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How do we evaluate a marginally low [B.sub.12] level?


The best way to evaluate a low-normal [B.sub.12] level is to check serum methylmalonic acid and homocysteine levels (1) (strength of recommendation [SOR]: B, based on consistent level 2 or 3 studies). Give 1 or 2 mg of oral vitamin [B.sub.12] a day if levels are marginally low and either methylmalonic acid or both methylmalonic acid and homocysteine are elevated (SOR: A).


When faced with low-normal serum [B.sub.12], either further evaluation or empiric treatment is warranted

With the advent of methylmalonic acid, homocysteine testing, and the proven efficacy of oral [B.sub.12], medicine has come a long way from Shilling tests and monthly intramuscular shots in the diagnosis and management of [B.sub.12] deficiency. "Normal" serum [B.sub.12] may not accurately reflect true tissue [B.sub.12] stores. Therefore, if serum [B.sub.12] is borderline low, I routinely get methylmalonic acid and homocysteine for patients in whom I need to "prove" deficiency (for myself, patients, or third-party agents) or monitor closely (ie, those with neurologic symptoms).

Once deficiency is confirmed, search for a cause. Since 1000 mcg of oral [B.sub.12] treats nearly all causes of [B.sub.12] deficiency (including pernicious anemia and deficiency from gastric bypass surgery), empiric treatment is a reasonable alternative as long as serum [B.sub.12] and symptoms are monitored for therapeutic response. Bottom line: since early detection and treatment could potentially prevent permanent neurologic sequelae, when faced with a low-normal serum [B.sub.12], it should not be dismissed as "normal"--either further evaluation or empiric treatment is warranted.

Robert C. Oh, MD, MPH

Tripler Army Medical Center, Honolulu, Hawaii

* Evidence Summary

A low-normal [B.sub.12] level is 150 to 350 pg/ mL. Levels less than 150 pg/mL indicate deficiency. Levels greater than 350 pg/mL indicate adequate [B.sub.12] supply. (2)

Vitamin [B.sub.12] 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 [B.sub.12] 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 [B.sub.12] deficiency. Studies have shown that it compares favorably with current combined measures ([B.sub.12] 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 [B.sub.12] at doses of 1000 to 2000 mcg/d is a simple and cost-effective treatment option for any [B.sub.12]-deficient person, and may actually be superior to intramuscular replacement. (5,6) A Cochrane Collaboration review of oral vitamin [B.sub.12] replacement found that these high doses seemed as effective as intramuscular vitamin [B.sub.12] in all [B.sub.12]-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 [B.sub.12] 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 [B.sub.12] if methylmalonic acid or both methylmalonic acid and homocysteine are elevated. Give folate if only homocysteine is elevated. Give vitamin [B.sub.12] if homocysteine elevation persists in spite of adequate folate replacement. (2)

Monitor for correction of low-normal [B.sub.12] 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 [B.sub.12] levels and metabolites but significant [B.sub.12] deficiency signs and symptoms have responded dramatically to [B.sub.12] replacement. (7) Therefore, it is reasonable to treat and monitor for response as an alternative approach to the evaluation of a low-normal [B.sub.12] level. Pennypacker et al (2) state that "the ultimate gold standard for vitamin [B.sub.12] deficiency may be the reduction in homocysteine and methylmalonic acid concentrations and improvement in clinical symptoms or signs in response to vitamin [B.sub.12] 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.


If serum vitamin [B.sub.12] is low, check homocysteine and methylmalonic acid levels; monitor patients with neurolooic symptoms


(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 outpatients. 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, Allen 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.

David D. Cravens, MD, MSPH, CMD

Department of Family and

Community Medicine, University of Missouri-Columbia School of Medicine

Joan Nashelsky, MLS

WISE--Women in Science and Engineering, University of Iowa
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Title Annotation:CLINICAL INQUIRIES: From the Family Physicians Inquiries Network
Author:Cravens, David D.; Nashelsky, Joan
Publication:Journal of Family Practice
Geographic Code:1USA
Date:Jan 1, 2007
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