Megaloblastic Anaemia

Question 1

What is megaloblastic anaemia?

Answer 1

Red blood cells of increased size
- Mean corpuscular volume >100fL

Occurs in:
―Vitamin B12 deficiency /abnormal metabolism
―Folate deficiency/abnormal metabolism
- both lead to defects of DNA synthesis

Symptoms:
- Mild jaundice due to breakdown of RBCs to Bilirubin
- Glossitis due to alterations in metabolism that lead to you losing these
cells more often
- Stomatitis

Question 2

What is folic acid?

Answer 2

• Folic Acid is a collective term for pteroylglutamic acids
• Involved in carbon transfer reactions of amino acid metabolism and DNA synthesis and methylation
• Inadequate folate status during early pregnancy increases the risk of neural tube defects (NTDs) in newborns.

Question 3

How are folate and vitamin B12 involved in DNA synthesis?

Answer 3

Folic acid is imported into cells and reduced to tetrahydrofolate (THF)

THF is converted to 5-methyltetrahydrofolate (mTHF) by MHTFR,
this process facilitates nucleic acid synthesis (thymidine)

This process is reversible as mTHF can be demethylated. During this process the carbon is donated into the methionine cycle through the methylation of homocysteine by methionine synthase and its cofactor vitamin B12.

Hence, need both Folate and B12 for DNA synthesis

Question 4

What occurs to RBC morphology in folate and B12 deficiency?

Answer 4

When folate and B12 are deficient DNA synthesis in the S phase is impaired and thymidine production is reduced.

This causes asynchronous cell division, where the nucleus does not mature, but the cytoplasm does, leading to enlarged cells.

These cells then undergo intramedullary apoptosis in the bone marrow.

As a result the BM compensates by trying to produce new RBCs, but without the effective DNA it can only form lots of reticulocyte precursors (progenitor cells), but development stops at this point, making the bone marrow hyperplasic.

Since the cells never mature to reticulocytes we don’t actually see an increased concentration of retics (normal count).

This results in a decrease in DNA synthesis and inhibits DNA replication.

Failure of DNA synthesis is also seen with hypersegmented polymorphonuclear neutrophils common.
- should have 3-5 segments usually but in B12 and folate deficiency
neutrophils have 7+
- Increased red cell apoptosis produces more bilirubin (transfers to
liver, causing jaundice) and LDH

Question 5

What is pernicious anaemia?

Answer 5

Pernicious anaemia is caused by autoimmune attack on the gastric mucosa.

It represents 20%–50% of the causes of vitamin B12 deficiency in adults
• More females to males affected 1.6:1
• Peak occurrence 60 years

Auto-antibodies to gastric parietal cells are present in 90% of cases but are not specific as they may occur in other disorders, eg Addison’s disease and in 16% of randomly selected women over 60 years
• Auto-antibodies to intrinsic factor are more specific.
• They are found in the serum in 55% of cases and in gastric juice in
80%.