What is macrocytic anaemia?
Anaemia in which the red cells have a larger than normal size = measured using MCV
How is MCV measured?
Using analysers = use light scatter properties
When would a cell be classed as a macrocyte?
MVC > 100fl
What are the types of macrocytosis?
Genuine = true increase in MCV
Spurious (also known as false)
What are the categories of genuine macrocytosis?
Megaloblastic and non-megaloblastic
What are normal red cell precursors called?
Erythroblasts or normoblasts = have a nucleus and are marrow-based
What happens to normoblasts once they contain an adequate amount of Hb?
They stop dividing and lose their nucleus
What characterises macrocytic anaemia?
Lack of red cells due to predominant defects in DNA synthesis and nuclear maturation in precursors
What is a megaloblast?
Abnormally large nucleated red cell precursor with an immature nucleus
What is abnormal about megaloblast maturation?
Division is reduced and apoptosis increases
Why do megaloblasts end up bigger?
Immature nucleus prevents division plus cytoplasmic development and Hb accumulation are normal
What happens once the Hb level in the megaloblast is optimal?
The nucleus is extruded to leave behind a macrocyte
Why does macrocytosis cause anaemia?
Overall there are fewer cells despite the fact that they are bigger
What are the cause of megaloblastic macrocytic anaemia?
B12 deficiency, folate deficiency, drugs, rare inherited abnormalities
What processes do B12 and folate regulate?
DNA synthesis and nuclear maturation
DNA modification and gene activity
How does B12 enter the body?
Enters in food and is released in the stomach by acid = binds to rapid binder protein from saliva as protection
Where is intrinsic factor secreted from?
Gastric parietal cells = occurs in response to food in stomach
What happens to intrinsic factor and B12-rapid binder complex once they leave the stomach?
Travel to duodenum = B12 is released from complex and binds to intrinsic factor
Where does the intrinsic factor-B12 complex travel to once it leaves the small bowel?
Travels to distal small bowel where it attaches to receptors and enters the bloodstream = occurs in ileum
What does the intrinsic factor-B12 complex bind to once it is in the bloodstream?
Transcohalamin receptors
What are some causes of B12 deficiency?
Vegan diet, pernicious anaemia, atrophic gastritis, Coeliac, Crohn’s, bacterial overgrowth
What is pernicious anaemia?
Autoimmune condition causing destruction of gastric parietal cells
What does pernicious anaemia result in?
Intrinsic factor deficiency plus B12 malabsorption and deficiency
How are folates absorbed?
Dietary folates converted to monoglutamate
Absorbed in jejunum
What are the causes of folate deficiency?
Malabsorption = Crohn’s, Coeliac
Excess utilisation = haemolysis, exfoliating dermatitis, pregnancy, malignancy
Dietary insufficiency
Why does folate deficiency present earlier than B12 deficiency?
Stores of folate
What are some symptoms that occur in both folate and B12 deficiency?
Weight loss, diarrhoea, infertility, sore tongue, jaundice, developmental problems, signs of anaemia (e.g fatigue)
What are some of the neurological conditions that occur in B12 deficiency?
Dorsal column abnormalities, neuropathy, dementia, psychiatric issues
What is pancocytopenia?
Low number of all cells = can occur in some patients with B12 or folate deficiency
How can B12 or folate deficiency be diagnosed?
Low red cell count = macrocytic anaemia
Blood film
Assay B12 and folate levels in serum
What are the auto-antibodies associated with B12 and folate deficiency?
Anti-GPC and anti-IF auto-antibodies
What does the blood film of a patient with B12 or folate deficiency show?
Macroovalocytes and hypersegmented neutrophils (more the 3-5 segments)
How is megaloblastic macrocytic anaemia treated?
Vitamin B12 injections for life for pernicious anaemia
Folic acid 5mg oral tablets
Red cell transplant only if life threatening anaemia
What are the causes of non-megaloblastic macrocytic anaemia?
Alcohol, liver disease and hypothyroidism = may not be associated with anaemia
Marrow failure = myelodysplasia, myeloma, aplastic anaemia (all cause anaemia)
What is spurious macrocytosis?
Volume of mature red cell is normal but MCV is still measured as high
What are the causes of spurious macrocytosis?
Reticulocytosis and cold-agglutinins
What causes reticulocytosis?
Increase in reticulocyte numbers occurs as marrow response to acute blood or haemolysis
Why does reticulocytosis cause a falsely high MCV and result in spurious macrocytosis?
Reticulocytes are bigger than mature red cells and are analysed alongside red cells for MCV measurement
What are cold-agglutinins?
Proteins produced by cancers and infection
How do cold-agglutinins cause spurious macrocytosis?
Cause clumping of red cells in samples at temperature <37 = falsely measured as one giant cell
How can falsely high MCV measurements due to cold agglutinins be prevented?
Warm blood samples to 37 degrees
What causes patients with pernicious anaemia to appear mildly jaundiced?
Intramedullary haemolysis = causes ineffective erythropoiesis
How does ineffective erythropoiesis cause jaundice?
Red cells die prematurely in marrow
HB and LDH are released from dead red cells
Hb is converted to bilirubin
How can pancytopenia complicate megaloblastic macrocytic anaemia?
Nuclear maturation defects can affect multiple lineages