Iron Overload in Patients With Heavily Transfused Sickle Cell Disease—Correlation of Serum Ferritin With Cardiac T2* MRI (CMRTools), Liver T2* MRI, and R2-MRI (Ferriscan®)

Abstract

The treatment of sickle cell disease (SCD) is mainly supportive, except for a minority, who receive bone marrow transplantation (BMT). Serum ferritin (SF) is routinely available but is notoriously unreliable as a tool for iron-overload assessment since it is an acute-phase reactant. Although blood transfusion is one of the most effective ways to deal with specific acute and chronic complications of SCD, this strategy is often associated with alloimmunization, iron overload, and hemolytic reactions. This study, thus, aims to evaluate iron overload in patients with SCD on chronic blood transfusions and specifically, correlate SF with the current standard of care of iron-overload assessment using MRI-based imaging techniques. Amongst a historic cohort of 58 chronically transfused patients with SCD, we were able to evaluate 44 patients who are currently alive and had multiple follow-up testing. Their mean age (±SD) was 35 (9) years and comprised of 68.2% of women. The studied iron-overload parameters included cardiac T2* MRI, liver iron concentration (LIC) by Liver T2* MRI, and serial SF levels. Additionally, in a smaller cohort, we also studied LIC by FerriScan© R2-MRI. Chronic blood transfusions were necessary for severe vaso-occlusive crisis (VOC) (38.6%), severe symptomatic anemia (38.6%), past history of stroke (15.9%), and recurrent acute chest syndrome (6.9%). About 14 (24%) patients among the original cohort died following SCD-related complications. Among the patients currently receiving chelation, 26 (96%) are on Deferasirox (DFX) [Jadenu® (24) or Exjade® (2)], with good compliance and tolerance. However, one patient is still receiving IV deferoxamine (DFO), in view of the significantly high systemic iron burden. In this evaluable cohort of 44 patients, the mean SF (±SD) reduced marginally from 4,311 to 4,230 ng/ml, mean Liver T2* MRI dropped from 12 to 10.3 mg/gm dry weight, while the mean cardiac T2*MRI improved from 36.8 to 39.5 ms. There was a mild to moderate correlation between the baseline and final values of SF ng/ml, r = 0.33, p = 0.01; Cardiac T2* MRI ms, r = 0.3, p = 0.02 and Liver T2* MRI mg/kg dry weight, r = 0.6, p < 0.001. Overall, there was a positive correlation between SF and Liver T2* MRI (Pearson's r = 0.78, p < 0.001). Cardiac T2*MRI increased with the decreasing SF concentration, showing a negative correlation which was statistically significant (Pearson's r = −0.6, p < 0.001). Furthermore, there was an excellent correlation between SF ng/ml and LIC by FerriScan© R2-MRI mg/g or mmol/kg (Spearmen's rho = −0.723, p < 0.008) in a small subset of patients (n = 14) who underwent the procedure. In conclusion, our study demonstrated a good correlation between serial SF and LIC by either Liver MRI T2* or by FerriScan© R2-MRI, even though SF is an acute-phase reactant. It also confirms the cardiac sparing effect in patients with SCD, even with the significant transfusion-related iron burden. About 14 (24%) patients of the original cohort died over the past 15 years, indicative of a negative impact of iron overload on disease morbidity and mortality.

Iron stores in steady‐state sickle cell disease children accessing care at a sickle cell disease clinic in Kumasi, Ghana: A cross‐sectional study

“…As a result, SCD patients may experience elevation of iron stores. In the present study, the majority of SCD children have ever been hemotransfused, which concur with the findings of several studies 24,25,43 Furthermore, we found that the increasing number of hemotransfusions significantly increased serum ferritin concentration. Specifically, it was demonstrated that SCD children who had received at least three hemotransfusions have higher median serum ferritin than those who received 1–2 and no hemotransfusions in that order, and the median difference was statistically significant.…”

“…However, the study has some limitations that can strengthen our findings when they are addressed in future studies. First, we did not perform liver biopsy or magnetic resonance interference which has been shown to provide an excellent assessment of elevated iron stores (iron overload) 43,45 to confirm our findings. Second, serum creatinine reactive protein levels were not measured to confirm the steady state of the study participants due to limited funds.…”

Mitapivat improves ineffective erythropoiesis and iron overload in adult patients with pyruvate kinase deficiency

“… 4 This may be because of the high erythropoietic drive causing severe hepcidin deficiency, which, in turn, leads to iron depletion of macrophages and lowering of the secretion of ferritin. 28 , 29 , 30 The incongruency between LIC and ferritin levels at baseline further highlights the high prevalence of iron overload even in patients who are not regularly transfused, and the importance of iron screening in all patients with PK deficiency. 4 …”

Molecular characterization of HAMP rs10421768 gene and phenotypic expression of hepcidin; a case-control study among sickle cell anaemia patients in Ghana

“…An average healthy person’s body has 4 g of iron, whereas people who receive multiple and frequent transfusions can accumulate 5 to 10 g annually. Long-term transfusion can lead to iron overload which may result in further complications including heart failure, growth retardation, endocrine problems and splenomegaly [ 11 , 12 ].…”