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Researchers are continuing to investigate whether enhanced folate intake from foods or

folic acid supplements may reduce the risk of cancer.

ADVERSE EFFECTS OF FOLIC ACID SUPPLEMENTS

Although folate is safe and almost free of toxicity [73], concerns that folic acid

fortification could mask symptoms of vitamin B12 deficiency and precipitate neurological

complications have been raised [74]. Other examples of potential safety issues are the

interactions with drugs, hypersensitivity reactions, increase of twinning rate and genetic

selection [73, 74].

Folic Acid and Masking of B12 Deficiency

Folic acid is generally considered to be safe [73]. Although the risk of toxicity is low,

there are some concerns about its interaction with vitamin B12 [76]. Vitamin B12 deficiency

could affect up to 10–15% of the population over 60 years of age and it is often undiagnosed.

Permanent nerve damage could theoretically occur if vitamin B12 deficiency is not treated.

Folic acid supplements can correct the anemia associated with vitamin B12 deficiency.

Unfortunately, folic acid will not correct changes in the nervous system that result from

vitamin B12 deficiency. The US Institute of Medicine [77] determined that there is suggestive,

but not conclusive, evidence that folic acid, in addition to masking vitamin B12 deficiency,

precipitates or exacerbates the neurological damage caused by vitamin B12 deficiency.

This concern is related to public health fears of introducing additional folic acid to the

whole population (through food fortification), and uncertainty about unforeseen risks,

especially in vulnerable groups such as children and also the elderly in whom vitamin B12

deficiency is a particular risk.

Recent evidence suggests, however, that small doses of folic acid (200 to 400μg daily)

are unlikely to cause this problem [78] The risk of "masking" the condition increases at folic

acid intakes exceeding 1,000μg a day [78]. The Institute of Medicine [77] has in fact

established a tolerable upper intake level (UL) for folate of 1,000 µg for adult men and

women, and a UL of 800 µg for pregnant and lactating (breast-feeding) women less than 18

years of age. Therefore, supplements should not exceed the UL to prevent folic acid from

masking symptoms of vitamin B12 deficiency. In fact, evidence that such masking actually

occurs is scarce, and there is no evidence that folic acid fortification in Canada or the US has

increased the prevalence of vitamin B12 deficiency or its consequences [74].

However, it could be important to be aware of the B12 status before taking a supplement

that contains folic acid.

Folic Acid and Health: An Overview 49

Folic Acid and Anticonvulsivant Drugs

Long-term antiepileptic phenytoin therapy can result in folate deficiency, whereas

supplementation with folic acid might lower serum phenytoin. No appreciable changes in

values of phenytoin drug concentrations were found in relation to food fortification in a large

trial in Canada [79]. Furthermore, evidence does not lend support to a substantial increase in

seizure frequency in patients who are treated with oral folic acid [75].

Folic Acid and Twinning Rates

The use of multivitamin supplements containing folic acid has been associated with an

increase in twinning rates [80-82]. Twin pregnancies are at greater risk for infant morbidity

and mortality [83]. This positive association may in part be explained by residual

confounding of in-vitro fertilization and ovarian stimulation, or by the effect of other

vitamins on the multivitamins consumed [84-86]. Post fortification twinning rates were not

higher in the USA [87, 89] and similarly, in the extensive intervention study in China, folic

acid supplements showed no effect [90]. This debate is not yet closed [91].

Folic Acid and Genetic Selection

It has been hypothesized that increased amounts of folic acid during the periconceptional

period could lead to a genetic selection by improving the survival of embryos carrying the

MTHFR 677C→T mutation. This could raise homocysteine concentrations if folate intake is

subsequently restricted in the child [92, 93].

Folic Acid and Hypersensitivity Reactions

A few case reports have described hypersensitivity reactions to oral and parenteral folic

acid, but most reactions were probably due to other components of the folic acid drug [94].

Folic Acid and Methotrexate for Cancer

Methotrexate is a drug used to treat cancer which interferes with folate metabolism;

infact, it inhibits the production of tetrahydrofolate, which is the active form of folic acid.

Unfortunately it can be toxic [95-97] and Folinic acid is a form of folate that can help

"rescue" or reverse the toxic effects of methotrexate [98]. Folic acid supplements have little

established role in cancer chemotherapy [99,100]. It is important for anyone receiving

methotrexate to follow medical advice on the use of folic or folinic acid supplements.

50 Rossana Salerno-Kennedy

Folic Acid and Methotrexate for Non-Cancerous Diseases

Low dose methotrexate is also used to treat a wide variety of non-cancerous diseases

such as rheumatoid arthritis, lupus, psoriasis, asthma, sarcoidoisis, primary biliary cirrhosis,

and inflammatory bowel disease [101]. Low doses of methotrexate can deplete folate stores

and cause side effects that are similar to folate deficiency. Both high folate diets and

supplemental folic acid may help reduce the toxic side effects of low dose methotrexate

without decreasing its effectiveness [102,103]. Anyone taking low dose methotrexate for the

health problems listed above should consult with a physician about the need for a folic acid

supplement.

CONCLUSION

It is only recently that folate deficiency has been associated with the risk of neural tube

defects (NTDs), cardiovascular disease, mental disorders and some forms of cancer; there is

not sufficient data available concerning the relationship with osteoporosis.

The evidence for a reduction in risk with increased folic acid intake is powerful for

NTDs and is increasing for cardiovascular disease. There may also be benefit in terms of

prevention of colorectal cancer and Alzheimer's disease, but more clinical trials are needed.

Findings suggest that folate supplementation might decrease or increase the risk of diseases

depending on dosage and timing, but there is also an emerging picture which takes in

consideration a more complex interaction of multiple nutritional and genetic factors.

Supplements are already recommended for women during the peri-conceptional period

but, given that not all women are happy to take it and that pregnancies may also be

unplanned, there is a need to ensure adequate folate intake by some other means. Food

fortification is one method, but strategies for increasing consumption of natural food folates

could also be explored and, in particular, whether sufficient amounts can be absorbed from

these foods to protect against disease. Finally, research in relation to safety issues of folic

acid fortification is required.

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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.

FOLIC ACID AND CANCER

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

lead to cancer [51]. It is not clear whether folate itself has a direct link to the risk of cancer of

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

MTHFR genotype.

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

48 Rossana Salerno-Kennedy

effect of folic acid on the rates of cervical intraepithelial neoplasia regression or progression

[50].

 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.

42 Rossana Salerno-Kennedy

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).

DIETARY SOURCES

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,

preparation and processing.

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.

RDI

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:

1998 RDAs for Folate

Men Women

(19+) (19+) Pregnancy Breast feeding

400 µg 400 µg 600 µg 500 µg

1 µg of food folate = 0.6 µg folic acid from supplements and fortified foods

CLINICAL DEFICIENCY

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

and in leukaemia

• 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

with folate deficiency.

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].

FOLIC ACID AND PREGNANCY

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

44 Rossana Salerno-Kennedy

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

defects [20].

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

include [28]:

• 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

arteries to obstruction

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

regularly used multivitamins.

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

46 Rossana Salerno-Kennedy

interest because blood levels of Hcy might be reduced by increasing the intake of folic acid

and vitamins B6 and B12.

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].