Diagnosis and treatment pitfalls

We are getting a growing number of patients with B12 related symptoms who are not or no longer treated. The reasons may be that they have sub-normal B12 levels or their B12 levels have not been tested at all because they aren’t anaemic. Sometimes treatment has been stopped after the inititial dose of intramuscular (i.m.) injections. Below you will find pitfalls in the diagnosis and treatment of B12 deficiency. They are described in the new NHG (Dutch College of General practitioners) guidelines. We think it is important to list and explain any possible diagnosis and treatment misunderstandings here.

1. B12 deficiency often occurs without anaemia.

When there is a suspicion of symptomatic B12 deficiency it is important to measure the B12 serum determination (in addition to excluding other diseases, such as thyroid diseases and Lyme), even if anaemia has not been diagnosed.

The still widespread misconception that there has to be anaemia for a diagnosis of ‘real’ B12 deficiency causes many unnecessary misdiagnoses (Iqtidar, 2012), often resulting in a lot of suffering (and expenses). Please take a look at our preliminary research results into the relationship between B12 deficiency and anaemia (n=161.541): http://wp.me/P5dzwH-7i .

2. Measuring vitamin B12 values during or after treatment, with the aim to measure the efficacy of the treatment, is of no use. (See also point 3 and 4, note 2)

Supplementation (1000 mcg hydro(xo)cobalamine B12 injections, 2 times a week intramuscularly or deep subcutaneously for five weeks, or once a week for ten weeks) is primarily done when deficiency has been diagnosed. When B12 values are measured again, after the injections, they should be very high. This cannot be taken as a reason to stop the injections.

This also applies for testing MMA and homocesteine. If these values have dropped to standard level it is only an indication that treatment is effective and should not be used to measure treatment efficacy (’values are good, let’s stop treatment’). Supplementation can only be phased down towards a maintenance dose when symptoms have largely disappeared. Phasing down is a slow process. Stopping treatment entirely (because B12, MMA or homocysteine values are back to standard) without the causes having been removed is not the correct way of treating a patient. Symptoms will return (see point 3). A sudden return to the maintenance dose is often ineffective, particularly when the patient was experiencing symptoms long before the diagnosis was made.

Tissue healing takes a long time (the exact period varies per patient). Symptoms may continue even when biochemistry has become normal again. When neurological symptoms occur, we advise treatment of injecting twice a week for one or two years (source: Farmacotherapeutisch Kompas).

3. Do not stop medical treatment if the causes of B12 deficiency have not been solved.

If injections are stopped when the cause of B12 deficiency has not been treated, symptoms will return, seriously affecting the patient.

4. Overdosage is impossible, even for children.

B12-supplementation is not toxic. Even the (Dutch) Health Council (Gezondheidsraad) has issued no upper limits for B12/ Cobalamin intake. E.g.: CyanoKit, used for cases of smoke poisoning, involves administering lifesaving injections of vitamin hydro(xo)cobalamin, corresponding to 5.000 B12 injections at a time. B12 levels may rise to levels of 15.000 to 75.000 pmol/L. Apart from red-colored urine (in case of intravenous administration), innocent skin discoloration, and possible soft stools, no side effects have been reported at the intervention evaluation. The B12 serum level after injection has no bearing on the amount of B12 that reaches the tissue and, therefore, on the efficacy of the treatment.

Note: B12 deficiency in children may dangerously affect their growth and development. When in doubt, we advise you not to hesitate. Sub-standard B12 levels in pregnant women can also negatively affect the child’s development.

Note 2: Raised B12 lab values without supplementation (exceeding standard values) are important indicators of other diseases, such as liver and hematological conditions. Raised levels (or standard levels) with B12 supplementation is not a valid marker. Patient symptoms will always be the most important thing to monitor.

5. Recovery from B12 deficiency always takes a long time.

After having had no treatment or undertreatment for years, people often wish for a quick recovery. Some may notice a slight improvement right at the beginning of the treatment, for others this may take some time. ‘Recovered’ doesn’t always mean ‘cured’. For some patients the process towards recovery and becoming symptom-free will take years Recovery of neurological and neuro-psychiatric, nerve and muscle tissue damage will last quite a long time, especially with long-lasting deficiency. More injections may be helpful, particularly when peple suffer from neurological complaints and tiredness. We have noticed that the complaint ‘I just cannot handle much yet’ lingers the longest.

6. Temporary worsening of symptoms after suppletion.

Sometimes unexplained worsening of symptoms can be seen after having been administered several supplementations, even as long as weeks later. These symptoms disappear after a while. The cause of this has not been adequately researched yet. There is a probability that damaged cells are broken down, giving room for recovery. A mistake that is sometimes made is stopping treatment because of the worsening symptoms, but when B12 has been diagnosed that actually is the wrong route to take; in that case supplementation really is necessary.

7. Vitamin B12 deficiency may cause severe neurological and neuropsychiatric symptoms.

B12 deficiency may generate mild to severe (neuro)psychiatric complaints. This fact is often ignored in the medical field. Such complaints have been described in literature from 1900 onwards and may precede abnormal blood counts. Vitamin B12 plays a part in a broad range of bodily processes, resulting in symptoms such as painful muscles, hips, feet and hands but also functional deficiency of bodily functions. Mild to severe depression, panic disorder, bipolar disorder and psychoses may also occur. Psychiatric symptoms like that actually may have physical causes. Please read our article about the benefit of a proper B12 and folate deficiency differential diagnosis for patients with depressions, mood swings and psychoses: http://wp.me/P5dzwH-24.

8. Do not take B12 tablets or melting tablets without having been tested for B12.

Our motto: do not take B12 (melting) tablets without having been tested for B12. We get a growing number of patients who have been taking (melting) tablets for B12 related symptoms. When symptoms hadn’t vanished, not even after three months, or had come back after an initial recovery, they consulted a doctor in order to get injections. Testing for B12 at that point showed values that seemed elevated, which prevents proper diagnosis. Such patients will then not be treated, because of the seemingly ‘excellent B12 values’. Please read our article on B12 (melting) tablets, sprays and use of plasters, at the bottom of the page.

Note: There can be treatment based on values prior to supplementation. All values that are measured after supplementation cannot be used to assess how effective treatment is. Blood will remain showing increased B12 levels for a long time.

9. Vitamin B12 deficiency has a large number of causes.

The vitamin B12 absorption process is one of the most intricate bodily processes. as a result of the molecular structure of B12 (folic acid is absorbed intestinally more easily). A lot can go wrong ‘along the way’. Antibodies to intrinsic factor and parietal cells are just two of the causes of malabsorption. Not finding these antibodies shouldn’t give rise to the conclusion that there is no B12 deficiency. 20% of patients with pernicious anaemia definitely don’t have any antibodies. Besides, there may be other causes. On this subject, see: https://www.ntvg.nl/artikelen/fysiologie-en-pathofysiologie-van-de-intrinsic-factor-secretie-en-de-cobalaminevitamine/volledig

10. Vitamin B12 deficiency in children and youth.

Prevalence of B12 deficiency is highest in elderly people: in nursing homes the percentage is 25% to 35%. But too often we tend to forget that B12 deficiency can be present in youth and that the incidence/prevalence in youth is a lot higher than is generally assumed: ‘Thirty-nine percent of subjects had plasma vitamin B12 concentrations < 258 pmol/L, 17% had concentrations < 185 pmol/L, and 9% had concentrations < 148 pmol/L, with little difference between age groups’ (Tucker, et al, 2000).

11. Vitamin B12 is not addictive.

B12 is not addictive, but patients do need recovery, therefore more injections, given the often long history of symptoms. They are afraid symptoms will return after an initial recovery.

12. Oral supplementation does not have our preference.

B12 deficiency is a serious illness which, if untreated, can lead to lasting neurological and cognitive damage and disability. Untreated B12 deficiency may even lead to death. Every year people die unnecessarily of B12 and folate deficiency (CBS, 2016). We prefer injections for patients with distinct conditions because the effect of oral supplementation has not been scientifically established sufficiently and patients run the risk of permanent damage as a result of this serious illness.

Patients that come to our practice sometimes show initial recovery as a result of oral supplementation, but quite soon relapse and may not even recover in the end. When that happens, patients must be injected. So, the assumption that ‘the patient doesn’t have B12 deficiency, because oral supplementation doesn’t cure the patient’ is incorrect. What works for some patients, may be ineffective for others. There is no generally effective treatment, partly because of the large number of underlying causes. Injecting prevents possible absorption problems, which yields optimal results to patients.

If there is a relapse due to undertreatment or (wrongly) withdrawing treatment without having taken away the cause, recovery usually takes longer. Please do not take that risk, a human being is not the same as ‘lab value’.

13. Phasing out treatment towards a maintenance (too) low dosage-frequency.

In our practice we notice that the Dutch College of General Practitioners (NHG) guidelines[1] are not sufficiently effective for a lot of patients, and that symptoms appear again after switching to injections once every two or three months. We repeat: customized treatment is necessary. A patient needs to be relatively free of symptoms ( and this can take more than two years) in order to quietly start phasing out treatment. If symptoms do appear again, the dosage-frequency has been too low.

When obvious neurological symptoms (e.g. aphasia, tingling, ataxia, mood disorders, depression, cognitive problems) are present, it is recommended to give frequent injections twice a week, as is clearly defined in the package leaflet of hydroxocobalamine. Overdosage is impossible; that is the reason why the (Dutch) Health Council (Gezondheidsraad 2003) has not set an upper limit for the intake of B12 supplementation.

14. B12 deficiency may have a hereditary factor.

Sometimes entire families suffer from B12 deficiency. If that is the case, we test the parent(s) first, before testing the (young) children.

15. B12 deficiency in vegans and vegetarians.

Vegetarians and vegans run a very high risk of developing B12 deficiency, because B12 is only present in animal products. As a result of underlying (hereditary) absorption disorders oral supplementation may prove insufficient to supplement the deficiency. In those cases symptoms indicating B12 deficiency may arise, and injections are necessary. Synthetic cyanocobalamin which is often found in tablets or meat substitutes is not enough and is always less than the B12 value in meat products.

Please take into account that the B12 values of patients who have been taking B12 supplements, are usually false high and do not indicate a possible deficiency. If a vegan or vegetarian person has developed symptoms despite B12 supplements we advise him or her to see a doctor who knows about deficiency among vegans and vegetarians. Their B12 values should not be used to prove the effectiveness of the treatment.

16. B12 deficiency after gastric bypass surgery.

We see a growing number of obesity patients who have had gastric bypass surgery. As in this group of patients B12 symptomology often is not recognized and the effect of oral supplementation regularly is insufficient (as a result of the destruction of intrinsic factor production, among other things), a large number of them suffer from B12 deficiency. Because their serum B12 can be false high as a result of taking tablets and, moreover, most of the time they don’t have anaemia, B12 deficiency is usually not considered. This has significant implications for these patients who delay seeking help for their complaints, running the risk of those complaints becoming more serious or even permanent. Some patients don’t tolerate the large tablets and experience nausea, which prevents them from taking vitamin supplements and minerals. The risk also applies to people who have had gastric surgery because of stomach cancer.

In conclusion: in the light of the irreversibility of the symptoms and the possible invalidity as a result of undertreatment it is important to supply adequate supplementation (intramuscular) when there is evident symptomology. Our motto remains: listen to the patient’s complaints.

[1] The NHG guidelines state: twice a week for 5 weeks, or once a week for 10 weeks, followed by a maintenance dosage of once every two months.