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PubMed1988

Magnetic resonance imaging of iron overload in children treated with peritoneal dialysis.

The ability of magnetic resonance imaging (MRI) to detect iron overload in children with end-stage renal disease (ESRD) was studied in 18 multiply transfused patients, aged 15.5 +/- 4.8 years, and 5 nontransfused children without evidence of renal disease. In the transfused patients, the serum ferritin (SF) level was compared to (a) a subjective rating of signal intensity of MRI images (scale of 0-10), (b) mean T1 values of liver and spleen, and (c) computer-assisted measurements of spin echo intensity (SEI) of liver, spleen, muscle and fat tissue. On subjective evaluation, the mean signal intensity was significantly lower in transfused patients than in controls and a significant correlation with the SF levels was observed for ratings of both liver and spleen. Mean T1 values of liver and spleen did not correlate with the SF levels. On computer analysis, the ratios of SEI of fat/liver, fat/spleen, muscle/liver and muscle/spleen were significantly correlated with the SF levels as well as the subjective evaluation sources. These data indicate that MRI is a suitable technique of documenting the presence and degree of iron overload in multiply transfused children with ESRD.

Adolescent↗
PubMed2004

The impact of iron overload and genotype on gonadal function in women with thalassaemia major.

OBJECTIVE: The purpose of this study is to evaluate the impact of chronic iron overload and genotype on gonadal function in women with thalassaemia major. PATIENTS AND METHODS: The study population consists of 101 women aged 15-48 years who were treated between 1981 and 1999. These women were divided into two groups according to their genotype: [A=no modifying genetic factor and B=presence of modifying factors], and into four groups according to their menstrual history: NM (normal menstruation), OLM (oligomenorrhea), PA (primary amenorrhea), and SA (secondary amenorrhea). RESULTS: Women with NM maintained eumenorrhoea for 14.62 years, whereas those with SA did so for 6.94 years. The serial values of both FSH and LH after stimulation with GnRH were lower in women with SA and PA (p<0.05) compared to women with OLM and NM. The average value of the minimum, mean and maximum ferritin levels over a period of 20 years displayed an increasing trend from women with NM to those with SA and PA. The lower levels of ferritin in women in Group A did not protect them from developing SA. In addition women with SA, who belong to Group A, had a shorter duration of eumenorrhoea compared to the ones with SA who belong to Group B. CONCLUSIONS: Although the pathogenesis of gonadal dysfunction in thalassaemia is known to be the consequence of iron overload, this study demonstrates that genotype acts as an independent variable, contributing to the development of SA in thalassaemic women.

Adolescent↗
PubMed1978

Hepatic sinusoidal cells in iron overload. Ultrastructural observations.

The ultrastructure of sinusoidal cells was studied in 18 liver biopsies from patients with homozygous beta-thalassemia. No conspicuous iron was seen in sinusoidal cells from biopsies obtained before transfusion therapy was initiated, although electron-dense iron was present in some parenchymal cells. Biopsies following the high transfusion regime showed progressive increase in the size and number of iron-containing lysosomes in both parenchymal and sinusoidal cells. This study confirms the view that transfusional iron is largely segregated in reticuloendothelial cells. Examination of stained and unstained sections showed the Kupffer cells and endothelial cells had different types of iron-containing lysosome that were also dissimilar from most iron-containing lysosomes seen in hepatocytes. The described cell-specific morphological features of the lysosomes facilitate the identification of various cells during iron overload. The importance of phagocytic sinusoidal cells during chronic iron overload is stressed.

Adolescent↗
PubMedDate not supplied

Does rapidly progressive iron overload in a young girl with sideroblastic anemia also signify the presence of hereditary hemochromatosis?

A severely anemic 3-year-old girl with refractory sideroblastic anemia and fulminant, fatal hemochromatosis is described. The patient had transfusion-dependent anemia with clinical cardiac, liver, and endocrine dysfunction that resulted from iron loading. The patient was minimally transfused, and deferoxamine chelation was started at age 34 months. Despite treatment, the patient died at age 46 months as a result of severe iron overload. Sideroblastic anemia and iron overload in childhood are reviewed, and a pathophysiologic mechanism for the patient's clinical course is postulated.

Anemia, Sideroblastic↗
PubMed1999

Activation of an iron uptake mechanism from transferrin in hepatocytes by small-molecular-weight iron complexes: implications for the pathogenesis of iron-overload disease.

The liver is one of the principal sites of iron overload in diseases such as hemochromatosis and beta thalassemia. Hence, much effort has been invested in examining the mechanisms of Fe uptake by hepatocytes. In the present study we have examined the effect of small molecular weight (M(r)) Fe complexes on Fe uptake from iron 59-labeled transferrin (Tf) and 59Fe-labeled citrate by primary cultures of hepatocytes. This was important to assess because Fe-citrate and saturated diferric Tf coexist in the serum of patients with untreated Fe overload. Preincubation of hepatocytes with the low-M(r) Fe complex ferric ammonium citrate (FAC; 25 microg/mL; (Fe) = 4.4 microg/mL) followed by incubation with 59Fe-Tf or 59Fe-citrate ((Fe) = 0.25 to 25 micromol/L) resulted in the marked stimulation of 59Fe uptake. For example, at a physiologically relevant Tf-Fe concentration of 25 micromol/L, there was an 8-fold increase in 59Fe uptake by cells incubated with FAC compared to control cells. In contrast, at Tf-Fe concentrations of 0.25 to 2.5 micromol/L, 59Fe uptake in FAC-treated cells was only 1-fold to 3-fold greater than that in the corresponding controls. These data suggest that the FAC-activated Fe uptake process predominates at physiologically relevant Tf concentrations above the saturation of the Tf receptor (TfR). This is the first study to demonstrate that preincubation of hepatocytes with Iow-M(r)Fe complexes can markedly increase Fe uptake from diferric Tf. In conclusion, these results may help to explain the loading of hepatocytes with Fe that occurs in Fe-overload disease despite marked down-regulation of the TfR.

Animals↗
PubMed1992

Serum bactericidal activity for Yersinia enterocolitica in hemodialysis patients: effects of iron overload and deferoxamine.

Human serum has been shown to be bactericidal for most strains of Yersinia enterocolitica. Systemic Y enterocolitica infections have been reported in iron-overloaded hemodialysis patients treated with deferoxamine. Both iron and deferoxamine are known to enhance the growth of Y enterocolitica. We inoculated sera from 12 hemodialysis patients whose serum ferritin levels ranged from 26 to 6,855 micrograms/mL (ng/mL), as well as three controls, with Yersinia organisms. After latencies of 0 to 24 hours, inoculated sera were then plated on blood agar. Bactericidal activity was demonstrated in all sera and the degree of activity did not correlate with ferritin levels. Bactericidal activity was also demonstrated in sera from three deferoxamine treated patients. We conclude that in vitro, sera of end-stage renal failure patients, with and without iron overload, are as bactericidal as control sera for Y enterocolitica and that deferoxamine therapy does not interfere with that bactericidal activity.

Adult↗
PubMed1999

Erythrocytapheresis for chronically transfused children with sickle cell disease: an effective method for maintaining a low hemoglobin S level and reducing iron overload.

Cerebrovascular accident (CVA) is a major complication of sickle cell disease during childhood. Long-term transfusion reduces the hemoglobin S level and generally prevents recurrent stroke, but it also results in progressive iron overload that requires regular chelation therapy. Erythrocytapheresis offers an alternative approach aimed at reducing the iron accumulation. We reviewed the results of erythrocytapheresis in eight sickle cell patients (mean age of 12.1 years) at high risk for a first or recurrent stroke. They were maintained at the standard pre-transfusion hemoglobin S (Hb S) level of 30%. Over an average of 9 months of erythrocytapheresis, none of the patients developed complications related to the procedure or to the increased blood use. Ferritin levels decreased by a mean of 26.5% in all patients. When evaluating the ferritin level in five patients, who remained on chelation therapy with deferoxamine (DFO), the level dropped by a mean of 32%. The levels remained stable in the three patients who were not on DFO. The procedure is safe and effective in reducing iron overload and can obviate the need for chelation therapy, even when the target Hb S is maintained at the standard 30% range.

Adolescent↗
PubMed2003

Effect of iron overload and dietary fat on indices of oxidative stress and hepatic fibrogenesis in rats.

BACKGROUND/AIMS: Oxidative stress is presumed to play an important role in hepatic fibrogenesis. Diets high in polyunsaturated fatty acids (PUFA) enhance fibrosis and have been associated with increased oxidative damage in some models of liver injury. The aim of this study was to determine the effects of dietary fat of varying PUFA content on iron-induced oxidative stress and fibrosis. METHODS: Rats were given parenteral iron and diets supplemented with coconut oil, safflower oil or menhaden oil. RESULTS: Hepatic iron overload was associated with induction of heme oxygenase-1, a sensitive indicator of oxidative stress, and with modest increases in hydroxyproline and procollagen I mRNA levels without histologically evident fibrosis, all of which were unaffected by dietary fat. In addition, iron loading was associated with increases in cysteine, gamma-glutamylcysteine and glutathione. Dietary fat brought about the expected alterations in peroxidizability, but did not alter indices of oxidative damage. CONCLUSION: These data highlight the distinction between oxidative stress and oxidative damage and suggest that the former is not sufficient to elicit overt fibrosis. Furthermore, while hepatic iron overload leads to oxidative stress, there is an associated upregulation of antioxidant defenses involving thiol metabolism that may be a critical factor limiting the accumulation of oxidative damage.

Animals↗
PubMed1994

Haemochromatosis as a window into the study of the immunological system: a novel correlation between CD8+ lymphocytes and iron overload.

In the present study we report a serial investigation of the numbers of the peripheral blood cells--erythrocytes, polymorphonuclear neutrophils, total lymphocytes, T-lymphocyte subpopulations (CD2, CD4, CD8), B lymphocytes and monocytes--in a group of 21 patients with haemochromatosis during the time of intensive phlebotomy treatment, i.e., from iron overload until the onset of iron deficiency. A remarkable individual stability of all blood cell populations studied was found in all patients. Patients differed in their relative proportions of CD4+ and CD8+. Each individual's CD4/CD8 ratio, as well as the absolute numbers, remained unaffected with time, confirming the existence of a strict homeostatic regulation of the relative numbers of the two major peripheral T lymphocytes. A significant positive correlation between CD4/CD8 ratios and the amount of iron mobilised by phlebotomy was found during this study. A novel correlation between the relative proportions of CD4+ and CD8+ cells and iron overload is confirmed by the follow-up of iron re-entry in the serum transferrin pool in the treated patients.

Adult↗
PubMed2006

Association of hepatic iron overload with invasive fungal infection in liver transplant recipients.

Invasive fungal infection is a serious complication of orthotopic liver transplantation, but its risk factors remain incompletely defined. Iron overload has already been associated with increased risk of fungal infections, but it has not yet been assessed as a risk factor in liver transplantation. We retrospectively studied a cohort of 153 consecutive patients who underwent their first liver transplantation at a single center and who survived at least 7 days after transplantation. The association between various pretransplant patient characteristics, including hepatic explant iron and risk of invasive fungal infections, was analyzed by univariate and multivariate models. Iron in the hepatic explant was assessed by Perl's Prussian blue stain by a pathologist blinded to clinical outcome. During the first year after transplantation, 28 of 153 patients developed a total of 31 invasive fungal infections, of which 21 (68%) were caused by Candida, 7 (23%) by Aspergillus, 2 (6%) by Cryptococcus, and 1 (3%) by Saccharomyces. Stainable iron in the hepatic explant was found in 48 patients (31%). Stainable iron in the hepatic explant was found to be strongly and independently associated with posttransplantation fungal infections in multivariate analysis (hazard ratio 3.09; 95% confidence interval 1.45-6.56; P = 0.003). Hepatic iron overload is strongly and independently associated with posttransplantation invasive fungal infections. Studies to confirm this finding in other centers and define the mechanism are warranted.

Adolescent↗
PubMed1993

Morphologic investigations of the guinea pig model of iron overload.

We have developed a guinea pig model of iron overload toxicity. Animals were administered intraperitoneal iron dextran 3 times a week to achieve total body iron load of 0.25, 0.5, 1.0, 1.5, and 2.0 g Fe/kg body weight in less than 30 days. Quantitation of tissue iron levels with atomic absorption indicated increased iron deposition in liver and heart of the iron-loaded guinea pigs (p < 0.001). Additionally, the iron-loaded pigs demonstrated decreased nuclear magnetic resonance spectroscopy T1 relaxation times in both liver and heart (p < 0.001). Serum iron, total body iron capacity, and transferrin saturation values were also determined in guinea pigs treated with 0.25, 0.5, and 1.0 g Fe/kg body weight. Serum iron and total iron-binding capacity were significantly increased at 0.5 and 1.0 g Fe/kg; transferrin saturation was elevated at 0.25 and 1.0 g Fe/kg. kg. Histologic examination of liver, heart, and bone marrow as well as ultrastructural studies on liver and heart confirmed increased iron deposition in treated animals. At the low iron dose level of 0.5 g Fe/kg, liver iron particles were primarily confined to Kupffer cells with minimal hepatocellular localization. Increased hepatocellular iron deposition was observed with larger doses of loaded iron. Myocardial iron was most prominent in interstitial cells of the epicardium, endocardium, myocardium, and coronary adipose tissue. Ultrastructurally, the presence of iron particles in perinuclear, membrane-bound structures (consistent with lysosomes) was confirmed using x-ray microanalysis. These morphological studies suggest that in this animal model siderosis of hepatic mononuclear phagocyte and myocardial interstitial cells may be the initial lesions leading to further biochemical and functional abnormalities. Correlation between tissue iron measurements and both light and electron microscopic changes, presented in this report, serve to introduce the iron-loaded guinea pig as a model for the study of iron-induced tissue damage.

Animals↗
PubMed1996

Role of non-transferrin bound iron in iron overload and liver dysfunction in long term survivors of acute leukaemia and bone marrow transplantation.

AIMS: To determine whether nontransferrin bound iron is present in the serum of long term survivors of acute leukaemia and bone marrow transplantation who have liver dysfunction as indicated by consistently raised serum aspartate aminotransferase (AST) activities. METHODS: Thirty eight patients, who were at least three years from the end of treatment, were studied. Serum samples were analysed for hepatitis C, hepatitis B, AST, ferritin, and non-transferrin bound iron. A bleomycin based assay was used to detect non-transferrin bound iron. Patient and blood bank records were examined to determine the number of units of transfused blood received by each patient. RESULTS: Ten patients had consistently raised serum AST activities. Of these, two had evidence of hepatitis C infection, one had chronic hepatitis B infection and one had chronic graft versus host disease affecting the liver. None of these four patients had detectable non-transferrin bound iron. The remaining six patients had no obvious reason for raised AST activities, but four had non-transferrin bound iron detectable in their serum as compared with only two out of 28 patients with normal AST activities. Patients with abnormal AST activities had higher serum ferritin concentrations than those with normal AST, though serum ferritin was raised in 21 of 28 patients without liver dysfunction. CONCLUSION: Non-transferrin bound iron may be found in this group of patients, suggesting that iron overload is the cause of the observed liver dysfunction. Non-transferrin bound iron may also be a more specific indicator of iron overload than the serum ferritin concentrations.

Adult↗
PubMed1997

Antioxidant activity of vitamin C in iron-overloaded human plasma.

Vitamin C (ascorbic acid, AA) can act as an antioxidant or a pro-oxidant in vitro, depending on the absence or the presence, respectively, of redox-active metal ions. Some adults with iron-overload and some premature infants have potentially redox-active, bleomycin-detectable iron (BDI) in their plasma. Thus, it has been hypothesized that the combination of AA and BDI causes oxidative damage in vivo. We found that plasma of preterm infants contains high levels of AA and F2-isoprostanes, stable lipid peroxidation end products. However, F2-isoprostane levels were not different between those infants with BDI (138 +/- 51 pg/ml, n = 19) and those without (126 +/- 41 pg/ml, n = 10), and the same was true for protein carbonyls, a marker of protein oxidation (0.77 +/- 0.31 and 0.68 +/- 0.13 nmol/mg protein, respectively). Incubation of BDI-containing plasma from preterm infants did not result in detectable lipid hydroperoxide formation (</=10 nM cholesteryl ester hydroperoxides) as long as AA concentrations remained high. Furthermore, when excess iron was added to adult plasma, BDI became detectable, and endogenous AA was rapidly oxidized. Despite this apparent interaction between excess iron and endogenous AA, there was no detectable lipid peroxidation as long as AA was present at >10% of its initial concentration. Finally, when iron was added to plasma devoid of AA, lipid hydroperoxides were formed immediately, whereas endogenous and exogenous AA delayed the onset of iron-induced lipid peroxidation in a dose-dependent manner. These findings demonstrate that in iron-overloaded plasma, AA acts an antioxidant toward lipids. Furthermore, our data do not support the hypothesis that the combination of high plasma concentrations of AA and BDI, or BDI alone, causes oxidative damage to lipids and proteins in vivo.

Adult↗
PubMed1994

Erythrocytapheresis therapy to reduce iron overload in chronically transfused patients with sickle cell disease.

Chelation therapy with deferoxamine is effective in preventing the risk of transfusional iron overload, but treatment failure is common because of noncompliance. To reduce the transfusional iron load, we have evaluated longterm erythrocytapheresis in 14 subjects with sickle cell disease and stroke (11) or other complications (3) as an alternative to simple transfusion. Subjects were treated with erythrocytapheresis using the Haemonetics V50 (Haemonetics Corp, Braintree, MA) to maintain the target pretransfusion hemoglobin S (Hb S) level less than 50% for 6 to 71 months. The transfusional iron load and the donor blood usage were analyzed for a 6- to 36-month study period and were compared with similar data from a subset of 7 subjects previously treated with conventional (target Hb S < 30%) and modified (target Hb S < 50%) simple transfusion protocols. The effect of erythrocytapheresis on iron accumulation was determined by assessment of serum ferritin levels in the absence of iron chelation. The mean transfusional iron load and donor blood usage with erythrocytapheresis were 19 +/- 14 mg iron/kg/yr (range, 6 to 50) and 188.4 +/- 55.2 mL packed-red blood cells (RBC)/kg/yr (range, 107 to 281), respectively. Of 6 subjects receiving no iron chelation therapy, 5 maintained normal or nearly normal serum ferritin levels during 11 to 36 months of erythrocytapheresis. In comparison with conventional simple transfusion and modified simple transfusion, erythrocytapheresis reduced iron loading by 87% (P < .01) and 82% (P < .01), respectively, but increased donor blood usage by 23% and 73%, respectively. Subjects with pre-erythrocytapheresis Hb levels > or = 8.0 g/dL had lower iron accumulation (P < .001) and less donor blood usage (P < .005) than subjects with Hb levels < or = 8.0 g/dL. Although donor blood usage is increased in comparison with simple transfusion, long-term erythrocytapheresis markedly reduces or prevents iron accumulation. This form of transfusion therapy allows the cessation of iron chelation in well-chelated subjects and, if used as the initial form of transfusion therapy, may prevent long-term complications of sickle cell disease without risk of iron overload and the need for chelation therapy.

Adolescent↗
PubMed2000

Relation between HFE mutations and mild iron-overload expression.

The identification of the HFE gene involved in hemochromatosis allows genetic tests based on mutation analysis to be performed. However, discrepancies in the correlation between HFE genotypes and iron-loading status have arisen. We investigated 708 patients with various signs or symptoms suggesting a putative iron overload that, nevertheless, did not reach the current criteria for hemochromatosis diagnosis. Most of the patients (91.4%) included in our study displayed one of three classical iron marker values above the threshold defined for iron overloading. HFE mutation analysis allowed us to identify 45.7% of carrier chromosomes in the studied group of patients that showed higher frequencies of HFE mutations compared with controls. In addition, the frequencies of compound C282Y/H63D heterozygous, H63D/H63D homozygous, and C282Y heterozygous genotypes were higher than those in HH probands and controls; they accounted for 16, 5.6, and 22.5% of the patients, respectively. All genotypic groups had a significantly higher value of serum ferritin concentration compared to the normal value; only the C282Y homozygotes and compound heterozygotes with H63D had a transferrin saturation significantly higher than the normal value. On the whole the H63D homozygous and compound heterozygous patients constitute an intermediate phenotypic group between HH and controls. Some of them may reach the critical overloading defined for HH diagnosis along with a potential risk of developing complications, whereas others only show a partial phenotypic expression.

Adult↗
PubMed2003

Platelet count increase following phlebotomy in iron overloaded patients with liver cirrhosis.

Thrombocytopenia is a frequent hematological complication in patients with liver cirrhosis, but its pathogenesis is not clearly understood. We evaluated the effect of iron depletion by phlebotomy on platelet count in 62 consecutive iron overloaded patients with liver cirrhosis and thrombocytopenia. After a median follow-up of 30.2 months we observed a significant increase of platelet count in all patients (from mean baseline levels of 110.1 up to 168.22109/l at the end of follow-up, P<0.001) with platelet count normalization in 42 of them (67.7%). In addition, we observed a significant improvement of serum ALT levels (from pretreatment mean values of 126.7 up to 59.7 U/l at the end of follow-up, P<0.001) along with the reduction of serum ferritin levels and transferrin saturation during phlebotomy. Different pathogenetic mechanisms involving both humoral (erythropoietin and thrombopoietin, TPO) and physical (portal hypertension and hypersplenism) factors are here discussed to explain the platelet count increase following phlebotomy. Our results show that phlebotomy is effective not only in lowering iron overload, but also in improving liver function and thrombocytopenia in patients with liver cirrhosis.

Aged↗
PubMed1990

Characterization and accumulation of ferritin in hepatocyte nuclei of mice with iron overload.

After a single subcutaneous dose of iron-dextran (600 mg of iron/kg), iron overload developed in C57BL/10ScSn mice. At 4, 24 and 78 wk liver nonheme iron concentrations were 67-, 42- and 21-fold higher than controls, respectively. Much of the iron was in macrophages, but hepatocytes were also strongly positive for Perls' stainable iron. One feature was the development of iron-positive nuclear inclusions in hepatocytes. After a delay of at least 8 wk when no stainable iron was evident, a maximum of 37% of periportal hepatocytes contained inclusions by 24 wk. Although this proportion remained constant for the remainder of the study, the size of the inclusions (which were not membrane-limited) increased to greater than 3 microns in diameter, occupying greater than 25% of the nuclear volume. The presence of iron in the inclusions was confirmed by energy dispersive x-ray microanalysis. Immunocytochemical studies showed that the iron was present as aggregates of ferritin. Quantitation of nonaggregated ferritin molecules by image analyses after electron microscopy demonstrated that within 4 wk ferritin levels in cytoplasm and nucleoplasm had greatly increased but that there was a concentration gradient of approximately one order of magnitude across the nuclear envelope. These findings are consistent with the hypothesis that in iron-loaded mouse hepatocytes there is a slow passage of ferritin-molecules through the nuclear pores; the gradient is maintained by the continual aggregation of ferritin within the nucleus. Intranuclear ferritin may provide a source of iron for catalyzing hydroxyl radical formation in nuclei during some toxic, carcinogenic and aging processes.

Animals↗
PubMed2002

Amlodipine decreases iron uptake and oxygen free radical production in the heart of chronically iron overloaded mice.

Hereditary hemochromatosis is a disorder of iron metabolism, which is currently the most prevalent autosomal recessive disorder in the world, with an expression of the homozygous form occurring in approximately 1 in 200 individuals of European descent. Approximately one third of patients with hemochromatosis die of iron-induced cardiac complications. Although the exact mechanism is not known, it is believed that the toxicity of excess iron in biological systems is due to its ability to catalyze the generation of harmful reactive oxygen free radical species (ROS), which can damage proteins, lipids, and DNA. There is preliminary evidence to suggest that non-transferrin-bound iron uptake in the myocardium may occur through voltage-dependent L-type calcium channels, and that calcium channel blockers (CCBs) may possess antioxidant properties. Accordingly, the authors hypothesized that the administration of amlodipine besylate would (1) decrease iron uptake in the myocardium and (2) decrease oxygen free radical production as measured by cytotoxic aldehyde-derived peroxidation products in a murine model of iron overload cardiomyopathy. The findings show that the CCB amlodipine is partially effective in limiting iron uptake in the heart and significantly inhibits the production of ROS in chronically iron-loaded mice. These are important preliminary findings because they suggest that CCBs may have significance in the clinical management of genetic disorders of iron metabolism.

Aldehydes↗