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PubMed1997

Iron overloading inhibits endochondral ossification.

The development of bone disease in patients with chronic renal failure is well known. Renal patients frequently suffer anemia and iron oral therapy and/or transfusions are used to treat them. Recent findings show that iron could be a factor that provokes bone lesions but the alterations it causes are not well known. The aim of this work was to study the effect of iron intoxication on endochondral ossification, a recognized model for bone growth evaluation. Male Wistar rats weighing 250-300 g were used. They received 88 mg of dextran-iron per day intraperitoneally during 34 days. The experimental and control groups were killed on day 34. A histomorphometric study of the endochondral plate was performed on histologic sections of tibiae. The results obtained show that iron overloading inhibits endochondral ossification.

Animals↗
PubMed1989

Intranasal administration of deferoxamine to iron overloaded patients.

We examined the effect of intranasal administration of deferoxamine on iron excretion in seven patients with iron overload secondary to chronic transfusion therapy. Deferoxamine was administered in doses of 0.75 to 3.0 gm given over 12 hours in a variety of dosing schedules. There was a probable, though not significant, dose response relationship between the amount of iron excreted and the dose administered. The amount of iron excreted was 10%-15% of that obtained using the same dosage of deferoxamine given by the subcutaneous route over the same time period. Hourly administration was more effective than less frequent administration. Addition of taurodeoxycholate to deferoxamine did not increase its absorption as measured by the levels of iron excretion. Side effects were few and consisted mainly of mild nasal irritation and a bad taste in the mouth. Nasal administration of deferoxamine may be a useful adjunct to iron chelation in patients receiving chronic transfusion therapy, particularly in those who are noncompliant with parenteral means of administration.

Administration, Intranasal↗
PubMed1994

[Treatment of iron overload states with oral administration of the chelator agent, L1 (Deferiprone)].

Nine iron overloaded patients were treated with L1--Deferiprone (1,2-dimethyl-3-hydroxypyrid-4-one) in daily dose 3 g (40-50 mg/kg) for 12 weeks. In 7 patients the efficiency of L 1 treatment was compared to the therapeutic effect of the same dose of desferrioxamine (Desferal). A significant increase in urinary iron excretion was observed after administration of both chelating agents. Iron excretion after L 1 treatment was approximately 65% of that obtained with Desferal. The amount of excreted iron correlated with the amount of iron stores before chelation. A significant decrease in transferrin saturation, serum and red cell ferritin was observed after treatment with Desferal, L 1 administration caused a significant decrease only in serum ferritin level. However, all the parameters reflecting iron stores remained increased when compared to normal values after 12 weeks of chelation therapy. An incomplete absorption from gut and some reutilization of chelated iron may be responsible for less potent iron chelation by L 1 in comparison to Desferal. A low tolerance of the drug together with repeated nausea and vomiting were the most frequent adverse effects observed in the course of L1 administration. L 1 treatment had to be discontinued due to repeated vomiting in one patient and due to progressive granulocytopenia and thrombocytopenia in another patient. Because of the side effects more clinical studies with L 1 are needed before its introduction in wide clinical practice.

Administration, Oral↗
PubMed1996

Effects of alpha-tocopherol and beta-carotene on hepatic lipid peroxidation and blood lipids in rats with dietary iron overload.

The ability of dietary antioxidants to reduce lipid peroxidation induced by iron overload was examined in weanling male Sprague-Dawley rats. Animals were fed ad libitum a modified AIN-76A diet (control) or control diet with 0.5% alpha-tocopherol acid succinate, 0.5% crystalline trans-beta-carotene, or 0.5% alpha-tocopherol acid succinate + 0.5% trans-beta-carotene for four weeks. In the following four-week period, the animals received the above diets with 10,000 micrograms Fe/g; a control group continued to receive 35 micrograms Fe/g, and a high-iron group received 10,000 micrograms Fe/g with no antioxidants. After four weeks of dietary supplementation with alpha-tocopherol. Beta-carotene or alpha-tocopherol + beta-carotene, liver concentrations of alpha-tocopherol and beta-carotene increased significantly (p < 0.001). Liver lipid peroxidation, measured by the lipid-conjugated diene assay, increased significantly from 0.012 mumol/mg of lipid in the controls to 0.021 mumol/mg of lipid in animals receiving the high-iron diet. However, lipid peroxidation was significantly reduced in all animals fed the antioxidants, with the group fed alpha-tocopherol + beta-carotene having a lower level than the high-iron group. Total serum cholesterol was elevated in animals fed a high-iron diet and in animals fed the high-iron diet with alpha-tocopherol. In contrast, total serum cholesterol levels in the two groups of animals receiving the diets containing high iron with beta-carotene alone or high iron with beta-carotene + alpha-tocopherol were significantly reduced to the level of the control group. High-density lipoprotein cholesterol also decreased to baseline in the animals receiving beta-carotene alone. Modulation of lipid peroxidation by alpha-tocopherol or beta-carotene may be an important mechanism for reducing oxidative stress.

Animals↗
PubMed1995

Iron overload facilitates hepatic fibrosis in the rat alcohol/low-dose carbon tetrachloride model.

The role of iron deposition in initiating hepatic fibrosis in iron overload disorders is not clearly established, and it is becoming increasingly recognized that iron may be interacting with other potential liver-damaging agents. The authors therefore examined the interplay of iron and alcohol in rats administered subtoxic doses of carbon tetrachloride (CCl4) vapor at 20 ppm in customized chambers. At birth, the offspring of seven pregnant Porton rats were divided into two groups: one group was fed a normal rat chow diet and the other a diet supplemented with 3% (w/w) carbonyl iron for 10 weeks after weaning. In this latter group, the mothers were fed an iron supplement while breastfeeding. At 10 weeks, the animals from the first group (normal chow) were divided into two groups of six animals and fed a Lieber-DeCarli liquid diet with daily exposure to CCl4 vapor: group 1, liquid diet+CCl4; group 2, liquid diet+alcohol 150 kcal/l+CCl4. The animals from the second iron-supplemented group were divided into two groups of six animals and fed a liquid diet with 3% (w/v) carbonyl iron and exposed to CCl4 vapor for 10 weeks: group 3, liquid diet+iron+CCl4; group 4, liquid diet+iron+alcohol supplement+CCl4. Two animals from each group of six had a liver biopsy at 4, 6, and 8 weeks, and all animals were killed after 10 weeks of CCl4 exposure. After the first 10-week iron loading period, the rats fed the carbonyl iron-supplemented diet had a 10-fold elevation in hepatic iron concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1983

Iron overload of spleen, liver and kidney as a consequence of hemolytic anaemia.

Iron overload in spleen, liver and kidney induced by hemolytic anaemia due to a 90-day oral exposure of rats to diuron (N-3,4-dichlorphenyl-N,N-dimethylurea), an urea herbicide, was studied by histochemistry, transmission electronmicroscopy, morphometry and energy dispersive X-ray microanalysis. Increasing dosages of diuron provoked a hemosiderosis in the spleen followed by erythrocytic sequestration and the formation of haemopoietic foci coinciding with Kupffer cell siderosis of the liver. A strong enlargement of the spleen red pulp on the one hand faces an unchanged total white pulp volume as well as no alterations of the white pulp microscopic structure on the other. The electron dense bodies of the endothelial cells did not contain iron whereas hepatocytes possess two types of lysosomes, homogeneous iron containing ones at the sinusoidal site and complex structured ones without detectable iron at the biliary site. The formation of the homogeneous lysosomes is suggested to be due to the hepatocytic reception of hemoglobin-haptoglobin-complexes after intravascular hemolysis. The lysosomes of the biliary site seem to be engaged in hemoglobin degradation. A partial nephrohydrosis due to hemosiderotic events in succession of intravascular hemolysis including hemoglobin reabsorption from the primary urine could be observed. It is assumed that exocytosis might play a major role in hemosiderin removal from kidney tubule cells.

Anemia, Hemolytic↗
PubMedDate not supplied

Evaluation of iron overload in healthy adult residents of Mexico City.

BACKGROUND: We described the effects of age, gender and body mass index (BMI) on the prevalence of iron overload (IO) in blood donors from Mexico City. METHODS: A cross-sectional study of clinically healthy adults was performed. We evaluated serum ferritin (SF) concentration to allow us to establish groups with normal iron stores (SF >30 microg/L) and with IO (SF >200 microg/L and >300 microg/L for women and men), in the following ages groups: 18-29 years, 30-49 years, and 50-64 years, divided by gender. RESULTS: The study included 1757 subjects. Prevalence of IO was 12% in men and 4.8% in women, and prevalence increased in parallel with increasing age (15.6, 25.0 and 29.9% and 3.5, 5.2 and 9.6%, for men and women, respectively). Regression analysis showed that in men there was a significant association of SF and IO with age, BMI and recent blood donation (p <0.01). In women, no differences were seen for BMI and recent blood donation. CONCLUSIONS: IO is highly prevalent in blood donors residing in Mexico City, more so in men than in women. Age, gender and BMI had a positive association with iron stores. This report is the initial contribution towards the study of IO in the Mexican population.

Adolescent↗
PubMed2006

[Comparison between phlebotomy and erythrocytapheresis of iron overload in patients with HFE gene mutations].

BACKGROUND AND OBJECTIVE: Large-volume erythrocytapheresis (EA) is an useful and speedy method to treat iron overload (IO). We assesed the efficacy of EA in patients with HFE gene mutations and IO compared to the classical phlebotomies. PATIENTS AND METHOD: Data from 9 patients with IO treated with EA, using a discontinuous flow cell separator as a single needle procedure, for a period of 2 years, were compared to 9 matched patients who underwent conventional phlebotomies. RESULTS: The mean volume of red blood cells removed in each EA was 275 ml, with a median reduction of 23 g/l for haemoglobin and 55 microg/l for serum ferritin levels (vs. 17 microg/l between phlebotomies). The liver function test returned to normal values in 4 out of 5 patients undergoing EA, but none of the phlebotomies. The time required to achieve iron depletion was 3 times shorter in EA group. CONCLUSIONS: EA is an effective and safe procedure that achieves iron depletion more quickly than manual phlebotomies. Nevertheless, to determine its cost-effectiveness, economical, prospective, randomized studies are warranted.

Adult↗
PubMedDate not supplied

Ultrastructural evidence for the presence of ferritin-iron in the biliary system of patients with iron overload.

Ferritin-like particles were observed in bile canaliculi of patients with iron overload. These particles have been further investigated by: a staining method enhancing the size and contrast of ferritin protein, and electron probe microanalysis detecting the presence of the elements iron and phosphorus. Morphological observation of coated vesicles in the cytoplasm adjacent to the bile canaliculi and coated pits in the canalicular membrane suggests a transport mechanism via membrane-bound organelles. Support is given to the theory that part of the iron, stored in the liver, leaves the hepatocyte by excretion of ferritin into the bile.

Anemia, Sideroblastic↗
PubMed2004

The impact of the mutations of the HFE gene and of the SLC11A3 gene on iron overload in Greek thalassemia intermedia and beta(s)/beta(thal) anemia patients.

In this study, we evaluated the impact of mutations of the HFE and ferroportin gene on iron overload in thalassemia intermedia and betas/betathal patients. Neither HFE (C282Y and H63D) nor ferroportin(Val162del) mutations were determinants of total body iron status, as assessed by ferritin levels, in either group of patients.

Adult↗
PubMed2000

Increased sensitivity to the inhibitory effect of excess iodide on thyroid function in patients with beta-thalassemia major and iron overload and the subsequent development of hypothyroidism.

OBJECTIVE: Patients with beta-thalassemia frequently develop primary hypothyroidism and other endocrine disorders due to iron overload. We studied whether administration of excess iodide to patients with apparently normal thyroid function could uncover an underlying thyroid disease. DESIGN AND METHODS: Twenty-five patients, 10 prepubertal (mean age 11+/-3 years) and 15 adults (mean age 23+/-5 years) with normal thyroid hormone and TSH levels, a normal response of TSH to TRH and negative thyroid peroxidase antibodies received 20mg iodide three times daily for three weeks, and thyroid hormone and TSH levels were measured weekly during, and for three weeks after, iodide administration and every 3 months thereafter for the next 5 years. RESULTS: During iodide administration there was a significant decrease in thyroid hormone concentrations which remained within normal levels, and a significant increase in TSH concentrations which in 14 out of 25 (56%) patients reached the hypothyroid level. Baseline TSH values were higher in those patients who developed subclinical hypothyroidism (2.31+/-0.71mU/l vs 1. 34+/-0.64mU/l, P=0.0016). Subclinical hypothyroidism developed in 70% of prepubertal and in 47% of adult patients. Serum ferritin was elevated in all patients. Nine of the fourteen patients (64.3%) who developed subclinical hypothyroidism during iodide administration developed hypothyroidism during the 5-year follow-up compared with only one of the eleven patients with a normal response to iodide (P=0.004). CONCLUSIONS: Patients with beta-thalassemia should not be exposed to excess iodide due to increased sensitivity to its inhibitory effects on thyroid function. The susceptible individuals frequently develop permanent hypothyroidism in the following years.

Adolescent↗
PubMed2002

Autosomal dominant reticuloendothelial iron overload associated with a 3-base pair deletion in the ferroportin 1 gene (SLC11A3).

We describe a family with autosomal dominant inheritance of increased body iron stores characterized by raised serum ferritin concentration and normal transferrin saturation. Liver biopsy showed iron deposition in Kupffer cells without fibrosis. The clinical features of HFE-related hemochromatosis were absent, as were the Cys282Tyr and His63Asp mutations. Venesection therapy was poorly tolerated, suggesting a defect in iron release from reticuloendothelial stores. A 3-base pair deletion in exon 5 of the ferroportin 1 gene (SLC11A3) predicting Val162 deletion was found in affected members, but not in unaffected individuals or in 100 control subjects. Consensus structural predictions of the transmembrane helices showed that the deletion is in the extracellular loop between the third and fourth predicted transmembrane helices and lies within a spatial cluster of other known ferroportin 1 mutations. These results indicate that this extracellular cluster is functionally important for iron transport, and its disruption leads to iron overload.

Adult↗
PubMed1991

A 31P-NMR study on the energy state of rat liver in an experimental model of chronic dietary iron overload.

31P-NMR spectroscopy of rat liver perchloric acid extracts was utilized to assess the hepatic energy state in an experimental model of chronic dietary iron overload. Oral administration of iron for a period of 65 days that induces a steady ten-fold increase in hepatic iron concentration causes a significant decrease in the hepatic ATP level not associated with appreciable modifications of ADP and Pi levels. The phosphorylation ratio appears on the average decreased. The values of the energy state parameters revert to the normal if the concentration of iron in the liver is reversed below the critical level upon withdrawal of iron treatment after 45 days for a period of 20 days. The implication of these energy modifications for the pathogenesis of cell damage in the siderosis is discussed.

Adenosine Diphosphate↗
PubMed2005

Caffeic acid inhibits oxidative Stress and reduces hypercholesterolemia induced by iron overload in rats.

The effects of caffeic acid, a major phenolic compound of the diet, on oxidative stress and cholesterolemia are studied in rats submitted to oxidative stress by iron overload. Male Wistar rats were fed semi-synthetic diets containing regular (50 mg/kg diet) or high (2000 mg/kg) doses of iron with and without caffeic acid (6460 mg/kg) for 4 weeks. The high doses of iron induced an increase of lipid oxidation in the liver, as measured by thiobarbituric acid-reactive substances (TBARS), and an increase of cholesterolemia. Caffeic acid fully prevented the pro-oxidant effects of high iron doses (p < 0.001). It also reduced lipid peroxidation in rats fed the low iron dose (p < 0.05). Caffeic acid also increased vitamin E levels in plasma (2.74 micromol/L to 4.09 micromol/L for normal diet; p < 0.001; 2.78 micromol/L to 4.94 micromol/L for iron supplemented diet p < 0.001). Iron-induced hypercholesterolemia was inhibited by caffeic acid (1.07 g/L to 0.82 g/L; p < 0.001). These results demonstrate the antioxidative capacity of caffeic acid, a highly bioavailable polyphenol, in an in vivo model of oxidative stress.

Animals↗
PubMed1982

Ascorbic acid and iron levels in plasma and liver of vitamin C deficient guinea pigs after iron overload and desferrioxamine administration.

The effect of desferrioxamine on the reduction of tissue iron and the corresponding level of tissue ascorbic acid have been investigated in female guinea pigs on Vitamin C deficient diet. Plasma and liver AA concentrations were measured after stopping treatment (day 0) and on the following 24 days. Vitamin C intake with the diet enhances rapid absorption of iron into the tissue with corresponding increased catabolism of tissue ascorbic acid. Desferrioxamine reduced tissue iron concentrations without causing pronounced loss of liver ascorbic acid. It is concluded that alterations in tissue ascorbic acid are caused by iron overload in guinea pigs without the pronounced involvement of desferrioxamine.

Animals↗
PubMed1993

Selection of a new generation of orally active alpha-ketohydroxypyridine iron chelators intended for use in the treatment of iron overload.

The prospect of selecting oral alpha-ketohydroxypyridine chelators intended for clinical use in iron overload has been examined using several animal models of efficacy and toxicity. Studies using iron dextran-loaded mice labelled with 59Fe have shown that only the 1-substituted methyl, ethyl, (n)propyl, allyl, cyclopropyl, 2'-methoxyethyl, 3'-ethoxypropyl, or 2-methyl- or 2-ethyl-3-hydroxypyrid-4-one chelators were orally effective in increasing iron (59Fe) excretion by comparison to intraperitoneally administered desferrioxamine at the same dose (250 mg/kg). In contrast, chelators containing -H, mono- or dihydroxyalkyl and diethoxyethyl 1-substituents caused very little or no increase in iron (59Fe) excretion by the oral or intraperitoneal routes. In vitro studies using ferritin and haemosiderin have shown that equivalent iron release took place with both groups of chelators irrespective of their in vivo effects. In most cases there was no correlation between the n-octanol/water partition coefficient (Kpar) and iron removal efficacy but positive correlation between the lipophilicity and acute or subacute toxicity of these chelators in rats. The most toxic chelator in the chronic toxicity studies in rats was the lipophilic 1,2-diethyl-3-hydroxypyrid-4-one (EL1NEt). The most effective chelator in increasing iron excretion in mice and rabbits was 1-allyl-2-methyl-3-hydroxypyrid-4-one (L1NAII), and the chelator with the highest safety margin in mice and rats was 1,2-dimethyl-3-hydroxypyrid-4-one (L1). Overall the oral effectiveness in increasing iron excretion by these chelators in animals does not appear to be related to their lipophilicity or their ability to mobilise polynuclear iron in vitro but rather to other properties possibly related to their rate of biotransformation and excretion.

Absorption↗
PubMed1997

Iron overload is a risk factor for zygomycosis.

Well-recognized risk factors for zygomycosis include diabetic ketoacidosis, immunocompromise, and deferoxamine therapy for iron or aluminum overload, usually in patients undergoing kidney dialysis. We report a case of fatal nasal-orbital-cerebral zygomycosis in an 82-year-old man with known myelodysplasia and well-controlled diabetes. He was not receiving deferoxamine. Despite radical surgery and amphotericin B therapy, he died; primary hemochromatosis with gross iron overload was found post mortem. Experimental evidence suggests iron overload without deferoxamine therapy may be a risk factor for zygomycosis; the findings in this case would support this hypothesis.

Aged↗
PubMed1984

Studies of iron overload. Rat liver siderosome ferritin.

To investigate storage of ferritin and its transition to hemosiderin under conditions of iron overload, rats were either given multiple injections of iron dextran over 4 to 5 weeks or fed a diet containing 1.3% Fe as ferric ammonium citrate for 60 days. Then, preparations of liver siderosomes (heavily iron-laden lysosomes) were examined for content of buffer-soluble ferritin and buffer-insoluble, ferritin-related protein, total nonheme iron and protein, cathepsin D activity, and ability to incorporate 14C-leucine into ferritin. Total liver nonheme iron, ferritin protein and iron, and cathepsin D activity were also determined. Although parenteral iron loading produced higher total nonheme iron in livers than dietary loading, the iron content of ferritin was approximately 20% in both groups, reflecting saturation of ferritin with iron. Siderosome nonheme iron content was greater than 40% in relation to protein. The siderosomes contained little buffer-soluble ferritin; on isoelectric focusing this was composed of isoferritins present also in cytosol ferritin. Buffer-insoluble ferritin protein, identified in siderosomes by immunofluorescence, was solubilized and found to contain immunoreactive material corresponding to L and H subunits of buffer-soluble ferritin. Transmission electron microscopy indicated the presence of relatively large quantities of "ferritin" in siderosomes, and it is argued that this was mostly buffer insoluble (denatured) or represented ferritin [FeOOH]x cores divested of protein shells. Although siderosomes had substantial cathepsin D activity, the known resistance of ferritin to this and other proteases makes it unlikely that proteolysis is an early event in the decomposition of ferritin in siderosomes. Heavily iron-laden siderosomes did not take up newly labeled ferritin or ferritin protein or 14C-precursor within 24 hours of labeling, when 14C-labeled ferritin was abundant in cytosol. The author proposes a sequence of steps leading from sequestration of buffer-soluble cytosol ferritin to storage of insoluble "hemosiderin."

Animals↗