End-organ damage resulting from accumulation of iron in cells Pierre Brissot

University Hospital Pontchaillou, Rennes, France

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

Iron physiology

Iron physiology Transferrin

Iron physiology

Iron physiology

Iron physiology

Iron physiology

Iron physiology Transferrin

Iron physiology

Iron physiology

Iron physiology

Iron physiology HEPCIDIN

Iron physiology

Iron physiology

Iron physiology Ferritin

Transferrin 3 mg Iron physiology

Ferritin

1000 mg

Transferrin saturation Fe

NTBI = non-transferrin bound iron.

Tf Sat <45%

Serum

Correlation between serum ferritin levels and transfusion burden 16000 14000 12000 10000 8000 6000 4000 2000 0 0 20 40 60 80 100 120 140 160 180 200 220 Blood unit transfused Kattamis C et al. The Management of Genetic Disorders 1979;351 –359

Correlation between serum ferritin levels and transfusion burden 16000 14000 12000 10000 8000 6000 4000 2000 0 0 (R=0.968) 20 40 60 80 100 120 140 160 Blood unit transfused 180 200 220

Kattamis C et al.

The Management of Genetic Disorders

1979;351 –359

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

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

Spectrum of chronic iron overload

● Transfusional iron overload ● Genetic iron overload

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

Version 2, 2006

Transfusion therapy results in iron overload

200mg

60kg thalassemia patient 45 blood units /year 9g iron / year (transfusions)

+

1g iron / year (digestive absorption) 10g iron /year Overload can occur after 10-20 transfusions

Spectrum of chronic iron overload Spleen IRON Blood Digestive tract

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

Spectrum of chronic iron overload

Anaemia

HEPCIDIN Spleen IRON Blood Digestive tract

Spectrum of chronic iron overload

● Transfusional iron overload ● Genetic iron overload

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

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

Spectrum of chronic iron overload

HFE or non HFE mutation

HEPCIDIN Spleen IRON Blood Digestive tract

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

Dangerous iron species NTBI (Non Transferrin Bound Iron) Fe

NTBI = non-transferrin bound iron.

Transferrin saturation > 45% Loréal O, et al. J Hepatol. 2000;32:727-33

Dangerous iron species LPI (Labile Plasma Iron) Fe Transferrin saturation > 75%

LPI = labile plasma iron.

Pootrakul P Blood 2004 - Le Lan C Blood 2005

NTBI (LPI) Dangerous iron species

Dangerous iron species

Dangerous iron species

Dangerous iron species R.O.S

(Reactive Oxygen Species)

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

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.

Visceral targets of iron overload: liver

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

Visceral targets of iron overload: heart

Post-mortem cardiac iron deposits correlate with blood transfusions 100 80 60 40 20 0 0 –25 26 –50 51 –75 76 –100 101–200 201–300 Units of blood transfused

Buja LM & Roberts WC.

Am J Med

1971;51:209 –221

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

Visceral targets of iron overload: endocrine system ? % of haemochromatosis patients have diabetes Waalen J, et al. Best Pract Res Clin Haematol. 2005;18:203-20.

5–10% of thalassaemia patients have diabetes Khalifa AS, et al. Pediatr Diabetes. 2004;5:126-32.

Impact of iron overload on endocrine glands

Impact of iron overload on skeleton

Skin pigmentation in iron overload Genetic haemochromatosis Thalassaemia

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

Differential siderosis distribution

Hepatocyte siderosis Kupffer cell siderosis

Differential overall severity

50 40 30 20 10 0 0

Thalassaemia major

10 20

Genetic haemochromatosis

Threshold for cardiac disease and early death Increased risk of complications normal

30 Age (years) 40 50 Olivieri NF, Brittenham GM. Blood. 1997;89:739 –61.

Differential visceral impact

Genetic Iron Overload Transfusional Iron Overload

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.

Hepatomegaly in C 282 Y/C 282 Y haemochromatosis

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.

Hepatocellular carcinoma in C 282 Y/C 282 Y haemochromatosis

Arthropathy in C 282 Y /C282 Y haemochromatosis

Impact specificity for genetic non-HFE -related overload

●

Juvenile haemochromatosis 1

– young age – cardiac failure – endocrine complications

1. Papanikolaou G, et al. Nat Genet. 2004;36:77-82.

Impact specificity for genetic non-HFE -related overload

●

Juvenile haemochromatosis 1

● – young age – cardiac failure – endocrine complications

Ferroportin disease 2

– mild clinical expression

1. Papanikolaou G, et al. Nat Genet. 2004;36:77-82.

2. Pietrangelo A. Blood Cells Mol Dis. 2004;32:131-8.

Impact specificity for genetic non-HFE -related overload

●

Juvenile haemochromatosis 1

● – young age – cardiac failure – endocrine complications

Ferroportin disease 2

– mild clinical expression ●

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.

Differential visceral impact

Genetic Iron Overload Transfusional Iron Overload

Impact specificity for ß-thalassaemia

● Cohen AR, et al. Hematology. 2004:14-34.

● Porter JB, Davis BA. Best Pract Res Clin Haematol. 2002;15:329-68.

Impact of β-thalassaemia on the cardiovascular system Heart: 1st cause of mortality

Venous thrombosis

Eldor A, Rachmilewitz EA. Blood. 2002;99:36-43.

Pulmonary hypertension

Fisher CA, et al. Br J Haematol.

2003;121:662-71

Impact of β-thalassaemia on growth and sexual development

Short stature

Raiola G, et al. J Pediatr Endocrinol Metab. 2003;16:259-66.

Lower height of pituitary gland

Argyropoulou MI, et al.

Neuroradiology.

2001;43:1056-8

Hypogonadism (50% patients )

Clin Endocrinology (Oxf).

1995;42:581-6

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

Correlation between iron burden and endocrine complications 4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 2000 No endocrinopathies At least one endocrinopathy

Jensen CE

et al

.

Eur J Haematol

1997;59:76 –81

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

Effect of iron overload on survival in β-thalassaemia 1 0.8

0.6

0.4

0.2

p < 0.001

0 0 10 20 30 Ladis V, et al. Ann N Y Acad Sci. 2005;1054:445 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 40 50 Age (years)

Impact specificity for myelodysplasia

● Heart failure ● Hepatic impairment ● Endocrine abnormalities (diabetes and inadequate hypothalamic-pituitary-adrenal reserve) Unclear how many of these problems are actually caused by other factors: – chronic anaemia – concomitant diseases – complications of bone marrow failure – aging process

Gattermann N. Hematol Oncol Clin North Am. 2005;19(Suppl 1):13-7.

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

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