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Beta-thalassaemia major
This condition leads to chronic, life-threatening anaemia and requires lifelong medical management, typically starting in infancy. It affects individuals who inherit two altered copies of the HBB gene.
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Overview
Beta-thalassaemia major is a serious inherited blood disorder impacting how the body produces haemoglobin. Haemoglobin is the protein in red blood cells responsible for carrying oxygen from the lungs to other parts of the body. In this condition, the production of the beta-globin chain, a key component of adult haemoglobin, is significantly reduced or absent [PMID:33678566]. This leads to a shortage of healthy red blood cells, a condition known as anaemia.
Without enough healthy haemoglobin, the body's tissues and organs do not receive enough oxygen. This can result in various health problems. Beta-thalassaemia major is the most severe form of beta-thalassaemia and generally becomes apparent during early childhood. It is more common in populations from the Mediterranean, Middle East, and parts of Asia.
Symptoms & clinical features
Symptoms of beta-thalassaemia major usually appear within the first two years of life. Children often present with severe anaemia, which can manifest as extreme tiredness (fatigue), pallor (unusually pale skin), and irritability. Other common signs include poor feeding, slowed growth and development, and frequent infections.
Over time, the body's attempt to compensate for the lack of healthy red blood cells can lead to an enlarged liver and spleen (hepatosplenomegaly). Changes in bone structure, particularly in the face and skull, may also become apparent due to the bone marrow expanding to produce more red blood cells [PMID:31839849]. Jaundice, a yellowing of the skin and eyes, can also occur.
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Affected organs
Beta-thalassaemia major primarily affects the blood and bone marrow, which is the soft tissue inside bones where blood cells are made. The ineffective production of red blood cells causes the bone marrow to become overactive and expand, potentially leading to bone deformities, especially in the face and skull. The spleen and liver often become enlarged as they work harder to remove damaged red blood cells and produce new ones, which can impact their normal function.
The severe anaemia associated with the condition places a strain on the heart, and iron overload, a common complication of treatment, can damage the heart, liver, and endocrine glands (which produce hormones) if not carefully managed.
Risks & severity
Beta-thalassaemia major is a severe, life-long condition. Without appropriate treatment, it can lead to life-threatening complications, typically within the first few years of life. The severity stems from profound anaemia and the body's compensatory mechanisms, which can lead to organ damage [PMID:33678566].
Long-term risks are largely associated with chronic anaemia and complications from treatment, particularly iron overload. Iron overload can cause damage to the heart, liver, and various endocrine organs, leading to conditions like heart failure, liver fibrosis, diabetes, and delayed puberty. Regular medical care is essential to manage these risks and improve the long-term outlook for individuals with beta-thalassaemia major.
Genetic causes
Beta-thalassaemia major is caused by pathogenic variants in the HBB gene. This gene provides instructions for making the beta-globin protein, which is a crucial component of adult haemoglobin. Adult haemoglobin (haemoglobin A) consists of two alpha-globin proteins and two beta-globin proteins.
Pathogenic variants in the HBB gene reduce or eliminate the production of beta-globin. This imbalance means that the available alpha-globin forms unstable complexes, leading to the destruction of developing red blood cells in the bone marrow and a shortened lifespan for mature red blood cells. The lack of functional haemoglobin ultimately results in severe anaemia.
- HBB hemoglobin subunit beta
Inheritance pattern
Beta-thalassaemia major follows an autosomal recessive inheritance pattern. This means that an individual must inherit two altered copies of the HBB gene, one from each parent, to develop the condition. People who inherit only one altered copy of the HBB gene are typically called carriers. Carriers usually do not have symptoms of beta-thalassaemia major and are often unaware they carry the altered gene; they may have a mild form of anaemia called beta-thalassaemia minor or beta-thalassaemia trait.
When two carriers of an HBB pathogenic variant have children, there is a 25% chance with each pregnancy that their child will inherit two altered copies and develop beta-thalassaemia major. There's also a 50% chance the child will be a carrier and a 25% chance the child will not inherit any altered copies of the gene.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
Diagnosis & testing
Diagnosis of beta-thalassaemia major typically begins with a full blood count (FBC) which may show microcytic (small) and hypochromic (pale) red blood cells and severe anaemia. Haemoglobin electrophoresis or high-performance liquid chromatography (HPLC) can then be used to identify the types and amounts of haemoglobin present, revealing a reduced or absent level of haemoglobin A and increased levels of foetal haemoglobin (haemoglobin F).
Genetic testing, specifically sequencing of the HBB gene, confirms the diagnosis by identifying the specific pathogenic variants. In the UK, genetic testing for suspected thalassaemias falls under the NHS Genomic Medicine Service (GMS) pathways, with an associated R-code (e.g., R151 for 'Constitutional anaemia'). Referrals for genetic testing are usually made by a haematologist or paediatrician, often in conjunction with a clinical geneticist or genetic counsellor.
Management & lifestyle
Management for beta-thalassaemia major is complex and lifelong, focusing on managing anaemia and preventing complications. The primary treatment is regular red blood cell transfusions, typically every 2-4 weeks, to maintain adequate haemoglobin levels and suppress ineffective red blood cell production [PMID:31839849].
Repeated blood transfusions lead to iron overload, which can be toxic to organs. Therefore, iron chelation therapy is crucial to remove excess iron from the body. Other aspects of care include monitoring for potential complications such as heart problems, liver issues, and endocrine dysfunction. A multidisciplinary team, including haematologists, endocrinologists, and genetic counsellors, provides comprehensive care within the NHS framework.
UK care pathway
In the UK, individuals with suspected or confirmed beta-thalassaemia major access care through the NHS. The diagnostic pathway often involves haematology services, leading to referrals for genetic testing via the NHS Genomic Medicine Service. The relevant R-code for genetic testing for constitutional anaemias like thalassaemia is R151. Clinical genetics services and genetic counsellors play a vital role in providing information, discussing inheritance patterns, and offering support to affected individuals and their families.
Frequently asked questions
What is the difference between beta-thalassaemia major and minor?
Beta-thalassaemia major is a severe condition requiring lifelong treatment, where individuals inherit two altered HBB genes. Beta-thalassaemia minor (or trait) occurs when someone inherits only one altered HBB gene; they are typically carriers with no or very mild symptoms and generally do not require treatment.
Can beta-thalassaemia major be cured?
Currently, the only potential cure for beta-thalassaemia major is a stem cell transplant (bone marrow transplant). This procedure carries significant risks and is not suitable for all patients. Gene therapy is a promising area of research but is not yet a standard treatment option.
Why do people with beta-thalassaemia major need regular blood transfusions?
Regular blood transfusions are essential to supply healthy red blood cells, which carry oxygen throughout the body. This helps to alleviate severe anaemia symptoms, support normal growth and development, and reduce the burden on the bone marrow.
What is iron chelation therapy and why is it important?
Iron chelation therapy involves taking medicines that help remove excess iron from the body. This is crucial because regular blood transfusions lead to a build-up of iron, which can damage organs such as the heart and liver if left untreated. Adhering to chelation therapy is vital for long-term health.
What support is available for families affected by beta-thalassaemia major in the UK?
Families in the UK can access support through specialist NHS haematology centres, genetic counselling services, and patient organisations. These resources provide medical care, emotional support, and information on managing the condition and navigating healthcare pathways.
References
- Wainscoat JS, Thein SL, Weatherall DJ. Thalassaemia intermedia. Blood reviews. 1987. PMID: 3332112
- Grech L, Borg K, Borg J. Novel therapies in β-thalassaemia. British journal of clinical pharmacology. 2022. PMID: 34004015
- Aliberti L, Gagliardi I, Gamberini MR. Beta-thalassaemia major: Prevalence, risk factors and clinical consequences of hypercalciuria. British journal of haematology. 2022. PMID: 35768889
- Cheung YF, So EK, Hwang GY. Left and Right Atrial Function and Remodeling in Beta-Thalassaemia Major. Pediatric cardiology. 2019. PMID: 30972436
- Noureldine MHA, Taher AT, Haydar AA. Rheumatological complications of beta-thalassaemia: an overview. Rheumatology (Oxford, England). 2018. PMID: 28371817
- De Sanctis V, Soliman A, Yassin M. Iron overload and glucose metabolism in subjects with β-thalassaemia major: an overview. Current diabetes reviews. 2013. PMID: 23687960
- Poole JE, Cohn RJ, Roode H. Beta-thalassaemia--the Johannesburg experience. South African medical journal = Suid-Afrikaanse tydskrif vir geneeskunde. 1989. PMID: 2652340
- Saad GS, Musallam KM, Taher AT. The surgeon and the patient with β-thalassaemia intermedia. The British journal of surgery. 2011. PMID: 21480198