thalassemia dr.k.v.giridhar
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April 12, 2023 1
Thalassemia
Dr.K.V.GiridharAssociate Prof. of Pediatrics
GMC. Anantapur, A.P., India.
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• VON JAKSCH ANEMIA• COOLEY’S ANEMIA • GREEK WORD• ‘THALASSA’=MEDITTERANIAN
SEA, émia’=blood• first observed around MS
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THALASSEMIA
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Etiological classification of Anaemia
Anaemia
Decreased production
IDA
Bone marrow
suppression
Increased loss
Haemorrhage
Increased destruction
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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
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STRUCTURE OF HEMOGLOBIN• Hb is a spherical molecule consisting of 4
peptide subunits (globins) = quartenary structure (tetramer)
• Hb of adult (Hb A) is a tetramer consisting of 2 alfa- and 2 β-globins → each globin contains 1 heme group with a central Fe2+ ion (ferrous ion)
7
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Hemoglobin consists of two parts
1. Globin 96%2. Heme 4%
Heme portion: Heme portion is synthesized mainly from acetic acid and glycine in the mitochondria of young RBC
Globin portion: Globin is composed of four large polypeptide chains. Globin is synthesized by ribosomes
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SYNTHESIS OF GLOBIN
Various types of globin combines with haem to form different haemoglobin
Eight functional globin chains, arranged in two clusters i.e,
- cluster (, , and globin “E” genes) on the short arm of chromosome 11
- cluster ( and globin “Z” genes) on the short arm of chromosome 16
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SYNTHESIS OF HAEMProtoporphyrin ring with an iron
atom in centre
The main site is mitochondria
Mature red cell does not contain mitochondria
10
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3 major types of Hb
1. Adult Hb (Hb A) - 2 α and 2 β chains forming a tetramer
• 97% adult Hb• Postnatal life Hb A replaces Hb F by 6 months2. Fetal Hb (HbF) – 2α and 2γ chains• 1% of adult Hb• 70-90% at term. Falls to 25% by 1st month and
progressively3. Hb A2 – Consists of 2 α and 2 δ chains• 1.5 – 3.0% of adult Hb
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INHERITANCE
• Autosomal recessive
• Beta thal - point mutations on chromosome 11
• Alpha thal - gene deletions on chromosome 16
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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
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CLASSIFICATION OF THALASSEMIA(type)
• α Thalassemia• β Thalassemia• γ Thalassemia• δ Thalassemia• δ β Thalassemia
• Hereditary Persistence of Fetal Hb (HPFH)
• Hemoglobin Lepore syndrome
• Sickle cell Thalassemia
• Hb C Thalassemia• Hb D Thalassemia
(Punjab)• Hb E Thalassemia
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CLASSIFICATION OF β THALASSEMIA(genetic)
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
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α-thalassemia(genetic)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
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Patho Physiology
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Fate of RBC
(Bilirubin metabolism)
18
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PATHOPHYSIOLOGY• Since Beta chain synthesis reduced -1. gamma 2ץ and delta δ2 alpha2 chain
combines to produce Hb F (α2 2ץ ) , 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
• Finally results in anenia
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PATHOPHYSIOLOGY
Anemia due to 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 MARROW EXPANSION
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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
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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
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SPLENOMEGALY
• Extra medullary hematopoeisis• Work hypertrophy due to
constant hemolysis• Hypersplenism (progressive
splenomegaly)
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JAUNDICE
• Unconjugated hyperbilirubinemia - hemolysis
• Hepatitis - transfusion, hemochromatosis
• GB stones - obstructive jaundice• cholangitis
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INFECTIONS -CAUSES
• Increased iron in body• Blockage of monocyte-
macrophage system• Hypersplenism- leukopenia• Infections associated with
transfusions
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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,, arrythmias, heart block, sterile pericarditis
• Deposition in pancreas -diabetes mellitus
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ACCUMULATION OF IRON
• Adrenal insufficiency• Hypothyroidism,
hypoparathyroidism• Lungs: restrictive lung defects• Increased susceptibity to
infections (iron favours bacterial growth) espc : Yersinia infections
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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
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CLINICAL FEATURES (THAL MAJOR)
BY CHILDHOOD:Growth retardationSevere anemia-cardiac dilatation
Transfusion dependantIcterus Changes in skeletal system
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SKELETAL CHANGESCHIPMUNK FACIES (HEMOLYTIC FACIES):• Frontal bossing, maxillary hypertrophy,
depression of nasal bridge , Malocclusion of teethPARAVERTEBRAL MASSES:• Broad expansion of ribs at vertebral attachment• ParaparesisPATHOLOGICAL FRACTURES:• Cortical thinning• Increased porosity of long bones DELAYED PNEUMATISATION OF SINUSES
PREMATURE FUSION OF EPIPHYSES - Short stature
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Others
• Delayed menarche• Gall-stones, leg ulcers• Pericarditis• Diabetes/ cirrhosis of liver• Evidence of hypersplenism
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CLINICAL FEATURES (THAL INTERMEDIA)
• Moderate pallor, usually maintains Hb >6gm%
• Anemia worsens with infections (erythroid stress)
• Less transfusion dependant• Skeletal changes present, progressive
splenomegaly• Growth retardation• Longer survival than Thal major
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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
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DIAGNOSIS - BLOOD PICTURE
•Hb – reduced (3-9mg/dl)• RBC count – increased•WBC, platelets – normal• RBC indices – MCV & MCH,MCHC reduced,
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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%)
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DIAGNOSIS
• T. bilirubin, I. bilirubin – increased • S. Fe, ferritin elevated,
Transferrin –saturated• B.M. study: hyperplastic
erythropoesis
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DIAGNOSIS
• Red cell survival – decreased• Folate levels- concurrently
decreased• Free erythrocyte porphyrin -
normal• Serum uric acid-raised• Haemosiderinuria
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IRON OVERLOAD ASSESSMENT
• S. Ferritin• Urinary Fe excretion• Liver biopsy• Chemical analysis of tissue Fe• Endomyocardial biopsies• Myocardial MRI indexes• Ventricular function – ECHO, ECG
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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
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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%
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Treatment:• Blood Transfusion at 4-6 wks
interval (Hb~ 9.5 gm/dl) Packed RBCs are transfused• (if we desired to maintain–Hb at
Hypertransfusion>10gm/dl,• Supertransfusion : >12 gm/dl) • 10-15ml/kg PRBC raises Hb by 3-
5gm/dl • Neocytes transfusion• If regular transfusions- no
hepatomegaly, no abnormalfacies (but results in Iron over load)
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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
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Adverse effects: DESFERRIOXAMINE
Cardiotoxicity – arrythmiasEyes - cataract Ears - sensorimotor hearing loss Bone dysplasia-growth
retardationRapid infusion- histamine
related reaction- hypotension, erythema, pruritis
Infection, sepsis
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CHELATION THERAPY- DEFERIPRONE
• Oral chelator - > 2yrs old Dose: 50-100mg/kg/day
• Adverse effects:Reversible arthropathy Drug induced lupusAgranulocytosis
• Other oral chelatorsDeferrothiocinePyridoxine hydrazineICL-670 – removes Fe from myocardial cells
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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
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BONE MARROW TRANSPLANTATION
• BEST METHOD FOR CURE• Risk factors: Hepatomegaly >2cmPortal fibrosisIron overloadOlder age
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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
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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
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Prognosis:
• Life expectancy: 15-25 yrs• Untreated: < 5 yrs
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Prevention:
• Antenatal diagnosis• Termination of pregnancy if
Thal major• Preventing marriage b/w
traits
PRENATAL DIAGNOSIS• β/α ratio: <0.025 in
fetal blood – Thal major
• Chorionic villous biopsy at 10-12 wks
• amniocentesis at 15-18th wk gestation Analysis of fetal DNA
• PCR to detect β globin gene
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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
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Treatment:
• Counselling- treatment usually not required
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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- 4ץ )
Excess of β-chains in the adult (Hb H- β4)
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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
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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
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ALPHA THALASSEMIA
• Silent carrier – asymptomatic ,no RBC abnormalities
• Trait – aymptomatic , minimal anemia
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Hb H DISEASE
• Seen 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
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Hb BARTS
• Hb Barts has γ4, then later in infancy β4
• Severe hypoxia as Hb Barts has high affinity for oxygen
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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
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• DIAGNOSIS
• Hb electrophoresis: 80-90 % Hb Bart’s Hb H Hb Portland No Hb A, Hb A2 or Hb F• Treatment: immediate exchange
transfusion
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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
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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
April 12, 2023 66
Thank you
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