CLINICAL INQUIRIES

From the Family Physicians Inquiries Network

How do we evaluate a marginally low B₁₂ level?

Department of Family and Community Medicine, University of Missouri–Columbia School of Medicine

WISE—Women in Science and Engineering, University of Iowa

  Evidence Summary

A low-normal B₁₂ level is 150 to 350 pg/mL. Levels less than 150 pg/mL indicate deficiency. Levels greater than 350 pg/mL indicate adequate B₁₂ supply.²

Vitamin B₁₂ is a necessary coenzyme in the metabolism of methylmalonic acid to succinyl choline, and is also a necessary coenzyme with folate in the metabolism of homocysteine to methionine. Therefore, a vitamin B₁₂ deficiency leads to elevated levels of unmetabolized methylmalonic acid and homocysteine. At a local lab the normal range of methylmalonic acid is 0.00 to 0.40 umol/L, and homocysteine’s normal range is 4.0 to 10.0 mmol/L. Normal levels might vary by laboratory. Other conditions, such as renal insufficiency, may also cause elevation of methylmalonic acid and homocysteine.³

Holotranscobalamin may become a first-choice assay for diagnosing early vitamin B₁₂ deficiency. Studies have shown that it compares favorably with current combined measures (B₁₂ levels, methylmalonic acid, homocysteine). Like current assays, holotranscobalamin is also affected by renal function. It requires further investigation to establish relevant cutoff levels before it can be recommended as a diagnostic strategy.⁴

Oral vitamin B₁₂ at doses of 1000 to 2000 mcg/d is a simple and cost-effective treatment option for any B₁₂-deficient person, and may actually be superior to intramuscular replacement.^5,6 A Cochrane Collaboration review of oral vitamin B₁₂ replacement found that these high doses seemed as effective as intramuscular vitamin B₁₂ in all B₁₂-deficient patients—even those with pernicious anemia, Crohn’s disease, ileal resection, or malabsorption states. The authors of the review recommend a “further large, pragmatic trial in a primary care setting” to determine whether oral vitamin B₁₂ is effective for patients with major common cases of malabsorption and to provide additional evidence for cost effectiveness.⁶

Recommendations from Others

Current guidelines recommend giving vitamin B₁₂ if methylmalonic acid or both methylmalonic acid and homocysteine are elevated. Give folate if only homocysteine is elevated. Give vitamin B₁₂ if homocysteine elevation persists in spite of adequate folate replacement.²

Monitor for correction of low-normal B₁₂ and metabolites with follow-up blood test after 1 to 2 months of treatment. The negative predictive value of normal metabolites (methylmalonic acid and homocysteine) is unknown.

Individuals with normal vitamin B₁₂ levels and metabolites but significant B₁₂ deficiency signs and symptoms have responded dramatically to B₁₂ replacement.⁷ Therefore, it is reasonable to treat and monitor for response as an alternative approach to the evaluation of a low-normal B₁₂ level. Pennypacker et al² state that “the ultimate gold standard for vitamin B₁₂ deficiency may be the reduction in homocysteine and methylmalonic acid concentrations and improvement in clinical symptoms or signs in response to vitamin B₁₂ treatment.”

The views expressed in this abstract/manuscript are those of the author(s) and do not reflect the official policy or position of the Department of the Army, Department of Defense, or the US Government.

REFERENCES

1. Clarke R, Refsum H, Birks J, et al. Screening for vitamin B-12 and folate deficiency in older persons. Am J Clin Nutr 2003;77:1241–1247.
2. Pennypacker LC, Allen RH, Kelly JP, et al. High prevalence of cobalamin deficiency in elderly out-patients. J Am Geriatr Soc 1992;40:1197–1204.
3. Hvas AM, Juul S, Gerdes LU, Nexo E. The marker of cobalamin deficiency, plasma methylmalonic acid, correlates to plasma creatinine. J Intern Med 2000;247:507–512.
4. Hvas AM, Nexo E. Holotranscobalamin—a first choice assay for diagnosing early vitamin B deficiency? J Intern Med 2005;257:289–298.
5. Kuzminski AM, Del Giacco EJ, Sllen RH, Stabler SP, Lindenbaum J. Effective treatment of cobalamin deficiency with oral cobalamin. Blood 1998;92:1191–1198.
6. Vidal-Alaball J, Butler CC, Cannings-John R, et al. Oral vitamin B12 versus intramuscular vitamin B12 for vitamin B12 deficiency. Cochrane Database Syst Rev 2005;(3):CD004655.
7. Solomon LR. Cobalamin-responsive disorders in the ambulatory care setting: unreliability of cobalamin, methylmalonic acid, and homocysteine testing. Blood 2005;105:978–985.

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