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 OncologyFoundation Franco and Piera Cutino

Iron load

WHICH IS THE PHYSIOLOGICAL REGULATION OF IRON METABOLISM ?

Porter J. Hematol/Oncol Clinics. 2005;19(suppl 1):7.

Red

Erythron 2g

20–30 mg/day

Macrophages 0.6 g

1–2 mg/day

Gut

Transferrin

20–30 mg/day 2–3 mg/day

20–30 mg/dayOtherparenchyma

0.3 g

Hepatocytes1 g

Simplified Iron Turnover and Storage

Hepcidin - An Iron-Regulatory and Host Defense Peptide

Hormone

With permission from Rivera S, et al. Blood. 2005;106:2196-2199.

Spleen

Liver

Duodenum

Hep

cidin

Hepcidin

Hepcidin

Fpn

Fpn

Fpn

PlasmaFe-Tf

How Hepcidin Regulates Iron

Bone marrowand other sitesof iron usage

Nemeth E, et al. Science. 2004;306:2090-2093.Courtesy of Tomas Ganz, PhD, MD, and Elizabeta Nemeth, MD.

Fpn

Fe

ferritin

Low Hepcidin High Hepcidin

Fe

hepcidin

ferritin

Iron releaseinto plasma

Iron-exporting cells (duodenal enterocytes,

macrophages, hepatocytes)

X

Fpn

Iron uptakeIron uptake

Nemeth E, et al. Science. 2004;306:2090-2093.Courtesy of Tomas Ganz, PhD, MD, and Elizabeta Nemeth, MD.

Iron load

WHICH ARE THE MAIN CAUSES OF IRON LOAD ?

Conditions Associated with Iron Overload

Transfusional Nontransfusional Age of onsetCauses Causes

Thalassaemia major1 Type 2 haemochromatosis (rare)2 ChildhoodBlackfan Diamond Anaemia1 2a hemojuvelin2 (Risks from HH)Fanconi’s Anaemia1 2b hepcidin2

Early stroke with HbSS1

Severe haemolytic anaemias1

Aplastic anaemia1,2 Type 1 haemochromatosis1 Typically adultOther transfusion in HbSS1 Thalassaemia intermedia1

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

Hereditary haemochromatosis

Iron-loading Anaemias

Anaemia of Inflammation

Iron-refractory iron-deficiency anaemia

Hepcidin-secreting tumors

HepcidinIron

Normal homeostasis

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…)

PlasmaFe-Tf

Spleen

Bone marrow

RBC

Liver

Duodenum×

Hepcidin

Hepcidin

Hepcidin

Hepcidin deficiency

×

×Erythroid Signal

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.

● 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

Transfusional Iron Overload

1. Porter JB. Br J Haematol 2001;115:239–252 3. Ballas SK. Semin Hematol 2001;38 (1 Suppl 1):30–36

2. Kushner JP et al. Hematology 2001;47–61 4. Brittenham GM et al. New Engl J Med 1994;331:567–573

Adapted from Porter JB. Hematol/Oncol Clinics 2005;19(suppl 1):7.

Parenchyma

Hepatocytes

Hepatocytes

Parenchyma

Erythron

Macrophages

Gut

Transfusion

20–40 mg/day(0.4–0.5 mg/kg/day)

Transferrin

NTBI

NTBI = non–transferrin-bound iron.

Transfusional Iron Overload

Iron load

HOW IS IT POSSIBLE TO DEFINE IRON LOAD ?

● 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)

.

OverCommon Definition of Iron

Overload

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*

Body iron (mg/kg) = 10.6× hepatic iron concentration (mg/g dry weight)

Sample <1 mg Dry Weight (n=23)

Body

iron

sto

res

(mg/

kg)

300

250

200

150

100

50

0

r=0.83

0 5 10 15 20 25Hepatic iron concentration (mg/g dry weight)

Angelucci et al. N Engl J Med. 2000;343:327.

Liver Iron Concentration by Liver Biopsy Predicts Total Body Iron

Stores

0 5 10 15 20 25

300

250

200

150

100

50

0

r=0.98

Body

iron

sto

res

(mg/

kg)

Hepatic iron concentration (mg/g dry weight)

Sample >1 mg Dry Weight (n=25)

Biopsy for LIC

• DisadvantagesPatient acceptance and safetyDistribution artefactEffect of fibrosis Sample size often insufficient

≥1 mg dry weight >4 mg wet weight

Method not standardisedColorometricvs AAWet /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 diseaseEmond, 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

Non-cirrhotic

Ambu, et al. 1995

“Cubes”

(1,000–3,000 mg wet weight),19% -thalassaemia

Part-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)

St Pierre TG, et al. Blood. 2005;105:855-61.

R2 (s-1)Transverse relaxation rate R2 (s-1)

• 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

300

250

200

150

100

50

00 10 20 30 40

Biopsy iron concentration (mg/g dry tissue)

Mea

n tr

ansv

erse

rela

xatio

n ra

te R

2 (s-1

)

Hepatitis

Hereditary hemochromatosis

Beta-thalassemia/hemoglobin E

Beta-thalassemia

St Pierre TG, et al. Blood. 2005;105:855-61.

Correlation between R2 and needle biopsy LIC (dry weight)

Sensitivity and specificity of R2-LIC measurements to biopsy LIC

LIC threshold1

(mg Fe/g dry weight)

Clinical relevance1 Sensitivity2 Specificity2

1.8 Upper 95% of normal 94%(86–97)

100%(88–100)

3.2 Suggested lower limit of optimal range for LICs for chelation therapy in transfusional iron overload

94%(85–98)

100%(91–100)

7.0 Suggested upper limit of optimal range for LICs for transfusional iron overload and threshold for increased risk of iron- induced complications

89%(79–95)

96%(86–99)

15.0 Threshold for greatly increased risk for cardiac disease and early death in patients with transfusional iron overload

85%(70–94)

92%(83–96)

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.

Global Heart T2* (ms)

50403020100

Liv

er

T2

* (m

s)30

20

10

0

R= -0.2; P=0.3

No correlation was shown between global heart T2* values and liver T2*

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 andD. J. Pennell. Cardiovascular T2-star (T2*) magnetic resonance forthe early diagnosis of myocardial iron overload. European Heart Journal (2001) 22, 2171–2179

Cardiac Siderosis

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

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.

Normal values of heart iron

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 iron is heterogeneously distributed with prevalence in the subepicardium

Heterogeneity of iron distribution in haemochromatotic myocardium

JensenJensenMAGMA 2001MAGMA 2001

OlsonOlsonJACC 1987JACC 1987

OlsonOlsonJACC 1989JACC 1989

BujaBujaAm J Med 1971Am J Med 1971 FitchettFitchett

Cardiov Res1980Cardiov Res1980Grugre NRGrugre NR

Mag Res Med 2006Mag Res Med 2006

Heart Single Slice (T2*) and heterogeneity distribution of heart

iron

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

basal

medium

Interstudy reproducibility of Multislice T2* tecnique was good

4.7%

(Pepe et al. JMRI 2006)

Multislice

(Westwood et al JMRI 2003)

2.3%

9.3%

Single slice

5.8%

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.

a) Normal picture b) hypointensity suggesting organ

iron overload

G. Fiorelli, S. Zatelli, SEE, 2000, “Clinica e Terapia della Talassemia”, Firenze

Magnetic Resonance Imaging of hypophysis

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.

Normal: control groupB.THAL: total group of patients with thalassaemiaGroup 1: pubertal thalassaemic Group 2: thalassaemia patients with hypogonadismGroup 3: adult thalassaemia patients without hypogonadism

Decreased Hypophysis MRI signal in thalassemia patients with

hypogondadism

Sensitivity 75% Specificity 89%

T2* pancreatic images analysis

Pepe A, Positano V, Santarelli MF et al JMRI 2006Positano V, Pepe A, Santarelli MF et al NMR in biomedicine 2007Positano V, Pepe A, Santarelli MF et al MRI 2009HIPPO 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

TO TAILOR CHELATION TREATMENT ON SINGLE ORGAN DAMAGE

HYPOPHISYS

HEART LIVER

PANCREAS

Normal Iron overloading NormalIron overloading

Normal Iron overloading NormalIron overloading

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

OverDEFINITON OF IRON LOAD IS

CHANGING

 

WHICH IS THE CORRELATION BETWEEN IRON LOAD , COMPLICATIONS AND SURVIVAL ?

Iron load

C. Borgna-Pignatti et al. Haematologica, 2004

The control of Iron Overload using desferrioxamine treatment was associated

with thalassemia survival improving

CARDIAC DISEASE-FREE SURVIVAL RELATED TO THE SERUM FERRITTIN LEVELS

Pro

port

ion

with

out

Car

diac

Dis

ease

Years of Chelation Therapy0 2 1

416

64 8 10

12

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

Olivieri NF, et al. NEJM 1994; 331:574-578

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.

Cohort

N° 417

Deaths 77

Person-years 9930,1

Follow-up 1980-2009

Age (years) (mean±sd) 30±8.5

Age start Tx (months) (mean±sd 17,5±35,5

Age start DFO s.c. (mean±sd) 5,7±9

Mean Ferritin (±sd) 1977±1157

Gender (M - F) 218 - 192

YES(%) NO(%)

Past-Hearth Failure 42(11.8) 315(88.2)

Cirrhosis 30(8.8) 311(91.2)

Arrythmia 63(17.2) 304(82.8)

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)

Demographics and clinical findings at baseline during long-term prospective study on thalassemia major survival

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 2,8(1,6;4,9) <0,0001 379(53)Mean Ferritin (<2500 versus ≥ 2500)

4,2(2,6;6,5) <0,0001 417(77)

Summary of overall survival based on separate cox

regression models for single complications

0.00

0.25

0.50

0.75

1.00

0 10 20 30analysis time

prescomp = 0 prescomp = 1

Kaplan-Meier survival estimates, by prescomp0.

000.

250.

500.

751.

00

0 10 20 30analysis time

aritmia = 0 aritmia = 1

Kaplan-Meier survival estimates, by aritmia

0.00

0.25

0.50

0.75

1.00

0 10 20 30analysis time

cirrosi = 0 cirrosi = 1

Kaplan-Meier survival estimates, by cirrosi

KAPLAN–MEIER SURVIVAL CURVES FOR SINGLE COMPLICATION

HR=10,7(p<0.0001)HR=8.1(p<0.0001)

HR=6.8(p<0.0001)

0.00

0.25

0.50

0.75

1.00

0 10 20 30analysis time

ferrit_2cat = 0 ferrit_2cat = 1

Kaplan-Meier survival estimates, by ferrit_2cat

HR=4.2(p<0.0001)

COMPLICATION AND IRON OVERLOAD

CIRRHOSIS(512 Thalassemia Major patients)

IRON OVERLOAD WAS MEASURED AS HEART AND LIVER T2* MRI SIGNAL.HATCHED LINES SHOW NORMAL VALUES FOR HEART AND LIVER

P=0,555 P=0,525

Complications and Iron Overload

Complications and Iron OverloadARRHYTHMIAS

(582 Thalassemia Major patients)

IRON OVERLOAD WAS MEASURED AS HEART AND LIVER T2* MRI SIGNAL.HATCHED LINES SHOW NORMAL VALUES FOR HEART AND LIVER

P=0,559 P=0,622

 

MAY THE NUMBER OF COMPLICATIONS TO INFLUENCE SURVIVAL ?

Iron load

Staging for the risk of death in Thalassemia Major based on complications

•HIGH RISK: Condition in which the hazard risk for death due to interactions among complications is >9

•MEDIUM RISK : Condition in which the hazard risk for death due to interactions among complications is between 6 and 9

•LOW RISK: 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*

High Risk 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)

Medium Risk Arrhythmia*Past-Heart Failure 8,4(<0,0001) 25,3(<0,0001)Arrhythmia*Splenectomy 7(<0,0001) 8,5(<0,0001)

Low Risk Hypogonadysm*Hypothyroidism 4,2(<0,0001) 5,2(0,007)

Hypogonadysm*Splenectomy 3,2(0,001) 3,4(0,025)

*Ferritin >2500

0.0

00.2

50.5

00.7

51.0

0

0 10 20 30analysis time

diab_card_cirr_ipot_presc = 0 diab_card_cirr_ipot_presc = 1

Kaplan-Meier survival estimates, by diab_card_cirr_ipot_presc

0.0

00.2

50.5

00.7

51.0

0

0 10 20 30analysis time

diab_card_ipog_ipot = 0 diab_card_ipog_ipot = 1

Kaplan-Meier survival estimates, by diab_card_ipog_ipot

0.00

0.25

0.50

0.75

1.00

0 10 20 30analysis time

diab_card_presc_arit = 0 diab_card_presc_arit = 1

Kaplan-Meier survival estimates, by diab_card_presc_arit

LOW RISKMEDIUM RISK

HIGH RISK

HR=4(p=0.007)

HR=18,7(p<0.0001)

HR=8.9(p<0.0001)

Kaplan-Meier survival curves based on the interaction among multiple complications

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

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

Cohort flow

SVR01

Mortality

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

100

98

96

94

92

90

88

86

84

82

80

78

76

Follow-up(years)

Surv

ival p

robabili

ty (

%)

Number at riskGroup: 0

86 86 85 85 84 82 57 55 48 46 45 44 41 38 34 31 31Group: 1

55 55 55 55 55 53 52 52 51 51 51 48 47 46 45 42 42

Log Rank (Mantel Cox): p = 0.007

(V. Di Marco, M. Capra, A. Maggio, R. Malizia, M. Rizzo, C. Gerardi et al,)

Improved survival in 141 thalassemia with chronic C hepatitis treated with IFN monotherapy

78%

96%

Causes of death for the entire population of patients and for those born after 1970

from Borgna-Pignatti et al,Haematologica 2005;89:1187-9

All patients (N=1073) Patients born after 1970 (N=720)

N % N %

Heart Failure 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

Total 221 61

)

CLINICAL FINDINGS OF THAL PATIENTS AND HCC:A SINGLE CENTER EXPERIENCE AT HOSPITAL“V.

CERVELLO”, PALERMO (ITALY)

● 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

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PASSARELLO CRISTINAVINCIGUERRA MARGHERITA

GIAMBONA ANTONINO

Nursing StaffD’AGUANNO GIUSEPPINA

DE LUCA MARIA LUISADI LIBERTO GIUSEPPE

Support StaffLO PICCOLO SALVATOREMANISCALCO SERAFINO

Acceptance / SecretaryBENINATI GIADA

DAMIANO LOREDANASANSONE ROSITRAVIA AURORA

THANKS TO

Satistical consultingVITRANO ANGELA