Thalassemia
Related Terms
Alpha-thalassemia, alpha thalassemia major, alpha thalassemia minor, alpha thalassemia trait, anemia, beta-thalassemia, beta thalassemia intermedia, beta thalassemia minor, Cooley's anemia, erythroblastic anemia, hemoglobin H disease, hemoglobinopathies, hereditary leptocytosis, hydrops fetalis, Mediterranean anemia, sickle cell anemia, sickle cell disease, thalassaemia (British), thalassemia, thalassemia intermedia, thalassemia (beta type), thalassemia major, thalassemia minor, thalassemia trait, thalassemic syndrome.
Background
Thalassemia (British spelling "thalassaemia") is caused by a mutated or missing gene that is part of hemoglobin production. Hemoglobin is a protein in red blood cells that is responsible for carrying oxygen. Thalassemia is a hemoglobinopathy, which is a disease of globin protein structures. In thalassemia, the levels of hemoglobin are reduced and there are fewer red blood cells circulating in the blood than normal. A reduced number of red blood cells is also known as anemia, which may be mild or severe.
The structure of the most common form of hemoglobin comprises four protein chains: two alpha hemoglobin (or alpha-globin) proteins and two beta hemoglobin (beta-globin) proteins. Alpha thalassemia occurs when there is a defect in one of the two genes that make alpha hemoglobin and it is classified according to the number of defective genes and the severity of anemia. Beta thalassemia occurs as a result of defective beta hemoglobin proteins and is also classified by the number of defective beta genes and the severity of anemia. The most severe form of beta thalassemia is sometimes called Cooley's anemia.
There is a third form of thalassemia, delta thalassemia, which is not as clinically important as the alpha and beta forms. Only about 3% of hemoglobin contains any delta chains. Therefore, a defect in a delta gene has a limited effect on hemoglobin. Often an individual with delta defects has normal blood cell counts. Even though there is no immediate physical consequence of delta thalassemia, it can interfere with the diagnosis of beta thalassemia, which can be severe.
Thalassemia is an inherited disease that may be inherited as an autosomal recessive or dominant trait depending on the type. Most thalassemias are inherited as recessive traits. Thalassemia is autosomal dominant in a very small percentage of beta thalassemia cases. A person who has only one mutated or defective gene typically does not experience symptoms and is called a carrier (thalassemia trait or thalassemia minor).
It is estimated that 60 to 80 million people worldwide carry the beta thalassemia trait and an estimated 1,000 cases of thalassemia exist in the United States. People with thalassemia are less likely to become infected with malaria, a common infectious disease caused by parasites of the genus Plasmodium (P. falciparum, P. vivax, P. ovale, and P. malariae). This is because the red blood cells affected by thalassemia are somewhat resistant to infection from the malaria parasite. Thalassemia carriers retain some of this resistance to malaria because some of their red blood cells are abnormal. Therefore, thalassemia occurs more frequently in areas where malaria is also common, including sub-Saharan Africa and other tropical or sub-tropical regions.
Beta thalassemia is considered to be a fairly common blood disorder that is thought to affect several thousand infants every year. Beta thalassemia is more common among people of Mediterranean origin (Greek, Italian, Middle Eastern) and people of Asian and African descent. Alpha thalassemias mostly affect people of Southeast Asian, Indian, Chinese, or Filipino origin.
Signs and symptoms may vary depending on the type and severity of thalassemia. Typically, symptoms that appear are a result of a decrease in circulating oxygen from low hemoglobin and anemia. Some common symptoms include fatigue, shortness of breath, jaundice, and bone deformities in the face. Laboratory tests may also reveal anemia and an enlarged spleen.
Severe thalassemia is treated with blood transfusions and an iron chelator to prevent iron toxicity. Thalassemia can only be cured with a successful bone marrow transplant, but a donor match is necessary and there are risks associated with the procedure. Although thalassemia can be severe and difficult to cure, there are treatment options available. With the proper treatment, patients diagnosed with thalassemia often live normal or near-normal lives.
Signs and symptoms
Signs and symptoms may vary depending on the type and severity of thalassemia. Typically, symptoms that appear are caused by a decrease in circulating oxygen from anemia and low hemoglobin. Some common symptoms may include fatigue, shortness of breath, jaundice, and bone deformities in the face. Laboratory tests may reveal anemia and an enlarged spleen.
Carriers of alpha thalassemia trait and beta thalassemia trait generally do not have symptoms. Alpha and beta thalassemia trait carriers may develop a mild form of anemia.
The onset of thalassemia intermedia disorders may occur in early childhood or later in life. Symptoms are mild to moderate and may include poor and abnormal bone growth.
Thalassemia major disorders usually appear early in childhood, which may be as early as two years of age. Symptoms may include poor appetite, slow growth, jaundice, delayed puberty, and enlarged liver, spleen, and heart. A symptom of life-threatening anemia is low oxygen circulation. A person that is born with alpha thalassemia major or hydrops fetalis usually dies before or shortly after birth.
Diagnosis
Blood tests: Thalassemia can be diagnosed by a complete blood count (CBC) and hemoglobin (HB) studies. A CBC will determine the amounts of hemoglobin and red blood cells that are present. Carriers will have a normal hemoglobin level but may have a slightly reduced red blood cell count. People with more severe forms of thalassemia will have a lower level of red blood cells and hemoglobin. Hemoglobin studies can distinguish between the types and amount of circulating hemoglobin. The normal types of circulating hemoglobin are HB A, A2, and F. Any variation in the level of these hemoglobin types may indicate a diagnosis of thalassemia. A diagnosis can be made by distinguishing between the variations in the hemoglobin subtypes.
Detection of beta thalassemia usually involves measuring the mean corpuscular volume (size of red blood cells). If the patient has beta thalassemia, the mean corpuscular volume will be slightly decreased. Hemoglobin tests will show an increased fraction of hemoglobin A2 (>2.5%) and a decreased fraction of hemoglobin A (<97.5%) for beta thalassemias.
In patients with decreased red blood cell count (anemia), further tests need to be performed to determine if thalassemia is the cause of the anemia. To do this, iron levels can be drawn to rule out iron deficiency anemia.
Genetic (DNA) testing: DNA tests may also be performed to confirm the presence of a mutated gene that may cause beta, alpha, or delta thalassemia. DNA tests are often used to confirm results from other tests, such as blood tests.
Prenatal genetic testing: Thalassemia may be diagnosed prior to birth by analyzing blood samples taken from the fetus. Diagnosis of thalassemia in a developing fetus may also be done through amniocentesis, in which the amniotic fluid surrounding the unborn baby is sampled through a needle. Blood cells from the amniotic fluid may indicate thalassemia. Genetic tests may also be performed on blood or amniotic fluid. Because taking a blood sample may cause harm to a developing fetus, taking samples of amniotic fluid is generally preferred. It is important to note that any prenatal test carries a risk of miscarriage.
Chorionic villus sampling (CVS): Chorionic villus sampling (CVS) is another type of prenatal diagnosis that can detect genetic problems in a fetus. Samples are taken from the chorionic villus or placental tissue. Any prenatal test carries a risk of miscarriage.
Pre-implantation genetic diagnosis (PGD): A new procedure called pre-implantation genetic diagnosis (PGD) may be performed on embryos produced by in vitro (artificial) fertilization. This test allows parents to implant and carry only the embryos that do not carry the mutated genes that cause thalassemia.
Complications
Mild forms of thalassemia do not shorten lifespan but severe thalassemia may lead to heart failure and death as early as 20 to 30 years of age. The use of transfusions and chelation therapy may improve the outcome. A successful bone marrow transplant will cure the disease.
If thalassemia major goes untreated, there may be an increased susceptibility to infection. Heart failure and liver problems may also occur.
Because there is not enough hemoglobin to bind the iron in the blood, there may be too much free iron in the blood. Therefore, iron toxicity may occur as a side effect of treatment. This can lead to heart, liver, and endocrine system damage. The concurrent use of deferasirox (Exjade?), an iron-chelating agent, may reduce the toxicity of iron therapy. A chelating agent binds to a specific substance and creates an inactive complex. Deferasirox binds to free iron and the complex it forms is then eliminated. This decreases free iron concentrations and reduces iron toxicity.
Treatment
General: Treatment of thalassemia varies depending on the severity of disease. All treatment of thalassemia should be supervised by a hematologist. Carriers or thalassemia trait carriers do not typically require treatment due to a lack of symptoms. Thalassemia trait and thalassemia minor are rarely life-threatening and require less treatment than thalassemia intermedia or thalassemia major. Thalassemias often occur together with folic acid deficiency and rarely iron deficiency (only in thalassemia minor). If untreated, severe thalassemia may result in heart failure and death as early as 20 to 30 years of age. Research is being done to examine the use of gene therapy in curing thalassemia before birth. In adults, research has been done on stimulating fetal hemoglobin production after birth.
Blood transfusion: Thalassemia intermedia, thalassemia major, and Cooley's anemia often require frequent blood transfusions and folate supplements. The transfusions are usually done every two to four weeks to keep the hemoglobin and red blood cell levels normal. A blood transfusion helps treat thalassemia by supplying normal, functioning blood components that help the cells of the body get enough oxygen. Frequent blood transfusions carry the risk of acquiring viral diseases (hepatitis, etc) and iron toxicity.
Bone marrow transplant: Thalassemia can be cured with a successful bone marrow transplant (BMT). A BMT can also reduce dependence on blood transfusions. BMT has been shown to be more effective when performed early in the disease progression. A BMT may provide cells that produce normal, functioning hemoglobin that may be otherwise nonfunctional in thalassemia. A proper donor must be found to do a BMT, and this procedure is considered high-risk due to possible complications. Complications that can occur from a BMT may include infection from the procedure and the body's rejection of and attack on the transplanted cells (Graft-versus-host disease).
Chelation therapy: Patients with thalassemia often require frequent blood transfusions depending on the severity of the disease. Because there is not enough hemoglobin to bind the iron in the blood of patients with thalassemia, there may be too much free iron in the blood. Iron supplements should be avoided and iron chelation therapy may be used to bind extra iron and prevent damage to the liver and heart. Iron chelation can be given intravenously (deferoxamine) or orally (deferasirox or Exjade?). A chelating agent binds to a specific substance and creates an inactive complex. Deferasirox binds to free iron and the complex it forms is then eliminated. This decreases free iron concentrations and reduces iron toxicity.
Surgery: A typical complication of thalassemia is enlargement of the spleen. In severe cases, the spleen can be removed surgically. The spleen is an essential part of a normal immune system and without one an individual may be prone to infections.
Integrative therapies
Note: The integrative therapies listed below should be used only under the supervision of a qualified healthcare provider and should not be used in replacement of other proven therapies.
Good scientific evidence:
Chelation:
One of the original uses of chelation therapy with calcium disodium EDTA was the treatment of heavy metal poisoning. Chelation remains an accepted therapy in medical institutions for lead toxicity, and several studies report lower levels of lead in the blood and slower progression of kidney failure. Chelation therapy may also be used when toxic levels of iron, arsenic, or mercury are present. Patients with thalassemia that require frequent blood transfusions often have elevated iron levels and possible iron toxicity. Avoid with heart disease, liver disease, kidney disease, immune system disorders, bleeding disorders, or if taking drugs that increase the risk of bleeding. Avoid if pregnant or breastfeeding due to potential toxic effects.
Unclear or conflicting scientific evidence:
Antineoplastons: Antineoplastons are a group of naturally occurring peptide fractions that have been studied for the treatment of various cancers, though antineoplaston therapy is not approved by the U.S. Food and Drug Administration (FDA). In recent years, antineoplastons have also been suggested as treatment for other conditions such as sickle cell anemia and thalassemia, but there is a lack of sufficient evidence from high-quality studies to support the use of antineoplastons for these indications.
Avoid if allergic or hypersensitive to antineoplastons. Use cautiously with high risk of medical or psychiatric disorders, an active infection due to a possible decrease in white blood cells, high blood pressure, heart conditions, chronic obstructive pulmonary disease, liver disease or damage, or kidney disease or damage. Avoid if pregnant or breastfeeding.
Wheatgrass: Evidence suggests that wheatgrass may be beneficial for patients with beta thalassemia. Its use may decrease the number of blood transfusions needed. However, further research is needed before a firm conclusion can be drawn. Wheatgrass is generally considered safe. Serious side effects have not been found in several studies using wheatgrass juice daily and there have been no other reports of adverse effects in the available literature. Because wheatgrass is grown in soils or water and consumed raw, it is possible that there may be contamination from bacteria, molds, or other substances. Allergic reactions to wheatgrass have been reported.
Zinc:
Limited human study has noted that children with beta-thalassemia who took oral zinc supplements for one to seven years increased in height more than those who did not take zinc. More research is needed to confirm these findings. Zinc is generally regarded as safe and well-tolerated when taken at recommended doses. Few studies have reported side effects with nausea, vomiting, or diarrhea being the most common side effects.
Traditional or theoretical uses lacking sufficient evidence:
Prevention
General: Because thalassemia is an inherited condition, there is currently no known way to prevent the disease. However, a number of options are available for parents with family histories of thalassemia.
Genetic testing and counseling: Individuals who have thalassemia may meet with genetic counselors to discuss the risks of having children with the disease. Genetic counselors can explain the options and the associated risks of various tests, including pre-implantation genetic diagnosis (PGD), amniocentesis, and chorionic villus sampling (CVS). PGD may be used with in vitro (artificial) fertilization. In PGD, embryos are tested for the genes that cause thalassemia and only the embryos that are free of those mutations may be implanted. This procedure is considered controversial.
Author information
This information has been edited and peer-reviewed by contributors to the Natural Standard Research Collaboration (www.naturalstandard.com).
Bibliography
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Fowkes FJ, Allen SJ, Allen A, et al. Increased microerythrocyte count in homozygous alpha(+)-thalassaemia contributes to protection against severe malarial anaemia. PLoS Med. 2008 Mar 18;5(3):e56.
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Causes
Thalassemia is caused by mutations, or genetic errors, in genes that produce hemoglobin. These mutations result in reduced levels of hemoglobin, which is a protein in red blood cells that is responsible for carrying oxygen.
The structure of hemoglobin is made up of four protein chains: two alpha hemoglobin (or alpha-globin) proteins and two beta hemoglobin (or beta-globin) proteins. Due to the reduced level of hemoglobin, there are fewer red blood cells circulating in the blood of individuals with thalassemia. Reduced numbers of red blood cells, also known as anemia, may be mild or severe.
Thalassemia is an inherited disorder, meaning that it is passed on from a parent to a child. It is often inherited as an autosomal recessive trait, meaning that two copies of a mutated gene (one inherited from each parent) are needed to cause the disorder. However, some forms of thalassemia may be autosomal dominant, in which case only one copy of a mutated gene is needed to cause the disorder.
A person who inherits a thalassemia gene or genes from one parent and normal genes from the other parent is called a carrier (thalassemia trait or thalassemia minor) and may pass the defective gene to offspring. Carriers typically have no signs and symptoms but may have mild anemia. If a person inherits more than one copy of the gene mutation, the disease is called thalassemia intermedia or thalassemia major. Patients are typically symptomatic with moderate to severe anemia.
Beta thalassemia: Mutations that result in abnormally low levels of beta-hemoglobin cause a condition known as beta thalassemia. The HBB gene is responsible for making beta hemoglobin and a mutation that causes decreased production of beta hemoglobin results in beta thalassemia. A related condition, called sickle cell disease, results when mutations in the HBB gene cause defective rather than reduced levels of hemoglobin B.
Beta thalassemia is classified based on the level of reduction in beta production. A reduction in beta hemoglobin leads to low levels of hemoglobin and may cause anemia depending on the severity. Mild forms of thalassemia are commonly called beta-plus thalassemia, while severe forms are often referred to as beta-zero-thalassemia. Beta-zero thalassemia is caused by the complete absence of beta protein production while beta-plus thalassemia is caused by a deficiency of beta protein production.
People with beta thalassemia minor or beta thalassemia trait only carry one gene defect, are often asymptomatic, and have only mild anemia. When both gene defects are inherited, but only moderate anemia occurs, it is called beta thalassemia intermedia. If severe anemia occurs, then the disease is called beta thalassemia major. Severe beta thalassemia is also called Cooley's anemia.
Beta defects are typically autosomal recessive, but in a small percentage of cases the HBB mutation follows an autosomal dominant pattern of inheritance. In a recessive disorder, if one parent is a carrier, there is a 50% chance with each birth that the child will also be a carrier and a 0% chance that the child will inherit the disease. If both parents are carriers, there is a 25% chance with each birth that the child will inherit the disease and a 50% chance that each child will be a carrier. Carriers typically have no signs and symptoms but some may have a mild form of anemia. If the disease is autosomal dominant and one parent has the disorder, there is a 50% risk that their child will have the disorder. If both parents have the disorder, there is a 75% chance that their child will have the disorder.
Alpha thalassemia: Alpha thalassemia is an autosomal recessive disorder that affects the production of alpha hemoglobin. There are two genes responsible for the production of alpha hemoglobin: HBA1 and HBA2. Two of each of these genes are inherited from each parent, so each individual has a total of four genes that make up alpha hemoglobin. Alpha thalassemia occurs when one or more of these four genes is defective. The classification of alpha thalassemia depends on how many genes are defective and the severity of symptoms.
When only one gene is defective, the person will have no sign of the alpha thalassemia. However, they can still pass the mutated gene to a child and are known as "silent carriers" of alpha thalassemia. Individuals who inherit two defective genes are said to have the alpha thalassemia trait (or alpha thalassemia minor). They are also considered carriers and may have mild anemia. Inheriting three genes results in hemoglobin H disease and is usually associated with moderate to severe anemia. If all four genes are defective, then this disorder is called alpha thalassemia major or hydrops fetalis. This is a very rare and serious disease that typically results in death shortly after birth.
Delta thalassemia: Only about 3% of hemoglobin contains any delta chains, and thus a defect in the delta genes is negligible in terms of severity of effects. Often an individual with delta defects has normal blood cell counts. Even though there are no immediate physical consequences of delta thalassemia, the defect can interfere with the diagnosis of beta thalassemias, which can be severe.
Risk factors
It is estimated that 60 to 80 million people worldwide carry the beta thalassemia trait, and an estimated 1,000 cases of thalassemia exist in the United States. Beta thalassemia is considered to be a fairly common blood disorder that is thought to affect several thousand infants every year.
Certain populations have a higher frequency of thalassemia. Beta thalassemia is more common among people of Mediterranean origin (Greek, Italian, Middle Eastern) and people of Asian and African descent. Alpha thalassemias mostly affect people of Southeast Asian, Indian, Chinese, or Filipino origin. Individuals with a family history of thalassemia have a higher risk of developing the disorder.
Autosomal recessive inheritance: Thalassemia is caused by a mutation in a gene that contains the instructions for making hemoglobin. Most thalassemias are inherited as an autosomal recessive trait except in a very small percentage of beta thalassemia cases. Therefore, individuals who inherit two copies of this mutation (one from each parent) will develop thalassemia. Individuals who inherit only one copy of the mutation may not have symptoms of thalassemia but are known as "carriers" (thalassemia trait or thalassemia minor) because they can pass on the mutation to their children.
If one parent carries the thalassemia trait, or only has one copy of the mutated gene, then each child will have a 50% chance of inheriting one mutated gene and also being a carrier. If both parents are carriers, each child has a 25% chance of inheriting two mutated genes, a 50% chance of inheriting only one mutation, and a 25% chance of inheriting neither of the mutations. Thus, if both parents are carriers, approximately one out of every four children will have a form of thalassemia.
If one parent has thalassemia and the other parent does not carry the trait, then all of the children will be carriers. If one parent has thalassemia and the other parent is a carrier, then each child has a 50% chance of having thalassemia and a 50% chance of being a carrier. If both parents have thalassemia, then all of their children will also have thalassemia.
Autosomal dominant inheritance: In a very small percentage of beta thalassemia cases, the disorder is inherited as an autosomal dominant trait. This means that just one copy of the mutated gene is needed for the disorder to occur. In other words, if one parent has beta thalassemia, there is a 50% chance that his/her child will have the disorder. If both parents have beta thalassemia, there is a 75% chance that the child will inherit the condition.
Types of the disease
Thalassemias are classified as alpha, beta, and rarely delta, depending on which hemoglobin gene is defective. These defects lead to reduced production of the proteins that make up hemoglobin.
Thalassemias can occur together with other hemoglobin defects. Some of the common combinations are with hemoglobin C, E, and S (HbC, HbE, and HbS), in which defective forms of beta hemoglobin cause a related disorder called sickle cell disease (SCD). These combinations result in a mix of different types of anemia (hemolytic and sickle cell) and possible splenomegaly (enlargement of the spleen).
Beta thalassemia: A mutation in the HBB gene, which is responsible for making beta hemoglobin, causes beta thalassemia. The classification of beta thalassemia depends on the level of reduction in beta production. A reduction in beta hemoglobin may result in anemia, depending on the level of functional hemoglobin.
People with beta thalassemia minor or beta thalassemia trait only carry one gene defect and are often asymptomatic or have mild anemia. Mild forms of thalassemia are commonly called beta-plus thalassemia, while severe forms are often referred to as beta-zero-thalassemia. There is a complete absence of beta protein production in beta-zero thalassemia, while beta-plus thalassemia is marked by a deficiency in beta protein production. When two thalassemia gene defects are inherited and moderate anemia is present, the disease is called beta thalassemia intermedia.
Beta thalassemia with severe anemia, in which two thalassemia gene mutations are inherited, is called beta thalassemia major. Severe beta thalassemia is also called Cooley's anemia. Beta defects typically follow an autosomal recessive pattern of inheritance although in a small percentage of cases, the HBB mutation is inherited as an autosomal dominant trait.
Treatment consists of blood transfusions and treatment of transfusion-caused iron overload especially for beta thalassemia major or Cooley's anemia. Beta-thalassemia may only be cured with successful bone marrow transplantation. However, there are risks associated with bone marrow transplants like infection and rejection of the transplant. These risks can be life-threatening and should always be monitored by a healthcare professional.
Alpha thalassemia: There are two genes responsible for the production of alpha hemoglobin: HBA1 and HBA2. Two of each of these genes are inherited from each parent, so each individual has a total of four genes that make alpha hemoglobin.
Alpha thalassemia is classified based on how many of the four genes are defective and the severity of symptoms. When only one gene is defective, the person is called a silent carrier and may have mild or no symptoms of the disease. People with the alpha thalassemia trait or alpha thalassemia minor are carriers with two defective genes and mild anemia. Inheriting three genes results in hemoglobin H disease and is usually associated with severe anemia. If all four genes are defective, then this disorder is called alpha thalassemia major or hydrops fetalis. This is a very rare and serious disease that typically results in death shortly after birth. Alpha thalassemia is inherited as an autosomal recessive trait.
Delta thalassemia: Only about 3% of hemoglobin contains any delta chains, and defects in the delta genes are not very severe. Often an individual with delta defects has normal blood cell counts. Even though there is no immediate physical consequence of delta thalassemia, it can interfere with the diagnosis of beta thalassemias, which can be severe.