Normal haemoglobin synthesis:
Normal Hb molecule consists of 4 subunits each consisting of a heam core with a polypeptide attached. The heam core is constant while the polypeptide chains occur in paris.4 different polypeptide chains occur normally.
There are 3 types of normal Hb.
HbA- (97% adult Hb-2a+2b )
Hb A2- (3% adult Hb-2a + 2d )
Fetal Hb-( Hb F-2a +2g ). Fetal Hb is replaced by adult Hb during the first year.
Thalassemias:
These are a heterogenous group of disorders with a genetically determined reduction in the rate of synthesis of one or more types of normal Hb peptide.
These are characterized by absence or reduced synthesis of normal hemoglobin chain. There is no structural abnormality in globin chain.
They are common in the meditererranean, Middle East and India.
The severity of the diseases depends on:
The degree of globin chain abnormality
Whether the patient is homozygous or heterozygous for the defect.
Homozygous:
An individual in whom the members of a pair of genes determining a particular characteristics are identical.
Heterozygous:
An individual in whom the members of a pair of genes determining a particular characteristics are dissimilar.
Classification:
Depending on a and b chain-
a-Thalassaemia- Reduction of a chain synthesis.
b-Thalassaemia- Reduction of b chain synthesis.
Hemoglobin molecule contains protoporphyrin ring with iron at its center known as heme and two types of globins. Reduced synthesis of any one chain of hemoglobin causes decreased intracellular hemoglobin concentration producing hypochromic red cells. Simulteniously a relative excess of complementary globin chain which become unstable and precipitate in the red blood cells. This precipitate Hb may damage the red cells membrane that lead to hemolysis.
Classification of Thalassemias:
On the Basis of affected HB chain:
a Thalassemias
Silent carrier
a -Thalassemia trait
Haemoglobin H diseases
Hydrops fetalis.
b Thalassemias
b Thalassemias Major
b Thalassemias intermedia
Thalassemia minor
a Thalassemias
Disorders in which there is defective synthesis of a chains with resulting depression of production of the Hb that contain a chain.
There is less production of Hb A(a2b2), Hb A2 (a2d2), Hb F (a2g2).
There are normally 4 a genes (aa/aa)
In the a thalassaemias the genetic defects are illustrated as follows;
Silent carrier :(a / a a)
This is due to deletion of single a gene.
Clinically it is asymptomatic and absence of red cells abnormalities.
Hb Barts hydrops syndrome:(--/--)
Synthesis of excessive amount of g chain in the fetus results in the formation of Hb barts(g4)
All 4 genes for the a chain are absent. Fetal Hb cannot be formed and the fetus dies in utero.
Hb-H disease (- a /--):
Synthesis of excessive amount of b chain in the fetus results in the formation of Hb H (b4)
Only one a gene is present. This leads to an excess of b chains which form tetramers called Hb-H
There is moderate microcytic hypochromic anaemia with splenomegaly.
These Hb have high affinity for oxygen and fail to deliver oxygen to the tissue.
a - thalassaemia traits ( - a /- a):
Even if two a genes are absent, the remaining two are active and the symptoms and anaemia are usually mild.
Diagnosis:
Haemoglobin electrophoresis and genotyping.
b–Thalassaemia
The genetic mutation of b thalassaemia leads to a decreased rate of chain synthesis and consequently a reduction in the normal amount of normal Hb-A in the red cell.
On the basis of extent of chain synthesis, two main types of thalasaemia are recognized.
b–Thalassaemia major:
Two defective b genes.characterised by major or total suppression of chain synthesis and is the homozygous form of the diseases
The excess of a genes leads to severe anaemia with haemolysis. The marrow becomes hyperplastic and there is atrophy of bones. The main form of Hb is HbF-which persists into adult life.
b–Thalassaemia minor:
One defective b gene.
The anaemia is mild. The red cells microcytic hypochromic and a mistaken diagnosis of iron deficiency anaemia can be made. These subjects act as carriers for b Thalassaemia major.
Clinical types 0f b Thalassaemia :
Thalassaemia major:
There is total suppression of b chain synthesis. It is homozygous state for either b0 or b+ thalassaemia gene.
The diseases is commonly seen in the Mediterranean areas, North Africa, Middle south and far eastern countries including Bangladesh.
The diseases is manifested within six months of life and is characterized by
Severe anaemia,
Enlargement of skull and malar bones and
Hepatosplenomegaly.
Without treatment life expectancy is about 5-6 years.
With treatment child may survive upto adulthood.
Laboratory diagnosis:
Haematological values:
Hb%- Markedly reduced(3.9gm/dl)
RBC- Reduced
WBC- Leukocytosis
PCV-Reduced
MCV-Reduced
MCHC-Reduced
MCH-Reduced
In Blood film:
RBC- Microcyte predominant
Reticulocyte increased (5-15%)
Fragmented cell, target cell and tear drop cells are present.
Anisopoikilocytosis present.
WBC- Leukocytosis
Platelets-Normal
In bone marrow:
Cellularity – Hypercellular
M:E ratio – Reduced
Erythropoesis-Hyperactive ( erythroid hyperplasia)
Granulopoesis- Normal
Megakaryopoesis- normal
Biochemical finding:
Serum unconjugated bilirubin-Increased
Serum iron- Normal
Heptoglobin and haemopexin-Reduced
Serum uric acid-Raised
Osmotic fragility of red cells-Increased.
Special test:
Hb electrophoresis.
Alkali deneturation test (for Hb-F)
Heinz body detection
Sickle test
Hb solubility test
Thalassaemia intermedia:
Most of these cases suffer from mild to moderate anaemia. The condition is not life threatening.
Blood picture is that of mild to moderate iron deficiency.
Diagnosis is made by haemoglobin electrophoresis.
Thalassaemia minor:
This disorder is the heterozygous state for the b thalassaemia gene. It is characterized by a moderate reduction in chain synthesis as directed by a b thalassaemia gene inherited from one parent.The disorder is relatively common.
Clinically it is usually very mild disorder with little or no anaemia, no symptom and a normal life expectency.The spleen may be palpable.
The condition is commonly not diagnosed until adolescence or adult life, and may be detected in a routine hematological screening examination. Often first diagnosis in pregnancy.
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