Low vitamin B12 or suspected B12 deficiency (metformin, PPI, vegan diet, older person, pernicious anaemia)
BioMG follows French guidelines. Adapt it to the guidelines and the tests available where you practise.
Suspected deficiency or borderline B12: confirm
Laboratory tests (before any supplementation)
- Serum vitamin B12
- FBC
- Serum folate (at the same time as B12)
- Serum methylmalonic acid (if B12 between 180 and 350 ng/L with symptoms; not reimbursed in France)if needednon-French guideline“Indeterminate” B12 result (180 to 350 ng/L, i.e. 133 to 258 pmol/L) in a patient with symptoms or signs of deficiency [2]. If nitrous oxide is suspected, methylmalonic acid or homocysteine is the initial test, not B12 [2].
- Plasma homocysteine (if methylmalonic acid is not available; not reimbursed in France)if needednon-French guidelineAlternative to methylmalonic acid; homocysteine also rises in folate deficiency [2]. Suspected deficiency due to nitrous oxide: possible initial test [2].
- Holotranscobalamin (if pregnancy; not reimbursed in France)if needednon-French guidelineNICE makes it the initial test in pregnancy, when total B12 falls even without deficiency (expert opinion) [2,4]. It is not listed in the French laboratory fee schedule (NABM) [3], and NICE considers it markedly more expensive than total B12 [4]: outside pregnancy, total B12 remains the first-line test.
Also consider
- High MCV without anaemia? For a high MCV without anaemia, see the page Macrocytosis without anaemia.
Do not order
- Serum vitamin B12 as the initial test for deficiency related to nitrous oxide: prefer methylmalonic acid or homocysteine [2].
- Red cell folate as a routine test: serum folate is enough in most cases; red cell folate is considered only when suspicion is strong with normal serum folate, once B12 deficiency has been excluded [5].
Confirmed deficiency without obvious cause: look for autoimmune gastritis (pernicious anaemia)
Laboratory tests
- Anti-intrinsic factor antibodies
- Anti-gastric parietal cell antibodies (if anti-intrinsic factor negative and suspicion persists)if needednon-French guidelineAutoimmune gastritis still suspected despite negative intrinsic factor antibodies [2]. These antibodies are not always present and, when present, do not always indicate the disease [2].
- Serum gastrin (if anti-intrinsic factor negative and suspicion persists)if needednon-French guidelineSecond-line test when autoimmune gastritis remains suspected despite negative intrinsic factor antibodies [2].
- IgA anti-tissue transglutaminase antibodies (tTG-IgA) (if the cause remains unknown)if needednon-French guidelineCause of the deficiency still unknown after the first investigations: offer coeliac disease serology [2].
- Serum ferritin (if autoimmune gastritis suspected or confirmed)if needednon-French guidelineThe American Gastroenterological Association (2021) asks for iron deficiency to be sought in atrophic gastritis, whatever its cause: in some series it affects up to half of the gastritis cases involving the gastric body and often precedes B12 deficiency (expert opinion) [7]. NICE describes this reduced iron absorption without providing for a test [2].
- TSH (if autoimmune gastritis with symptoms, even non-specific ones)if neededThe American Gastroenterological Association (2021) asks for autoimmune thyroid disease to be sought in every patient with autoimmune gastritis, the two often being associated (expert opinion) [7]. The HAS (French National Authority for Health) assesses thyroid function in the presence of symptoms, even non-specific, when there is a history of autoimmune disease, and does not recommend it in an asymptomatic person [8], hence the condition.
Also consider
- Vegan diet? See the page “Vegetarian and vegan diets”.
Do not order
- Anti-parietal cell antibodies as a first-line test: reserved for cases where intrinsic factor antibodies are negative despite suspected autoimmune gastritis; their presence does not always indicate the disease [2].
- Repeat B12 measurement in a patient treated with intramuscular injections: unnecessary [2].
On long-term metformin or PPI: when to test B12
Laboratory tests
- Serum vitamin B12 (if suggestive symptoms, or periodically if an associated risk factor)
- FBC
Sources (21)
- Evatt ML, Terry PD, Ziegler TR, Oakley GP Jr. Association between vitamin B12-containing supplement consumption and prevalence of biochemically defined B12 deficiency in adults in NHANES III. Public Health Nutr. 2010;13:25-31.
- National Institute for Health and Care Excellence. Vitamin B12 deficiency in over 16s: diagnosis and management. NICE guideline NG239, 6 mars 2024.
- Assurance maladie. Nomenclature des actes de biologie médicale (NABM), version 105 : actes 1490 (anticorps anti-cellules pariétales), 1491 (anticorps anti-facteur intrinsèque) et 0764 (gastrine) ; absence d'acte pour l'holotranscobalamine, l'acide méthylmalonique et l'homocystéine.
- National Institute for Health and Care Excellence. Vitamin B12 deficiency in over 16s: diagnosis and management. NICE guideline NG239, 6 mars 2024 : Rationale and impact.
- Devalia V, Hamilton MS, Molloy AM, on behalf of the British Committee for Standards in Haematology. Guidelines for the diagnosis and treatment of cobalamin and folate disorders. Br J Haematol. 2014;166(4):496-513.
- Patel H, McGuirk R. Vitamin B12 Deficiency: Common Questions and Answers. Am Fam Physician. 2025;112(3):294-300.
- Shah SC, Piazuelo MB, Kuipers EJ, Li D. AGA Clinical Practice Update on the Diagnosis and Management of Atrophic Gastritis: Expert Review. Gastroenterology. 2021;161(4):1325-1332.e7.
- Haute Autorité de santé. Prise en charge des hypothyroïdies chez l'adulte. Fiche de synthèse, mars 2023.
- Haute Autorité de santé, Conseil national professionnel d'hépato-gastroentérologie. Diagnostic de l'infection par Helicobacter pylori chez l'adulte. Fiche pertinence des soins, mai 2017.
- Medicines and Healthcare products Regulatory Agency (Royaume-Uni). Metformin and reduced vitamin B12 levels: new advice for monitoring patients at risk. Drug Safety Update, 20 juin 2022.
- ANSM, Base de données publique des médicaments. Résumé des caractéristiques du produit GLUCOPHAGE 500 mg (metformine), rubriques 4.4 et 4.8, fiche mise à jour le 29 septembre 2026, consultée le 12 octobre 2026.
- ANSM, Base de données publique des médicaments. Résumé des caractéristiques du produit MOPRAL 20 mg (oméprazole), rubrique 4.4, consulté le 11 octobre 2026.
- American Diabetes Association Professional Practice Committee for Diabetes. 3. Prevention or Delay of Diabetes and Associated Comorbidities: Standards of Care in Diabetes—2026. Diabetes Care. 2026;49(Suppl 1):S50-S60.
- Bundesärztekammer, Kassenärztliche Bundesvereinigung, AWMF. Nationale VersorgungsLeitlinie Typ-2-Diabetes, 2023, chapitre 5 : Medikamentöse Therapie des Glukosestoffwechsels.
- Zorginstituut Nederland. Farmacotherapeutisch Kompas : metformine, rubrique « Waarschuwingen en voorzorgen ».
- Freedberg DE, Kim LS, Yang YX. The Risks and Benefits of Long-term Use of Proton Pump Inhibitors: Expert Review and Best Practice Advice From the American Gastroenterological Association. Gastroenterology. 2017;152(4):706-715.
- Medicines and Healthcare products Regulatory Agency. Metformin and reduced vitamin B12 levels: new advice for monitoring patients at risk. Drug Safety Update, 20 juin 2022.
- Base de données publique des médicaments. GLUCOPHAGE 1000 mg, résumé des caractéristiques du produit, rubrique 4.8 (CIS 61052830).
- National Institute for Health and Care Excellence. Vitamin B12 deficiency in over 16s: diagnosis and management. NICE guideline NG239. 2024. (facteurs de risque : médicaments)
- Base de données publique des médicaments. MYSOLINE 250 mg, résumé des caractéristiques du produit, rubrique 4.8 (CIS 65201684).
- National Institute for Health and Care Excellence. Vitamin B12 deficiency in over 16s: diagnosis and management. NICE guideline NG239. 2024. (facteurs de risque : médicaments)