Only One Chance

Introduction

It’s an old saying: “You’ve got only one chance to make a first impression”. This is true for many situations: when you meet your future spouse, or when you are in a job interview, or your first appearance as a player in a premier league game. Your future spouse will silently disappear if you talk too much about yourself or misbehave on your first date. And if you do not remember the company’s name where your job interview takes place, the chance of being selected as a new co-worker is zero. When you get a red card for a foul or score an own goal, not the best you can do in a first match.

Measuring serum B12 concentration

A medical specialist received a letter stating, “you have treated people with normal serum B12 concentrations with B12 injections, for which there is no proof”. Actually, the person writing this serious accusation does not realize that approximately half the people with symptomatic B12 deficiency have serum B12 concentrations within the so-called ‘normal range’ for the general population. This normal range is usually referred to as blood values between 140 and 600 pmol/l. However, have you ever wondered how really bad the serum B12 measurement is in practice? Let me give you an ultra-brief summary:

• There is considerable variability between the different commercially available serum B12 assays; the serum B12 concentration of a given person may be 240 pmol/l with one assay, and 440 pmol/l with a different assay
• There is also considerable variability with just one and the same serum B12 assay; the first lab may measure and report a value of 220 pmol/l, and a different lab may measure and report 380 pmol/l, again in the same blood sample (!)
• There is day-to-day variation of serum B12; as an example, a concentration of 150 pmol/l on one day may be 120 pmol/l on another day. Some studies have reported a difference between days of over 100 pmol/l
• Serum B12 concentrations may be influenced by specific changes in our genetic material, our DNA; until now, over 15 DNA alterations are known to influence serum B12; for some of the changes, it has been demonstrated that they increase the concentration of the so-called ‘inactive’ B12, but not the ‘active’ B12. So, you measure a higher B12, but part of that B12 is inactive, so useless
• Oral B12 supplementation, even in the form of a multivitamin preparation, may result in serum B12 concentrations just within the ‘normal´ range without abolishing symptoms. This can obscure the correct diagnosis (as I mentioned in one of the first paragraphs)

Symptoms

Everyone who frequently reads the information on the Pernicious Anaemia Society (PAS) website knows that symptomatic B12 deficiency does not limit itself to one and only one specific symptom. B12 has many functions in our body, so unfortunately a deficiency will give rise to a wide variety of symptoms, like ‘brain fog’, memory problems, cognitive impairment, insomnia, headaches, especially migraine, behavioural changes, learning problems, nominal aphasia, mood swings, irritability, depression, anxiety, hallucinations, delusions, psychosis, peripheral paraesthesia (‘pins and needles’), numbness, neuropathic pains, poor balance, reduced vibration sense or proprioception (joint position sense), tinnitus, ataxia, taste impairment, sometimes myelopathy, fatigue, anaemia (either with larger red blood cells, or with normal size of the red blood cells when there is also iron deficiency), other reduction in blood cells, abdominal complaints, malabsorption, failure to thrive, weight loss, diarrhoea, hyperpigmentation, glossitis, (aphthous) stomatitis, infertility, urinary tract infections, joint and muscle pain, muscle weakness, spasticity, seizures, cardiomyopathy, urinary and/or faecal incontinence, postural hypotension/dizziness, erectile dysfunction, to name a few.

There are doctors who deny that B12 deficiency can cause 50 different complaints, signs and symptoms. Well, I am sure you just re-counted the number of symptoms in my list and concluded that there were only 49. Many of you will have also concluded that I missed a few. However, not all people with B12 deficiency have the same number, variety or severity of symptoms. Many of these symptoms are not specific to B12 deficiency but can also occur in other disorders.

What we DO know, however, is that only 20% (or even less) of the people with symptomatic B12 deficiency have anaemia or altered size of the red blood cells. This means that the term ‘pernicious anaemia’ does by no means capture the full spectrum of B12 deficiency. One of the possible reasons that anaemia is much less prominent in B12 deficiency than – let’s say – 30 years ago, is that many countries have started mandatory fortification of food with folate. Actually, in the 1950s, many people with a diagnosis of pernicious anaemia were treated with high doses of folate, as B12 injections were not yet available. Folate usually helped very nicely to resolve the anaemia, but it resulted in severe neuropathy symptoms in many people because of the ongoing B12 deficiency. In 2003, the famous Ralph Carmel wrote in the New England Journal of Medicine: “The administration of folic acid can mask the megaloblastic anaemia caused by cobalamin deficiency. More critically, this masking, although neither complete nor permanent, can permit neurologic dysfunction to develop and sometimes become irreversible. A few authors have proposed that folate may actually worsen the neurologic dysfunction.” Only when B12 injections became available was folate treatment abandoned, leaving many victims with irreversible B12-deficiency-related neurological damage.

An often-used term for symptoms, for which no explanation is found, is ‘medically unexplained symptoms’. There is a lot of medical literature about this. In 1986, a group of doctors wrote in an article: “This group (of 41 chronically ill patients) had somatization disorder diagnosed by specific criteria. They can be easily recognized by primary care physicians by their multiple complaints, negative physical examination results, and a history of multiple medical examinations.” Now, let’s consider the level of rigor by which people with unexplained symptoms have been examined in the past. Just look at the history of people with ME (‘myalgic encephalomyelitis’) or with Long-Covid, and how they have been ill-diagnosed and not well treated, and you realize how mediocre the specific evaluation of many people with unexplained symptoms may have been. Even in the most recent years, such people underwent simple lab testing to exclude “significant diseases”, with serum B12 levels of just within the reference ranges often labelled as “normal”.

Actually, for several disorders, we know that the symptoms can span many bodily or organ systems. As a matter of fact, many disorders like those of the mitochondria (our energy factories within the cell) are, by default, disorders of which the symptoms span many organ systems. Just look at this figure at the website of the organization MitoAction:
https://www.mitoaction.org/mitochondrial-disease/symptoms/.

B12 deficiency usually affects – like mitochondrial disorders – many organ systems, especially the various parts of the nervous system. Even simple anaemia affects many organ systems: fatigue, pallor, abdominal complaints, high heart rate, shortness of breath when climbing stairs, and dizziness.

Wrong

A dramatic first impression was made by the manager of an insurance company (let’s call him Mr. Tacco). In one of his ‘dear doctor’ letters, he writes that “there is no proof that intramuscular B12 injections are better than oral tablets, so stop treating people with B12 injections”. Besides the fact that he is trying to sit in a doctor’s chair, he is somewhat wrong. In symptomatic B12 deficiency due to B12 malabsorption, parenteral administration of B12 is the default therapy. In the last 25 years, several studies have tried to assess whether this could be replaced by oral supplementation. Because injections are thought to be “cumbersome, and painful, and expensive”. Unfortunately, studies on this topic have mainly focused on normalising serum B12 concentrations with oral supplementation and should be interpreted with caution since the specific goal of treatment in symptomatic B12 deficiency is alleviating symptoms, and NOT to normalize B12 concentrations in the blood.

In a recent review (2018) by the famous Cochrane Institute, it was reported that studies which had been published on this topic only provided very low-quality evidence that oral B12 is as efficacious as intramuscular B12. In practice, some people with B12 deficiency may be able to switch to very high dose (e.g. at least 2000 mcg daily) oral supplementation instead of continuing parenteral supplementation, but………. it is impossible to predict in whom this can be done safely, and many people are at risk of worsening symptoms. These symptoms may remain permanently.

B12 supplementation is given to people with demonstrated or likely B12 deficiency. We will discuss the problems in diagnosing this later. However, it is essential to realize that there is also a disorder called vitamin B12-responsive neuropathy. The well-known geriatrician-haematologist Larry Solomon, working at Yale University in the USA, wrote 20 years ago: ‘if I had treated only those people who actually had too low serum B12 and elevated MMA values, then I would not have treated approximately two-thirds of the people with a favourable response to B12 supplementation (note: partly via injections, partly via oral supplementation) ”….

Prospective monitoring

In daily practice, I often ask my patients with B12 deficiency to maintain a sheet with their most prominent symptoms. They fill this in proactively, so before starting treatment, and then 1-2 months later, and six months later. For a good evaluation, it is essential to follow this rule: “DO NOT TRY TO REMEMBER WHAT YOUR SYMPTOMS WERE SIX MONTHS AGO, OR EVEN LONGER.” Your memory changes over time. I have had a few illnesses myself in the most recent 10 years. As an example, I find it rather hard to remember how awful I really felt when I was admitted to the hospital in 2018 because of sepsis. Luckily, I was treated well and recovered. It took several weeks before I was able to bicycle (a favourite Dutch hobby) more than a few kilometres, but nowadays, I only have faint memories of how sick I really was.

So, in Picture 7, you see a list of symptoms reported by one of my patients. I asked her to list her symptoms and grade them on a scale of 1 to 10, 1 being very minor, and 10 being a very heavy or severe symptom. Then, she repeated this evaluation after 1 month, and again after 6 months. You can see which symptoms improved considerably (green arrows), and which symptoms remained unchanged (red arrows). This dramatically helps to quantify the improvement during treatment, in this situation, twice-weekly intramuscular injections of hydroxocobalamin, and it also identified which symptoms probably were unrelated to the deficiency.

Gambling

Recently, I came across a text on a medical website where the following advice was given to doctors: “Review all patients with an active diagnosis of vitamin B12 to identify if the diagnostic guidelines were followed. If not, consider pausing treatment and retesting. This will require an element of transparency and patient consent.”

Now, this again is the main reason to realize that in trying to diagnose B12 deficiency, as mentioned earlier, you can only make ONE first impression. When, in the past, monitoring of symptoms had been done poorly, there may be some people who do not need parenteral B12 supplementation. From my point of view, this is a real “do not try this at home” scenario. One, it may well be that levels of serum B12 in the blood gradually decrease when treatment is stopped, but still remain within the low-normal range for several months or even a few years. Two, people with genuine B12 deficiency are, after withdrawal, at risk of developing worse symptoms, which may even persist after resuming treatment. This is gambling with a patient’s health. Three, B12 supplementation is used, and the optimal frequency of administration is established in order to stay symptom-free. B12 supplementation is also indicated to prevent the development of symptoms. Four, there are several medical papers describing the benefits of parenteral B12 supplementation in people with peripheral neuropathy, for instance related to diabetes, who have normal serum B12 levels. In several European countries, this is an official indication for treatment.

Charles was one of my patients: he had been diagnosed with B12 deficiency ten years ago. In 2019, an internal medicine specialist could not find an objective cause for his B12 deficiency, and supplementation was stopped. Approximately one year later, he experienced a severe worsening of his previously very mild neuropathy, and lab evaluation yielded a serum B12 of 220 pmol/l (which is normal, remember!?), but an elevated serum MMA of 1300 nmol/l, supporting the existence of true B12 deficiency. His B12 injections were restarted, but unfortunately, this was without any effects on his symptoms. Currently, he has severe persisting neuropathy despite intramuscular injection of hydroxocobalamin on alternating days, and the use of pregabalin, amitriptyline and a morphine preparation. He can not drive a car anymore; his life is ruined.

Resistance

It is known from a disease called diabetes mellitus, that there can be resistance to the actions of the hormone insulin – the main regulator of blood glucose concentrations – in many individuals. People who are more insulin-resistant need a higher dose of insulin to maintain their blood glucose levels within the normal range. Several factors may influence the degree and severity of insulin resistance, one of them being the amount of regular physical exercise; more exercise makes the body more sensitive to insulin’s actions. Although stress is also a factor which may influence insulin resistance, no doctor treating individuals with diabetes would consider that those needing higher doses of insulin are mentally unstable, making up their disease, or suffering from the placebo effect.

For the treatment of people with hypertension (high blood pressure), there are several medication options. Often, treatment is started with a diuretic drug or a so-called ACE-inhibitor. When one drug is not sufficient to control high blood pressure, a second and third drug are added, often together with a salt-restricted diet. Although stress is also a factor which may influence someone’s blood pressure, no doctor treating individuals with hypertension would consider that those needing a higher dose and more different types of blood-pressure-lowering drugs are mentally unstable, making up their disease, or suffering from the placebo effect.

Yet, that is what happens when a person with symptomatic B12 deficiency experiences that she or he needs more frequent supplementation than once every 3 months. Surveys from PAS and clinical experience teach us that there is a subgroup of individuals (almost 50%) who need more frequent injections to remain symptom-free. This may vary from twice weekly to once every 2-4 weeks (source: https://www.youtube.com/watch?v=bJlaLu2OKv0).

It is not understood why certain patients require more frequent B12 treatment. This topic has gained much recent interest, and initial studies evaluating a possible effect of the bacteria in our gut are ongoing; initial results have been reported at an earlier Pernicious Anaemia Society meeting, and these presentations can be found online on the PAS website and / or YouTube. However, there may be other causes why some people with B12 deficiency require more frequent injections. These include the competing effects of the formation of cobalamin-like molecules in our body (the so-called cobalamin analogues or pseudo-cobalamins), which may impair the proper action of the ‘good’ cobalamin. There is also recent data which suggest that genetic alterations of the receptor by which B12 is transported into nerve tissue and the brain, may lead to a lower B12 uptake. Finally, one very recent study in the USA has demonstrated that in some individuals with neurological symptoms, the presence in the blood of antibodies against this receptor may interfere with the proper uptake of B12 into the brain. So, the B12 in the serum is OK, but in the brain, it is low.

We really need more information on this important topic: “Why do some individuals need more frequent B12 injections than others?”. This was established as an important research question to be funded as part of the James Lind Alliance priority-setting partnership with the Pernicious Anaemia Society. All current information points in the direction of a valid somatic reason, and not the so-called placebo effect, the belief that the need for more frequent injections is “in the mind”. As a matter of fact, no doctor will -at first impression- consider that my patient Charles, mentioned earlier, who needs three strong types of medication to suppress his severe neuropathy symptoms, needs so many medications because he is suffering from the placebo effect. Yet, when someone with B12 deficiency reports that symptoms re-occur 4-5 weeks after a B12 injection, and wants to inject more often, all of a sudden, this person is mislabelled as ‘suffering from the placebo effect’ of B12 injections.

Wishing you a lovely Christmas season and a very Happy New Year!

Bruce HR Wolffenbuttel