Treating Vitamin B12 Deficiency: What Formulation Is Best?

Douglas S. Paauw, MD

Disclosures

March 09, 2020

Oral B12: A Cheap, Effective Choice

The Schilling test measures cobalamin absorption by assessing increased urine radioactivity after an oral dose of radioactive cobalamin. It is not readily available in most countries , however, so a measure of serum vitamin B12 levels is the test of choice in most institutions.

Blood transfusions are rarely required in patients with B12 deficiency. Response to B12 replacement typically occurs within a few days of initiating treatment. This makes it unnecessary to subject the patient to the hazards of blood transfusion.

Since the defect is one of absorption, replacement should be administered parenterally, specifically in the form of intramuscular cyanocobalamin (if intramuscular administration is contraindicated or refused, cobalamin deficiency can be managed by oral replacement therapy, at doses of 300 to 1000 mcg daily, it is an expensive mode of treatment which requires close medical supervision to avoid relapse).
Harrison's Textbook of Medicine (13th ed); 1994.

Pernicious anemia is now more accurately recognized as megaloblastic anemia resulting from vitamin B12 deficiency due to lack of intrinsic factor (IF). Historically, we were taught that pernicious anemia was an absorption defect requiring parenteral replacement of B12. Oral replacement therapy could be used for the rare patient but it was a decidedly distant second option.

The research underpinning the recommendation for parenteral B12 as the first-line therapy dates back to the 1940s. Knowing that IF is required for the gut absorption of B12 from dietary sources, researchers combined small oral doses of B12 (6-150 µg) with animal-derived IF. Although this strategy was effective in promoting the absorption of B12, the small vitamin doses used weren't sufficient to raise serum B12 levels in deficient patients. Investigators assumed that the case was closed and parenteral B12 remained the treatment of choice.

However, a second physiologic mechanism known as "mass action," which had not been recognized at the time, offered an alternative. Mass action is triggered by very large doses (1000 µg) of oral B12. Because they exceed the capacity of available IF, such large amounts of B12 are poorly absorbed but the huge gradient permits enough B12 absorption to meet the body's requirement for B12.

The mass-action strategy wasn't tested until 1968, when a multicenter study of oral B12 replacement was published in Scandinavia, a part of the world with a higher incidence of B12 deficiency.

In that study, 64 patients with known B12 deficiency received 500-1000 µg of oral B12 daily. Over the 5-year observation period, all of the participants' serum B12 levels, as well as their hemoglobin and hematocrit levels, returned to normal. None of the patients developed neurologic or hematologic abnormalities due to B12 deficiency.

While the results of this admittedly small study led to widespread adoption of oral therapy in Sweden, they did not change practice in the United States. In fact, that study just got lost in the literature for the next 30 years.

Finally, another small study, conducted in the United States among 38 newly diagnosed B12-deficient patients, confirmed the earlier findings from Sweden. In the US study, patients were randomly assigned to receive 2000 µg of oral cyanocobalamin daily for 4 months or 1000 µg of IM cyanocobalamin given as a loading dose over the first month and then every 30 days until the conclusion of the 4-month study. Both treatments were equally effective. The oral regimen resulted in serum cobalamin concentrations that were more than three times greater than those obtained with the parenteral schedule.

The issue was finally put to bed with the publication of a Cochrane review in 2018. While the evidence was deemed to be of low quality, the Cochrane reviewers concluded that oral and IM vitamin B12 were similarly effective in normalizing serum B12 levels.

The lessons learned about use of oral preparations of B12 can be extended to other clinical scenarios. B12 deficiencies are common complications post-gastrectomy. A small study of patients followed for a mean period of 65 months after total gastrectomy concluded that oral supplementation is effective and safe in patients and should be the preferential form used.

One other factor, emphasized by the Cochrane reviewers, further tips the scales toward oral replacement: Oral B12 is substantially less expensive than parenteral B12. Currently, oral B12 costs between $2 and $5 per month. And the oral preparation is a lot easier for the patient. Perhaps now the case really is closed.

Douglas S. Paauw, MD, is the Rathmann Family Foundation Endowed Chair in Patient-Centered Clinical Education and a professor of general internal medicine at the University of Washington. He was elected to Mastership in the American College of Physicians (ACP) in 2009. He is a frequent lecturer at the ACP annual meeting, presenting yearly standing-room-only lectures on drug interactions and medical myths.

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