update on thalassaemia kk maran

UPDATE ON THALASSAEMIAUPDATE ON THALASSAEMIA

Epidemiology of thalassemia

THALASSAEMIATHALASSAEMIA Di Malaysia

Pembawa thalassaemia (Thalassaemia minor/trait) 600,000 – 1 juta orang 5% daripada populasi penduduk

Thalassaemia Major 2500 pesakit

Melayu, Cina & Bumiputera Sabah & Sarawak

Di Malaysia Pembawa thalassaemia (Thalassaemia minor/trait)

600,000 – 1 juta orang 5% daripada populasi penduduk

Thalassaemia Major 2500 pesakit

Melayu, Cina & Bumiputera Sabah & Sarawak

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ObjectivesObjectivesObjectivesObjectives

1.1. To promote awareness on β-thalassemia To promote awareness on β-thalassemia disease & carrier statusdisease & carrier status

2.2. To provide population screening on To provide population screening on voluntary basis for those age 16 years & voluntary basis for those age 16 years & aboveabove

3.3. To provide counseling for all those To provide counseling for all those confirmed as β-thalassemia carriersconfirmed as β-thalassemia carriers

1.1. To promote awareness on β-thalassemia To promote awareness on β-thalassemia disease & carrier statusdisease & carrier status

2.2. To provide population screening on To provide population screening on voluntary basis for those age 16 years & voluntary basis for those age 16 years & aboveabove

3.3. To provide counseling for all those To provide counseling for all those confirmed as β-thalassemia carriersconfirmed as β-thalassemia carriers

WHAT IS THALASSEMIA ?WHAT IS THALASSEMIA ?

Inherited disease of blood that reduces the amount of haemoglobin body can make and so can cause anaemia.

Inherited disease of blood that reduces the amount of haemoglobin body can make and so can cause anaemia.

GENETIC DISEASE

What is Haemoglobin (Hb)?What is Haemoglobin (Hb)?

Blood vessel

Platelet White blood cell Red blood cell

The hemoglobin moleculeThe hemoglobin molecule

Resides in RBCs, responsible for carrying and transporting O2

Is a tetramer, consist of four polypeptide groups, 2 α and 2 β chains (α2β2)

Up to 4 O2 molecules can bind to the 4 heme groups.

Resides in RBCs, responsible for carrying and transporting O2

Is a tetramer, consist of four polypeptide groups, 2 α and 2 β chains (α2β2)

Up to 4 O2 molecules can bind to the 4 heme groups.

Haemoglobin MoleculeHaemoglobin Molecule

Genes for HaemoglobinGenes for Haemoglobin

BETA THALASSEMIA Lack of beta chain

BETA THALASSEMIA Lack of beta chain

Most of thalassemia result from point mutation within or close to the globin gene complex.

Each mutation result in reduction or abolition of globin chain function.

Most of thalassemia result from point mutation within or close to the globin gene complex.

Each mutation result in reduction or abolition of globin chain function.

BETA THALASSEMIA

CLINICAL SYNDROMEo Thalassemia Minor or Thalassemia Trait (ß+/ßa) or

(ßo/ßa) o Thalassemia Intermedia (ß+/ß+) or (ß+/ßo)o Thalassemia Major or Cooley's Anemia (ßo/ßo)

BETA THALASSEMIA

CLINICAL SYNDROMEo Thalassemia Minor or Thalassemia Trait (ß+/ßa) or

(ßo/ßa) o Thalassemia Intermedia (ß+/ß+) or (ß+/ßo)o Thalassemia Major or Cooley's Anemia (ßo/ßo)

Beta ThalassaemiaBeta Thalassaemia

Beta Thalassaemia Trait (Minor)Beta Thalassaemia Trait (Minor)

Beta Thalassaemia MajorBeta Thalassaemia Major

Both parents thalassaemia major = 100% fetal thalassaemia major.

1 parent thalassaemia major + 1 parent thalassaemia trait = 50% thalassaemia major, 50% thalassaemia trait

1 parent thalassaemia major + 1 normal parent = 100% thalassaemia trait

Both parents thalassaemia major = 100% fetal thalassaemia major.

1 parent thalassaemia major + 1 parent thalassaemia trait = 50% thalassaemia major, 50% thalassaemia trait

1 parent thalassaemia major + 1 normal parent = 100% thalassaemia trait

ALPHA THALASSEMIAALPHA THALASSEMIA

Lack of Alpha Chain More than 95% of thal are

due to deletion of one or both of the tandem globin genes located on chromosome 16.

Lack of Alpha Chain More than 95% of thal are

due to deletion of one or both of the tandem globin genes located on chromosome 16.

Alpha ThalassaemiaAlpha Thalassaemia

Alpha ThalassaemiaAlpha Thalassaemia

ALPHA THALASSEMIAALPHA THALASSEMIA

5 possible genotypes:5 possible genotypes:

Type Genotype

Normal /

+ heterozygote -/

+homozygote -/-

o heterozygote --/

ohomozygote --/--

o +double hetero --/-

LAB INVESTIGATIONSLAB INVESTIGATIONS

Screening Test

1. Full Blood Count2. Full Blood Picture3. Reticulocyte count.4. S. Iron/TIBC, S. Ferritin

Screening Test

1. Full Blood Count2. Full Blood Picture3. Reticulocyte count.4. S. Iron/TIBC, S. Ferritin

Diagnostic Test

1. Hb Analysis

Confirmatory Test 1. DNA Analysis

INVESTIGATIONSFBC

INVESTIGATIONSFBC

INVESTIGATIONSFBP - smear

INVESTIGATIONSFBP - smear

Immune haemolytic A

Thalassemia trait Thalassemia major

INVESTIGATIONSReticulocytes count

INVESTIGATIONSReticulocytes count

Reticulocytes

- are juvenile red cells.

- Number of reticulocytes in periperal blood is a fairly accurate reflection of erythropoietic activity.

Range of retic count in health =

50-100x109/l

(0.5 – 2.5%)

INVESTIGATIONSHb Analysis

INVESTIGATIONSHb Analysis

THALASSEMIA SYNDROMES THALASSEMIA SYNDROMES

SEA α0 α-thal 2 , 3.7 del

Molecular diagnosis Molecular diagnosis

Methods are based on the polymerase chain reaction. dot blot analysis, reverse dot blot analysis, the amplification refractory mutation system (ARMS), denaturing gradient gel electrophoresis, mutagenically separated PCR, gap-PCR and Restriction endonuclease analysis.

Methods are based on the polymerase chain reaction. dot blot analysis, reverse dot blot analysis, the amplification refractory mutation system (ARMS), denaturing gradient gel electrophoresis, mutagenically separated PCR, gap-PCR and Restriction endonuclease analysis.

Confirmatory DiagnosisConfirmatory Diagnosis Currently molecular diagnosis available in Malaysia at:

1. IMR2. HUKM3. UMMC4. Some private labs outsource to Singapore or

Australia5. HKL to commence next year

Currently molecular diagnosis available in Malaysia at:

1. IMR2. HUKM3. UMMC4. Some private labs outsource to Singapore or

Australia5. HKL to commence next year

Management of Thalassaemia Intermedia/Major

Management of Thalassaemia Intermedia/Major

Transfusions Should be avoided Indicated if situations of poor growth or abnormal facies

Splenectomy In the presence of hypersplenism or decline in Hb levels

Iron chelation When ferritin exceeds 1000 micrograms/L Less frequent than the thalassaemia major patients

Supplements Folate

Transfusions Should be avoided Indicated if situations of poor growth or abnormal facies

Splenectomy In the presence of hypersplenism or decline in Hb levels

Iron chelation When ferritin exceeds 1000 micrograms/L Less frequent than the thalassaemia major patients

Supplements Folate

SETIAPBULAN

SEPANJANGHAYAT

Complications of Thalassamia and Treatment

Complications of Thalassamia and Treatment

Acute febrile illness Complications due to iron overload

Cardiac complications Endocrine complications – DM, hypothyrodism, delayed puberty,

short stature Skin Other organs

Complications from excessive erythropoiesis Challenge on the facial appearance Osteoporosis and osteopenia

Transfusion related complications – Hep B/C/ HIV Psychosocial problems

Lack of self-esteem, lack of confidence, adjustment, etc. Poor academic results (due to absence) Discrimination against employment, relationships, etc.

Acute febrile illness Complications due to iron overload

Cardiac complications Endocrine complications – DM, hypothyrodism, delayed puberty,

short stature Skin Other organs

Complications from excessive erythropoiesis Challenge on the facial appearance Osteoporosis and osteopenia

Transfusion related complications – Hep B/C/ HIV Psychosocial problems

Lack of self-esteem, lack of confidence, adjustment, etc. Poor academic results (due to absence) Discrimination against employment, relationships, etc.

Treatment – Iron chelation

Giving DesferrioxamineGiving Desferrioxamine

Peralatan Membancuh ubat Ubat dalam syringe

Cucuk bawah kulit Tampal plaster Mesin dalam sarung

(Sarawak Thalassaemia Association)

Haematopoietic cell transplant (BMT)Haematopoietic cell transplant (BMT)

The only curative option A form of gene therapy Replace defective haematopoietic system from

compatible donors Acute mortality rate Chronic morbidity Must be offered to all transfusion dependent patients

as early as possible

The only curative option A form of gene therapy Replace defective haematopoietic system from

compatible donors Acute mortality rate Chronic morbidity Must be offered to all transfusion dependent patients

as early as possible

CURE vs

DEATH

CURE vs

DEATH

CUREClass 1: 91 %Class 2: 83 %Class 3: 58 %Adults : 62 %

DEATHClass 1 7%Class 2 13%Class 3 21%Adults 34%

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Algorithm Algorithm PerkhidmatPerkhidmatanan

FBC

HPLC

Βeta-Thalassaemia Carrier Voluntary Screening

Walk-in for voluntary screening (KK/KPL)

Register – “Thalassaemia Screening” (PER-PL102)

2Check & treat for Iron Deficiency

Anaemia

Within normal limit; alpha-thalassaemia cannot be excluded

RESPONSIBILITY

Pembantu Tadbir Pembantu Rendah Am

(PRA) Pembantu Perawatan

Kesihatan (PPK)

1Post-test counseling

aHb↓ MCH <27

aHb – normal MCH >27

aHb – normal MCH <27

(Keep blood for HPLC)

Counseling & Send blood for

DNA Analysis to IMR

Beta-thalassaemia / Hb E carriers

Counseling & Beta-Thalassaemia Carrier

National Registry

No response

Blood taking

Juruteknologi Makmal Perubatan (JTMP)

Penolong Pegawai Perubatan

Jururawat Terlatih

2Pegawai Perubatan 2Pakar Perubatan Keluarga

Pegawai Perubatan Pakar Perubatan Keluarga

Pakar Perubatan Keluarga Pegawai Perubatan Penolong Pegawai

Perubatan Jururawat Terlatih

Pre-test counseling Penolong Pegawai

Perubatan Jururawat Terlatih

3Register Recall Register

3Penolong Pegawai Perubatan

aReturn for Hb & MCH results

1Penolong Pegawai Perubatan

1Jururawat Terlatih

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Kad Status PembawaKad Status Pembawa

Prenatal DiagnosisPrenatal Diagnosis

To diagnose whether the fetus has Thalassaemia.

Why do we want to diagnose? If fetus is normal, increased surveillance is not

required. Reassuring to the parent. If fetus is affected, surveillance is increased. ? Termination of pregnancy

To diagnose whether the fetus has Thalassaemia.

Why do we want to diagnose? If fetus is normal, increased surveillance is not

required. Reassuring to the parent. If fetus is affected, surveillance is increased. ? Termination of pregnancy

Prenatal DiagnosisPrenatal Diagnosis

Chorionic Villus Sampling (CVS) Amniocentesis Fetal Blood Sampling (FBS) Pre-implantation Genetic Diagnosis (PGD)

Chorionic Villus Sampling (CVS) Amniocentesis Fetal Blood Sampling (FBS) Pre-implantation Genetic Diagnosis (PGD)

Chorionic Villus SamplingChorionic Villus Sampling

Sampling of placental tissue.

10-13 weeks gestation. Transvaginal /

Transabdominal.

Sampling of placental tissue.

10-13 weeks gestation. Transvaginal /

Transabdominal.

AmniocentesisAmniocentesis

Aspiration of amniotic fluid (15-20ml). 15-16 weeks gestation.

Aspiration of amniotic fluid (15-20ml). 15-16 weeks gestation.

Fetal Blood SamplingFetal Blood SamplingCan be done during 16-18 weeks of gestation

Hydrops FetalisHydrops Fetalis

Thank youThank you