Beta Thalassaemia

Beta thalassaemia is an inherited blood disorder that affects the body’s ability to make hemoglobin, the iron-rich protein that enables red blood cells to carry oxygen throughout the body. This condition can range from mild forms that cause no symptoms to severe forms requiring lifelong treatment with regular blood transfusions.

Table of contents

• What is beta thalassaemia?
• Types of beta thalassaemia
• Causes and inheritance
• Symptoms and signs
• Who is affected by beta thalassaemia?
• How is beta thalassaemia diagnosed?
• Treatment options
• Living with beta thalassaemia

What is beta thalassaemia?

Beta thalassaemia is an inherited blood disorder that limits the body’s ability to make beta-globin, an important protein that helps make hemoglobin and red blood cells^[1]. Hemoglobin is the iron-containing protein in red blood cells that carries oxygen to cells throughout the body^[2].

When a person has beta thalassaemia, they don’t have enough beta-globin chains for their body to make hemoglobin. This means they don’t have enough healthy red blood cells, leading to a condition called anemia, which is when the body doesn’t have enough red blood cells or hemoglobin^[1]. Without sufficient hemoglobin, red blood cells do not develop normally, causing a shortage of mature red blood cells. The low number of mature red blood cells leads to anemia and other associated health problems^[2].

Beta thalassaemia is one of two main types of thalassaemia. The other type is alpha thalassaemia^[1].

Types of beta thalassaemia

Healthcare providers classify beta thalassaemia types by their symptoms, which range from mild to severe^[1]. The three main types are:

• Beta thalassaemia minor (also called beta thalassaemia trait): This type may not cause symptoms or only cause mild symptoms. People with beta thalassaemia trait usually do not require any specific treatment^[1][5]. They might have mild anemia but can live normal lives.
• Beta thalassaemia intermedia: This type causes mild to moderate symptoms. People with beta thalassaemia intermedia have moderately severe anemia and some will need blood transfusions and other medical treatment^[5]. The signs and symptoms of thalassaemia intermedia appear in early childhood or later in life^[2]. Affected individuals have mild to moderate anemia and may also have slow growth, bone abnormalities, and an increased risk of developing abnormal blood clots^[2].
• Beta thalassaemia major (also known as Cooley’s anemia or transfusion-dependent thalassaemia): This type causes the most severe symptoms. Providers may call this transfusion-dependent thalassaemia because people with it need blood transfusions for the rest of their lives^[1]. The signs and symptoms of thalassaemia major appear within the first 2 years of life. Children develop life-threatening anemia. They do not gain weight and grow at the expected rate and may develop yellowing of the skin and whites of the eyes^[2].

There are hundreds of different genetic changes that can cause beta thalassaemia. Some changes prevent the production of any beta-globin, referred to as beta-zero (β0) thalassaemia. Other changes allow some beta-globin to be produced but in reduced amounts, called beta-plus (β+) thalassaemia^[2].

Causes and inheritance

Beta thalassaemia happens when there’s a change (genetic variation or mistake) in the hemoglobin beta (HBB) gene. This gene tells the body how to make beta-globin chains, which is one of the two types of protein chains that make up hemoglobin. The other is alpha-globin^[1].

The HBB gene is located on chromosome 11. Over 200 different disease-causing changes (mutations) have been identified in this gene^[2][3]. These mutations are primarily point mutations that affect how the gene is read and used by the body to make beta-globin^[3].

Beta thalassaemia is inherited in an autosomal recessive pattern, which means both copies of the HBB gene in each cell have variants. A person will have a type of beta thalassaemia if they inherit the changed gene from one or both of their biological parents^[1][2].

The parents of an individual with an autosomal recessive condition each carry one copy of the altered gene, but they typically do not show signs and symptoms of the condition. Sometimes, however, people with only one HBB gene variant in each cell develop mild anemia. These mildly affected people are said to have thalassaemia minor^[2].

Inheriting changed genes from both parents increases the chance a person will have a more serious type of the condition. A person may have the less serious type if they inherit a changed gene from one parent and a normal gene from the other parent^[1].

Symptoms and signs

Beta thalassaemia may not cause symptoms in its mild form. When it does cause symptoms, it creates anemia-related symptoms that may be mild to severe^[1].

People with beta thalassaemia may experience:

• Extreme tiredness (fatigue)^[1][5]
• Dizziness or weakness^[1]
• Frequent headaches^[1]
• Skin paleness^[1][5]
• Shortness of breath^[1][5]
• Heart palpitations (fast heartbeat)^[1][5]
• Yellow skin or eyes (jaundice)^[1][5]
• Dark or tea-colored urine^[1]
• Swollen belly^[1]
• Weak or misshapen bones in the arms, legs and face^[1]
• Moodiness or irritability^[5]
• Slow growth^[5]

Babies with beta thalassaemia may be especially fussy and get frequent infections. The condition symptoms may start when a baby is 3 to 6 months old or before they turn 2^[1]. Children born with beta thalassaemia major will have symptoms early in life, including pale skin, fussiness, poor appetite, and having many infections^[5].

Over time, without treatment, more symptoms can appear including slowed growth, belly swelling, yellowing of the skin, and enlargement of the spleen, liver, and heart. Bones can also become thin, brittle, and deformed^[5]. Puberty may be delayed in some adolescents with thalassaemia major^[2].

People with beta thalassaemia are also at an increased risk of developing abnormal blood clots^[2].

Who is affected by beta thalassaemia?

Beta thalassaemia is a fairly common blood disorder worldwide. Thousands of infants with beta thalassaemia are born each year^[2].

Beta thalassaemia occurs most frequently in people from Mediterranean countries, North Africa, the Middle East, India, Central Asia, and Southeast Asia^[2]. The highest prevalence of beta-thalassaemia mutations is in people of Mediterranean, Middle Eastern, and Asian descent^[3].

The only risk factor for developing beta thalassaemia is having a family history of the disease^[5].

How is beta thalassaemia diagnosed?

Healthcare providers will do a physical exam and blood tests to diagnose beta thalassaemia. Beta thalassaemia major, the most severe type, is diagnosed in early childhood. Children with beta thalassaemia major usually receive a diagnosis by the time they’re 2 years old^[1].

Tests to diagnose beta thalassaemia may include:

• Complete blood count (CBC): Blood tests can reveal the number of red blood cells and irregular changes in their size, shape or color^[1]
• Reticulocyte count: This measures young red blood cells^[1]
• Hemoglobin electrophoresis: This test can be used to look for gene changes and identify different types of hemoglobin^[1]
• Genetic tests: These identify the genetic change in hemoglobin that causes the condition^[1]

Laboratory findings suggestive of thalassaemia include small red blood cells with less color than normal (microcytic hypochromic anemia)^[3]. In beta thalassaemia trait, hemoglobin A2 and F will be elevated on test results^[7].

Prenatal tests like amniocentesis or chorionic villus sampling (CVS) may detect the genetic change during pregnancy^[1]. Testing can be done before a baby is born to find out if the baby has thalassaemia and determine how serious the condition might be^[6].

In states with newborn screening programs, infants will be diagnosed as having a hemoglobin disorder through these screening programs^[7].

Treatment options

Mild forms of thalassaemia trait don’t need treatment. For moderate to severe thalassaemia, several treatment options are available^[6].

Blood transfusions

Blood transfusions are the main way to treat moderate or severe thalassaemia^[8]. One way to treat anemia is to provide the body with more red blood cells to carry oxygen. This can be done through a blood transfusion, a safe, common procedure in which a person receives blood through a small plastic tube inserted into one of their blood vessels^[8].

Some people with thalassaemia—usually with thalassaemia major—need regular blood transfusions because their body makes such low amounts of hemoglobin^[8]. It’s common to need these every few weeks. People with the most severe type, beta thalassaemia major, may need a blood transfusion about once a month. Those with less severe types may only need them occasionally^[10].

People with thalassaemia intermedia may need blood transfusions sometimes, such as when they have an infection or an illness. People with thalassaemia minor or trait usually do not need blood transfusions because they either do not have anemia or have only a mild anemia^[8].

Iron chelation therapy

People who receive a lot of blood transfusions are at risk for iron overload. Each unit of transfused red blood cells contains approximately 200 mg of elemental iron^[13]. Red blood cells contain a lot of iron, and over time, the iron from all of the transfusions can build up in the body. When it builds up, the iron collects in places like the heart, liver, and brain, and can make it hard for these organs to work properly^[8].

Treatment to remove excess iron caused by regular blood transfusions is known as chelation therapy. It’s very important because high levels of iron in the body can damage organs^[10]. To prevent iron overload, people with thalassaemia may need chelation therapy, which is when doctors give a medicine—either a pill or a shot under the skin—to remove excess iron before it builds up in the organs^[8].

There are three chelating agents currently available in the United States:

• Deferoxamine (DFO): Given as an infusion, where a pump slowly feeds the liquid medicine through a needle into the skin over 8 to 12 hours; this is done 5 or 6 times a week^[10]
• Deferiprone (DFP): Taken as a tablet or liquid 3 times a day; it’s sometimes used alongside DFO to reduce the number of infusions needed^[10]
• Deferasirox (DFX): Taken once a day as a tablet that is swallowed or dissolved in a drink^[10]

Folic acid supplementation

Many times people with thalassaemia are prescribed a supplemental B vitamin, known as folic acid, to help treat anemia. Folic acid can help red blood cells develop. Treatment with folic acid is usually done in addition to other therapies^[8].

Other treatments

Luspatercept is a medication that can be used as an erythroid maturation agent for patients with beta thalassaemia^[13].

Some people may need removal of the spleen (splenectomy) if it gets too big or causes pain^[5].

Other medical problems may require specific treatments. For example, hormone medicine may be used to help trigger puberty in children with delayed puberty and treat low hormone levels. Vaccinations and antibiotics may be recommended to prevent and treat infections. Thyroid hormones may be used if there’s a problem with the thyroid gland. Medicines called bisphosphonates may be used to help strengthen bones^[10].

Stem cell or bone marrow transplants

Stem cell or bone marrow transplants are the only cure for thalassaemia, but they’re not done very often because of the significant risks involved^[10]. Stem cells are produced in bone marrow, the spongy tissue found in the centre of some bones, and have the ability to develop into different types of blood cells.

For a stem cell transplant, stem cells from a healthy donor are given through a drip into a vein. These cells then start to produce healthy red blood cells to replace the cells affected by thalassaemia^[10].

A stem cell transplant is an intensive treatment that carries a number of risks. The main risk is graft versus host disease, which is a life-threatening problem where the transplanted cells start to attack the other cells in the body^[10].

Gene therapy

In January 2024, the U.S. Food and Drug Administration (FDA) approved CASGEVY™, a cell-based gene therapy for the treatment of transfusion-dependent beta-thalassaemia in patients 12 years and older. The product is made from patients’ own blood stem cells. The stem cells are taken, modified, and given back as a one-time, single-dose infusion as part of a blood stem cell transplant^[8].

Living with beta thalassaemia

For people with thalassaemia, a healthy lifestyle means managing the disorder and making healthy choices. The most important thing a person can do is stick to their transfusion and chelation schedules to prevent severe anemia and possible organ damage from iron overload^[15].

Managing thalassaemia

Thalassaemia is a treatable disorder that can be well-managed with blood transfusions and chelation therapy. A person with thalassaemia will need to receive medical care on a regular basis from a hematologist (a medical specialist who treats diseases or disorders of the blood) or a doctor who specializes in treating patients with thalassaemia^[15].

Healthy lifestyle choices

To help reduce the chances of developing some of the problems associated with thalassaemia, it’s a good idea to^[16]:

• Have a healthy, balanced diet—a person does not usually need a special diet, although sometimes they may be advised to take supplements such as folic acid, calcium or vitamin D
• Exercise regularly—regular exercise, particularly weight-bearing and aerobic exercise, can help strengthen bones and reduce the risk of osteoporosis
• Avoid smoking and drinking excessive amounts of alcohol—this can help keep bones and heart healthy
• Try to avoid infection—wash hands with soap and water regularly, avoid close contact with sick people when possible, and ensure all vaccinations are up-to-date

For people living with thalassaemia, because too much iron may build up in the blood, foods high in iron may need to be limited. Iron can be found in meat, fish, and some vegetables (such as spinach). Other products, like cereal and orange juice, may contain extra iron. Persons with thalassaemia should discuss with their doctor whether or not they should limit the amount of iron in their diet^[15].

Although some people with thalassaemia may have trouble participating in vigorous forms of exercise, many people with thalassaemia can participate in moderate physical activities including biking, running, and walking. If a person with thalassaemia has problems with their joints, there are many kinds of low-impact activities to choose from including yoga, swimming, or water aerobics^[15].

Vaccinations

Vaccines are a great way to prevent many serious infections. Children and adults with thalassaemia should get all recommended vaccinations, including a flu vaccination. People with thalassaemia are considered “high risk” for certain infections, especially if they have had their spleen removed^[15].

Pregnancy and family planning

Women with thalassaemia major or other severe types can have a healthy pregnancy, but it’s a good idea to speak to the care team for advice first. It may be useful to find out if a partner is a carrier of thalassaemia and discuss the effects of this with a genetic counsellor. Some people with thalassaemia need fertility treatment to help them get pregnant. During pregnancy there’s an increased risk of problems, such as heart problems in the mother and growth problems in the baby^[16].

Support and relationships

Having warm, supportive relationships is an important part of life. Friends, including co-workers, classmates, and family members can offer support in managing thalassaemia (such as offering a ride to the transfusion center, gentle reminders about chelation schedules) and coping with stress of daily life^[15].

Regular monitoring

People with thalassaemia may need extra monitoring and regular check-ups to watch for heart problems and other complications^[1]. Make sure to take medicine as advised and attend all check-ups. Talk to the doctor or nurse at check-ups if finding it hard to manage the condition. There is support available^[16].