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
Iron physiology
Ferritin
1000 mg
Transferrin
3 mg
Transferrin saturation
Fe
NTBI = non-transferrinbound iron.
Tf Sat <45%
Serum
Ferritin
IRON
STORES
Body iron stores
Correlation between serum ferritin levels
and transfusion burden
Serum ferritin (ng/mL)
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
Serum ferritin (ng/mL)
16000
14000
(R=0.968)
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
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
60kg thalassemia patient
45 blood units /year
200mg
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
Digestive
tract
Blood
Spectrum of chronic iron overload
Thalassaemia major
Sickle cell disease
Myelodysplastic syndrome
Anaemia
hepcidin
200 mg
Iron
overload
Spectrum of chronic iron overload
Anaemia
HEPCIDIN
Spleen
IRON
Digestive
tract
Blood
Spectrum of chronic iron overload
● Transfusional iron overload
● Genetic iron overload
Genetic iron overload disorders
Transferrin Receptor 2
TfR2
Hepcidin
juvenile
HFE
Clip
C282Y
Hemojuvelin
juvenile
Ferroportin
Aceruloplasminaemia
Genetic iron overload disorders
TfR2
Hepcidin
juvenile
HFE
Clip
C282Y
Hemojuvelin
juvenile
Ferroportin
Aceruloplasminaemia
Spectrum of chronic iron overload
HFE or non HFE mutation
HEPCIDIN
Spleen
IRON
Digestive
tract
Blood
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-transferrinbound 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
Dangerous iron species
NTBI
(LPI)
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
Patients with cardiac iron (%)
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
Hepatic iron (mg/g dry weight)
Differential overall severity
Thalassaemia major
50
40
Genetic
haemochromatosis
30
Threshold for
cardiac disease and early death
20
Increased risk of complications
10
0
normal
0
10
20
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
C282Y/C282Y haemochromatosis
Cirrhosis in C282Y/C282Y
haemochromatosis
Role of co-factors
Alcohol
Steatosis
Fletcher LM, Powell LW. Alcohol.
2003;30:131-6.
Powell 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
● Juvenile haemochromatosis1
– 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 haemochromatosis1
– young age
– cardiac failure
– endocrine complications
● Ferroportin disease2
– 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 haemochromatosis1
– young age
– cardiac failure
– endocrine complications
● Ferroportin disease2
– mild clinical expression
● 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.
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
Lower height of
pituitary gland
Argyropoulou MI, et al.
Neuroradiology.
2001;43:1056-8
Short stature
Raiola G, et al.
J Pediatr
Endocrinol Metab.
2003;16:259-66.
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
serum ferritin (µg/L)
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.
Survival probability
Effect of iron overload on survival in
β-thalassaemia
Mild (ferritin < 2,000 μg/L)
n = 319
1
0.8
Moderate (ferritin
2,000–4,000 μg/L)
n = 182
0.6
0.4
Severe (ferritin
> 4,000 μg/L)
n = 146
0.2
p < 0.001
0
0
10
20
30
Ladis V, et al. Ann N Y Acad Sci. 2005;1054:445
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