end-organ damage resulting from accumulation of iron in cells pierre brissot university hospital...
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![Page 1: End-organ damage resulting from accumulation of iron in cells Pierre Brissot University Hospital Pontchaillou, Rennes, France](https://reader030.vdocuments.net/reader030/viewer/2022033100/56649d8c5503460f94a733aa/html5/thumbnails/1.jpg)
End-organ damage resulting from accumulation of
iron in cells
Pierre Brissot
University Hospital Pontchaillou,
Rennes, France
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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
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Iron physiology
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Transferrin
Iron physiology
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Iron physiology
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Iron physiology
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Iron physiology
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Iron physiology
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Iron physiology
Transferrin
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Iron physiology
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Iron physiology
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Iron physiology
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Iron physiology
HEPCIDIN
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Iron physiology
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Iron physiology
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Ferritin
Iron physiology
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Transferrin
Ferritin
Iron physiology
3 mg
1000 mg
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Fe
Transferrin saturation
NTBI = non-transferrin-bound iron.
Tf Sat <45%
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IRONSTORESBody iron stores
Serum Ferritin
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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
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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)
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The human body has many mechanisms to absorb, transfer, and store iron…
but almost none to excrete it !
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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
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Spectrum of chronic iron overload
● Transfusional iron overload
● Genetic iron overload
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Spectrum of chronic iron overload
Thalassaemia majorSickle cell diseaseMyelodysplastic syndrome
Anaemia
Iron overload
200 mg
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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
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IRON
Spleen
Digestive tract
Blood
Spectrum of chronic iron overload
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Spectrum of chronic iron overload
Thalassaemia majorSickle cell diseaseMyelodysplastic syndrome
Anaemia
Iron overload
200 mg
hepcidin
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IRON
Spleen
Digestive tract
HEPCIDIN
Blood
Spectrum of chronic iron overload
Anaemia
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Spectrum of chronic iron overload
● Transfusional iron overload
● Genetic iron overload
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Hepcidin
Clip
HFE
Transferrin Receptor 2
TfR2
Ferroportin
Acerulo-plasminaemia
Hemojuvelinjuvenile
C282Y
juvenile
Genetic iron overload disorders
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Hepcidin
Clip
HFE
TfR2
Ferroportin
Acerulo-plasminaemia
Hemojuvelinjuvenile
C282Y
juvenile
Genetic iron overload disorders
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IRON
Spleen
Digestive tract
HEPCIDIN
Blood
Spectrum of chronic iron overload
HFE or non HFE mutation
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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
![Page 35: End-organ damage resulting from accumulation of iron in cells Pierre Brissot University Hospital Pontchaillou, Rennes, France](https://reader030.vdocuments.net/reader030/viewer/2022033100/56649d8c5503460f94a733aa/html5/thumbnails/35.jpg)
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.
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LPI (Labile Plasma Iron)
Dangerous iron species
Fe
Transferrin saturation > 75%Pootrakul P Blood 2004 - Le Lan C Blood 2005
LPI = labile plasma iron.
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NTBI
(LPI)
Dangerous iron species
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Dangerous iron species
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Dangerous iron species
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R.O.S(Reactive Oxygen Species)
Dangerous iron species
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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
![Page 42: End-organ damage resulting from accumulation of iron in cells Pierre Brissot University Hospital Pontchaillou, Rennes, France](https://reader030.vdocuments.net/reader030/viewer/2022033100/56649d8c5503460f94a733aa/html5/thumbnails/42.jpg)
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.
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Visceral targets of iron overload: liver
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Visceral targets of iron overload: heart
Caines AE, et al. J Heart Lung Transplant. 2005;24:486-8.
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Visceral targets of iron overload: heart
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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
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Cario H, et al. Horm Res. 2003;59:73-8.
Visceral targets of iron overload: endocrine system
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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.
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Impact of iron overload on endocrine glands
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Impact of iron overload on skeleton
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Skin pigmentation in iron overload
Genetic haemochromatosis Thalassaemia
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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
![Page 53: End-organ damage resulting from accumulation of iron in cells Pierre Brissot University Hospital Pontchaillou, Rennes, France](https://reader030.vdocuments.net/reader030/viewer/2022033100/56649d8c5503460f94a733aa/html5/thumbnails/53.jpg)
Hepatocyte siderosis Kupffer cell siderosis
Differential siderosis distribution
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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
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Differential visceral impact
Genetic Iron Overload
Transfusional Iron Overload
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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.
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Hepatomegaly in C282Y/C282Y haemochromatosis
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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.
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Hepatocellular carcinoma in C282Y/C282Y haemochromatosis
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Arthropathy in C282Y/C282Y haemochromatosis
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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
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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
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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
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Differential visceral impact
Genetic Iron Overload
Transfusional Iron Overload
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● 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
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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
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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
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Gullo L, et al. Pancreas. 1993;8:176-80.
Exocrine pancreas damage in β-thalassaemia
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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
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Bone deformities
Abu Alhaija ES, et al. Eur J Orthod. 2002;24:9-19.
Impact of β-thalassaemia on the skeleton
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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
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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)
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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
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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