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  • 1. The ThalassaemiasThe ThalassaemiasDR.RAFI AHMED GHORIProfessorMedical Unit I1LUMHS Jamshoro.
  • 2.
  • 3. HaemoglobinHaemoglobin
  • 4. Haemoglobin SynthesisHaemoglobin Synthesis
  • 5. HISTORICAL INTRODUCTIONHISTORICAL INTRODUCTION FIRST RECOGNIZED in 1925 byThomas B. Cooley inSeries of infants profoundly anaemic withsplenomegaly during first year of life. VARIOUSLY CALLEDvon Jakschs anaemia, splenic anaemia,erythroblastosis, Mediterranean anaemia,or Cooleys anaemia. IN 1936 GEORGE WHIPPLE AND LESLEYBRADFORD, invented the word THALASSAEMIAfrom the Greek for Mediterranean Sea.
  • 6. DEFINITIONDEFINITIONHETEROGENEOUS group ofGENETIC disorders ofHAEMOGLOBIN SYNTHESIS, allof which result froma REDUCED RATE of productionof one or more of the GLOBINCHAIN(S) OF HAEMOGLOBIN.
  • 7. CLASSIFICATIONCLASSIFICATIONGENETICALLYα-THALASSAEMIAS α+β-THALASSAEMIAS βº β+δβ-THALASSAEMIA (δβ) º Haemoglobin Lepore (δβ) +(εγδβ) º-THALASSAEMIAδ-THALASSAEMIACLINICALLYThalassaemia major Severe transfusiondependent.Thalassaemiaintermedia Anaemia andSplenomegaly Does not requireregular transfusion.Thalassaemia minor Symptomless carrierstate
  • 8. β-THALASSAEMIASβ-THALASSAEMIASTYPE OFTHALASSAEMIAFINDINGS INHOMOZYGOTEFINDINGS INHETEROZYGOTEβº Thalassaemia majorHbs F & A2Thalassaemia minorRaised Hb A2β+ Thalassaemia majorHbs F, A &A2Thalassaemia minorRaised Hb A2δβ Thalassaemia intermediaHb F onlyThalassaemia minorHb F5-15%; HbA2 normal(δβ)+(Lepore) Thalassaemia major orintermediaHbs F and LeporeThalassaemia minorHb F5-15%; HbA2 normalεγδβ Not viable Neonatal haemolysisThalassaemia minor in adults,Normal Hbs F & A2
  • 9. β-THALASSAEMIASβ-THALASSAEMIASMost important types of thalassaemiaDISTRIBUTIONMediterranean,parts of north andwest Africa,Middle East,Indiansubcontinent, South-East Asia.HIGH-INCIDENCE ZONE:Yugoslavia andRomania,southern parts of Russia,southern regions of China.Particularly common in South-EastAsia ,southern China,Thailand,Malaypeninsula,Indonesia ,Pacific islandpopulations.
  • 10. MOLECULARMOLECULAR PATHOLOGYPATHOLOGY over 100 differentmutations. Completeinactivation ofthe β-globin genesleading to thephenotype of βº-thalassaemia Reduced outputfrom the genes andhence the pictureof β+-thalassaemia.
  • 11. PATHOPHYSIOLOGYPATHOPHYSIOLOGY
  • 12. SEVERESEVERE HOMOZYGOUSHOMOZYGOUS β-THALASSAEMIASβ-THALASSAEMIASCLINICAL FEATURESCLINICAL FEATURESMOST SEVERE FORMSpresent within the first year of life with Failure to thrive Poor feeding Intermittent bouts of fever Failure to improve after an intercurrentinfection. Affected infant looks paleSplenomegaly is already present
  • 13. THALASSAEMICTHALASSAEMICCHILDCHILD
  • 14. SEVERESEVERE HOMOZYGOUSHOMOZYGOUS β-THALASSAEMIASβ-THALASSAEMIASCLINICAL FEATURESCLINICAL FEATURESIN THE WELL-TRANSFUSED CHILD Normal early growth and development. Minimal Splenomegaly. Failure of growth spurt. Tissue siderosis.DiabetesHypoparathyroidism.Adrenal insufficiency.liver failure.Delayed or absent 2˚ sexual characters.Short stature.Psychological problems.Progressive cardiac damage.
  • 15. ThalassaemicThalassaemicadultadult
  • 16. SEVERESEVERE HOMOZYGOUSHOMOZYGOUS β-THALASSAEMIASβ-THALASSAEMIASCLINICAL FEATURESCLINICAL FEATURESINADEQUATELY TRANSFUSED CHILD Retarded growth and development. Progressive splenomegaly Hypersplenism(anaemia, thrombocytopenia and a bleeding tendency). Bossing of the zygomata giving rise to theclassical mongoloid facies. Recurrent fractures. Increased proneness to infection. Hyperuricaemia and secondary gout. Poorly formed teeth and malocclusion. Chronic sinusitis and deafness. Features of Iron overload in adults.
  • 17. BOSSINGOF THEZYGOMATAgiving riseto theclassicalmongoloidfacies.
  • 18. X-RAYX-RAYSKULLSKULLHair onHair onSkullSkull
  • 19. SEVERESEVERE HOMOZYGOUSHOMOZYGOUS β-THALASSAEMIASβ-THALASSAEMIASHAEMATOLOGICAL CHANGESHAEMATOLOGICAL CHANGES Severe anaemia. Hb values range from 2 to 8g/dl. RBCs are hypochromic and microcytic. MCH, MCV are reduced. Peripheral blood film showsMarked hypochromia, Poiklocytosis, Hypochromic,macrocytes, Misshapen microcytes, AnisochromiaBasophilic, stippling. Elevation in the reticulocyte count. The bone marrow shows marked erythroidhyperplasia with a myeloid/erythroid(M/E) ratio of unity or less.
  • 20. SEVERESEVERE HOMOZYGOUSHOMOZYGOUS β-THALASSAEMIASβ-THALASSAEMIASBIOCHEMICAL CHANGESBIOCHEMICAL CHANGES Elevated bilirubin. Absent haptoglobins. Shortened 51Cr red-cell survival. Elevated serum iron. Totally saturated iron-binding capacity. High plasma ferritin level. liver biopsies show a marked increase iniron both in the reticuloendothelial andparenchymal cells. vitamin E and ascorbate depletion. Hyperglycemia(Frank diabetes).
  • 21. SEVERESEVERE HOMOZYGOUSHOMOZYGOUS β-THALASSAEMIASβ-THALASSAEMIASHAEMOGLOBIN CHANGESHAEMOGLOBIN CHANGES(Hb Electrophoresis)(Hb Electrophoresis)ELEVATED Hb F .IN βº-THALASSAEMIANO Hb A.Hb consists of F and A2.IN Β+-THALASSAEMIAHb F 30 to 90 %.Hb A2 level is usually normal.
  • 22. HETEROZYGOUS β-THALASSAEMIAHETEROZYGOUS β-THALASSAEMIA Usually symptom free. During stress (pregnancy),they may becomeanaemic. Splenomegaly is rarely present.HAEMATOLOGICAL CHANGES Mild anaemia with Hb levels 9 to 11g/dl. Hypochromia and microcytosis. Low MCH and MCV. Moderate erythroid hyperplasia.HAEMOGLOBIN CHANGES Elevated Hb A2.(4 to 6% range). Slight elevation of Hb F in the 1 to 3% rangein about 50 per cent of cases.
  • 23. β-THALASSAEMIA IN ASSOCIATIONβ-THALASSAEMIA IN ASSOCIATIONWITH HAEMOGLOBIN VARIANTSWITH HAEMOGLOBIN VARIANTSIndividuals inherit a β-thalassaemia genefrom one parent and a gene for astructural Hb variant from the other.SICKLE-CELL Β-THALASSAEMIAHAEMOGLOBIN C THALASSAEMIAHAEMOGLOBIN E Β-THALASSAEMIAThis is the most common severe form ofthalassaemia in South-East Asia.Clinical picture can closely resemblehomozygous βº-thalassaemia.
  • 24. BOSSING OFBOSSING OFHEADHEADININHAEMOGLOBIN EHAEMOGLOBIN EΒ-THALASSAEMICΒ-THALASSAEMICCHILDCHILD
  • 25. THE δβ-THALASSAEMIASTHE δβ-THALASSAEMIAS Deletions of the β&δ-globin genes. Mispaired synapsis and unequal crossingover (β&δ-fusion genes). β&δ-fusion chains + α-chains = Lepore haemoglobins.HOMOZYGOTES Mild anaemia Hb(8 to 10g/dl). Moderate splenomegaly. Symptomless except during stress. Hb electrophoresis 100% Hb F.CARRIERS Thalassaemic blood pictures. Hb F (5 to 20 %)and normal Hb A2.
  • 26. THE α-THALASSAEMIASTHE α-THALASSAEMIASSevere homozygous forms cause deathin utero or in the neonatal periodMilder forms do not produce majordisability.DISTRIBUTIONMediterranean region, parts of WestAfrica, Middle East, isolated partsof the Indian subcontinent,throughout South-East Asia,southern China, Thailand, Malaypeninsula, Indonesia, Pacificisland populations.
  • 27. THE α-THALASSAEMIASTHE α-THALASSAEMIASDEFINITION AND INHERITANCEDEFINITION AND INHERITANCEIN THE FETUS, Deficiency of α-chains leads to theproduction of excess γ-chains, whichform γ4-tetramers, or Hb Barts. Homozygous inheritance of αº-thalassaemiaIN ADULTS, Deficiency of α-chains leads to anexcess of β-chains which form β4-tetramers, or Hb H. Coinheritance of both αº- and α+-thalassaemia.
  • 28. THE α-THALASSAEMIASTHE α-THALASSAEMIASTYPE HOMOZYGOTES HETEROZYGOTESαº Hb Bart’s hydrops Thalassaemia minorα+(deletion) Thalassaemia minor Normal blood pictureα+(non-deletion)Hb H disease Normal blood picture
  • 29. THE α-THALASSAEMIASTHE α-THALASSAEMIASPATHOPHYSIOLOGYPATHOPHYSIOLOGYFETUS ADULTNormalα2γ2Hb Fα2β2Hb Aα-Thalassaemiaα2 γ2 α2 β2excess excessγ4β2Hb Bart’s Hb HHIGH O2 AFFINITY HIGH O2 AFFINITYUnstable InclusionsHYPOCHROMIAHEMOLYSISHYPOXIA
  • 30. THE α-THALASSAEMIASTHE α-THALASSAEMIASThe Hb Barts hydrops syndromeThe Hb Barts hydrops syndromeCLINICAL PICTURE Stillbirth b/w 28 and 40wks. HYDROPS FETALISgross pallor,generalized oedema,massive hepatosplenomegaly. Very large, friableplacenta. Hb is 6 to 8g/dl. Nucleated RBCs on bloodCOMPLICATIONSFetal deathToxaemia ofpregnancyObstetricdifficultiesNo α-chains at all.Neither fetal nor adult haemoglobin.Common cause of fetal loss.
  • 31. HYDROPSHYDROPSFETALISFETALIS
  • 32. THE α-THALASSAEMIASTHE α-THALASSAEMIASHaemoglobin H diseaseHaemoglobin H disease αº-thalassaemia from one parent and α+ from the other.CLINICAL FEATURES•variable degree ofanaemia, splenomegaly•Bone changes unusual.•survive into adult life.•HypersplenismHaemolysis,infection,worsening of the anaemia.•Sulphonamides may pptthe anaemiaHAEMATOLOGICAL CHANGES•Hb 7 to 10g/dl.•Thalassaemic changeson blood film.•Reticulocytosis•Inclusion bodies onbrilliant cresyl blue.•5 to 40 per cent HbH,Hb A,normal orreduced level of HbA2.
  • 33. Haemoglobin H diseaseHaemoglobin H disease(Poiklocytosis,Target cells,Anisocytosis,Pallorred cells)
  • 34. α-THALASSAEMIAS TRAIT withα-THALASSAEMIAS TRAIT withGOLF BODIESGOLF BODIES
  • 35. MarrowMarrowExpansionExpansionininThalassaemicThalassaemic
  • 36. Fractures in aFractures in aThalassaemicThalassaemic
  • 37. OTHER FORMS OFOTHER FORMS OFα -THALASSAEMIAα -THALASSAEMIAα-THALASSAEMIA/MENTAL RETARDATION(ATR) SYNDROMESATR 16.ATRX.HAEMOGLOBIN H AND LEUKAEMIA
  • 38. THALASSAEMIA INTERMEDIATHALASSAEMIA INTERMEDIADEFINITION AND PATHOGENESISDEFINITION AND PATHOGENESISNOT transfusion dependent.Much more severe anaemia than carriers for α- orβ-thalassaemia.Hb C or E thalassaemia, the various δβ-thalassaemias and haemoglobin Lepore disorderscan result in Thalassaemia Intermedia.α- thalassaemia determinant inheritance as well asbeing homozygous for β- thalassaemia.Reduced degree of globin-chain imbalance withreduced severity of the dyserythropoiesis.
  • 39. Thalassaemia intermediaThalassaemia intermediaCLINICAL FEATURESMay be virtually symptom-free, with moderateanaemia.Other have Hb 5 to 7g/dl with• Marked splenomegaly,• Severe skeletal deformities• Heavily iron-loaded• Recurrent leg ulceration• Folate deficiency• Extramedullary haemopoietic tumour masses.• Gallstones• Infection
  • 40. ExtramedullaryExtramedullaryhaemopoietichaemopoietictumour masses.tumour masses.
  • 41. BLOOD FEATURES inBLOOD FEATURES inThalassaemia intermediaThalassaemia intermedia
  • 42. THE LABORATORY DIAGNOSISTHE LABORATORY DIAGNOSISOF THALASSAEMIAOF THALASSAEMIABlood Complete Picture Serum Fe , Ferritin, TIBC.Hb ELECTROPHORESIS.Bone Marrow Biopsy.X-Rays Skull, Chest, Spine, Long Bonesetc….U/S Abdomen.
  • 43. PREVENTIONPREVENTION genetic counselling about the choice ofmarriage partners at antenatal clinics. Prenatal diagnosisPRENATAL DIAGNOSIS Globin-chain synthesis studies of fetalblood samples obtained by fetoscopy at18 to 20 weeks of gestation. Fetal DNA analysis on amniocentesis. Direct analysis of fetal DNA obtained bychorion biopsy at about the tenth weekof gestation.
  • 44. TREATMENTTREATMENTREGULAR BLOOD TRANSFUSIONof either washed or frozen red cells,every 6 to 8 weeks to maintain the Hbb/w 9 and 14g/dl.SPLENECTOMYif hypersplenism develops. Chelating agents, DESFERRIOXAMINE30 to 40mg/kg as an overnight infusionlasting 8 to 12h. using a butterflyneedle placed subcutaneously in theanterior abdominal wall.
  • 45. TREATMENTTREATMENTORAL CHELATING AGENTS.HYDROXYUREA for raisingfetal haemoglobin productionBMT 80 per cent chance ofcuring the disease.
  • 46.  Q NO-2 A 16 year old boy was admitted to hospital with 3 dayhistory of pain abdomen and jaundice. It was proceeded by sore throat,fever and myalgia. He had experienced similar episodes at the age 6,12 and 14 and on each occasion he had made uneventful recovery. Histemperature was 390 C. he had mild jaundice, pallor, congested throatand spleen palpable 5 cm below the left costal margin. Rest ofexamination was normal. Laboratory investigation: Blood – Hb 9.8g/dl, WBC 6400/cmm. Platelet 10000/cmm, mono spot test – negative,serum bilirubin 33 mmol/L, ALT 23 iu/L, urine urobilinogen +++. What type of jaundice is he suffering from? List four possible causes. List four tests which you would like to do?
  • 47. THE ENDTHE ENDTHANKYOU