The Effect of Supplemental Ascorbate on Defersirox Iron Chelation In the Iron-Loaded Gerbil

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2059-2059
Author(s):  
Maya Otto-Duessel ◽  
Casey Brewer ◽  
Aleya Hyderi ◽  
Jens Lykkesfeldt ◽  
Ignacio Gonzalez-Gomez ◽  
...  
Keyword(s):  
Iron Overload ◽  
Iron Content ◽  
Iron Concentration ◽  
Iron Chelation ◽  
Iron Dextran ◽  
Iron Loading ◽  
Liver Iron ◽  
Cardiac Iron ◽  
Liver Iron Content ◽  
Wet Weight

Abstract Abstract 2059 Introduction: Iron dextran injections are often used to induce iron overload in rodents, for the purposes of assessing iron chelation therapy. In gerbils, we have previously described that deferasirox therapy preferentially clears hepatocellular iron when compared with reticuloendothelial stores. Ascorbate deficiency, which is common in humans with iron overload, produces similar profound disparities between reticuloendothelial and parenchymal iron stores. We postulated that iron-induced ascorbate deficiency might be exaggerating reticuloendothelial iron retention in gerbils receiving deferasirox therapy. This study examined the effect of supplemental ascorbate on spontaneous iron loss and deferasirox chelation efficiency in the iron-dextran loaded gerbil. Methods: 48 female gerbils underwent iron dextran loading at 200 mg/kg/week for 10 weeks. Sixteen animals were sacrificed at 11 weeks to characterize iron loading; eight were on standard rodent chow and eight had chow supplemented with 2250 ppm of ascorbate. 32 additional animals that were not ascorbate supplemented during iron loading transitioned into the chelation phase. Half were subsequently placed on ascorbate supplemented chow and both groups were assigned to receive either deferasirox 100 mg/kg/day five days per week or sham chelation. Animals received iron chelation for twelve weeks. Liver histology was assessed using H & E and Prussian blue stains. Iron loading was ranked and graded on a five-point scale by an experienced pathologist screened to the treatment arm. Iron quantitation in liver and heart was performed by atomic absorption. Results: Table 1 one summarizes the findings. During iron dextran loading, ascorbate supplementation lowered wet weight liver iron concentration but not liver iron content suggesting primarily changes in tissue water content. Spontaneous iron losses were insignificant, regardless of ascorbate therapy. Deferasirox lowered liver iron content 56% (4.7% per week) in animals without ascorbate supplementation and 48.3% (4.0% per week) with ascorbate supplementation (p=NS). Cardiac iron loading, unloading and redistribution were completely unaffected by ascorbate supplementation. Spontaneous iron redistribution was large (1.9% – 2.3% per week). Deferasirox chelation did not lower cardiac iron to a greater degree than spontaneous cardiac iron redistribution. Histologic grading paralleled tissue wet weight iron concentrations. Ascorbate treatment lowered the rank and absolute iron score in liver during iron loading (p=0.003) and there was a trend toward lower iron scoring in sham treated animals (p=0.13). Ascorbate had no effect on histological score or relative compartment distributions of iron in deferasirox chelated animals (p=0.5). Ascorbate supplementation was sufficient to increase total plasma ascorbate levels from 25 ± 12.2 uM to 38.4 ± 11 uM at 10 weeks (p=0.03). In the liver, ascorbate increased from 1203 ± 212 nmol/g of tissue to 1515 ± 194 nmol/g of tissue (p=0.01) with supplementation. No significant change in total ascorbate was observed in the heart. Discussion: We hypothesized that ascorbate supplementation might improve reticuloendothelial iron accessibility to deferasirox by facilitating redox cycling. Although gerbils synthesize their own ascorbate, supplementation was able to raise both serum and hepatic total ascorbate levels. However, increasing ascorbate did not change either the amount or distribution of tissue iron in deferasirox-treated animals. Disclosures: Nick: Novartis: Employment. Wood:Novartis: Research Funding; Ferrokin Biosciences: Consultancy.

ICL670 Removes Cardiac Iron in a Gerbil Model of Iron Overload.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2695-2695 ◽  
Author(s):  
John C. Wood ◽  
Maya Otto-Duessel ◽  
Ignacio Gonzales ◽  
Michelle Aguilar ◽  
Hanspeter Nick ◽  
...  
Keyword(s):  
Iron Content ◽  
Chelation Therapy ◽  
Iron Concentration ◽  
Iron Loading ◽  
Liver Iron Concentration ◽  
Liver Iron ◽  
Myocyte Hypertrophy ◽  
Cardiac Iron ◽  
Liver Iron Content ◽  
Wet Weight

Abstract Introduction: Deferasirox (ICL670) is a novel tridentate oral iron chelator currently being evaluated for the treatment of transfusional iron overload. Phase III clinical trials have demonstrated that once-daily ICL670 (20 mg/kg) is equally effective at controlling liver iron concentration as standard deferoxamine therapy (40 mg/kg/day, 5 days per week). While ICL670’s long serum half-life should offer good protection against cardiac iron accumulation, little is known regarding its ability to remove stored cardiac iron. Therefore, we compared the relative efficacy of ICL670, deferiprone (L1), and deferoxamine (DFO) in removing cardiac iron from iron-loaded gerbils. Methods: 37 8–10 week old female gerbils underwent ten weekly iron dextran injections of 200 mg/kg/D, followed by a 13 day equilibration period. Five animals were then sacrificed to determine pre-chelation iron burdens. Chelation was initiated in 3 groups of 8 animals (ICL670 100 mg/kg/D po QD, L1 375 mg/kg/D po divided TID, DFO 200 mg/kg/D sub Q divided BID) five days per week and maintained for 12 weeks. The remaining 8 animals received sham chelation. All animals underwent ECG and treadmill assessment at baseline, following iron loading, and after completing chelation therapy. Animals were sacrificed for liver and heart iron measurement (Mayo Medical Laboratory) and semiquantitative histology. Hearts were evaluated for iron loading/distribution, tissue fibrosis, and myocyte hypertrophy, while livers were scored for iron loading/distribution and fibrosis. Results: Chelator-independent iron excretion and redistribution was evident, unlike in humans. Cardiac and liver iron contents fell 30.4% and 23.2%, respectively, with sham chelation; all subsequent chelator comparisons are reported with respect to the sham-chelated animals. ICL670 reduced cardiac iron content 20.5%. There were no changes in cardiac weight, myocyte hypertrophy, fibrosis, or wet-to-dry weight ratio. ICL670 treatment reduced liver iron content 51%. Iron elimination was greatest in hepatocytes with no detectable Kupfer-cell iron clearance. L1 produced comparable reductions in cardiac iron content (18.6%). Wet weight cardiac iron concentration fell nearly 30% but this was offset by greater cardiac mass (16.5% increase). Histologic analysis demonstrated decreased iron staining but increased myocyte hypertrophy. L1 decreased liver iron content 24.9%. Wet weight liver iron concentration fell 43.8% but was offset by a 30% increase in liver weight and water content. Iron elimination was balanced between Kupfer cells and hepatocytes. DFO did not reduce biochemically-assayed cardiac or liver iron content, although it improved histologic iron scores in both organs. Hearts from DFO treated animals were enlarged and had greater fibrosis. Cardiac and liver iron contents were closely correlated (r = 0.66), but ICL670 animals had lower hepatic iron contents for any given cardiac iron content. Iron loading broadened QRS duration by 10.6%; this effect was antagonized by both L1 and ICL670 therapy. PR, QRS, and QTc interval were weakly correlated with cardiac and liver iron contents. Treadmill exercise time was independent of chelation therapy. Conclusion: ICL670 and L1 were equally effective in removing stored cardiac iron in a gerbil animal model but ICL670 removed more hepatic iron for a given cardiac iron burden.

Magnetic Ressonance Imaging (MRI) in the Evaluation of Iron Overload in Patients with Beta Thalassaemia. The Brazilian National Program Preliminary Results.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3825-3825
Author(s):  
Nelson Hamerschlak ◽  
Laercio Rosemberg ◽  
Alexandre Parma ◽  
Fernanda F. Assir ◽  
Frederico R. Moreira ◽  
...  
Keyword(s):  
Iron Overload ◽  
Ventricular Function ◽  
Iron Content ◽  
Chelation Therapy ◽  
Iron Concentration ◽  
Iron Chelation ◽  
Inverse Correlation ◽  
Liver Iron ◽  
Liver Iron Content ◽  
Cooperative Program

Abstract Magnetic Ressonance Imaging (MRI) using T2 star (T2*) tecnique appears to be a very useful method for monitoring iron overload and iron chelation therapy in thalassaemia. In Brazil, we have around 400 thalassaemic major patients all over the country. They were treated with hipertransfusion protocols and desferroxamine and/or deferiprone chelation. We developed a cooperative program with the Brazilian Thalassaemic Patients Association (ABRASTA) in order to developT2* tecnique in Brazil to submit brazilian patients to an annual iron overload monitoring process with MRI.. We performed the magnetic ressonance T2* using GE equipment (GE, Milwaukee USA), with validation to chemical estimation of iron in patients undergoing liver biopsy. Until now, 60 patients were scanned, median age=23,2 (12–54); gender: 18 male (30%) and 42 female (70%). The median ferritin levels were 2030 ng/ml (Q1=1466; Q3=3296). As other authors described before, there was a curvilinear inverse correlation between iron concentration by biopsy, liver T2*(r=0,92) and also there were a correlation with ferritin levels. We also correlated myocardial iron measured by T2* with ventricular function.. As miocardial iron increased, there was a progressive decline in ejection fraction and no significant correlation was found between miocardial T2* and the ferritin levels. Liver iron content can be predicted by ferritin levels. On the other hand, cardiac disfunction is the most important cause of mortality among thalassaemic patients. Since Miocardio iron content cannot be predicted from serum ferritin or liver iron, and ventricular function can only detect those with advance disease, intensification and combination of chelation therapy, guided by T2* MRI tecnique should reduce mortality from the reversible cardiomyopathy among thalassaemic patients.

Serum Ferritin Predicts Liver but Not Cardiac Iron Burden by Noninvasive MRI in Sickle Cell Disease (SCD.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1421-1421 ◽  
Author(s):  
Robert I. Liem ◽  
Cynthia Rigsby ◽  
Richard J. Labotka ◽  
Andrew DeFreitas ◽  
Alexis A. Thompson
Keyword(s):  
Iron Overload ◽  
Serum Ferritin ◽  
Iron Content ◽  
Iron Loading ◽  
Cell Disease ◽  
Liver Iron ◽  
Cardiac Iron ◽  
Liver Iron Content ◽  
The Mean

Abstract BACKGROUND: Assumptions about iron loading as well as the utility of ferritin to predict transfusional iron overload among individuals with sickle cell disease (SCD) are largely based on extrapolation from data generated in patients with thalassemia major (TM). Yet recent studies suggest the natural history of iron overload in patients with SCD differs significantly from chronically transfused patients with TM. We sought to evaluate the extent of myocardial and hepatic siderosis using noninvasive imaging in chronically transfused patients with SCD and examine its clinical associations, including relationship to long-term trends in serum ferritin, transfusion history, chelation status and markers of hemolysis and inflammation. METHODS: We evaluated 17 subjects (mean age 15±3.6 yrs, range 9 to 20). The mean transfusion duration was 7.3±3.6 yrs (range 2 to 15). Thirteen (76%) patients were on chelation with deferasirox at the time of screening; 4 were not on chelation Rx. MRI T2*/R2* of the heart and liver using a multiple gradient echo sequence was performed on a single 1.5T GE scanner. Hepatic iron concentration (HIC) values were predicted from liver R2* values. RESULTS: Mean HIC in subjects was 9.9±6.7 mg/gm liver dry weight (range 2.5 to 20.8) and was ≥15 mg/gm in 6/17 (35%) subjects. The mean long-term serum ferritin (past 5 yrs, or duration of transfusion if < 5yrs) was 2318±1122 ng/mL (range 541 to 4225). Using Pearson’s correlation coefficient, we observed a significant relationship between HIC and ferritin (r=0.765, p=<0.001). We generated a receiver operator characteristic (ROC) curve to assess the utility of ferritin as a predictor of elevated HIC, using a threshold HIC thought to predict serious iron-related complications. A ferritin cut-off value ≥2164 ng/mL correctly identified 80% of cases of HIC ≥15 mg/gm (AUC 0.96, p=0.003) in our subjects with 83% sensitivity and 73% specificity. Despite markedly elevated HIC and ferritin values in some subjects, none had myocardial siderosis. All 17 subjects had cardiac MRI T2* values in the normal range > 25 ms. Cardiac iron load measured by T2* did not correlate with HIC or serum ferritin. We examined C-reactive protein (CRP) and B-type natriuretic peptide (BNP) as markers for inflammation and myocardial strain, respectively, in our subjects but neither demonstrated a significant relationship to ferritin or MRI findings. BNP, however, did correlate modestly with both age (r=−0.574, p=0.013) and left ventricular ejection fraction on cardiac MRI (r=0.510, p=0.036). A subset of subjects (n=8) had histologic iron measurements by percutaneous liver biopsy (LBx) within 6 months of MRI. While liver iron content by LBx correlated significantly with HIC by MRI (r=0.759, p=0.03), liver iron content by LBx did not correlate with ferritin (r=0.312, p=0.452). CONCLUSION: We found that serum ferritin is a good predictor of liver iron by MRI R2*, and that long term ferritin values ≥2164 ng/mL predict significant hepatic iron overload as assessed by this noninvasive method. We did not observe appreciable cardiac iron loading in our subjects with SCD, which otherwise might have been predicted by elevated HIC alone, as in individuals with TM. These data suggest that reliable, long term surveillance of transfusion-induced iron overload in SCD may be achieved using serum ferritin and HIC by MRI R2* as surrogate markers of hepatic siderosis rather than relying on liver iron content measured invasively by LBx. Also, previously determined thresholds for significant cardiac iron loading in TM, based on degree of hepatic siderosis, may not be applicable in SCD. Further investigation into alternative mechanisms of iron loading or distribution in these related but distinct disorders is warranted.

Antioxidant Mediated Effects in a Gerbil Model of Iron Overload.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3813-3813
Author(s):  
Maya Otto-Duessel ◽  
Michelle I. Aguilar ◽  
Rex Moats ◽  
John C. Wood
Keyword(s):  
Vitamin E ◽  
Iron Uptake ◽  
Serum Iron ◽  
Iron Concentration ◽  
Iron Loading ◽  
Taurine Supplementation ◽  
Liver Iron ◽  
Cardiac Iron ◽  
Liver Iron Content ◽  
Gpx Activity

Abstract Introduction: Iron cardiomyopathy is a lethal complication of monthly blood transfusion therapy in patients with thalassemia major. Medications or nutritional supplements that could potentially reduce cardiac iron uptake or toxicity would have clinical significance. The amino acid taurine is ubiquitous in both rodent and human myocytes, but its physiologic role is poorly understood. In mice, taurine supplementation decreases cardiac iron and oxidative toxicity. Since taurine could produce these effects through a direct antioxidant action or through modulation of iron uptake via calcium channels, we compared taurine’s benefits with a combination of vitamin E and selenium in the gerbil model of iron cardiomyopathy. We hypothesized that taurine supplementation would decrease cardiac iron levels and iron toxicity in a parallel manner while vitamin/selenium would only decrease cardiac iron toxicity. Methods: Twenty-four animals were divided into four groups (control, iron, taurine, vitamin E + selenium). Supplementation was initiated 2 weeks prior to the iron loading period and continued throughout the 10 weeks of iron injection (200mg/kg/week). Taurine (12.5 g/L) and selenium (1.67g/L) were administered via drinking water, while vitamin E (400mg/gerbil/day) was injected subcutaneously daily. Post mortem assessment of heart and liver iron content, malondialdehyde (MDA) levels, glutathione peroxidase (GPx) activity, aspartate aminotransferase (AST) levels, alanine transaminase (ALT) levels, histology, serum, and enzyme analyses were performed. Results: No significant differences were found in heart and liver iron content between treatment groups, although dry-weight liver iron concentrations was increased in taurine-treated animals (p<0.03). Serum iron increased with iron loading (751 ± 66 ug/dL versus 251 ± 54 ug/dL, p < 0.001) and was further increased by taurine treatment (903 ± 136 ug/dL, p = 0.03). Iron overload increased cardiac malondialdehyde (MDA) levels and decreased heart and liver gluthathione peroxidase (GPx) activity, and increased serum AST consistent with oxidative stress. Taurine ameliorated these changes but results were significant only for liver GPx activity. Despite raising organ selenium levels, selenium and vitamin E supplementation did not improve oxidative markers (MDA, GPx) and actually worsened cardiac GPx levels. Discussion: Prior murine work suggested selective cardioprotective effects of taurine mediated, in part, through decreased cardiac iron levels. In the gerbil model, taurine improved hepatic GPx, despite increasing liver iron concentration and serum iron. Qualitatively similar behavior was observed in the heart, but values did not reach statistical significance. Therefore, taurine exhibits antioxidant behavior that is not mediated by decreasing organ iron concentration; oxidative protection was superior to the effects produced by selenium/vitamin E supplementation. The etiology of the increased liver and serum iron concentrations is unclear but probably reflects interference with spontaneous iron losses. While taurine supplementation appears promising, future studies are needed to clarify interspecies variability in its behavior.

Comparing the Value of Serum Ferritin, Transfusion History and Magnetic Resonance Imaging for the Prediction of Iron Overload In MDS and AML Patients Undergoing Allogeneic Stem Cell Transplantation.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3493-3493
Author(s):  
Martin Wermke ◽  
Jan Moritz Middeke ◽  
Nona Shayegi ◽  
Verena Plodeck ◽  
Michael Laniado ◽  
...  
Keyword(s):  
Iron Overload ◽  
Serum Ferritin ◽  
Iron Content ◽  
Iron Concentration ◽  
Transferrin Saturation ◽  
Resonance Imaging ◽  
Liver Iron Concentration ◽  
Liver Iron ◽  
Liver Iron Content ◽  
Transfusion History

Abstract Abstract 3493 An increased risk for GvHD, infections and liver toxicity after transplant has been attributed to iron overload (defined by serum ferritin) of MDS and AML patients prior to allogeneic hematopoietic stem cell transplantation (allo-HSCT). Nevertheless, the reason for this observation is not very well defined. Consequently, there is a debate whether to use iron chelators in these patients prior to allo-HSCT. In fact, serum ferritin levels and transfusion history are commonly used to guide iron depletion strategies. Both parameters may inadequately reflect body iron stores in MDS and AML patients prior to allo-HSCT. Recently, quantitative magnetic resonance imaging (MRI) was introduced as a tool for direct measurement of liver iron. We therefore aimed at evaluating the accurateness of different strategies for determining iron overload in MDS and AML patients prior to allo-HSCT. Serologic parameters of iron overload (ferritin, iron, transferrin, transferrin saturation, soluble transferrin receptor) and transfusion history were obtained prospectively in MDS or AML patients prior to allo-SCT. In parallel, liver iron content was measured by MRI according to the method described by Gandon (Lancet 2004) and Rose (Eur J Haematol 2006), respectively. A total of 20 AML and 9 MDS patients (median age 59 years, range: 23–74 years) undergoing allo-HSCT have been evaluated so far. The median ferritin concentration was 2237 μg/l (range 572–6594 μg/l) and patients had received a median of 20 transfusions (range 6–127) before transplantation. Serum ferritin was not significantly correlated with transfusion burden (t = 0.207, p = 0.119) but as expected with the concentration of C-reactive protein (t = 0.385, p = 0.003). Median liver iron concentration measured by MRI was 150 μmol/g (range 40–300 μmol/g, normal: < 36 μmol/g). A weak but significant correlation was found between liver iron concentration and ferritin (t = 0.354; p = 0.008). The strength of the correlation was diminished by the influence of 5 outliers with high ferritin concentrations but rather low liver iron content (Figure 1). The same applied to transfusion history which was also only weakly associated with liver iron content (t = 0.365; p = 0.007). Levels of transferrin, transferrin saturation, total iron and soluble transferrin receptor did not predict for liver iron concentration. Our data suggest that serum ferritin or transfusion history cannot be regarded as robust surrogates for the actual iron overload in MDS or AML patients. Therefore we advocate caution when using one of these parameters as the only trigger for chelation therapy or as a risk-factor to predict outcome after allo-HSCT. Figure 1. Correlation of Liver iron content with Ferritin. Figure 1. Correlation of Liver iron content with Ferritin. Disclosures: No relevant conflicts of interest to declare.

Combination of Tmprss6-ASO and the Iron Chelator Deferiprone Improves Erythropoiesis and Reduces Iron Overload in a Mouse Model of Beta-Thalassemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4024-4024
Author(s):  
Carla Casu ◽  
Mariam Aghajan ◽  
Rea Oikonomidau ◽  
Shuling Guo ◽  
Brett P. Monia ◽  
...  
Keyword(s):  
Iron Content ◽  
Research Funding ◽  
Serum Iron ◽  
Iron Absorption ◽  
Iron Concentration ◽  
Iron Chelation ◽  
Iron Chelator ◽  
Liver Iron ◽  
Hepcidin Expression ◽  
Liver Iron Content

Abstract Patients affected by non-transfusion dependent thalassemia (NTDT) do not require chronic blood transfusion for survival. However, transfusion-independence in such patients is not without side effects. Ineffective erythropoiesis (IE), the hallmark of disease, leads to a variety of serious clinical morbidities. In NTDT the master regulator of iron homeostasis, hepcidin, is chronically repressed. Consequently, patients absorb abnormally high levels of iron, which eventually requires iron chelation to prevent the clinical sequelaes associated with iron overload. It has been shown that in mice affected by NTDT (Hbbth3/+), a second-generation antisense oligonucleotide (Tmprss6-ASO) can reduce expression of transmembrane serine protease Tmprss6, the major suppressor of hepcidin expression. This leads to reduction of hemichrome formation in erythroid cells, amelioration of IE and splenomegaly, and increased hemoglobin levels (Guo et al, JCI, 2013). Now we propose the use of Tmprss6-ASO in combination with iron chelators for the treatment of NTDT using Hbbth3/+ mice as a preclinical model. Our hypothesis is that use of chelators will benefit from the positive effect of Tmprss6-ASO on erythropoiesis and iron absorption, further ameliorating organ iron content. To this end, Hbbth3/+ animals were treated with Tmprss6-ASO at 100 mg/kg/week for 6 weeks with or without the iron chelator deferiprone (DFP) at a dose of 1.25 mg/ml. Additional animals were treated with DFP alone. We fed the animals with a commercial or physiological diet, containing 200 or 35 ppm of iron, respectively. We did not observe major differences in the treated animals fed the commercial or physiological iron diet and, for this reason, the data were combined for simplicity. Administration of DFP alone was successful in decreasing organ iron content. Compared to untreated Hbbth3/+ animals, we observed a reduction of 30% and 33% in the liver and spleen, respectively, and no change in the kidney. However, erythropoiesis was not improved (looking at IE, splenomegaly, RBC production and total Hb levels). This was associated with increased serum iron levels (+25%). In Tmprss6-ASO treated Hbbth3/+ animals, we observed an improvement in liver iron content (36% reduction), amelioration of IE, and increased RBC and Hb synthesis (~2 g/dL). Compared to treatment with Tmprss6-ASO alone, combination of DFP with Tmprss6-ASO achieved the same level of suppression of Tmprss6 in the liver (~90%) and reduction of serum iron parameters. This was associated with improvement of IE, decreased reticulocyte counts and splenomegaly, and increased RBC and Hb synthesis (~2 g/dL). While we observed that both Tmprss6-ASO and DFP separately reduced liver iron content to the same extent (~30-36%), combination treatment further reduced iron concentrations in the liver and kidney (69% and 19%, respectively), with no changes in the spleen. Additional analyses are in progress to evaluate the amount of hepcidin in serum as well as expression of erythroferrone, the erythroid regulator of hepcidin. Our first conclusion is that administration of an iron chelator alone is not sufficient to improve erythropoiesis despite that organ iron content is reduced. We speculate that when iron is removed from the liver, hepcidin expression becomes more susceptible to the suppressive effect of IE rather than the enhancing effect of reduced liver organ iron concentration. In addition, the combined effect of iron mobilized from organs and unchanged (or even augmented) iron absorption leads to increased serum iron concentration. As we have shown previously, amelioration of IE in this model requires decreased erythroid iron intake and hemichrome formation. Therefore, iron chelation alone is likely insufficient to improve erythropoiesis. Additional experiments are in progress to further elucidate this mechanism. Our second conclusion is that use of Tmprss6-ASO together with DFP combines the best effects of these two drugs, in particular on erythropoiesis and organ iron content. In animals that received the combined treatment, kidney and liver iron concentrations were further decreased compared to the single treatments. This indicates that Tmprss6-ASO might be extremely helpful in the treatment of NTDT and it could further improve iron related-chelation therapies. Disclosures Casu: Merganser Biotech LLC: Employment; Isis Pharmaceuticals, Inc.: Employment. Aghajan:Isis Pharmaceuticals, Inc.: Employment. Guo:Isis Pharmaceuticals, Inc.: Employment. Monia:Isis Pharmaceuticals, Inc.: Employment. Rivella:bayer: Consultancy, Research Funding; isis Pharmaceuticals, Inc.: Consultancy, Research Funding; merganser Biotech LLC: Consultancy, Research Funding, Stock options , Stock options Other.

Dose Response of Deferoxamine, Deferiprone, and ICL670 Chelation Therapy in a Gerbil Model of Iron Overload.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3621-3621 ◽  
Author(s):  
John C. Wood ◽  
Maya Otto-Duessel ◽  
Michelle Aguilar ◽  
Hanspeter Nick ◽  
Thomas D. Coates ◽  
...  
Keyword(s):  
Dose Response ◽  
Iron Content ◽  
Chelation Therapy ◽  
Iron Chelation ◽  
Iron Loss ◽  
Iron Dextran ◽  
Liver Iron ◽  
Cardiac Iron ◽  
Iron Excretion ◽  
Iron Concentrations

Abstract Introduction: The Mongolian gerbil mimics many of the cardiac functional impairments observed in iron cardiomyopathy, however relatively few chelation studies have been performed in this model. The purpose of this study was to characterize the dose-response of deferoxamine, ICL670, and deferiprone (L1) with respect to liver and cardiac iron chelation in the gerbil Methods: Thirty three adult Mongolian gerbils underwent subcutaneous iron dextran loading with 1500 mg/kg iron dextran divided into three, weekly doses. Chelation began at 4 weeks and continued for 4 weeks. Animals were divided into 9 treatment groups of three animals each(DFO 50, 100, and 200 mg/kg/day (subQ BID), ICL670 25, 50, and 100 mg/kg/day(PO QD), and L1 125, 250, and 500 mg/kg/day(PO TID), 5 days per week). Three control animals were sacrificed at 4 weeks and 8 weeks to estimate sponatenous iron loss. Histology and quantitative iron were performed in all animals. Results: Iron loading yielded liver iron concentrations of 26.6±3.8 mg/g(dry wt) and cardiac iron concentrations of 3.7±0.5 mg/g(dry wt) at 4 weeks (normal < .5 mg/g for both organs). However, organ iron content fell 6.4% in liver and 8.9% in heart per week in animals without chelation therapy, reflecting high spontaneous iron excretion. All three chelators exhibited significant dose-responsiveness for liver iron elimination. However, only ICL670 chelation at 100 mg/kg reduced liver iron content greater than for controls. In fact, animals treated with low dose L1 and DFO had higher iron levels than controls, probably by interfering with spontaneous iron elimination. None of the agents chelated the heart effectively. In fact, 88% of the L1 group, 56% of the ICL670 group and 22% of the DFO group had cardiac iron levels outside the normal range predicted from the 8 wk control animals. Conclusion: Iron chelation in the gerbil model requires doses nearly 3.6 fold greater than in humans to produce discernable iron loss above background iron excretion in short-term studies. Subtherapeutic dosing may actually increase iron levels relative to control animals by decreasing spontaneous iron excretion. Groupwise Iron Concentration and Content HIC(mg/g dry) HIC(mg/g wet) Organ FE(mg) CIC(mg/g dry) CIC(mg/g wet) Organ FE(mg) Control(4wk) 26.6±3.8 7.0±1.4 27.5±2.6 3.74±0.5 0.74±0.1 0.32±0.05 Control(8wk) 23.1±1.1 5.9±0.5 20.5±2.2 2.64±0.19 0.52±0.03 0.20±0.01 DFO 50mg/kg 31.0±3.0 8.2±1.5 28.9±3.4 2.73±0.32 0.56±0.03 0.20±0.02 DFO100mg/kg 25.3±3.3 6.8±1.2 25.0±4.9 3.20±0.46 0.90±0.46 0.33±0.18 DFO200mg/kg 23.5±1.4 5.9±0.4 17.6±2.4 2.77±0.20 0.53±0.07 0.18±0.03 L1 125mg/kg 32.2±1.3 7.7±1.1 23.8±3.4 3.63±0.25 0.79±0.02 0.23±0.02 L1 250mg/kg 29.3±7.4 8.5±2.7 26.7±6.2 3.56±0.85 0.71±0.12 0.21±0.04 L1 500mg/kg 18.5±0.9 5.0±0.6 19.4±1.8 2.68±0.43 0.57±0.08 0.20±0.04 ICL 25mg/kg 24.3±6.3 6.2±1.3 21.5±5.6 3.47±0.09 0.74±0.02 0.25±.02 ICL 50mg/kg 27.6±1.7 6.7±1.1 19.7±4.3 3.22±0.05 0.64±0.14 0.23±0.04 ICL100mg/kg 18.5±3.7 4.1±1.1 13.8±1.8 2.96±0.38 0.59±0.09 0.23±0.04

Liver and Cardiac Iron Measurements in Very Young Chronically Transfused Patients Show Dangerous Levels of Iron Loading

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1086-1086
Author(s):  
Vasilios Berdoukas ◽  
Mammen Puliyel ◽  
Adam Bush ◽  
Thomas Hofstra ◽  
Bhakti P. Mehta ◽  
...  
Keyword(s):  
Iron Overload ◽  
Research Funding ◽  
Iron Status ◽  
Iron Concentration ◽  
Thalassemia Major ◽  
Iron Loading ◽  
Liver Iron ◽  
Body Iron ◽  
Cardiac Iron ◽  
Total Body

Abstract Abstract 1086 Recurrent blood transfusion results in significant iron overload that can cause serious organ damage and death if not properly treated. Liver iron concentration (LIC) is the best indicator of total body iron status and can be measured non-invasively by magnetic resonance imaging (MRI). In the past, it was recommended that LIC assessments by liver biopsy begin after about 6 years of age (yo). MRI is also an excellent way to monitor iron cardiomyopathy, which remains a major cause of death in chronically transfused patients. To understand how rapidly iron overload develops, we reviewed the 1316 MRI iron studies we have performed since 2002 and summarized the LIC and cardiac R2* in a subset of 127 subjects who had their first MRI studies before 10 yo. Because of the known serious pitfalls in the assessment of total body iron by measurement of ferritin, LIC is measured by MRI in our center as standard of care in all patients on chronic transfusion soon after the start of iron chelation therapy. Most children less than 6 years of age require general anesthesia for this procedure. In some older children cooperation can be achieved by distraction techniques. Thirty three percent had sickle cell disease (SCD), 33% thalassemia major (TM), 11% Blackfan Diamond anemia (DBA), 3% congenital dyserythropoietic anemia (CDA), and 8.6% had other transfusion dependent anemias (OTRAN) and 11.4% had studies done not related to transfusion. This paper will focus on the 114 subjects whose MRI was done to evaluate transfusion related iron overload. The median age at first MRI was 6 years with 25% having their first study before 3.7and 10% before 2.1 yo. The median LIC was 9.8 mg/g dry weight (dw) and 10% of subjects had a first LIC > 22 mg/g dw. Only 2.5% had evidence of cardiac iron (T2* < 20ms). The median LICs (mg/g dw) were 8.9 for SCD, 11.8 for TM, 13 for DBA, 6.1 for CDA, and 8.7 OTRAN and were not statistically different. The minima ranged from 0.6 in OTRAN to 4.2 for CDA and the maxima ranged from 25 in CDA to 39.7 for SCD. There was significant iron loading even when we restricted the analysis to 27 subjects with a first MRI at < 3.5 yo; SCD (2.3 median (med), 2.8 maximum (max)), TM (14.6 med, 35 max), DBA (13 med, 15 max),CDA (6.6 med, 25 max) and OTRAN (5.8 med, 11 max). There were 4 subjects who had evidence of cardiac iron loading. Two had DBA with T2* of 18 ms and 16 ms at 2.5 and 3.7 years of age respectively. A third DBA subject had a T2* of 20 ms at only 4.6 yo. Two TM subjects had a T2* of 15 ms at 6.6 and 9.1 yo respectively. These data indicate that there is significant elevation in LIC by the age of 3.5 years with a median LIC of 11 mg/g dw and 25% of subjects having a LIC > 15 mg/g dw. These are very high levels of iron loading. Furthermore, 2.5% of subjects in this age already have evidence of cardiac iron loading. On the basis of such findings, direct measurement of liver iron by MRI is essential as soon as possible after the start of regular transfusions and cardiac iron should be measured early in high risk children with Diamond Blackfan anemia and thalassemia major. Disclosures: Berdoukas: ApoPharma Inc.: Consultancy. Carson:ApoPharma Inc.: Honoraria; Novartis Inc: Speakers Bureau. Wood:Novartis: Research Funding; Ferrokin Biosciences: Consultancy; Cooleys Anemia Foundation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Coates:Novartis Inc: Speakers Bureau.

MRI Prospective Survey on Cardiac and Hepatic Iron in Thalassemia Intermedia Patients Treated with Desferrioxamine, Deferiprone and Deferasirox

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4041-4041
Author(s):  
Antonella Meloni ◽  
Aurelio Maggio ◽  
Anna Pietrapertosa ◽  
Pier Paolo Bitti ◽  
Sabrina Armari ◽  
...  
Keyword(s):  
Iron Overload ◽  
Iron Concentration ◽  
Iron Chelation ◽  
Hepatic Iron ◽  
Thalassemia Intermedia ◽  
Liver Iron ◽  
Cardiac Iron ◽  
Number Of Patients ◽  
Mri Scans ◽  
Magnetic Resonance Imaging Mri

Abstract Background. Few studies have evaluated the efficacy of iron chelation therapy in thalassemia intermedia (TI) patients. Our study aimed to prospectively assess by quantitative Magnetic Resonance imaging (MRI) the efficacy of the three available chelators in monotherapy in transfusion dependent (TD) TI patients. Methods. Among the 325 TI patients enrolled in the MIOT (Myocardial Iron Overload in Thalassemia) network, we selected 103 TI patients TD with an MRI follow-up (FU) study at 18±3 months who had been received one chelator alone between the two MRI scans. Iron overload was assessed by the T2* multiecho technique. Hepatic T2* values were converted into liver iron concentration (LIC) values. Results. Three groups of patients were identified: 27 patients (13 females, mean age 40.12±10.31 years) treated with desferioxamine (DFO – mean dosage 37.52±8.69 mg/kg/die), 23 patients (14 females, mean age 34.73±10.67 years) treated with deferiprone (DFP– dosage 71.70±14.46mg/kg/die) and 14 patients (9 females, mean age 36.63±10.92 years) treated with deferasirox (DFX – mean dosage 27.75±5.04 mg/kg/die). Excellent/good levels of compliance were similar in the DFO (92.6%), DFP (100%) and DFX (100%) groups (P=0.345). The mean starting age of regular transfusion was 14.73±15.89 years. At baseline in DFO group two patients (7.4%) showed a global heart T2*<20 ms and one of them showed no cardiac iron at the FU. At baseline in DFP group two patients (8.7%) showed a global heart T2*<20 ms and one of them showed no cardiac iron at the FU. All the 5 patients (35.7%) under DFX therapy with pathological global heart T2* at the baseline remained at the same status at the FU. The percentage of patients who maintained a normal global heart T2* value was comparable for DFO (100%), DFP (100%) and DFX (88.9%) groups (P=0.164). Among the 46 patients with hepatic iron at baseline (MRI LIC ≥3 mg/g/dw), the reduction in the MRI LIC values was significant only in the DFO group (DFO: -3.39±6.38 mg/g/dw P=0.041; DFP: -2.25±6.01 mg/g/dw P=0.136 and DFX: -0.36±5.56 mg/g/dw P=0.875). The decrease in MRI LIC values was comparable among the groups (P=0.336). The number of patients with a MRI LIC<3 mg/g/dw went up from 10 (37%) to 11 (40.7%) in the DFO group, from 6 (26.1%) to 8 (34.8%) in the DFP group and from 2 (14.3%) to 8 (57.1%) in the DFX group. The percentage of patients who maintained a normal MRI LIC value was comparable for DFO (90%) vs DFP (50%) and DFX (100%) groups (P=0.191). Conclusion: Prospectively in transfusion-dependent TI patients at the dosages used in the clinical practice, DFO and DFP showed 100% efficacy in maintaining a normal global heart T2* value while DFX had 100% efficacy in maintaining a normal LIC value. Further prospective studies involving more patients with iron at the baseline are needed to establish which is the most effective drug in reducing iron levels. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Pepe: Chiesi: Speakers Bureau; ApoPharma Inc.: Speakers Bureau; Novartis: Speakers Bureau.

Comparative study on iron content detection by energy spectral CT and MRI in MDS patients.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e19032-e19032
Author(s):  
Yao Zhang ◽  
Chao Xiao ◽  
Jing Li ◽  
Lu-Xi Song ◽  
You-Shan Zhao ◽  
...  
Keyword(s):  
Iron Overload ◽  
Iron Content ◽  
Detection Rate ◽  
Iron Concentration ◽  
High Iron Content ◽  
Liver Iron ◽  
Detection Rates ◽  
Cardiac Iron ◽  
Advantages And Disadvantages ◽  
The Difference

e19032 Background: Myelodysplastic syndrome(MDS) patients may have iron overload due to long-term RBC transfusion or combined with abnormal iron metabolism.what are the differences of iron content detection by magnetic resonance imaging (MRI) and dual energy spectrum computed tomography (DECT)? What are the advantages and disadvantages of the two methods in the state of high and low iron deposition? Can the two methods complement each other? The purpose of this study was to compare the difference of liver/cardiac iron content detection in MDS patients by DECT and MRI under different adjust serum ferritin (ASF) levels. Methods: Liver and cardiac iron content were detected by DECT and MRI. Patients divided into different subgroups according to ASF. Compared the detection rate between DECT and MRI group, and correlation between liver/cardiac iron content detected by DECT/MRI and ASF in each subgroups. Results: The detection rate of iron overload(IO) in DECT group was lower than that of MRI group with ASF < 1000ng/ml subgroup,DECT and MRI had similar detection rates of moderate to severe IO with 1000≤ ASF < 5000ng/ml subgroup, detection rate of severe IO in MRI was lower than that of DECT with 5000ng/ml ≤ ASF subgroup. In patients underwent DECT and MRI examination at the same time, ASF was significantly correlated with hepatic VIC but not with liver iron concentration (LIC), and LIC correlated with ASF after removed these data of ASF > 5000 mg/L. LIC expression are not significantly different among 1000≤ ASF < 5000ng/ml and 5000 ng/ml ≤ASF subgroup. LIC and liver virtual iron content (VIC) were all significant correlation with ASF when ASF < 2500ng/ml, liver VIC was still correlation with ASF but LIC was not when 2500ng/ml≤ ASF. Neither cardiac VIC nor myocardial iron content (MIC) correlation with ASF in these subgroups. Conclusions: This study showed that MRI and DECT can be used complementary to each other. In high iron content, such as ASF ≥5000ng/ml, DECT detection is more reliable. In patients with low iron content, such as SF < 1000 ng/ml, MRI detection is more reliable. According to ASF, the appropriate detection method can be selected to evaluate the iron content more accurately.

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