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UllaWartiovaara-Kautto
KirsiJahnukainen

Thalassaemias

Essentials

  • Thalassaemias are non-immunological, haemolytic, hereditary disorders typically causing microcytic anaemia.
  • Iron supplementation should not be begun unless the patient has iron deficiency confirmed by low ferritin concentration. N.B.! For anaemia during pregnancy in immigrants, see separate instructions below here.
  • Patients with severe thalassaemia or symptomatic, moderately severe thalassaemia belong in specialized care.
  • Patients of fertile age with moderately severe to severe thalassaemia and those with mild thalassaemia whose partners are also carriers of a haemoglobinopathy mutation require genetic counselling.

Aetiology

  • Thalassaemia is caused by genetic mutations in the alpha or beta globin genes, leading to insufficient or imbalanced production of haemoglobin alpha or beta chains and haemolysis (cf. sickle cell anaemia Sickle Cell Disease).
  • Alpha thalassaemia is caused by mutations in the alpha globin gene (HBA), of which people have two pairs, i.e. four copies. The severity of alpha thalassaemia depends on how many gene copies bear the mutation.
  • Beta thalassaemia and combination thalassaemia (HbE beta or HbC beta) are caused by mutations in the beta globin gene (HBB), of which people have one pair, or two copies. The disease is inherited as an autosomal recessive trait.

Epidemiology

  • The carrying of globin gene mutations is most common in regions endemic for malaria in Mediterranean countries, Africa, India and the Far East. With immigration, thalassaemias are also encountered in other countries.

Symptoms

  • For types of thalassaemia, see table T1.
  • Thalassaemia minor is usually clinically asymptomatic.
  • Thalassaemia intermedia
    • Anaemia (mild or moderate) may cause fatigue, a lowered exercise tolerance and, in children, delayed growth and pubertal development. Some patients will need red blood cell transfusions temporarily during pregnancy or the period of most rapid growth.
    • There may be enlargement of the spleen, causing pressure symptoms, pain and cytopenias.
    • Chronic haemolysis may lead to cholelithiasis.
    • Even without red cell transfusion, some people develop with age an iron overload that may cause disturbances in, for instance, liver or heart function or in hormonal activity.
  • Thalassaemia major
    • Red blood cell transfusion-dependent severe anaemia (Hb usually below 70 g/l)
    • Even without red cell transfusion, significant iron overload may develop, leading to functional disorders (for instance, of the liver or the heart and hormonal activity)
    • Skeletal changes (deformation, pain), symptomatic enlargement of the spleen, biliary and neurocognitive problems.

Types of thalassaemia

Severity of thalassaemiaType of thalassaemia
Thalassaemia minor
(or asymptomatic carrying)
  • Mutation in one or two of four alpha globin gene copies
  • Mutation causing the mild form of the disease in one of two beta globin gene copies
Thalassaemia intermedia (moderately severe)
  • HbH disease, or a form of alpha thalassaemia with mutations in three of four alpha globin gene copies
  • Some heterozygous carriers of the beta globin gene mutation (β0)
  • Some combination thalassaemias, i.e. combined carrying of various globin gene mutations (such as beta thalassaemia mutation combined with HbE mutation)
Thalassaemia major (severe)
  • Homozygous carriers of beta globin gene mutations with mutations in both gene copies; symptoms from infancy
  • Some patients with combination thalassaemia or HbH disease; typically with symptoms in adolescence or adulthood

Laboratory findings

  • Thalassaemia minor
    • Haemoglobin normal or no more than slightly lower than normal (> 90 g/l)
    • MCV low despite normal iron stores (plasma ferritin > 30 µg/l, in children > 15 µg/l)
    • Mild erythrocytosis
    • Possibly slight changes in haemolysis parameters
  • Thalassaemia intermedia and major
    • In thalassaemia intermedia Hb usually < 90 g/l, in thalassaemia major < 70 g/l
    • Findings consistent with chronic haemolytic anaemia (LD elevated, haptoglobin cannot be measured) but no marked reticulocytosis
    • Microcytosis
    • Elevated plasma ferritin (usually > 300-400 µg/l)
    • N.B.! Plasma transferrin receptor levels are also elevated but the patients do not have iron deficiency. Instead, the elevated levels are due to haemolysis and ineffective erythropoiesis.

Diagnosis of thalassaemia

  • Analysis of blood haemoglobin fractions, plasma ferritin and basic blood count with platelet count
    • Analysis of haemoglobin fractions can only identify beta thalassaemias, beta combination thalassaemias or carrying of such thalassaemias. Even clinically significant alpha thalassaemia cannot be diagnosed or excluded by analysis of haemoglobin fractions but a gene test is needed.
  • Measurement of spleen size by ultrasound examination, if thalassaemia is suspected.
  • If in initial investigations in primary health care the patient has been found to have any of the conditions listed below, they should be referred to specialized care, to a paediatric unit or, in case of adults, a haematology unit, for further investigations (such as genetic testing), treatment and follow-up.
    • Significant or moderately severe anaemia (in adults, blood haemoglobing repeatedly < 90-95 g/l in the absence of iron Iron Deficiency Anaemia or folic acid / vitamin B12 deficiency Megaloblastic Anaemia; in children, haemoglobin repeatedly < 90 g/l in the absence of iron deficiency Anaemia in Children or anaemia is associated with delayed growth)
    • A clearly enlarged spleen (in adults > 15 cm, in children exceeding the age-appropriate limits) causing symptoms
    • Iron overload (plasma ferritin repeatedly > 400 µg/l in adults or exceeding the age-appropriate limits in children, and secondary causes of high ferritin levels, such as infections, are excluded)
  • If referring for genetic counselling only, refer the patient directly to a clinical genetics unit here.

Treatment and follow-up

  • Patients with thalassaemia (minor, intermedia or major) should not be given iron supplementation unless they have confirmed iron deficiency anaemia.
  • If ferritin concentration is low, the cause of the iron deficiency must be established and treatment started normally (cf. Iron deficiency anaemia Iron Deficiency Anaemia).
  • If there are signs of active haemolysis, folic acid supplementation (1-5 mg/day) should be started.
  • Nearly all patients will need calcium/vitamin D supplementation.
  • If a patient with thalassaemia intermedia needs a red blood cell transfusion, it should be performed, in order to reduce immunization risk, using phenotyped red blood cells, if at all possible Blood Transfusion: Indications, Administration and Adverse Reactions.

Treatment chain

  • Thalassaemia minor
    • There is no need for monitoring but if the patient is of fertile age and, particularly, if his/her spouse is genetically from a region endemic for haemoglobin mutations, , the spouse must be examined to exclude even mild haemoglobinopathy and a clinical geneticist consulted, as necessary here.
    • For pregnant women, see below here
  • Thalassaemia intermedia
    • Symptomatic patients (fulfilling one or more of the following criteria: Hb < 90 g/l, plasma ferritin > 400 µg/l, splenic or general symptoms) should be monitored and treated at a specialized haematology unit.
    • Asymptomatic patients (Hb > 90 g/l, plasma ferritin < 400 µg/l, no splenic symptoms) should be followed up in primary health care once a year.
      • Annual checkups should include blood count and ferritin levels and assessing growth, pubertal development and exercise tolerance.
      • Upper abdominal ultrasonography to monitor spleen size and to detect gallstones can be done every 2 years.
      • Any iron deficiency should be treated in the normal way.
    • As asymptomatic thalassaemia intermedia becomes symptomatic during pregnancy in most cases, haemoglobin levels need to be monitored more frequently at maternity health centres, consulting the specialized care maternity outpatient department, as necessary (see below here).
  • Thalassaemia major
    • The patients need specialized care.

Pregnant women

  • If anaemia develops (Hb below 90 g/l or significant decrease from previous level), check plasma ferritin level.
    • If there is iron deficiency, start iron supplementation. If oral iron is not sufficient, use an intravenous dosage form.
    • If there is no iron deficiency, refer the patient to a maternity outpatient department in specialized care for further investigations and possible blood transfusions. If a patient with thalassaemia minor is pregnant and anaemia has become worse during pregnancy (in the absence of iron deficiency), the need for phenotyping depends on the patient's history of developing anaemia.
  • After pregnancy, the patient will again become asymptomatic.
  • N.B.! A pregnant thalassaemia patient's spouse's blood count, ferritin and haemoglobin fractions should be checked as early in the pregnancy as possible if the family has not been given genetic counselling and the spouse is from a region endemic for thalassaemia.
  • Patients with thalassaemia should start using folic acid supplementation as soon as planning pregnancy starts, unless they already use it (dosage 5 mg once daily).

Genetic counselling

  • The need for genetic counselling should be assessed in patients of fertile age who have thalassaemia or carry a thalassaemia gene.
  • It is important to identify couples at risk of having a child with thalassaemia major or intermedia (e.g. if both parents are carriers).
  • If the spouse is from a region endemic for thalassaemia, blood count, ferritin and haemoglobin fractions should be checked in primary health care before consulting a clinical geneticist. Spouses of non-endemic descent (including all grandparents) need no tests apart from blood count, if it is normal. Check also local recommendations.
  • A clinical geneticist should be consulted if thalassaemia (or the beta thalassaemia - HbS combination) is possible based on the spouse's basic investigation.
  • The spouse should be examined and genetic counselling provided as soon as planning a pregnancy starts, if possible.

    References

    • Thalassemia International Federation http://thalassaemia.org.cy
    • Taher AT, Musallam KM, Cappellini MD. β-Thalassemias. N Engl J Med 2021;384(8):727-743 [PubMed]
    • Piel FB, Weatherall DJ. The α-thalassemias. N Engl J Med 2014;371(20):1908-16 [PubMed]