The inherited Diseases of Haemoglobin are an emerging Global Health Burden. 1st Pan-Asian Conference on Haemoglobinopathies Keynote speech.

1. The Inherited Diseases of
Hemoglobin are an Emerging
Global Health Burden
Suthat Fucharoen
(grsfc@mahidol.ac.th)
Thalassemia Research Center
Institute of Molecular Biosciences,
Mahidol University, Thailand

2. Acknowledgements
Prof. Prawase Wasi
Mahidol University, Sir David Weatherall
Thailand Oxford University
UK

3. Contribution of genetic and congenital disorders
to infant and childhood mortality
in a typical developed country

4. Global distribution of hemoglobin disorders, in terms of
births of affected infants per 1000 births (WHO, 1996)

5. Global E id i l
Gl b l Epidemiology of Hemoglobin Disorders
fH l bi Di d
• Around 7% of the global population carries an
abnormal hemoglobin gene
b lh l bi
• 300,000-500,000 children are born with clinically
significant hemoglobin disorders annually
i ifi th l bi di d ll
• About 80% of affected children are born in
developing countries
• About 70% are born with Sickle Cell Disease
and th rest with Thalassemia Syndromes
d the t ith Th l i S d
• 50-80% of children with SCD die each year in low and
middle income countries
iddl i ti
• 50,000-100,000 children with thalassemia major die
each year in low and middle income countries
h i l d iddl i ti

6. Hemoglobin disorders
as a common entry point
‐ They are highly prevalent in many populations
‐ Survival and quality of life can be greatly improves by
simple protective measures, such as transfusion programs
for thalassemia
f th l i
‐ Carriers can be detected by cheap and simple
hematological tests, and carrier couples can be advised
h l l d l b d d
prospectively of their risk
‐ Prenatal diagnosis is highly acceptable to couple at risk
Diagnosis registers can be used for service audit
g g
‐ Screening strategies and DNA‐based laboratory methods
introduced for hemoglobin disorders can be extended to
other inherited disorders

7. WHO Working Group, 1981
1. A. Boyo (Lagos, Nigeria)
A B (L Ni i ) 8. A. Pantelakis (Athens, Greece)
8 A P t l ki (Ath G )
2. A. Cao (Sardinia, Italy) 9. A.Motulsky (Seattle, USA)
3. Der kalostian (Beirut, Lebanon) 10. A. Piel (Geneva, Switzerland)
4 J Hercules (Betheada USA)
4. J. (Betheada, 11. J.
11 J Rosa (Paris France)
(Paris,
5. A. Kuliev (Genewa, Switzerland) 12. P. Wasi (Bangkok, Thailand)
6. D. Loukopoulos (Athens, Greece) 13. D.J. Weatherall (Oxford, UK)
7. B.
7 B Modell (London, UK)
(London 14. R.
14 R Williamson (London, UK)
(London

8. List of relevant documents
WHO's Genomic Resource Centre ‐ www.who.int/genomics/en
WHO, 1989. Report of the fifth WHO working group on the feasibility study on hereditary disease community control programmes (Hereditary
anaemias) . WHO, Geneva, Switzerland. (WHO/HDP/WG/HA/89.2)
WHO, 1991. Guidelines for the Management of Sickle Cell Disease. WHO G
WHO G id li f th M t f Si kl C ll Di WHO, Geneva, Switzerland (WHO/HDP/SCD/91.2)
S it l d (WHO/HDP/SCD/ )
WHO, 1993. Report of a joint WHO/TIF meeting on the prevention and control of haemoglobinopathies. WHO, Geneva, Switzerland
(WHO/HDP/TIF/WG/93.1)
WHO, 1994. Educational materials on prenatal diagnosis for Sickle‐cell disorder. WHO, Geneva, Switzerland (WHO/HDP/EM/PN.SCD/94.2).
WHO, 1994. Guidelines for the Control of Haemoglobin Disorders. WHO, Geneva, Switzerland (WHO/HDP/HB/GL/94.1).
WHO, 1995. Prevention and Control of Haemoglobinopathies. WHO Bulletin, v73(3):375‐386.
WHO, 1997. Inherited Haemoglobin Disorders: an increasing global health problem. WHO Bulletin, v.75 (3):15‐39.
WHO, 1999. Services for the Prevention and Management of Genetic Disorders and Birth Defects in Developing Countries. WHO, Geneva, Switzerland
(WHO/HGN/WAOPBD/99.1)
WHO, 2000. Primary Health Care Approaches for Prevention and Control of Congenital and Genetic Disorders. WHO, Geneva, Switzerland
(WHO/HGN/WG/00.1)
WHO, 2002. Minutes of a WHO meeting on haemoglobin disorders. WHO, Geneva, Switzerland (WHO/HGN/HB/02.4)
WHO 2002 Minutes of a WHO meeting on haemoglobin disorders WHO Geneva Switzerland (WHO/HGN/HB/02 4)
WHO, 2002. Report of the Advisory Committee on Health Research. Genomics and World Health. WHO, Geneva, Switzerland (ISBN 92 4 154554 2).
WHO, 2003. Genetic Approaches to Haemoglobin Disorders and Primary health Care. WHO, Geneva, Switzerland (WHO/HGN/TIF/CONS/03.1)
WHO, 2006. Report by Secretariat to Executive Board: Sickle‐cell anaemia. EB117, Doc. EB117/34. WHO, Geneva, Switzerland [ www.who.int/gb ]
WHO, 2006. Report by Secretariat to World Health Assembly: Sickle‐cell anaemia. WHA59, Doc.A59/9. WHO, Geneva, Switzerland [ www.who.int/gb ]
WHO, 2006. Report by Secretariat to Executive Board: Thalassaemia and Other Haemoglobinopathies. EB118, Doc. EB118/5. WHO, Geneva, Switzerland
[ www.who.int/gb ]
[ h i / b ]
WHO, 2006. Executive Board Resolution on Sickle Cell Anaemia. EB117.R3. WHO, Geneva, Switzerland [ www.who.int/gb ]
WHO, 2006. World Health Assembly Resolution on Sickle Cell Anaemia. WHA59.20. WHO, Geneva, Switzerland [ www.who.int/gb ]
WHO, 2006. Executive Board Resolution on Thalassaemia and Other Haemoglobinopathies. EB118.R1. WHO, Geneva, Switzerland [ www.who.int/gb ]
WHO, 2006. Report of a joint WHO/MOD meeting on Management of Birth Defects and Haemoglobin Disorders. WHO, Geneva, Switzerland.
WHO, 2008. Report of a joint WHO‐TIF meeting on Management of Haemoglobin Disorders. WHO, Geneva, Switzerland.
, p f j g g f g , ,
WHO, 2010. World Health Assembly Resolution on Birth Defects. WHA63.17. WHO, Geneva, Switzerland [ www.who.int/gb

9. World Health Organization
EB117.R3 Resolution,
EB117 R3 Resolution 2006

10. World Health Organization
WHA59.20 Resolution, 2006
,

11. World Health Organization
EB118.R1 Resolution, 2006
,

12. Resolutions on Hemoglobinopathies
Thalassaemia and other
Haemoglobinopathies Urges M b St t
U Member States:
EB118, May 2006 – Resolution EB118.R1
 Implement and reinforce national
programs on HB disorders
 Evaluate the impact of national
programs
 Intensify the training of all health
professionals
 Promote community education
y
 Promote international
cooperation
 Develop and strengthen medical
Sickle cell anaemia genetic services
WHA59, May 2006 – Resolution WHA59.20  Support basic and applied
research

13. Resolutions on Hemoglobinopathies
Thalassaemia and other
Haemoglobinopathies
EB118, May 2006 – Resolution EB118.R1 Requests the Director-General
 p
provide technical support and
pp
advice to national programs
 expand the training and expertise
of personnel
 support the further transfer of
affordable technologies
 drafting guidelines on prevention
and management
 fostering the establishment of
regional groups of experts;
Sickle cell anaemia  support needed research
WHA59, May 2006 – Resolution WHA59.20

14. NWHO meeting of experts
Geneva, 17-19 May 2006
Priorities:
• support continued research for the
collection and refinement of data relevant for
the control of birth defects and hemoglobin
disorders
• provide practical advice and support for
countries wishing to develop medical
services for care and prevention of birth
defects and haemoglobin disorders
• promote human resource capacity
development and technology transfer

15. WHO-TIF Meeting of Experts, Cyprus,
November 2007

16. A proposed 5-year plan of Action
1: Reviewing th
1 R i i the current status of epidemiology and
t t t f id i l d
control services for Hemoglobin (Hb) disorders globally
2: Identification of local and regional problems, needs and
problems
priorities for improving control policies
3: Initiation of Guidelines for the control of Hb disorders
4: Supporting the establishment of new and promoting the
services of existing expert centers
5: Promotion of the establishment of regional expert
advisory groups
6: Fund raising to support programs of control of Hb
disorders
7: Development of cost-effective approaches and
p pp
interventions for the control of Hb disorders
8: Promotion of the establishment of a World Day for
Hemoglobin Disorders
H l bi Di d
9: Collaboration between potential stakeholders

17. List of WHA / EB resolutions (in genetics)
WORLD HEALTH ASSEMBLY
WHA57.13 22 May 2004 Genomics and world health
WHA59.
WHA59.20 27 May 2006 Sickle cell anaemia
WHA63.17
WHA63 17 21 May 2010 Birth defects
EXECUTIVE BOARD
EB116/3 26 May 2005 Control of genetic diseases
EB117.R3
EB117.R3 25 Jan 2006 Sickle cell anaemia
EB118.R1
EB118 R1 29 May 2006 Thalassaemia and other
haemoglobinopathies

19. ‐Thal/Hb E
‐Thal 2/Hb E
Hb E
‐Thal 2 ‐Thal ( ‐Thal)2
‐Thal/Hb E
Hb H Disease c ‐Thal 2
‐ ‐Thal 1/ ‐Thal
‐Thal 1 (‐Thal 1)2
‐Thal 1
Hb Bart s
Hb Bart’s Hydrops
,
Hb H Disease Hb AEBart s Disease
‐ ‐Thal 1/Hb E
c Hb CS ‐
c Hb CS
Hb Constant Spring Hb E
(Hb CS) (Hb CS) 2
(Hb E) 2
(More than 60 genotypes )

20. Thailand, 1985
Pune,1
987

21. The Thalassemia Situation in Cambodia
Untreated thalassemia
May 2005
National Pediatric Hospital
19 year old male
Hematocrit – 4 %
? Hb E/ thalassaemia

22. 38%
Prevalence of Thalassemia &
Hemoglobinopathies i Maldives
H l bi thi in M ldi 23%
44%
8%
15%
10%
Maldives

23. UNION OF MYANMAR
Myanmar – Thalassemia
(Aung-Than-Batu et al 1968,1971)
• β thalassemia trait – 0 5%
0.5%
• α thalassemia trait - 10%
• HbE trait - 26%

24. In Myanmar alone, 1‐4.9 per 1000 live birth suffer from severe
form of thalassemia (Thalassemia major) (MODELL, 1986)
Assuming an annual birth rate of 1.4 million, 1400 –7000 new
cases of severe thalassemia each and every year in Myanmar
500 Couples
HbE  thalassemia
HbE‐‐thalassemia,
ONE in every 500 couples are at‐risk
HbH disease
TWO in every 500 couples are at‐risk
Hb Bart s Hydrops Fetalis
Hb Bartʼs Hydrops Fetalis
NONE in every 500 couples are at‐risk
(Ne Win et al, 2003 Myan Milit Med; 2005 Ann Rep)

26. The distribution and the frequency (%) of
thalassemia beta carriers in Indonesia

‐thalassemia
HbE
P’baru
4 2
Dayak
Batak
njar
1 5 3
Ban
sa
0
D
B
P
M’has
Kaili
5 2
nang
kasar
8 1
ng
4
Min
P’ban
M’k
3 9
Bangka
6
va
5
or
Sumba
a
Jav
Bali
i
8
Alo
Sasak
k
1 6
Bima
4 3 3
6 5
4 33
7
A.S. Sofro & F. Lanni, University of Gajah Mada

27. Thalassemia situation in Indonesia
Severe thalassemia patients in Jakarta
1400
1200
Type of thalassemias: 1000
• 52% Beta thalassemia 800
• 46% Beta/HbE
B t /HbE 600
• 2% HbH + others 400
200
0
1988 1998 2005

28. INDONESIA
Estimation of new -thalassemia patients
• Population 224 million
• Annual birth rate: 2.3%
• Carrier frequency 5% - 3,000 new patients/year
• Only 3,000 patients registered
3 000
The expected number of
thalassemia major patients
th l i j ti t
Wahidiyat et al., 1988
al

29. Southeast/East Asia (2010)
No Country/ Total 0-thal +-thal -thal Hb E Hb S
Region Population (m) (%) (%) (%) (%) (%)
1 Bangladesh 143.9 0 41 2.5 4.0 0
2 Bhutan 2.1 0 32 + 4.0 0
3 DPR, Korea 24 ND ND ND ND ND
4 India 1,210.2 0 41 1.6 1.0 1.9
5 Indonesia 237.4 + 7.7 4.0 1.9 0
6 Maldives 0.37 0 32 16 1.0 0.1
7 Myanmar
M anmar 59.1
59 1 0.4
04 32 2.2
22 25 0
8 Nepal 28.0 0 32 1.0 3.0 0
9 Sri Lanka 20.0 0 40.8 2.5 2.5 0
10 Thailand 64.7 5.0 21 5.3 33 0
11 Timor-Leste 1.13 ND ND ND ND ND
Grand Total 1,790.9
(Modified from Modell
)

30. Thalassemia diagnosis in different SEARO countries
Country Blood Cell OF Hb Analysis DNA
Analyzer Analysis
Electrophoresis HPLC/LPLC/CE
p  
Bangladesh (+) - (+) (+) (+) (+)
Bhutan ND ND ND ND ND ND
DPR Korea ND ND ND ND ND ND
India (+) + + (+) + +
Indonesia (+) - + (+) (+) (+)
Maldives (+) - + + (+) -
Myanmar (+) - (+) - (+) (+)
Nepal ND ND ND ND ND ND
Sri Lanka + - + (+) (+) (+)
Thailand + + + + + +
Timor-Leste ND ND ND ND ND ND

31. Thalassemia treatment available in different SEARO countries
Country Blood Iron BM/ PND National
Transfusion Chelation Stem cell Program
Transplant
DFO L1 Exjade
Bangladesh (+) (+) (+) (+) - - -
Bhutan ND ND ND ND ND ND ND
DPR Korea ND ND ND ND ND ND ND
India (+) (+) + + (+) (+) (+)
Indonesia (+) (+) (+) (+) - (+) -
Maldives + + + + - + +
Myanmar
y ( )
(+) ( )
(+) + ( )
(+) - - -
Nepal ND ND ND ND ND ND ND
Sri Lanka + + + + - - (+)
Thailand
Th il d + + + (+)
( ) + + +
Timor-Leste ND ND ND ND ND ND ND

32. Treatment of Thalassemia
1. Conventional Treatment
- Blood Transfusion
- Iron Chelation
2. Treatment of Complication
- I f ti
Infections
- Heart Failure etc.
2.
2 Hemoglobin F Stimulation
l bi Si l i
4. Cure
- Bone Marrow and Stem Cells
Transplantation
- Gene Therapy

33. Estimated Direct Cost for the Management of
g
One β‐Thalassemia Major for 30 Years: 2006
Items 1 10 years
1‐10 years 11 20 years
11‐20 years 21 30 years
21‐30 years
1. Blood transfusion 2,500 (1 unit) 5,000 (2 units) 7,500 (3 units)
plus filter/month
2. Desferrioxamine 5,000 (20 vials) 10,000 (40 vials) 150,000 (60 vials)
Vial/month
3. Hospital care
H it l 2,000 2,000 2,000
1 day/month
4
4. Other: Lab 1,000 1,000 1,000
tests/month
5. Total cost/month 10,500 18,500 26,500
6. Total cost/year 126,000 222,000 318,000
7. Total cost/10 years 1,260,000 2,220,000 3,180,000
Grand total 6,660,000 Baht (150,000 Euro )
(1 Euro = 44 Baht) (Leelahavarong P et al 2010)

34. Thalassemia in Thailand
‐Thalassemia (‐thal1 and ‐thal2) 20 ‐ 30%
Hb Constant Spring ( -thal 2 like effect ) 1 ‐ 8%
-Thalassemia
Th l i 3 ‐
3 9%
Hemoglobin E 10 ‐ 53%
Total number of thalassemic patients and the number of
births per year (total births = 800,000/year)
Diseases Couple at risk Birth Living
(per year) (per year) patients
Homozygous -thalassemia
thalassemia 828 207 2,070
2 070
-Thalassemia/Hb E 12,852 3,213 96,390
,
Hb Bart s hydrops fetalis 3332 833 0
Hb H disease 22,400 5,600 336,000
Total ,
39,412 9,853
, 434,460
,
Modified from Fucharoen S. and Winichagoon P., 1988

35. Comparison of the cost of treatment and and prevention of
severe thalassemia in 1000 pregnant women in Thailand
Prevention Expected Treatment
No. Birth (av. life= 30 yrs)
Hb Bart’s hydrops 48,280 B 42,500 B
fetus (US$ 1379) 2 (US$ 1 214)
1,214)
Beta thalassemic 48,280 B **26,400,000 B
Disease* (US$ 1379) 4# (US$ 754,285)
(* include both homozygous beta thalassemia and beta thal/HbE,
#1 homozygous beta thalassemia and 3 beta thal/HbE ,
** cost per case = 6,660,000 B)
6 660 000

36. Control Program
C l P
Strategy
1
• Treatment of Existing Cases
g
2
• Prevention Birth of New Cases

37. Preliminary data on serum ferritin in ADULT and
pediatric patients after 6mths of GPO-L-ONE-2
3 mths 6mths
Average s erum ferritin reduction after 6 mths of DFP
0 Pediatrics - 57.6 - 20.6
1 2 3 Adults - 934 -1260
-200
-400 Average dose in ped. = 75-80 MKD
ng/mL )
-600 Average dose in adult = 50-55 MKD
SF (n
-800
-1000
-1200
-1400
0 3mths 6mths
pediatrics (n=33) adults (n=30)

38. Prevention of Thalassemia
Screening Counseling
General
Premarital
Preconceptional
Prenatal
Postnatal
-Screening test: -Diagnostic test:
- MCV/OF - Hb typing
- DCIP - genotyping

40. Immunochromatographic Strip Test for -Thalassemia
1. 0.1 ml. 2. Insert strip, 3.
3 wash
h 4. Read
4 R d result
lt
blood leave 2 min.
+ hemolysis
agentt
3 minutes

41. Tongsong T, Wanapirak C,Sirivatanapa P, Sanguansermsri T, Sirichotiyakul S, Piyamonkol W, Chanprapaph P.
Prenatal control of severe thalassemia: Chiang Mai strategy
Prenat Diagn 2000; 20: 229-234

42. Hb Bart’s Hydrops Fetalis
20 19
20
15 Hydrops
11
10
5 3
2
0 0 0 0 0 0
‘94 ‘95 ‘96 ‘97 ‘98 ‘99 ‘00 ‘01 ‘02 ‘03
Wanapirak C. et al, 2004

43. New registration for  thal major
eg s o o jo
6 6
5
4
3 CMU h i l
hospital
3
2
1
0 0 0 0 0 0 0 0 0
ʻ94
94 ʻ95 ʻ96
95 96 ʻ97
97 ʻ98 ʻ99
98 99 ʻ00
00 ʻ01
01 ʻ02 ʻ03
02 03
Wanapirak C. et al, 2004

44. New registration for  thal/Hb E
7
7
6
5 5 CMU hospital
5
4
3
2
2
1 1
1
0 0 0 0 0
ʻ94
94 ʻ95
95 ʻ96
96 ʻ97
97 ʻ98
98 ʻ99
99 ʻ00
00 ʻ01
01 ʻ02
02 ʻ03
03
Wanapirak C. et al, 2004

45. Case Registration (year)
g (y )
CMU MOPH
40
35 35
30 31
25 25 24 26 24
ber
22 22 Hb E/beta-thal
Numb
20 21
beta-Thal major
15 15
10 11 10 11
9 9
5 5 4
3 3
0 0
93 94 95 96 97 98 99 00 01 02
Year

46. National P
N i l Program on the Prevention and
h P i d
Control of Thalassemia in Thailand
(Starting: 1994)
Thalassemia Foundation
University
of Thailand
Ministry of Public Health

47. Thalassemia in Developing Countries
1. Many communicable diseases
2. Poverty
3. Limited data on frequency and lack of data
Li it d d t f d l k f d t
on economic issue
4. Lack of awareness: government/NGO
5. Ethical, social, religious and legal issues

48. ELSI and Thalassemia
1. Should thalassemia be treated in poor
country?
t ?
2. Lack of education
2 Lack of education
3
3. Social and religious issues
g
4. Government and social policy on PND
5. Lack of regulatory/ethics organization

49. Global Control of Hemoglobinopathies
1. North-south or north-south-south university
partnerships
2. Identification of local mutations
3. Training and technology transfer
4. National control program established
5.
5 Future: Regional network to be established

50. Country Report
1.
1 Australia (John Prior)
2. Bangladesh (Syed Khairul Amin)
3. C bod (Sam Vuthy, Robyn Devenish)
Cambodia (S Vu y, oby eve s )
4. China, Guangxi (Chen Ping)
Prawase Wasi
5. China, Hong Kong (Vivian Chan) Mahidol University
6. India (Roshan Colah)
7. Indonesia (Iswari Setianingsih)
8.
8 Laos (Douangdao Souk Aloun)
9. Malaysia (Elizabeth George)
10. Maldives (Naila Firdous)
( ) Sir David Weatherall
Oxford University
11. Myanmar (Sann Sanda Khin)
12. Singapore (Hai Yang Law)
13. Sri Lanka (Shanthimala de Silva)
14. Taiwan (Ching-Tien Peng)
15.
15 Thailand (Vichai Tienthavorn) Alan Bittles
16. Vietnam (Lam Thi My) Edith Cowan University

51. ASIAN NETWORK FOR THALASSAEMIA CONTROL
Miracle Grand Hotel
Bangkok, July 2-4, 2005
Organizers:
- Thalassemia Research Center, Mahidol University
, y
- Department of Maternal and Child Health,
Ministry of Public Health, Thailand
y ,
- Thalassemia Foundation of Thailand

52. Asian Network for Thalassemia Control
July 4, 2005
Miracle Grand Hotel
Bangkok, Thailand

53. Conclusion:
1. We have common problems
p
2. Magnitude of problems is not well established
in some countries
3. Different levels of knowledge and technology
in member countries
4. Heterogeneity of disease severity
Proposed a Twin Center Concept:
Bridge countries with knowledge and technology
to the one that just getting start.
Questions:
How to get start? Where is the fund?

54. Proposes:
1) Set up Regional Working Group on Hemoglobinopathies
(RWGH)
2) Provides partial support to run the RWGH
3) Have a regular annual meeting of the working group, rotate
to all member countries
4) The annual meeting should be mainly sponsored by local
government (with partial support from SEARO)
t ( ith ti l tf
5) The RWGH can help local organizer (of annual meeting) to
organize education symposium or laboratory workshop for
the local people (administrators, doctors, technicians, nurses)
6) The RWGH will help to develop lab manual (for diagnosis),
GCP guidelines, etc.
7) The RWGH will help training of personals (doctor, nurse,
technicians,
technicians counselor etc.)
etc )
SEARO should work in collaboration with other regions