Thalassaemia: A Comprehensive Review for the MRCP (UK) Part 1 Exam

Welcome to this comprehensive review of thalassaemia, specifically tailored for postgraduate medical doctors preparing for the MRCP (UK) Part 1 examination. As you advance your career in Internal Medicine, a solid understanding of haematological disorders, including Thalassaemia, is crucial.

This blog post, brought to you by MEDIT & CME Academy, will provide a structured overview of this important topic.

Introduction to Thalassaemia

Thalassaemia, a key topic within Clinical Haematology for the MRCP (UK) Part 1, comprises a group of inherited blood disorders characterised by reduced or absent synthesis of globin chains, leading to anaemia. Mastering this topic is essential for success in the exam. Let's delve into the specifics.

Learning Outcomes

By the end of this post, you should be able to:

1. Define thalassaemia and describe its genetic basis, including mutations affecting globin chain synthesis (α-globin in α-thalassaemia and β-globin in β-thalassaemia).

2. Explain the pathophysiology of thalassaemia, including ineffective erythropoiesis, chronic hemolysis, and iron overload due to transfusions and increased gastrointestinal absorption.

3. Classify thalassaemia based on genetic defects (genotype) and clinical severity (phenotype):

4. α-thalassaemia: Silent carrier, α-thalassaemia trait, HbH disease, hydrops fetalis.

5. β-thalassaemia: Minor (trait), intermedia, major (Cooley’s anaemia).

6. Recognize the clinical presentation of thalassaemia:

7. Mild forms (trait): Asymptomatic or mild microcytic anaemia. These patients are transfusion independent.

8. Severe forms: Pallor, failure to thrive, hepatosplenomegaly, bone deformities (frontal bossing, maxillary overgrowth), and growth retardation.These patients are mostly transfusion dependent

9. Interpret laboratory investigations for thalassaemia, including:

10. Full blood count (FBC): Microcytic hypochromic anaemia with high RBC count.

11. Peripheral blood smear: Target cells, basophilic stippling, nucleated red blood cells.

12. Haemoglobin electrophoresis: Increased HbA₂ and/or HbF in β-thalassaemia; HbH in α-thalassaemia.

13. Genetic testing for α- and β-globin gene mutations.

14. Differentiate thalassaemia from iron deficiency anaemia based on laboratory findings.

15. Discuss the management of thalassaemia, including:

16. Mild forms: Usually require no treatment.

17. Severe forms: Regular blood transfusions, iron chelation therapy (deferasirox, deferoxamine), folic acid supplementation.

18. Curative treatment: Bone marrow transplantation for β-thalassaemia major.

19. Describe the complications of thalassaemia, including iron overload (affecting heart, liver, and endocrine organs), transfusion-related infections, and extramedullary haematopoiesis.

20. Explain the role of genetic counseling, carrier screening, and prenatal diagnosis in preventing severe thalassaemia syndromes.

21. Discuss advances in emerging therapies, including gene therapy and novel pharmacological agents targeting ineffective erythropoiesis.

Genetics and Pathophysiology

Thalassaemias are caused by mutations in the genes responsible for globin chain synthesis. Alpha-thalassaemia arises from deletions or mutations affecting the α-globin genes on chromosome 16, while beta-thalassaemia results from mutations in the β-globin gene on chromosome 11. These mutations lead to reduced (β+) or absent (β0) synthesis of the affected globin chain.

The resulting imbalance in globin chain production causes ineffective erythropoiesis (premature destruction of red blood cell precursors in the bone marrow) and chronic haemolysis (increased destruction of red blood cells in the circulation).

Additionally, repeated blood transfusions, a cornerstone of treatment for severe thalassaemia, contribute to iron overload, as does increased gastrointestinal iron absorption due to the chronic anaemia.

Classification and Clinical Presentation

Alpha-Thalassaemia

• Silent Carrier: Carries one affected alpha-globin gene. Clinically asymptomatic with normal blood indices.

• Alpha-Thalassaemia Trait: Carries two affected alpha-globin genes. Mild microcytic anaemia may be present.

• HbH Disease: Carries three affected alpha-globin genes. Moderate to severe microcytic hypochromic anaemia, splenomegaly, and HbH inclusions.

• Hydrops Fetalis: Carries four affected alpha-globin genes. Incompatible with life; results in severe anaemia and oedema in utero.

Beta-Thalassaemia

• Beta-Thalassaemia Minor (Trait): Heterozygous for the beta-globin mutation. Mild microcytic anaemia; often asymptomatic. Elevated HbA2 on haemoglobin electrophoresis.

• Beta-Thalassaemia Intermedia: Variable clinical severity; can range from mild anaemia to more significant transfusion requirements.

• Beta-Thalassaemia Major (Cooley’s Anaemia): Homozygous or compound heterozygous for beta-globin mutations. Severe anaemia requiring regular transfusions, leading to iron overload. Presents with pallor, failure to thrive, hepatosplenomegaly, and characteristic bone deformities like frontal bossing and maxillary overgrowth.

Laboratory Investigations

Key investigations include:

• Full Blood Count (FBC): Demonstrates microcytic hypochromic anaemia. RBC count may be normal or elevated in thalassaemia trait, helping to differentiate it from iron deficiency.

• Peripheral Blood Smear: Shows target cells, basophilic stippling, and nucleated red blood cells.

• Haemoglobin Electrophoresis: Crucial for diagnosis. In beta-thalassaemia, it reveals elevated HbA₂ and/or HbF. In HbH disease (alpha-thalassaemia), HbH is detected.

• Genetic Testing: Confirms the diagnosis by identifying specific α- and β-globin gene mutations.

Differential Diagnosis

It’s important to differentiate thalassaemia from other causes of microcytic anaemia, particularly iron deficiency. In thalassaemia, ferritin and serum iron levels are typically normal or elevated, whereas they are low in iron deficiency anaemia.

Management

Management strategies vary depending on the severity of the condition:

• Mild Thalassaemia (Trait): Usually requires no specific treatment. Genetic counselling is important.

• Severe Thalassaemia:

• Regular Blood Transfusions: To maintain adequate haemoglobin levels.

• Iron Chelation Therapy: Essential to prevent iron overload. Deferasirox, deferoxamine and deferiprone are commonly used.

• Folic Acid Supplementation: Supports red blood cell production.

• Bone Marrow Transplantation (Allogeneic Haematopoietic Stem Cell Transplant): Potentially curative for β-thalassaemia major.

Complications

Complications of thalassaemia include:

• Iron Overload: Can damage the heart, liver, and endocrine organs.

• Transfusion-Related Infections: Requires careful screening of blood products.

• Extramedullary Haematopoiesis: Can lead to masses in the spleen, liver, and other organs.

• Growth Retardation and Endocrine Dysfunction: Due to chronic anaemia and iron overload.

Prevention and Emerging Therapies

Genetic counselling, carrier screening, and prenatal diagnosis are crucial for preventing severe thalassaemia syndromes. Emerging therapies, including gene therapy and novel pharmacological agents targeting ineffective erythropoiesis, hold promise for future treatment.

Conclusion

A thorough understanding of thalassaemia, encompassing its genetics, pathophysiology, clinical presentation, and management, is essential for the MRCP (UK) Part 1 exam. This review provides a solid foundation for your studies.

Remember to consult relevant guidelines and research to stay updated on the latest advancements in the field.

Enhance your understanding of Clinical Haematology and boost your chances of success in the MRCP (UK) Part 1 exam by enrolling in our comprehensive short course at CME Academy. Together, WE leaRn BETTER!