Vitamin B12

Vitamin B12 deficiency - overview

***UPDATE JUNE 2024***

The NICE Guideline NG239 has now been published:

• Vitamin B12 deficiency in over 16s: diagnosis and management

This guideline has been reviewed by the BNSSG Formulary Team and APMOC and adoption recommended in full. 

There are currently differences in the thresholds and reporting of vitamin B12 levels in BNSSG compared to the guideline above as detailed in the guidance below.

Prevalence

It is estimated that 1-2% of the general population have vitamin B12 deficiency and around ten times this in older adults.

Reference Ranges - NBT

There is an update on new reference ranges for serum vitamin B12 on the NBT pathology website: Vitamin B12 | North Bristol NHS Trust (nbt.nhs.uk)

Further advice on reference ranges is given in the Management section below.

UHBW reference ranges are due to be updated later in 2023.

Repeat vitamin B12 testing for patients on replacement therapy

Please do not send requests for vitamin B12 levels for patients established on long term replacement therapy as this is unnecessary and uninformative.

Metformin and vitamin B12

MHRA advice was published in June 2022 stating the following:

'Decreased vitamin B12 levels, or vitamin B12 deficiency, is now considered to be a common side effect in patients on metformin treatment, especially in those receiving a higher dose or longer treatment duration and in those with existing risk factors. We are therefore advising checking vitamin B12 serum levels in patients being treated with metformin who have symptoms suggestive of vitamin B12 deficiency. We also advise that periodic monitoring for patients with risk factors for vitamin B12 deficiency should be considered.' (3)

Local implementation of this advice is under discussion and updates will be published here when available.

Summary

The following summary is based on current available guidelines and advice from local specialists pending the guideline review described above

Please consider the following before testing for vitamin B12:

• Clinical features of vitamin B12 deficiency are highly variable.
• Testing patients outside the recognised clinical features of vitamin B12 (and folate) deficiency is likely to increase the number of equivocal test results and should be avoided. 
• Vitamin B12 assays are performed on automated analysers. There is poor agreement between assays and sometimes significant fluctuation in results over time.
• Laboratory findings of mildly reduced B12 levels are commonly found and not necessarily pathological. Finding of spuriously low levels are known to occur in myeloma, HIV infection, pregnancy, COCP treatment.
• Avoid screening tests for vitamin B12 levels in pregnancy or in patients taking the COCP without clinical symptoms or FBC findings to suggest deficiency.

When to suspect vitamin B12 deficiency

• Haematological
  • Macrocytosis (MCV >100fl) / macrocytic anaemia. (In macrocytosis MCV > 115fl is more specific to vitamin B12/folate deficiency vs other causes). Consider other causes of macrocytosis – see Remedy guidance.
  • Pancytopenia
• Neurological syndromes of vitamin B12 deficiency

• most common neurological findings are symmetric paraesthesia or numbness and gait problems. Symmetrical neuropathy arms > legs;
• features of spinal cord disease - progressive weakness, ataxia, and paraesthesia: but may not be present in early in the disease
• may include axonal or optic neuropathy and slowed mentation

• Neuropsychiatric symptoms (including cognitive decline) can be present even in the absence of anaemia or macrocytosis.

Assessment of vitamin B12 levels may therefore be considered if there are the following symptoms (4):

• anaemia – e.g. fatigue, (or unexplained macrocytic anaemia)
• glossitis
• paraesthesia
• disturbed vision (optic atrophy)
• unexplained neurological or psychiatric symptoms, including depression and confusion
• problems with memory, understanding and judgement (including as part of dementia screen, although a casual role of low vitamin B12 is not proven)
• hyperpigmentation
• long term use of drugs such as metformin, colchicine, PPIs- (NB currently testing is only advised if there is clinical suspicion of deficiency).

Monitoring of vitamin B12 should be considered in patients with the following: 

• Conditions that predispose to malabsorption e.g. coeliac disease, Crohn’s disease, gastrectomy
• Vegan/vegetarian dietary restrictions (without vitamin B12 supplements)
• autoimmune conditions
• genetic predisposition to vitamin B12 deficiency, such as intrinsic factor receptor or transcobalamin II deficiency

Assessment & Investigations

Investigation of low B12 levels can be undertaken in primary care and should usually be done before starting treatment (unless severe neurology).

Investigations:

• Anti-intrinsic factor antibodies should be tested if pernicious anaemia is suspected regardless of B12 level- may be found in up to 35% of cases of pernicious anaemia. Life-long replacement therapy is indicated.
• Look for other evidence of malabsorption

B12 or folate deficiency does not normally require referral for haematology outpatient assessment.

Haematology advice and guidance can be requested if uncertainty regards management persist.

Special situations:

• Pregnancy: Vitamin B12 testing should be avoided in pregnancy as results are unreliable (levels naturally decrease in pregnancy). If there is clinical suspicion of deficiency is strong, consider testing but interpret the results with caution. Discussion with the laboratory and additional tests may be needed. An alternative approach may be a short course of therapy and reassessment post-pregnancy. See also the Folic acid and vitamin B12 in pregnancy page.
• Oral contraceptive pill: Only test if strong clinical suspicion as difficult to interpret vitamin B12 results. Asymptomatic women with mild reduction 145-190ng/l do not need replacement, review diet.
• Food-B12 malabsorption e.g. gastric acid suppressants or metformin:  only test if strong clinical suspicion. Trial of oral cyanocobalamin could be considered and reviewed at 6 months.

Management

Please use the following guidelines when making management decisions regarding treatment:

• Vitamin B12 deficiency in over 16s: diagnosis and management | Guidance | NICE

There are currently differences in the thresholds and reporting of vitamin B12 levels in BNSSG compared to the guideline above as detailed below.

Current advice from local haematologists and biochemists suggests that treatment of Vitamin B12 levels should be considered according to the table below. Treatment of patients with vitamin B12 levels that are in the borderline range (between 100 and 914) should take into account patient symptoms and clinical findings and should not be based on the test result alone.

High vitamin B12 levels

This is often a non-pathological finding and rarely due to a haematological condition. The most common cause of high vitamin B12 in the absence of B12 replacement therapy is liver disease.  Vitamin B12 may be elevated in haematological malignancy including myeloproliferative disorders and these disorders are excluded by a normal FBC.

Assessment in Primary Care

Check that the patient has not been taking supplements that include vitamin B12.

Assess general health and for risk factors for liver disease.

Investigations in Primary care:

These will be determined by the clinical history examination and blood results. Unless a haematological malignancy is suspected from the FBC report, discussion with or referral to Haematology is not required. Assessment for liver disease may be appropriate.

Resources

(1) British Society of Haematology Guidelines for the diagnosis and treatment of cobalamin and folate disorders (2014)

(2) For guidelines and suggested interpretation of test results please see page 15 of the  UHBristol Haematology Guidelines for Primary Care (PDF)

(3) Metformin and reduced vitamin B12 levels: new advice for monitoring patients at risk - GOV.UK (www.gov.uk)

(4) Vitamin B12 & folate anaemia - Illnesses & conditions | NHS inform

(5) NICE draft guideline: Vitamin B12 deficiency in over 16s

Efforts are made to ensure the accuracy and agreement of these guidelines, including any content uploaded, referred to or linked to from the system. However, BNSSG ICB cannot guarantee this. This guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer, in accordance with the mental capacity act, and informed by the summary of product characteristics of any drugs they are considering. Practitioners are required to perform their duties in accordance with the law and their regulators and nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties.

Information provided through Remedy is continually updated so please be aware any printed copies may quickly become out of date.