Why the Implementation of a Mandatory Folic Acid Supplementation Should be Opposed in the UK

Friday, 16 December, 2016

Folic acid is a synthetic compound which is used in supplements and fortified foods. Currently scientists around the world are debating the adverse effects of excessive folic acid use within the general population.

Folate and Folic Acid

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Folate (vitamin B9) is essential for numerous metabolic processes including DNA synthesis and regulation of gene expression. Natural folate sources are found in a variety of foods such fruits, vegetables and grains. Deficiency of folate is common, with causes ranging from diet and lifestyle, to pathological and pharmacological processes and leads to macrocytic anaemia, peripheral neuropathy and increases the risk of neural tube defects (NTD) such as spina bifida and anencephaly.

Folic acid is metabolised differently to naturally occurring forms of folates. It requires a two-step reduction, via dihydrofolate reductase (DHFR) before it has any coenzyme activity, and this occurs mainly in the liver. This reaction allows folic acid to be used for metabolic processes but most tissues, including the liver, have limited ability to reduce folic acid due to low activity of DHFR. It is also known that the process ofabsorption and biotransformation of folic acid to its active form (5-methyltetrahydrofolate) is saturated at doses in region of 200–400μg of folic acid. The limitation of this metabolic process results in the inability to metabolise high doses of folic acid, which leads to the appearance of unmetabolised folic acid in the circulation. Since the consumption of folic acid has increased in many countries worldwide, either because of mandatory fortification or voluntary supplementation, concerns have arisen regarding the potential adverse effects unmetabolised folic acid may have.

Folic Acid Supplements 

Because of the well-known role of folate in prevention of NTD, numerous countries have implemented strategies to increase folate intake, including mandatory grain fortification. As a result, the intake of folate in these countries is often higher than the recommended dietary allowance for many groups of people. Although folate is believed to be non-toxic, the potential adverse effects of excessive intake of folic acid have not been highlighted well by authorities. In the UK, mandatory folic acid supplementation has not been implemented; however, high-strength folic acid supplements and fortified foods, such as cereals and breakfast spreads, can be found in most food stores. In fact, Viapath’s studies have shown that, in patients from the UK, cereals contributed to 26% of their total folate intake.

Despite studies showing positive results in relation to NTD in the USA, and many other countries such as Canada, Chile and Argentina, it has been debated as to whether this intervention should be implemented in Europe. Many countries in Europe do not fortify their grains with folic acid, partially due to earlier reports linking folic acid with cancer

Is there a Link Between Folic Acid and Cancer?

Folic acid intakes have been linked to increased cancer risk. Proposed mechanisms include folic acid enhancing DNA synthesis and replication within cells, while reducing the natural killer cell response to carcinogenic cells. For example observational research carried out in Chile by Hirsh et al. (Eur J Gastroenterol Hepatol, 2009) showed that after folic acid fortification was implemented in this country, there was a 162% increase in colorectal cancer in the 45–64 year group and a 192% in the 65–79 year group, compared with the pre-fortification period.

Conversely, studies which concluded that high levels of folic acid did not increase the risk of colorectal cancer have also been published. A study by Stevens et al. (Gastroenterology, 2011) showed that doses up to 660 μg per day caused no increased risk of colorectal cancer and suggested that doses up to 800 μg and day should not be expected to increase the risk of colorectal cancer.

Folic Acid and Pregnancy

Folic acid is very effective at preventing NTD but recent work from India by Krishnaveni et al. (Diabetologica, 2014) demonstrated that high levels of folic acid during gestation were associated with insulin resistance and greater adiposity in children at 5 years of age which may be contributing to increasing levels of childhood obesity and type 2 diabetes mellitus.

Masking vitamin B12 deficiency with high levels of folic acid needs to be considered when folic acid supplements are taken, as the diagnosis and treatment of vitamin B12 deficiency may be delayed, potentially leading to irreversible neurological damage. Moreover high serum folate concentrations combined with low vitamin B12 status have been associated with an increased risk of cognitive impairment in subjects over 60 years old.

Studies have also shown that having a high folic acid to vitamin B12 ratio during pregnancy increases the risk of baby being small for gestation age (SGA) at birth. Being SGA may lead to increase rates of hypertension, coronary heart disease and type 2 diabetes mellitus in the middle aged.

In addition to above, recent studies on animals suggest that high levels of folic acid supplements may be hepatotoxic particularly for those with lower levels of the methylene tetrahydrofolate reductase (MTHFR) protein.

Folic Acid and Drug Interventions

Unmetabolised folic acid has been shown to interact with antiepileptics, possibly inducing seizures in patients taking drugs such as phenytoin, carbamazepine and phenobarbital. For example, studies looking at the interaction with phenytoin suggest that folic acid acts as a co-factor in phenytoin metabolism, with higher levels of folic acid increasing the efficiency of breakdown by raising the affinity of the metabolising hepatic enzymes.

What is the Future of Mandatory Folic Acid Fortification in the UK?

Folate is a vital component of a human diet, with deficiency causing impairment of many metabolic processes. However, in modern society with greater awareness, availability and access to folic acid, hypertoxicity rather than deficiency may become an issue and the excessive use of folic acid may impact on multiple areas of public health.

 

No clear consensus regarding the safety of folic acid has yet been reached and gaps in knowledge are still present. The debate about the adverse outcomes and lifetime exposure to folic acid excess continues.

In light of the evidence so far, suggesting additional supplementation with folic acid may be harmful to certain groups of people if their diet is assumed to be adequate in folate and absorption is normal. Countries planning on fortification strategies need to thoroughly assess all of the risks and benefits and the UK should oppose mandatory folic acid supplementation until this has been done.

For more information about the adverse effects of excessive folic acid use, please refer to the recent article:

Patel KR, Sobczyńska-Malefora A. The adverse effects of an excessive folic acid intake. Eur J Clin Nutr. 2016 Oct 12. doi: 10.1038/ejcn.2016.194. [Epub ahead of print] Review.PMID:27731331 https://www.ncbi.nlm.nih.gov/pubmed/27731331 or contact Dr Agata Sobczyńska-Malefora at agata [dot] malefora [at] viapath [dot] co [dot] uk

For more information on folate status testing at Viapath, please refer to Viapath’s Below:

5-methyltetrahydrofolate (plasma/serum)

5-methyltetrahydrofolate (whole blood)

Folate (serum)

Folate (whole blood/red cells)

Homocysteine