5..the thalassaemias

The ThalassaemiasThe Thalassaemias

DR.RAFI AHMED GHORI

Professor

Medical Unit I1

LUMHS Jamshoro.

Haemoglobin Haemoglobin

Haemoglobin SynthesisHaemoglobin Synthesis

HISTORICAL INTRODUCTIONHISTORICAL INTRODUCTIONFIRST RECOGNIZED in 1925 byThomas B. Cooley inSeries of infants profoundly anaemic with splenomegaly during first year of life.

VARIOUSLY CALLED von Jaksch's anaemia, splenic anaemia, erythroblastosis, Mediterranean anaemia, or Cooley's anaemia.

IN 1936 GEORGE WHIPPLE AND LESLEY BRADFORD, invented the word THALASSAEMIA from the Greek for Mediterranean Sea.

DEFINITIONDEFINITION HETEROGENEOUS group of GENETIC disorders of HAEMOGLOBIN SYNTHESIS, all of which result from

a REDUCED RATE of production of one or more of the GLOBIN CHAIN(S) OF HAEMOGLOBIN.

CLASSIFICATIONCLASSIFICATIONGENETICALLY

α-THALASSAEMIAS α+

β-THALASSAEMIAS βº β+

δβ-THALASSAEMIA (δβ) º Haemoglobin Lepore (δβ) +

(εγδβ) º-THALASSAEMIA

δ-THALASSAEMIA

CLINICALLY

Thalassaemia major Severe transfusion dependent.

Thalassaemia intermedia

Anaemia and Splenomegaly

Does not require regular transfusion.

Thalassaemia minor Symptomless carrier state

β-THALASSAEMIASβ-THALASSAEMIASTYPE OF THALASSAEMIA

FINDINGS IN HOMOZYGOTE

FINDINGS IN HETEROZYGOTE

βº Thalassaemia major

Hbs F & A2

Thalassaemia minor

Raised Hb A2

β+ Thalassaemia major

Hbs F, A &A2

Thalassaemia minor

Raised Hb A2

δβ Thalassaemia intermedia

Hb F only

Thalassaemia minor

Hb F5-15%; HbA2 normal

(δβ)+(Lepore) Thalassaemia major or intermedia

Hbs F and Lepore

Thalassaemia minor

Hb F5-15%; HbA2 normal

εγδβ Not viable Neonatal haemolysis Thalassaemia minor in adults,

Normal Hbs F & A2

β-THALASSAEMIASβ-THALASSAEMIASMost important types of thalassaemia DISTRIBUTIONMediterranean,parts of north and west Africa,Middle East,Indian subcontinent, South-East Asia.

HIGH-INCIDENCE ZONE:Yugoslavia and Romania,southern parts of Russia, southern regions of China. Particularly common in South-East Asia ,southern China,Thailand,Malay peninsula,Indonesia ,Pacific island populations.

MOLECULARMOLECULAR PATHOLOGYPATHOLOGYover 100 different mutations.

Complete inactivation of the β-globin genes leading to the phenotype of βº-thalassaemia

Reduced output from the genes and hence the picture of β+-thalassaemia.

PATHOPHYSIOLOGYPATHOPHYSIOLOGY

SEVERE SEVERE HOMOZYGOUSHOMOZYGOUS β-THALASSAEMIAS β-THALASSAEMIAS CLINICAL FEATURESCLINICAL FEATURES MOST SEVERE FORMS

present within the first year of life with Failure to thrive Poor feeding Intermittent bouts of fever Failure to improve after an intercurrent infection.

Affected infant looks pale Splenomegaly is already present

THALASSAEMIC THALASSAEMIC CHILDCHILD

SEVERE SEVERE HOMOZYGOUSHOMOZYGOUS β-THALASSAEMIAS β-THALASSAEMIAS CLINICAL 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.

Thalassaemic Thalassaemic

adultadult

SEVERE SEVERE HOMOZYGOUSHOMOZYGOUS β-THALASSAEMIAS β-THALASSAEMIAS CLINICAL FEATURESCLINICAL FEATURESINADEQUATELY TRANSFUSED CHILD Retarded growth and development. Progressive splenomegaly Hypersplenism (anaemia, thrombocytopenia and a bleeding tendency). Bossing of the zygomata giving rise to the

classical 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.

BOSSING OF THE ZYGOMATA

giving rise to the classical mongoloid facies.

X-RAYX-RAYSKULLSKULLHair on Hair on SkullSkull

SEVERE SEVERE HOMOZYGOUSHOMOZYGOUS β-THALASSAEMIAS β-THALASSAEMIAS HAEMATOLOGICAL CHANGESHAEMATOLOGICAL CHANGESSevere anaemia. Hb values range from 2 to 8g/dl. RBCs are hypochromic and microcytic.MCH, MCV are reduced. Peripheral blood film shows Marked hypochromia, Poiklocytosis, Hypochromic, macrocytes, Misshapen microcytes, Anisochromia

Basophilic, stippling.Elevation in the reticulocyte count.The bone marrow shows marked erythroid hyperplasia with a myeloid/erythroid (M/E) ratio of unity or less.

SEVERE SEVERE HOMOZYGOUSHOMOZYGOUS β-THALASSAEMIAS β-THALASSAEMIAS BIOCHEMICAL 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 in iron both in the reticuloendothelial and parenchymal cells.

vitamin E and ascorbate depletion. Hyperglycemia(Frank diabetes).parathyroid or adrenal insufficiency.

SEVERE SEVERE HOMOZYGOUSHOMOZYGOUS β-THALASSAEMIAS β-THALASSAEMIAS HAEMOGLOBIN CHANGESHAEMOGLOBIN CHANGES(Hb Electrophoresis)(Hb Electrophoresis)

ELEVATED Hb F .

IN βº-THALASSAEMIANO Hb A.Hb consists of F and A2.

IN Β+-THALASSAEMIA Hb F 30 to 90 %. Hb A2 level is usually normal.Reduced Hb A level.

HETEROZYGOUS β-THALASSAEMIAHETEROZYGOUS β-THALASSAEMIA

Usually symptom free. During stress (pregnancy),they may become anaemic.

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% range in about 50 per cent of cases.

β-THALASSAEMIA IN ASSOCIATION β-THALASSAEMIA IN ASSOCIATION WITH HAEMOGLOBIN VARIANTSWITH HAEMOGLOBIN VARIANTS

Individuals inherit a β-thalassaemia gene from one parent and a gene for a structural Hb variant from the other.

SICKLE-CELL Β-THALASSAEMIAHAEMOGLOBIN C THALASSAEMIAHAEMOGLOBIN E Β-THALASSAEMIAThis is the most common severe form of thalassaemia in South-East Asia.

Clinical picture can closely resemble homozygous βº-thalassaemia.

BOSSING OF BOSSING OF HEADHEAD IN IN

HAEMOGLOBIN E HAEMOGLOBIN E Β-THALASSAEMIC Β-THALASSAEMIC

CHILDCHILD

THE δβ-THALASSAEMIASTHE δβ-THALASSAEMIAS Deletions of the β&δ-globin genes. Mispaired synapsis and unequal crossing over (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-THALASSAEMIAS

Severe homozygous forms cause death in utero or in the neonatal period

Milder forms do not produce major disability.

DISTRIBUTIONMediterranean region, parts of West Africa, Middle East, isolated parts of the Indian subcontinent, throughout South-East Asia, southern China, Thailand, Malay peninsula, Indonesia, Pacific island populations.

THE α-THALASSAEMIASTHE α-THALASSAEMIAS DEFINITION AND INHERITANCEDEFINITION AND INHERITANCE IN THE FETUS, Deficiency of α-chains leads to the production of excess γ-chains, which form γ4-tetramers, or Hb Bart's.

Homozygous inheritance of αº-thalassaemia

IN ADULTS, Deficiency of α-chains leads to an excess of β-chains which form β4-tetramers, or Hb H.

Coinheritance of both αº- and α+ -thalassaemia.


TYPE HOMOZYGOTES HETEROZYGOTES

αº Hb Bart’s hydrops Thalassaemia minor

α+(deletion) Thalassaemia minor Normal blood picture

α+(non-deletion)

Hb H disease Normal blood picture


PATHOPHYSIOLOGYPATHOPHYSIOLOGYFETUS ADULT

Normalα2γ2

Hb F

α2β2

Hb A

α-Thalassaemiaα2 γ2 α2 β2

excess excess

γ4 β2Hb Bart’s Hb H

HIGH O2 AFFINITY HIGH O2 AFFINITY

Unstable InclusionsHYPOCHROMIA

HEMOLYSIS

HYPOXIA


The Hb Bart's hydrops syndromeThe Hb Bart's hydrops syndrome

CLINICAL PICTURE Stillbirth b/w 28 and 40 wks.

HYDROPS FETALIS gross pallor,generalized oedema, massive hepatosplenomegaly. Very large, friable placenta.

Hb is 6 to 8g/dl. Nucleated RBCs on blood film.

COMPLICATIONS Fetal deathToxaemia of pregnancyObstetric difficulties

No α-chains at all.Neither fetal nor adult haemoglobin.Common cause of fetal loss.

HYDROPS HYDROPS FETALISFETALIS


Haemoglobin H disease Haemoglobin H disease αº-thalassaemia from one parent and α+ from the other.

CLINICAL FEATURES

•variable degree of anaemia, splenomegaly

•Bone changes unusual.

•survive into adult life.

•Hypersplenism Haemolysis,infection, worsening of the anaemia.

•Sulphonamides may ppt the anaemia

HAEMATOLOGICAL CHANGES

•Hb 7 to 10g/dl.

•Thalassaemic changes on blood film.

•Reticulocytosis

•Inclusion bodies on brilliant cresyl blue.

•5 to 40 per cent Hb H,Hb A,normal or reduced level of Hb A2.

Haemoglobin H disease Haemoglobin H disease (Poiklocytosis,Target cells,Anisocytosis,Pallor red cells)

α-THALASSAEMIAS TRAIT with α-THALASSAEMIAS TRAIT with GOLF BODIESGOLF BODIES

Marrow Marrow Expansion Expansion

in in Thalassaemic Thalassaemic

Fractures in a Fractures in a Thalassaemic Thalassaemic

OTHER FORMS OF OTHER FORMS OF α -THALASSAEMIAα -THALASSAEMIA

α-THALASSAEMIA/MENTAL RETARDATION (ATR) SYNDROMES

ATR 16. ATRX.

HAEMOGLOBIN H AND LEUKAEMIA

THALASSAEMIA INTERMEDIATHALASSAEMIA INTERMEDIA DEFINITION AND PATHOGENESISDEFINITION AND PATHOGENESISNOT transfusion dependent.Much more severe anaemia than carriers for α- or

β-thalassaemia. Hb C or E thalassaemia, the various δβ-

thalassaemias and haemoglobin Lepore disorders can result in Thalassaemia Intermedia.

α- thalassaemia determinant inheritance as well as being homozygous for β- thalassaemia.

Reduced degree of globin-chain imbalance with reduced severity of the dyserythropoiesis.

Thalassaemia intermediaThalassaemia intermedia CLINICAL FEATURESMay be virtually symptom-free, with moderate

anaemia.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

Extramedullary Extramedullary haemopoietic haemopoietic

tumour masses.tumour masses.

BLOOD FEATURES in BLOOD FEATURES in Thalassaemia intermediaThalassaemia intermedia

THE LABORATORY DIAGNOSIS THE LABORATORY DIAGNOSIS OF THALASSAEMIAOF THALASSAEMIA

Blood Complete Picture Serum Fe , Ferritin, TIBC.Hb ELECTROPHORESIS.Bone Marrow Biopsy.X-Rays Skull, Chest, Spine, Long Bones

etc….U/S Abdomen.

PREVENTIONPREVENTIONgenetic counselling about the choice of marriage partners at antenatal clinics.

Prenatal diagnosis

PRENATAL DIAGNOSIS Globin-chain synthesis studies of fetal blood samples obtained by fetoscopy at 18 to 20 weeks of gestation.

Fetal DNA analysis on amniocentesis.Direct analysis of fetal DNA obtained by chorion biopsy at about the tenth week of gestation.

TREATMENTTREATMENT

REGULAR BLOOD TRANSFUSION of either washed or frozen red cells, every 6 to 8 weeks to maintain the Hb b/w 9 and 14g/dl.

SPLENECTOMY if hypersplenism develops.

Chelating agents, DESFERRIOXAMINE 30 to 40mg/kg as an overnight infusion lasting 8 to 12h. using a butterfly needle placed subcutaneously in the anterior abdominal wall.

TREATMENTTREATMENT

ORAL CHELATING AGENTS.HYDROXYUREA for raising fetal haemoglobin production

BMT 80 per cent chance of curing the disease.

Q NO-2 A 16 year old boy was admitted to hospital with 3 day history 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. His temperature was 390 C. he had mild jaundice, pallor, congested throat and spleen palpable 5 cm below the left costal margin. Rest of examination was normal. Laboratory investigation: Blood – Hb 9.8 g/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?

THE ENDTHE END

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Health & Medicine

5..the thalassaemias