What’s the pathophysiology of iron overload?

The human body has no means to excrete iron.

Transfusion results in iron accumulation

Under normal conditions, intestinal iron absorption is approximately 1-2 mg/day, and under maximal stimulation iron absorption may reach a maximum of 3-5 mg/day, amounting to an annual iron accumulation of approximately 1-2g.1 By contrast, transfused blood contains ~200 mg of iron per unit. Patients receiving 2-4 units of blood per month, will have an annual accumulation of 5-10g of iron.1

Iron accumulation can overwhelm the body’s iron storage systems

With continued transfusion, the reticuloendothelial system (primarily in the liver) can no longer retain all the extra iron.

Iron then enters plasma in amounts that exceed the transport capacity of circulating transferrin. As a consequence, non-transferrin-bound iron (NTBI) appears in the plasma as a heterogeneous mixture of iron complexes that appear to be the major mediators of hepatic and extrahepatic tissue damage in transfusional iron overload.2

Non-bound iron subsequently collects in the liver, heart and endocrine organs

NTBI enters specific cells, particularly hepatocytes, cardiomyocytes, anterior pituitary cells, and pancreatic beta cells. In these cells, iron accumulation leads to the generation of reactive oxygen species, resulting in damage to lipids, proteins, DNA, and subcellular organelles, including lysosomes and mitochondria. This injury may result in cellular dysfunction, apoptosis, and necrosis that translates grossly as target organ toxicity and dysfunction.2

Iron accumulation in organ tissues is evident from children as young as 6 years of age.3

Cardiac iron loading has been observed in sickle cell and myelodysplastic syndrome patients but did not always occur even in patients with high liver iron concentration.4,5

Non-transfused patients have progressive iron accumulation

In non-transfusion-dependent thalassemia patients (NTDT), ineffective erythropoiesis leads to suppression of the hepatic iron regulatory hormone hepcidin and subsequent increase in intestinal iron absorption.6 This extra iron is primarily stored in the liver until the hepatic capacity is saturated, when extra-hepatic iron loading and toxicity can manifest.6

Next: Clinical Consequences

Diagnostics

Measuring Labile Plasma Iron (LPI) Find out more…

References

  1. Cappellini MD, Cohen A, Porter J, et al. Guidelines for the management of transfusion dependent thalassemia (TDT). 3rd Ed. Nicosia, Cyprus: Thalassemia International Federation; 2014.
  2. Brittenham GM. Iron-chelating therapy for transfusional iron overload. N Engl J Med. 2011;364(2):146-156.
  3. Yang G, Liu R, Peng P, et al. How early can myocardial iron overload occur in beta thalassemia major? PLoS One. 2014;9(1):e85379.
  4. Pascal L, Beyne-Rauzy O, Brechignac S, et al. Cardiac iron overload assessed by T2* magnetic resonance imaging and cardiac function in regularly transfused myelodysplastic syndrome patients. Br J Haematol. 2013;162(3):413-415.
  5. Meloni A, Puliyel M, Pepe A, et al. Cardiac iron overload in sickle-cell disease. Am J Hematol. 2014;89(7):678-683.
  6. Musallam KM, Rivella S, Vichinsky E, et al. Non-transfusion- dependent thalassemias. Haematologica. 2013;98(6):833-844.