What to Know About Thalassemia

What is Thalassemia?

Thalassemia is a group of inherited diseases of the blood. Persons with thalassemia are not able to properly produce hemoglobin, resulting in anemia ¹.

Hemoglobin is a protein in red blood cells that carries oxygen and nutrients to cells in the body ². It also carries carbon dioxide from the body to the lungs, where it is exhaled.

There are two main types of thalassemia; “alpha thalassemia” and “beta thalassemia,” and each has several variations.

Thalassemia also has several other names:

• erythroblastic anemia
• Mediterranean anemia
• microcytemia, beta type
• thalassemia, beta type

The condition is genetic and occurs most frequently in people of Italian, Greek, Middle Eastern, Southern Asian and African ancestries ³.

It is passed on the children by parents who carry a mutated thalassemia gene. Not all children who inherit a mutated gene from one parent with thalassemia will develop the condition.

A child with only one mutated gene is known as a thalassemia carrier. Most carriers lead normal and healthy lives.

However, a child who inherits two thalassemia trait genes - one from each parent - will have the disease. A child of two carriers has a 25 percent chance of receiving two trait genes and developing the disease, and a 50 percent chance of being a thalassemia trait carrier ⁴.

Approximately 100,000 babies worldwide are born with severe forms of thalassemia each year. Most of those stricken with alpha thalassemia have milder forms of the disease and varying forms of anemia.

The more severe form of the disease is thalassemia major, also called Cooley's Anemia.

It is a serious disease that requires regular blood transfusions and extensive medical care ⁵.

In many cases, the most severe form of alpha thalassemia results in fetal or newborn death.

Blood tests, prenatal testing, and genetic studies can all be used to diagnose thalassemia. These can also be used to determine if someone is just a carrier.

When both parents are diagnosed as carriers, it might be wise to contact a genetic counselor to discuss possible options and outcomes before starting a family.

Different Types of Thalassemia

There are two main types of thalassemia. Alpha thalassemia occurs when there is a change in the genes that make a protein called alpha globin.

Four genes help the body make alpha globin. A baby gets two of these genes from each parent. There are four kinds of alpha thalassemia: ⁶

• Carrier thalassemia is caused by one missing gene or a gene change for alpha thalassemia. When this happens, a baby is a carrier who may or may not have symptoms.

• Alpha thalassemia minor (alpha thalassemia trait) is caused by two missing genes or gene changes. A child may have mild anemia or not show any signs or symptoms.

• Hemoglobin H disease is caused by three missing genes or gene changes that can result in a baby suffering from anemia. It puts them at risk of developing serious complications.

• Alpha thalassemia major (hydrops fetalis) is the most severe form of thalassemia. It is caused by four missing genes or gene changes. It is the most serious form of alpha thalassemia. It can lead to stillbirth or the death of a baby shortly after birth.

Beta thalassemia is the more common form of thalassemia. It occurs when there is a change in the genes that make a protein called beta globin.

Two genes that help the body make beta globin. A baby gets one from each parent. There are several kinds of beta thalassemia:

• Beta thalassemia minor (beta thalassemia trait) is caused by one gene change. Most people with this kind have no signs or symptoms, or only mild anemia. They can pass the gene change on to their children.

• Beta thalassemia intermedia is caused by two gene changes and generally results in mild anemia.

• Beta thalassemia major (Cooley’s anemia, beta-zero (ß0) thalassemia, Mediterranean anemia) is the most serious form of beta thalassemia and is caused by two gene changes. Most children with this kind may seem healthy at birth but develop severe anemia during the first few years of life. Without treatment, serious health complications can occur. It is sometimes called Mediterranean anemia because it affects people from that region of the world more often than others. It is also called Cooley’s anemia because pediatrician Thomas Benton Cooley first described in 1925.

• Beta-plus thalassemia is a mild form of sickle cell anemia. It is a mutation in each copy of the HBB gene that causes red blood cells to be small and pale. They form a “sickle” or crescent shape. Sometimes, a gene change for beta thalassemia can happen along with a gene change for another genetic condition called sickle cell disease (also called SCD). This condition is called sickle beta thalassemia or S beta thalassemia ⁷.

Causes of Beta Thalassemia

Mutations in the HBB gene cause beta thalassemia. Thalassemia is inherited by being passed from a parent to a child through genes.

Genes are the instructions for a body to grow and function. When a mutated gene is passed on, it is possible that thalassemia can develop.

The HBB gene provides instructions for making protein chains called beta-globin, a subunit of hemoglobin. Hemoglobin has four total subunits. Two protein chains are subunits of beta-globin, and two are subunits of alpha-globin.

When the HBB gene mutates, it can diminish or prevent the production of beta-globin. When no beta-globin is produced, this is known as beta-zero thalassemia or B0 thalassemia.

When beta-globin is produced in reduced amounts, this is known as beta-plus thalassemia or B+ thalassemia.

When insufficient amounts of beta-globin are produced, the amount of functional hemoglobin results. Without enough hemoglobin, red blood cells do not produce normally.

This causes a shortage of mature red blood cells which can lead to anemia or other related health problems.

Hemoglobin also carries carbon dioxide from throughout the body to a person’s lungs, where it is exhaled. Reduced functional hemoglobin can impact this vital function as well.

Having B0 or B+ thalassemia does not indicate the severity of a carrier’s thalassemia.

People who inherit faulty hemoglobin genes from one parent but normal genes from the other are considered carriers ⁸. Carriers generally only suffer from mild anemia but can pass the faulty genes on to their children.

People with more severe forms of thalassemia inherit faulty genes from both parents.

The Genetic Pattern of Inheritance of Thalassemia

A person needs four genes to make enough alpha-globin protein. If one or more of the genes is missing, a person will have alpha thalassemia trait or disease ⁹.

The alpha-globin gene is located on chromosome 16.

• If a person is only missing one gene, they are a "silent" carrier. This means they won't have any signs of illness.
• If they are missing two genes, they have alpha thalassemia trait (also called alpha thalassemia minor). They may have mild anemia.
• If they are missing three genes, they likely have hemoglobin H disease. This form of thalassemia causes moderate to severe anemia.

In a few rare cases, a baby can be missing all four genes. This is called alpha thalassemia major or hydrops fetalis, and babies with this condition usually die before or shortly after birth.

Example of an inheritance pattern for alpha thalassemia

Source: National Heart, Lung, and Blood Institute.

A person needs two genes (one from each parent) to make enough beta-globin protein. If one or both of these genes are altered, they will have beta thalassemia. The beta globin gene is located on chromosome 11.

• If they have one altered gene, they are a carrier. This condition is called beta thalassemia trait or beta thalassemia minor and causes mild anemia. People with this condition are known as heterozygotes.
• If both genes are altered, they will have beta thalassemia intermedia (causing moderate anemia) or beta thalassemia major (causing severe anemia).

Example of an Inheritance Pattern for Beta Thalassemia:

Source: National Heart, Lung, and Blood Institute.

When the mutated gene is present in the parent, each child has a has:

• a 25% chance of being affected
• a 50% chance of being an asymptomatic carrier
• a 25% chance of being unaffected and not a carrier.

Who Gets Thalassemia?

There are two primary risk factors for getting thalassemia. Family history is a primary factor because thalassemias are inherited.

If a parent has a missing or mutated gene, there is a chance their children may also have thalassemia.

The other risk factor is ancestry. Thalassemias occur most often among people of Mediterranean, Italian, Greek, Transcaucasus, Middle Eastern, Southern Asian, African and African-American descent.

The highest incidences of thalassemia are reported in Cyprus, Sardinia, and Southeast Asia.

In Lebanon, beta-thalassemia is the predominant genetic defect. It can be traced to their origins of Sunni Muslims who have the highest beta-thalassemia carrier rate and greatest heterogeneity, with 16 different mutations.

Shiite Muslims follow closely with 13 mutations. Maronites carry seven different mutations.

Due to population migration and to a lesser degree, the slave trade, beta-thalassemia is also common in northern Europe, North and South America, the Caribbean, and Australia.

Signs and Symptoms of Thalassemia

Thalassemias create a lack of oxygen in the bloodstream, and the severity of a person’s symptoms depend on the severity of the condition.

Silent carriers of alpha thalassemia show no signs or symptoms of the condition. It is so minor that the body’s hemoglobin still functions within normal ranges.

People with alpha or beta thalassemia trait may have mild anemia. However, they may also show no signs or symptoms as well. Mild anemia will make a person feel tired. It is sometimes misdiagnosed as iron-deficiency anemia.

People with beta thalassemia intermedia have mild to moderate anemia. They may also suffer from slowed growth and delayed puberty, or bone problems because thalassemia can cause bone marrow to expand.

This can lead to brittle bones that can break easily. Another health issue that may develop is an enlarged spleen because thalassemia causes this vital organ to work harder than normal.

When this happens, anemia can become worse, and occasionally, the spleen will need to be removed.

People suffering from hemoglobin H disease or beta thalassemia major show signs and symptoms by age two. They may be prone to severe anemia and many other health problems, including:

• A pale and listless appearance
• Poor appetite
• Dark urine, a sign that red blood cells are breaking down
• Slowed growth and delayed puberty
• Jaundice
• An enlarged spleen, liver, or heart
• Bone problems, especially with facial bones ¹⁰

Complications Associated with Thalassemia

The type and severity of complications associated with thalassemia depend on which type and whether or not it is treated.

For example, with beta thalassemia major in some developing countries, treatments that include long-term transfusion programs are not available. Those who are not transfused regularly typically die before they turn 20.

Complications typically include:

• Growth restriction
• Pallor
• Jaundice
• Brown pigmentation of the skin
• Poor musculature
• Genu valgum
• Hepatosplenomegaly
• Leg ulcers
• Development of masses from extramedullary hematopoiesis
• Skeletal changes that result from expansion of the bone marrow, including:
  • Deformities of the long bones of the legs
  • Typical craniofacial changes (frontal bossing, malar prominence, depressed nasal bridge, tendency toward upslanted palpebral fissures, and hypertrophy of the maxillae, which tends to expose the upper teeth)
  • Osteoporosis

Another complication is anemia hemochromatosis. Patients with thalassemia may present symptoms consistent with anemia of chronic disease (ACD).

ACD is also present in chronic infections, some types of cancer, and arthritis. The HFE gene mutates in patients suffering from the common iron overload disease hemochromatosis.

Complications first start to appear at six months to 24 months of age. Initially, these complications may include feeding problems, diarrhea, irritability, recurrent bouts of fever, and progressive enlargement of the abdomen caused by splenomegaly.

If transfusions are intermittent or poorly executed, then an individual could be at risk for complications of iron overload.

Iron overload occurs mainly from increased intestinal absorption of iron caused by a deficiency of hepcidin.

By age 10 or 11, those with beta thalassemia major start developing severe complications due to iron overload. Complications from iron overload include:

• In children, growth restriction and failure of sexual maturation
• In adults, involvement of the heart (dilated cardiomyopathy), liver (fibrosis and cirrhosis), and endocrine glands (resulting in diabetes mellitus and insufficiency of the parathyroid, thyroid, pituitary, and, less commonly, adrenal glands)
• Hypersplenism
• Chronic hepatitis (resulting from infection with the viruses that cause hepatitis B and hepatitis C)
• Cirrhosis (from iron overload and chronic hepatitis)
• HIV infection
• Venous thrombosis
• Osteoporosis

Heart disease due to iron overload is the leading cause of death in people who have thalassemias.

Infections are also principal cause of complications and the second most common cause of death. People who have had their spleens removed are at even higher risk for infections because they no this infection-fighting organ.

Beta-thalassemia intermedia is less severe but can still produce complications such as:

• Pallor
• Jaundice
• Cholelithiasis
• Liver and spleen enlargement
• Moderate to severe skeletal changes
• Leg ulcers
• Extramedullary masses of hyperplastic erythroid marrow
• Osteopenia and osteoporosis
• Thrombotic complications from iron accumulation and hypercoagulable state secondary to the lipid membrane composition of the abnormal red blood cells

Transfusions are generally not required or only on an occasional basis for those who suffer from beta-thalassemia intermedia,

Beta-thalassemia minor typically presents no complications.

Diagnosis of Beta Thalassemia

A person is diagnosed with thalassemia through blood tests and genetic studies.

Prenatal testing is done as early as the 11th week of pregnancy using chorionic villi sampling (CVS). Testing can also be completed during the 16th week of pregnancy through amniocentesis.

If it is determined that both parents are carriers of thalassemia, genetic counseling may be appropriate. This will determine whether to move forward with a family or to have a fetus tested for thalassemia.

For parents with the trait who want to give birth to healthy babies, a new technique called pre-implantation genetic diagnosis (PGD) can be used with in vitro fertilization.

Embryos created in-vitro are tested for the thalassemia gene before being implanted into the mother, allowing only healthy embryos to be selected.

Carrier Screening for Beta Thalassemia

Genetic screening will help families determine the chances of passing on a mutated hemoglobin gene that causes thalassemias to their offspring.

If you know of family members who have thalassemias, talking with your doctor and a genetic counselor can help determine your risk for passing the disorder to your children.

Carrier testing for at-risk relatives is also done by hematologic testing. When the hematologic analysis indicates a beta thalassemia carrier state is present, molecular genetic testing can be performed to identify a pathogenic variant.

The recommended genetic testing approach for beta-thalassemia is single-gene testing of the HBB gene.

Some doctors and families may have concerns regarding the use of prenatal testing if the testing is being considered for pregnancy termination rather than early diagnosis.

Most medical professionals consider decisions regarding prenatal testing to be the choice of the parents, but a discussion of these issues is appropriate.

Treatments and Care Options for Beta Thalassemia Patients

Treatments and care options depends on the type and severity of a case of thalassemia. Because it is genetic, there currently is no cure for the condition other than through a bone marrow transplant.

Researchers are continuing to make significant progress that may one day result in more effective treatments and possibly a cure.

People who are carriers of thalassemia or who have alpha or beta thalassemia trait have very mild or no symptoms. As a result, they will need minimal or no treatment at all.

For moderate and severe forms of thalassemia, several treatment options are employed:

Blood transfusions. Putting new blood into a body gives people with thalassemia new red blood cells.

Blood transfusions are required as frequently as every two to four weeks for those who suffer from beta thalassemia major. The procedure typically takes one to four hours and is considered a very safe procedure.

In a few cases, there may be reaction to the transfusion that could affect the lungs and heart or produce a fever.

Red blood cells live only for about 120 days. So, patients need repeated transfusions to maintain a healthy supply of red blood cells.

Blood transfusions allow young people to enjoy normal activities and live into adulthood. This treatment is lifesaving, but it's expensive and carries a small risk of transmitting infections and viruses, such as hepatitis.

Iron chelation therapy. Hemoglobin is an iron rich protein. As a result, all blood transfusions can cause too much iron to build up in the blood.

When this happens, patients are given medicine to help them get rid of the excess iron. The medicine is called iron chelation therapy.

A patient may get the medicine in a pill (Deferasirox, brand name Exjade®, or Deferiprone, brand name Ferriprox®) or medicine (Desferoxamine, brand name Desferal®) by IV.

Desferoxamine is given slowly under the skin, usually with a small portable pump used overnight. This therapy takes time and can be mildly painful. Side effects include problems with vision and hearing.

Deferasirox is a pill taken once daily. Side effects include headache, nausea, vomiting, diarrhea, joint pain, and tiredness.

Folic acid supplements. Patients may be given a folic acid supplement to make up for nutrients that you don’t get enough of in the foods you eat.

For thalassemia patients, a supplement may be given to help treat anemia. Folic acid is a B vitamin that every cell in the body needs for proper health and development.

Bone marrow transplant. This is considered a stem cell transplant procedure that can be used to treat anemia in thalassemia patients.

In a bone marrow transplant, a patient will get new stem cells that could grow to make healthy new cells.

Bone marrow transplants are used only in the most severe cases because they do have a fair amount of risk attached.

A bone marrow transplant works best when the donor is an exact match to the patient, like an identical twin. If it is successful, a bone marrow transplant can cure thalassemia.

Treatment research.  Current efforts to find new treatments for thalassemia include exploring the possibility of inserting a normal hemoglobin gene into stem cells in bone marrow.

This will allow people who have thalassemias to make their own healthy red blood cells and hemoglobin.

Research is also taking place on ways to trigger a person’s ability to make fetal hemoglobin after birth. This type of hemoglobin is found in fetuses and newborns.

After birth, the body switches to making adult hemoglobin. Making more fetal hemoglobin might make up for the lack of healthy adult hemoglobin found in thalassemia patients.

Cord blood transplants offer a good chance at a cure. If a child is diagnosed before birth with thalassemia and another healthy child who is not affected and who is also a sibling, it may be possible to pursue bone marrow transplantation later on by using marrow from the unaffected child to cure the affected sibling.

Treating complications. Because thalassemia can impact many bodily functions over time, there is also a concerted need to treat health complications from thalassemia as well.

This might include treating infections, heart and liver diseases, osteoporosis, and other illnesses.

Treatment might be needed for heart or liver diseases, infections, osteoporosis, and other health problems.

Patients with thalassemia major who undergo transfusion and chelation therapy will need monthly physical examinations by a primary care doctor.

Also, every three months there will need to be a liver function assessment, a determination of serum ferritin concentration, and assessment of growth and development (during childhood).

Annually, patients will need to undergo the following:

• Ophthalmologic and audiologic examinations
• Complete cardiac evaluation, and evaluation of thyroid, endocrine pancreas, parathyroid, adrenal, and pituitary function
• Liver ultrasound evaluation and determination of serum alpha-fetoprotein concentration in adults with hepatitis C and iron overload for early detection of hepatocarcinoma
• Bone densitometry to assess for osteoporosis in adults
• Liver and myocardial MRI
• Gallbladder echography

As part of a treatment regimen, patients will also need to avoid consuming alcohol and iron-containing preparations.

For pregnant women, safe pregnancy is possible if they have beta thalassemia due to advancements in treatments.

More studies are needed but sometimes, women with thalassemia intermedia who had never previously received a blood transfusion or who had received a minimal quantity of blood could be at risk for severe alloimmune anemia if they need blood transfusions during pregnancy.

Prognosis and Living with Beta Thalassemia

Several medical advancements mean that treatments for thalassemias have improved in recent years. People with major and intermediate forms of the condition are now living longer and healthier lives.

Specifically, several noninvasive methods have been introduced that measure organ iron before the appearance of clinical symptoms, new chelators, and increased blood safety measures.

However, that quality of life does depend on following a strict treatment regimen.

Every effort must be made to practice a high degree of self care to remain as healthy as possible. Not following a regimen can lead to fatal complications.

A treatment plan will include blood transfusions and taking iron chelation medicine as directed. You will need to avoid alcohol, as well.

Iron chelation treatment can be time consuming and somewhat painful. But taking medicine is crucial because the leading cause of death among people who have thalassemias is heart disease caused by iron overload.

Iron buildup damages your heart, liver, and other organs.

Several chelation treatments are now available, including injections and pills. Your doctor will talk with you about which treatment is best for you.

If a doctor prescribes folic acid, also make sure to follow treatment protocol as well. Folic acid is a B vitamin that helps to build healthy red blood cells.

A person may also need to take additional vitamin or mineral supplements as well.

Be sure to go to all scheduled doctor’s appointments and get all tests that a doctor prescribes. These can include:

• Monthly complete blood counts and tests for blood iron levels every three months
• Yearly tests for heart function, liver function, and viral infections including hepatitis and HIV
• Yearly tests to check for iron buildup in your liver
• Yearly vision and hearing tests
• Regular checkups to make sure blood transfusions are working
• Lung function tests as needed
• Genetic tests as needed
• Tests to match your tissues with a possible donor if a stem cell transplant is under consideration

It is also important to get vaccinations as needed, especially if a person has had their spleen removed.

Closely monitor for signs of infection and take preventative measures to lower risk.

This might include frequently washing hands, staying away from large crowds during flu season, and keeping the skin around the site where you get blood transfusions as clean as you can.

Finally, living with thalassemia can be emotionally draining. If you suffer from fear, depression or stress related to this condition, consider getting psychological help.

This may include therapy, joining a support group, or medicines to alleviate symptoms.

For More Information on Thalassemia

There are several organizations and resources you can access for more information on thalassemia conditions:

Cooley's Anemia Foundation
330 Seventh Avenue
#900
New York NY 10001
Phone: 800-522-7222 (toll-free)
Fax: 212-279-5999
Email: [email protected]
www.cooleysanemia.org

My46 Trait Profile
Beta-thalassemia
NCBI Genes and Disease
Thalassemia
Thalassaemia International Federation (TIF)
PO Box 28807
Nicosia 2083
Cyprus
Phone: +357 22 319129
Fax: +357 22 314552
Email: [email protected]cy
www.thalassaemia.org.cy

National Haemoglobinopathy Registry
MDSAS NHR Administrator
5 Union Street
City View House
Manchester M12 4JD
United Kingdom
Phone: 0161 277 7917
Email: [email protected]
 www.nhr.nhs.uk

U.S. National Library of Medicine Clinical Trials for Beta Thalassemia

March of Dimes

National Organization for Rare Disorders (NORD)

The Norton & Elaine Sarnoff Center for Jewish Genetics

University of Kansas Medical Center Resource List

MedlinePlus Anemia

MedlinePlus Thalassemia

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