t8 thalassaemia

8/15/2019 T8 Thalassaemia

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he thalassaemias and

he thalassaemias and

related

elated

disorders

DR.YASEEN M. TAHER


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The thalassaemias are the commonest single - gene

disorders. Thalassaemia was first recognized by Cooley

and Lee in 1925 as a form of severe anaemia associated

with splenomegaly and bone changes in children.

The term thalassaemia ! is derived from the "ree#

$ % & % ' ' % (meaning the sea !) since many of

the early cases came from the *editerranean region


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Definition andclassification

The thalassaemias are classified intoα , β , δ β , γ δ β, δ , γ and ε γ δ βthalassaemias according to thetype of globin chain(s) that is

produced in reduced amounts

The two major categories

are theα and β

thalassaemiaswhile the rareforms include the γ , δ and ε γδ β thalassaemias.


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Functionally, some thalassaemia mutations

cause acomplete absenceof globin chainsynthesis, and these are calledα 0 or β 0thalassaemias; in others, the globin chain isproduced at areduced rateand these aredesignatedα + or β + thalassaemias.

Theδ β thalassaemias are subdivided inthe same way


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Clinically, the thalassaemias are classified according to their severity

intomajor, intermediate and minor forms.

Thalassaemia majoris a severe and transfusion - dependentdisorder.

Thalassaemia minoris the symptomless trait or carrier state.

Thalassaemia intermediais characterized by anaemia (with orwithout splenomegaly), though not of such severity as to requireregular transfusion. In practice, thalassaemia intermedia

encompasses a wide spectrum of clinical severities intermediatebetween the two extremes of thalassaemia major and trait


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The β thalassaemias

The β thalassaemias pose by far the mostimportant public health problems because they arecommon and usually produce severe anaemia in

their homozygous and compound heterozygousstates.


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Pathophysiology

The molecular defects in βthalassaemia result in

absent or reduced β - chainproduction while α - chainsynthesis is unaffected.

The imbalance in globin

chain production leads to anexcess of α - chains. Thefree α - globin chains arehighly unstable andprecipitate in red cell

precursors,formingintracellular inclusions thatinterfere with red cellmaturation


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Clinical findings in severe β thalassaemia

Severe β thalassaemia usually presents in the first

year of life. Typically there is failure to thrive, with poorweight gain and growth with developmental delay.

The parents may have noticed that the infant is paleand jaundiced, with a protruding abdomen. There maybe a family history of severe anaemia,


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Examination confirms the pallor and

jaundice, with palpable hepatosplenomegaly.There may be evidence of marked erythroidhyperplasia, with signs of the typical ‘thalassaemic facies ’including expansion ofthe skull vault and maxillary bones.

The symptoms and signs are not specifi cand differential diagnoses include

gastrointestinal or hepatic disease, andmalignancy.


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Laboratory diagnosis of severe β thalassaemia

The full blood count shows a low haemoglobin, usuallyless than 5 g/dL.Mean corpuscular haemoglobin (MCH)and mean corpuscular volume (MCV) are low, with a verywide red cell distribution width. The nucleated cell countmay be very high due to the presence of large numbers ofnucleated red cells.

A blood film shows marked anisopoikilocytosis, withbasophilic stippling and small red cell fragments


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Thereticulocyte countis elevated but less thanexpected for the degree of anaemia, in keeping with theineffective erythropoiesis.

Renal functionis normal, butliver functiontestsshow elevation of bilirubin, aspartate aminotransferaseand lactate dehydrogenase, with a normal alanineaminotransferase.

Erythropoietin levelswill be high, with solubletransferrin receptor levels up to 30 time greater thannormal. White cell and platelet counts should be normalunless there is hypersplenism.


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A bone marrow aspirateis not essential to

make the diagnosis, but if performed shows verymarked erythroid hyperplasia, withdyserythropoiesis.

Immunoelectron microscopy confirms that theinclusions in β thalassaemia consist ofprecipitated α - globin chains


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Haemoglobin analysis is needed to confi rm thediagnosis, typically using eitherelectrophoretic or

chromatographic techniques. This will usually show anincreased amount of HbA 2,

with the vast majority of the remainder consisting ofHbF;small amounts of HbAmay be present depending on

the β – globin mutation, the age of the child and whetherthe child has been transfused.Absence of HbAconfirms a diagnosis of β0 thalassaemia, whilepresence ofHbA (pre - transfusion sample) confirms

β+ thalassaemia.


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Management of severe β thalassaemia

Blood transfusions

The aim of regular transfusions is to correct anaemiaand suppress the abnormal erythroid hyperplasia.

Correcting anaemia improves oxygen delivery to thetissues and facilitates normal growth and development.Suppression of erythropoiesis stops bony distortion,limits excessive iron absorption and reduces

extramedullary haemopoiesis.


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The current recommended practice is to use redcell units that have not been stored more than 2

weeks.

In general, the transfusion rate is5 to6/ml/kg/hour. In the case of patients with cardiacfailure, blood should be infused at a slower rate (nomore than 3 to 4 ml/Kg/h), and the administration ofdiuretics before transfusion is advised.


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The recommended interval between

transfusions should take into account thepatient's practical needs,as long as apretransfusional Hb ranging between 9 and10.5 g/dl is maintained.

It is important to keep an accurate record ofthe amount transfused, in order to calculatethe iron intake of the patient.


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Iron overload Iron overload inevitably complicates regular bloodtransfusions and is the source of many seriouscomplications. Each unit of transfused blood containsabout 200 – 250 mg iron, compared with the 1 mg ironnormally absorbed each day.

Despite the increased iron, serum hepcidin remainsinappropriately low, which further contributes to iron

loading through increased intestinal iron absorption.


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The body has no mechanism for excreting iron and iron-chelating drugs are necessary to avoid toxic ironaccumulation.

Iron chelation is usually started after about 1 year ofmonthly blood transfusions. Ideally, children delaystarting chelation until they are 3 years old, as drugtoxicity is thought to be highest in the young; it is usuallynecessary to start chelation earlier in children who starttransfusions in the fi rst year of life, although in general

low doses are used.


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After only a few years of transfusion, however,transferrin is completely saturated in the majorityof patients.In thalassemia major, serum ferritinhas, in general, been found to correlate well with

iron stores, as measured by phlebotomy, and withliver iron, either measured directly by liver biopsyor by MRI.


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Serial measurements of serum ferritinremain a reliable means, and the easiest one,

to evaluate iron overload and efficacy ofchelation therapy.


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Chelation

Currently, three drugs are usedfor iron chelation:

desferrioxamine, deferiprone anddeferasirox.


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Splenectomy Splenectomy, associated with sporadic blood

transfusions, has for many years represented themainstay of therapy in thalassemia. It was oftenperformed shortly after diagnosis because thespleen soon reached an enormous size and

caused severe hypersplenism, frequently leadingto profound neutropenia and thrombocytopenia.


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The α thalassaemias

Normal individuals have

four α - globin genesarranged as linked pairs,α 2 and α 1, at the tip ofeach chromosome 16,the normal α genotypebeing represented as αα / α α

t8 thalassaemia

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