Thalassemia is a group of inherited blood disorders that can be passed from parents to their children and affect the amount and type of hemoglobin the body produces.
Hemoglobin (Hb or Hgb) is a substance present in all red blood cells (RBCs). It is important for proper red blood cell function because it carries the oxygen that RBCs deliver around the body. One portion of hemoglobin called heme is the molecule with iron at the center. Another portion is made of up four protein chains called globins. Each of the four globin chains holds a heme group containing one iron atom. Depending on their structure, the globin chains are designated as alpha, beta, gamma, or delta.
Not all hemoglobin is the same. Different types of hemoglobin are classified according to the type of globin chains they contain. The type of globin chains present is important in hemoglobin’s ability to transport oxygen.
Normal hemoglobin types include:
Hemoglobin A – this is the predominant type of Hb in adults (about 95-98%); Hb A contains two alpha (α) protein chains and two beta (ß) protein chains.
Hb A2 – makes up about 2-3.5% of Hb found in adults; it has two alpha (α) and two delta (δ) protein chains.
Hb F – makes up to 2% of Hb found in adults; it has two alpha (α) and two gamma (γ) protein chains. Hb F is the primary hemoglobin produced by a developing baby (fetus) during pregnancy. Its production usually falls to a low level within a year after birth.
People with thalassemia have one or more genetic mutations that they have inherited and that result in a decreased production of normal hemoglobin. When the body doesn’t make enough normal hemoglobin, red blood cells do not function properly and oxygen delivery suffers. This can lead to anemia with signs and symptoms that can range from mild to severe, depending on the type of thalassemia that a person has. Examples of signs and symptoms include weakness, fatigue, and pale skin (pallor). See the Classifications section for more about the signs, symptoms, and complications of the different types of thalassemia.
For hemoglobin, there are four genes in our DNA that code for the alpha globin chains and two genes (each) for the beta, delta, and gamma globin chains. Since everyone inherits a set of chromosomes from each parent, each person inherits two alpha globulin genes and one beta globulin gene from each parent. (For general information on genetics, see The Universe of Genetic Testing.) A person may inherit mutations in either the alpha or beta globin genes.
With thalassemias, mutations in one or more of the globin genes cause a reduction in the amount of the particular globin chain produced. This can upset the balance of alpha to beta chains, resulting in unusual forms of hemoglobin or an increase in the amount of normally minor hemoglobin, such as Hb A2 or Hb F. The thalassemias are usually classified by the type of globin chain whose synthesis is decreased. For example, the most common alpha chain-related condition is called alpha thalassemia. The severity of this condition depends on the number of genes affected.
Other types of mutations in the genes coding for the globin chains can result in a globin that is structurally altered, such as hemoglobin S, which causes sickle cell. The inherited disorders that result in the production of an abnormal hemoglobin molecule are described in the article on Hemoglobin Abnormalities. Together, thalassemia and hemoglobin abnormalities are called hemoglobinopathies.
Alpha thalassemia is caused by a deletion or mutation in one or more of the four alpha globin gene copies. The mutation causes a decrease in the production of alpha globin. The more genes that are affected, the less alpha globin is produced by the body. The four different types of alpha thalassemia are classified according to the number of genes affected and include:
Silent Carrier State (1 gene affected)
People who have mutation(s) in only one alpha globin gene are silent carriers. They usually have normal hemoglobin levels and red cell indices but can pass on the affected gene to their children. These individuals have no signs or symptoms and are usually identified only after having a child with thalassemia. The only way to identify a silent carrier is by DNA analysis (see Thalassemia Tests).
Alpha Thalassemia Trait (2 genes affected)
People who have alpha thalassemia trait have red blood cells (RBCs) that are smaller (microcytic) and paler (hypochromic) than normal, have a decreased MCV (mean corpuscular volume, a measurement of the average size of a single RBC), and have a mild chronic anemia. They generally do not have other signs and sometimes may lack symptoms. This form of anemia does not respond to iron supplements. Diagnosis of alpha thalassemia trait is usually done by exclusion of other causes of microcytic anemia. Confirmatory testing by DNA analysis is available but is not routinely done.
Hemoglobin H Disease (3 genes affected)
With this condition, the large decrease in alpha globin chain production causes an excess of beta chains, which then come together into groups of 4 beta chains, known as Hemoglobin H, which is visible inside red blood cells on a specially stained blood smear. Hb H disease can cause moderate to severe anemia and serious health problems such as an enlarged spleen, bone deformities, and fatigue. The signs and symptoms associated with Hb H disease vary widely. Some individuals are asymptomatic while others have severe anemia, requiring regular medical care. Hemoglobin H disease is found most often in individuals of Southeast Asian or Mediterranean descent.
Alpha Thalassemia Major (also called hydrops fetalis, 4 genes affected).
This is the most severe form of alpha thalassemia. In this condition, no alpha globin is produced, therefore, no normal hemoglobin is produced. Fetuses affected by alpha thalassemia major become anemic early during the pregnancy. They retain excess fluids (hydropic) and frequently have enlarged hearts and livers. This diagnosis is frequently made in the last months of pregnancy when a fetal ultrasound indicates a hydropic fetus. There are also risks for the pregnant mother. About 80% of the time, the mother will have “toxemia” (protein in the urine, high blood pressure, swollen ankles and feet) and can develop severe postpartum bleeding (hemorrhage). Fetuses with alpha thalassemia major are usually miscarried, stillborn, or die shortly after birth. In very rare cases, children with alpha thalassemia have survived through in utero blood transfusions and extensive medical care.
Alpha thalassemia is found most commonly in individuals of Southeast Asian, Southern Chinese, Middle Eastern, Indian, African, and Mediterranean descent.
Beta thalassemia is caused by mutations in one or both of the beta globin genes. There have been more than 250 mutations identified, but only about 20 are the most common. The severity of the anemia caused by beta thalassemia depends on which mutations are present and whether there is decreased beta globin production (called beta+ thalassemia) or if production is completely absent (called beta thalassemia). The different types of beta thalassemia include:
Beta Thalassemia Trait or Beta Thalassemia Minor
Individuals with this condition have one normal gene and one with a mutation, causing a mild decrease in beta globin production. They usually have no health problems other than abnormally small red blood cells and a possible mild anemia that will not respond to iron supplements. An individual’s children can inherit this gene.
In this condition, an affected person has two abnormal genes, causing moderate to severe decrease in beta globin production. These individuals may develop symptoms later than those with thalassemia major (see below) and often with milder symptoms. They rarely require treatment with blood transfusion. The severity of the anemia and health problems experienced depends on the mutation types present. The dividing line between thalassemia intermedia and thalassemia major is the degree of anemia and the number and frequency of blood transfusions required. Those with thalassemia intermedia may need occasional transfusions but do not require them on a regular basis.
Thalassemia Major or Cooley’s Anemia
This is the most severe form of beta thalassemia. These individuals have two abnormal genes that cause either a severe decrease or complete lack of beta globin production, preventing the production of significant amounts of normal hemoglobin (Hb A). This condition usually appears within the first two years of life and causes life-threatening anemia, poor growth, and skeletal abnormalities during infancy. This anemia requires lifelong regular blood transfusions and considerable ongoing medical care. Over time, these frequent transfusions lead to excessive amounts of iron in the body. Left untreated, this excess iron can deposit in the liver, heart, and other organs and can lead to a premature death from organ failure. Therefore, individuals undergoing transfusion may need chelation therapy to reduce iron overload.
Beta thalassemia is found most commonly in populations of Mediterranean, African, and Southeast Asian descent in the U.S. This is likely associated with the incidence of malaria in those regions since thalassemia can increase malaria tolerance. In those regions, thalassemia incidence may be as high as 10%.
Other forms of thalassemia occur when a gene for beta thalassemia is inherited in combination with a gene for a hemoglobin variant. The most important of these are:
Hb E-beta thalassemia
Hb E is one of the most common hemoglobin variants. It is found predominantly in people of Southeast Asian and African descent. If a person inherits one Hb E gene and one beta thalassemia gene, the combination produces Hb E-beta thalassemia, which causes a moderately severe anemia similar to beta thalassemia intermedia.
Hb S-beta thalassemia or sickle cell-beta thalassemia
Hb S is one of the most well known of the hemoglobin variants. Inheritance of one Hb S gene and one beta thalassemia gene results in Hb S-beta thalassemia. The severity of the condition depends on the amount of beta globin produced by the beta gene. If no beta globin is produced, the clinical picture is similar to sickle cell disease but with even worse baseline anemia.
Laboratory Tests for Thalassemia
Several laboratory tests may be used to help detect and diagnose thalassemia:
Complete blood count (CBC)
The CBC is an evaluation of the cells in the blood. Among other things, the CBC determines the number of red blood cells present and how much hemoglobin is in them. It evaluates the size and shape of the red blood cells present, reported as the red cell indices. These include the mean corpuscular volume (MCV), a measurement of the size of the red blood cells. A low MCV is often the first indication of thalassemia. If the MCV is low and iron deficiency has been ruled out as a cause, thalassemia should be considered.
Blood smear (also called peripheral smear and manual differential)
In this test, a trained laboratory professional examines a thin layer of blood that is treated with a special stain, on a slide, under a microscope. The number and type of white blood cells, red blood cells, and platelets are evaluated to see if they are normal and mature. With thalassemia, the red blood cells often appear smaller than normal (microcytic, low MCV). Red cells may also:
Be paler than normal (hypochromic)
Vary in size and shape (anisocytosis and poikilocytosis)
Be nucleated (normal, mature RBCs do not have a nucleus)
Have uneven hemoglobin distribution (producing “target cells” that look like a bull’s-eye under the microscope)
The greater the percentage of abnormal-looking red blood cells, the greater the likelihood of an underlying disorder and decreased ability of the RBCs to carry oxygen.
These may include: iron, ferritin, unsaturated iron binding capacity (UIBC), total iron binding capacity (TIBC), and percent saturation of transferrin. These tests measure different aspects of the body’s iron storage and usage. The tests are ordered to help determine whether an iron deficiency is the cause of a person’s anemia. One or more of them may also be ordered to help monitor the degree of iron overload in an individual with thalassemia.
Alpha thalassemia is sometimes confused with iron deficiency anemia because both disorders have smaller than usual (microcytic) red blood cells. If someone has thalassemia, his or her iron levels are not expected to be low. Iron therapy will not help people with alpha thalassemia and may lead to iron overload, which can cause organ damage over time.
Erythrocyte porphyrin tests may be used to distinguish an unclear beta thalassemia minor diagnosis from iron deficiency or lead poisoning. Individuals with beta thalassemia will have normal porphyrin levels, but those with the latter conditions will have elevated porphyrin.
Hemoglobinopathy (Hb) evaluation (hemoglobin electrophoresis)
This test assess the type and relative amounts of hemoglobin present in red blood cells. Hemoglobin A (Hb A), composed of both alpha and beta globin, is the type of hemoglobin that normally makes up 95% to 98% of hemoglobin in adults. Hemoglobin A2 (HbA2) is usually 2% to 3% of hemoglobin in adults, while hemoglobin F usually makes up less than 2%.
Beta thalassemia upsets the balance of beta and alpha hemoglobin chain formation and causes an increase in those minor hemoglobin components. So individuals with the beta thalassemia major usually have larger percentages of Hb F. Those with beta thalassemia minor usually have elevated fraction of Hb A2. Hb H is a less common form of hemoglobin that may be seen in some cases of alpha thalassemia. Hb S is the hemoglobin more common in people with sickle cell disease.
Hemoglobinopathy (Hb) evaluations are used for state-mandated newborn hemoglobin screening and prenatal screening when parents are at high risk for hemoglobin abnormalities.
These tests are used to help confirm mutations in the alpha and beta globin-producing genes. DNA testing is not routinely done but can be used to help diagnose thalassemia and to determine carrier status, if indicated.
For beta thalassemia, the hemoglobin beta gene, HBB, may be analyzed or sequenced to confirm the presence of thalassemia-causing mutations. Genetic tests may also be given for other HBB mutations such as Hb S mutation, which is associated with sickle cell disease. More than 250 mutations have been associated with beta thalassemia, though some cause no signs or symptoms. However, others decrease the amount of beta globin production and some prevent it completely. The presence of one of those mutations confirms a diagnosis of beta thalassemia.
The primary molecular test available for alpha thalassemia detects common mutations (e.g., deletions) in the two alpha genes HBA1 and HBA2. Each person has two copies of each of these genes, called alleles, in their cells, one from their mother and one from their father. These alleles govern alpha globin production and if mutations lead to functional loss of one or more of alpha genes, alpha thalassemia occurs.
Since having relatives who carry mutations for thalassemia increases a person’s risk of carrying the same mutant gene, family studies may be done to evaluate carrier status and the types of mutations present in other family members if deemed necessary by a healthcare practitioner.
Genetic testing of amniotic fluid is used in the rare instances a fetus is at increased risk for thalassemia. This is especially important if both parents likely carry a mutation because that increases the risk that their child may inherit a combination of abnormal genes, causing a more severe form of thalassemia.
Most individuals with mild thalassemia traits require no treatment. They may want to consider genetic counseling, however, because they may pass the mutant gene on to their children.
People with hemoglobin H disease or beta thalassemia intermedia will experience variable amounts of anemia throughout their life. They can live relatively normal lives but will require regular monitoring and may occasionally need blood transfusion. Folic acid supplementation is often given, but iron supplementation is not recommended.
Those with beta thalassemia major will usually require regular blood transfusions, as frequently as every few weeks, and chelation therapy to remove iron throughout their life. These transfusions help maintain hemoglobin at a high enough level to provide oxygen to the body and prevent growth abnormalities and organ damage. Frequent transfusions, however, can raise body iron to toxic levels, resulting in deposits of iron in the liver, heart, and other organs. Regular iron chelation therapy is used to help decrease iron in the body.
Bone marrow transplant known as hematopoietic stem cell transplantation can also be used for treatment of beta thalassemia major.
Fetuses with alpha thalassemia major are usually miscarried, stillborn, or die shortly after birth. Experimental treatments, such as fetal blood transfusions and even fetal marrow transplant, have been successful in a very few cases in bringing a baby to term.