Multiparametric Cardiac Magnetic Resonance Survey in Children With Thalassemia Major: A Multicenter Study.

BACKGROUND: Cardiovascular magnetic resonance (CMR) plays a key role in the management of thalassemia major patients, but few data are available in pediatric population. This study aims at a retrospective multiparametric CMR assessment of myocardial iron overload, function, and fibrosis in a cohort of pediatric thalassemia major patients. METHODS AND RESULTS: We studied 107 pediatric thalassemia major patients (61 boys, median age 14.4 years). Myocardial and liver iron overload were measured by T2* multiecho technique. Atrial dimensions and biventricular function were quantified by cine images. Late gadolinium enhancement images were acquired to detect myocardial fibrosis. All scans were performed without sedation. The 21.4% of the patients showed a significant myocardial iron overload correlated with lower compliance to chelation therapy (P<0.013). Serum ferritin ≥2000 ng/mL and liver iron concentration ≥14 mg/g/dw were detected as the best threshold for predicting cardiac iron overload (P=0.001 and P<0.0001, respectively). A homogeneous pattern of myocardial iron overload was associated with a negative cardiac remodeling and significant higher liver iron concentration (P<0.0001). Myocardial fibrosis by late gadolinium enhancement was detected in 15.8% of the patients (youngest children 13 years old). It was correlated with significant lower heart T2* values (P=0.022) and negative cardiac remodeling indexes. A pathological magnetic resonance imaging liver iron concentration was found in the 77.6% of the patients. CONCLUSIONS: Cardiac damage detectable by a multiparametric CMR approach can occur early in thalassemia major patients. So, the first T2* CMR assessment should be performed as early as feasible without sedation to tailor the chelation treatment. Conversely, late gadolinium enhancement CMR should be postponed in the teenager age.

Hemodialysis-associated hemosiderosis in the era of erythropoiesis-stimulating agents: a MRI study.

BACKGROUND: Most dialysis patients receiving erythropoesis-stimulating agents (ESA) also receive parenteral iron supplementation. There are few data on the risk of hemosiderosis in this setting. METHODS: We prospectively measured liver iron concentration by means of T1 and T2* contrast magnetic resonance imaging (MRI) without gadolinium, in a cohort of 119 fit hemodialysis patients receiving both parenteral iron and ESA, in keeping with current guidelines. RESULTS: Mild to severe hepatic iron overload was observed in 100 patients (84%; confidence interval, [CI] 76%-90%), of whom 36% (CI, 27%-46%) had severe hepatic iron overload (liver iron concentration >201 µmol/g of dry weight). In the cross-sectional study, infused iron, hepcidin, and C-reactive protein values correlated with hepatic iron stores in both univariate analysis (P<.05, Spearman test) and binary logistic regression (P <.05). In 11 patients who were monitored closely during parenteral iron therapy, the iron dose infused per month correlated strongly with both the overall increase and the monthly increase in liver iron concentration (respectively, rho=0.66, P=.0306 and rho=0.85, P=0.0015, Spearman test). In the 33 patients with iron overload, iron stores fell significantly after iron withdrawal or after a major reduction in the iron dose (first MRI: 220 µmol/g (range: 60-340); last MRI: 50 µmol/g (range: 5-210); P <.0001, Wilcoxon's paired test). CONCLUSIONS: Most hemodialysis patients receiving ESA and intravenous iron supplementation have hepatic iron overload on MRI. These findings call for a revision of guidelines on iron therapy in this setting, especially regarding the amount of iron infused and noninvasive methods for monitoring iron stores.

Spin density projection-assisted R2 magnetic resonance imaging of the liver in the management of body iron stores in patients receiving multiple red blood cell transfusions: an audit and retrospective study in South Australia.

AIM: To assess the impact of non-invasive monitoring of liver iron concentration (LIC) on management of body iron stores in patients receiving multiple blood transfusions. METHOD: A retrospective audit was conducted on clinical data from 40 consecutive subjects with haemolytic anaemias or ineffective haematopoiesis who had been monitored non-invasively for LIC over a period of at least 1 year. LIC was measured with spin density projection-assisted proton transverse relaxation rate-magnetic resonance imaging. RESULTS: Nineteen clinical decisions were explicitly documented in the case notes as being based on LIC results. Decisions comprised initiation of chelation therapy, increasing chelator dose, decreasing chelator dose and change of mode of delivery of deferioxamine from subcutaneous to intravenous. The geometrical mean LIC for the cohort dropped significantly (P= 0.008) from 6.8 mg Fe/g dry tissue at initial measurement to 4.8 mg Fe/g dry tissue at final measurement. The proportion of subjects with LIC in the range associated with greatly increased risk of cardiac disease and death (>15 mg Fe/g dry tissue) dropped significantly (P= 0.01) from 14 of 40 subjects at initial measurement to 5 of 40 subjects at final measurement. No significant changes in the geometrical mean of serum ferritin or the proportion of subjects with serum ferritin above 2500 or 1500 µg/L were observed. CONCLUSIONS: The data are consistent with previous observations that introduction of non-invasive monitoring of LIC can contribute to a decreased body iron burden through improved clinical decision making and improved feedback to patients and hence improved adherence to chelation therapy.

Grape seed extract alleviates high-fat diet-induced obesity and heart dysfunction by preventing cardiac siderosis.

Obesity is a tremendous public health problem, characterized by ectopic accumulation of fat into non-adipose tissues, leading to oxidative stress and chronic inflammation, in which the heart is the most severely affected organ. We used an experimental model of high-fat-diet (HFD)-induced obesity to analyze the link between oxidative stress and heart dysfunction. We also studied the cardioprotective effect of a grape seed and skin extract (GSE). Exposure of rats to HFD during 45 days induced heart hypertrophy, inflammation as assessed by plasma CRP elevation and contractile dysfunction as revealed after ischemia/reperfusion of Langendorff-perfused hearts. HFD also induced cardiac steatosis and lipotoxicity, which are linked to an oxidative stress status, worsened by increased siderosis and resulting in Ca(2+) overload. Importantly, GSE alleviated all the deleterious effects of HFD treatment. These studies suggest that GSE is a safe anti-obesity and cardioprotective agent that should also find potential applications in other inflammatory damaging conditions as stroke.

Deferasirox: oral, once daily iron chelator--an expert opinion.

Iron overload is a serious and potentially fatal condition that results from multiple blood transfusions required over a long period of time to treat certain types of anemias such as, that caused by beta-thalassemia, sickle cell disease and myelodysplastic syndrome. Deferoxamine, which has been used since four decades as an iron chelator has limited efficacy due to its demanding therapeutic regimen, leading to poor compliance. Deferasirox, once daily oral iron chelator provides an effective alternative to Deferoxamine in the treatment of transfusional hemosiderosis. In this review, the role of Deferasirox as an ideal iron chelator has been discussed. Pubmed searches on Deferasirox were carried out for the same. Several studies demonstrated the safety and efficacy of Deferasirox in reducing iron burden in iron-overloaded patients with beta-thalassemia, sickle cell anemia and myelodysplastic anemia. Thus, convenient, effective and tolerable chelation therapy with oral Deferasirox is likely to be a significant development in the treatment of transfusional iron overload, due to its ability to provide constant chelation coverage and the potential to improve compliance.

[Hereditary iron overload]. / Surcharges héréditaires en fer.

The field of hereditary iron overload has known, in the recent period, deep changes mainly related to major advances in molecular biology. It encompasses now a series of genetic entities. The mechanistic understanding of iron overload development and iron toxicity has greatly improved. The diagnostic approach has become essentially noninvasive with a major role for biological tests. From the therapeutic viewpoint, the phlebotomy treatment is now enriched by the possibility of resorting to oral chelation and by innovative perspectives directly linked to our improvement in the molecular understanding of these diseases.

Quantification of myocardial iron overload by cardiovascular magnetic resonance imaging T2* and review of the literature.

Heart failure due to myocardial iron overload remains the leading cause of death in patients with transfusion-dependent anemias. Iron overload-induced cardiomyopathy is reversible if intensive chelation therapy is instituted on time. Thus, early detection of myocardial iron deposition is imperative to prevent overt heart failure. Conventional cardiac monitoring, including physical examination, electrocardiography, echocardiography or serum ferritin levels fail to predict manifest or subclinical myocardial involvement resulting from iron overload. Cardiovascular magnetic resonance imaging T2* (cMRI-T2*, pronounced T2 star) times correlate well with myocardial iron levels. This timely review focuses on the utility of cMRI-T2*, for the preclinical detection of myocardial iron overload and monitoring of myocardial iron content during chelation therapy.

Taurine supplementation reduces oxidative stress and improves cardiovascular function in an iron-overload murine model.

BACKGROUND: Iron overload has an increasing worldwide prevalence and is associated with significant cardiovascular morbidity and mortality. Elevated iron levels in the myocardium lead to impaired systolic and diastolic function and elevated oxidative stress. Taurine accounts for 25% to 50% of the amino acid pool in myocardium, possesses antioxidant properties, and can inhibit L-type Ca2+ channels. Thus, we hypothesized that this agent would reduce the cardiovascular effects of iron overload. METHODS AND RESULTS: Iron-overloaded mice were generated by intraperitoneal injection of iron either chronically (5 days per week for 13 weeks) or subacutely (5 days per week for 4 weeks). Iron overload causes increased mortality, elevated oxidative stress, systolic and diastolic dysfunction, hypotension, and bradycardia. Taurine supplementation increased myocardial taurine levels by 45% and led to reductions in mortality and improved cardiac function, heart rate, and blood pressure in iron-overloaded mice. Histological examination of the myocardium revealed reduced apoptosis and interstitial fibrosis in iron-overloaded mice supplemented with taurine. Taurine mediated reduced oxidative stress in iron-overloaded mice along with attenuation of myocardial lipid peroxidation and protection of reduced glutathione level. CONCLUSIONS: These results demonstrate that treatment with taurine reduces iron-mediated myocardial oxidative stress, preserves cardiovascular function, and improves survival in iron-overloaded mice. The role of taurine in protecting reduced glutathione levels provides an important mechanism by which oxidative stress-induced myocardial damage can be curtailed. Taurine, as a dietary supplement, represents a potential new therapeutic agent to reduce the cardiovascular burden from iron-overload conditions.

Liver iron stores in patients with secondary haemosiderosis under iron chelation therapy with deferoxamine or deferiprone.

Total body iron stores including liver and spleen iron were assessed by non-invasive SQUID biomagnetometry. The liver iron concentration was measured in groups of patients with beta-thalassaemia major or other posttransfusional siderosis under treatment with the oral iron chelator deferiprone (n = 19) and/or with parenteral deferoxamine (n = 33). An interquartile range for liver iron concentrations of 1680-4470 micrograms/g liver was found in these patients. In both groups a poor correlation between liver iron and serum ferritin values was observed. Repeated measurements of liver and spleen iron concentrations as well as determination of liver and spleen volume by sonography were performed in six patients under continuous deferiprone treatment for 3-15 months. In this group detailed information was obtained on the whole body iron store (5-36g) and the iron excretion rates (14-34 mg/d) for each patient. As indicated by decreasing liver iron concentrations, five out of six subjects showed a negative iron balance (2-13 mg/d). Conventional measurements of both serum ferritin and urine iron excretion gave fluctuating results, thus being only of limited use in the control of iron depletion therapy. The non-invasive biomagnetic liver iron quantification is a precise and clinically verified technique which offers more direct information on the long-term efficacy of an iron depletion therapy than the hitherto used methods. This technique may be of use in the clinical evaluation of new oral iron chelators.

Iron overload in thalassemia: comparative analysis of magnetic resonance imaging, serum ferritin and iron content of the liver.

BACKGROUND: Iron overload in patients with thalassemia is a common feature which requires continuous chelation therapy and monitoring. Serum ferritin determination is widely accepted as a simple method for following iron load in patients with primary hemochromatosis; however, several reports on thalassemic patients emphasize that ferritinemia is not accurate and that other methods such as direct measurement of iron in the liver (HIC) and magnetic resonance imaging (MRI) are more precise. MATERIALS AND METHODS: In order to contribute to the general understanding of iron load in thalassemia we used liver MRI to study 33 thalassemic patients, most of whom were also evaluated for iron content by liver biopsy. The data were then compared with serum ferritin levels. RESULTS: Ferritin levels ranged between 276 and 8031 ng/mL, and liver iron content ranged from 1.6 to 31.0 mg/g dry weight; grade III or IV liver siderosis was recorded in 23/33 patients, just as 23/33 patients were found to have severe or very severe siderosis at MRI. Significant correlations with ferritin levels were recorded between grade IV and grades III, II and I (p < 0.01, p = 0.02, and p = 0.03, respectively). Ferritinemia also showed significant linearity with liver iron content (r = 0.603, p = 0.001). No significant differences of levels were recorded, however, between patients found to have severe and those with mild iron load at MRI (p = 0.073). CONCLUSIONS: Our study shows that serum ferritin levels exhibit a tendency to be significantly correlated with the true status of hemochromatosis in thalassemic patients; however, the discrepancies recorded in several patients and the scarce or total lack of correlation with MRI suggest exploring other approaches to this problem in order to make proper decisions about therapy.

A mutation in the ceruloplasmin gene is associated with systemic hemosiderosis in humans.

We identified a mutation in the ceruloplasmin (Cp) gene in a Japanese family with aceruloplasminemia, some of whose members showed extrapyramidal disorders, cerebellar ataxia, and diabetes mellitus. A post-mortem study of the proband revealed excessive iron deposition mainly in the brain, liver and pancreas. The G to A transition at the splice acceptor site introduces a premature termination codon at the amino acid position 991 by defective splicing, thereby truncating the carboxyl terminus of Cp in affected individuals. We conclude that the mutation in the Cp gene is associated with systemic hemosiderosis in humans.

Transfusional hemosiderosis in sickle cell anemia: another cause of an echogenic pancreas.

We report four sickle cell anemia patients who have received multiple blood transfusions and have been non-compliant on Desferal chelation therapy. Abdominal ultrasonography demonstrated an echogenic pancreas in all four patients. Magnetic resonance imaging in three patients revealed decreased signal intensity in all sequences in the pancreas and liver. All four patients had marked iron deposition on liver biopsy. To our knowledge, increased echogenicity of the pancreas secondary to hemosiderosis (2 degrees hemochromatosis) in sickle cell patients has not been reported in the radiologic literature.

Pharmacokinetics of aluminoxamine and ferrioxamine and dose finding of desferrioxamine in haemodialysis patients.

We investigated the pharmacokinetics of desferrioxamine and its chelated compounds aluminoxamine and ferrioxamine in normal volunteers and haemodialysis patients with and without iron overload. Desferrioxamine was administered in a single dose of 30 mg per kg body-weight was a 30-min infusion to five healthy volunteers and to 20 haemodialysis patients (five patients without haemosiderosis and 15 patients with haemosiderosis). The interdialytic half-life of ferrioxamine was 2.2 h in normal volunteers, 13.3 h in dialysis patients without haemosiderosis, and 24.6 h in patients with haemosiderosis. There was no interdialytic elimination of aluminoxamine. In a second study, seven dialysis patients received 5, 10, and 20 mg per kg body-weight desferrioxamine in a random order with a time interval of 2 weeks. The peak serum concentrations after these doses were 4.1 +/- 2.9, 6.4 +/- 2.9, and 10.7 +/- 7.1 mumol/l for ferrioxamine and 2.8 +/- 1.5, 3.1 +/- 1.5, and 4.2 +/- 1.7 mumol/l for aluminoxamine. Thus, a 4-fold increase in desferrioxamine dosage resulted in a 2.7-fold increase in peak ferrioxamine levels and in only a 1.5-fold increase in peak aluminoxamine levels. We conclude that dialysis patients, especially those with haemosiderosis, are exposed to persistently elevated ferrioxamine levels. Weekly doses of 5-10 mg/kg of desferrioxamine would be sufficient for aluminium chelation therapy.

Methods for evaluating iron stores and efficacy of chelation in transfusional hemosiderosis.

An accurate determination of the total amount and distribution of body iron stores is essential for prognostic purposes and to evaluate the efficacy of chelation therapy. In the clinical setting, a rough estimate of the total body iron burden may be obtained in patients with transfusion-dependent anemias by calculating the amount of blood administered plus the amount absorbed by the gastrointestinal route, which is influenced by the level of Hb and by bone marrow activity. An increase in serum iron and a decrease in total iron binding capacity are early indicators of iron overload, but their sensitivity and specificity are not very high. In normal individuals, serum ferritin correlates well with iron stores, as measured by phlebotomy, and with directly measured liver iron. However, plasma ferritin, being an acute phase reactant, is increased in cases of chronic disease, disseminated malignancy, or inflammatory disorders. Non-transferrin bound iron, i.e. iron that circulates in plasma unbound to transferrin, is potentially toxic since it is capable of taking part in free radical-mediated reactions that result in irreversible tissue damage. This iron can be measured with a HPLC based assay. At present the most accurate way of estimating the iron burden is by direct measurement of iron concentration in tissues. The liver is the most accessible. The measurement is done by atomic absorption spectrometry on ashed or lyophilized samples obtained by needle biopsy, and correlates well with the total amount of blood transfused and with the extent of hepatic fibrosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Chronic dietary iron overload in rats results in impaired calcium sequestration by hepatic mitochondria and microsomes [corrected].

The purpose of these experiments was to determine whether chronic dietary iron overload causes impairment of hepatic mitochondrial and/or microsomal calcium sequestration. Experimental iron overload was produced by feeding three groups of rats a chow diet supplemented with 3.0% (wt/wt) carbonyl iron for up to 8 weeks achieving graded increases in hepatic iron concentrations ranging from 1360 to 3170 micrograms/g. At low levels of iron overload, there were no changes in mitochondrial oxidative metabolism or calcium sequestration, whereas at moderate and high degrees of iron loading, both of these parameters were significantly reduced. In contrast, there were significant decreases in microsomal cytochrome P450 levels and microsomal calcium sequestration at all three levels of iron loading. These abnormalities occurred at hepatic iron concentrations at which the authors have previously found evidence of hepatic organelle lipid peroxidation. These alterations in organelle calcium sequestration may impair intracellular calcium homeostasis in the liver and contribute to subsequent cellular injury.

Hepatic computed tomography for monitoring the iron status of haemodialysis patients with haemosiderosis treated with recombinant human erythropoietin.

1. A randomized, partial-crossover study was conducted in uraemic patients with dialysis-associated anaemia and transfusional iron overload to evaluate the effects of desferrioxamine chelation therapy and of recombinant human erythropoietin treatment on hepatic iron storage determined by computed tomography, as well as by serum ferritin concentration and transferrin saturation. 2. Twenty-one haemodialysis patients with moderate iron overload, confirmed by values of serum ferritin concentration, transferrin saturation and hepatic computed tomography density exceeding 1000 micrograms/l, 45% and 68 Hounsfield units respectively, were randomly allocated to three groups and were followed for 12 months. 3. During the first 6 months group 1 (n = 7) received desferrioxamine chelation therapy (30 mg/kg intravenously three times a week) and group 2 (n = 7) underwent recombinant human erythropoietin treatment (36 units/kg intravenously three times a week). Thereafter, in the second 6 months of observation patients in group 1 were switched to receive recombinant human erythropoietin. Because of a poor response in the desferrioxamine-treated group in the initial 6 months, patients in group 2 continued on the maintenance dose of recombinant human erythropoietin (18 units/kg three times a week) until the end of the trial. Patients in group 3 (n = 7) were maintained on placebo throughout the study. 4. In comparison with placebo, recombinant human erythropoietin treatment, but not desferrioxamine chelation therapy, reduced serum ferritin concentration, transferrin saturation and hepatic computed tomography density, and was associated with a rise in haemoglobin and packed cell volume. Hepatic computed tomography density, serum ferritin concentration and transferrin saturation decreased in 13 out of 14 patients (93%) during treatment with recombinant human erythropoietin.(ABSTRACT TRUNCATED AT 250 WORDS)