Progression of Organ Dysfunction in Iron Overloaded Patients with β Thalassemia and Sickle Cell Disease.
Authors: Fung Ellen B. , Harmatz Paul , Madden Jacqueline , Vichinsky Elliott ,   The Multi-Center Iron Overload Study Group
Published: October 2019

Abstract
Iron overload occurs equally in transfused patients with thalassemia (Thal) and sickle cell disease (SCD). However, organ dysfunction that occurs frequently in patients with Thal has not been reported in SCD. A 5-year, prospective, multi-center study is being conducted to assess the incidence and rate of development of iron related organ dysfunction in tranfused Thal and SCD subjects compared to a group of non-transfused subjects with SCD. Data are collected annually by patient interview and medical record review. Differences between the groups at baseline were analyzed by t-test or χ2. ANCOVA was used to analyze longitudinal data to control for differences at baseline. 204 subjects with SCD (44% Male, 24.7 ±0.9 yrs: Mean ± SEM), 144 subjects with Thal (52% M; 25.6±0.7 yrs) and 54 non-transfused subjects with SCD (Control: 50% M, 22.2 ±1.3 yrs) were eligible and have completed baseline assessment. To date, 70% of the sample has completed 1 year of follow-up, 31% have completed 2 years. Since baseline assessment, 3% have been lost to follow-up and 16 case subjects (4%) have died. At baseline, LIC (Thal: 19.6±1.1 vs. SCD: 20.0±1.2 mg/g dry wt) did not differ between the two case groups, however, serum ferritin was significantly higher in the SCD group (p=0.006). Ferritin increased significantly at year 1 (p=0.02) in SCD compared to Thal, with a similar trend towards a 4 mg/g dry wt increase in LIC (p=0.07). Thal subjects were more likely to be receiving chelation therapy at all timepoints (p<0.001); 16% of SCD cases never received chelation therapy despite significant iron burden. Thal subjects were 5x more likely than SCD and 2x more likely than controls to be taking antioxidant supplements (p<0.001). Overall, Thal subjects were more likely to have gonadal failure (p<0.001), thyroid dysfunction (p=0.002), have sustained a fracture (p=0.003) and be taking bisphosphonates (p=0.007) and hormone replacements (p<0.001) compared to subjects with SCD or Controls. Only 15% of adult females with Thal had successful pregnancies compared to SCD (34%) and Controls (27%, p=0.02). Each of these differences remained significant at one year of follow-up, and all variables with the exception of thyroid dysfunction were independent of years of transfusion or LIC. Surprisingly, there were no differences in cardiac dysfunction or heart medication usage between the 2 case groups at any timepoint. At baseline, roughly 10% of SCD and Thal subjects vs. 0% of controls had abnormal echocardiograms (LVEF<55%). In contrast, the general health of subjects with SCD was worse than Thal. SCD subjects were more likely to have kidney disease (p<0.001), hypertension (p=0.001) and were hospitalized more frequently (p<0.001). Iron overloaded SCD subjects were 5x more likely than SCD Controls and 3x more likely than Thal to have died (p=0.02). Subjects who died were more likely to be hyptertensive (p=0.007), on heart medications (p<0.001), or have had an abnormal ECHO (p=0.01). These data suggest that despite a trend towards an increase in iron stores in SCD, subjects with Thal continue to have significantly more endocrine dysfunction than those with SCD. What is surprising is the similar incidence and progression of cardiac disease in the 2 iron overloaded groups. Further collection of longitudinal data may provide clarification of these findings. Supported in part by NIH grants: R01DK05777801 and M01 RR01271