Thalassemia

Presented By- Dr. Armaan Singh

Thalassemia is a form of inherited autosomal recessive blood disorders characterized by abnormal formation of haemoglobin. The abnormal haemoglobin formed results in improper oxygen transport and destruction of red blood cells.[1] Thalassemia is caused by variant or missing genes that affect how the body makeshemoglobin, the protein in red blood cells that carries oxygen. People with thalassemia make less hemoglobin and have fewer circulating red blood cells than normal, which results in mild or severe anemia. Thalassemia will be present as microcytic anemia. There are two α genes on each chromosome 16, giving α thalassaemia the unique feature of gene duplication. There is only one β-globin gene on chromosome 11.

α thalassaemia*Normal: genotype α,α/α,α.

*α+ thalassaemia heterozygous (genotype α,-/α,α): borderline haemoglobin level and mean corpuscular volume (MCV), low mean corpuscular haemoglobin (MCH); clinically asymptomatic.

*α+ thalassaemia homozygous (genotype α,-/α,-): slightly anaemic, low MCV and MCH; clinically asymptomatic.

*αo thalassaemia heterozygous (genotype α,α/,--): slightly anaemic, low MCV and MCH; clinically asymptomatic.

*HbH disease (genotype α,-/-,-): HbH. Anaemic, very low MCV and MCH; splenomegaly, variable bone changes.

*α thalassaemia major (genotype -,-/-,-): Hb Bart's. Severe non-immune intrauterine haemolytic anaemia. Hb Bart's hydrops fetalis, usually fatal.

β thalassaemia*Normal: genotype β2/β2.

*β-thalassaemia trait (genotype -/β2): HbA2 >4%. Slightly anaemic, low MCV and MCH; clinically asymptomatic.

*β thalassaemia intermedia (genotype -/βo or β+/β+): high HbF, variable. Anaemic (symptoms usually develop when the haemoglobin level remains below 7.0 g/dL), very low MCV and MCH; splenomegaly, variable bone changes, variable transfusion dependency.

*β thalassaemia major (genotype -o/-o): HbF >90% (untransfused). Severe haemolytic anaemia, very low MCV and MCH; hepatosplenomegaly, chronic transfusion dependency.

Signs*Presentation varies with severity. Thalassaemia minor rarely has any physical abnormalities with haemoglobin ≥9 g/dL. In patients with the severe forms, the findings on physical examination vary widely depending on how well the disease is controlled. In severe, untreated cases there may be:

*Hepatosplenomegaly.

*Bony deformities (frontal bossing, prominent facial bones, and dental malocclusion).

*Marked pallor and slight to moderate jaundice.

*Exercise intolerance, cardiac flow murmur or heart failure secondary to severe anaemia.

*These features are absent in well-treated patients but there are often still problems:

*Growth restriction is common even with well-controlled chelation therapy.

*Iron overload can cause endocrinopathy with diabetes, thyroid, adrenal and pituitary disorders.

Differential diagnosis*Other causes of microcytic anaemia - eg, iron-deficiency anaemia, sideroblastic anaemia and anaemia of chronic disease. 

*Acute leukaemia may require bone marrow aspiration to differentiate.

*Rhesus incompatibility is rare now and post-mortem haemoglobin electrophoresis should differentiate in cases of hydrops fetalis.

*Diamond-Blackfan syndrome is a rare congenital cause of erythroid aplasia. It causes a severe normochromic, macrocytic anaemia usually in infancy and is often associated with craniofacial or upper limb anomalies.

Investigations: *FBC shows a microcytic, hypochromic anaemia (β-thalassaemia carrier status is often confused with iron deficiency due to reduced MCV and MCH). In the severe forms of thalassaemia, the haemoglobin level ranges from 2-8 g/dL. White blood cell (WBC) count is usually elevated from the haemolytic process. Platelet count may be depressed in splenomegaly.

*Serum iron level is elevated, with saturation as high as 80%. Ferritin is also raised.

*Haemoglobin electrophoresis usually reveals the diagnosis. Normal HbA2 is between 1.5 and 3.0% whilst HbA2 >3.5 % is diagnostic.:

*ECG and echocardiogram are used to monitor cardiac function.

*HLA typing is required where bone marrow transplantation is considered.

*Eye examinations, hearing tests and renal function tests are required in the monitoring of desferrioxamine therapy. Bone marrow aspiration is sometimes needed at diagnosis to exclude other conditions that may mimic thalassaemia major's presentation. Liver biopsy is used to assess iron deposition and the degree of haemochromatosis.