Thalassemia
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Thalassemia. Dr. Kalpana Malla MD Pediatrics Manipal Teaching Hospital. AKA. VON JAKSCH ANEMIA COOLEY’S ANEMIA “THALASSA” : GREEK WORD - GREAT SEA – first observed - MEDITTERANIAN SEA. THALASSEMIA. DEFINTION.

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Thalassemia

Thalassemia

Dr. KalpanaMalla

MD Pediatrics

Manipal Teaching Hospital

Download more documents and slide shows on The Medical Post [ www.themedicalpost.net ]


Thalassemia

AKA

  • VON JAKSCH ANEMIA

  • COOLEY’S ANEMIA

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


Thalassemia

THALASSEMIA


Defintion

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

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 2γchains

  • 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

INHERITANCE


Classification

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


Classification1

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 (α2ץ2)

    Hb A2 (α2δ2)


Classification of thalassemia

CLASSIFICATION OF β THALASSEMIA


Thalassemia1

α-thalassemia


Classification of thalassemias

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

  • α Thalassemia

  • β Thalassemia

  • γ Thalassemia

  • δ Thalassemia

  • δ β Thalassemia

  • εγδβ Thalassemia


Molecular pathogenesis

MOLECULAR PATHOGENESIS

  • 1.Promoter region mutations -> Transcription defects

  • 2.Chain terminator mutations -> Translation defects

  • 3.Splicing mutations -> RNA splicing defects (processing defects)


Pathophysiology

PATHOPHYSIOLOGY

  • Since ẞ chain synthesis reduced -

    1. gamma ץ2 and delta δ2 chain combines with normally produced α chains ( Hb F (α2ץ2) , Hb A2 (α2δ2) - 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


Pathophysiology1

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

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

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

SPLENOMEGALY

  • Extra medullary hematopoeisis

  • Work hypertrophy due to constant hemolysis

  • Hypersplenism (progressive splenomegaly)


Jaundice

JAUNDICE

  • Unconjugated hyperbilirubinemia - hemolysis

  • Hepatitis - transfusion, hemochromatosis

  • GB stones - obstructive jaundice

  • cholangitis


Infections causes

INFECTIONS -CAUSES

  • Poor nutrition

  • Increased iron in body

  • Blockage of monocyte-macrophage system

  • Hypersplenism- leukopenia

  • Infections associated with transfusions


Accumulation of iron

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 iron1

ACCUMULATION OF IRON

  • Lungs: restrictive lung defects

  • Adrenal insufficiency

  • Hypothyroidism, hypoparathyroidism

  • Increased susceptibity to infections (iron favours bacterial growth) espc : Yersinia infections


Clinical features thal major

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 major1

CLINICAL FEATURES (THAL MAJOR)

BY CHILDHOOD:

  • Growth retardation

  • Severe anemia-cardiac dilatation

  • Transfusion dependant

  • Icterus

  • Changes in skeletal system


Skeletal changes

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

Others

  • Delayed menarche

  • Gall-stones, leg ulcers

  • Pericarditis

  • Diabetes/ cirrhosis of liver

  • Evidence of hypersplenism


Clinical features thal intermedia

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

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

DIAGNOSIS - BLOOD PICTURE

  • Hb – reduced (3-9mg/dl)

  • RBC count – increased

  • WBC, platelets – normal

  • RBC indices – MCV & MCH,MCHC reduced, RDW normal


Blood picture

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

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


Diagnosis1

DIAGNOSIS

  • Red cell survival – decreased using

  • Folate levels- concurrently decreased

  • Free erythrocyte porphyrin - normal

  • Serum uric acid-raised

  • Haemosiderinuria


Diagnosis hb electrophoresis

DIAGNOSIS – Hb ELECTROPHORESIS

Thal. Major - Hb F: 98 %

Hb A2: 2 %

Hb A: 0 %


Radiological changes

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


Thalassemia

X ray skull:

“ hair on end” appearance

or

“crew-cut”

appearance


Iron overload assessment

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

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

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


Adverse effects desferrioxamine

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

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

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

BONE MARROW TRANSPLANTATION

  • BEST METHOD FOR CURE

  • Risk factors:

  • Hepatomegaly >2cm

  • Portal fibrosis

  • Iron overload

  • Older age


Newer therapies

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

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

Prognosis:

  • Life expectancy: 15-25 yrs

  • Untreated: < 5 yrs


Prenatal diagnosis

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

Prevention:

  • Antenatal diagnosis

  • Termination of pregnancy if Thal major

  • Preventing marriage b/w traits


Thalassemia minor trait

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


Treatment1

Treatment:

  • Counselling- treatment usually not required


Thalassemia2

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

ALPHA THALASSEMIA - CLASSIFICATION


Alpha thalassemia

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 thalassemia1

ALPHA THALASSEMIA

  • Silent carrier – asymptomatic ,no RBC abnormalities

  • Trait – aymptomatic , minimal anemia


Hb h disease

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


Hb barts

Hb Barts has γ4, then later in infancy β4

Severe hypoxia as Hb Barts has high affinity for oxygen

Hb BARTS


Haemoglobin bart s

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


Thalassemia

  • 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 thalassemia

DIAGNOSIS OF αTHALASSEMIA

  • CBC, PS, BM study

  • Heinz bodies in HbH disease – brilliant cresyl blue

  • Hb electrophoresis – for HbH and Hb Barts

  • α/β chain ratio decreased


Treatment2

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

Thank youDownload more documents and slide shows on The Medical Post [ www.themedicalpost.net ]


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