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This episode makes reference to guidelines produced by the "National Institute for Health and Care Excellence" in the UK, also referred to as "NICE". The content on this channel reflects my professional interpretation/summary of the guidance and I am in no way affiliated with, employed by or funded/sponsored by NICE.
My name is Fernando Florido and I am a General Practitioner in the United Kingdom. In this episode I will go through the recently published NICE guideline on vitamin B12 deficiency in adults, focusing on those that are relevant to Primary Care only.
I am not giving medical advice; this video is intended for health care professionals; it is only my summary and my interpretation of the guidelines and you must use your clinical judgement.
There is a podcast version of this and other videos that you can access here:
Primary Care guidelines podcast:
· Apple podcast: https://podcasts.apple.com/gb/podcast/primary-care-guidelines/id1608821148
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The NICE guideline “Vitamin B12 deficiency in over 16s: diagnosis and management” (NICE guideline NG239 can be found here:
· https://www.nice.org.uk/guidance/ng239
The links to the resource “Oral vitamin B12 replacement: ongoing care and follow up” can be found here:
The B12 pandemic guidance by the British Society of Haematology can be found here:
· https://apps.nhslothian.scot/refhelp/guidelines/haematology/b12deficiency/
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Transcript
If you are listening to this podcast on YouTube, for a better experience, switch to the video version. The link is in the top right corner of the video and in the episode description.
Hello and welcome, I am Fernando, a GP in the UK. Today, we are looking at the NICE guideline on vitamin B12 deficiency in adults, published as recently as March 2024, focusing on what is relevant in Primary Care only.
Make sure to stay for the entire episode because, at the end, I will tell you how to access an interactive flowchart that I have created and that summarises the guidance.
Right, so let’s jump into it.
Let’s start by looking at common symptoms and signs of vitamin B12 deficiency, which are:
· anaemia or macrocytosis on a FBC, but we should not rule out a diagnosis of vitamin B12 deficiency based solely on the absence of either anaemia or macrocytosis
· difficulty concentrating or short-term memory loss, also sometimes described as 'brain fog'
· glossitis and mouth ulcers
· unexplained fatigue
· eyesight problems related to optic nerve dysfunction like
o blurred vision
o a visual field loss or scotoma and
o optic atrophy signs on fundoscopy
· neurological or mobility problems including
o balance issues and falls due to impaired proprioception or sensory ataxia
o impaired gait and
o paraesthesia, and finally
· it can also be associated with mental health problems, including symptoms of depression, anxiety or psychosis.
There are also common risk factors for vitamin B12 deficiency. Before looking at them, let’s briefly look at the physiology of vit B12 in the human body.
In food, vitamin B-12 is generally bound to protein, so in the stomach, gastric enzymes such as pepsin separate the vitamin B12 from the protein using. Then, the freed vitamin B12 then combines with a protein produced by parietal cells in the stomach, called intrinsic factor. The vitamin B12-IF complex is taken to the cells in the terminal ileum, where the vitamin B12 is absorbed. So, in summary, for vit B12 to be absorbed effectively, we need a sufficient dietary intake and normal physiological processes in the stomach and terminal ileum.
So, with that in mind, the common risk factors for vitamin B12 deficiency are:
· diet low in vitamin B12, for example, in people who:
o follow a vegan diet or low in animal-source foods
o people who do not consume items fortified with vitamin B12
o people who have an allergy to some foods such as eggs, milk or fish
o and people who have difficulties following a well-balanced diet, e.g.:
§ in dementia, frailty, and mental illness
§ in low-income situations and
§ in eating disorders
· other risk factors include conditions such as:
o atrophic gastritis
o coeliac disease or another autoimmune condition and
o previous gastrointestinal surgery like:
§ bariatric surgery and
§ gastrectomy or terminal ileal resection
· some medicines like:
o colchicine
o H2-receptor antagonists and proton pump inhibitors
o metformin and
o some antiepileptics like phenobarbital, pregabalin, primidone and topiramate
· a family history of vitamin B12 deficiency or an autoimmune condition and finally
· recreational nitrous oxide use.
We should use our clinical judgement as to when to check for vitamin B12 levels, paying attention as to whether patients have symptoms, signs and risk factors.
In order to diagnose vitamin B12 deficiency, we will use either total B12 (or serum cobalamin) or active B12 (serum holotranscobalamin) unless:
· the test needs to be done during pregnancy (when we should always use active B12 or serum holotranscobalamin), or if
· recreational nitrous oxide is the suspected cause, when we will use plasma homocysteine or serum methylmalonic acid (or MMA)
We should not delay vitamin B12 replacement while waiting for the test results in:
· suspected megaloblastic anaemia,
· neurological symptoms or
· suspected vitamin B12 secondary to medication.
We will use caution when interpreting test results if:
· they are already using an over-the-counter preparation containing vitamin B12 because they may mask a deficiency but may not fully treat it or if
· they are taking the combined oral contraceptive pill because this can lower total B12 concentrations without causing a true deficiency.
· We also need to be aware that people of Black ethnicity may have a higher reference range for serum vitamin B12 concentrations.
The NICE guideline gives Vit B12 thresholds to decide whether the vitamin B12 deficiency is unlikely, confirmed or whether the value is indeterminate, but it also recommends using local validated thresholds if they exist. So, in the absence of local guidance we will follow these thresholds:
· If total B12 is less than 180 nanograms per litre or active B12 is less than 25 pmol per litre, then the vit B12 deficiency is confirmed.
· If total B12 is more than 350 nanograms per litre or active B12 is more than 70 pmol per litre, then the vit B12 deficiency is unlikely and we will investigate other causes of their symptoms and if they are still experiencing symptoms 3 to 6 months later, we will repeat the vit B12 test.
· And finally, if total B12 is between 180 and 350 nanograms per litre or active B12 is between 25 and 70 pmol per litre, then the vit B12 levels are considered to be indeterminate, meaning that vit B12 deficiency is possible but not confirmed. In these cases, we will measure serum MMA concentrations if there are symptoms or signs of deficiency. While waiting for the results, we will start vit B12 replacement if
o they could deteriorate rapidly, for example, neurological or haematological conditions such as ataxia or anaemia
o if they have a suspected irreversible cause of vitamin B12 deficiency (for example, autoimmune gastritis, a gastrectomy, terminal ileal resection or some types of bariatric surgery or if
o they are pregnant or breastfeeding.
If the vitamin B12 deficiency is confirmed, we will investigate further and we will:
· Check for anti-intrinsic factor antibody if autoimmune gastritis is suspected bearing in mind that a negative test result does not rule out the presence of autoimmune gastritis.
· If autoimmune gastritis is still suspected despite a negative anti-intrinsic factor antibody test, we will consider further investigations such as:
o an anti-gastric parietal cell antibody test
o a test to measure gastrin levels
o a CobaSorb test to measure whether vitamin B12 can be absorbed and
o gastroscopy with gastric body biopsy and
· if the cause of the vitamin B12 deficiency is still unknown, we will test for coeliac disease
In terms of the management of the vitamin B12 deficiency, the management will vary depending on the cause.
In malabsorption due to:
· autoimmune gastritis,
· a total gastrectomy, or a complete terminal ileal resection
we will offer lifelong intramuscular vitamin B12 replacement
In malabsorption for other reasons like coeliac disease, or bariatric surgery:
· we will consider intramuscular instead of oral vitamin B12 replacement.
· But if we offer an oral preparation, we will prescribe at least 1 mg a day.
In medicine- or nitrous oxide-induced vitamin B12 deficiency we will:
· give either intramuscular or oral vitamin B12 replacement, based on clinical judgement and
· we will advise to stop nitrous oxide and consider stopping the medication causing the deficiency if appropriate.
If the vitamin B12 deficiency is due to diet:
· we will give dietary advice
· we will consider oral vitamin B12 replacement, and, during pregnancy or breastfeeding, we will give at least 1 mg daily and
· we will consider intramuscular vitamin B12 injections if the condition deteriorates rapidly or there are concerns about adherence to oral treatment
We will also explain that some over the counter supplements may not contain enough vitamin B12 or the right type to be effective and advise them to pick an oral supplement that contains cyanocobalamin, methylcobalamin or adenosylcobalamin.
In unknown causes of vitamin B12 deficiency we will consider oral instead of intramuscular vitamin B12 replacement and review the response to treatment.
Initial follow-up appointments after starting vitamin B12 replacement should be:
· at 3 months or earlier depending on severity of symptoms, or
· at 1 month if they are pregnant or breastfeeding.
In oral supplementation, we will ask about symptoms and if they have not sufficiently improved, got worse or are new we will:
· increase the oral dosage to the maximum licensed dosage or
· if they are already taking the maximum, switch to intramuscular injections and
· consider further testing with serum MMA, or plasma homocysteine.
If the symptoms have resolved, we will continue with oral vitamin B12 replacement if the cause has not been addressed (for example, the person is still taking a medicine that could affect vitamin B12 absorption), or the cause of deficiency is unknown.
But we will consider stopping treatment if:
· the symptoms have resolved and
· the cause has been addressed (for example, the person has increased their dietary intake of the vitamin) although
· we will advise to come back if symptoms develop.
For people receiving intramuscular replacement, we will not repeat the initial diagnostic test. If the symptoms have not improved enough, we will:
· increase the frequency of injections if needed, in line with the summary of product characteristics and
· think about alternative diagnoses and
· agree a date for reassessment of the person's symptoms.
If a person has, or is suspected of having, an irreversible cause of vitamin B12 deficiency:
· we will continue with lifelong intramuscular injections, even if their symptoms have resolved, and
· we will advise them to come back if symptoms recur
If the person's symptoms have resolved, and they have either a reversible cause that has not been addressed (for example, continuing medication), or the cause is unknown:
· we will continue with intramuscular injections and
· we will continue to follow up.
But if the cause has been resolved and the symptoms have disappeared, we will:
· think about stopping or reducing the frequency of injections and
· advise them to come back if symptoms recur.
As we have seen, the guideline covers deficiency caused by autoimmune gastritis. But let’s pause for a minute. Is autoimmune gastritis the same as pernicious anaemia? Well, NICE does not use the term pernicious anaemia in this guideline. So, let’s see why:
Autoimmune gastritis can destroy the parietal cells in the stomach, which can prevent the absorption of vitamin B12, and also impair iron absorption.
Although pernicious anaemia can be a consequence of chronic, severe vitamin B12 deficiency caused by autoimmune gastritis, pernicious anaemia in its true sense (that is, life-threatening anaemia) is now extremely rare and for this reason, this term has not been used in the recommendations.
Also, although autoimmune gastritis is associated with the presence of auto-antibodies against gastric parietal cells and intrinsic factor, which can be detected blood tests, we should also bear in mind that they are not always present and, even when they are present, this is not always indicative of autoimmune gastritis.
We also need to take into account that people who have autoimmune gastritis:
· are at higher risk of developing gastric neuroendocrine tumours and
· may also be at higher risk of developing gastric adenocarcinoma.
So, we will refer them promptly for gastrointestinal endoscopy if they develop new, or worsening, upper gastrointestinal symptoms (for example, dyspepsia, nausea or vomiting)
To end the video, NICE has created a 2-page visual summary on ongoing care and follow-up options for oral and intramuscular vitamin B12 replacement. Let’s have a look at it.
So, for people on oral vitamin B12 replacement
At follow up
If the symptoms are not sufficiently improved
We will either increase the oral dose to the maximum licensed dose or, if they are on this already, we will switch to intramuscular administration, taking into account the patient’s preferences.
If there are new or worsening symptoms
We will see if the diagnosis was made using MMA or plasma homocysteine
If the answer is no, we will think about alternative diagnoses and consider testing serum MMA or, if not available, plasma homocysteine, continuing treatment until the results are received.
When the results are received …
if the deficiency is still present, we will either increase the oral dose to the maximum licensed dose or, if they are on this already, we will switch to intramuscular administration, taking into account the patient’s preferences.
However, if the results do not show a deficiency, we will explore alternative diagnoses to explain the symptoms.
If the answer to the question about MMA or plasma homocysteine testing is yes
Then we will consider alternative diagnoses and, taking into account the patient’s preference, we will either increase the oral dose of vit B12 to the maximum or, if the patient is already on the maximum oral dose, we will switch to intramuscular injections
Finally, if the symptoms have improved or resolved
If the cause has not been addressed or is unknown
We will continue with the oral replacement and continue follow up.
On the other hand, if the cause has been addressed,
We will consider stopping treatment, advising the patient to seek medical advice if the symptoms get worse, reappear or new ones emerge.
Now let’s have a look at the summary for patients on intramuscular vit B12 replacement
So, at follow up
If there are new symptoms, they are worsening or have not sufficiently improved
We will increase the frequency of injections, we will think about alternative diagnoses and we will continue reviewing the patient.
Conversely, if the symptoms have improved or resolved
If the cause is irreversible,
We will continue with lifelong injections, advising the patient to seek medical advice if the symptoms reappear, get worse or new ones appear.
However, if the cause is reversible but it has not been addressed or is unknown,
We will continue with the injection and regular reviews.
And finally, if the cause has been resolved,
We will think about stopping or reducing the frequency of the injections, advising the patient to seek medical advice if the symptoms get worse, reappear or new ones emerge.
I have created an interactive flowchart that incorporates these visual summaries as well as other NICE guidance and also advice given by the British Society of Haematology. You can access it in the episode description. I hope that you find it helpful.
We have come to the end of this episode. Remember that this is not medical advice and it is only my summary and my interpretation of the guidelines. You must always use your clinical judgement.
Thank you for listening and goodbye.
