Thalassemia

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Dr. Kalpana MallaMD Pediatrics

Manipal Teaching Hospital

• VON JAKSCH ANEMIA• COOLEY’S ANEMIA

• “THALASSA” : GREEK WORD - GREAT SEA – first observed - MEDITTERANIAN SEA

AKA

THALASSEMIA

• 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

DEFINTION

1. 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 – 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

BASICS - 3 types of Hb

INHERITANCE

• Autosomal recessive

• Beta thal - point mutations on chromosome 11

• Alpha thal - gene deletions on chromosome 16

• 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 ( 4ץ )

• 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 2ץ )

Hb A2 (α2 δ2)

CLASSIFICATION

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

NO. OF GENES PRESENT

GENOTYPE CLINICAL CLASSIFICATION

4 genes αα/αα Normal3 genes αα/- α Silent carrier2 genes - α/- α

or αα/- - α thalassemia trait

1 gene -α/- - Hb H Ds0 genes - -/- - Hb Barts / Hydrops

fetalis

α-thalassemia

• 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

CLASSIFICATION OF THALASSEMIAS

• 1.Promoter region mutations -> Transcription defects• 2.Chain terminator mutations -> Translation defects• 3.Splicing mutations -> RNA splicing

defects (processing defects)

MOLECULAR PATHOGENESIS

• Since ẞ chain synthesis reduced -1. gamma 2ץ and delta δ2 chain combines

with normally produced α chains ( 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

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

PATHOPHYSIOLOGY

• 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

EFFECTS OF MARROW EXPANSION

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

• Extra medullary hematopoeisis• Work hypertrophy due to constant

hemolysis• Hypersplenism (progressive

splenomegaly)

SPLENOMEGALY

• Unconjugated hyperbilirubinemia - hemolysis• Hepatitis - transfusion, hemochromatosis• GB stones - obstructive jaundice• cholangitis

JAUNDICE

• Poor nutrition• Increased iron in body• Blockage of monocyte-macrophage

system• Hypersplenism- leukopenia• Infections associated with transfusions

INFECTIONS -CAUSES

• 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

• Lungs: restrictive lung defects• Adrenal insufficiency• Hypothyroidism, hypoparathyroidism• Increased susceptibity to infections (iron

favours bacterial growth) espc : Yersinia infections

ACCUMULATION OF IRON

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 retardationSevere anemia-cardiac dilatationTransfusion dependantIcterus Changes in skeletal system

CLINICAL FEATURES (THAL MAJOR)

CHIPMUNK 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

SKELETAL CHANGES

Others

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

• 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 INTERMEDIA)

• 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

CLINICAL FEATURES (THAL MINOR)

DIAGNOSIS - BLOOD PICTURE

• Hb – reduced (3-9mg/dl)• RBC count – increased• WBC, platelets – normal• RBC indices – MCV & MCH,MCHC

reduced, RDW normal

• 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%)

BLOOD PICTURE

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

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

DIAGNOSIS

DIAGNOSIS – Hb ELECTROPHORESISThal. 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%

• 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

Radiological changes

X ray skull:

“ hair on end” appearance

or“crew-cut” appearance

IRON OVERLOAD ASSESSMENT

• 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

• ( 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

CHELATION THERAPY - DESFERRIOXAMINE

Cardiotoxicity – arrythmiasEyes - cataract Ears - sensorimotor hearing loss Bone dysplasia-growth retardationRapid infusion- histamine related

reaction- hypotension, erythema, pruritis

Infection, sepsis

Adverse effects: DESFERRIOXAMINE

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

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 >2cmPortal fibrosisIron overloadOlder age

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

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

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 15-

18th 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- 4ץ )Excess of β-chains in the adult (Hb H- β4)

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 - CLASSIFICATION

• 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

ALPHA THALASSEMIA

• 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 H DISEASE

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

• CBC, PS, BM study• Heinz bodies in HbH disease – brilliant cresyl

blue• Hb electrophoresis – for HbH and Hb Barts • α/β chain ratio decreased

DIAGNOSIS OF α THALASSEMIA

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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