Macrocytosis and macrocytic anaemia

Question 1

What is macrocytic anaemia?

Answer 1

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

Question 2

How is red cell size expressed?

Answer 2

MCV - >100 fl

Units; femtolitres

Question 3

What is a useful reference point on a blood film?

Answer 3

Lymphocyte nucleus; should be a constant and should be the same size as the RBC

Question 4

What are the 2 different categories of macrocytosis?

Answer 4

Megaloblastic

Non-megaloblastic

Question 5

Do red cell precursors in the bone marrow have a nucleus?

Answer 5

YES; erythroblasts are red cell precursors found in the bone marrow and contain a nucleus

Question 6

Do reticulocytes have a nucleus?

Answer 6

No; immediate precursor to mature red blood cell. Contain RNA

Question 7

At what point of cell division of the red cell will it become enucleated?

Answer 7

Hb accumulates
Reduction in size as cell division occurs triggering nuclear maturation
At critical Hb content, the cell will stop dividing and become enucleated (still in bone marrow)

Question 8

What is a megaloblast?

Answer 8

An abnormally large nucleated red cell precursor with an immature nucleus

Question 9

What are megaloblastic anaemias characterized by?

Answer 9

Lack of red cells due to predominant defects in DNA synthesis and nuclear maturation but RNA and Hb are preserved

Question 10

Will cytoplasmic development occur normally in megaloblastic cells?

Answer 10

Yes; Hb occurs normally and so the precursor cell is bigger with an immature nucleus
Once Hb is optimal; the nucleus is extruded leaving behind a big red cell = macrocyte

Question 11

Why does anaemia occur in macrocytosis?

Answer 11

Many cells with an immature nucleus will undergo apoptosis and so overall there is a reduction in red cell numbers

Question 12

What is the difference between a macrocytic red cell and a megaloblast?

Answer 12

Macrocytic red cell = large mature red cell

Megaloblastic = large primitive cell with an immature nucleus in bone marrow

Question 13

Why are cells larger in megaloblastic anaemia?

Answer 13

Not due to a larger cell per se; it is a failure to become smaller

Question 14

What can cause megaloblastic anaemia?

Answer 14

B12 deficiency
Folate deficiency
Drugs
Rare inherited abnormalities

Question 15

Why are B12 and folate important?

Answer 15

B12 and folate are essential co-factors in linked biochemical reactions that regulate:
DNA synthesis and nuclear maturation (blood cell)
DNA modification and gene activity (nervous system)

Question 16

Describe the absorption of B12 from the diet?

Answer 16

Dietary sources
Acid in stomach will result in B12 dissociation from food and will bind to haptocorrin
Gastric parietal cells (fundus and body of stomach) secrete intrinsic factor
In duodenum; pancreatic secretions increase pH which results in B12 dissociating from haptocorrin and binding to IF
B12 bound to IF will bind to cubulin receptors in the ileum where it will be absorbed into circulation

Question 17

In what parts of the gut is B12 absorbed?

Answer 17

Distal - ileum

However; a functioning gastric parietal system is required for the secretion of intrinsic factor

Question 18

What is pernicious anaemia?

Answer 18

Autoimmune conditions with resulting destruction of gastric parietal cells resulting in IF factor deficiency with B12 deficiency

Question 19

What other disorders is pernicious anaemia assoc with?

Answer 19

Autoimmune disorders such as hashimoto’s, vitiligo, addison’s disease

Question 20

How is folate absorbed?

Answer 20

Dietary folates converted to monoglutamate

Absorbed in jejunum (diffusion and active)

Question 21

How much B12 is stored in the body?

Answer 21

2-4 years worth

Question 22

How much folate is stored in the body?

Answer 22

4 months

Question 23

What is the daily requirement of B12?

Answer 23

1.5 micrograms/ day

Question 24

What is the daily requirement of folate?

Answer 24

200 micrograms/ day

Question 25

What can cause folate deficiency?

Answer 25

Inadequate intake Malabsorption; coeliac, crohns Excess utilisation; haemolysis, exfoliating dermatitis, pregnancy, malignancy Drugs; anticonvulsants, methotrexate, trimethoprim

Question 26

What are clinical features common to both B12 and folate deficiency?

Answer 26

Anaemia; SOB, fatigue, motor development delay, heart failure Wt loss, diarrhoea, infertility Sore tongue Jaundice

Question 27

What neurological problem is specific to B12 deficiency?

Answer 27

Subacute combined degeneration of the spinal cord; dorsal column in particular Neuropathy Dementia Psychiatric manifestation

Question 28

How is macrocytic anaemia diagnosed?

Answer 28

Macrocytic anaemia; low red cell count Pancytopenia can occur Assay of B12 and folate

Question 29

What will the blood film show in macrocytic anaemia?

Answer 29

``` Macroovalocytes Hypersegmented neutrophils (normal 3-5 segments) ```

Question 30

What autoantibodies are assoc with pernicious anaemia?

Answer 30

Anti-IF - more specific, less sensitive | Anti gastric-parietal cell (GPC) - more sensitive, less specific

Question 31

How is megaloblastic anaemia treated?

Answer 31

Vit B12 injections Folic acid tablets (5mg per day) If life-threatening anaemia; transfuse red cells

Question 32

What can cause non-megaloblastic macrocytosis?

Answer 32

Alcohol Liver dx Hypothyroidism Marrow failure; myelodysplasia, myeloma, aplastic anaemia

Question 33

What is spurious macrocytosis?

Answer 33

Volume of mature red cell is normal but MCV is high

Question 34

What can cause a false macrocytosis?

Answer 34

Increase in reticulocyte numbers due to acute blood loss or red cell breakdown Cold-agglutinins disease

Question 35

What are the causes of macrocytic anaemia with an increased retic count?

Answer 35

Haemorrhage | Haemolysis

Question 36

Why can patients with pernicious anaemia present with jaundice?

Answer 36

Intramedullary haemolysis; red cells die prematurely in marrow

Question 37

What are sources of folate?

Answer 37

Liver, green leafy veg, kidney beans, yeast extract, whole grains Fortified food

Question 38

What are the dietary sources of vit B12?

Answer 38

Animal; meat and eggs | Bacterial preparations of vit B12

Question 39

Specifically, what pathways will folate and B12 interact with in biochemical terms?

Answer 39

``` Folate cycle (DNA/nucleoside synthesis) = uridine to thymidine conversion Methionine cycle (DNA modification/ gene activity) = production of S-adenosyl methionine ```