UpToDate
Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Clinical manifestations and diagnosis of vitamin B12 and folate deficiency

Author
Stanley L Schrier, MD
Section Editor
William C Mentzer, MD
Deputy Editor
Jennifer S Tirnauer, MD

INTRODUCTION

This topic review discusses the symptoms, clinical manifestations, and diagnosis of vitamin B12 and folate deficiency, vitamins that are required for normal hematopoiesis and neurologic function. Vitamin B12 and folate deficiencies are often considered together, although folate deficiency has become exceedingly rare in individuals who are living in developed countries and consuming a normal diet.

Separate topic reviews discuss the treatment of these deficiencies, their causes and pathophysiology, and other causes of macrocytic anemia:

Treatment – (See "Treatment of vitamin B12 and folate deficiencies".)

Pathophysiology – (See "Causes and pathophysiology of vitamin B12 and folate deficiencies".)

Other macrocytic anemias – (See "Macrocytosis/Macrocytic anemia".)

                                
To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:

Subscribers log in here

Literature review current through: Oct 2017. | This topic last updated: Jun 28, 2017.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
References
Top
  1. Scaglione F, Panzavolta G. Folate, folic acid and 5-methyltetrahydrofolate are not the same thing. Xenobiotica 2014; 44:480.
  2. Kelly GS. Folates: supplemental forms and therapeutic applications. Altern Med Rev 1998; 3:208.
  3. Stouten K, Riedl JA, Droogendijk J, et al. Prevalence of potential underlying aetiology of macrocytic anaemia in Dutch general practice. BMC Fam Pract 2016; 17:113.
  4. Theisen-Toupal J, Horowitz G, Breu A. Low yield of outpatient serum folate testing: eleven years of experience. JAMA Intern Med 2014; 174:1696.
  5. Lindenbaum J, Rosenberg IH, Wilson PW, et al. Prevalence of cobalamin deficiency in the Framingham elderly population. Am J Clin Nutr 1994; 60:2.
  6. Carmel R. Prevalence of undiagnosed pernicious anemia in the elderly. Arch Intern Med 1996; 156:1097.
  7. Gudgeon P, Cavalcanti R. Folate testing in hospital inpatients. Am J Med 2015; 128:56.
  8. Crider KS, Bailey LB, Berry RJ. Folic acid food fortification-its history, effect, concerns, and future directions. Nutrients 2011; 3:370.
  9. http://www.ffinetwork.org/global_progress/ (Accessed on April 25, 2017).
  10. Stabler SP. Clinical practice. Vitamin B12 deficiency. N Engl J Med 2013; 368:149.
  11. Hunt A, Harrington D, Robinson S. Vitamin B12 deficiency. BMJ 2014; 349:g5226.
  12. Hvas AM, Nexo E. Diagnosis and treatment of vitamin B12 deficiency--an update. Haematologica 2006; 91:1506.
  13. Green R. Vitamin B12 deficiency from the perspective of a practicing hematologist. Blood 2017.
  14. Mazokopakis EE, Starakis IK. Recommendations for diagnosis and management of metformin-induced vitamin B12 (Cbl) deficiency. Diabetes Res Clin Pract 2012; 97:359.
  15. Bauman WA, Shaw S, Jayatilleke E, et al. Increased intake of calcium reverses vitamin B12 malabsorption induced by metformin. Diabetes Care 2000; 23:1227.
  16. Toh SY, Zarshenas N, Jorgensen J. Prevalence of nutrient deficiencies in bariatric patients. Nutrition 2009; 25:1150.
  17. Carmel R. How I treat cobalamin (vitamin B12) deficiency. Blood 2008; 112:2214.
  18. Amess JA, Burman JF, Rees GM, et al. Megaloblastic haemopoiesis in patients receiving nitrous oxide. Lancet 1978; 2:339.
  19. Garakani A, Jaffe RJ, Savla D, et al. Neurologic, psychiatric, and other medical manifestations of nitrous oxide abuse: A systematic review of the case literature. Am J Addict 2016; 25:358.
  20. https://ods.od.nih.gov/factsheets/VitaminB12-HealthProfessional/ (Accessed on April 03, 2017).
  21. https://ods.od.nih.gov/factsheets/Folate-HealthProfessional/ (Accessed on April 03, 2017).
  22. Devalia V, Hamilton MS, Molloy AM, British Committee for Standards in Haematology. Guidelines for the diagnosis and treatment of cobalamin and folate disorders. Br J Haematol 2014; 166:496.
  23. Reynolds EH. The neurology of folic acid deficiency. Handb Clin Neurol 2014; 120:927.
  24. Lindenbaum J, Healton EB, Savage DG, et al. Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or macrocytosis. N Engl J Med 1988; 318:1720.
  25. Lever EG, Elwes RD, Williams A, Reynolds EH. Subacute combined degeneration of the cord due to folate deficiency: response to methyl folate treatment. J Neurol Neurosurg Psychiatry 1986; 49:1203.
  26. Green R, Miller JW. Folate deficiency beyond megaloblastic anemia: hyperhomocysteinemia and other manifestations of dysfunctional folate status. Semin Hematol 1999; 36:47.
  27. Okada A, Koike H, Nakamura T, et al. Slowly progressive folate-deficiency myelopathy: report of a case. J Neurol Sci 2014; 336:273.
  28. Green R, Datta Mitra A. Megaloblastic Anemias: Nutritional and Other Causes. Med Clin North Am 2017; 101:297.
  29. Pittock SJ, Payne TA, Harper CM. Reversible myelopathy in a 34-year-old man with vitamin B12 deficiency. Mayo Clin Proc 2002; 77:291.
  30. Hemmer B, Glocker FX, Schumacher M, et al. Subacute combined degeneration: clinical, electrophysiological, and magnetic resonance imaging findings. J Neurol Neurosurg Psychiatry 1998; 65:822.
  31. Tangney CC, Tang Y, Evans DA, Morris MC. Biochemical indicators of vitamin B12 and folate insufficiency and cognitive decline. Neurology 2009; 72:361.
  32. Sharrief AZ, Raffel J, Zee DS. Vitamin B(12) deficiency with bilateral globus pallidus abnormalities. Arch Neurol 2012; 69:769.
  33. Tucker KL, Hannan MT, Qiao N, et al. Low plasma vitamin B12 is associated with lower BMD: the Framingham Osteoporosis Study. J Bone Miner Res 2005; 20:152.
  34. Dhonukshe-Rutten RA, Lips M, de Jong N, et al. Vitamin B-12 status is associated with bone mineral content and bone mineral density in frail elderly women but not in men. J Nutr 2003; 133:801.
  35. Goerss JB, Kim CH, Atkinson EJ, et al. Risk of fractures in patients with pernicious anemia. J Bone Miner Res 1992; 7:573.
  36. Merriman NA, Putt ME, Metz DC, Yang YX. Hip fracture risk in patients with a diagnosis of pernicious anemia. Gastroenterology 2010; 138:1330.
  37. Carmel R, Lau KH, Baylink DJ, et al. Cobalamin and osteoblast-specific proteins. N Engl J Med 1988; 319:70.
  38. Kim GS, Kim CH, Park JY, et al. Effects of vitamin B12 on cell proliferation and cellular alkaline phosphatase activity in human bone marrow stromal osteoprogenitor cells and UMR106 osteoblastic cells. Metabolism 1996; 45:1443.
  39. Stone KL, Bauer DC, Sellmeyer D, Cummings SR. Low serum vitamin B-12 levels are associated with increased hip bone loss in older women: a prospective study. J Clin Endocrinol Metab 2004; 89:1217.
  40. Cagnacci A, Baldassari F, Rivolta G, et al. Relation of homocysteine, folate, and vitamin B12 to bone mineral density of postmenopausal women. Bone 2003; 33:956.
  41. Pruthi RK, Tefferi A. Pernicious anemia revisited. Mayo Clin Proc 1994; 69:144.
  42. Antony AC. Megaloblastic anemias. In: Hematology: Basic principles and practice, 4th ed, Hoffman R, Benz EJ, Shattil SJ, et al. (Eds), Churchill Livingstone, New York 2005. p.519.
  43. Oberley MJ, Yang DT. Laboratory testing for cobalamin deficiency in megaloblastic anemia. Am J Hematol 2013; 88:522.
  44. Matchar DB, McCrory DC, Millington DS, Feussner JR. Performance of the serum cobalamin assay for diagnosis of cobalamin deficiency. Am J Med Sci 1994; 308:276.
  45. Metz J, McGrath K, Bennett M, et al. Biochemical indices of vitamin B12 nutrition in pregnant patients with subnormal serum vitamin B12 levels. Am J Hematol 1995; 48:251.
  46. Naurath HJ, Joosten E, Riezler R, et al. Effects of vitamin B12, folate, and vitamin B6 supplements in elderly people with normal serum vitamin concentrations. Lancet 1995; 346:85.
  47. Solomon LR. Cobalamin-responsive disorders in the ambulatory care setting: unreliability of cobalamin, methylmalonic acid, and homocysteine testing. Blood 2005; 105:978.
  48. Morkbak AL, Hvas AM, Milman N, Nexo E. Holotranscobalamin remains unchanged during pregnancy. Longitudinal changes of cobalamins and their binding proteins during pregnancy and postpartum. Haematologica 2007; 92:1711.
  49. Hamilton MS, Blackmore S, Lee A. Possible cause of false normal B-12 assays. BMJ 2006; 333:654.
  50. Yang DT, Cook RJ. Spurious elevations of vitamin B12 with pernicious anemia. N Engl J Med 2012; 366:1742.
  51. Carmel R, Agrawal YP. Failures of cobalamin assays in pernicious anemia. N Engl J Med 2012; 367:385.
  52. Stabler SP, Allen RH, Savage DG, Lindenbaum J. Clinical spectrum and diagnosis of cobalamin deficiency. Blood 1990; 76:871.
  53. Lindenbaum J, Savage DG, Stabler SP, Allen RH. Diagnosis of cobalamin deficiency: II. Relative sensitivities of serum cobalamin, methylmalonic acid, and total homocysteine concentrations. Am J Hematol 1990; 34:99.
  54. Norman EJ, Morrison JA. Screening elderly populations for cobalamin (vitamin B12) deficiency using the urinary methylmalonic acid assay by gas chromatography mass spectrometry. Am J Med 1993; 94:589.
  55. Savage DG, Lindenbaum J, Stabler SP, Allen RH. Sensitivity of serum methylmalonic acid and total homocysteine determinations for diagnosing cobalamin and folate deficiencies. Am J Med 1994; 96:239.
  56. Hvas AM, Ellegaard J, Nexø E. Increased plasma methylmalonic acid level does not predict clinical manifestations of vitamin B12 deficiency. Arch Intern Med 2001; 161:1534.
  57. Carmel R. 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.
  58. Carmel R. Pepsinogens and other serum markers in pernicious anemia. Am J Clin Pathol 1988; 90:442.
  59. Alonso N, Granada ML, Salinas I, et al. Serum pepsinogen I: an early marker of pernicious anemia in patients with type 1 diabetes. J Clin Endocrinol Metab 2005; 90:5254.
  60. Galloway M, Rushworth L. Red cell or serum folate? Results from the National Pathology Alliance benchmarking review. J Clin Pathol 2003; 56:924.
  61. Kaptan K, Beyan C, Ural AU, et al. Helicobacter pylori--is it a novel causative agent in Vitamin B12 deficiency? Arch Intern Med 2000; 160:1349.
  62. Stopeck A. Links between Helicobacter pylori infection, cobalamin deficiency, and pernicious anemia. Arch Intern Med 2000; 160:1229.
  63. Hsing AW, Hansson LE, McLaughlin JK, et al. Pernicious anemia and subsequent cancer. A population-based cohort study. Cancer 1993; 71:745.
  64. Vannella L, Lahner E, Osborn J, Annibale B. Systematic review: gastric cancer incidence in pernicious anaemia. Aliment Pharmacol Ther 2013; 37:375.
  65. Murphy G, Dawsey SM, Engels EA, et al. Cancer Risk After Pernicious Anemia in the US Elderly Population. Clin Gastroenterol Hepatol 2015; 13:2282.
  66. Talley NJ, Chute CG, Larson DE, et al. Risk for colorectal adenocarcinoma in pernicious anemia. A population-based cohort study. Ann Intern Med 1989; 111:738.
  67. Boursi B, Mamtani R, Haynes K, Yang YX. Pernicious anemia and colorectal cancer risk - A nested case-control study. Dig Liver Dis 2016; 48:1386.
  68. Minoli G, Prada A, Gambetta G, et al. The ASGE guidelines for the appropriate use of upper gastrointestinal endoscopy in an open access system. Gastrointest Endosc 1995; 42:387.
  69. Pritchard DM, Hooper M. Letter: gastric cancer and pernicious anaemia--only a minority of UK pernicious anaemia patients have had a gastroscopy. Aliment Pharmacol Ther 2016; 43:1106.