Managing Pernicious Anaemia in the time of Corononavirus

By Willemina Rietsema, GP in Oxfordshire

Stopping B12 treatment

A time of stress and need to be creative

The stresses on GPs and surgeries are immense during this coronavirus crisis. Some of the workforce are self-isolating, the rest are hard-pressed to keep the service going. Moreover, we are trying to reduce the number of face-to-face contacts to the absolute minimum. This includes some of the regular appointments for routine care.

However, this should never come at the price of causing harm to patients. The Pernicious Anaemia Society is getting frequent worried phone calls from members desperate that their B12 injections have been postponed due to the coronavirus crisis. This makes them feel very unwell, and extremely worried that they will sustain irreversible neurological damage. Interrupting or postponing treatment with vitamin B12 causes harm, both physically and psychologically.

Moreover, at this time we need to give people the best possible chance of fighting covid-19, if they were to get infected. This includes providing adequate B12 for the immune system to function optimally. The immune reaction to disease depends on fast replication of cells, which itself depends on adequate availability of B12 and folate.

Managing B12 deficiency in the time of coronavirus

So what can GP surgeries do when there simply is not the time or staff to deal with routine injections? At this time of crisis, we are all having to be creative, and take a little more calculated risk than we normally feel comfortable with. We are assessing more people by phone, get pictures sent by email, while safetynetting extra carefully.

For managing pernicious anaemia at this time, there are several options:

  1. Ask the patient if there is a nurse among their family or friends who might give them the injections. Then a prescription for B12, needles and syringes suffices.
  2. Ask the patient if they are happy to self-inject subcutaneously. This is currently off-licence, though in the past the BNF licensed B12 for subcutaneous injection. It was changed to i.m. without any research evidence that i.m. was better than s.c. There is no reason vitamin B12 should work any differently when diffusing into the blood from the subcutaneous fat than from muscle. Patients will need to be taught how to self-inject, as for any of the other self-administered medications, such as insulin, dalteparin and biologicals. This may be done via video link, and/or by recommending a trusted online video, perhaps uploaded to the practice website. Of course injection technique and safety will need to be checked at regular intervals.
  3. Prescribe 1,000 mcg cyanocobalamin tablets, to take 1-2 tablets daily. In patients with Pernicious Anaemia, oral B12 cannot get absorbed through the intrinsic factor route, because they do not have any. However, there is a second, much more limited route of absorption, passively through the intestinal mucosa. About 1% of any oral dose is absorbed this way. Therefore of a 1,000 mcg dose, c. 10 mcg gets absorbed, which is enough for the daily requirement.However, some patients report that this does not work well for them, and they experience a relapse in their symptoms. Particularly in patients with any bowel condition (e.g. Crohn’s, coeliac disease, small bowel overgrowth, bile acid malabsorption, short bowel) this may not work. Therefore careful monitoring of symptoms (see below) is essential when changing patients from parenteral to oral B12. If symptoms return on oral medication, either the dose needs to be increased to 2,000 mcg daily, or they need to be restarted on parenteral B12.Please note: oral medication is not suitable for initial loading after diagnosis. On 1,000 mcg daily it takes c. three months for B12-deplete patients to become replete again. During this time further neurological damage can occur. Therefore if at all possible, patients should always be given parenteral loading doses.
  4. If patients are happy to buy their own sublingual tablets or sprays, this may be encouraged. The dose should be at least 1000 microgram per day. Preparations can be bought from chemists and health food stores. B12 gets absorbed by the oral mucosa, as demonstrated by Rima Obeid and team in a randomised control trial of B12-enriched toothpaste in a population of older people.
However, this medication will need to remain on the patient’s medication list, so that adherence can be checked during the annual medication review. Again, if symptoms of B12 deficiency return, even after months or years, parenteral treatment will have to be resumed. Not all patients will realise, if they feel unwell again, that this may be due to their stopping taking B12.

Stopping B12 treatment is dangerous for patients

For people with B12 deficiency, whether due to Pernicious Anaemia or any other caue, doing without their regular treatment is simply not an option. Many struggle with the two to three-month interval as it is. Making the interval longer puts them at serious risk of:

  • Irreversible neurological damage. The whole of the nervous system absolutely depends on sufficient supply of vitamin B12.
  • Severe loss of quality of life, due to symptoms such as debilitating fatigue, insomnia (B12 is required for synthesis of melatonin), mental illness, and neurological symptoms.
  • Inability to work, at a time when many jobs are already on the line.
  • It seems reasonable to assume that patients who feel unwell due to lack of B12 will be less able to fight the coronavirus, should they get infected.

Stopping B12 treatment is as dangerous, albeit more slowly, as stopping anticoagulation in patients with AF.

For many patients, their injections don’t last long enough

Some clinicians assume (incorrectly) that 1000 mcg of B12 should last patients at least 200 days, calculating from a 5 mcg daily requirement for the vitamin. Research indicates that the daily requirement may be closer to 10 mcg daily. Unfortunately, B12 is not stored in the body. After an injection, as much B12 as possible is captured by the transport protein in the blood (Transcobalamin II) and delivered to the cells. All non-protein-bound B12 is quickly excreted by the kidneys. One product leaflet for B12 states 50-98% of injected B12 is excreted with the urine. This explains why patients may experience relapse as early as 4 weeks after their last injection. When I ask patients, about 80% of them report that their symptoms return weeks or months before the next injection is due. It makes them feel unwell and puts them at risk of neurological damage.

It’s like filling the car’s fuel tank: whatever excess is poured in, simply runs over. And if you’re only allowed one fill in three months .. the car simply won’t run for one or two months. That is how many patients feel on three-monthly injections. For one or two months out of every three they are too exhausted to function. If anything, we should be shortening the interval between injections, not making it longer. There is no risk with shorter intervals. Any excess B12 is eliminated by the kidneys.

The BNF recently (2019) changed its guidance for the frequency of injections of hydroxocobalamin:

• Every 2 months in patients who have neurological symptoms
• Every 2 or 3 months when there are no neurological symptoms.

More frequent injections are off-licence, but without risk and may be of great benefit to patients’s wellbeing and neurological function.

The symptoms of B12 deficiency

The symptoms of B12 deficiency follow from the metabolic functions of vitamin B12. It is needed for:

  1. Methylation – B12 is cofactor in the process that synthesises the nearly universal methyldonor in the body: S-adenosyl-methionine. Methylation is needed for synthesis of myelin, neurotransmitters (including adrenalin and melatonin), epigenetics, protein repair and much more.
  2. Cell multiplication – While B12 is cofactor, methylfolate is the methyldonor in the above process. As a result, methylfolate is converted to tetrahydrofolate, which is required for purine synthesis – which in turn is required for DNA synthesis. Therefore both B12 and folate deficiency can result in anaemia and intestinal atrophy. However, not all patients with B12 deficiency develop anaemia. If there is enough folate coming in from another source, they will be able to maintain cell replication, but not methylation. In those patients neurological symptoms and damage are the key to diagnosis.
  3. Fatty acid metabolism in the mitrochondria, producing succinyl-CoA, which enters the Krebs (citric acid) cycle. This likely contributes to the fatigue most patients experience.

My mnemonic for the symptoms of B12 deficiency is:

A. Any neurological symptoms:

  • Mind: ‘brain fog’, poor memory, poor concentration, word finding difficulties, dementia, parkinsonism, insomnia. In about 1% of patients with deficiency, optic neuropathy.
  • Mood: anxiety, depression – sometimes to the point of suicidality. Some even experience hallucinations and psychosis.
  • Sensory: pins and needles or numbness in feet and/or hands, or sometimes increased sensitivity to pain.
  • Motor: muscle weakness, ataxia, reduced reflexes (if peripheral neuropathy) or increased reflexes and/or upgoing plantars (if central neuropathy).
  • Autonomic: postural hypotension, incontinence (which often seems to be urgency incontinence).

B. Problems due to lack of cell division in fast dividing tissues:

  • Anaemia, or any cytopaenia (including leucocytes, lymphocytes, platelets)
  • Mouth ulcers, malabsorption, diarrhoea due to macrocytosis and atrophy of the intestinal mucosa as demonstrated by Foroozan and Trier.
  • Frequent infections are reported – e.g. UTIs, presumably due to reduced immune cell function.

C. The debilitating fatigue which seems to be the most common symtpom of B12 deficiency may be due to a combination of neurological factors, anaemia, and the role of B12 in the mitochondria.

If colleagues/health care professionals have any questions, please send them to in**@pa***.uk

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