Vitamin B12 (Cobalamin) Deficiency

Primer

Vitamin B12 (also referred to as cobalamin, cyanocobalamin) is a coenzyme required for various metabolic functions in the body, including fat metabolism, carbohydrate metabolism, and protein synthesis. It plays an additional critical roles in hematopoiesis and a major role synthesizing and maintaining myelin in the central and peripheral nervous system.

Sources

  • Vitamin B12 is most commonly found in dairy and meat products.

Populations at Risk

  • Low levels of vitamin B12 can be associated with hematological disorders, cognitive impairment, and a range of psychiatric symptoms.
  • Low levels of vitamin B12 is more common among long-term vegans and the elderly.
  • Since there is no standard definition of B12 deficiency, it is challenging to establish the prevalence of the condition.[1]

Neuropsychiatric Symptoms

Vitamin B12 deficiency is an important cause of reversible neuropsychiatric symptoms and often overlooked.[2][3][4] Many case reports and series have reported psychosis,[5] hallucinations,[6][7] mood, irritability, dementia, catatonia,[8] delirium, hallucinations, and other neuropsychiatric symptoms in B12 deficiency.[9][10] The specific association between the role of B12 deficiency and neuropsychiatric symptoms is not well understood due to the lack of studies.

A Quick Review on Vitamins

Vitamins are either water-soluble (vitamins B and C), or fat-soluble (vitamins A, D, E, K)
  • Fat-soluble vitamins are dependent on absorption from the ileum and pancreas. Toxicity is easier with fat soluble vitamins because these vitamins accumulate in fat. Malabsorption syndromes such as cystic fibrosis and/or celiac disease) can result in fat-soluble vitamin deficiencies.
  • Water-soluble vitamins are usually important coenzymes in cellular processes or precursors to coenzymes. All are excreted easily from the body, except for vitamins B12 and B9. B vitamin deficiency can result in glossitis, dermatitis, and diarrhea. For certain vitamin B deficiencies (B1 and B12), there can be neuropsychiatric and cognitive symptoms as well. Broadly, the B vitamins include:

Pathophysiology

  • Very large reserve pools of B12 are stored primarily in the liver and can last for several years.
  • Causes of B12 deficiency include:
    • Medication-Related
      • Histamine 2 (H2) receptor antagonists
      • Proton pump inhibitors
      • Metformin
      • Anticonvulsants (especially phenobarbital, pregabalin, primidone, or topiramate)
    • Dietary insufficiency
      • B12 can be low in vegetarians or vegans, or in the elderly when there is malnutrition.
        • This is because B12 is generally only found in meat and dairy products.
      • Chronic alcohol use
    • Decreased absorption
      • Gastric/bariatric surgery, inflammatory bowel disorders, H. Pylori infection, HIV
      • Deficiency of intrinsic factor (IF), such as from atrophic gastritis, leading to pernicious anemia
      • GI dysfunction such as hypochlorhydria
      • Long-term use of proton pump inhibitors
    • Inadequate utilization
      • Vitamin B12 is binds to the transport protein, transcobalamin II. In individuals with a transcobalamin II deficiency, this process is disrupted, and B12 cannot be delivered to sites of utilization and storage.
    • Inhalant-Related Disorders
      • Nitrous oxide is a commonly abused inhalant drug and can precipitate vitamin B12 deficiency when used chronically and acutely, especially in individuals with pre-existing low vitamin B12 reserve.[11][12]

Investigations

  • There are a variety of tests used to determine serum B12 levels, including cobalamin, holotranscobalamin, methylmalonic acid (MMA), and total homocysteine (Hcy).
  • A complete blood count (CBC) will show macrocytic, megaloblastic anemia, with hypersegmented polymorphonuclear leukocytes
    • Note that if someone is taking vitamin B9 (folate) supplementation, this can mask the hematologic symptoms of B12 deficiency, but not the neurologic symptoms.
  • A serum B12 level should be ordered first – if the B12 levels are borderline low, then you should also order:
    • Serum methylmalonic acid (normal level, <400)
      • Elevated levels of methylmalonic acid (MMA) is more sensitive and specific for the diagnosis of B12 deficiency
    • Serum homocysteine (normal level, <14)
  • Levels of B12 also do not correlate well with clinical symptoms.
    • Elderly patients may have “normal” B12 levels with clinically significant B12 deficiency.

Summary of Laboratory Tests to Assess Vitamin B12 Deficiency

Adapted From: Ontario Health Technology Assessment Series Vol. 13 No. 23, pp. 1–45, November 2013
Laboratory Test Rationale for Test Cut Offs Advantages Disadvantages
Cobalamin Decreases in vitamin B12 deficiency • Normal lab ranges vary greatly between labs, ranging from 150 to 350 pmol/L (110-258 pg/mL)
• In adults, BC Guidelines suggest that B12 levels > 150 pmol/L are sufficient and unlikely to indicate B12 deficiency
• A minimum level of 400-475 pmol/L (300 to 350 pg/mL) is desirable in the elderly.[13]
BC guidelines
• The conversion is 1 pg/mL = 1.355 pmol/L[14] 		• Easily accessible
• Most affordable
• Most commonly used test with the most literature about abnormal cut-offs 		Sensitivity and specificity is unclear
Holotranscobalamin • Decreases with vitamin B12 deficiency
• Newer test, clinical utility unclear 		20-50 pmol/L High sensitivity Specificity unclear
Methymalonic acid (MMA) Increases with vitamin B12 deficiency Normal level <260-412 µmol/L (varies) High sensitivity Questionable specificity
Total homocysteine (Hcy) Increases with vitamin B12 deficiency Normal level <14 µmol/L High sensitivity Low specificity influenced by lifestyle factors (smoking, alcohol consumption, coffee consumption)

Physical Exam

  • On neurological examination, there may be a subacute combined degeneration of the dorsal and lateral columns of the spinal cord with symptoms including symmetric paresthesias, numbness, gait disorder, positive Babinski and patellar hyper-reflexia.[15]

Treatment

  • If an individual is hospitalized, unable to take medications by mouth, or have severe neurological/psychiatric symptoms, then intramuscular (IM) administration of synthetic B12 (cyanocobalamin) is the treatment of choice. Otherwise, oral intake should be encouraged as it is typically as effective as IM.[16]

Vitamin B12 Dosing

Oral • Cyancobalamin 1000mcg PO daily
• Ranges from 300 to 2000mcg have been commonly used with no evidence of toxicity
IM • Cyancobalamin 1000 mcg for 5 to 10 days to saturate B12 stores
• Then 1000 to 2000 mcg qmonthly until normalization of the hemoglobin and hematocrit
• Then 1000 mcg monthly to maintain remission

Resources

Guidelines

For Providers

References

1) Vitamin B12 and Cognition: Ontario Health Technology Assessment Series; Vol. 13: No. 23, pp. 1–45, November 2013 26
2) Brett, A. S., & Roberts, M. S. (1994). Screening for vitamin B 12 deficiency in psychiatric patients. Journal of general internal medicine, 9(9), 522-524.
3) Bottiglieri, T. (1996). Folate, vitamin B12, and neuropsychiatric disorders. Nutrition reviews, 54(12), 382-390.
4) Lindenbaum, J., Healton, E. B., Savage, D. G., Brust, J. C., Garrett, T. J., Podell, E. R., ... & Allen, R. H. (1988). Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or macrocytosis. New England journal of medicine, 318(26), 1720-1728.
5) Tufan, A. E., Bilici, R., Usta, G., & Erdoğan, A. (2012). Mood disorder with mixed, psychotic features due to vitamin b12 deficiency in an adolescent: case report. Child and Adolescent Psychiatry and Mental Health, 6(1), 1-5.
6) Carvalho, A. R., Vacas, S., & Klut, C. (2017). Vitamin B12 deficiency induced psychosis–a case report. European Psychiatry, 41(S1), s805-s805.
7) Roohi, J., & Roohi, F. (2019). Case 5-2019: A Woman with Delusional Thinking and Paresthesia of the Right Hand. The New England journal of medicine, 380(21), 2081-2082.
8) Berry, N., Sagar, R., & Tripathi, B. M. (2003). Catatonia and other psychiatric symptoms with vitamin B12 deficiency. Acta Psychiatrica Scandinavica, 108(2), 156-159.
9) Hector, M., & Burton, J. R. (1988). What are the psychiatric manifestations of vitamin B12 deficiency?. Journal of the American Geriatrics Society, 36(12), 1105-1112.
10) Jayaram, N., Rao, M. G., Narasimha, A., Raveendranathan, D., Varambally, S., Venkatasubramanian, G., & Gangadhar, B. N. (2013). Vitamin B12 levels and psychiatric symptomatology: a case series. The Journal of neuropsychiatry and clinical neurosciences, 25(2), 150-152.
11) Sethi, N. K., Mullin, P., Torgovnick, J., & Capasso, G. (2006). Nitrous oxide "whippit" abuse presenting with cobalamin responsive psychosis. Journal of medical toxicology : official journal of the American College of Medical Toxicology, 2(2), 71–74.
12) Garakani, A., Jaffe, R. J., Savla, D., Welch, A. K., Protin, C. A., Bryson, E. O., & McDowell, D. M. (2016). Neurologic, psychiatric, and other medical manifestations of nitrous oxide abuse: a systematic review of the case literature. The American journal on addictions, 25(5), 358-369.
13) Hanna, S., Lachover, L., & Rajarethinam, R. P. (2009). Vitamin B12 deficiency and depression in the elderly: review and case report. Primary care companion to the Journal of clinical psychiatry, 11(5), 269.
14) Mount Sinai: Vitamin B12 level
15) BCGuidelines.ca: Cobalamin (Vitamin B12) and Folate Deficiency
16) Verhaeverbeke, I., Mets, T., Mulkens, K., & Vandewoude, M. (1997). Normalization of low vitamin B12 serum levels in older people by oral treatment. Journal of the American geriatrics society, 45(1), 124-125.