1. Thalassemia Dr. Kalpana Malla MD Pediatrics Manipal Teaching Hospital
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Thalassemia
Dr. Kalpana Malla
MD Pediatrics
Manipal Teaching Hospital
Download more documents and slide shows on The Medical Post [ ]

2. AKA VON JAKSCH ANEMIA COOLEY’S ANEMIA
“THALASSA” : GREEK WORD - GREAT SEA – first observed - MEDITTERANIAN SEA

3. THALASSEMIA

4. DEFINTION
Thalassemia sydromes are a heterogenous group of inherited anemias characterised by reduced or absent synthesis of either alpha or Beta globin chains of Hb A
Most common single gene disorder

5. BASICS - 3 types of Hb 1. Hb A - 2 α and 2 β chains forming a tetramer
97% adult Hb
Postnatal life Hb A replaces Hb F by 6 months
2. Fetal Hb – 2α and 2γ chains
1% of adult Hb
70-90% at term. Falls to 25% by 1st month and progressively
3. Hb A2 – Consists of 2 α and 2 δ chains
1.5 – 3.0% of adult Hb

6. INHERITANCE Autosomal recessive
Beta thal - point mutations on chromosome 11
Alpha thal - gene deletions on chromosome 16

7. Classification
If synthesis of α chain is suppressed – level of all 3 normal Hb A (2α ,2β),A2 (2α ,2 δ),F(2α ,2γ) reduced – alpha thalassemia
If β chain is suppressed - adult Hb is suppressed - beta thalassemia

8. CLASSIFICATION α-thalassemia β-thalassemia Hb H (β4)
Hb-Bart’s (ץ4)
β-thalassemia
β+ thal : reduced synthesis of β globin chain, heterozygous
β 0 thal : absent synthesis of β globin chain, homozygous Hb A - absent
Hb F (α2 ץ2)
Hb A2 (α2 δ2)

9. CLASSIFICATION OF β THALASSEMIA
GENOTYPE
CLINICAL SEVERITY
β thal minor/trait
β/β+, β/β0
Silent
β thal intermedia
β+ /β+, β+/β0
Moderate
β thal major
β0/ β0
Severe

10. α-thalassemia 4 genes αα/αα Normal 3 genes αα/- α Silent carrier
NO. OF GENES PRESENT
GENOTYPE
CLINICAL CLASSIFICATION
4 genes
αα/αα
Normal
3 genes
αα/- α
Silent carrier
2 genes
- α/- α or αα/- -
α thalassemia trait
1 gene
α/- -
Hb H Ds
0 genes
- -/- -
Hb Barts / Hydrops fetalis

11. CLASSIFICATION OF THALASSEMIAS
Hereditary Persistence of Fetal Hb (HPFH)
Hemoglobin Lepore syndrome
Sickle cell Thalassemia
Hb C Thalassemia
Hb D Thalassemia (Punjab)
Hb E Thalassemia

12. MOLECULAR PATHOGENESIS
1.Promoter region mutations -> Transcription defects
2.Chain terminator mutations -> Translation defects
3.Splicing mutations -> RNA splicing defects (processing defects)

13. PATHOPHYSIOLOGY Since ẞ chain synthesis reduced -
1. gamma ץ2 and delta δ2 chain combines with normally produced α chains ( Hb F (α2 ץ2) , Hb A2 (α2 δ2) - Increased production of Hb F and Hb A2
2. Relative excess of α chains → α tetramers forms aggregates →precipitate in red cells → inclusion bodies → premature destruction of maturing erythroblasts within the marrow (Ineffective erythropoiesis) or in the periphery (Hemolysis)→ destroyed in spleen

14. PATHOPHYSIOLOGY
Anemia result from lack of adequate Hb A → tissue hypoxia→↑EPO production → ↑ erythropoiesis in the marrow and sometimes extramedullary → expansion of medullary cavity of various bones
Liver spleen enlarge → extramedullay hematopoiesis

15. EFFECTS OF MARROW EXPANSION
Pathological fractures due to cortical thinning
Deformities of skull and face
Sinus and middle ear infection due to ineffective drainage
Folate deficiency
Hypermetabolic state -> fever, wasting
Increased absorption of iron from intestine

16. HEPATOMEGALY Extra medullary erythropoeisis
Iron released from breakdown of endogenous or transfused RBCs cannot be utilized for Hb synthesis – hemosiderosis
Hemochromatosis
Infections – transfusion related - Hep B,C, HIV
Chronic active hepatitis

17. SPLENOMEGALY Extra medullary hematopoeisis
Work hypertrophy due to constant hemolysis
Hypersplenism (progressive splenomegaly)

18. JAUNDICE Unconjugated hyperbilirubinemia - hemolysis
Hepatitis - transfusion, hemochromatosis
GB stones - obstructive jaundice
cholangitis

19. INFECTIONS -CAUSES Poor nutrition Increased iron in body
Blockage of monocyte-macrophage system
Hypersplenism- leukopenia
Infections associated with transfusions

20. ACCUMULATION OF IRON
Deposition in pituitary - endocrine disturbance - short stature, delayed puberty, poor sec. sexual characteristics
Hemochromatosis - cirrhosis of liver
Cardiomyopathy (cardiac hemosiderosis) -cardiac failure, sterile pericarditis, arrythmias, heart block
Deposition in pancreas -diabetes mellitus

21. ACCUMULATION OF IRON Lungs: restrictive lung defects
Adrenal insufficiency
Hypothyroidism, hypoparathyroidism
Increased susceptibity to infections (iron favours bacterial growth) espc : Yersinia infections

22. CLINICAL FEATURES (THAL MAJOR)
INFANTS:
Age of presentation: 6-9 mo (Hb F replaced by Hb A)
Progressive pallor and jaundice
Cardiac failure
Failure to thrive, gross motor delay
Feeding problems
Bouts of fever and diarrhea
Hepatosplenomegaly

23. CLINICAL FEATURES (THAL MAJOR)
BY CHILDHOOD:
Growth retardation
Severe anemia-cardiac dilatation
Transfusion dependant
Icterus
Changes in skeletal system

24. SKELETAL CHANGES CHIPMUNK FACIES (HEMOLYTIC FACIES):
Frontal bossing, maxillary hypertrophy, depression of nasal bridge , Malocclusion of teeth
PARAVERTEBRAL MASSES:
Broad expansion of ribs at vertebral attachment
Paraparesis
PATHOLOGICAL FRACTURES:
Cortical thinning
Increased porosity of long bones
DELAYED PNEUMATISATION OF SINUSES
PREMATURE FUSION OF EPIPHYSES - Short stature

25. Others Delayed menarche Gall-stones, leg ulcers Pericarditis
Diabetes/ cirrhosis of liver
Evidence of hypersplenism

26. CLINICAL FEATURES (THAL INTERMEDIA)
Moderate pallor, usually maintains Hb >6gm%
Anemia worsens with pregnancy and infections (erythroid stress)
Less transfusion dependant
Skeletal changes present, progressive splenomegaly
Growth retardation
Longer survival than Thal major

27. CLINICAL FEATURES (THAL MINOR)
Usually ASYMPTOMATIC
Mild pallor, no jaundice
No growth retardation, no skeletal abnormalities, no splenomegaly
MAY PRESENT AS IRON DEFICIENCY ANEMIA (Hypochromic microcytic anemia)
Unresponsive/ refractory to Fe therapy
Normal life expectancy

28. DIAGNOSIS - BLOOD PICTURE
Hb – reduced (3-9mg/dl)
RBC count – increased
WBC, platelets – normal
RBC indices – MCV & MCH,MCHC reduced, RDW normal

29. BLOOD PICTURE
PS: microcytic hypochromic anemia, anisopoikilocytosis, target cells, nucleated RBC, leptocytes, basophilic stippling, tear drop cells
Cytoplasmic incl bodies in α thal
Post splenectomy : Howell-Jolly and Heinz bodies
Reticulocyte count increased (upto 10%)

31. DIAGNOSIS Osmotic fragility test : increased- resistance to h’lysis
T. bilirubin, I. bilirubin – increased
Haptoglobulin and hemopexin – depleted
S. Fe, ferritin elevated, Transferrin –saturated
B.M. study: hyperplastic erythropoesis

32. DIAGNOSIS Red cell survival – decreased using
Folate levels- concurrently decreased
Free erythrocyte porphyrin - normal
Serum uric acid-raised
Haemosiderinuria

33. DIAGNOSIS – Hb ELECTROPHORESIS
Thal. Major - Hb F: 98 %
Hb A2: 2 %
Hb A: 0 %
HEMOGLOBIN
MAJOR
MINOR
NORMAL
Hb F
10-98%
variable
<1%
Hb A
Absent
80-90%
97%
Hb A2
5-10% (increased)
1-3%

34. Radiological changes
Small bones (hand ) – earliest bony change, rectangular appearance,medullary portion of bone is widened &bony cortex thinned out with coarse trabecular pattern in medulla
Skull – widened diploid spaces – interrupted porosity gives hair on end appearance
Delayed pneumatization of sinuses – maxilla appears overgrown with prominent malar eminences

35. X ray skull:
“ hair on end” appearance or
“crew-cut”
appearance

37. IRON OVERLOAD ASSESSMENT
S. Ferritin
Urinary Fe excretion
Liver biopsy
Chemical analysis of tissue Fe
Endomyocardial biopsies
Myocardial MRI indexes
Ventricular function – ECHO, ECG

38. Treatment: BT at 4-6 wks interval (Hb~ 9.5 gm/dl)
Packed RBC, leucocyte-poor
Hb to be maintained –
Hypertransfusion : >10 gm/dl
Supertransfusion : >12 gm/dl
If regular transfusions- no hepatomegaly, no facies
10-15ml/kg PRBC raises Hb by 3-5gm/dl –
Neocytes transfusion
Mean cell age : 30 days
2-4 times more expensive

39. CHELATION THERAPY - DESFERRIOXAMINE
( 1 unit of blood contains 250 mg iron)
Iron-chelating agents: desferrioxamine-
Dose: 30-60mg/kg/day
IV / s/c infusion pump over 12 hr period 5-6 days /wk
Start when ferritin >1000ng/ml
Best >5 yrs
Vitamin C 200 mg on day of chelation - enhances DFO induced urinary excretion of Fe

40. Adverse effects: DESFERRIOXAMINE
Cardiotoxicity – arrythmias
Eyes - cataract
Ears - sensorimotor hearing loss
Bone dysplasia-growth retardation
Rapid infusion- histamine related reaction- hypotension, erythema, pruritis
Infection, sepsis

41. CHELATION THERAPY- DEFERIPRONE
Oral chelator - > 2yrs old Dose: mg/kg/day
Adverse effects:
Reversible arthropathy
Drug induced lupus
Agranulocytosis
Other oral chelators
Deferrothiocine
Pyridoxine hydrazine
ICL-670 – removes Fe from myocardial cells

42. TREATMENT - SPLENECTOMY
Deferred as long as possible. At least till 5-6 yrs age
Splenectomy (indications):
Massive splenomegaly causing mechanical discomfort
Progressively increasing blood transfusion requirements (> ml/kg/yr) packed RBC

43. BONE MARROW TRANSPLANTATION
BEST METHOD FOR CURE
Risk factors:
Hepatomegaly >2cm
Portal fibrosis
Iron overload
Older age

44. Newer therapies: Hb F AUGEMENTATION Hydroxyurea Myelaran
GENE MANIPULATION AND REPLACEMENT
Remove defective β gene and stimulate γ gene
5-azacytidine increases γ gene synthesis
Hb F AUGEMENTATION
Hydroxyurea
Myelaran
Butyrate derivatives
Erythropoetin in Thal intermedia

45. OTHER SUPPORTIVE MEASURES
Tea – thebaine and tannins– chelate iron
Vitamin C – increases iron excretion
Restrict Fe intake – decrease meat, liver, spinach
Folate – 1 mg/day
Genetic counselling
Psychological support
Hormonal therapy – GH, estrogen, testosterone, L-thyroxine
Treatment of CCF

46. Prognosis:
Life expectancy: yrs
Untreated: < 5 yrs

47. PRENATAL DIAGNOSIS β/α ratio: <0.025 in fetal blood – Thal major
Chorionic villous biopsy at wks
amniocentesis at 15-18th wk gestation Analysis of fetal DNA
PCR to detect β globin gene

48. Prevention: Antenatal diagnosis Termination of pregnancy if Thal major
Preventing marriage b/w traits

49. Thalassemia minor/ trait:
Hb N or mildly reduced - MCV/ MCH reduced
PBS- anisopoikilocytosis, microcytosis, hypochromia, target cells
Serum bilirubin- N or mildly raised
Hb electrophoresis
HbA2: %
Hb A: %
Hb F: 1-5 %
Moderate reduction of β-chain synthesis

50. Treatment:
Counselling- treatment usually not required

51. α-thalassemia: Deletion on alpha globin locus on Chr 16
Defective synthesis of α-globin chain
Excess of ץ- chains - in the fetus (Hb Bart- ץ4)
Excess of β-chains in the adult (Hb H- β4)

52. ALPHA THALASSEMIA - CLASSIFICATION
CLINICAL CLASSIFICATION
GENOTYPE
NO. OF GENES PRESENT
Silent carrier
αα/- α
3 genes
α thalassemia trait
- α/- α or αα/- -
2 genes
Hemoglobin H disease
-α/- -
1 gene
Hb Barts / Hydrops fetalis
- -/- -
0 genes

53. ALPHA THALASSEMIA Highest prevalence in Thailand
α chains shared by fetal as well as adult life. Hence manifests both times
These thalassemias don’t have ineffective erythropoesis because β and γ are soluble chains and hence not destroyed always
α Thalassemia trait mimics Fe deficiency anemia
Silent carrier – silent – not identified hematologically, diagnosed when progeny has Hb Barts/ Hb H

54. ALPHA THALASSEMIA Silent carrier – asymptomatic ,no RBC abnormalities
Trait – aymptomatic , minimal anemia

55. Hb H DISEASE Not very transfusion dependant Bony deformities
Seen in SEA, middle east
Moderate anemia (Hb 8-9 gm/dl), mild jaundice
Splenomegaly, gall stones
PBS similar to thal major
Hb electrophoresis: Hb H 2-40 %; rest are Hb A, HbA2, HbF
Not very transfusion dependant
Bony deformities

56. Hb BARTS Hb Barts has γ4, then later in infancy β4
Severe hypoxia as Hb Barts has high affinity for oxygen

57. Haemoglobin Bart’s: Stillborn or die within a few hours
Most severe manifestation of alpha thalassemia
Hydrops fetalis – Fatal unless intrauterine transfusions
Stillborn or die within a few hours
Severe anemia , edematous, mildly jaundiced, ascites, hepatosplenomegaly, cardiac failure
Looks like Rh incompatilibity
Increased incidence of toxemia
of pregnancy

58. DIAGNOSIS Hb electrophoresis: 80-90 % Hb Bart’s Hb H Hb Portland
No Hb A, Hb A2 or Hb F
Treatment: immediate exchange transfusion

59. DIAGNOSIS OF α THALASSEMIA
CBC, PS, BM study
Heinz bodies in HbH disease – brilliant cresyl blue
Hb electrophoresis – for HbH and Hb Barts
α/β chain ratio decreased

60. Treatment: Generally not reqd
Blood transfusion , iron chelation therapy – For transfusion dependent cases
Avoidance of oxidant drugs
Prompt treatment of infections
Folic acid supplementation
Splenectomy
BM transplantation, gene therapy

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