INTRODUCTION:

Thalassemias are group of inherited blood disorders characterized by abnormal hemoglobin production¹ .The word thalassemiaderives from the Greek word “thalassa”, means "sea", and New Latin -emia (from Greek haema "blood"). It was named so because the condition called "Mediterranean anemia" was first described in people of Mediterranean ethnicities. "Mediterranean anemia" was renamed thalassemia major once the genetics were better understood. The word thalassemia was first used in 1932.^2,3

Symptoms depend on the type and can vary from none to severe.¹ Often there is mild to severe anemia (low red blood cells).⁴ Anemia can result in feeling tired and pale skin.⁴ There may also be bone problems, an enlarged spleen, yellowish skin, dark urine, and among children slow growth.⁴

Thalassemias are genetic disorders inherited from a person's parents.⁵ There are two main types, alpha thalassemia and beta thalassemia.¹

The severity of alpha and beta thalassemia depends on how many of the four genes for alpha globin or two genes for beta globin are missing.5 Diagnosis is typically by blood tests including a complete blood count, special hemoglobin tests, and genetic tests.⁶ Diagnosis may occur before birth through prenatal testing.

Treatment depends on the type and severity. Treatment for those with more severe disease often includes regular blood transfusions, iron chelation, and folic acid.⁷ Iron chelation may be done with deferoxamine or deferasirox.⁷ Occasionally, a bone marrow transplant may be an option.⁴Complications may include iron overload from the transfusions with resulting heart or liver disease, infections, and osteoporosis.⁴ If the spleen becomes overly enlarged, surgical removal may be required.⁴

As of 2013, thalassemia occurs in about 280 million people, with about 439,000 having severe disease.8 It is most common among people of Italian, Greek, Middle Eastern, South Asian, and African descent.1 Males and females have similar rates of disease.⁹It resulted in 16,800 deaths in 2015, down from 36,000 deaths in 1990.^10,11 Those who have minor degrees of thalassemia, similar to those with sickle-cell trait, have some protection against malaria, explaining why they are more common in regions of the world where malaria exists.¹²

Figure1: The hand of a person with severe anemia (left side) compared to one with out

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 accumulate potentially fatal iron levels.¹³

· Infection:

People with thalassemia have an increased risk of infection. This is especially true if the spleen has been removed.¹⁴

· 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.¹⁵

· 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. The child may develop normally according to their growth pattern until they are 9 or 10 years old, but the growth velocity begins to slow down after this.Puberty also may be delayed in children with thalassemia.¹⁶

· Pale or Jaundiced Appearance:

A person with thalassemia may seem pale and listless and the skin and whites of the eyes take on a jaundiced or yellowish color. Severe thalassemia as a result of beta thalassemia major or hemoglobin H disease tends to cause these symptoms. They appear especially among children under two years with the condition.

· Heart problems:

Diseases, such as congestive heart failure and abnormal heart rhythms, may be associated with severe thalassemia.¹⁷

· Enlarged or Affected Organs:

Certain organs tend to become enlarged in those with severe anemia. The liver, heart, or spleen may become larger than the normal size. Thalassemia tends to have the following effects on specific organs¹⁸:

· Heart:

Irregular heartbeat, cardiomyopathy or heart muscle problems that impact the heart’s ability to pump blood, and even heart failure

· Liver:

Swelling and scarring or cirrhosis

· Thyroid:

Hypothyroidism or an underactive thyroid and parathyroid glands

· Spleen:

Enlarged and less effective in its immune function

· Gallbladder:

Inflammation of the gallbladder or cholecystitis, gallstones, and abdominal pain

· Delayed Puberty And Impact on Sexual Health:

Those with thalassemia major also have to deal with endocrine dysfunction that affects growth and development. Hypogonadism, where the sex organs do not function properly, may also manifest due to excessive iron loading on the pituitary gland. Your body may produce lower levels of female sex hormone estrogen and male sex hormone testosterone. Puberty may be delayed or arrested. Secondary hypogonadism could develop when you are older. Women could find their menstrual periods suddenly stopping for several months, a condition called secondary amenorrhea. Men could see their sexual drive dip or may even have azoospermia, where their semen does not contain any sperm. These may affect fertility¹⁶.

· Diabetes:

One of the possible complications from thalassemia major is the development of diabetes. This could be due to the repeated blood transfusion, which strains the pancreas and damages it. Iron overload in the body may also hamper insulin production because it is toxic to pancreatic beta cells that make insulin. Some people with thalassemia also have insulin resistance linked to iron overload in the liver. So you could have insulin resistance, insulin deficiency, or both.

· Dark Colored Urine:

When your red blood cells break down, they may enter your urine stream. This causes you to pass dark colored urine. Experts warn that if it is colored like dark tea or cola, your body is breaking down more red blood cells than normal. Light brown or darker yellow urine is a result of the bilirubin produced when red blood cells break down and is common in those with thalassemia intermedia. It may also occur in those undergoing transfusions around the time they need their next transfusion⁴.

CAUSE:

The causes of thalassemia are:

· Inheriting abnormal and mutated genes involved in haemoglobin production from the parents

· If either of the parents is a carrier for thalassemia, an individual may become a carrier of the disease himself, though he will not have any symptoms. He may also develop what is called thalassemia minor in which case he may develop minor symptoms.

FACTORS THAT INCREASE THE RISK OF THALASSEMIA INCLUDE:

· Family history:

This condition is usually passed from parents to children through mutated haemoglobin genes. An individual is at an increased risk of having this condition if he have a family history of thalassemia.

· Certain regional ancestry:

Thalassemia is observed to predominantly occur most often among African-Americans and in people of Mediterranean and Southeast Asian ancestry.

PATHOPHYSIOLOGY¹⁸

· Normally, the majority of adult hemoglobin (HbA) is composed of four protein chains, two α and two β globin chains arranged into a heterotetramer. In thalassemia, patients have defects in either the α or β globin chain, causing production of abnormal red blood cells (In sickle-cell disease, the mutation is specific to β globin

· The thalassemias are classified according to which chain of the hemoglobin molecule is affected. In α-thalassemias, production of the α globin chain is affected, while in β-thalassemia, production of the β globin chain is affected.

There are two primary forms of thalassemia:^19,20

· Alpha Thalassemia:

thalassemia occurs if there are problems with some or all of the alpha-globin genes. Normally, each person has four genes for alpha globin. Alpha thalassemia occurs when one or more of the genes that control the making of alpha globins is absent or defective.

There are four main types of Alpha Thalassemia disease:

· Alpha Thalassemia Major:

which is a very serious disease in which severe anemia begins even before birth. Pregnant women carrying affected fetuses are themselves at risk for serious pregnancy and delivery complications.

· Alpha Thalassemia Minor:

when children have two missing or mutated genes this condition is called alpha thalassemia minor. Children with this condition may have red blood cells that are smaller than normal and may also have slight anemia.

· Hemoglobin H disease:

If there are three missing or mutated genes it is called hemoglobin H disease. The symptoms can be moderate to severe.

· Silent Alpha Thalassemia Carrier:

If a child is missing one gene or has orne abnormal gene the child is a silent alpha thalassemia carrier. Silent alpha thalassemia carriers show no signs or symptoms of the disease, but can pass thalassemia on to their own children.

· Beta Thalassemia disease²¹:

Beta thalassemia occurs when there are problems with one or both of the beta-globin genes.This is the most common type of thalassemia. In Beta thalassemia, there is decreased production of normal adult haemoglobin (Hb A), which is the predominant type of haemoglobin in our bodies from birth to death. In people with beta thalassemia, low levels of haemoglobin lead to a lack of oxygen in many parts of the body.Two genes are involved in making the beta haemoglobin chain. You get one from each of your parents. If you inherit:

· A single mutated gene:

you have what is called thalassemia minor you'll have mild anemia, which is a slight lowering of the haemoglobin level in the blood. This situation can very closely resemble that with mild iron-deficiency anemia.

· Two mutated genes:

then you have what is called thalassemia major, or Cooley anemia. Babies with this condition usually have the symptoms of severe anemia in their first year of life. They do not possess the ability to produce normal, adult haemoglobin and constantly suffer from chronic fatigue. A milder form, called thalassemia intermedia, also may occur with two mutated genes.

DIAGNOSIS:

Thalassemia can be diagnosed via a complete blood count, hemoglobin electrophoresis, and DNA testing.²². A physical examination might also help the doctor to make a diagnosis.

Most children with moderate to severe thalassemia show signs and symptoms within their first two years of life. If the doctor suspects the child has thalassemia, he or she may confirm a diagnosis using blood tests.

If the child has thalassemia, blood tests may reveal:

· A low level of red blood cells

· Smaller than expected red blood cells

· Pale red blood cells

· Red blood cells that are varied in size and shape

· Red blood cells with uneven hemoglobin distribution, which gives the cells a bull's-eye appearance under the microscope

Blood tests may also be used to:

· Measure the amount of iron in your child's blood :

· Evaluate his or her hemoglobin

· Perform DNA analysis to diagnose thalassemia or to determine if a person is carrying mutated hemoglobin genes

Prenatal testing²³:

Testing can be done before a baby is born to find out if he or she has thalassemia and determine how severe it may be. Tests used to diagnose thalassemia in fetuses include:

· Chorionic villus sampling.:

This test is usually done around the 11th week of pregnancy and involves removing a tiny piece of the placenta for evaluation.

· Amniocentesis.:

This test is usually done around the 16th week of pregnancy and involves taking a sample of the fluid that surrounds the fetus.

Assisted reproductive technology:

A form of assisted reproductive technology that combines preimplantation genetic diagnosis with in vitro fertilization may help parents who have thalassemia or who are carriers of a defective hemoglobin gene give birth to healthy babies. The procedure involves retrieving mature eggs and fertilizing them with sperm in a dish in a laboratory. The embryos are tested for the defective genes, and only those without genetic defects are implanted into the uterus.

PREVENTION:

Prevention is the only measure that can drastically reduce the incidences of severe hemoglobinopathies (blood disorders). Prevention is what allowed countries like Italy, Greece, and Cyprus to go from historically high rates of thalassemia to almost none. In affluent areas the prevention of thalassemia is largely dependent on prenatal care.If newly pregnant couples come in for prenatal care, tests for blood disorders like thalassemia are conducted, amongst many other crucial exams to ensure the growth of a healthy embryo. If the new pregnancy is tested positive for thalassemia parents are counseled on their options, including early termination. This form of screening and prevention has been very effective so that no more than 20-30 new births with thalassemia occur in Italy yearly as opposed to the expected several hundreds.

The American College of Obstetricians and Gynecologists recommends all people thinking of becoming pregnant be tested to see if they have thalassemia.²⁴ Genetic counseling and genetic testing are recommended for families who carry a thalassemia trait.

A screening policy exists in Cyprus to reduce the rate of thalassemia, which, since the program's implementation in the 1970s (which also includes prenatal screening and abortion), has reduced the number of children born with the disease from one of every 158 births to almost zero.²⁴

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.²⁵

Large scale awareness campaigns are being organized in India²⁶ both by government and non-government organizations in favor of voluntary premarital screening to detect carriers of thalassemia and marriage between both carriers are strongly discouraged.

Figure 2: Preventive measures

MANAGEMENT:

Mild thalassemia: people with thalassemia traits do not require medical or follow-up care after the initial diagnosis is made.²⁷ People with β-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; iron deficiency can develop, though, during pregnancy or from chronic bleeding.²⁸Counseling 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.²⁹

Blood transfusions:

People with severe thalassemia require medical treatment. A blood transfusion regimen was the first measure effective in prolonging life.²⁷

Medications:

Multiple blood transfusions can result in iron overload. The iron overload related to thalassemia may be treated by chelation therapy with the medications deferoxamine, deferiprone, or deferasirox.³¹ These treatments have resulted in improving life expectancy in those with thalassemia major.³⁰

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.³⁰

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.³⁰

Deferiprone is a medication that is given by mouth. Nausea, vomiting, and diarrhea are relatively common with its use.³⁰It is available in both Europe and the United States.^30,31 It appears to be the most effective agent when the heart is significantly involved.³⁰

There is no evidence from randomized controlled trial to support zinc supplementation in thalassemia.³²

Bone marrow transplant:

Bone marrow transplantation may offer the possibility of a cure in young people who have an HLA-matched donor.³³Success rates have been in the 80–90% range.³³ Mortality from the procedure is about 3%.³⁴ There are no randomized controlled trials which have tested the safety and efficacy of non-identical donor bone marrow transplantation in persons with β- thalassemia who are dependent on blood transfusion.³⁵

If the person does not have an HLA-matched compatible donor, another method called bone marrow transplantation (BMT) from haploidentical mother to child (mismatched donor) may be used. In a study of 31 people, the thalassemia-free survival rate 70%, rejection 23%, and mortality 7%. The best results are with very young people.³⁶

LIFESTYLE AND HOME REMEDIES:

Thalassemia can be managed effectively by following the treatment plan and adopting healthy-living habits. The following tips will help:

· Avoid excess iron.

Unless your doctor recommends it, don't take vitamins or other supplements that contain iron.

· Eat a healthy diet.

Eating a balanced diet that contains plenty of nutritious foods can help you feel better and boost your energy. Your doctor also may recommend you take a folic acid supplement to help your body make new red blood cells. Also, to keep your bones healthy, make sure your diet contains adequate calcium and vitamin D. Ask your doctor what the right amounts are for you and whether you need to take a supplement.

· Avoid infections.:

Protect yourself from infections with frequent hand-washing and by avoiding sick people. This is especially important if you've had to have your spleen removed. You'll also need an annual flu shot, as well as the meningitis, pneumococcal and hepatitis B vaccines to prevent infections. If you develop a fever or other signs and symptoms of an infection, see your doctor for treatment.

EPIDEMIOLOGY:

The beta form of thalassemia is particularly prevalent among Mediterranean peoples, and this geographical association is responsible for its naming.³⁷ Thalassemia resulted in 25,000 deaths in 2013 down from 36,000 deaths in 1990.³⁸

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 (30% of the population) being in the Maldives.

Nowadays, it is found in populations living in Africa, the Americas, and in Tharu people in the Terai region of Nepal and India.³⁹It is believed to account for much lower malaria sicknesses and deaths,⁴⁰accounting 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.⁴¹ 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%⁴² in Thailand, and 3–8% in populations from Bangladesh, China, India, Malaysia and Pakistan. Thalassemias also occur in descendants of people from Mediterranean countries (e.g. Greece, Italy, Spain, and others), in Latin America.

Society and culture:

In 2008, in Spain, a baby was selectively implanted 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 vitrofertilization. The baby's supply of immunologically compatible cord blood was saved for transplantation to his brother. The transplantation was considered successful.⁴² 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.⁴³

SUMMARY POINTS:

· The changing demographic features of thalassaemia, with its widely variable phenotypes, have implications for diagnosis, counselling, and management

· Carriers of thalassaemia require no specific treatment but should be protected from iron supplementation, which may be detrimental

· Antenatal and neonatal screening for thalassaemia may reduce the number of severely affected children

· Monitoring iron overload and chelation therapy in transfusion dependent thalassaemia patients is essential to prevent fatal cardiomyopathy and liver cirrhosis

· The only potential cure for β thalassaemia is hematopoietic stem cell transplantation.

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Received on 17.05.2018 Accepted on 05.09.2018

Asian J. Pharm. Res. 2018; 8(3): 195-202.

DOI: 10.5958/2231-5691.2018.00034.5