End-organ damage resulting from accumulation of iron in cells Pierre Brissot University Hospital Pontchaillou, Rennes, France
Dec 22, 2015
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