THALASSAEMIAS

•	Pathophysiology.
•	Classification.
•	History.
•	Clinical examination.
•	Investigations.

Pathophysiology

1.	Introduction

a.	The thalassemias are inherited disorders of Hb synthesis resulting from an alteration in the rate of globin chain production.

b.	A decrease in the rate of production of a certain globin chain(s) impedes Hb synthesis and creates an imbalance with the other, normally produced globin chains.

c.	Since 2 types of chains pair with each other to form normal Hbs, an excess of the normally produced type is present and accumulates in the cell as an unstable product leading to the destruction of the cell.

2.	Distribution

a.	Most common monogenic disease worldwide.

b.	Derived from the Greek word ‘thalasa’ meaning ‘the sea’ due to its Mediterranean origin.

c.	Distributed mainly across the Mediterranean, Middle East, Indian subcontinent and South East Asia.

3.	Globin chain productioin

a.	The globin chain as a unit is a major building block for Hb: together with heme, it produces the Hb molecule.

b.	Two different pairs of globin chains form a tetrameric structure with a heme moiety in the center.

c.	All normal Hbs are formed from 2 alpha chains and 2 non-alpha chains.

d.	Various types of Hb are formed, depending on the types of chains pairing together.

4.	Properties of Hemoglobins

Hb	Chains	Properties	
A	22	The only physiologically important normal adult Hb.	
F	22	Major physiologic post-embryonal fetal Hb. Optimal in low intrauterine oxygen tension due to left-shifted oxygen-Hb dissociation curve.	
A2	22	< 3% of circulating Hb in normal individuals. Slightly increased in most -thalassemias (useful in differential of microcytic, hypochromic anemia due to iron deficiency).	
Gower 1
Gower 2
Portland	22
22
22	Normal embryonic Hbs, disappear after 8 weeks gestation. Hb Portland seen at birth in severe -thalassemia.	\widctlpar
H	4	Abnormal Hb seen in HbH disease. Unstable, produces inclusion bodies in RBC, causes hemolysis.	
Bart’s	4	Abnormal Hb seen in neonates with -thal 2 (0 – 2%), -thal 1(2 – 8%), HbH disease (10 – 40%), and in Hb Bart’s hydrops (80%). Marker for ‘silent carriers’. 	

5.	Hemoglobin synthesis

a.	Newborn infant: 70% HbF.

b.	Normal adult:

i.	> 96% HbA.

ii.	< 3.5% HbA2.

iii.	< 1% HbF.

c.	Elevated HbA2: beta-thalassemia trait.

Classification

1.	Thalassemia is:

a.	A heterogenous group of disorders.

b.	A haemoglobinopathy:

i.	structural defect (qualitative): HbE.

ii.	production defect (quantitative): -thalassemia.

c.	An inherited abnormality: autosomal recessive.

d.	Involves decreased rate of synthesis (+/+) or complete absence of 1 or more globin chains (0/0). 

2.	-Thalassemia

a.	There are 4 genes for -globin because the gene is duplicated on chromosome 16: there are 2 -globin genes per chromosome.

b.	> 95% of -thalassemia mutations involve deletions of either one or both globin genes; remaining 5% are due to point mutations.

3.	Silent carrier -thalassemia (-thal 2)

a.	One of the alpha genes is deleted, leaving only 3 of 4 genes.

b.	Patients are hematologically healthy except for occasional low RBC indices.

c.	In this form, the diagnosis cannot be confirmed by Hb electrophoresis.

4.	-thalassemia trait (-thal 1)

a.	Caused by deletion of 2 alpha genes on one chromosome 16 (heterozygous 0) or one from each chromosome (homozygous +).

b.	This trait is characterized by mild anemia and low RBC indices. 

5.	Hb H disease

a.	Caused by deletion or inactivation of 3 alpha globin chains.

b.	Mild to moderately severe anemia requiring blood transfusions.

c.	Features: splenomegaly, icterus and abnormal red cell indices.

d.	HbH detectable as inclusion bodies in RBC using brilliant cresyl blue staining giving a ‘golf ball’ appearance.

e.	These inclusions are 4 tetramers which are unstable and physiologically useless.

f.	HbH damages membrane of RBCs leading to accelerated cell destruction with can result in severe life-threatening anemia together with reduced -globin chains. 

6.	Hb Bart’s hydrops fetalis syndrome

a.	Loss of all 4 alpha genes: incompatible with postnatal life.

b.	Lack of -globin chains leads to accumulation of physiologically useless and unstable 4 tetramers or HbBart’s.

c.	Severe anemia causes congestive heart failure and death in utero or shortly after birth.

d.	Total body edema (hydrops) due to congestive heart failure. 

7.	-Thalassemia

a.	There are 2 genes for -globin located on the short arm of chromosome 11. 

b.	Over 150 different molecular defects are known, mostly involving single nucleotide substitutions or oligonucleotide insertions / deletions.

c.	Mutation can be at:

i.	promoter sequence.

ii.	exons or introns: either frame shift mutation if there is deletion or addition or open up cryptic splice sites if GT is formed from mutation. 

iii.	other sites: point mutation.

d.	End result is functionally:

i.	0: complete or near complete absence of  chain production.

ii.	+: decreased rate of synthesis of  chain. 

8.	-thalassemia minor

a.	Either heterozygous + or 0: clinically not much difference.

b.	Clinical features:

i.	mild anemia Hb 10g/dl or no anemia.

ii.	MCV always < 75 fl.

iii.	mild splenomegaly.

iv.	not transfusion dependent. 

9.	-thalassemia major

a.	Basic defect:

i.	homozygous disease: decreased synthesis of -globin chain of hemoglobin.

ii.	normal synthesis of the -globin chain leading to accumulation of unstable aggregates within the RBCs, resulting in ineffective erythropoiesis and hemolysis. 

b.	Manifests only after birth: severe anemia from 3 – 6 months when switch from  to -chain production normally occurs.

c.	Hb levels: < 7 – 8g/dL.

d.	Clinical features:

i.	bone marrow hyperplasia due to increased but ineffective RBC synthesis resulting in facial and other bone deformities.

ii.	hepatosplenomegaly due to hemolysis and haemopoiesis.

iii.	small, stature, poor weight gain, poor energy levels and susceptibility to infection.

e.	Fatal without regular blood transfusions. 

10.	Thalassemia intermedia

a.	This is a clinical syndrome, resulting from several different gene defects:

i.	homozygous -thalassemia with persisting HbF.

ii.	homozygous -thalassemia with coexisting -thalassemias.

iii.	heterozygous -thalassemia (trait) with coexisting extra -chains. 

b.	Severe anemia, but can survive without chronic blood transfusions.

c.	Hb levels: 9 – 10 g/dL.

d.	Enlarged spleen from accelerated clearance of damaged RBCs from bloodstream.

e.	Hyperplasia of bone marrow due to increased hematopoiesis to replace RBCs.

f.	Therapeutic splenectomy in some patients slows rate of RBC destruction, thus avoiding transfusions and bone deformities.

11.	-Thalassaemia / HbE

a.	Distribution:

i.	most common structural hemoglobin variant with thalassemic properties in the world.

ii.	prevalent throughout Southeast Asia.

b.	Basic defect:

i.	HbE is not only a structural variant, but is also synthesized inefficiently as compared to HbA, causing a clinical phenotype of a mild form of -thalassemia.

ii.	the interaction of HbE with -thalassemia results in thalassemia phenotypes ranging from a condition indistinguishable from thalassemia major to a mild form of thalassemia intermedia.

c.	Mild -thalassemia/HbE:

i.	usually does not require treatment.

ii.	Hb: 9 – 12 g/dL.

d.	Moderately severe -thalassemia/HbE:

i.	majority of cases.

ii.	manifest symptoms similar to thalassemia intermedia and normally do not require blood transfusions.

e.	Severe -thalassemia/HbE:

i.	clinical picture of thalassemia major.

ii.	Hb level: 4 – 5 g/dL.

iii.	needs regular transfusion.