1. End-organ damage resulting from accumulation of iron in cells Pierre Brissot University Hospital Pontchaillou, Rennes, France

2. End-organ damage resulting from accumulation of iron in cells ●Iron physiology ●Spectrum of chronic iron overload diseases ●Main “culprit” iron species ●Main visceral targets ●Impact specificity according to patient groups

3. Iron physiology

4. Transferrin Iron physiology

9. Transferrin

10. Iron physiology

13. HEPCIDIN

14. Iron physiology

16. Ferritin Iron physiology

17. Transferrin Ferritin Iron physiology 3 mg 1000 mg

18. Fe Transferrin saturation NTBI = non-transferrin- bound iron. Tf Sat <45%

19. IRON STORES Body iron stores Serum Ferritin

20. Correlation between serum ferritin levels and transfusion burden Kattamis C et al. The Management of Genetic Disorders 1979;351–359 Serum ferritin (ng/mL) Blood unit transfused

21. Correlation between serum ferritin levels and transfusion burden Kattamis C et al. The Management of Genetic Disorders 1979;351–359 Serum ferritin (ng/mL) Blood unit transfused (R=0.968)

22. The human body has many mechanisms to absorb, transfer, and store iron… but almost none to excrete it !

23. End-organ damage resulting from accumulation of iron in cells ●Iron physiology ●Spectrum of chronic iron overload diseases ●Main “culprit” iron species ●Main visceral targets ●Impact specificity according to patient groups

24. Spectrum of chronic iron overload ●Transfusional iron overload ●Genetic iron overload

25. Spectrum of chronic iron overload Thalassaemia major Sickle cell disease Myelodysplastic syndrome Anaemia Iron overload 200 mg

26. Version 2, 2006 60kg thalassemia patient Transfusion therapy results in iron overload 45 blood units /year 200mg Overload can occur after 10-20 transfusions 9g iron / year (transfusions) 1g iron / year (digestive absorption) + 10g iron /year

27. IRON Spleen Digestive tract Blood Spectrum of chronic iron overload

28. Thalassaemia major Sickle cell disease Myelodysplastic syndrome Anaemia Iron overload 200 mg hepcidin

29. IRON Spleen Digestive tract HEPCIDIN Blood Spectrum of chronic iron overload Anaemia

30. Spectrum of chronic iron overload ●Transfusional iron overload ●Genetic iron overload

31. Hepcidin HFE Transferrin Receptor 2 TfR2 Ferroportin Acerulo- plasminaemia Hemojuvelin juvenile C 282 Y juvenile Genetic iron overload disorders

32. Hepcidin HFE TfR2 Ferroportin Acerulo- plasminaemia Hemojuvelin juvenile C 282 Y juvenile Genetic iron overload disorders

33. IRON Spleen Digestive tract HEPCIDIN Blood Spectrum of chronic iron overload HFE or non HFE mutation

34. End-organ damage resulting from accumulation of iron in cells ●Iron physiology ●Spectrum of chronic iron overload diseases ●Main “culprit” iron species ●Main visceral targets ●Impact specificity according to patient groups

35. Fe NTBI (Non Transferrin Bound Iron) Dangerous iron species Transferrin saturation > 45% Loréal O, et al. J Hepatol. 2000;32:727-33 NTBI = non-transferrin- bound iron.

36. LPI (Labile Plasma Iron) Dangerous iron species Fe Transferrin saturation > 75% Pootrakul P Blood 2004 - Le Lan C Blood 2005 LPI = labile plasma iron.

37. NTBI (LPI) Dangerous iron species

40. R.O.S (Reactive Oxygen Species) Dangerous iron species

41. End-organ damage resulting from accumulation of iron in cells ●Iron physiology ●Spectrum of chronic iron overload diseases ●Main “culprit” iron species ●Main visceral targets ●Impact specificity according to patient groups

42. Visceral targets of iron overload: liver Brissot P. In: Barton JC, Edwards CQ, eds. Hemochromatosis: Genetics, pathophysiology, diagnosis, and treatment. Cambridge University Press: Cambridge; 2000. p. 250-7; Prati D, et al. Haematologica. 2004;89:1179-86.

43. Visceral targets of iron overload: liver

44. Visceral targets of iron overload: heart Caines AE, et al. J Heart Lung Transplant. 2005;24:486-8.

45. Visceral targets of iron overload: heart

46. 0–25 26–5051–7576–100101–200201–300 0 20 40 60 80 100 Units of blood transfused Patients with cardiac iron (%) Buja LM & Roberts WC. Am J Med 1971;51:209–221 Post-mortem cardiac iron deposits correlate with blood transfusions

47. Cario H, et al. Horm Res. 2003;59:73-8. Visceral targets of iron overload: endocrine system

48. 5–10% of thalassaemia patients have diabetes Khalifa AS, et al. Pediatr Diabetes. 2004;5:126-32. ? % of haemochromatosis patients have diabetes Waalen J, et al. Best Pract Res Clin Haematol. 2005;18:203-20.

49. Impact of iron overload on endocrine glands

50. Impact of iron overload on skeleton

51. Skin pigmentation in iron overload Genetic haemochromatosis Thalassaemia

52. End-organ damage resulting from accumulation of iron in cells ●Iron physiology ●Spectrum of chronic iron overload diseases ●Main “culprit” iron species ●Main visceral targets ●Impact specificity according to patient groups

53. Hepatocyte siderosisKupffer cell siderosis Differential siderosis distribution

54. Threshold for cardiac disease and early death Olivieri NF, Brittenham GM. Blood. 1997;89:739–61. 50403020100 20 30 40 50 Age (years) Hepatic iron (mg/g dry weight) Increased risk of complications normal Thalassaemia major Genetic haemochromatosis 0 Differential overall severity

55. Differential visceral impact Genetic Iron Overload Transfusional Iron Overload

56. Differential visceral impact Genetic Iron Overload ●Brissot P, et al. Curr Hematol Rep. 2004;3:107-15. ●Pietrangelo A. N Engl J Med. 2004;350:2383-97.

57. Hepatomegaly in C 282 Y/C 282 Y haemochromatosis

58. Cirrhosis in C 282 Y/C 282 Y haemochromatosis Role of co-factors Alcohol Fletcher LM, Powell LW. Alcohol. 2003;30:131-6. Steatosis Powell EE, et al. Gastroenterology 2005;129:1937-43.

59. Hepatocellular carcinoma in C 282 Y/C 282 Y haemochromatosis

60. Arthropathy in C 282 Y /C282 Y haemochromatosis

61. Impact specificity for genetic non-HFE-related overload 1. Papanikolaou G, et al. Nat Genet. 2004;36:77-82. ●Juvenile haemochromatosis 1 –young age –cardiac failure –endocrine complications

62. Impact specificity for genetic non-HFE-related overload 1. Papanikolaou G, et al. Nat Genet. 2004;36:77-82. 2. Pietrangelo A. Blood Cells Mol Dis. 2004;32:131-8. ●Ferroportin disease 2 –mild clinical expression ●Juvenile haemochromatosis 1 –young age –cardiac failure –endocrine complications

63. Impact specificity for genetic non-HFE-related overload ●Hereditary aceruloplasminaemia 3 –Anaemia and neurological components 1. Papanikolaou G, et al. Nat Genet. 2004;36:77-82. 2. Pietrangelo A. Blood Cells Mol Dis. 2004;32:131-8. 3. Loréal O. J Hepatol. 2002;36:851-6. ●Ferroportin disease 2 –mild clinical expression ●Juvenile haemochromatosis 1 –young age –cardiac failure –endocrine complications

64. Differential visceral impact Genetic Iron Overload Transfusional Iron Overload

65. ●Cohen AR, et al. Hematology. 2004:14-34. ●Porter JB, Davis BA. Best Pract Res Clin Haematol. 2002;15:329-68. Impact specificity for ß-thalassaemia

66. Heart: 1st cause of mortality Pulmonary hypertension Fisher CA, et al. Br J Haematol. 2003;121:662-71 Venous thrombosis Eldor A, Rachmilewitz EA. Blood. 2002;99:36-43. Impact of β-thalassaemia on the cardiovascular system

67. Impact of β-thalassaemia on growth and sexual development Short stature Raiola G, et al. J Pediatr Endocrinol Metab. 2003;16:259-66. Hypogonadism (50% patients ) Clin Endocrinology (Oxf). 1995;42:581-6 Lower height of pituitary gland Argyropoulou MI, et al. Neuroradiology. 2001;43:1056-8

68. Gullo L, et al. Pancreas. 1993;8:176-80. Exocrine pancreas damage in β-thalassaemia

69. Correlation between iron burden and endocrine complications Jensen CE et al. Eur J Haematol 1997;59:76–81 2000 2200 2400 2600 2800 3000 3200 3400 3600 3800 4000 No endocrinopathies serum ferritin (µg/L) At least one endocrinopathy

70. Bone deformities Abu Alhaija ES, et al. Eur J Orthod. 2002;24:9-19. Impact of β-thalassaemia on the skeleton

71. Effect of iron overload on survival in β-thalassaemia Age (years) Mild (ferritin < 2,000 μg/L) n = 319 Moderate (ferritin 2,000–4,000 μg/L) n = 182 Severe (ferritin > 4,000 μg/L) n = 146 p < 0.001 Survival probability 0 0.2 0.4 0.6 0.8 1 0 10 20 30 40 50 Ladis V, et al. Ann N Y Acad Sci. 2005;1054:445

72. Impact specificity for myelodysplasia ●Heart failure Unclear how many of these problems are actually caused by other factors: Gattermann N. Hematol Oncol Clin North Am. 2005;19(Suppl 1):13-7. –chronic anaemia –concomitant diseases –complications of bone marrow failure –aging process ●Hepatic impairment ●Endocrine abnormalities (diabetes and inadequate hypothalamic-pituitary-adrenal reserve)

73. Summary ●Chronic iron overload, whatever its origin, is potentially harmful ●Iron toxicity implicates NTBI (LPI) ●Iron toxicity targets many organs, mainly: –liver and joints in haemochromatosis –heart and endocrine system in transfusional iron overload ●Iron toxicity generates not only morbidity but mortality

74. Conclusion ●The design of new drugs and novel therapeutic approaches for counteracting or preventing the damaging effects of iron overload represents an important health challenge