Thalassaemia



Last Review Date: November 23, 2018


What is it?

Thalassaemia is a group of inherited disorders that affect the amount of haemoglobin a person produces. Haemoglobin refers to a family of compounds all made up of haem (an iron-containing complex), and various globins (protein chains that surround the haem complex). Haemoglobin (Hb) molecules are found in all red blood cells, and are the reason for their red colour. They bind oxygen in the lungs, carry it through the bloodstream, and release it to the body’s tissues. Different types of haemoglobin are classified according to the type of protein chains they contain.

Normal adult haemoglobins include:

  • Haemoglobin A (makes up about 95% - 98% of adult Hb). HbA contains two alpha (α) protein chains and two beta (ß) chains.
  • HbA2 (makes up about 2% - 3.5% of adult Hb), has two alpha (α) and two delta (δ) chains
  • HbF (up to 2%). This is the primary haemoglobin produced by the fetus during gestation. Its production usually falls to a low level within a year after birth. HbF has two alpha (α) and two gamma (γ) chains.

Mutations in the genes coding for the globin chains can cause disorders in haemoglobin production. There are 4 genes that code for alpha globin chains and 2 genes that code for the beta globin chains.

Inherited disorders of haemoglobin production fall into two categories:

  • Thalassaemia: decreased production of normal haemoglobins
  • Haemoglobinopathy: production of an abnormal haemoglobin molecule

Thalassaemias are a group of disorders in which mutations in one or more of the alpha or beta globin genes cause a reduction in the amount of the HbA produced. This leads to a reduction in HbA, the relative increase in the amount of minor haemoglobins HbA2 and HbF, and perhaps detection of unusual haemoglobin types.

The thalassaemias are usually classified by the type of globin chain whose synthesis is reduced.


Thalassaemia Classifications


Alpha thalassaemia

Alpha thalassaemia is due to a deletion or mutation in one or more of the 4 alpha globin gene copies. The more genes affected, the less alpha globin produced. The four different types of alpha thalassaemia include:

  • Alpha thalassaemia trait (1 affected gene). The silent carrier will have normal haemoglobin levels and red cell indices which are normal or show a slightly decreased MCH (hypochromia). Carriers can pass on the affected gene to their offspring. Often these individuals are identified only after having a child with HbH disease or alpha thalassaemia trait.
  • Alpha thalassaemia trait (2 affected genes). Patients who have alpha thalassaemia trait have smaller (microcytic), paler (hypochromic) red blood cells and a mild chronic anaemia but do not generally experience any symptoms. This is an anaemia that does not respond to iron supplements. Diagnosis of alpha thalassaemia trait is usually by exclusion of other causes of microcytic anaemia. Confirmatory testing by DNA analysis is an important part of the testing process for Alpha thalassaemia because there are two copies (HbA1 and HbA2) of the alpha-chain gene on each chromosome. If the person has lost both copies from one chromosome this has different implications for passing on a more serious form of the disease to their children than if they have lost one copy from each of the two different chromosome. See the section on DNA analysis below.
  • Haemoglobin H disease (3 affected genes). With this condition, the large decrease in the amount of alpha globin chains produced causes an excess of beta chains which then aggregate into beta4 tetramers (groups of 4 beta chains), known as haemoglobin H. HbH disease can cause moderate to severe anaemia and splenomegaly (enlarged spleen). The clinical picture associated with HbH disease is extremely variable. Some individuals are asymptomatic while others have severe anaemia. Haemoglobin H disease is found most often in individuals of Southeast Asian or Eastern Mediterranean descent.
  • Alpha thalassaemia major (also called hydrops fetalis, 4 affected genes). This is the most severe form of alpha thalassaemia. In this condition, no alpha globin is produced, therefore, no HbA or HbF are produced. Fetuses affected by alpha thalassaemia major become anaemic early in pregnancy. They become hydropic (retain fluids), 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. About 80% of the time the mother will have toxaemia and can develop severe postpartum haemorrhage (bleeding). Fetuses with alpha thalassaemia major are usually miscarried, stillborn, or die shortly after birth.

Individuals with alpha thalassaemia may be misdiagnosed as iron deficient by unwary doctors, as iron deficiency also leads to small pale (microcytic hypochromic) red cells. It is important that iron therapy in thalassaemic patients is only given when specific iron tests (ferritin, serum iron, TIBC, transferrin) have confirmed iron deficiency. This is especially important in alpha thalassaemia, where there is a small potential for dangerous iron overload to develop.

Alpha thalassaemia is found most commonly in individuals with an ethnic background of Southeast Asia, Southern China, the Middle East, India, Africa and the Mediterranean.
 

Beta thalassaemia

Beta thalassaemia is due to mutations, in one or both of the beta globin genes. There are 100 to 200 mutations that have been identified but only about 20 are common. The severity of the anaemia caused by beta thalassaemia depends on which mutations are present and on whether they decrease beta globin production (called beta+ thalassaemia) or completely eliminate it (called beta0 thalassaemia). The different types of beta thalassaemia include:

  • Beta thalassaemia trait. A person with this condition has one normal gene and one with a mutation. They will usually experience no health problems other than microcytosis (small red blood cells) and a possible mild anaemia that will not respond to iron supplements. This gene mutation can be passed on to an individual’s children.
  • Thalassaemia intermedia. In this condition, an affected person has two abnormal genes but is still producing some beta globin. The severity of the anaemia and health problems experienced depends on the mutations present. The dividing line between thalassaemia intermedia and thalassaemia major is the degree of anaemia and the number and frequency of blood transfusions required to treat it. Those with thalassaemia intermedia may need occasional transfusions but do not require them on a regular basis.
  • Thalassaemia major. This is the most severe form of beta thalassaemia. The patient has two abnormal genes that cause either a severe decrease or complete lack of beta globin production, preventing the production of significant amounts of HbA. This condition usually appears in an infant after 3 months of age and causes life-threatening anaemia. This anaemia 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 into the liver, heart and other organs, and can lead to a premature death from organ failure.

Other forms of thalassaemia occur when a gene for beta thalassaemia is inherited in combination with a gene for a haemoglobin variant. The most important of these are:

  • HbE – beta thalassaemia. HbE is one of the most common haemoglobin variants, found predominantly in people of Southeast Asian descent. If a person inherits one HbE gene and one beta thalassaemia gene, the combination produces HbE-beta thalassaemia which causes a moderately severe anaemia similar to beta thalassaemia intermedia.
  • HbS – beta thalassaemia or sickle cell – beta thalassaemia. HbS is one of the most well known of the haemoglobin variants. Inheritance of one HbS gene and one beta thalassaemia gene results in HbS-beta thalassaemia. 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 almost identical to sickle cell disease.

Laboratory tests

FBC (full blood count). The FBC is a snapshot of the cells and fluid in your bloodstream. Among other things, the FBC will tell the doctor how many red blood cells are present, how much haemoglobin is in them, and measure the size and shape of the red blood cells present. These variables are call red cell indices and include the MCH (mean corpuscular haemoglobin) and MCV (mean corpuscular volume), as measurements of the haemoglobin content and size of the red blood cells. A low MCH or MCV is often the first indication of thalassaemia. If the MCH or MCV is low and iron-deficiency has been ruled out, the person may be a thalassaemia trait carrier. if iron deficiency is present it is difficult to rule out thalassaemia.


Find out about the Full Blood Count

Blood film (smear). In this test a thin stained layer of blood is examined on a slide, under a microscope. The number and type of white blood cells, red blood cells, and platelets can be manually counted and be evaluated to see if they are normal and mature. A variety of disorders affect normal blood cell production. With thalassaemia, the red blood cells are often microcytic (small) with a low MCV. They may also be:

  • Hypochromic (pale – indicating less haemoglobin than normal)
  • Vary in size (anisocytosis) and shape (poikilocytosis)
  • Be nucleated (not normal in a mature RBC)
  • Be distorted to produce “target cells”, which look like a bull’s-eye under the microscope.

Iron studies. These may include: iron, ferritin, UIBC, TIBC, and percent saturation of transferrin. These tests measure different aspects of the body’s iron storage and usage. They are ordered to help determine whether an iron deficiency is causing and/or exacerbating a patient’s anaemia. One or more of them may also be ordered to help monitor the degree of iron overload in a patient with thalassaemia.

Haemoglobinopathy (Hb) evaluation. This test measures the type and relative amounts of haemoglobins present in the red blood cells. Haemoglobin A, composed of both alpha and beta globin, is the major normal type of haemoglobin found in adults. A greater percentage of HbA2 and/or HbF is usually seen in beta thalassaemia trait. HbH may be seen in alpha thalassaemia, but only when at least two of the four alpha genes are deleted or mutated.

DNA analysis. In many cases DNA analysis is not required because the diagnosis can be made from the results of the above tests. DNA analysis is most commonly used in families affected by alpha-thalassaemia. This test is used to investigate deletions and mutations in the alpha and less commonly the beta globin producing genes. Family studies can be done to evaluate carrier status and the types of mutations present in other family members. DNA testing is an important tool in establishing an accurate diagnosis of thalassaemia. In particular in alpha thalassaemia it is important to know if a person with alpha thalassaemia trait has two mutated genes on one chromosome or one on each chromosome. DNA analysis is also the only reliable way of diagnosing carriers who have only one of four alpha genes deleted or mutated and who have normal haemoglobin and red cells in the basic blood tests.

For more on inheritance of thalassaemias see this NSW Health Genetics Education Fact Sheet.


Treatment

Most individuals with thalassaemia require no treatment. All individuals with a diagnosis of thalassaemia who are planning a family are strongly encouraged to seek genetic counselling to understand the implications for their offspring. This requires the laboratory to perform genetic testing of their partner so that the genetic counsellor provides accurate information about the risk of passing on affected genes to their children and the severity of the thalassasemia or haemoglobinopathy that may develop.

Patients with haemoglobin H disease or beta thalassaemia intermedia will experience variable amounts of anaemia throughout their life. They can lead relatively normal lives but will require regular monitoring and may occasionally need a blood transfusion. Folic acid supplementation is often given to help combat anaemia but iron supplementation is to be avoided unless iron deficiency has been confirmed with more specific tests.

Often changes in the red cell indices are observed when a woman is pregnant, this may at times lead to severe anaemia. Understanding the impact of the diagnosis of thalassaemia on pregnancy and the possible health consequences for a couple’s offspring is one of the most important reasons to obtain an accurate diagnosis of thalassaemia.

Those with beta thalassaemia major will usually require blood transfusions about every 3 or 4 weeks throughout their life. These transfusions help maintain haemoglobin at a high enough concentration to provide oxygen to the body and prevent growth abnormalities and organ damage. Frequent transfusions, however, raise 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. This involves the administration of a drug that binds with the iron and helps flush it out of the body through the urine. A splenectomy may also be required.

Fetuses with alpha thalassaemia major are usually miscarried, stillborn, or die shortly after birth. Treatment is centred on identifying the condition, and either terminating the pregnancy or monitoring the mother for complications. Experimental treatments, such as fetal blood transfusions, have been successful in a very few cases in bringing a baby to term.


Related pages

On this site
Tests: Full blood count (FBC), haemoglobin, ferritin, TIBC & transferrin, iron, iron studies, haemoglobin variants, blood film
Conditions: Anaemia
Inside the lab: Genetic testing

Elsewhere on the web
Thalassaemia Australia
Healthdirect Australia - thalassaemia
Better Health Channel: Thalassaemia
NSW Centre for Genetics Education – Factsheet. Thalassaemia (pdf)