An Overview on Thalasemia

8/10/2019 An Overview on Thalasemia

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International Research Journal for Inventions in Pharmaceutical Sciences, July 2013 Vol 1 Issue 1 1

International Research Journal for Inventions in

Pharmaceutical Sciences

www.irjips.com

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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Sathi babu Talluri et al .An Overview on Thalassemia


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


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


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

An Overview on Thalasemia

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