Assessment of Cardiac Iron Overload in Chonically Transfused Patients with Thalassemia, Sickle Cell Anemia, and Myelodysplastic Syndromes
Authors: De Montalembert Mariane , Ribeil Jean-Antoine , Brousse Valentine , Guerci-Bresler Agnes , Stamatoullas Aspasia , Vannier Jean Pierre , Lahary Agnes , Touati Mohamed , Bouabdallah Krimo , Cavazzana Marina , Chauzit Emmanuelle , Baptiste Amandine , Lefebvre Thibaud , Puy Herve , Elie Caroline , Karim Zoubida , Ernst Olivier , Rose Christian 
Published: October 2019

Abstract

Background. Cardiac iron overload is the major cause for death in regularly transfused thalassemic (Thal) patients. Its impact in myelodysplastic syndrome (MDS) patients is debated. Heart seems to be spared in regularly transfused patients with sickle cell anemia (SCA), which is supposed to be related to a later onset on transfusions and to the use of erythrocytapheresis rather than simple transfusion. Our aim was to assess the prevalence of cardiac iron overload, defined as a T2*cardiovascular magnetic resonance (MR) <20ms, and to look for predisposing factors.
Patients and methods. Patients were enrolled if they were regularly followed in a center where the exact number of erythrocyte concentrates (EC) could be obtained, had received in the previous year more than 8 EC, were older than 6 years (limit for MRI without sedation), had no known heart disease related to another pathology, and had given informed consent.
All patients underwent 1.5T myocardial T2*MR imaging after validation of the procedures in the different sites. Assessment of Liver Iron Content (LIC) used two signal intensity ratio of gradient echo imaging (R2*) MRI protocols. Serum Non-Transferrin Bound Iron (NTBI) was measured by the FeROSTM eLPI kit, and serum hepcidin by LC-MSMS.
Results. 20 Thal, 41 SCA and 25 MDS patients were evaluable. We divided SCA in 2 groups, according to the procedure recorded at the time of the study, manual exchange transfusion (G1, N = 30 patients), or erythrocytapheresis (G2, N=11 patients).
We found cardiac overload in 0, 3 (15%), and 4 (16%) of SCA, Thal, and MDS patients respectively. Serum ferritins at beginning of chelation were not statistically different in all categories of patients, as well as Ferritin and LIC at the time of the study. Increased LIC and abnormal T2* were associated in Thal and MDS patients (p=0.04), with no correlation between abnormal T2* and parameters of transfusion and chelation.
Plasmatic iron level was increased in Thal and MDS patients but remained at normal range in SCA patients. NTBI level was high in Thal and MDS but completely absent in SCA groups.
The major discrepancy was in the values of hepcidin, which were collapsed in Thal, at normal range in SCA, and highly elevated in MDS patients.
Discussion and conclusion.
We confirm that SCA patients are relatively protected from cardiac iron overload. This results probably from massive consummation of iron through effective erythropoiesis, making toxic free iron (NTBI) less available in the circulation. In addition, since iron overload in SCA results from a massive outflow of hemoglobin (Hb) due to intravascular hemolysis and transfusion, the heme/Hb-bound iron must be efficiently handled in liver macrophages, limiting its release in the bloodstream.
In Thal patients, underlying defects in erythropoietic processes, together with low hepcidin that stimulates intestinal iron absorption and increases NTBI, must provoke more organ damages. Hepcidin levels were high in MDS patients, suggesting that transfusion-dependent iron overload was a more effective regulator of hepcidin production than dyserythropoiesis. The % of T2*<20 ms we observed in MDS patients (16%) was quite comparable with previous publications.
Finally, we observe that, in opposition with previous reports, SCA patients undergoing eythrocytapheresis may experience severe iron overload and need iron chelation.
Table 1. Thal SCA G1 SCA G2 MDS p Age at beginning of transfusion (yrs) 8.5[0-45] 7[0-45] 16.5[1-55] 66[38-83] <0.001 Duration of transfusion (yrs) 10[1-39] 7[1-22] 10.5[0-25] 3[1-10] <0.001 N EC since diagnosis 359[21-1360] 139[24-791] 201[14-888] 77[16-544] 0.0005 N CE/yr 24[8-67] 21[4-62] 35[17-58] 27[7-65] 0.09G1vsG2=0.03 % patientschelated 95 90 72.7 72 0.12 Age at beginning of chelation (yrs) 11[1-48] 9[2-47] 18[6-31] 68[38-84] <0.0005 Ferritin at beginning of chelation (ng/ml) 1148[713-2400] 2075[448-3670] 1500[905-2804] 2398[482-5140] 0.22 N T2*<20 ms 3(15%) 0 0 4(16%) 0.01 LIC (mg/g d.w.) 10.4[0.8-20.2] 10.7[0.8-37.1] 14[0.8-19.7] 15.2[3.0-45.3] 0.29 Plasmatic iron(μmol/l) 36.9[31-57] 22.5[6-42.2] 21[13-46] 38.2[11.9-72] <0.001 NTBI (mg/ml) 7.1[0-31.1] 0[0-18.3] 0[0-12.4] 4.45[0-25.5] 0.0005 Ferritin (ng/ml) 870[169-4339] 2739[393-5596] 2404[33-20030] 1611[223-6813] 0.08 Hepcidin (ng/ml) 1.35[0-12.3] 9.95[0-67.9] 2.10[0-52.4] 36.35[3-143.2] <0.001 Deferasirox dosage<0.5 μg/ml 3/8(38%) 3/10(29%) 3/5(60%) 0/11(0%) 0.03

Disclosures
De Montalembert: Addmedica: Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau. Guerci-Bresler:ARIAD: Speakers Bureau; BMS: Speakers Bureau; Novartis: Speakers Bureau; PFIZER: Speakers Bureau.