Macrocytosis and Macrocytic Anaemias Flashcards
What cell does macrocytosis refer to?
RBC’s
What is macrocytosis?
Anaemia in which the red cells have a larger than normal volume
What measurement assesses RBC size?
MCV – Mean Corpuscular (cellular) Volume
What is the units of MCV?
Femtolitres (1femtolitre = 10-15L).
What would the blood results be of a patient with macrocytic anaemia?
- Low Hb
- Low RCB’s
- High MCV
What would the blood results be of a patient with macrocytosis (without the anaemia)?
- Normal Hb
- Normal RBC’s
- High MCV
On a blood film, what is the size of RBC’s normally comparable to?
The nucleus of lymphocytes
If a RBC is smaller than the nucleus of a lymphocyte then it can be described as?
Microcytic
If a RBC is larger than the nucleus of a lymphocyte then it can be described as?
Macrocytic
Outline what the causes of an apparent macrocytosis can be grouped into
- True - megaloblastic or non-megaloblastic
2. Spurious (false)
What is an erythroblast/normoblast?
A normal red cell precursor with a nucleus
What is the basic structure of a mature red cell?
Flexible cell membrane surrounding soluble proteins and electrolytes
Do red cell precursors have a nucleus?
No – the reticulocyte doesn’t, but the other precursors do (erythroblasts)
Where are red cell precursors usually found?
Bone marrow
What is a reticulocyte?
An immediate precursor of the red cell that has lost its nucleus, but still has a little bit of RNA in it
Outline 3 things that happen to erythroid cells in bone marrow as they develop.
- Accumulate Hb
- Reduce in size
- Stop dividing and lose nucleus (regulated by Hb content)
Describe megaloblastic development.
Involves the development of an abnormally large nucleated red cell precursor with an immature nucleus.
What are megaloblastic anaemias characterised by? (in terms of what is defective and what is preserved)
Predominant defects in DNA synthesis and nuclear maturation, with relative preservation of RNA and haemoglobin synthesis
What happens in more mature erythroblasts?
Division reduces and apoptosis increases
What happens in the few erythroblasts that survive as ‘megaloblasts’? What does this lead to? And why does this make a patient anaemic?
Cytoplasm development occurs normally and triggers enucleation
- this leads to a ‘bigger-than-normal’ red cell.
- the patient is anaemic because there are FEWER of these big red cells
What is the end result in enucleation?
Nucleus is more immature, and chromatin is less condensed
The larger cell size in megaloblastic anaemia is not due to an increase in the size of the developing cell but ….
A failure to become smaller
Suggest some causes of megaloblastic anaemia.
- B12 deficiency
- Folate deficiency
- Others – drugs, rare inherited abnormalities
Why does lack of B12 or folate cause megaloblastic anaemia?
B12 and folate are essential co-factors for nuclear maturation, enabling chemical reactions that provide enough nucleosides for DNA synthesis
B12 and folate biochemical reactions are interlinked Name 2 ‘cycles’ which these are involved in.
- Methionine cycle
2. Folate cycle
What is the folate cycle important for? And what reaction does folic acid specifically catalyse?
Important for nucleoside synthesis
Conversion of uridine to thymidine in nucleoside synthesis (know for exams!!!)
What does the methionine cycle do?
Produces s-adenosyl methionine, a methyl donor (potential impact on DNA, RNA, proteins, lipids, folate intermediates)
What do B12 and folate both catalyse?
The conversion of homocysteine to methionine
What is the folate cycle important for?
The DNA cycle and nucleic acid synthesis
What is the methionine cycle aka?
The methylation cycle
What is the measurement of things like homocysteine and other metabolites useful for?
Diagnosing B12/folate deficiency
- Some of the metabolites may increase
What is vitamin B12 also known as?
Cobalamin
What kind of pH do we need for vitamin B12 to be released from foods?
Acidic
What is the role of intrinsic factor?
Intrinsic factor is secreted into the lumen of the stomach from gastric parietal cells in response to the presence of food in the stomach
What is the route taken by vitamin B12 and intrinsic factor after having been in the stomach?
B12 and intrinsic factor travel together into the proximal small bowel where the pancreas secretes its enzymes, creating an alkaline environment in which B12 can finally bind to intrinsic factor
What does the B12-intrinsic factor complex do?
Travels to the terminal ileum where there are cubulin receptors to which it binds, and then becomes internalised
Where does B12 and intrinsic factor become absorbed?
Terminal ileum
Outline some potential areas of the body where vitamin B12 deficiency can occur.
- From mouth
- Pancreas
- Stomach
- Small bowel
What kind of stomach problems can results in a vitamin B12 deficiency?
Basically anything that reduces acid production
- Pernicious anaemia
- Atrophic gastritis
- PPI’s/H2 receptor antagonists
- Gastrectomy/bypass
What kind of diet can result in vitamin B12 deficiency?
Veganism/vegetarianism
What kind of pancreatic problems can results in a vitamin B12 deficiency?
Chronic pancreatitis
What kind of jejunum problem can result in a vitamin B12 deficiency?
- Bacterial overgrowth
* Coeliac disease
What kind of duodenal problem can result in a vitamin B12 deficiency?
- Resection
* Crohn’s
What is pernicious anaemia?
An autoimmune condition resulting in the destruction of gastric parietal cell
What is the effect of destruction of gastric parietal cells in PA?
Intrinsic factor deficiency, with B12 malabsorption and deficiency.
What is pernicious anaemia associated with?
- Atrophic gastritis.
- Personal or family history of other autoimmune disorders e.g. hypothyroidism, vitiligo, Addison’s disease
Look out for a question about a person with hypothyroidism who has become anaemic !!!
What are dietary folates converted to?
Monoglutamate
Where is monoglutamate absorbed?
In the jejunum – both actively and via diffusion
Think B12 is absorbed Below folate.
ileum vs jejunum
T
Where is folate absorbed?
Jejunum
Where is B12 absorbed?
Ileum
What foods to we get vitamin B12 from?
Animals - meat, eggs etc
What foods do we get folate from?
Leafy green veg
Outline causes of folate deficiency.
- Inadequate Intake (from diet)
- Malabsorption - coeliac, crohn’s
- Excess Utilisation - haemolytic, pregnancy,
- Drugs - Anticonvulsants.
What anticonvulsant can predispose someone to a folate deficiency?
Phenytoin
What signs and symtoms are common to both folate and vitamin B12 deficiency?
- Sx/signs of anaemia.
- Weight loss, diarrhoea, infertility.
- Fatigue.
- Sore tongue (glossitis).
- Jaundice.
- Developmental problems.
What problem tends to manifest more greatly with vit B12 deficiency?
Neurological problems
** Think B12 for Brain **
How does B12 deficiency result in neurological problems?
Affects myelin
What neurological problems arise with vitamin B12 deficiency?
- Posterior/dorsal column abnormalities
- Neuropathy
- Dementia
- Psychiatric manifestations
Neurological findings may occur in the absence of haematological findings.
T
What condition arises if folic acid is given without B12 replacement?
Subacute combined degeneration of the cord
What are the lab findings in macrocytic anaemia?
- Macrocytic anaemia red cells low.
- Blood film findings
- Pancytopenia (all cells low) in some patients
What is the characteristic blood film appearance seen in lab of macrocytic anaemia due to vitamin B12 or folate deficiency?
Macro-ovalocytes + Hypersegmented neutrophils (more than the normal 3-5 nuclear segments).
What is pancytopenia?
Decrease in RBC’s, WBC’s and platelets
How should megaloblastic anaemia be treated?
The cause should be treated
How is pernicious anaemia treated?
With vitamin B12 (hydroxycobalamin in Europe) injections for life
(note – high dose oral hydroxycobalamin may be effective)
Folic acid tablets (5mg per day) orally
What is the last resort treatment for pernicious anaemia?
Red cell transfusion – only if there is potential life-threatening anaemia
What does non-megaloblastic macrocytosis occur due to?
Red cell membrane changes
Suggest some causes of non-megaloblastic macrocytosis.
- Alcohol
- Liver disease
- Hypothyroidism
- Marrow failure (associated with anaemia)
If there is isolated macrocytosis, think about excess alcohol intake
T
What does megaloblastic macrocytosis occur due to?
A problem of the nucleus
What is spurious macrocytosis?
‘false macrocytosis’ – the size of the mature red cell is normal, but the MCV is measured as being high
What is spurious macrocytosis usually due to?
A mis-interpretation by the analyser.
What are the 2 potential causes of spurious macrocytosis?
- Increased reticulocyte numbers
2. Cold agglutinations
What do increased reticulocyte numbers occur due to?
Occurs as a marrow response to acute blood loss or red cell breakdown (haemolysis).
Why does increased reticulocyte numbers result in spurious macrocytosis?
Reticulocytes are bigger than mature red cells, and are analysed along with these for the MCV measurement
Why does cold agglutinins result in spurious macrocytosis?
The clumps of ‘agglutinated’ red cells are registered as 1 ‘giant’ cell
The reticulocyte count is raised in acute situations because the body is trying to counteract blood loss or haemolysis by producing more red blood cells.
T
How may some patients with PERNICIOUS ANAEMIA appear?
Mildly jaundiced
Why do people with pernicious anaemia appear mildly jaundiced?
Due to intramedullary haemolysis
There is ineffective erythropoiesis, meaning red cells die prematurely in the marrow. Haemoglobin and lactate dehydrogenase (LDH) are then released from dead red cells.
And haemoglobin is converted to bilirubin.
What can complicate severe megaloblastic anaemia? Why?
Pancytopenia
- Nuclear maturation defects can affect multiple lineages
