Thalassemia dr.k.v.giridhar
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Thalassemia dr.k.v.giridhar Thalassemia dr.k.v.giridhar Presentation Transcript

  • Thalassemia Dr.K.V.Giridhar Associate Prof. of Pediatrics GMC. Anantapur, A.P., India. 28 April 2014 1
  • • VON JAKSCH ANEMIA • COOLEY‟S ANEMIA • GREEK WORD • „THALASSA‟=MEDITTERANIAN SEA, émia‟=blood • first observed around MS 28 April 2014 2
  • THALASSEMIA 28 April 2014 3 View slide
  • Etiological classification of Anaemia Anaemia Decreased production IDA Bone marrow suppression Increased loss Haemorrhage Increased destruction 28 April 2014 4 View slide
  • 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 28 April 2014 5
  • 28 April 2014 6
  • 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) 728 April 2014 7
  • 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 28 April 2014 8
  • 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 28 April 2014 9
  • SYNTHESIS OF HAEM Protoporphyrin ring with an iron atom in centre The main site is mitochondria Mature red cell does not contain mitochondria 10 28 April 2014 10
  • 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 months 2. Fetal Hb (HbF) – 2α and 2γ chains • 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 28 April 2014 11
  • INHERITANCE 28 April 2014 12 • Autosomal recessive • Beta thal - point mutations on chromosome 11 • Alpha thal - gene deletions on chromosome 16
  • 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 28 April 2014 13
  • 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 28 April 2014 14
  • CLASSIFICATION OF β THALASSEMIA(genetic) 28 April 2014 15 CLASSIFICATI ON 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
  • 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 28 April 2014 16
  • Patho Physiology 28 April 2014 17
  • Fate of RBC (Bilirubin metabolism) 18 28 April 2014 18
  • PATHOPHYSIOLOGY • Since Beta chain synthesis reduced - 1. gamma 2 and delta δ2 alpha2 chain combines to produce Hb F (α2 2) , 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 28 April 2014 19
  • 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 28 April 2014 20
  • 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 28 April 2014 21
  • 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 hepatitis28 April 2014 22
  • SPLENOMEGALY • Extra medullary hematopoeisis • Work hypertrophy due to constant hemolysis • Hypersplenism (progressive splenomegaly) 28 April 2014 23
  • JAUNDICE • Unconjugated hyperbilirubinemia - hemolysis • Hepatitis - transfusion, hemochromatosis • GB stones - obstructive jaundice • cholangitis 28 April 2014 24
  • INFECTIONS -CAUSES • Increased iron in body • Blockage of monocyte-macrophage system • Hypersplenism- leukopenia • Infections associated with transfusions 28 April 2014 25
  • 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 28 April 2014 26
  • ACCUMULATION OF IRON • Adrenal insufficiency • Hypothyroidism, hypoparathyroidism • Lungs: restrictive lung defects • Increased susceptibity to infections (iron favours bacterial growth) espc : Yersinia infections 28 April 2014 27
  • 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 28 April 2014 28
  • CLINICAL FEATURES (THAL MAJOR) BY CHILDHOOD: Growth retardation Severe anemia-cardiac dilatation Transfusion dependant Icterus Changes in skeletal system 28 April 2014 29
  • 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 stature28 April 2014 30
  • Others • Delayed menarche • Gall-stones, leg ulcers • Pericarditis • Diabetes/ cirrhosis of liver • Evidence of hypersplenism 28 April 2014 31
  • 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 28 April 2014 32
  • 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 April 2014 33
  • DIAGNOSIS - BLOOD PICTURE • Hb – reduced (3-9mg/dl) • RBC count – increased • WBC, platelets – normal • RBC indices – MCV & MCH,MCHC reduced, 28 April 2014 34
  • 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%) 28 April 2014 35
  • 28 April 2014 36
  • DIAGNOSIS • T. bilirubin, I. bilirubin – increased • S. Fe, ferritin elevated, Transferrin –saturated • B.M. study: hyperplastic erythropoesis 28 April 2014 37
  • DIAGNOSIS • Red cell survival – decreased • Folate levels- concurrently decreased • Free erythrocyte porphyrin - normal • Serum uric acid-raised • Haemosiderinuria 28 April 2014 38
  • IRON OVERLOAD ASSESSMENT • S. Ferritin • Urinary Fe excretion • Liver biopsy • Chemical analysis of tissue Fe • Endomyocardial biopsies • Myocardial MRI indexes • Ventricular function – ECHO, ECG 28 April 2014 39
  • 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 28 April 2014 40
  • X ray skull “ hair on end” appearance or “crew-cut” appearance 28 April 2014 41
  • DIAGNOSIS – Hb ELECTROPHORESIS Thal. Major - Hb F: 98 % Hb A2: 2 % Hb A: 0 % 28 April 2014 42 HEMOGLOB IN MAJOR MINOR NORMAL Hb F 10-98% variable <1% Hb A Absent 80-90% 97% Hb A2 variable 5-10% (increased) 1-3%
  • 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) 28 April 2014 43
  • 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 28 April 2014 44
  • 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 28 April 2014 45
  • 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 28 April 2014 46
  • 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 28 April 2014 47
  • BONE MARROW TRANSPLANTATION • BEST METHOD FOR CURE • Risk factors: Hepatomegaly >2cm Portal fibrosis Iron overload Older age 28 April 2014 48
  • 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 28 April 2014 49
  • 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 28 April 2014 50
  • Prognosis: • Life expectancy: 15-25 yrs • Untreated: < 5 yrs 28 April 2014 51
  • Prevention: • Antenatal diagnosis • Termination of pregnancy if Thal major • Preventing marriage b/w traits 28 April 2014 52
  • 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 28 April 2014 53
  • 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 28 April 2014 54
  • Treatment: • Counselling- treatment usually not required 28 April 2014 55
  • 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) 28 April 2014 56
  • ALPHA THALASSEMIA - CLASSIFICATION CLINICAL CLASSIFICATIO N 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 28 April 2014 57
  • 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 28 April 2014 58
  • ALPHA THALASSEMIA • Silent carrier – asymptomatic ,no RBC abnormalities • Trait – aymptomatic , minimal anemia 28 April 2014 59
  • 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 28 April 2014 60
  • Hb BARTS • Hb Barts has γ4, then later in infancy β4 • Severe hypoxia as Hb Barts has high affinity for oxygen 28 April 2014 61
  • 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 28 April 2014 62
  • • DIAGNOSIS • Hb electrophoresis: 80-90 % Hb Bart‟s Hb H Hb Portland No Hb A, Hb A2 or Hb F • Treatment: immediate exchange transfusion 28 April 2014 63
  • 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 28 April 2014 64
  • 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 28 April 2014 65
  • Thank you 28 April 2014 66