Transfusion-Induced Iron Overload

Updated: May 07, 2021
  • Author: Geneva E Guarin, MD, MBA; Chief Editor: Emmanuel C Besa, MD  more...
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Practice Essentials

The human body has no active mechanism for the excretion of iron. [1]  Normally, the amount of iron absorbed from the small intestine is balanced by the iron lost through sweat, menstruation, shedding of hair and skin cells, and rapid turnover and excretion of enterocytes, with daily absorption and excretion of iron both being about 1 mg in a healthy individual. [2, 3] Day-to-day iron requirements, as iron is needed by virtually all body cells and especially erythrocytes, are met by recycling between various compartments.

A unit of transfused blood contains approximately 250 mg of iron. [4] In patients who receive numerous transfusions—notably those with thalassemia major, sickle cell disease, myelodysplastic syndrome, aplastic anemia, hemolytic anemia, and refractory sideroblastic anemias, who may become transfusion dependent—the excess iron from the transfused erythrocytes gradually accumulates in various tissues, causing morbidity and mortality. See Pathophysiology and Presentation.

Iron chelation therapy is used to prevent the accumulation of iron to harmful levels. Liver and cardiac transplantation should be considered for appropriate patients with end-stage disease. See Treatment and Medication.




Iron absorption Iron absorption

The dynamics of iron regulation in the body is multifaceted and is altered in transfusion-induced iron overload.

Hepcidin, a 25-amino acid peptide synthesized in liver, is also known as the “iron hormone." [5] Circulating hepcidin reduces iron export into the plasma by binding to the iron export protein ferroportin 1 (FPN1) on the surface of enterocytes, macrophages, and other cells and causing its internalization and degradation. Thus, iron-deficiency states exhibit reduced hepcidin and iron-excess states have high levels of hepcidin to maintain the amount of iron secreted into the circulation. [6]

Several factors can influence hepcidin production, including the HFE gene, hypoxia, and increased erythropoietin production. [7] Most forms of hereditary hemochromatosis exhibit a deficiency of hepcidin. [8]

In some disorders, such as β-thalassemia, excessive intestinal absorption also adds to the transfusion-induced iron overload. In thalassemia intermedia, high erythropoietic drive causes hepcidin deficiency. The lack of hepcidin results in hyperabsorption of dietary iron and body iron overload. In contrast, in thalassemia major, transfusions decrease erythropoietic drive and increase the iron load, resulting in relatively higher hepcidin levels. In the presence of higher hepcidin levels, dietary iron absorption is moderated and macrophages retain iron, but body iron stores increase due to the inability to excrete iron in transfused red blood cells. [9]

When the plasma iron-binding protein transferrin is oversaturated, as in transfusion-induced iron overload, the excess iron circulates as relatively free non–transferrin-bound iron (NTBI). This NTBI is rapidly taken up by liver and other tissues. Transferrin-bound iron (TBI) is also taken up by these cells through the hepcidin mechanism, which is increased in such states. [10] It is this excessive iron that damages tissues.

A specific portion of NTBI is the chelatable labile plasma iron (LPI), which is not found in healthy individuals. [11] This is the most toxic component due to high reduction-oxidation (redox) potential that generates oxygen-free radicals such as superoxide anion in the cells, which damages DNA, proteins, and membrane lipids in the cell. [12]  Iron toxicity occurs as a result of the ferrous reactive forms of iron that reacts with oxidants, forming a complex that rapidly degrades proteins and DNA of a cell. High levels of reactive oxygen species are then produced, damaging the structure and genetic material of tissues. [13]

Reduced marrow activity also has a significant effect on the level of NTBI/LPI. In patients with marrow failure or ineffective erythropoiesis, which are the same patients who typically require chronic blood transfusion, levels of NTBI are much higher. [13]  In addition, hyperabsoroption of iron from the diet is observed in patients with ineffective erythropoiesis, making them iron loaded even in the absence of blood transfusion. [13]

Hemosiderin is an abnormal, insoluble form of iron storage. It consists of ferritin trapped in lysosomal membranes. [14] Unlike ferritin, it does not circulate in blood but is deposited in tissues and is unavailable when cells need iron. [15]

Major organs affected by this surplus iron include the heart, lung, liver, and endocrine glands. See Complications




United States

Amongst 342 patients with transfusion-dependent thalassemia in the National Institutes of Health (NIH) registry, 23% had iron overload as documented by a liver iron concentration of 15 mg/g dry weight or greater. [16] Around 15,000 patients with sickle cell disorder and estimated and 5,000 with myelodysplastic syndromes and other acquired refractory anemias require blood transfusions. [17]


In a Japanese cohort of transfusion-dependent patients with myelodysplastic syndrome and aplastic anemia, one third of all deaths were attributable to iron overload (97% of the deceased had a serum ferritin >1000 ng/mL). Cardiac failure was responsible for 24% and liver failure for 7% of all deaths. On average, each patient was transfused with more than 60 units of red blood cells per year. [18]

In a Greek population of thalassemia major patients who were transfusion dependent, 51% had moderate (defined as serum ferritin > 2000 mcg/L) to severe iron overload (defined as serum ferritin > 4000 mcg/L). [19]


Mortality in chronically transfused patients with thalassemia and sickle cell disease is 3 times that of the general United States population. The most common cause of morbidity is cardiomyopathy (30%) that is induced by iron overload. [20]


The prevalence of mild to moderate iron overload was similar in black and white veterans in one autopsy study that evaluated the hepatic iron concentration of 256 specimens. [21]


An analysis of data from 1861 patients with β-thalassemia major from Italy showed that failure of puberty was the major clinical endocrine problem in these patients, and it was present in 51% of boys and 47% of girls, all older than 15 years. Secondary amenorrhea was recorded in 23% of the patients with β-thalassemia major. [22]


Several distinct groups can be recognized in terms of the initiation of transfusion therapy. The average age of patients undergoing transfusion initiation is 4 years in thalassemia and 13 years in sickle cell disease [20] ; in adults, the average age at transfusion initiation is in the 40s for aplastic anemia, [23] and in the 60s for myelodysplasia. [24]