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 cobalamin is 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.
Vitamin B 12: 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 ( diagram ).
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) .
Vitamin B 12: deficiency

Vitamin 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.
Causes of vitamin B 12 deficiency

The most common causes of vitamin B 12 deficiency are 1) an autoimmune condition known as pernicious anemia and 2) food-bound vitamin B 12 malabsorption. Although both causes become more common with age, they are two separate conditions (3) .
Vitamin B 12: pernicious anemia

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 1,000 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

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

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 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 vitamin B 12 deficiency

Other causes of deficiency include surgical resection 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 vitamin 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 . In alcoholics, vitamin B 12 intake and absorption are reduced, while elimination is increased (5) . 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 .
Symptoms of vitamin B 12 deficiency

Vitamin B 12 deficiency results in impairment of the activities of B 12 -requiring enzymes. 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 ( 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. This impairment of DNA synthesis affects the rapidly dividing cells of the bone marrow earlier than other cells, resulting in the production of large, immature, 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 vitamin 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 vitamin B 12 deficiency , or the increased vulnerability of the rapidly dividing cells along the gastrointestinal tract to impaired DNA synthesis (5) .
Vitamin B 12: the Recommended Dietary Allowance (RDA)

The current RDA was revised by the Food and Nutrition Board (FNB) of the Institute of Medicine in 1998. Because of the increased risk of f ood-bound vitamin B 12 malabsorption in older adults, the FNB recommended that adults over 50 years of age get most of the RDA from fortified food or vitamin B 12 -containing supplements (5) .

Recommended Dietary Allowance (RDA) for Vitamin B 12
Life Stage Age Males (mcg/day) Females (mcg/day)
Infants 0-6 months 0.4 (AI) 0.4 (AI)
Infants 7-12 months 0.5 (AI) 0.5 (AI)
Children 1-3 years 0.9 0.9
Children 4-8 years 1.2 1.2
Children 9-13 years 1.8 1.8
Adolescents 14-18 years 2.4 2.4
Adults 19-50 years 2.4 2.4
Adults 51 years and older 2.4* 2.4*
Pregnancy all ages - 2.6
Breastfeeding all ages - 2.8

* Vitamin B 12 intake should be from supplements or fortified foods , due to the age-related increase in food bound malabsorption.
Disease Prevention
Homocysteine and cardiovascular disease

Evidence is mounting that an elevated plasma homocysteine concentration is an independent risk factor for cardiovascular diseases , including heart disease, stroke, and peripheral vascular disease . The amount of homocysteine in the blood is regulated by at least three vitamins : folate, vitamin B 12 , and vitamin B 6 ( 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) . The results of a sequential supplementation trial in 53 men and women indicated that after folic acid supplementation , vitamin B 12 became the major determinant of plasma homocysteine (9) . Some evidence indicates 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 vitamin B 12 and folate deficiency, in the absence of impaired kidney function (10) . 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 ( diagram ). Thus, vitamin 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 (11) .
Breast cancer

A case-control study compared prediagnostic levels of serum folate, vitamin B6 , and vitamin B 12 in 195 women later diagnosed with breast cancer and 195 age-matched women who were not diagnosed with breast cancer (12) . 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 quintile (1/5) compared to those women in the four highest quintiles. The investigators found no relationship between breast cancer and serum levels of vitamin B 6 , folate, or homocysteine. Because this study was obsrvational , it cannot be determined whether decreased serum 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 (13) . Randomized controlled 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. Increasing evidence indicates that the homocysteine -lowering effect of folic acid plays a critical role in lowering the risk of NTD (14) . Homocysteine may accumulate in the blood when there is inadequate folate and/or vitamin B 12 for effective functioning of the methionine synthase enzyme . 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 and dementia

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 (15) . 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 . Moderately increased homocysteine levels, as well as decreased folate and vitamin B 12 levels have also been associated with Alzheimer's disease and vascular dementia . A 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 (16) . 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. 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. Low serum vitamin B 12 (< 150 pmol/L) or folate (< 10 nmol/L) levels were associated with a doubling of the risk of developing Alzheimer's disease in 370 elderly men and women followed over 3 years (17) . In a sample of 1092 men and women without dementia followed for an average of 10 years, those with higher plasma homocysteine levels at baseline had a significantly higher risk of developing Alzheimer's disease and other types of dementia (18) . Those with plasma homocysteine levels greater than 14 mmol/L had nearly double the risk of developing Alzheimer's disease.
Depression

Observational studies have found as many as 30% of patients hospitalized for depression to be deficient in vitamin B 12 (19) . A recent cross-sectional study of 700 community-living, physically disabled women over the age of 65 found that vitamin B 12 deficient women were twice as likely to be severely depressed as non- deficient women (20) . 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 .
Vitamin B 12: sources
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.

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.
Vitamin B 12: supplements

Cyanocobalamin is the principal form of vitamin B 12 used in supplements but methylcobalamin is also available. Cyanocobalalmin is available by prescription in an injectable form and as a nasal gel for the treatment of pernicious anemia . Over the counter preparations containing cyanocobalamin include multivitamin , vitamin B-complex , and vitamin B 12 supplements (21) .
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 (1000 mcg) daily by mouth or 1 mg monthly by intramuscular (IM) injection have been used to treat pernicious anemia , without significant side effects. When h igh 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 Zollinger-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 (22) . Another class of gastric acid inhibitors known as H 2 -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 H 2 -receptor antagonists have not been found to cause overt vitamin B 12 deficiency even after long-term use (23) . 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, a medication for individuals with type 2 (non-insulin dependent) 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 (24) 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 . 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 (, 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 1000 mcg (1 mg) daily.
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.

References

Written by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Reviewed by:
Jeffrey Blumberg, Ph.D., F.A.C.N.
Professor and Associate Director
Jean Mayer USDA Human Nutrition Research Center on Aging
Tufts University

Last updated 03/05/2003 Copyright 2000-2003 Linus Pauling Institute

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