Macrocytosis and macrocytic anaemia Flashcards
What is macrocytic anaemia?
Anaemia in which the red cells have a larger volume than normal
How is red cell size expressed?
MCV - >100 fl
Units; femtolitres
What is a useful reference point on a blood film?
Lymphocyte nucleus; should be a constant and should be the same size as the RBC
What are the 2 different categories of macrocytosis?
Megaloblastic
Non-megaloblastic
Do red cell precursors in the bone marrow have a nucleus?
YES; erythroblasts are red cell precursors found in the bone marrow and contain a nucleus
Do reticulocytes have a nucleus?
No; immediate precursor to mature red blood cell. Contain RNA
At what point of cell division of the red cell will it become enucleated?
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)
What is a megaloblast?
An abnormally large nucleated red cell precursor with an immature nucleus
What are megaloblastic anaemias characterized by?
Lack of red cells due to predominant defects in DNA synthesis and nuclear maturation but RNA and Hb are preserved
Will cytoplasmic development occur normally in megaloblastic cells?
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
Why does anaemia occur in macrocytosis?
Many cells with an immature nucleus will undergo apoptosis and so overall there is a reduction in red cell numbers
What is the difference between a macrocytic red cell and a megaloblast?
Macrocytic red cell = large mature red cell
Megaloblastic = large primitive cell with an immature nucleus in bone marrow
Why are cells larger in megaloblastic anaemia?
Not due to a larger cell per se; it is a failure to become smaller
What can cause megaloblastic anaemia?
B12 deficiency
Folate deficiency
Drugs
Rare inherited abnormalities
Why are B12 and folate important?
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)
Describe the absorption of B12 from the diet?
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
In what parts of the gut is B12 absorbed?
Distal - ileum
However; a functioning gastric parietal system is required for the secretion of intrinsic factor
What is pernicious anaemia?
Autoimmune conditions with resulting destruction of gastric parietal cells resulting in IF factor deficiency with B12 deficiency
What other disorders is pernicious anaemia assoc with?
Autoimmune disorders such as hashimoto’s, vitiligo, addison’s disease
How is folate absorbed?
Dietary folates converted to monoglutamate
Absorbed in jejunum (diffusion and active)
How much B12 is stored in the body?
2-4 years worth
How much folate is stored in the body?
4 months
What is the daily requirement of B12?
1.5 micrograms/ day
What is the daily requirement of folate?
200 micrograms/ day
What can cause folate deficiency?
Inadequate intake
Malabsorption; coeliac, crohns
Excess utilisation; haemolysis, exfoliating dermatitis, pregnancy, malignancy
Drugs; anticonvulsants, methotrexate, trimethoprim
What are clinical features common to both B12 and folate deficiency?
Anaemia; SOB, fatigue, motor development delay, heart failure
Wt loss, diarrhoea, infertility
Sore tongue
Jaundice
What neurological problem is specific to B12 deficiency?
Subacute combined degeneration of the spinal cord; dorsal column in particular
Neuropathy
Dementia
Psychiatric manifestation
How is macrocytic anaemia diagnosed?
Macrocytic anaemia; low red cell count
Pancytopenia can occur
Assay of B12 and folate
What will the blood film show in macrocytic anaemia?
Macroovalocytes Hypersegmented neutrophils (normal 3-5 segments)
What autoantibodies are assoc with pernicious anaemia?
Anti-IF - more specific, less sensitive
Anti gastric-parietal cell (GPC) - more sensitive, less specific
How is megaloblastic anaemia treated?
Vit B12 injections
Folic acid tablets (5mg per day)
If life-threatening anaemia; transfuse red cells
What can cause non-megaloblastic macrocytosis?
Alcohol
Liver dx
Hypothyroidism
Marrow failure; myelodysplasia, myeloma, aplastic anaemia
What is spurious macrocytosis?
Volume of mature red cell is normal but MCV is high
What can cause a false macrocytosis?
Increase in reticulocyte numbers due to acute blood loss or red cell breakdown
Cold-agglutinins disease
What are the causes of macrocytic anaemia with an increased retic count?
Haemorrhage
Haemolysis
Why can patients with pernicious anaemia present with jaundice?
Intramedullary haemolysis; red cells die prematurely in marrow
What are sources of folate?
Liver, green leafy veg, kidney beans, yeast extract, whole grains
Fortified food
What are the dietary sources of vit B12?
Animal; meat and eggs
Bacterial preparations of vit B12
Specifically, what pathways will folate and B12 interact with in biochemical terms?
Folate cycle (DNA/nucleoside synthesis) = uridine to thymidine conversion Methionine cycle (DNA modification/ gene activity) = production of S-adenosyl methionine
