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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.
DEFINITIONDEFINITIONHETEROGENEOUS group ofGENETIC disorders ofHAEMOGLOBIN SYNTHESIS, allof which result froma REDUCED RATE of productionof one or more of the GLOBINCHAIN(S) OF HAEMOGLOBIN.
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
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
β-THALASSAEMIASβ-THALASSAEMIASMost important types of thalassaemiaDISTRIBUTIONMediterranean,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.
MOLECULARMOLECULAR PATHOLOGYPATHOLOGY over 100 differentmutations. Completeinactivation ofthe β-globin genesleading to thephenotype of βº-thalassaemia Reduced outputfrom the genes andhence the pictureof β+-thalassaemia.
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 paleSplenomegaly is already present
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.
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.
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.
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).
SEVERESEVERE HOMOZYGOUSHOMOZYGOUS β-THALASSAEMIASβ-THALASSAEMIASHAEMOGLOBIN CHANGESHAEMOGLOBIN CHANGES(Hb Electrophoresis)(Hb Electrophoresis)ELEVATED Hb F .IN βº-THALASSAEMIANO Hb A.Hb consists of F and A2.IN Β+-THALASSAEMIAHb F 30 to 90 %.Hb A2 level is usually normal.
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.
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-THALASSAEMIAHAEMOGLOBIN C THALASSAEMIAHAEMOGLOBIN E Β-THALASSAEMIAThis is the most common severe form ofthalassaemia in South-East Asia.Clinical picture can closely resemblehomozygous βº-thalassaemia.
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.
THE α-THALASSAEMIASTHE α-THALASSAEMIASSevere homozygous forms cause deathin utero or in the neonatal periodMilder 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.
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.
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
THE α-THALASSAEMIASTHE α-THALASSAEMIASPATHOPHYSIOLOGYPATHOPHYSIOLOGYFETUS ADULTNormalα2γ2Hb Fα2β2Hb Aα-Thalassaemiaα2 γ2 α2 β2excess excessγ4β2Hb Bart’s Hb HHIGH O2 AFFINITY HIGH O2 AFFINITYUnstable InclusionsHYPOCHROMIAHEMOLYSISHYPOXIA
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 bloodCOMPLICATIONSFetal deathToxaemia ofpregnancyObstetricdifficultiesNo α-chains at all.Neither fetal nor adult haemoglobin.Common cause of fetal loss.
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.
Haemoglobin H diseaseHaemoglobin H disease(Poiklocytosis,Target cells,Anisocytosis,Pallorred cells)
Fractures in aFractures in aThalassaemicThalassaemic
OTHER FORMS OFOTHER FORMS OFα -THALASSAEMIAα -THALASSAEMIAα-THALASSAEMIA/MENTAL RETARDATION(ATR) SYNDROMESATR 16.ATRX.HAEMOGLOBIN H AND LEUKAEMIA
THALASSAEMIA INTERMEDIATHALASSAEMIA INTERMEDIADEFINITION AND PATHOGENESISDEFINITION AND PATHOGENESISNOT 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.
Thalassaemia intermediaThalassaemia intermediaCLINICAL FEATURESMay 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
BLOOD FEATURES inBLOOD FEATURES inThalassaemia intermediaThalassaemia intermedia
THE LABORATORY DIAGNOSISTHE LABORATORY DIAGNOSISOF THALASSAEMIAOF THALASSAEMIABlood Complete Picture Serum Fe , Ferritin, TIBC.Hb ELECTROPHORESIS.Bone Marrow Biopsy.X-Rays Skull, Chest, Spine, Long Bonesetc….U/S Abdomen.
PREVENTIONPREVENTION genetic counselling about the choice ofmarriage partners at antenatal clinics. Prenatal diagnosisPRENATAL 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.
TREATMENTTREATMENTREGULAR 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.
TREATMENTTREATMENTORAL CHELATING AGENTS.HYDROXYUREA for raisingfetal haemoglobin productionBMT 80 per cent chance ofcuring the disease.
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?