Micronutrient Information Center

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Summary

• Vitamin B₁₂ or cobalamin plays essential roles in folate metabolism and in the synthesis of the citric acid cycle intermediate, succinyl-CoA. (More information)
• Vitamin B₁₂ deficiency is commonly associated with chronic stomach inflammation, which may contribute to an autoimmune vitamin B₁₂ malabsorption syndrome called pernicious anemia and to a food-bound vitamin B₁₂ malabsorption syndrome. Impairment of vitamin B₁₂ absorption can cause megaloblastic anemia and neurologic disorders in deficient subjects. (More information)
• Normal function of the digestive system required for food-bound vitamin B₁₂ absorption is commonly impaired in individuals over 60 years of age, placing them at risk for vitamin B₁₂ deficiency. (More information)
• Vitamin B₁₂ and folate are important for homocysteine metabolism. Elevated homocysteine levels in blood are a risk factor for cardiovascular disease (CVD). Although B vitamin supplementation has been proven effective to control homocysteine levels, current data from intervention trials have not shown that lowering homocysteine levels decreases CVD risk. (More information)
• The preservation of DNA integrity is dependent on folate and vitamin B₁₂ availability. Poor vitamin B₁₂ status has been linked to increased risk of breast cancer in some, but not all, observational studies. There is a need to evaluate whether supplemental vitamin B₁₂, along with folic acid, could help reduce breast cancer incidence. (More information)
• Low maternal vitamin B₁₂ status has been associated with an increased risk of neural tube defects (NTD), but it is not known whether vitamin B₁₂ supplementation could help reduce the risk of NTD. (More information)
• Vitamin B₁₂ is essential for the preservation of the myelin sheath around neurons and for the synthesis of neurotransmitters. While hyperhomocysteinemia may increase the risk of cognitive impairment, it is not clear whether vitamin B₁₂ deficiency contributes to the risk of dementia in the elderly. Although B-vitamin supplementation lowers homocysteine levels in older subjects, the long-term benefit is not yet known. (More information)
• Both depression and osteoporosis have been linked to diminished vitamin B₁₂ status and high homocysteine levels. (More information)
• Products of animal origin constitute the primary source of vitamin B₁₂. Older individuals and vegans are advised to use vitamin B₁₂ fortified foods and supplements to meet their needs. (More information)
• The long-term use of certain medications, such as inhibitors of stomach acid secretion, can adversely affect vitamin B₁₂ absorption. (More information)

Vitamin B₁₂ has the largest and most complex chemical structure 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 vitamin B₁₂ activity. Methylcobalamin and 5-deoxyadenosylcobalamin are the forms of vitamin B₁₂ used in the human body (1). The form of cobalamin used in most nutritional supplements and fortified foods, cyanocobalamin, is readily converted to 5-deoxyadenosylcobalamin and methylcobalamin in the body. In mammals, cobalamin is a cofactor for only two enzymes, methionine synthase and L-methylmalonyl-coenzyme A mutase (2).

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 in turn 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, RNA, and proteins (3). Aberrant methylation of DNA and proteins, which causes alterations in chromatin structure and gene expression, are a common feature of cancer cells. Inadequate function of methionine synthase can lead to an accumulation of homocysteine, which has been associated with increased risk of cardiovascular disease (Figure 1).

Cofactor for L-methylmalonyl-coenzyme A mutase

5-Deoxyadenosylcobalamin is required by the enzyme that catalyzes the conversion of L-methylmalonyl-coenzyme A to succinyl-coenzyme A (succinyl-CoA), which then enters the citric acid cycle (Figure 2). Succinyl-CoA plays an important role in the production of energy from lipids and proteins and is also required for the synthesis of hemoglobin, the oxygen-carrying pigment in red blood cells (3).

Deficiency

In healthy adults, vitamin B₁₂ deficiency is uncommon, mainly because total body stores can exceed 2,500 μg, daily turnover is slow, and dietary intake of only 2.4 μg/day is sufficient to maintain adequate vitamin B₁₂ status (see RDA) (4). In elderly individuals, vitamin B₁₂ deficiency is more common mainly because of impaired intestinal absorption that can result in marginal to severe vitamin B₁₂ deficiency in this population.

Causes of vitamin B₁₂ deficiency

Intestinal malabsorption, rather than inadequate dietary intake, can explain most cases of vitamin B₁₂ deficiency (5). Absorption of vitamin B₁₂ from food requires normal function of the stomach, pancreas, and small intestine. Stomach acid and enzymes free vitamin B₁₂ from food, allowing it to bind to R-protein (also known as transcobalamin-1 or haptocorrin), found in saliva and gastric fluids. In the alkaline environment of the small intestine, R-proteins are degraded by pancreatic enzymes, freeing vitamin B₁₂ to bind to intrinsic factor (IF), a protein secreted by specialized cells in the stomach. Receptors on the surface of the ileum (final part of the small intestine) take up the IF-B₁₂ complex only in the presence of calcium, which is supplied by the pancreas (5). Vitamin B₁₂ can also be absorbed by passive diffusion, but this process is very inefficient—only about 1% absorption of the vitamin B₁₂ dose is absorbed passively (2). The prevalent causes of vitamin B₁₂ deficiency are (1) an autoimmune condition known as pernicious anemia, and (2) a disorder called food-bound vitamin B₁₂ malabsorption. Both conditions have been associated with a chronic inflammatory disease of the stomach known as atrophic gastritis.

Atrophic gastritis

Atrophic gastritis is thought to affect 10%-30% of people over 60 years of age (6). The condition is frequently associated with the presence of autoantibodies directed toward stomach cells (see Pernicious anemia) and/or infection by the bacteria, Helicobacter pylori (H. pylori) (7). H. pylori infection induces chronic inflammation of the stomach, which may progress to peptic ulcer disease, atrophic gastritis, and/or gastric cancer in some individuals. Diminished gastric function in individuals with atrophic gastritis can result in bacterial overgrowth in the small intestine and cause food-bound vitamin B₁₂ malabsorption. Vitamin B₁₂ levels in serum, plasma, and gastric fluids are significantly decreased in individuals with H. pylori infection, and eradication of the bacteria has been shown to significantly improve vitamin B₁₂ serum concentrations (8).

Pernicious anemia

Pernicious anemia has been estimated to be present in approximately 2% of individuals over 60 years of age (9). Although anemia is often a symptom, the condition is actually the end stage of an autoimmune inflammation of the stomach known as autoimmune atrophic gastritis, resulting in destruction of stomach cells by one's own antibodies (autoantibodies). Progressive destruction of the cells that line the stomach causes decreased secretion of acid and enzymes required to release food-bound vitamin B₁₂. Antibodies to intrinsic factor (IF) bind to IF preventing formation of the IF-B₁₂ complex, further inhibiting vitamin B₁₂ absorption. About 20% of the relatives of pernicious anemia patients also have the condition, suggesting a genetic predisposition. It is also thought that H. pylori infection could be involved in initiating the autoimmune response in a subset of individuals (10). Further, co-occurrence of autoimmune atrophic gastritis with other autoimmune conditions, especially autoimmune thyroiditis and type 1 diabetes mellitus, has been reported (11, 12).

Treatment of pernicious anemia generally requires injections of vitamin B₁₂ to bypass intestinal absorption. High-dose oral supplementation is another treatment option, because consuming 1,000 μg (1 mg)/day of vitamin B₁₂ orally should result in the absorption of about 10 μg/day (1% of dose) by passive diffusion. In fact, high-dose oral therapy is considered to be as effective as intramuscular injection (4).

Food-bound vitamin B₁₂ malabsorption

Food-bound vitamin B₁₂ malabsorption is defined as an impaired ability to absorb food- or protein-bound vitamin B₁₂; individuals with this condition can fully absorb the free form (13). While the condition is the major cause of poor vitamin B₁₂ status in the elderly population, it is usually associated with atrophic gastritis, a chronic inflammation of the lining of the stomach that ultimately results in the loss of glands in the stomach (atrophy) and decreased stomach acid production (see Atrophic gastritis). Because stomach acid is required for the release of vitamin B₁₂ from the proteins in food, vitamin B₁₂ absorption is diminished. Decreased stomach acid production also provides an environment conducive to the overgrowth of anaerobic bacteria in the stomach, which further interferes with vitamin B₁₂ absorption (3). Because vitamin B₁₂ in supplements is not bound to protein, and because intrinsic factor (IF) is still available, the absorption of supplemental vitamin B₁₂ is not reduced as it is in pernicious anemia. Thus, individuals with food-bound vitamin B₁₂ malabsorption do not have an increased requirement for vitamin B₁₂; they simply need it in the crystalline form found in fortified foods and dietary supplements.

Other causes of vitamin B₁₂ deficiency

Other causes of vitamin B₁₂ deficiency include surgical resection of the stomach or portions of the small intestine where receptors for the IF-B₁₂ complex are located. Conditions affecting the small intestine, such as malabsorption syndromes (celiac disease and tropical sprue), may also result in vitamin B₁₂ deficiency. Because the pancreas provides critical enzymes, as well as calcium required for vitamin B₁₂ absorption, pancreatic insufficiency may contribute to vitamin B₁₂ deficiency. Since vitamin B₁₂ is found only in foods of animal origin, a strict vegetarian (vegan) diet has resulted in cases of vitamin B₁₂ deficiency. Moreover, alcoholics may experience reduced intestinal absorption of vitamin B₁₂ (2), and individuals with acquired immunodeficiency syndrome (AIDS) appear to be at increased risk of deficiency, possibly related to a failure of the IF-B₁₂ receptor to take up the IF-B₁₂ complex (3). Further, long-term use of acid-reducing drugs has also been implicated in vitamin B₁₂ deficiency (see Drug interactions).

Inherited disorders of vitamin B₁₂ absorption

Rare cases of inborn errors of vitamin B₁₂ metabolism have been reported in the literature (reviewed in 5). Imerslund-Gräsbeck syndrome is an inherited vitamin B₁₂ malabsorption syndrome that causes megaloblastic anemia and neurologic disorders of variable severity in affected subjects. Similar clinical symptoms are found in individuals with hereditary IF deficiency (also called congenital pernicious anemia) in whom the lack of IF results in the defective absorption of vitamin B₁₂. Additionally, mutations affecting vitamin B₁₂ transport in the body have been identified (14).

Symptoms of vitamin B₁₂ deficiency

Vitamin B₁₂ deficiency results in impairment of the activities of vitamin B₁₂-requiring enzymes. Impaired activity of methionine synthase results 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). While individuals with mild vitamin B₁₂ deficiency may not experience symptoms, blood levels of homocysteine and/or MMA may be elevated (15).

Megaloblastic anemia

Diminished activity of methionine synthase in vitamin B₁₂ deficiency inhibits the regeneration of tetrahydrofolate (THF) and traps folate in a form that is not usable by the body (Figure 3), resulting in symptoms of folate deficiency even in the presence of adequate folate levels. Thus, in both folate and vitamin B₁₂ deficiencies, 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 (3). Supplementation with folic acid will provide enough usable folate to restore normal red blood cell formation. However, if vitamin B₁₂ deficiency is 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 (16).

Neurologic symptoms

The neurologic symptoms of vitamin B₁₂ deficiency include numbness and tingling of the hands and, more commonly, the feet; difficulty walking; memory loss; disorientation; and dementia with or without mood changes. Although the progression of neurologic complications is generally gradual, such symptoms may not be reversed with treatment of vitamin B₁₂ 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 B₁₂ deficiency in about 25% of cases (17). Although vitamin B₁₂ deficiency is known to damage the myelin sheath covering cranial, spinal, and peripheral nerves, the biochemical processes leading to neurological damage in vitamin B₁₂ deficiency are not yet fully understood (18).

Gastrointestinal symptoms

Tongue soreness, appetite loss, and constipation have also been associated with vitamin B₁₂ deficiency. The origins of these symptoms are unclear, but they may be related to the stomach inflammation underlying some cases of vitamin B₁₂ deficiency and to the progressive destruction of the lining of the stomach (17).

The Recommended Dietary Allowance (RDA)

The RDA for vitamin B₁₂ was revised by the Food and Nutrition Board (FNB) of the US Institute of Medicine in 1998 (Table 1). Because of the increased risk of food-bound vitamin B₁₂ malabsorption in older adults, the FNB recommended that adults over 50 years of age get most of the RDA from fortified food or vitamin B₁₂-containing supplements (17).

Disease Prevention

Cardiovascular disease

As mentioned above, chronic atrophic gastritis and infection by H. pylori can cause deficiency in vitamin B₁₂ secondary to malabsorption disorders (see Causes of vitamin B₁₂ deficiency). However, the occurrence of H. pylori infection and chronic atrophic gastritis did not modify the five-year incidence of cardiovascular accidents (stroke and heart attack) or mortality in a large cohort study of nearly 10,000 men and women over 50 years old (19). Yet, vitamin B₁₂ status was not assessed in this study, despite the high prevalence of vitamin B₁₂ deficiency in older individuals.

Homocysteine and cardiovascular disease

Epidemiological studies indicate that even moderately elevated levels of homocysteine in the blood raise the risk of cardiovascular disease (CVD) (20), though the mechanism by which homocysteine may increase the CVD risk remains the subject of a great deal of research (21). The amount of homocysteine in the blood is regulated by at least three vitamins: folate, vitamin B₆, and vitamin B₁₂ (see Figure 1 above). An early analysis of the results of 12 randomized controlled trials showed that folic acid supplementation (0.5-5 mg/day) had the greatest lowering effect on blood homocysteine levels (25% decrease); co-supplementation with folic acid and vitamin B₁₂ (500 μg/day) provided an additional 7% reduction (32% decrease) in blood homocysteine concentrations (22). The results of a sequential supplementation trial in 53 men and women indicated that after folic acid supplementation, vitamin B₁₂ became the major determinant of plasma homocysteine levels (23). It is thought that the elevation of homocysteine levels might be partly due to vitamin B₁₂ deficiency in individuals over 60 years of age. Two studies found blood methylmalonic acid (MMA) levels to be elevated in more than 60% of elderly individuals with elevated homocysteine levels. In the absence of impaired kidney function, an elevated MMA level in conjunction with elevated homocysteine suggests either a vitamin B₁₂ deficiency or a combined vitamin B₁₂ and folate deficiency (24). Thus, it appears important to evaluate vitamin B₁₂ 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 CVD, see the article on Folate.

Intervention studies

Although increased intake of folic acid and vitamin B₁₂ is effective in decreasing homocysteine levels, the combined intervention of these B vitamins did not lower risk for CVD. Indeed, several randomized, placebo-controlled trials have been conducted to determine whether homocysteine-lowering through folic acid, vitamin B₁₂, and vitamin B₆ supplementation reduces the incidence of CVD. A recent meta-analysis of data from 11 trials, including nearly 45,000 participants at risk of CVD, showed that B-vitamin supplementation had no significant effect on risk of myocardial infarction (heart attack) or stroke, nor did it modify the risk of all-cause mortality (25). Other meta-analyses that included patients with chronic kidney disease have confirmed the lack of effect of homocysteine-lowering on risk of myocardial infarction and death. However, stroke risk was significantly reduced by 7%-12% with the B-vitamin supplementation (26, 27). Another meta-analysis of 12 clinical trials measuring flow-mediated vasodilation (FMD; a surrogate marker of vascular health) in response to homocysteine reduction revealed that B-vitamin supplementation was accompanied by an improved FMD in short-term <8 weeks) but not in long-term studies conducted in subjects with preexisting vascular diseases (28). Yet, some of the studies included in these meta-analyses did not use vitamin B₁₂, and folate administration on its own has shown a protective role on vascular function and stroke risk (29). Besides, the high prevalence of malabsorption disorders and vitamin B₁₂ deficiency in elderly individuals might warrant the use of higher doses of vitamin B₁₂ than those used in these trials (30); in cases of malabsorption, only high-dose oral therapy or intramuscular injections can overcome vitamin B₁₂ deficiency (4).

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 B₁₂ traps folate in a form that is unusable by the body for DNA synthesis. Both vitamin B₁₂ and folate deficiencies result in a diminished capacity for methylation reactions (see Figure 3 above). Thus, vitamin B₁₂ 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 series of studies in young adults and older men indicated that increased levels of homocysteine and decreased levels of vitamin B₁₂ in the blood were associated with a biomarker of chromosome breakage in white blood cells (reviewed in 31). In a double-blind, placebo-controlled study, the same biomarker of chromosome breakage was minimized in young adults who were supplemented with 700 μg of folic acid and 7 μg of vitamin B₁₂ daily in cereal for two months (32).

Breast cancer

A case-control study compared prediagnostic levels of serum folate, vitamin B₆, and vitamin B₁₂ in 195 women later diagnosed with breast cancer and 195 age-matched, cancer-free women. Among postmenopausal women, the association between blood levels of vitamin B₁₂ and breast cancer suggested a threshold effect. The risk of breast cancer was more than doubled in women with serum vitamin B₁₂ levels in the lowest quintile compared to women in the four highest quintiles (33). However, the meta-analysis of this study with three additional case-control studies found no protection associated with high compared to low vitamin B₁₂ serum levels (34). A case-control study in Mexican women (475 cases and 1,391 controls) reported that breast cancer risk for women in the highest quartile of vitamin B₁₂ intake (7.3-7.7 μg/day) was 68% lower than those in the lowest quartile (2.6 μg/day). Stratification of the data revealed that the inverse association between dietary vitamin B₁₂ intake and breast cancer risk was stronger in postmenopausal women compared to premenopausal women, though both associations were statistically significant. Moreover, among postmenopausal women, the apparent protection conferred by folate was only observed in women with the highest vitamin B₁₂ quartiles of intake (35). However, more recent case-control and prospective cohort studies have reported weak to no risk reduction with vitamin B₁₂ intakes in different populations, including Hispanic, African American and European American women (36, 37). A meta-analysis of seven case-control and seven prospective cohort studies concluded that the risk of breast cancer was not modified by high versus low vitamin B₁₂ intakes (34). There was no joint association between folate and vitamin B₁₂ intakes and breast cancer risk. Presently, there is little evidence to suggest a relationship between vitamin B₁₂ status and breast cancer. In addition, results from observational studies are not consistently in support of an association between high dietary folate intakes and reduced risk for breast cancer (see the article on Folate). There is a need to evaluate the effect of folate and vitamin B₁₂ supplementation in well-controlled, randomized, clinical trials, while considering various factors that modify breast cancer risk, such as menopausal status, ethnicity, and alcohol intake.

Neural tube defects

Neural tube defects (NTD) may result in anencephaly or spina bifida, which are mostly fatal congenital malformations of the central nervous system. The defects arise from failure of embryonic neural tube to close, which occurs between the 21^st and 28^th days after conception, a time when many women are unaware of their pregnancy (38). 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 reducing the risk of NTD (39). Homocysteine may accumulate in the blood when there is inadequate folate and/or vitamin B₁₂ for effective functioning of the methionine synthase enzyme. Decreased vitamin B₁₂ levels and elevated homocysteine concentrations have been found in the blood and amniotic fluid of pregnant women at high risk of NTD (40). The recent meta-analysis of 12 case-control studies, including 567 mothers with current or prior NTD-affected pregnancy and 1,566 unaffected mothers, showed that low maternal vitamin B₁₂ status was associated with an increased risk of NTD (41). Yet, whether vitamin B₁₂ supplementation may be beneficial in the prevention of NTD has not been evaluated (42).

Cognitive decline, dementia, and Alzheimer's disease

The occurrence of vitamin B₁₂ deficiency prevails in the elderly population and has been frequently associated with Alzheimer's disease (reviewed in 43). One study found lower vitamin B₁₂ levels in the cerebrospinal fluid of patients with Alzheimer's disease than in patients with other types of dementia, though blood levels of vitamin B₁₂ did not differ (44). The reason for the association of low vitamin B₁₂ status with Alzheimer's disease is not clear. Vitamin B₁₂ deficiency, like folate deficiency, may lead to decreased synthesis of methionine and S-adenosylmethionine (SAM), thereby adversely affecting methylation reactions. Methylation reactions are essential for the metabolism of components of the myelin sheath of nerve cells as well as for synthesis of neurotransmitters (18). Other metabolic implications of vitamin B₁₂ deficiency include the accumulation of homocysteine and methylmalonic acid, which might contribute to the neuropathologic features of dementia (43).

Observational studies

A large majority of cross-sectional and prospective cohort studies have associated elevated homocysteine concentrations with measures of poor cognitive scores and increased risk of dementia, including Alzheimer's disease (reviewed in 45). 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 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 blood levels of folate and vitamin B₁₂. Measures of general nutritional status indicated that the association of increased homocysteine levels and diminished vitamin B₁₂ status with Alzheimer's disease was not due to dementia-related malnutrition (46). In a sample of 1,092 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. Specifically, those with plasma homocysteine levels greater than 14 μmol/L had nearly double the risk of developing Alzheimer's disease (47). A study in 650 elderly men and women reported that the risk of elevated plasma homocysteine levels was significantly higher in those with lower cognitive function scores (48). A prospective study in 816 elderly men and women reported that those with hyperhomocysteinemia (homocysteine levels >15 μmol/L) had a significantly higher risk of developing Alzheimer's disease or dementia. Although raised homocysteine levels might be partly due to a poor vitamin B₁₂ status, the latter was not related to risk of Alzheimer's disease or dementia in this study (49).

A recent systematic review of 35 prospective cohort studies assessing the association between vitamin B₁₂ status and cognitive deterioration in older individuals with or without dementia at baseline did not support a relationship between vitamin B₁₂ serum concentrations and cognitive decline, dementia, or Alzheimer's disease (50). Nevertheless, studies utilizing more sensitive biomarkers of vitamin B₁₂ status, including measures of holo-transcobalamin (holo-TC; a vitamin B₁₂ carrier) and methylmalonic acid, showed more consistent results and a trend toward associations between poor vitamin B₁₂ status and faster cognitive decline and risk of Alzheimer's disease (51-55). Besides, it cannot be excluded that the co-occurrence of potential confounders like elevated homocysteine level and poor folate status might mitigate the true contribution of vitamin B₁₂ status to cognitive functioning (45).

Intervention studies

High-dose B-vitamin supplementation has been proven effective for treating hyperhomocysteinemia in elderly individuals with or without cognitive impairment. However, homocysteine-lowering trials have produced equivocal results regarding the prevention of cognitive deterioration in this population. A systematic review and meta-analysis of 18 randomized, placebo-controlled trials examining the effect of B-vitamin supplementation did not find that the decrease in homocysteine level prevented or delayed cognitive decline among older subjects (56). A more recent randomized, double-blind, placebo-controlled clinical trial in 900 older individuals at high risk of cognitive impairment found that daily supplementation of 400 μg of folic acid and 100 μg of vitamin B₁₂ for two years significantly improved measures of immediate and delayed memory and slowed the rise in plasma homocysteine concentrations (57). However, supplemented subjects had no reduction in homocysteine concentrations compared to baseline, nor did they perform better in processing speed tests compared to placebo. Another two-year, randomized, placebo-controlled study in elderly adults reported that a daily regimen of 800 μg of folic acid, 500 μg of vitamin B₁₂, and 20 mg of vitamin B₆ significantly reduced the rate of brain atrophy compared to placebo treatment (0.5% vs. 3.7%). Interestingly, a greater benefit was seen in those with high compared to low homocysteine concentrations at baseline, suggesting the importance of lowering homocysteine levels in prevention of brain atrophy and cognitive decline (58, 59). The authors attributed the changes in homocysteine levels primarily to vitamin B₁₂ (59). Finally, the most recent randomized, double blind, placebo-controlled trial in over 2,500 individuals who suffered a stroke showed that the normalization of homocysteine concentrations by B-vitamin supplementation (2 mg of folic acid, 500 μg of vitamin B₁₂, and 25 mg of vitamin B₆) did not improve cognitive performance or decrease incidence of cognitive decline compared to placebo (60). Currently, there is a need for larger trials to evaluate the effect of B-vitamin supplementation on long-term outcomes, such as the incidence of Alzheimer's disease.

Depression

Observational studies have found as many as 30% of patients hospitalized for depression are deficient in vitamin B₁₂ (61). A cross-sectional study of 700 community-living, physically disabled women over the age of 65 found that vitamin B₁₂-deficient women were twice as likely to be severely depressed as non-deficient women (62). A population-based study in 3,884 elderly men and women with depressive disorders found that those with vitamin B₁₂ deficiency were almost 70% more likely to experience depression than those with normal vitamin B₁₂ status (63). The reasons for the relationship between vitamin B₁₂ deficiency and depression are not clear but may involve a shortage in S-adenosylmethionine (SAM). SAM is a methyl group donor for numerous methylation reactions in the brain, including those involved in the metabolism of neurotransmitters whose deficiency has been related to depression (64). Severe vitamin B₁₂ deficiency in a mouse model showed dramatic alterations in the level of DNA methylation in the brain, which might lead to neurologic impairments (65). This hypothesis is supported by several studies that have shown supplementation with SAM improves depressive symptoms (66-69).

Increased homocysteine level is another nonspecific biomarker of vitamin B₁₂ deficiency that has been linked to depressive symptoms in the elderly (70). However, in a recent cross-sectional study conducted in 1,677 older individuals, higher vitamin B₁₂ plasma levels, but not changes in homocysteine concentrations, were correlated with a lower prevalence of depressive symptoms (71). Few studies have examined the relationship of vitamin B₁₂ status, homocysteine levels, and the development of depression over time. In a randomized, placebo-controlled, intervention study with over 900 older participants experiencing psychological distress, daily supplementation with folic acid (400 μg) and vitamin B₁₂ (100 μg) for two years did not reduce the occurrence of symptoms of depression despite significantly improving blood folate, vitamin B₁₂, and homocysteine levels compared to placebo (72). However, in a long-term randomized, double-blind, placebo-controlled study among sufferers of cerebrovascular accidents at high risk of depression, daily supplementation with 2 mg of folic acid, 25 mg of vitamin B₆, and 500 μg vitamin B₁₂ significantly lowered the risk of major depressive episodes during a seven-year follow-up period compared to placebo (73). Although it cannot yet be determined whether vitamin B₁₂ deficiency plays a causal role in depression, it may be beneficial to screen for vitamin B₁₂ deficiency in older individuals as part of a medical evaluation for depression.

Osteoporosis

High homocysteine levels may affect bone remodeling by increasing bone resorption (breakdown), decreasing bone formation, and reducing bone blood flow. Another proposed mechanism involves the binding of homocysteine to the collagenous matrix of bone, which may modify collagen properties and reduce bone strength (reviewed in 74). Alterations of bone biomechanical properties can contribute to osteoporosis and increase the risk of fractures in the elderly. Since vitamin B₁₂ is a determinant of homocysteine metabolism, it was suggested that the risk of osteoporotic fractures in older subjects might be enhanced by vitamin B₁₂ deficiency. A meta-analysis of four observational studies, following a total of 7,475 older individuals for 3 to 16 years, found a weak association between an elevation in vitamin B₁₂ of 50 picomoles/L in blood and a reduction in fracture risk (75). A randomized, placebo-controlled trial in 559 elderly individuals with low serum levels of folate and vitamin B₁₂ and at increased risk of fracture evaluated the combined supplementation of very high doses of folic acid (5 mg/day) and vitamin B₁₂ (1.5 mg/day). The two-year study found that the supplementation improved B-vitamin status, decreased homocysteine concentrations, and reduced risk of total fractures compared to placebo (76). However, a multicenter study in 5,485 subjects with cardiovascular disease or diabetes mellitus showed that daily supplementation with folic acid (2.5 mg), vitamin B₁₂ (1 mg), and vitamin B₆ (50 mg) lowered homocysteine concentrations but had no effect on fracture risk compared to placebo (77). Another small, randomized, double-blind trial in 93 individuals with low vitamin D status found no additional benefit of B-vitamin supplementation (50 mg/day of vitamin B₆, 0.5 mg/day of folic acid, and 0.5 mg/day of vitamin B₁₂) on markers of bone health over a one-year period beyond that associated with vitamin D and calcium supplementation. Yet, the short length of the study did not permit a conclusion on whether the lowering of homocysteine through B-vitamin supplementation could have long-term benefits on bone strength and fracture risk (78). A large intervention study conducted in older people with no preexisting conditions is under way to evaluate the effect of B-vitamin supplementation on markers of bone health and incidence of fracture; this trial might clarify whether B vitamins could have a protective effect on bone health in the elderly population (79).

Sources

Food sources

Only bacteria can synthesize vitamin B₁₂ (80). Vitamin B₁₂ is present in animal products, such as meat, poultry, fish (including shellfish), and to a lesser extent dairy products and eggs (1). Fresh pasteurized milk contains 0.9 μg per cup and is an important source of vitamin B₁₂ for some vegetarians (17). Those strict vegetarians who eat no animal products (vegans) need supplemental vitamin B₁₂ to meet their requirements. Recent analyses revealed that some plant-source foods, such as certain fermented beans and vegetables and edible algae and mushrooms, contain substantial amounts of bioactive vitamin B₁₂ (81). Together with B-vitamin fortified food and supplements, these foods may contribute, though modestly, to prevent vitamin B₁₂ deficiency in individuals consuming vegetarian diets. Also, individuals over the age of 50 should obtain their vitamin B₁₂ in supplements or fortified foods (e.g., fortified cereals) because of the increased likelihood of food-bound vitamin B₁₂ malabsorption with increasing age.

Most people do not have a problem obtaining the RDA of 2.4 μg/day of vitamin B₁₂ in food. According to a US national survey, the average dietary intake of vitamin B₁₂ is 5.4 μg/day for adult men and 3.4 μg/day for adult women. Adults over the age of 60 had an average dietary intake of 4.8 μg/day (42). However, consumption of any type of vegetarian diet dramatically increases the prevalence of vitamin B₁₂ deficiency in individuals across all age groups (82). Some foods with substantial amounts of vitamin B₁₂ are listed in Table 2, along with their vitamin B₁₂ content in micrograms (μg). For more information on the nutrient content of specific foods, search USDA's FoodData Central.

Supplements

Cyanocobalamin is the principal form of vitamin B₁₂ used in oral supplements, but methylcobalamin is also available as a supplement. Cyanocobalamin 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 multivitamins, vitamin B-complex supplements, and single-nutrient, vitamin B₁₂ supplements (83).

Safety

Toxicity

No toxic or adverse effects have been associated with large intakes of vitamin B₁₂ from food or supplements in healthy people. Doses as high as 2 mg (2,000 μg) daily by mouth or 1 mg monthly by intramuscular (IM) injection have been used to treat pernicious anemia without significant side effects (84). When high doses of vitamin B₁₂ are given orally, only a small percentage can be absorbed, which may explain the low toxicity (4). Because of the low toxicity of vitamin B₁₂, no tolerable upper intake level (UL) has been set by the US Food and Nutrition Board (17).

Drug interactions

A number of drugs reduce the absorption of vitamin B₁₂. 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 B₁₂ from food but not from supplements. Long-term use of proton-pump inhibitors has been found to decrease blood vitamin B₁₂ levels. However, vitamin B₁₂ deficiency does not generally develop until after at least three years of continuous therapy (85, 86). Another class of gastric acid inhibitors known as histamine₂ (H₂)-receptor antagonists (e.g., cimetidine, famotidine, and ranitidine), often used to treat peptic ulcer disease, has also been found to decrease the absorption of vitamin B₁₂ from food. It is not clear whether the long-term use of H₂-receptor antagonists could cause overt vitamin B₁₂ deficiency (87, 88). Individuals taking drugs that inhibit gastric acid secretion should consider taking vitamin B₁₂ in the form of a supplement because gastric acid is not required for its absorption. Other drugs found to inhibit vitamin B₁₂ absorption from food include cholestyramine (a bile acid-binding resin used in the treatment of high cholesterol), chloramphenicol and neomycin (antibiotics), and colchicine (medicine for gout treatment). Metformin, a medication for individuals with type 2 diabetes, was found to decrease vitamin B₁₂ absorption by tying up free calcium required for absorption of the IF-B₁₂ complex (89). However, the clinical significance of this is unclear (90). It is not known whether calcium supplementation can reverse vitamin B₁₂ malabsorption; therefore, calcium supplementation is not currently prescribed for the prevention or treatment of metformin-induced vitamin B₁₂ deficiency (91). Previous reports that megadoses of vitamin C destroy vitamin B₁₂ have not been supported (92) and may have been an artifact of the assay used to measure vitamin B₁₂ levels (17).

Nitrous oxide, a commonly used anesthetic, oxidizes and inactivates vitamin B₁₂, thus inhibiting both of the vitamin B₁₂-dependent enzymes, and can produce many of the clinical features of vitamin B₁₂ deficiency, such as megaloblastic anemia or neuropathy. Since nitrous oxide is commonly used for surgery in the elderly, some experts feel vitamin B₁₂ deficiency should be ruled out prior to its use (6, 15).

Large doses of folic acid given to an individual with an undiagnosed vitamin B₁₂ deficiency could correct megaloblastic anemia without correcting the underlying vitamin B₁₂ deficiency, leaving the individual at risk of developing irreversible neurologic damage (17). For this reason, the Food and Nutrition Board of the US Institute of Medicine advises that all adults limit their intake of folic acid (supplements and fortification) to 1,000 μg (1 mg) daily.

Linus Pauling Institute Recommendation

A varied diet should provide enough vitamin B₁₂ to prevent deficiency in most individuals 50 years of age and younger. Strict vegetarians and women planning to become pregnant should take a multivitamin supplement daily or eat fortified cereal, which would ensure a daily intake of 6 to 30 μg of vitamin B₁₂ in a form that is easily absorbed. Higher doses of vitamin B₁₂ supplements are recommended for patients taking medications that interfere with its absorption (see Drug interactions).

Older adults (>50 years)

Because vitamin B₁₂ malabsorption and vitamin B₁₂ deficiency are more common in older adults, the Linus Pauling Institute recommends that adults older than 50 years take 100 to 400 μg/day of supplemental vitamin B₁₂.

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Authors and Reviewers

Originally written in 2000 by: 
Jane Higdon, Ph.D. 
Linus Pauling Institute
Oregon State University

Updated in March 2003 by: 
Jane Higdon, Ph.D. 
Linus Pauling Institute 
Oregon State University

Updated in August 2007 by: 
Victoria J. Drake, Ph.D. 
Linus Pauling Institute 
Oregon State University

Updated in January 2014 by: 
Barbara Delage, Ph.D. 
Linus Pauling Institute 
Oregon State University

Reviewed in April 2014 by: 
Joshua W. Miller, Ph.D. 
Professor and Chair, Department of Nutritional Sciences 
Rutgers, The State University of New Jersey

Last updated 6/4/15  Copyright 2000-2023  Linus Pauling Institute

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References