Numerous times over the past couple decades I’ve regrettably had to contradict a colleague when a patient has been told that their serum levels of vitamin B12 are adequate and supplementation is not warranted. A study just published in the journal Neurology offering yet more evidence that serum vitamin B12 levels within the typical normal range can mislead about serious consequences of B12 deficiency in the brain. The authors’ intent was to…

“…investigate the interrelations of serum vitamin B12 markers with brain volumes, cerebral infarcts, and performance in different cognitive domains in a biracial population sample cross-sectionally.”

They examined serum markers of vitamin B12 in relation to neuropsychological tests of 5 cognitive domains and brain MRI studies obtained on average 4.6 years later among 121 older community dwelling adults. The data paint an important picture:

“Concentrations of all vitamin B12–related markers, but not serum vitamin B12 itself, were associated with global cognitive function and with total brain volume. Methylmalonate levels were associated with poorer episodic memory and perceptual speed, and cystathionine and 2-methylcitrate with poorer episodic and semantic memory. Homocysteine concentrations were associated with decreased total brain volume. The homocysteine-global cognition effect was modified and no longer statistically significant with adjustment for white matter volume or cerebral infarcts. The methylmalonate-global cognition effect was modified and no longer significant with adjustment for total brain volume.”

In other words, the decrease in total brain volume due to vitamin B12 insufficiency appeared to the mediating the impact on function of the markers besides homocysteine (also associated with brains infarcts)—and serum B12 did not correlate with the MRI or cognitive testing results. For lay readers, your brain can be shrinking with concomitant loss of cognitive function due to B12 insufficiency and the blood test for B12 can still appear normal. The authors’ conclusion needs to become common knowledge among all practitioners:

“Methylmalonate, a specific marker of B12 deficiency, may affect cognition by reducing total brain volume whereas the effect of homocysteine (nonspecific to vitamin B12 deficiency) on cognitive performance may be mediated through increased white matter hyperintensity and cerebral infarcts. Vitamin B12 status may affect the brain through multiple mechanisms.”

Note: methylmalonate (methylmalonic acid) in urine or serum, while not perfect, are practicable. This study also adds more evidence to the importance of homocysteine and brain health.

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If you are faced with a puzzling case of chronic cough in the absence of infection or allergy, a study published recently in The American Journal of Clinical Nutrition shows that a functional vitamin B12 deficiency should be considered. The authors state:

“Chronic cough is characterized by sensory neuropathy. Vitamin B-12 (cobalamin) deficiency (Cbl-D) causes central and peripheral nervous system damage and has been implicated in sensory neuropathy and autonomic nervous system dysfunction.”

The authors set about evaluating whether Cbl-D has a role in chronic, unexplained cough by examining the laryngeal threshold (how much inhaled histamine it took to provoke a 25% decrease in the mid-inspiratory flow), bronchial threshold (how much to provoke a 20% decrease in forced expiratory volume), and cough threshold (how much to cause 5 or more coughs) before and after intramuscular injections of cobalamin in 42 patients with chronic, unexplained cough. (27 of them were cobalamin deficient [Cbl-D] at the beginning of the study and the rest were normal.) What did their data show?

“Cbl-D patients had a higher prevalence of laryngeal hyper-responsiveness than did Cbl-N patients, a thinner oropharyngeal epithelium, a lower number of myelinated nerve fibers, and a higher immunoreactive score for nerve growth factor (NGF). After cobalamin supplementation, symptoms and laryngeal, bronchial, and cough thresholds were significantly improved in Cbl-D but not in Cbl-N patients.”

Besides the fact that vitamin B12 may help resolve chronic cough, there are two points particularly worth noting: (1) the degree to which B12 deficiency can damage nerve tissue, and (2) supplementation will make a difference only if there is a deficiency. The last may seem obvious, but it’s surprising how many supplementation trials are conducted without discriminating deficient from replete subjects. The authors conclude:

“This study suggests that Cbl-D may contribute to chronic cough by favoring sensory neuropathy as indicated by laryngeal hyperresponsiveness and increased NGF expression in pharyngeal biopsies of Cbl-D patients. Cbl-D should be considered among factors that sustain chronic cough, particularly when cough triggers cannot be identified.”

I have not found serum levels of B12 to be a good indicator of cobalamin sufficiency. While not perfect, serum or urine methylmalonic acid (MMA) are more reliable.

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Patients with advanced diabetes whose insulin receptors have sustained years of damaging insult sometimes require the medication metformin. Clinicians and patients alike need to bear in mind that metformin tends to cause a deficiency of the critical nutrient cofactor vitamin B12. Research just published in the British Medical Journal reminds us that this is not in question or a matter of opinion. The authors set out to…

“…study the effects of metformin on the incidence of vitamin B-12 deficiency (<150 pmol/l), low concentrations of vitamin B-12 (150-220 pmol/l), and folate and homocysteine concentrations in patients with type 2 diabetes receiving treatment with insulin.”

Incidentally, this reference for vitamin B-12 is extremely low and far from optimal. After following 390 patients with type 2 diabetes who were treated with 850 mg metformin or placebo three times a day for 4.3 years, what did they conclude from their data?

“Long term treatment with metformin increases the risk of vitamin B-12 deficiency, which results in raised homocysteine concentrations. Vitamin B-12 deficiency is preventable; therefore, our findings suggest that regular measurement of vitamin B-12 concentrations during long term metformin treatment should be strongly considered.”

Do remember that serum B12 is not a reliable indicator. To ascertain that your genetic and circumstantial needs for this critical cofactor are actually being methylmalonic acid, measured in serum or urine, is much more reliable.

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Judging from the tone of this paper just published in the journal Diabetes Care, there are still too few professionals and lay people alike who are not aware that Vitamin B12 must be attended to when taking the type 2 diabetes drug metformin. The authors focus on the varying severity of diabetic neuropathy and observe:

“Long-term use of metformin is associated with malabsorption of vitamin B12 (cobalamin [Cbl]) and elevated homocysteine (Hcy) and methylmalonic acid (MMA) levels, which may have deleterious effects on peripheral nerves.”

It won’t surprise any readers of these posts that their data showed…

“Metformin-treated patients had depressed Cbl levels and elevated fasting MMA and Hcy levels. Clinical and electrophysiological measures identified more severe peripheral neuropathy in these patients; the cumulative metformin dose correlated strongly with these clinical and paraclinical group differences.”

Their conclusion:

“Metformin exposure may be an iatrogenic cause for exacerbation of peripheral neuropathy in patients with type 2 diabetes. Interval screening for Cbl deficiency and systemic Cbl therapy should be considered upon initiation of, as well as during, metformin therapy to detect potential secondary causes of worsening peripheral neuropathy.”

Remember, when taking metformin you need to check your B12 levels, not by measuring it in the serum (blood) which is unreliable, but with methylmalonic acid in the blood or urine (not perfect but better) and keeping an eye on homocysteine.

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An important study was just published in the journal Endocrine Practice (the journal of the American Association of Clinical Endocrinologists) that set out to determine if undiagnosed Vitamin B12 deficiency is common among people with type 2 diabetes, even when not taking Metformin (which itself causes B12 deficiency). Their findings: “Almost one-half of type 2 diabetes subjects not taking Metformin had biochemically proven vitamin B12 deficiency.” (And they used a very low benchmark, <200 microgram/dL, to qualify as “low”, which we would call severe deficiency.) Their important conclusion that needs to be more widely communicated: “We conclude that Vitamin B12 deficiency is common amongst type 2 diabetes subjects and is nutritional in nature…This indeed is an important finding, as taking oral Vitamin B12 supplementation is easy, convenient and readily accepted by patients. This is a novel finding and stresses the need for aggressive and early diagnosis and treatment to avoid complications of Vitamin B12 deficiency.” Why wait for type 2 diabetes to develop? Take care of any deficiency, a potential contributing cause, earlier at a preventive stage.

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As you know, vitamin B12 is a critical nutrient for brain and nervous system health. Deficiencies commonly occur due to diet or poor assimilation. Here is a report published in the journal General Hospital Psychiatry describing a psychotic episode resulting from cobalamin (vitamin B12) deficiency. Interestingly, this occurred without any hematologic (blood) symptoms or preceding neurological manifestations. I have personally seen a case like the one described here.

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Do keep in mind that Vitamin B12 is so important for the nervous system that low levels accelerate neurodegeneration to the degree that the brain shrinks markedly, as described in this paper published in the journal Neurology. [A cautionary note for any doctors reading this post: brain volume loss was, surprisingly, not associated with high levels of methylmalonic acid or homocysteine. The association was with serum B12 <308 pmol/L, low levels of holotranscobalamin and transcobalamin saturation.]

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There is abundant evidence that metformin, a medication commonly used for type 2 diabetes, impairs the absorption of Vitamin B12 (even by broad pathological reference standards, not to mention the more sensitive functional reference ranges). Few patients seem to be told about this even though it has been well known for a long time:

1. Use of Metformin Is a Cause of Vitamin B₁₂ Deficiency
2. Risk Factors of Vitamin B112 Deficiency in Patients Receiving Metformin
3. Metformin-related vitamin B12 deficiency
4. Metformin increases total serum homocysteine levels in non-diabetic male patients
5. Malabsorption of vitamin B12 during biguanide therapy
6. Association of metformin, elevated homocysteine and methylmalonic acid

For vitamin B12 I recommend the sublingual methylcobalamin form.

(Metformin is a type of biguanide. Homocysteine and methylmalonic acid levels go up with B12 deficiency.)

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