folic acid

A recent study has investigated whether there is an association between synthetic folic acid or natural folate and clinical outcomes in bladder cancer.

Folate is a type of B vitamin found naturally in foods such as fruits and vegetables and plays a pivotal role in helping the body produce and maintain new cells. In 1998 the synthetic form of folate, folic acid, was implemented as a mandatory food fortification (adding vitamins and minerals to food) in the US. This, in combination with folic acid supplements, has resulted in a significant increase in blood measurements of folate in the US population. The accumulation of unmetabolized folic acid in blood and urine, however, has been shown to speed up cell division which may result in accelerated tumor growth and hence promote cancer.

Bladder cancer has one of the highest recurrence rates of all cancers and is the fifth most common cancer in the United States. Given the risk factors associated with bladder cancer, including smoking, poor diet, alcohol intake, and genetic predisposition, and how different foods or supplements can potentially affect treatment outcomes, cancer patients are highly concerned about food choices and dietary supplementation. Due to the high rate of recurrence and disease progression for bladder cancer, efforts in identifying modifiable factors such as dietary factors, like folic acid, that could affect the risks of recurrence and progression are a strong focus.

The kidney excretes excess folic acid. Unmetabolized folic acid accumulates in the urine, which comes into close contact with the bladder epithelial cells. These cells line the surfaces of the organs, skin, and urinary tract urinary tract. This has the potential to exert a cancer-promoting environment which may lead to the manifestation of non-muscle-invasive bladder cancer (NMIBC) which accounts for more than 80% of new cases of bladder cancer in the US.

Previous studies have suggested an association between folic acid supplements and increased cancer risk

Previous animal studies have suggested there is a potential association between increased cancer risk and accelerated tumour progression with folic acid supplementation, along with several clinical trials which have provided evidence suggesting also that large doses of folic acid may increase the risk of cancer. However, a meta-analysis of all available trials suggests otherwise, that folic acid supplementation has no significant effect on the overall risk of cancer.

Hence, a recent study by US researchers published in the American Journal of Clinical Nutrition investigated whether there is an association between the risk of recurrence and progression with folic acid and natural folate consumption in patients diagnosed with NMIBC. The evidence-based cohort study included 619 NMIBC patients who were already a part of a large ongoing cohort study on bladder cancer. Each participant’s diet was assessed for their folate intake when they were diagnosed.

Synthetic folic acid increased risk while natural folate lowered risk

Of the 619 patients, 303 had tumour recurrence and 108 progression events after the average follow-up of 5.2 years. The researchers observed a positive association between synthetic folic acid supplementation and the recurrence of disease.

NMIBC patients who had a higher folic acid intake at diagnosis were more likely to have multifocal tumours; or more than one tumour present in a single organ that appears to have originated from the same original tumour, not the same as multiple tumours. However, natural folate intake was reported to have an inverse association with the risk of tumour progression. Meaning, high natural folate intake was linked to a decreased risk of cancer progression, but high folic acid intake was associated with an increased risk of recurrence and multifocal tumours.

Some limitations associated with this study include that the dietary data was self-reported, therefore this data is subject to measurement errors and the majority of the study population were non-Hispanic whites. Therefore, these results may not be generalizable for other ethnic/racial groups. Also, dietary intake was only evaluated during the year before diagnosis and patients may have changed their diet after diagnosis. Some patients my have increased their dietary supplementation of folic acid after diagnosis and hence may have led to an underestimation of the positive association between folic acid intake and recurrence.

High consumption of synthetic folic acid may be harmful to patients

The evidence provided in this study indicates there is an association between a high intake of synthetic folic acid and an increased risk of recurrence specifically in NMIBC and multifocal tumours at diagnosis. Therefore, these results indicate that a high consumption of synthetic folic acid, as opposed to natural folate, may be harmful for NMIBC patients. This raises important questions surrounding the safety of folic acid fortification and the use of folic acid supplements, especially among NMIBC patients. Hence, nutritional consultation regarding folate and folic acid intake would be advisable for NMBIC patients.

Written by Lacey Hizartzidis, PhD

Reference: Tu H, Dinney CP, Ye Y, Grossman HB, Lerner SP, Wu X. Is folic acid safe for non-muscle-invasive bladder cancer patients? An evidence-based cohort study. Am J Clin Nutr. 2018 Feb 1;107(2):208-216. doi: 10.1093/ajcn/nqx019.

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