Vitamin B12 and folate deficiencies are grouped together in this article due to overlapping features, with important distinctions outlined
Background Information
Pathophysiology
Vitamin B12 Deficiency
Vitamin B12 (cobalamin) acts as a co-factor to 2 enzymatic reactions: [Ref]
| Enzyme | Reaction | Consequence in deficiency |
|---|---|---|
| Methionine synthase | Homocysteine → methionine | Defective DNA synthesis and methylation → megaloblastic anaemia (dys-synchrony between the maturation of cytoplasm and the nuclei) |
| Methylmalonyl-CoA mutase | Methylmalonyl-CoA → succinyl-CoA | Accumulation of methylmalonic acid and abnormal fatty acid metabolism → disrupted myelin synthesis → neurological deficits |
Folate (B9) Deficiency
Folate deficiency primarily impairs DNA synthesis, resulting in:
- Megaloblastic anaemia
- Neurological involvement is RARE and not characteristic (mainly seen in B12 deficiency)
Folate acts as a co-factor for:
- DNA synthesis (purine and thymidylate synthesis)
- Methylation reactions (including homocysteine to methionine)
- Amino acid metabolism
Aetiology
Vitamin B12 Deficiency
Most common cause: pernicious anaemia (autoimmune gastritis)
- Autoimmune destruction of gastric parietal cells (which normally secrete intrinsic factor)
- → Lack of intrinsic factor → impaired vitamin B12 absorption at the terminal ileum
Absorption of vitamin B12:
- Vitamin B12 binds to haptocorrin
aka transcobalamin I
(produced by the salivary gland), which protects it from gastric acid - In the duodenum, vitamin B12 binds to intrinsic factor (produced by gastric parietal cells)
- Vitamin B12-intrinsic factor complex is absorbed in the terminal ileum
Importantly, vitamin B12 can only be absorbed in the terminal ileum, if it is bound to intrinsic factor.
Other causes are rare:
| Nutritional |
|
| Drugs |
|
| Malabsorption |
|
Folate (B9) Deficiency
| Nutritional |
|
| Malabsorption |
|
| Drugs |
|
| Increased requirements |
|
Clinical Features
Note that vitamin B12 deficiency can present without anemia, where the clinical manifestations may primarily be dermatological and neuropsychiatric.
Clinical features of folate deficiency are largely similar to those of B12 deficiency, except that neurological involvement is RARE and not characteristic of folate deficiency.
| Haematological features (anaemia) | Symptoms:
Signs:
|
| Dermatological features |
|
| Neurological features |
|
| Psychiatric features |
|
Vitamin B12 classically cause a mix of upper and lower motor neuron signs, due to concurrent involvement of the spinal cord and peripheral nerves
- Spinal cord involvement (subacute combined degeneration of the cord) → upper motor neuron signs (e.g. spasticity, hypertonia, Babinski sign)
- Peripheral nerve involvement → lower motor neuron signs (e.g. symmetrical distal paraesthesia, absent ankle reflex)
Diagnosis
Confirming Deficiency
Perform the following initial tests, if vitamin B12 or folate deficiency is suspected:
| Test | Findings in B12 / folate deficiency |
|---|---|
| FBC | Macrocytic anaemia
|
| Peripheral blood smear | Hypersegmented neutrophils
Presence of hypersegmented neutrophils confirms megaloblastic anaemia, which helps differentiate from causes of macrocytic, non-megaloblastic anaemia (e.g. alcohol use, liver disease). |
| Serum cobalamin (B12) test | ↓ (in B12 deficiency)
Choice of test:
The following factors may affect the interpretation of total or active B12 test result:
|
| Folate levels | ↓ (in folate deficiency) |
If the serum B12 tests are inconclusive / equivocal, and B12 deficiency is suspected → consider measuring the serum methylmalonic acid levels.
Measuring serum homocysteine and methylmalonic acid levels can help distinguish between B12 and folate deficiency. [Ref]
↑ Methylmalonic acid is specific for B12 deficiency, such that: [Ref]
- B12 deficiency causes ↑ homocysteine and ↑ methylmalonic acid levels
- Folate deficiency only causes ↑ homocysteine level
Investigating Underlying Cause
Key clinical history to ask for:
- Dietary history
- Medication review
Vitamin B12 Deficiency
1st line: testing for pernicious anaemia (autoimmune gastritis)
- Initial test of choice: anti-intrinsic factor antibody test
- 2nd line tests (if anti-intrinsic factor antibody is -ve but pernicious anaemia still suspected)
- Anti-gastric parietal cell antibody
- Gastrin levels
- CobaSorb test
- Gastroscopy with gastric body biopsy (specialist test)
2nd line: coeliac testing
- Initial test of choice: IgA tTG + total IgA (see the Coeliac Disease article for more information)
- NICE: “Offer serological testing for coeliac disease where the cause of vitamin B12 deficiency is still unknown after further investigations”
Rationale of why coeliac testing is a 2nd line test: B12 deficiency is the least common deficiency (compared to iron and folate) in coeliac disease, as coeliac disease primarily affects the duodenum and jejunum.
Folate (B9) Deficiency
1st line: coeliac testing
- Initial test of choice: IgA tTG + total IgA (see the Coeliac Disease article for more information)
Rationale: coeliac disease is the main cause of folate malabsorption.
Management
Do NOT delay vitamin B12 replacement while waiting for the test results of people with suspected megaloblastic anaemia and neurological symptoms.
Vitamin B12 Deficiency
First step to guide management is whether there is neurological involvement or not.
Neurological Involvement
Seek urgent specialist advice (neurologist / haematologist)
If specialist management not immediately available, consider IM vitamin B12 (hydroxocobalamin)
- Loading phase: once on alternate days until no further improvement
- Maintenance phase: once every 2 months
NO Neurological Involvement
Management depends on the suspected underlying cause:
| Underlying cause | Management |
|---|---|
| Malabsorption | Lifelong IM vitamin B12 is necessary in :
For other causes of malabsorption (e.g. coeliac disease, Crohn’s disease, partial gastrectomy) → IM vitamin B12 should be considered over oral. |
| Medication |
|
| Recreational NO |
|
| Dietary |
|
| Unknown cause |
|
Different forms of vitamin B12:
- IM: hydroxocobalamin
- Oral: cyanocobalamin
Folate (B9) Deficiency
Offer oral folic acid (5mg daily)
- Most patients would require treatment for 4 months
- Some patients may need to take folic acid for longer, or even for life
It is important to note that when BOTH B12 and folate deficiencies are co-present, it is important to correct B12 deficiency FIRST, before correcting folate deficiency. [Ref]
Rationale: folic acid is harmful in B12 deficiency. If folate deficiency is corrected first, it may worsen neurological complications, or allow them to progress by masking symptoms (as folic acid can improve anaemia in B12 deficiency, but it will NOT correct the neurological damage). [Ref]
References
NICE guideline Vitamin B12 deficiency in over 16s: diagnosis and management