A T2* MRI Prospective Survey on Cardiac and Hepatic Iron in Non-Trasfusion-Dependent Thalassemia Intermedia Patients Treated with Desferrioxamine

Abstract Background. In thalassemia intermedia (TI) patients no observational study prospectively evaluated in the real life the efficacy of the desferrioxamine (DFO) therapy in removing or preventing iron overload from the heart and the liver by T2* Magnetic Resonance Imaging (MRI). The efficacy endpoint of this study is represented by the changes in cardiac T2* and MRI LIC (liver iron concentration) values in non-transfusion dependent (NTD) TI patients after 18 months of desferrioxamine therapy. Methods. Among the 325 TI patients enrolled in the MIOT (Myocardial Iron Overload in Thalassemia) network, we selected 129 TI patients NTD. We considered 29 patients who had been received DFO alone between the two MRI scans. Cardiac iron overload was assessed by the T2* multiecho technique. Hepatic T2* values were converted into liver iron concentration (LIC) values. Results. Mean age was 39.69 ± 8.12 years and 14 (48.3%) patients were females. Patients started regular chelation therapy at a mean age of 21.92 ± 15.89 years. The mean administered dosage of DFO via subcutaneous route was 38.46 ± 10.27 mg/kg body weight on 3.32 ± 1.54 days/week. The percentage of patients with excellent/good levels of compliance to the chelation treatment was 82.1%. At baseline only one patient showed cardiac iron overload (global heart T2*=15.23 ms) but he recovered at the FU (global heart T2*=26.93 ms). All patients without cardiac iron maintained the same status at the follow-up (FU). Eighteen patients (62.1%) had hepatic iron overload (MRI LIC ≥3 mg/g/dw) at the baseline. For this subgroup, the baseline and the FU LIC values were, respectively, 9.15 ± 7.97 mg/g/dw and 7.41 ± 6.28 mg/g/dw. The reduction in MRI LIC values was not significant (P=0.102). Out of the 11 patients with a baseline MRI LIC <3 mg/g/dw, only one (9.1%) showed hepatic iron at the FU. The Figure shows the evolution of different hepatic iron overload risk classes between the baseline and the FU. Conclusions. In this small population of sporadically or non transfused TI patients, DFO showed 100% efficacy in maintaining a normal global heart T2* value. As regards as the hepatic iron overload, the DFO therapy did not prevent the transition to a worst class in 2 patients. Figure 1 Figure 1. Disclosures Pepe: Chiesi: Speakers Bureau; ApoPharma Inc.: Speakers Bureau; Novartis: Speakers Bureau.

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Association Between Cardiac Iron Clereance and Hepatic Siderosis

Blood ◽

10.1182/blood.v128.22.4833.4833 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4833-4833

Author(s):

Alessia Pepe ◽

Laura Pistoia ◽

Domenico D'Ascola ◽

Maria Rita Gamberini ◽

Francesco Gagliardotto ◽

...

Keyword(s):

Iron Overload ◽

Iron Concentration ◽

Thalassemia Major ◽

Hepatic Iron ◽

Liver Iron Concentration ◽

Liver Iron ◽

Cardiac Iron ◽

Follow Up Study ◽

Hepatic Iron Overload

Abstract Introduction. The aim of this multicenter study was to evaluate in thalassemia major (TM) if the cardiac efficacy of the three iron chelators in monotherapy was influenced by hepatic iron levels over a follow up of 18 months. Methods. Among the 2551 TM patients enrolled in the MIOT (Myocardial Iron Overload in Thalassemia) network we evaluated prospectively the 98 patients those with an MR follow up study at 18±3 months who had been received one chelator alone between the 2 MR scans and who showed evidence of significant cardiac iron (global heart T2*<20 ms) at the basal MRI. Iron overload (IO) was measured by T2* multiecho technique. We used cardiac R2* (equal to 1000/T2*) because cardiac R2* is linearly proportional to cardiac iron and hepatic T2* values were converted into liver iron concentration (LIC) values. Results. We identified 3 groups of patients: 47 treated with deferasirox (DFX), 11 treated with deferiprone (DFP) and 40 treated with desferrioxamine (DFO). Percentage changes in cardiac R2* values correlated with changes in LIC in both DFX (R=0.469; P=0.001) and DFP (R=0.775; P=0.007) groups. All patients in these 2 groups who lowered their LIC by more than 50% improved their cardiac iron (see Figure 1). Percentage changes in cardiac R2* were linearly associated to the log of final LIC values in both DFX (R=0.437; P=0.002) and DFP groups (R=0.909; P<0.0001). Percentage changes in cardiac R2* were not predicted by initial cardiac R2* and LIC values. In each chelation group patients were divided in subgroups according to the severity of baseline hepatic iron overload (no, mild, moderate, and severe IO). The changes in cardiac R2* were comparable among subgroups (P=NS) (Figure 2). Conclusion. In patients treated with DFX and DFP percentage changes in cardiac R2* over 18 months were associated with final LIC and percentage LIC changes. In each chelation group percentage changes in cardiac R2* were no influenced by initial LIC or initial cardiac R2*. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Pepe: Chiesi Farmaceutici and ApoPharma Inc.: Other: Alessia Pepe is the PI of the MIOT project, that receives no profit support from Chiesi Farmaceutici S.p.A. and ApoPharma Inc..

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Central Role of LIC-R2 (Ferriscan®) Determination in Patients with Hemoglobinopathies: Licnet Experience

Blood ◽

10.1182/blood.v124.21.4034.4034 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4034-4034

Author(s):

Giuseppina Calvaruso ◽

Angela Vitrano ◽

Francesco Gioia ◽

Filippo Cassarà ◽

Saveria Campisi ◽

...

Keyword(s):

Iron Overload ◽

Iron Concentration ◽

Hepatic Iron ◽

Liver Iron Concentration ◽

Altman Plot ◽

Liver Iron ◽

Concentration Difference ◽

Hepatic Iron Overload ◽

Transfusion Requirements ◽

Secondary Endpoints

Abstract The main cause of mortality in the thalassemia population remains iron-induced cardiac failure (Borga-Pignatti et al Ann N Y Acad Sci 2005); in addition iron overload in the liver, pancreas and other organs causes progressive damage . Iron overload in human tissues can be treated by chelation therapy. Thus, early detection of iron overload is crucial. Nowdays liver iron overload in human tissues can be monitored noninvasively by magnetic resonance imaging (MRI) by two techniques, T2* and R2 MRI (Ferriscan®). There is not too much literature that compares the two methods in hemoglobinopathies. Our center instituted a network, LICNET (Liver Iron Cutino Network), promoted from Piera Cutino partnership and addressed to the diagnostics of iron overload in liver by R2 MRI in patients with hemoglobinopathies. Patients with thalassemia Major (TM), thalassemia intermedia (TI) and Sickle-Cell/b-thalassemia (S/b-T)), were retrospectively considered for this study. Primary endpoint was to evaluate agreement between T2* and R2 MRI measures of liver iron concentration (LIC) using a Bland-Altman (B-A) method that compares differences between observations on the same patient made with the two methods (Bland & Altman Lancet 1986). Secondary endpoints were to evaluate: 1) hepatic iron overload in our population; 2) difference in R2 LIC in patients with different chelation regimen; 3) relation between hepatic iron overload versus transfusion requirements. LIC was measured by calculating T2* and by measuring R2 using commercial Ferriscan® technique (St Pierre TG et al Blood 2005). To convert liver T2* to LIC a regression equation was used: LIC T2*=0.0254×R2*+0.202 (where R2*=1000/T2*) (Wood JC et al Blood 2005). LICNET involves 14 Italian thalassemia and radiology centers. Overall 301 adult patients with hemoglobinopathies (TM (177), TI (74) and S/b-T (50)) underwent to iron evaluation from 2012 to 2014. The mean age at R2 MRI evaluation was 33.2±10.7, 41.2±13.8 and 38.7±13.9, respectively in TM, TI and S/b-T. Iron overload was assessed in patients where most of the patients have been treated with deferasirox (DFX) therapy (TM (28.8%), TI (25.7%) and S/b-T (26.0%)), the remaining cohorts were treated with deferoxamine (DFO), deferiprone (DFP) chelation both alone and in combination or sequential administration. One hundred and twelve observations were measured both for T2* and R2. Concerning the primary endpoint, in the B-A plot it was observed that T2* method yielded a higher LIC than Ferriscan (differences>0), the estimated bias (estimated mean difference) was 2.6 (95% LoA – 17.8; 22.9), and this difference increased at high levels of iron content (Estim. Diff= -1.18+0.32Average mg/g/dw, p=0.0001) (Fig. 1). Secondary endpoints showed that hepatic iron overload determined by T2* was not statistically different among 3 cohorts of patients while it was border line by LIC-R2 (p=0.2608 and p=0.0672). Furthermore, DFX treated patients showed lower LIC-R2 determination in comparison with other treatment (Table 1). Finally, the increase of transfusion requirements was not associated with more severe iron overload in patients with TI and S/b-T. This may be in relation with compliance and type of chelation treatment. These findings show that LIC-R2 (Ferriscan®) is crucial to have accurate and reliable measures for iron body burden control in hemoglobinopathies. Table 1. Liver iron concentration determined by Ferriscan (R2) in patients with hemoglobinopathies treated by different chelation regimens. TM TI S/ b -T Chelation Therapy LIC R2 (mean±sd) LIC R2 (mean±sd) LIC R2 (mean±sd) DFO 5.3±5.7 8.5±7.7 20.9±19.9 DFP 12.9±12.3 12.5±8.1 12.7±20.2 DFX 7.6±9.2 6.1±7.1 3.7±3.2 Combined DFO+DFP 10.1±12.1 17.8 (n=1) --- Sequential DFO-DFP 4.3±3.1 --- --- Combined DFO+DFX --- 9.7 (n=1) --- Figure 1. Bland- Altman plot of Liver iron concentration: difference LIC T2* and LIC-R2 versus average of values measured by T2* and Ferriscan Figure 1. Bland- Altman plot of Liver iron concentration: difference LIC T2* and LIC-R2 versus average of values measured by T2* and Ferriscan Disclosures No relevant conflicts of interest to declare.

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Mild hepatic iron overload in dysmetabolic hyperferritinemia: MRI may overestimate the liver iron concentration values

Annals of Hematology ◽

10.1007/s00277-011-1346-5 ◽

2011 ◽

Vol 91 (6) ◽

pp. 961-961 ◽

Cited By ~ 2

Author(s):

Agustin Castiella ◽

Jose M. Alustiza ◽

Eva Zapata ◽

Jose I. Emparanza ◽

Pedro Otazua ◽

...

Keyword(s):

Iron Overload ◽

Iron Concentration ◽

Hepatic Iron ◽

Liver Iron Concentration ◽

Liver Iron ◽

Hepatic Iron Overload

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Deferiprone Has a Dose-Dependent Effect on Liver Iron Concentration

Blood ◽

10.1182/blood.v126.23.2159.2159 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2159-2159 ◽

Cited By ~ 1

Author(s):

Alessia Pepe ◽

Tommaso Casini ◽

Liana Cuccia ◽

Francesco Sorrentino ◽

Rosamaria Rosso ◽

...

Keyword(s):

Iron Overload ◽

Iron Concentration ◽

Hepatic Iron ◽

Liver Iron Concentration ◽

Liver Iron ◽

Hepatic Iron Overload ◽

Group 2 ◽

Dose Dependent ◽

Dose Dependent Effect ◽

Group 1

Abstract Purpose: The aim of this multi-centre study was to retrospectively assess in thalassemia major (TM) if deferiprone (DFP) had a dose-dependent effect on liver iron concentration (LIC) assessed by quantitative magnetic resonance imaging (MRI). Methods: Among the 958 TM patients enrolled in the MIOT (Myocardial Iron Overload in Thalassemia) network, we identified hose with an MRI follow up study at 18±3 months who had been received DFP monotherapy and had no changes in dose of DFP between the 2 MRI scans. Patients were divided into two groups according to the DFP dose: 79 patients with ≤ 75 mg/kg/d (group 1) and 39 with > 75 mg/kg/d (group 2). Hepatic iron overload was measured by the T2* multiecho technique and T2* values were converted into LIC values using the calibration curve introduced by Wood et al. Results: The two groups had comparable baseline MRI LIC values. The table shows the evolution of different iron overload risk classes between the baseline and the FU MRI. The percentage of patients that worsened their status was significantly higher in group 1 than in group 2 (26.6% vs 7.7%; P=0.016). Subgroup analysis in patients with hepatic iron overload at baseline (MRI LIC > 3mg/g/dw) was conducted: 48 patients from group 1 (DFP dose: mean 70.6±11.2 mg/kg/d, median 75 mg/kg/d) and 30 from group 2 (DFP dose: mean 85.2±6.6 mg/kg/d, median 84 mg/kg/d). The two subgroups had comparable baseline MRI LIC values (10.2±8.1 mg/g dw vs 11.1±8.7 mg/g dw (P=0.314). While the mean change in subgroup 2 ( -1.8±6.3mg/g/dw, P=0.131) was more favourable than in subgroup 1 (+0.1±7.7 mg/g/dw, P=0.903), the change in MRI LIC values did not reach statistical significance between the two subgroups (P=0.579) (Figure 1), which may be due to small cohort evaluated. Conclusions: In TM patients the worsening in MRI LIC can be prevented by increasing the dose of deferiprone above the widely used regimen of 75 mg/kg body weight. Our results are consistent with the iron balance studies performed by Grady RW et al. Table 1. Evolution of different iron overload risk classes between the baseline and the FU MRI. The underlined numbers represent the patients who remained in the same risk class. DFP dose ≤ 75 mg/kg/d (N=79) FU LIC <3 mg/g dw 3-7 mg/g dw 7-15 mg/g dw ≥15 mg/g dw Baseline LIC <3 mg/g dw (N=31) 21 7 3 0 3-7 mg/g dw (N=22) 10 4 6 2 7-15 mg/g dw (N=14) 0 6 5 3 ≥15 mg/g dw (N=12) 1 0 5 6 Total at the FU 32 17 19 11 DFP dose > 75 mg/kg/d (N=39) FU LIC <3 mg/g dw 3-7 mg/g dw 7-15 mg/g dw ≥15 mg/g dw Baseline LIC <3 mg/g dw (N=9) 6 2 1 0 3-7 mg/g dw (N=14) 3 11 0 0 7-15 mg/g dw (N=8) 0 4 4 0 ≥15 mg/g dw (N=8) 1 0 2 5 Total at the FU 10 17 7 5 Figure 1. Changes of MRI LIC values in patients with basal MRI LIC > 3 mg/g/dw. Figure 1. Changes of MRI LIC values in patients with basal MRI LIC > 3 mg/g/dw. Disclosures Pepe: Chiesi: Speakers Bureau; ApoPharma Inc: Speakers Bureau; Novartis: Speakers Bureau.

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

Blood ◽

10.1182/blood.v124.21.4041.4041 ◽

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.

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Correlation of Serum Ferritin Levels with Liver and Heart Mri T2 and Liver Iron Concentration in Beta Thalassemia Intermediate Patients: A Contemporary Issue

Blood ◽

10.1182/blood.v128.22.4829.4829 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4829-4829 ◽

Cited By ~ 1

Author(s):

Mehran Karimi ◽

Fatemeh Amirmoezi ◽

Sezaneh Haghpanah ◽

Seyed pouria Ostad ◽

Mehrzad Lotfi ◽

...

Keyword(s):

Iron Overload ◽

Serum Ferritin ◽

Iron Concentration ◽

Beta Thalassemia ◽

P Value ◽

Hepatic Iron ◽

Liver Iron Concentration ◽

Liver Iron ◽

Hepatic Iron Overload ◽

T2 Mri

Abstract Background: B-Thalassemia intermediate (B-TI) is a genetic disease that is milder than beta thalassemia major. The accumulation of iron in different organs causes tissue damage. The T2* magnetic resonance imaging (MRI) technique is currently the gold standard for iron load detection. However, it is expensive and needs an expert radiologist to report findings. Therefore, we conducted this study to determine an optimal cut-off value of ferritin in proportion to T2 MRI for early detection of cardiac and hepatic iron overload in patients with beta thalassemia intermediate. Methods: This cross-sectional study was conducted on 108 patients with B-TI who referred to tertiary Hospital, Shiraz University of Medical Sciences, Shiraz, Iran. Serum ferritin, hepatic and cardiac T2 MRI were assessed. The ROC curve was used to determine the sensitivity and specificity of cut-off value. Results: Serum ferritin levels showed a statistically significant negative correlation with T2 hepatic MRI (r= -0.290, P value=0.003) and positive correlation with LIC (r= 0.426, P value ˂ 0.001) in the patients with BTI. However, T2 cardiac MRI was not significantly correlated with serum ferritin levels (P value= 0.073).According to the analysis of ROC curves, the best cut-off value for ferritin to show early diagnosis of liver iron overload was 412 ng/ml. calculated sensitivities and specificities were 0.78 and 0.82 for T2 liver MRI and 0.76 and 0.86 for liver iron concentration (LIC) respectively. Conclusion: Serum ferritin levels of 412 ng/ml might be considered as a cut-off point to evaluate hepatic iron overload before using expensive, not readily available T2 MRI. This level of serum ferritin (around 500 ng/ml) could be considered for starting iron chelation therapy in patients with B-TI in areas where T2 MRI is not available. Disclosures No relevant conflicts of interest to declare.

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Myocardial and Hepatic Iron Overload and Cardiac Function In Sickle/Thalassemia Patients Of Italian Origin

Blood ◽

10.1182/blood.v122.21.2252.2252 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2252-2252

Author(s):

Antonella Meloni ◽

Giovan Battista Ruffo ◽

Daniele De Marchi ◽

Antonio Cardinale ◽

Anna Pietrapertosa ◽

...

Keyword(s):

Cardiac Function ◽

Iron Overload ◽

Conflicts Of Interest ◽

Iron Concentration ◽

Hepatic Iron ◽

Liver Iron ◽

Hepatic Iron Overload ◽

The Mean ◽

Magnetic Resonance Imaging Mri ◽

Italian Origin

Abstract Introduction Sickle-thalassemia results from the combined heterozygosity for sickle-cell and β-thalassemia genes. This study evaluates myocardial and hepatic iron overload and cardiac function in Italian patients and explores their correlation with transfusions, age and sex. Methods Fifty-nine sickle-thalassemia patients (29 males, mean age 35.6±14.1 years), enrolled in the MIOT network underwent magnetic resonance imaging (MRI). T2* value for all 16 myocardial segments and global heart T2* value were calculated. Hepatic T2* value was converted into liver iron concentration (LIC). Cine images were acquired to quantify biventricular volumes and ejection fraction (EF). Results 55 (93%) patients had all segmental T2* values normal (>20 ms). Of the 4 patients with abnormal segmental T2* values, all showed an heterogeneous myocardial iron overload (some segments with T2*>20 ms and other with T2*<20 ms) and only one had a global T2*<20 ms. The mean global heart T2* value was 34.4±6.2 ms. The mean LIC was 5.9±6.5 mg/g/dw and 30 patients (50.8%) had a pathological value (≥ 3 mg/g dw). There was a statistically significant positive correlation between global heart T2* and age but with poor linearity (R=0.368; P=0.004) and there was not a significant correlation between age and LIC. Males and females had comparable global heart T2* values and LIC values. Twenty patients were regularly transfused, 32 received sporadic transfusions while 7 were not transfused. The comparison among the three groups is shown in Table 1. We did not find significant differences in the global heart T2* value while patients regularly transfused had significantly higher LIC than sporadically transfused patients. Biventricular volumes indexed by body surface area and ejection fractions were comparable among the groups. Conclusions In respect of MIO, the sickle/thalassemia patients are similar to patients with homozygous SCD for which iron overloading is relatively rare. Hepatic iron overload may develop also in no regularly-transfused patients, maybe due to increased absorption of iron from the digestive tract, characteristic of both SCD and thalassemia intermedia patients. This finding underlines the importance to monitor by MRI also no regularly transfused sickle/thalassemia patients. Disclosures: No relevant conflicts of interest to declare.

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Efficacy of deferasirox in reducing and preventing cardiac iron overload in β-thalassemia

Blood ◽

10.1182/blood-2009-04-217455 ◽

2010 ◽

Vol 115 (12) ◽

pp. 2364-2371 ◽

Cited By ~ 119

Author(s):

Dudley J. Pennell ◽

John B. Porter ◽

Maria Domenica Cappellini ◽

Amal El-Beshlawy ◽

Lee Lee Chan ◽

...

Keyword(s):

Iron Overload ◽

Iron Reduction ◽

Geometric Mean ◽

Iron Concentration ◽

Left Ventricular ◽

Left Ventricular Ejection ◽

Liver Iron ◽

Ventricular Ejection Fraction ◽

Cardiac Iron ◽

Cardiac Iron Overload

Cardiac iron overload causes most deaths in β-thalassemia major. The efficacy of deferasirox in reducing or preventing cardiac iron overload was assessed in 192 patients with β-thalassemia in a 1-year prospective, multicenter study. The cardiac iron reduction arm (n = 114) included patients with magnetic resonance myocardial T2* from 5 to 20 ms (indicating cardiac siderosis), left ventricular ejection fraction (LVEF) of 56% or more, serum ferritin more than 2500 ng/mL, liver iron concentration more than 10 mg Fe/g dry weight, and more than 50 transfused blood units. The prevention arm (n = 78) included otherwise eligible patients whose myocardial T2* was 20 ms or more. The primary end point was the change in myocardial T2* at 1 year. In the cardiac iron reduction arm, the mean deferasirox dose was 32.6 mg/kg per day. Myocardial T2* (geometric mean ± coefficient of variation) improved from a baseline of 11.2 ms (± 40.5%) to 12.9 ms (± 49.5%) (+16%; P < .001). LVEF (mean ± SD) was unchanged: 67.4 (± 5.7%) to 67.0 (± 6.0%) (−0.3%; P = .53). In the prevention arm, baseline myocardial T2* was unchanged from baseline of 32.0 ms (± 25.6%) to 32.5 ms (± 25.1%) (+2%; P = .57) and LVEF increased from baseline 67.7 (± 4.7%) to 69.6 (± 4.5%) (+1.8%; P < .001). This prospective study shows that deferasirox is effective in removing and preventing myocardial iron accumulation. This study is registered at http://clinicaltrials.gov as NCT00171821.

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Correlation of Serum Ferritin Levels and Liver Iron Concentration Determined by R2* MRI in Patients with Thalassemia Intermedia.

Blood ◽

10.1182/blood.v110.11.3818.3818 ◽

2007 ◽

Vol 110 (11) ◽

pp. 3818-3818

Author(s):

Ali Taher ◽

F. El Rassi ◽

H. Ismaeel ◽

S. Koussa ◽

A. Inati

Keyword(s):

Iron Overload ◽

Serum Ferritin ◽

Care Center ◽

Iron Concentration ◽

Iron Chelation ◽

Thalassemia Intermedia ◽

Liver Iron Concentration ◽

Liver Iron ◽

Cross Sectional ◽

Transfusion Therapy

Abstract Background: Unlike patients with thalassemia major (TM), those with thalassemia intermedia (TI) do not require regular blood transfusion therapy but remain susceptible to iron overload due to increased intestinal iron uptake triggered by ineffective erythropoiesis. TI patients can accumulate 1–3.5 g of excess iron per year, and effective monitoring of iron burden is an important element of patient management. Assessment of serum ferritin (SF) levels is a convenient and widely used method, and a correlation between SF and liver iron concentration (LIC) has been demonstrated in patients with TM. SF levels may, however, be a poor indicator of LIC in patients with TI and the limited data available on the SF:LIC correlation prove equivocal; in fact, reports suggest a discrepancy between LIC and SF in patients with TI. This is the largest study to use R2* MRI to evaluate the SF:LIC correlation in patients with TI. Methods: This was a cross-sectional study of randomly selected, infrequently/non-transfused TI patients treated at a chronic care center in Hazmieh, Lebanon. Patient charts were reviewed and a medical history was compiled. Blood samples were taken for SF assessment, and LIC was determined by R2* MRI. Results: Data from 74 TI patients were included in this analysis (33 male, 41 female; mean age 26.5 ± 11.5 years). Of this group, 59 (79.7%) patients were splenectomized, 20 were transfusion-naive, 45 had received several transfusions in their lifetime but none in the past year, and 9 patients were regularly transfused 2–4 times per year. Overall mean SF values were 1023 ± 780 ng/mL (range 15–4140); mean LIC levels were 9.0 ± 7.4 mg Fe/g dry weight [dw] (range 0.5–32.1). In contrast to previous findings, a significant positive correlation between mean LIC and SF values was seen in the whole group (R=0.64; P<0.001), and in a subset of splenectomized patients (R=0.62; P<0.001). In comparison with data obtained from a randomly selected group of patients with TM treated at the center, SF levels in TI were seen to be significantly lower, while the mean LIC values were similar in both groups of TI and TM. For a given LIC, SF values were lower in patients with TI than those with TM (Figure). Conclusions: Evaluation of iron levels shows that many patients with TI have SF and LIC levels above the recommended threshold levels, indicating a risk of significant morbidity/mortality. Similar to TM, a significant correlation between SF and LIC was observed in patients with TI; however, the relationship between SF and LIC was different between TI and TM (for the same LIC, the SF values in TI were lower than those in TM). Therefore, use of the current threshold for iron overload based on SF values in TM will lead to significant underestimation of the severity of iron overload in patients with TI. This may result in delayed chelation therapy, and expose patients to morbidity and mortality risks associated with iron overload. Disease-specific management approaches are therefore required in patients with TI. This includes either regular assessments of LIC, ideally by non-invasive R2* MRI, or lowering the SF threshold for initiating iron chelation in patients with TI. Figure Figure

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ß-Thalassemic Mice Require Functional Hfe to Modulate Hepcidin Expression In Response to Iron Overload

Blood ◽

10.1182/blood.v116.21.2063.2063 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2063-2063

Author(s):

Pedro Ramos ◽

Sara Gardenghi ◽

Robert W Grady ◽

Maria de Sousa ◽

Stefano Rivella

Keyword(s):

Iron Overload ◽

Iron Concentration ◽

Dry Weight ◽

Thalassemia Intermedia ◽

Liver Iron Concentration ◽

Ineffective Erythropoiesis ◽

Liver Iron ◽

Hepcidin Expression ◽

Smad Protein ◽

Over Time

Abstract Abstract 2063 ß-Thalassemia is a genetic disorder characterized by decreased or absent production of ß-globin chains, leading to ineffective erythropoiesis, anemia and iron overload. Hepcidin, the hormone that controls iron homeostasis, is regulated by several mechanisms, including erythropoiesis, iron overload, inflammation and hypoxia. In the absence of transfusion therapy, patients with ß-thalassemia major exhibit a severe ineffective erythropoiesis that suppresses hepcidin expression. However, in patients or animal affected by ß-thalassemia intermedia (th3/+), iron overload is associated with a milder form of ineffective erythropoiesis. In this study we investigated whether th3/+ mice retain the ability to modulate hepcidin expression in response to iron load, despite their increased erythropoietic activity. We analyzed some of the genes involved in the regulation of hepcidin, in particular, genes that are upregulated by iron overload in wt mice. These included Bmp6, a strong modulator of Hamp in response to iron, and Id1, Atoh8 and Smad7, other targets of the Bmp/Smad pathway. Analysis of the phosphorylation of the Smad protein complex is in progress. In addition, we generated mice affected by ß-thalassemia intermedia lacking the Hfe gene (Hfe-th3/+), in an attempt to determine whether or not this gene is involved in hepcidin regulation in this disorder. We analyzed th3/+ mice at 2, 5 and 12 months of age. In 2-month-old th3/+ mice hepcidin expression was significantly low compared to wt mice. As th3/+ mice age and their iron overload worsens, hepcidin expression increases showing similar and elevated levels in th3/+ compared to wt animals, respectively at 5 and 12 months. At 2 months, hepcidin expression normalized to liver iron concentration exhibited even lower levels in th3/+ mice compared to wt animals. This ratio did not change in aging th3/+ animals, despite the fact that their liver iron concentration increased over time (0.66, 1.24, and 1.45 ug/mg of dry weight at 2, 5 and 12 months, respectively). The expression levels of Bmp6, Id1, Atoh8 and Smad7 followed a similar pattern, being generally downregulated at 2 months compared to wt mice. However, as iron overload progressed, th3/+ mice exhibited increased expression of these genes compared to wt mice. Similar to what was observed with hepcidin, their expression was low in th3/+ mice at all ages when normalized to liver iron concentration. These observations indicate that hepcidin expression in ß-thalassemia increases over time and is regulated by the relative levels of ineffective erythropoiesis and iron overload. We also investigated the relationship between Hfe and hepcidin in response to iron in ß-thalassemia. We transplanted the ß-thalassemic phenotype into lethally irradiated wt or Hfe-KO mice, generating th3/+ and Hfe-th3/+ animals, respectively. Compared to th3/+ mice, we observed that Hfe-th3/+ animals had increased hepatic iron (3.09 vs 1.29 ug/mg of dry weight, p≤0.05) and serum iron (232 vs 162 ug/dL, p≤0.05), with no significant changes in splenic iron concentration. The Hfe-th3/+ mice also exhibited increased hemoglobin levels (9.4 vs 7.8 g/dL, p≤0.001) due to an increase in both red cell counts (8.9 vs 8.0 ×106 cells/uL, p≤0.01) and mean corpuscular hemoglobin levels (10.6 vs 9.7 pg, **p≤0.05). However, this did not reduce splenomegaly or ineffective erythropoiesis. We also analyzed the levels of hepcidin, Bmp6, Id1, Smad7 and Atoh8 in 5-month-old mice. At his time point expression of most of these genes was similar between wt, th3/+ and Hfe-th3/+ mice. Only expression of Bmp6 was elevated in the two thalassemic groups compared to wt mice. When the levels of hepcidin, Bmp6, Id1, Smad7 and Atoh8 expression were normalized to liver iron content, we observed significant reductions in Hfe-th3/+ mice compared to th3/+ animals. Taken together, these observations indicate that iron overload can partially counteract the repressive effect of ineffective erythropoiesis on hepcidin expression in th3/+ mice. Moreover, lack of Hfe further impairs the ability of hepcidin and other iron regulated genes to respond to iron overload, aggravating this feature in thalassemic mice. Overall, this indicates that Hfe plays a positive role in the regulation of hepcidin in ß-thalassemia. Disclosures: No relevant conflicts of interest to declare.

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