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  1. 1. Thalassemia Dr. Kalpana Malla MD Pediatrics Manipal Teaching HospitalDownload more documents and slide shows on The Medical Post [ ]
  4. 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. 5. BASICS - 3 types of Hb1. 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
  6. 6. INHERITANCE• Autosomal recessive• Beta thal - point mutations on chromosome 11• Alpha thal - gene deletions on chromosome 16
  7. 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. 8. CLASSIFICATION• α-thalassemia Hb H (β4) Hb-Bart’s ( 4)• 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 2) Hb A2 (α2 δ2)
  9. 9. CLASSIFICATION OF β THALASSEMIACLASSIFICATION GENOTYPE CLINICAL SEVERITYβ thal minor/trait β/β+, β/β0 Silentβ thal intermedia β+ /β+, β+/β0 Moderateβ thal major β0/ β0 Severe
  10. 10. α-thalassemiaNO. OF GENES GENOTYPE CLINICAL CLASSIFICATIONPRESENT4 genes αα/αα Normal3 genes αα/- α Silent carrier2 genes - α/- α α thalassemia trait or αα/- -1 gene -α/- - Hb H Ds0 genes - -/- - Hb Barts / Hydrops fetalis
  11. 11. CLASSIFICATION OF THALASSEMIAS• α Thalassemia • Hereditary Persistence• β Thalassemia of Fetal Hb (HPFH)• γ Thalassemia • Hemoglobin Lepore• δ Thalassemia syndrome• δ β Thalassemia • Sickle cell Thalassemia• εγδβ Thalassemia • Hb C Thalassemia • Hb D Thalassemia (Punjab) • Hb E Thalassemia
  12. 12. MOLECULAR PATHOGENESIS• 1.Promoter region mutations -> Transcription defects• 2.Chain terminator mutations -> Translation defects• 3.Splicing mutations -> RNA splicing defects (processing defects)
  13. 13. PATHOPHYSIOLOGY• Since ẞ chain synthesis reduced -1. gamma 2 and delta δ2 chain combines with normally produced α chains ( Hb F (α2 2) , Hb A2 (α2 δ2) - Increased production of Hb F and Hb A22. 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. 14. PATHOPHYSIOLOGYAnemia result from lack of adequate Hb A → tissue hypoxia→↑EPO production → ↑ erythropoiesis in the marrow and sometimes extramedullary → expansion of medullary cavity of various bonesLiver spleen enlarge → extramedullay hematopoiesis
  15. 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. 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. 17. SPLENOMEGALY• Extra medullary hematopoeisis• Work hypertrophy due to constant hemolysis• Hypersplenism (progressive splenomegaly)
  18. 18. JAUNDICE• Unconjugated hyperbilirubinemia - hemolysis• Hepatitis - transfusion, hemochromatosis• GB stones - obstructive jaundice• cholangitis
  19. 19. INFECTIONS -CAUSES• Poor nutrition• Increased iron in body• Blockage of monocyte-macrophage system• Hypersplenism- leukopenia• Infections associated with transfusions
  20. 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. 21. ACCUMULATION OF IRON• Lungs: restrictive lung defects• Adrenal insufficiency• Hypothyroidism, hypoparathyroidism• Increased susceptibity to infections (iron favours bacterial growth) espc : Yersinia infections
  22. 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. 23. CLINICAL FEATURES (THAL MAJOR)BY CHILDHOOD:Growth retardationSevere anemia-cardiac dilatationTransfusion dependantIcterusChanges in skeletal system
  24. 24. 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
  25. 25. Others• Delayed menarche• Gall-stones, leg ulcers• Pericarditis• Diabetes/ cirrhosis of liver• Evidence of hypersplenism
  26. 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. 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. 28. DIAGNOSIS - BLOOD PICTURE• Hb – reduced (3-9mg/dl)• RBC count – increased• WBC, platelets – normal• RBC indices – MCV & MCH,MCHC reduced, RDW normal
  29. 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. 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. 31. DIAGNOSIS• Red cell survival – decreased using• Folate levels- concurrently decreased• Free erythrocyte porphyrin - normal• Serum uric acid-raised• Haemosiderinuria
  32. 32. DIAGNOSIS – Hb ELECTROPHORESISThal. Major - Hb F: 98 % Hb A2: 2 % HEMOGLOBIN Hb A: 0 % MAJOR MINOR NORMALHb F 10-98% variable <1%Hb A Absent 80-90% 97%Hb A2 variable 5-10% (increased) 1-3%
  33. 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. 34. X ray skull:“ hair on end” appearance or“crew-cut” appearance
  35. 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. 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. 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. 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. 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. 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. 41. BONE MARROW TRANSPLANTATION• BEST METHOD FOR CURE• Risk factors:Hepatomegaly >2cmPortal fibrosisIron overloadOlder age
  42. 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. 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. 44. Prognosis:• Life expectancy: 15-25 yrs• Untreated: < 5 yrs
  45. 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. 46. Prevention:• Antenatal diagnosis• Termination of pregnancy if Thal major• Preventing marriage b/w traits
  47. 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. 48. Treatment:• Counselling- treatment usually not required
  49. 49. α-thalassemia:• Deletion on alpha globin locus on Chr 16• Defective synthesis of α-globin chain• Excess of - chains - in the fetus (Hb Bart- 4)Excess of β-chains in the adult (Hb H- β4)
  50. 50. ALPHA THALASSEMIA - CLASSIFICATIONCLINICAL GENOTYPE NO. OF GENES PRESENTCLASSIFICATIONSilent carrier αα/- α 3 genesα thalassemia trait - α/- α or αα/- - 2 genesHemoglobin H disease -α/- - 1 geneHb Barts / Hydrops - -/- - 0 genesfetalis
  51. 51. 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
  52. 52. ALPHA THALASSEMIA• Silent carrier – asymptomatic ,no RBC abnormalities• Trait – aymptomatic , minimal anemia
  53. 53. 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
  54. 54. Hb BARTS• Hb Barts has γ4, then later in infancy β4• Severe hypoxia as Hb Barts has high affinity for oxygen
  55. 55. 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
  56. 56. • DIAGNOSIS• Hb electrophoresis: 80-90 % Hb Bart’s Hb H Hb Portland No Hb A, Hb A2 or Hb F• Treatment: immediate exchange transfusion
  57. 57. 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
  58. 58. 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
  59. 59. Thank youDownload more documents and slide shows on The Medical Post [ ]