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The best way to evaluate a low-normal B12 level is to check serum methylmalonic acid and homocysteine levels1 (strength of recommendation [SOR]: B, based on consistent level 2 or 3 studies). Give 1 or 2 mg of oral vitamin B12 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 B12, either further evaluation or empiric treatment is warranted
Robert C. Oh, MD, MPH
Tripler Army Medical Center, Honolulu, Hawaii
With the advent of methylmalonic acid, homocysteine testing, and the proven efficacy of oral B12, medicine has come a long way from shilling tests and monthly intramuscular shots in the diagnosis and management of B12 deficiency. “Normal” serum B12 may not accurately reflect true tissue B12 stores. Therefore, if serum B12 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 B12 treats nearly all causes of B12 deficiency (including pernicious anemia and deficiency from gastric bypass surgery), empiric treatment is a reasonable alternative as long as serum B12 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 B12, it should not be dismissed as “normal”—either further evaluation or empiric treatment is warranted.
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.”
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.
The best way to evaluate a low-normal B12 level is to check serum methylmalonic acid and homocysteine levels1 (strength of recommendation [SOR]: B, based on consistent level 2 or 3 studies). Give 1 or 2 mg of oral vitamin B12 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 B12, either further evaluation or empiric treatment is warranted
Robert C. Oh, MD, MPH
Tripler Army Medical Center, Honolulu, Hawaii
With the advent of methylmalonic acid, homocysteine testing, and the proven efficacy of oral B12, medicine has come a long way from shilling tests and monthly intramuscular shots in the diagnosis and management of B12 deficiency. “Normal” serum B12 may not accurately reflect true tissue B12 stores. Therefore, if serum B12 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 B12 treats nearly all causes of B12 deficiency (including pernicious anemia and deficiency from gastric bypass surgery), empiric treatment is a reasonable alternative as long as serum B12 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 B12, it should not be dismissed as “normal”—either further evaluation or empiric treatment is warranted.
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 best way to evaluate a low-normal B12 level is to check serum methylmalonic acid and homocysteine levels1 (strength of recommendation [SOR]: B, based on consistent level 2 or 3 studies). Give 1 or 2 mg of oral vitamin B12 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 B12, either further evaluation or empiric treatment is warranted
Robert C. Oh, MD, MPH
Tripler Army Medical Center, Honolulu, Hawaii
With the advent of methylmalonic acid, homocysteine testing, and the proven efficacy of oral B12, medicine has come a long way from shilling tests and monthly intramuscular shots in the diagnosis and management of B12 deficiency. “Normal” serum B12 may not accurately reflect true tissue B12 stores. Therefore, if serum B12 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 B12 treats nearly all causes of B12 deficiency (including pernicious anemia and deficiency from gastric bypass surgery), empiric treatment is a reasonable alternative as long as serum B12 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 B12, it should not be dismissed as “normal”—either further evaluation or empiric treatment is warranted.
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.”
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.
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.
Evidence-based answers from the Family Physicians Inquiries Network