Macrocytic Anaemia Flashcards
What is macrocytic anaemia?
Anaemia (reduced red cells and Hb) where the red cells have an increased volume
If FBCs show low Hb, low RBCs and high MCV, what is this?
Macrocytic anaemia
If FBCs show normal Hb, normal RBCs and high MCV, what is this?
Macrocytosis (no anaemia)
On a blood film, normally a red blood cell should be the same size as what?
The nucleus of a small lymphocyte
How do you recognise a macrocyte on a blood film?
It will be much larger than the nucleus of a lymphocyte
The genuine (true) causes of macrocytosis can be divided into what two categories?
Megaloblastic and non-megaloblastic
What does it mean to be megaloblastic?
To have abnormal DNA synthesis
What are the main causes of megaloblastic macrocytic anaemia?
B12 and folate deficiency
What are the main causes of non-megaloblastic macrocytic anaemia?
Hypothyroidism, alcohol, pregnancy, marrow failure
What are the spurious (false) causeses of macrocytosis?
Reticulocytosis and cold-agglutinins
Describe briefly what normally happens to a developing erythroblast?
Accumulate Hb, reducing in size as they divide. They then stop dividing and lose their nucleus once Hb content is optimal.
What is an erythoblast/normoblast?
A normal red cell precursor with a nucleus
What is a megaloblast?
An abnormally large red cell precursor with an immature nucleus
Megaloblastic anaemias are characterised by predominant defects in what? What is preserved?
DNA synthesis and nuclear maturation / RNA and Hb synthesis
What happens during cell division in erythropoiesis when there are megaloblasts?
Less division and more apoptosis
In erythropoiesis of a macrocyte, once Hb levels are optimal, what happens?
The nucleus is extruded but leaves behind an abnormally large cell (macrocyte) because the cells didn’t divide due to their immature nucleus
If macrocytes are large red blood cells, why does their presence cause anaemia?
Because there are fewer of them since they get apoptosed
As a key message, the larger cell size in megaloblastic anaemia is not due to what? But is due to what?
An increase in the size of the developing cell / a failure to divide and become smaller
Why does a lack of B12 or folate cause megaloblastic macrocytic anaemia?
Because they are essential co-factors for nuclear maturation which enable chemical reactions to allow DNA synthesis
Nucleosides needed for DNA synthesis are formed from what?
Switching on and silencing of certain genes
Silencing of genes to form nucleosides occurs through what?
Methylation of DNA
Vitamin B12 and folate biochemical reactions are interlinked via what?
The folate and methionine cycles
The folate cycle is important for what? The conversion of what is especially important to be able to build DNA?
Nucleoside synthesis - conversion of uridine to thymidine
The methionine cycle is important for what?
Production of a methyl donor to latch onto DNA/RNA/proteins to switch off genes
How do the folate and methionine cycles interact?
The folate cycle produces vitamin B12 which is used in the methionine cycle to convert homocysteine to methionine
What is the relevance of the folate and methionine cycles interacting?
A deficiency in B12 or folate can cause problems in both cycles (i.e. a true deficiency of one can cause a functional deficiency of the other)
Where do we get vitamin B12 from?
Animal products e.g. meat, fish, eggs and milk
When vitamin B12 is consumed, it enters the acid environment of the stomach and binds to what? What is the purpose of this?
R-binder (released from the gastric mucosa) / to stop B12 being broken down with food
In response to food in the stomach, the parietal cells of the stomach release what?
Intrinsic factor
What happens with regards to vitamin B12 absorption when pancreatic alkaline secretions are produced?
B12 is released from the R-binder and instead binds to intrinsic factor and travels to the gut to be absorbed in the ileum
What is a cause of B12 deficiency due to inadequate intake?
Vegan diet
What are some causes of B12 deficiency due to problems in the stomach?
Pernicious anaemia, atrophic gastritis, PPI/H2 antagonist use, gastrectomy/bypass
What is a cause of B12 deficiency due to problems in the pancreas?
Chronic pancreatitis
What are some causes of B12 deficiency due to problems in the small bowel?
Coeliac, Crohn’s, bacterial overgrowth or resection
What is the most common cause of B12 deficiency in adults? What is this?
Pernicious anaemia - an autoimmune condition which results in the destruction of gastric parietal cells leading to intrinsic factor deficiency
What are some other conditions that pernicious anaemia may be related to?
Atrophic gastritis and a personal or family history of other autoimmune conditions
Why can people with pernicious anaemia appear slightly jaundiced?
There is intramedullary haemolysis
Dietary folate is converted to what? Where is it absorbed? How?
Monoglutamate / jejunum and duodenum / both actively and passively
What is a cause of folate deficiency related to inadequate intake?
Alcoholics (since they tend to neglect their diet)
What are some causes of folate deficiency related to malabsorption?
Coeliac disease and Crohn’s disease
What are some causes of folate deficiency due to excess utilisation?
Haemolysis, exfoliating dermatitis, pregnancy, malignancy
What are some drugs which can cause folate deficiency?
Anticonvulsants, methotrexate, trimethoprim
Where does dietary folate come from?
Liver, leafy green veg and fortified cereals
What is the daily requirement of B12? How long is it stored for?
1.5mcg / 2-4 years
What is the daily requirement of folate? How long is it stored for?
200mcg / 4 months
What are some clinical features common to both B12 and folate deficiency?
Symptoms of anaemia, weight loss/diarrhoea, infertility, sore tongue, jaundice
What can B12 and folate deficiency cause in children?
Developmental problems
Neurological problems are more likely to occur as a result of a deficiency of what? What is important to be aware of about these problems?
B12 / the changes are irreversible so treat them with B12 supplements ASAP even if diagnosis is not confirmed
What are some examples of the neurological problems which can occur with B12 deficiency?
Posterior/dorsal column abnormalities (subacute combined degeneration of the cord), neuropathy, dementia, psychiatric manifestations
What type of anaemia will B12/folate deficiency cause? What would be the values of each of the following: a) RBCs? b) Hb? c) MCV?
Macrocytic anaemia / low, low, high
What will a blood film of megaloblastic macrocytic anaemia show?
Macrovalocytes (enlarged, oval shaped RBCs) and hypersegmented neutrophils
As part of the laboratory diagnosis of B12/folate deficiency, you can assay their levels in the serum. This is flawed as low levels may not indicate a deficiency in who? And who with normal levels may still be deficient?
Young women COCP / older people
If megaloblastic macrocytic anaemia is found, you should check for which auto-antibodies? Which one is sensitive but not specific? Which one is more specific but not sensitive?
Anti-IF and anti-GPC / anti-GPC / anti-IF
What is the last line investigation for megaloblastic macrocytic anaemia?
Bone marrow examination to look for macrocytes (not usually required)
The mainstay of treatment for megaloblastic macrocytic anaemia is what?
Treat the underlying cause
What is the treatment for pernicious anaemia?
Vit B12 (hydroxycobalamin) injections for life
What is the treatment for folate deficiency?
Folic acid supplements 5mg/day orally
When should a red cell transfusion be used for megaloblastic macrocytic anaemia?
If the anaemia is life threatening
Most non-megaloblastic macrocytoses are caused by what?
Interference with the red cell membrane
What are some examples of pathological non-megaloblastic macrocytosis which are not associated with anaemia?
Alcohol, liver disease, hypothyroidism
What is the main cause of non-megaloblastic macrocytosis which is associated with anaemia? Give some examples.
Marrow failure e.g. myeloma, myelodysplasia, aplastic anaemia
What is the physiological cause of non-megaloblastic macrocytosis?
Pregnancy
What is spurious macrocytosis?
When the volume of the mature red cell is normal, but the MCV is high
Why does reticulocytosis cause spurious macrocytosis?
Because reticulocytes are bigger than mature red cells but these are analysed together to give MCV measurement and since in reticulocytosis there are increased reticulocytes, this increases the average MCV
What are cold-agglutinins and why can they cause spurious macrocytosis?
Clumps of agglutinated red cells - they get registered as 1 giant cell
Cold-agglutinins are associated with what?
Lymphoma and certain infections
