The burden of iron overload in sickle cell disease: insights from South Carolina, USA.
La sobrecarga de hierro en la anemia falciforme: perspectivas desde Carolina del Sur, EEUU.
Keywords:
Anemia, Sickle Cell, Iron Overload, Liver Iron Concentration, Ferritin, Liver Function Tests, Chelation Therapy
Abstract
Red blood cell transfusions can lead to iron overload (IO) in sickle cell disease (SCD). We aimed to determine the relationship between SCD patients with IO and SCD comorbidities. Iron chelation regimen for IO in SCD patients was also studied. A cohort of 245 SCD adult patients receiving care at the Medical University of South Carolina (MUSC) was studied. Information was obtained from medical records. Statistical analysis was performed to examine correlations and odds ratios with 95% confidence intervals. We identified 85 (34.7%) participants who met IO criteria. The results showed a significant association of IO with stroke (OR= 14.67, p= 0.0001), pulmonary hypertension (OR= 4.75, p= 0.0006), acute chest syndrome (OR= 2.46, p= 0.003), and deep vein thrombosis (OR= 1.84, p= 0.04). There was a strong correlation between liver iron concentration (LIC) and ferritin levels (r= 0.5148, p<0.0001). Liver enzymes correlated well with LIC and ferritin levels. Eighty-six percent of participants (74/85) were on chelation therapy, but only 19% of them achieved a good response to the treatment. One-third of SCD individuals developed IO, associated with several comorbidities. Comprehensive measures must include periodic determinations of LIC and ferritin, followed by appropriate chelation therapy to prevent organ damage.
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References
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Coates TD, Wood JC. How we manage iron overload in sickle cell patients. Br J Haematol. 2017;177(5):703-716. https://doi.org/10.1111/bjh.14575.
Badawy SM, Liem RI, Rigsby CK, Labotka RJ, DeFreitas RA, Thompson AA. Assessing cardiac and liver iron overload in chronically transfused patients with sickle cell disease. Br J Haematol. 2016;175(4):705- 713. https://doi.org/10.1111/bjh.14277.
Porter J, Garbowski M. Consequences and management of iron overload in sickle cell disease. Hematology Am Soc Hematol Educ Program. 2013;2013(1):447-456. https://doi.org/10.1182/asheducation-2013.1.447.
Noetzli LJ, Coates TD, Wood JC. Pancreatic iron loading in chronically transfused sickle cell disease is lower than in thalassaemia major. Br J Haematol. 2011;152(2):229-233. https://doi.org/10.1111/j.1365-2141.2010.08476.x.
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Fung EB, Harmatz P, Milet M, Ballas SK, De Castro L, Hagar W, et al; MultiCenter Study of Iron Overload Research Group. Morbidity and mortality in chronically transfused subjects with thalassemia and sickle cell disease: A report from the multi-center study of iron overload. Am J Hematol. 2007;82(4):255-265. https://doi.org/10.1002/ajh.20809.
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Feld JJ, Kato GJ, Koh C, Shields T, Hildesheim M, Kleiner DE, et al. Liver injury is associated with mortality in sickle cell disease. Aliment Pharmacol Ther. 2015;42(7):912-921. https://doi.org/10.1111/apt.13347.
Verduzco LA, Nathan DG. Sickle cell disease and stroke. Blood. 2009;114(25):5117- 5125. https://doi.org/10.1182/blood-2009-05-220921.
Yawn BP, Buchanan GR, Afenyi-Annan AN, Ballas SK, Hassell KL, James AH, et al. Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members. JAMA. 2014;312(10):1033-1048. https://doi.org/10.1001/jama.2014.10517. Erratum in: JAMA. 2015;313(7):729.
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Brunson A, Lei A, Rosenberg AS, White RH, Keegan T, Wun T. Increased incidence of VTE in sickle cell disease patients: risk factors, recurrence and impact on mortality. Br J Haematol. 2017;178(2):319-326. https://doi.org/10.1111/bjh.14655.
Naik RP, Streiff MB, Haywood C, Nelson JA, Lanzkron S. Venous Thromboembolism in Adults with Sickle Cell Disease: A serious and under-recognized complication. Am J Med. 2013;126(5):443-449. https://doi.org/10.1016/j.amjmed.2012.12.016.
Ma H, Huang Y, Tian W, Liu J, Yan X, Ma L, Lai J. Endothelial transferrin receptor 1 contributes to thrombogenesis through cascade ferroptosis. Redox Biol. 2024; 70:103041. https://doi.org/10.1016/j.redox.2024.103041.
Gladwin MT, Sachdev V. Cardiovascular abnormalities in sickle cell disease. J Am Coll Cardiol. 2012;59 (13):1123-1133. https://doi.org/10.1016/j.jacc.2011.10.900.
Gladwin MT, Barst RJ, Gibbs JS, Hildesheim M, Sachdev V, Nouraie M, et al, walk-PHaSST Investigators and Patients. Risk factors for death in 632 patients with sickle cell disease in the United States and United Kingdom. PLoS One. 2014;9(7):e99489. https://doi.org/10.1371/journal.pone.0099489.
Adam SS, Flahiff CM, Kamble S, Telen MJ, Reed SD, De Castro LM. Depression, quality of life, and medical resource utilization in sickle cell disease. Blood Adv. 2017;1(23):1983-1992. https://doi.org/10.1182/bloodadvances.2017006940
Kang H, Han M, Xue J, Baek Y, Chang J, Hu S, et al. Renal clearable nanochelators for iron overload therapy. Nat Commun 2019;10(1):5134. https://doi.org/10.1038/s41467-019-13143-z.
Li S, Han Q, Liu C, Wang Y, Liu F, Pan S, et al. Role of ferroptosis in chronic kidney disease. Cell Commun Signal. 2024;22(1):113. https://doi.org/10.1186/s12964-023-01422-8.
Wilson SR, Sears M, Williams E, Drapekin J, Sivakumar I, Padrino S, et al. GR-NDaD investigators. Gaps in the diagnosis and management of iron overload in sickle cell disease: a ‘real-world’ report from the GRNDaD registry. Br J Haematol. 2021;195(5):e157-e160. https://doi.org/10.1111/bjh.17762.
Puliyel M, Sposto R, Berdoukas VA, Hofstra TC, Nord A, Carson S, et al. Ferritin trends do not predict changes in total body iron in patients with transfusional iron overload. Am J Hematol. 2014;89(4):391-394. https://doi.org/10.1002/ajh.23650.
Cippà PE, Boucsein I, Adams H, Krayenbuehl PA. Estimating Iron Overload in Patients with Suspected Liver Disease and Elevated Serum Ferritin. Am J Med. 2014;127(10):1011.e1-1011.e3. https://doi.org/10.1016/j.amjmed.2014.03.016.
Ginès P, Castera L, Lammert F, Graupera I, Serra-Burriel M, Allen AM, et al. LiverScreen Consortium Investigators. Population screening for liver fibrosis: Toward early diagnosis and intervention for chronic liver diseases. Hepatology. 2022;75(1):219-228. https://doi.org/10.1002/hep.32163.
Porter J, Bowden DK, Economou M, Troncy J, Ganser A, Habr D, et al. Health-Related Quality of Life, Treatment Satisfaction, Adherence and Persistence in β-Thalassemia and Myelodysplastic Syndrome Patients with Iron Overload Receiving Deferasirox: Results from the EPIC Clinical Trial. Anemia. 2012;2012:297641. https://doi.org/10.1155/2012/297641.
Chou ST, Alsawas M, Fasano RM, Field JJ, Hendrickson JE, Howard J, et al. American Society of Hematology 2020 guidelines for sickle cell disease: transfusion support. Blood Adv. 2020; 28;4(2):327-355. https://doi.org/10.1182/bloodadvances.2019001143.
Harmatz P, Butensky E, Quirolo K, Williams R, Ferrell L, Moyer T, et al. Severity of iron overload in patients with sickle cell disease receiving chronic red blood cell transfusion therapy. Blood. 2000;96(1):76- 79. https://doi.org/10.1182/blood.V96.1.76.
Theocharidou E, Suddle AR. The Liver in Sickle Cell Disease. Clin Liver Dis. 2019;23(2):177-189. https://doi.org/10.1016/j.cld.2018.12.002.
Coates TD, Wood JC. How we manage iron overload in sickle cell patients. Br J Haematol. 2017;177(5):703-716. https://doi.org/10.1111/bjh.14575.
Badawy SM, Liem RI, Rigsby CK, Labotka RJ, DeFreitas RA, Thompson AA. Assessing cardiac and liver iron overload in chronically transfused patients with sickle cell disease. Br J Haematol. 2016;175(4):705- 713. https://doi.org/10.1111/bjh.14277.
Porter J, Garbowski M. Consequences and management of iron overload in sickle cell disease. Hematology Am Soc Hematol Educ Program. 2013;2013(1):447-456. https://doi.org/10.1182/asheducation-2013.1.447.
Noetzli LJ, Coates TD, Wood JC. Pancreatic iron loading in chronically transfused sickle cell disease is lower than in thalassaemia major. Br J Haematol. 2011;152(2):229-233. https://doi.org/10.1111/j.1365-2141.2010.08476.x.
Marsella M, Borgna-Pignatti C. Transfusional iron overload and iron chelation therapy in thalassemia major and sickle cell disease. Hematol Oncol Clin North Am 2014;28(4):703-727, vi. https://doi.org/10.1016/j.hoc.2014.04.004.
Fung EB, Harmatz P, Milet M, Ballas SK, De Castro L, Hagar W, et al; MultiCenter Study of Iron Overload Research Group. Morbidity and mortality in chronically transfused subjects with thalassemia and sickle cell disease: A report from the multi-center study of iron overload. Am J Hematol. 2007;82(4):255-265. https://doi.org/10.1002/ajh.20809.
Ballas SK. Iron overload is a determinant of morbidity and mortality in adult patients with sickle cell disease. Semin Hematol. 2001;38 (1 Suppl 1):30-36. https://doi.org/10.1016/S0037-1963(01)90058-7.
Njoku F, Pugh N, Brambilla D, Kroner B, Shah N, Treadwell M, et al. Mortality in adults with sickle cell disease: Results from the sickle cell disease implementation consortium (SCDIC) registry. Am J Hematol. 2024;99(5):900-909. https://doi.org/10.1002/ajh.27279.
Piel FB, Jobanputra M, Gallagher M, Weber J, Laird SG, McGahan M. Co-morbidities and mortality in patients with sickle cell disease in England: A 10-year cohort analysis using hospital episodes statistics (HES) data. Blood Cells Mol Dis. 2021; 89:102567. https://doi.org/10.1016/j.bcmd.2021.102567.
Webb J, Kwiatkowski JL. Stroke in patients with sickle cell disease. Expert Rev Hematol. 2013;6(3):301-316. https://doi.org/10.1586/ehm.13.25.
van Tuijn CFJ, Schimmel M, Van Beers EJ, Nur E, Biemond BJ. Prospective evaluation of chronic organ damage in adult sickle cell patients: A seven‐year follow‐up study. Am J Hematol. 2017;92(10):E584-E590. https://doi.org/10.1002/ajh.24855.
Fortuna V, Lima J, Oliveira GF, Oliveira YS, Getachew B, Nekhai S, et al. Ferroptosis as an emerging target in sickle cell disease. Curr Res Toxicol. 2024;7:100181. https://doi.org/10.1016/j.crtox.2024.100181.
DiMartino LD, Baumann AA, Hsu LL, Kanter J, Gordeuk VR, Glassberg J, et al; Sickle Cell Disease Implementation Consortium. The sickle cell disease implementation consortium: Translating evidence-based guidelines into practice for sickle cell disease. Am J Hematol. 2018;93(12):E391-E395. https://doi.org/10.1002/ajh.25282.
Garcia-Casal MN, Pasricha SR, Martinez RX, Lopez-Perez L, Peña-Rosas JP. Serum or plasma ferritin concentration as an index of iron deficiency and overload. Cochrane Database Syst Rev. 2021;5(5): Cd011817. https://doi.org/10.1002/14651858.CD011817.
Feld JJ, Kato GJ, Koh C, Shields T, Hildesheim M, Kleiner DE, et al. Liver injury is associated with mortality in sickle cell disease. Aliment Pharmacol Ther. 2015;42(7):912-921. https://doi.org/10.1111/apt.13347.
Verduzco LA, Nathan DG. Sickle cell disease and stroke. Blood. 2009;114(25):5117- 5125. https://doi.org/10.1182/blood-2009-05-220921.
Yawn BP, Buchanan GR, Afenyi-Annan AN, Ballas SK, Hassell KL, James AH, et al. Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members. JAMA. 2014;312(10):1033-1048. https://doi.org/10.1001/jama.2014.10517. Erratum in: JAMA. 2015;313(7):729.
Estcourt LJ, Hopewell S, Trivella M, Hambleton IR, Cho G. Regular long-term red blood cell transfusions for managing chronic chest complications in sickle cell disease. Cochrane Database Syst Rev. 2019;2019(10):CD008360. https://doi.org/10.1002/14651858.cd008360.pub5.
Brunson A, Lei A, Rosenberg AS, White RH, Keegan T, Wun T. Increased incidence of VTE in sickle cell disease patients: risk factors, recurrence and impact on mortality. Br J Haematol. 2017;178(2):319-326. https://doi.org/10.1111/bjh.14655.
Naik RP, Streiff MB, Haywood C, Nelson JA, Lanzkron S. Venous Thromboembolism in Adults with Sickle Cell Disease: A serious and under-recognized complication. Am J Med. 2013;126(5):443-449. https://doi.org/10.1016/j.amjmed.2012.12.016.
Ma H, Huang Y, Tian W, Liu J, Yan X, Ma L, Lai J. Endothelial transferrin receptor 1 contributes to thrombogenesis through cascade ferroptosis. Redox Biol. 2024; 70:103041. https://doi.org/10.1016/j.redox.2024.103041.
Gladwin MT, Sachdev V. Cardiovascular abnormalities in sickle cell disease. J Am Coll Cardiol. 2012;59 (13):1123-1133. https://doi.org/10.1016/j.jacc.2011.10.900.
Gladwin MT, Barst RJ, Gibbs JS, Hildesheim M, Sachdev V, Nouraie M, et al, walk-PHaSST Investigators and Patients. Risk factors for death in 632 patients with sickle cell disease in the United States and United Kingdom. PLoS One. 2014;9(7):e99489. https://doi.org/10.1371/journal.pone.0099489.
Adam SS, Flahiff CM, Kamble S, Telen MJ, Reed SD, De Castro LM. Depression, quality of life, and medical resource utilization in sickle cell disease. Blood Adv. 2017;1(23):1983-1992. https://doi.org/10.1182/bloodadvances.2017006940
Kang H, Han M, Xue J, Baek Y, Chang J, Hu S, et al. Renal clearable nanochelators for iron overload therapy. Nat Commun 2019;10(1):5134. https://doi.org/10.1038/s41467-019-13143-z.
Li S, Han Q, Liu C, Wang Y, Liu F, Pan S, et al. Role of ferroptosis in chronic kidney disease. Cell Commun Signal. 2024;22(1):113. https://doi.org/10.1186/s12964-023-01422-8.
Wilson SR, Sears M, Williams E, Drapekin J, Sivakumar I, Padrino S, et al. GR-NDaD investigators. Gaps in the diagnosis and management of iron overload in sickle cell disease: a ‘real-world’ report from the GRNDaD registry. Br J Haematol. 2021;195(5):e157-e160. https://doi.org/10.1111/bjh.17762.
Puliyel M, Sposto R, Berdoukas VA, Hofstra TC, Nord A, Carson S, et al. Ferritin trends do not predict changes in total body iron in patients with transfusional iron overload. Am J Hematol. 2014;89(4):391-394. https://doi.org/10.1002/ajh.23650.
Cippà PE, Boucsein I, Adams H, Krayenbuehl PA. Estimating Iron Overload in Patients with Suspected Liver Disease and Elevated Serum Ferritin. Am J Med. 2014;127(10):1011.e1-1011.e3. https://doi.org/10.1016/j.amjmed.2014.03.016.
Ginès P, Castera L, Lammert F, Graupera I, Serra-Burriel M, Allen AM, et al. LiverScreen Consortium Investigators. Population screening for liver fibrosis: Toward early diagnosis and intervention for chronic liver diseases. Hepatology. 2022;75(1):219-228. https://doi.org/10.1002/hep.32163.
Porter J, Bowden DK, Economou M, Troncy J, Ganser A, Habr D, et al. Health-Related Quality of Life, Treatment Satisfaction, Adherence and Persistence in β-Thalassemia and Myelodysplastic Syndrome Patients with Iron Overload Receiving Deferasirox: Results from the EPIC Clinical Trial. Anemia. 2012;2012:297641. https://doi.org/10.1155/2012/297641.
Published
2025-12-08
How to Cite
Vizcaíno, G., Abrams, C. M., Foster, C. B., Flórez, H., Dávila, N., & Rainey, S. C. (2025). The burden of iron overload in sickle cell disease: insights from South Carolina, USA.: La sobrecarga de hierro en la anemia falciforme: perspectivas desde Carolina del Sur, EEUU. Investigación Clínica, 66(4), 378-389. https://doi.org/10.54817/IC.v66n4a03
Section
Original Works
