Thalassaemia

Question 1

Beta Thalassaemia Trait

Answer 1

The thalassaemias are a group of genetic disorders characterised by a reduced production rate of either alpha or beta chains. Beta-thalassaemia trait is an autosomal recessive condition characterised by a mild hypochromic, microcytic anaemia. It is usually asymptomatic

Features
mild hypochromic, microcytic anaemia - microcytosis is characteristically disproportionate to the anaemia
HbA2 raised (> 3.5%) (Hb electrophoresis positive HbA2)
Disproportionate Microcytic Anaemia - Think beta thalassaemia trait!

Question 2

Beta Thalassaemia Trait - Example Question

Answer 2

A 32-year-old patient who is 10 weeks pregnant attends for her antenatal booking clinic. This is her first pregnancy, and she tells you she has been feeling lethargic and has a poor appetite. She has no past medical history of note.

On examination, she looks pale and appears comfortable at rest. Her chest is clear, heart sounds I&II are present and her abdomen is soft non-tender. She has some oedema of both ankles bilaterally. Her blood pressure is 111/75 mmHg and her heart rate is 79/min.

Investigations in clinics are as follows:

Hb	94 g/l
MCV	69 fl
Platelets	168 * 109/l
WBC	9.1 * 109/l
Hb electrophoresis	positive HbA2
Rhesus	negative
Blood Group	AB

Na+ 139 mmol/l
K+ 3.9 mmol/l
Urea 7.6 mmol/l
Creatinine 99 µmol/l

What is the single most likely underlying condition?

	Alpha thalassaemia trait
	> Beta thalassaemia trait
	Beta thalassemia major
	Iron deficiency anaemia
	Sideroblastic anaemia

The two main differentials in this patient who has been identified as having a symptomatic microcytic anaemia during pregnancy are iron deficiency anaemia and beta thalassaemia trait. The clue that this is beta thalassaemia trait rather than iron deficiency anaemia is that the MCV is surprisingly low for the level of haemoglobin. In iron deficiency anaemia you would expect the MCV to be much higher for a fairly modest decrease in haemoglobin.

In addition, the Hb electrophoresis shows +ve HbA2 which supports the diagnosis of beta thalassaemia trait. Of course, it would be wise to send off iron studies in this patient to assess for a coexistent iron deficiency anaemia.

Question 3

Beta Thalassaemia Trait - NB Anaemia not proportional to MCV: Example Question

Answer 3

A 57 year old female presents to pre-assessment surgical clinic prior to an elective arthroscopy of her left knee that she injured while playing tennis. She is otherwise asymptomatic, has no other medical history and is a lifelong non-smoker. She drinks 10 units of alcohol per week. Recently, she has experienced hot flushes and irregular periods, which she puts down to undergoing the menopause. Examination of her cardiovascular, respiratory and abdominal systems are unremarkable.

Her blood results are as follows:

Hb 9.5 g/dl
MCV 59 fl
Platelets 389 * 109/l
WBC 4.5 * 109/l
Red cell distribution width 13% (normal range 11.5-14.5%)
Blood film anisocytosis, hypochromia, target cells

Which investigation is most likely to reveal the diagnosis?

	Serum ferritin
	Total iron binding capacity
	Serum iron
	> Haemoglobin electrophoresis
	Bone marrow biopsy

The patient is asymptomatic with a microcytic anaemia. Note the disproportionately lower MCV compared to the level of haemoglobin and the normal red cell distribution width: the first is a distinctive feature of thalassaemia beta minor (trait) while the second suggests that all red cells made by the marrow of similar haemoglobin quality, such as in an underlying genetic trait such as thalassaemia beta minor. In contrast, iron deficiency normally demonstrate a significant haemoglobin drop by the time MCV is at such a low value while increasing the RDW during early to mid stages of iron deficiency, as some red cells are produced normally while some are profoundly microcytic.

Diagnosis of thalassaemia beta minor is by haemoglobin electrophoresis. However, diagnosis of iron deficiency is reliant on a combination of indicators: serum iron alone is not necessarily diagnostic as it also appears in anaemia of chronic disease. Serum ferritin is perhaps the most reliable indicator of plasma and marrow iron stores but be wary that it may be increased in inflammatory states, hence mask an underlying iron deficiency anaemia. Total iron binding capacity (TIBC) is a measure of transferrin, to which iron is bound to in plasma. Again, it is a useful indicator of iron stores but can be altered by pregnancy or the oral contraceptive pill. An iron deficiency anaemia picture is generally diagnosed by a combination of all three: low serum iron, high TIBC, low ferritin.

Question 4

Alpha Thalassaemia

Answer 4

Alpha Thalassaemia = Due to a deficiency of alpha chains in Hb

Overview:

• 2 separate alpha-globulin genes are located one each chromosome 16
• clinical severity depends on the number of alpha-chains present:

> If 1 or 2 alpha chains are absent, then the blood picture = HYPOCHROMIC + MICROCYTIC but Hb is typically Normal

> Loss of 3 alpha chains results in a HYPOCHROMIC MICROCYTIC ANAEMIA with SPLENOMEGALY = HbH Disease

> If all 4 alpha chains are absent (e.g. Homozygote) = Death in utero (hydrous fetalis, Bart’s hydrops)

Question 5

Thalassaemia

Answer 5

The thalassaemias are a group of recessively autosomal inherited disorders in globin chain production

• it is charcterised by decreased or absence of either the alpha or the beta chains of normal adult human haemoglobin molecule, resulting in alpha and beta thalassaemia respectively
• alpha thalassaemia major is incompatible with life, beta thalassaemia major results in severe anaemia requiring lifelong blood transfusion
• Inheritance of an affected gene from both parents results in a disorder and inheritance of only one affected gene results in a healthy carrier, sometimes called a trait
• thalassaemias are the commonest genetic disorders in the world - 150 million people carry the beta-thalassaemia gene - and occur in a very high frequency in a tropical belt extending from Africa, throughout the Mediterranean region, the Middle East, the Indian subcontinent, and throughout South West Asia. They occur sporadically in every population. It is possible that the heterozygote state provides protection against falciparum malaria, thus explaining its high carrier rate in certain populations

Question 6

Thalassaemia Classification

Answer 6

Classification
The thalassaemias are classified according to which chain of the globin molecule is affected. In α thalassaemia, the production of α globin is deficient and in β thalassaemia the production of β globin is defective.

There are two α genes on each chromosome 16, giving α thalassaemia the unique feature of gene duplication. There is only one β-globin gene on chromosome 11.

α thalassaemia
Normal: genotype α,α/α,α.

α+ thalassaemia heterozygous 
(genotype α,-/α,α): 
- borderline haemoglobin level and mean corpuscular volume (MCV)
- low mean corpuscular haemoglobin (MCH)
- clinically asymptomatic

α+ thalassaemia homozygous 
(genotype α,-/α,-)
- slightly anaemic
- low MCV and MCH
- clinically asymptomatic

αo thalassaemia heterozygous 
(genotype α,α/,--)
- slightly anaemic
- low MCV and MCH
- clinically asymptomatic

HbH disease (genotype α,-/-,-): HbH

• Anaemic
• very low MCV and MCH
• splenomegaly
• variable bone changes

α thalassaemia major (genotype -,-/-,-):
Hb Bart’s. Severe non-immune intrauterine haemolytic anaemia.
Hb Bart’s hydrops fetalis, usually fatal

β thalassaemia
Normal: genotype β2/β2

β-thalassaemia trait (genotype -/β2):

• HbA2 >4%.
• Slightly anaemic
• Low MCV and MCH
• clinically asymptomatic

β thalassaemia intermedia
 (genotype -/βo or β+/β+)
- high HbF
- Anaemic (symptoms usually develop when the haemoglobin level remains below 7.0 g/dL)
- very low MCV and MCH
- splenomegaly
- variable bone changes
- variable transfusion dependency

β thalassaemia major (genotype -o/-o):

• HbF >90% (untransfused)
• Severe haemolytic anaemia
• Very low MCV and MCH
• hepatosplenomegaly
• chronic transfusion dependency.