Iron excess

Labile plasma iron is nontransferrin bound iron capable of entering cells in the heart, liver and endocrine organs which can cause progressive tissue damage.

As transferrin’s  capacity for iron is saturated, non-transferrin iron becomes available in the plasma and rapidly deposited in the tissues.

Occurs as the result of red blood cell transfusions.

Each unit of red blood cells contains 200-250 mg of iron and can lead to iron overload after only 10-20 transfusions.

After receiving about 20 units of RBCs, the patient will receive approximately 5 g of unexretable iron.

Death of transfused red cells over time in the absence of ongoing erythropoiesis results in formation nontransferrin-bound iron once transferrin-binding capacity is exceeded.

Patients with iron overload begin to have non–transferrin bound iron when the transferin saturation exceeds 70%.

Non-transf2242in bound Iron is taken up inappropriately by highly vascular organs such as the liver, heart, pancreas, leading to elevated levels of intracellular iron, with non–transferrinbound iron gaining intracellular access through iron permeases.

Patients with thalassemia and other transfusion dependent anemias receive approximately 0.4mg/kg/day of heme iron or almost 50 times the physiologic rate of iron absorption.

Transfused red blood cells are eventually phagocytosed by reticuloendothelial macrophages in the liver, spleen and bone marrow.

Macrophages digest hemoglobin and freed iron from heme is released into the cytosol.

Iron is stored in reticuloendothelial macrophages until capacity is exceeded and excess iron is released into the plasma.

When transferrin saturation increases hepatocytes are recruited for iron storage for excess iron.

When transfusions exceed macrophage, hepatocyte and transferrin capacity, non-transferrin bound iron appears in the plasma as heterogenous iron complexes and are the major mediators of extrahepatic tissue damage in transfusional iron overload.

Non-transferrin bound iron increases levels reactive oxygen species and is associated with inflammation, fibrosis, an organ dysfunction.

As blood levels of non-transferrin bound iron increase, tissue absorption of toxic non-transferrin bound iron results in iron deposits in tissues and organs.

Regular transfusions or administed in transfusion dependent patients to achieve a target level of 9 to 10. 5 g.

Transfusion dependent patients or monitored for overload with the use of serum ferritin measurements and hepatic and myocardial MRI and iron  chelation is administered shortly after transfusion of ten red cell units or when the serum ferritin level is 1000 nanograms per milliliter or higher.

MRI allows imaging and quantification of tissue iron so that chelation therapy based on organ specific iron loading can be achieved.

Repeated measurements showing serum ferritin levels above 2500 ng/mL are associated with increased risk of heart disease and death, whereas levels below 1000 mg per millimeter are associated with prolonged survival.
 Liver iron concentrations above 7 mg program or associated with increased risk of Liver disease, and concentrations above 15 mg program are associated with an increased risk of heart disease.
T2 weighted measurements of myocardial iron of less than 20 ms are associated with cardiac arrhythmias and less than 10 ms are associated with heart failure or death.

Myocardial iron deposition increases incidence of cardiac events in patients with myelodysplastic syndrome and transfusion dependence compared to patients without transfusion dependece.

Without iron chelation therapy patients with excess iron die from endocrine and cardiac complications in the second decade of life.

Non-transferrin bound plasma iron enters cells such as hepatocytes, myocytes, anterior pituitary cells, and pancreatic beta cells.

Iron toxicity is dose-related and improved survival in patients with myelodysplastic syndrome with ferritin levels less than 1000 ng per/mL.

MDS patients treated with iron chelation have improved survival compared with patients he did not receive such treatments.

Blood transfusions are positively correlated with hepatic iron overload and transfusion volume.

Reducing iron burden improves outcome in idiopathic hemochromatosis treated with phlebotomy.

Iron accumulation in cells leads to the generation reactive oxygen species, results in damage to lipids, DNA, proteins, and subcellular organelles, such a lysosomes and mitochondria: eventually resulting in impaired cell function, apoptosis and necrosis.

Chelating drugs form complexes with iron and increase its excretion, clear non-transf2242in bound iron, remove excess iron from cells, and can restore body iron to normal levels.

Chelation therapy with desf2242ioxamine reduces organ damage and prolonged life expectancy in transfused thalassemia patients.

Two iron chelating agents available: parenteral dederoxamine mesylate (Desferal), and deferasirox (Exjade).

Transfusion related iron excess in myelodysplastic syndrome associated with risks for organ complications.

Inverse relationship between elevations in serum f2242itin concentration and median overall survival in myelodysplastic syndrome.

Damage to the liver with cirrhosis, diabetes, increased susceptibility to infections are relevant for iron excess associated with myelodysplastic syndrome, whereas heart disease, is a common cause of death in iron overloaded patients with beta-thalassemia and myelodysplastic disease.

Serum ferritin greater than 1000 microgm/mL associated with a significant decreased in overall survival in refractory anemia or refractory anemia with ringed sideroblasts.

Recommended level for treatment is 1,000 ng/mL.

Management of iron excess may provide survival benefits.

During a three year follow-up of patients with MDS and iron overload those patients that received red blood cell transfusions expeienced more cardiac complications more frequently than those who did not receive transfusions (Goldberg SL).

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