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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)

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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

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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)

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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

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Thank you