Transcript Slide 1

Iron load
3rd Pan-European Conference on
Haemoglobinopathies & Rare Anaemias
Limassol, 24 – 26 October 2012
Aurelio Maggio
“Villa Sofia-Cervello” Hospital Palerm
Department of Hematology and Oncology
Foundation Franco and Piera Cutino
Iron load
WHICH IS THE PHYSIOLOGICAL REGULATION
OF IRON METABOLISM ?
Simplified Iron Turnover and
Storage
Erythron
2g
20–30 mg/day
20–30 mg/day
Other
parenchyma
0.3 g
Hepatocytes
1g
Red
Transferrin
Macrophages
0.6 g
20–30 mg/day
2–3 mg/day
1–2 mg/day
Gut
Porter J. Hematol/Oncol Clinics. 2005;19(suppl 1):7.
Hepcidin - An Iron-Regulatory
and Host Defense Peptide
Hormone
With permission from Rivera S, et al. Blood. 2005;106:2196-2199.
How Hepcidin Regulates Iron
Spleen
Hepcidin
Liver
Fpn
Fpn
Fpn
Plasma
Fe-Tf
Bone marrow
and other sites
of iron usage
Duodenum
Nemeth E, et al. Science. 2004;306:2090-2093.
Courtesy of Tomas Ganz, PhD, MD, and Elizabeta Nemeth, MD.
Low Hepcidin
High Hepcidin
Iron uptake
Iron uptake
ferritin
Iron-exporting cells
(duodenal enterocytes,
macrophages,
hepatocytes)
ferritin
Fpn
X
Fpn
hepcidin
Fe
Iron release
into plasma
Nemeth E, et al. Science. 2004;306:2090-2093.
Courtesy of Tomas Ganz, PhD, MD, and Elizabeta Nemeth, MD.
Fe
Iron load
WHICH ARE THE MAIN CAUSES OF IRON LOAD ?
Conditions Associated with
Iron Overload
Transfusional
Causes
Nontransfusional
Causes
Age of onset
Thalassaemia major1
Blackfan Diamond Anaemia1
Fanconi’s Anaemia1
Early stroke with HbSS1
Type 2 haemochromatosis (rare)2
2a hemojuvelin2
2b hepcidin2
Childhood
(Risks from HH)
Type 1 haemochromatosis1
Thalassaemia intermedia1
Typically adult
Severe haemolytic anaemias1
Aplastic anaemia1,2
Other transfusion in HbSS1
Myelodysplasia (MDS)3
Repeated myeloablative
chemotherapy1
Slide courtesy of Dr. J. Porter.
1. Porter JB. Br J Haematol. 2001;115:239. 2. Brittenham G. In Hoffman R, et al, ed. Hematology: Basic
Principles and Practice, 4th ed. Philadelphia, PA: Churchill Livingstone, 2004. 3. Taher A, et al. Semin
Hematol. 2007;44:S2.
Non transfusional causes:
diseases of Hepcidin
Dysregulation
Iron
Hepcidin
Normal homeostasis
Hereditary haemochromatosis
Iron-loading Anaemias
Anaemia of Inflammation
Iron-refractory iron-deficiency anaemia
Hepcidin-secreting tumors
Ganz T. J Am Soc Nephol. 2007;18:394-400.
Ganz T, Nemeth E. Am J Physiol Gastrointest Liver Physiol. 2006;290:G199-G203.
Courtesy of Tomas Ganz, PhD, MD.
Iron-loading Anaemias (-thal…)
Liver
Spleen
Hepcidin
deficiency
Plasma
Fe-Tf
RBC
Duodenum
Erythroid Signal
Bone
marrow
Nemeth E, Ganz T. Haematologica. 2006;91:727-732. Pak M, et al. Blood. 2006;108:3730-3735.
Papanikolaou G, et al. Blood. 2005;105:4101-4105. Tanno T, et al. Nat Med. 2007;13;1096-1101.
Courtesy of Tomas Ganz, PhD, MD, and Elizabeta Nemeth, MD.
Transfusional Iron Overload
● One unit of transfused blood contains around 200–250 mg of
iron1
● Iron accumulates with repeated infusions
 Chronic transfusion-dependent patients have an iron excess
of ~0.4–0.5 mg/kg/day2 (1 g/month)
 Signs of iron overload can be seen after 10–20 transfusions1
•
Iron overload can have a significant impact on morbidity and
mortality3,4
1. Porter JB. Br J Haematol 2001;115:239–252
1):30–36
2. Kushner JP et al. Hematology 2001;47–61
1994;331:567–573
3. Ballas SK. Semin Hematol 2001;38 (1 Suppl
4. Brittenham GM et al. New Engl J Med
Transfusional Iron Overload
Transfusion
Erythron
Parenchyma
20–40 mg/day
(0.4–0.5 mg/kg/day)
Parenchyma
Hepatocytes
Hepatocytes
NTBI
Transferrin
Gut
NTBI = non–transferrin-bound iron.
Adapted from Porter JB. Hematol/Oncol Clinics 2005;19(suppl 1):7.
Macrophages
Iron load
HOW IS IT POSSIBLE TO DEFINE IRON LOAD ?
Common Definition
of
Iron
Over
Overload
●
PERSISTENT SERUM FERRITIN LEVEL >1000 ng/ml or worst >2500 ng/ml
without any other signs of inflammation .THESE STATEMENTS ARE BASED
ON RETROSPECTIVE AND PROSPECTIVE SURVIVAL STUDIES (Borgna
Pignatti et al. Haematologica 2004;Olivieri NF et al.NEJM 1994; Maggio et al.
Blood Cells Mol Dis 2009)
●
LIVER IRON CONCENTRATION > 3.2 mg/gr/ dried weight >57,14 micro M/g /
dried weight. THIS STATEMENT IS BASED ON HEREDITARY
HEMOCHROMATOSIS CLINICAL STUDIES (Olivieri NF and Britthenam GM,
Blood 1997)
.
Iron load
HOW IS IT POSSIBLE TO DETECT BODY IRON
LOAD ?
Indirect and direct methods to
detect iron load
Correlation between serum ferritin
levels to hepatic iron concentration
in Thalassemia Major
The New England Journal of Medicine, Olivieri NF, Brittenham GM, Matsui D,
et al. Volume 332, pp 918-922, 1995. Copyright 1995. Massachusetts Medical Society.
All rights reserved.
Contrasting relationship of
LIC to ferritin in TI and TM
Origa, Hamatologica 2007, 92 583
Why not just use serum
ferritin ?
● Advantages

Simple

Widely available

Serum ferritin broadly correlated with body iron (macrophages)

Validated as predictor of complications of iron overload in TM
● Disadvantages

Origin of serum ferritin differs above values of 4K

Raised by inflammation or tissue damage

Lowered by vitamin C deficiency

Relationship of ferritin to body iron varies in different diseases

Low relative to LIC in Thal Intermedia (hepatocellular> macrophages)

Higher and variable in SCD
Sensitivity and Specificity of Transferrin
Saturation and Serum Ferritin Concentration
for Detection of C282Y/C282Y Homozygosity*
Liver Iron Concentration
by Liver Biopsy Predicts Total Body Iron
Stores
Sample <1 mg Dry Weight (n=23)
Sample >1 mg Dry Weight (n=25)
300
300
r=0.98
250
250
Body iron stores (mg/kg)
Body iron stores (mg/kg)
r=0.83
200
150
100
50
0
0
5
10
15
Hepatic iron concentration
(mg/g dry weight)
20
25
200
150
100
50
0
0
5
10
15
Hepatic iron concentration
(mg/g dry weight)
Body iron (mg/kg) = 10.6× hepatic iron concentration (mg/g dry weight)
Angelucci et al. N Engl J Med. 2000;343:327.
20
25
Biopsy for LIC
• Disadvantages
 Patient acceptance and safety
 Distribution artefact
 Effect of fibrosis
 Sample size often insufficient
≥1 mg dry weight
>4 mg wet weight
 Method not standardised
Colorometricvs AA
Wet /Dry ratio in different labs
Photos courtesy of Dr. John Porter, with permission.
Porter. Br J Haematol. 2001;115:239.
2 cm
Uneven Distribution of Liver Iron of
Thalassemia Patients(mg/g/dw)
Ambu et al. J Hepatol, 1995
Heterogeneity of iron concentration
throughout the liver
Sample size and type
CV of LIC
Pathology
Source
Needle biopsy
(< 4 mg dry weight)
19%
Normal
Emond, et al. 1999
Kreeftenberg, et al. 1984
Needle biopsy
(< 4 mg dry weight)
> 40%
End-stage
liver disease
Emond, et al. 1999
Kreeftenberg, et al. 1984
Needle biopsy
(9 mg dry weight)
9%
Normal
Barry, Sherlock. 1971
“Cubes”
(200–300 mg wet weight)
17%
24%
-thalassaemia
Ambu, et al. 1995
“Cubes”
(1,000–3,000 mg wet weight),
19%
-thalassaemia
Part-cirrhotic
Non-cirrhotic
Clark, et al. 2003
CV = coefficient of variation.
Ambu R, et al. J Hepatol. 1995;23:544-9; Barry M, Sherlock S. Lancet. 1971;1:100-3; Clark PR, et al.
MagnReson Med. 2003;49:572-5; Emond MJ, et al. Clin Chem. 1999;45:340-6; Kreeftenberg HG, et
al. ClinChimActa. 1984;144:255-62.
Proton transverse relaxation rate
(R2) image and distribution (Ferriscan)
• Axial images with a multislice single spin-echo (SSE) pulse
sequence
• Pulse repetition time TR of 2500 ms
• Slice thickness of 5 mm
• 25 minute acquisition
R2 (s-1)
St Pierre TG, et al. Blood. 2005;105:855-61.
Transverse relaxation rate R2 (s-1)
Correlation between R2 and
needle biopsy LIC (dry weight)
Mean transverse relaxation rate R2 (s-1)
300
250
200
150
Beta-thalassemia/hemoglobin E
100
Beta-thalassemia
Hepatitis
Hereditary hemochromatosis
50
0
0
10
20
30
40
Biopsy iron concentration (mg/g dry tissue)
St Pierre TG, et al. Blood. 2005;105:855-61.
Sensitivity and specificity of
R2-LIC measurements to biopsy LIC
LIC
threshold1
Clinical relevance1
Sensitivity2
Specificity2
94%
100%
(86–97)
(88–100)
94%
100%
(85–98)
(91–100)
89%
96%
(79–95)
(86–99)
85%
92%
(70–94)
(83–96)
(mg Fe/g dry weight)
1.8
3.2
7.0
15.0
Upper 95% of normal
Suggested lower limit of optimal range
for LICs for chelation therapy in
transfusional iron overload
Suggested upper limit of optimal range
for LICs for transfusional iron overload
and threshold for increased risk of ironinduced complications
Threshold for greatly increased risk for
cardiac disease and early death in
patients with transfusional iron overload
1. Olivieri NF, Brittenham GM. Blood. 1997;89:739-61. 2. St Pierre TG, et al. Blood. 2005;105:855-61.
“Management of chronic viral hepatitis in
patients with thalassemia: recommendations
from an international panel”
V. Di Marco, M. Capra, E Angelucci, C Borgna-Pignatti1, P Telfer, P Harmatz, A Kattamis, L Prossamariti, A Filosa,
D Rund, M Rita Gamberini, P Cianciulli, M De Montalembert, F Gagliardotto, G Foster, J Didier Grangè, F Cassarà,
A Iacono, M Domenica Cappellini, G. M. Brittenham, D Prati, A Pietrangelo, A Craxì, A Maggio, and on behalf of
the Italian Society for the Study of Thalassemia and Haemoglobinopathies and Italian Association for the Study of
the Liver
“These evidences on accuracy of noninvasive methods for
assessment of liver iron concentration are sufficient to consider
MRI-R2 methodology as a worldwide available alternative to liver
biopsy for liver iron measurement”
Blood Journal,September 26, 2010
Choice of Single Slice MR
technique for measuring
myocardial iron
•
Gradient-echo T2* advantages
Does not require the analysis of SIRs quantitative evaluation
Shorter time acquisition than SE techniques
Less motion artifacts
Greater sensitivity
Greater reproducibility
Calibration of Septal Cardiac
T2* Signal vs Heart Iron
Carpenter JP et al, On T2* magnetic resonance and cardiac iron. Circulation. 2011 Apr 12;123(14):1519-28.
No correlation was shown between global
heart T2* values and liver T2*
30
20
R= -0.2; P=0.3
10
0
0
10
20
30
Global Heart T2* (ms)
40
50
Cardiac Siderosis
Discordance of liver and heart iron
deposition
L. J. Anderson, S. Holden, B. Davis, E. Prescott, C. C. Charrier,
N. H. Bunce, D. N. Firmin, B. Wonke, J. Porter, J. M. Walker and
D. J. Pennell. Cardiovascular T2-star (T2*) magnetic resonance for
the early diagnosis of myocardial iron overload. European Heart Journal (2001) 22, 2171–
2179
MAIN FINDINGS IN PATIENTS SUBMITTED TO
FERRISCAN DETERMINATION (LIC-R2)
Thal.Major
Thal.Intermedia Beta trait -sickle cell
Mean age
24
39
29
Male
17
3
3
Female
21
5
1
N° of patients
38
8
4
Mean Ferritin (ng/ml)
1818
1186
538
Average LIC R2 (mg/g/dw)
11,01
7,98
4,28
Blood requirement
(ml/Kg/year)
125,9
70,9
-----
Cardiac T2*
29,65
37
No value
Pre-trasfusional Hb value
9,08
8,59
8,5
Normal values of heart iron
Jensen P.D. et al., MAGMA, (2001)
Population: 5 Normal Autopsy Controls
Results: 224 ± 59 (range 165 to 312) µg/gr/dw
Olson L.J. et al., JACC, (1987)
Population: 14 Normal Autopsy Controls
Results: 399 (range 183 to 674) µg/gr/dw
Consideration:
Small iron burden variations in sites as the heart could be earlier
detected by cardiac T2* MRI without any influence on the overall body
iron burden mainly stored in the liver.
Heart iron is heterogeneously distributed
with prevalence in the subepicardium
Olson LJ et al. Cardiac iron deposition in idiopathic hemochromatosis: histologic and analytic
assessment of 14 hearts from autopsy. JACC 1987 Dec; 10(6):1239-43
Heart Single Slice (T2*) and
heterogeneity distribution of heart
iron
Grugre NR
Mag Res Med 2006
Buja
Am J Med 1971
Fitchett
Cardiov Res1980
Heterogeneity of iron
distribution in
haemochromatotic
myocardium
Jensen
MAGMA 2001
Olson
JACC 1987
Olson
JACC 1989
Myocardial Iron Overload in Thalassemia
MIOT- network
• > 1000 availabilty MR scans/yr
• Standard acquisition and post-processing
• Central data-base
70 centers
Heart T2* MRI multiecho multislice to
better study heterogeneity pattern of
heart iron
apical
medium
basal
Interstudy reproducibility of Multislice
T2* tecnique was good
Single slice
Multislice
(Pepe et al. JMRI 2006)
(Westwood et al JMRI 2003)
Multislice multiecho T2* :
Interstudy intercenters reproducibility in
thalassemia patients
CV = 9%
ICC=0.96
A. Ramazzotti, A. Pepe, V. Positano, M. Brizi, M.Midiri, G. Valeri, G. Sallustio, A. Luciani, P. Cianciulli, A. Maggio, M.
Centra, V. Caruso, V. DeSanctis, G. Rossi,, D. De Marchi, M. Lombardi
J Magn Reson Imaging 2009; 30:62–68.
Magnetic Resonance Imaging
of hypophysis
A) NORMAL PICTURE
B) HYPOINTENSITY SUGGESTING ORGAN
IRON OVERLOAD
G. Fiorelli, S. Zatelli, SEE, 2000, “Clinica e Terapia della Talassemia”, Firenze
Decreased Hypophysis MRI signal
in thalassemia patients with
hypogondadism
Sensitivity 75%
Specificity 89%
Normal: control group
B.THAL: total group of patients
with thalassaemia
Group 1: pubertal thalassaemic
Group 2: thalassaemia patients
with hypogonadism
Group 3: adult thalassaemia
patients without hypogonadism
Christoforidis A, et al. MRI for the determination of pituitary iron overload in children and young adults
with beta-thalassaemia major. Eur J Radiol. 2007 Apr;62(1):138-42.
T2* pancreatic images analysis
Pepe A, Positano V, Santarelli MF et al JMRI 2006
Positano V, Pepe A, Santarelli MF et al NMR in biomedicine 2007
Positano V, Pepe A, Santarelli MF et al MRI 2009
HIPPO MIOT IFC-CNR® (International Patent PCT/IB2006/000880
CORRELATION AMONG T2* PANCREAS SIGNAL
AND OTHER IRON LOAD PARAMETERS
MRI IS ABLE TO DETECT SINGLE ORGAN IRON
IRON LOAD
HYPOPHISYS
Normal
PANCREAS
Iron overloading
Iron overloading
Normal
TO TAILOR CHELATION TREATMENT
ON SINGLE ORGAN DAMAGE
HEART
Normal
LIVER
Iron overloading
Iron overloading
Normal
DEFINITON OFOver
IRON LOAD IS
CHANGING
1.
IRON LOAD IS NOT ONLY PERSISTENCE OF HIGH SERUM FERRITIN
LEVELS OR HIGH LIVER IRON CONCENTRATION BUT EVEN SINGLE
ORGAN IRON LOAD
2. THE SITE OF SINGLE IRON LOAD IS CRUCIAL FOR PROGNOSIS OF THE
PATIENT INDIPENDENTLY OF THE SEVERITY OF OVERALL BODY IRON
BURDEN.
THEREFORE, IT MUST BEEN EVEN DEFINED AS IRON LOAD:
●
LOWER HEART T2* VALUES (<10 ms ). THIS STATEMENT IS BASED ON THE
ASSOCIATION BETWEEN LOWER HEART T2* VALUES AND RISK FOR HEART
FAILURE (Kirk et al., Circulation 2009)
●
LOWER HYPOPHISIS AND PANCREAS T2* VALUES
Iron load
WHICH IS THE CORRELATION BETWEEN IRON
LOAD , COMPLICATIONS AND SURVIVAL ?
The control of Iron Overload using
desferrioxamine treatment was associated
with thalassemia survival improving
C. Borgna-Pignatti et al. Haematologica, 2004
CARDIAC DISEASE-FREE SURVIVAL RELATED
TO THE SERUM FERRITTIN LEVELS
Proportion without
Cardiac Disease
1,00
0,75
0,50
0,25
0,00
0
2
4
6
8
10
12
14
16
Years of Chelation Therapy
Olivieri NF, et al. NEJM 1994; 331:574-578
Cardiac disease-free survival
= less than 33% of ferritin levels > 2500 ng/ml
= from 33 to 67% of ferritin levels > 2500 ng/ml
= more than 67% of ferritin levels > 2500 ng/ml
Different single complications are associated with
higher risk for death in comparison with serum
ferritin levels
Maggio A, Vitrano A, Capra M, et al.,Blood Cells Mol Dis. 2009 Feb 20.
Demographics and clinical findings at
baseline during long-term prospective
study on thalassemia major survival
Cohort
YES(%)
NO(%)
N°
417
Past-Hearth Failure
42(11.8)
315(88.2)
Deaths
77
Cirrhosis
30(8.8)
311(91.2)
9930,1
Arrythmia
63(17.2)
304(82.8)
1980-2009
Diabetes
48(12.5)
335(87.5)
Hypoparathyroidism
29(8.7)
303(91.3)
Cardiopathy
48(27.6)
126(72.4)
Hypothyroidism
54(15.6)
292(84.4)
Splenectomy
158(41.7)
221(58.3)
Hypogonadism
170(48.9)
178(51.1)
Person-years
Follow-up
Age (years) (mean±sd)
Age start Tx (months) (mean±sd
Age start DFO s.c. (mean±sd)
Mean Ferritin (±sd)
Gender (M - F)
30±8.5
17,5±35,5
5,7±9
1977±1157
218 - 192
Summary of overall survival based on separate cox
regression models for single complications
Complication
HR(95% CI)
p-value
n. subjects (Deaths)
Past-Heart Failure
10,7(5,8;19,7)
<0,0001
357(41)
Cirroshis
8,1(3,9;16,6)
<0,0001
341(31)
Arrythmia
6,8(3,8;12,1)
<0,0001
367(47)
Diabetes
5,3(3,1;9)
<0,0001
383(59)
Hypoparathyroidism
5,1(2,3;11,4)
<0,0001
332(28)
Cardiopathy
3,9(2,1;7,4)
<0,0001
174(41)
Hypothyroidism
3,4(1,6;7,3)
0,001
346(28)
Hypogonadism
2,9(1,3;6,5)
0,01
348(31)
Splenectomy
Mean Ferritin (<2500 versus ≥ 2500)
2,8(1,6;4,9)
4,2(2,6;6,5)
<0,0001
<0,0001
379(53)
417(77)
KAPLAN–MEIER SURVIVAL CURVES FOR SINGLE COMPLICATION
1.00
Kaplan-Meier survival estimates, by cirrosi
0.50
0.50
0.75
0.75
1.00
Kaplan-Meier survival estimates, by prescomp
HR=8.1(p<0.0001)
0.25
0.00
0.00
0.25
HR=10,7(p<0.0001)
0
10
20
30
0
analysis time
prescomp = 0
20
30
analysis time
prescomp = 1
cirrosi = 0
0.50
0.50
0.75
0.75
cirrosi = 1
Kaplan-Meier survival estimates, by ferrit_2cat
1.00
Kaplan-Meier survival estimates, by aritmia
1.00
10
0.25
HR=4.2(p<0.0001)
0.00
0.00
0.25
HR=6.8(p<0.0001)
0
10
20
analysis time
aritmia = 0
30
0
10
20
analysis time
aritmia = 1
ferrit_2cat = 0
ferrit_2cat = 1
30
Complications and Iron Overload
CIRRHOSIS
(512 Thalassemia Major patients)
COMPLICATION
AND IRONP=0,525
OVERLOAD
P=0,555
IRON OVERLOAD WAS MEASURED AS HEART AND LIVER T2* MRI SIGNAL.HATCHED LINES SHOW
NORMAL VALUES FOR HEART AND LIVER
Complications and Iron Overload
ARRHYTHMIAS
(582 Thalassemia Major patients)
P=0,559
P=0,622
IRON OVERLOAD WAS MEASURED AS HEART AND LIVER T2* MRI SIGNAL.HATCHED LINES SHOW
NORMAL VALUES FOR HEART AND LIVER
Iron load
MAY THE NUMBER OF COMPLICATIONS TO
INFLUENCE SURVIVAL ?
Staging for the risk of death in Thalassemia
Major based on complications
•HIGH RISK:
•MEDIUM RISK :
•LOW RISK:
Condition in which the hazard risk for death
due to interactions among complications is >9
Condition in which the hazard risk for death
due to interactions among complications is
between 6 and 9
Condition in which the hazard risk for death
due to interactions among complications is<6
Summary of overall survival based on the
interaction of two complications
No Ferritin
Ferritin*
HR(p-value)
HR(p-value)
Arrhythmia*Diabetes
11,4(<0,0001)
32,3(<0,0001)
Diabetes*Past-Heart Failure
9,01(<0,0001)
35,4(<0,0001)
8,4(<0,0001)
25,3(<0,0001)
7(<0,0001)
8,5(<0,0001)
4,2(<0,0001)
5,2(0,007)
3,2(0,001)
3,4(0,025)
High Risk
Medium Risk
Arrhythmia*Past-Heart Failure
Arrhythmia*Splenectomy
Low Risk
Hypogonadysm*Hypothyroidism
Hypogonadysm*Splenectomy
*Ferritin >2500
Kaplan-Meier survival estimates, by diab_card_cirr_ipot_presc
0.75
1.00
Kaplan-Meier survival curves based on the
interaction among multiple complications
0.00
0.25
0.50
HR=18,7(p<0.0001)
HIGH RISK
0
10
20
30
analysis time
1.00
Kaplan-Meier survival estimates, by diab_card_presc_arit
HR=4(p=0.007)
0.50
0.50
0.25
HR=8.9(p<0.0001)
0.25
MEDIUM RISK
0
LOW RISK
0.00
0.00
diab_card_cirr_ipot_presc = 1
0.75
Kaplan-Meier survival estimates, by diab_card_ipog_ipot
0.75
1.00
diab_card_cirr_ipot_presc = 0
10
20
analysis time
diab_card_ipog_ipot = 0
30
0
10
20
analysis time
diab_card_ipog_ipot = 1
diab_card_presc_arit = 0
diab_card_presc_arit = 1
30
Conclusions
• THESE FINDINGS SUGGEST AS COMPLICATIONS
INDIPENDENTLY FROM IRON
LOAD,IMPAIRING
ORGAN FUNCTION, DECREASING SURVIVAL
• THEREFORE, OUR NEXT FUTURE CHALLENGE IS TO
PREVENT
AND/OR
TO
EARLY
TREAT
COMPLICATIONS FOR IMPROVING ORGAN FUNCTION
AND DECREASING RISK FOR DEATH
Cohort flow
404 patients by 5 Talassemia centres
included in the cohort in 1993
14 patients (3.5%) underwent
bone marrow transplant for TM
46 patients (11.4%) died for
TM-related and unrelated causes
43 patients (10.6%)
lost to observation
301patients (74.5%)
302 followed from 1993 to 2012
Improved survival in 141 thalassemia with chronic
C hepatitis treated
with IFN monotherapy
Mortality
100
98
96
94
92
90
88
86
84
82
80
78
76
96%
SVR
0
1
Log Rank (Mantel Cox): p = 0.007
1
2
3
4
5
6
78%
7 8 9 10 11 12 13 14 15 16 17
Follow-up(years)
Number at risk
Group: 0
86 86 85 85 84 82 57 55 48 46 45 44 41 38 34 31 31
Group: 1
55 55 55 55 55 53 52 52 51 51 51 48 47 46 45 42 42
(V. Di Marco, M. Capra, A. Maggio, R. Malizia, M. Rizzo, C. Gerardi et al,)
Causes of death for the entire population
of patients and for those born after 1970
All patients (N=1073)
Patients born after 1970 (N=720)
N
%
N
%
133
60.2
31
50.8
Infection
15
6.8
9
14.8
Arrhythmia
15
6.8
4
6.6
Myocardial infraction
4
1.8
Cyrrhosis
9
4.1
Thrombosis
9
4.1
2
3.3
Malignancy
8
3.6
2
3.3
Diabetes
7
3.2
2
3.3
Accident
4
1.8
1
1.6
Renal Failure
3
1.4
HIV/AIDS
3
1.4
2
3.3
Familial autoimmune
disorder
2
0.9
1
1.6
Anorexia
1
0.5
1
1.6
Hemolytic Anemia
1
0.5
1
1.6
Thrombocytopenia
1
0.5
Unknown
6
2.7
5
8.2
Heart Failure
Total
221
from Borgna-Pignatti et al,Haematologica 2005;89:1187-9
61
CLINICAL FINDINGS OF THAL PATIENTS AND HCC:A
SINGLE CENTER EXPERIENCE AT HOSPITAL“V.
CERVELLO”, PALERMO (ITALY)
)
TAKE THREE MESSAGES
TO
Over
HOME
●
IRON METABOLISM IS STRINGETLY REGULATED BY THE HEPCIDIN LEV
●
DYSREGULATION OF HEPCIDN LEVELS AND TRANSFUSIONS ARE THE
MAIN CAUSES OF IRON LOAD
●
TODAY YOU HAVE TO CONSIDER NOT ONLY BODY IRON LOAD DUE TO
HIGH LIVER IRON CONCENTRATION OR HIGH SERUM FERRITIN LEVELS
BUT EVEN SINGLE ORGAN IRON LOAD
●
SINGLE OR MULTIPLE COMPLICATIONS MAY INFLUENCE SURVIVAL,
IMPAIRING THE ORGAN DAMAGE, INDIPENDENTLY FROM IRON LOAD.
FUTURE CHALLENGE IS TO PREVENT AND/OR TREAT THESE EARLIER
.
THANKS TO
Nursing Staff
D’AGUANNO GIUSEPPINA
DE LUCA MARIA LUISA
DI LIBERTO GIUSEPPE
Clinical care
DI SALVO VERONICA
GIANGRECO ANTONINO
RENDA DISMA
CALVARUSO GIUSEPPINA
BARONE RITA
RIGANO PAOLO
Prenatal Diagnosis of
Thalassemia
Gene-Therapy
BAIAMONTE ELENA
D’APOLITO DANILO
MOTTA VALENTINA
SPINA BARBARA
STEFANO LIA
ACUTO SANTINA
FIORENTINO GERMANA
Support Staff
LO PICCOLO SALVATORE
MANISCALCO SERAFINO
CANNATA MONICA
CASSARÀ FILIPPO
LETO FILIPPO
LO GIOCO PINA
PASSARELLO CRISTINA
VINCIGUERRA MARGHERITA
GIAMBONA ANTONINO
Acceptance / Secretary
BENINATI GIADA
DAMIANO LOREDANA
SANSONE ROSI
TRAVIA AURORA
Hemochromatosis and in
utero transplantation
FECAROTTA EMANUELA
PIAZZA TIZIANA
RENDA MARIA CONCETTA
Cystic Fibrosis and Other
Congenital Anemias
AGRIGENTO VERONICA
SCLAFANI SERENA
D’ALCAMO ELENA
Mechanisms of Fetal
Hemoglobin Activation
PECORARO ALICE
TROIA ANTONIO
DI MARZO ROSALBA
Satistical consulting
VITRANO ANGELA