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

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

Transferrin

Iron physiology

Iron physiology

Iron physiology

Iron physiology

Iron physiology

Iron physiology

Transferrin

Iron physiology

Iron physiology

Iron physiology

Iron physiology

HEPCIDIN

Iron physiology

Iron physiology

Ferritin

Iron physiology

Transferrin

Ferritin

Iron physiology

3 mg

1000 mg

Fe

Transferrin saturation

NTBI = non-transferrin-bound iron.

Tf Sat <45%

IRONSTORESBody iron stores

Serum Ferritin

Correlation between serum ferritin levels

and transfusion burden

Kattamis C et al. The Management of Genetic Disorders 1979;351–359

Ser

um

fer

riti

n (

ng

/mL

)

Blood unit transfused

0

2000

4000

6000

8000

10000

12000

14000

16000

0 20 40 60 80 100 120 140 160 180 200 220

Correlation between serum ferritin levels

and transfusion burden

Kattamis C et al. The Management of Genetic Disorders 1979;351–359

Ser

um

fer

riti

n (

ng

/mL

)

Blood unit transfused

0

2000

4000

6000

8000

10000

12000

14000

16000

0 20 40 60 80 100 120 140 160 180 200 220

(R=0.968)

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 majorSickle cell diseaseMyelodysplastic syndrome

Anaemia

Iron overload

200 mg

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

IRON

Spleen

Digestive tract

Blood

Spectrum of chronic iron overload

Spectrum of chronic iron overload

Thalassaemia majorSickle cell diseaseMyelodysplastic syndrome

Anaemia

Iron overload

200 mg

hepcidin

IRON

Spleen

Digestive tract

HEPCIDIN

Blood

Spectrum of chronic iron overload

Anaemia

Spectrum of chronic iron overload

● Transfusional iron overload

● Genetic iron overload

Hepcidin

Clip

HFE

Transferrin Receptor 2

TfR2

Ferroportin

Acerulo-plasminaemia

Hemojuvelinjuvenile

C282Y

juvenile

Genetic iron overload disorders

Hepcidin

Clip

HFE

TfR2

Ferroportin

Acerulo-plasminaemia

Hemojuvelinjuvenile

C282Y

juvenile

Genetic iron overload disorders

IRON

Spleen

Digestive tract

HEPCIDIN

Blood

Spectrum of chronic iron overload

HFE or non HFE mutation

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

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.

LPI (Labile Plasma Iron)

Dangerous iron species

Fe

Transferrin saturation > 75%Pootrakul P Blood 2004 - Le Lan C Blood 2005

LPI = labile plasma iron.

NTBI

(LPI)

Dangerous iron species

Dangerous iron species

Dangerous iron species

R.O.S(Reactive Oxygen Species)

Dangerous iron 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

0–25 26–50 51–75 76–100 101–200 201–3000

20

40

60

80

100

Units of blood transfused

Pat

ien

ts w

ith

car

dia

c ir

on

(%

)

Buja LM & Roberts WC. Am J Med 1971;51:209–221

Post-mortem cardiac iron deposits correlate with blood transfusions

Cario H, et al. Horm Res. 2003;59:73-8.

Visceral targets of iron overload: endocrine system

Visceral targets of iron overload: endocrine system

5–10% of thalassaemia patients have

diabetesKhalifa AS, et al. Pediatr Diabetes. 2004;5:126-32.

? % of haemochromatosis patients have diabetesWaalen J, et al. Best Pract Res Clin

Haematol. 2005;18:203-20.

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

Hepatocyte siderosis Kupffer cell siderosis

Differential siderosis distribution

Threshold for cardiac disease and early death

Olivieri NF, Brittenham GM. Blood. 1997;89:739–61.

50403020100

10

20

30

40

50

Age (years)

He

pat

ic ir

on (

mg

/g d

ry w

eig

ht)

Increased risk of complications

normal

Thalassaemia major

Genetic haemochromatosis

0

Differential overall severity

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 C282Y/C282Y haemochromatosis

Cirrhosis in C282Y/C282Y haemochromatosis

Role of co-factors

AlcoholFletcher LM, Powell LW. Alcohol. 2003;30:131-6.

SteatosisPowell EE, et al.

Gastroenterology 2005;129:1937-43.

Hepatocellular carcinoma in C282Y/C282Y haemochromatosis

Arthropathy in C282Y/C282Y haemochromatosis

Impact specificity for genetic non-HFE-related overload

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

● Juvenile haemochromatosis1

– young age– cardiac failure – endocrine complications

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 disease2

– mild clinical expression

● Juvenile haemochromatosis1

– young age– cardiac failure – endocrine complications

Impact specificity for genetic non-HFE-related overload

● Hereditary aceruloplasminaemia3

– 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 disease2

– mild clinical expression

● Juvenile haemochromatosis1

– young age– cardiac failure – endocrine complications

Differential visceral impact

Genetic Iron Overload

Transfusional Iron Overload

● 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

Heart: 1st cause

of mortality

Pulmonary hypertensionFisher 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

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

Gullo L, et al. Pancreas. 1993;8:176-80.

Exocrine pancreas damage in β-thalassaemia

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

se

rum

fe

rrit

in (

µg

/L)

At least one endocrinopathy

Bone deformities

Abu Alhaija ES, et al. Eur J Orthod. 2002;24:9-19.

Impact of β-thalassaemia on the skeleton

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 < 0.001Su

rviv

al p

rob

abil

ity

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

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)

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