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Thalassemia

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

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  1. Thalassemia Dr. KalpanaMalla MD Pediatrics Manipal Teaching Hospital Download more documents and slide shows on The Medical Post [ www.themedicalpost.net ]

  2. AKA • VON JAKSCH ANEMIA • COOLEY’S ANEMIA • “THALASSA” : GREEK WORD - GREAT SEA – first observed - MEDITTERANIAN SEA

  3. THALASSEMIA

  4. 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

  5. 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

  6. Autosomal recessive Beta thal - point mutations on chromosome 11 Alpha thal - gene deletions on chromosome 16 INHERITANCE

  7. 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

  8. 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)

  9. CLASSIFICATION OF β THALASSEMIA

  10. α-thalassemia

  11. 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

  12. MOLECULAR PATHOGENESIS • 1.Promoter region mutations -> Transcription defects • 2.Chain terminator mutations -> Translation defects • 3.Splicing mutations -> RNA splicing defects (processing defects)

  13. 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

  14. 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

  15. 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

  16. 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

  17. SPLENOMEGALY • Extra medullary hematopoeisis • Work hypertrophy due to constant hemolysis • Hypersplenism (progressive splenomegaly)

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

  19. INFECTIONS -CAUSES • Poor nutrition • Increased iron in body • Blockage of monocyte-macrophage system • Hypersplenism- leukopenia • Infections associated with transfusions

  20. 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

  21. ACCUMULATION OF IRON • Lungs: restrictive lung defects • Adrenal insufficiency • Hypothyroidism, hypoparathyroidism • Increased susceptibity to infections (iron favours bacterial growth) espc : Yersinia infections

  22. 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

  23. CLINICAL FEATURES (THAL MAJOR) BY CHILDHOOD: • Growth retardation • Severe anemia-cardiac dilatation • Transfusion dependant • Icterus • Changes in skeletal system

  24. 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

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

  26. 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

  27. 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

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

  29. 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%)

  30. 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

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

  32. DIAGNOSIS – Hb ELECTROPHORESIS Thal. Major - Hb F: 98 % Hb A2: 2 % Hb A: 0 %

  33. 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

  34. X ray skull: “ hair on end” appearance or “crew-cut” appearance

  35. IRON OVERLOAD ASSESSMENT • S. Ferritin • Urinary Fe excretion • Liver biopsy • Chemical analysis of tissue Fe • Endomyocardial biopsies • Myocardial MRI indexes • Ventricular function – ECHO, ECG

  36. 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

  37. 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

  38. 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

  39. 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

  40. 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

  41. BONE MARROW TRANSPLANTATION • BEST METHOD FOR CURE • Risk factors: • Hepatomegaly >2cm • Portal fibrosis • Iron overload • Older age

  42. 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

  43. 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

  44. Prognosis: • Life expectancy: 15-25 yrs • Untreated: < 5 yrs

  45. 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

  46. Prevention: • Antenatal diagnosis • Termination of pregnancy if Thal major • Preventing marriage b/w traits

  47. 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

  48. Treatment: • Counselling- treatment usually not required

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