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Thalassemias, Especially The Cooley’s Anemia (Beta Thalassemia Major)

Updated on January 20, 2014

Thalassemia Traits

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Introduction

These are genetic disorders in which the synthesis of normal polypeptide chains forming adult hemoglobin is suppressed. The condition may manifest with varying degrees of severity. In decreasing order of severity, they may be classified as thalassemia major, thalassemia intermediate, thalassemia minor and thalassemia minima. Another scheme of nomenclature takes into account the polypeptide chain involved. The condition is designated alpha or beta thalassemia if the synthesis of alpha chain or beta chain is depressed respectively. In some cases of beta thalassemia, the adjacent delta chain gene is also affected and this gives rise to delta-beta thalassemia. Several genetic mechanisms have been shown to be responsible for thalassemia, These are gene deletion, gene loss due to unequal crossover, defective transcription nRNA, unstable mRNA, and nucleotide mutation leading to premature termination of polypeptide chain synthesis.

Interaction of the genes for abnormal hemoglobins and thalassemia gives rise to heterozygous states showing the characteristics of both. Homozygous thalassemia presents as a severe hemolytic anemia, whereas in the heterozygous state, beta-thalassemia is asymptomatic or onl mildly symptomatic. It is beta thalassemia which is most commonly seen in places like India.

Beta Thalassemia Minor

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Beta thalassemia major (Cooley’s Anemia)

Also known as homozygous beta thalassemia, this is the most severe form of thalassemia. In homozygous beta0 thalassemia, there is no synthesis of beta chains, while in homozygous beta+ thalassemia, beta chains are present, but only in small amounts. In most cases, the formation of gamma chains is also reduced.

Pathogenesis

Due to the absence of beta chain synthesis, the alpha chains which are in excess are precipitated to form inclusions within the erythroid precursors. These alpha globin inclusions lead to impairment of erythoid cell replication, membrane function, migration from bone marrow and red cell survival. Such cells are selectively destroyed in the bone marrow. Erythropoiesis becomes ineffective and this in turn stimulates further erythropoiesis. The relative excess of alpha chains in which production of gamma chains continues, some of the alpha chains combine with them to form fetal hemoglobin and such cases are clinically less severe. Hyperplasia or erythroid marrow leads to skeletal changes, thalassemic facies, increased cardiac output, hyperdynamic heart failure, arthralgia and recurrent fractures.

Due to diversion of a major part of the cardiac output to the marrow and consequent hypoperfusion of other parts, muscular development is poor. There is considerable increase of absorption of Iron from the intestines and this results in Iron overload.

Clinical Features Of Beta Thalassemia

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Clinical Manifestation

The child is quite normal at birth and for the first few weeks or months of life, but anemia appears and gradually increases from the 6th to 24th week. Gross hepatosplenomegaly causes protuberance of the abdomen. The limbs are thin. Overgrowth of malar bones, depression of the nasal bridge, protrusion of the upper row of teeth and bossing of the fronto parietal regions contribute to the classical thalassemic (Chipmunk) facies. There is increased susceptibility to infection. The child is more susceptible to inter-current infection which may be the presenting complaint, anemia being detected incidentally. Anemia and hepatosplenomegaly increase with time.

The hemoglobin level is generally 3-4 g/dl on presentation. Erythrocytes are hypochromic and microcytic with the presence of anisopoikilocytosis, schistocytes, target cells, basophilic stippling and normoblasts. Presence of target cells in a large number is suggestive of the diagnosis. Other features indicating hemolysis are the presence of Howell-Jolly bodies, Cabot’s rings and reticulocytosis. Leucocyte count is generally normal but in some cases, leukemoid blood picture may occur. Osmotic fragility of red cells is decreased. Marrow is hypercellular with marked erythroid hyperplasia. “Hair-on-end” appearance on skull x-ray and thinning and widening of metacarpal shafts indicate enlargement of marrow tissue.

Detecting Beta Thalassemia

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Diagnosis And Prognosis

Diagnosis

Thalassemia should be looked for in all children showing persistent or progressive anemia, hepatosplenomegaly and the characteristic facies. Positive family history strengthens the diagnosis. Microcytic hypochromic anemia unresponsive to Iron therapy and the presence of numerous target cells and other evidence of hemolysis are strongly suggestive of thalassemia.

The diagnosis is established by estimating the fetal hemoglobin level which is increased (even up to 80%). Fetal hemoglobin is easily estimated by alkali denaturation test. Hemoglobin A is considerably diminished. Hemoglobin A2 may be increased in most of the cases though it can be normal at times. The abnormal hemoglobins are identified by electrophoresis in paper, cellulose acetate or starch block, using appropriate buffer solutions. Further identification is done by studying the polypeptide chains. Genetic characterization is facilitated by gene mapping and DNA splicing techniques or chain synthesis studies using reticulocytes. In Iron deficiency anemia, which is the commonest cause for hypochromic microcytic anemia in India Hb A2 levels are subnormal.

Course and prognosis

Children do not survive without adequate blood transfusions. With passage of time hemosiderosis eventually develops. Damage to several organ systems manifest as delayed puberty and maturation, diabetes, cirrhosis of liver and heart failure. A majority of patients succumb before the age of 20 years.

© 2014 Funom Theophilus Makama

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