Week 1- macrocytic anaemia

Question 1

What is macrocytosis?

Answer 1

Macro= big
Cytosis= excess of
Basically means big cells

Question 2

What is macrocytic anaemia then?

Answer 2

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

Question 3

How can size be measured/expressed?

Answer 3

MCV- mean corpuscular (cellular) volume. Units used are fentolitres.

Question 4

Case 1
Hb- 100 Normal range- 130-180
RBC- 3.42 Normal range- 4.5-6.0
MCV- 115 Normal range- 80-100

Answer 4

Haemoglobin is low.
Red blood cells are low
MCV is high. This means the cells have increased in size, however red blood cells are low and Hb is low. This means macrocytic anaemia.

Question 5

Case 2

Hb- 170 Normal range- 130-180
RBC- 5.44 Normal range- 4.5-6.0
MCV- 105 Normal range- 80-100

Answer 5

This person has macrocytosis because the cells are enlarged but they are not anaemic.

Question 6

What is a RBC often compared to to determine whether it is microcytic or macrocytic?

Answer 6

Often compared to a nucleus of a small lymphocyte.
Smaller= microcytic
Larger= macrocytic

Question 7

What can the causes of macrocytosis be categorised into?

Answer 7

Genuine (true)

• megaloblastic
• non megaloblastic

Spurious (false)

Question 8

What does megaloblastic mean?

Answer 8

First of all- define normal
Erythroblast/normoblast are the normal red cell precursors with a nucleus. Red cell precursors tend to have a nucleus (excluding reticulocytes) and are marrow based.
A megaloblast is an abnormally large red cell precursor with an immature nucleus (ITS NOT NORMAL).

Question 9

Which stage of development of RBC’s is there no Hb content in the RBC?

Answer 9

Pronormoblast (erythroblasts).

Question 10

When does haemoglobin start appearing in RBC’s in their development?

Answer 10

At the early normoblast stage. (This is different to the pronormoblast stage).

Question 11

What is a megablastic cell?

Answer 11

An abnormally large nucleated red cell precursor with an immature nucleus.

Question 12

What are megablastic anaemias characterised by?

Answer 12

A defect in DNA synthesis of a cell meaning the nucleus maturation is delayed relative to that of the cytoplasm. This results in a bigger than normal cell.

Question 13

Do any erythroblasts survive as megaloblasts?

Answer 13

A few survive. Generally apoptosis occurs but in the few that survive, the nucleus is ejected but the cell is larger than normal (the cell doesn’t get bigger, it just fails to get smaller). However, overall there are fewer of these cells leading to the overall anaemia.

Question 14

Why do erythroblasts change in colour as they develop?

Answer 14

Go from blue to red as the haemoglobin is forming.

Question 15

What are the causes of megaloblastic anaemia?

Answer 15

B12 deficiency
Folate deficiency
Others- drug, rare inherited abnormalities.

Question 16

Why does lack of B12 and folate cause megaloblastic anaemia?

Answer 16

They are essential co-factors for nuclear maturation. They enable chemical reactions that provide enough nucleosides (nucleotide without the phosphate group) for DNA synthesis.

Question 17

Which two biochemical cycles do B12 and folate mediate?

Answer 17

Methionine and folate cycle

Question 18

What is the folate cycle important for?

Answer 18

Nucleoside synthesis (uridine to thiamine conversion)

Question 19

What does the methionine cycle do?

Answer 19

Produces s-adenosyl methionine, a methyl donor. This has potential impacts on DNA, RNA, proteins, lipids, folate intermediates.

Question 20

Are vitamin B12 and folate cycles linked?

Answer 20

YES.

Question 21

How does B12 get into the body?

Answer 21

Found in the diet only (eggs and meats for example).

Question 22

What is B12 also known as?

Answer 22

Cobalamins

Question 23

How does the body absorb vitamin B12?

Answer 23

Vitamin B12 is released by the acidic pH of the stomach.

Once it is free’d, the B12 binds to haptocorrin until it reaches the duodenum where it becomes bound to intrinsic factor (synthesised by the parietal cells of the gastric mucosa).

The pancreas produces enzymes making the conditions alkaline for B12 and intrinsic factor to bind and be absorbed. It attaches to cubulin receptors and is absorbed in the terminal ileum.

Once absorbed, it disconnects from intrinsic factor and enters the circulation bound to another protein.

Question 24

In which situations do people get vitamin B12 deficiencies?

Answer 24

Pernicious anemia- autoimmune destruction of parietal cells with consequent impairment of intrinsic factor secretion.
Vegan diet- dont consume animal products which contain B12.
Food bound cobalamin malabsorption- the food doesn’t release the vitamin B12. This can be caused by atrophic gastritis, use of PPI’s,

Question 25

What is pernicious anaemia associated with?

Answer 25

Atrophic gastritis and other autoimmune conditions (hypothyroidism, vitiligo, Addisons disease).

Question 26

How is folate brought into the body?

Answer 26

Dietary folate is converted to monoglutamate. This is absorbed in the jejunem

Question 27

Name some dietary sources of folate? How is folate destroyed?

Answer 27

Leafy veg, yeast. | Destroyed via cooking.

Question 28

How much does the body store of folate? How long will this last?

Answer 28

Body has 4 months worth of folate.

Question 29

How much does the body store of vitamin B12? How long does this last?

Answer 29

Has 2-4 years.

Question 30

What is the daily intake of folate and vitamin B12?

Answer 30

Vitamin B12- 1-3 micrograms/day | Folate- 100micrograms/day

Question 31

what are the causes of folate deficiency?

Answer 31

Inadequate intake (dietary cause is more likely than vitamin B12 because of the smaller stored folate) Malabsorption (coeliac disease, crohns disease) Excess utilisation (haemolysis, exfoliating dermatitis, pregnancy, malignancy) Drugs- anticonvulsants.

Question 32

What are the clinical features of B12/folate deficiency?

Answer 32

Symptoms/signs of anaemia Weight loss, diarrhoea, infertility Sore tongue, jaundice Developmental problems With vitamin B12 deficiency you are more likely to get neurological problems. Believed that B12 is involved in myelin synthesis.

Question 33

What is pancytopenia?

Answer 33

Anaemia (low red cells), thrombocytopenia (low platelets), and neutropenia (low neutrophils)

Question 34

What will the blood film show of patients with macrocytic anaemia?

Answer 34

``` Macrovalocytes (oval shaped, large red cells) Hypersegmented neutrophils (normally nucleus split into 3-5 segments) ```

Question 35

How would you diagnose B12 or folate deficiency via lab tests?

Answer 35

Assay B12 and folate serum levels- however low levels may not mean deficiency and high levels may not mean normal Check for auto-antibodies- (anti-gastric parietal cell and anti-intrinsic factor)

Question 36

How do you treat megaloblastic anaemia?

Answer 36

Treat the cause where possible. Vitamin B12 injections for life in pernicious anaemia Folic acid tablets- orally. Only blood transfuse in life threatening situations.

Question 37

What are the non-megaloblastic causes of macrocytic anaemia?

Answer 37

Alcohol Liver failure Hypothyroidism The above may not be associated with anaemia Marrow failure- myelodysplagia, myeloma, aplastic anaemia- these are all associated with anaemia.

Question 38

What is spurious macrocytosis in regards to the Mcv?

Answer 38

The size of the mature red cell is normal but the MCV is high. It is generally a fault with the analyser.

Question 39

What causes spurious macrocytosis?

Answer 39

An increase in reticulocyte numbers as a marrow response (these are bigger than normal mature red cells) in response to acute blood loss or red cell breakdown (haemolysis) Cold agglutins disease.

Question 40

What will be different about the investigation into spurious macrocytosis?

Answer 40

The cells will be polychromatic- as the reticulocytes still have the remnants of the RNA- they will be blue in colour.

Question 41

What is cold agglutins disease?

Answer 41

The immune system produces a protein causing the red cells to stick together (agglutinate) appearing as one large cell giving a false MCV reading.

Question 42

What is the structural approach to macrocytosis?

Answer 42

First look at the reticulocyte count. If this is increased- likely to be marrow response to haemorrhage or increased haemolysis. If this is normal/decreased look at the blood film. Look for macrovalcytes and hyperhsegmented nuclei. If these are present check the serum B12 and folate levels.

Question 43

What is the structural approach to macrocytosis?

Answer 43

First look at the reticulocyte count. If this is increased- likely to be marrow response to haemorrhage or increased haemolysis. If this is normal/decreased look at the blood film. Look for macrovalcytes and hyperhsegmented nuclei. If these are present check the serum B12 and folate levels. If no macrovalcytes or hyperhsegmented nuclei are present- look for other conditions like liver disease, hyperthyroidism.

Question 44

Why can patients with pernicious anaemia appear jaundiced?

Answer 44

Intramedullary haemolyisis (breakdown of red cells immaturely)- causes bilirubin build up and therefore jaundice.