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Thalassemia: An overview

Article  in  Journal of the Scientific Society · January 2014

DOI: 10.4103/0974-5009.126696

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Review Article

Thalassemia: An overview
Ramesh Aggarwal,
Anupam Prakash1,
Abstract
Meenakshi Aggarwal2 This article provides an insight towards diagnosing and managing thalassemias. It begins by
Department of Medicine, Lady Hardinge describing the structure of normal hemoglobin and elaborates on our understanding of the
Medical College and Associated pathophysiology of thalassemia. An overview of transfusion therapy and its complications
Smt. SK and Dr. Ram Manohar Lohia including endocrinopathies and cardiomyopathy has also been discussed.
Hospital, Departments of 1Medicine, and
2
Microbiology, Lady Hardinge Medical
College and Smt. SK Hospital, New Delhi,
India

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. Key words: Cooley’s anemia, thalassemia, β thalassemia
E-mail: rameshlhmc@gmail.com

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,
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DOI:
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Journal of the Scientific Society, Vol 41 / Issue 1 / January-April 2014
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 hemoglobin
The 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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Aggarwal, et al.: An overview of Thalassemia
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-thalassemia
The 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
4 Journal of the Scientific Society, Vol 41 / Issue 1 / January-April 2014
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-thalassemia
β-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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Aggarwal, et al.: An overview of Thalassemia
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 transfusion
Severe 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 hemsiderosis
Thalassemia patients on chronic transfusion are
susceptible for acquiring bloodborne infections apart
Journal of the Scientific Society, Vol 41 / Issue 1 / January-April 2014
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 transplantation
Bone 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 therapy
Gene 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]
Prevention
Thalassemia 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.
Prognosis
Patients 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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Aggarwal, et al.: An overview of Thalassemia

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