Management of thalassemia

Treatment of the inherited blood disorder thalassemia depends upon the level of severity. For mild forms of the condition, advice and counseling are often all that are necessary. For more severe forms, treatment may consist in blood transfusion; chelation therapy to reverse iron overload, using drugs such as deferoxamine, deferiprone, or deferasirox; medication with the antioxidant indicaxanthin to prevent the breakdown of hemoglobin; or a bone marrow transplant using material from a compatible donor, or from the patient's mother. Population screening has had some success as a preventive measure. Treatment of the inherited blood disorder thalassemia depends upon the level of severity. For mild forms of the condition, advice and counseling are often all that are necessary. For more severe forms, treatment may consist in blood transfusion; chelation therapy to reverse iron overload, using drugs such as deferoxamine, deferiprone, or deferasirox; medication with the antioxidant indicaxanthin to prevent the breakdown of hemoglobin; or a bone marrow transplant using material from a compatible donor, or from the patient's mother. Population screening has had some success as a preventive measure. Patients with thalassemia gradually accumulate high levels of iron (Fe) in their bodies. This build-up of iron may be due to the disease itself, from irregular hemoglobin not properly incorporating adequate iron into its structure, or it may be due to the many blood transfusions received by the patient. This overload of iron brings with it many biochemical complications. Two key substances involved in iron transport and storage in the body are ferritin and transferrin. Ferritin is a protein present within cells that binds to Fe (II) and stores it as Fe (III), releasing it into the blood whenever required. Transferrin is an iron-binding protein present in blood plasma; transferrin acts as a transporter, carrying iron through blood and providing cells with the metal through endocytosis. Transferrin is highly specific to iron (III), and binds to it with an equilibrium constant of 1023 M−1 at a pH of 7.4. Thalassemia results in nontransferrin-bound iron being available in blood as all the transferrin becomes fully saturated. This free iron is toxic to the body since it catalyzes reactions that generate free hydroxyl radicals. These radicals may induce lipid peroxidation of organelles like lysosomes, mitochondria, and sarcoplasmic membranes. The resulting lipid peroxides may interact with other molecules to form cross links, and thus either cause these compounds to perform their functions poorly, or render them non-functional altogether. This iron overload may be treated with chelation therapy. Deferoxamine, deferiprone and deferasirox are the three most widely used iron-chelating agents. The drug deferoxamine, also known as desferoxamine B and DFO-B, is a trihydroxamic acid that is produced by the actinobacteria Streptomyces pilosus. It binds iron, decreasing the toxic reactions catalysed by the unbound metal, and it also decreases the uptake of iron by tissues. Deferoxamine achieves this by acting as a hexadentate iron-chelating ligand: it binds to all six coordination sites on nontransferrin-bound iron, effectively deactivating it. Deferoxamine is mostly specific to ferric iron (Fe3+) and coordinates to Fe3+ using the oxygen atoms on its multiplehydroxyl and carbonyl groups, forming a structure called ferrioxamine. This drug-iron complex is mostly excreted by the kidneys as it is water-soluble. Approximately one-third of ferrioxamine could also be excreted through the feces in bile. Deferoxamine is administered via intravenous, intramuscular, or subcutaneous injections. Oral administration is not possible as deferoxamine is rapidly metabolized by enzymes and is poorly absorbed from the gastrointestinal tract. The required parenteral administration represents one of deferoxamine’s downfalls as it is harder for patients to follow up with their therapy due to the financial and emotional burdens experienced.Deferoxamine was proven to cure many clinical complications and diseases that result from iron overload. It beneficially affects cardiac disease, such as myocardial disease which occurs as a result of iron accumulation in the heart. Deferoxamine was also shown to improve liver function by arresting the development of hepatic fibrosis which occurs as a result of iron accumulation in the liver. Deferoxamine also has positive effects on endocrine function and growth. Endocrine abnormalities in thalassemic patients involve the overloaded iron interfering with the production of insulin-like growth factor (IGF-1), as well as stimulating hypogonadism, both of which cause poor pubertal growth. A study showed that 90% of patients who were regularly treated with deferoxamine since childhood had normal pubertal growth, which fell to 38% for patients treated only with low doses of deferoxamine since their teens. Another endocrine abnormality that thalassemic patients face is diabetes mellitus, which results from iron overload in the pancreas impairing insulin secretion. Studies have shown that patients who were regularly treated with deferoxamine have a reduced risk of developing diabetes mellitus. Deferoxamine could lead to toxic side effects if doses greater than 50 mg/kg body weight are administered. These side effects may include auditory and ocular abnormalities, pulmonary toxicity, sensorimotor neurotoxicity, as well as changes in renal function. Another toxic effect of deferoxamine mostly observed in children is the failure of linear growth. This reduction in height may occur as a result of deferoxamine chelating metals other than iron which are required for normal growth.Deferoxamine has an affinity constant (Ka) of 1031 for Fe3+, 1014 for Cu2+ and 1010 for Zn2+, and so may coordinate to zinc and copper when little iron is available for chelation. Zinc is needed for the proper functioning of various metalloenzymes involved in bone formation. Zinc chelation may cause zinc deficiency in the body, which can thus lead to a reduced growth rate, reduced collagen formation and defective bone mineralization. Similarly, copper functions as an enzyme cofactor in bone formation. Copper chelation may result in copper deficiency as well, leading to metaphyseal cupping and osteoporosis. For example, abnormal collagen is formed when copper is deficient as the enzyme lysyl oxidase, which uses copper as a cofactor and catalyzes the oxidative deamination step that is important for cross-linking of collagen, cannot function properly. Studies have shown that even though the blood serum of patients receiving deferoxamine was not deficient in copper and zinc, deficiencies of the metals in the metaphyseal matrix were observed. The toxic effect of deferoxamine on linear growth could also be due to excess deferoxamine accumulating in tissues and interfering with iron-dependent enzymes which are involved in the post-translational modification of collagen. Patients who receive vitamin C supplements have shown improved iron excretion by deferoxamine. This occurs due to the expansion of the iron pool brought about by vitamin C, which deferoxamine subsequently has access to. However, vitamin C supplementation could also worsen iron toxicity by promoting the formation of free radicals. Therefore, only 100 mg of vitamin C should be taken 30 minutes to one hour after deferoxamine administration.