Journal of Pathology of Nepal (2014) Vol.

4, 663 - 671
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Review Article

Beta thalassemia - a review

Jha R1, Jha S2
1
Department of Pathology, Tribhuwan University Teaching Hospital, Kathmandu, Nepal
2
Department of Pathology, Manipal College of Medical Sciences, Pokhara, Nepal

ABSTRACT
Keywords:
Beta Thalassemia; Thalassemia is a globin gene disorder that results in a diminished rate of synthesis of one or more of
Carrier detection; the globin chains. About 1.5% of the global population (80 to 90 million people) are carriers of beta
Mutation; Thalassemia. More than 200 mutations are described in beta thalassemia. However not all mutations are
Prental diagnosis. common in different ethnic groups. The only effective way to reduce burden of thalassemia is to prevent
birth of homozygotes. . Diagnosis of beta thalassemia can be done by fetal DNA analysis for molecular
defects of beta thalassemia or by fetal blood analysis. Hematopoietic stem cell transplantation is the only
available curative approach for Thalassemia. Many patients with thalassemia in underdeveloped nations
die in childhood or adolescence. Programs that provide acceptable care, including transfusion of safe
blood and supportive therapy including chelation must be established.

INTRODUCTION

Thalassemia is the name given to a globin gene disorder that Types of Beta thalassemia
results in a diminished rate of synthesis of one or more of the
globin chains and, consequently, a reduced rate of synthesis Different types of beta thalassemia are as follows:2
of the hemoglobin or hemoglobins of which that chain
constitutes a part.1 Beta-thalassemia syndromes are a group Beta-thalassemia
of hereditary blood disorders characterized by reduced or
absent beta globin chain synthesis.2 The condition was first • Thalassemia major ( Cooley’s Anemia): refers to a
described by Cooley and Lee in 1925. More than a decade severe clinical phenotype that occurs when patients
later, Wintrobe and colleagues described milder form of are homozygous or compound heterozygous for
Cooley's anemia in both parents of the children with classic more severe beta chain mutations (e.g. severe B+/B+
Cooley's anemia. The word thalassemia is described from mutations, B+/B0, B0/B0)
Greek word “thalas” meaning sea and “haimas” meaning
blood because all early cases were reported in children of • Thalassemia intermedia: An in between clinical
Mediterranean origin.1 phenotype with heterogeneous genetic mutations that
still allow for some Beta chain production (e.g. B+/B0,
Correspondence: B+/B+). Some rare cases also exist in which both beta
Dr Runa Jha, MD and alpha mutations coexist
Department of Pathology
Tribhuwan University Teaching Hospital • Thalassemia minor (Beta Thalassemia carrier/trait): a
Maharajgunj, Kathmandu, Nepal, Email: [email protected] mild clinical phenotype when one normal copy of the
664 Jha R et al.

beta globulin gene is present (e.g. B+/B, B0/B) Fr 41-42(-TTCT) and Fr 8-9 (+G). In study by Satpute SB
et al, IVS I-5 (G–C) mutation was detected in 65.07 %
- Beta-thalassemia with associated Hb anomalies followed by IVS I-1 (G–T) (9.52 %) in Indian population.8

• HbC/Beta-thalassemia 619 bp deletion at the 3’ end of beta-globin gene makes it

nonfunctional. Frame shift mutations +1 codon 8/9 (+G)
• HbE/Beta-thalassemia and -4 codon 41/42 (–TCTT) change the ribosome reading
frame and causes premature termination of translation.
• HbS/Beta-thalassemia (clinical condition more similar Mutation IVS I-1 (G–T) causes change in splice junction
to sickle cell disease than to thalassemia major or causing ineffective RNA processing. IVS I-5 (G–C) destroys
intermedia) consensus sequences around splice junction which are
essential for splicing. Mutation at codon 15 (G–A) causes
- Hereditary persistence of fetal Hb and beta- a nonsense codon, terminating the synthesis of b-globin at
thalassemia a premature stage.9

- Autosomal dominant forms Hereditary transmission

- Beta-thalassemia associated with other manifestations The beta thalassemias are inherited in an autosomal
recessive manner. The parents of an affected child are
• Beta-thalassemia-tricothiodystrophy obligate heterozygotes and carry a single copy of a disease
causing beta globin gene mutation. At conception, each
• X-linked thrombocytopenia with thalassemia child of heterozygotes parents has 25% chance of being
affected, 50% chance of being an asymptomatic carrier, and
Epidemiology 25% chance of being unaffected and not carrier.2

Beta-thalassemia is prevalent in Mediterranean countries, Pathophysiology

the Middle East, Central Asia, India, Southern China and
the Far East as well as countries along the north coast of The reduced amount (ß+) or absence (ß0) of beta globin
Africa and in South America. The highest carrier frequency chains result in a relative excess of unbound alpha globin
is reported in Cyprus (14%), Sardinia (10.3%) and Southeast chains that precipitate in erythroid precursors in the bone
Asia.3 Population migration and intermarriage between marrow, leading to their premature death and hence to
different ethnic groups has introduced thalassemia in almost ineffective erythropoiesis. The degree of globin chain
every country of the world. It has been estimated that about reduction is determined by the nature of the mutation at
1.5% of the global population (80 to 90 million people) are the beta globin gene located on chromosome 11. Peripheral
carriers of beta Thalassemia. However, accurate data on hemolysis contributing to anemia is less prominent in
carrier rates in many populations are lacking, particularly thalassemia major than in thalassemia intermedia, and
in areas of the world known or expected to be heavily occurs when insoluble alpha globin chains induce membrane
affected.4 Madan et al report overall carrier frequency of damage to the peripheral erythrocytes. Anemia stimulates
beta thalassemia carrier to be 4.05% and the birth incidence the production of erythropoietin with consequent intensive
of beta thalassemia homozygotes to be 11,316 per year but ineffective expansion of the bone marrow (up 25 to
in India.5 WHO report estimates that 3% are carriers of 30 times normal), which in turn causes the typical bone
beta thalassemia in Bangladesh.6 An estimated 5000-9000 deformities. Prolonged and severe anemia and increased
children with beta thalassemia are born per year in Pakistan erythropoietic drive also result in hepatosplenomegaly and
and the estimated carrier rate is 5 to 7%, with 9.8 million extramedullary erythropoiesis.2
carriers in the total population.7 Google search using term “
beta thalassemia in Nepal” didn’t show any published data Clinical Description
that would indicate the burden of beta thalassemia in Nepal
but unpublished hospital records of Tribhuwan University Thalassemia major: Homozygotes for beta-thalassemia may
Teaching Hospital shows beta thalassemia more prevalent develop either thalassemia major or thalassemia intermedia.
in the tharu community. Individuals with thalassemia major usually come to medical
attention within the first 2 years of life and require regular
Genetics of Beta thalassemia. blood transfusion to survive. Those presenting later do not
require transfusion and receive a diagnosis of thalassemia
More than 200 mutations are described in beta thalassemia. intermedia.10
However not all mutations are common in different ethnic
groups. The five common mutations found in Indian Affected infants with thalassemia major fail to thrive and
subcontinent are IVSI-1 (G→T), IVSI-5 (G→C), Del 619, become progressively pale. Feeding problems, diarrhea,
Beta thalassemia 665

irritability, recurrent bouts of fever and enlargement of the such as Howell–Jolly bodies, target cells, lymphocytosis,
abdomen, caused by hepato splenomegaly, may occur. If a thrombocytosis and giant platelets. Pappenheimer bodies
regular transfusion program that maintains a minimum Hb are very prominent and nucleated red cells are markedly
concentration of 9.5 to 10.5 g/dl is initiated, then growth increased. The bone marrow aspirate shows gross erythroid
and development are normal until the age of 10 to 11 years. hyperplasia. There is quite severe dyserythropoiesis with
After the age of 10–11 years, affected individuals are at nuclear lobulation and fragmentation, basophilic stippling,
risk of developing severe complications related to post defective hemoglobinization and the presence of alpha
transfusion iron overload, depending on their compliance chain precipitates. Actively phagocytic macrophages are
with chelation therapy.10 Survival of individuals who have prominent and pseudo-Gaucher cells are present. Iron stores
been well transfused and treated with appropriate chelation are increased.1
may extend beyond the age of 30 years. Complications of
iron overload in children include growth retardation and Biochemical tests show increased bilirubin, increased
failure or delay of sexual maturation. Later iron overload urinary urobilinogen and hyperuricaemia. Haptoglobin is
related complications include involvement of the heart decreased or absent, free hemoglobin may be detectable in
(dilated myocardiopathy or rarely arrythmias), liver (fibrosis the plasma and methemalbumin may be present.1
and cirrhosis) and endocrine glands (diabetes mellitus,
hypogonadism and insufficiency of the parathyroid, thyroid, In the case of homozygotes or compound heterozygotes
pituitary, and, less commonly, adrenal glands). Myocardial for B0 Thalassemia (B0 B0), techniques such as
disease caused by transfusional siderosis is the most hemoglobin electrophoresis and High performance liquid
important life-limiting complication of iron overload in beta chromatography (HPLC) show only hemoglobin F and
thalassemia. Cardiac complications are reported to cause hemoglobin A2. In these cases HbA is absent, HbF is 95–
71% of deaths in individuals with beta thalassemia major.11 98% and HbA2 is 2–5% When there is homozygosity for
B+ thalassemia (B+ B+) or compound heterozygosity for
The most relevant features of untreated or poorly transfused B0 and B+ thalassemia (B+ B0), hemoglobin A is also
individuals are growth retardation, pallor, jaundice, brown present. Such cases show HbA between 10 and 30%, HbF
pigmentation of the skin, poor musculature, genu valgum, between 70–90% and HbA2 between 2–5%.10
hepatosplenomegaly, leg ulcers, development of masses
from extramedullary hematopoiesis and skeletal changes Beta-thalassemia intermedia: Individuals with thalassemia
that result from expansion of the bone marrow. intermedia present later than thalassemia major, have
milder anemia and by definition do not require or only
These skeletal changes include deformities of the long occasionally require transfusion. At the severe end of the
bones of the legs and typical craniofacial changes (bossing clinical spectrum, patients present between the ages of
of the skull, prominent malar eminence, depression of the 2 and 6 years and although they are capable of surviving
bridge of the nose, tendency to a mongoloid slant of the without regular blood transfusion, growth and development
eye, and hypertrophy of the maxillae, which tends to expose are retarded. At the other end of the spectrum are patients
the upper teeth). Individuals who have not been regularly who are completely asymptomatic until adult life with only
transfused usually die before the third decade.10 mild anemia.2

The hemoglobin concentration, red blood cells (RBC), Principle symptoms are pallor, jaundice, cholelithiasis,
hematocrit (Hct), mean corpuscular volume (MCV), mean liver and spleen enlargement, moderate to severe skeletal
corpuscular hemoglobin (MCH) and mean corpuscular changes, leg ulcers, extramedullary masses of hyperplastic
hemoglobin concentration (MCHC) are reduced erythroid marrow, a tendency to develop osteopenia and
and red cell distribution width (RDW) is increased. osteoporosis and thrombotic complications.12,13 Patients with
The hemoglobin is usually in the range 3–7g/dl, the thalassemia intermedia have an increased predisposition to
MCV 50–60fl and the MCH 12–18pg. The blood film thrombosis as compared to thalassemia major, especially if
shows marked anisocytosis, poikilocytosis (including splenectomised. Such events include deep vein thrombosis,
fragments and teardrop poikilocytes), hypochromia and portal vein thrombosis, stroke and pulmonary embolism.14
microcytosis. Basophilic stippling, Pappenheimer bodies Although individuals with thalassemia intermedia are at
and target cells may be noted. Circulating nucleated risk of iron overload secondary to increased intestinal iron
red cells showing defective hemoglobinization and absorption, hypogonadism, hypothyroidism and diabetes
dyserythropoietic features are present. In children with are not common.15
massive splenomegaly, hypersplenism leads to aggravation
of the anemia, neutropenia and thrombocytopenia. The Patients with thalassemia intermedia have a moderate
absolute reticulocyte count is rarely high, although it anemia and show a markedly heterogeneous hematological
tends to increase after splenectomy. If the spleen has been picture, ranging in severity from that of the beta-thalassemia
removed, the usual features of hyposplenism are present carrier state to that of thalassemia major.10 Flow chart for the
666 Jha R et al.

Figure 1: Flow chart for carrier identification of beta Thalassemia

identification of ß Thalassemia is shown in figure 1. The bone marrow aspirate shows increased cellularity as a
consequence of erythroid hyperplasia. Some erythroblasts
Beta-thalassemia carrier state/Thalassemia Minor: show defective hemoglobinization and cytoplasmic
Carriers of beta-thalassemia are clinically asymptomatic. vacuolation.1
The characteristic hematological features are microcytosis,
hypochromia and increased HbA2 level.10 An iron stain may show heavy siderotic granulation. In
the neonatal period, babies with beta Thalassemia trait,
The blood count characteristically shows a normal or in contrast with those with alpha Thalassemia trait, have
slightly reduced hemoglobin concentration, elevation of the a normal hemoglobin concentration and normal red cell
RBC and reduction of the MCH and MCV. The MCHC is indices. Differences from normal start to appear around the
usually normal. The red cell distribution width (RDW) is age of 3 months.1
usually normal. Mean values for hematological variables
(hemoglobin concentration, MCV and MCH) differ Diagnosis
significantly between ß+ and ß0 Thalassemia trait, but there
is considerable overlap. The hemoglobin concentration falls Clinical diagnosis: Thalassemia major is usually suspected
in pregnancy as the plasma volume rises .When a patient in an infant younger than two years of age with severe
with ß Thalassemia trait develops megaloblastic anemia or microcytic anemia, mild jaundice and hepatosplenomegaly.
significant liver disease, the MCV and MCH may rise into the Thalassemia intermedia presents at a later age with
normal range. The same will occur with the administration similar but milder clinical findings. Carriers are usually
of drugs such as zidovudine or hydroxycarbamide.1 asymptomatic, but sometimes may have mild anemia.

The blood film varies from almost normal with only mild Hematologic Diagnosis: RBC indices show microcytic
microcytosis to markedly abnormal. Abnormal features, in anemia. Thalassemia major is characterized by reduced
addition to microcytosis, include anisocytosis, hypochromia Hb level (<7 g/dl), MCV > 50 < 70 fl and MCH > 12< 20
and poikilocytosis. Individuals with a more severe pg. Thalassemia intermedia is characterized by Hb level
phenotype may have prominent basophilic stippling, target between 7 and 10 g/dl, MCV between 50 and 80 fl and MCH
cells and small numbers of irregularly contracted cells. between 16 and 24 pg. Thalassemia minor is characterized
Some thalassemic individuals have prominent elliptocytes. by reduced MCVand MCH, with increased Hb A2 level.2
The percentage of reticulocytes may be slightly elevated.
Beta thalassemia 667

used are the primer-specific amplification (ARMS,

Amplification Refractory Mutation System) and the reverse
oligonucleotide hybridisation with specific oligonucleotide
probes (RDB, Reverse Oligonucleotide-probe analysis.
If targeted mutation analysis fails to detect the mutation,
beta globin gene sequence analysis can be used to detect
unknown mutations in the beta globin gene ).16

Dominant Beta thalassemia

Most individuals who are heterozygous for a beta

Thalassemia mutation have clinicopathological features
described as ‘Thalassemia minor’, i.e. the blood count
and film are abnormal but there are no abnormal physical
findings or symptoms. However, some mutations produce
clinically apparent abnormalities in heterozygotes,
mainly splenomegaly, anemia, jaundice and an increased
incidence of gallstones. This is referred to as dominant
beta thalassemia.1 Dominant beta Thalassemia is rare,
but cases are found scattered throughout the world. The
clinicopathological features are those of Thalassemia
intermedia. Red cell survival is less than in typical Beta
Thalassemia trait and the reticulocyte count is increased.
Patients may require occasional blood transfusions.
There is extramedullary hemotopoiesis and iron overload
may occur. The blood film is usually very abnormal with
Figure 2 a: HPLC pattern in normal subjects prominent basophilic stippling and circulating nucleated red
cells. The bone marrow shows erythroid hyperplasia and
Peripheral blood smear: Affected individuals show RBC dyserythropoiesis .1
microcytosis, hypochromia, anisocytosis, poikilocytosis
(spiculated tear-drop and elongated cells) and nucleated RBC Problems linked to diagnosis of beta thalassemia trait
(i.e., erythroblasts). The number of erythroblasts is related
to the degree of anemia and is markedly increased after The best approach to screen the Thalassemia traits is
splenectomy. Carriers have less severe RBC morphologic determining the Hb A2 level. The large majority of beta
changes than affected individuals. Erythroblasts are thalassemia carriers present with a high Hb A2 level and
normally not seen.10 this often accompanied by moderate increase in Hb F level .
The Hb A2 level may be modified by many factors.
HPLC/electrophoresis: The Hb pattern in beta-thalassemia
varies according to beta-thalassemia type. In ß0 thalassemia Nutritional anemia: Iron deficiency lowers the hemoglobin
homozygotes HbA is absent and HbF constitutes the 92- A2 percentage both in individuals with no defect of globin
95% of the total Hb. In beta+ thalassemia homozygotes genes and in those with Thalassemia trait. it is preferable
and ß+/ ß0 genetic compounds HbA levels are between 10 not to attempt to exclude a diagnosis of b Thalassemia trait
and 30% and HbF between 70 to 90%. HbA2 is variable in patients with severe or moderately severe iron deficiency,
in beta thalassemia homozygotes and it is enhanced in beta but rather to correct the iron deficiency and then measure
thalassemia minor.10 Figure 2a and 2b shows the HPLC the hemoglobin A2 percentage if the red cell indices do
pattern in normal individual and patient with ß Thalassemia not return to normal. An exception to this generalization
trait. Hb electrophoresis pattern in various conditions is is in the case of pregnant women in whom a diagnosis of
shown in figure 3. beta Thalassemia trait is required without delay. In such
circumstances, it may be necessary to measure hemoglobin
Molecular Genetic Analysis: A limited number of molecular A2 in the partner and, if he is found to have beta Thalassemia
defects are prevalent in every at risk population. This may trait, to consider proceeding to molecular analysis in women
be very useful in practice, because a panel of most frequent with borderline hemoglobin A2 percentages. Folic acid
mutations to be searched for can be designed according deficiency can also lower the percentage of hemoglobin A2
to the carrier's ethnic origin. Known mutation detection and interfere with the diagnosis of beta Thalassemia trait.1
is carried out by a number of polymerase chain reaction
(PCR) based techniques. Among them, the most commonly Coinheritance of other Hemoglobinopathies: In beta
668 Jha R et al.

Neonates: Beta Thalassemia cannot be diagnosed from the

hemoglobin A2 percentage in neonates as levels are low.
However, by 6–12 months of age, the average hemoglobin
A2 percentage is higher than in other infants.1

Silent and almost silent beta thalassemia: There are beta

gene mutations that can cause clinically significant disease
in homozygotes and compound heterozygotes. These
mutations are divided into into two groups: ‘silent beta
Thalassemia trait’ and ‘almost silent beta thalassemia trait’.
In silent beta thalassemia trait, both the red cell indices
and the haemoglobin A2 percentage are normal. Most of
these cases are missed in the routine diagnostic laboratory.
In almost silent beta Thalassemia trait, the red cell indices
are abnormal but the hemoglobin A2 percentage is not
increased.10

Differentiating Beta Thalassemia from iron deficiency

anemia

Differentiation between iron deficiency anemia and

thalassemia trait may pose problem. If serum iron , ferritin
and HbA2 levels are known it will help. Indices derived
from automated hematology analyzer may also help in
rapid differentiation of microcytosis of thalassemia and
iron deficiency anemia. Formula suggested by England and
Fraser is (Derived factor, DF=MCV-RBC-(5xHb) divided
by 3.4). Values over 2 are seen with iron deficiency anemia
where as values less than indicate thalassemia trait.19
Figure 2b: HPLC pattern in Thalassemia trait Other ratios suggested are Mentzer ratio, Srivastava Ratio
and Shine and Lal product.20
Thalassemia carriers presenting with a normal HbA2 level,
another cause is a co-inherited δ globin abnormality.17 Beta-thalassemia associated with HbE anomalies
Hemoglobin Knossus, a ‘thalassemic hemoglobinopathy’,
is also responsible for some cases of beta Thalassemia trait The interaction of HbE and beta-thalassemia results
with normal hemoglobin A2. When an individual has both in thalassemia phenotypes ranging from a condition
hemoglobin H disease and beta Thalassemia heterozygosity, indistinguishable from thalassemia major to a mild form
the hemoglobin A2 may be normal.1 of thalassemia intermedia. Depending on the severity of
symptoms three categories may be identified:2
Conversely, falsely increased levels of HbA2 may result
from the co-existence of a variant with electrophoretic or - Mild HbE/beta-thalassemia: It is observed in about
chromatographic properties close to that of HbA2. As a rule, 15% of all cases in Southeast Asia. This group of patients
this situation has to be verified when a level of HbA2 higher maintains Hb levels between 9 and 12 g/dl and usually does
than 8 percent is observed. The presence of a Thalassemia not develop clinically significant problems. No treatment is
will generally be ruled out by considering hematological required.
data showing absence of microcytosis and hypochromia.
Nevertheless, two common variants, which elute on CE- - Moderately severe HbE/beta-thalassemia: The majority
HPLC in the HbA2 window, are really thalassemic Hb. of HbE/beta-thalassemia cases fall into this category. The
The first one is HbE, frequent in populations from South Hb levels remain at 6-7 g/dl and the clinical symptoms
East Asia, and the second is Hb Lepore. Since many other are similar to thalassemia intermedia. Transfusions are not
thalassemic defects are present in the same populations as required unless infections precipitate further anemia.
HbE, a large variety of clinical phenotype associated with
HbE is observed. These range from very mild ones, the - Severe HbE/beta-thalassemia: The Hb level can be as
simple heterozygous state for HbE, to severe ones, which low as 4-5 g/dl. Patients in this group manifest symptoms
associate HbE to ß0 thalassaemia.18 similar to thalassemia major and are treated as thalassemia
major patients.
Beta thalassemia 669

Fetal blood sampling is done by cordocentesis at 18 to 20

wk gestation. Maternal contamination is ruled out using the
Kleihauer-Betke method. If no maternal cells are present, it
is analyzed by HPLC. The Hb A levels in fetuses affected
with beta thalassemia major have ranged from 0 to 0.5 per
cent and these were distinguishable from heterozygous
babies where the Hb A levels were >1.3 per cent.21

Non invasive methods for prenatal diagnosis

Studies have been done on various noninvasive methods of

obtaining fetal DNA from maternal blood. Trophoblasts,
lymphocytes and nucleated erythrocytes (NRBCs) are the
3 cell types used as a source of fetal DNA. The cell-free
fetal DNA (cffDNA) in maternal plasma are also researched
as an alternative to fetal cells for noninvasive prenatal
diagnosis.16,21 Various methods of preimplantation genetic
diagnosis of Beta Thalassemia is also available.22

Treatment

Treatment of beta Thalassemia is life long. Management

includes regular blood transfusions, iron chelating treatment,
management of complications including osteoporosis,
Figure 2 c: HPLC pattern in Thalassemia major cardiac dysfunction, endocrine problems, hepatitis B and C
infection, HIV infection. Without access to regular chelation
treatment and medical care, the majority of children with
Prenatal Diagnosis Thalassemia major do not reach the age of 20.23

The only effective way to reduce burden of thalassemia Regular transfusion therapy to maintain hemoglobin levels
is to prevent birth of homozygotes. Programmes for of at least 9 to 10 g per deciliter allows for improved growth
identification of all individuals carrying a gene for beta and development and also reduces hepatosplenomegaly due
Thalassemia, providing genetic counseling of these carriers to extramedullary hematopoiesis as well as bone deformities.
and prenatal diagnosis where both parents are carriers are Impairment of growth and endocrinopathies, particularly
important. Several Mediterranean and western countries hypogonadism, are common features of thalassemia.
have achieved a significant change in the homozygote This is mainly due to chronic anemia as well as from iron
population since the last two decades. Other countries overload. Hormonal replacement is indicated for residual
which also have Thalassemia Control Programs include endocrine insufficiency. Hypogonadotropic hypogonadism
Canada, Israel, Turkey, Thailand, Lebanon, West Bank and impairs fertility but can be corrected with the use of
Gaza Strip, Malaysia, China, Iran, Egypt, and Pakistan.5 hormonal replacement in male patients. A small number
of female patients have been able to become pregnant,
Detection of particular molecular defect in both parents is a either spontaneously (if they have received adequate
prerequisite for prenatal diagnosis of the disease. Diagnosis chelation therapy) or with assisted reproductive techniques.
of beta thalassemia can be done by fetal DNA analysis Considerable morbidity in older patients results from bone
for molecular defects of beta thalassemia or by fetal disease due to osteopenia and osteoporosis. Bone-disease
blood analysis . Fetal DNA for analysis can be obtained management includes the careful monitoring of chelation,
from either amniocytes obtained at 15 to 18 weeks or lifestyle adjustments (increased calcium intake and physical
chorionic villi obtained at 10 to 12 weeks of gestation. At activity and refraining from smoking), hormonal therapy,
present the most widely used procedure is chorionic villi and vitamin D therapy.24
sampling, because of the clear advantage of being carried
out during the first trimester of pregnancy. The risk of fetal If the annual red cell requirement exceeds 180-200 ml/
mortality associated with both methods is in the order of Kg of splenectomy should be considered, provided that
1-2%. Chorionic villi may be obtained transcervically or other reasons for increased consumption, such as hemolytic
transabdominally, the last being most widely used, mainly reactions, have been excluded.2 Iron overload causes most
because it has a low infection rate and a lower incidence of of the mortality and morbidity associated with thalassemia.
amniotic fluid leakage.16 Iron deposition occurs in visceral organs (mainly in the
670 Jha R et al.

hydroxyurea, and various butyrate derivatives to increase

the synthesis of fetal hemoglobin. Antioxidants , gene
therapies and molecular therapies to correct defect caused
by the thalassemia mutation are also under investigation.2,24

Prognosis

Prognosis of thalassemia minor is excellent. An increased

risk for cholelithiasis has been demonstrated Patients
with thalassemia intermedia who do not usually have
severe hemosiderosis are less prone to cardiac problems
.However, pulmonary hypertension, thromboembolic
complications, overwhelming postsplenectomy sepsis, and
the development of hepatocarcinoma may reduce survival
in this group of patients. With no treatment, the natural
history of thalassemia major patient is was death by age
five. With regular transfusion, these patients can survive to
second decade and iron chelators have further prolonged
survival in recent years.2

In developed parts of the world, such as the United States

and Europe, there are approximately 10,000 homozygous
patients with thalassemia, and the number of new cases
has been progressively decreasing because of effective
prevention methods. Comprehensive, high-quality medical
care is available in these countries, with longer life
expectancy and a relatively good quality of life. In contrast,
the treatment of thalassemia is entirely different in less
developed countries, where safe transfusion and chelation
Figure 3: Cellulose acetateHb Electrophoresis at alkaline pH. From right
are not universally available. Consequently, many patients
to left , a)normal control with dark band at HbA position ; b) HbE/beta
Thalassemia with dark band at HbA2 position and another band at HbF with thalassemia in underdeveloped nations die in childhood
position; c) beta Thalassemia post transfusion showing band at equally or adolescence. Programs that provide acceptable care,
dark band at HbA as well as HbF position; d) beta Thalassemia major with including transfusion of safe blood and supportive therapy
dark band at HbF and faint band at HbA position
including chelation, must be established. Thalassemia
prevention protocols must be developed in these countries,
heart, liver, and endocrine glands), causing tissue damage with the use of better education and screening and improved
and ultimately organ dysfunction. An encouraging new access to prenatal diagnosis.24
approach to chelation therapy is the sequential combined
administration of deferiprone and deferoxamine.24 REFERENCES
1. Bain BJ. The alpha,beta,delta and gamma thalassaemias and related
Hematopoietic stem-cell transplantation is the only conditions. In Haemoglobinopathy Diagnosis, 2nd Edition. Wiley-
available curative approach for thalassemia, it has been Blackwell. Oxford; 2006:63-138.
limited by the high cost and the scarcity of HLA-matched, 2. Galanello R, Origa R.Beta-thalassemia. Orphanet Journal of Rare
related donors.24 The outcome of BMT is related to Diseases 2010, 5:11. doi: 10.1186/1750-1172-5-11. Crossref
the pretransplantation clinical conditions, specifically 3. Flint J, Harding RM, Boyce AJ, Clegg JB: The population genetics
the presence of hepatomegaly, extent of liver fibrosis, of the hemoglobinopathies. Bailliere's Clinical Hematology
history of regular chelation and hence severity of iron 1998;11:1-50. Crossref
accumulation. In patients without the above risk factors, 4. Vichinsky EP: Changing patterns of thalassemia worldwide. Ann N
stem cell transplantation from an HLA identical sibling has Y Acad Sci 2005;1054:18-24. Crossref
a disease free survival rate over 90%.2 If transplantation is 5. Madan N, Sharma S, Sood SK, Colah R, Bhatia HM. Frequency of
successful, transfusions and usually chelation therapy, are Beta thalassaemia and other Haemoglobinopathies in Northern and
Western India. Indian J Hum Genet 2010;16:16-25. Crossref
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6. Khan WA. Thalassemia in Bangladesh. DS (Children) Hosp J
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