Premarital Screening for Thalassemia and Sickle Cell Anemia - Essay Example

Premarital screening (testing) for Thalassemia and Sickle Cell Anemia Introduction Thalassemia and Sickle Cell Disease fall into the category ofhemoglobinopathies. Both these conditions are inherited as autosomal recessive. The clinically significant phenotypes of variable severity are as a result of homozygous or genetic compound states They share common features like premature destruction of red blood cells, elevated erythropoietin levels and increased erythropoietin levels in the marrow and other sites to compensate for the loss of red cells and accumulation of the products of hemoglobin catabolism due to increased rate of red cell destruction (Aster, 2007). Definitions The thalassemias are a group of heterogenous group of inherited disorders caused by genetic defects as a consequence of which decreased synthesis of either the alpha or beta chain of HbA occurs (Aster, 2007, pg.632). When deficient synthesis of beta chain occurs, it is known as beta-thalassemia and when alpha synthesis is affected, it is known as alpha-thalassemia. Sickle cell anemia is a type of disease characterized by production of defective hemoglobins because of which sickling of red cells occurs in certain conditions (Aster, 2007, pg.628). Epidemiology Thalassemia has a wide distribution, particularly in areas where malaria has been endemic like in the Middle East, Southeast Asia, India and China). It is most common around the Mediterranean Sea, especially in Italy and Greece (Al-Suliman, 2006). The prevalence of the β-thalassemia gene is estimated to range between 0.01 to 0.15 in various areas of Saudi Arabia (Al-Suliman, 2006). Several reports from Arab countries indicate that β-thalassemia carriers have common genetic abnormalities, and the frequency of this disorder varies from country to country in the Middle East and is reported as 1% to 15% (Al-Suliman, 2006). In a study by Karimi and colleagues (2002), the prevalence of beta-thalassemia trait was estimated to be 5-10%. Hemoglobin S is most common in persons of African ancestry. In some regions of Africa, it has been estimated that up to 40% of the population is heterozygous for hemoglobin S. The gene is also present in Mediterranean, Middle Eastern, and Indian populations. Ten percent of American blacks are estimated to be heterozygous and 1 in 650 as homozygous (Schwarting, 2007). Pathology The normal hemoglobin of humans contains 4 globin chains. These are denoted as 2 α and 2 non-α chains. There are 3 normal variants of hemoglobin based on the nature of the non-α chains. The commonest variant is Hemoglobin A (α2β2) which accounts for 95% to 98% of the total in adults. The adults also posses minor amounts of hemoglobin F (α2γ2) and A2 (α2δ2) along with Hemoglobin A2 (Schwarting, 2007). The alpha genes are coded by 4 α genes, paired on each chromosome 16. The non-α genes, namely two γ, one δ, and one β gene per chromosome, are on chromosome 11. Other genes of less significance, the embryonic globin genes zeta and epsilon (ε) are on chromosomes 16 and 11 (Schwarting, 2007). There are basically 2 types of thalassemias- alpha thalassemia and beta thalassemia. These are generally classified according to the affected globin chain. The two most clinically significant forms involve deficits of α and β chains. Thalassemias involving γ and δ globin chain synthesis have also been described but are not common. In β- thalassemia the defects in the genes are mainly point mutations. There are about 100 different point mutations known to cause beta- thalassemia. The gene coding for beta chain is on the chromosome 11. Some of the common mutations are: 1. Promoter region mutations: These occur within promoter sequences and prevent RNA polymerase from binding normally. Some normal hemoglobin is synthesized. This is called β+ Thalassemia (Aster, 2007). 2. Chain terminator mutations: There are 2 types of these mutations. One causes a new stop codon within an exon, the second consists of small insertions or deletions that shift the mRNA reading frames and introduce down stream stop codons that terminate protein synthesis. In both case, there is premature chain termination preventing the synthesis of beta hemoglobin. This is called βo Thalassemia (Aster, 2007). 3. Splicing mutations: These are the commonest cause of beta- thalassemia. They affect introns more than exons. The thalessemia produced by this method is β+0 thalassemia. The result is that transcription of the gene is entirely (βo) or partly (β1) suppressed. Beta-thalassemia is an autosomally recessive disorder (Aster, 2007). The above gene mutations lead to impaired beta- globin synthesis. It results in anemia due to 3 mechanisms: 1. There is deficit of hemoglobin-A synthesis which produces "under- hemoglobinized," hypochromic, microcyic red cells with sub-normal oxygen carrying capacity. 2. There is imbalance in alpha and beta chain synthesis and this causes diminished survival of red cells and their precursors. 3. The unpaired free alpha chains precipitate within the normoblasts forming insoluble inclusions which lead to cell membrane damage. In alpha thalassemia, the most common gene defect is deletion of alpha- globin genes. There are 4 alpha- globin genes, the severity of the disease depends on the number of genes affected. α Thalassemia is associated with excess β or γ chains, which can then form the tetrameric hemoglobin H (β4) and hemoglobin Bart (γ4) (Schwarting, 2007). Hemoglobins H and Bart are both unstable and precipitate in the cytoplasm, forming Heinz bodies, but to a lesser degree than α4 tetramers. The red cells with α Thalassemia have high oxygen affinities and cause decreased tissue oxygen delivery (Schwarting, 2007). Sickle cell anemia is caused by a point mutation at the sixth position of the beta-globin chain. The mutation causes substitution of valine residue for a glutamic acid residue (Aster, 2007). This causes defective beta chain production and the molecules thus produced are known as HbS molecules. The disease process occurs when deoxygenated which causes the molecules to aggregate and polymerize. In prolonged deoxygenated states, the HbS molecules assemble together to long needle-like fibers within the cells producing a sickle- appearance. This process of sickling is a reversible phenomenon, reversing occurs with reoxygenation. However after repeated sickling the cell membrane gets damaged and the cells become permanently sickled and sticky even in oxygenated conditions. The membrane damage causes influx of calcium and efflux of potassium and water leading to intracellular dehydration and raised mean hemoglobin concentration. This causes permanent sickling and stickiness which makes the cells cause microvascular occlusions. The microvascular occlusions and chronic hemolysis are the causes for clinical manifestations of the disease (Aster 2007, pg.628). The irreversibly sickled cells are rigid and are mechanically fragile. Hence they get hemolysed while passing through the spleen. Some amount of intravascular hemolysis occurs due to mechanical fragility. Also, the increased stickiness of the reversible and irreversible sickle cells cause microvascular occlusion and ischemia (Schwarting, 2007). Figure-1: Assembly of subunit chains to form different hemoglobins Hgb (Schwarting, 2007). Clinical manifestations The clinical manifestations in patients with thalassemia varies significantly, depending on the severity of the condition and the age at the time of diagnosis. Most patients with thalassemia traits are asymptomatic. Those with more severe forms of the disease, manifest some pallor and slight icteric discoloration of the sclerae with splenomegaly, leading to slight enlargement of the abdomen. In some, the clue to the disease is taken from unexplained hypochromic and microcytic picture in a routine blood picture. In the later stages, the patient may present with marked bone marrow erythroid hyperplasia due to impaired oxygen delivery and raised erythropoietin levels. The marrow space is expanded, causing facial and cranial bone deformities. Also, extramedullary hemopoiesis occurs which leads to hepatosplenomegaly and formation of soft tissue masses (Schwarting, 2007). As far as alpha Thalassemia is concerned, those who are silent carriers are asymptomatic. On the other hand, homozygous (four genes affected) α thalassemia, also termed α hydrops fetalis, is incompatible with life. Thalassemia trait (two genes affected) is associated with a mild microcytic anemia and Hemoglobin H disease (3 genes affected) is associated with moderate microcytic anemia (Schwarting, 2007). Those with sickle cell disease present with episodic painful crises due to obstruction of microvasculature which leads to ischemia and hypoxic cell injury. The crises can be painful and are triggered by various stimuli like underlying infection, acidosis, or dehydration. These patients may also go through aplastic crisis wherein the bone marrow fails to compensate for the high level of red cell loss and hemoglobin levels drop rapidly with no reticulocyte response. Sudden pooling of erythrocytes, especially in the spleen, resulting in a decreased circulating blood volume and low hemoglobin levels can occur and this is known as sequestration crisis and can present as hypovolemic shock (Schwarting, 2007). Investigations Homozygous β Thalassemia, also known as Cooley anemia is characterized by moderate-to-severe, microcytic and hypochromic anemia. Hemoglobin electrophoresis will reveal excess of α chains. In the β0 type, fetal hemoglobin accounts for most of the hemoglobin, although increased levels (5%–8%) of hemoglobin A2 are also present. In addition to microcytosis and hypochromia, blood smears demonstrate striking anisopoikilocytosis with target cells, basophilic stippling and circulating normoblasts (Schwarting, 2007). Heterozygous β thalassemia is associated with microcytosis and hypochromia. Thalassemia trait (two genes affected) is associated with a mild microcytic anemia. Hemoglobin A2 is not increased, allowing distinction between α and β thalassemia traits (Schwarting, 2007). Hemoglobin H disease (3 genes affected) is associated with moderate microcytic anemia. Increased hemoglobin Bart (up to 25% in infancy) and variable levels of hemoglobin H can be detected. Precipitated hemoglobin H (Heinz bodies) can also be demonstrated by supravital staining of a blood smear (Schwarting, 2007). Homozygous patients (hemoglobin SS) have severe normocytic or macrocytic anemia. Blood smear examination reveals marked anisopoikilocytosis and polychromasia. Classic sickle cells and target cells, as well as a variety of other abnormally shaped erythrocytes can be seen. Hemoglobin electrophoresis shows hemoglobin S as 80% of total hemoglobin (Schwarting, 2007). Figure-2: Thalassemia. The peripheral blood erythrocytes are hypochromic and microcytic and show anisocytosis, poikilocytosis, and target cells (arrows). (Schwarting, 2007) Figure-3: Sickle cell anemia. Sickled cells (straight arrows) and target cells (curved arrows) are evident (Schwarting, 2007) Treatment These hemoglobinopathies are not curable. Patients with thalassemia minor usually do not require treatment. For those with thalassemia major, hypertransfusional support is the main stay of treatment. The goal would be to maintain the patients Hb at 9-10 g/dL, thus improving the patients sense of well-being while simultaneously suppressing enhanced erythropoiesis (Takeshita, 2007). Simultanoeusly iron chelation with desferrioxamine must be given. As a last hope, allogeneic hematopoietic transplantation may be curative in some patients with thalassemia major (Takeshita, 2007). Rarely patients with thalassemia major may require splenectomy. For those with alpha thalassemia, the main stay of treatemnt is folate and vitamin C supplementation. Blood transfusion is given only if indicated. Those with Hemoglobin H may need splenectomy if the need for transfusions increases (Bleibel, 2007). In sickle cell anemia, the main role in treatment is management of acute crises. The treatment includes IV fluids, analgesia, oxygen supplementation and blood transfusion. The patient must be advised measures to prevent sickle cell crisis. These include adherence to an immunization schedule, pneumococcal vaccine, hepatitis vaccine, foot care and protective shoes, periodic health care visits and biannual medical visit for those older than 30 years (Taher, 2007). Premarital testing for Thalassemia and Sickle cell anemia. Preventive genetics services based on population screening are now an integral part of many maternal and child health programmes in most of the countries all over the world. New developments in DNA technology, ultrasound scanning, and assay of factors in maternal blood are greatly increasing their potential to improve human health (Kuliev, 1990). Due to a high prevalence of inherited blood disorders in certain parts of the world, premarital screening is very useful for detecting hemoglobinopathies like Thalassemia and sickle cell anemia which are inherited autosomally. The role of premarital screening is to identify carriers of hemoglobin disorders so that appropriate information can be provided on the risk of having children with these severe forms of disease. The screening also provides the parents with options for avoiding it. In any country, appropriate knowledge of the frequency and heterogeneity of the hemoglobinopathies in the target population is an absolute necessity to plan a strategy and to choose the most appropriate laboratory methods for carrier identification (Galanello 2005). For example, in Saudi Arabia, high hemoglobin A2 with an absence of hemoglobin F is the most commonly encountered type of ß-thalassemia trait and is typically characterized by the microcytic and hypochromic red blood cells (Al-Suliman 2006). The first premarital screening of thalassemia carriers started as early as 1975 during which period Silvestroni and colleagues (1978) performed the tests in intermediate schools in Latium seems to be the beginning of a new preventive school health service aimed at the prophylaxis of thalassemia. Screening for sickle cell anemia started much before that. The Virginia Sickle Cell Anemia Awareness Program began identifying such couples as early as 1970 (Neal- Cooper, 1988). Prior to this era, though the physicians and health professionals knew much about genetic causes of hemoglobinopathies, little was done to prevent the occurrence of disease in the child (Naylor, 1975). The main aim of the premarital tests is of course identification of carriers of the diseases. These carriers are identified on the basis of few hematological values which can be identified by simple blood tests like complete blood picture. The common hematological values used to identify the carriers of Thalassemia are mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH). If any abnormality is detected in these, then hemoglobin electrophoresis is performed. During electrophoresis, increased HbA2 is seen in β 2+ thalassemia carrier state and increased HbF is seen in β β thalassemia carriers. β ±–thalassemia carriers have normal HbA2 and HbF. Figure. 4:  Main hematological parameters of thalassemias (Galanello, 2005). Premarital testing should be done in such a way that no carrier eludes detection. There are two possible methodological approaches for identification of homozygous thalassemia carrier: 1. A primary screening in which the common hematological parameters are evaluated is done. In cases of reduced MCV and/or MCH values, secondary screening tests involving hemoglobin electrophoresis is done. This type of testing is recommended in countries with low frequency and limited heterogeneity of Thalassemia (Galanello, 2005). MCH Read More