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Iron Toxicity and Clinical Sequelae

Iron Toxicity and Clinical Sequelae. John B. Porter, MA, MD, FRCP Professor Department of Haematology University College London London, United Kingdom. Learning Objectives.

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Iron Toxicity and Clinical Sequelae

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  1. Iron Toxicity and Clinical Sequelae John B. Porter, MA, MD, FRCP ProfessorDepartment of HaematologyUniversity College LondonLondon, United Kingdom

  2. Learning Objectives • Analyze the mechanisms contributing to the development of iron overload and the clinical consequences of iron overload on the liver, heart, and endocrine system. • Utilizing an understanding of the factors contributing to the development of iron overload, identify patients at risk in the practice setting.

  3. Topics • Causes of iron overload • Mechanisms of iron-overload–mediated toxicity • Molecular level • Non–transferrin-bound iron—extracellular • Labile iron pool—intracellular • Free radical formation • Microscopic level • Macroscopic level • Clinical impact consequences of iron overload

  4. Conditions Associated with Iron Overload Transfusional Nontransfusional Age of onset Complications Thalassaemia major1 Type 2 haemochromatosis (rare)2 Childhood Blackfan Diamond Anaemia1 2a hemojuvelin2(Risks from HH) Fanconi’s Anaemia1 2b hepcidin2 Early stroke with HbSS1 Severe haemolytic anaemias1 Aplastic anaemia1,2 Type 1 haemochromatosis1 Typically adult Other transfusion in HbSS1 Thalassaemia intermedia1 Myelodysplasia (MDS)3 Repeated myeloablative chemotherapy1 Slide courtesy of Dr. J. Porter. • Porter JB. Br J Haematol. 2001;115:239. 2. Brittenham G. In Hoffman R, et al, ed. Hematology: Basic Principles and Practice, 4th ed. Philadelphia, PA: Churchill Livingstone, 2004. 3. Taher A, et al. Semin Hematol. 2007;44:S2.

  5. Acquired, Nontransfusional Forms of Iron Overload • Chronic liver disease • Hepatitis C • Alcoholic liver disease • Nonalcoholic steatohepatitis • Porphyria cutanea tarda • Portacaval shunting • Inappropriately high dietary intake • Latrogenic (eg, treatment of microcytosis) • African (Bantu) siderosis* *Dietary and hereditary components. Bacon BR. In Goldman L, ed. Cecil’s Textbook of Medicine, 23rd ed. Philadelphia, PA: Saunders-Elsevier, 2008.

  6. Rare Abnormalities of Iron Distribution Condition Cause Iron Distribution Effects Aceruloplasminaemia Plasma reductase Retina Retinopathy AR1,2 Basal ganglia Extrapyramidal Pancreas Diabetes Hallervorden-Spatz Pantotenate kinase Basal ganglia Extrapyramidal AR3 cysteine accumulation Neuroferritinopathy Ferritin light chain Basal ganglia Extrapyramidal AD4 Forebrain Parkinsonian Cerebellum Freidrich’s Ataxia5,6 Frataxin Mitochondrial Ataxia AR oxidative stress Sensory neurons Spinal cord Dorsal root ganglia Myocardium Cardiomyopathy AR = autosomal recessive; AD = autosomal dominant. 1. Mariani R, et al. Gut. 2004;53:756-8. 2. Hellman NE, et al. Gut. 2000;47:858-60. 3. Hayflick SJ. Curr Opin Pediatr. 2003;15:572-7. 4. Crompton DE, et al. Blood Cells Mol Dis. 2002;29:522-31. 5. Koepen A, et al. Acta Neuropahtol. 2007;114:163-73. 6. Michael, et al. Cerebellum. 2007;5:257-67.

  7. How Does Transfusional Iron Loading Develop?

  8. Simplified Iron Turnover and Storage Erythron 2g 20–30 mg/day Other parenchyma 0.3 g Hepatocytes 1 g 20–30 mg/day Red Transferrin Macrophages 0.6 g 2–3 mg/day 20–30 mg/day 1–2 mg/day Gut Porter J. Hematol/Oncol Clinics. 2005;19(suppl 1):7.

  9. Rate of Iron Loading from Transfusion • Simple estimation1 • 1 unit contains 200 mg of iron • Adult may receive 4–10 g/y from transfusion • More-precise method2 • Volume of blood transfused x mean haematocrit of processed blood obtained from the transfusion centre x 1.08 • For exchange transfusion need to know • Volume and haematocrit transfused • Volume and haematocrit removed • Taher A, et al. Semin Hematol. 2007;44:S2. • Porter JB. Br J Haematol. 2001;115:239.

  10. Transfusional Iron Overload Transfusion Erythron Parenchyma 20–40 mg/day (0.3–0.7 mg/kg/day) Parenchyma Hepatocytes NTBI Red Hepatocytes Macrophages Transferrin Gut NTBI = non–transferrin-bound iron. Adapted from Porter JB. Hematol/Oncol Clinics. 2005;19(suppl 1):7-12.

  11. Liver Iron and Risk from Iron Overload 50 250 Thalassaemia major 40 200 30 HH homozygote 150 Hepatic Iron (µmol/g wet weight) HepaticIron (mg/g, dry weight) 20 Threshold for cardiac disease and early death 100 Increased risk of complications 10 50 HH heterozygote Normal 0 0 0 10 20 30 40 50 Age (years) HH = hereditary haemochromatosis. Olivieri N, Brittenham G. Blood. 1997;89:739.

  12. How Do Inherited Nontransfusional Forms of Iron Loading Develop?

  13. Effect of Hepcidin on Iron Turnover Erythron 20–30 mg/day Hepatocytes 20–30 mg/day IL6 Iron Hypoxia Macrophages - Transferrin + 2–3 mg/day 20–30 mg/day Prohepcidin 1–2 mg/day Gut Hepcidin Adapted from Porter JB. Hematol/Oncol Clinics. 2005;19(suppl 1):7.

  14. TfR21 HJV2 Oral iron1 Iron stores1,2 LPS2 IL-62 HFE1 Factors Affecting Hepcidin Expression? Hepcidin - + • Erythropoiesis1 • Anaemia1 • Hypoxia1 • NTBI? Tf = transferrin; TfR = transferrin receptor; HJV = hemojuvelin; LPS = lipopolysaccharide; IL = interleukin; NTBI = non–transferrin-bound iron. 1. Leong W, Lönnerdal B. J Nutr. 2004;134:1. 2. Lee P, et al. Proc Natl Acad Sci U S A. 2004;101:9263.

  15. Classification of Haemochromatosis With permission from Worwood M. Blood Rev. 2005;19:69.

  16. Why Is Iron Overload Toxic?

  17. Redox Cycling of Iron Fe2+ Fe3+ - e- + e- Slide courtesy of Dr. J. Porter.

  18. Hydroxyl Radical (HO.) Generation Haber Weiss Reaction O2.- + H2O2 -----> O2 + OH- + HO. Catalysed by Iron in two steps; (Fenton reaction) Fe3++ O2.- -----> Fe2++ O2 Fe2++ H2O2 -----> Fe3++OH- + HO. Porter J. Hematol/Oncol Clinics 2005;19(suppl 1):7.

  19. Lipid Peroxidation by HO. . H2O Hydrogen abstraction ( H.) Molecular rearrangement . + O2 Oxygen uptake Peroxyl radical propagates peroxidation byabstracting H. from another fatty acid O O . Lipid hydroperoxide Decomposition eg, to MDA O O H Porter J. Hematol/Oncol Clinics 2005;19(suppl 1):7.With permission from Gutteridge JM, Halliwell B. Baillieries Clin Haematol. 1989;2:195.

  20. Consequences of Iron-Mediated Toxicity Increased free iron Hydroxyl radical generation Lipid peroxidation Organelle damage TGF-b1 Lysosomal fragilityEnzyme leakage Collagensynthesis Cell death Fibrosis Gutteridge JMC, Halliwell B. BailleresClin Haematol. 1989;2:195-256. Bacon BR, et al, J Clin Invest. 1983;71:429-439.Myers BM, et al. J Clin Invest. 1991;88:1207-1215. Tsakamota H, et al. J Clin Invest. 1995;96:620-630.Houglum K, et al. Hepatology.1997;26:605-610.

  21. Nature of NTBI • Nature of NTBI • Citrate iron • Polymeric Slowly chelated • Oligomeric • Dimeric • Monomeric Rapidly chelated • Protein-bound iron • Binds weakly to albumin • As citrate oligomers bound to albumin • Other NTBI = non–transferrin-bound iron. Evans R et al. J Biol Inorg Chem. 2007;13:57.

  22. Uptake of NTBIReceptors • Divalent metal transporter (DMT1)1 • Enterocytes • Erythron (negatively regulated by iron loading) • ? Other • L-type calcium-dependent channels2 • Myocardium (positively induced by iron loading) • Anterior pituitary (positively induced by iron loading) • T-type calcium channels3 • Hepatocytes (positively induced by iron loading) 1.Bacon BR. In Goldman L, ed. Cecil’s Textbook of Medicine, 23rd ed. Philadelphia, PA: Saunders-Elsevier, 2008. 2. Oudit GY, et al. Circulation. 2004;109:1877. 3. Rafique et al. Blood. 2006;108:1542a.

  23. 0 20 40 60 80 Antioxidant Capacity in Iron Overload • 48 thalassaemia major (age 11–22 years) • Vitamin E and NTBI negatively correlate (r = -0.81) • No correlation with serum ferritin Lycopene Ubiquinol Vitamin E Ubiquinone Vitamin A B-carotene Vitamin C % Decrease of Control Slide courtesy of Dr. J. Porter. De Luca C, et al. Free Radic Res. 1999;30:453.

  24. Ferritin Non-transferrin iron LVDCC Labile iron pool(LIP) Lysosomal degradation Free-radical generation Iron proteins Organelle damage Intracellular Iron-Mediated Toxicityfrom Labile Intracellular Iron Transferrin iron LVDCC = L-type voltage-dependent calcium channel. Porter JB. AmJ Hematol. 2007;82:1136.

  25. Where Is Iron Toxic ?

  26. Transfusional Iron Overload Transfusion Erythron Parenchyma 20–40 mg/day (0.3–0.7 mg/kg/day) Parenchyma Hepatocytes NTBI Hepatocytes Macrophages Transferrin Gut NTBI = non–transferrin-bound iron. Adapted from Porter JB. Hematol/Oncol Clinics 2005;19(suppl 1):7.

  27. Iron Distribution in Transfusional Overload • Transfusional overload distribution differs from absorption distribution at early stages1 • Why great variability in iron distribution in different tissues? • Liver, endocrine glands, anterior pituitary1 • Very little in brain, skeletal muscle1 • Liver iron correlates with units transfused2 1. Porter JB. Hematol/Oncol Clinics 2005;19(suppl 1):7. 2. Taher A, et al. Semin Hematol. 2007;44:S2.

  28. Distribution of Body Iron at Postmortem in TM in Prechelation Era Skeletal muscle Testes Kidney Heart Adrenal Salivary gland Thyroid Pancreas Liver Parathyroid Minimum Maximum 0 2 4 6 8 F e % d . w . Tm = thalassaemia major; d.w. = dry weight. Adapted from Modell B, Mathews R. Birth Defects Orig Artic Ser. 1976;12:13.

  29. Liver and Iron Content Postmortem in Thalassaemia Major Heart Liver

  30. Causes of Death in Thalassaemia Age (years) 0–4 5–9 10–14 15–19 >20 Total Heart disease 0 6 39 35 16 96 Infection 2 6 9 3 0 20 Liver disease 0 0 2 7 1 10 Malignancy 2 2 1 1 2 8 Endocrine disease 0 0 2 1 1 4 Accident 0 0 2 2 0 4 Thromboembolism 0 0 2 1 1 4 Anaemia 2 0 0 0 0 2 Other 0 1 1 0 1 3 Unknown 0 1 3 3 18 Total 6 16 61 53 23 159 n = 1078 Zurlo MG, et al. Lancet. 1989;2:27.

  31. 131 transfused adult patients 101 leukaemias 30 other anaemias 100 80 60 40 20 0 26–50 51–75 76–100 101–200 201–300 0–25 Blood Transfusion and Cardiac Iron Deposits at Postmortem in the Prechelation Era Patients with Cardiac Iron (%) Units of Blood Transfused Slide courtesy of Dr. J. Porter. Buja LM, Roberts WC. Am J Med. 1971;51:209.

  32. Blood Transfusion Predicts Heart Iron in Unchelated Patients 20 18 16 14 12 Estimated Heart Iron (µmol/g) 10 8 Upper Normal Limit 6 4 2 0 25 50 75 100 125 150 Blood Units Transfused Slide courtesy of Dr. J. Porter. Jensen PD, et al. Blood. 2003;101:4632.

  33. Is the Heart Equally at Risk of Iron Loading in All Forms of Transfusional Iron? UCLH patients with cardiac MRI Sickle (n = 37) Myelodysplasia (n = 7) Diamond Blackfan (n = 7) PK deficiency (n = 9) Congenital sideroblastic (n = 4) Thalassaemia intermedia (n = 23) Thalassaemia major (n = 108) 0 20 40 60 80 Patients (%, n) with T2* < 20 ms Glanvillle J, et al. Presented at ASH 2006. Blood. 2006;108:abstract 1553.

  34. NTBI in Sickle Cell or Thalassaemia Major Matched for Liver Iron Concentration Patients Treated at UCLH 8 P = 0.0001 7 6 5 4 NTBI (µM) 3.38 ± 2.4 3 2 1 0.17 ± 1.8 0 -1 -2 HbSS Thalassaemia major LIC = 4.34 LIC = 4.22 Slide courtesy of Dr. J. Porter. Shah F. Presentation at ASH Dec 2002. Blood 2002;100:668a.

  35. Which Forms of Iron Are Most Toxic?

  36. Labile Toxic Iron Pools? • NTBI in plasma? • Correlates with antioxidant depletion • Promotion of lipid peroxidation in vitro • BUT which species? • Labile iron pools (LIP) in cells? • In vitro: clear evidence linking free iron to lipid peroxidation and organelle damage • Clinical evidence? • Improvement in cardiac performance with intravenous desferrioxamine precedes changes in cardiac iron • BUT direct link of NTBI or LIP to clinical damage not established Porter J. Hematol/Oncol Clinics. 2005;(suppl 1):S7.

  37. Absolute Tissue Levels? • Evidence (serum ferritin) >2500 µg/L & cardiac disease-free survival1 • Liver iron association with cardiac death2 • Of 15/53 thalassaemia major patients with cardiac disease, all had liver iron >15 mg/g dry weight3 • Association or causation? • But • Iron in different tissues at postmortem does not correlate with damage to those organs3 • Link of cardiac iron to damage & death not known3 • Olivieri NF, et al. N Engl J Med. 1994;331:574. • Brittenham GM, et al. N Engl J Med. 1994;331:567. • Porter JB. Hematol/Oncol Clinics. 2005;19(suppl 1):S7.

  38. Intracellular Iron Levels and Toxicity • Concepts • “Safe iron” • No toxicity in heterozygotes of hereditary haemochromatosis where liver levels < 7mg/g dry weight.1 • “Dangerous iron” • High risk of cardiac death if liver >15 mg/g dry weight.1 • Limitations • Uneven distribution within and between tissues2 • Relationship between heart iron and mortality unknown2 1. Porter JB. Br J Haematol. 2001;115:239. 2. Porter J. Hematol/Oncol Clinics. 2005;19(suppl 1):7.

  39. Functional Consequences of Transfusional Iron Overload • Liver1 • Heart1 • Endocrine system1 • Cancer • Other potential sequelae • Arthropathy2 • Hyperpigmentation2 1. Porter JB. Hematol/Oncol Clinics. 2005;19(suppl 1):S7. 2. Brittenham G. In Hoffman R, et al, ed. Hematology: Basic Principles and Practice, 4th ed. Philadelphia, PA: Churchill Livingstone, 2004.

  40. Organ Systems Affected by Iron Overload Organ Consequences Pituitary Hypogonadotrophic hypogonadism1 Hypothyroidism1 Thyroid Hypoparathyoidism1 Parathyroid Heart Cardiomyopathy1 Liver Cirrhosis, carcinoma1 Pancreas Diabetes1 Pigmentation2 Skin Gonads Hypogonadotrophic hypogonadism1 Joints Arthropathy2 1. Taher A, et al. Semin Hematol. 2007;44:S2. 2. Brittenham G. In Hoffman R, et al, ed. Hematology: Basic Principles and Practice, 4th ed. Philadelphia, PA: Churchill Livingstone, 2004.

  41. Conclusions • Conditions associated with iron overload include transfusional iron overload as well as hereditary and acquired nontransfusional iron overload • Because the body has no mechanism for excretion of excess iron, iron can accumulate • Iron accumulation results in • Increased free iron • Hydroxyl radical generation • Lipid peroxidation • This results in cell death and fibrosis, with impact on a variety of organ systems and functional consequences • Heart • Liver • Endocrine system

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