What is the pathophysiology of 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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Iron absorption

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

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