An Overview Of Thalassemia Biology Essay

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Thalassemias are the most common single gene disorder in the world. It was estimated that 7 percent of the world's population is carriers of hemoglobin disorder. Approximately 300,000-400,000 babies are born with severe form of hemoglobin disorder each year.1 The name thalassemia was derived from Greek terms "thalassa anemia" that means anemia by the sea. According to the name, thalassemias are prevalent along the Mediterranean Sea.2

Thalassemias are commonly found in Mediterranean basin, parts of Africa, Middle East, Indian sub-continent, South East Asia, Melanesia, and Pacific Islands.1 Asian, Indian, and Middle Eastern regions are accounted for 95% of thalassemia births worldwide.2 Particular types of thalassemia are more common in specific regions and ethnic groups, for example, β-thalassemia is more common in Mediterranean countries while α-thalassemia is more common in South East Asia such.3 Thalassemias have spread through migration; therefore, practically there is no thalassemia free region in the world.


Thalassemias are a group of genetic disorders characterized by the absence or reduced synthesis of one or more of the globin subunits of haemoglobin.4 Based on their clinical manifestations, thalassemias are inherited in autosomal recessive mode.4 Genes that regulate globin chain synthesis are located on two different chromosomes. Chromosome 11 is the site of β-like globin cluster with 5 functional genes (ε/Gγ /Aγ/δ/β) which produce β-, γ-, and δ-globin chains. The α-like globin gene cluster is located on chromosome 16 and consists of 3 functional genes (ζ/α2/α1) which mainly produce α-globin chain.3 The structural haemoglobin variant occurs mostly when mutation in globin genes causes changes in a single amino acid without reduction of globin chain synthesis. HbE, HbS, and HbC are the most prevalent haemoglobin variants.1


Thalassemias can be classified by both clinical and genetic approaches. Clinically, thalassemias can be classified into minor, intermedia, and major.4 Minor thalassemia is usually asymptomatic and manifest as mild anemia with variable microcytosis while major thalassemia manifests as fatal and severe anemia that requires a routine blood transfusion since infancy.5 Thalassemia intermedia forms a spectrum between minor and major thalassemias. Genetically, thalassemias are classified into α, β, γ, δβ, δ, and εγδβ thalassemias based on globin chains that are underproduced.4 However, only α- and β-thalassemias have significant impacts on public health. Another form of thalassemia that becomes very common globally is HbE/β-thalassemia which comes from the interaction between HbE and β-thalassemia.3


Beta thalassemia, characterized by underproduction of β-globin chains, is mainly caused by point mutation.4,5 βo denotes complete absence of β globin production; β+ refers to some residual production of β globin.6 Normal synthesis of α-globin chains results in excess of α-globins that later precipitates in red cell precursors and circulating red blood cells. Precipitation of α-globin chains leads to ineffective erythropoiesis in bone marrow and reduced red blood cell (RBC) survival in peripheral blood by damaging red cell membranes. Ineffective erythropoiesis together with hemolysis is the etiologies of anemia in β-thalassemia.3,4

Anemia induces erythropoietin production, bone marrow expansion, and extramedullary hematopoiesis which in turn cause skeletal deformity and various metabolic abnormalities.4 The abnormal red cells are entrapped and removed by the spleen leading to splenomegaly. Increased iron absorption together with RBC tranfusion induces systemic iron overload.4,5 The excess iron will be deposited in organ tissues especially in the liver, myocardium, and endocrine glands causing organ failure. Iron overload is the primary cause of deaths in thalassemias.5

The number of α-globin genes is four in total, two per haploid genome.4 Normal α-globin genotype is written as αα/αα. Alpha thalassemia is mostly caused by deletion of one or more α-globin genes.4,6 Single α-globin gene deletion results in silent carrier state (a-/aa), two-±-globin gene deletion results in ±-thalassemia trait (--/aa or -±/-±) , three-±-globin gene deletion results in HbH disease (--/-a), and four-±-globin gene deletion (--/--) results in fetal hydrops.3,7

Imbalanced globin synthesis is the primary defect in α-thalassemia similar to β-thalassemia. In α-thalassemia, the production of α-globin chains is reduced, and there are excess β- and γ- globins as a result. Unlike β- thalassemia, the excess β- and γ- globins are able to form soluble tetramers (β4 or HbH and γ4 or Hb Barts).4 These tetramers are relatively stable until they tend to precipitate during ageing red blood cells. Damage to red blood cell membrane leads to hemolysis which plays important role in causing anemia for α-thalassemia.4

Clinical Feature

Beta thalassemia minor is asymptomatic with mild microcytic anemia that is undetected unless laboratory examination is done.8 Beta thalassemia major requires regular blood transfusion to sustain life. Severe form of β-thalassemia mostly occurs during the first year of life. It manifests as pallor, due to severe anemia, and failing to thrive or unable to grow adequately.4 Feeding problem, diarrhea, and enlargement of abdomen caused by splenomegaly are also common symptoms of β-thalassemia major in early life. Inadequately transfused children will grow retarded, pale, showing conditions of hypermetabolic states such as poor musculature, lethargy, and reduced body fat.4

Deformities on skull and other bones are commonly found. Those defects are caused by erythroid hyperplasia with intramedullary expansion and cortical bone thinning.8 Enlargement of the liver and spleen is usually found in physical examination. Iron overload from transfusion and increased iron absorption leads to many complications. Iron deposition in the heart may cause heart failure, while deposition in endocrine organs causes endocrine dysfunctions which are usually in form of hypogonadism, diabetes mellitus, and hypothyroidism.4

Clinical manifestations of α-thalassemia usually depend on the number of deleted genes. One or two deletions of α-globin genes do not have a significant clinical manifestation. Three deletions of α-globin genes manifests as HbH disease.7 Clinical features of a person with HbH disease could range from mild to moderately severe anemia due to chronic hemolysis. Common clinical findings are pallor, scleral icterus, and hepatosplenomegaly.4 Patients with HbH disease usually do not need regular blood transfusion. Four α-globin genes deletion results in hemoglobin Bart's hydrops fetalis syndrome. Infants with this disease usually die in utero.7


Beta thalassemia carrier is diagnosed through hematological examination and hemoglobin electrophoresis. Findings on complete blood count are mild anemia with hypochromia and microcytosis. Hypochromic, microcytic red cell indices are defined as mean cell hemoglobin (MCH) values below 27 pg or mean cell volume (MCV) values below 80 fL.4 Target cells are usually found in peripheral blood smear. Increased level of HbA2 above 3.5% confirms the diagnosis of β-thalassemia trait.4

Beta thalassemia major is present with severe anemia, low MCV and MCH, elevated red blood cell distribution width (RDW). Findings on peripheral blood smear are hypochromia, microcytosis, nucleated red blood cells, basophilic stippling, hypochromic macrocytes, and immature leucocytes.3 Plain radiographic examination on skull may reveal "hair on end" appearance that is found in patients who are not adequately transfused.3 Investigation on iron overload is important in evaluation and management of chelation therapy.5 Serum ferritin, liver biopsy, and cardiac magnetic resonance (CMR) are examinations to evaluate iron deposition in visceral organs, especially the liver and heart.3,5

Diagnosis of α-thalassemia carrier is difficult. Red blood cell indices in silent carrier state of α-thalassemia are usually normal or slightly below borderline level.4 In α-thalassemia trait, the laboratory findings are significant reduction on MCV and MCH level with normal hemoglobin pattern.4 Therefore, definitive method to diagnose those conditions is DNA analysis.4

HbH disease is present with anemia and significantly low MCV and MCH. HbH inclusion bodies which make red blood cells resemble golf ball are shown by brilliant cresyl blue stain.7 The diagnosis of HbH disease is confirmed by hemoglobin electrophoresis.4 Hematological findings in hydrops fetalis demonstrate severe anemia and increased MCV. Peripheral blood smear presents marked anisopoikilocytosis, severe hypochromia, and nucleated RBCs.4 High percentage of Hb Bart will be found in hemoglobin electrophoresis.4


Thalassemia minor does not require specific treatment. On the other hand, blood transfusion is the basic treatment for severe form of thalassemia. Maintaining pre-transfusion hemoglobin level in the range of 9-10 g/dL allows normal growth and suppresses extramedullary hematopoiesis.5,8 It can be achieved by transfusing packed RBC 10-15 mL/kg every 3-5 weeks.3 Patients should receive leucoreduced packed red cells to prevent adverse reaction and platelet alloimmunisation.3

Blood transfusion alone is not enough to treat patients with thalassemia major. Iron chelation therapy is important because these patients usually die from cardiac complication due to iron toxicity.3 Chelating agents such as deferoxamine and deferiprone are effective and able to improve life expectancy. Deferoxamine, the earlier drug, is usually administered subcutaneously five days per week, but it results in poor compliance. Hence there have been newer drugs such as deferiprone that can be consumed orally and deferasirox, a once daily oral iron chelator.5 Combination between deferoxamine and oral chelating agent has been proved to be effective.3,5 Iron chelation therapy must be monitored due to its side effects such as neurosensory complications, hypersensitivity reactions, hepatic dysfunction, and cytopenia.3

Splenectomy is often performed to thalassemia patients when the spleen becomes hyperactive that leads to excessive destruction of red blood cells and increasing the need of blood transfusion.3 Splenectomy is performed when the patient needs more than 200-250 mL/kg of PRBC per year to maintain Hb level of 10 g/dL.3

Thalassemia patients are commonly found with deficiency of vitamin C, vitamin E, and folic acid. Therefore, the supplementation of those substances is recommended.3 Patients should also avoid food with high iron content. Today hematopoietic stem-cell transplantation is the only known curative treatment for thalassemia while gene therapy is still being developed.5


Preventing marriage between thalassemia carriers is the main method to avoid the birth of baby with severe form of thalassemia. Population screening programs in Montreal, Sardinia, Greece, and Cyprus to find thalassemia carriers have successfully reduced new cases of thalassemia.4 The success was attributed to public education program, development of effective screening program, and facilities for antenatal detection.1 Screening is effective at antenatal period (i.e. prenatal diagnosis) or at earlier stage where people are expected to take part in screening program voluntarily. Measurement of RBC counts and red cell indices including MCV, MCH, and RBC are the basic examinations.3 People with reduced MCV and MCH need to be evaluated further using haemoglobin electrophoresis or even DNA analysis.4 Finally, people who are screened must participate in genetic counselling to consult their results.