Iron Overload Dick Wells
Outline ¡ A functional definition of iron overload
¡ Iron toxicity – from atoms to organs
¡ Treatment of iron overload
Am I overloaded yet? A functional definition of iron overload
Andrews NC. N Engl J Med. 1999;341:1986–1995
Body Iron Distribution
There is no physiologic mechanism to remove excess iron
1 % blood cells digested/d 25 mg iron released
ferroportin
spleen
Fe(III)
Fe(II)
Fe
Absorption of iron balances daily loss
ferroportin
Transferrin iron is used for production of new blood cells
Hepcidin blocks ferropor0n, preven0ng iron export into plasma
Hepcidin
Iron released into plasma is incorporated into transferrin
TfSat normally 0.2-0.55 (No non-Tf-bound iron)
DMT1
ferritin
hephaestin
Labile ceIl iron
Dcyb
Fe(III) Fe(II)
Fe(III) Fe(II)
duodenum
The Iron Balance
ferroportin
Transfusion therapy results in iron overload
¡ Normal iron influx through gut is 1–2 mg/day
¡ 1 blood unit contains 200-250 mg iron
¡ Iron overload can occur after 10–20 transfusions
Iron from transfused
RBC
Iron from increased absorption
Free Iron: The Essence of Iron Overload
100%
30%
Normal: no free iron produced Iron overload
Subsequent formation of free
iron in plasma
Saturation of transferrin due to • Frequent blood transfusions, and • Ineffective erythropoiesis leading to
increased iron absorption
Fe
Fe Fe
Fe Fe
Fe Fe
Uncontrolled iron loading of organs
Pituitary
Parathyroid Thyroid
Heart Liver Pancreas
Gonads
Tran
sfer
rin s
atur
atio
n %
“Free” Iron
Haem biosythesis
Fe-S cluster biogenesis
Fe(II) Fe(III)
Fe(III) Fe(III) Transferrin
Transferrin receptors
DMT1
Fe(II)
Ferritin
Other Fe utilization pathways
Dcyb
Endosome Mitochondria
LCI (Labile cell iron)
Free iron in our cells
Plasma
Summary Iron Balance ¡ There is no mechanism for excreting excess iron
¡ Iron normally is associated with proteins ¡ Haemoglobin and enzymes
¡ Transferrin (plasma transport)
¡ Ferritin (intracellular storage)
¡ “Free” iron is rare
¡ When iron stores are high, free iron appears in the plasma and can get into cells
What problems are caused by
free iron?
Iron supports dangerous radicals
Iron Toxicity: From Atoms to Organs
Fe
Iron and Free Radicals ¡ Cell metabolism produces hydrogen
peroxide (H2O2) as a biproduct
¡ H2O2 is not itself very toxic
¡ Reactive oxygen intermediate (ROI)
¡ Free iron reacts with H2O2 to form highly toxic free radicals
¡ Reactive oxygen species (ROS)
Fe3+ Fe2+
Free iron
LCI
O2
H2O2
O2-
OH.
ROI
ROS
Mitochondria
Lipid Protein
DNA
Cellular targets of labile iron
TfR
DMT
DMT-Divalent metal transporter TfR-Transferrin receptor ROI-reactive oxygen intermediates ROS-reactive oxygen species
Regulated Unregulated
Saturated transferrin
Cellular Effects of Free Iron
O2
OH.
Altered signaling Proliferation
Fibrosis
Apoptosis Mutagenesis
Membrane damage Cell lysis
Inefficient energy metabolism Apoptosis
Senescence
What problems do these cellular effects
cause in organs?
Uncontrolled iron loading of organs
Pituitary
Parathyroid Thyroid
Heart Liver Pancreas
Marrow
Gonads
Iron Overload Morbidity and Mortality
Hepatic fibrosis ! Cirrhosis
Arrhythmia
Hypogonadism
Diabetes
Hypothyroidism
Hypoparathyroidism
Cardiomyopathy
~ 7 g iron
How do we know these problems are
caused by iron?
Surv
ival
(%)
0
60
80
50
40
30
20
10
70
90
100
0 28 26 24 22 20 18 16 14 12 10 8 6 4 2 30 32 34 36 38 40 Time (years)
300–365 225–300 150–225 75–150 0–75
Infusions/year
Iron Overload Effect of iron chelation
Chelation = survival
Are the effects of iron the same, no matter what the
underlying disease?
Comparison of organ dysfunction in thalassaemia major and sickle cell disease
Vichinsky E. Am J Hematol. 2005;80:70-4. NS = not significant.
Characteristic Thalassaemia major
Sickle cell disease
p value
Age 18.4 ± 2.1 14.8 ± 1.0 NS Duration of transfusion 12 years 6 years Serum ferritin (µg/L)
2,122 ± 289 2,916 ± 233 0.04
Liver iron (mg Fe/g dry wt)
14.8 ± 2.2 14.3 ± 1.4 NS
Transfusions (n/year)
12.2 ± 1.8 6.0 ± 0.6 0.002
Cardiac disease 20% 0% 0.002
Gonadal failure 33% 0% < 0.001
Growth delay 27% 9% NS
Hypothyroidism 7% 0% NS
Viral hepatitis 33% 2% < 0.001
Fibrosis 81% 29% 0.02
Factors 1. Duration of transfusion 2. TM vs. SCD
Why should this be?
Despite similar Fe measures, SCD patients have fewer end-organ complications
O2
H2O2
O2-
ROI OH.
ROS
Inflammation Primes the Antioxidant Response
GPX-glutathione peroxidase SOD-superoxide dismutase ROI-reactive oxygen intermediates ROS-reactive oxygen species
H2O Catalase GPX SOD
Inflammatory State (SCD)
Cytokines
NRF2
Inflammation in SCD primes the antioxidant response and reduces Fe-catalyzed ROS
Fe
What is the effect of iron overload
in MDS?
Does iron overload contribute to mortality in MDS?
Sanz et al., Blood 2008 112 (abstract 640)
Registry data Overall survival
by serum ferritin level (n=762)
<1000 1000-1500
>2500 1500-2000
Prop
ortio
n su
rviv
ing
40 80 120 Survival (months)
RA, RARS, 5q-
?
Malcovati et al., Haematologica, 2007
MDS Classification: Causes of death in MDS
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$!"#
%!"#
&!"#
'!"#
(!!"#
)*+,-./0# 1.23,-./0#
456.-789#
:.-789#
!"#$%&'()&*$
+,-.*/0,$
12..(),3$
456.'$
“Direct”
“Indirect”
The goals of therapy are different in low-risk and high risk MDS
Malcovati et al., J. Clin. Oncol. 2005 Balduini et al., Hematologica 1999
The heart in MDS
Goldberg et al., ASH 2008
“MDS cardiomyopathy”: chronic anaemia + iron overload + the aged myocardium
Rates of heart disease in US
medicare patients
0 20 40 60 80 100
Medicare database
MDS
MDS (transfused)
MDS (not transfused)
Cardiac iron in patients with MDS
N Cardiac iron
Units transfused
Serum ferritin (µg/L)
Chelated
Jensen et al. 2003 12 9 44–254 (median 115)
1,740–8,715 0
Chacko et al. 2007 11 1 23–257 (median 112)
1,109–6,651 6
Konen et al. 2007 10 1 50–140 (median 89)
1,260–4,450 7
Di Tucci et al. 2008 26 2 14–234 (median 69)
T2*< 20 at > 100 units
1,300–6,241 2
Pascal et al. 2010 76 14 -- 282-7339 54
Di Tucci AA, et al. Haematologica. 2008;93:1385-8. Chacko J, et al. Br J Haematol. 2007;138:587-93.
Jensen PD, et al. Blood. 2003;101:4632-9. Konen E, et al. Am J Hematol. 2007;82:1013-6. Pascal et al., ASH 2010, Abstract 2906
HOWEVER: There is no obvious relationship between cardiac iron and heart problems in
MDS
Should iron chelation be given in MDS?
Ferroscepticism ¡ DeLoughery TG. Iron: The
fifth horseman of the apocalypse? Am J Hematol. 2009
¡ Steensma DP. Myelodysplasia paranoia: iron as the new radon. Leuk Res. 2009
¡ Tefferi A, Stone RM. Iron chelation therapy in myelodysplastic syndrome—Cui bono? Leukemia. 2009
Data?
TELESTO
Iron chelation and survival in MDS Leitch (Clin Leuk Res 2008) ¡ 178 pt ¡ OS in ICT >160 mo ¡ OS in non-ICT = 40 mo ¡ p<0.03
¨ Rose (ASH 2007) ¡ 170 pt ¡ OS 115 vs. 51 mo ¡ p< 0.0001
¡ Fox (ASH 2009) ¡ 186 pt (matched pairs) ¡ OS in ICT = 75 mo ¡ OS in non-ICT = 49 mo ¡ P=0.002
Fox Blood 2009; 114 (abstract 1747)
¡ Lower-risk MDS if life exp > 1y
¡ Higher-risk MDS if BMT candidate
¡ Either desferal or exjade as first line
¡ Target ferritin < 1000 ng/mL
Fe(II)
Ferritin
Translation LCI
(Labile cell iron)
Direct and Indirect Measurement of Iron
Ac0ve IRP
Blocks ferri0n mRNA
Ferritin IRE
IRP
Fe(II)
Serum ferritin
LIC
Ø Biopsy Ø MRI Ø SQUID
MRI = magnetic resonance imaging; SQUID = superconducting quantum interference device.
Unexpected effects of iron in MDS
Iron and Haematopoiesis in MDS
Analysis of trial data to study haematological responses in the MDS patients in EPIC (N=341)
Gattermann et al., ASH 2010, Abstract 2912
Overall erythroid response rate = 22.6%
Iron and AML in MDS
How could IOL promote development of AML?
o Fe causes DNA damage in vitro o Fe accelerates development of
AML in mouse model
Chan et al., ASH 2010, Abstract 122
HSC MDS AML
Iron
ROS
Loss of mitochondrial membrane poten0al
Loss of respiratory enzyme ac0vi0es
Apoptosis Lipid peroxida0on DNA muta0on
Liver cirrhosis Endocrine
disturbances Cardiac failure
Iron overload
Free ironà LCI à ROS
Summary Iron Toxicity
BM suppression MDS à AML
Blood transfusion Increased Fe absorption
Conclusions ¡ Iron is both essential and toxic -- balance is
maintained by an intricate network of proteins
¡ Chronic RBC transfusion overwhelms this network, resulting in the presence of “free iron”, which causes cell and organ damage via generation of free radicals
¡ Fe toxicity leaves different footprints in TM, SCD, and MDS
¡ Chelation therapy can prevent chronic Fe toxicity but must be monitored by indirect (ferritin) or direct (LIC) means
Any questions?
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