Macrocytic anaemia and vitamin B12 and folate Flashcards
Macrocytic anaemia
- Anaemias where the average red cell size is greater than normal (increased MCV)*
- >100 fl*
types of maxcrocytic anaemia
- Megaloblastic anaemia
- Macronormoblastic erythropoiesis
- Stress erythropoiesis
causes of macrocytic anaemia
- vitamin B12 anaemia
- Folate deficiency
- myelodysplasia
- liver disease
- alcohol toxicity
Megaloblastic anaemia
- Interference with DNA synthesis during erythropoiesis causes development of nucleus to be retarded in relation to maturation of cytoplasm
- Cell division delayed and erythroblasts continue to grow to form megaloblasts which give rise to larger red cells
causes of megaloblastic anaemia
- Vitamin B12 / folate deficiency
- Drugs that interfere with DNA synthesis (e.g. some anti- cancer)
- Some erythroid leukaemias where DNA synthesis is retarded
Macronormoblastic erythropoiesis
Normal relationship between development of nucleus and cytoplasm is retained but erythroblasts are larger than normal and give rise to larger red cells
cause of macronormoblastic erythropoiesis
- liver disease
- alcohol toxicity
- myelodysplastic syndrome
Stress erythropoiesis
- Conditions associated with a high reticulocyte count (reticulocytes are larger than normal red cells)
- High level of erythropoietin leads to an expanded and accelerated erythropoiesis
causes of stress erythropoiesis
- Recovery from blood loss due to haemorrhage
- Recovery from haemolytic anaemia
folate is the
synthetic form of folic acid
what synthesises folate
bacteria and plants
what are good sources of folate
- Present in a wide variety of animal and vegetable food sources
- Green leafy vegetables (foliage)
where is folate absorbed
duodenum and jejunum
once the folate has been absorbed in the duodenum and jejunum what is it converted to
- tetrahydrofolate (FH4) by intestinal cells
- Taken up by liver- store
importance of folate
- Metabolic role to provide carbons for other reactions
- E.g. synthesis of nucleotides bases required for DNA and RNA synthesis
cause of folate deficiency
- Dietary deficiency (poor diet)
-
Increased requirements
- Pregnancy
- Increased erythropoiesis e.g. haemolytic anaemia
- Severe skin disease e.g. psoriasis
- Disease of duodenum and jejunum (e.g. coeliac disease and crohns disease)
- Drugs which inhibit dihydrofolate reductase e.g. methotrexate
- Alcoholism
- Urinary loss of folate in liver disease and heart failure
symtoms of folate deficiency
- Anaemia related
- Reduced sense of taste
- Diarrhoea
- Numbness and tingling in feet and hands
- Muscle weakness
- Depression
why is folic acid taken before conception and during the first 12 weeks of pregnancy
to prevent neural tube defects in babies e.g. spina bifida
vitamin B12 is also known as
cyancobalamin
what sort of vitamin is Vitamin B12 (cyanocobalamin)
Water soluble vit
vitamin B12 is an
- essential cofactor fo DNA synthesis (due to its role in folate metabolism)
- required for normal eryhtropoiesis
- essential for normal function and development of the CNS
what produces vitamin B12
bacteria
sources of B12
- Largely obtained from foods of animal origin (produced by commensal bacteria)
- Essential that people on a vegan diet eat foods fortified with B12 or take a B12 supplement daily or weekly
vitamin B12 absorption
- B12 released from food proteins by proteolysis in stomach where it then binds to haptocorrin
- Haptocorrin B12 complex digested by pancreatic proteases in small intestine releasing B12 which then binds intrinsic factor (produced by gastric parietal cells).
- Intrinsic factor–B12 complex binds to cubam receptor which mediates uptake of complex by receptor- mediated endocytosis into enterocytes
- After lysosomal release in enterocytes, B12 exits via basolateral membrane through MDR1
- Binds to transcobalamin in blood and transported around bloodstream
- Majority of B12 is stored in the liver (store enough to provide B12 requirements for ~3-6 years)
pernicious anaemia
- Decreased or absent intrinsic factor (causes progressive exhaustion of B12 reserves
cause of pernicious anaemia
- Autoimmune disease
- 2 types of antibody
- Blocking Ab blocks binding of B12 to IF
- Binding Ab prevents receptor mediated endocytosis
- 2 types of antibody
causes of vitamin B12 deficeincy
- Dietary deficiency
- Lack of intrinsic factor (Pernicious anaemia)
- Disease of the ileum (Crohns disease, ileal resection, tropical sprue)
- Lack of transcobalamin (congenital defect)
- Chemical inactivation of B12 e.g. frequent use of anaesthetic gas nitrous oxide
- Parasitic infestation (tapeworm can trap b12)
- Some drugs can chelate intrinsic factor (e.g. hypercholesterolaemia drug cholestyramine)
symptoms of B12 deficiency
- Anaemia related
- Glossitis and mouth ulcers
- Diarrhoea
- Paraesthesia
- Disturbed vision
- irritability
how can B12/folate deficiency also affect the NS
- Folate deficiency in pregnancy can cause neural tube defects
- Vitamin B12 deficiency associated with focal demyelination
Subacute combined degeneration of the cord
B12 defiicency more often resuls in
reversible peripheral neuropathy
which serious condition can B12 deficiency result in
- subacute combined degeneration (irreversible) of the cord- involving degeneration of posterior and lateral columns of the spinal cord
symptoms of subacute combined degeneration of the cord
- Gradual onset weakness, numbness and tingling in arms, legs and trunk which progressively worsens
- Changes in mental state
relationship between B12 and Folate
lack of B12 will trap folate in the stable methyltetrahydrofolate form prveneting its use in other reactions such as synthesis of thymidine for DNA synthesis
Why do B12 and folate deficiency cause a megaloblastic anaemia?
- Both folate and B12 deficiency lead to thymidine deficiency
- In absence of thymidine, uracil is incorporated into DNA instead
- DNA repair enzymes detect these errors and constantly repair excision
- Results in asynchronous maturation between nucleus and cytoplasm
- Nucleus doesn’t fully mature
- Cytoplasm matures at the normal rate
- Large nuclei and open chromatin
- Mature red cells also large leading to macrocytic anaemia
megaloblastic features in peripheral blood film
As B12/foalte deficiency progresses a pancytopenia ca also develop i.e. low platelets and neutrophils as well
Investigations for megaloblastic anaemia
treatment of vitamien B12 and folate deficiency
