Abstract
Although cobalamin (vitamin B12) deficiency was described over a century ago, it is still difficult to establish
the correct diagnosis and prescribe the right treatment. Symptoms related to vitamin
B12 deficiency may be diverse and vary from neurologic to psychiatric. A number of individuals
with vitamin B12 deficiency may present with the classic megaloblastic anemia.
In clinical practice, many cases of vitamin B12 deficiency are overlooked or sometimes even misdiagnosed. In this review, we describe
the heterogeneous disease spectrum of patients with vitamin B12 deficiency in whom the diagnosis was either based on low serum B12 levels, elevated biomarkers like methylmalonic acid and/or homocysteine, or the improvement
of clinical symptoms after the institution of parenteral vitamin B12 therapy. We discuss the possible clinical signs and symptoms of patients with B12 deficiency and the various pitfalls of diagnosis and treatment.
Abbreviations and Acronyms:
CoA (coenzyme A), holoTC (holotranscobalamin), IF (intrinsic factor), IM (intramuscularly), MMA (methylmalonic acid)To read this article in full you will need to make a payment
One-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Mayo Clinic Proceedings: Innovations, Quality & OutcomesAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Neurologic aspects of cobalamin deficiency.Medicine (Baltimore). 1991; 70: 229-245
- Vitamin B12 deficiency.N Engl J Med. 2013; 368: 149-160
- Vitamin B12 and subacute combined degeneration of the spinal cord.Int Z Vitaminforsch Beih. 1948; 20: 228-233
- Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or macrocytosis.N Engl J Med. 1988; 318: 1720-1728
- B12 deficiency and psychiatric disorders: case report and literature review.Biol Psychiatry. 1981; 16: 197-205
- Causes of hyperhomocysteinemia and its pathological significance.Arch Pharm Res. 2018; 41: 372-383
- Predictive value of folate, vitamin B12 and homocysteine levels in late-life depression.Br J Psychiatry. 2008; 192: 268-274
- Vitamin B12 deficiency in relation to functional disabilities.Nutrients. 2013; 5: 4462-4475
- Vitamin B12 deficiency.BMJ. 2014; 349: g5226
- Vitamin B12 deficiency (published correction appears in Nat Rev Dis Primers. 2017;3:17054).Nat Rev Dis Primers. 2017; 3: 17040
- A high prevalence of biochemical evidence of vitamin B12 or folate deficiency does not translate into a comparable prevalence of anemia.Food Nutr Bull. 2008; 29: S74-S85
- Vitamin B12 and folate and the risk of anemia in old age: the Leiden 85-Plus Study.Arch Intern Med. 2008; 168: 2238-2244
- The prevalence of anemia, iron, vitamin B12, and folic acid deficiencies in community dwelling elderly in Ankara, Turkey.Arch Gerontol Geriatr. 2015; 60: 344-348
- Vitamin B12 deficiency in the institutionalized elderly: a regional study.Exp Gerontol. 2015; 69: 221-225
- Low cobalamin levels as predictors of cobalamin deficiency: importance of comorbidities associated with increased oxidative stress.Am J Med. 2016; 129: 115.e9-115.e16
- Thyroid function, cardiovascular risk factors, and incident atherosclerotic cardiovascular disease: the Atherosclerosis Risk in Communities (ARIC) Study.J Clin Endocrinol Metab. 2017; 102: 3306-3315
- A review of the cut-off points for the diagnosis of vitamin B12 deficiency in the general population.Clin Chem Lab Med. 2015; 53: 1149-1159
- Cobalamin-responsive disorders in the ambulatory care setting: unreliability of cobalamin, methylmalonic acid, and homocysteine testing.Blood. 2005; 105: 978-985
- Rapid healing of a patient with dramatic subacute combined degeneration of spinal cord: a case report.BMC Res Notes. 2017; 10: 18
- The difficulties with vitamin B12.Pract Neurol. 2016; 16: 308-311
- A vitamin B-12 supplement of 500 μg/d for eight weeks does not normalize urinary methylmalonic acid or other biomarkers of vitamin B-12 status in elderly people with moderately poor vitamin B-12 status.J Nutr. 2013; 143: 142-147
- Serum vitamin B12 concentrations within reference values do not exclude functional vitamin B12 deficiency in PKU patients of various ages.Mol Genet Metab. 2011; 102: 13-17
- Utility of measuring vitamin B12 and its active fraction, holotranscobalamin, in neurological vitamin B12 deficiency syndromes.J Neurol. 2011; 258: 393-401
- Cobalamin deficiency.Subcell Biochem. 2012; 56: 301-322
- Methylmalonic acid and homocysteine as indicators of vitamin B-12 deficiency in cancer.PLoS One. 2016; 11: e0147843
- Metabolic vitamin B12 deficiency: a missed opportunity to prevent dementia and stroke.Nutr Res. 2016; 36: 109-116
- Laboratory assessment of vitamin B12 status.J Clin Pathol. 2017; 70: 168-173
- Elevation of total homocysteine in the serum of patients with cobalamin or folate deficiency detected by capillary gas chromatography-mass spectrometry.J Clin Invest. 1988; 81: 466-474
- Modeling a methylmalonic acid-derived change point for serum vitamin B-12 for adults in NHANES.Am J Clin Nutr. 2013; 98: 460-467
- Serum methylmalonic acid and holotranscobalamin-II as markers for vitamin B12 deficiency in end-stage renal disease patients.Ann Clin Lab Sci. 2013; 43: 243-249
- Comparison of four automated serum vitamin B12 assays.Clin Chem Lab Med. 2015; 53: 1205-1213
- Vitamin B12-responsive severe leukoencephalopathy and autonomic dysfunction in a patient with “normal” serum B12 levels.J Neurol Neurosurg Psychiatry. 2010; 81: 1369-1371
- Exome sequencing identifies ACSF3 as a cause of combined malonic and methylmalonic aciduria.Nat Genet. 2011; 43: 883-886
- A common polymorphism in HIBCH influences methylmalonic acid concentrations in blood independently of cobalamin.Am J Hum Genet. 2016; 98: 869-882
- Genomic mutations associated with mild and severe deficiencies of transcobalamin I (haptocorrin) that cause mildly and severely low serum cobalamin levels.Br J Haematol. 2009; 147: 386-391
- Helicobacter pylori serologic status has no influence on the association between fucosyltransferase 2 polymorphism (FUT2 461 G→A) and vitamin B-12 in Europe and West Africa.Am J Clin Nutr. 2012; 95: 514-521
- An update on vitamin B12-related gene polymorphisms and B12 status.Genes Nutr. 2018; 13: 2
- The FUT2 secretor variant p.Trp154Ter influences serum vitamin B12 concentration via holo-haptocorrin, but not holo-transcobalamin, and is associated with haptocorrin glycosylation.Hum Mol Genet. 2017; 26: 4975-4988
- Holotranscobalamin, a marker of vitamin B-12 status: analytical aspects and clinical utility.Am J Clin Nutr. 2011; 94: 359S-365S
- Screening for metabolic vitamin B12 deficiency by holotranscobalamin in patients suspected of vitamin B12 deficiency: a multicentre study.Ann Clin Biochem. 2012; 49: 184-189
- Utility and limitations of biochemical markers of vitamin B12 deficiency.Eur J Clin Invest. 2013; 43: 231-237
- Biochemical markers of vitamin B12 deficiency combined in one diagnostic parameter: the age-dependence and association with cognitive function and blood hemoglobin.Clin Chim Acta. 2013; 422: 47-53
- Combined indicator of vitamin B12 status: modification for missing biomarkers and folate status and recommendations for revised cut-points.Clin Chem Lab Med. 2015; 53: 1215-1225
- Possible cause of false normal B-12 assays.BMJ. 2006; 333 ([letter]): 654-655
- Spurious elevations of vitamin B12 with pernicious anemia.N Engl J Med. 2012; 366 ([letter]): 1742-1743
- Undetected vitamin B12 deficiency due to false normal assay results.Blood Transfus. 2013; 11: 627-629
- False-normal vitamin B12 results in a patient with pernicious anaemia.Clin Biochem. 2015; 48: 1366-1367
- Failures of cobalamin assays in pernicious anemia [letter] [published correction appears in N Engl J Med. 2012;367(10):976].N Engl J Med. 2012; 367: 385-386
- Does folic acid harm people with vitamin B12 deficiency?.QJM. 1995; 88: 357-364
- Autoimmune polyendocrine syndromes.N Engl J Med. 2004; 350: 2068-2079
- Type 1 diabetes and autoimmune polyglandular syndrome: a clinical review.Neth J Med. 2009; 67: 376-387
- Autoimmune polyglandular syndromes.Nat Rev Endocrinol. 2010; 6: 270-277
- Coexistence of Addison's disease and pernicious anemia: is the new classification of autoimmune polyglandular syndrome appropriate?.Acta Clin Croat. 2015; 54: 232-235
- Reassessment of the relative prevalences of antibodies to gastric parietal cell and to intrinsic factor in patients with pernicious anaemia: influence of patient age and race.Clin Exp Immunol. 1992; 89: 74-77
- Do intrinsic factor antibodies assays provide univocal answers in Biermer's disease?.J Clin Lab Anal. 2008; 22: 337-339
- Comparison of five commercially available ELISA kits for the determination of intrinsic factor antibodies in a vitamin B12 deficient adult population.Int J Lab Hematol. 2016; 38: e12-e14
- Limited value of testing for intrinsic factor antibodies with negative gastric parietal cell antibodies in pernicious anaemia.J Clin Pathol. 2009; 62: 439-441
- Proton pump inhibitors: review of emerging concerns.Mayo Clin Proc. 2018; 93: 240-246
- Proton pump inhibitors, H2-receptor antagonists, metformin, and vitamin B-12 deficiency: clinical implications.Adv Nutr. 2018; 9: 511S-518S
- Long-term treatment with metformin in type 2 diabetes and methylmalonic acid: post hoc analysis of a randomized controlled 4.3year trial.J Diabetes Complications. 2018; 32: 171-178
- High prevalence of cobalamin deficiency in elderly outpatients.J Am Geriatr Soc. 1992; 40: 1197-1204
- Food-cobalamin malabsorption in elderly patients: clinical manifestations and treatment.Am J Med. 2005; 118: 1154-1159
- Vitamin B12 among vegetarians: status, assessment and supplementation.Nutrients. 2016; 8: 767
- American Society for Metabolic and Bariatric Surgery Integrated Health Nutritional Guidelines for the Surgical Weight Loss Patient 2016 Update: Micronutrients.Surg Obes Relat Dis. 2017; 13: 727-741
- Early changes in vitamin B12 uptake and biomarker status following Roux-en-Y gastric bypass and sleeve gastrectomy.Clin Nutr. 2019; 38: 906-911
- Improving bariatric patient aftercare outcome by improved detection of a functional vitamin B12 deficiency.Obes Surg. 2016; 26: 1500-1504
- Severe motor neuropathy or neuronopathy due to nitrous oxide toxicity after correction of vitamin B12 deficiency.Muscle Nerve. 2015; 51: 614-616
- Nitrous oxide misuse and vitamin B12 deficiency.BMJ Case Rep. 2016; 2016 (bcr2016215728)
- When the laughing stops: subacute combined spinal cord degeneration caused by laughing gas use.J Addict Med. 2017; 11: 235-236
- Biochemical and hematologic manifestations of gastric intrinsic factor (GIF) deficiency: a treatable cause of B12 deficiency in the Old Order Mennonite population of southwestern Ontario.JIMD Rep. 2015; 18: 69-77
- Long-term outcome of 4 patients with transcobalamin deficiency caused by 2 novel TCN2 mutations.J Pediatr Hematol Oncol. 2017; 39: e430-e436
- Seven patients with transcobalamin deficiency diagnosed between 2010 and 2014: a single-center experience.J Pediatr Hematol Oncol. 2017; 39: 38-41
- High frequency of vitamin B12 deficiency in asymptomatic individuals homozygous to MTHFR C677T mutation is associated with endothelial dysfunction and homocysteinemia.Am J Physiol Heart Circ Physiol. 2007; 293: H860-H865
- Association of vitamin B12 deficiency with homozygosity of the TT MTHFR C677T genotype, hyperhomocysteinemia, and endothelial cell dysfunction.Isr Med Assoc J. 2015; 17: 288-292
- Association between MTHFR 677C>T polymorphism and vitamin B12 deficiency: a case-control study.J Med Biochem. 2018; 37: 141-147
- Should vitamin B12 status be considered in assessing risk of neural tube defects?.Ann N Y Acad Sci. 2018; 1414: 109-125
- Associations of maternal vitamin B12 concentration in pregnancy with the risks of preterm birth and low birth weight: a systematic review and meta-analysis of individual participant data.Am J Epidemiol. 2017; 185: 212-223
- Wnt signaling pathways are dysregulated in rat female cerebellum following early methyl donor deficiency.Mol Neurobiol. 2019; 56: 892-906
- Molecular and cellular effects of vitamin B12 in brain, myocardium and liver through its role as co-factor of methionine synthase.Biochimie. 2013; 95: 1033-1040
- Pregnant women of South Asian ethnicity in Canada have substantially lower vitamin B12 status compared with pregnant women of European ethnicity.Br J Nutr. 2017; 118: 454-462
- Vitamin B12 and folate concentrations during pregnancy and insulin resistance in the offspring: the Pune Maternal Nutrition Study.Diabetologia. 2008; 51: 29-38
- Low plasma vitamin B12 in pregnancy is associated with gestational 'diabesity' and later diabetes.Diabetologia. 2009; 52: 2350-2358
- Vitamin B12: one carbon metabolism, fetal growth and programming for chronic disease.Eur J Clin Nutr. 2014; 68: 2-7
- Cobalamin status from pregnancy to early childhood: lessons from global experience.Adv Nutr. 2017; 8: 971-979
- Vitamin B-12 status in infancy is positively associated with development and cognitive functioning 5 y later in Nepalese children.Am J Clin Nutr. 2017; 105: 1122-1131
- Clinical and neurological findings of severe vitamin B12 deficiency in infancy and importance of early diagnosis and treatment.J Paediatr Child Health. 2013; 49: 820-824
- Vitamin B12-dependent taurine synthesis regulates growth and bone mass.J Clin Invest. 2014; 124: 2988-3002
- Genetic and non-genetic influences during pregnancy on infant global and site specific DNA methylation: role for folate gene variants and vitamin B12.PloS One. 2012; 7: e33290
- Mild transcobalamin I (haptocorrin) deficiency and low serum cobalamin concentrations.Clin Chem. 2003; 49: 1367-1374
- New basis of the neurotrophic action of vitamin B12.Clin Chem Lab Med. 2003; 41: 1435-1437
- The multi-faceted basis of vitamin B12 (cobalamin) neurotrophism in adult central nervous system: lessons learned from its deficiency.Prog Neurobiol. 2009; 88: 203-220
- Improving neuropathy scores in type 2 diabetic patients using micronutrients supplementation.Diabetes Res Clin Pract. 2011; 93: 86-94
- Vitamin B12 may be more effective than nortriptyline in improving painful diabetic neuropathy.Int J Food Sci Nutr. 2009; 60: 71-76
- Effectiveness of vitamin B12 on diabetic neuropathy: systematic review of clinical controlled trials.Acta Neurol Taiwan. 2005; 14: 48-54
- Vitamin B supplementation for diabetic peripheral neuropathy.Singapore Med J. 2016; 57: 55-59
- Relationships between cobalamin, epidermal growth factor, and normal prions in the myelin maintenance of central nervous system.Int J Biochem Cell Biol. 2014; 55: 232-241
- Low levels of cobalamin, epidermal growth factor, and normal prions in multiple sclerosis spinal cord.Neuroscience. 2015; 298: 293-301
- Increased concentrations of homocysteine in the cerebrospinal fluid in patients with fibromyalgia and chronic fatigue syndrome.Scand J Rheumatol. 1997; 26: 301-307
- Response to vitamin B12 and folic acid in myalgic encephalomyelitis and fibromyalgia.PloS One. 2015; 10: e0124648
- Chemotherapy-induced peripheral neuropathy (CIPN) and vitamin B12 deficiency.Support Care Cancer. 2015; 23: 1843-1850
- B vitamin complex and chemotherapy-induced peripheral neuropathy.Curr Oncol Rep. 2017; 19: 76
- Decreased brain levels of vitamin B12 in aging, autism and schizophrenia.PloS One. 2016; 11: e0146797
- Randomized, placebo-controlled trial of methyl B12 for children with autism.J Child Adolesc Psychopharmacol. 2016; 26: 774-783
- The human serum metabolome of vitamin B-12 deficiency and repletion, and associations with neurological function in elderly adults.J Nutr. 2017; 147: 1839-1849
- More good news! Another step forward in B12 research. Pernicious Anaemia Society website.(Published June 29, 2018. Accessed December 28, 2018)
- NHG-Standpunt Diagnostiek van vitamine-B12-deficiëntie.https://www.nhg.org/sites/default/files/content/nhg_org/images/nhg-standpunt_vitamine_b12-2.pdfDate accessed: December 28, 2018
- Oral vitamin B12 versus intramuscular vitamin B12 for vitamin B12 deficiency.Cochrane Database Syst Rev. 2005; : CD004655
- Effective treatment of cobalamin deficiency with oral cobalamin.Blood. 1998; 92: 1191-1198
- The availability of therapeutic hydroxocobalamin to cells.Blood. 1984; 63: 335-341
- Oral versus intramuscular cobalamin treatment in megaloblastic anemia: a single-center, prospective, randomized, open-label study.Clin Ther. 2003; 25: 3124-3134
- Oral vitamin B12 versus intramuscular vitamin B12 for vitamin B12 deficiency.Cochrane Database Syst Rev. 2018; 3: CD004655
- Use of vitamin B12 in the treatment and prevention of nitroprusside-induced cyanide toxicity.Crit Care Med. 1993; 21: 465-467
- Clinical trials of ultra-high-dose methylcobalamin in ALS.Brain Nerve. 2007; 59 ([in Japanese]): 1141-1147
- Rosacea fulminans triggered by high-dose vitamins B6 and B12.J Eur Acad Dermatol Venereol. 2001; 15: 484-485
- Brain mechanisms of the placebo effect: an affective appraisal account.Annu Rev Clin Psychol. 2017; 13: 73-98
- Effect of oral vitamin B-12 with or without folic acid on cognitive function in older people with mild vitamin B-12 deficiency: a randomized, placebo-controlled trial.Am J Clin Nutr. 2006; 84: 361-370
- Systematic review and meta-analysis of randomized placebo-controlled trials of folate and vitamin B12 for depression.Int Psychogeriatr. 2015; 27: 727-737
- Effectiveness of vitamin B12 in treating recurrent aphthous stomatitis: a randomized, double-blind, placebo-controlled trial.J Am Board Fam Med. 2009; 22: 9-16
- Vitamin B12 in low back pain: a randomised, double-blind, placebo-controlled study.Eur Rev Med Pharmacol Sci. 2000; 4: 53-58
Article info
Footnotes
Potential Competing Interests: The authors report no conflicts of interest.
Identification
Copyright
© 2019 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc.
User license
Creative Commons Attribution – NonCommercial – NoDerivs (CC BY-NC-ND 4.0) | How you can reuse 
Elsevier's open access license policy
Creative Commons Attribution – NonCommercial – NoDerivs (CC BY-NC-ND 4.0)
Permitted
For non-commercial purposes:
- Read, print & download
- Redistribute or republish the final article
- Text & data mine
- Translate the article (private use only, not for distribution)
- Reuse portions or extracts from the article in other works
Not Permitted
- Sell or re-use for commercial purposes
- Distribute translations or adaptations of the article
Elsevier's open access license policy
