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Unfortunately, many diagnoses of B12 deficiency are still made or dismissed based solely on a single measurement of vitamin B12 levels in the blood. Why is that unfortunate? Well, first of all, there is remarkable variability between the results obtained with different commercially available B12 blood tests. The same sample of blood can come in at 240 µmol/L in one lab and almost double that in another.
Secondly, there is significant day-to-day variation of serum B12 within one individual. Here, researchers tested people once a week for 10 weeks, and the variation in each individual could be as much as 100 points or more.
One way B12 deficiency can be missed is when someone takes a B12 supplement right before getting tested. So based on their blood levels, it looks like they have more than enough even if they’re actually suffering a serious deficiency. On the other hand, perhaps as many as one in five people who test positive for B12 deficiency based on low blood B12 levels may not actually be deficient. And then there are those with symptomatic B12 deficiency who test fine.
As many as 5% of patients who end up being diagnosed with vitamin B12 deficiency have blood B12 concentrations above a commonly used cut-off of about 150 µmol/L, and even more have abnormal methylmalonic acid (MMA) or homocysteine levels, which are signs of functional B12 deficiency even if overt symptoms are not apparent. Levels of these metabolites may not normalize until our blood levels get up to around 400 µmol/L. So maybe the traditional cut-off is too low. And it’s not just lab test abnormalities; those with marginal B12 levels score worse on hand dexterity tasks, suggesting they have covert diminished nerve function.
Most seriously, we can have life-threatening B12 deficiency with normal blood levels. Here, these two people were misdiagnosed as having a bone marrow cancer, since it couldn’t be B12—look how high their levels are. As many as one-third of patients with one of the most dreaded outcomes of B12 deficiency, subacute combined degeneration of the spinal cord, had normal or even elevated levels of B12 in their blood. We’re not sure why, but sometimes the test just fails. Well, that’s not good.
Now if your test result is really low, like under 100 pg/mL, there’s about a 90% chance you are truly B12 deficient, but if the cut-off amount is higher like 200 pg/mL, then actual B12 deficiency could be missed as much as half the time if you aren’t showing symptoms. The reason it’s so hard to pin down the rate of false positives and false negatives is there’s no gold standard test to compare it to. Some studies suggest measuring the levels of the biologically active form of B12. But a wide variation in levels is also shown depending in part on which lab is running the blood test.
Some recommend using a combination of tests to improve accuracy. For example, testing one or both of the functional measures of vitamin B12, MMA (methylmalonic acid) and homocysteine, perhaps especially when values are in that so-called “grey zone” between 150 and 300 pmol/L or so. Those functional measures are pretty sensitive, meaning if you are B12-deficient, there’s more than a 95% chance these tests will pick that up. But there are problems with so-called specificity, meaning there are other reasons values can be abnormal, like diminished kidney function in the case of MMA, and folate deficiency in the case of homocysteine.
In summary, accurate assessment of vitamin B12 status is problematic, and there is no consensus as to the best biomarker or combination of biomarkers to use. From a public health standpoint, what if we just make sure everyone’s getting their B12? At least twenty-five countries have mandatory fortification of staples with vitamin B12, and that certainly helps. But in terms of testing, if you have classic B12 deficiency symptoms, even if you have normal B12 levels in your blood, and even if your MMA and homocysteine levels are normal, a therapeutic trial of B12 supplementation should be considered. This means why not just try B12 and see if your symptoms improve? For example, if you have neuropathy symptoms, numbness, pins and needles, loss of a sense of position, or experience a vibration sensation, maybe you should try going all out with B12 injections to be absolutely sure. Are B12 injections necessary to correct B12 deficiency, though? Can it just be treated with oral B12, and what’s the best source? I’ll answer all those questions next.
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