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Sources: 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.
Biochemistry: 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.
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 B12
Food Source Serving Size/Amount # of mcg/serving
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 Literature Homocysteine:
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
B12deficiency 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 B12status 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.
Breast Cancer
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.
Male Infertility:
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.
Diabetic Neuropathy:
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.
Multiple Sclerosis:
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.
Summary:
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.By
Ken Adams, M.D.
