Transcript α-thalassemia

Thalassemia
Dr. Kalpana Malla
MD Pediatrics
Manipal Teaching Hospital
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AKA
• VON JAKSCH ANEMIA
• COOLEY’S ANEMIA
• “THALASSA” : GREEK WORD - GREAT SEA
– first observed - MEDITTERANIAN SEA
THALASSEMIA
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
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
INHERITANCE
• Autosomal
recessive
• Beta thal - point
mutations on
chromosome 11
• Alpha thal - gene
deletions on
chromosome 16
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
CLASSIFICATION
• α-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)
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
α-thalassemia
NO. OF GENES
PRESENT
GENOTYPE
CLINICAL CLASSIFICATION
4 genes
3 genes
2 genes
αα/αα
Normal
αα/- α
Silent carrier
- α/- α
α thalassemia trait
or αα/- -
1 gene
0 genes
-α/- - -/- -
Hb H Ds
Hb Barts / Hydrops
fetalis
CLASSIFICATION OF THALASSEMIAS
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α Thalassemia
β Thalassemia
γ Thalassemia
δ Thalassemia
δ β Thalassemia
εγδβ Thalassemia
• Hereditary Persistence
of Fetal Hb (HPFH)
• Hemoglobin Lepore
syndrome
• Sickle cell Thalassemia
• Hb C Thalassemia
• Hb D Thalassemia
(Punjab)
• Hb E Thalassemia
MOLECULAR PATHOGENESIS
• 1.Promoter region mutations -> Transcription defects
• 2.Chain terminator mutations -> Translation defects
• 3.Splicing mutations
-> RNA splicing defects
(processing defects)
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
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
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
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
SPLENOMEGALY
• Extra medullary hematopoeisis
• Work hypertrophy due to constant
hemolysis
• Hypersplenism (progressive
splenomegaly)
JAUNDICE
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Unconjugated hyperbilirubinemia - hemolysis
Hepatitis - transfusion, hemochromatosis
GB stones - obstructive jaundice
cholangitis
INFECTIONS -CAUSES
• Poor nutrition
• Increased iron in body
• Blockage of monocyte-macrophage
system
• Hypersplenism- leukopenia
• Infections associated with transfusions
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
ACCUMULATION OF IRON
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Lungs: restrictive lung defects
Adrenal insufficiency
Hypothyroidism, hypoparathyroidism
Increased susceptibity to infections (iron
favours bacterial growth) espc : Yersinia
infections
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
CLINICAL FEATURES (THAL MAJOR)
BY CHILDHOOD:
Growth retardation
Severe anemia-cardiac dilatation
Transfusion dependant
Icterus
Changes in skeletal system
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
Others
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Delayed menarche
Gall-stones, leg ulcers
Pericarditis
Diabetes/ cirrhosis of liver
Evidence of hypersplenism
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
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
DIAGNOSIS - BLOOD PICTURE
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Hb – reduced (3-9mg/dl)
RBC count – increased
WBC, platelets – normal
RBC indices – MCV & MCH,MCHC
reduced, RDW normal
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%)
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
DIAGNOSIS
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Red cell survival – decreased using
Folate levels- concurrently decreased
Free erythrocyte porphyrin - normal
Serum uric acid-raised
Haemosiderinuria
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
variable
5-10% (increased)
1-3%
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
X ray skull:
“ hair on end”
appearance
or
“crew-cut”
appearance
IRON OVERLOAD ASSESSMENT
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S. Ferritin
Urinary Fe excretion
Liver biopsy
Chemical analysis of tissue Fe
Endomyocardial biopsies
Myocardial MRI indexes
Ventricular function – ECHO, ECG
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
CHELATION THERAPY - DESFERRIOXAMINE
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( 1 unit of blood contains 250 mg iron)
Iron-chelating agents: desferrioxamineDose: 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
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
CHELATION THERAPY- DEFERIPRONE
• Oral chelator - > 2yrs old Dose: 50-100mg/kg/day
• Adverse effects:
Reversible arthropathy
Drug induced lupus
Agranulocytosis
• Other oral chelators
Deferrothiocine
Pyridoxine hydrazine
ICL-670 – removes Fe from myocardial cells
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
BONE MARROW TRANSPLANTATION
• BEST METHOD FOR CURE
• Risk factors:
Hepatomegaly >2cm
Portal fibrosis
Iron overload
Older age
Newer therapies:
• GENE MANIPULATION AND REPLACEMENT
• Remove defective β gene and stimulate γ gene
• 5-azacytidine increases γ gene synthesis
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Hb F AUGEMENTATION
Hydroxyurea
Myelaran
Butyrate derivatives
Erythropoetin in Thal intermedia
OTHER SUPPORTIVE MEASURES
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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
Prognosis:
• Life expectancy: 15-25 yrs
• Untreated: < 5 yrs
PRENATAL DIAGNOSIS
• β/α ratio: <0.025 in
fetal blood – Thal major
• Chorionic villous biopsy
at 10-12 wks
• amniocentesis at 1518th wk gestation
Analysis of fetal DNA
• PCR to detect β globin
gene
Prevention:
• Antenatal diagnosis
• Termination of pregnancy if Thal major
• Preventing marriage b/w traits
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: 3.5- 7 %
• Hb A: 90-95 %
• Hb F: 1-5 %
• Moderate reduction of β-chain synthesis
Treatment:
• Counselling- treatment usually not
required
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)
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
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
ALPHA THALASSEMIA
• Silent carrier – asymptomatic ,no RBC
abnormalities
• Trait – aymptomatic , minimal anemia
Hb H DISEASE
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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
Hb BARTS
• Hb Barts has γ4, then later in infancy β4
• Severe hypoxia as Hb Barts has high affinity for
oxygen
Haemoglobin Bart’s:
• 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
• DIAGNOSIS
• Hb electrophoresis:
80-90 % Hb Bart’s
Hb H
Hb Portland
No Hb A, Hb A2 or Hb F
• Treatment: immediate exchange transfusion
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
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
Thank you
Download more documents and slide shows on The
Medical Post [ www.themedicalpost.net ]