Vitamin B-12

Vitamin B-12 is the largest and most complex of all the vitamins.

VITAMIN B-12

Vitamin B-12 is the largest and most complex of all the vitamins.  It is unique among vitamins in that it contains a metal ion, cobalt. For this reason cobalaminis the term used to refer to compounds having B-12 activity. Methylcobalamin and 5-deoxyadenosyl cobalamin are the forms of vitamin B-12 used in the human body (1).  The form of cobalamin used in most supplements, cyanocobalamin, is readily converted to 5-deoxyadenosyl and methylcobalamin.

FUNCTION

Cofactor for methionine synthase: Methylcobalamin is required for the function of the folate-dependent enzyme, methionine synthase.  This enzyme is required for the synthesis of the amino acid, methionine, from homocysteine. Methionine is required for the synthesis of S-adenosylmethionine, a methyl group donor used in many biological methylation reactions, including the methylation of a number of sites within DNA and RNA (2).  Methylation of DNA may be important in cancer prevention. Inadequate function of methionine synthase can lead to an accumulation of homocysteine, which has been associated with increased risk of cardiovascular diseases (see Disease Prevention).

Cofactor for L-methylmalonyl-CoA mutase: 5-Deoxyadenosylcobalamin is required by the enzyme that catalyzes the conversion of L-methylmalonyl-CoA to succinyl-CoA.  This biochemical reaction plays an important role in the production of energy from fats and proteins.  Succinyl CoA is also required for the synthesis of hemoglobin, the oxygen carrying pigment in red blood cells (2).

DEFICIENCY

B-12 deficiency is estimated to affect 10%-15% of individuals over the age of 60 (3). Absorption of vitamin B-12 from food requires normal function of the stomach, pancreas, and small intestine.  Stomach acid and enzymes free vitamin B-12 from food, allowing it to bind to other proteins, known as R proteins (2). In the alkaline environment of the small intestine, R proteins are degraded by pancreatic enzymes, freeing vitamin B-12 to bind to intrinsic factor (IF), a protein secreted by specialized cells in the stomach.  Receptors on the surface of the small intestine take up the IF-B-12 complex only in the presence of calcium, which is also supplied by the pancreas (4). Vitamin B-12 can also be absorbed by passive diffusion, but this process is very inefficient, allowing only about 1% absorption of a vitamin B-12 dose (2).

Causes of vitamin B-12 deficiency: The most common causes of vitamin B-12 deficiency are pernicious anemia and food-bound vitamin B-12 malabsorption. Although both causes become more common with age, they are two separate conditions (3).

Pernicious anemia

      has been estimated to be present in approximately 2 % of individuals over 60 (

5

      ). Although anemia is often a symptom, the condition is actually the end stage of an autoimmune inflammation of the stomach, resulting in destruction of stomach cells by one’s own antibodies.  Progressive destruction of the cells that line the stomach cause decreased secretion of acid and enzymes required to release food bound vitamin B-12.  Antibodies to intrinsic factor (IF) bind to IF preventing formation of the IF-B-12 complex, further inhibiting vitamin B-12 absorption.  If the body’s vitamin B-12 stores are adequate prior to the onset of pernicious anemia, it may take years for symptoms of deficiency to develop. About 20% of the relatives of pernicious anemia patients also have pernicious anemia, suggesting a genetic predisposition.  Treatment of pernicious anemia generally requires injections of vitamin B-12, bypassing intestinal absorption. High-dose oral supplementation is another treatment option, because consuming 1000 mcg (1 mg)/day of vitamin B-12 orally should result in the absorption of about 10 mcg/day (about 1%) by passive diffusion (

3

      ).

Food-bound vitamin B-12 malabsorption is defined as an impaired ability to absorb food or protein-bound vitamin B-12, although the free form is fully absorbable (6). In the elderly, food-bound vitamin B-12 malabsorption is thought to result mainly from atrophic gastritis, a chronic inflammation of the lining of the stomach, which ultimately results in the loss of glands in the stomach (atrophy) and decreased stomach acid production. Because stomach acid is required for the release of vitamin B-12 from the proteins in food, vitamin B-12 absorption is diminished. Decreased stomach acid production also provides an environment more conducive to the overgrowth of anaerobic bacteria in the stomach, interfering further with vitamin B-12 absorption (2). Because vitamin B-12 in supplements is not bound to protein, and because intrinsic factor (IF) is still available, the absorption of supplemental vitamin B-12 is not reduced as it is in pernicious anemia.  Thus, individuals with food-bound vitamin B-12 malabsorption do not have an increased requirement for vitamin B-12; they simply need it in the form of a supplement rather than from food.

Atrophic gastritis is thought to affect 10% – 30% of people over 60 years of age, and is frequently associated with infection by the bacteria, Heliobacter pylori. H. pylori infection induces a chronic inflammation of the stomach which may progress to peptic ulcer disease, atrophic gastritis, and/or gastric (stomach) cancer in some individuals. The relationship of H. pylori infection to atrophic gastritis, gastric cancer, and vitamin B-12 deficiency is presently an area of active research (3).

Other causes of deficiency include surgical resection (removal) of the stomach or portions of the small intestine where receptors for the IF-B-12 complex are located.  Conditions affecting the small intestine, such as malabsorption syndromes (celiac disease and tropical sprue) may also result in vitamin B-12 deficiency. Because the pancreas provides critical enzymes as well as calcium required for vitamin B-12 absorption, pancreatic insufficiency may contribute to B-12 deficiency. Since vitamin B-12 is found only in foods of animal origin, a strict vegetarian (vegan) diet has resulted in cases of vitamin B-12 deficiency (see Food Sources).  In alcoholics, vitamin B-12 intake and absorption are reduced, while elimination is increased (4). Individuals with acquired immunodeficiency syndrome (AIDS) appear to be at increased risk of deficiency, possibly related to a failure of the IF-B-12 receptor to take up the IF-B-12 complex (2). Long-term use of acid-reducing drugs has also been implicated in vitamin B-12 deficiency (see Drug Interactions).

Symptoms of vitamin B-12 deficiency: Vitamin B-12 deficiency results in impairment of the activities of B-12-requiring enzymes (see Function). Impaired activity of methionine synthase may result in elevated homocysteine levels, while impaired activity of L-methylmalonyl-CoA mutase results in increased levels of a metabolite of methylmalonyl-CoA, called methylmalonic acid (MMA).  Individuals with mild vitamin B-12 deficiency may not experience symptoms, although blood levels of homocysteine and/or MMA may be elevated (7).

Megaloblastic anemia:

      Diminished activity of methionine synthase in vitamin B-12 deficiency inhibits the regeneration of tetrahydrofolate (THF) and traps folate in a form that is not usable by the body (see

Diagram

      ), resulting in symptoms of folate deficiency even in the presence of adequate folate levels. Thus, in both folate and vitamin B-12 deficiency, folate is unavailable to participate in DNA synthesis (see

Folic Acid

      ).  This impairment of DNA synthesis affects the rapidly dividing cells of the bone marrow earlier than other cells, resulting in the production of large, hemoglobin-poor red blood cells.  The resulting anemia is known as megaloblastic anemia and is the symptom for which the disease, pernicious anemia, was named (

2

      ). Supplementation of folic acid will provide enough usable folate to restore normal red blood cell formation. However, if vitamin B-12 deficiency was the cause, it will persist despite the resolution of the anemia. Thus, megaloblastic anemia should not be treated with folic acid until the underlying cause has been determined (

4

      ).

Neurologic symptoms: The neurologic symptoms of vitamin B-12 deficiency include numbness and tingling of the arms and more commonly the legs, difficulty walking, memory loss, disorientation, and dementia, with or without mood changes. Although the progression of neurologic complications is generally gradual, they are not always reversible with treatment of vitamin B-12 deficiency, especially if they have been present for a long time. Neurologic complications are not always associated with megaloblastic anemia, and are the only clinical symptom of vitamin B-12 deficiency in about 25% of cases (5).  Although vitamin B-12 deficiency is known to damage the myelin sheath covering cranial, spinal, and peripheral nerves, the biochemical processes leading to neurological damage in B-12 deficiency are not well understood (2).

Gastrointestinal symptoms: A sore tongue, appetite loss, and constipation have also been associated with vitamin B-12 deficiency. Their origins are unclear, but may be related to the stomach inflammation underlying some cases of B-12 deficiency, or the increased vulnerability of the rapidly dividing cells along the gastrointestinal tract to impaired DNA synthesis (5).

The Recommended Dietary Allowance (RDA): The current RDA was revised by the Food and Nutrition Board (FNB) of the Institute of Medicine in 1998 (5).

Adults ages 50 and younger: 2.4 micrograms (mcg) of vitamin B-12/day
Adults ages 51 and older:
2.4 mcg of vitamin B-12/day from supplements or fortified foods, due to the age-related increase in food bound malabsorption (see Deficiency)
Pregnant women:
2.6 mcg of vitamin B-12/day

DISEASE PREVENTION

Homocysteine and cardiovascular diseases: Evidence is mounting that an elevated blood homocysteine level is an independent risk factor for cardiovascular diseases (heart disease, stroke, and peripheral vascular diseases).  The amount of homocysteine in the blood is regulated by at least three vitamins:  folic acid, vitamin B-12, and vitamin B-6 (see Diagram).  Analysis of the results of 12 homocysteine-lowering trials showed folic acid supplementation (0.5-5 mg/day) to have the greatest lowering effect on blood homocysteine levels (25%), with vitamin B-12 (0.5 mg/day or 500 mcg/day) providing an additional 7% reduction (8).  However, there is evidence indicating that vitamin B-12 deficiency is a major cause of elevated homocysteine levels in people over the age of 60.  Two studies found blood methylmalonic acid (MMA) levels to be elevated in more than 60 % of elderly individuals with elevated homocysteine levels.  An elevated MMA level in conjuction with elevated homocysteine suggests either a vitamin B-12 deficiency, or a combined B-12 and folate deficiency, in the absence of  impaired kidney function (9).  Thus, it is important to evaluate vitamin B-12 status as well as kidney function in older individuals with elevated homocysteine levels, prior to initiating homocysteine-lowering therapy. For more information regarding homocysteine and cardiovascular diseases see Folic Acid.

Cancer: Folate is required for synthesis of DNA and there is evidence that decreased availability of folate results in strands of DNA that are more susceptible to damage. Deficiency of vitamin B-12 traps folate in a form that is unusable by the body for DNA synthesis. Both vitamin B-12 and folate deficiencies result in a diminished capacity for methylation reactions (seeDiagram). Thus, B-12 deficiency may lead to an elevated rate of DNA damage and altered methylation of DNA, both of which are important risk factors for cancer.  A recent series of studies in young adults and older men indicated that increased levels of homocysteine and decreased levels of vitamin B-12 in the blood were associated with a biomarker of chromosome breakage in white blood cells.  In a double-blind placebo- controlled study the same biomarker of choromosome breakage was minimized in young adults who were supplemented with 700 mcg of folic acid and 7 mcg of vitamin B-12 daily in cereal for two months (10).

A recent case control study compared prediagnostic levels of serum folate, vitamin B-6, and vitamin B-12 in 195 women later diagnosed with breast cancer and 195 age-matched women who were not diagnosed with breast cancer (11).  Among women who were postmenopausal at the time of blood donation, the association between blood levels of vitamin B-12 and breast cancer suggested a threshold effect. The risk of breast cancer was more than doubled in those women with serum vitamin B-12 levels in the lowest 20% (quintile) compared to those women in the four highest quintiles.  The investigators found no relationship between breast cancer and blood levels of vitamin B-6, folate, or homocysteine. Because this study was observational, it cannot be determined whether decreased blood levels of vitamin B-12 were a cause or a result of breast cancer. Previously, there has been little evidence to suggest a relationship between vitamin B-12 status and breast cancer risk. However, the above studies point to a need for further investigation of the relationship between vitamin B-12 status and cancer risk.

Neural tube defects: Neural tube defects (NTD) may result in anencephaly or spina bifida, devastating and sometimes fatal birth defects. The defects occur between the 21st and 27th days after conception, a time when many women do not realize they are pregnant (12). Randomized trials have demonstrated 60% to 100% reductions in NTD cases when women consumed folic acid supplements in addition to a varied diet during the month before and the month after conception (see Folic Acid). Increasing evidence indicates that the homocysteine-lowering effect of folic acid plays a critical role in lowering the risk of NTD (13).  Homocysteine may accumulate in the blood when there is inadequate folate and/or vitamin B-12 for effective functioning of the methionine synthase enzyme (see Function).  Decreased vitamin B-12 levels in the blood and amniotic fluid of pregnant women have been associated with an increased risk of NTD, suggesting that adequate vitamin B-12 intake in addition to folic acid may be beneficial in the prevention of NTD.

Alzheimer’s disease: Individuals with Alzheimer’s disease often have low blood levels of vitamin B-12.  One study found lower vitamin B-12 levels in the cerebrospinal fluid of patients with Alzheimer’s disease than in patients with other types of dementia, though blood levels of vitamin B-12 did not differ (14). The reason for the association of low vitamin B-12 status with Alzheimer’s disease is not clear. Vitamin B-12 deficiency, like folate deficiency, may lead to decreased synthesis of methionine and S-adenosylmethionine, adversely affecting methylation reactions  essential for the metabolism of components of the myelin sheath of nerve cells, as well as neurotransmitters. Elevated blood homocysteine levels have been associated with Alzheimer’s disease in several studies, suggesting that homocysteine-related cerebrovascular disease may play a role in the pathology of dementia (14). A recent case control study of 164 patients with dementia of Alzheimer’s type included 76 cases in which the diagnosis of Alzheimer’s disease was confirmed by examination of the brain cells after death. Compared to 108 control subjects without evidence of dementia, subjects with dementia of Alzheimer’s type and confirmed Alzheimer’s disease had higher blood homocysteine levels and lower folate and vitamin B-12 levels (15). Measures of general nutritional status indicated that the association of increased homocysteine levels and diminished vitamin B-12 status with Alzheimer’s disease was not due to dementia-related malnutrition. However, clarification of the nature of the relationship of vitamin B-12 status to Alzheimer’s disease risk will require further study before recommendations can be made.

Depression: Observational studies have found as many as 30% of patients hospitalized for depression to be deficient in vitamin B-12 (16). A recent cross-sectional study of 700 community-living physically disabled women over the age of 65 found that vitamin B-12 deficient individuals were twice as likely to be severely depressed as non-deficient individuals (17).  The reasons for the relationship between vitamin B-12 deficiency and depression are not clear. Vitamin B-12 and folate are required for the synthesis of  S-adenosylmethionine, a methyl group donor essential for the metabolism of neurotransmitters, whose bioavailability has been related to depression.  Because few studies have examined the relationship of vitamin B-12 status and the development of depression over time, it cannot yet be determined if vitamin B-12 deficiency plays a causal role in depression.  However, due to the high prevalence of vitamin B-12 deficiency in older individuals, it may be beneficial to screen them for vitamin B-12 deficiency as part of a medical evaluation for depression.

FOOD SOURCES

Only bacteria can synthesize vitamin B-12.  Vitamin B-12 is present in animal products such as meat, poultry, fish (including shellfish) and to a lesser extent milk, but it is not generally present in plant products or yeast (1). Fresh pasteurized milk contains 0.9 mcg per cup and is an important source of vitamin B-12 for some vegetarians (5).  Those vegetarians who eat no animal products need supplemental vitamin B-12 to meet their requirements.  Also, individuals over the age of 50 should obtain their vitamin B-12 in supplements or fortified foods, like fortified cereal, because of the increased likelihood of food-bound vitamin B-12 malabsorption (see Deficiency).

Most people do not have a problem obtaining the RDA of 2.4 mcg/day of vitamin B-12 in food.  In the United States, the average intake of vitamin B-12 is about 4.5 mcg/day for young adult men, and 3 mcg/day for young adult women.  In a sample of adults over the age of 60, men were found to have an average dietary intake of 3.4 mcg/day and women 2.6 mcg/day (5). Some foods with substantial amounts of vitamin B-12 are listed in the table below along with their vitamin B-12 content in micrograms (mcg). For more information on the nutrient content of foods you eat frequently, search the USDA food composition database.

Food Serving Vitamin B-12 (mcg)
Clams (steamed) 3 ounces 84.0
Mussels (steamed) 3 ounces 20.4
Crab (steamed) 3 ounces 8.8
Salmon (baked) 3 ounces* 2.4
Rockfish (baked) 3 ounces 1.0
Beef (cooked) 3 ounces 2.1
Chicken (roasted) 3 ounces 0.3
Turkey (roasted) 3 ounces 0.3
Egg (poached) 1 large 0.4
Milk 8 ounces 0.9
Brie (cheese) 1 ounce 0.5

*A three-ounce serving of meat or fish is about the size of a deck of cards.

SAFETY

Toxicity: No toxic or adverse effects have been associated with large intakes of vitamin B-12 from food or supplements in healthy people.  Doses as high as 1 mg (1,000 mcg) daily by mouth or 1 mg monthly by intramuscular (IM) injection have been used to treat pernicious anemia, without significant side effects.  When high doses of vitamin B-12 are given orally only a small percentage can be absorbed, which may explain its low toxicity.  Because of the low toxicity of vitamin B-12, no tolerable upper intake level (UL) was set by the Food and Nutrition Board in 1998 when the RDA was revised (5).

Drug interactions:
A number of drugs reduce the absorption of vitamin B-12.  Proton pump inhibitors (e.g., omeprazole and lansoprazole), used for therapy of Zoellinger-Ellison syndrome and gastroesophageal reflux disease (GERD), markedly decrease stomach acid secretion required for the release of vitamin B-12 from food but not supplements. Long-term use of proton pump inhibitors has been found to decrease blood vitamin B-12 levels.  However, vitamin B-12 deficiency does not generally develop until after at least three years of continuous therapy (18). Another class of gastric acid inhibitors known as H2-receptor antagonists (e.g., Tagamet, Pepsid, Zantac), often used to treat peptic ulcer disease, has also been found to decrease the absorption of vitamin B-12 from food. Because inhibition of gastric acid secretion is not as prolonged as with proton pump inhibitors H2-receptor antagonists have not been found to cause overt vitamin B-12 deficiency even after long-term use (19). Individuals taking drugs that inhibit gastric acid secretion should consider taking vitamin B-12 in the form of a supplement, because gastric acid is not required for its absorption. Other drugs found to inhibit the absorption of vitamin B-12 from food include cholestyramine (a bile acid-binding resin used in the treatment of high cholesterol), chloramphenicol, neomycin (antibiotics), and colchicine (anti-gout). Metformin (Glucophage) a medication for individuals with Type II (adult onset) diabetes decreases vitamin B-12 absorption by tying up free calcium required for absorption of the IF-B-12 complex. This effect is correctable by drinking milk or taking calcium carbonate tablets along with food or supplements (4). Previous reports that megadoses of vitamin C resulted in the destruction of vitamin B-12 have not been supported (20) and may have been an artifact of the assay used to measure vitamin B-12 levels (5).

Nitrous oxide, a commonly used anesthetic inhibits both vitamin B-12 dependent enzymes and can produce many of the clinical features of vitamin B-12 deficiency, such as megaloblastic anemia or neuropathy (see Deficiency).  Because nitrous oxide is commonly used for surgery in the elderly, some experts feel vitamin B-12 deficiency should be ruled out prior to its use (3,7).

Large doses of folic acid given to an individual with an undiagnosed vitamin B-12 deficiency could correct megaloblastic anemia without correcting the underlying vitamin B-12 deficiency, leaving the individual at risk of developing irreversible neurologic damage (5).  For this reason the Food and Nutrition Board of the Institute of Medicine advises that all adults limit their intake of folic acid (supplements and fortification) to 1,000 mcg (1 mg) daily (see Folic Acid: Safety).

LINUS PAULING INSTITUTE RECOMMENDATION

A varied diet should provide enough vitamin B-12 to prevent deficiency in most individuals 50 years of age and younger.  Individuals over the age of 50, strict vegetarians, and women planning to become pregnant should take a multivitamin tablet daily or eat a fortified breakfast cereal, which would ensure a daily intake of 6 to 30 mcg of vitamin B-12 in a form that is easily absorbed.

Older adults (65 years and over): Because vitamin B-12 malabsorption and vitamin B-12 deficiency are more common in older adults, some respected nutritionists recommend 100 to 400 mcg/day of supplemental vitamin B-12, an amount provided by a number of vitamin B-complex supplements. Vitamin B-12 injections are not necessary unless an individual has been diagnosed with pernicious anemia.

REFERENCES

  1. Brody, T. Nutritional Biochemistry. San Diego, CA: Academic Press, 1999: pages 516-524.
  2. Shane, B. Folic acid, vitamin B-12, and vitamin B-6. In Stipanuk, M. Ed. Biochemical and Physiological Aspects of Human Nutrition. Philadelphia, PA: W.B. Saunders Co., 2000: pages 483-518.
  3. Baik, H.W. & Russell, R.M. Vitamin B-12 deficiency in the elderly. Annual Review of Nutrition. 1999; volume 19: pages 357-77. (PubMed)
  4. Herbert, V. Vitamin B-12. In Ziegler, E.E. & Filer, L.J. Eds. Present Knowledge in Nutrition. Washington D.C.: ILSI Press, 1996: pages 191-205.
  5. Institute of Medicine, Food and Nutrition Board. Dietary Reference Intakes: Thiamin, Riboflavin, Niacin, Vitamin B-6, Vitamin B-12, Pantothenic Acid, Biotin, and Choline. Washington, DC: National Academy Press, 1998: pages 306-356. (National Academy Press)
  6. Ho, C. et al. Practitioners’ guide to meeting the vitamin B-12 recommended dietary allowance for people aged 51 years and older. Journal of the American Dietetic Association. 1999; volume 99: pages 725-777. (PubMed)
  7. Weir, D.G. & Scott, J.M. Vitamin B-12 “Cobalamin”. In Shils, M. et al. Eds. Nutrition in Health and Disease, 9th Edition. Baltimore: Williams & Wilkins, 1999: pages 447-458.
  8. Homocysteine Lowering Trialists’ Collaboration. Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials. British Medical Journal (BMJ). 1998; volume 316: pages 894-898. (PubMed)
  9. Stabler, S.P. et al. Vitamin B-12 deficiency in the elderly: current dilemmas. American Journal of Clinical Nutrition. 1997; volume 66: pages 741-749. (PubMed)
  10. Fenech, M. Micronucleus frequency in human lymphocytes is related to plasma vitamin B-12 and homocysteine. Mutation Research. 1999; volume 428: pages 299-304. (PubMed)
  11. Wu, K. et al. A prospective study on folate, B-12, and pyridoxal 5′-phosphate (B-6) and breast cancer.  Cancer Epidemiology Biomarkers and Prevention. 1999; volume 8: pages 209-217. (PubMed)
  12. Eskes, T. Open or closed? A world of difference: a history of homocysteine research. Nutrition Reviews. 1998; volume 56: pages 236-244. (PubMed)
  13. Mills, J.L. et al. Homocysteine and neural tube defects. Journal of Nutrition. 1996; volume 126 (supplement): pages 756S-760S. (PubMed)
  14. Nourhashemi, F. et al. Alzheimer disease: protective factors. American Journal of Clinical Nutrition. 2000; volume 71 (supplement): pages 643S-649S. (PubMed)
  15. Clarke, R. et al. Folate, vitamin B-12, and serum total homocysteine levels in confirmed Alzheimer disease. Archives of Neurology. 1998; volume 55: pages 1449-1455. (PubMed)
  16. Hutto, B.R. Folate and cobalamin in psychiatric illness. Comprehensive Psychiatry. 1997; volume 38: pages 305-314. (PubMed)
  17. Penninx, B.W. et al. Vitamin B-12 deficiency and depression in physically disabled older women: epidemiologic evidence from the Women’s Health  and Aging Study. American Journal of Psychiatry. 2000; volume 157: pages 715-721.(PubMed)
  18. Kasper, H. Vitamin absorption in the elderly. International Journal of Vitamin and Nutrition Research. 1999; volume 69: pages 169-172.
  19. Termanini, B. et al. Effect of long-term gastric acid suppressive therapy on serum vitamin B-12 levels in patients with Zollinger-Ellison syndrome. American Journal of Medicine. 1998; volume 104: pages 422-430. (PubMed)
  20. Simon, J.A. & Hudes, E.S. Relation of serum ascorbic acid to serum vitamin B-12, serum ferritin, and kidney stones in U.S. adults. Archives of Internal Medicine. 1999; volume 159: pages 619-624. (PubMed).

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