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Thalassemia Download more documents and slide shows on The Medical Post [ ] Dr. Kalpana Malla MD Pediatrics Manipal Teaching Hospital.

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Presentation on theme: "Thalassemia Download more documents and slide shows on The Medical Post [ ] Dr. Kalpana Malla MD Pediatrics Manipal Teaching Hospital."— Presentation transcript:

1 Thalassemia Download more documents and slide shows on The Medical Post [ ] Dr. Kalpana Malla MD Pediatrics Manipal Teaching Hospital



4 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 DEFINTION

5 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 2γ chains 1% of adult Hb 70-90% at term. Falls to 25% by 1 st month and progressively 3. Hb A2 – Consists of 2 α and 2 δ chains 1.5 – 3.0% of adult Hb BASICS - 3 types of Hb

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

7 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 Classification

8 α-thalassemia Hb H (β 4 ) Hb-Bart’s ( ץ 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 (α 2 ץ 2 ) Hb A 2 (α 2 δ 2 ) CLASSIFICATION

9 CLASSIFICATION OF β THALASSEMIA CLASSIFICATIONGENOTYPECLINICAL SEVERITY β thal minor/traitβ/β+, β/β0Silent β thal intermediaβ+ /β+, β+/β0Moderate β thal majorβ0/ β0Severe

10 NO. OF GENES PRESENT GENOTYPECLINICAL CLASSIFICATION 4 genesαα/ααNormal 3 genesαα/- αSilent carrier 2 genes- α/- α or αα/- - α thalassemia trait 1 gene-α/- -Hb H Ds 0 genes- -/- -Hb Barts / Hydrops fetalis α-thalassemia

11 α Thalassemia β Thalassemia γ Thalassemia δ Thalassemia δ β Thalassemia εγδβ Thalassemia Hereditary Persistence of Fetal Hb (HPFH) Hemoglobin Lepore syndrome Sickle cell Thalassemia Hb C Thalassemia Hb D Thalassemia (Punjab) Hb E Thalassemia CLASSIFICATION OF THALASSEMIAS

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

13 Since chain synthesis reduced - 1. gamma ץ 2 and delta δ 2 chain combines with normally produced α chains ( Hb F (α 2 ץ 2 ), Hb A 2 (α 2 δ 2 ) - Increased production of Hb F and Hb A 2 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 PATHOPHYSIOLOGY

14 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 PATHOPHYSIOLOGY

15 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 EFFECTS OF MARROW EXPANSION

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

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

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

20 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 IRON

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

22 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 MAJOR)

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

24 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 SKELETAL CHANGES

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

26 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 INTERMEDIA)

27 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 CLINICAL FEATURES (THAL MINOR)

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

29 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%) BLOOD PICTURE


31 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

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

33 DIAGNOSIS – Hb ELECTROPHORESIS Thal. Major - Hb F: 98 % Hb A2: 2 % Hb A: 0 % HEMOGLOBIN MAJOR MINOR NORMAL Hb F10-98%variable<1% Hb AAbsent80-90%97% Hb A2variable5-10% (increased)1-3%

34 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 Radiological changes

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


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

38 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

39 ( 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 CHELATION THERAPY - DESFERRIOXAMINE

40  Cardiotoxicity – arrythmias  Eyes - cataract  Ears - sensorimotor hearing loss  Bone dysplasia-growth retardation  Rapid infusion- histamine related reaction- hypotension, erythema, pruritis  Infection, sepsis Adverse effects: DESFERRIOXAMINE

41 CHELATION THERAPY- DEFERIPRONE Oral chelator - > 2yrs old Dose: mg/kg/day Adverse effects:  Reversible arthropathy  Drug induced lupus  Agranulocytosis Other oral chelators  Deferrothiocine  Pyridoxine hydrazine  ICL-670 – removes Fe from myocardial cells

42 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 (> ml/kg/yr) packed RBC

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

44 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

45 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

46 Prognosis: Life expectancy: yrs Untreated: < 5 yrs

47 PRENATAL DIAGNOSIS β/α ratio: <0.025 in fetal blood – Thal major Chorionic villous biopsy at wks amniocentesis at th wk gestation Analysis of fetal DNA PCR to detect β globin gene

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

49 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 HbA 2 : % Hb A: % Hb F: 1-5 % Moderate reduction of β-chain synthesis

50 Treatment: Counselling- treatment usually not required

51 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- ץ 4 )  Excess of β-chains in the adult (Hb H- β 4 )

52 CLINICAL CLASSIFICATION GENOTYPENO. OF GENES PRESENT Silent carrierαα/- α3 genes α thalassemia trait- α/- α or αα/- -2 genes Hemoglobin H disease-α/- -1 gene Hb Barts / Hydrops fetalis - -/- -0 genes ALPHA THALASSEMIA - CLASSIFICATION

53 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 THALASSEMIA

54 Silent carrier – asymptomatic,no RBC abnormalities Trait – aymptomatic, minimal anemia ALPHA THALASSEMIA

55 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 H DISEASE

56 Hb BARTS Hb Barts has γ4, then later in infancy β4 Severe hypoxia as Hb Barts has high affinity for oxygen

57 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

58 DIAGNOSIS Hb electrophoresis: % Hb Bart’s Hb H Hb Portland No Hb A, Hb A2 or Hb F Treatment: immediate exchange transfusion

59 CBC, PS, BM study Heinz bodies in HbH disease – brilliant cresyl blue Hb electrophoresis – for HbH and Hb Barts α/β chain ratio decreased DIAGNOSIS OF α THALASSEMIA

60 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

61 Thank you Download more documents and slide shows on The Medical Post [ ]

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