3Journal of the Scientific Society, Vol 41 / Issue 1 / January-April 2014

INTRODUCTION

Thalassemia syndromes are genetically transmitted autosomal recessive hemoglobinopathy characterized by reduced rate of synthesis of one or more of the globin polypeptide chains of hemoglobin.[1] This clinical spectrum of this disease can vary in severity from asymptomatic laboratory abnormalities to death in utero.

HUMAN HEMOGLOBIN: STRUCTURE AND FUNCTION

Human hemoglobin consists of a tetramer of globin polypeptide chains: A pair of α-like chains with 141 amino acids and a pair of β-like chains with 146 amino acids.[2] Each globin polypeptide chain enfolds a single heme moiety, which can bind a single oxygen molecule. Thus one molecule of hemoglobin can bind and transport four molecules of oxygen. Unpaired polypeptide chains of hemoglobin are insoluble and tend to form inclusions,

which can damage red blood cells (RBC). However, the tetramer formed by α and β chains are soluble and prevent any cell damage. Normal globin production is regulated so that any new chain formed will have a partner to pair. In thalassemia syndromes, this regulation is impaired resulting in overproduction of either α or β chain and underproduction of other. This mismatch results in accumulation of unpaired chains and hence insolubility and precipitation of such globin chains. The major adult hemoglobin A (HbA) has two α and two β chains (α2 β2), minor adult hemoglobin has two α and two δ chains (α2 δ2) and fetal hemoglobin has two α and two γ chains (α2 γ2).

Genetics of human hemoglobinThe human hemoglobins are encoded in two gene clusters: α-like globin genes present on chromosome 11 and β-like globin genes on chromosome 16. Normally an individual inherits two β-globin genes and 2-α globin genes from each parent i.e., normal adult hemoglobin is α2 β2. Depending upon whether the genetic defects or deletion lies in transmission of α or β globin chain gene, thalassemias are classified into α and β-thalassemias.[3] Thus, patient with α-thalassemias have impaired production of α chains whereas patient with β-thalassemias have impaired production of β chains. Each of two main types of thalassemias may occur as heterozygous (minor) or homozygous state (major). The former is generally asymptomatic while the latter is severe congenital hemolytic anemia.

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10.4103/0974-5009.126696

Address for correspondence: Dr. Ramesh Aggarwal, Department of Medicine, Lady Hardinge Medical College and Associated Smt. SK and Dr. Ram Manohar Lohia Hospital, New Delhi, India. E-mail: rameshlhmc@gmail.com

Thalassemia: An overview

Ramesh Aggarwal, Anupam Prakash1, Meenakshi Aggarwal2

Department of Medicine, Lady Hardinge Medical College and Associated Smt. SK and Dr. Ram Manohar Lohia Hospital, Departments of 1Medicine, and 2Microbiology, Lady Hardinge Medical College and Smt. SK Hospital, New Delhi, India

Abstract

This article provides an insight towards diagnosing and managing thalassemias. It begins by describing the structure of normal hemoglobin and elaborates on our understanding of the pathophysiology of thalassemia. An overview of transfusion therapy and its complications including endocrinopathies and cardiomyopathy has also been discussed.

Key words: Cooley’s anemia, thalassemia, β thalassemia

rEviEw articlE

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EPIDEMIOLOGY

The overall prevalence of β-thalassemia in India is 3-4% with an estimate that around 10,000-12,000 children are born every year with β-thalassemia major. A recent study in India showed that the overall prevalence of β-thalassemia trait[4] was 2.78 % and varied from 1.48% to 3.64% in different states, whereas the prevalence of β-thalassemia trait in 59 ethnic groups varied from 0% to 9.3% respectively. β-thalassemia is prevalent in Mediterranean countries, the Middle East, Central Asia, India, Southern China and countries along the north coast of Africa and in South America.[5] α-thalassemias is prevalent in peoples of Western African and South Asian descent. About 15% of American blacks are silent carriers for α-thalassemias.[6-8] In India, the prevalence of α-thalassemia is estimated[9] to be around 12.9%. Region-wise and caste-wise analysis showed the highest prevalence of α-thalassemia among the Punjabi population originating from the northern region of India. The Maldives has the highest incidence of thalassemia in the world with a carrier rate of 18% of the population. Thalassemia is common in areas where malaria is endemic like Asia and Africa because the abnormal RBC provides an unfavorable environment for the malarial parasite to complete its life cycle.[10]

CLINICAL FEATURES

α-thalassemiaThe patients with α-thalassemia may remain asymptomatic and are frequently suspected on the basis of a routine blood count. The four classic α-thalassemias syndromes are:[11]

1. Silent thalassemia: (-α/αα): This condition arises when only a single α allele on one chromosome is deleted. The patient remains asymptomatic in a silent carrier state.

2. Thalassemia trait: a) -α/-α homozygous α-thal-2: It arises when single

α allele on each chromosome is deleted. b) —/αα heterozygous α-thal-1: It occurs when both

alleles on one chromosome are deleted.

These conditions are generally asymptomatic and are detected on routine blood investigation.3. Hemoglobin H (HbH) disease: (—/α) Heterozygous

α-thal-1/α-thal-2.

This condition arises when the offspring is doubly heterozygous for α-thal-2 and α-thal-1. The normal HbA production is reduced to 25-35% and unpaired chains accumulate in RBC’s. In fetus unpaired γ chains

form tetramers called Hb Barts, whereas in adults unpaired β chains form tetramers called HbH. The accumulated HbH form inclusions and precipitates in erythrocytes. Patients manifest with thalassemia intermedia having moderate hemolytic anemia and ineffective erythropoiesis. Variable degree of jaundice, splenomegaly and sometimes hypersplenism complicate the clinical picture.4. Hydrops fetalis: (—/—) Homozygous α-thal-1.

This homozygous state cause total absence of α globin in fetus and hence no useful hemoglobin is produced beyond the embryonic stage. Instead the excess γ globin forms tetramers (Hb Barts) which has very high affinity for oxygen. As a result the fetal tissues are not able to extract oxygen from this hemoglobin and suffer from tissue asphyxia, edema hence called hydrops fetalis, retardation in brain growth, skeletal and cardiovascular deformities and gross enlargement of the placenta ultimately leading to death in utero.

β-thalassemiaβ-thalassemias can be classified into:1. Thalassemia minor or β-thalassemia carrier or

β-thalassemia trait.2. Thalassemia intermedia.3. Thalassemia major or Cooley’s anemia or

Mediterranean anemia.

Anemia is mild in thalassemia minor and it increases in severity from intermedia to major froms. Children develop pallor, jaundice, feeding problems, growth retardation, hepatosplenomegaly and sometimes endocrine dysfunction. Ineffective erythropoiesis and compensated erythroid hyperplasia produce bone marrow expansion. Maxillary marrow hyperplasia and frontal bossing lead to characteristic “chipmunk” facies.[12] Skeletal deformities like genu valgum and pathological fractures of long bones and vertebrae may occur early due to cortical invasion by erythroid elements. Susceptibility to infection and improper transfusion of blood may lead to death in first decade of life in severe cases.

DIAGNOSIS

• Thalassemia minor: It is characterized by mild anemia with hematocrit rarely <30-33%. There is profound microcytosis and hypochromia. Mean corpuscular volume (MCV) and mean corpuscular Hb (MCH) are reduced. Hemoglobin electrophoresis shows increased HbA2 level.

• Thalassemia intermedia: It is characterized by Hb level between 7 and 10 g/dl, MCV between 50 and

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80 fl and MCH between 16 and 24 pg. The affected RBC’s show microcytosis, hypochromia anisocytosis, poikilocytosis and nucleated RBC.

• Thalassemia major: Patients will have severe anemia with Hb level (<7 g/dl), MCV < 70 fl and MCH < 20 pg. The peripheral smear shows profound microcytosis apart from features as in thalassemia intermedia. Both HbA2 and HbF levels can be elevated in this form.

• α-thalassemia trait: Hemoglobin is usually normal and there may be mild microcytosis and hypochromia. HbA2 and HbF levels are normal.

• HbH disease resembles thalassemia intermedia.

MANAGEMENT

The management of thalassemia is guided by the severity of anemia, suppression of excessive erythropoiesis and prevention of excess iron overload.

Blood transfusionSevere anemia with hemoglobin <7 g% for more than 2 weeks is widely accepted as an indication to start blood transfusion.[13] The goal should be aimed to maintain a pre pretransfusional Hb level of 9 to 10 g/dl and a post-transfusion Hb level of 13 to 14 g/dl. Such regime generally prevents growth impairment, organ damage and bone deformities. Care should be taken to avoid faster transfusion exceeding 5 ml/kg/h and amount of transfused RBC should not exceed 15 to 20 ml/kg/day. The frequency of transfusion is usually every 2 to 4 weeks.

Patients with thalassemia intermedia may survive without chronic transfusion but the development of hypersplenism may require splenectomy in such patients. Vaccination against Streptococcus pneumoniae, Hemophilus influenzae and Neisseria meningitidis may be required in such individuals. These individuals may develop iron overload from increased gastrointestinal absorption of iron even without transfusion and therefore chelation therapy is started when the serum ferritin concentration exceeds 300 ng/ml.

Carriers of α-thalassemia generally do not need treatment because their anemia is very mild. Prophylactic iron should never be given to carriers of α-thalassemia as they are at risk of developing iron overload. Individuals with HbH disease may require blood transfusions and splenectomy. Oxidative drugs should be avoided in these patients.

Transfusional hemsiderosisThalassemia patients on chronic transfusion are susceptible for acquiring bloodborne infections apart

from developing iron overload. Patients who receive more than 100 units of packed RBCs usually develop hemosiderosis. Serum ferritin, liver biopsy and imaging modalities like magnetic resonance imaging and super-conducting quantum-interference device can measure iron overload in the body. Complications arising from iron overload are cirrhosis, endocrine dysfunction[14,15] (glucose intolerance, hypogonadism, hypothyroidism, hypoparathyroidism) and cardiomyopathy. To prevent these complications iron chelating agents like desferoxamine (parenteral use) and deferasirox (oral use) should be used early when starting transfusion therapy.

Bone marrow and cord blood transplantationBone marrow transplantation (BMT) remains the only definitive cure currently available for patients with thalassemia. However the major limitation of allogenic BMT[16] is the lack of an human leukocyte antigen-identical sibling donor. Cord blood transplantation is another option where with a low risk of graft versus host disease.

Gene therapyGene therapy for thalassemia is not very successful and the future of this therapy will depend on efficiency of gene delivery and various other factors such as viral titers, non-oncogenic insertion, the variable expression of globin genes and the variable contributions of the β-thalassemia phenotype.[17]

PreventionThalassemia can be diagnosed antenatally by genetic analysis. Amniocentesis or chorionic villous sampling provides fetal deoxyribonucleic acid sample, which can be analyzed for presence of thalassemia. Genetic counseling can be done to the individuals at risk regarding the genetic risk of having affected children and the natural history of the disease.

PrognosisPatients with thalassemia minor have excellent prognosis. Thalassemia intermedia may survive without blood transfusions till adulthood. However as the requirement for transfusion increases and associated complications like hypersplenism develop the prognosis become unfavorable. Earlier thalassemia major was lethal by the age of 5 years without any treatment. However with the early initiation of blood transfusion and iron chelation therapy these children can survive up to second and third decades. Carriers of α-thalassemia have excellent prognosis and survive like other normal individuals. HbH disease may remain healthy or suffer from complications especially iron overload. Infants

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diagnosed with Hydrops fetalis syndrome usually die in the perinatal period.

REFERENCES

1. Galanello R, Origa R. Beta-thalassemia. Orphanet J Rare Dis 2010;5:11.

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6. Bernini L. Geographic distribution of alpha-thalassemia. In: Steinberg MH, Forget BG, Higgs DR, Nagel RL, editors. Disorders of Hemoglobin. 1st ed. Cambridge, United Kingdom: Cambridge University Press; 2001. p. 878-94.

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8. Flint J, Harding RM, Boyce AJ, Clegg JB. The population genetics of the haemoglobinopathies. Baillieres Clin Haematol 1993;6:215-62.

9. Nadkarni A, Phanasgaonkar S, Colah R, Mohanty D, Ghosh K. Prevalence and molecular characterization of alpha-thalassemia syndromes among Indians. Genet Test 2008;12:177-80.

10. Fodde R, Losekoot M, van den Broek MH, Oldenburg M, Rashida N, Schreuder A, et al. Prevalence and molecular heterogeneity of alfa+ thalassemia in two tribal populations from Andhra Pradesh, India. Hum Genet 1988;80:157-60.

11. Weatherall DJ. Genetic variation and susceptibility to infection: The red cell and malaria. Br J Haematol 2008;141:276-86.

12. Harteveld CL, Higgs DR. Alpha-thalassaemia. Orphanet J Rare Dis 2010;5:13.

13. Toman HA, Hassan R, Hassan R, Nasir A. Craniofacial deformities in transfusion-dependent thalassemia patients in Malaysia: Prevalence and effect of treatment. Southeast Asian J Trop Med Public Health 2011;42:1233-40.

14. Giardina P, Forget B. Thalassemia syndromes. In: Hoffman R, Benz E, Shattil S, Furie B, Silberstein LE, McGlave P et al., editors. Hematology: Basic Principles and Practice. 5th ed. Philadelphia, PA: Churchill Livingstone; 2008. p. 535-63.

15. Prakash A, Aggarwal R. Thalassemia major in adults: Short stature, hyperpigmentation, inadequate chelation, and transfusion-transmitted infections are key features. N Am J Med Sci 2012;4:141-4.

16. Angelucci E, Baronciani D. Allogeneic stem cell transplantation for thalassemia major. Haematologica 2008;93:1780-4.

17. Breda L, Kleinert DA, Casu C, Casula L, Cartegni L, Fibach E, et al. A preclinical approach for gene therapy of beta-thalassemia. Ann N Y Acad Sci 2010;1202:134-40.

How to cite this article: Aggarwal R, Prakash A, Aggarwal M. Thalassemia: An overview. J Sci Soc 2014;41:3-6.

Source of Support: Nil. Conflict of Interest: None declared.

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