This is part of Rare diseases.

Diagnosis: Thalassemia

Synonyms: --


Date of publication: 2005-11-29
Version: 1.1

The disease

Thalassemia is a group of inherited blood disorders characterised by mild to severe anaemia caused by haemoglobin deficiency in the red blood cells. In individuals with thalassemia, the production of the oxygen-carrying blood pigment haemoglobin is abnormally low, or the molecule structure of the haemoglobin is altered.

There are two main types of thalassemia: alpha thalassemia and beta thalassemia. In each variant a different part of the haemoglobin protein is defective. Individuals with mild thalassemia may be practically symptom-free throughout their lives. Intermediate to severe cases are associated with a variety of symptoms, such as anaemia, enlarged liver and spleen, increased susceptibility to infection, slow growth, thin and brittle bones, and heart failure.


A national survey carried out in 2004 identified approximately 35 individuals with severe beta thalassemia in Sweden. The disorder is common in parts of the world with a history of malaria epidemics, and it is estimated that about 3 per cent of the world's population are carriers of a gene for thalassemia.

In a WHO survey carried out in 1994, it was estimated that about 26,000 babies are born with severe beta thalassemia each year, while 4,500 are affected by the most severe form of alpha thalassemia, resulting in foetal or neonatal death. Alpha thalassemia primarily occurs in individuals with Southeast Asian ancestry, and the beta type is common in the Mediterranean region, North Africa, the Middle East, India and Southeast Asia.

Screening programmes detecting carriers of the genetic trait for beta thalassemia and the availability of prenatal diagnostics (for example in Greece and Italy) have significantly reduced the number of infants born with beta thalassemia. As a result of immigration flows to northern Europe, more children are currently born with the condition in this area than in the Mediterranean region.


Haemoglobin (Hb) is a protein pigment in the red blood cells that delivers oxygen to peripheral tissues in the body and makes the blood red. After the neonatal period, the predominant type of haemoglobin is haemoglobin A (HbA). Each haemoglobin A molecule consists of four protein chains: two alpha globin chains and two beta globin chains (a2b2). In healthy individuals, the rate at which beta and alpha chains are produced is regulated so that proportional amounts of each type of globin are available to form haemoglobin.

In alpha or beta thalassemia, very little or no alpha or beta globin is produced, or the protein is structurally defective. The cause of the abnormality is an alteration (a mutation) in the genes that regulate globin chain production. Alpha thalassemia results from deficient or structurally abnormal alpha chains, and beta thalassemia results from deficient or structurally abnormal beta chains. The severity of the symptoms in the two forms of thalassemia mainly depends on how much the production of globins is reduced, or the extent to which the structure of the protein is altered and its function impaired.

Alpha thalassemia: Four genes located on chromosome 16 control the production of alpha globin. Alpha thalassemia results when one or more of these genes, or parts of them, are missing (a deletion) or carry a point mutation (a change in a single base pair of DNA). Deletions impair the production of alpha chains. A point mutation may also impair the production or slightly alter the protein structure, resulting in a dysfunctional alpha chain. Alpha thalassemia is often clinically divided into subcategories that reflect the severity of the symptoms:

  1. A "silent carrier" is a person with thalassemia who is symptom free
  2. Alpha thalassemia minor (two genes involved)
    Hb-H disease (three-gene deletion alpha thalassemia)
  3. Hydrops fetalis (four genes involved)

The characteristic symptoms of alpha thalassemia are mainly caused by low haemoglobin levels resulting from reduced alpha chain production. The loss of three out of four genes only results in moderate anaemia. If all four genes are deleted, however, the foetus often dies in the womb owing to severe anaemia and oedema (swelling), a condition known as hydrops fetalis.

Beta thalassemia: There is one beta globin gene on each copy of chromosome 11. As many as 200 mutations in these genes either suppress the production of beta chains or alter the globin structure, thereby impairing its function. Individuals with only one defective gene have beta thalassemia minor, while those with two mutated genes have beta thalassemia major. The severity of the disorder also depends on the type of gene mutation that causes the condition. Another factor that determines the severity is whether the individual, in addition to beta Thalassemia, is also affected by the alpha variant, and on his or her capacity to produce other globin chains (especially foetal haemoglobin gamma chains). Like alpha thalassemia, beta thalassemia is clinically divided into four subcategories:

  1. Symptom-free "silent carriers"
  2. Beta thalassemia minor
  3. Beta thalassemia intermedia
  4. Beta thalassemia major

Symptoms arise when the low beta globin chain production causes a surplus of alpha chains in the red blood cells. The excess alpha chains form insoluble aggregates that damage the red cell membrane, leading to premature red blood cell breakdown (haemolysis). The production of red blood cells in the bone marrow is also impaired, and many blood cells fail to mature (inefficient erythropoiesis).

In thalassemia major the body tries to compensate for the impaired maturation process by accelerating the pace of red blood cell production in the bone marrow. The liver and the spleen, which do not normally produce red blood cells, are also activated. As a result of this extreme activity, the bone marrow cavities expand and the liver and spleen are enlarged. The blood volume increases, and as a consequence the heart is under great pressure. The low haemoglobin concentration also lowers the oxygen level in the bloodstream. This is a serious condition that increases the risk of heart failure and is fatal if not treated.

For unknown reasons, iron absorption in the gastro-intestinal tract is often enhanced in individuals with beta thalassemia. This may lead to iron overload and subsequent organ damage.


Alpha thalassemia: Two genes on each chromosome 16 contain the blueprint for alpha globin production. As one chromosome is inherited from the mother and one from the father, each parent contributes two alpha globin genes to the child. Around 30 mutations causing alpha thalassemia are currently known, usually involving the loss of alpha globin genes in one or both chromosomes.

Thalassemia minor, caused by deletion of two genes on the same chromosome, is particularly common in Southeast Asia. Despite the fact that individuals with thalassemia minor have few if any symptoms, there is an increased risk that they will give birth to children with Hb-H disease or hydrops fetalis. These disorders are rare in people originating from Africa or the Mediterranean region, where only one gene on each chromosome is usually deleted.

Beta thalassemia: One gene on each copy of chromosome 11 contributes to the production of beta globin chains. Over 200 mutations are currently identified as impairing the production of beta globin protein. The mutations lead either to partial or total failure of beta globin production, the beta globin chain being structurally and functionally altered.

If beta globin protein is completely absent, the mutated gene is known as beta0, while beta+ is a gene that produces a small amount of normal beta protein or structurally impaired beta globin.

If one of the beta globin genes is normal, the individual is affected by beta thalassemia minor. In cases where the beta genes in both chromosomes 11 are mutated, the symptoms vary depending on how the globin synthesis is affected (b+b+, b+b0 or b0b0). The severity of symptoms also depends on the individual's inherited capacity to produce other haemoglobin chains, and on whether alpha globin synthesis is also disturbed.


Alpha thalassemia: People with alpha thalassemia minor are only mildly anaemic and their general health is usually not affected. Individuals with Hb-H disease have moderate or severe anaemia with haemoglobin values between 70- 100 g/l (a normal value is 120-160 g/l). Although characteristic symptoms may present, they do not necessarily affect the person's life greatly. Individuals with Hb-H disease are often affected by liver and spleen enlargement or jaundice (icterus), caused by the rapid breakdown of haemoglobin. In some cases, gall bladder disease, leg ulcers and folic acid deficiency also present. Acute anaemia (haemolytic crises) may occur as a result of infection or when taking certain medications, such as sulpha. As a consequence, the breakdown of red blood cells increases.

Beta thalassemia: Individuals with beta thalassemia minor are only mildly anaemic and are usually symptom-free. The anaemia is exacerbated by iron and folic acid deficiencies as well as by infection. Approximately 10 per cent are affected by liver and spleen enlargement. In beta thalassemia major, the symptoms usually present during the first year of life. Anaemia causes pallor, fatigue, slow growth and delayed intellectual and motor development. If the condition is left untreated during the first few years, the bone marrow cavities may expand, and the cortex of the long bones may become abnormally thin. The bones become frail and brittle and the risk of bone fracture increases. As a consequence of the upper jaw bone expanding, the face develops abnormally with an overbite, protruding teeth in the upper jaw and widely set eye sockets.

Erythrocytes (cells in the bone marrow that produce red blood cells) may also aggravate in the chest and in the liver and spleen, which become abnormally enlarged. If blood transfusions are not carried out, most children with the disorder die between the ages of two to three as a consequence of heart failure caused by the large blood volume, or oxygen deprivation caused by anaemia.

Today, blood transfusions are a standard treatment and as a result the anaemic symptoms can be almost completely relieved. Instead, iron overload causes the most pronounced symptoms. All individuals with beta thalassemia who are on chronic blood transfusion therapy are affected by iron overload. Excess iron accumulates in the cells and causes organ damage. If the condition is not treated (using iron chelation therapy), life-threatening progressive heart failure develops by the age of 10-15. The endocrine glands are also affected, which may cause diabetes, hypothyroidism, growth hormone deficiency, delayed puberty or parathormone deficiency. To prevent progression of iron-induced organ damage, chelating agents, mainly desferrioxamine are used. However, treatment with chelators does not completely eliminate iron accumulation, and over time iron toxicity may be fatal.

In thalassemia intermedia the anaemia is less severe, and the haemoglobin level normally remains above 70g/l. In these cases, the individual child's growth, skeletal development and heart condition should be taken into account when determining the need for regular transfusions. Just as in beta thalassemia, there is a risk that iron overload caused by blood transfusions and increased intestinal absorption may lead to heart failure and endocrine dysfunction.


Alpha thalassemia: The most severe forms of alpha thalassemia are symptomatic at birth and the moderate cases manifest in early infancy. Mild cases of alpha thalassemia may be difficult to diagnose as the blood test known as haemoglobin electrophoresis, which analyses the prevalence of different types of haemoglobin molecules, does not indicate any abnormalities. To establish the diagnosis, one often has to rely on haematological findings characteristic of the disorder, ethnic origin, absence of beta thalassemia and family history of the disease. Hb-H disease is easier to diagnose, as the electrophoresis will detect the presence of abnormal haemoglobin (beta 4), which is characteristic of the disorder.

Beta thalassemia: In children the condition usually presents as anaemia, and the age of onset is between six months and two years. A detailed disease history that includes family occurrences and ethnic origin is often helpful when making the diagnosis. In a medical examination it is particularly important to observe signs of slow growth and physical development, and to look for liver or spleen enlargement. In most cases of thalassemia, the individual is affected by anaemia, which manifests clinically as small red blood cells with low haemoglobin content. It is important to detect cases of iron deficiency, not only because the condition may cause anaemia, but also because it may mask the diagnosis of mild beta thalassemia.

The diagnosis is usually confirmed in a haemoglobin electrophoresis test. In beta thalassemia minor, the HbA2 (a2d2) level rises when the child is between one and a half and two years old, and in many cases the HbF (a2g2) level is also abnormally high. In severe beta thalassemia, these indications are more pronounced.

In both alpha and beta thalassemia it is possible to determine the exact genetic mutation that causes the disorder. This genetic information is particularly useful as it allows prenatal diagnosis by carrying out a placental biopsy (chorionic villus sampling). The type of gene defect will also help predict the clinical severity, although there is no clear connection between genotype and clinical outcome.


Alpha thalassemia: Even individuals with very low alpha globin production are normally not anaemic to the extent that the condition interferes with their daily lives, and blood transfusions are generally not required. However, infections may cause the haemoglobin concentration to drop dramatically, in which case transfusions are needed. Folic acid deficiency is common as a result of chronic red blood cell destruction and the compensatory production increase it induces. Individuals with alpha thalassemia should therefore take folic acid supplements. Gall bladder disease, leg ulcers and increased susceptibility to infection are also common symptoms that require adequate medical treatment.

Beta thalassemia: In general, individuals with beta thalassemia minor require no treatment, but children may need to take folic acid supplements until they are fully grown. Like individuals with mild alpha thalassemia, people with beta thalassemia may under certain conditions be affected by severe anaemia requiring treatment. Individuals with beta thalassemia minor should be offered information and genetic counselling, as there is a risk that they will have children with severe beta thalassemia. Genetic testing of family members may be necessary.

Individuals with beta thalassemia intermedia should be examined regularly to monitor their growth, skeletal development, and heart and circulatory status. As the years go by, they should also undergo regular examination to detect any complications arising owing to iron overload. As the Hb level may decline with age, it should be tested regularly in order to assess the need for blood transfusions.

Thalassemia major should be diagnosed as early as possible in order to prevent growth restriction, frail bones and infections in the first year of life. It may be difficult to distinguish thalassemia major from thalassemia intermedia, and the infant's haemoglobin levels and development should therefore be monitored closely. If Hb is lower than 70 or the child shows signs of poor growth and development, regular transfusion is the treatment of choice. According to the WHO, the aim of this treatment is to retain a median haemoglobin value of 115-120g /l. This can usually be achieved by carrying out transfusions of concentrated red blood cells at intervals of every three to four weeks. An alternative treatment regime, advocated by many practitioners in several large medical centres, is to schedule transfusions so as to prevent the Hb level from dropping below 90.

Multiple transfusions result in gradual iron build-up. Sooner or later, treatment with iron-binding chelators (usuallyrioxamine) will be required in order to prevent organ damage. The WHO recommends iron chelator therapy after 10-15 blood transfusions, or when the iron level, measured as ferritin value in the bloodstream, exceeds 1000 ng/ml. Unfortunately, this is a demanding treatment as the current principal chelator should be administered either through intravenous infusion or subcutaneously (into the fat tissues under the skin). A common treatment regime is to administer the drug subcutaneously via a mechanical pump for 10 to 12 hours, five to six days a week. Today, iron chelators are also available as tablets (deferriprone) that are an option in some cases, preferably in combination with desferrioxamine treatment.

When children with thalassemia major are treated, it is important to monitor their growth and development. The effects of the iron chelator treatment should be evaluated regularly by using various techniques to measure iron storage, and assessing potential injury to vital organs such as the heart and liver. There is no good correlation between ferritin value, the iron content in a liver biopsy, or an MRT (magnetic resonance imaging) that assesses the amount of iron deposition in the liver or heart. People are differently predisposed to iron absorption in different organs. This means that an assessment of iron in the liver is not valid for the heart or vice versa. As desferrioxamine has side effects affecting vision and hearing, it is important to have the eyes and ears examined annually.

Before hypertransfusions and iron chelator therapy were available, individuals with thalassemia died during infancy. Today the situation is different, and many people who have received these treatments from an early age are now in their thirties or forties. There are any indications that the intensive iron chelation therapy currently in use significantly increases the life span and improves the quality of life of individuals with thalassemia. However, the treatment requires that the patients are cared for by experienced medical staff.

Active psychological and social support is essential, especially during the teens when identification with one's peers is particularly important for establishing a sense of self. This process often causes a need to test limits and to challenge constraints imposed both by the disease and the child's parents. The experience of feeling different often weakens the motivation to be treated, and as a result interventions may be less successful and the risk of organ damage increases. Psychological support from a psychologist or counsellor may be very helpful, both for the individual with thalassemia and for close relations.

Today thalassemia major can be cured by stem cell transplantation. A prerequisite is usually that the affected individual has siblings with identical tissue type (HLA type). If this is the case, a transplantation of blood stem cells (a haematopoietic transplantation, often referred to as a "bone marrow transplant"), can be carried out. All blood cells are produced by stem cells in the bone marrow in the cavities of the bone. In a stem cell transplantation, diseased stem cells are replaced by stem cells from a healthy donor. The HLA tissue type is inherited from the parents, and each sibling has a 25 per cent chance of inheriting the same type as the affected child. The results of the transplantation are usually very satisfactory if the intervention is carried out before any organ injury has presented. However, as the procedure is still associated with risks, there are no general guidelines that determine who should receive a transplant. In cases where there is a sibling with identical HLA, transplantation should be seriously considered after the parents have been well informed about the intervention. In the near future, transplants from unrelated donors are likely to become more common in cases of thalassemia.

Practical advice

Individuals who have been diagnosed with thalassemia minor should receive a letter from their doctor containing information about their condition, in order to prevent unnecessary investigation of their anaemia.

National and regional resources in Sweden

There are physicians with competence in thalassemia treatment at Swedish regional paediatric clinics.

Resource personnel

Resource personnel for children:

Senior Physician Jonas Abrahamsson, Queen Silvia Children's Hospital, SE-416 85 Göteborg, Sweden. Tel +46 (0)31-343 40 00, email: jonas.abrahamsson@vgregion.se.

Professor Rolf Ljung, Paediatric Clinic, Malmö University Hospital, SE-205 02 Malmö, Sweden. Tel +46 (0)40-33 10 00, email: rolf.ljung@skane.se.

Professor Ildiko Marky, Queen Silvia Children's Hospital, SE-416 85 Göteborg, Sweden. Tel +46 (0)31-343 40 00, email: ildiko.marky@pediat.gu.se.

Resource personnel for adults:

Professor Robert Hast, Haematological Clinic, Karolinska University Hospital, Solna, SE-171 76 Stockholm, Sweden. Tel +46 (0)8-517 726 02, email: robert.hast@medks.ki.se.

Courses, exchanges of experience, recreation

The Thalassemia International Federation (the address is listed under Organisations for the disabled/patient associations) organises courses and other activities.

Organizations for the disabled/patient associations

The Thalassemia International Federation is an international patient association. Address: P.O. Box 28807, Nicosia, Cyprus, email: thalassemia@cytanet.com.cy, Internet: www.thalassemia.org.cy.

National Association for Patients with Liver Disease, Box 2918, SE-187 29 Täby, Sweden. Email: kansli@rfl-lever.se, www.rfl-lever.se.

Courses, exchanges of experience for personnel

Network for paediatric nurses. Contact person: Anna Hansson, Paediatric Clinic, ward 3, MAS University Hospital, Malmö, Sweden. Tel +046 (0)40-33 16 43.

The Swedish Paediatric Haematology Health Care Planning Group (Vårdplaneringsgruppen för pediatrisk hematologi, VPH), belonging to the Swedish Paediatricians´ Section for Haematology and Oncology (http://orebroll.se/vph), have put together a "mini care programme for thalassemia 2003".

Research and development (R&D)

Research on thalassemia is closely associated with basic research in molecular biology. There is intensive ongoing work to learn more about the mechanisms that govern the expression of haemoglobin genes from the foetal stages to old age. The aim is to find ways of increasing the production of foetal haemoglobin in individuals with beta thalassemia, as this is one way of relieving the symptoms. Researchers are also looking intensively for new iron chelators that can be administered orally, as available therapies are very taxing for the patients. Finally, methods for blood stem cell transplantation are continuously being developed. In the future it is likely that more stem cell donors will be available, and the procedure will be safer with fewer side effects.

Information material

An information folder on Thalassemia, which summarises the information in this database text, is available free of charge from the customer service department of the Swedish National Board of Health and Welfare (in Swedish only, article number 2002-12-148). Address: SE-120 88 Stockholm, Sweden. Tel: +46 75 247 38 80, fax: +46 35 19 75 29, email: publikationsservice@socialstyrelsen.se. Postage will be charged for bulk orders.

A "Mini care programme for thalassemia 2003" (written by Rolf Ljung, listed under Resource personnel). Published by the Swedish Paediatric Haematology Health Care Planning Group (Vårdplaneringsgruppen för pediatrisk hematologi, VPH), belonging to the Swedish Paediatricians´ Section for Haematology and Oncology. The "Mini care programme" (in Swedish) is available at: www.blf.net/onko/page4/page29/page29.html.

There are several excellent websites, both for professional caregivers and for other categories:

In the international patient association's webpage: www.thalassemia.org.cy, there is, for example, books are available for download, for example "What is Thalassemia".

Cooley's Anemia Foundation:

United Kingdom Thalassemia Society, London, UK: www.ukts.org.

Joint Center for Sickle Cell and Thalassemic Disorders: http://sickle.bwh.harvard.edu/index.html.


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Database references

OMIM (Online Mendelian Inheritance in Man). Internet: www.ncbi.nlm.nih.gov/omim
Search word: thalassemia

Document information

The Swedish Information Centre for Rare Diseases, produced and edited this information material.

The medical expert who wrote the draft of this information material is Senior Physician Jonas Abrahamsson, Queen Silvia Children's Hospital, Göteborg, Sweden.

The revision of the material was assisted by Professor Rolf Ljung, Malmö University Hospital, Sweden.

The relevant organisations for the disabled/patient associations have been given the opportunity to comment on the content of the text.

The expert group on rare diseases of the Swedish National Board of Health and Welfare approved the material prior to publication.

Date of publication: 2005-11-29
Version: 1.1
Publication date of the Swedish version: 2004-06-22

For enquiries contact The Swedish Information Centre for Rare Diseases, The Sahlgrenska Academy at the University of Gothenburg, Box 400, SE-405 30 Gothenburg, Sweden, tel: +46 31 786 55 90, email: ovanligadiagnoser@gu.se.


About the database

This knowledge database provides information on rare diseases and conditions. The information is not intended to be a substitute for professional medical care, nor is it intended to be used as a basis for diagnosis or treatment.