Posted on 02 Mar 2011 02:51
By Ken Adams, M.D. and Scott E. Conard, M.D.
Sources and Physiologic Functions
Liver, kidney, muscle meats, eggs, cheese, milk, and fish are excellent sources of vitamin B12. It is not found in plant foods or in yeast. Fermented foods such as soy sauce, tempeh, and miso, and fortified foods such as soymilk are also good sources of this vitamin.
Vitamin B12 is water-soluble. Cobalamine contains the element cobalt surrounded by a porphyrin like ring. The coenzyme forms of cobalamine are 5'deoxyadenosylcobalamine and methylcobalamine. Four types of cobalamin play a role in human metabolism, including cyanocobalamin (the form known as B12), methylcobalamin (the main form in the serum), and adenosylcobalamin (the main storage form in the liver). Cobalamin acts as coenzyme in two known pathways of human metabolism: demethylation of the folate derivative needed for the thymidylate synthesis, and conjugation of folic acid into the active polymer forms of folate. Cobalamin deficiency may produce a functional folate deficiency by trapping folate in these pathways and limiting its regeneration. Cobalamin is essential for the regeneration of tetrahydrofolate needed in purine and thymidine synthesis. Vitamin B12 is essential for growth, blood cell formation, nutrient metabolism, thyroid functioning, and myelin formation. It prevents accumulation of methyl melonoic acid, and thus, prevents production and incorporation of abnormal fatty acids into the nerve cell membrane. This may account for some of the neurological manifestations associated with deficiency. It may have a role in homocysteine metabolism and thus, control of atherosclerosis.
Populations at risk
Vitamin B12 deficiency is commonly caused by pernicious anemia (PA). The major defect in PA is gastric atrophy and absence of intrinsic factor, which is essential for B12 absorption. Disorders of gastric mucosa, intestinal infections, malabsorption secondary to gastrectomy, total ileal disease, or resection and genetic defects in the absorption and transport mechanisms may result in development of deficiency state. Strict vegetarianism over an extended period of time and tapeworm infestation are the other risk factors. A study showed that the vegans had B12 intakes below the RNI; and 35% of the long-term vegetarians and vegans had serum vitamin B12 concentrations below the reference range. Cigarette smoking also affects vitamin B12 status. A univariate analysis showed significantly lower plasma, red blood cell (RBC), and buccal mucosa of vitamin B12 concentrations in cigarette smokers compared to non-cigarette smokers.
Signs and Symptoms of Deficiency
The major defect of B12deficiency is an impairment of growth, particularly of rapidly dividing cells such as immature RBC. Infants with severe deficiency present with anemia and neurological problems, such as flaccidity, poor muscular control, twitching, and abnormal electroencephalogram. In adults, it is characterized by megaloblastic anemia and later development of neuropsychiatric symptoms. Neurological symptoms include numbness of the hands and feet, parasthesias, decreased vibration sense, and ataxia. CNS symptoms may occur without anemia and are irreversible. Poor growth, sore, smooth tongue, spleenomegaly, thrombocytopenia, and leucopenia are also seen.
Vitamin B12 toxicity
There are no signs of vitamin B12 toxicity, per se. There are a few rarely reported side effects that might be attributable to the vitamin, but such side effects are not necessarily related to the dose. These possible side effects include: diarrhea, blood clots in the legs, feelings of swelling over the entire body. These are the signs of an allergic reaction: hives or a rash, itching, swelling of the lips, mouth, or throat, wheezing or other difficulty breathing.
Vitamin B12 is usually considered a non-toxic substance. Even taking it by injection at high doses does not seem to increase the risk for toxicity
Elevated levels of Vitamin B12 can occur in polycythemia vera. Polycythemia vera is a disease state in which the proportion of blood volume that is occupied by red blood cells increases. Diagnosis is characterized by an absolute increase in red blood cells and in the total blood volume, although it is not unusual to also have increases in white blood cells and platelets. A bone marrow examination may be done. However, it is not functional in determining a definitive diagnosis. Laboratory studies confirm the diagnosis by showing increased RBC mass and normal arterial oxygen saturation in association with splenomegaly (spleen enlargement) or two of the following: thrombocytosis, leukocytosis, elevated leukocyte alkaline phosphatase level, or elevated serum vitamin B12 or unbound B12-binding capacity.
Vitamin B12 Recommendations: RDA in μg (mcg)
- Infants birth to 6 mos - 0.3mcg
- Infants 6 mos to 1 yr - 0.5mcg
- Children 1 yr to 3 yr - 0.7mcg
- Children 4 yr to 6 yr - 1.0mcg
- Children 7 yr to 10 yr - 1.4mcg
- Adolescent males 11yr to 14 yr - 2.0mcg
- Adolescent females 11 yr to 14 yr - 2.0mcg
- Adolescent males 15 yr to 18 yr - 2.0mcg
- Adolescent females 15 yr to 18 yr - 2.0mcg
- Adult males 19 yr to 50 yr - 2.0mcg
- Adult females 19 yr to 50 yr - 2.0mcg
- Adult males 51 yr plus - 2.0mcg
- Adult females 51 yr plus - 2.0mcg
- Pregnant Women - 2.2mcg
- Lactating Mothers (1st 6 months) - 2.6mcg
- Lactating Mothers (2nd 6 months) - 2.6mg
Cyanocobalamin Vitamin B12 Food Sources
|Liver (beef braised)||3.5 oz||71 mcg|
|Liver (veal braised)||3.5 oz||36.50 mcg|
|Eggs (boiled)||1 egg||0.56 mcg|
|Cheddar Cheese||3.5 oz||0.83 mcg|
|Monterey Cheese||3.5 oz||0.23 mcg|
|Milk 2%||8 fl oz||0.89 mcg|
|Clams (raw)||3 oz (4 large or 9 small)||42.05 mcg|
|Tuna (canned in water)||3 oz||2.54 mcg|
The total homocysteine (tHcy) level in the serum is related to pregnancy complications, neural tube defects, mental disorder, and cognitive impairment in the elderly. In addition, over 80 clinical and epidemiological studies provide ample evidence that an elevated tHcy level is a common cardiovascular risk factor. The effect of vitamin B12 on the tHcy level is modest with a maximum of a 10 - 15% reduction. However, a low serum B12 level may prevent an optimal response to folic acid. There also exists the concern that folic acid supplementation alone may correct the hematological findings associated with B12 deficiency, but may precipitate the neurological sequelae of B12 deficiency.
Cobalamin deficiency in the elderly
Vitamin B12 deficiency is present in up to 15% of the elderly population. This is documented by elevated methylmalonic acid with or without elevated total homocysteine concentrations in combination with low or low-normal vitamin B12concentrations. Clinical signs and symptoms of vitamin B12deficiency are insensitive in elderly subjects, and comorbidity in these subjects makes responses to therapy difficult to interpret. Clear-cut megaloblastic anemia and myelopathy or neuropathy are rare in elderly vitamin B12deficient subjects. Many elderly subjects with hyperhomocysteinemia have undiagnosed vitamin B12deficiency with elevated serum methylmalonic acid concentrations. Therefore, such elderly subjects should not receive folic acid supplementation before their vitamin B12 status is diagnosed. Results of a study showed potential usefulness of serum MMA and Hcys in identifying subclinical or tissue deficiency of vitamin B12. Clinicians should be aware of the risk of vitamin B12 deficiency in older people and of current screening algorithms using serum metabolites. Large amounts of oral vitamin B12supplementation may be effective in lowering serum methylmalonic acid values in the elderly. However, the dose of vitamin B12in most common multivitamin preparations is too low for this purpose. The traditional treatment of pernicious anemia in the United States is injections of vitamin B12. However, several studies in subjects with pernicious anemia showed that oral doses of 300-1000 mg are effective in raising serum vitamin B12concentrations and preventing clinical abnormalities. It is likely that similar doses of vitamin B12(100-1000 mg) would be effective in elderly subjects with less complete malabsorption.
Undiagnosed pernicious anemia is a common finding in the elderly, especially among black and white women. Findings from a study by Carmel show that almost 800,000 elderly people in the United States have undiagnosed and untreated pernicious anemia and, thus, would be at possible risk for masked cobalamin deficiency if exposed to large amounts of folate. This number does not include those elderly with cobalamin deficiency caused by other disorders or the still unknown number of younger people with unrecognized pernicious anemia and other causes of deficiency.
Low cobalamin concentrations are common in the elderly. Although only a minority of such persons displays 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. One study demonstrated no significant difference in either free or protein-bound cobalamin absorption between healthy middle-aged and older adults, and no alteration in cobalamin absorption in subjects identified as having mild to moderate atrophic gastritis. Thus, the high prevalence of low cobalamin levels in older people cannot be explained by either the aging process or mild to moderate atrophic gastritis. The diminished absorption should not be viewed as a natural consequence of aging. According to the American Journal of Clinical Nutrition, 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 decreased progression of depletion is the most likely cause and this explains why mild pre-clinical low levels are connected most frequently with food-cobalamin malabsorption rather than with pernicious anemia.
The effects of hypochlorhydria and acidic drink ingestion on protein-bound vitamin B12 absorption was investigated in elderly subjects. Omeprazole causes hypochlorhydria and thus, protein-bound vitamin B12 malabsorption, and ingestion of an acidic drink improves protein-bound vitamin B12 absorption. Omeprazole therapy acutely decreased cyanocobalamin absorption in a dose-dependent manner. Patients taking cimetidine should also take vitamin B12 supplements. About 10-20% of elderly are deficient in cobalamine. There was a high (14.5%) prevalence of cobalamin deficiency as demonstrated by elevations in serum methylmalonic acid and homocysteine in addition to low or low normal serum cobalamin levels in elderly outpatients. The serum cobalamin level was insensitive for screening since similar numbers of patients with low normal serum cobalamin levels of 201-300 pg/mL compared with patients with low cobalamin levels (< or = 200 pg/mL) had markedly elevated metabolites which fell with cobalamin treatment. The latter study suggested that the lower limit of the normal range for Cbl level should be increased to 300 pg/mL.
Hearing impairment is one of the four most prevalent chronic conditions in the elderly. Houston et. al., in their recent article, suggested that poor vitamin B12and folate status might be associated with age-related auditory dysfunction.
Data suggest that serum cobalamin levels decrease in normal aging. This association is present only in the non-demented group, but not the demented group. In one study, a lower cobalamin concentration was observed in Alzheimer's disease sufferers still living in their own homes compared with institutionalized persons with AD, which may be related to, but not fully explained, by eating habits. Patients with AD living in their own homes are at risk of developing cobalamin deficiency, and monitoring of serum cobalamin concentrations might be useful in this group. One small study in 22 elderly patients with low serum cobalamin, showed that vitamin B12 may be beneficial in the treatment of Alzheimers. A study in 50 Chinese subjects suggested that cobalamin deficiency did not invariably cause cognitive impairment in older people. In another study, vitamin B12 replacement did not result in the slowing of the progression of dementia.
As it becomes clear that most low cobalamin concentrations in the elderly are neither artifacts nor normal expressions of aging, but represent a mild clinical deficiency state (and occasionally a clinically overt one), and as it has become clearer that in one half of the cases absorption of cobalamin is impaired in one way or another, the usual dismissal of patients with low cobalamin concentrations should be reexamined. A broad spectrum of options can be formulated, though none of these alter the common consensus that symptomatic deficiency must always be treated promptly. The options include the following:
1. Do nothing about cobalamin concentrations unless they become clinically noticeable. The arguments in support of this include the sheer number of patients involved, the costs, skepticism about medical intervention for biochemical changes, the fact that only a small minority of affected patients are symptomatic, the likelihood that whatever progression exists is very slow, and the fact that studies have shown no ill effects, even after many years of withholding treatment. The counter arguments are that absence of overt symptoms do not necessarily equal a state of well-being, that the underlying gastric disturbance is one half of the affected people which suggests that the cobalamin deficiency will persist and probably progress, that prevention has at least as much merit as cure, and that preclinical cobalamin deficiency may be a sentinel of serious underlying diseases, such as pernicious anemia in premyelopathic stage or celiac disease.
2. Automatically treat all patients with low cobalamin concentrations. The arguments in support of this hypothesis are that it is a cheap efficient way to ensure that no one who might benefit goes untreated, that a detailed work-up may be neither practical nor effective in view of its expense and the limited availability of many of the newer tests, and that cobalamin is not toxic and will not harm those who might receive it unnecessarily. The arguments against this approach are the resulting failure to identify serious underlying diseases that may have caused the deficiency in some of the patients, the failure to identify in some a need for more complex treatment or attention to complications, and the possibility that the amount and presumably the oral route of cobalamin therapy that such an approach dictates may prove inadequate to some patients. It is worth noting that cobalamin deficiency, even though less frequent than in nonsupplemented individuals, was still found in elderly patients who were taking cobalamin supplements. Thus, although cobalamin supplements are likely to work satisfactorily in people with food-cobalamin malabsorption, this has never been established and may be more complex than assumed. One can ask whether cobalamin pills taken with meals bind to the food proteins and fail to be absorbed by someone with food-cobalamin malabsorption. Moreover, it is not certain that all patients with unsuspected pernicious anemia (estimated to occur in 2% of all elderly and 10-20% of those with low cobalamin concentrations) will absorb enough cobalamin from a pill, especially if doses < 100 mg are taken, or if it is taken haphazardly, as routine supplements often are.
3. Give cobalamin supplements to all elderly people, regardless of their cobalamin concentrations. The arguments in favor of this, beyond those already stated in the preceding option, are that a problem of such proportions may benefit from equally broad solutions, that it saves the cost of widespread cobalamin testing (which in any case may provide falsely normal and falsely abnormal results), and that it may have potential benefits for patients with very early stages of negative balance. The counterarguments are that supplements recommended population-wide tend to lead to high intakes by those who are more affluent, health conscious, and functionally intact, and tend to be ignored by the poor and the impaired.
4. Continue the traditional medical approach of individual evaluation and therapy. The arguments for this approach are based on its laudable goal of making the specific diagnosis; identifying possibly treatable underlying diseases; addressing prognostic issues; treating those who need it with specific, tailored therapeutic approaches; and avoiding treatment of those who do not need it. The arguments against it are the cost in time and money of evaluating millions of people, and the uncertainty of what constitutes optimal diagnostic evaluation, given that currently standard, clinical tests such as blood counts and Schilling tests give negative results in most cases.
The choice to be made among these options and their variations can reflect only personal philosophies and biases at this time. To the concerns already mentioned, could be added uncertainty about the possible adverse effects created by changes in folate status and other changes. Unprotected exposure to nitrous oxide, a widely used inhalant during surgery may constitute another common and under-appreciated source of clinical risk for the elderly with marginal cobalamin status. All these issues must be carefully weighed when devising an optimal approach to the common problem of mild, preclinical cobalamin deficiency in the elderly.
HIV disease progression
In a study conducted in HIV positive men, participants with low serum vitamin B12 concentrations (< 120 pmol/L) had significantly shorter AIDS-free time than those with adequate vitamin B12 concentrations (median AIDS-free time = 4 vs. 8 y, respectively, P = 0.004). In a cross sectionals study, Remacha et. al. found that HIV-1 infected patients that had lower serum vitamin B12 concentrations had lower hemoglobin, leukocytes, CD4+ lymphocytes, and CD4+/CD8+ lymphocytes than HIV-1 infected patients with normal serum vitamin B12 concentrations. Ninety percent of the patients with low serum vitamin B12 concentrations had AIDS compared with only 66% of patients with adequate vitamin B12 concentrations. Similar results were noted in other studies. Another study showed that subjects with low CD4 lymphocyte counts, low serum vitamin B12 levels, anemia, or low neutrophil counts were more likely to have hematologic toxic effects when treated with AZT. Low serum concentrations of vitamin B6 and folate were not associated with either progression to AIDS or decline in CD4+ lymphocyte count. Therefore, Serum vitamin B12 concentrations seem to be an early and independent marker of HIV-1 disease progression. The effectiveness of vitamin B12 replacement therapy in slowing disease progression, however, is still unknown and should be the focus of further research.
Menopausal women with lower median B12 concentrations were found to have a higher risk for the development of breast cancer when compared to controls. In the same study, an increased risk of breast cancer was observed among women in the lowest fifth of the distribution of vitamin B12 as compared to women in the other four higher fifths, suggesting a threshold effect for B12. However, the possibility cannot be excluded that an unidentified protective factor for breast cancer associated with higher B12 concentrations might have led to the protective association between vitamin B12 and breast cancer. The mechanisms underlying the association between B12 and breast cancer might be explained by the role of B12 as a co-substrate in the synthesis of methionine, for which a methyl group is transferred from methyl tetrahydrofolate to homocysteine. Thus, lower concentrations of B12 might result in reduced synthesis of de novo methyl groups, leading to DNA hypomethylation, which may play a role in carcinogenesis. Through diminished availability of unsubstituted tetrahydrofolate, which is involved in reactions generating thymidilate and purines, lower B12 concentrations might also lead to reduced DNA synthesis and, thus, impaired DNA repair mechanisms.
Vitamin B12 deficiencies can lead to reduced sperm counts and lowered sperm motility. Thus, it is suggested that B12 supplements might improve fertility in men who are truly deficient in this vitamin.
In a double-blind study, patients with diabetic neuropathy who received methylcobalamin showed statistical improvement in the somatic and autonomic symptoms with regression of signs of diabetic neuropathy. Motor and sensory nerve conduction studies showed no statistical improvement after 4 months. The drug was easily tolerated by the patients and no side effects were encountered. In another study, intrathecal injection of methylcobalamine (2,500 micrograms in 10 ml of saline) in patients with symptomatic diabetic neuropathy showed improvement in paresthesia, burning pains, and heaviness. The mean peroneal motor-nerve conduction velocity did not change significantly. Methylcobalamin caused no side effects with respect to subjective symptoms or characteristics of spinal fluid. Thus, these findings suggest that a high concentration of methylcobalamin in spinal fluid is highly effective and safe for treating the symptoms of diabetic neuropathy.
A massive dose of methyl vitamin B12 (60 mg every day for 6 months) was administered to 6 patients with chronic progressive MS, a disease which usually had a morbid prognosis and widespread demyelination in the central nervous system. Although the motor disability did not improve clinically, the abnormalities in both the visual and brainstem auditory evoked potentials improved more frequently during the therapy than in the pre-treatment period. Thus, it is suggested that a massive dose methyl vitamin B12 therapy may be useful as an adjunct to immunosuppressive treatment for chronic progressive MS. Another study showed that serum cobalamin deficiency is uncommon in multiple sclerosis.
Vitamin B12 is essential for purine and thymidine synthesis. It is also essential for growth, blood cell formation, nutrient metabolism, thyroid functioning, and myelin formation. It helps in maintaining the integrity of nerve cell membrane and is also needed in the production of the mood affecting substance called SAM (S-adenosyl methionine). Cobalamin deficiency may produce a functional folate deficiency by trapping folate in metabolic pathways and limiting its regeneration, and also functions with folate in lowering plasma homocysteine levels, which is an independent risk factor for coronary artery disease.
A number of claims have been made about the conditions in which Vitamin B12 may be supportive: pernicious anemia, Crohn's disease, Vitiligo, Tinnitus, Atherosclerosis, High Cholesterol, Diabetes, Osteoporosis, Retinopathy, HIV support, Shingles (herpes zoster/postherpetic neuralgia, Hepatitis, asthma, and infertility in males.
Evidence strongly supports that Vitamin B12 has a modest effect in lowering the tHcy and optimizes the response to folic acid. There also exists the concern that folic acid supplementation alone may correct the hematological findings associated with B12 deficiency, but may precipitate the neurological sequelae of B12 deficiency. The total homocysteine (tHcy) level in the serum is related to pregnancy complications, neural tube defects, mental disorder, and cognitive impairment in the elderly. Vitamin B12 may have a protective effect in the risk of breast cancer. Low B12 concentrations are shown to be associated with increased risk of breast cancer, which may be because lower concentrations of B12 might result in reduced synthesis of de novo methyl groups leading to DNA hypomethylation, which may play a role in carcinogenesis. Serum vitamin B12 concentrations seem to be an early and independent marker of HIV-1 disease progression, although the effectiveness of vitamin B12 replacement therapy in slowing disease progression is still unknown. Further role of B12 in homocysteine lowering is discussed in Homocysteine section. Clinicians should be vigilant to the possibility of cobalamin deficiency in the context of neuropsychiatric illnesses.
Vitamin B12 deficiency is common in elderly population, most of whom are undiagnosed with elevated serum methyl malonoic acid concentrations. Although the high prevalence of low cobalamin levels in older people cannot be explained by either ageing process or mild to moderate atropic gastritis, undiagnosed pernicious anemia and food-cobalamin malabsorption are very common in the elderly. Patients with Alzheimer's disease living in their own homes are also at increased risk of developing a cobalamin deficiency. Poor vitamin B12 and folate status might be associated with age-related auditory dysfunction. Thus, it appears that in one half of the cases, absorption of cobalamin is impaired in one way or the other, and the usual dismissal of patients with low cobalamin concentrations should be re-examined.
In general populations who are prone to be deficient, like patients with pernicious anemia and those with disorders of gastric mucosa, intestinal infections, gastrectomy, ileal disease, or resection, and genetic defects in absorption and transport mechanisms, should receive supplementation. Strict vegetarians and cigarette smokers should consume adequate amounts in their diet to prevent development of hematological and neurological symptoms of B12 deficiency. Delay in diagnosing and treating vitamin B12 deficiency may result in permanent neurological damage.
Our recommendations for adults is 800 μg/d. This amount can be obtained from approximately 1.4 boiled eggs, 1 serving of cheddar cheese, 8 fl oz of milk with 2% fat and 1/100 servings of liver (beef braised). Patients with pernicious anemia are traditionally treated with vitamin B12 injections, while oral doses of 300-1000 μg/d are shown to be equally effective in raising serum vitamin B12 concentrations and preventing clinical abnormalities. Doses of 100-1000 μg/d may be effective in the elderly patients. Anyone supplemented with more than a 1000 μg/d of folic acid may be initially evaluated to prevent potential problems.
See also Vitamin B12 in Health and Disease.
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