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PubMed2006

Increased hepatic telomerase activity in a rat model of iron overload: a role for altered thiol redox state?

Telomeres are repeated sequences at chromosome ends that are incompletely replicated during mitosis. Telomere shortening caused by proliferation or oxidative damage culminates in replicative arrest and senescence, which may impair regeneration during chronic liver injury. Whereas the effects of experimental liver injury on telomeres have received little attention, prior studies suggest that telomerase, the enzyme complex that catalyzes the addition of telomeric repeats, is protective in some rodent liver injury models. Thus, the aim of this study was to determine the effects of iron overload on telomere length and telomerase activity in rat liver. Mean telomere lengths were similar in iron-loaded and control livers. However, telomerase activity was increased 3-fold by iron loading, with no change in levels of TERT mRNA or protein. Because thiol redox state has been shown to modulate telomerase activity in vitro, hepatic thiols were assessed. Significant increases in GSH (1.5-fold), cysteine (15-fold), and glutamate cysteine ligase activity (1.5-fold) were observed in iron-loaded livers, whereas telomerase activity was inhibited by treatment with N-ethylmaleimide. This is the first demonstration of increased telomerase activity associated with thiol alterations in vivo. Enhanced telomerase activity may be an important factor contributing to the resistance of rodent liver to iron-induced damage.

Animals↗
PubMed1976

Splenectomy, iron overload and liver cirrhosis in beta-thalassemia major.

In order to evaluate the interrelations of splenectomy, iron overload and cirrhosis, histologic specimens of liver and spleen were examined and correlated in 12 children with beta-thalassemia major. All patients had received blood transfusions since infancy. Correlations seemed to exist between splenic hemosiderosis and splenic weight, and between the latter and the age at time of splenectomy. All liver samples showed varying hemosiderosis, not correlated with the number of transfusions or the children's age. Irregular liver cirrhosis existed in three children, 7, 8, and 14 years after splenectomy. No cirrhosis existed in any of the children where the spleen was in situ. Splenectomy in children with thalassemia may carry the long-term risk of liver cirrhosis.

Adolescent↗
PubMed1993

Electron paramagnetic resonance spectroscopy of stable free radicals in the liver compared with ultrastructural and functional damage in a rat model of alcohol- and iron-overload.

1. Electron paramagnetic resonance spectroscopy was used to study free-radical signals in freeze-clamped frozen liver tissue from rats after a 1 year period of dietary supplementation with alcohol, iron, or alcohol and iron. In alcohol-fed, iron-fed and alcohol- and iron-fed animals, mild histological damage was seen on light microscopy and evidence of mitochondrial and nuclear injury was identified by electron microscopy. 2. Subcellular fractionation studies showed an increase in the activity of the peroxisomal marker catalase (P < 0.01) in alcohol-fed rats compared with controls, but a fall of 82% (P < 0.001) in alcohol- and iron-fed animals. The activity of the mitochondrial marker succinate dehydrogenase rose by 7% (not significant) in alcohol-fed animals and by 17% (not significant) in iron-fed animals, but fell by 94% (P < 0.001) in alcohol- and iron-fed animals, suggesting serious impairment of mitochondrial function. 3. Iron overload was substantial in the iron-fed animals and there was an excellent correlation between liver iron concentration and iron-derived signals by electron paramagnetic resonance spectroscopy (P < 0.001). A clear free-radical signal of g = 2.003-2.005 was detected in all liver samples, but there was no significant difference in the magnitude of this signal in any study group. 4. The absence of any increase in the stable free-radical signal, even in the presence of considerable hepatic damage, does not support the hypothesis that free radicals mediate alcoholic liver disease in this animal model, although the results cannot be taken as proof against this hypothesis.

Animals↗
PubMed1989

Iron overload and the predisposition of cells to antioxidant consumption and peroxidative damage.

We have investigated the effects of iron overload in vivo on the tocopherol levels and the extent of lipid peroxidation in rat liver microsomes and their response to subsequent oxidative stress in vitro. The results demonstrate a direct correlation between consumption of antioxidant defences and the induction and extent of malondialdehyde production in microsomes prepared from iron-loaded rats. The data are consistent with the requirement for iron (II)/iron (III) ratios in lipid peroxidation in control microsomes.

Animals↗
PubMed1998

Iron-overload disease in infants involving fetal growth retardation, lactic acidosis, liver haemosiderosis, and aminoaciduria.

BACKGROUND: Several cases of a distinctive lethal neonatal disorder have been found in the Children's Hospital, Helsinki, Finland. However, the combination of presenting features is not typical of any known metabolic disease. We have analysed all known cases of this disorder in the hospital since 1965 and in Finland since 1990 to define clinical features of the disease. METHODS: We studied 17 newborn infants with severe growth retardation from 12 Finnish families and traced their genealogy. In addition to routine clinical studies, diagnostic workup included analysis of respiratory-chain function in isolated muscle mitochondria and necropsy specimens, pyruvate dehydrogenase complex activities in fibroblasts, analysis of aminoacids and organic acids in urine, staining of tissue samples for iron, and assay of liver iron content. FINDINGS: The infants were born near term (mean 37.8 [SD 3] gestational weeks) but were severely growth retarded (birthweight 1690 [460] g--ie, -3.8 [SD 0.6] SD score for gestational age). By age 24 h, mean pH was 7.00 (0.12), lactate 12.2 (7.5) mmol/L, and pyruvate 121 (57) micromol/L. All had aminoaciduria and failed to thrive; nine died neonatally (age 2-12 days), and eight died in infancy (1-4 months). The liver of four infants showed microscopic haemosiderosis and increased iron content (2.8-5.5 mg iron/g dry weight). In those four infants serum ferritin concentration (1260-2700 microg/L) and transferrin saturation (61-100%) were high, transferrin concentration (0.54-0.76 g/L) was low. INTERPRETATION: We describe a previously unrecognised clinical picture of a genetic disease, which presents with fetal growth retardation and lactic acidosis after birth. Genealogical studies indicate an autosomal-recessive mode of inheritance for this disease, which is distinct from other lactic acidoses, neonatal haemochromatosis, and hepatitis. The diagnostic criteria are: fetal growth retardation; severe lactic acidosis; aminoaciduria; iron overload with haemosiderosis of the liver, increased serum ferritin concentration, hypotransferrinaemia, and increased transferrin iron saturation. Organ dysfunction may be partly due to the toxic effects of free iron.

Acidosis, Lactic↗
PubMed1977

[Iron overload: effect on specific and nonspecific immunity].

Acute overload with an iron salt in mice enhanced the virulence of a relatively avirulent type of Salmonella typhimurium in a dose-dependent fashion. Iron administration also partly abolished specific immunity. Ferritin iron did not display the virulence-enhancing effect.

Animals↗
PubMed2001

Variable phenotypic presentation of iron overload in H63D homozygotes: are genetic modifiers the cause?

BACKGROUND: First considered as a polymorphism of the HFE gene, the H63D mutation is now widely recognised as a haemochromatosis associated allele. But few H63D homozygotes with clinical manifestations of hereditary haemochromatosis (HH) have been reported. Concurrently, an increasing number of genes have been shown to interact with HFE in iron metabolism. AIMS: To describe the clinical expression of iron overload (IO) associated with H63D homozygosity, and search for potential genetic modifiers (within the HFE or other genes) that could explain the variability of the phenotypes. PATIENTS AND METHODS: We retrospectively analysed the clinical phenotype of 56 H63D homozygotes referred for a personal or family history of IO. For each subject we examined intragenic HFE haplotypes and transferrin receptor (TfR) gene polymorphisms and searched for the Y250X mutation on the TFR2 gene. Additionally, we sequenced the HFE gene of H63D homozygotes with HH. RESULTS: Fifty of 56 subjects had biological and/or clinical abnormalities of iron metabolism. Up to two thirds of patients (n=34) had no acquired cause of IO. Among these, 12 had a phenotypic diagnosis of HH. In the iron loaded group there was a strong prevalence of male patients. No correlation was found between the potential genetic modifiers and phenotypes. No additional mutation of HFE was identified. CONCLUSION: The variable phenotypes associated with H63D homozygosity do not appear to be linked to other HFE mutations, to the TFR2 Y250X mutation, or to HFE or TfR gene intragenic polymorphisms. The exact role of H63D homozygosity in IO and HH needs to be further investigated in unselected populations.

Adult↗
PubMed2004

Unusual splenic sinusoidal iron overload in sickle cell/haemoglobin D-Punjab disease.

Sickle cell/haemoglobin D-Punjab disease is a disorder with similar clinical features to sickle cell anaemia. This report describes the case of an 11 year old boy with this disease who was treated with regular transfusions from infancy. He underwent splenectomy at the age of 10 years for hypersplenism. Histology of the spleen revealed a striking pattern of heavy sinusoidal endothelial iron loading, with only moderate uptake by macrophages. Possible explanations for this unusual distribution of iron include phagocytosis of sickled erythrocytes by sinusoidal endothelial cells or direct endothelial iron uptake via transferrin receptors. Transfusion programmes ameliorate the symptoms of sickle cell disease but the dangers of iron overload should always be remembered.

Anemia, Sickle Cell↗
PubMed2003

Safety, tolerability, and pharmacokinetics of ICL670, a new orally active iron-chelating agent in patients with transfusion-dependent iron overload due to beta-thalassemia.

ICL670 is an orally active representative of a new class of tridentate iron chelator developed for the treatment of blood transfusion-dependent iron overload in chronic anemias. In this randomized, double-blind study, patients with transfusion-dependent beta-thalassemia received single oral doses of ICL670 ranging from 2.5 to 80 mg/kg to investigate its safety, tolerability, and pharmacokinetics and to obtain preliminary information on pharmacodynamic effects. ICL670 was well tolerated, and no safety problems occurred up to 80 mg/kg. A plasma half-life of 11 to 19 hours was found for ICL670, supporting once-daily oral administration. AUC0-24 h and Cmax of ICL670 increased nearly proportionally with the dose. The urinary excretion of ICL670 and its iron complex was less than 0.1% of the dose, and this was in accordance with the expected predominant iron fecal excretion induced by ICL670 (based on preclinical experiments). Notwithstanding, a positive trend toward increased amounts of urinary excreted iron was observed when the AUC0-24 h of ICL670 and the iron complex exceeded specific threshold values at the 40- and 80-mg/kg dose levels.

Administration, Oral↗
PubMed2006

A case of rhesus hemolytic disease with hemophagocytosis and severe iron overload due to multiple transfusions.

BACKGROUND: A newborn with cholestatic hepatic disease and hemophagocytic lymphohistiocytosis due to rhesus hemolytic disease (RHD) is reported. OBSERVATION: A 34 weeks' gestation baby with RHD, who had received multiple intrauterine transfusions (IUT), developed cholestatic hepatic disease and secondary hemophagocytic lymphohistiocytosis (HLH). Her serum ferritin level increased to 5,527 ng/mL, and liver biopsy showed severe iron overload. Treatment with intravenous desferrioxamine resulted in a marked decrease in serum ferritin levels and normalization of liver function CONCLUSION: We suggest that patients who have undergone IUT be evaluated for hyperferritinemia. If hyperferritinemia is noted, chelation therapy should be considered. As another rare finding, HLH can complicate the course of RHD.

Adult↗
PubMed2006

Antioxidant and lysosomotropic properties of acute D-propranolol underlies its cardioprotection of postischemic hearts from moderate iron-overloaded rats.

The benefits of acute D-propranolol (D-Pro, non-beta-adrenergic receptor blocker) pretreatment against enhanced ischemia/reperfusion (I/R) injury of hearts from moderate iron-overloaded rats were examined. Perfused hearts from iron-dextran-treated rats (450 mg/kg/week for 3 weeks, intraperitoneal administration) exhibited normal control function, despite iron treatment that elevated plasma iron and conjugated diene levels by 8.1-and 2.5-fold, respectively. However, these hearts were more susceptible to 25 mins of global I/R stress compared with non-loaded hearts; the coronary flow rate, aortic output, cardiac work, left ventricular systolic pressure, positive differential left ventricular pressure (dP/dt), and left ventricular developed pressure displayed 38%, 60%, 55%, 13%, 41%, and 15% lower recoveries, respectively, and a 6.5-fold increase in left ventricular end-diastolic pressure. Postischemic hearts from iron-loaded rats also exhibited 5.6-, 3.48-, 2.43-, and 3.45-fold increases in total effluent iron content, conjugated diene levels, lactate dehydrogenase (LDH) activity, and lysosomal N-acetyl-beta-glucosaminidase (NAGA) activity, respectively, compared with similarly stressed non-loaded hearts. A comparison of detection time profiles during reperfusion suggests that most of the oxidative injury (conjugated diene) in hearts from iron-loaded rats occurred at later times of reperfusion (8.5-15 mins), and this corresponded with heightened tissue iron and NAGA release. D-Pro (2 microM infused for 30 mins) pretreatment before ischemia protected all parameters compared with the untreated iron-loaded group; pressure indices improved 1.2- to 1.6-fold, flow parameters improved 1.70- to 2.96-fold, cardiac work improved 2.87-fold, and end-diastolic pressure was reduced 56%. D-Pro lowered total release of tissue iron, conjugated diene content, LDH activity, and NAGA activity 4.59-, 2.55-, 3.04-, and 4.14-fold, respectively, in the effluent of I/R hearts from the iron-loaded group. These findings suggest that the enhanced postischemic dysfunction and tissue injury of hearts from iron-loaded rats was caused by excessive iron-catalyzed free radical stress, and that the membrane antioxidant properties of D-Pro and its stabilization of sequestered lysosomal iron by D-Pro may contribute to the cardioprotective actions of D-Pro.

Animals↗
PubMed2000

T2 relaxation rate as an index of pituitary iron overload in patients with beta-thalassemia major.

OBJECTIVE: In transfusion-dependent ss-thalassemia major, increased iron deposition in the pituitary gland has a cytotoxic effect, leading mainly to hypogonadotropic hypogonadism. Early detection and quantification of iron in the pituitary gland are of particular importance for successful treatment. The purpose of this study was to evaluate the T2 relaxation rate (1/T2) as a marker of pituitary siderosis. SUBJECTS AND METHODS: In 29 patients with ss-thalassemia major and 40 controls, we assessed the 1/T2 of the pituitary gland in a 1.5-T MR unit, using a multiecho spin-echo sequence. In all patients, an extensive endocrine evaluation was performed, including measurements of spontaneous and stimulated levels of gonadotropins, thyroid hormones, growth hormone, insulinlike growth factor, and adrenal hormones. RESULTS: A positive correlation was found between the 1/T2 and the serum ferritin level (r = 0.73, p < 0.001). The 1/T2 was higher in patients (mean, 0.020 msec(-1); SD, 0.006) compared with that of controls (mean, 0.011 msec(-1); SD, 0.001; p < 0.001). The 1/T2 was higher in patients with hypogonadotropic hypogonadism (mean, 0.024 msec(-1); SD, 0.006) in comparison with that of patients without any pituitary dysfunction (mean, 0.017 msec(-1); SD, 0.004; p < 0.05). CONCLUSION: The T2 relaxation rate could be used as an index of pituitary iron overload, and it might be of value to monitor treatment with deferoxamine in patients with ss-thalassemia major.

Adult↗
PubMed1981

[Diagnosis of iron overload and hemochromatosis (author's transl)].

During the last years major advances have been achieved in the diagnosis of iron overload and idiopathic hemo-chromatosis (IHC). The mode of inheritance of this disease in known today and early diagnosis can be made by use of new genetic markers; thus, early treatment may prevent irreversible late complications. The diagnostic procedure is discussed, based on 74 own cases with IHC. Diagnosis has to rely on clinical features and laboratory tests. Measurements of serum iron, transferrin saturation and of serum ferritin are most important non invasive diagnostic tests. Our findings confirm that ferritin measurements may be normal in some precirrhotic patients. Measurement of serum iron seems to discriminate most accurately between heterozygous and homozygous relatives. The pathogenesis of IHC still remains unclear in spite of many recent efforts to clarify it. Early diagnosis and phlebotomy have dramatically improved the prognosis of IHC.

Anemia, Hemolytic↗
PubMed2006

Deferasirox and deferiprone remove cardiac iron in the iron-overloaded gerbil.

INTRODUCTION: Deferasirox effectively controls liver iron concentration; however, little is known regarding its ability to remove stored cardiac iron. Deferiprone seems to have increased cardiac efficacy compared with traditional deferoxamine therapy. Therefore, the relative efficacy of deferasirox and deferiprone were compared in removing cardiac iron from iron-loaded gerbils. METHODS: Twenty-nine 8- to 10-week-old female gerbils underwent 10 weekly iron dextran injections of 200 mg/kg/week. Prechelation iron levels were assessed in 5 animals, and the remainder received deferasirox 100 mg/kg/D po QD (n = 8), deferiprone 375 mg/kg/D po divided TID (n = 8), or sham chelation (n = 8), 5 days/week for 12 weeks. RESULTS: Deferasirox reduced cardiac iron content 20.5%. No changes occurred in cardiac weight, myocyte hypertrophy, fibrosis, or weight-to-dry weight ratio. Deferasirox treatment reduced liver iron content 51%. Deferiprone produced comparable reductions in cardiac iron content (18.6% reduction). Deferiprone-treated hearts had greater mass (16.5% increase) and increased myocyte hypertrophy. Deferiprone decreased liver iron content 24.9% but was associated with an increase in liver weight and water content. CONCLUSION: Deferasirox and deferiprone were equally effective in removing stored cardiac iron in a gerbil animal model, but deferasirox removed more hepatic iron for a given cardiac iron burden.

Animals↗
PubMed1997

Cardiac function during iron chelation therapy in adult non-thalassaemic patients with transfusional iron overload.

It is well-documented that iron chelation by desferrioxamine protects/improves the cardiac function in blood transfusion-dependent children suffering from beta-thalassaemia. In patients who do not become dependent upon blood transfusion until adulthood (ANT-patients), iron chelation by desferrioxamine may affect the cardiac function in unknown ways, presumably because age-related changes in the heart may cause iron chelation to affect the cardiac function in different ways. We therefore followed the left ventricular ejection fraction (LVEF) by multigated radionuclide angiography in 16 iron-loaded ANT-patients during iron chelation alone and after increasing the efficacy of chelation by vitamin C supplementation. During 12 months of iron chelation the mean LVEF fell significantly from 63.3% to 58.0% (p=0.04). Individual changes in LVEF did not correlate significantly with age but with the pretreatment liver iron concentration. After initiation of vitamin C supplementation, the mean LVEF increased from 55.9% to 65.3% (p=0.01). Our data suggest that in ANT-patients prolonged desferrioxamine treatment without vitamin C supplementation may be associated with reduced LVEF, whereas vitamin C supplementation seems to benefit the cardiac function. Similar findings have not been described in beta-thalassaemia and may hence be specific for ANT-patients. However, our findings have to be confirmed by controlled studies.

Adolescent↗
PubMed1988

The effect of iron overload on the mitochondrial porphyrin level in the hexachlorobenzene induced experimental porphyria.

Liver mitochondria isolated from rats treated with hexachlorobenzene plus iron, present a lower content of total porphyrin in respect to that of mitochondria from rats fed hexachlorobenzene alone. The in vitro mitochondrial porphyrin accumulation processes have been studied in mitochondria from iron loaded rats. It has been found that under these conditions the active porphyrin uptake process, which is driven by the K+ transmembrane gradient, is maximally inhibited in the presence of pentachlorophenol at a concentration similar to that found in vivo in the hexachlorobenzene experimental porphyria. By contrast the same degree of inhibition is presented by control mitochondria only in the presence of pentachlorophenol plus valinomycin, a condition which collapses the transmembrane K+ gradient. A strict correlation between porphyrin uptake and K+ concentration has been found in control as well as in iron treated mitochondria. A possible involvement of peroxidative reactions in the mitochondrial membranes has been proposed as a cause of the changes in the permeability properties of the mitochondrial membranes in the experimental chronic hepatic porphyria under conditions of iron overload.

Animals↗
PubMed1994

Iron overload in beta 2-microglobulin-deficient mice.

The present paper describes the results of a comparative histological and quantitative analysis of iron distribution in tissues of beta 2m-/- and beta 2m+/- mice of different ages. Progressive hepatic iron overload, indistinguishable from that observed in human hemochromatosis, was found only in mice homozygous for the mutated beta 2m gene. Total iron measurements done by flame atomic absorption showed statistically significant differences between liver samples from 5 beta 2m+/- heterozygotes (468 +/- 174 micrograms/g of dry weight) and 9 mice homozygous for the mutated beta 2m gene with average total hepatic iron levels of 1583 +/- 423 micrograms/g of dry weight.

Animals↗