Vitamin B12 and Folic Acid Deficiency Flashcards
What is vitamin B12 and what types of food is it commonly found in?
Cobalamin (vitamin B12) is a bacterial product that is ingested + stored by animals.
Found in meat, cheese, salmon, cod, milk, eggs
How much B12 is needed every day and how much is found in hepatic stores?
1.5-3 mcg/day required
Store: 2-5 mg (will last several years)
What is Vitamin B12 needed for?
DNA synthesis
Integrity of the nervous system (involved in myelination)
Broadly speaking, what can cause Vitamin B12 deficiency?
Dietary deficiency (vegans) Decreased absorption
What types of food have lots of folic acid?
Leafy green vegetables
What can cause folic acid deficiency?
Dietary deficiency
Increased demand for folate
Impaired absorption
What is the dietary requirement of folic acid?
400-600 mcg
Run out of folate much quicker than B12
What is folic acid required for?
DNA synthesis Homocysteine metabolism (potentially toxic)
Where does B12 absorption occur? What happens when it is in excess?
Small intestine
Stored
When stores saturated, excreted in urine
What are the 2 methods of B12 absorption?
- In duodenum, slow + inefficient
2. B12 must combine with intrinsic factor (made by parietal cells of stomach). B12-IF binds to ileal receptors
Deoxythymidine (dTMP) is a major building block of DNA synthesis. How is it produced?
Produced by methylation of deoxyuridine (dUMP)
For this to take place: need release of methyl groups from methyl-THF by the action of B12 as a cofactor accompanied by the conversion of homocysteine to methionine.
In what reaction is B12 a co-factor?
Conversion of homocysteine to methionine
Enzyme = methionine synthetase
State 6 clinical features of B12 and folate deficiency.
Anaemia (macrocytic + megaloblastic) Jaundice (due to ineffective erythropoiesis) Angular Cheilosis Glossitis Sterility (in males) Weight loss + change of bowel habit
State 5 causes of macrocytic anaemia.
Vitamin B12/ Folate deficiency Liver disease / alcoholism Hypothyroidism Drugs that interfere with DNA synthesis e.g. Azathioprine Haematological disorders: Myelodysplasia Aplastic anaemia Reticulocytosis e.g. chronic haemolytic anaemia
How can you differentiate between the blood film of someone with B12/Folate deficiency and someone with liver disease or alcoholism causing macrocytosis?
B12/Folate deficiency = OVAL macrocytes (Megaloblastic)
Liver disease + alcoholism = ROUND macrocytes
What is a reticulocyte?
A young red blood cell with no nucleus
Describe how the appearances of cells of the red cell lineage change as they mature.
Become smaller + their cytoplasm becomes pinker
Nucleus starts off quite diffuse (open chromatin), becomes more + more compact until it is spit out
What 2 things do you look at when determining the maturity of a red blood cell?
Chromatin: how open is it?
Colour of the cytoplasm: how blue is it?
What is meant by ‘megaloblastic changes’?
Morphological changes in red cell precursors in the BM
Asynchronous maturation of the nucleus + cytoplasm.
Results in immature, open nucleus with mature cytoplasm.
Broadly speaking, what are megaloblastic changes the result of?
Defective DNA synthesis
Which of the causes of macrocytic anaemia also show megaloblastic changes in the bone marrow?
B12/Folate deficiency
Myelodysplasia
Drugs that interfere with DNA synthesis
Describe the changes to red and white blood cells in megaloblastic anaemia
RBC’s:
Asynchrony between maturation of nucleus + cytoplasm
Large red cells
Anisocytosis
WBC’s:
Giant metamyelocytes (due to asynchronous maturation)
Hypersegmented neutrophils
What may cause decreased intake of folate?
Ignorance, Poverty, Apathy
Elderly, Sick, Eating disorders, Alcoholics
What are the consequences of folate deficiency for DNA synthesis?
Can’t methylate dUMP to dTMP, which affects DNA synthesis.
Also leads to the accumulation of homocysteine (can’t be converted to methionine)
State 3 physiological and 3 pathological causes of increased folate demand.
Physiological (increased growth): Pregnancy Adolescence Premature babies Pathological (rapid cell turnover): Malignancy Erythroderma (whole body rash) Haemolytic anaemia
State 3 causes of malabsorption of folate.
Coeliac Disease
Surgery or IBD (e.g. Crohn’s disease)
Drugs (e.g. colestyramine, sulfasalazine + methotrexate)
State 3 tests to identify folate deficiency.
Full blood count
Blood film
Serum folate
What would you expect the serum folate and red cell folate of a patient with B12 deficiency to be and why?
Serum folate = high
Red cell folate = LOW
Because B12 is required for folate to enter RBC’s
What are the 3 main consequences of folate deficiency?
Megaloblastic anaemia
Neural tube defects in developing foetus
Increased risk of thrombosis in association with variant enzymes involved in homocysteine metabolism
What are the2 types of neural tube defects?
Spinal cord = spina bifida
Brain = anencephaly
What are the NICE guidelines for women to reduce risk of neural tube defects?
400 mcg folic acid preconception to 12 weeks gestation
Homocysteine accumulates in folate deficiency. What are the consequences of this?
Very high homocysteine levels are associated independently with:
Atherosclerosis
Premature vascular disease
Mildly elevated homocysteine is associated with cardiovascular disease + probably with arterial + venous thrombosis.
How did the FDA in the USA attempt to reduce the incidence of NTDs due to folate deficiency?
Fortify grain with folate
Which groups of people are at particular risk of vitamin B12 deficiency due to decreased intake?
Vegans
State 3 factors that can affect the absorption of B12.
AI: pernicious anaemia (severe lack of intrinsic factor)
Surgery: resection of parts of the GI tract
Inflammatory bowel conditions: Crohn’s, chronic pancreatitis, bacterial overgrowth, parasitic infection
What are the 2 main consequences of B12 deficiency?
Macrocytic + megaloblastic anaemia
Neurological problems due to demyelination
Subacute combined degeneration of the spinal cord
Bilateral peripheral neuropathy
Optic atrophy
Dementia
What may cause reduction in intrinsic factor leading to impaired B12 absorption?
Post-gastrectomy
Gastric atrophy
Antibodies to IF or parietal cells
State 5 symptoms and signs of B12 deficiency.
Symmetrical parasthesia Muscle weakness Difficulty walking + loss of balance Visual impairment Psychiatric disturbance
What is the role of B12 in DNA synthesis?
Both B12 and folate are needed for the production of dTMP (deoxythymidine), which is a crucial building block in DNA synthesis
State 3 tests used to diagnose B12 deficiency.
Plasma homocysteine (high in B12 + folate deficiency)
Serum methylmalonic acid levels
Look for anti-IF antibodies
What is the Schilling test for B12 absorption?
Give 2 capsules of B12 with different radioisotopes.
1 capsule will be B12 alone
1 capsule will be B12 + IF
Collect urine for 24 hours after administration + measure the presence + relative proportion of each isotope.
What is pernicious anaemia and what does it result in?
Autoimmune condition associated with severe lack of IF
Males have decreased life expectancy
Increased risk of stomach cancer
Which antibodies are found in pernicious anaemia?
Anti-IF antibodies (40-60% of adults with PA)
Anti-gastric parietal cell antibodies (80-90% of adults with PA)
How is B12 deficiency treated?
Injections of B12 3x/week for 2 weeks then every 3 months
Which cells are majorly affected in B12 and Folate deficiency?
Rapidly dividing cells: Bone marrow Epithelial surface of mouth + gut Gonads (spermatogenesis) Embryonic
How could B12 deficiency be indicated on examination?
Absent reflexes
Upgoing plantar responses
What 3 things are essential for B12 absorption?
Intact stomach
Intrinsic factor
Functioning small intestine
What 4 infections may cause B12 deficiency?
H Pylori
Giardia
Fish tapeworm
Bacterial overgrowth
What 3 drugs are associated with low B12?
Metformin
PPI’s e.g. Omeprazole
Oral contraceptive pill
What are the outcomes of the schilling test?
- Normal = excretion of radioactive b12 in urine
No B12 in urine = Pernicious anaemia/ small bowel disease - Pernicious anaemia: excretion of radioactive B12 (absorbed as given with IF)
Small bowel disease: No B12 in urine
