RHR: Why B12 Deficiency Is Significantly Underdiagnosed

RHR: Why B12 Deficiency Is Significantly Underdiagnosed

by Chris Kresser

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Revolution Health Radio podcast, Chris Kresser

Vitamin B12 deficiency is much more common than statistics indicate, and it can have devastating consequences. It has been associated with everything from brain fog, cognitive decline, and heart disease to learning disabilities, infertility, and autoimmune disease. When you don't have enough B12, it can affect virtually every system and tissue in the body. Despite this, B12 deficiency is rarely tested for—and even when it is tested, the lab results are problematic. Today I discuss the right way to get your B12 tested and how to treat it if you are deficient.

In this episode we discuss:

  • The problem with conventional B12 serum testing
  • The prevalence of B12 deficiency
  • Why even omnivores may be deficient
  • The serious consequences of B12 deficiency going undiagnosed
  • Lab results: what to look for
  • Nutrients rich in vitamin B12

Show notes:

Chris Kresser: Hey, everybody, Chris Kresser here. Welcome to another episode of Revolution Health Radio. This week, we have a question from Kristin. Let’s give it a listen.

Kristin: Hey, Chris, my name is Kristin. I have a question for you in regards to vitamin B12 and deficiency in it. I was doing some research on vitamin B12 a while back because I have severe anxiety and panic attacks, and I noticed that sometimes people that have symptoms like that have B12 deficiency. But I also came across some articles in regards to our fingernails and how the half moons will be gone if we have vitamin B12 deficiency. I don’t know if that’s something that is common in functional medicine to look at, is the fingernails, or stuff like that. But that’s really been interesting to me lately and I would just really love to know your opinion on that. Thanks.

Chris: That’s a great question. I often get questions like this related to the fingernails as markers of nutritional deficiency, and there is some limited data on nutritional deficiency showing up in the fingernails. It can be one of the many diagnostic criteria for nutritional deficiencies, but in some cases, the data is stronger than they are in other cases, and I wouldn’t use fingernails as the sole way of diagnosing a nutritional deficiency. I would think about it as one sign that could point us toward doing further diagnostic workup for nutritional deficiencies that would include lab testing, blood testing in most cases, sometimes urine testing. But I would never make a definitive diagnosis of a nutritional deficiency just based on the fingernails alone.

Why you should have your vitamin B12 tested—and the right way to test it

Let’s talk a little bit more about B12 and diagnosing the B12 deficiency because it’s really, really important. B12 deficiency turns out to be much more common than statistics indicate, and it can have really devastating consequences. B12 deficiency has been associated with or can actually cause premature aging or logical disorders that are similar in presentation to MS or even Parkinson’s, brain fog, memory problems, cognitive decline; stroke, heart disease, and other vascular problems, primarily due to elevated homocysteine levels—B12 is required to convert homocysteine back into methionine; developmental or learning disabilities in children; impaired immune function, autoimmune disease, and cancer; male and female infertility; and numerous other symptoms because B12 plays a very, very important role in the body. As you can see, when you don’t have enough B12, it can affect virtually every system and tissue in the body.

The Problem with Conventional B12 Serum Testing

Now, one of the biggest issues with diagnosing B12 deficiency is that the conventional serum B12 test that most doctors use only picks up a small fraction of people who are actually B12 deficient. I mean, that’s a big enough problem on its own. I suppose we could say an even bigger problem is that very few doctors even use that conventional serum B12 test. I’ve had so many patients that I have diagnosed with B12 deficiency in their 40s, 50s, even 60s or older who have never once in their entire life been tested for B12, which is just crazy to me given how important it is, given how easy it is to test for B12 and how cheap that serum B12 test is. That’s a big problem. A lot of doctors aren’t including serum B12 in their workup.

But as I just said, even if they are including it, chances are they’re missing a lot of people with B12 deficiency because the serum B12 test measures a total amount of B12 in the blood, but it doesn’t rule out functional B12 deficiency.

There are more sensitive markers for B12 deficiency that are now available including methylmalonic acid (MMA), which can be measured both in the serum or the urine. And not so much in the US but in Europe and other parts of the world, there’s another marker called holotranscobalamin II, or holoTC. That’s in fact the most sensitive marker for B12 deficiency. It is capable of detecting B12 deficiency at the earliest stage, stage one. These markers are much more sensitive to B12 deficiency than serum B12, which means they’ll go out of range at an earlier stage of B12 deficiency.

Then we also have homocysteine, which is a marker of B12 deficiency, although it’s not exclusively related to B12. Homocysteine can be high in cases of folate deficiency or even B6 deficiency as well. Homocysteine is more sensitive than serum B12, but it doesn’t only reflect B12 deficiency. If you see it high, that tells you that either B12, folate, or B6 is low, and you need to do some additional testing with these other markers to determine whether the cause of the elevated homocysteine is related to B12 or if it’s related to folate or B6.

Those are the additional markers you can use. Serum B12 is still a useful test and can still detect deficiency in some patients, but those people are people that are in stage three or four of 12 deficiency. There are four stages: One, two, three, and four—and serum B12 doesn’t typically go out of range until stage three or four, so you’re missing people in stage one or two if that’s the only marker that’s used. Homocysteine and methylmalonic acid can detect people in stage two deficiency. Holotranscobalamin or holoTC is the only marker, unfortunately, that they can detect people in stage one deficiency. It’s a mystery to me why it’s not available in the US. It is in a few teaching hospitals—I think Mayo Clinic, maybe Cleveland Clinic and a few other places around the country offer it—but you can’t get it drawn at your typical lab. I’ve been hoping that that will change for years, but unfortunately, it hasn’t yet.

The Prevalence of B12 Deficiency

We talked a little bit about the important roles of B12 and why you should get tested, but I want to mention a little bit more about the prevalence of B12 deficiency because there is an incorrect notion in the medical world that B12 deficiency is rare and it only really affects people on a plant-based diet like vegans and vegetarians. There is even a bigger myth in the vegan and vegetarian world that B12 deficiency is not common in those worlds.

The problem is, those ideas are based in using only serum B12 as a marker for B12 deficiency. If you use serum B12 as the only marker for B12 deficiency rather than some of these newer tests, the statistics suggest that only 7 percent of vegetarians are B12 deficient. Interestingly enough, they still show that 52 percent of vegans are deficient. Even using a relatively insensitive marker like serum B12, you still see over 50 percent of vegans deficient in it, 7 percent of vegetarians. But in a more recent study, using the more sensitive markers that I just talked about that are capable of detecting B12 deficiency at an earlier stage, a whopping 83 percent of vegans were B12 deficient and 68 percent of vegetarians were B12 deficient. Now remember, only 7 percent were deficient using serum B12, but 68 percent were deficient using these more accurate and sensitive markers.

Why Even Omnivores May Be Deficient

Now in terms of omnivores, only 5 percent were deficient. But I can tell you having worked with patients for a very long time—most of whom are on a Paleo type of diet or a nutrient-dense diet where they’re consuming animal products—I see B2 deficiency fairly regularly. One of the reasons for that is that deficiency of a certain nutrient doesn’t just come down to how much of that nutrient you’re getting from your diet. It comes down to how well you are absorbing that nutrient in the gut and also what the demand for that nutrient is because of certain physiological processes in the body. It also comes down to whether you have genetic polymorphisms that affect your utilization of that nutrient.

Let’s use folate as an example—well, let’s use B12 as an example since that’s what we’re talking about here. There are some polymorphisms that affect B12 metabolism and the use of B12 in the body. MTRR and MTR are both genes that are connected to B12 metabolism. If you have single nucleotide polymorphisms or SNPs in those genes, MTRR and MTR, that can be measured with a test like 23andMe, those can impact B12 metabolism and they may indicate a greater need for B12 than you would have if you didn’t have polymorphisms in those genes.

And then there are conditions like SIBO, bacterial overgrowth in the small intestine, that have been shown to decrease absorption of B vitamins like B12 in the small intestine because the bacteria in the small intestine can actually utilize B vitamins as well. They’ll take them for themselves and you will get less of them. Hypochlorhydria, or low stomach acid, which, as I’ve written and spoken about elsewhere, I think is a major cause of reflux in people and a very common condition that can also decrease the absorption of B12. Even if someone is consuming enough B12, if they have low stomach acid, they have SIBO or they have genetic polymorphisms that affect their ability to absorb and then utilize B12, then these people can also be deficient even though they’re not vegetarian or vegan and so that’s really important to understand.

The Serious Consequences of B12 Deficiency Going Undiagnosed

Another crucial concept to get is that B12 depletion can take years to become clinically evident. I mentioned that there are four stages of B12 deficiency. In stage one and two, there will be no observable … usually no signs or symptoms of B12 deficiency. In other words, it’s not measurable using any other markers. It doesn’t start to cause anemia at that level and it’s not going to show up in other markers and it may even be completely asymptomatic. In fact, B12 deficiency doesn’t cause macrocytic anemia until stage 4, so that’s in the very last stage of B12 deficiency.

Unfortunately, some of the more serious effects of B12 deficiency such as nerve damage are irreversible. We have this really tricky situation where B12 deficiency is underdiagnosed because it’s not being adequately tested for. The symptoms and clinical signs can take years to become evident, but some of the more serious effects of B12 deficiency can actually be irreversible if the B12 deficiency has progressed to an advanced stage and has gone on for long enough.

I think it’s a major issue. This is why I’ve written two really detailed articles about the important effects of B12 and the problems with diagnosis and how to accurately diagnose it. We’ll definitely include a link to those articles in the show notes for the show. There are actually books that have been written about B12 deficiency. Sally Pacholok and Jeffrey Stuart have a book, Could It Be B12?: An Epidemic of Misdiagnoses, that covers this topic in great detail and goes into even some of the history and all of the conditions that can be caused by B12 deficiency and more background on what we’ve been talking about in this podcast.

Lab Results: What to Look For

I would encourage everybody to, at the very least, have their serum B12 measured. But as I have mentioned, that’s in many cases inadequate to detect stage one and stage two deficiency. Homocysteine is a marker that you shouldn’t have any trouble getting your primary care practitioner to order. It’s well known. It’s recognized as a marker for cardiovascular disease, and it’s pretty cheap. They should at least be familiar with that, and if you request a serum homocysteine, that’s probably a good starting place. Remember though, if it comes back high, it doesn’t guarantee you a B12 deficiency. It could also be folate or B6, but that might be enough ammunition to then get your clinician to order some of the more advanced tests for detecting B12 deficiency like serum or urine methylmalonic acid. I personally have found that urine methylmalonic acid is superior to serum, possibly because it’s more concentrated in urine than in the blood. I’ve just seen it be more sensitive and more consistent with the other markers of B12 deficiency then than serum methylmalonic acid. If you live in Europe or outside of the United States, you also might be able to get a holotranscobalamin, or a holoTC, which is again, the most sensitive marker for B12 deficiency.

If you can’t get your doctor to order those tests, you can order some of these tests perhaps through companies like DirectLabs.com, although there is quite a bit of nuance to interpreting these tests. It’s really helpful to have somebody who is experienced in interpreting these tests.

Another thing I want to say about these labs, if you’ve been listening to my work for any length of time, you may be aware that the conventional lab ranges that are used for these markers and many other lab markers are often not accurate. Conventional ranges are typically designed to detect frank disease rather than an optimal level, and serum B12 and even homocysteine are no exception. Most labs define B12 deficiency at less than 200 pg/mL, but it is well documented in the scientific literature that many people experience signs and symptoms of B12 deficiency at levels between 200 and 350. In Japan and Europe, I believe the lower end of the range is 400 and up or even 500 and up in either Japan or Europe. I can’t recall.

And so, if you get the B12 tests back and the level is 300, it’s going to be marked as normal, but at that level there’s a really good chance that you are in the earlier stages of B12 deficiency, and then if you were to measure homocysteine or MMA, that those would be out of range as well. With homocysteine, the range typically goes up to 13, 14, or even 15 in some labs, but I’ve seen lots of research suggesting that with B12 or folate deficiency, that can show up on homocysteine levels, start getting higher than eight. Homocysteine level above eight doesn’t necessarily reflect B12 deficiency, but it would be cause in my mind for doing further testing. Keep in mind that homocysteine is an inverse marker, which means when it’s high, that suggests B12 is low, and both serum and urine methylmalonic acid are also inverse markers, so when they’re high, that suggests that B12 is low.

Be aware that high serum B12 does not necessarily rule out functional B12 deficiency. This is what I was referring to when I said there’s some nuance on how to interpret these markers. In fact, I have come to view a high serum B12 when the patient is not supplementing or not eating really extreme amounts of B12 foods like liver as a potential red flag for active B12 deficiency.

Nutrients Rich in Vitamin B12

If you do actually have B12 deficiency, then there is much bigger discussion about how to address that. Eating B12-rich foods in my opinion is the best way. If you do eat animal products, B12 is richest in liver, clams, oysters, organ meats, and shellfish—once again, top of the list in terms of the most nutrient-dense foods. If you just ate a serving of liver and a serving of clams, oysters, or mussels each once a week, you would probably be able to meet your needs for B12 for the entire week. Other seafood like fish eggs, octopus, crab, and lobster are good sources for B12. Beef, lamb, even cheese and eggs are good sources of B12 as well, but they pale in comparison to the organ meats and shellfish in terms of the amount of B12 per serving.

A common myth amongst vegetarians and vegans is that it’s possible to get B12 from plant sources like seaweed, fermented soy, spirulina, brewer’s yeast, etc., but many of those plant foods actually contain B12 analogues called cobamides that block the intake of and increase the need for true B12. My intention here is not to bash vegetarian and vegan diets. As many of you know, I was a macrobiotic vegan myself at one point, but just helping to educate people about how to make wise choices. If you are on a vegetarian or vegan diet, you should be definitely getting your B12 levels measured with the more sensitive markers that I have mentioned, and then if your levels are low, you should be supplementing with B12, which is really quite easy to do.

We won’t go into a lot of detail on supplementation because I’ve written about that before, and I will just provide a link to the articles, which have some recommendations there.

Okay. Thanks again, Kristen, for sending in your question, and please do continue to send in your questions, everybody, to chriskresser.com/podcastquestion. Thanks for listening. Talk to you next time.

18 Comments

Join the conversation

  1. I discovered that i am b12 deficient in 2014. Along with that i had low ferritin. As doctors prescribed taking b12 shots, i started taking them but i was looking for the reason behind this deficiency. My brother has wheat allergy(celiac) so one of the doctors asked me also to get tested.But it was negative. My digestion was never good. I had bloating, gas, vomitings, headaches and hair fall. Recently i thought to quit milk and results are amazing, no more gas bloating and headaches. Its been only a month.
    I am confused whether i am having wheat allergy or not(I am on a strict non celiac diet from the past 1 year), coz i have read that for some people it doesn’t show in their test and celiac runs in the family(my brother has it).
    second question is can lactose intolerance leads to low b12 and ferritin? Please somebody help.

  2. Please talk about Pernicious anemia which was not addressed in this talk. Eating foods high in B12 will not be absorbed is my understanding. Also Intrinsic Factor Antibodies which no one talks about! Can PA be reversed like some of the other autoimmune conditions like lupus and RA? Thanks!

    • Just checking in again Chris. I respect your research, and it seems like this study should raise some alarms for revisiting your past conclusions and recommendations. Actually, I think most of people in the industry entirely missed this news.

      I’m especially curious if you think methylcobalamin (vs. cyano) could possibly mitigate, or even more worrisomely, exasperate the proposed one-carbon metabolism mechanism? Also factors like taking sublingually, which were not part of the study.

    • Observational studies should not have conclusions. There are too many factors to say one thing or another is a problem. You have to have specific studies to actually determine anything. There was an observational study that said betacarotene was bad for smokers. That was later proved to be incorrect. Also the group studied were predominately smokers and coffee drinkers who didn’t eat very much. Their lifestyle create the higher risk for lung cancer not the betacarotene.

  3. Chris I’ve been reading a lot about vitamin b6 toxicity and is has me quite confused on weather to take just a b12 supplement or one that your recommend like methyl guard for low vitamin b12

    • Hi Zack, Just wondering if you could post me the links you have been looking at regarding B6 toxicity as I was out on high levels of active (P5P) B6 by my nutritional therapist after I tested positive for pyroluria. I have had great results from it but would be interested in possible problems. Many thanks

  4. Same question here: what is going on when B12 shows up too high in serum, when someone is not supplementing? Is it “pooling” in the blood? Is this a genetic issue or can gut dysbiosis also be the cause?

    I would be very grateful for your insights into this!

  5. I always have high serum b12 due to TCN I and II polymorphisms, and plenty of them. It backs up in my blood and doesn’t get to tissues. I am 57, and had peripheral neuropathyin my feet starting at 20, immune problems also in my 20’s (I reacted horrendously to carrying male fetuses), autoimmune issues all over the place, snow white hair since my late 30’s, now struggling a bit with long-term memory and slight weakness on my right side. I can only tolerate 5mg. of B12 first thing in the morning; otherwise it prevents sleep that night. What’s a girl to do if she can’t drive it into the tissue?! Please, please suggest something – my life is circling the drain… By the way, all b12 markers except serum are abnormal, including HoloTC. I was almost included in an NIH study, but my MMA was not abnormal enough….

    • Jill: Did you mean 5 micrograms? 5 milligrams is quite a lot of B12. Doses by mouth are usually measured by micrograms, with the smaller sublingual lozenges being 1,000 micrograms. Five milligrams is the equivalent of 5,000 micrograms. It’s not dangerous, but it should be more than sufficient for just about anyone–unless you need injections and can’t absorb it at all, but most people are supposed to be able to absorb enough, since the minimum RDA is like 3 micrograms.

      • No, I take 5000mcg./5mg. though not every day. I’m not your average bear. Because of the many genetic defects in TCN I and II, I can’t get B12 from my blood into my tissue. So I have to load the dose in order to do what others can do without thinking. Injections would kill me since any more B12 would keep me awake (for days) – again, owing to all the processing difficulties.
        I just wondered if anyone knew how to potentiate the TCN I and II pathways with food or supplements, etc.
        By the way, even in normal people, very little of supplemented B12 actually gets taken up by the body, unless it comes from liver, which provides all the right co-factors for its metabolism.

  6. B12 makes me weak and more exhausted. Right after I take B12 I can sleep for hours so I don’t know what to do. I seem to have adverse reactions to ALL supplements. If something should energize me it does the opposite.

  7. About 1/3 of my customers come to me with B12 deficiency related issues. I almost always recommend to do things the old fashioned way… eat your liver, clams, oysters and organ meats.

    Food should come first, supplements second but this is not what they want to hear (nor) is it why they came to me in the first place. I’d say that 1/20 will give it a go… the other 19/20 usually purchase the Grass Fed Beef Liver.

    Aside from B12, liver also provides real preformed vitamin A (retinol), folate, choline, CoQ10 and heme iron. It really is an amazing food… it offers incredible nourishment… everyone should be consuming.

  8. How harmful is B12 excess? My test results seem to indicate excess, but UMMA is high, suggesting B12 deficiency – perhaps absorption issue? What would be the correct interpretation of these seemingly contradictory results – am I deficient or excess? I’m an omnivore & normally supplement w/Bs in daily multi-vit and alt days w/protein brkfst drink, however I was fasting & suspended all vits at least 24hrs and protein drink suspended 48hrs prior to testing. Thank you!

    Note: I’m MTHFR Compound Heterozygous C677T & A1298C.

    Item Result Ref Rg
    Vit B6 41.4 2.0 – 32.8 ug/L
    Folate > 20 > 5.4 while deficient 20)
    Vit B12 > 1999 211 – 946
    MMA, serum 230 0 – 378 nmol/L
    MMA, urine 3.2 1.6 – 29.7 umol/L
    MMA, normalized H 2.6 0.4 – 2.5 umol/mmol cr
    or UMMA

    1 yr prior results * NOT fasting; drawn 1.5hrs after taking multi w/B vits, but NO protein drink:
    Homocysteine, Serum/Plasma 5.6* Ref Rg < 10.4 UMOL/L
    MMA, serum 312* Ref Rg 87 – 318 nmol/L

    • I have the same question! My B12 & Folate serum levels were way beyond the numbers that are considered optimal, with B12 at 1959 pb/mL (optimal is > 400) and Folate at >1469 ng/mL (optimal is > 750). Homocysteine at 9 μmol/L (optimal is < 11)

      I've had very few SNPs but know that I'm homozygous for MTHFR C677T.

      I am also wondering how to interpret these serum B12 levels. Does an excessively high number mean that the B12 is merely in the blood my body/cells are not using it efficiently?

      Thanks Chris (and team)!

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