GPAC: Guidelines and Protocols Advisory Committee

B12 Deficiency - Investigation & Management of Vitamin B12 and Folate Deficiency

Effective Date: December 15, 2006

Summary | Flow Sheet | Patient Guide | Full Guideline in PDF

Recommendations and Topics

Scope

Highlights

1. Indications for Investigation of Vitamin B12 Deficiency

2. Diagnosis of Vitamin B12 deficiency

3. Treatment of vitamin B12 deficiency

4. Folate deficiency

Rationale

References

Sponsors

Appendix 1: Common Food Sources of Vitamin B12 and Folate

Scope

This guideline summarizes the current knowledge of the investigation and management of vitamin B12 (cobalamin) and folate deficiency in adults.

Highlights

• Oral vitamin B12 is as effective as parenteral administration in treating B12 deficiency in most cases
• As food in Canada is now fortified with folic acid, low blood folate levels are rarely encountered and routine ordering of folate tests is no longer justified
• Health Canada recommends that women planning pregnancy should consider a daily supplement of 0.4 mg folic acid beginning at least three months before conception to help reduce the risk of first occurrence of a neural tube defect. A recent study indicates adding other vitamins to folic acid may further reduce the incidence of neural tube and other birth defects¹

RECOMMENDATION 1: Indications for Investigation of Vitamin B12 Deficiency

Vitamin B12 deficiency may be suspected in the following circumstances:

• macrocytic anemia, or macrocytosis with oval macrocytes
• unexplained neurologic symptoms, such as paresthesias, numbness, or cognitive changes
• elderly people with poor diet and/or with neuropsychiatric symptoms
• vegan diet (long-term)
• inflammatory bowel disease
• history of gastric or small intestine surgery
• long-term use of histamine (H₂) receptor antagonists or proton pump inhibitors

RECOMMENDATION 2: Diagnosis of Vitamin B12 deficiency

For investigation of suspected vitamin B12 deficiency, measurement of serum vitamin B12 is the standard test; however, it is important that serum B12 levels be interpreted in light of clinical symptoms, because the test has the following limitations:

• It measures total, not metabolically active vitamin B12
• The levels are not easily correlated with clinical symptoms
• There is a large "grey zone" between the normal and abnormal levels
• The reference intervals may vary between laboratories and the results should be interpreted accordingly.

The conventional reference interval for serum vitamin B12 is 150-600 pmol/L. Using this reference interval, the following interpretation is recommended:

Note:

1. Clinically significant vitamin B12 deficiency may occur with vitamin B12 levels in the normal range, particularly in elderly patients.
2. The most serious cause of vitamin B12 deficiency is lack of intrinsic factor resulting in pernicious anemia. If pernicious anemia is suspected from history and clinical examination, consultation with a specialist is recommended.
3. Women taking oral contraceptives may have decreased blood vitamin B12 levels, which may not represent a deficiency state; rather this may be due to a decrease in cobalamin-carrier protein.

RECOMMENDATION 3: Treatment of vitamin B12 deficiency

Oral replacement of vitamin B12 is the treatment of choice in most cases, including pernicious anemia. Patients with significant neurological symptoms, however, should receive initial intramuscular injections of 1000 µg vitamin B12, followed by oral doses of 1000-2000 µg/day. The duration of therapy depends on the cause of deficiency. In the case of pernicious anemia, treatment is life-long. Early treatment of vitamin B12 deficiency is particularly important because neurologic symptoms may be irreversible.

RECOMMENDATION 4: Folate deficiency

Folic acid deficiency is associated with megaloblastic anemia² and birth defects (especially neural tube defects),^1,3 and may be associated with cardiovascular disease,⁴ and certain types of cancer.⁵

• As all cereal-based foods in Canada are now fortified with folic acid, folic acid deficiency is rare. As less than one per cent of all folate tests are abnormal,^{(J.Heathcote, BC Biomedical Laboratories, D.Holmes, St. Paul's Hospital, personal communication)} testing is rarely indicated.
• If folate deficiency is suspected, it is reasonable to give folic acid orally (3-5 mg/day) without doing laboratory investigation for deficiency.
• Pregnant women and those planning to become pregnant should take 0.4 mg folic acid daily starting at least three months before conception and continuing throughout the pregnancy.
• In suspected B12 deficiency, folic acid alone should not be given as it may exacerbate/precipitate neurological symptoms.

Rationale

Vitamin B12 is found in animal products, primarily meat, seafood, dairy products and eggs.⁶ Folate is found in a variety of foods, with the most common sources found in vegetables, fruit, cereals, and dairy products.⁶ The recommended daily allowance of vitamin B12 is 2.4 µg,⁷ body stores are 2-5 mg, and the time to exhaust body stores is 2-5 years.² The recommended daily allowance of folate is 400 µg for an adult, and 600 µg during pregnancy.⁷ Common food sources of vitamin B12 and folate are found in Appendix 1.

Vitamin B12 deficiency is unusual among younger people except for strict long-term vegans.⁸ Pernicious anemia is the most important result of vitamin B12 deficiency; however, there has been some evidence for the association of vitamin B12 deficiency and psychiatric problems in the elderly. A prospective survey of elderly (> 60 yrs) North Americans revealed that 1.9 per cent of the population had unrecognized and untreated pernicious anemia.⁹

Vitamin B12 deficiency can occur due to inadequate intake or impaired absorption. Reduction in gastric acid production during aging probably accounts for most of the increased prevalence of vitamin B12 deficiency with age, because gastric acid is required to release vitamin B12 bound to proteins in food.¹⁰ H. pylori infection¹¹ and long-term use of drugs that interfere with acid production such as H₂ blockers and proton pump inhibitors can also exacerbate deficiency.¹⁰ In pernicious anemia, autoimmune destruction of parietal cells gradually decreases availability of intrinsic factor (IF) which is required for B12 absorption. Gastrectomy or gastric bypass may also impede intestinal absorption due to reduction of intrinsic factor.

In patients with hematologic/clinical abnormalities suggestive of vitamin B12 deficiency, serum vitamin B12 should be measured. Patients with serum vitamin B12 <75 pmol/L usually have clinical or metabolic evidence of vitamin B12 deficiency.² In most patients with symptoms of vitamin B12 deficiency, the serum vitamin B12 level is below the reference interval (<150 pmol/L). However, it is estimated that between three to five per cent of clinical vitamin B12 deficiencies occur in the range of 150-220 pmol/L and in some cases (0.2 per cent) can occur above this level.^12,13

In most cases oral vitamin B12 (1000 - 2000 µg/day) is as effective in treating vitamin B12 deficiency as parenteral vitamin B12.¹⁴ In such doses, a small but adequate portion of vitamin B12 is absorbed even in the absence of intrinsic factor. Routine use of oral treatment in place of injection will reduce the costs of vitamin B12 treatment considerably.¹⁵ Patients with significant neurological deficit, however, should receive initial intramuscular injections of vitamin B12, followed by oral replacement. Timely treatment with vitamin B12 is essential because cognitive dysfunction can be prevented by early intervention.¹⁶

Folate deficiency can occur due to inadequate intake, increased demand (pregnancy, infancy), diseases where there is rapid cellular proliferation (i.e. haemolytic anemias), malabsorption, alcoholism, and drug interactions (i.e. anti-convulsants, oral contraceptives, sulfasalazine, methotrexate).² Folate deficiency is usually suspected when there is unexplained anemia, or macrocytosis.² With the implementation of folic acid fortification of foods in Canada, the average folate levels have increased significantly in the population, and consequently, folate deficiency is now uncommon. In two laboratories in British Columbia, 99.8 per cent and 99.1 per cent of folate tests were normal.^{J.Heathcote, BC Biomedical Laboratories, D.Holmes, St. Paul's Hospital, personal communication)} When folate deficiency is clinically suspected, a therapeutic trial of folate may be considered without laboratory investigation for deficiency.² In rare cases of undiagnosed pernicious anemia resulting from vitamin B12 deficiency, folate administration alone may exacerbate symptoms.

References

1. Goh YI, Bollano E, Einarson TR, Koren G. Prenatal multivitamin supplementation and rates of congenital anomalies: A Meta-Anaylsis. J Obstet Gynaecol Can 2006;28(8):680-689.
2. Snow CF. Laboratory diagnosis of vitamin B12 and folate deficiency. A guide for the primary care physician. Arch Intern Med 1999;159:1289-1298.
3. Ray J.G. Folic acid food fortification in Canada. Nutrition Reviews 2004;62(6):S35-S39.
4. Voutilainen S, et al. Serum folate and homocysteine and the incidence of acute coronary events: the Kuopio Ischaemic Heart Disease Risk Factor Study. Am J Clin Nutr 2004;80:317-23.
5. Stover PJ. Physiology of folate and vitamin B12 in health and disease. Nutrition Reviews. 2004;62(6):S3-S12.
6. Health Canada. Nutrient value of some common foods.1999; [55 pages]. Available at URL: http://www.hc-sc.gc.ca/fn-an/alt_formats/hpfb-dgpsa/pdf/nutrition/nvscf-vnqau_e.pdf Accessed July 10, 2006.
7. Health Canada. Dietary reference intakes reference values for vitamins. 2006 [4 screens]. Available at URL: http://www.hc-sc.gc.ca/fn-an/nutrition/reference/table/ref_vitam_tbl_e.html Accessed July 05, 2006.
8. Rauma AL, Torronen R, Hanninen O, et al. Vitamin B12 status of long-term adherents of a strict uncooked vegan diet ("living food diet") is compromised. J Nutr 1995;125(10):2511-2515.
9. Carmel R. Prevalence of undiagnosed pernicious anemia in the elderly. Arch Intern Med 1996; 156(10):1097-1100.
10. Carmel, R. Current concepts in cobalamin deficiency. Annu Rev Med 2000;51:357-375.
11. Stopeck A. Links between Helicobacter pylori infection, cobalamin deficiency and pernicious anemia. Arch Intern Med 2000;160(9):1229-1230.
12. Allen RH, Stabler SP, Savage DG, Lindenbaum J. Diagnosis of cobalamin deficiency I: usefulness of serum methylmalonic acid and total homocysteine concentrations. Am J Hematol 1990;34:90-98.
13. 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(2):99-107.
14. Kuzminski AM, Del Giacco EJ, Allen RH, et al. Effective treatment of cobalamin deficiency with oral cobalamin. Blood 1998;92(4):1191-1198.
15. van Walraven C, Austin P, Naylor CD. Vitamin B12 injections versus oral supplements. How much money could be saved by switching from injections to pills? Can Fam Physician 2001;47:79-86.
16. Martin DC, Francis J, Protetch J, Huff FJ. Time dependency of cognitive recovery with cobalamin replacement: report of a pilot study. J Am Geriatr Soc. 1992;40(2):168-172.
17. Health Canada. Nutrition for a healthy pregnancy: national guidelines for the childbearing years. Ottawa: Minister of Public Works and Government Services Canada. 1999; [1 screen]. Available at URL: http://www.hc-sc.gc.ca/fn-an/nutrition/prenatal/national_guidelines-lignes_directrices_nationales-07-table3_e.html Accessed July 21, 2006.

Sponsors

This guideline was developed by the Guidelines and Protocols Advisory Committee, and supersedes the guideline for vitamin B12 and folate deficiency developed in July of 2003. This guideline has been approved by the British Columbia Medical Association and adopted by the Medical Services Commission.

Revised Date: April 1, 2007

This guideline is based on scientific evidence current as of the effective date.

Appendix 1: Common Food Sources of Vitamin B12 and Folate

Disclaimer

The Clinical Practice Guidelines (the "Guidelines") have been developed by the Guidelines and Protocols Advisory Committee on behalf of the Medical Services Commission. The Guidelines are intended to give an understanding of a clinical problem, and outline one or more preferred approaches to the investigation and management of the problem. The Guidelines are not intended as a substitute for the advice or professional judgment of a health care professional, nor are they intended to be the only approach to the management of clinical problems.

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