Vitamin B12

Vitamin B12 is also called cobalamin because it contains the metal cobalt. This vitamin helps maintain healthy nerve cells and red blood cells. It is also needed to help make DNA, the genetic material in all cells.

Vitamin B12 is bound to the protein in food. Hydrochloric acid in the stomach releases B12 from proteins in foods during digestion. Once released, vitamin B12 combines with a substance called gastric intrinsic factor (IF). This complex can then be absorbed by the intestinal tract.

Vitamin B12 is naturally found in animal foods including fish, meat, poultry, eggs, milk, and milk products. Fortified breakfast cereals are a particularly valuable source of vitamin B12 for vegetarians. Vegetarians who do not supplement their diet with vitamin B12 tend to have elevated homocysteine levels. Elevated homocysteine is probably a cause of early mortality, heart disease, stroke and recurrent pregnancy loss. It also may be a partial cause of Alzheimer's disease, neural tube defects, and certain eye disorders. Vegetarians who eat B12-fortified foods or supplements in amounts of 3 to 100 g per day will minimize any elevated homocysteine problems due to a low B12 intake.

When is a deficiency of vitamin B12 likely to occur? Results of two national surveys, the National Health and Nutrition Examination Survey (NHANES III-1988-94) and the Continuing Survey of Food Intakes by Individuals (CSFII 1994-96) found that most children and adults in the United States consume recommended amounts of vitamin B12. A deficiency may still occur as a result of an inability to absorb B12 from food and in strict vegetarians who do not consume any animal foods. As a general rule, most individuals who develop a vitamin B12 deficiency have an underlying stomach or intestinal disorder that limits the absorption of vitamin B12. Sometimes the only symptom of these intestinal disorders is subtly reduced cognitive function resulting from early B12 deficiency. Anemia and dementia follow later.

Signs, symptoms, and health problems associated with vitamin B12 deficiency include anemia, fatigue, weakness, constipation, loss of appetite, and weight loss. Deficiency also can lead to neurological changes such as numbness and tingling in the hands and feet. Additional symptoms of B12 deficiency are difficulty in maintaining balance, depression, confusion, dementia, poor memory, and soreness of the mouth or tongue. Signs of vitamin B12 deficiency in infancy include failure to thrive, movement disorders, delayed development, and megaloblastic anemia.

Many of these symptoms are very general and can result from a variety of medical conditions other than vitamin B12 deficiency. It is important to have a physician evaluate these symptoms so that appropriate medical care can be given.

What is the relationship between vitamin B12 homocysteine, and cardiovascular disease? Cardiovascular disease involves any disorder of the heart and blood vessels that make up the cardiovascular system. Coronary heart disease occurs when blood vessels which supply the heart become clogged or blocked, increasing the risk of a heart attack. Vascular damage can also occur to blood vessels supplying the brain, and can result in a stroke.

Cardiovascular disease is the most common cause of death in industrialized countries such as the U.S. and is on the rise in developing countries. The National Heart, Lung, and Blood Institute of the National Institutes of Health has identified many risk factors for cardiovascular disease, including an elevated LDL-cholesterol level, high blood pressure, a low HDL-cholesterol level, obesity, and diabetes. In recent years, researchers have identified another risk factor for cardiovascular disease, an elevated homocysteine level. Homocysteine is an amino acid normally found in blood, but elevated levels have been linked with coronary heart disease and stroke. Elevated homocysteine levels may impair endothelial vasomotor function, which determines how easily blood flows through blood vessels. High levels of homocysteine also may damage coronary arteries and make it easier for blood clotting cells called platelets to clump together a form a clot, which may lead to a heart attack.

Vitamin B12, folate, and vitamin B6 are involved in homocysteine metabolism. In fact, a deficiency of vitamin B12, folate, or vitamin B6 may increase blood levels of homocysteine. Recent studies found that supplemental vitamin B12 and folic acid decreased homocysteine levels in subjects with vascular disease and in young adult women. The most significant drop in homocysteine level was seen when folic acid was taken alone. A significant decrease in homocysteine levels also occurred in older men and women who took a multivitamin/ multimineral supplement for 56 days.

Evidence supports a role for supplemental folic acid and vitamin B12 for lowering homocysteine levels, however this does not mean that these supplements will decrease the risk of cardiovascular disease. Clinical intervention trials are underway to determine whether supplementation with folic acid, vitamin B12, and vitamin B6 can lower risk of coronary heart disease. It is premature to recommend vitamin B12 supplements for the prevention of heart disease until results of ongoing randomized, controlled clinical trials positively link increased vitamin B12 intake from supplements with decreased homocysteine levels AND decreased risk of cardiovascular disease.

1. Zschocke J, Schindler S, Hoffmann GF, Albani M. Nature and Nurture in Vitamin B12 Deficiency. Arch Dis Child. 2002 Jul;87(1):75-6.

We report on a child in whom severe nutritional vitamin B12 deficiency was exacerbated by a genetic impairment of the folate cycle, causing reduced CSF concentrations of the methyl group donor 5-methyltetrahydrofolate. Some patients with vitamin B12 deficiency may benefit from high dose folic acid supplementation, even if plasma concentrations are high.

2. Malouf M, Grimley EJ, Areosa SA. Folic Acid With or Without Vitamin B12 for Cognition and Dementia. Cochrane Database Syst Rev. 2003; (4):CD004514.

Folates are vitamins essential to the development of the central nervous system. Insufficient folate activity at the time of conception and early pregnancy can result in congenital neural tube defects. In adult life folate deficiency has been known for decades to produce a characteristic form of anaemia megaloblastic. More recently degrees of folate inadequacy, not severe enough to produce anaemia, have been found to be associated with high blood levels of the amino acid homocysteine. Such degrees of folate inadequacy can arise because of insufficient folates in the diet or because of inefficient absorption or metabolic utilisation of folates due to genetic variations. Conventional criteria for diagnosing folate deficiency may be inadequate for identifying people capable of benefiting from dietary supplementation. High blood levels of homocysteine have been linked with the risk of arterial disease, dementia and Alzheimer's disease. There is therefore interest in whether dietary supplements of folic acid (an artificial chemical analogue of naturally occurring folates) can improve cognitive function of people at risk of cognitive decline associated with ageing or dementia, whether by affecting homocysteine metabolism or through other mechanisms. There is a risk that if folic acid is given to people who have undiagnosed deficiency of vitamin B12 it may lead to neurological damage.

Vitamin B12 deficiency produces both an anaemia identical to that of folate deficiency but also causes irreversible damage to the central and peripheral nervous systems. Folic acid will correct the anaemia of vitamin B12 deficiency and so delay diagnosis but will not prevent progression to neurological damage. For this reason trials of folic acid supplements may involve simultaneous administration of vitamin B12. Apparent benefit from folic acid given in the combination would therefore need to be corrected for any effect of vitamin B12 alone. A separate Cochrane review of vitamin B12 and cognitive function is being prepared.

Objectives: To examine the effects of folic acid supplementation, with or without vitamin B12, on elderly healthy and demented people, in preventing cognitive impairment or retarding its progress.

Search Strategy: Trials were identified from a search of the Cochrane Dementia and Cognitive Improvement Specialized Register Group on 9 April 2003 using the terms: folic acid, folate, vitamin B9, leucovorin, methyltetrahydrofolate, vitamin B12, cobalamin, cyanocobalamin, dementia, cognitive function, cognitive impairment, Alzheimer's disease, vascular dementia, mixed dementia and controlled trials. MEDLINE and EMBASE (both all years) were searched for additional trials on healthy people.

Selection Criteria: All double-blind placebo-controlled randomized trials, in which supplements of folic acid with or without vitamin B12 were compared with placebo for elderly healthy people or people with any type of dementia or cognitive impairment.

Data Collection and Analysis: The reviewers independently applied the selection criteria and assessed study quality. One reviewer extracted and analysed the data. In comparing intervention with placebo, weighted mean differences, and standardized mean difference or odds ratios were estimated. MAIN RESULTS: Four randomized controlled trials fulfilled the inclusion criteria for this review. One trial (Bryan 2002) enrolled healthy women, and three (Fioravanti 1997; Sommer 1998; VITAL 2003) recruited people with mild to moderate cognitive impairment or dementia with or without diagnosed folate deficiency. Fioravanti 1997 enrolled people with mild to moderate cognitive impairment or dementia as judged by scores on the Mini-Mental State Examination (MMSE) and Global Deterioration Scale and with serum folate level<3ng/l. One trial (VITAL 2003) studied the effects of a combination of vitamin B12 and folic acid on patients with mild to moderate cognitive impairment due to Alzheimer's disease or mixed dementia. The analysis from the included trials found no benefit from folic acid with or without vitamin B12 in comparison with placebo on any measures of cognition and mood for healthy or cognitively impaired or demented people: Folic acid effect and healthy participants: there was no benefit from of oral 750 mcg folic acid per day for five weeks compared with placebo on measures of cognition and mood of 19 healthy women aged 65 to 92.

Folic acid effect and people with mild to moderate cognitive decline or dementia: there were no statistically significant results in favour of folic acid with or without vitamin B12 on any measures of cognitive function. Scores on the Mini-Mental State Examination (MMSE) revealed no statistically significant benefit from 2 mg per day folic acid plus 1mg vitamin B12 for 12 weeks when compared with placebo (WMD 0.39, 95% CI -0.43 to 1.21, P=0.35). Cognitive scores on the Alzheimer's Disease Scale (ADAS-Cog) showed no statistically significant benefit from 2 mg /day folic acid plus 1 mg /day vitamin B12 for 12 weeks compared with placebo (WMD 0.41, 95% -1.25 to 2.07, P=4.63). The Bristol Activities of Daily Living Scale (BADL) revealed no benefit from 2mg per day of folic acid plus 1 mg vitamin B12 for 12 weeks in comparison with placebo (WMD -0.57, 95%CI -1.95 to 0.81, P=0.42). None of the sub tests of the Randt Memory Test (RMT) showed statistically significant benefit from 15 mg of folic acid orally per day for 9 weeks when compared with placebo.

One trial (Sommer 1998) reported a significant decline compared with placebo in two cognitive function tasks in demented patients who had received high doses of folic acid (10 mg /day) for unspecified periods. One trial (VITAL 2003) showed that 2 mg folic acid plus 1 mg vitamin B12 daily for 12 weeks significantly lowered serum homocysteine concentrations (P <0.0001). There was no beneficial effect of 750 mcg of folic acid per day on measures of cognition or mood in older healthy women. In patients with mild to moderate cognitive decline and different forms of dementia there was no benefit from folic acid on measures of cognition or mood. Folic acid plus vitamin B12 was effective in reducing the serum homocysteine concentrations. Folic acid was well tolerated and no adverse effects were reported. More studies are needed.

3. Pilarczyk M, Porebiak J, Fidor A, Nastaj M, Jaworski J, Stelmasiak Z. Vitamin B12 Deficiency as a Potential Cause of Dementia. Ann Univ Mariae Curie Sklodowska. 2004;59(2):408-9.

There is a patient case with dementia and brain MRI massive abnormalities, probably in the course of vitamin B12 deficiency.

4. Green R, Miller JW. Vitamin B12 Deficiency is the Dominant Nutritional Cause of Hyperhomocysteinemia in a Folic Acid-fortified Population. Clin Chem Lab Med. 2005;43(10):1048- 51.

Prevalence rates for folate deficiency and hyperhomocysteinemia have been markedly reduced following the introduction of folic acid fortification in the United States. We report the prevalence of hyperhomocysteinemia in a population of community-dwelling elderly Latinos in the post-folic acid fortification era. We measured homocysteine, total vitamin B12, holotranscobalamin, red blood cell folate, and serum creatinine in 1096 subjects aged > or =60 years. Hyperhomocysteinemia was observed in 16.5% of the subjects. The population attributable risk percentages for hyperhomocysteinemia were 29.7% for total B12 <148 pmol/L, 36.4% for holotranscobalamin <35 pmol/L, and 41.4% for creatinine >115 micromol/L. In contrast, the population attributable risk percentage for hyperhomocysteinemia was only 0.3% for red blood cell folate <365 nmol/L. We conclude that in the post-folic acid fortification era, low vitamin B12 status has become the dominant nutritional determinant of hyperhomocysteinemia. Steps to either reduce the prevalence of vitamin B12 deficiency or to identify and treat individuals with vitamin B12 deficiency could further reduce the prevalence of hyperhomocysteinemia.

5. Cobalamin, the Stomach, and Aging. Am J Clin Nutr. 1997 Oct;66(4):750- 9.

Low cobalamin concentrations are common in the elderly. Although only a minority of such persons display clinically obvious symptoms or signs, metabolic data clearly show cellular deficiency of cobalamin in most cases. The evidence suggests that this is not a normal physiologic expression of the aging process. Rather, the elderly seem at increased risk for mild, preclinical cobalamin deficiency. Classical disorders such as pernicious anemia are the cause of this deficiency in only a small proportion of the elderly. A more frequent problem is food-cobalamin malabsorption, which usually arises from atrophic gastritis and hypochlorhydria but other mechanisms seem to be involved in some patients. The diminished absorption should not be viewed as a natural consequence of aging. The partial nature of this form of malabsorption produces a more slowly progressive depletion of cobalamin than does the more complete malabsorption engendered by disruption of intrinsic factor-mediated absorption. The slower progression of depletion probably explains why mild, preclinical deficiency is associated with food-cobalamin malabsorption more often than with pernicious anemia. Decisions about the optimal management of the very common problem of mild, preclinical cobalamin deficiency in the elderly await further clarification of the processes and the complex issues involved, including the possibility that routine nitrous oxide use during surgery, proposed dietary changes, and other practices may further stress the marginal cobalamin status of many elderly people.

6. Boers GH. Hyperhomocysteinaemia: A Newly Recognized Risk Factor for Vascular Disease. Neth J Med. 1994 Jul;45(1):34-41.

In the past decade significant progress has been made in understanding of hyperhomocysteinaemia and its association with the proneness to premature development of vascular disease. Pooled data from a large number of studies demonstrate that mild hyperhomocysteinaemia after standardized methionine loading is present in 21% of patients with coronary artery disease, in 24% of patients with cerebrovascular disease, and in 32% of patients with peripheral vascular disease. A relative risk of 13.0 (95% confidence interval 5.9-28.1) of vascular disease at relatively young age can be calculated in subjects with such abnormal response to methionine loading. Pathological homocysteine levels are affected by genetic defects in homocysteine metabolism which have still not been completely clarified and which are more complex than originally supposed. Furthermore, a variety of non-genetic determinants such as deficiency of folate or vitamin B12 has to be taken into account. Mild hyperhomocysteinaemia can be reduced to normal in virtually all cases by simple and safe treatment with vitamin B6, folic acid, and betaine, each of which is involved in methionine metabolism. A clinically beneficial effect of such an intervention, which is currently under investigation, could make large-scale screening mandatory for this risk factor.

7. Rimm EB, Willett WC, Hu FB, Sampson L, Colditz GA, Manson JE, Hennekens C, Stampfer MJ. Folate and Vitamin B6 from Diet and Supplements in Relation to Risk of Coronary Heart Disease Among Women. JAMA. 1998 Feb 4;279(5):359-64.

Hyperhomocysteinemia is caused by genetic and lifestyle influences, including low intakes of folate and vitamin B6. However, prospective data relating intake of these vitamins to risk of coronary heart disease (CHD) are not available. OBJECTIVE: To examine intakes of folate and vitamin B6 in relation to the incidence of nonfatal myocardial infarction (MI) and fatal CHD. DESIGN: Prospective cohort study. SETTING AND PATIENTS: In 1980, a total of 80082 women from the Nurses' Health Study with no previous history of cardiovascular disease, cancer, hypercholesterolemia, or diabetes completed a detailed food frequency questionnaire from which we derived usual intake of folate and vitamin B6. MAIN OUTCOME MEASURE: Nonfatal MI and fatal CHD confirmed by World Health Organization criteria. RESULTS: During 14 years of follow-up, we documented 658 incident cases of nonfatal MI and 281 cases of fatal CHD.

After controlling for cardiovascular risk factors, including smoking and hypertension and intake of alcohol, fiber, vitamin E, and saturated, polyunsaturated, and trans fat, the relative risks (RRs) of CHD between extreme quintiles were 0.69 (95% confidence interval [CI], 0.55-0.87) for folate (median intake, 696 microg/d vs 158 microg/d) and 0.67 (95% CI, 0.53-0.85) for vitamin B6 (median intake, 4.6 mg/d vs 1.1 mg/d). Controlling for the same variables, the RR was 0.55 (95% CI, 0.41-0.74) among women in the highest quintile of both folate and vitamin B6 intake compared with the opposite extreme. Risk of CHD was reduced among women who regularly used multiple vitamins (RR=0.76; 95% CI, 0.65-0.90), the major source of folate and vitamin B6, and after excluding multiple vitamin users, among those with higher dietary intakes of folate and vitamin B6. In a subgroup analysis, compared with nondrinkers, the inverse association between a high-folate diet and CHD was strongest among women who consumed up to 1 alcoholic beverage per day (RR =0.69; 95% CI, 0.49-0.97) or more than 1 drink per day (RR=0.27; 95% CI, 0.13-0.58). These results suggest that intake of folate and vitamin B6 above the current recommended dietary allowance may be important in the primary prevention of CHD among women.

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