B12 Deficiency: Still America’s #1 Missed Diagnosis

Over the years of writing Health Tips, I was surprised to discover that one I’d written a few years ago about vitamin B12 deficiency had received the most comments and questions from readers. Since there have been some interesting developments in both the diagnosis and treatment of B12 deficiency, and since B12 deficiency remains so common, this seems like a good opportunity for some updates.

The symptoms of low levels of vitamin B12 can been pretty vague. You’re just not feeling right and you’re tired, maybe a little depressed, a bit achy. Your digestion might somehow feel off and you’re not thinking clearly. Balancing a checkbook becomes an exercise in higher math.

Your doctor’s empathetic, not at all dismissive of your symptoms, but after a physical exam and some apparently appropriate tests with normal results she can’t find anything really wrong. On the surface, this is reassuring. After all, the main reason we go to doctors is to ascertain that nothing serious is going on.

Still, could she be overlooking something?

All about B12
One of the eight B vitamins, B12 is involved in the metabolism of every cell in your body. Years ago B12 was called “maturation factor” because cells need B12 to mature from being young and ineffectual whippersnappers to fully functioning, mature cells. Imagine a child, about seven years old, who’s stuck at that age and can’t grow into adolescence and later adulthood. Now imagine a magical substance that will allow her to grow and mature. That’s vitamin B12.

In fact, B12 is so potent a factor in cell maturation that some of the original studies on it showed that cells in the bone marrow (where blood is manufactured) when deliberately deprived of B12 could mature in just a few hours when B12 was added. This phenomenon explained how B12-deficient patients reported feeling magically rejuvenated within a day or two of their first B12 injection.

Years ago, I read that the late Bruno Bartoletti, conductor of the Lyric Opera orchestra, would not go onstage unless he’d had a B12 injection earlier that day. At the time, I thought it was a placebo effect. Now I think differently.

B12 deficiencies
Three major systems in your body are affected by B12 deficiency: your blood, nervous system, and, less often, gastrointestinal tract. These three are targets because their cells either have a high turnover rate (blood and intestinal lining) or need a lot of B12 to function smoothly (nervous system). The symptoms of low B12 are related to each of these areas.

  • Low B12’s effect on blood is a specific type of anemia called megaloblastic anemia (as distinct from the more common iron deficiency anemia). A megaloblast is an immature, undeveloped red blood cell, large and bulky (megalo=large, blast=immature form). Remember, B12 is needed for this cell to mature, so with insufficient B12 megaloblasts accumulate in your bone marrow and large red cells called macrocytes appear in your blood. Symptoms are the same as for anemia from any cause: fatigue, breathlessness, and lightheadedness. Your skin becomes a pale yellow, most likely because the red cells that do make it to maturity are very fragile and easily broken, releasing their yellow bilirubin pigment.
  • In the nervous system, B12 deficiency causes symptoms affecting the nerves (numbness, tingling, tremors, balance problems) and the mind (depression, brain fog, mood swings, and, in rare cases, hallucinations and psychosis).
  • In the GI tract, deficiency can cause digestive symptoms and weight loss because you’re not absorbing food efficiently.

The irony is that with all these there’s usually just one predominant symptom, and making a connection to low B12 can easily be delayed until other symptoms start to appear. For example, if your only symptom is tingling in your hands, you might undergo all sorts of diagnostic tests before your doctor thinks “Maybe we should check her B12 level.”

But even if you manage to get your doctor to test your B12 level, you’re only halfway there because the blood test is just not very good.

The normal range for B12 in the US is 200 to 800 pg (picograms)/milliliter of blood. But it’s been shown that symptoms can begin as low as 400 pg/ml, so the US “normals” are definitely not OK. In Europe and Japan, anything below 550 pg/ml is considered abnormal. Therefore, if your level is, for example, 350 pg/ml, your doctor reads a printout for you that reports “normal B12” and she doesn’t initiate treatment. I’ve had patients come in with B12 levels of 201 pg/ml with the word “normal” scribbled across it by the doctor.

A far better test for early B12 deficiency is measuring your blood levels of methylmalonic acid (MMA) because this will show the very first sign that something’s amiss with B12. You can have a perfectly normal B12 level, but if your MMA is elevated B12 deficiency troubles are on the horizon. The real problem is that you’ll have to ask for an MMA test without sounding like a smartass who’s been spending too much time on the internet

What causes B12 deficiency?
The list of causes is lengthy, but by far the most common is dietary. Vegetarians who aren’t paying attention to the B12 in their food choices will have downward-drifting B12 levels, and virtually all vegans not taking vitamin B12 supplements ultimately develop deficiencies. Even vegan organizations acknowledge it’s not possible to get adequate B12 while following a strictly vegan diet, and that’s because the richest sources are animal products.

Other causes of B12 deficiency include pernicious anemia, an uncommon (and spookily named) autoimmune disease that destroys parietal stomach cells. These cells produce a substance called intrinsic factor, necessary for B12 absorption. Also, since you need stomach acid to absorb B12, long-term use of acid-suppressing proton pump inhibitors (such as Nexium, etc.) can lead to B12 deficiency, as can chronic intestinal conditions such as Crohn’s disease, celiac disease, and intestinal parasites.

The missed diagnosis
The main danger of missing a diagnosis of low B12 is that, while quite rare, the damage to your nerves and even brain can be permanent. Other serious consequences: your anemia can get so severe it causes heart failure and collapse. Or you could be misdiagnosed with a major depressive disorder or even psychosis and take unneeded psychiatric medications for months (or years) before someone notices you look yellowish and you’re finally diagnosed with megaloblastic anemia.

There are three reasons why this diagnosis is missed:

  1. Although it’s not an expensive test, B12 isn’t measured during routine blood tests. Doctors generally don’t order a B12 evaluation if there’s no evidence of anemia (which would be picked up on a routine blood test). However, the fatigue and nervous system and GI symptoms can precede anemia by months.
  1. Doctors rarely ask (and patients rarely volunteer) information about their eating habits. In medical school, we’re taught that the US diet is plenty good enough to prevent any vitamin deficiencies. To which I now respond, “Ha!” I agree most of us eat plenty of food (obesity levels are still on the rise), but it’s often food whose nutritional value has been castrated. Also, all vegetarians and vegans should be regularly tested for possible B12 deficiency, but if your doc doesn’t know your eating habits you won’t be tested.
  1. Taking the B vitamin folic acid (folate) or eating a lot of folate-containing foods without adding B12 can actually mask the symptoms of a developing B12 deficiency. Although folate will keep your blood count normal even if your B12 is falling, the folate will not protect your brain and nervous system. You’ll have no evidence of megaloblastic anemia (because of the folate), but symptoms of numbness, tingling, balance problems, and emotional issues will continue unchecked. By eating so many folate-containing green vegetables, beans, and lentils, vegetarians and vegans inadvertently mask their own slowly developing B12 deficiency.

Treatment is easy
It’s virtually impossible to take too much B12 as any excess of this water-soluble vitamin is eliminated via urine. Nutritional guru Alan Gaby, MD, has commented that the only way too much B12 will kill you is if you fill your bathtub with it and drown.

Foods high in B12 are animal products: meat, poultry, seafood, dairy, and eggs, with eggs having the least. Because all animals store B12 in their livers, eating liver is an excellent, though not particularly popular, treatment for B12 deficiency. Your grandmother or great grandmother likely remembers a time when her doctor told someone in the family to eat more liver.

Although B12 injections have been used for decades as the fastest way to raise B12 levels, the latest research is saying that well chosen forms of oral B12 will probably work just as well. The Integrative Therapeutics product B12 Active is a chewable, cherry-flavored tablet containing 1,000 mcg of methylcobalamin. Taken daily, it generally restores B12 levels to a normal range in one month.

This brings up another confusing point. Most B12 in both injections and pills is called cyanocobalamin, which, yes indeed, does contain a totally nontoxic form of Agatha Christie’s favorite murder weapon, cyanide. But what’s the difference between the two? When it comes to raising your personal B12 levels, both work equally well. To be honest, the main reason for the prevalence of cyanocobalamin is cost. Totally synthetic, cyanocobalamin is cheap to make.

Methylcobalamin, the natural B12 form that your body actually prefers because it doesn’t have to detoxify the cyano part, is simply more expensive to manufacture. However, there is one completely new cyanocobalamin product worth mentioning. Eligen B12 (available by prescription) contains B12 combined with a carrier called salcaprozate that enhances B12 absorption into the stomach. B12 levels go up as quickly as they do with injections so you can avoid your doctor’s needles. However, I suspect Eligen B12 is not superior to the Integrative Therapeutics product mentioned above.

I think this all answers most of the questions and comments that followed my previous B12 article, but if you have more send them along.

Be well,
David Edelberg, MD


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40 comments on “B12 Deficiency: Still America’s #1 Missed Diagnosis
  1. Deb S says:

    Can you discuss the role of lithium, if any, in the absorption of B12 from blood plasma into cells? I was told that depending on their genetics, some people need more lithium or the B12 does not penetrate the cells and remains at high levels in the blood.

  2. Teresa Strong says:

    I have another story of how B12 deficiency can be missed. For a number of years, my doctors saw I had megoblastic anemia, but my b12 and folic acid were very high. It was finally discovered that I have MTHFR C677T genetic defect which can give you both B12 and folic acid deficiency while giving you high B12 and folic acid levels because your body cannot break down synthetic B12 and folic acid into useable forms.

  3. Irene Frederick says:

    Dr. E . . . Your articles are THE best… clearly understandable,
    with all the info needed so a person may incorporate a new plan of action, if they choose. I appreciate the time and energy you put into writing these articles . . . THANK YOU!!!!

  4. sam barbary says:

    Can you have a normal methymalonic acid level result which would indicate normal B-12 levela and still be B-12 deficient? I have heard that if one does not have the cofactors to synthesize B-12, symptoms of B-12 deficiency would still exist. So the real question is how do you know if you have the correct cofactors? Basically, you are deficient if your body cant absorb or sythesize it even though you consume enough B-12.

    Thank you


  5. Beth says:

    Dr. E, is salcaprozate still effective if someone’s intrinsic factor is depleted?

  6. Cathy says:

    Can low b12 cause hair loss? I had my colon removed and a jpouch made from the lower third of my small intestine due to ulcerative colitis. I

  7. Davis S. says:

    Teresa Strong, it sounds like I might be in the same boat as you. How are you treating your MTHFR situation…your whole situation in general? Thanks!

  8. Dr E says:

    Hi Debra
    The association between B12 and lithium is simply úncertain´at this point. An association is theoretically possible but not clinically evident.

    Hi Teresa
    Yours is a typical MTHFR story. If your doctor suspects B12 or folate deficiencies and the levels come back elevated, ask for an MTHFR test. If positive, you´ll need the methyl forms of both folate and B12 but you´ll need to start with low doses as you´ll be sensitive to the sudden rush as these nutritionals become available to your cells

    Hi Sam
    Basically, see the above note and get MTHFR testing.

    Hi Beth
    According to the published data, the answer to your question is ýes but look at the company´s website and as it is a small company, I suspect they´ll answer your question personally

    Hi Cathy
    The answer is ýes

    Dr E

  9. sam barbary says:

    Thank you , Doctor for your response. I’ll let you know what happens.


  10. Cheryl T says:

    If you have MTHFR you need to determine if you are an overmethylator or undermethylator. If you are an undermethylator you would take Methylcobalamin and methylfolate. If you are an overmethylator like I am you cannot take methyls. So I take Hydroxo B12 and folinic acid. I take a prescription called Leucovorin which is folinic acid.

  11. Kathleen pepsnik- good says:

    Thank you for what you do . You really are the healer
    People need. I pray for you – you are the best!!!!!

  12. Karen C says:

    I have been reading a lot about b12 deficiency and wonder if it can can cause hair loss? I had mine tested and it was around 450, but I do have other symptoms along with the hair loss.

  13. Dr E says:

    Hi Karen C
    Although low B-12 can cause hair loss, your level is okay and should not be the culprit. The three commonest causes of hair loss are: stress; underactive thyroid (even minimally underactive thyroid); low iron.
    Have your doctor run appropriate tests if these have not been done

  14. Robert S says:

    I actually have been taking Eligen B12, the product you mentioned, since late March, because of my pernicious anemia, which caused my B12 levels to sink as low as 200 at one point. Since my doctor put me on it in late March my levels have been consistently around 2000pg/ml! I had been taking OTC B12 sublingual 1000mg but because of my condition my doc told me I was not absorbing the B12 and passing most of it, so my levels had not been improving.

  15. Pearl M says:

    I’ve been to 3 major Chicago universities and then Mayo, all in the last 8 months.
    I’m getting sicker and sicker and have lost 26 lbs in the last 7 weeks.
    I’ve now learned my serum B12 is >2000 BUT my transcobalamin or B12 binding capacity is critically low at <88 (normal range 65-1340). Hematologist doesn't know what to do with me. Bone marrow biopsy two weeks ago came back normal

  16. Kathleen Hough says:

    There is a wonderful liquid vegan safe B12 product by Global Healing Center. it has 2500 mcg of B12 as 80% methylcobalamin, 20% adenosylcobalamin. I have been taking this for a couple of months and have seen increased energy, and no more brain fog.

    It is recommended by Anthony William, Medical Medium as one of the most imp. supplements. He has a book coming out this month you might want to consider.

  17. KS says:

    Hi. I had a strange event while driving a few weeks ago where I felt tingling in both hands (pinkies and thumbs), swimming vision (not blurry or fuzzy), weak knees/legs, and a flash of energy in my chest (without racing heart or pulse). For a few weeks before, I’ve had very negative thoughts (highly unusual for me, a very happy person). Symptoms are on-going and easing up (significantly after one session of acupuncture). Went to an integrative health cardiologist; EKG was normal. After researching your excellent site, I thought for sure this could be Vitamin B12 and/or D deficiency. Received blood test results today which are normal — no MTHFR mutation, B12 (623), D (300), TSH (2.05), T4 (5.4), T3 (83), Free T4 (0.98), Free T3 (2.31). Low omegas though (3.8). I have half my thyroid (no supplement) and stage IV endometriosis. Otherwise, “good” health. Ideas on what’s going on? Thank you.

  18. Dr E says:

    Hi KS
    All your numbers are indeed excellent. The abruptness of the symptoms and their quick resolution sounds most like a hypoglycemic episode (low blood sugar). Think about what you ate (or did not eat) that day and see if this is a possibility

  19. KS says:

    Thanks, Doc. I appreciate you taking the time to reply. It’s so odd, as the symptoms are intermittent across a few weeks now (although receding), with a burst of finger tingling (10 minute events occurring twice), sometimes accompanied by or followed by very anxious or negative thoughts. Never had a panic attack or reason for it (thankfully), but I wonder if that’s a cause for these symptoms over the past few weeks. I’ll keep a food log to watch the hypoglycemia angle too. Thanks again.

  20. Bev Dawn says:

    Hello Dr D.E.
    I really appreciate all your comments here it is very kind of you to take the time most sites ask for payment which I don’t have. I also thank those that pose the Q’s. It has made things a lot clearer. Even though I am still a little confused as to whether or not to have the injections my doc has said is the best and quickest way to bring my level back up or to ask if I could have the Eligin B12. I have read some reviews that patients say themselves…of being very unwell even wks and months after having the injections .. In fact all the same symptoms that I am having due to the lack of B12.. This I find very strange, one would think that these symptoms should / would be much less not worse! ( Or could it be that they are not absorbing the B12 from the injections?). On the other hand I read that the Eligin B12 is not as quick or as effective as the injections.
    I went for a pre op and they found my platelets low – 50 instead of 150. I then told them of all my symptoms which I put down to my poor / loss of appetite and age -62- Yet working and very active – family saying I was overdoing things. They took further blood test and said that everything was fine but for the B12 which was very low but did not give me a reading. Could you suggest … Injections or Oral.
    Kind Regards
    Bev 🙂 🙂

  21. P Marie says:

    Dr Edelberg
    Can you explain why my B12 level is over 2000, but my blood smear shows macrocytes and my MCV is 102 and the B12 binding capacity test is <80, done at Quest.

    My doctor says I'm not deficient because B12 is over 2000!

  22. Dr E says:

    Hi P Marie
    Actually there are several causes of macrocytosis and B-12 deficiency is only one of them. Most macrocytosis is harmless but it might be worthwhile consulting with a hematologist (blood specialist)

  23. P Marie says:

    I’ve seen two hematologist: one at Rush and one at Mayo. Mayo only was concerned about ruling out myeloprolific diseases, leukemias, etc.
    No one addressed my elevated MCV and macrocytes. RBCs on the low side.
    Been getting chest pressure. Cardiac ruled out.
    Also positive for the IFBA and MTHFR compound heterozygous.

  24. Jennifer says:

    Hello Dr Edelber,

    I found your article to be very enlightening. Have been suffering from a number if symptoms, but I find the breathlessness to be the most difficult to deal with. Lab results: MCV 98, MCH 32.6, MCHC 33.2, B12 206. Told there isn’t a problem with labs and referred for a sleep study. Have had lipid panel (all good), stress test (great results), but am wondering if I need to find a different doctor or if his advice seems within reason.

  25. Dr. R says:

    Hi Jennifer. Your B12 is in the low range of normal. We’d usually recommend oral supplementation to raise your levels.

  26. STam says:

    My 11 year old son has a history of fevers, infections, night terrors and anxiety. His immunologist ran several tests to rule out immune deficiency; these tests included a B12 binding Capacity test. His serum B12 was normal and his Folic Acid levels were high, the binding test also came back low. What are our next steps here – the immunologist told us to refer to our primary care doctor…..and they also are not sure what to do???!!

  27. Cecilia says:

    HI there, I have had low levels of b12 in the past and even had some neurological symptoms, which after ruling out others things via MRI etc the neurologist pointed to low B12 as the culprit (200s this was about 4 years ago). I have been having issues in my legs again (some burning, muscle cramping etc) and wanted to see if my levels were low again.Recently I have been taking b12 vitamins and wonder if this could somehow mask the blood results if I took a good amount of vitamins in the days leading up to the blood test? I asked about a MMA test and Homosystene test but my doc declined to do those unfortunately. My test last week read normal ( 700s)but I was taking the oral 5000 once daily in the few days leading up to it. I am a strict vegetarian and try to get all my vitamins through food clearly I have a history of running low. Just wondering if those other tests could indicate a deficiency even with a normal B12 serum? My hemoglobin was normal. Any suggestions or thoughts would be welcome. Thank you

  28. Dr E says:

    Hi Cecilia
    There are other causes for your symptoms than low B12. It sounds as if your neurologist is a good diagnostician. Tell him about these and let him choose what tests would be helpful

  29. Som says:

    After my annual exam, my b12 leve was 358, whihc is in range but on lower side. I am veggie, but do take dairy products daily. Doc advised to jsut take 1000mcg sublingual b12 supplement. I started taking it. but with 506 days I started getting weird sensation in my legs… its like sweetish pain/sensation/tingling…while walking its better but can feel more when resting bed. What is this?

  30. Dr. R says:

    Hi Som. There are many possible reasons for your symptoms. Speak with your primary care physician for re-testing of B12 as well as vitamin D, CBC, CMP, and thyroid panel. Hopefully, you’ll be able to uncover some additional clues.

  31. Som says:

    thanks. my vit D is low at 18 and so taking the booster weekly dose. thyroid is good (2.1). RBC WBS all are in range. Blood pressure/urine all are good. I never had these symptoms. Only began once I started with sublingual b12 (cyanocobalamin).

  32. Mary says:

    If you are still around–is Methylmalonic acid level always elevated in B12 deficiency? Diagnosed with B12 neuromyelopathy but my MMA has always been normal (lower end of normal to be exact). Thanks if you see this and answer.

  33. Dr E says:

    Hi Mary
    This may be due to you being in the third of patients who carry a gene called MTHFR. This is an easy test for your doctor to run and if you are ‘positive’ you may be taking the wrong form of B12, cobalamin instead of methylcobalamin. Discuss with your doctor

  34. Mary says:

    Also, does MMA return to normal in B12 shots?

  35. Alina J. says:

    Hi Dr. E,

    If you’re still active on this thread, I would highly appreciate your opinion on this.

    My husband has B12 deficiency, his levels are around 160.
    The doctor recommended B12 injections (50 mcg) once every month, but I wonder if that is the appropriate dosage since there’s been no improvement in his symptoms.
    He still has numbness and tingling in his hands and feet, fatigue, weakness in his legs.

    Also he has constant hip pain.. could this be related to the B12 deficiency? We went to the specialist for this issue and they said everything is fine, they don’t know where the pain could come from.

    Thank you!!

  36. Dr E says:

    His B12 dose is inadequate. He should be on 1,000 mcg injections every week until his blood level is between 900 and 1,000. He should be tested for failure to absorb B-12. The test is called Intrinsic Factor Antibody. If it is positive, once his levels are normal, he will need monthly injections for life.
    The symptoms are most likely B12 deficiency but may take weeks to months to resolve even if blood levels return to normal

  37. Nancy says:

    Hi Dr,
    I had a 313 b-12 serum, but with symptoms. I convinced my Dr to order the MMA and Homosysteine and the MMA was (493) and the Homosysteine was just 1 point over the high limit for the lab. I am still waiting on the IF factor results. Doctor has yet to speal with me, but am I still considered deficient if the homosysteine is just 1 point over high? These symptoms started 3 years ago and more symptoms have come up and gotten worse.

  38. Dr E says:

    You are B12 deficient and you would likely benefit from B12 injections

  39. Hi Dr. Edelberg!
    I’m a new practicing provider (just graduated with my DNP from Rush actually 🙂 and was wondering if you could help me with a new patient case?
    – Pt is 32yo F with extensive PMH who presents with 8 month hx of pain, numbness & tingling in her BLE, and recently has worsened constant sensation of cold feet as well as worsening numbness causing periodic falls during her normal daily activity. Other medical hx includes (not limited to): fatigue, HA, IBS, vertigo, GERD, Back pain, Iron def anemia, constipation, adrenal insufficiency..
    Historically w/her chronic back pain, I ordered lumbar and c spine xrays, both normal besides mild degenerative disc space changes to c5-6.
    I then ordered an EMG- normal, no evidence of radiculopathy ,plexopathy, or mononeuropathy. Motor recruitment and units all normal.

    -Recent (limited) blood work 2/2019 :
    B12 binding capacity-636
    Hct 34.5 ( noticed this is the only CBC value consistently low for pt in past 5-6 yrs)
    All other values for CBC, TSH, Free T4, Iron, and Ferritin normal.
    In 2/2018 Folate- 16.8 & B12-640

    I will seeing this patient again soon for further workup, and the lab tests I’m thinking about around are:
    CMP, Vit D, Folic acid, ESR, Methylmalonic acid, serum homocysteine, IF antibody

    I’d SO appreciate your time and thoughts. Do you have any suggestions or corrections to those labs listed and/or my diagnostic workup-train of thought? (I want to make sure my ordered tests are appropriate and not ‘overboard’) Very curious to hear your input! Thanks Dr. E!

  40. Dr E says:

    Hi Molly
    Did you actually send that at 2AM?!
    For a female in that age group with”unexplained” neuro symptoms, MS needs to be considered. I suggest consulting with a neurologist. Over at Rush, you’ve got the best MSspecialists in the Midwest

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