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.

Finally, the earliest studies on oral vitamin B₁₂ replacement using low doses of vitamin B₁₂ were failures, which gave evidence to the thinking that the only way vitamin B₁₂ could be replaced would be via parenteral administration.

Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington Medical School. He is the Rathmann Family Foundation Chair in Patient-Centered Clinical Education. Contact Dr. Paauw at [email protected].

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.

Finally, the earliest studies on oral vitamin B₁₂ replacement using low doses of vitamin B₁₂ were failures, which gave evidence to the thinking that the only way vitamin B₁₂ could be replaced would be via parenteral administration.

Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington Medical School. He is the Rathmann Family Foundation Chair in Patient-Centered Clinical Education. Contact Dr. Paauw at [email protected].

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.

Finally, the earliest studies on oral vitamin B₁₂ replacement using low doses of vitamin B₁₂ were failures, which gave evidence to the thinking that the only way vitamin B₁₂ could be replaced would be via parenteral administration.

Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington Medical School. He is the Rathmann Family Foundation Chair in Patient-Centered Clinical Education. Contact Dr. Paauw at [email protected].