Clinical UM Guideline

This document addresses the use of vitamin B12 blood test, methylmalonic acid blood test, and holotranscobalamin blood test for individuals with suspected or known vitamin B12 deficiency.

Medically Necessary:

Vitamin B12 blood testing is considered medically necessary for any of the following indications:

1. Alcohol dependence; or
2. Anemia; or
3. Autoimmune condition such as intrinsic factor deficiency, thyroid disease, or pernicious anemia; or
4. Blood dyscrasia (for example cytopenia, leukopenia, or thrombocytopenia); or
5. Diabetes mellitus with neurologic symptoms; or
6. Disorders of sulphur amino acid metabolism; or
7. Disruption of gastrointestinal anatomy or function (for example achlorhydria, gastrectomy, gastric bypass, gastric cancer, ileal resection, inflammatory bowel disease); or
8. Failure to thrive (pediatric); or
9. Glossitis; or
10. Homocystinuria; or
11. Inadequate dietary intake of vitamin B12 such as strict vegan diet without vitamin B12 supplementation; or
12. Infection known to be associated with vitamin B12 deficiency such as bacterial overgrowth syndrome, fish tapeworm infection, Helicobacter pylori infection, or human immunodeficiency virus (HIV); or
13. Malabsorption; or
14. Malignancy affecting absorption of nutrients or affecting blood or hematopoiesis; or
15. Malnutrition; or
16. Methylenetetrahydrofolate Reductase (MTHFR) deficiency; or
17. Neurologic or motor symptom abnormality; or
18. Pancreatic insufficiency; or
19. Unexplained mental status or cognitive changes; or
20. Chronic use of H₂ blocking agent and proton pump inhibitor (PPI) minimum of 1 year or metformin minimum of 4 months

Methylmalonic acid (MMA) testing is considered medically necessary for ANY of the following indications:

1. Vitamin B12 levels are low or borderline-low; or
2. Newborn screening; or
3. Use of metformin for Type 2 diabetes mellitus with neurologic symptoms.

Not Medically Necessary:

Vitamin B₁₂ and MMA testing is considered not medically necessary when the criteria above are not met and for all other indications.

Holotranscobalamin testing as a marker for vitamin B12 deficiency is considered not medically necessary for all indications.

The following codes for treatments and procedures applicable to this guideline are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

Vitamin B12 testing
When services are Medically Necessary:

When services may be Medically Necessary when criteria are met:
For the procedure codes listed above for all other diagnoses.

When services are Not Medically Necessary:
For the procedure codes listed above when criteria are not met, and for the following:

MMA testing
When services may be Medically Necessary when criteria are met:

When services are Not Medically Necessary:
For the procedure and diagnosis codes listed above when criteria are not met, and for all other diagnoses not listed.

Vitamin B12 and Methylmalonic acid (MMA) Blood Testing

Vitamin B12, also known as cyanocobalamin, is a water-soluble vitamin occurring naturally in food sources derived from animal products. Vitamin B12 is also available as a mineral/multivitamin supplement in various doses and may be prescribed by a medical professional. Vitamin B12 is necessary for the development, myelination, and proper function of the central nervous system, hematopoietic cell formation, DNA synthesis, and also serves as cofactor for 2 enzymes. Vitamin B12 testing is not recommended for adults with average risk of deficiency. Risk factors for vitamin B12 deficiency include dietary deficiency, decreased absorption, autoimmune conditions, genetic conditions, or prolonged use of certain medications such as metformin or proton pump inhibitors. Deficiency symptoms in adults may lead to nerve damage, neurologic changes, depression, difficulty maintaining balance, and anemia. Vitamin B12 deficiency in the pediatric population include failure to thrive, developmental delays, movement disorders, and megaloblastic anemia.

MMA testing is useful as a confirmation test in asymptomatic high-risk individuals with low-normal levels of Vitamin B12 and as part of newborn screening to detect inborn errors of metabolism. MMA reacts with Vitamin B12 to produce coenzyme A (CoA) which ensures proper cellular function and in the setting of vitamin B12 deficiency MMA levels will be elevated. Numerous articles and practice guidelines have been published addressing the various risk factors indicated for B12 and MMA testing for vitamin B12 deficiency (Lee, 2019; NCCN, 2021; Snow, 1999; Quigley, 2020; Vashi, 2016)  

In 2017, Langan published key recommendations for the workup and management of vitamin B12 deficiency. The recommendations for practice include the following:

Patients with risk factors for vitamin B12 deficiency should be screened with a complete blood count and serum vitamin B12 level. (Evidence rating: C: consensus, disease-oriented evidence, usual practice, expert opinion, or case series.)
A serum methylmalonic acid level may be used to confirm vitamin B12 deficiency when it is suspected but the serum vitamin B12 level is normal or low-normal. (Evidence rating: C)

Holotranscobalamin

Holotranscobalamin testing assesses the level of transcobalamin circulating in the blood that is directly available to cells. Transcobalamin is the only protein that transports vitamin B12 into all cells of the body. Holotranscobalamin does not test the circulating, also known as free, vitamin B12. This limits the utility of the holotranscobalamin test as a diagnostic workup for malabsorption deficiency.

Published literature includes case reports, review articles, and comparison studies. There is a lack of acceptance for use of holotranscobalamin testing because there are no published guidelines indicating that it should be used in addition to total vitamin B12 levels, or in place of total B12 testing.

In 2021, Rothen published the results of a secondary data analysis to determine the best laboratory testing strategy for vitamin B12 deficiency. The study evaluated testing including vitamin B12 alone, holotranscobalamin alone, both vitamin B12 and holotranscobalamin, and reflex testing of holotranscobalamin when vitamin B12 levels were in the defined grey zone of 138-299 pmol/L. At least one sample was obtained for 7925 individuals and simultaneous testing of vitamin B12 and holotranscobalamin was completed in 3044 samples. Low cobalamin was detected in 591 samples, with vitamin B12 low in 305 samples and holotranscobalamin low in 436 samples. Concordant low values were detected in 150 samples and contradicting results occurred in 441 samples. A total of 2403 sample results were in the grey zone and the reflex holotranscobalamin found a total of 583 samples with cobalamin deficiency. With a restrictive grey zone of 138-219 pmol/L, a total of 511 samples were identified with cobalamin deficiency resulting in 86% of the 591 samples having both measurements simultaneously. This study shows that vitamin B12 and holotranscobalamin show poor concordance. The authors conclude, “Laboratory results alone are insufficient to determine unequivocally which patients need substitution. In this field of uncertainty, laboratory diagnostics must be complemented by patient history and clinical symptoms.”

Peer Reviewed Publications:

1. Lam JR, Schneider JL, Zhao W, Corley DA. Proton pump inhibitor and histamine 2 receptor antagonist use and vitamin B12 deficiency. JAMA. 2013; 310(22):2435-2442.
2. Langan RC, Goodbred AJ. Vitamin B12 deficiency: recognition and management. American Family Physician 2017; 96(6):384-389.
3. Lee SM, Oh J, Chun MR, Lee SY. Methylmalonic acid and homocysteine as indicators of vitamin B12 deficiency in patients with gastric cancer after gastrectomy. Nutrients. 2019; 11(2):450.
4. Moridani M, Ben-Poorat S. Laboratory investigation of vitamin B12 deficiency. Laboratory Medicine. 2006; 37(3):166-174.
5. Rothen JP, Walter PN, Tsakiris DA, et al. Identification of patients with cobalamin deficiency crucially depends on the diagnostic strategy. Clin Lab. 2021; 67(5). Available at: https://pubmed.ncbi.nlm.nih.gov/33978377/. Accessed on September 6, 2023.
6. Snow CF. Laboratory diagnosis of vitamin B12 and folate deficiency: a guide for the primary care physician. Arch Intern Med. 1999; 159(12):1289–1298.
7. Vashi P, Edwin P, Popiel B, et al. Methylmalonic acid and homocysteine as indicators of vitamin B-12 deficiency in cancer. PLoS One. 2016; 11(1):e0147843.

Government Agency, Medical Society, and Other Authoritative Publications:

1. National Institutes of Health. Vitamin B12 fact sheet for healthcare professionals. Updated: December 22, 2022. Available at: https://ods.od.nih.gov/factsheets/VitaminB12-HealthProfessional/#h3. Accessed on September 6, 2023.
2. NCCN Clinical Practice Guidelines in Oncology™ (NCCN). © 2011 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website at: http://www.nccn.org/index.asp. Accessed on September 6, 2023.
   • Gastric Cancer (V2.2023). Revised August 29, 2023.
   • Myelodysplastic Syndromes (V1.2023). Revised September 12, 2022.
3. Quigley EMM, Murray JA, Pimentel M. AGA clinical practice update on small intestinal bacterial overgrowth: expert review. Gastroenterology. 2020; 159(4):1526-1532.

Vitamin B12
Methylmalonic acid
Holotranscobalamin

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.