Thalassemia iron overload

Chelators of transition metals, mainly iron and copper, are usually considered as antioxidants because of their ability to inhibit free radical-mediated damaging processes. Actually, the so-called chelating therapy has been in the use probably even earlier than antioxidant therapy because it is an obvious pathway to treat the development of pathologies depending on metal overload (such as calcium overload in atherosclerosis or iron overload in thalassemia) with compounds capable of removing metals from an organism. Understanding of chelators as antioxidants came later when much attention was drawn to the possibility of in vivo hydroxyl radical formation via the Fenton reaction ... 

Chelators of iron, which are now widely applied for the treatment of patients with thalassemia and other pathologies associated with iron overload, are the intravenous chelator desferal (desferrioxamine) and oral chelator deferiprone (LI) (Figure 19.23, see also Chapter 31). Desferrioxamine (DFO) belongs to a class of natural compounds called siderophores produced by microorganisms. The antioxidant activity of DFO has been studied and compared with that of synthetic hydroxypyrid-4-nones (LI) and classic antioxidants (vitamin E). It is known that chronic iron overload in humans is associated with hepatocellular damage. Therefore, Morel et al. [370] studied the antioxidant effects of DFO, another siderophore pyoverdin, and hydroxypyrid-4-ones on lipid peroxidation in primary hepatocyte culture. These authors found that the efficacy of chelators to inhibit iron-stimulated lipid peroxidation in hepatocytes decreased in the range of DFO > hydroxypyrid-4-ones > pyoverdin. It seems that other siderophores are also less effective inhibitors of lipid peroxidation than DFO [371],... 

Overproduction of free radicals by erythrocytes and leukocytes and iron overload result in a sharp increase in free radical damage in T1 patients. Thus, Livrea et al. [385] found a twofold increase in the levels of conjugated dienes, MDA, and protein carbonyls with respect to control in serum from 42 (3-thalassemic patients. Simultaneously, there was a decrease in the content of antioxidant vitamins C (44%) and E (42%). It was suggested that the iron-induced liver damage in thalassemia may play a major role in the depletion of antioxidant vitamins. Plasma thiobarbituric acid-reactive substances (TBARS) and conjugated dienes were elevated in (3-thalassemic children compared to controls together with compensatory increase in SOD activity [386]. The development of lipid peroxidation in thalassemic erythrocytes probably depends on a decrease in reduced glutathione level and decreased catalase activity [387]. 

Desferrioxamine (DFO-B), the natural siderophore initially isolated from Streptomyces pilosus, is the only iron chelator currently used for clinical treatment of iron-overload disease such as thalassemia, sickle cell anemia and hemochromatosis ° . ... 

When injected, it forms a stable water-soluble iron complex (ferrioxamine) that prevents the iron from entering into further chemical reactions and is readily excreted in the urine giving the urine a characteristic reddish colour. Some of it is also excreted in the faeces via the bile. It can also chelate aluminium and thus is useful in aluminium overload. It is primarily a chelator used in acute iron poisoning and chronic iron overload as in thalassemia patients needing multiple transfusions. 

It is an orally active iron chelator. It is useful in acute iron poisoning, iron overload in cirrhosis, transfusion siderosis in thalassemia patients. Adverse effects are anorexia, vomiting, altered taste, joint pain and neutropenia. 

Chronic iron toxicity (iron overload), also known as hemochromatosis, results when excess iron is deposited in the heart, liver, pancreas, and other organs. It can lead to organ failure and death. It most commonly occurs in patients with inherited hemochromatosis, a disorder characterized by excessive iron absorption, and in patients who receive many red cell transfusions over a long period of time (eg, patients with thalassemia major). 

Chronic iron overload in the absence of anemia is most efficiently treated by intermittent phlebotomy. One unit of blood can be removed every week or so until all of the excess iron is removed. Iron chelation therapy using parenteral deferoxamine is much less efficient as well as more complicated, expensive, and hazardous, but it may be the only option for iron overload that cannot be managed by phlebotomy, such as the iron overload experienced by patients with thalassemia major. 

Rapid intravenous administration may result in hypotension. Adverse idiosyncratic responses such as flushing, abdominal discomfort, and rash have also been observed. Pulmonary complications (eg, acute respiratory distress syndrome) have been reported in some patients undergoing deferoxamine infusions lasting longer than 24 hours, and neurotoxicity and increased susceptibility to certain infections (eg, with Yersinia enterocolitica) have been described after long-term therapy of iron overload conditions (eg, thalassemia major). 

Deferasirox is a tridentate chelator with a high affinity for iron and low affinity for other metals, eg, zinc and copper. It is orally active and well absorbed. In the circulation, it binds iron, and the complex is excreted in the bile. Deferasirox was recently approved for the oral treatment of iron overload caused by blood transfusions, a problem in the treatment of thalassemia and myelodysplastic syndrome. 

Desferrioxamine reduces the incidence of heart and liver disease in thalassemia patients. In patients for whom desferrioxamine effectively controls iron overload, there is a 91% rate of cardiac disease-free survival after 15 years of therapy.7 There are negative effects of desferrioxamine treatment for example, too high a dose stunts a child s growth. 

Thalassemia Major. Transfusion-dependem thalassemia major patients liuvc abnormal growth and sexual maturation al puberty, presumably as a result of pituitary iron overload. Still poorly understood, this disorder is reported to respond well to deferoxamine iron chelation therapy, particularly if administered before the age of maturity. 

Patients with beta-thalassemia major have an increased risk of primary hypothyroidism. In 23 patients with beta-thalassemia amiodarone was associated with a high risk of overt hypothyroidism (33 versus 3% in controls) (43). This occurred at up to 3 months after starting amiodarone. The risk of subclinical hypothyroidism was similar in the two groups. In one case overt hypothyroidism resolved spontaneously after withdrawal, but the other patients were given thyroxine. After 21-47 months of treatment three patients developed thyrotoxicosis, with remission after withdrawal. There were no cases of hyperthyroidism in the controls. The authors proposed that patients with beta-thalassemia may be more susceptible to iodine-induced hypothyroidism, related to an underlying defect in iodine in the thyroid, perhaps associated with an effect of iron overload. 

DFO is generally indicated for treatment of acute iron intoxication and chronic iron overload due to transfusion depended anemias (including thalassemia). DFO is not recommended in primary hemochromatosis (PDR). 

Under normal circumstances, transferrin is one-fourth to one-third saturated with iron. The level of saturation may decrease in systemic infection or cancer and in iron deficiency anemia, the most common nutritional deficiency in the United States. In individuals with iron deficiency anemia, transferrin levels are increased. The level of saturation with iron increases in iron overload syndromes such as hereditary hemochromatosis or as a result of repeated blood transfusions, as is the case in thalassemia patients. Determinations of total plasma iron (TI) and plasma total iron binding capacity (TIBC) are routinely performed in the clinical biochemistry laboratory. The TIBC value reflects transferrin levels in plasma the amount of iron that can be bound by transferrin is equal to TIBC x 0.7. Total plasma iron levels in iron deficiency anemia become abnormal before hemoglobin levels show any change. 

The continued absorption of iron causes its deposition in various tissues starting with liver and spleen and followed by myocardium. Deposition of iron in the myocardium usually results in death by intractable cardiac failure. Patients suffer from hypoparathyroidism and hypogonadism. Patients with the severe form of thalassemia are more susceptible to bacterial infection, possibly due to the increase in serum iron, which may favor bacterial growth. Iron overload is less common in the adult forms of Q -thalassemia. This is most likely the result of a fundamental difference between a and -thalassemia. As mentioned, the excess of Q -globin chains cannot form viable tetramers and causes red-cell destruction. The excess jS-chains present in a-thalassemia are able to form solnble homodimers and do not precipitate in the bone marrow. This is paralleled in the fetal state when excess y-chains form solnble homodimers. Hence, a-thalassemia is characterized by a severe degree of inefficient erythropoiesis and a milder degree of anemia. 

Ascorbic acid promotes the absorption of iron, a reason for caution in giving high doses to patients with iron overload (SEDA-9, 324). In particular, patients with hemochromatosis, polycythemia, and leukemia who present with marked iron overload should keep their intake of ascorbic acid to a minimum (42). However, ascorbic acid can also interfere with the distribution of iron in the body in these patients. One consequence is that in patients with iron overload who also have scurvy, iron tends to be deposited in the reticuloendothelial system rather than the parenchymal cells, which may reduce the risks of damage to the liver, heart, or endocrine glands. It has conversely been noted that in beta-thalassemia major... 

Brittenham GM, Griffith PM, Nienhuis AW, McLaren CE, Young NS, Tucker EE, AUen CJ, FarreU DE, Harris JW. Efficacy of deferoxamine in preventing compUcations of iron overload in patients with thalassemia major. N Engl J Med 1994 331(9) 567-73. 

Iron-overload disease, or hemochromatosis, may occur as a consequence of an, as yet, undefined genetic defect, or as a secondary effect of another medical disorder, such as thalassemia. In the former condition, primary hemochromatosis, iron accumulates in various tissues because of a lack of control of iron absorption from the gut. In the latter, or secondary hemochromatosis, the accumulation of iron results from the breakdown of red blood cells and the consequent need for frequent blood transfusions, which lead to an increase in the levels of tissue iron. In both cases the predominant store for iron is hemosiderin (147). 

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