Guideline sources The following summarized guidelines for the evaluation and management of vitamin B12 deficiency are prepared by our editorial team based on guidelines from the European Association of Urology (EAU 2023), the American Diabetes Association (ADA 2023), the European Association for the Study of the Liver (EASL 2022), the Italian Society of Digestive Endoscopy (SIDE/SIGE 2022), the European Society for Radiotherapy and Oncology (ESTRO/EACTS/ERS/ESTS 2020), the Kidney Disease: Improving Global Outcomes Foundation (KDIGO 2020; 2012), the American Society of Anesthesiologists (ASA/ACE/OS/AACE/ASMBS/OMA 2020), the European Society for the Study of Coeliac Disease (ESsCD 2019), the British Society of Gastroenterology (BSG 2019), the National Comprehensive Cancer Network (NCCN 2018), the European Academy of Dermatology and Venereology (EADV/UEMS/EFA/ETFAD/EDF/EAACI/ESDaP/ESPD 2018), the American Association of Family Physicians (AAFP 2017), the American Society for Metabolic and Bariatric Surgery (ASMBS 2017), the United Kingdom Kidney Association (UKKA 2017), the European Association for the Study of Obesity (EASO 2017), the British Society for Haematology (BSH 2017; 2014), the Maastricht V/Florence Consensus Report (Maastricht V/Florence 2017), the Society of Critical Care Medicine (SCCM/ASPEN 2016), the Endocrine Society (ES 2016), the Society for Vascular Surgery (SVS 2015), the European Crohn's and Colitis Organisation (ECCO 2015), the American Academy of Sleep Medicine (AASM 2015), the Society for Cardiovascular Angiography and Interventions (SCAI/PCNA/STS/AATS/AHA/ACC 2014), the American Heart Association (AHA/ACC 2014), the American Academy of Dermatology (AAD 2014), the American https://web.pathway.md/diseases/recYHz3w3IJPUyTKp 1/11 6/29/23, 3:43 AM Vitamin B12 deficiency Pathway College of Endocrinology (ACE/OS/AACE 2013), the American College of Gastroenterology (ACG 2013), the American Society for Parenteral and Enteral Nutrition (ASPEN 2013), the Obesity Society (OS/AACE 2013), the European Federation of Neurological Societies (EFNS 2010), and the American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM/AAN 2009). 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 Pathway Vitamin B12 deficiency Diagnosis and management Guidelines 1. Screening and diagnosis Indications for screening (general principles): obtain screening with a CBC and serum vitamin B12 level measurement in patients with risk factors for vitamin B12 deficiency. B Indications for screening, elderly patients: As per OS/ACE/AACE 2013 guidelines, consider screening for vitamin B12 deficiency in elderly individuals given its high prevalence with advancing age. C As per OS/ACE/AACE 2013 guidelines, assess vitamin B12 levels periodically in older adult individuals. A As per EFNS 2010 guidelines, assess vitamin B12 level at the time of Alzheimer's disease diagnosis. E Indications for screening (vegetarians): consider monitoring serum vitamin B12 levels in vegetarians and particularly strict vegans. C Indications for screening, patients on metformin: As per ADA 2023 guidelines, consider obtaining periodic measurements of vitamin B12 levels in metformin-treated patients, especially in patients with anemia or peripheral neuropathy. C As per KDIGO 2020 guidelines, screen for vitamin B12 deficiency in patients on metformin therapy > 4 years. B As per BSH 2014 guidelines, monitor serum vitamin B12 levels in the presence of strong clinical suspicion of deficiency in patients with T2DM on metformin therapy. B As per OS/ACE/AACE 2013 guidelines, assess vitamin B12 levels periodically in patients on metformin therapy. A Indications for screening, inflammatory bowel disease: As per ESsCD 2019 guidelines, obtain testing for vitamin B12 and folate deficiencies in adult patients with newly diagnosed celiac disease. B https://web.pathway.md/diseases/recYHz3w3IJPUyTKp 2/11 6/29/23, 3:43 AM Vitamin B12 deficiency Pathway As per ECCO 2015 guidelines, obtain proper surveillance in patients with IBD at risk for vitamin B12 or folic acid deficiency (such as small bowel disease or resection). Measure serum levels of vitamin B12 and folic acid at least annually, or if macrocytosis is present in the absence of thiopurine use. B Show 2 more As per ACG 2013 guidelines, evaluate and treat vitamin B12 and folate deficiencies in patients with newly diagnosed celiac disease. B Indications for screening, chronic kidney disease: As per UKKA 2017 guidelines, consider measuring serum vitamin B12 and folate concentrations to diagnose the cause of anemia in selected (based on the initial assessment) patients with CKD. B As per KDIGO 2012 guidelines, obtain a standard anemia panel (CBC, absolute reticulocyte count, serum ferritin level, and serum transferrin saturation) and measurement of serum vitamin B12 and folate levels as part of the initial evaluation of anemia in patients with CKD, regardless of age and CKD stage. Indications for screening (polyneuropathy): consider measuring vitamin B12 levels with metabolites (MMA with or without homocysteine) in all patients with distal symmetric polyneuropathy. C Indications for screening (pre-bariatric surgery): Obtain routine preoperative screening of vitamin B12 and folate deficiencies in all patients undergoing bariatric surgery. B Assess serum MMA level as the assay of choice for evaluating vitamin B12 deficiency in symptomatic or asymptomatic patients, and in patients with a history of vitamin B12 deficiency or preexisting neuropathy. B Indications for screening, post-bariatric surgery: As per ASA/OMA/ASMBS/OS/ACE/AACE 2020 guidelines, obtain screening for vitamin B12 deficiency every trimester as part of nutritional surveillance and laboratory screening for nutrient deficiencies in patients becoming pregnant after bariatric procedures. B As per ASMBS 2017 guidelines, assess postoperative vitamin B12 and folate status in patients undergone sleeve gastrectomy, Roux-en-Y gastric bypass, or biliopancreatic diversion with duodenal switch. B Show 2 more As per ASPEN/SCCM 2016 guidelines, assess for and treat vitamin B12 and folate deficiencies in ICU patients with obesity and a history of bariatric surgery. E As per BSH 2014 guidelines, monitor serum vitamin B12 levels in patients undergone bariatric surgery. B As per ASPEN 2013 guidelines, consider screening for vitamin B12 deficiency in acutely ill hospitalized patients with a history of bariatric surgery (including sleeve gastrectomy, gastric bypass, or biliopancreatic diversion with or without duodenal switch). C As per OS/AACE 2013 guidelines: Obtain baseline and postoperative evaluation for vitamin B12 deficiency in all patients undergoing bariatric surgery and annually in patients undergone procedures excluding the https://web.pathway.md/diseases/recYHz3w3IJPUyTKp 3/11 6/29/23, 3:43 AM Vitamin B12 deficiency Pathway lower part of the stomach (such as laparoscopic sleeve gastrectomy, Roux-en-Y gastric bypass). B Obtain evaluation for vitamin B12 deficiency in patients undergone malabsorptive bariatric surgical procedures presenting with anemia and negative routine screening for iron deficiency anemia. B As per OS/AACE 2013 guidelines, obtain nutritional surveillance and laboratory screening for folate and vitamin B12 deficiencies every trimester in patients becoming pregnant following bariatric surgery. B Indications for screening (post-radical cystectomy): measure vitamin B12 levels annually in the follow-up of patients treated with radical cystectomy and bowel diversion with curative intent. E Indications for screening (primary adrenal insufficiency): consider obtaining periodic screening for vitamin B12 deficiency in patients with primary adrenal insufficiency. C Indications for screening, hematological disorders: As per NCCN 2018 guidelines, obtain vitamin B12 and folate level measurements in patients with chronic myeloid leukemia with grade 3/4 anemia. B As per BSH 2017 guidelines, obtain CBC, blood film examination, and vitamin B12 level measurement in all patients presenting with eosinophilia. B Diagnostic criteria: suspect vitamin B12 or folate deficiency in patients with a blood film showing oval macrocytes and hypersegmented neutrophils in the presence of an elevated MCV. B Show 2 more 2. Diagnostic investigations Serum vitamin B12 and folate: assess serum vitamin B12 and folate levels in patients with suspected vitamin B12 deficiency. A Serum homocysteine and methylmalonic acid: As per AAFP 2017 guidelines, consider obtaining serum MMA level measurement to confirm vitamin B12 deficiency in patients with normal or low-normal serum vitamin B12 levels where vitamin B12 deficiency is still suspected. C As per BSH 2014 guidelines: Obtain further evaluation with MMA, serum total homocysteine, or holotranscobalamin in patients with serum cobalamin levels > 148 pmol/L in the presence of a strong clinical suspicion of cobalamin deficiency, and administer a trial of hydroxocobalamin to ascertain any clinical improvement. B Consider obtaining serum total homocysteine and/or MMA, depending on availability, as supplementary tests to determine biochemical cobalamin deficiency in the presence of clinical suspicion of deficiency but an indeterminate serum cobalamin level. C Serum holotranscobalamin: Consider measuring serum holotranscobalamin levels, if available, for the assessment of cobalamin status. B https://web.pathway.md/diseases/recYHz3w3IJPUyTKp 4/11 6/29/23, 3:43 AM Vitamin B12 deficiency Pathway Obtain further evaluation including holotranscobalamin in patients with serum cobalamin levels > 148 pmol/L in the presence of a strong clinical suspicion of cobalamin deficiency. B Evaluation for pernicious anemia: obtain anti-intrinsic factor antibodies in patients with suspected pernicious anemia presenting with anemia, neuropathy, and/or glossitis, regardless of serum vitamin B12 levels. A Show 3 more Screening for Helicobacter pylori infection: As per SIGE 2022 guidelines, test for and eradicate H. pylori infection in patients with iron, vitamin B12 deficiency anemia, or idiopathic thrombocytopenia. B Test for and eradicate H. pylori infection in patients with unexplained vitamin B12 deficiency. B Screening for gastric cancer: consider performing a baseline endoscopy with biopsies in 50 years old patients with laboratory evidence of pernicious anemia, defined by vitamin B12 deficiency and either positive anti-parietal cell or anti-intrinsic factor antibodies. Take biopsies from the greater and lesser curves since atrophic gastritis affects the corpus in pernicious anemia. C 3. Medical management Vitamin B12 supplementation, without neurological involvement: As per AAFP 2017 guidelines, administer oral or injectable preparations for vitamin B12 replacement recognizing that injectable therapy leads to more rapid improvement. Consider administering injectable vitamin B12 preparations in patients with severe vitamin B12 deficiency. B As per ASMBS 2017 guidelines: Initiate vitamin B12 supplementation of 1,000 g/day to achieve normal levels in post- bariatric surgery patients with vitamin B12 deficiency, and then resume dosages recommended to maintain normal levels. B Initiate folate supplementation of 1,000 g/day to achieve normal levels in post-bariatric surgery patients with folate deficiency, and then resume dosages recommended to maintain normal levels. B As per BSH 2014 guidelines: Administer vitamin B12 (1,000 g IM 3 times/week for 2 weeks) for the treatment of patients without neurological involvement. A Consider initiating an empiric trial of oral cyanocobalamin (50 g/day for 4 weeks) for the treatment of patients with serum levels of subclinical deficiency on 2 occasions. Instruct patients to seek immediate medical attention if symptoms of neuropathy develop. Reassess cobalamin levels after 3 months, and obtain second-line tests if there is no improvement. C As per OS/ACE/AACE 2013 guidelines, administer oral vitamin B12 (1,000 g/day of oral crystalline cobalamin) in patients with vitamin B12 deficiency, as well as advise increasing the intake of vitamin B12 in food. A Vitamin B12 supplementation, with neurological involvement: https://web.pathway.md/diseases/recYHz3w3IJPUyTKp 5/11 6/29/23, 3:43 AM Vitamin B12 deficiency Pathway As per AAFP 2017 guidelines, administer vitamin B12 preparations in patients with vitamin B12 deficiency. Consider administering injectable vitamin B12 preparations in patients with severe neurologic symptoms. B As per BSH 2014 guidelines: Administer vitamin B12 (1,000 g IM every 2 days until clinical improvement ceases) for the treatment of patients with neurological involvement. A Consider reviewing the need for continuation of alternate day therapy after 3 weeks of treatment. As per OS/ACE/AACE 2013 guidelines, administer parenteral (IM or SC) vitamin B12 replacement for early treatment of patients with neurologic symptoms, pernicious anemia, or malabsorptive bariatric surgery. A 4. Specific circumstances Pediatric patients: treat vitamin B12 deficiency promptly in infants to prevent long-term neurological sequelae. A Pregnant patients: Recognize that serum cobalamin levels fall during pregnancy and are less reliable in determining underlying deficiency. A Consider obtaining holotranscobalamin, if available, rather than serum cobalamin in determining vitamin B12 deficiency in pregnancy. B Administer a short course of empirical hydroxocobalamin during pregnancy in the presence of strong suspicion of underlying deficiency, and obtain further investigations postpartum. B Patients on metformin: consider initiating oral cobalamin 50 g for 1 month in patients with vitamin B12 deficiency on metformin therapy. Consider obtaining subsequent monitoring of serum cobalamin after 6 months and then at yearly intervals. C Patients on hormone therapy: avoid obtaining further investigation in asymptomatic female patients on oral contraceptives (or HRT) with mildly reduced serum vitamin B12. Advise these patients to review their dietary intake of cobalamin-rich foods, and consider initiating cobalamin supplements. D Patients with pernicious anemia: Initiate lifelong cobalamin replacement in patients with vitamin B12 deficiency and positive anti-intrinsic factor antibodies. A Initiate lifelong cobalamin replacement in patients with vitamin B12 deficiency and negative anti-intrinsic factor antibodies where no other causes of deficiency have been identified, as these patients may have anti-intrinsic factor-negative pernicious anemia. B Patients with chronic liver disease: optimize Hgb levels by treating iron, folic acid, vitamin B6, and vitamin B12 deficiencies in patients with cirrhosis, especially likely to undergo invasive procedures. B Patients with found-bound cobalamin malabsorption: consider initiating low-dose oral vitamin B12 replacement in patients with food-bound vitamin B12 malabsorption. C https://web.pathway.md/diseases/recYHz3w3IJPUyTKp 6/11 6/29/23, 3:43 AM Vitamin B12 deficiency Pathway 5. Preventative measures Prophylactic vitamin B12 supplementation, post-bariatric surgery: As per AAFP 2017 guidelines, initiate oral vitamin B12 supplementation (1 mg/day) and continue indefinitely in patients post-bariatric surgery. B As per ASMBS 2017 guidelines: Initiate vitamin B12 supplementation in all patients post-bariatric surgery at doses depending on the route of administration: Situation Guidance 350-500 g/day PO (disintegrating tablet, sublingual, or liquid) As directed by the manufacturer Nasal spray 1,000 g/month. B Parenteral (IM or SC) Initiate folate supplementation (400-800 g/day PO; 800-1,000 g/day in females of childbearing age) in all patients post-bariatric surgery. B As per EASO 2017 guidelines, initiate micronutrient supplementation in all pregnant patients following bariatric surgery, in the form of prenatal multivitamin preparations, B12 injections, and oral calcium supplements. B As per OS/AACE 2013 guidelines: Consider initiating oral crystalline vitamin B12 supplementation 1,000 g/day to maintain normal vitamin B12 levels in patients undergone bariatric surgery. B Consider administering intranasally vitamin B12 supplementation of 500 g/week. C . Consider administering IM or SC B12 supplementation of 1,000 g/month to 1,000-3,000 g every 6- 12 months if normal vitamin B12 levels cannot be maintained with oral or intranasal routes. C Initiate vitamin B12 supplements (parenterally as sublingual, SC, or IM preparations, or PO, if determined to be adequately absorbed) as needed to maintain vitamin B12 levels in the normal range in patients undergone laparoscopic sleeve gastrectomy, Roux-en-Y gastric bypass or biliopancreatic diversion with duodenal switch. B Prophylactic vitamin B12 supplementation (patients on pemetrexed): initiate vitamin B12 and folic acid supplementation in patients receiving pemetrexed. B Prophylactic vitamin B12 supplementation (patients on metformin): insufficient evidence to recommend prophylactic administration of oral cobalamin in patients on metformin therapy. I Prophylactic vitamin B12 supplementation, cardiovascular disease: As per ACC/AHA 2014 guidelines, do not use folic acid supplements, with or without vitamins B6 and B12, for secondary prevention in patients with NSTEMI. D As per STS/SCAI/PCNA/AATS/AHA/ACC 2014 guidelines, do not use folate, vitamin B12, or vitamin B6 supplements to reduce cardiovascular risk or improve clinical outcomes in patients with stable ischemic heart disease and elevated levels of homocysteine. D https://web.pathway.md/diseases/recYHz3w3IJPUyTKp 7/11 6/29/23, 3:43 AM Vitamin B12 deficiency Pathway Prophylactic vitamin B12 supplementation (peripheral artery disease): avoid using folic acid and vitamin B12 supplements for the treatment of intermittent claudication. D Prophylactic vitamin B12 supplementation, atopic dermatitis: As per UEMS/ESPD/ESDaP/EFA/ETFAD/EAACI/EADV/EDF 2018 guidelines, insufficient evidence to support the use of topical preparations of vitamin B12 in avocado oil for routine use in patients with atopic dermatitis. I As per AAD 2014 guidelines, insufficient evidence to support the use of vitamin B12 supplements for the treatment of atopic dermatitis. I Prophylactic vitamin B12 supplementation (sleep-wake disorder): insufficient evidence to support the use of vitamin B12 supplements in patients with delayed sleep-wake phase disorder or non-24-hour sleep-wake rhythm disorder. I Clinical findings Symptoms Past medical history Depression Celiac disease Erectile dysfunction Hashimoto's disease Exercise intolerance IBD Fatigue Iron deficiency anemia Fecal incontinence Metformin Gait disturbance Obesity Headache Optic neuritis Hearing loss Orthostatic hypotension Impaired or absent taste Pernicious anemia Irritability Stomach cancer Limb weakness Vitiligo Loss of balance Past surgical history Malabsorption Palpitations Bariatric surgery Paresthesia Neurological exam Personality or behavioral changes Abnormal proprioception Shortness of breath Ataxia Sleepiness Babinski sign Stiffness Cognitive impairment Tinnitus Hyperreflexia Urinary incontinence Hyporeflexia Visual disturbances Neuropathy Weakness Paraparesis Medication history vibration sensation Lhermitte's phenomenon H2RAs PPIs Diagnostic maneuvers https://web.pathway.md/diseases/recYHz3w3IJPUyTKp 8/11 6/29/23, 3:43 AM Vitamin B12 deficiency Pathway Abnormal Romberg's test Social history Lab findings Vegetarianism serum MMA Head and neck exam serum homocysteine Glossitis serum holotranscobalamin Oral ulcers serum vitamin B12 Integument exam Serological findings Hyperpigmentation serum anti-intrinsic factor antibodies Jaundice Pallor Hematological findings Anemia Macrocytic anemia Neutrophil hypersegmentation Pancytopenia References 1. 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