What are the clinical consequences of iron overload?

Iron overload is associated with significant morbidity and mortality

Iron toxicity accounts for most morbidity and mortality in Thalassemia

In transfusion dependent thalassemia (TDT), hepatic disease and hepatocellular,1,2 endocrine disorders,3,4 and cardiomyopathy,5,6 are established consequences of iron overload. Cardiac disease has been considered a primary cause of death in TDT patients,2 although recent observations highlight a more notable role for liver disease in TDT mortality (Figure 1).7

Figure 1: Deaths due to heart and liver disorders between 2000 and 2010 in patients with hemoglobinopathies in Greece.7 

Studies have shown that even patients with non-transfusion-dependent thalassemia (NTDT) can suffer from clinical morbidities attributed to iron overload.8 Iron-related complications start emerging at the age of 10 years, and become more frequent with advancing age.8 Iron overload has been particularly associated with vascular and endocrine disease in NTDT patients.8 Damaging effects to the liver, ultimately leading to fibrosis and hepatic cancer have also been reported.8 

Iron overload is associated with poorer outcomes in Sickle Cell Disease (SCD)

Target organ damage in patients with SCD is linked to the duration of transfusion therapy.9 Hepatic fibrosis can develop in up to one third of iron overloaded SCD patients.10,11 Iron overload is associated with increased hospitalization frequency and mortality in SCD patients.12,13

Patients with Myelodysplastic Syndromes (MDS) also face the challenges of iron overload

Transfused MDS patients experience a higher prevalence of morbidities compared to MDS patients who have not required transfusion (Figure 2).14 In studies of transfused MDS and aplastic anemia patients, iron overload was shown to damage critical organs including the heart and liver.14,15

Iron overload is a prognostic factor in MDS patients associated with increased mortality16,17and risk of leukemic transformation.17

Figure 2: Prevalence of comorbid conditions among transfused and non-transfused patients with myelodysplastic syndromes from a retrospective review of 2003 Medicare Standard Analytic Files.14 

Next: Diagnosing Iron Overload

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References

  1. Angelucci E, Muretto P, Nicolucci A, et al. Effects of iron overload and hepatitis C virus positivity in determining progression of liver fibrosis in thalassemia following bone marrow transplantation. Blood. 2002;100(1):17-21.
  2. Borgna-Pignatti C, Vergine G, Lombardo T, et al. Hepatocellular carcinoma in the thalassaemia syndromes. Br J Haematol. 2004;124(1):114-117.
  3. Cunningham MJ, Macklin EA, Neufeld EJ, et al. Complications of beta-thalassemia major in North America. Blood. 2004;104(1):34-39.
  4. Belhoul KM, Bakir ML, Saned MS, et al. Serum ferritin levels and endocrinopathy in medically treated patients with beta thalassemia major. Ann Hematol. 2012;91(7):1107-1114.
  5. Kirk P, Roughton M, Porter JB, et al. Cardiac T2* magnetic resonance for prediction of cardiac complications in thalassemia major. Circulation. 2009;120(20):1961-1968.
  6. Carpenter JP, Roughton M, Pennell DJ, et al. International survey of T2* cardiovascular magnetic resonance in beta- thalassemia major. Haematologica. 2013;98(9):1368-1374.
  7. Voskaridou E, Ladis V, Kattamis A, et al. A national registry of haemoglobinopathies in Greece: deducted demographics, trends in mortality and affected births. Ann Hematol. 2012;91(9):1451- 1458.
  8. Musallam KM, Rivella S, Vichinsky E, et al. Non-transfusion- dependent thalassemias. Haematologica. 2013;98(6):833-844.
  9. Fung EB, Harmatz PR, Lee PD, et al. Increased prevalence of iron-overload associated endocrinopathy in thalassaemia versus sickle-cell disease. Br J Haematol. 2006;135(4):574-582.
  10. Vichinsky E, Butensky E, Fung E, et al. Comparison of organ dysfunction in transfused patients with SCD or beta thalassemia. Am J Hematol. 2005;80(1):70-74.
  11. Olivieri NF, Pakbaz Z, Vichinsky E. Hb E/beta-thalassaemia: a common & clinically diverse disorder. Indian J Med Res. 2011;134:522-531.
  12. Fung EB, Harmatz P, Milet M, et al. 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.
  13. Aduloju SO, Palmer S, Eckman JR. Mortality in sickle cell patient transitioning from pediatric to adult program: 10 years Grady Comprehensive Sickle Cell Center experience. Blood. 2008;112:abstract 1426.
  14. Goldberg SL, Chen E, Corral M, et al. Incidence and clinical complications of myelodysplastic syndromes among United States Medicare beneficiaries. J Clin Oncol. 2010;28(17):2847- 2852.
  15. Takatoku M, Uchiyama T, Okamoto S, et al. Retrospective nationwide survey of Japanese patients with transfusion- dependent MDS and aplastic anemia highlights the negative impact of iron overload on morbidity/mortality. Eur J Haematol. 2007;78(6):487-494.
  16. Malcovati L, Porta MG, Pascutto C, et al. Prognostic factors and life expectancy in myelodysplastic syndromes classified according to WHO criteria: a basis for clinical decision making. J Clin Oncol. 2005;23(30):7594-7603.
  17. Sanz G, Nomdedeu B, Such E, et al. Abstract 640: Independent impact of iron overload and transfusion dependency on survival and leukemic evolution in patients with myelodysplastic syndrome. Blood. 2008;112:abstract 640.