Is oral vitamin B₁₂ therapy effective?

An 88-year-old Scandinavian man is seen for weakness and fatigue. Physical examination reveals a normal mental status and evidence of bilateral lower-extremity neuropathy. His hematocrit is 24%, with a hemoglobin of 8 g/dL and a mean corpuscular value of 118 fL. The serum cobalamin level is 64 pg/mL (normal >200 pg/mL), and the plasma methylmalonic acid level is high. A diagnosis of pernicious anemia is made.

What do you recommend for treatment?

A) Intramuscular hydroxycobalamin 1,000-mcg load daily for 1 week, then 1,000 mcg monthly.

B) Intramuscular hydroxycobalamin 1,000 mcg monthly.

C) Vitamin B₁₂ 1,000 mcg orally.

Myth: Replacement of vitamin B12 deficiency because of pernicious anemia must not be done orally.

For decades, it has been taught that vitamin B₁₂ deficiency in patients with pernicious anemia is due to poor B₁₂ absorption caused by a lack of intrinsic factor, and that replacement must be given intramuscularly.

This belief was presented in the following statement of the USP Anti-Anemia Preparations Advisory Board: “In the management of a disease for which parenteral therapy with vitamin B₁₂ is a completely adequate and wholly reliable form of therapy, it is unwise to employ a type of treatment which is, at best, unpredictably effective” (JAMA 1959;171:2092-4).

This belief is still being propagated, as this quote from an article published recently attests: “Pernicious anemia is caused by inadequate secretion of gastric intrinsic factor necessary for vitamin B₁₂ absorption and thus cannot be treated with oral vitamin B₁₂ supplements; rather, vitamin B₁₂ must be administered parenterally” (Autoimmun. Rev. 2014;13:565-8).

Studies dating back to the 1950s showed that B₁₂ could be absorbed orally in patients with pernicious anemia, and that two mechanisms of absorption of B₁₂ exist: one involving intrinsic factor and one that does not (J. Clin. Invest. 1957;36:1551-7; N. Engl. J. Med. 1959;260:361-7). The earliest studies of vitamin B₁₂ used low doses of vitamin B₁₂, and some of the studies also used oral intrinsic factor. These studies failed to show adequate vitamin B₁₂ absorption.

In the early 1960s, several studies showed that oral replacement with vitamin B₁₂ could lead to correction of anemia (Acta Med. Scand. 1968;184:247-58; Arch. Intern. Med. 1960;106:280-92; Ann. Intern. Med. 1963;58:810-17). When doses of cyanocobalamin 300 mcg or greater were used, normalization of serum B₁₂ levels was readily achievable. In one study, 64 patients receiving 500 mcg or 1,000 mcg of B₁₂ orally daily for pernicious anemia all had normal serum B₁₂ levels, normalization of hemoglobin levels, and no neurologic complications at follow-up through 5 years.

In a dose-finding trial in elderly patients with B₁₂ deficiency, doses of 500 mcg or more were needed to normalize mild vitamin B₁₂ deficiency (Arch. Intern. Med. 2005;165:1167-72) Using very high doses of daily oral vitamin B₁₂ (1,000-2,000 mcg) leads to blood levels of vitamin B₁₂ as high or higher than are achieved with monthly intramuscular administration of vitamin B₁₂ (Acta Med. Scand. 1978;204:81-4; Blood 1998;92:1191-8; Cochrane Database Syst. Rev. 2005;3:CD004655).

The cost of vitamin B₁₂ replacement is comparable orally and parenterally. The cost of 100 tablets of 1,000 mcg of vitamin B₁₂ is about $5-$10. Ten doses of B₁₂ for injection (1,000 mcg) is about $15, but charges for administration either by clinic personnel or a visiting nurse dramatically increase the monthly cost. If patients are able to give themselves the B₁₂ injection, the additional cost is the cost of the monthly syringe, needle, and alcohol wipes.

Given the evidence and the costs, why is oral vitamin B₁₂ not widely used for replacement?

Most physicians do not believe that vitamin B₁₂ can be replaced orally. In a survey of internists, 94% were not aware of an available, effective oral therapy for B₁₂ replacement (JAMA 1991;265:94-5). In the same survey, 88% of the internists stated that an oral replacement form of B₁₂ would be useful in their practice. These data are more than 20 years old, but physician knowledge in this area is slow to develop. When I lecture on the topic of medical myths and poll the audience about B₁₂ replacement, 60%-80% still recommend intramuscular replacement instead of oral replacement.

This myth combines several features seen in medical myths.

First, it makes some sense from a pathophysiologic standpoint, as intrinsic factor is needed to absorb the small amounts of vitamin B₁₂ in our usual diets. It is easy to understand why one would think that without intrinsic factor, vitamin B₁₂ couldn’t be absorbed and would require intramuscular replacement.

In addition, the studies that refuted the myth were published at a time when high-dose oral vitamin B₁₂ was not available in the United States, so oral replacement did not become standard practice.