1. Thalassemia
Dr. Kalpana Malla
MD Pediatrics
Manipal Teaching Hospital
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2. AKA
⢠VON JAKSCH ANEMIA
⢠COOLEYâS ANEMIA
⢠âTHALASSAâ : GREEK WORD - GREAT SEA
â first observed - MEDITTERANIAN SEA
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 ι and 2 β chains forming a tetramer
⢠97% adult Hb
⢠Postnatal life Hb A replaces Hb F by 6 months
2. Fetal Hb â 2Îą and 2Îł chains
⢠1% of adult Hb
⢠70-90% at term. Falls to 25% by 1st month and
progressively
3. Hb A2 â Consists of 2 Îą and 2 δ chains
⢠1.5 â 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 Îą chain is suppressed â level of all
3 normal Hb A (2ι ,2β),A2 (2ι ,2 δ),F(2ι ,2γ)
reduced â alpha thalassemia
⢠If β chain is suppressed - adult Hb is suppressed
- beta thalassemia
8. CLASSIFICATION
⢠ι-thalassemia
Hb H (β4)
Hb-Bartâs ( 4)
⢠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 (Îą2 2)
Hb A2 (ι2 δ2)
9. CLASSIFICATION OF β THALASSEMIA
CLASSIFICATION 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
13. PATHOPHYSIOLOGY
⢠Since Ạchain synthesis reduced -
1. gamma 2 and delta δ2 chain combines with
normally produced Îą chains ( Hb F (Îą2 2) , Hb A2
(ι2 δ2) - Increased production of Hb F and Hb A2
2. Relative excess of Îą chains â Îą tetramers forms
aggregates âprecipitate in red cells â inclusion
bodies â premature destruction of maturing
erythroblasts within the marrow (Ineffective
erythropoiesis) or in the periphery
(Hemolysis)â destroyed in spleen
14. PATHOPHYSIOLOGY
Anemia result from lack of adequate Hb A
â tissue hypoxiaââEPO production â
â erythropoiesis in the marrow and
sometimes extramedullary â expansion
of medullary cavity of various bones
Liver spleen enlarge â 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 â hemosiderosis
⢠Hemochromatosis
⢠Infections â transfusion related - Hep B,C,
HIV
⢠Chronic active hepatitis
17. SPLENOMEGALY
⢠Extra medullary hematopoeisis
⢠Work hypertrophy due to constant
hemolysis
⢠Hypersplenism (progressive
splenomegaly)
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:
ď˝Growth retardation
ď˝Severe anemia-cardiac dilatation
ď˝Transfusion dependant
ď˝Icterus
ď˝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 â reduced (3-9mg/dl)
⢠RBC count â increased
⢠WBC, platelets â normal
⢠RBC indices â 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 ι thal
⢠Post splenectomy : Howell-Jolly and
Heinz bodies
⢠Reticulocyte count increased (upto 10%)
30.
31. DIAGNOSIS
⢠Osmotic fragility test : increased- resistance
to hâlysis
⢠T. bilirubin, I. bilirubin â increased
⢠Haptoglobulin and hemopexin â depleted
⢠S. Fe, ferritin elevated, Transferrin â
saturated
⢠B.M. study: hyperplastic erythropoesis
32. DIAGNOSIS
⢠Red cell survival â decreased using
⢠Folate levels- concurrently decreased
⢠Free erythrocyte porphyrin - normal
⢠Serum uric acid-raised
⢠Haemosiderinuria
33. DIAGNOSIS â Hb ELECTROPHORESIS
Thal. Major - Hb F: 98 %
Hb A2: 2 %
HEMOGLOBIN
Hb A: 0 %
MAJOR MINOR NORMAL
Hb F 10-98% variable <1%
Hb A Absent 80-90% 97%
Hb A2 variable 5-10% (increased) 1-3%
34. Radiological changes
⢠Small bones (hand ) â earliest bony change,
rectangular appearance,medullary portion of
bone is widened &bony cortex thinned out
with coarse trabecular pattern in medulla
⢠Skull â widened diploid spaces â interrupted
porosity gives hair on end appearance
⢠Delayed pneumatization of sinuses â maxilla
appears overgrown with prominent malar
eminences
35. X ray skull:
â hair on endâ
appearance
or
âcrew-cutâ
appearance
36.
37. IRON OVERLOAD ASSESSMENT
⢠S. Ferritin
⢠Urinary Fe excretion
⢠Liver biopsy
⢠Chemical analysis of tissue Fe
⢠Endomyocardial biopsies
⢠Myocardial MRI indexes
⢠Ventricular function â ECHO, ECG
38. Treatment:
⢠BT at 4-6 wks interval (Hb~ 9.5 gm/dl)
Packed RBC, leucocyte-poor
⢠Hb to be maintained â
⢠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 â
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
41. CHELATION THERAPY- DEFERIPRONE
⢠Oral chelator - > 2yrs old Dose: 50-100mg/kg/day
⢠Adverse effects:
ďśReversible arthropathy
ďśDrug induced lupus
ďśAgranulocytosis
⢠Other oral chelators
ďśDeferrothiocine
ďśPyridoxine hydrazine
ďśICL-670 â 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 (>180-200
ml/kg/yr) packed RBC
43. BONE MARROW TRANSPLANTATION
⢠BEST METHOD FOR CURE
⢠Risk factors:
ďśHepatomegaly >2cm
ďśPortal fibrosis
ďśIron overload
ďśOlder age
44. Newer therapies:
⢠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 â thebaine and tanninsâ chelate iron
⢠Vitamin C â increases iron excretion
⢠Restrict Fe intake â decrease meat, liver, spinach
⢠Folate â 1 mg/day
⢠Genetic counselling
⢠Psychological support
⢠Hormonal therapy â GH, estrogen, testosterone,
L-thyroxine
⢠Treatment of CCF
51. Îą-thalassemia:
⢠Deletion on alpha globin locus on Chr 16
⢠Defective synthesis of Îą-globin chainď
⢠Excess of - chains - in the fetus (Hb Bart- 4)
ďExcess of β-chains in the adult (Hb H- β4)
53. ALPHA THALASSEMIA
⢠Highest prevalence in Thailand
⢠ι chains shared by fetal as well as adult life.
Hence manifests both times
⢠These thalassemias donât have ineffective
erythropoesis because β and γ are soluble chains
and hence not destroyed always
⢠ι Thalassemia trait mimics Fe deficiency anemia
⢠Silent carrier â silent â not identified
hematologically, diagnosed when progeny has Hb
Barts/ Hb H
55. Hb H DISEASE
⢠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 Bartâs:
⢠Most severe manifestation of alpha thalassemia
⢠Hydrops fetalis â 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 Bartâs
Hb H
Hb Portland
No Hb A, Hb A2 or Hb F
⢠Treatment: immediate exchange transfusion
59. DIAGNOSIS OF Îą THALASSEMIA
⢠CBC, PS, BM study
⢠Heinz bodies in HbH disease â brilliant cresyl
blue
⢠Hb electrophoresis â for HbH and Hb Barts
⢠ι/β chain ratio decreased
60. Treatment:
⢠Generally not reqd
⢠Blood transfusion , iron chelation therapy â
For transfusion dependent cases
⢠Avoidance of oxidant drugs
⢠Prompt treatment of infections
⢠Folic acid supplementation
⢠Splenectomy
⢠BM transplantation, gene therapy
61. Thank you
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Medical Post [ www.themedicalpost.net ]