Macrocytosis and Macrocytic Anaemia

Question 1

Define macrocytosis

Answer 1

Macrocytosis is the enlargement of red blood cells, MCV > 100

Question 2

Define macrocytic anaemia

Answer 2

Anaemia in which the red cells have a larger than normal volume

Question 3

How would you differentiate between macrocytosis and macrocytic anaemia ?

Answer 3

In macrocytosis there would be an increased MCV >100 but Hb and RBC counts would be normal

In macrocytic anaemia MCV >100, but Hb low and RBC may be low

Question 4

What are the normal ranges for MCV ?

Answer 4

• microcytic = MCV<80
• normocytic = MCV 80-100
• Macrocytic = MCV >100

When assessing red blood cell size on blood film a general rule of thumb is to compare them to the nucleus of a normal small lymphocyte

Question 5

What are the 2 main classes of macrocytosis ?

Answer 5

1. Genuine (true) increase in cell size
2. Suprious (False) increase in cell size

Question 6

Define erythroblast/normoblast

Answer 6

This is a normal red cell precursor with a nucleus

Question 7

Define in simple terms a mature red cell ?

Answer 7

Membrane surrounding soluble proteins and electrolytes

Question 8

At what cell stage does enucleation of the precursor cells for erythrocytes occur and what precursor cell is formed in the process and why does this enucleation occur?

Answer 8

1. Orthochromatic/late normoblast looses its nucleus and in the process forms a recticulocyte
2. This happens because the precursor cells have now accumulated enough Hb

Question 9

Define a megaloblast

Answer 9

An abnormally large nuccleated red cell precursor with an immature nucleus

The immature nucleus has more finely dispersed chromatin so stains slightly less than normal

Question 10

What are megaloblastic anaemias characteristically due to ?

Answer 10

Defects in DNA synthesis and nuclear maturation with relative preservation of RNA and haemoglobin synthesis

Question 11

In the maturation of megaloblasts what is the key differences ?

Answer 11

• There is reduced cell divisions and increased apoptosis
• But note some megaloblasts do fully mature hence macrocytic anaemia

Question 12

Why does someone usually become anaemic when they have megaloblasts ?

Answer 12

Because:

1. In the few erythroblasts that survive as ‘megaloblasts’, cytoplasm development occurs normally and triggers enucleation (despite the increased apoptosis)
2. This leads to a ‘bigger-than-normal’ red cell because it has essentially divided less, think about the haematopoietic tree where there is
3. But overall, there are fewer of these and hence the patient is anaemic

Question 13

What is the key take home message regarding megaloblastic anaemia in how the resulting mature erythrocytes are increased in MCV?

Answer 13

The larger cell size in megaloblastic anaemia is not due to an increase in the size of the developing cell, but

A FAILURE TO BECOME SMALLER

Question 14

What are the main causes of megaloblastic anaemia ?

Answer 14

1. B12 deficiency
2. Folate deficiency
3. Others - Drugs, Rare inherited abnormalities

Question 15

In general terms why does lack of B12 or folate result in megaloblastic anaemia ?

Answer 15

• B12 and folate are essential co-factors for nuclear maturation.
• Enable chemical reactions that provide enough nucleosides for DNA synthesis

Bascially deficiency of either of the 2 results in block of DNA synthesis due to the inability of methylate deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP)

Question 16

What are the 2 cycles called which B12 and folate is involved in for

Answer 16

• Folate cycle - the actual things going round this cycle is essentially folate where as B12 plays a role in both cycles but is not the thing being changed etc
• Methionine cycle (methlyation cycle)

They are both interlinked and ==> both involved in both of these cycles

Question 17

Speicfically describe how B12 deficiency results in block of DNA synthesis

Answer 17

Deficiency of B12 results in the reduced supply of coenzyme methylene tetrahydrofolate (methylene THF) needed for the uridine to thymidine conversion

Def. of B12 does this by slowing the demethylation of methly THF to THF hence preventing cells from reciveing THF which is then converted into methylene THF

Question 18

Specifically describe how folate deficiency results in block of DNA synthesis i.e.

Answer 18

Deficiency of folate results in the reduced supply of coenzyme methylene tetrahydrofolate (methylene THF) needed for the uridine to thymidine conversion

Question 19

What is the product produced by the folate cycle and what is produced by the methioine cycle and what are they important for ?

Answer 19

1. Folate cycle important for nucleoside synthesis ==> DNA sythesis as these are the building blocks of DNA, it is important as conversion of uridine to thyimine occurs in this cycle
2. Methionine cycle produces s-adenosyl methionine, a methyl donor

Question 20

What is the main function of B12

Answer 20

The methylation of homocystiene to methionine with demethylation of methly THF to THF

Note that methyl THF i.e. folate is required for this too

Question 21

Describe the absorption and transport of B12 into the body

Answer 21

1. Dietary B12 is release from protein complexes by gastric enzymes causing acidic pH (e.g. HCL)
2. Immediately bound by haptocorrin (transcobalamin I)
3. This complex is then cleaved in the duodenum and then B12 immediately bind to intrinsic factor produced by gastric parietal cells of the gastric mucosa (note that binding occurs in the duodenum)
4. Its then carried to the terminal ileum where B12 is then absorbed
5. B12 then binds to transcobalamin II or haptocorrin where it is then transported to the tissues or the liver for storage

Question 22

Describe the transport and absorption of folate

Answer 22

1. Folic acid itself is not present in nature but follates are present in food.
2. These follates are broken down in the upper GI tract
3. Absorbed in the jejunum where they are converted to methyl THF which is the main form in the serum