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Indian Journal of Medical Sciences, Vol. 58, No. 10, October, 2004, pp. 445-449 Practitioners section Thalassemia Syndromes Shah Asha BSES MG Hospital and Holy Family Hospital, 6/32, Hari-Kripa, S. V. Road, Santacruz (W), Mumbai - 400 054 Code Number: ms04076 Thalassemia is an inherited blood disorder in which the body is unable to make adequate hemoglobin. This is due to an inborn error of metabolism that leads to absence or reduced synthesis of one or more types of globin polypeptide chains of the hemoglobin molecule. GEOGRAPHICAL DISTRIBUTION The thalassemias are wide-spread with about 5% of the world population affected by it. It is most prevalent around the Mediterranean Sea i.e. countries like Greece, Italy, Turkey and North African countries. It is also seen in Saudi Arabia, Iran, Afghanistan, Pakistan India and south East Asian countries like Thailand and Indonesia. The prevalence is highest in Italy, Greece and Cyprus. In India, prevalence of Thalassemia is very high among certain communities like Punjabi, Sindhi, Gujarati, Bengali, Parsee, Lohana and certain tribes, i.e. northern, western and eastern parts, while it is much less in the south of India. STRUCTURE OF NORMAL HEMOGLOBIN The hemoglobin molecule is made up of two parts - heme and globin. Heme is a porphyrin containing iron. Globin is made up of four polypeptide chains of two types - alpha and beta. Thus each globin molecule is made up of two alpha chains and two beta chains. This hemoglobin is called hemoglobin A because this forms the major part of hemoglobin found in adults. In adults there is another small fraction of hemoglobin called called Hb A2, the globin portion of which is made up of two alpha chains and two delta chains. Normally the concentration of HbA2 is less than 3.5% of the total hemoglobin. During fetal life, the major part of hemoglobin is Hb F, the globin of which is made up of two alpha chains and two gamma chains. The concentration of HbF falls after birth and in adults HbF is less than 2-3% of the total hemoglobin. The genetic control of gamma, alpha and beta chains is interrelated, so that after birth, the production of gamma chains slows down and beta chains increases correspondingly. INHERITENCE OF THALASSEMIA Like all body characteristics and functions, hemoglobin formation is also controlled by a pair of genes, one inherited from each parent. Normal persons have inherited normal genes from both the parents and thus form normal hemoglobin. Thalassemia carriers or traits have one normal and one abnormal gene. They are usually healthy because the normal gene masks the function of the abnormal gene. If a person inherits abnormal genes from both the parents, as occurs in thalassemia major, body cannot form enough hemoglobin and hence survival depends on regular transfusions. TYPES OF THALASSEMIA In thalassemia there is impaired production of alpha or beta chains. If the production of alpha chains is impaired, the condition is called alpha thalassemia and if the production of beta chains is impaired the condition is called beta thalassemia. If the person is heterozygous i.e. has only one abnormal gene, the clinical picture is very mild - called respectively as alpha thalassemia minor or beta thalassemia minor depending upon whether alpha or beta chains are affected. When both the genes are defective i.e. homozygous state, then condition is celled thalassemia major as the patient has severe clinical manifestations. A child might inherit a beta thalassemia trait from one parent and a trait of another abnormal hemoglobin from another parent like Hb S, Hb E, Hb D, etc. Such a patient is heterozygous for two different abnormal hemoglobins and the clinical picture is variable. All these conditions together are labeled as the thalassemia syndromes. BETA THALASSEMIA MAJOR Also called as Cooley′s anemia, is one of the most common hemoglobinopathies in India and results due to impaired production of beta chains of hemoglobin. A child would suffer from this disease if he inherits abnormal gene from both the parents. Though the condition is inherited and present since birth, clinical manifestations appear only at 6 - 24 months of life, rarely earlier. This is because in fetal life and in early infancy, HbF is the major hemoglobin present and production of beta chains begins only after birth. Infants are well at birth but develop anemia between 6 - 24 months of age. The infant becomes weak and lethargic, fails to thrive and has progressive anemia. The infant develops all symptoms and signs due to persistent anemia like excessive crying, irritability, poor appetite, delayed milestones of development like sitting, standing and walking. The bone marrow expands to compensate for anemia and as a result there occur marked skeletal changes leading to frontal and parietal bossing, malar prominence, protrusion of upper jaw leading to mal occlusion of teeth, distortion of ribs, vertebrae and weakening of long bones. The patient also is thin and undernourished. There is enlargement of the liver and spleen and abdomen stands out prominently in contrast to thin extremities. All these changes constitute the typical appearance of a thalassemic child. Persistent hypoxia leads to increase in heart rate and later on enlargement of the heart. There also occurs increase in total body iron, even in absence of transfusions due to increased iron absorption secondary to anemia. This problem is further aggravated by repeated red cell transfusions and iron overload is a major complication of treatment of thalassemia with regular transfusions. This excess iron gets deposited in various organs like pancreas, heart, liver, thyroid, gonads etc. resulting in their dysfunction. Thus the patient may suffer from diabetes, congestive cardiac failure, cirrhosis of liver, hypothyroidism, infertility later in life. DIAGNOSIS Anemia is usually moderate to severe at the time of diagnosis. The white cell count may be falsely elevated due to presence of nucleated red cells. Platelet count is normal. Examination of peripheral smear provides diagnostic information. There is marked hypochromia, microcytosis, anisocytosis, poikilocytosis, target cells and nucleated red cells - irrespective of the hemoglobin level. Diagnosis is confirmed by hemoglobin electrophoresis which shows increase in fetal hemoglobin (HbF). HbF may vary fron 25% - 95% HbF should be estimated before giving transfusion as after transfusion, HbF is lowered because of suppression of erythropoiesis and HbA in the transfused blood. Family members should always be screened for Thalassemia trait. Screening family members is also useful in certain doubtful cases, in patients who have already received transfusion before the diagnosis of thalassemia is established. In these cases, hemoglobin electrophoresis of the patient may be inconclusive but demonstrating that both the parents have thalassemia trait would help diagnosing thalassemia in the patient. In addition patients investigations would reveal all the general biochemical and radiological features of hemolytic anemia discussed in the earlier section on hemolytic anemia like mild indirect hyperbilirubinemia, increased reticulo-cyte count, hypercellular bone marrow, "hair on end" appearance on lateral skull X ray etc. TREATMENT Treatment of thalassemia poses a challenge to the patience of patient, his parents and the physician. Regular red cell transfusions to maintain hemoglobin above 10gm% is the mainstay of treatment. Earlier ( i.e. in 1960s) transfusions were given to maintain hemoglobin between 6-8 gm% but this regimen leads to facial and skeletal deformities, poor growth as well as cardiac problems due to chronic anemia and hypoxia. The current trend is to maintain hemoglobin to near normal levels. This leads to normal growth and development. Since the deficiency in thalassemia is that of red cells only packed red cells and NOT whole blood should be transfused and that too using a leucocyte filter to avoid any allergic reactions or antibody formation which may create problems during future transfusions. Blood transfusions are usually required every 3-4 weeks, to maintain pre transfusion hemoglobin above 10 gm% and post transfusion hemoglobin at about 12 gm%. Tranfusions should be given in an out patient setting and in a thalassemia care centre which has medical and para medical staff trained to care for these patients. This is beneficial to the patients as they meet other patients with similar illness, leading to better psychological acceptance of the disease and its treatment. Also, they learn about the disease and outcome of treatment from one another and share experiences which lead to better compliance. With repeated transfusions there is always risk of transmitting viral infections like hepatitis B and C and HIV. These should be carefully monitored periodically and if diagnosed treatment should be started immediately. Splenectomy is indicated when hypersplenism sets in as indicated by increase in the transfusion requirements. Splenectomy may also be done if massive enlargement of the spleen produces intolerable discomfort. Splenectomy increases the risk of serious infections and hence should be avoided till 6 years of age. The patient should be immunized with pneumococcal, meningococcal and H influenzae vaccines atleast 2 - 4 weeks prior to splenectomy. Oral penicillin 250 mg once daily should be given for atleast 5 years post splenectomy. Even minor infections should be treated with antibiotics promptly in a splenectomised patient and he should be hospitalized if fever does not subside within 48 - 72 hours. Iron overload is inevitable in a thalassemic patient who is on regular red cell transfusions. It is monitored by estimating serum ferritin levels regularly and if the levels exceed 1500 ìg/l the patient should be started on iron chelating agents. Desferal is an effective iron chelator and should be started as early as possible to prevent complications of excess iron. The daily dose of desferral is about 30 - 70 mg/kg. It is administered subcutaneously on abdomen or thigh over 8 hours by using an infusion pump, 5 - 7days/week, depending upon the extent of iron overload. With good patient compliance, it is very effective and has hardly any toxicity. Regular transfusions and optimal chelation of excess iron lead to normal life span in a patient with thalassemia. Deferiprone is an orally effective iron chelator available at a cost much lower than desferal. The daily dose is 50 - 75 mg/kg/day. Side effects like neutropenia, arthropathy, and gastrointestinal intolerance are the limiting factors for deferiprone therapy. There have been few case reports of deferiprone enhancing hepatic fibrosis. Allogenic bone marrow transplantation is currently the only therapy to cure thalassemia in a patient who has an HLA identical sibling donor. It means freedom from transfusions, iron chelation, and all the complications that come with it. Since the procedure requires a sibling who is HLA identical, it can only be applied to a small percentage of patients. It is associated with high morbidity and, in some cases, even mortality. Moreover it is very expensive- cost of a bone marrow transplant in India could be 800,000 - 10,00,000 Rupees and hence many patients cannot afford it. Gene therapy is being tried - by replacing the defective globin gene with a normal functional gene but it is technically difficult and not yet available as a therapeutic option. Thus prevention of the birth of a thalassemic child still remains the major cure for this disease. This can be achieved by increasing awareness about thalssemia, by screening siblings and parents of the patient to identify carriers of the disease, screening the communities in which thalassemia is very common, screening the couple before they plan to have a baby and prenatal diagnosis if the woman is pregnant i.e. testing the fetus for thalassemia major and aborting it if found to have the disease. BETA THALASSEMIA MINOR OR THALASSEMIA TRAIT These patients are either asymptomatic or have mild anemia and rarely moderate degree of anemia. Clinical examination is normal except for mild anemia. Usually patients are given iron and vitamin supplements to which they do not respond. The peripheral blood smear shows microcytosis, hypochromia, anisocytosis, poikilocytosis and target cells. Serum iron studies are normal, except in those who have coexisting iron deficiency - a condition not uncommon in our country. Diagnosis is made by hemoglobin electrophoresis which shows increase in Hb A2 to more than 3.5%. HbF is usually normal but may be elevated in some cases. TREATMENT The condition usually requires no treatment. Folic acid supplements may help to prevent relative folate deficiency which may occur as a result of increased cell turnover. Though red cells are hypochromic and microcytic, they do not need iron. Unfortunately, this fact is ignored by many and results in injudicious prescription of hematinics containing iron to all who look pale or have anemia. Not only is this therapy of no use but it could lead to iron overload and its complications. Thus use of iron supplements is contraindicated unless there is coexisting iron deficiency. Iron supplements are required in pregnant women with beta thalassemia minor, but serum iron should be carefully monitored. These patients should be educated about thalassemia major if they do not have a child suffering from the disease in their family. They should be told about means of preventing the birth of a thalassemia major baby i.e. by sceening the spouse of the affected patient and by prenatal diagnosis. ALPHA THALASSEMIA MAJOR This condition occurs as a result of homozygous defect in alpha chain production. Alpha chains are required for both - HbA and HbF. Thus production of even fetal hemoglobin is impaired and the condition is incompatible with life resulting in intrauterine death of the fetus. These fetuses contain hemoglobin Barts - abnormal hemoglobin formed by combining four gamma chains. ALPHA THALASSEMIA MINOR This condition is clinically and hematologically almost unrecognizable in adults. However cord blood may show up to 10% Hb Barts. Blood stained with brilliant cresyl blue may show occasional red cells with Hb H inclusion bodies. Hemoglobin H is an abnormal hemoglobin which contains four beta chains. Patients have mild anemia refractory to hematinics. Copyright 2004 - Indian Journal of Medical Sciences |
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