Transfusional Iron Overload and Chronic anemia
Chronic anemias can occur as a consequence of inborn errors during the formation of red blood cells (erythropoiesis). These errors lead to recurring anemia as well as other, often severe, symptoms that result from the transport of erythrocytes with incorrect structures, reduced lifespan and/or reduced ability to transport oxygen. Chronic anemias may be due to inherited mutations (e.g. thalassaemia, sickle cell disease [SCD]) or environmental factors (e.g. myelodysplastic syndromes [MDS]).
Various therapeutic methods have been developed for chronic anemias, both for the treatment of symptoms and disease prevention. The most common treatment method is regular blood transfusion therapy to alleviate symptoms. Blood transfusions can markedly extend life expectancy in patients with chronic anemias [1;2]. For example, without transfusion, the inherited condition thalassaemia major is frequently fatal by the age of 5 years. Transfusion therapy can also reduce or eliminate compensatory bone marrow expansion, permitting normal or near-normal growth and development [3].
Transfusion extends life expectancy in severe chronic anemia
Regular blood transfusions markedly extend life expectancy in patients with thalassaemia major [4]
Pathophysiology of transfusional iron overload
Each unit of blood contains 200 mg of heme iron [2], more than 100 times the iron normally absorbed from the diet on a given day. When transfused red blood cells become senescent, they are degraded and their iron recycled by reticuloendothelial macrophages. The iron is then bound to transferrin and released into the circulation, where it is distributed to body tissues. As the human body has no active mechanism with which to remove iron, iron overload is an inevitable consequence of regular transfusion therapy.
When iron overload occurs, transferrin becomes saturated, resulting in the presence of non-transferrin bound iron (NTBI) in the plasma. Whereas tissue uptake of transferrin-bound iron is regulated by the expression of membrane-bound transferrin receptor (responsible for transport of transferrin into cells [5]), NTBI is taken up in an uncontrolled manner, often by susceptible tissues. This leads to pools of unbound iron within cells, which mediate toxicity by the formation of reactive oxygen species (ROS) [6]. ROS react with cellular components such as the plasma membrane, lysosomes, and organelle membranes, leading to cellular leakage, dysfunction, and ultimately cell death [7;8].
The organ damage that occurs with transfusional iron overload is similar to that seen in hereditary hemochromatosis, although iron accumulation occurs far more rapidly, and the distribution of iron to reticuloendothelial macrophages is proportionally greater [9]. Hemochromatosis is characterized by iron accumulation primarily in the liver, heart, and pancreas. However, whereas chronic anemias are related to errors in erythropoiesis, the main cause of hemochromatosis is a reduction or absence in expression of hepcidin due to one of several mutations (in particular the HFE gene) [10].
In normal iron homeostasis, hepcidin downregulates intestinal absorption of iron and its release from macrophages, and therefore minimizes the amount of iron that enters into plasma. However, in conditions of chronic iron overload blood transfusion leads to an increase in erythrocytes, which are broken down by macrophages. This initially results in an increase in iron levels in the reticuloendothelial system. Hepcidin expression also downregulates iron release from this system, leading to a build-up in the reticuloendothelial system and eventual saturation (a stage that is reduced or absent in patients with hemochromatosis). Subsequently, iron is deposited in various tissues leading to tissue damage.
Transfusional iron overload can generally be identified from a patient's history, assuming that accurate records of the number of transfusions have been kept. Signs of iron overload can usually be seen after 10-12 transfusions [2].
There are numerous methods available for the detection and assessment of iron levels, both as total body and specific tissue levels. Each method is associated with advantages and disadvantages.
Iron overload in patients with hemochromatosis is normally treated with periodic phlebotomy until ferritin levels have returned to normal (approximately <50 ng/mL). Due to the underlying anemia that initially led to the need for transfusions, phlebotomy is not usually a viable option for patients with transfusional iron overload [2]. In these cases, treatment with an iron-chelating agent is required.
  References
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