This can result from one of two
things; either the result of less severe defects in homocysteine metabolic
enzymes, or inadequate amounts of folic acid, and /or
vitamin B6, and/or
||Folate and Homocysteine
It is well documented that homocysteinemia metabolism is associated with
vascular conditions. The accumulation of excess quantities of homocysteine
accompanies errors of metabolism that decrease the conversion of homocysteine to
cystathione or methionine. These pathways require vitamin B6 or folic acid
and vitamin B12 for the proper metabolism of homocysteine. While the
connection between elevated homocysteine concentrations in genetic
homocysteinemia was recognized in 1969, the ability of folate deficiency to
elevate serum homocysteine has only been generally recognized in the last ten
An extraordinarily high serum homocysteine level in humans is a firmly
established health problem. In recent years, however, the possibility that
slightly to moderately elevated homocysteine levels among the general population
has been increasingly substantiated as a health problem indicator. This is
in spite of the fact that the homocysteine values were within what has been
considered the normal range for serum homocysteine concentration. While
extremely high blood homocysteine levels due to rare enzymatic defects in
various points of homocysteine metabolic pathways do occur, they are rare and
usually result in health problems at a young age. Moderate elevations, on
the other hand, appear to be much more common.
Folic acid supplements have been shown to lower the homocysteine concentrations
of both homocysteinemic subjects and non-folate-deficient subjects. Because
vitamin B6 and vitamin B12 are also involved in homocysteine metabolism, most
recent studies have examined the role of all three nutrients on elevated
homocysteine levels. Compared with a group of healthy controls, subjects with an
elevated plasma homocysteine concentration had significantly lower plasma
concentrations of vitamin B6, vitamin B12, and folic acid. In a placebo
controlled, follow-up study using the same patients, a daily supplement of 10
mg. vitamin B6, 1 mg. folic acid, and .4 mg vitamin B-12 normalized the elevated
plasma homocysteine concentrations within six weeks. These authors concluded
that, "because hyperhomocysteinemia is implicated as a risk factor, appropriate vitamin therapy may be both efficient
and cost-effective to control elevated homocysteine concentrations."
A recently published study examining the role of these three vitamins on
homocysteine concentrations demonstrated that inadequate folic acid intake is
the main determinant of homocysteine-related health problems. Other recent
studies have shown that homocysteine levels rose inversely with folate status.
Interestingly, homocysteine concentrations did not reach a stable low level until
folate intake reached approximately 400 micrograms per day or more. Shockingly,
the Recommended Dietary Allowance for folic acid was recently lowered from 400 to 200 micrograms
per day. Additional data has suggested that as much as forty percent of the
population is not consuming an adequate amount of folic acid to keep
homocysteine concentrations low. Even in people with elevated homocysteine
levels that are unresponsive to high dietary levels of folic acid (400
mcg./day), folic acid supplements in the range of 1-2 mg per day are usually
effective in lowering elevated homocysteine concentrations. It appears that
certain people, due to their genetic endowment, require different amounts of
dietary folic acid to properly metabolize homocysteine.
As fascinating as the evidence for homocysteine is,
the exact mechanism(s) by which homocysteinemia does its job has
been somewhat elusive. One hypothesis has been that the damage comes from the
toxic effect of homocysteine on endothelium by impairing the production
of endothelium-derived relaxing factor. Another line of thinking has suggested
that homocysteine directly stimulates the proliferation of smooth-muscle cells
in the endothelium.
Perhaps the most interesting theories of how homocysteinemia promotes problems comes from homocysteines relationship with copper and iron.
In the case
of iron, it has been demonstrated that homocysteine induces iron-catalyzed lipid
vitamin E was very effective at slowing
oxidation caused by homocysteine, providing further evidence for the
protective effects of vitamin E.
Another documented result of elevated homocysteine concentrations is a
detrimental effect on copper status, including decreased tissue levels of
copper, decreased activities of copper-dependent antioxidant enzymes like
ceruloplasmin and superoxide dismutase, decreased activity of
glutathione, and a significant increase in lipid peroxidation in
organ tissues. Notably, some organs seem especially susceptible to lipid
peroxidation resulting from homocysteinemia-induced copper deficiency, because
other tissues such as the liver were not similarly affected.
As the data continues to accumulate, and homocysteinemia gains wider acceptance
as a determinant of health risk, we can only hope that the population
becomes as aware of its homocysteine concentration (both easily measured with a blood test); and most importantly,
that vitamins B6, B12 and folic acid become routinely recommended by physicians
as a safe and inexpensive measure to reduce this easily controlled risk-factor, namely homocysteinemia.
Folate and Chromosomes
The possible role of folic acid deficiency was
first suggested by the evidence of chromosomal abnormalities
present in folate-deficient people. These chromosomal abnormalities were
helped by folic acid supplementation. Increased levels
of chromosomal aberrations have been observed in lymphocytes from individuals
with low serum levels of folic acid.
Unfortunately, as previously discussed, serum levels of folic acid may
significantly underestimate the true incidence of subclinical folate deficiency.
The equivocal results found in some studies may result from this
underestimation, as significant tissue deficiencies may exist in spite of normal
serum folic acid levels. In line with this reasoning, a study was conducted on
the effect of smoking on folate levels in buccal mucosal cells. The folate
levels in these cells, taken from the mouth mucosa, were thought to more
accurately reflect tissue folate status than serum levels of folic acid. These
researchers found that the correlation between plasma folate and oral mucosal
folate was not of statistical significance, suggesting that plasma folate levels
do not reflect the folate levels in oral mucosal cells. In fact, smokers were
twelve times more likely to have a buccal mucosal cell folate deficiency than
were nonsmokers, despite the fact that their plasma folate levels were at the
low end of the normal range and not considered deficient. Although blood micronutrient levels are
presumed to reflect tissue levels, data on tissue nutrient levels is limited.
Thus, the accumulating epidemiological evidence of folates role may seriously underestimate the role of folate, because almost
all of these studies utilize the easily collected serum folate level. It is
likely that these studies may be showing us only the tip of the iceberg and that
large studies utilizing tissue folate measurement would show a very strong
association between localized tissue deficiencies of folate and the development
of health problems.
Because of all the evidence that most persons are consuming diets inadequate in
folate content for optimum health, many people consume supplements containing
folic acid. Although estimates of the incidence of subclinical folate deficiency
have varied, some research has suggested that it is widespread. In one well-done
study that examined metabolic evidence for folic acid deficiency (elevated
homocysteine levels), in addition to the more commonly measured serum folic acid
level, it was found that the incidence of metabolic evidence of folic acid
deficiency is substantially higher than could be estimated from the serum
concentration of folic acid. While the incidence of low serum folic acid was
found in only five percent of the subjects, metabolic evidence of folic acid
deficiency was found in thirty percent. It seems likely that subclinical
deficiency is more common than thought, mainly because the commonly tested serum
level of folic acid is not a good measure of true folate status. This is
especially relevant to persons with increased folic acid utilization and
requirements such as smokers, drinkers, pregnant women, and the elderly.
The safety and toxicity of folic acid has been reviewed, and folic acid is
generally regarded as non-toxic for normal humans. There has been some concern
expressed, however, that large amounts of
folic acid (>1 mg./day) is not advised. Although the
above found little documented evidence of this actually occurring (one or
two documented cases over a ten year period), persons taking folic acid
supplements would be well advised to concurrently consume a vitamin B12
supplement. Certainly the research supports the idea that folic acid
supplementation of 200-1000 micrograms per day is safe for virtually all persons
and that this level of supplementation can prevent or correct clinical and
subclinical evidence of folate deficiency in the vast majority of persons.
Unfortunately, the optimal intake of folate is undetermined. The supplemental
form of folate, folic acid, is considered more bioavailable than many food folates.
Additionally, the necessary dietary intake to ensure both adequate serum and
tissue folate levels in different groups of individuals (i.e. smokers) is
unknown. Based on the knowledge to date, 500 to 1000 micrograms per day of
supplemental folic acid should be adequate and safe for most individuals. Based
on bioavailability studies, approximately twice this amount of food folates
would be necessary. Few of us do, however, consume this amount on a regular
basis. Given its safety and many potential benefits, it is hard to justify not
supplementing with folic acid. With all the potential benefits of folic acid, we
can only hope for the day when it is required that foods be fortified with folic
acid, perhaps along with vitamin B-12. The benefits of this to the population at
large, many of whom are consuming an inadequate amount of folate in their diet,
could be enormous.
- For dietary supplement use only,
- Keep Folic Acid (folate)
supplements out of reach of children,
- Do not exceed recommended dosage,
- If you have a bad reaction or side
effects, discontinue use immediately,
- When using Folic Acid (folate)
supplements, please inform your
- If you are pregnant, lactating
or have a medical condition, consult your health care
professional before using this or any other nutritional
- If negative side effects of allergic
reaction occurs, discontinue immediately.
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