• A Correction to this article was published on 20 July 2017


Vitamin B12 (B12; also known as cobalamin) is a B vitamin that has an important role in cellular metabolism, especially in DNA synthesis, methylation and mitochondrial metabolism. Clinical B12 deficiency with classic haematological and neurological manifestations is relatively uncommon. However, subclinical deficiency affects between 2.5% and 26% of the general population depending on the definition used, although the clinical relevance is unclear. B12 deficiency can affect individuals at all ages, but most particularly elderly individuals. Infants, children, adolescents and women of reproductive age are also at high risk of deficiency in populations where dietary intake of B12-containing animal-derived foods is restricted. Deficiency is caused by either inadequate intake, inadequate bioavailability or malabsorption. Disruption of B12 transport in the blood, or impaired cellular uptake or metabolism causes an intracellular deficiency. Diagnostic biomarkers for B12 status include decreased levels of circulating total B12 and transcobalamin-bound B12, and abnormally increased levels of homocysteine and methylmalonic acid. However, the exact cut-offs to classify clinical and subclinical deficiency remain debated. Management depends on B12 supplementation, either via high-dose oral routes or via parenteral administration. This Primer describes the current knowledge surrounding B12 deficiency, and highlights improvements in diagnostic methods as well as shifting concepts about the prevalence, causes and manifestations of B12 deficiency.

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The authors thank N. DeGeorge and L. Texeira for their administrative and editing support. The authors also thank K. Eriksen (MRC Elsie Widdowson Laboratory, Cambridge, UK), S. Moore (MRC Unit The Gambia and Division of Women's Health, King's College London, UK), R. Wessells and S. Hess (Program in International and Community Nutrition, University of California, USA), and G. Kac (Nutritional Epidemiology Observatory, Rio de Janeiro Federal University, Brazil) for providing data from The Gambia, Niger and Brazil to construct Figure 2.

Author information


  1. Department of Pathology and Laboratory Medicine, University of California Davis, 4400 V Street, PATH Building, Davis, California 95817, USA.

    • Ralph Green
  2. USDA, ARS Western Human Nutrition Research Center, University of California Davis, Davis, California, USA.

    • Lindsay H. Allen
    •  & Alex Brito
  3. Laboratory of Clinical Biochemistry, Haukeland University Hospital, Bergen, Norway.

    • Anne-Lise Bjørke-Monsen
    •  & Per Magne Ueland
  4. Inserm UMRS 954 N-GERE (Nutrition Génétique et Exposition aux Risques Environnementaux), University of Lorraine and INSERM, Nancy, France.

    • Jean-Louis Guéant
  5. School of Environmental and Biological Sciences, Rutgers University, New Brunswick, New Jersey, USA.

    • Joshua W. Miller
  6. School of Medicine and School of Biochemistry and Immunology, Trinity College Dublin, University of Dublin, Dublin, Ireland.

    • Anne M. Molloy
  7. Department of Clinical Medicine, Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark.

    • Ebba Nexo
  8. Department of Medicine, University of Colorado Denver, Denver, Colorado, USA.

    • Sally Stabler
  9. Centre for Inflammatory Diseases, Monash Institute of Medical Research, Clayton, Victoria, Australia.

    • Ban-Hock Toh
  10. Section for Pharmacology, Department of Clinical Science, University of Bergen, Bergen, Norway.

    • Per Magne Ueland
  11. Diabetes Unit, King Edward Memorial Hospital, Pune, Maharashtra, India.

    • Chittaranjan Yajnik


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Introduction (R.G.); Epidemiology (L.H.A., A.B., A.M.M., A.-L.B.-M., J.W.M. and P.M.U.); Mechanisms/pathophysiology (J.-L.G. and B.-H.T.); Diagnosis, screening and prevention (E.N. and C.Y.); Management (S.S.); Quality of life (S.S.); Outlook (R.G.); Overview of Primer (R.G.).

Competing interests

R.G. has previously served on speakers’ bureaus and as a consultant for Emisphere Technologies. J.W.M. has served on a scientific steering committee for Emisphere Technologies. A.M.M. received an honorarium as a speaker at the Abbott Transformation Forum, Manchester, UK. S.S. indirectly benefits from the activities of a company formed by the University of Colorado aimed at measuring vitamin B12-related metabolites. Otherwise she does not have any conflict of interest. All other authors declare no competing interests.

Corresponding author

Correspondence to Ralph Green.

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