Pediatric Clinics of North America - CIPERJ

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Pediatr Clin N Am 55 (2008) 461–482 Oral Iron Chelators Janet L. Kwiatkowski, MD, MSCE a,b, * a University of Pennsylvania School of Medicine, 34th Street and Civic Center Boulevard, Philadelphia, PA 19104, USA b Division of Hematology, The Children’s Hospital of Philadelphia, 34th Street and Civic Center Boulevard, Children’s Seashore House, 4th Floor, Hematology, Philadelphia, PA 19104, USA Transfusion-related iron overload Regular red cell transfusions are used in the management of many hematologic disorders in children. In b-thalassemia major, transfusions relieve severe anemia, suppress compensatory bone marrow hyperplasia, and prolong survival. Regular red cell transfusions also are used frequently in children who have sickle cell disease, primarily to prevent and treat devastating complications, such as stroke [1]. Other conditions that may be treated with transfusion therapy include Diamond-Blackfan anemia that is poorly responsive to steroids; Fanconi anemia; hemolytic anemias, such as pyruvate kinase deficiency; sideroblastic anemias; congenital dyserythropoietic anemias; and myelodysplastic syndromes. In humans, iron is required for many essential functions, including oxygen transport, oxidative energy production, mitochondrial respiration, and DNA synthesis [2]. Iron loss is limited to small amounts in the stool, urine, desquamated nail and skin cells, and menstrual losses in women, and humans lack physiologic mechanisms to excrete excess iron. Chronic red cell transfusion therapy leads to progressive iron accumulation in the absence of chelation therapy because the iron contained in the transfused red cells is not excreted efficiently. Each milliliter of packed red cells contains approximately 1.1 mg of iron. A regular transfusion regimen usually consists of 10 to 15 mL/kg of packed red cells administered every 3 to 4 weeks to maintain a trough hemoglobin level of 9 to 10 g/dL in patients who have thalassemia and other congenital * Division of Hematology, The Children’s Hospital of Philadelphia, 34th Street and Civic Center Boulevard, Children’s Seashore House, 4th Floor, Hematology, Philadelphia, PA 19104. E-mail address: kwiatkowski@email.chop.edu 0031-3955/08/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.pcl.2008.01.005 pediatric.theclinics.com
462 KWIATKOWSKI anemias and to maintain the hemoglobin S percentage at less than 30% in children who have sickle cell disease. This leads to an average iron accumulation of approximately 0.3 to 0.5 mg/kg per day, although there is considerable interpatient variability in iron loading. In addition, gastrointestinal iron absorption is increased greatly in patients who have ineffective erythropoiesis, such as thalassemia, and in some red cell enzyme deficiencies, in particular pyruvate kinase deficiency. The increased absorption of dietary iron can cause iron overload even in the absence of transfusions, although at a slower rate than that associated with chronic transfusions. Serial phlebotomy may be used to treat iron overload in some patients who have congenital anemia, but chelation therapy is needed to remove iron for those who have more severe anemia or transfusion dependence. Hereditary hemochromatosis Iron overload can result from hereditary causes that lead to increased intestinal absorption of dietary iron. Hepcidin, a small peptide produced by the liver in response to high iron levels and inflammation, inhibits iron absorption [3]. Dysregulation of hepcidin now seems central in many of the hereditary forms of hemochromatosis. The most common form of hereditary hemochromatosis is caused by mutations in the HFE gene, which prevent the appropriate up-regulation of hepcidin expression in response to increased iron levels [4]. A mutation causing a cysteine-to-tyrosine substitution (C282Y) in the HFE protein is common in those of Northern European ancestry and a second mutation causing a histidine-to-aspartic acid substitution (H63D) is distributed worldwide. Homozygosity for the C282Y mutation or compound heterozygosity for C282Y/H63D is associated with the development of iron overload, although clinical penetrance is variable. Clinical manifestations, including bronzing of the skin, cirrhosis, arthropathies, diabetes mellitus, and endocrinopathies, usually do not develop until middle age. Cardiac disease also can occur, although less commonly than with transfusional iron overload (discussed later). Mutations in the hepcidin gene or in another protein involved in hepcidin regulation, hemojuvelin, lead to a juvenile form of hemochromatosis with symptoms presenting by the third decade of life [5]. The standard treatment for hereditary hemochromatosis is phlebotomy to reduce iron stores, although iron chelation therapy may be used in patients who are unable to tolerate the procedure. Organ toxicity related to iron overload Free iron is toxic to cells and, therefore, iron normally is shielded by forming tight complexes with proteins. In plasma, iron is bound to transferrin, which transports iron to the cells. The main storage form of iron is ferritin, whereas hemosiderin is another iron storage protein, consisting of
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Pediatr Clin N Am 55 (2008) xiii-xi
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Pediatr Clin N Am 55 (2008) 287-304
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DECISION ANALYSIS IN PEDIATRIC HEMA
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Nietert et al [30] Treatment of sic
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VENOUS THROMBOEMBOLISM IN CHILDREN
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PEDIATRIC ARTERIAL ISCHEMIC STROKE
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CARE OF PATIENTS WITH VASCULAR ANOM
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358 RODRIGUEZ & HOOTS Fig. 1. X-lin
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Table 1 Clotting factor concentrate
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Table 1 (continued ) Factor VIII (o
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364 RODRIGUEZ & HOOTS was administe
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366 RODRIGUEZ & HOOTS Antifibrinoly
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368 RODRIGUEZ & HOOTS infections an
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370 RODRIGUEZ & HOOTS Fig. 3. Schem
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372 RODRIGUEZ & HOOTS protein is no
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374 RODRIGUEZ & HOOTS [2] Berntorp
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376 RODRIGUEZ & HOOTS [42] Carcao M
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378 ROBERTSON et al von Willebrand
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380 ROBERTSON et al Fig. 2. A propo
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382 ROBERTSON et al a heterogenous
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384 ROBERTSON et al of considering
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386 ROBERTSON et al Type 2M Type 2M
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388 ROBERTSON et al Desmopressin is
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390 ROBERTSON et al References [1]
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392 ROBERTSON et al [46] Nesbitt IM
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394 BLANCHETTE & BOLTON-MAGGS A key
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396 BLANCHETTE & BOLTON-MAGGS recep
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398 BLANCHETTE & BOLTON-MAGGS and p
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400 BLANCHETTE & BOLTON-MAGGS Fig.
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402 BLANCHETTE & BOLTON-MAGGS in di
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404 BLANCHETTE & BOLTON-MAGGS the s
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406 BLANCHETTE & BOLTON-MAGGS findi
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408 BLANCHETTE & BOLTON-MAGGS as a
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Page 140 and 141: 424 FASANO & LUBAN Leukocyte reduct
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Page 164 and 165: THALASSEMIA UPDATE 449 hypochromia
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Page 168 and 169: THALASSEMIA UPDATE 453 delivery of
Page 170 and 171: THALASSEMIA UPDATE 455 thromboses i
Page 172 and 173: THALASSEMIA UPDATE 457 On the basis
Page 174 and 175: THALASSEMIA UPDATE 459 [31] Kan YW,
Page 178 and 179: ORAL IRON CHELATORS 463 large iron-
Page 180 and 181: ORAL IRON CHELATORS 465 of 50 child
Page 182 and 183: ORAL IRON CHELATORS 467 Table 2 Com
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512 TRACY & RICE German experience
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514 TRACY & RICE Table 1 Effect of
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516 TRACY & RICE decreased bilirubi
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518 TRACY & RICE [13] Bader-Meunier
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