Thalassemia (thal-uh-SEE-me-uh) is an inherited blood disorder characterized by less hemoglobin and fewer red blood cells in your body than normal. Several types of thalassemia exist, including alpha-thalassemia, beta-thalassemia intermedia, Cooley’s anemia and Mediterranean anemia.
Hemoglobin is the substance in your red blood cells that allows them to carry oxygen. The low hemoglobin and fewer red blood cells of thalassemia may cause anemia, leaving you fatigued.
If you have mild thalassemia, you may not need treatment. But, if you have a more severe form of thalassemia, you may need regular blood transfusions. You can also take steps on your own to cope with fatigue, such as choosing a healthy diet and exercising regularly.
Your body makes three types of blood cells: red blood cells, white blood cells, and platelets (PLATE-lets). Red blood cells contain hemoglobin, an iron-rich protein that carries oxygen from your lungs to all parts of your body. Hemoglobin also carries carbon dioxide (a waste gas) from your body to your lungs, where it’s exhaled.
Hemoglobin has two kinds of protein chains: alpha globin and beta globin. If your body doesn’t make enough of these protein chains or they’re abnormal, red blood cells won’t form correctly or carry enough oxygen. Your body won’t work well if your red blood cells don’t make enough healthy hemoglobin.
Genes control how the body makes hemoglobin protein chains. When these genes are missing or altered, thalassemias occur.
Thalassemias are inherited disorders—that is, they’re passed from parents to children through genes. People who inherit faulty hemoglobin genes from one parent but normal genes from the other are called carriers. Carriers often have no signs of illness other than mild anemia. However, they can pass the faulty genes on to their children.
People who have moderate to severe forms of thalassemia have inherited faulty genes from both parents.
The thalassemias are inherited disorders of Hb synthesis that result from an alteration in the rate of globin chain production. A decrease in the rate of production of a certain globin chain or chains (α, β, γ, δ) impedes Hb synthesis and creates an imbalance with the other, normally produced globin chains.
Because 2 types of chains (α and non-α) pair with each other at a ratio close to 1:1 to form normal Hbs, an excess of the normally produced type is present and accumulates in the cell as an unstable product, leading to the destruction of the cell. This imbalance is the hallmark of all forms of thalassemia. For this reason, most thalassemias are not considered hemoglobinopathies because the globin chains are normal in structure and because the defect is limited to a decreased rate of production of these normal chains. However, thalassemichemoglobinopathies are recognized, as discussed below.
The type of thalassemia usually carries the name of the underproduced chain or chains. The reduction varies from a slight decrease to a complete absence of production. For example, when β chains are produced at a lower rate, the thalassemia is termed β+, whereas β-0 thalassemia indicates a complete absence of production of β chains from the involved allele.
The consequences of impaired production of globin chains ultimately result in the deposition of less Hb into each RBC, leading to hypochromasia. The Hb deficiency causes RBCs to be smaller, leading to the classic hypochromic and microcytic picture of thalassemia. This is true in almost all anemias caused by impairment in production of either of the 2 main components of Hb: heme or globin. However, this does not occur in the silent carrier state, since both Hb level and RBC indices remain normal.
In the most common type of β thalassemia trait, the level of Hb A2 (δ2/α2) is usually elevated. This is due to the increased use of δ chains by the excessive free α chains, which results from a lack of adequate β chains with which to pair. The δ gene, unlike β and α genes, is known to have a physiologic limitation in its ability to produce adequate δ chains; by pairing with the α chains, δ chains produce HbA2(approximately 2.5-3% of the total Hb).
Some, but not all, of the excessive α chains are used to form Hb A2 with the δ chains, whereas the remaining α chains precipitate in the cells, reacting with cell membranes, intervening with normal cell division, and acting as foreign bodies, leading to destruction of RBCs. The degree of toxicity caused by the excessive chains varies according to the type of such chains (eg, the toxicity of α chains in β thalassemia is more prominent than the toxicity of β chains in α thalassemia).
β thalassemia is mostly related to a point mutation in the β globin gene. However, large deletions that may involve the entire β gene, or even extend to delete the neighboring δ gene, have been previously reported. Four new such mutations were identified in French patients. In 3 of these mutations, the deletion has extended to involve the δ gene, resulting in failure to produce any Hb A2. In such cases, the β/δ thalassemia is to be differentiated from the phenotypically similar condition known as hereditary persistence of fetalhemoglobin (HPFH). The importance of differentiating the conditions is reflected in prenatal and newborn screening for hemoglobinopathy.
In the severe forms, such as β thalassemia major or Cooley anemia, the same pathophysiology applies with substantial exaggeration. The significant excess of free α chains caused by the deficiency of β chains causes destruction of the RBC precursors in the bone marrow (ie, ineffective erythropoiesis).
Globin chain production
To understand the genetic changes that result in thalassemia, one should be familiar with the physiologic process of globin chain production in the healthy individual. The globin chain as a unit is a major building block for Hb: together with heme, it produces the Hb molecule (heme plus globin equals Hb). Two different pairs of globin chains form a tetrameric structure with a heme moiety in the center. All normal Hbs are formed from 2 α-like chains and 2 non-α chains. Various types of Hb are formed, depending on the types of chains pairing together. Such Hbs exhibit different oxygen-binding characteristics, normally related to the oxygen delivery requirement at different developmental stages in human life.
In embryonic life, ζ chains (α-like chains) combine with γ chains to produce Hb Portland (ζ2/γ2) and with ε chains to produce Hb Gower-1 (ζ2/ε2).
Thalassemia symptoms include:
- Pale appearance
- Yellow discoloration of skin (jaundice)
- Facial bone deformities
- Slow growth
- Abdominal swelling
- Dark urine
The signs and symptoms you experience depend on the type and severity of thalassemia you have. Some babies show signs and symptoms of thalassemia at birth, while others may develop signs or symptoms during the first two years of life. Some people who have only one affected hemoglobin gene don’t experience any thalassemia symptoms.
Doctors diagnose thalassemias using blood tests, including a complete blood count (CBC) and special hemoglobin tests.
- A CBC measures the amount of hemoglobin and the different kinds of blood cells, such as red blood cells, in a sample of blood. People who have thalassemias have fewer healthy red blood cells and less hemoglobin than normal in their blood. People who have alpha or beta thalassemia trait may have red blood cells that are smaller than normal.
- Hemoglobin tests measure the types of hemoglobin in a blood sample. People who have thalassemias have problems with the alpha or beta globin protein chains of hemoglobin.
Moderate and severe thalassemias usually are diagnosed in early childhood. This is because signs and symptoms, including severeanemia, often occur within the first 2 years of life.
People who have milder forms of thalassemia might be diagnosed after a routine blood test shows they have anemia. Doctors might suspect thalassemia if a person has anemia and is a member of an ethnic group that’s at increased risk for thalassemias. (For more information, go to “Who Is at Risk for Thalassemias?”)
Doctors also test the amount of iron in the blood to find out whether the anemia is due to iron deficiency or thalassemia. Iron-deficiency anemia occurs if the body doesn’t have enough iron to make hemoglobin. The anemia in thalassemia occurs because of a problem with either the alpha globin or beta globin chains of hemoglobin, not because of a lack of iron.
Because thalassemias are passed from parents to children through genes, family genetic studies also can help diagnose the disorder. These studies involve taking a family medical history and doing blood tests on family members. The tests will show whether any family members have missing or altered hemoglobin genes.
If you know of family members who have thalassemias and you’re thinking of having children, consider talking with your doctor and a genetic counselor. They can help determine your risk for passing the disorder to your children.
If you’re expecting a baby and you and your partner are thalassemia carriers, you may want to consider prenatal testing.
Prenatal testing involves taking a sample of amniotic fluid or tissue from the placenta. (Amniotic fluid is the fluid in the sac surrounding a growing embryo. The placenta is the organ that attaches the umbilical cord to the mother’s womb.) Tests done on the fluid or tissue can show whether your baby has thalassemia and how severe it might be.
Treatment for thalassemia depends on which type you have and how severe it is.
Treatments for mild thalassemia
Signs and symptoms are usually mild with thalassemia minor and little, if any, treatment is needed. Occasionally, you may need a blood transfusion, particularly after surgery, after having a baby or to help manage thalassemia complications.
Some people with beta-thalassemia intermedia may need treatment for iron overload. Although most people with this condition don’t need the blood transfusions that often cause iron overload, people with beta-thalassemia intermedia may have increased digestive absorption of iron, leading to an excess of iron. An oral medication called deferasirox (Exjade) can help remove the excess iron.
Treatments for moderate to severe thalassemia
Treatments for moderate to severe thalassemia may include:
- Frequent blood transfusions. More-severe forms of thalassemia often require frequent blood transfusions, possibly every few weeks. Over time, blood transfusions cause a buildup of iron in your blood, which can damage your heart, liver and other organs. To help your body get rid of the extra iron, you may need to take medications that rid your body of extra iron.
- Stem cell transplant. Also called a bone marrow transplant, a stem cell transplant may be used to treat severe thalassemia in select cases. Prior to a stem cell transplant, you receive very high doses of drugs or radiation to destroy your diseased bone marrow. Then you receive infusions of stem cells from a compatible donor. However, because these procedures have serious risks, including death, they’re generally reserved for people with the most severe disease who have a well-matched donor available — usually a sibling.