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PubMed1998

Treatment of iron overload in the "ex-thalassemic". Report from the phlebotomy program.

After successful marrow transplantation (BMT) iron overload remains an important cause of morbidity in Thalassemia. After BMT, patients have normal erythropoiesis capable of producing a hyperplastic response to phlebotomy so that this procedure can be contemplated as a method of mobilizing iron from overloaded tissues. Forty-one patients (mean age 16 +/- 2.9 years) with prolonged follow-up (range 2-7 years) after BMT were submitted to a moderate intensity phlebotomy program (6 ml/kg blood withdrawal at 14-day intervals) to reduce iron overload. Values are expressed as mean +/- SD or as median with a range (25th-75th percentile). Serum ferritin decreased from 2,587 (2,129-4,817) to 280 (132-920) micrograms/l (p < 0.0001), total transferrin increased from 2.34 +/- 0.37 to 2.9 +/- 0.66 g/l (p = 0.0001), transferrin saturation decreased from 90% +/- 14% to 39% +/- 34% (p < 0.0001). Liver iron concentration evaluated on liver biopsy specimens decreased from 20.8 (15.5-28.1) to 3 (0.9-14.6) mg/g dry weight (p < 0.0001). Alanine amino-transaminase from 5.2 +/- 3.4 to 1.6 +/- 1.2 (p < 0.0001) times the upper level of normality. The histological grading for chronic hepatitis (Histology Activity Index) decreased from 4.2 +/- 2.4 to 2.3 +/- 1.8 (p < 0.0001). Phlebotomy is a safe, efficient, and widely applicable method to decrease iron overload in "ex-thalassemic."

Adolescent↗
PubMed2000

Successful chelation therapy in a case of neonatal iron overload following intravascular intrauterine transfusion.

OBJECTIVE: We report a newborn infant who was successfully treated with chelation therapy having developed severe liver disease secondary to iron overload following multiple intrauterine, intravascular transfusions (IVTs). STUDY DESIGN: Case report with review of the literature. RESULTS: An infant was born at 33 weeks' gestation having received multiple IVTs for severe rhesus hemolytic disease. At birth there was severe anemia with hydrops and ascites. Severe liver disease was present with portal hypertension, coagulopathy and abnormal liver enzymes. A liver biopsy showed histologic features consistent with iron overload. The serum ferritin was in excess of 4000 micrograms/l. A 7-week course of deferoxamine resulted in a marked reduction in ferritin levels and significant improvement in liver function. CONCLUSION: The possibility of neonatal iron overload following multiple IVTs should be borne in mind. Successful chelation therapy is possible in such cases.

Blood Transfusion, Intrauterine↗
PubMed1996

Iron overload in patients with chronic hepatitis C: a clinicopathologic study.

Recent studies suggest that increased hepatic iron may impair the response to interferon therapy in patients with chronic hepatitis C. We reviewed the records and liver biopsies of 72 patients with chronic hepatitis C to determine the prevalence of iron overload and to evaluate whether there is a correlation between serum and hepatic iron concentrations and activity of liver disease. Patients with other causes of liver disease or iron overload were excluded. Necroinflammatory activity and fibrosis were evaluated using modified Knodell score. Hepatic iron was assessed using Brissot's grading system. Increased serum iron and ferritin levels were found in 29% and 43% patients, respectively. Hepatic iron grades 0, I, II, III, and IV were present in 37%, 35%, 25%, 3%, and 0% of patients, respectively. A significant correlation was found between hepatic iron grade and serum ferritin (P = .0001). There was no correlation between hepatic iron grade and histological activity index or fibrosis score. In summary, we found a high proportion of patients with chronic hepatitis C had mild to moderate increase in hepatic iron content even when patients with alcoholism and recurrent transfusions were excluded. However, very few patients had severely increased iron load.

Adolescent↗
PubMed1990

Failure of deferoxamine to improve iron overload in chronic hemodialysis patients.

We prospectively studied the in vivo dialytic clearance of iron after deferoxamine (DFO) administration in four stable iron-overloaded chronic hemodialysis patients by quantifying iron concentration in blood entering and leaving the dialyzer and in dialysate after infusions of DFO. No significant arteriovenous iron differences were demonstrated. The mean ratio of venous to arterial iron approached identity at 1.005. All dialysate concentrates used contained large amounts of iron (300-610 micrograms/dl). No changes in efferent versus afferent dialysate iron concentration could be demonstrated. We conclude (a) iron removal during dialysis with DFO was not demonstrated; (b) the dialysate concentrate tested contained large amounts of iron; (c) in view of potentially significant toxicity, and lack of demonstrable therapeutic benefit, caution in prescribing DFO chelation therapy for iron overload is recommended.

Deferoxamine↗
PubMed1989

Lipid composition and fluidity of liver plasma membranes from rats with chronic dietary iron overload.

Liver plasma membranes isolated from rats with chronic dietary iron overload showed a large modification of their phospholipid fatty acid composition. Specifically, a significant decrease in polyunsaturated fatty acids and a parallel increase in saturated fatty acids was observed. This pattern was consistent with the in vivo occurrence of lipoperoxidative reactions in the liver plasma membranes. However, neither change in the cholesterol/phospholipid molar ratio nor in the lipid/protein ratio was detected. Direct measurement of the plasma membrane fluidity state by electron spin resonance spectrometry did not reveal any difference between control and iron-treated rats. These findings indicate that chronic dietary iron overload can induce lipid peroxidation of rat liver plasma membranes, but this event does not bring about modification in the physical state of the membrane.

Animals↗
PubMed2005

Left ventricular diastolic function compared with T2* cardiovascular magnetic resonance for early detection of myocardial iron overload in thalassemia major.

PURPOSE: To compare left ventricular (LV) diastolic function with myocardial iron levels in beta thalassemia major (TM) patients, using cardiovascular magnetic resonance (CMR). MATERIALS AND METHODS: We studied 67 regularly transfused patients with TM and 22 controls matched for age, gender, and body surface area. The early peak filling rate (EPFR) and atrial peak filling rate (APFR) were determined from high-temporal-resolution ventricular volume-time curves. Myocardial iron estimation was achieved using myocardial T2* measurements. RESULTS: Myocardial iron loading was found in 46 TM patients (69%), in whom the EPFR correlated poorly with T2* (r = -0.20, P = 0.19). The APFR (r = 0.49, P < 0.001) and EPFR/APFR ratio (r = -0.62, P < 0.001) correlated better with T2*. The sensitivity of the diastolic parameters for detecting myocardial iron loading ranged from 4% (EPFR and APFR) to 17% (EPFR/APFR ratio). CONCLUSION: Myocardial iron overload results in diastolic myocardial dysfunction, but low sensitivity limits the use of a single estimation for early detection of iron overload, for which T2* has a superior categorical limit of normality.

Adult↗
PubMed2004

Identification of a human mutation of DMT1 in a patient with microcytic anemia and iron overload.

Divalent metal transporter 1 (DMT1) is a transmembrane protein crucial for duodenal iron absorption and erythroid iron transport. DMT1 function has been elucidated largely in studies of the mk mouse and the Belgrade rat, which have an identical single nucleotide mutation of this gene that affects protein processing, stability, and function. These animals exhibit hypochromic microcytic anemia due to impaired intestinal iron absorption, and defective iron utilization in red cell precursors. We report here the first human mutation of DMT1 identified in a female with severe hypochromic microcytic anemia and iron overload. This homozygous mutation in the ultimate nucleotide of exon 12 codes for a conservative E399D amino acid substitution; however, its pre-dominant effect is preferential skipping of exon 12 during processing of pre-messenger RNA (mRNA). The lack of full-length mRNA would predict deficient iron absorption in the intestine and deficient iron utilization in erythroid precursors; however, unlike the animal models of DMT1 mutation, the patient is iron overloaded. This does not appear to be due to up-regulation of total DMT1 mRNA. DMT1 protein is easily detectable by immunoblotting in the patient's duodenum, but it is unclear whether the protein is properly processed or targeted.

Anemia, Hypochromic↗
PubMed1998

[Intensive intravenous chelation in thalassemic patients with iron overload].

The effects of an alternative chelation program in thalassemic patients with severe iron overload are investigated. The schedule of treatment, feasible at home, consists in the administration of deferoxamine intravenously (100 mg/kg/die 8 hours 10 days a month), followed by 50 mg/kg/die subcutaneously in the remaining 20 days of the month. The results in 34 patients who underwent this program over 8 months are reported. After intensive chelation therapy serum ferritin and transaminase levels were significantly lower, and daily urinary iron excretion values were significantly higher when compared to the levels observed before the treatment. After the period of study, echocardiography revealed an ejection fraction (EF) significantly higher in 15 out of 34 cardiopathic patients. In conclusion, the alternative chelation program is effective in reducing iron overload of thalassemic patients, protecting them also against cardiac disease.

Adolescent↗
PubMed1985

Distribution of ferritin and hemosiderin in the liver, spleen and bone marrow of normal, phlebotomized and iron overloaded rats.

The distribution of ferritin has been studied in many tissues, but has not yet been established on the cellular level. We investigated the cellular distribution of ferritin in the liver, spleen and bone marrow using the immunoperoxidase method, and compared it with that of hemosiderin. We also examined changes in the distribution of these proteins after phlebotomy and iron overload. In normal rats, ferritin was seen in centrilobular hepatocytes, Kupffer cells, macrophages in the red and white pulp of the spleen and central macrophages in bone marrow. Hemosiderin was observed almost exclusively in the red pulp and partly in tangible body macrophages of the white pulp. After phlebotomy, neither ferritin nor hemosiderin were detectable in these cells except for ferritin-positive cells in the white pulp, which showed little change after either phlebotomy or iron overload. In iron overloaded rats, both ferritin and hemosiderin increased in hepatocytes and reticulo-endothelial (RE) cells. Ferritin-positive cells in the liver were mainly located in the periportal area. These results indicated that hepatocytes and RE cells except for those in the white pulp may play an important role in iron storage, and that ferritin-positive cells in the white pulp may have a function other than iron reserve. They also suggested that the zonal distribution of ferritin-positive hepatocytes may be due to microcirculation in the hepatic lobules.

Anemia↗
PubMed2001

Severity of iron overload in hemochromatosis: effect of volunteer blood donation before diagnosis.

BACKGROUND: An effort was made to determine if volunteer blood donation before diagnosis decreases the severity of iron overload at diagnosis in persons with hemochromatosis. STUDY DESIGN AND METHODS: A study was performed in 1089 persons in the United States with hemochromatosis who responded to a convenience sample survey and in 124 C282Y/C282Y hemochromatosis probands diagnosed during routine medical care. RESULTS: Less than half of questionnaire respondents (46.2%) and probands (35.5%) reported that they had been volunteer blood donors; 5.4 percent and 4.0 percent, respectively, had donated >20 units of blood. In either subject group, there were no significant differences according to age in the mean numbers of units that needed to be removed by therapeutic phlebotomy to induce iron depletion in subgroups of men and women, respectively. Similarly, there was no significant correlation of units of voluntary blood donation or of therapeutic phlebotomy index (= therapeutic phlebotomy units/age in years) with the number of therapeutic phlebotomy units needed to induce iron depletion. When questionnaire respondents were stratified by sex, there was no significant correlation of units of blood donation with the number of therapeutic phlebotomy units needed to induce iron depletion or with the therapeutic phlebotomy index. CONCLUSION: Routine blood donation does not, on average, decrease the severity of iron overload in persons with hemochromatosis. These findings have implications for the understanding of the severity of iron overload and its complications in hemochromatosis, for advising persons with hemochromatosis about treatment, and for considering persons with hemochromatosis as possible blood donors.

Adult↗
PubMed1992

Iron overload of the bone marrow by trimethylhexanoyl-ferrocene in rats.

Iron-deficient female Wistar rats were fed a diet which contained 0.5% 3,5,5-trimethylhexanoyl (TMH)-ferrocene over a 57-week period. The state of iron deficiency was characterized by means of the absence of stainable iron in the bone marrow. After the first days on the iron-enriched diet, ferritin-containing siderosomes were found, in numerous erythroblasts up to orthochromatic normoblasts and in reticulocytes, i.e. the dispensed iron was used for haemoglobin synthesis. After 1 week the first macrophages showed a positive Perls' Prussian blue reaction. In the cytoplasm they stored the iron in the form of free ferritin molecules and lysosomally as aggregated ferritin and/or haemosiderin. The iron loading of the macrophages increased in both of the storage qualities proportionally with duration of the feeding period and reached a maximum after 38 weeks. Final stages showed extremely iron-loaded macrophages with high concentrations of free ferritin molecules and large siderosomes, partially flowing together to still greater units. Iron deposits within endothelial cells of bone marrow sinusoids can be observed for the first time after 4 weeks. In these cells the iron is stored as ferritin in siderosomes of relatively small and uniform size; free ferritin molecules in the cytosol were of only slight concentration. The TMH-ferrocene model of iron overload shows in the bone marrow: (1) an unimpeded utilization of the iron component for erythropoiesis, (2) development of excessive iron overload of the bone marrow in macrophages and endothelial cells of sinusoids and (3) a pattern of distribution of iron as seen in secondary haemochromatosis.

Anemia, Hypochromic↗
PubMed1998

T2 relaxation time study of iron overload in b-thalassemia.

Myocardial iron deposition occurs as a result of blood transfusion therapy in b-thalassemia major patients. Since this deposition causes various cardiac complications, it is of interest to assess the iron content of the myocardium in relation to the clinical picture of the patients. Two different MRI indices were used to achieve this purpose: the T2 relaxation time and the heart/skeletal muscle signal intensity ratio. ECG gated spin echo images were obtained from 54 adult thalassemic patients, with a mean age of 26 (18-44) years, at TE = 22 ms and 60 ms, using a 1.5 T system. Patients were divided into 2 groups (A and B), according to their serum ferritin levels (> or < 2000 ng ml(-1)). Results were compared with nine controls, with a mean age of 25 (18-43) years. Heart T2 relaxation time in controls (44.3 +/- 3.5 ms) was higher than in group A (29.9 +/- 5.7 ms, P < 0.001) and group B (33.4 +/- 6.8 ms, P < 0.01). T2 was measurable in 66% of group A and 83% of group B patients. The heart/muscle signal intensity ratio in group A (0.45 +/- 0.27) was lower than in group B (0.82 +/- 0.33, P < 0.001) and the controls (1.15 +/- 0.20, P < 0.001). The heart/muscle signal intensity ratio was measurable in 94% of the patients and demonstrated an inverse relationship with the serum ferritin levels (r = -0.52, P < 0.01). This study indicates that the heart/muscle ratio is a sensitive index of iron overload and it can be measured in the majority of patients, irrespective of tissue iron concentration, thereby offering an advantage over the use of T2 relaxation time.

Adolescent↗
PubMed2000

Chelator-induced iron excretion in iron-overloaded marmosets.

In order to test new orally active iron chelators in a predictive way, a primate model has been developed. This model makes use of the marmoset monkey (Callithrix jacchus) and its overall design is similar to a previously reported monkey model. However, this new model enables a higher compound throughput and requires lower amounts of test compound because the animals are much easier to handle and have much lower body weights. The marmosets were iron-overloaded by three intraperitoneal injections of iron (III) hydroxide polyisomaltose. For the iron-balance studies, the animals were kept in metabolic cages and were maintained on a low-iron diet in order to reduce faecal background. After compound administration, the excretion of iron in urine and faeces was followed for 2 d. A series of well-known chelators was tested for validation of the model. In particular, comparison of the iron-clearing properties of DFO, L1, CP94 and HBED in marmosets and humans demonstrated the predictive value of the model and justify our expectation that if iron chelators such as CGP65015, ICL670A and CGP75254A are active in marmosets, they will be active in humans as well.

Animals↗
PubMed1976

Reassessment of the use of desferrioxamine B in iron overload.

Treatment of transfusion-induced iron overload by daily intramuscular injection of the chelator desferrioxamine has not produced impressive urinary iron excretion. We attempted to augment net iron excretion by altering both the route and quantity of chelator administered. Two ascorbic acid-replete patients excreted a mean of 14.5 mg of iron per 24 hours after a single intramuscular injection of 750 mg of desferrioxamine. Excretion increased to a mean of 44.9 mg when this dose was delivered by a continuous 24-hour intravenous infusion. When the intravenous dose of chelator was increased incrementally to as high as 16,000 mg per 24 hours, iron excretion increased up to 180 mg per day. At these high-dose levels, efficiency of binding of iron to chelator was compromised. Constant exposure of the labile iron pool to a chelating agent markedly enhances net iron excretion in splenectomized transfusion-dependent patients.

Adolescent↗
PubMed1983

Diagnostic efficacy of hepatic computed tomography in the detection of body iron overload.

To determine whether or not hepatic computed tomography density is an alternative to liver biopsy for the diagnosis of body iron overload, hepatic computed tomography density was determined in healthy controls, patients with idiopathic hemochromatosis, and patients with liver disease. Hepatic computed tomography density was obtained from a single computed tomography slice taken through the liver on a General Electric CT/T 8800 scanner. In 69 controls, hepatic computed tomography density ranged from 11 to 36 units (mean = 30). Given an upper limit of normal of 36 computed tomography units, 4 of 6 untreated patients with idiopathic hemochromatosis had elevated hepatic computed tomography density compared with 0 of 8 patients after venesection (X2 = 7.5, p = 0.01). Hepatic computed tomography density correlated directly with serum ferritin (r = 0.72, p = 0.01). In 58 consecutive patients with clinical or biochemical evidence, or both, of liver disease who underwent liver biopsy for diagnostic purposes, 0 of 52 patients with normal hepatic iron had an elevated hepatic computed tomography density as compared with 4 of 6 patients with excess iron (X2 = 35, p less than 0.001). An elevated hepatic computed tomography density associated with an elevated serum ferritin indicates iron overload; however, a normal hepatic computed tomography density does not exclude iron overload. When computerized tomography is applied to patients with an unexplained elevation of the serum ferritin, it provides a noninvasive alternative to liver biopsy for the detection of excess hepatocellular iron.

Adult↗
PubMed2006

Chronic iron overload stimulates hepatocyte proliferation and cyclin D1 expression in rodent liver.

Hepatomegaly is commonly observed in hepatic iron overload due to human hemochromatosis and in animal models of iron loading, but the mechanisms underlying liver enlargement in these conditions have received scant attention. In this study, male rats were treated with iron dextran or dextran alone for 6 months. Chronic iron loading resulted in a > 50-fold increase in hepatic iron concentration. Both liver weights and liver/body weight ratios were increased approximately 2-fold in the iron-loaded rats (P < 0.001 for both). Hepatocyte nuclei expressing proliferating cell nuclear antigen (PCNA), a marker of S phase, were significantly increased in the iron-loaded livers, suggesting enhanced proliferation. To assess the mechanisms by which iron promotes proliferation, the expression of tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-6, hepatocyte growth factor (HGF), and transforming growth factor-alpha (TGF-alpha) were assessed by reverse transcription-polymerase chain reaction (RT-PCR). Of these growth-associated factors, only TNF-alpha messenger RNA (mRNA) was significantly increased by iron loading (about 3-fold; P = 0.005). Because cyclin D1 is required for entry of hepatocytes into the cell cycle after partial hepatectomy or treatment with direct mitogens, levels of immunoreactive cyclin D1 were examined and found to be significantly increased in the iron-loaded livers. The increase in cyclin D1 protein in the iron-loaded livers was paralleled by an increase in the abundance of its transcript as measured by real-time PCR. Taken together, these results suggest that iron is a direct mitogen in the liver and raise the possibility that chronic stimulation of hepatocyte proliferation may play a role in the pathophysiology of iron overload states.

Animals↗
PubMed2002

Iron overload exacerbates experimental meningoencephalitis by Cryptococcus neoformans.

This study was aimed at investigating the effects of iron overload on the onset and outcome of cerebral cryptococcosis. To this purpose, iron dextran-administered mice were intracerebrally challenged with virulent melanogenic and avirulent non-melanogenic strains of Cryptococcus neoformans. The results shown here provide the first evidence that iron overload exacerbates the outcome of cryptococcal meningoencephalitis, irrespective of the fungal strain employed; pathogen colonization of the brain is facilitated, local cytokine response is delayed and/or prevented.

Animals↗
PubMed1980

iron-overload-associated myopathy in patients on maintenance haemodialysis: a histocompatibility-linked disorder.

Unexplained proximal muscle weakness developed in 10 patients on chronic maintenance haemodialysis. Proximal muscle biopsy in 7 patients disclosed iron deposition in muscle fibres and/or macrophages. All 10 patients had severe iron overload (serum-ferritin level > 1000 ng/ml). Since HLA-A3, B7, and B14 antigens are associated with idiopathic haemochromatosis and, therefore, are linked with alleles regulating iron metabolism, HLA type was reviewed in 61 haemodialysis patients, including the 10 myopathic patients. Serum-ferritin levels showed a significant correlation (p<0.001) with the presence of the HLA-antigens. Close relatives of these patients with HLA-antigen-associated iron-overload myopathy did not have raised serum-ferritin levels. Patients on maintenance haemodialysis who have inherited the "haemochromatosis alleles" thus have an increased risk of iron overload and muscle iron deposition.

Adult↗