Thalassemia is a group of inherited disorders in which the body does not make enough hemoglobin, causing anemia. Typical symptoms include weakness, paleness, shortness of breath, headaches, dizziness, and fainting. Hemoglobin is the major component of red blood cells and is responsible for oxygen transport.
The adult hemoglobin, hemoglobin A, is composed of four protein subunits, 2-alpha and 2-beta. The fetal hemoglobin, which is predominant during the fetal stage and the first few months of life, has two alpha and two gamma chains. The alpha subunit is encoded by two HbA genes on chromosome 16. Each individual has four copies of alpha hemoglobin genes, two from each parent.
The beta subunit is encoded by the Hbb gene on chromosome 11. Each individual has two copies of HBB gene, one from each parent. There are two major types of thalassemia, alpha thalassemia and beta thalassemia, depending on which gene is mutated. In alpha thalassemia, patients with a single mutated copy typically have no symptoms.
They are called silent carriers because they may transmit the mutated gene to their offspring. Patients with two mutated copies are set to have alpha-thalassemia trait or alpha-thalassemia minor. They may have a significant portion of red blood cells that are smaller than usual called microcytic anemia, but only mild or no symptoms.
When three of the four copies are mutated, alpha chain production is markedly reduced, resulting in formation of abnormal hemoglobin with four beta chains, called hemoglobin H in adults, or four gamma chains, called Bart's hemoglobin, in infants. Hemoglobin H disease typically manifests as moderate to severe anemia. Finally, defects in all four copies are lethal in utero. Babies usually die before or shortly after birth. In beta thalassemia, two classes of mutations exist, beta plus mutations causing a reduced production of beta-globin and beta-zero mutations that produce no beta-globin at all.
Various combinations of these mutations produce beta thalassemias of different degrees of severity, which are classified into three groups based on clinical symptoms, minor or trait, intermediate, and major. Beta thalassemia major results from severe beta-globin deficiency causing severe anemia. In an attempt to compensate, the bone marrow tries to produce more blood cells and becomes enlarged and hyperactive. Bone marrow hyperactivity causes thickening of cranial bones, producing a characteristic chipmunk face.
Affected long bones can become prone to fractures and impair growth. In another compensatory response, the gastrointestinal tract absorbs more dietary iron, causing iron overload, which becomes more severe as the patient is treated with repeated transfusions. Abnormal iron deposits may interfere with normal functions of the heart, liver, and endocrine system.
Abnormal hemoglobins lead to formation of large numbers of defective red blood cells, which are detected and destroyed in the spleen. As a result, the spleen is enlarged, and the level of bilirubin, a byproduct of heme breakdown, increases, causing jaundice. Diagnosis is by blood tests. Typical lab findings include low hemoglobin, high red blood cell distribution width, presence of microcytic, hypochromic, and other abnormal but characteristic forms of red blood cells.
Patients may also have high red cell count and high serum iron and ferritin. Hemoglobin electrophoresis can be done to measure different types of hemoglobin and detect abnormal forms. Patients with thalassemia trait may not require treatment.
Moderate to severe thalassemias are typically treated with blood transfusions, which are often combined with iron chelation therapy to prevent iron overload. Surgical removal of the spleen, splenectomy, and certain medications may help reduce transfusion requirements for some patients. The only definitive cure, however, is blood or bone marrow transplantation to replace the mutated hematopoietic stem cells. Are you a fan of Allela Medical Videos?
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