Thalassaemia refers to a group of disorders characterised by reduced or absent globin chain production.
Thalassaemia is one of the haemoglobinopathies, which refers to a group of autosomal recessive inherited disorders that affect the globin chains that form the protein component of haemoglobin.
Haemglobinopathies can be broadly divided into two types:
Thalassaemia can be further divided depending on the type of globin chain affected:
Haemoglobin is the main oxygen-carrying molecules within our red bloods cells.
Haemoglobin (Hb) is essential for the transport of oxygen around the body. It is composed of four globin chains and four heme molecules, which are the actual oxygen-binding structures that contain iron.
The combination of different globin chains determines the type of haemoglobin.
In the human body, there are two major gene clusters important for the synthesis of globin chains in the formation of haemoglobin:
We contain four alpha globin genes and two beta globin genes. With the alpha genes, two are inherited paternally and two inherited maternally. With the beta globin genes, one is inherited from each parent.
When we look at abnormal mutations seen in thalassaemia, we use the following denotation:
Beta thalassaemia is most common among Mediterranean, African, and Southeast Asian populations.
In the UK, it is estimated that around 1000 people have beta thalassaemia major (the most severe form) with around 300,000 carriers. The condition is most commonly seen in populations around the Mediterranean, Africa and Southeast Asia.
Beta thalassaemia in patients of Mediterranean origin are most likely to present with anaemia. This is because the mutation most commonly seen in this population leads to absent production of the beta globin chain.
In beta thalassaemia, mutations in the beta globin genes lead to reduced or absent production.
We each contain two copies of the beta globin gene. One is inherited paternally and one maternally. Beta thalassaemia is considered an autosomal recessive condition, but the clinical phenotype (i.e. anaemia) can be seen with even one abnormal beta globin gene. However, the severe form of the condition requires two abnormal genes.
More than 200 mutations have been identified in the beta globin gene that can cause a reduced or absent production of the beta globin chain.
Mutations seen can include:
There are three types of beta thalassaemia known as minor, intermedia and major.
The absence of beta globin chain production leads to an alpha/beta globin chain imbalance and chronic haemolytic anaemia.
Beta thalassaemia minor or trait is typically asymptomatic with mild microcytic anaemia. Patients with beta thalassaemia major have severe disease with chronic haemolytic anaemia and ineffective erythopoiesis.
Beta thalassaemia major typically presents after 6 months of age when there is a change from fetal haemoglobin (HbF) to normal adult haemoglobin (HbA). The reduced beta globin chain production leads to an imbalance in alpha and beta chains that causes ineffective erythropoiesis (i.e. formation of new red blood cells) with haemolysis in the bone marrow and peripheral blood. This is coupled with reduced red blood cell survival. In addition, there is increased iron absorption leading to overload, which is compounded by regular transfusions.
One of the hallmarks of beta thalassaemia is extramedullary haematopoiesis, which refers to haematopoiesis occurring outside the medulla of long bones. Typical sites include the spleen, liver and unusual bones including the skull. Despite the increase in haematopoiesis sites, it is still ineffective due to the absence of beta globin chains. There is an increased production of HbA2 that contains the delta chain and HbF that contains the beta-like gamma chain. However, this increased production is not sufficient to meet the demands of the body. In addition, excess alpha chains leads to the formation of unstable alpha tetramers that precipitate in red blood cells causing premature destruction.
Collectively, this results in chronic, transfusion-dependent anaemia.
Beta thalassaemia causes a range of clinical manifestation due to haemolysis, extramedullary haematopoiesis and iron overload.
The severity of anaemia and subsequent symptoms depends on the beta thalassaemia type:
Due to chronic haemolytic anaemia of abnormal red blood cells, patients may have evidence of a unconjugated hyperbilirubinaemia and gallstones from pigment stones.
Boney changes are common in patients with beta thalassaemia major due to ineffective erythropoiesis and extramedullary haematopoiesis.
Ineffective erythropoiesis leads to an increase in iron absorption from the gastrointestinal tract that is compounded by regular blood transfusions. Iron chelation therapy is needed from an early age to prevent complications. Disorders associated with iron overload include:
Anaemia is beta thalassaemia usually develops from 6-12 months of age.
Most patients with beta thalassaemia minor will be completely asymptomatic and not realise they have the underlying condition. Beta thalassaemia intermedia/major typically presents from 6 months of age with the usual switch from HbF to HbA.
The diagnosis of beta thalassaemia is usually obvious with the presentation of severe anaemia in the first year of life. Initial testing can confirm the presence of chronic haemolytic anaemia and diagnostic testing is important to confirm beta thalassaemia.
Diagnostic testing can be used to confirm the presence of beta thalassaemia. It involves haemoglobin analysis and genetic testing.
On haemoglobin analysis, patients with beta thalassaemia will have an increased proportion of HbA2 and HbF due to the absence of beta globin chains. Even in beta thalassaemia minor, there will be an elevation in HbA2.
Screening for thalassaemia is offered to all pregnant women within the UK.
Antenatal screening is offered to all pregnant women within the UK. It involves concurrent assessment of different haemoglobinopathies (i.e. thalassaemia and haemoglobin variants) at 10 weeks gestation. Family origin questionnaires are essential as part of the screening programme to determine the risk of being a carrying of a haemoglobinopathy gene.
In beta thalassaemia, the level of HbA2 is quantified. Levels of HbA2 >3.5% is suggestive of being a beta thalassaemia carrier and further analysis of the father is required to determine the risk of beta thalassaemia in the fetus.
Screening for alpha thalassaemia is more difficult. This is because detection of alpha thalassaemia minima (aa/a-) or alpha thalassaemia trait (a-/a-) can only be completed by DNA testing as there are no specific biomarkers. Therefore, in pregnant mothers if the mean corpuscular haemoglobin is < 25 pg and they are from a high risk area (e.g. China, Southeast asian, etc) then testing of the biological father should be offered. If the biological father is also suspected of having alpha thalassaemia then both the mother and biological father should undergo DNA analysis.
Public Health England (PHE) have produced clear guidelines on the sickle cell and thalassaemia screening programme.
Beta thalassaemia requires lifelong adherence to transfusion programmes and iron chelation therapy.
The mainstay of treatment in beta thalassaemia major is chronic red blood cell transfusions to treat severe, asymptomatic anaemia. In addition, patients require monitoring for complications associated with iron overload and iron chelation therapy. Rarely, newer disease modifying agents and haematopoietic stem cell transplantation, which is potentially curative, can be considered. However, this is beyond the scope of these notes.
The aim of chronic blood transfusions is to keep the haemoglobin level at a constant stable state and reduce complications associated with ineffective and extrameullary haematopoiesis.
Patients will have pre-transfusion and post-transfusion haemoglobin targets. This usually involves regular transfusions every 2-3 weeks. Extended cross-matching is usually required to prevent alloimmunisation, which refers to development of an immune response to red blood cell antigens.
Iron overload is inevitable in patients with beta thalassaemia major and it can cause significant morbidity due to organ toxicity. Therefore, iron levels need to be monitored regularly using ferritin +/- formal iron studies and magnetic resonance imaging can be used to quantify the amount of iron deposition in organs. This is particularly important for hepatic and cardiac tissue.
Patients will usually be started on iron chelation therapy in childhood. There are various indications about when to start chelation therapy. Typical agents include Deferasirox, Deferoxamine and Deferiprone. These chelators bind iron and increase excretion through urine and/or faeces.
Splenectomy can be considered in selected patients with symptomatic splenomegaly, hypersplenism (decrease in blood counts) or a dramatic increase in transfusion requirements. Other treatments and monitoring depend on the complications associated with thalassaemia (e.g. hepatic disease, cardiac disease).
Patients with beta thalassaemia major have a reduced life expectancy.
Patients with beta thalassaemia major will not survive without lifelong transfusion programmes. Major mortality is associated with chronic anaemia and iron overload. Life-expectancy depends on the extent of complications associated with iron overload and concordance with life-long treatment. For example, significant cardiac involvement leads to earlier mortality.
Beta thalassaemia minor has no impact on patient morbidity or mortality.
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