Thalassemia

From Wikipedia, the free encyclopedia

Thalassemia
Classification and external resources
ICD-10
D56
ICD-9
282.4
141800 141850 142310 604131
OMIM
141800 141850 142310 604131
DiseasesDB 448 33334 33678 3087
MedlinePlus 000587
article/958850 article/206490
eMedicine
article/955496 article/396792
Patient UK Thalassemia
MeSH
D013789
Alpha-Thalassemia
GeneReviews
Beta-Thalassemia
Thalassemia (British English: thalassaemia) are forms of inherited autosomal recessive
blood disorders that originated in the Mediterranean region. In thalassemia, the disorder
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 have fewer circulating red blood cells than normal, which results in mild
or severe anemia. Thalassemia will be present as microcytic anemia.
Thalassemia can cause significant complications, including iron overload, bone
deformities and cardiovascular illness. However this same inherited disease of red blood
cells may confer a degree of protection against malaria (specifically, malaria caused by
the protozoan parasite Plasmodium falciparum), which is or was prevalent in the regions
where the trait is common. This selective survival advantage of 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.[1] [2]

Contents

1 Signs and symptoms

2 Cause
o 2.1 Evolution
3 Pathophysiology
o 3.1 Alpha () thalassemias

3.2 Beta () thalassemia

3.3 Delta () thalassemia
3.4 Combination with other hemoglobinopathies
4 Management
o 4.1 Medications
o 4.2 Carrier detection
o 4.3 Bone marrow transplant
5 Epidemiology
6 Etymology
7 Society and culture
8 References
9 External links
o
o
o

Signs and symptoms

Iron overload: People with thalassemia can get an overload of iron in their bodies,
either from the disease itself or from frequent blood transfusions. 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.[3]
Infection: people with thalassemia have an increased risk of infection. This is
especially true 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, such as 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.[4]

Cause

Thalassemia has an autosomal recessive pattern of inheritance

Both and thalassemias are often inherited in an autosomal recessive manner, 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 -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 hemoglobinopathy trait, there is a 25% risk with each
pregnancy for an affected child. Genetic counseling and genetic testing is recommended
for families that carry a thalassemia trait.
There are an estimated 60-80 million people in the world carrying the beta thalassemia
trait.[citation needed] This is a rough estimate; the actual number of those thalassemia major is
unknown due to the prevalence of thalassemia in less developed countries.[citation needed]
Countries such as Nepal, Bangladesh and Pakistan are seeing a large increase of
thalassemia patients due to lack of genetic counseling and screening.[citation needed] 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.[citation needed] There are an estimated 1,001 people living with thalassemia major in
the United States and an unknown number of carriers.[citation needed] Because of the
prevalence of the disease in countries with little knowledge of thalassemia, access to
proper treatment and diagnosis can be difficult.[citation needed]

Evolution
Having a single gene for thalassemia may protect against malaria and thus be an
advantage.[5]
People diagnosed with heterozygous (carrier) thalassemia have some protection against
coronary heart disease.[6]

Pathophysiology

Normally, the majority of adult hemoglobin (HbA) is composed of four protein chains,
two and two globin chains arranged into a heterotetramer. In thalassemia, patients
have defects in either the or globin chain causing production of abnormal red blood
cells (In sickle-cell disease, the mutation is specific to globin).
The thalassemias are classified according to which chain of the hemoglobin molecule is
affected. In thalassemias, production of the 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 chains are
encoded by two closely linked genes on chromosome 16.[7] Thus, in a normal person with
two copies of each chromosome, there are two loci encoding the chain, and four loci
encoding the chain. Deletion of one of the loci has a high prevalence in people of
African or Asian descent, making them more likely to develop thalassemias.
Thalassemias are not only common in Africans, but also in Greeks and Italians.

Alpha () thalassemias
Main article: Alpha-thalassemia
The thalassemias involve the genes HBA1[8] and HBA2,[9] inherited in a Mendelian
recessive fashion. There are two gene loci and so four alleles. It is also connected to the
deletion of the 16p chromosome. Thalassemias result in decreased alpha-globin
production, therefore fewer alpha-globin chains are produced, resulting in an excess of
chains in adults and excess chains in newborns. The excess chains form unstable
tetramers (called Hemoglobin H or HbH of 4 beta chains), which have abnormal oxygen
dissociation curves.

Beta () thalassemia
Main article: Beta-thalassemia
Beta thalassemias are due to mutations in the HBB gene on chromosome 11,[10] also
inherited in an autosomal-recessive fashion. The severity of the disease depends on the
nature of the mutation. Mutations are characterized as either o or thalassemia major if
they prevent any formation of chains, the most severe form of thalassemia; as either
+ or thalassemia intermedia if they allow some chain formation to occur; or as
thalassemia minor if only one of the two globin alleles contains a mutation, so that
chain production is not terribly compromised and patients may be relatively
asymptomatic.

Delta () thalassemia
It has been suggested that Delta-thalassemia be merged into this article.
(Discuss) Proposed since March 2014.
Main article: 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.[citation needed]

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/o thalassemia causes a moderately severe hemolytic anemia with
splenomegaly; hemoglobin C/+ thalassemia produces a milder disease.
hemoglobin D/thalassemia, common in north west parts of India and Pakistan
(Punjab region)

Management
Main article: Management of thalassemia
Mild thalassemia: people with thalassemia traits do not require medical or follow-up care
after the initial diagnosis is made.[11] People with -thalassemia trait should be warned
that their condition can be misdiagnosed as the more common iron deficiency anemia.
They should avoid routine use of iron supplements; yet iron deficiency can develop
during pregnancy or from chronic bleeding.[12] 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.[13]
Severe thalassemia: People with severe thalassemia require medical treatment. A blood
transfusion regimen was the first measure effective in prolonging life.[11]

Medications
Multiple blood transfusions can result in iron overload. The iron overload related to
thalassemia may be treated via chelation therapy with the medications deferoxamine,
deferiprone or deferasirox.[14] These treatments have resulted in improved life expectancy
in those with thalassemia major.[14]
Deferoxamine is only effective via daily injections which makes its long term use more
difficult. It has the benefit of being inexpensive and decent long term safety. Adverse
effects are primary skin reactions around the injection site and hearing loss.[14]

Deferasirox has the benefit of being an oral medication. Common side effects include:
nausea, vomiting and diarrhea. It however is not effective in everyone and is probably not
suitable in those with significant cardiac issues related to iron overload. The cost is also
significant.[14]
Deferiprone is given as an oral medication. Nausea, vomiting and diarrhea is relatively
common with its use. While available in Europe as of 2010 it is not available in North
America. It appears to be the most effective agent when the heart is significantly
involved.[14]

Carrier detection

A screening policy exists in Cyprus to reduce the incidence of thalassemia, which

since 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.[15]
In Iran as a premarital screening, the man's red cell indices are checked first, if he
has microcytosis (mean cell hemoglobin < 27 pg or mean red cell volume < 80 fl),
the woman is tested. When both are microcytic their hemoglobin A2
concentrations are measured. If both have a concentration above 3.5% (diagnostic
of thalassemia trait) they are referred to the local designated health post for
genetic counseling.[16]

Bone marrow transplant

Bone marrow transplantation may offer the possibility of a cure in young people who
have an HLA-matched donor.[17] Success rates have been in the 8090% range.[17]
Mortality from the procedure is about 3%.[18]
If the person does not have an HLA-matched compatible donor such as the first curative
method requires, there is another curative method called Bone Marrow
Transplantation(BMT) from haploidentical mother to child (mismatched donor), in which
the donor is the mother. It was invented in 2002 by Dr. Pietro Sodani. The results are
these: thalassemia-free survival rate 70%, rejection 23%, and mortality 7%. The best
results are with very young patients.[19]

Epidemiology
The beta form of thalassemia is particularly prevalent among Mediterranean peoples and
this geographical association is responsible for its naming[citation needed]. Globally in 2010 it
resulted in about 18,000 deaths.[20]
In Europe, the highest concentrations of the disease are found in Greece, coastal regions
in Turkey (particularly the Aegean Region such as Izmir, Balikesir, Aydin, Mugla, and
Mediterranean Region such as Antalya, Adana, Mersin), in parts of Italy, particularly
Southern Italy and the lower Po valley. The major Mediterranean islands (except the

Balearics) such as 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 high rates of thalassemia, including people from West Asia 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 in Africa, the Americas and also, in Tharu
people in the Terai region of Nepal and India.[21] It is believed to account for much lower
malaria sicknesses and deaths,[22] accounting for the historic ability of Tharus to survive
in areas with heavy malaria infestation, where others could not. Thalassemias are
particularly associated with people of Mediterranean origin, Arabs (especially
Palestinians and people of Palestinian descent), and Asians.[23] The Maldives has the
highest incidence of Thalassemia in the world with a carrier rate of 18% of the
population. The estimated prevalence is 16% in people from Cyprus, 1%[24] in Thailand,
and 38% in populations from Bangladesh, China, India, Malaysia and Pakistan.
Thalassemias also occur in descendants of people from Latin America and Mediterranean
countries (e.g. Greece, Italy, Portugal, Spain, and others).

Etymology
The name of this condition derives from the Greek Thalassa (), sea, and haema
(), blood. The term was first used in 1932.

Society and culture

In 2008, in Spain, a baby was selectively implanted in order to be a cure for his brother's
thalassemia. The child was born from an embryo screened to be free of the disease before
implantation with in vitro fertilization. The baby's supply of immunologically compatible
cord blood was saved for transplantation to his brother. The transplantation was
considered successful.[25] In 2009, a group of doctors and specialists in Chennai and
Coimbatore registered the successful treatment of thalassemia in a child using an
unaffected sibling's umbilical cord blood.[26]