B12 and Folate Deficiency Flashcards
What are Vitamin B12 and Folate required for?
B12 required for DNA synthesis and Nervous system integrity (involved in myelination)
Folate required for DNA synthesis and homocystine metabolism
What is vitamin B12 and what types of food is it commonly found in?
Cobalamin (vitamin B12) is a bacterial product that is ingested and stored by animals. It is 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 types of food have lots of folic acid?
Leafy green food
What is the dietary requirement of folic acid?
400-600 mcg You run out of folate much quicker than B12
Broadly speaking, what can cause Vitamin B12 and folate deficiency?
B12
Dietary deficiency (vegans)
Decreased absorption
Folate
Dietary deficiency
Increased demand ( pregnancy, adolescence, premature babies, malignancy, erythroderma, haemolytic anaemias)
Impaired absorption (Coeliac Disease Surgery or inflammatory bowel disease (e.g. Crohn’s disease) Drugs (e.g. colestyramine, sulfasalazine and methotrexate))
Describe the passage of vitamin B12 from entry into the
GI tract to the hepatic portal circulation.
It enters the stomach and binds to transcobalamin 1 (R protein –produced by the salivary glands)
The gastric parietal cells (at the bottom of the stomach) produce intrinsic factor
The B12 moves into the duodenum, bound to transcobalamin 1, and then pancreatic enzymes displace B12 from transcobalamin 1
The free B12 then binds to IF
The B12-IF complex continues all the way to the terminal ileum where it binds to specific receptors and is absorbed
The B12 then goes into the portal circulation and binds to transcobalamin 2 making active B12
NOTE: 1% IS ABSORBED ACROSS DUODENUM WITHOUT IF
Describe the absorption of folic acid.
Folic acid enters the GI tract as polyglutamates
The acidic pH of the stomach hydrolyses the polyglutamates to monoglutamates
The folic acid is absorbed as pteroglutamates
It is then methylated in the luminal cells to form methyl tetrahydroflorate
Deoxythymidine (dTMP) is a major building block of DNA synthesis. How is it produced?
It is produced by the methylation of deoxyuridine (dUMP) For the methylation to take place, you need the release of methyl groups from methyl-tetrahydrofolate by the action of B12 as a cofactor accompanied by the conversion of homocysteine to methionine.
In what reaction is B12 a co-factor?
The conversion of homocysteine to methionine
Enzyme = methionine synthetase
State some clinical features of B12 and folate deficiency.
All rapidly dividing cells affected by deficiency
- bone marrow
- Mouth and gut epithelium
- Gonads (SPERM ESPECIALLY)
- Embryos
Clincal features
- Anaemia, weak and fatigued
- Jaundice
- Glossitis (inflamed tongue) and angular cheilosis (corner of mouth inflammation)
- Weight loss, bowel habit changes
- Sterility
Anaemia will be macrocytc and megaloblastic
State some causes of macrocytic anaemia.
Vitamin B12/Folate deficiency
Liver disease and alcoholism
Hypothyroidism
Haematological disorders:
-Myelodysplasia (production of one or all types of blood cells by the bone marrow is disrupted)
-Aplastic anaemia (failure of blood cell production resulting in pancytopenia)
-Reticulocytosis (in response to haemolytic anaemia or bleeding)
Drugs that interfere with DNA synthesis e.g Azathioprine (immunosuppresant)
Prolonged nitrous oxide anaesthesia
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
Liver disease and 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.
They become smaller and their cytoplasm becomes pinker
Their nucleus starts off being quite diffuse (open chromatin) and it becomes more and more compact until it is spit out by the red cell
What two 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’?
These are changes seen in the red blood cell precursors in the bone marrow.
Megaloblastic change is when there is asynchronous maturation of the nucleus and cytoplasm.
You get an immature, open nucleus with mature cytoplasm.
Other findings (also due to DNA synthesis failures)
Anisocytosis
Large red cells
Hypersegmented neutrophils
Giant metamyelocytes
Dysplastic marrow and increased haemolysis
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
Prolonged nitrous oxide anaesthesia
Which groups are at particular risk of dietary folate deficiency?
Elderly
Sick
Eating disorders
Alcoholics
What are the consequences of folate deficiency for DNA synthesis?
Folate deficiency means that you can’t methylate dUMP to dTMP, which affects DNA synthesis.
It also leads to the accumulation of homocysteine (it can’t be converted to methionine without folate)
State some tests to identify folate deficiency.
Full blood count
Blood film Serum folate – useful as a screening test Shows diurnal variation Affected by recent changes in diet
Red cell folate – useful as confirmatory test
Also Anti-gliadin (transglutaminase) antibodies and Duodenal biopsy can diagnose coeliac as cause of malabsorption
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
This is because B12 is required for the folate to enter the red blood cells
What are the three main consequences of folate deficiency?
Megaloblastic anaemia
Neural tube defects - Spina bifeda, anencephaly in foetus
Increased risk of venous thromboembolism - due to various enzymes in homocystein metabolism
What are the NICE guidelines for women of standard and high risk of neural tube defects?
Standard Risk – 400 mcg folic acid preconception to 12 weeks gestation
High Risk – 5 mg folic acid preconception to 12 weeks gestation
Haemolytic anaemia – 5-10 mg before, during and after pregnancy
State some factors that can affect the absorption of B12.
Autoimmune – pernicious anaemia (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 two main consequences of B12 deficiency?
Macrocytic and megaloblastic anaemia
Neurological problems due to demyelination:
- Subacute combined degeneration of the spinal cord
- Neuropathy of central and peripheral nerves
- Cognitive impairment due to loss of white matter in the CNS
- Optic atrophy
What is the relationship between Hb level and neurological symptoms in B12 deficiency?
Inverse relationship between Hb level and neurological symptoms
What is subacute combined degeneration of the spinal cord and what are the symptoms?
Caused by demyelination of the posterior (dorsal) and lateral (pyramidal) tracts of the cervical and thoracic spinal cord
How do B12 deficient patients present?
- Paraethesiae
- Myopathy
- Walking difficulty
- Visual impairment
- Psychiatric distrubance
- Romberg’s sign (loss of propriception)
- Anaemia and Jaundice
Examination finding
- Loss of peripheral reflex
- Babinski’s sign
What is the test for B12 deficiency?
Serum cobalamin (B12) level
PROBLEM: it measures total cobalamin levels (bound to transobalamin 1, 2 and 3) so you see a lot of healthy patients with low transcobalamin This means that the clinical circumstances must be taken into account when interpreting the results.
State some new tests used to diagnose B12 deficiency.
Plasma homocysteine (high in B12 and folate deficiency) Serum methyl malonic acid levels Holotranscobalamin levels (transcobalamin II)
What is the Schilling test for B12 absorption?
Give two capsules of B12 with different radioisotopes. 1 capsule will be B12 alone 1 capsule will be B12 + intrinsic factor
Collect urine for 24 hours after administration and measure the presence and relative proportion of each isotope.
What is pernicious anaemia and what does it result in?
A form of anaemia resulting from the deficiency of B12
It can be caused by autoimmune atrophic gastritic with the loss of intrinsic factor
This results in macrocytic/megaloblastic anaemia with or without neurological damage
Which antibodies are found in pernicious anaemia?
Anti-intrinsic factor antibodies (in 40-60% of adults with PA)
Anti-gastric parietal cell antibodies (in 80-90% of adults with PA)
How are folate and B12 deficiency treated?
Oral folate or oral cyanobalamin for dietary deficiency or increased demand
Parenteral (IM/SC) hydroxycobalamin for malabsorption due to pernicious anaemia or bowel disease
