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Review Article
An Overview on ThalassemiaSathi babu Talluri1 *, Vishnu datta2, Siva girish babu Guttula3
1Department of Pharmaceutics, Aditya college of Pharmaceutical Sciences and Research, Surampalem,
East Godavari District, Andhra Pradesh, India.
2Department of Pharmaceutics, JSS College of Pharmacy, Mysore, Karnataka, India.
3Department of Pharmaceutics, SRM College of Pharmacy, Potheri, Kanchipuram District, TN, India.
Email id:[email protected]
Article Received on: 25/06/13, Revised on: 02/06/2013, Approved for publication: 08/07/2013
Abstract
Thalassemia is a form of inherited autosomal recessive blood disorders that originated inthe Mediterranean region. In thalassemia, the disease is caused by the weakening and destruction of red
blood cells. Thalassemia is caused by variant or missing genes that affect how the body makes
hemoglobin. Hemoglobin is the protein in red blood cells that carries oxygen. People with thalassemia
make less hemoglobin and fewer circulating red blood cells than normal, which results in mild orsevere anemia. Thalassemia will present as microcytic anemia which may be differentiated from iron
deficiency anemia using the mentzer index calculation. Thalassemia can cause significant complications,including iron overload, bone deformities and cardiovascular illness. However this same inherited diseaseof red blood cells may confer a degree of protection against malaria, which is or was prevalent in the
regions where the trait is common. This selective survival advantage on carriers (known as heterozygous
advantage) may be responsible for perpetuating the mutation in populations. In that respect, the various
thalassemias resemble another genetic disorder affecting hemoglobin, sickle-cell disease.
The thalassemia is classified according to which chain of the hemoglobin molecule is affected. In thalassemias, production of the globin chain is affected, while in thalassemiaproduction of the globin
chain is affected.Key words:Thalassemia, Autosomal, Variants, Microcytic anemia, Heterozygous.
IntroductionThalassemia is forms of inherited autosomal
recessive blood disorders that originated in
the Mediterranean region. In thalassemia, thedisease is caused by the weakening anddestruction of red blood cells. Thalassemia is
caused by variant or missing genes that affect
how the body makes hemoglobin.
Address for correspondence:
Sathi babu Talluri
E mail: [email protected]
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Hemoglobin is the protein in red blood cells thatcarries oxygen. People with thalassemia make
less hemoglobin and fewer circulating red blood
cells than normal, which results in mild orsevere anemia. Thalassemia will presentas microcytic anemia which may be
differentiated from iron deficiency anemia using
the mentzer index calculation.Thalassemia can cause significant
complications, including iron overload, bonedeformities and cardiovascular illness. Howeverthis same inherited disease of red blood cells
may confer a degree of protection
against malaria, which is or was prevalent in theregions where the trait is common. This selective
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survival advantage on carriers (known
as heterozygous advantage) may be responsiblefor perpetuating the mutation in populations. Inthat respect, the various thalassemias resemble
another genetic disorder affecting
hemoglobin, sickle-cell disease.[1]
[2]
Epidemiology
The beta form of thalassemia is particularlyprevalent among Mediterranean peoples and this
geographical association is responsible for itsnaming. In Europe, the highest concentrations of
the disease are found in Greece, coastal regionsin Turkey (particularly the Aegean Region suchas Izmir, Balikesir, Aydin, Mugla,and Mediterra
nean Region such as Antalya, Adana, Mersin), in
parts of Italy, particularly Southern Italy and thelower Po valley. The major Mediterranean
islands (except the Balearics) suchas Sicily, Sardinia, Malta. Corsica, Cyprus,
and Crete are heavily affected in particular.Other Mediterranean people, as well as those in
the vicinity of the Mediterranean, also have highrates of thalassemia, including people from WestAsia and North Africa. Far from the
Mediterranean, South Asians are also affected,
with the world's highest concentration of carriers(16% of the population) being in the Maldives.
Nowadays, it is found in populations living inAfrica, the Americas and also, in Tharu in
the Terairegion of Nepal and India.
[3]
It isbelieved to account for much lower malaria
sicknesses and deaths,[4]accounting for the
historic ability of Tharus to survive in areas withheavy malaria infestation, where others couldnot. Thalassemias are particularly associated
with people of Mediterranean origin, Arabs
(especially Palestinians and people of Palestiniandescent), and Asians.
[5]
The Maldives has the highest
incidence of Thalassemia in the world with acarrier rate of 18% of the population. The
estimated prevalence is 16% in peoplefrom Cyprus, 1%[6]
in Thailand, and 3-8% inpopulationsfrom Bangladesh, China, India, Malaysia and Pa
kistan. Thalassemias also occur in descendants of
people from Latin America and Mediterraneancountries (e.g. Greece, Italy, Portugal, Spain, and
others).
PathophysiologyNormally, hemoglobin is composed of
four protein chains, two and two globinchains arranged into a heterotetramer. In
thalassemia, patients have defects in either or
globin chain (unlike sickle-cell disease, whichproduces a specific mutant form of globin),
causing production of abnormal red blood cells.
Classification
The thalassemiasare classifiedaccording to which chain of the hemoglobinmolecule is affected. In thalassemias,
production of globin chain is affected, while in thalassemia production of the globin chain is
affected.
The globin chains are encoded by a
single gene on chromosome 11; globin chainsare encoded by two closely linked genes onchromosome 16. Thus, in a normal person with
two copies of each chromosome, thereare twoloci encoding the chain, andfourloci
encoding the chain. Deletion of one of the
loci has a high prevalence in people of African orAsian descent, making them more likely todevelop thalassemias. Thalassemias are not
only common in Africans, but also in Greeks andItalians.
Alpha () thalassemias
The thalassemias involve the genesHBA1[7]and HBA2,[8]inherited in a Mendelianrecessivefashion. There are two gene locii and so
four alleles. It is also connected to the deletion of
the 16p chromosome. Thalassemias result indecreased alpha-globin production, thereforefewer alpha-globin chains are produced, resulting
in an excess of chains in adults and excess
chains in newborns. The excess chains formunstable tetramers (called Hemoglobin H or HbH
of 4 beta chains), which have abnormal oxygendissociation curves.
Alpha-thalassemia is due to impairedproduction of 1, 2, 3 or 4 alpha globin chains,
leading to a relative excess of beta globin chains.The degree of impairment is based on whichclinical phenotype is present (how many chains
are affected).
It is most commonly inherited in aMendelian recessive fashion. It is also connected
to the deletion of the 16p chromosome. It can
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also be acquired, under rare
circumstances.[9]
Due to the low occurrence ofalpha-thalassemia, the disease can be mistakenfor iron deficiency anemia.[10]
Beta () thalassemia
Beta thalassemias are due tomutations in the HBB gene on chromosome
11,[11]
also inherited in an autosomal-recessivefashion. The severity of the disease depends on
the nature of the mutation. Mutations arecharacterized as either oor thalassemia major
if they prevent any formation of chains, themost severe form of thalassemia. Also, they arecharacterized as +or thalassemia intermedia if
they allow some chain formation to occur. In
either case, there is a relative excess of chains,but these do not form tetramers: Rather, they
bind to thered blood cell membranes, producingmembrane damage, and at high concentrations
they form toxic aggregates.Beta-thalassemia is a hereditary
disease affecting the hemoglobin which makesred blood cells red. As with about half of allhereditary diseases,[12]the inherited DNA
mutation causes errors in assembling the working
gene or messenger-type RNA (mRNA) that istranscribed from a chromosome's long strand of
DNA. In thalassemia, the working gene (mRNA)assembly error typically consists of not finding
the (mutated) boundary between the intronic andextronic portions of the DNA strand (as reflected
in the raw mRNA transcript), and consequently
including an additional, contiguous length ofnon-coding instructions into the mRNA, oradding just a discontinuous fragment of
it.[13]Because all the correct instructions can be
present, sometimes normal hemoglobin isproduced and the added genetic material, if itproduces pathology, interferes with the
regulation of desired levels of proteinproduction, enough to ultimately produce
anemia. Normal adult hemoglobin contains 2alpha and 2 beta subunits. Thalassemias typicallyaffect only the mRNAs for production of the betachains, hence the term "beta-thalassemia". Since
the mutation that prevents the spliceosome from
finding the correct boundary between intronicand extronic portions of the raw RNA transcript
can be a change in only a single DNA letter(a "Single Nucleotide Polymorphism" or SNP),
there are on-going efforts to find gene therapies
able to correct it.[14]
Symptoms and Prolonged DisordersExcess amounts of iron overload
within the body causes serious complications
within the liver, heart, and endocrine glands.Severe symptoms include liver cirrhosis, liver
fibrosis, and in extreme cases liver cancer. Heartfailure, growth impairment, diabetes, and
osteoporosis are major life threateningcontributors brought upon by TM. The main
cardiac abnormalities seen to have resulted fromThalassemia and iron overload, include,specifically left ventricular systolic and diastolic
dysfunction, pulmonary hypertension,
valveulopathies, arrhythmias, andpericarditis. [15][16]
Factors Affecting the Regulation of IronAbsorption:The regulation of iron absorption
within the gut ultimately depends upon 3 factors.The first factor consists of the degree of impaired
red-blood cell production that has taken placewithin the body. The second factor respectivelycorrelates with the degree of iron overload within
the blood. In continuation with this iron
overload, the third factor deals with theexpression and balance of Fpn 1 and Hamp 1
proteins controlling ferroportin levels in the gutrespectively. Since iron loading depends on the
volume of blood transfused and the amount ofiron accumulated from the food displaced in the
gut, these factors are significantly important in
the regulation of total iron absorption within thehuman body.
[17]
Delta () thalassemia
As well as alpha and beta chains present
in hemoglobin, about 3% of adult hemoglobin is
made of alpha and delta chains. Just as with beta
thalassemia, mutations that affect the ability of
this gene to produce delta chains can occur.
Relationship with beta thalassemia
The importance of recognizing theexistence of delta thalassemia is seen best in
cases where it may mask the diagnosis of beta
thalassemia trait. In beta thalassemia, there is anincrease in hemoglobin A2, typically in the range
of 4-6% (normal is 2-3%). However, the co-existence of a delta thalassemia mutation will
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decrease the value of the hemoglobin A2 into thenormal range, thereby obscuring the diagnosis ofbeta thalassemia trait.[20]This can be important in
genetic counseling, because a child who is the
product of parents each of whom has bethalassemia trait has a one in four chance ofhaving beta thalassemia major.
In combination with other
hemoglobinopathies
Thalassemia can co-exist with other
hemoglobinopathies. The most common of these
are:
Hemoglobin E/thalassemia: common
in Cambodia, Thailand, and parts of India;
clinically similar to thalassemia major or
thalassemia intermedia.
Hemoglobin S/thalassemia, common in
African and Mediterranean populations;
clinically similar to sickle cell anemia, with
the additional feature of splenomegaly
Hemoglobin C/thalassemia: common in
Mediterranean and African populations,hemoglobin C/othalassemia causes amoderately severe hemolytic anemia withsplenomegaly; hemoglobin C/+thalassemia
produce a milder disease.
Both and thalassemias are often
inherited in anautosomal recessive fashion,
although this is not always the case. Cases
of dominantly inherited and thalassemias
have been reported, the first of which was in an
Irish family with two deletions of 4 and 11 bp in
exon 3 interrupted by an insertion of 5 bp in the
Causes
-globin gene. For
the autosomal recessive forms of the disease,
both parents must be carriers in order for a child
to be affected. If both parents carry a
Name
[18,19]Description Alleles
Thalassemia
minor
Only one of globin alleles bears a mutation. Individuals will suffer frommicrocyticanemia. Detection usually involves lower than normal MCV value (3.5%) and a decrease in fractionof Hemoglobin A (
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hemoglobinopathy trait, there is a 25% risk with
each pregnancy for an affected child. There are
an estimated 60-80 million people in the world
carrying the beta thalassemia trait alone. This is
a very rough estimate; the actual number
of thalassemia major patients is unknown due to
the prevalence of thalassemia in less developed
countries. Countries such as India and Pakistan
are seeing a large increase of thalassemia
patients due to lack of genetic counseling and
screening. There is growing concern that
thalassemia may become a very serious problem
in the next 50 years, one that will burden the
world's blood bank supplies and the health
system in general. There are an estimated 1,001
people living with thalassemia major in theUnited States and an unknown number of
carriers. Because of the prevalence of the
disease in countries with little knowledge of
thalassemia, access to proper treatment and
diagnosis can be difficult.
Complications
Iron overload: People with thalassemia can get
an overload of iron in their bodies, either from
the disease itself or from frequent bloodtransfusions. Too much iron can result in
damage to the heart, liver and endocrine system,
which includes glands that produce hormones
that regulate processes throughout the body. The
damage is characterized by excessive deposits of
iron. Without adequate iron chelation therapy,
almost all patients with beta-thalassemia will
accumulate potentially fatal iron levels.[21]
Infection: People with thalassemia have an
increased risk of infection. This is especiallytrue if the spleen has been removed.
Bone deformities: Thalassemia can make
the bone marrow expand, which causes
bones to widen. This can result in abnormal
bone structure, especially in the face and
skull. Bone marrow expansion also makes
bones thin and brittle, increasing the risk of
broken bones.
Enlarged spleen: the spleen aids in fighting
infection and filters unwanted material, suchas old or damaged blood cells. Thalassemia
is often accompanied by the destruction of a
large number of red blood cells and the task
of removing these cells causes the spleen to
enlarge. Splenomegaly can make anemia
worse, and it can reduce the life of
transfused red blood cells. Severe
enlargement of the spleen may necessitate
its removal.
Slowed growth rates: anemia can cause a
child's growth to slow. Puberty also may be
delayed in children with thalassemia.
Heart problems: such as congestive heart
failure and abnormal heart rhythms
(arrhythmias), may be associated with
severe thalassemia.[22]
Benefits: Epidemiological evidence
from Kenya suggests another reason: protection
against severe malarial anemia may be the
advantage.[23]
People diagnosed
with heterozygous (carrier) thalassemia havesome protection against coronary heart
disease.[24]
Medical care
Mild thalassemia: patients with
thalassemia traits do not require medical or
follow-up care after the initial diagnosis is
made.[25]Patients with -thalassemia trait should
be warned that their condition can be
misdiagnosed for the common Iron deficiencyanemia. They should eschew empirical use
of Iron therapy; yet iron deficiency can develop
during pregnancy or from chronic
bleeding.[26]Counseling is indicated in all
persons with genetic disorders, especially when
the family is at risk of a severe form of disease
that may be prevented.[27]
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Severe thalassemia: Patients with severe
thalassemia require medical treatment. A blood
transfusion regimen was the first measure
effective in prolonging life.[25]
Drug treatment
Patients with thalassemia gradually
accumulate high levels of iron (Fe) in their
bodies. This build-up of iron may be due to the
disease itself, from irregular hemoglobin not
properly incorporating adequate iron into its
structure, or it may be due to the many blood
transfusions received by the patient. This
overload of iron brings with it many biochemical
complications.
Two key players involved in iron
transport and storage in the body
are ferritin and transferrin. Ferritin is a protein
present within cells that binds to Fe (II) and
stores it as Fe (III), releasing it into the blood
whenever required. Transferrin is an iron-
binding protein present in blood plasma;
transferrin acts as a transporter, carrying iron
through blood and providing cells with the metal
through endocytosis. Transferrin is highly
specific to iron (III), and binds to it withan equilibrium constant of 1023M1 at a pH of
7.4.[28]
Thalassemia results in non-transferrin-
bound iron being available in blood as all the
transferrin becomes fully saturated. This free
iron is toxic to the body since it catalyzes
reactions that generate free
hydroxyl radicals.[29]These radicals may
induce lipid peroxidation of organelles like
lysosomes, mitochondria, and sarcoplasmicmembranes. The resulting lipid peroxides may
interact with other molecules to form cross links,
and thus either cause these compounds to
perform their functions poorly, or render them
non-functional altogether.[29]
This iron overload may be treated with
chelation therapy.Deferoxamine, Deferiprone
and Deferasiroxare the three most widely used
iron-chelating agents.
Deferoxamine
Administration and action
Deferoxamine is administered
via intravenous, intramuscular, or subcutaneous
injections. Oral administration is not possible as
deferoxamine is rapidly metabolized by enzymes
and is poorly absorbed from the gastrointestinal
tract. The required parenteral administration
represents one of deferoxamines downfalls as it
is harder for patients to follow up with their
therapy due to the financial and emotionalburdens experienced.
[30]Deferoxamine was
proven to cure many clinical complications and
diseases that result from iron overload. It
beneficially affects cardiac disease, such as
myocardial disease which occurs as a result of
iron accumulation in the heart.[31]
Deferoxamine
was also shown to improve liver function by
arresting the development ofhepatic
fibrosis which occurs as a result of iron
accumulation in the liver.[32]Deferoxamine also
has positive effects on endocrine function and
growth. Endocrine abnormalities in thalassemic
patients involve the overloaded iron interfering
with the production of insulin-like growth factor
(IGF-1), as well as stimulating hypogonadism,
both of which cause poor pubertal growth. A
study showed that 90% of patients who were
regularly treated with deferoxamine since
childhood had normal pubertal growth, which
fell to 38% for patients treated only with low
doses of deferoxamine since theirteens.[29]Another endocrine abnormality that
thalassemic patients face is diabetes mellitus,
which results from iron overload in the pancreas
impairing insulinsecretion. Studies have shown
that patients who were regularly treated with
deferoxamine have a reduced risk of developing
diabetes mellitus.[33]
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Side effects
Deferoxamine could lead to toxic side
effects if doses greater than 50 mg/kg body
weight are administered. These side effects mayinclude auditory and ocular
abnormalities, pulmonary
toxicity, sensorimotor neurotoxicity, as well as
changes in renal function.[29]
Another toxic
effect of deferoxamine mostly observed in
children is the failure of linear growth. The toxic
effect of deferoxamine on linear growth could
also be due to excess deferoxamine
accumulating in tissues and interfering with
iron-dependent enzymes which are involved inthe post-translational modification of
collagen.[34]
Patients who receive vitamin
C supplements have shown improved iron
excretion by deferoxamine. This occurs due to
the expansion of the iron pool brought about by
vitamin C, which deferoxamine subsequently
has access to. However, vitamin C
supplementation could also worsen iron toxicity
by promoting the formation of free radicals.
Therefore, only 100 mg of vitamin C should be
taken 30 minutes to one hour after deferoxamine
administration.[35]
It has also been proven that
combined treatment with deferoxamine and
deferiprone leads to an increased efficiency in
chelation and doubles iron excretion.[36]
Deferiprone
Administration and action
Deferiprone is an iron chelator that is
orally active, its administration thus being much
easier than that for
deferoxamine.[37]Plasma levels for the iron-drug
complex climax after one hour of intake and the
drug has a half-life of 160 minutes. Most of the
iron-drug complex is therefore excreted within
three to four hours following administration,
the excretion occurring mostly in urine
(90%).[37]
When comparing deferiprone to
deferoxamine, it should be noted that they bothbind iron with similar efficiency. However,
drugs with different properties are able to access
different iron pools. DFP is smaller than
deferoxamine and can thus enter cells more
easily. Also, at the pH of blood, the affinity of
DFP for iron is concentration dependent: at low
DFP concentrations, the iron-drug complex
breaks down and the iron is donated to another
competing ligand. This property accounts for the
observed tendency of DFP to redistribute iron in
the body. For the same reason, DFP can shuttle
intracellular iron out to the plasma, and transfer
the iron to deferoxamine which goes on to expel
it from the body.[38]
DFP was also found to be significantly
more effective than deferoxamine in treating
myocardial siderosis in patients with thalassemia
major:[37]
DFP is thought to improve the
function of mitochondria in the heart by
accessing and redistributing labile iron in
cardiac cells.
Thalassemia patients may also be faced
with potential oxidative damage to brain cells as
the brain has high oxygen demands, but contains
relatively low levels of antioxidant agents for
protection against oxidation. The presence of
excess iron in the brain may lead to higher
concentrations of free radicals.
Hexadentate chelators, like deferoxamine, are
large molecules, and are thus unlikely to be able
to cross the blood-brain barrier to chelate the
excess iron. DFP, however, can do so and forms
a soluble, neutral iron-drug complex that can
cross cell membranes by non-
facilitated diffusion. Attaching the drug to
sugars may additionally enhance the penetration
of the blood-brain barrier, as the brain
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uses facilitated transport for its relatively high
levels of sugar intake.[40]
Side effects
DFP can be subjected
to glucuronidation in the liver, which may expel
as much as 85% of the drug from the body
before it has had a chance to chelate iron. DFP
also has a well-known safety profile,
withagranulocytosis being the most serious side
effect.[37]While agranulocytosis has been
reported in less than 2% of patients treated, it is
potentially life threatening and thus requires
close monitoring of the white blood cell
count.[39]Less serious side effects include
gastrointestinal symptoms, which were found in33% of patients in the first year of
administration, but fell to 3% in following
years; arthralgia; and zinc deficiency, with the
latter being a problem especially for individuals
with diabetes.[37]
Deferasirox
Administration and action
Deferasirox is most commonly marketed
under the brand name Exjade. It has one key
advantage over desferoxamine in that it can be
taken orally in pill form, and so does not
require intravenous or subcutaneous administrati
on. With a terminal elimination half-life of 816
hours, the deferasirox pill can be taken just once
every day. A once-daily dose of 20 mg/kg of
body weight has been found to be sufficient for
most patients for the maintenance of liver iron
concentration (LIC) levels, which are usually
measured as mg of iron per g of liver tissue.
Larger doses may be required for some patientsin order to reduce LIC levels.
[41] In a study by
Cappellini et al. it was shown that children
receiving the treatment displayed continual near-
normal growth and development over a 5-year
study period.[42]
Side effects
Deferasirox can, however, have a
wide variety of side effects. These may include
headaches, nausea, vomiting, and joint
pains.[43]
Some evidence has been shown of alink to gastrointestinal disorders experienced by
some people who have received the treatment.[42]
Indicaxanthin
Function
Hb undergoes the following oxidation reaction
during normal controlled breakdown of RBCs:
Hb Oxy-Hb Met-Hb [Perferryl-Hb]
Oxoferryl further oxidation steps
This reaction is experienced by
thalassemic RBCs to a greater extent because,
not only are there more oxidative radicals in
thalassemic blood, but thalassemic RBCs also
have limited antioxidant defense. Indicaxanthin
is able to reduce the perferryl-Hb, a reactive
intermediate, back to met-Hb. The overall effect
of this step is that Hb degradation is prevented,
which helps prevent accelerated breakdown of
RBCs.[44]
In addition, indicaxathin has been shownto reduce oxidative damage in cells and tissues
and does so by binding to radicals. The
mechanism of its function, however, is still
unknown.[44] Indicaxanthin has high
bioavailability and minimal side effects, like
vomiting or diarrhea.
Carrier detection
A screening policy exists in Cyprus to
reduce the incidence of thalassemia, whichsince the program's implementation in the
1970s (which also includes pre-natal
screening and abortion) has reduced the
number of children born with the hereditary
blood disease from 1 out of every 158 births
to almost zero.[45]
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In Iran as a premarital screening, the man's
red cell indices are checked first, if he
has microcytosis (mean cell hemoglobin
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