Thalassaemia

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A quick recap on haemoglobin

Haemoglobin is the functional unit of the RBC and its job is to bind to oxygen and transport it. It is a quarternary structure protein that is made up of 4 globin chains along with haem groups (Fe2+ ions held within a porphyrin ring).

At birth, the predominant form is HbF which is a2y2. This converts to HbA by ~20 weeks in most cases. y-globin has a higher affinity for oxygen allowing it to obtain oxygen at low concentrations even (for example, across the placenta).

The predominant form of haemoglobin in adults is a2ß2. This is known as HbA. The a-chain is encoded for on chromosome 16 while the ß is on chromosome 11. There is another form present in ~2% of adults which is HbA2 (a2δ2).

An a-globin chain is necessary for life past the embryonic stage.

Thalassaemia is a quantitative haemoglobinopathy, meaning that there is a reduction in the quantity of haemoglobin due to a deficiency in either the a-globin or ß-globin chains which leads to a build up of one chain → haemolysis.

There are 2 broad categories of thalassaemias:

1. Alpha thalassaemia
2. Beta thalassaemia

ALPHA THALASSAEMIA

There are 4 genes for the a-globin chain (2 on each chromosome 16). Depending on the number of defective genes we can see a spectrum of disease ranging from asymptomatic/mild anaemia all the way to fetal death.

1. a-thalassaemia minor - this occurs when there are 2 allele abnormalities.
2. HbH disease - this is when there are 3 allele abnormalities. Only about 1/3rd of the total HbA is produced. ß-globin accumulates to form tetramers known as HbH (ß4). These ß4 tetramers polymerise to form inclusion bodies in the circulating RBCs.
3. Hb Bart’s - this is when there are 4 mutations to the a-globin genes which leads to a total deficiency in a-globin. As we mentioned previously, an a-globin chain is necessary for life past the embryonic stage. So instead of having the normal HbF (a2y2), we instead get an accumulation of y-globin chains (y4). As we also mentioned, y-globin has a higher affinity for oxygen and when there are 4 y-globin chain, there is almost no oxygen delivered to the fetal tissue which leads to asphyxia, oedema, congestive heart failure and intra-uterine death. It is also termed Hb Bart’s hydrops fetalis (a disorder of severe oedema in at least 2 fetal compartments).

😷 Presentation

• Jaundice
• Fatigue
• Pronounced forehead and malar eminences (cheek bones) - this is due to expansion of the bone marrow in an attempt to increase erythropoiesis to compensate.
• Hypochromic, microcytic anaemia - This may be seen on an MCV.
• Splenomegaly - this is seen more in HbH disease. It also can lead to a haemolytic anaemia due to the haemolysis. This can then precipitate as jaundice.
• Gallstones - more common in HbH disease due to a rise of bilirubin with extravascular haemolysis.

🔍 Investigations

1. FBC - shows a microcytic anaemia (MCV <80)
2. Peripheral smear - shows hypochromic cells, nucleated RBCs, target cells, anispoikilocytosis.
3. Reticulocyte count - elevated.
4. Haemoglobin electrophoresis - can be used to diagnose.
5. Genetic testing - this is used to confirm diagnosis and aids family screening.
6. Iron studies - may cause raised serum iron and ferritin due to secondary haemochromatosis as a result of increased iron absorption (we will discuss this further below).

🧰 Management

Alpha-thalassaemia minor and alpha-thalassaemia trait

There is no particular management. It is important to ensure that they do not take unnecessary iron supplementation as they already have raised iron levels.

Simply monitoring of the FBC and monitoring for complications may be needed.

HbH management:

• Folic acid supplementation
• RBC transfusion - patients need to be monitored for iron overload carefully.
• Iron chelation - deferasirox or desferrioxamine
• Splenectomy may be performed if the patient develops painful splenomegaly, hypersplenism and pancytopenia subsequently.
• HSC transplantation is the curative option.

BETA THALASSAEMIA

The ß-globin chain is coded for by the HBB gene on chromosome 11. Depending on the degree of mutations, the presentation of the disease can vary quite a lot as well:

1. ß-thalassaemia minor - the heterozygous form of the disease. These individuals are asymptomatic carriers or they may have the thalassaemia trait (subclinical microcytic anaemia). It may also lead to a compensatory raise in HbF and HbA2.
2. ß-thalassaemia intermedia - this is the compound heterozygote form of the disease (2 different mutations). It generally presents in older children as a mild anaemia.
3. ß-thalassaemia major - this is the homozygous form of the disease. It presents at just a few months old with progressive pallor, abdominal distension, hepatosplenomegaly, infections, intracranial abnormalities and severe anaemia.

Pathophysiology

Reduced ß-globin synthesis leads to excessive a-globin causing aggregation of a-globulin. This will then lead to the haemolysis of the RBC within the spleen that causes splenomegaly and anaemia.

We also produce more EPO as a result, triggering extramedullary haematopoiesis which causes bone marrow expansion and cranial deformities (pronounced forehead and cheek bones).

With the increased erythropoiesis we get an increase in iron absorption, causing secondary haemochromatosis as the misformed globin molecules are unable to incorporate this iron into the haem group. This build up of iron can then cause cardiomyopathy and tachyarrhythmias.

Blood transfusions may be used to treat the disease but this worsens the haemochromatosis which can lead to endocrine, liver, pancreatic and myocardial dysfunction.

⚠️ Risk factors

• Family history - it is an autosomal recessive condition.
• Country of origin - Mediterranean, Middle East, Northern Africa, and Southeast Asia.

😷 Presentation

• Anaemia symptoms - such as fatigue, pallor and lethargy. It is more prominent in major but may also be present in intermedia. Pallor may be visible in thalassaemia trait.
• Abdominal distension - due to hepatosplenomegaly.
• Jaundice - due to the hameolysis and raised bilirubin levels.
• Craniofacial abnormalities - due to bone marrow expansion. There may also be misaligned teeth as a result.
• Heart failure - once it progresses far enough it can lead to heart failure and subsequent death.

🔍 Investigations

1. FBC - shows a microcytic anaemia (MCV <80)
2. Peripheral smear - shows hypochromic cells, nucleated RBCs, target cells, anispoikilocytosis.
3. Reticulocyte count - elevated.
4. Haemoglobin analysis
1. ß-thalassaemia major - minimal to no HbA, raised HbF and HbA2.
2. ß-thalassaemia intermedia - decreased HbA, raised HbF and HbA2.
3. ß-thalassaemia trait - mostly HbA, raised HbF and HbA2.

5. Genetic testing - this is used to confirm diagnosis and aids family screening.
6. Iron studies - may cause raised serum iron and ferritin due to secondary haemochromatosis as a result of increased iron absorption (we will discuss this further below).
7. X-ray of skull and long bones

ß-thalassaemia minor management:

Genetic counselling and education on avoiding iron supplementation unnecessarily.

ß-thalassaemia intermedia management:

Management depends on whether the patient is transfusion-dependent or not. Some patients have more profound anaemia and will be transfusion dependent to mitigate complication risks.

Non-transfusion dependent

There management is simply to manage complications that may arise, such as symptomatic anaemia. They may need transfusions at times of symptomatic anaemia. This will be coupled with iron chelation.

Genetic counselling is of course needed as well.

Transfusion dependent

1. Regular transfusions
2. Iron chelation and monitoring.
3. Genetic counselling

Splenectomy and HSC transplantation may be needed as well and can be considered.

ß-thalassaemia major management:

1. Regular transfusions
2. Iron chelation and monitoring.
3. Genetic counselling

Splenectomy and HSC transplantation may be needed as well and can be considered as they are the only curative option.