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B12 Deficiency

Tom Deloughery, MD and Rob Orman, MD

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B12 deficiency is common yet often misunderstood. Hematologist Tom Deloughery gives his opinion on testing, etiology, and management.



  • The best screening test for vitamin B12 deficiency is a methylmalonic acid (MMA)level.

  • An elevated MMA level is indicative of vitamin B12 deficiency.

  • Vitamin B12 deficiency is almost always due to a failure to absorb.  Underlying causes include pernicious anemia, atrophic gastritis, bariatric surgery, and the use of metformin or PPIs.

  • The best treatment of B12 deficiency is once daily dosing of 1000 micrograms of oral vitamin B12.


  • Should evaluation for vitamin B12 deficiency be considered for a patient with fatigue?  Yes, this is reasonable.

    • Subtle vitamin B12 deficiency is becoming more common, largely because so many people are taking proton pump inhibitors or H2 blockers.  Another cause of B12 deficiency is metformin use.  

  • How real is vitamin B12 deficiency?  If a patient is asymptomatic with a low B12 level, is treatment necessary?  The answer to this is debatable.

    • Dr. Deloughery believes that since vitamin B12 deficiency is simple to treat with supplementation and symptoms can be severe (namely anemia and neuropathy), it is best to initiate treatment before the patient is symptomatic.

    • If a patient is only experiencing fatigue and his/her B12 level is low, it is reasonable to correct the deficiency and see what happens, without guaranteeing that the treatment will be curative.

  • What are the best screening test for vitamin B12 deficiency?  A methylmalonic acid level.

    • The most accurate test for B12 deficiency is a methylmalonic acid (MMA)level.

    • Vitamin B12 is needed to convert methylmalonic acid to succinyl-CoA.  If tissues are lacking in B12, methylmalonic acid accumulates in the blood.

    • One of the nice things about the MMA test is that the level reflects what’s going on in the tissues.  

    • It is difficult to directly measure vitamin B12 in the blood, in part because it is bound to several proteins -- transcobalamin I and transcobalamin II.  Only about 10% of that is physiologically relevant.   

    • In addition, vitamin B12 levels fluctuate for many reasons, including due to the presence of estrogen, old age, use of birth control, pregnancy, and inflammation.

    • For older patients, the presentation of B12 deficiency is typically a low but normal B12 level and sky-high MMA level.

    • Most reference labs are performing MMA levels and they’re usually price competitive with vitamin B12 levels.  

  • When should one worry about a test result for vitamin B deficiency?  Does the cutoff vary depending on the patient’s age?

    • A high MMA level correlates with vitamin B12 deficiency.

    • The cutoff for B12 deficiency is either a MMA level of 0.4 mmol/L or 400 (nmol/L), depending on the units used by the individual lab.  

    • Since patients who are older or have renal disease can accumulate MMA, Deloughery will usually correct for that and not be concerned unless the MMA level is greater than 500 or 600 nmol/L.

    • Any MMA level greater than 1.0 mmol/L or 1000 nmol/L is  significant and warrants treatment.

  • How does a patient’s age affect consideration of the cause of vitamin B12 deficiency? Yes.

    • Vitamin B12 deficiency is almost always due to a failure to absorb.

    • For younger patients, diet is often the culprit.  Strict vegan patients who eat no milk, cheese or eggs for 6 years can develop B12 deficiency.  Pernicious anemia is another cause in this age group.

    • Most often, older patients become vitamin B12 deficient due to atrophic gastritis which leads to poor absorption.

    • Patients of any age who have had bariatric surgery are unable to absorb vitamin B12 and will require B12 replacement through injection.

    • In Alaska or the upper midwest where raw fish consumption is common, vitamin B12 deficiency can be caused by the tapeworm Diphyllobothrium latum.

  • When is the Schilling test helpful?  Almost never.

    • The purpose of the Schilling test is to determine if a patient has pernicious anemia.

    • The test is cumbersome to perform and requires a 24 hour urine collection.  Since there are easier ways to diagnose autoimmune diseases, such as by measuring antibodies to parietal cells or intrinsic factor, Deloughery rarely finds the Schilling test to be helpful.  

      • The test is performed by giving the patient an injection of B12 to block any B12 binding the sites.  Then the patient is given radiolabelled vitamin B12 to eat.  Since the binding sites are blocked, any B12 that is absorbed will be excreted.  Vitamin B12 absorption is determined by measuring the amount of radioactive B12 excreted in the urine.

  • If an elderly patient with vitamin B12 deficiency is suspected of having atrophic gastropathy, is an endoscopy necessary to verify this diagnosis?  No.

    • If the patient is otherwise asymptomatic with no other reason for endoscopy, an endoscopy is not required.  Deloughery recommends just repleting the patient with B12.

  • What tests are helpful in diagnosing pernicious anemia?

    • Pernicious anemia is caused by the failure of gastric parietal cells to make enough intrinsic factor to allow the absorption of dietary vitamin B12.  This can be caused by an autoimmune condition in which the body’s immune system attacks intrinsic factor protein or the parietal cells that produce it.

    • Two tests are used to make this diagnosis:

      • Parietal cell antibodies are specific for pernicious anemia.

      • Intrinsic factor antibodies are more sensitive for the diagnosis of pernicious anemia.

  • Which prescribed medications can impair vitamin B12 absorption?

    • Metformin and proton pump inhibitors are the two drugs which most significantly lower B12 absorption.  

    • Estrogen, pregnancy and oral contraceptives lower the B12 level, but don’t affect true B12 physiology.  While the patients may have low B12 levels, their MMA levels are normal.

  • What is the best way to replace vitamin B12?  Oral is just as good as the subcutaneous or intramuscular route.

    • A trial compared oral to intramuscular B12 replacement, and after 3 months the oral group had lower MMA and higher B12 levels.

    • Most vitamin B12 tablets contain 1000 micrograms of B12.  The daily requirement is only 6-12 micrograms.  For patients with pernicious anemia or atrophic gastritis, you can overwhelm the system and absorb B12 despite an impairment of parietal cells or intrinsic factor.  B12 can be absorbed in sufficient quantities nonspecifically, through mass action.

    • Patients who receive a 1000 microgram intramuscular injection of B12 will excrete 90% of it in the urine the following day.

    • Unless a patient adamantly wants to continue B12 injection therapy, oral therapy is best for virtually everyone.

  • What dose of oral vitamin B12 is recommended?  1000 micrograms.

    • Deloughery prescribes 1000 micrograms for everyone, since this dose is (ironically) less expensive than the 500 micrograms tablets.  

    • Taking a higher dose, or more than may be necessary, is not known to cause toxicity.

    • The pills are better tolerated when taken with food.

  • Do cyanocobalamin and methylcobalamin differ in bioavailability ?  No

    • The two agents are equally absorbed.  Deloughery is pragmatic and recommends taking whichever is the cheapest.

  • Once a patient is deemed vitamin B12 deficient and is started on oral therapy, can the treatment ever be stopped?  

    • In general, a patient who has been deficient before will be deficient again.  Deloughery thinks it is reasonable for most patients to continue lifelong treatment.

    • An exception might be someone who discontinued use of a PPI or metformin which was thought to be the cause of deficiency.

  • Are there foods that are so rich in vitamin B12 that they could be eaten rather than taking the vitamin in pill form?

    • While some foods such as yeast are rich in B12, by taking the pill form and overwhelming the absorptive system with a large dose, one is virtually guaranteed to adequately replenish the stores.

  • Do patients with vitamin B12 deficiency typically have anemia?  

    • Patients with B12 deficiency present in one of two ways:  

      • with classic anemia and only very subtle neurologic disease, or

      • with severe neurologic disease but a fairly normal complete blood count.

    • The CBC is not a good screening test for B12 deficiency.  If this disease is suspected, a MMA level should be checked.

Monica P. -

Could anyone post the reference for that B12 article comparing oral vs intravenous

Heidi J., MD -

Hi! This was an eye-opening segment - Thanks!
I have a question from the Canadians. I've spoken with several family docs across the country, and our access to MMA is spotty at best. I called our lab to see if I could order it as a FP because I'd never seen it on a req and some tests are restricted to consultant use. The lab said "yes, but please don't, it's about $100". In some provinces, patients have to pay out of pocket for this test, in the $100-250 range. So here it the question....Is MMA really that much better than B12 for diagnostics purposes and is it truly cost- competitive? If so, do you have some sources we could cite when we petition our lab medicine colleagues/health authorities to make MMA testing more accessible to primary care docs and their patients?

Thanks in advance!

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The Allergy That Isn't and the B-12 That Is Full episode audio for MD edition 183:18 min - 86 MB - M4AHippo Primary Care RAP February 2016 Summary 735 KB - PDF