How Do We Evaluate a Marginally Low B12 Level?

From the Clinical Inquiries Family Physicians Inquiries Network

David D. Cravens, MD, MSPH, CMD How do we evaluate Department of Family and Community Medicine, University of Missouri–Columbia School a marginally low B12 level? of Medicine Joan Nashelsky, MLS e v i d e n c e - b a s e d a n s w e r WISE—Women in Science and Engineering, University of Iowa The best way to evaluate a low-normal 1 or 2 mg of oral vitamin B12 a day

B12 level is to check serum methylmalonic if levels are marginally low and either acid and homocysteine levels1 (strength of methylmalonic acid or both methylmalonic recommendation [SOR]: B, based acid and homocysteine are elevated on consistent level 2 or 3 studies). Give (SOR: A).

c l i n i c a l ®c oDowden m m e n t a r yHealth Media

When faced with low-normal serum B12, Once deficiency is confirmed, search for Copyrighteither further evaluation a cause. Since 1000 mcg of oral B treats For personal use only 12 or empiric treatment is warranted nearly all causes of B12 deficiency (includ- With the advent of methylmalonic acid, ing pernicious anemia and deficiency from homocysteine testing, and the proven gastric bypass surgery), empiric treatment

efficacy of oral 12B , medicine has come a is a reasonable alternative as long as

long way from Shilling tests and monthly serum B12 and symptoms are monitored intramuscular shots in the diagnosis and for therapeutic response. Bottom line:

management of B12 deficiency. “Normal” since early detection and treatment could

serum B12 may not accurately reflect true potentially prevent permanent neurologic

tissue B12 stores. Therefore, if serum B12 is sequelae, when faced with a low-normal

borderline low, I routinely get methylma- serum B12, it should not be dismissed as lonic acid and homocysteine for patients “normal”—either further evaluation or in whom I need to “prove” deficiency (for empiric treatment is warranted. myself, patients, or third-party agents) or

monitor closely (ie, those with neurologic Robert C. Oh, MD, MPH symptoms). Tripler Army Medical Center, Honolulu, Hawaii

æ Evidence Summary of homocysteine to methionine. Therefore,

A low-normal B12 level is 150 to 350 pg/ a vitamin B12 deficiency leads to elevated mL. Levels less than 150 pg/mL indicate levels of unmetabolized methylmalonic deficiency. Levels greater than 350 pg/mL acid and homocysteine. At a local lab the 2 indicate adequate B12 supply. normal range of methylmalonic acid is

Vitamin B12 is a necessary coenzyme 0.00 to 0.40 umol/L, and homocysteine’s in the metabolism of methylmalonic acid normal range is 4.0 to 10.0 mmol/L. Nor- to succinyl choline, and is also a necessary mal levels might vary by laboratory. Other coenzyme with folate in the metabolism conditions, such as renal insufficiency, may

62 vol 56, No 1 / january 2007 The Journal of Family Practice

For mass reproduction, content licensing and permissions contact Dowden Health Media. also cause elevation of methylmalonic acid ment.7 Therefore, it is reasonable to treat and homocysteine.3 and monitor for response as an alterna- Holotranscobalamin may become a tive approach to the evaluation of a low- 2 first-choice assay for diagnosing early vi- normal B12 level. Pennypacker et al state tamin B12 deficiency. Studies have shown that “the ultimate gold standard for vi- that it compares favorably with current tamin B12 deficiency may be the reduc- combined measures (B12 levels, methylma- tion in homocysteine and methylmalonic lonic acid, homocysteine). Like current as- acid concentrations and improvement in says, holotranscobalamin is also affected clinical symptoms or signs in response to by renal function. It requires further inves- vitamin B12 treatment.” tigation to establish relevant cutoff levels before it can be recommended as a diag- 4 nostic strategy. references 1. Clarke R, Refsum H, Birks J, et al. Screening for Oral vitamin B12 at doses of 1000 to vitamin B-12 and folate deficiency in older persons. 2000 mcg/d is a simple and cost-effective Am J Clin Nutr 2003; 77:1241–1247. treatment option for any B12-deficient per- 2. Pennypacker LC, Allen RH, Kelly JP, et al. High son, and may actually be superior to in- prevalence of cobalamin deficiency in elderly out- tramuscular replacement.5,6 A Cochrane patients. J Am Geriatr Soc 1992; 40:1197–1204. 3. Hvas AM, Juul S, Gerdes LU, Nexo E. The marker Collaboration review of oral vitamin B12 of cobalamin deficiency, plasma methylmalonic replacement found that these high doses acid, correlates to plasma creatinine. J Intern Med seemed as effective as intramuscular vita- 2000; 247:507–512. 4. Hvas AM, Nexo E. Holotranscobalamin—a first min B12 in all B12-deficient patients—even choice assay for diagnosing early vitamin B defi- those with pernicious anemia, Crohn’s ciency? J Intern Med 2005; 257:289–298. disease, ileal resection, or malabsorption 5. Kuzminski AM, Del Giacco EJ, Allen RH, Stabler SP, Lindenbaum J. Effective treatment of cobala- states. The authors of the review recom- min deficiency with oral cobalamin. Blood 1998; mend a “further large, pragmatic trial in a 92:1191–1198. primary care setting” to determine wheth- 6. vidal-Alaball J, Butler CC, Cannings-John R, et al. Oral vitamin B12 versus intramuscular vitamin B12 er oral vitamin B12 is effective for patients for vitamin B12 deficiency. Cochrane Database with major common cases of malabsorp- Syst Rev 2005; (3):CD004655. fast track tion and to provide additional evidence 7. solomon LR. Cobalamin-responsive disorders in If serum vitamin 6 the ambulatory care setting: unreliability of cobala- for cost effectiveness. min, methylmalonic acid, and homocysteine testing. Blood 2005; 105:978–985. B12 is low, check homocysteine and Recommendations from Others The views expressed in this abstract/manuscript are methylmalonic Current guidelines recommend giving vi- those of the author(s) and do not reflect the official acid levels; tamin B if methylmalonic acid or both policy or position of the Department of the Army, 12 Department of Defense, or the US Government. methylmalonic acid and homocysteine are monitor patients elevated. Give folate if only homocysteine with neurologic is elevated. Give vitamin B if homocyste- 12 symptoms ine 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 replace-