The Pharmaceutical Journal Vol 263 No 7068 p673-677
October 23, 1999 Special Feature

Nutrition

Folic acid - new roles for a well known vitamin

By Pamela Mason, PhD, MRPharmS

New evidence has shown that increasing folic acid intake may help to prevent a variety of diseases. This article examines the potential roles for the vitamin

Until the 1980s, the main importance of folic acid was thought to lie in its ability to prevent certain well defined clinical consequences, such as macrocytic anaemia, which resulted from deficiency. However, the view that deficiency was the only risk was challenged for the first time when research showed that the risk of a mother having a baby affected by spina bifida, or other neural tube defect (NTD), could be reduced by the periconceptional ingestion of increased amounts of folic acid. Moreover, folic acid is now under considerable scrutiny regarding its ability to prevent not only NTDs, but also cardiovascular disease, colorectal cancer and mental illness.
Nomenclature Folic acid (pteroylglutamic acid) is a water-soluble vitamin of the B complex and the parent compound of a group of substances known as folates. It is important to distinguish between folic acid and folate because their bioavailability is somewhat different. Folic acid is the synthetic chemical added to foods during fortification and is also found in supplements. Folate is a generic term used to describe all of the compounds, found naturally in food and produced during metabolism, that exhibit the activity of folic acid.
Biochemistry Folate biochemistry is complex and parts of it are still being researched and unravelled. Dietary folates, which exist in several different forms, have to be hydrolysed to a particular form - the monoglutamate - before absorption can occur. Following hydrolysis, the monoglutamate form is reduced and methylated to produce 5-methyl-tetrahydrofolate (5-methyl-H4 folate), which is the form of the vitamin found circulating in the plasma.
To enter the cells, where it performs various functions, 5-methyl-H4 folate must be converted to tetrahydrofolate (H4 folate), while donating its methyl group to produce methionine (Figure 1: Some biochemical pathways involving folates (adapted from Scott JM. Folate and vitamin B12. Proc Nutr Soc 1999;58:441-8), reactions 1a, 1b). This reaction is controlled by the enzyme methionine synthase, an enzyme which is dependent on vitamin B12. Thus, for dietary folates to enter cells, vitamin B12 is essential.
In contrast, folic acid can enter cells by a process which is not dependent on vitamin B12 (Figure 1, reaction 2). This is important because administration of folic acid can "mask" vitamin B12 deficiency in patients with pernicious anaemia (discussed later).

Function

Folate has a variety of functions which can basically be divided into two categories. It participates in:

• Methylation reactions (Figure 1, the methylation cycle)
• Cell replication (Figure 1, the DNA cycle)

Methylation reactions The methylation cycle depends on both folate and vitamin B12 to produce methionine (as already discussed) (Figure 1, reaction 1b).
An example of a methylation reaction is the methylation of the protein in myelin (the insulation cover on nerves). When this process is interrupted, as it is during vitamin B12 deficiency, one of the clinical consequences is the demyelination of nerves, resulting in a neuropathy, which leads to ataxia, paralysis and, if untreated, ultimately to death.
Another methylation reaction involves the degradation of methionine. Methionine is an essential amino acid in human beings and is obtained exclusively from the diet. Any excess methionine is degraded to produce homocysteine. At this point, homocysteine can be either degraded to form pyruvate (Figure 1, reaction 3) which can then be used as a source of energy, or it can be remethylated to form methionine (Figure 1, reaction 1b). Vitamin B6 is essential in the former reaction, and vitamin B12 and folate in the latter.
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. As noted already, folic acid can enter cells by a process which does not rely on vitamin B12 (Figure 1, reaction 2). 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. This is why, in people with vitamin B12 deficiency, folic acid supplementation will treat the megaloblastic anaemia (due to deficient cell replication), but will not affect the neurological complications which occur as a result of the disruption of the methylation cycle.

Clinical deficiency

Folate deficiency results in a reduction of DNA synthesis and hence in cell division. While DNA synthesis occurs in all dividing cells, deficiency is most easily seen in tissues with high rates of cell turnover such as erythrocytes (red blood cells). The main clinical observation associated with folate deficiency is, therefore, megaloblastic anaemia.
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 (eg, coeliac disease) may suffer folate deficiency
• 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 (eg, phenytoin, sulphasalazine) is associated with folate deficiency

Neural tube defects

Cardiovascular disease

Marginal folate status is also associated with elevated plasma homocysteine levels, an emerging risk factor for cardiovascular disease mortality.^9-11
Mechanisms by which plasma homocysteine may be associated with an increased risk of cardiovascular disease have not been clearly established, but possibilities include:12

• 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

But what causes the level of plasma homocysteine to increase? As explained previously, homocysteine is derived from dietary methionine, and is removed by conversion to cystathionine, cysteine and pyruvate, or by remethylation to methionine.
Rare inborn errors of metabolism can cause severe elevations in plasma homocysteine levels. 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 homocysteine 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. What evidence is there for this? In the Framingham heart study,¹³ 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.
But can increased vitamin intake reduce cardiovascular disease risk? This question was examined in the nurse's health study,¹⁴ which showed that those with the highest intake of folate had a 31 per cent lower incidence of heart disease than those with the lowest intake. Those with the highest intake of vitamin B6 had a 33 per cent lower risk of heart disease, while in those with the highest intake of both vitamin B6 and folate, the risk of heart disease was reduced by 45 per cent. The risk of heart disease was reduced by 24 per cent in those who regularly used multivitamins.
Another question is whether homocysteine levels can be lowered with folate and other B vitamins. Folic acid (250μg daily), in addition to usual dietary intakes of folate, significantly decreased plasma homocysteine concentrations in healthy young women.¹⁵ Breakfast cereal fortified with folic acid reduced plasma homocysteine in men and women with coronary artery disease.¹⁶
Another study has demonstrated that the addition of vitamin B12 to either folic acid supplements or enriched foods (400μg folic acid daily), maximises the reduction of homocysteine.¹⁷ Furthermore, two meta-analyses^18,19 suggest that administration of folic acid reduces plasma homocysteine concentrations and that vitamin B12, but not vitamin B6, may have an additional effect.¹⁹
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, more data should be available during the next five years from at least six studies which are currently under way. These are designed to examine the role of folate and other B vitamins in reducing cardiovascular events.

Cancer

Marginal folate status also appears to be associated with certain cancers,²⁰ notably colon cancer, although at present it is unclear as to whether it is folate, or some other nutritional factor, that could be involved. Data, including that from two prospective studies^21,22 and four case-control studies,^23-26 indicate that inadequate intake of folate may increase the risk of colon cancer.
There is also some evidence, albeit limited, that use of supplements containing folic acid could reduce the risk of colon cancer.^27,28

Mental disorders

There is an apparent increase in mental disorders associated with reduced folate status.²⁹ Recent studies have found that Alzheimer's disease is associated with low blood levels of folate and vitamin B12 and elevated homocysteine levels.^30,31 However, whether this reduced vitamin status is a cause of the disease, or occurs as a result of having the disease, is unknown.

Adverse effects

Folic acid is generally considered to be safe, although there are some concerns about increasing intake. These relate 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.
Giving folic acid could delay the diagnosis of B12 deficiency by treating the associated anaemia but not the peripheral neuropathy. Recent evidence suggests, however, that small doses of folic acid (200 to 400μg daily) are unlikely to cause this problem.³² The risk of "masking" the condition increases at folic acid intakes exceeding 1,000μg a day.

Conclusion

The traditional view that the main role of folate is to prevent deficiency is now being challenged. There is increasing evidence that individuals with what is considered to be a normal folate status, and no signs of deficiency, could benefit from higher intakes of the vitamin. This may be due, not to a lack of folate per se, but to a genetic defect in the ability to assimilate it.
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 clinical trials are needed.
The fact that deficiency is now not the only consideration in folic acid nutrition has implications for setting dietary requirements. Although benefits seems to be obtained at quite low levels of intake (eg, 200 to 400μg folic acid daily), this is higher than the current recommendation of 200μg of folate daily for healthy, non-pregnant adults (200μg folate is roughly equivalent to 100μg folic acid). Moreover, the discovery of genetic variation in the ability to handle folic acid suggests that there is no such thing as a normal individual. This too has implications for setting dietary standards.
There is much debate as to the best means to increase folate intake. Current daily folate intakes in the UK are around 300μg in men and 200μg in women. Supplements are already recommended for women during the periconceptional period, but, given that half of pregnancies may 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. There will be a new report on folic acid from the Department of Health's committee on medical aspects of food policy (COMA) later this year which may help to clarify some of these issues.

Dr Mason is a pharmacist with a postgraduate qualification in nutrition

References