Cell replication Folate transfers single carbon atoms in reactions essential to the
synthesis of purines and pyrimidines and hence to the production of deoxyribonucleic acid
(DNA). Unlike the methylation cycle, the DNA cycle does not depend on vitamin B12. Folic
acid can thus maintain the supply of intracellular folate required for DNA synthesis. DNA
synthesis, and hence cell replication, can therefore take place in people with vitamin B12
deficiency, provided that folic acid is available as a source of folate.
A number of drugs interfere with the biosynthesis of folic acid and tetrahydrofolate.
Among these are the dihydrofolate reductase inhibitors (such as trimethoprim and
pyrimethamine), the sulfonamides (competitive inhibitors of para-aminobenzoic acid in the
reactions of dihydropteroate synthetase), and the anticancer drug methotrexate (inhibits both
folate reductase and dihydrofolate reductase).
Naturally occurring folate is found in a wide variety of foods, including green leafy
vegetables, liver, kidneys, grains, bread and nuts. Folates are extremely unstable. Sensitive to
light, heat and oxygen, they rapidly lose activity in foods during harvesting, storage,
By contrast, synthetic folic acid, which is added to various foods during fortification (as
well as dietary supplements), is stable for months or even years. It is also more than 90 per
cent bioavailable, compared with folates in foods which are only about 45 % bioavailable.
The Reference Daily Intake (RDI) is the average daily dietary intake level that is
sufficient to meet the nutrient requirements of nearly all (97% to 98% of) healthy individuals
in each life-stage and gender group. The 1998 RDIs for folate are expressed in a term called
the "dietary folate equivalent" (DFE). This was developed to help account for the differences
in absorption of naturally-occurring dietary folate and the more bioavailable synthetic folic
acid [19]. The 1998 RDAs for folate expressed in micrograms (µg) of DFE for adults are:
(19+) (19+) Pregnancy Breast feeding
1 µg of food folate = 0.6 µg folic acid from supplements and fortified foods
The main causes of folate deficiency are:
• Decreased dietary intake - This occurs in people eating inadequate diets, such as
some elderly people, some people on low incomes, and alcoholics who substitute
alcoholic drinks for good sources of nutrition
• Decreased intestinal absorption - Patients with disorders of malabsorption (e.g.,
coeliac disease) may suffer folate deficiency
Folic Acid and Health: An Overview 43
• Increased requirements - Increased requirement for folate, and hence an increased
risk of deficiency, can occur in pregnancy, during lactation, in haemolytic anaemia
• Alcoholism - Chronic alcoholism is a common cause of folate deficiency. This may
occur as a result of poor dietary intake or through reduced absorption or increased
excretion by the kidney. The presence of alcoholic liver disease increases the
likelihood of folate deficiency
• Drugs - Long term use of certain drugs (e.g., phenytoin, sulphasalazine) is associated
Folate deficiency has also been associated with neural tube defects [1], cardiovascular
disease [2], cancer of various sites [3], depression [4], dementia [5], and osteoporosis [6,7].
The traditional view that the only concern in relation to folate status was clinical
deficiency was challenged when it became clear that the risk of congenital malformations,
including neural tube defects (NTDs), could be reduced by increased folic acid intake during
the periconceptional period [13]. Neural tube defects result in malformations of the spine
(spina bifida), skull, and brain (anencephaly) [9]. Since the discovery of the link between
insufficient folic acid and neural tube defects (NTDs), governments and health organisations
worldwide have made recommendations concerning folic acid supplementation for women
intending to become pregnant [20]. It was suggested to take 400 micrograms of synthetic
folic acid daily from fortified foods and/or supplements [21]. This has also led to the
introduction in many countries of fortification, where folic acid is added to flour with the
intention of everyone benefiting from the associated rise in blood folate levels [20]. In
countries where mandatory fortification of flour was introduced, folate and homocysteine
status improved notably and neural tube defect rates fell by up to nearly 80% [20]. Despite
public-health campaigns, knowledge about the proper periconceptional time to use folic acid
supplements for the prevention of neural tube defects is not widespread in women and only a
maximum of half of them are following the recommendations [20]. Vulnerable groups are
people of low educational status, young people, immigrants, and women with unplanned
pregnancies. A substantial percentage of women still choose not to take the supplements even
though they are aware of the beneficial effects [20].
Why folic acid should influence the incidence of neural tube defects remains unclear.
Neural tube defects almost certainly occur as a result of complex genetic, nutritional and
environmental interactions, and some interesting clues have emerged in the area of genetics.
A defect in the methylene-tetrahydrofolate-reductase (MTHFR) gene, which occurs in about
5 to 15 per cent of white populations, has been identified [22]. This genetic defect appears to
result in an increased requirement for folates and an increased risk of recurrent early
pregnancy loss and NTDs [23]. In addition, elevated levels of plasma homocysteine have
been observed in mothers producing offspring with NTDs [24]. The possibility that this factor
could have toxic effects on the foetus at the time of neural tube closure is currently under
further investigation. Although folic acid does reduce the risk of birth defects, it is only one
part of the picture and should not be considered a cure. Even women taking daily folic acid
supplements at the reccomended dose have been known to have children with neural tube
FOLIC ACID AND CARDIOVASCULAR DISEASE
Low concentrations of folate, vitamin B12, or vitamin B6 may increase the plasma level of
the aminoacid Homocysteine (Hcy). As explained previously, homocysteine is derived from
dietary methionine, and is removed by conversion to cystathionine, cysteine and pyruvate, or
by remethylation to methionine.
There is evidence that an elevated homocysteine level is an independent risk factor for
cardiovascular disease (CVD) mortality [25-27]. Mechanisms by which plasma Hcy may be
associated with an increased risk of CVD have not been clearly established, but possibilities
• Oxidative damage to the vascular endothelium
• Inhibition of endothelial anticoagulant factors, resulting in increased clot formation
• Increased platelet aggregation
• Proliferation of smooth muscle cells, resulting in increased vulnerability of the
An increased level of plasma Hcy may be caused by rare inborn errors of its metabolism.
An example is homocystinuria, which occurs as a result of a genetic defect in the enzyme
cystathione synthase. Genetic changes in the enzymes involved in the remethylation pathway,
including methylene tetrahydrofolate reductase and methionine synthase, are also associated
with an increase in plasma homocysteine concentrations. All such cases are associated with
premature vascular disease, thrombosis and early death. Such genetic disorders are rare and
cannot account for the raised homocysteine levels observed in many patients with
cardiovascular disease. However, attention is now being given to the possibility that
deficiency of the various vitamins which act as co-factors for the enzymes involved in
homocysteine metabolism could result in increased Hcy concentrations. In particular, folate is
required for the normal function of methylene-tetrahydrofolate-reductase, vitamin B12 for
methionine-synthase and vitamin B6 for cystathione-synthase.
In theory, lack of any one of these three vitamins could cause hyperhomocysteinaemia,
and could therefore increase the risk of cardiovascular disease [28]. In the Framingham Heart
Study [29], the longest observed cohort study on vascular disease, it was shown that folic
acid, vitamin B6 and vitamin B12 are determinants of plasma homocysteine levels, with folic
acid showing the strongest association.
The question whether increased vitamin intake can reduce cardiovascular disease risk
was examined in the Nurse's Health Study [30]. The results showed that those with the
highest intake of folate had a 31 % lower incidence of heart disease than those with the
lowest intake. Those with the highest intake of vitamin B6 had a 33 % lower risk of heart
Folic Acid and Health: An Overview 45
disease, while in those with the highest intake of both vitamin B6 and folate, the risk of heart
disease was reduced by 45 %. The risk of heart disease was reduced by 24 % in those who
Another question is whether homocysteine levels can be lowered with folate and other B
vitamins. Studies have shown that folic acid (250μg daily), in addition to usual dietary
intakes of folate, significantly decreased plasma homocysteine concentrations in healthy
young women [31]. Breakfast cereal fortified with folic acid reduced plasma homocysteine in
men and women with coronary artery disease [32].
Another study has demonstrated that the addition of vitamin B12 to either folic acid
supplements or enriched foods (400μg folic acid daily) maximizes the reduction of
homocysteine [33]. Furthermore, two meta-analyses [34, 35] suggest that the administration
of folic acid reduces plasma homocysteine concentrations and that vitamin B12, but not
vitamin B6, may have an additional effect [35].
On the other hand, the NORVIT trial [36] has suggested that folic acid supplementation
may do more harm than good. As of 2006, studies have shown that giving folic acid to reduce
levels of homocysteine does not result in clinical benefit and have suggested that in
combination with B12 it may even increase some cardiovascular risks [36,37].
Unfortunately, a definitive answer to the most important question of whether or not
reducing homocysteine can reduce cardiovascular disease does not yet exist due to the lack of
published data. However, there is currently no evidence available to suggest that lowering
homocysteine with vitamins will reduce the risk of heart disease. Clinical intervention trials
are needed to determine whether supplementation with folic acid, vitamin B12 or vitamin B6
can lower the risk of developing coronary heart disease.
FOLIC ACID AND MENTAL DISORDERS
There is an apparent increase in mental disorders associated with reduced folate status
[38]. However, whether this reduced vitamin status is a cause of the disease, or occurs as a
result of having the disease, is unknown.
Studies have found that Alzheimer's disease (AD) is associated with low blood levels of
folate and vitamin B12 and elevated homocysteine (Hcy) levels [39, 40]. In particular, the
long-running Framingham Study, has shown that people with hyperhomocysteinemia (Hcy
>14 μmol/l) had nearly double the risk of developing AD [41]. This study was the first to
associate Hcy levels, measured several years earlier, with later diagnosis of AD and other
dementias. Furthermore, the association between Hcy and AD was found to be strong and
independent of other factors, such as age, gender, APOE genotype, and other known or
suspected risk factors for dementia and AD. Clarke et al. [42] have also shown that low
serum folate and consequently elevated concentrations of serum Hcy, was associated with
progressive atrophy of the medial temporal lobe in subjects with AD. The serum folate
seemed to have a strong negative association with the severity of atrophy of the neocortex in
the “Nun Study”, suggesting that atrophy may be specific to relatively low folate
concentrations [43]. Therefore, the relationship between Hcy and dementia is of particular
interest because blood levels of Hcy might be reduced by increasing the intake of folic acid
The recent Baltimore Longitudinal Study of Aging on 579 older individuals without
dementia (follow-up of 9.3 years) has suggested that consuming levels of folate at or above
RDA (400 micrograms) is associated with a reduced risk of AD [44]. It has also been
suggested that a fortification policy based on folic acid and vitamin B12, rather than folic acid
alone, is likely to be much more effective at lowering Hcy concentrations, with potential
benefits for reducing the risk of AD and vascular disease [44].
Several epidemiological studies also provide evidence that an elevated total plasma level
of Homocysteine (tHcy) is associated with an increased risk of psychiatric disorders such as
depression [45-48]. Most of these studies suggest that a significant association is observed for
tHcy levels above 12-15 μmol/L [45, 46]. For instance, the Hordaland Homocysteine Study
(HHS-II) has shown that subjects with tHcy > 15umol/L had a two-fold higher risk of having
depression compared with those with tHcy < 9 umol/L. In addition, it was observed that those
with Methyltetrahydrofolate Reductase (MTHFR) 677 TT genotype had a 70% higher risk of
depression compared with the CC genotype [45-48]. This effect is exacerbated in the
presence of low folate status, indicating a strong gene-nutrient interaction [45]. These data
may suggest that some depressed patients are genetically vulnerable and that they may
benefit from folic acid supplementation in addition to their antidepressant treatment. There is
some limited evidence from randomised controlled trials that using folic acid in addition to
antidepressant medication may have benefits [49]. However, the evidence is probably too
limited at present for this to be a routine treatment recommendation. To date, the association
between tHcy, depression score and risk of depression needs to be fully evaluated.
Several studies have recently implicated folate in modulating the risk of several cancers
[3], in particular, colorectal and breast cancer [50]. Folate is involved in the synthesis, repair,
and functioning of DNA and a deficiency of folate may result in damage to DNA that may
various sites, as other dietary factors (e.g. alcohol, methionine) as well as genetic
polymorphisms seem to modulate the risk. Polymorphism of a potentially wide range of other
enzymes involved in folate metabolism may also modulate the risk of cancer [50].
Although folate could prevent cancer in healthy people, it might also promote the
progression of pre-malignant and malignant lesions. Low folate status and antifolate
treatment, respectively, inhibit human tumor growth in these stages [52-56]. The results of
studies in animals suggest that the effect of folate on carcinogenesis is dependent on the stage
of the carcinogenic process and the dose of folate tested [56]; folate deficiency inhibits,
whereas folate supplementation promotes the progression of established tumors.
Concerning the association between folate and colon cancer, data from prospective
studies [57,58] and case-control studies [59-62], indicate that inadequate intake of folate may
increase the risk of this type of cancer.
Folic Acid and Health: An Overview 47
Recent epidemiological studies also support an inverse association between folate status
and the rate of colorectal adenomas and carcinomas. High dietary folate (including
supplements), but not folate from foods only, was inversely associated with the risk of
colorectal adenoma in women (RR= 0.66; 95% CI, 0.46-0.95) of the Nurses’ Health Study
[63], and in men (RR= 0.63; 95% CI, 0.41-0.98) of the Health Professional Follow-up Study
[64]. The relative risk of those with a high alcohol and low methionine and folate intake
compared with those with low alcohol and high folate and methionine consumption was 3.17
(95% CI, 1.69-5.95) (men and women combined). These findings suggest that maintaining
adequate folate levels may be important in reducing the risk of colon cancer. Animal trials
have also provided considerable support for the epidemiological findings [65], suggesting
that folate supplementation might decrease or increase cancer risk depending on timing and
dosage. Moreover, a recent cross-sectional study [66] has shown that high folate status in
smokers may confer increased or decreased risk for high risk adenoma, depending on the
Although not uniformly consistent, epidemiologic data also report an inverse association
between dietary intake and blood measurements of folate and the risk of breast cancer [67].
The risk of postmenopausal breast cancer may be increased among women with low intakes
of folate, especially those consuming alcohol-containing beverages [68]. Achieving adequate
circulating levels of folate may be particularly important in attenuating the risk of
postmenopausal breast cancer associated with family history, but only if alcohol use is
avoided or minimized [69]. More recent findings confirm the positive associations between
moderate alcohol consumption and breast cancer. However, they also suggest that a high
intake, generally attributable to supplemental folic acid, may increase the risk in
postmenopausal women. In particular, the Prostate, Lung, Colorectal, and Ovarian (PLCO)
Cancer Screening trial [70] has recently reported for the first time a potentially harmful effect
of high folate intake on breast cancer risk. In this study, the risk of developing breast cancer
was significantly increased by 20% in women taking supplemental folic acid intake ≥ 400
μg/d compared with those with no supplemental intake. Furthermore, although food folate
intake was not significantly related to breast cancer risk, total folate intake, mainly from folic
acid supplementation, significantly increased breast cancer risk by 32%. The data from the
PLCO trial also support prior observations made in epidemiologic, clinical, and animal
studies [50] suggesting that folate possesses dual modulatory effects on the development and
progression of cancer, depending on the timing and dose of folate intervention. Based on the
lack of compelling supportive evidence, routine folic acid supplementation should not be
recommended as a chemopreventive measure against breast cancer at present.
Data concerning the relationship between folate and other types of cancer are sparse and
controversial. A recent population-based prospective study [71] of 81,922 cancer free
Swedish women and men, has suggested that increased inatake of folate from food sources,
but not from supplements, may be associated with a reduced risk of pancreatic cancer. In the
same study, 61,084 women, aged 38-76 years, were also assessed for ovarian cancer risk and
the results have suggested that a high dietary folate intake may play a role in reducing the risk
of ovarian cancer, especially among women who consume alcohol [72]. The effect of folate
on carcinogenesis in the cervix remains uncertain. Two trials have shown no significant
effect of folic acid on the rates of cervical intraepithelial neoplasia regression or progression
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