Vitamin B12 and folate deficiencies Flashcards
what are the uses of B12 and folate by the body?
DNA synthesis
B12 also for nervous system integrity
absence leads to anaemia
what does folate contribute in DNA synthesis?
provides methyl group for homocysteine metabolism to occur and produce THF
what is affected by the lack of B12 and folate?
all rapidly dividing cells like RBCs, bone marrow, gut epithelium , gonads, embryos
what are the clinical features of B12 and folate def?
Anaemia – weak, tired, short of breath.
Pancytopenia
Jaundice – due to breakdown of RBCs.
Glossitis (inflammation of the tongue) and angular cheilosis (red swollen patches at corner of mouth) due to impaired repair
Weight loss and change of bowel habit due to impacted rapidly dividing cells of the gut.
Sterility – affects rapidly dividing sperm cells.
effect of B12 or folate def on red cells
association with large red cells and a large MCV (opposite to iron def)
this is a macrocytic, megaloblastic (morphological change in RBC precursor within bone marrow) anaemia
what are the other causes of macrocytic anaemias apart from B12 or folate def?
liver disease
hypothyroidism
drugs (e.g. azathioprine)
haematological disorders (e.g. myelodysplasia, aplastic anaemia and reticulocytosis).
what is the process of normal RBC maturation?
erythroblast
normoblast (early, intermediate and late) reticulocyte
RBC.
colour change in RBC maturation
from basophilic (blue) to polychromatic then RBC pink
thyroid disease on RBC
macrocytosis
no megaloblastic anaemia
what is megaloblastic anaemia?
asynchronous maturation of the nucleus and cytoplasm in the maturation process
characterised by the presence of early and developing cells
signs of megaloblastic anaemia on blood film
- nucleus present in pink RBC (it shouldn’t be)
- maturing red cells seen in BM
- changes in peripheral blood
what are the changes in peripheral blood in megaloblastic anaemia?
o Anisocytosis – variation in size of RBCs.
o Large RBCs
o Hypersegmented neutrophils (> 5 segments, normally 3-5)
o Giant metamyelocytes.
what are the tests done with macrocytosis?
o Blood test – folate, iron and B12 tests.
o Thyroid function test.
o Reticulocyte count and blood film.
what are the clinical disorders associated with hypersegmented neutrophils?
megaloblastic anaemia due to b12 or folate def
where in the diet is folate present
leafy vegetables
overcooking/canning/processing destroys it
what are the causes of folate deficiency?
- decreased uptake: alcoholics, elderly
- increased physiological demand in pregnancy, puberty, premature babies
- increased physiological demand in pathology e.g. malignancy, erythroderma, haemolytic anaemias
storage time for folate in the body
2-3 months
how is folate def diagnosed?
FBC
blood film
folate blood levels
history and examination e.g. skin disease
what are the consequences of folate def?
- megaloblastic, macrocytic anaemia
- neural tube defects (spina bifida and anencephaly)
- increased thrombosis risk associated with the enzymes involved in homocysteine metabolism
what is the effect of accumulating homocysteine due to lack of folate and metabolism?
increased risk of atherosclerosis and premature vascular disease
even mildly increased levels of HC is associated with CVD, art/ven thrombosis
what are the consequences of B12 def?
o Neurological problems – bilateral peripheral neuropathy, subacute combined degeneration of cord (can cause paralysis), optic atrophy and dementia. o Paraesthesia. o Muscle weakness. o Difficult walking. o Visual impairment. o Psychiatric disturbance.
what examination can be done to determine b12 def?
absence of reflexes
upping plantar responses
(combo of upper and lower motor neurone signs)
what are the causes of b12 def?
o Poor absorption – due to complexity of absorption
o Reduced dietary intake – difficult for this as stores are large and are found in all animal produce.
o Infections/infestations – abnormal bacterial flora, tropical sprue and fish tapeworm.
how does poor absorption cause B12 def?
- Method 1 – 1% - slow and inefficient (1% of all B12) absorption through the duodenum.
- Method 2 – 99% - B12 combines with IF and this binds to ileum receptors in the ileum.
what physical things are required for b12 absorption?
3 things are essential – intact stomach, Intrinsic Factor and a functioning small intestine.
what causes impaired B12 absorption?
- reduction in IF
- disease of small bowel and terminal ileum
- infections/infestations
- drugs
what are the causes of reduced IF causing impaired B12 absorption?
1) Post gastrectomy.
2) Gastric atrophy.
3) Pernicious anaemia – autoimmune condition associated with a severe lack of intrinsic factor.
Males have a decreased life expectancy as they can get cancer of the stomach.
what are present in the autoimmune condition of pernicious anaemia?
There is either a presence of:
o IF-antibodies
o Parietal cell antibodies – 90% in adults with PA but also in 16% of NORMAL females over 60.
what are the small bowel diseases that lead to b12 malabsorption?
- Crohn’s
- Coeliac
- Surgical resection
examples of infections/infestations
H. pylori, giardia (flagellate), fish tapeworm, bacterial overgrowth.
what drugs can cause b12 malabsorption
metformin
PPI like omeprazole
oral contraceptive pill
what can be measured in those with low B12 to diagnose them?
o Antibodies to parietal cells and IF. o Antibodies for coeliac disease. o Breath test for bacterial overgrowth. o Stool test for H. pylori and a test for giardia. o Schilling test
part 1 of schilling test
PART 1 –
- give IM injections of B12 to saturate stores
- patient drinks radiolabelled B12
- measure excretion of B12 in the urine.
normally expect it to come out (radioactive) in the urine as the stores are full, showing absorption of the nonlabelled B12 has taken place
If none is in the urine, there are several possibilities:
o Not absorbing B12 – pernicious anaemia, small bowel disease.
oHasn’t corrected B12 deficiency before the test.
part 2 of schilling test
PART 2 –
- repeat test but with addition of IF
- measure excretion of B12 in the urine.
Results:
Part 1: was Low excretion
Part 2: now Normal therefore pernicious anaemia with autoantibodies to the B12.
what would need to be measured when there is a normal B12 level?
methylmalonyl acid homocysteine
anti-intrinsic factor antibodies.
treatment of B12 def
o Injections of B12 (1000 micrograms)
- 3x a week for 2 weeks and thereafter every 3 months.
o If neurological involvement – B12 injections alternate days until no further improvement (up to 3 weeks) and thereafter every 2 months.
where is IF made?
in the stomach
how is B12 absorbed?
combines with IF made by parietal cells of the stomach
B12-IF complex binds to ileal receptors for absorption
what is pernicious anaemia caused by?
autoantibodies that bind to parietal cells or IF causing their destruction by phagocytes
slows down B12 absorption via the ileum–> pernicious anaemia
what is macrocytic anaemia?
increased MCV due to:
- Vitamin B12 or folate deficiency
- Liver disease
- Hypothyroidism
- Excessive alcohol consumption
- Drugs e.g. azathioprine, zidovudine
- Haematological disorders
what haemotalogical disorders can cause macrocytic anaemia?
- myelodysplastic syndrome
- aplastic anaemia (increased reticulocytosis)
- reticulocytosis (in chronic haemolytic anaemias)
why do immature cells e.g. pro erythroblasts, stain blue?
due to high RNA content
as they develop, progressively they have less RNA and more haemoglobin
what are megaloblasts?
cell with nucleus of unclumped chromatin
asynchronous nucleus and cytoplasm maturation
why do megaloblasts cause increased red cell production?
they are killed in the bone marrow so there is compensation
“ineffective erythropoiesis”
what are the abnormalities with white cells in megaloblastic anaemia?
giant metamyelocytes and hypersegmented neutrophils
what are the changes in the PERIPHERY in megaloblastic anaemia?
nb megaloblastic refers to changes in bone marrow
- anisocytosis
- high MCV
- low Hb (due to ineffective erythropoiesis)
- see hypersegmented neutrophils
- low platelets, WBC count
what are the causes of megaloblastic anaemia?
- vit b12 or folate def
- drugs that interfere with DNA synthesis directly e.g. azathioprine
- drugs that interfere with B12 or folate metabolism e.g. methotrexate
what changes to Vitb12 or folate may cause haematinic deficiencies?
- inadequate intake
- increased demand
- inadequate absorption
- excessive losses or utilization
what causes B12 def?
- inadequate intake (e.g. vegans, but this is rare)
- abnormal flora consumption
- increased demand
- poor absorption in small bowel (IF dysfunction)
what are the causes of intrinsic factor deficiency?
- post gastroectomy
- autoimmune gastric atrophy (pernicious anaemia)
what are the causes of poor B12 absorption?
- reduced Intrinsic Factor
- small bowel disease e.g. Crohns, Coeliacs, resection
- excessive loss
what are the neurological problems associated with B12 deficiency?
- peripheral neuropathy
- subacute combined degeneration of the spinal cord
- optic neuropathy
- dementia
what can be used to determine the cause of b12 def?
Schilling Test
Radiolabelled B12 is given orally and its excretion in the urine is measured, after first having saturated the serum B12-binding proteins by giving an intramuscular injection of non-radioactive B12.
how is the Schilling test interpreted?
Any radiolabelled B12 detected in the urine must have been successfully absorbed in the small intestine.
If the excretion is low then the test is repeated with the addition of intrinsic factor.
If this restores the excretion of B12 to normal it is possible to conclude that the defect lies with a lack of intrinsic factor secretion.
what is the diagnostic for pernicious anaemia?
anti-parietal cell and anti-intrinsic factor antibodies in the blood
what are the causes of folate def?
- inadequate intake (common)
- increased demand
- disease of jejunum (rarer)
- excessive losses (not common)
where is folate found?
animal and plant product but destroyed by cooking, canning and processing
what increases demand for folate?
Physiological: - pregnancy - lactation - adolescence - premature babies. Pathological: - an excessive turnover of cells as may occur with haemolytic anaemias, malignancy, erythroderma.
what are the consequences of folate deficiency?
1) megaloblastic anaemia.
2) neural tube defects in developing fetus–> spina bifida and anencephaly
3) possible increased risk of coronary artery disease if associated with variant enzymes in folate metabolic pathway.
4) pancytopenia (all cell precursors are affected)
why is red cell folate a better indicate for folate than serum folate?
red cell folate better indicate body stores of folate
serum folate reflects recent intake
