N(epsilon)-(carboxymethyl)lysine (CML), increased by approximately 3-fold, while levels of the protein oxidation marker, methionine sulfoxide (MetSO), were unchanged. Skin collagen was resistant to modification until the third week, when 2- to 3-fold increases in both CML and MetSO were observed. Our results document that iron overload increases lipid peroxidation, with concomitant increases in reactive aldehydes in plasma and chemical modification of tissue proteins. CML was a sensitive indicator of hepatocellular oxidative stress, compared to MetSO, while extensive modification of extracellular skin collagen was not observed until the late stages of iron overload and oxidative stress. These observations provide direct evidence for the contribution of reactive oxygen species, lipid peroxidation, and reactive carbonyl intermediates to the pathogenesis of iron-overload diseases.

Aldehydes↗
PubMedDate not supplied

Endocrine abnormalities in hemodialysis patients with iron overload: reversal with iron depletion.

The endocrine function was studied in 9 hemodialysis patients with iron overload (IO) before and after iron depletion. Diagnosis of IO was established by high serum ferritin (> 1100 micrograms/L), high hepatic CT density (> 70 Hounsfield units), and excessive iron stores in bone marrow aspirate (grade 6). At the start of the study, 8 patients had gonadal failure, 6 of whom had hypothalamopituitary disease, and 4 manifested thyroid abnormalities. At the end of the study, the hypothalamopituitary function and thyroid abnormalities improved in all patients except one who manifested hypothalamic disease. Primary gonadal failure persisted in the 8 patients. ACTH stimulation produced adequate increments in plasma cortisol at the start and end of the study. Pancreatic (beta cell) function was adequate at the end of the study as shown by normal oral glucose tolerance test and free insulin increments during the test. The CT scan and follow-up indicated significant iron mobilization from the liver, pancreas, and the adrenal glands. Hormonal studies were repeated in 4 of the 5 patients who manifested endocrine abnormalities and had received recombinant human erythropoietin (rHuEPO), 3 mo after discontinuation of the drug. Improvement in the endocrine function persisted in those patients. Our results indicated that dialysis patients exposed to iron overload are at risk for development of multiple endocrine defects. Fortunately, aggressive iron depletion can mobilize iron from these organs and reverse some of the defects.

Adult↗
PubMedDate not supplied

African iron overload.

African iron overload has been recognised in sub-Saharan Africa for seventy years. The condition is distinct from the well-characterised HLA-linked haemochromatosis described in Caucasians. Increased dietary iron intake predisposes to the condition. Recent evidence suggest that African iron overload may be caused by an interaction between increased dietary iron and a genetic defect not associated with the HLA-locus. Iron deposition is prominent both in macrophages and in hepatic parenchymal cells. Iron overload is distinct from alcoholic liver disease, although the excess dietary iron is derived from a traditional beverage that contains alcohol. African iron overload has clinical consequences. It is a cause of hepatic fibrosis and cirrhosis, and associations with diabetes mellitus, peritonitis, scurvy and osteoporosis have been described. African iron overload may be a cause of hepatocellular carcinoma. The disorder is associated with a poor outcome in tuberculosis, an infection that is highly prevalent in sub-Saharan Africa.

Adult↗
PubMed1991

Transferrin receptors and selective iron deposition in pancreatic B cells of iron-overloaded rats.

Iron overload was produced in Wistar rats by repeated intraperitoneal injections of ferric nitrilotriacetate (Fe(3+)-NTA) for one to six months. Pancreatic tissues from these iron-overloaded rats and untreated controls were examined for insulin (for B cells), glucagon (for A cells), transferrin receptor (TfR), transferrin (Tf) and ferritin (Ft) using immunohistochemical methods, and for iron by histochemical Berlin blue staining. In the islets of iron-overloaded rats, increased Ft staining appeared prior to deposition of Berlin blue-stainable iron, and the staining intensity of Ft and iron was stronger in B cells than in A cells. In the islets of untreated control rats, the staining intensity of TfR was stronger in B cells than in A cells. TfR staining of the islets was weaker in iron-overloaded rats than in the controls. These findings suggest that 1) iron uptake by islet cells in vivo is regulated and mediated by TfR, 2) intracytoplasmic Ft transforms into stainable iron in iron-overloaded rats, and 3) predominance of TfR expression in B cells may result in selective deposition of iron and predispose B cells to damage and diabetes mellitus in iron-overloaded rats.

Animals↗
PubMed1994

The effect of iron overload and iron reductive treatment on the serum concentration of carbohydrate-deficient transferrin.

The concentration of carbohydrate-deficient transferrin in serum (CDT) has been used as a reliable indicator of recent alcohol consumption. We have investigated the utility of this laboratory test in 20 patients with hereditary haemochromatosis (HH) by simultaneous evaluation of serum concentrations of liver transaminases, gamma-glutamyl transpeptidase, iron, transferrin and assessment of the liver iron concentration by magnetic resonance imaging. 11 patients were re-examined during iron depletion with phlebotomies. In all 11 patients intensive but not maintenance iron removal was associated with an increase in serum CDT, in three patients even to levels above the reference range. The mean serum CDT increased from 8.5 (SD 2.2) U/l to 16.6 (SD 7.2) U/l (P < 0.001). Iron mobilization from the liver was found particularly responsible for the increase in serum CDT. Independent of this finding we found a significant semi-logarithmic correlation (r = -0.77, P = 0.009) between the MRI determined liver iron concentration and serum CDT in the patients not on iron depletion. Our findings indicate that the utility of serum CDT as a measure of alcohol consumption in patients with HH may be compromised, especially during intensive iron depletion.

Adult↗