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PubMed1996

Iron accumulation in tissues of magnesium-deficient rats with dietary iron overload.

The mineral imbalances in magnesium-deficient rats with dietary iron overload were studied. Forty-four male Wistar rats were divided into six groups and fed six diets, two by three, fully crossed: magnesium adequate or deficient, and iron deficient, adequate, or excess. The concentrations of iron, magnesium, calcium, and phosphorus in tissues of the rats were measured. The results were as follows: (1) The excess iron intake reinforced the iron accumulation in liver and spleen of magnesium deficient rats; (2) The saturation of iron binding capacity was enormously elevated in the magnesium deficient rats fed excess iron; and (3) Dietary iron deprivation diminished the degree of calcium deposition in kidney of magnesium deficient rats. These results suggest that magnesium-deprived rats have abnormal iron metabolism losing homeostatic regulation of plasma iron, and magnesium deficient rats with dietary iron overload may be used as an experimental hemochromatosis model.

Analysis of Variance↗
PubMed2001

Iron overload without the C282Y mutation in patients with epilepsy.

To test the hypothesis that iron overload predisposes to epilepsy, transferrin saturation in 130 patients with epilepsy and sex and age matched 128 control subjects without epilepsy were studied. Mean transferrin saturation was significantly higher in the epilepsy group (39.9 (SD 19.6)%) than in the control group (29.1 (SD 14.9)%). Abnormally high transferrin saturations (men>60%, women>48%) were found in 10 patients with epilepsy but in only one subject without epilepsy. Antiepileptic drugs did not affect the transferrin saturation. Of the 11 with abnormally high transferrin saturation, two with epilepsy were heterozygotic for H63D in the haemochromatosis gene but no patient had the C282Y mutation. These results indicate that iron overload other than the C282Y mutation underlies epilepsy.

Adult↗
PubMed2005

[Human hepatic iron overload syndromes].

Recent advances in molecular genetics have led to a better understanding of hereditary iron overload syndromes, of which the most frequent are recessive HFE-hemochromatosis and, to a much lesser extent, dominant ferroportin disease. Acquired iron overload syndromes can be related to metabolic syndrome (insulin resistance syndrome), end-stage cirrhosis, or hematological disorders such as thalassemia and refractory anaemia.

Humans↗
PubMed1988

A screening test for detecting iron overload in population studies.

A simple, robust, inexpensive and reasonably accurate screening test, which involves colorimetric assessment of the unsaturated iron-binding capacity, was used to detect significant degrees of iron overload in a field setting. It was used in a survey of 152 men aged over 40 years who had previously been identified as having serum ferritin values above 400 micrograms/l and who were therefore potentially homozygous carriers of the HLA-linked iron-loading gene responsible for the clinical disorder idiopathic haemochromatosis (IHC). Such individuals almost always have a raised transferrin saturation and the screening test was compared with a standard method of measurement. The screening test accurately identified 7 out of 10 subjects with transferrin saturations above 62%. It also accurately identified 137 out of 142 subjects with saturation below 62%. There were 5 false-positive results; in all these subjects saturations were at the upper limit of normal or marginally raised. The test thus had a sensitivity of 77%, a specificity of 97%, an accuracy of 95% and a positive predictive accuracy of 67%. The test successfully identified a subgroup of subjects with serum ferritin values above 400 micrograms/l who appeared to have more severe degrees of iron overload. The screening test, which requires only 200 microliter serum and costs only 6.2 c, should not only be of potential value in identifying subjects at risk of developing the clinical manifestations of IHC but may prove even more useful in defining the prevalence of significant iron overload in the rural black population of South Africa.

Adult↗
PubMed1989

Evaluation of computed tomography in the assessment of liver iron overload. A study of 46 cases of idiopathic 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. Hepatic histologic examination together with biochemical determination remains the most accurate means to assess liver iron.

Fatty Liver, Alcoholic↗
PubMed1998

Effect of blood letting on serum aminotransferase levels of patients with chronic hepatitis C and iron overload.

OBJECTIVE: To confirm the existing evidence that blood letting reduces serum aminotransferase levels and to seek factors associated with a greater reduction in subjects with chronic hepatitis C and iron overload. DESIGN: Prospective, open label, non controlled study in two northern Italian hospitals. PATIENTS: Sixteen patients with histologically proven chronic hepatitis, positive hepatitis C virus serology, HCV-RNA detectable in their sera, and histological and biochemical signs of iron overload, nonresponders to interferon alpha therapy, underwent weekly phlebotomies until serum ferritin values < or = 50 ng/mL were obtained. Serum aminotransferases, serum ferritin and transferrin saturation were then measured and compared with values at baseline. RESULTS: Alanine aminotransferase and aspartate aminotransferase levels fell after phlebotomies from 193 +/- 107 IU/L to 115 +/- 53 IU/L (t = 4.94, p = 0.0001) and from 124 +/- 60 IU/L to 85 +/- 35 IU/L (t = 3.76, p = 0.002), respectively. The magnitude of the reduction correlated with baseline aminotransferase levels (r = 0.68, p = 0.004 for alanine aminotransferase and r = 0.63, p = 0.009 for aspartate aminotransferase), but not with those of serum ferritin and transferrin saturation percentage, nor with the quantity of iron removed. There was a trend towards a greater alanine aminotransferase reduction in patients with the highest baseline serum ferritin (r = 0.26, p = 0.14). CONCLUSIONS: Blood letting was effective in reducing serum aminotransferase levels of patients with chronic hepatitis C and iron overload, especially those with the highest baseline aminotransferase levels.

Adult↗
PubMed1975

Transfusional iron overload: the relationship between tissue iron concentration and hepatic fibrosis in thalassaemia.

The interrelationships between liver iron concentration, the duration of iron-loading, and hepatic fibrosis, assessed morphometrically, have been studied in 32 specimens of liver obtained from 19 heavily transfused patients with thalassaemia major whose age ranged from 4 to 19 yr. Similar observations were made in a matched group of thalassaemic patients treated with long-term chelation therapy. The degree of liver damage ranged from very slight increase in fibrous tissue to severe fibrosis and cirrhosis. The severity of the fibrosis was closely correlated both with liver iron concentration and with age. While the relationship between fibrosis and age was linear, both the severity and the rate of fibrosis were exponentially related to liver iron concentration, damage accelerating as liver iron concentration exceeded 3 per cent, dry weight. By producing a modest but significant reduction in liver iron concentration chelation therapy resulted in a disproportionate but predictable retardation in the progression of the fibrosis. The factors affecting the distribution of iron between parenchymal and reticuloendothelial cells were also examined. In general stainable iron was uniformly distributed between parenchymal and reticuloendothelial cells from the early stages of iron-loading. Parenchymal siderosis was relatively heavier in splenectomised patients and in patients with liver iron concentrations above 3 per cent, dry weight than in non-splenectomised patients or patients with liver iron levels of less than 3 per cent, dry weight, but this did not affect the severity of the fibrosis. The relevance of these findings to the traditional concepts of the pathology of transfusional siderosis is discussed.

Adolescent↗
PubMed1968

Significance for the diagnosis of iron overload of histochemical and chemical iron in the liver of control subjects.

Storage iron was examined in surgical liver biopsy specimens in 43 haematologically normal and otherwise healthy adult individuals. These patients had no history of unphysiological iron losses nor of unphysiological iron intake. Histochemical iron was estimated in parenchymal and Kupffer cells and graded from 0 to 4+. Stainable iron of grade 1+ or more was present in parenchymal cells in 23 of the 27 men. Six of them had a 3+ grade. In nine cases iron was also visible in Kupffer cells. Visible iron was absent in most of the menstruating women. The mean total nonhaemin iron concentration for the male group was 80.2 (19.4 to 227.0), for the postmenopausal women 50.7 (19.3 to 106.6), and for the menstruating women 23.5 (5.5 to 65.9) mg./100 g. dry weight. The mean value for the women was significantly lower than the mean value for the men. There was a significant correlation between the histochemical grades of iron and chemically determined nonhaemin iron, but the degree of overlapping was considerable. The presence of stainable iron in the parenchymal liver cells is a normal finding. The significance of the present results with reference to familial studies of haemochromatosis is discussed.

Adult↗
PubMed1994

Transient iron-overload with bleomycin-detectable iron present during cardiopulmonary bypass surgery.

Extracorporeal circulation of blood during cardiopulmonary bypass surgery exposes cells to non-physiological surfaces and shear stress which can activate several regulatory cascades, and neutrophils to release superoxide and hydrogen peroxide. Shear stresses generated by pumps and suction systems cause lysis of red blood cells and the release of haemoglobin. Together the release of reactive forms of oxygen and haemoglobin can lead to the appearance of low molecular mass chelatable iron (bleomycin-detectable iron). All patients undergoing open heart surgery appear to release iron to plasma transferrin, increasing its iron saturation. In 13% of patients, however, the transferrin became fully iron-saturated, and by the end of open-heart surgery we could detect bleomycin-chelatable iron in the plasma. Saturation of transferrin with iron eliminates its iron-binding antioxidant properties, which can result in a stimulation of iron-dependent radical damage to selected detector molecules.

Adult↗
PubMed1986

Hemochromatosis heterozygotes may have significant iron overload when they also have hereditary spherocytosis.

A family is described in which four of six siblings have both hereditary spherocytosis and evidence of abnormal iron metabolism. Three of the four have significant iron overload. HLA typing, which permits the detection of the gene for hemochromatosis, indicates that all family members with hereditary spherocytosis who have abnormal iron metabolism or significant iron overload are heterozygous for the hemochromatosis gene. Family members having hereditary spherocytosis but not the gene for hemochromatosis have normal iron studies as does a family member heterozygous for hemochromatosis but no hereditary spherocytosis. Based on the findings in this kindred, it appears that the combination of chronic hemolysis and the gene for hemochromatosis results in increased iron absorption that may lead to significant iron overload.

Adult↗
PubMed2005

Microcytic anemia and hepatic iron overload in a child with compound heterozygous mutations in DMT1 (SCL11A2).

Divalent metal transporter 1 (DMT1) mediates apical iron uptake in duodenal enterocytes and iron transfer from the transferrin receptor endosomal cycle into the cytosol in erythroid cells. Both mk mice and Belgrade rats, which carry an identical DMT1 mutation, exhibit severe microcytic anemia at birth and defective intestinal iron use and erythroid iron use. We report the hematologic phenotype of a child, compound heterozygote for 2 DMT1 mutations, who was affected by severe anemia since birth and showed hepatic iron overload. The novel mutations were a 3-bp deletion in intron 4 (c.310-3_5del CTT) resulting in a splicing abnormality and a C>T transition at nucleotide 1246(p. R416C). A striking reduction of DMT1 protein in peripheral blood mononuclear cells was demonstrated by Western blot analysis. The proband required blood transfusions until erythropoietin treatment allowed transfusion independence when hemoglobin levels between 75 and 95 g/L (7.5 and 9.5 g/dL) were achieved. Hematologic data of this patient at birth and in the first years of life strengthen the essential role of DMT1 in erythropoiesis. The early onset of iron overload indicates that, as in animal models, DMT1 is dispensable for liver iron uptake, whereas its deficiency in the gut is likely bypassed by the up-regulation of other pathways of iron use.

Anemia↗
PubMed1996

Hepatic iron overload in thalassemic patients: proposal and validation of an MRI method of assessment.

BACKGROUND: A simple, accurate, reproducible and noninvasive method of body iron overload assessment would be of great clinical use. Objective. The purpose of the study was the implementation of a 0. 5-T MRI method for liver iron overload measurement. MATERIALS AND METHODS: Thirty patients with thalassemia major took part in the study. Liver and paraspinal muscle signal intensity (SI) measurements were performed on T1-weighted images and normalized on a standard phantom, and a subjective hemochromatosis grading scale was made on both T1- and T2-weighted images. Serum ferritin levels and tissue iron from liver biopsy specimens were determined for comparison. RESULTS: A close correlation was found between bioptic liver iron and both the liver-to-phantom SI ratio (r = -0.88) and the subjective grading scale (rho = 0.89). Serum ferritin correlated poorly with liver iron deposition, whether assessed by biopsy (r = 0. 62) or MRI (r = -0.69). CONCLUSIONS: Both the subjective and the quantitative MRI methods proposed here are clinically valuable, with the former being adequate for a gross, the latter for an accurate estimation of tissue iron overload.

Adolescent↗
PubMed1995

Lipid peroxidation and changes in T lymphocyte subsets and lymphocyte proliferative response in experimental iron overload.

This study was undertaken to investigate the hypothesis that lipid peroxidation might be associated with immunological abnormalities in experimental hemosiderosis. The correlation between the degree of plasma and spleen lipid peroxidation with lymphocyte proliferative response and with the proportion of T lymphocyte subsets was studied in normal and iron overloaded male Sprague Dawley rats. The iron-loading protocol consisted of a total dose of iron-dextran (1.5 mg/Kg body weight) divided in daily i.m. injections over twenty consecutive days. Lipid peroxidation was measured by the thiobarbituric acid assay in plasma and in homogenates of spleen. Plasma lipid peroxide level increased rapidly after i.m. administration of iron-dextran and decreased sharply at 48 h after the last injection. Conversely, a progressive increase of lipid peroxidation in homogenates of spleen was observed in the course of the iron overload protocol, remaining high even at 50 days after initiation of iron-dextran injections. The increase of spleen lipid peroxide levels was associated with decreased lymphocyte proliferative response to Con A in iron overloaded rats. The addition of superoxide dismutase and catalase to lymphocyte cultures reversed the inhibition of the proliferative response, implicating reactive species of oxygen as the causative agents of these alterations. These effects may be related with the enhanced membrane and DNA damage occurring during intracellular and extracellular peroxidation. Negative correlations between helper/cytotoxic ratio and malondialdehyde levels were obtained in blood and spleen during iron administration. These results supports the hypothesis that lipid peroxidation plays a role in the immunological abnormalities observed in experimental hemosiderosis.

Animals↗
PubMed2005

Hepatocellular carcinoma caused by iron overload: a possible mechanism of direct hepatocarcinogenicity.

BACKGROUND/AIMS: Excess hepatic iron may be both directly and indirectly carcinogenic. The aim of this study was to determine if generation of reactive oxygen species and the resulting oxidative damage induced by free hepatic iron is directly hepatocarcinogenic. METHODS: Sixty male Wistar albino rats were iron-loaded by ferrocene supplementation of their diet. Biochemical parameters of oxidative damage and lipid peroxidation, DNA unwinding and strand breaks, and the Ames Mutagenesis Test were measured at 4 monthly intervals and correlated with the degree of hepatic iron overload, the presence of iron-free preneoplastic foci in the liver, and the development of hepatocellular carcinoma in comparison with 60 control rats. RESULTS: Levels of lipid hydroperoxides, malonaldehyde, 8-isoprostane and 8-hydroxy-2'-deoxyguanosine increased, reaching peak concentrations at 20-24 months, and correlating with an increase in the rate of DNA unwinding, strand breaks, and positive Ames Tests. Iron-free neoplastic foci became evident at 16 months and thereafter increased in number. Preneoplastic foci were present in five of eight rats remaining at 32 months and HCC had developed in one of the five. CONCLUSIONS: Our findings are compatible with the hypothesis that the direct hepatocarcinogenic effect of free iron is mediated by the generation of oxygen reactive species and oxidative damage that are mutagenic and carcinogenic.

Animals↗
PubMed1997

Dietary alpha-tocopherol supplementation on antioxidant defenses after in vivo iron overload in rats.

The effect of dietary alpha-tocopherol (alpha-T) supplementation on iron overload-dependent oxidative damage was studied. Male Wistar rats were fed diets supplemented with 2.5% carbonyl iron and/or 200 mg/kg of alpha-tocopheryl acetate for 6 weeks. Oxidation of lipids and proteins were increased by iron overload in rat liver, and alpha-T dietary supplementation effectively prevented these effects. Iron overload decreased both, catalase and Mn-superoxide dismutase activities by 49 and 54%, respectively, with no effect on glutathione peroxidase activity. Alpha-T supplementation did not prevent the inhibition measured in catalase and Mn-superoxide dismutase activities. Iron dietary excess had no effect on liver alpha-T and ubiquinol 9 (UQ9) content. Ubiquinol 10 (UQ10) content after iron overload was decreased by 58 and 54% in whole liver and liver mitochondria, respectively. Alpha-T supplementation led to significant increases in alpha-T, UQ9 and UQ10 content in liver, as compared to control values, and partially prevented the decrease in UQ10 content due to iron excess. The results presented here indicate that initial stages of iron overload led to oxidative damage in liver (evaluated in terms of lipid and protein oxidation) with a decline in antioxidant defenses. alpha-T supplementation affected the liver content of lipid soluble antioxidants, suggesting a concerted antioxidant response at the cellular level to modulate the effect of excess iron availability.

Animals↗