Thalassaemia

What is thalassaemia?

Thalassaemia is the name given to a group of inherited blood disorders that affect the body’s ability to create red blood cells.

Red blood cells

Red blood cells are very important because they carry a protein called haemoglobin around the body. Haemoglobin transports oxygen from the lungs to the rest of the body.

Haemoglobin is produced in the bone marrow (a spongy material found inside larger bones) using the iron that our body takes from food.

In cases of thalassaemia, the bone does not produce haemoglobin, causing

and reduced oxygen-carrying capacity. If your body does not receive enough oxygen, you will feel tired, breathless, drowsy and faint. The most serious types of thalassaemia can cause other complications, including organ damage, restricted growth, liver disease, heart failure and death.

Types of thalassaemia

Thalassaemia is caused by alterations (mutations) in the genes that make haemoglobin.

Haemoglobin is made up of matching chains of proteins (which are named after Greek letters of the alphabet). To work properly, haemoglobin needs a pair of alpha chain and a pair of beta chain proteins.

A mutation that affects the alpha chain causes alpha thalassaemia, and a mutation that affects the beta chain causes beta thalassaemia.

Alpha thalassaemia

The alpha chain is produced by four genes, two on each chromosome 16, and the severity of the condition depends on how many of those genes have been mutated.

• If one gene is mutated, there is little or no effect.
• If two genes are mutated, there may be symptoms of mild anaemia. This condition is known as the alpha thalassaemia trait. If two people with the alpha thalassaemia trait have a child, there is a one-in-four chance the child will inherit the most severe form of alpha thalassaemia (see below).
• If three genes are mutated, the result will be a condition called haemoglobin H disease. People with haemoglobin H disease will have lifelong (chronic) anaemia and may require regular blood transfusions.
• If all four genes are mutated, the result will be the most severe form of alpha thalassaemia, known as alpha thalassaemia major. Infants with this condition are unable to produce normal haemoglobin and are unlikely to survive pregnancy. There have been some cases of unborn babies being treated with blood transfusions while still in the womb, but this type of treatment has a low success rate.

Beta thalassaemia

Beta thalassaemia can range from moderate to severe. The most severe form of the condition is known as beta thalassaemia major (BTM). People with BTM will require

for the rest of their life.

The milder form of the condition is known as beta thalassaemia intermedia (BTI), also referred to as non-transfusion dependent thalassaemia (NTDT). The symptoms of BTI will vary from person to person. Some will experience symptoms of mild anaemia while others will require blood transfusions.

Read more information about the

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Alpha thalassaemia is also found in the UK, particularly among people of South Asian, Southeast Asian and Mediterranean descent, and also amongst Africans. In Africans it is typically the mildest form of the condition. People of Southeast Asian and Mediterranean descent are at risk of producing alpha thalassaemia major (ATM) due to their more severe form of alpha thalassaemia.

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Who is affected

Pregnant woman are checked for inherited disorders during routine [antenatal screening]. Thalassaemia is also diagnosed using a

although further tests may be needed to tell which type it is.

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Treating thalassaemia

The only known cures for thalassaemia are a

and cord blood transplantations (using blood cells taken from an unborn baby carried by a mother who also has an older affected child). These procedures can cause other complications and are not suitable for everyone.

One of the biggest problems with BTM is that it requires frequent blood transfusions, which in turn can lead to a build-up of iron in the body. This can cause serious health problems.

People who receive regular blood transfusions for BTM must undergo treatment called chelation therapy to remove the excess iron from their body.

Read information about

.

It can be challenging to live with BTM as frequent check-ups are needed to assess the risk of possible complications.

can include:

• an enlarged spleen (hypersplenism) - the spleen has problems recycling red blood cells, making it grow larger
• hormone complications - including delayed puberty and restricted growth
• heart complications – such as an irregular or disturbed heartbeat (arrhythmia)
• liver complications – such as
  hepatitis
  (swelling of the liver) or an enlarged liver (fibrosis)
• bone complications- such as bone and joint pain and
  osteoporosis
  (a condition where the bones become thin and brittle)

Symptoms of thalassaemia

Most babies born with beta thalassaemia will not show symptoms until they are around six months old. This is because infants begin life with a different sort of haemoglobin, known as foetal haemoglobin. This haemoglobin is replaced by normal haemoglobin six months after birth.

Symptoms of beta thalassaemia are the same as

and include:

• growth delay and poor feeding
• fatigue
• weakness
• shortness of breath
• a yellow discoloration of the skin (
  jaundice
  )

Children with beta thalassaemia major (BTM) or severe beta thalassaemia intermediate (BTI) may also experience skeletal deformities (where bones grow in unusual ways), as their body tries to compensate for the lack of haemoglobin by producing more bone marrow.

Problems can also be caused by excessive iron as your body will absorb more iron from food. Iron can also build up from

. Too much iron can cause tissue damage, particularly to the liver and spleen, making the body more vulnerable to infection.

Iron can also affect the body’s hormonal system, meaning that the development of the body during puberty may be delayed, or never happen at all.

Left untreated, BTM puts an intolerable strain on the body, and children with the condition are unlikely to live for more than five years. Death is usually the result of heart failure or infection.

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Causes of thalassaemia

While it is not known exactly what causes genetic mutations associated with thalassaemia, they have survived for generations because carriers of thalassaemia (alpha or beta) are protected against malaria.

This is why thalassaemia, and other related genetic blood disorders such as

, are more common in parts of the world where malaria is prominent, such as:

• countries in the Mediterranean basin such as Greece, Cyprus and Italy
• the Middle East
• Asia
• Sub-Saharan Africa

How thalassaemia is inherited

Every person receives two sets of genes, one from their father and one from their mother. If a person receives one set of mutated genes, they will have the thalassaemia trait.

If they then have a baby with somebody who also has the thalassaemia trait, there is a significant chance the baby will receive two sets of mutated genes and develop thalassaemia.

The chances of the thalassaemia trait being passed on are outlined below.

• There is a one-in-four chance the baby will receive a pair of normal haemoglobin genes.
• There is a one-in-two chance the baby will receive one normal gene and one mutated gene. In this case, they will not have thalassaemia, but will have the thalassaemia trait.
• There is a one-in-four chance the baby will receive a pair of mutated genes and will have thalassaemia.

If one parent has the thalassaemia trait and the other parent has normal haemoglobin, their baby will not get thalassaemia. However, there is a one-in-two chance that the baby will receive the thalassaemia trait.

Beta thalassaemia affects the two genes that the body uses to produce the beta chain found in haemoglobin. (Haemoglobin needs both an alpha and beta chain to work properly.)

If only one gene is mutated, the result is the beta thalassaemia trait. This produces either mild symptoms of

or, more commonly, none at all.

Beta thalassaemia major (BTM) occurs when both genes that produce the beta chain mutate. People with BTM are unable to produce normal haemoglobin and will require regular

for the rest of their life.

How is thalassaemia diagnosed?

Thalassaemia can be diagnosed using a blood test. Further DNA testing of the blood may be required so the exact type of thalassaemia can be determined.

Antenatal screening

The purpose of [antenatal screening] (screening that is carried out during pregnancy) is to check for inherited disorders such as

and to provide parents with information they need to make informed decisions.

Antenatal screening for the thalassaemia trait is available in areas where the condition is most common. These are typically cities and towns with large South Asian communities. In areas where thalassaemia is uncommon, a questionnaire on family origin is used as an initial screening tool to assess the risk of thalassaemia.

Pregnant women are routinely screened for the thalassaemia trait. If they test positive their partner will also be offered the test. If both parents have the thalassaemia trait, there is a 1 in 4 chance their baby will have thalassaemia.

Further testing is available (if you want it) to confirm whether your baby will definitely be born with thalassaemia. There are three methods of doing this:

• chorionic villus sampling
  (CVS) - during CVS, a small sample of placenta (the organ that is attached to the womb lining during pregnancy) is removed from the womb and tested
• amniocentesis
  - a small sample of the fluid inside the womb (amniotic fluid) is taken for testing
• foetal blood sampling (FBS)** - under
  local anaesthetic
  , a small sample of blood is taken from your baby’s umbilical cord, or from the umbilical vein as it passes through their liver

Counselling

Being told your baby will be born with thalassaemia can be traumatic and upsetting. You will be offered

to give you and your partner the opportunity to express your feelings and to ask questions about how the diagnosis may affect you.

The counsellor will inform you of different options available, allowing you to make a more informed decision about how to proceed with the pregnancy.

Pre-implantation genetic diagnosis (PGD)

Pre-implantation genetic diagnosis (PGD) is an option for couples who do not want to give birth to a child with thalassaemia but are unwilling to consider terminating a pregnancy.

PGD is similar to

(IVF). IVF is a method of helping infertile couples conceive by surgically removing an egg from the woman's ovaries and fertilising it with the man’s sperm in a laboratory.

As with IVF, PGD involves removing eggs from a woman’s ovaries, which are fertilised using a sample of sperm taken from her partner. The fertilised embryo can be tested for thalassaemia. If the results are negative, the embryo can then be implanted into the woman’s womb.

PGD is a new procedure only available at a number of specialist thalassaemia centres.

After birth

Unlike the related disorder sickle cell anaemia, newborn babies are not regularly screened for thalassaemia. There are two reasons:

• blood tests are usually unreliable during the first six months of life
• unlike sickle cell anaemia, thalassaemia does not present an immediate threat to a baby’s life (babies born with sickle cell anaemia have a high risk of catching serious infections and need immediate treatment with antibiotics)

If your baby does begin to develop symptoms as they grow older, the diagnosis can be confirmed using a blood test.

Assessing iron levels

People with beta thalassaemia major (BTM) will require regular blood transfusions, which will increase the level of iron in their body.

To remove the excess iron, they must have treatment called chelation therapy. This helps prevent serious complications from excess iron, such as heart or liver disease.

Read more information about

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Regular tests to measure iron levels are required to monitor the effectiveness of chelation therapy.

There are three main ways of assessing iron levels:

• blood tests
• magnetic resonance imaging (MRI) scans
• liver
  biopsy

Blood tests

Blood tests provide a convenient way of measuring the amount of iron in your blood, although they do not provide a detailed assessment of how much iron may be collecting in certain organs, such as in your brain. The measurements provided by blood tests can also be distorted by other factors, such as infection.

Blood tests are used to provide a general overview of how well your chelation therapy is working, but cannot be used in isolation.

It is usually recommended that a person with thalassaemia receives a blood test at least every three months.

MRI scans

A magnetic resonance imaging (MRI) scan uses powerful magnetic waves to build up a detailed picture of the inside of your body. MRI scans are able to detect and then measure any iron in your organs.

The two organs known to be most vulnerable to the effects of iron are the liver and the heart.

It is usually recommended that you have an MRI scan of your liver at least once a year and an MRI scan of your heart at least once every two years. More frequent scans may be required if high levels of iron are found in your heart and liver.

Liver biopsy

A liver biopsy uses minor surgery to remove a tiny section of your liver to test it for the presence of iron.

An MRI scan is usually preferred to a liver biopsy as it is more convenient (for both the doctor and the person having the scan). However, if a detailed assessment of the level of iron in the body is required, a liver biopsy may be necessary.

Treatment for thalassaemia

Treatment for beta thalassaemia major (BTM) is a lifelong process which requires different specialists to manage the complications of the condition.

If your child is diagnosed with BTM, they will be referred to a specialist clinic so a full assessment of the condition can be made.

Blood transfusions

The main treatment for BTM involves regular

to provide haemoglobin that the body needs. Regular blood transfusions can also prevent many of the complications of BTM, such as skeletal deformities.

Most people with BTM will require a transfusion every two to four weeks. The transfusion process takes four to six hours and will take place in a hospital. A small number of families living with thalassaemia have requested training to enable them to administer blood transfusions at home.

Blood transfusions are extremely safe due to the rigorous screening methods used for donated blood. However, the one drawback of regular blood transfusions is that they leave too much iron in the body. This, combined with additional iron taken from food, means people who receive blood transfusions for BTM must undergo treatment to remove excess iron from their body. This treatment is known as chelation therapy (see below).

Chelation therapy

Chelation therapy is vital for people with BTM. Excess iron damages the body’s cells and, over time (if left untreated), leads to extensive damage to organs.

Areas of the body particularly vulnerable to the effects of iron include:

• the heart: excess iron can cause irregular heartbeats (arrhythmias),
  heart failure
  (where the heart cannot pump enough blood around the body) and, most seriously, cardiac arrest (when the heart stops beating)
• the liver: excess iron can cause hardening of the liver (fibrosis) and scarring of the liver (cirrhosis)
• the glands that produce the body’s hormones: excess iron can cause
  diabetes
  and delayed growth and sexual development

Read more information about

that can arise from an overload of iron.

Chelation therapy will normally need to begin once your child has received 10-20 blood transfusions.

Medications used in chelation therapy are known as chelating agents. There are three chelating agents currently available, each with their own set of advantages and disadvantages:

• desferrioxamine
  (DFO)
• deferiprone
  (DFP)
• deferasirox
  (DFX)

Desferrioxamine (DFO)

DFO binds to iron molecules in the body and then releases them in urine and stools. It is thought to be the most effective chelating agent. However, it takes a long time and is inconvenient to administer.

DFO is usually given through a pump that slowly feeds the medicine through a needle into your child’s skin. This is known as an infusion.

As DFO takes a long time to start working, children will often need an infusion that lasts 10-12 hours, five to six nights a week. You and your child will be trained to administer the chelation therapy at home.

Taking DFO can be frustrating, especially for children and teenagers. While such feelings are understandable, it is important to emphasise to your children how important it is to take their DFO as directed, as missing doses could increase their risk of developing serious complications.

It is common to develop pain, swelling, itchiness and redness at the site of the injection.

Other common side effects of DFO include:

• headache
• nausea

If side effects become particularly troublesome or severe, tell your treatment team as your child’s dose may need to be adjusted or an additional chelating agent may be required.

Deferiprone (DFP)

DFP also binds to iron molecules in the body and releases them in urine.

DFP is available in tablet or liquid form, so is more convenient to take. However, DFP is not usually as effective as DFO, particularly in preventing liver damage, so is normally used in combination with DFO. Combining the two chelating agents means children do not have so many infusions each week (usually two a week, as opposed to five or six).

Another disadvantage of DFP is that it causes a wider range of potential side effects, some of which can be serious. Common side effects include:

• nausea
• abdominal pain
• headache
• vomiting
• joint pain
• diarrhoea
• fatigue

Potentially, the most serious side effect of DFP is agranulocytosis. Agranulocytosis is a condition where bone marrow no longer produces enough white blood cells. The body uses white blood cells to protect against infection, so agranulocytosis makes you extremely vulnerable to infection. If infection occurs, it could be very serious.

Most episodes of agranulocytosis occur during the first year of taking DFO, but episodes have been reported after many years of treatment. Therefore, it is important to look out for any sign of a possible infection, such as:

• a high temperature of 38C (100.4F) or above
• muscle and joint pain
• chills
• shortness of breath

If you develop symptoms that suggest you may have an infection, immediately stop taking DFP and contact your treatment team for advice.

Deferasirox (DFX)

DFX is a relatively new type of chelating agent that was licensed for use in the UK in 2006.

There is only a limited amount of evidence on how effective or safe the medication may be in the long term, but it appears to work as well as DFO in some people. However, the use of DFX as an alternative to DFO is not usually recommended in people with high levels of iron in their heart.

DFX is available in tablet form. Common side effects include:

• nausea
• vomiting
• diarrhoea
• abdominal pain
• skin rash

These side effects are usually mild to moderate and usually resolve once your body gets used to the medication.

There have been reports of people developing liver failure when taking DFX, with some cases resulting in death. However, most of these people already had a history of liver disease or another serious illness. As a precaution, you will be given regular liver function tests when taking DFX so the state of your liver can be carefully monitored.

There have also been reports of people developing

and internal bleeding when taking DFX. As a precaution, look out for symptoms such as:

• vomiting blood (the blood can appear bright red or have a darker, grainy appearance similar to coffee granules)
• passing stools (faeces) dark in colour or ‘tar-like’
• a sudden, sharp pain in your abdomen (tummy) that gets steadily worse

If you experience any of the symptoms above, stop taking DFX and contact your doctor immediately. If this is not possible, contact your local out-of-hours service or call NHS Direct on 0845 46 47.

Bone marrow transplant

One possible cure for thalassaemia is a

. The procedure involves replacing affected bone marrow with bone marrow donated from someone who does not have thalassaemia. The new bone marrow then begins producing healthy blood cells.

There are significant risks involved in having a bone marrow transplant. The new bone marrow can start producing cells that attack parts of your body. This is known as graft-versus-host disease (GVHD).

GVHD can affect many parts of your body, although your eyes, skin, stomach and intestines are most commonly affected. Symptoms of GVHD include:

• red spots on the hands, feet and face
• the spots then spread across the body into a rash
• the rash may develop into blisters
• high temperature (fever) of 38C (100.4F) or above
• bloody or watery diarrhoea
• stomach cramps
• jaundice
  (yellowing of the skin and whites of the eyes)

Other risks related to bone marrow transplants include an increased risk of strokes, seizures and tumours. Read more information about the

.

All families who have a child with a serious thalassaemia condition will be offered the opportunity to discuss bone marrow transplant as a possible treatment.

There is a greater chance of successfully treating thalassaemia using a bone marrow transplant when:

• the child is under 16 years of age (younger children have less organ damage from thalassaemia, so their chances of survival are greater)
• the child receives the transplanted bone marrow from a brother or sister who shares the same genetic tissue type

All human tissue carries a special genetic 'marker' or code, known as a human leukocyte antigen (HLA). As there are several billion possible combinations of HLA, it is extremely unlikely that the right type of bone marrow will be found from somebody who is not related.

The survival and success rates for a bone marrow transplant depend on a series of risk factors. The risk factors are:

• an enlarged liver
• liver damage
• previous poor control of iron levels

The probabilities for successful bone marrow transplant treatment in children under 16 receiving bone marrow from an HLA-matched donor are outlined below.

• For children with no risk factors, there is 95% chance of survival and a 90% chance that treatment will be successful.
• For children with one or two risk factors, there is an 86% chance of survival and an 82% chance treatment will be successful.
• For children with all three risk factors, there is a 79% chance of survival and a 58% chance treatment will be successful.

Cord blood transfusion

Another possible cure for thalassaemia is cord blood transfusion. This involves testing the HLA tissue type of an unborn baby without thalassaemia that is carried by a mother who already has a child with thalassaemia.

If the HLA of the unborn baby matches that of the older brother or sister, it is possible to take a sample of blood from the umbilical cord that can be used at a later date for transfusion.

This blood, known as cord blood, is useful because it is a rich source of stem cells. Stem cells can be used instead of bone marrow because they are capable of producing healthy red blood cells.

The advantage of cord blood transfusions is that there is a lower chance of GVHD occurring and the HLA match does not need to be as accurate as that needed for a bone marrow transplant.

To date, the number of cord blood transfusions for thalassaemia has been limited. Therefore, definitive information about the survival and success rates of the treatment is unavailable. However, one small study placed the success rate at 79% and there were no deaths.

If you are a mother of a child with thalassaemia and you conceive another child who does not have thalassaemia, your thalassaemia clinic can arrange for your unborn child to have their HLA type tested to see if they would be able to donate cord blood.

Beta thalassaemia intermediate (BTI)

Treatment for beta thalassaemia intermediate (BTI) depends on the severity of the symptoms. Some people will just require folic acid supplements to help the production of healthy red blood cells. Others will require occasional blood transfusions and chelation therapy, while those with the most severe symptoms will require a treatment programme similar to the one used for people with beta thalassaemia major (BTM).

If you have BTI, you will require regular check-ups so the progress of your condition can be monitored and any associated complications can be assessed.

Complications of thalassaemia

One of the most challenging aspects of living with and treating beta thalassaemia major (BTM) is the number of possible complications that can occur.

People with BTM (and some people with moderate-to-severe BTI) will need frequent check-ups, so the risk of possible complications can be regularly assessed.

Some common complications of BTM are outlined below.

Enlarged spleen (hypersplenism)

One of the functions of the spleen (an organ found behind the stomach) is to recycle red blood cells. In people with BTM, the blood cells are often abnormal in shape, so the spleen has problems recycling them. The result is that an increasing amount of blood stays in the spleen, making it grow larger.

This can lead to the spleen becoming overactive, when it starts to destroy healthy blood cells received during

, making effective treatment for BTM difficult. In these circumstances, the only treatment is to remove the spleen using a procedure known as a splenectomy.

The spleen also plays an important part in fighting infections. Therefore, if your child has their spleen removed, it is likely that vaccinations against potentially serious infections, such as

and , will be recommended.

Encourage your child to be alert to possible symptoms of infections, such as muscle pain or fever, and report them as soon as possible. This is because infections could have a more serious effect on them than most people.

Hormone complications

One of the glands that regulates the hormone system (the pituitary gland) is very sensitive to the effects of iron. It can, therefore, become damaged in some people with BTM, even if they stick to their chelation therapy.

Damage to the pituitary gland can result in a number of hormonal conditions, including delayed puberty and restricted growth. Hormone replacement therapy may be needed to correct these conditions.

Other complications that can appear after puberty include

and an or .

Children with BTM will need their height and weight checked every six months to make sure they are developing normally. Teenagers who have begun puberty will need their development assessed every year.

Heart complications

Iron overload can cause damage to the heart, leading to:

• an irregular or disturbed heartbeat (arrhythmia)
• impaired pumping of the heart (systolic dysfunction)
• build-up of fluid in the tissue of the heart (pleural effusions)
• heart failure

If you have BTM, you will need a check-up every six months to determine how well your heart is functioning. Every year, you will also need a full examination, carried out by a cardiologist (heart specialist), using an electrocardiogram (ECG) test to measure the electricity of your heart.

If damage to your heart is detected, it can be stopped and possibly reversed using more extensive chelation therapy. Medication, such as angiotensin-converting enzyme (ACE) inhibitors, can also be used to improve the functioning of your heart.

Liver complications

Iron overload can also cause damage to the liver, resulting in:

• hepatitis
  (swelling of the liver)
• an enlarged liver (fibrosis)
• cirrhosis
  (a progressive disease where the liver is increasingly damaged by scarring)

Chelation therapy can prevent further damage to the liver and antiviral medicines can be used to prevent further liver infection. Liver tests are recommended every three months to monitor the condition of the liver.

Bone complications

If your body is not receiving enough healthy red blood cells, it will try to compensate by expanding the bone marrow, which in turn will expand the bones. This can lead to skeletal deformities, bone and joint pain and

(a condition where the bones become thin and brittle.)

Low bone density is common, even in people who have been receiving regular blood transfusions. Those with low bone density are at increased risk of fracturing (breaking) their bones.

People with BTM are encouraged to eat a diet high in calcium and vitamin D, both of which help strengthen the bones. Foods high in calcium include:

• beans
• tofu
• sardines
• salmon
• broccoli
• oranges
• oats
• dairy products, such as milk and cheese

Foods that are high in vitamin D include:

• milk
• orange juice
• eggs
• fish
• liver

You may also be advised to take vitamin D and calcium supplements.

Regular exercise can also help strengthen bones. Adults should do at least 150 minutes (2 hours and 30 minutes) of moderate-intensity aerobic activity (i.e. cycling or fast walking) every week. Two types of activity particularly important in improving bone density and helping prevent osteoporosis are weight-bearing exercises, such as running and aerobics, and resistance exercises, such as weight training and press-ups.

Osteoporosis can be treated using medicines called bisphosphonates, which help maintain bone density and reduce the chances of fracture. However, bisphosphonates are not recommended for children and teenagers because they can interfere with normal bone development.