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Excess folate worsens B12 deficiency effects: study

By Stephen Daniells , 19-Dec-2007

The effects of vitamin B12 deficiency may be exacerbated by too much folate, suggests a new study from Tufts University.

Over 10,000 subjects were included in the new study, which found that levels of homocysteine and methylmalonic acid are at much higher levels in individuals who have a combination of vitamin B12 deficiency and high blood folate levels than in individuals who are also vitamin B12 deficient but have normal folate levels. "Finding that the combination of high blood folate levels and low vitamin B12 status is associated with even higher levels of these compounds is a strong indication that the high folate is interfering with the action of these B12-containing enzymes, thus resulting in the exacerbation or worsening of the vitamin B12 deficiency," said lead author Jacob Selhub. The results, published in the prestigious journal Proceedings of the National Academy of Sciences, could have knock-on effects for the ongoing debate over mandatory folic acid fortification of flour, still on the table in several countries. The debate is raging around the possible adverse effect produced by folic acid fortification, particularly in relation to delaying the detection of vitamin B12 deficiency (which can have severe neurological consequences) in older people.


In the UK, for example, the Food Standards Agency (FSA) last considered mandatory fortification in 2002, but the Scientific Advisory Group on Nutrition (SACN) decided not to adopt it at that time because of concerns that folate consumption in excess of 1000 micrograms (1mg) per day could delay the detection of vitamin B12 deficiency. Since then, some research has indicated that B12 deficiency would be masked only with folate consumption of more than 5000 micrograms per day. The new research used data from two National Health and Nutrition Examination Surveys (NHANES), on conducted before 1998 and prior to the introduction of mandatory fortification in the US, and the other 1999 and 2002, after mandatory folic acid fortification had been introduced. Folate is found in foods such as green leafy vegetables, chick peas and lentils, and an overwhelming body of evidence links has linked folate deficiency in early pregnancy to increased risk of neural tube defects (NTD) - most commonly spina bifida and anencephaly - in infants.


This connection led to the 1998 introduction of public health measures in the US and Canada, where all grain products are fortified with folic acid - the synthetic, bioavailable form of folate. "It is important to note that these adverse interactions between high folate blood levels and vitamin B12 deficiency were seen only in the study participants from the NHANES conducted between 1999 and 2002, after the fortification of flour and other cereals with folic acid," said Selhub. The researchers report that subjects with plasma levels of vitamin B12 greater than 148 picomoles per litre, concentrations of homocysteine and methylmalonic acid decreased significantly as plasma folate levels increased, after adjusting the results for potentially confounding factors, such as smoking habits, alcohol use, body mass index, and serum concentrations of creatinine and alanine aminotransferase. However, folate levels above about 20 nanomoles per litre in combination with lower vitamin B12 levels (less than 148 pmol/L) were associated with increased concentrations of homocysteine and methylmalonic acid.


"These observations provide a possible biochemical explanation for high folic acid intake's exacerbation of the clinical manifestations of vitamin B12 deficiency," wrote the authors. Previous studies reported that B12 may be the more important than the other B vitamins for determining homocysteine levels and subsequently the risk of dementia. Epidemiological studies have reported that high levels of the amino acid homocysteine are associated with suspected or confirmed dementia. Indeed, the Framingham study reported that people with homocysteine levels above 14 micromoles per litre of serum had twice the risk of dementia. Selhub stated that high folate may only be detrimental if B12 levels are low. "There is no reason to avoid foods with naturally occurring folate and it essential to consume B12 containing products such as eggs, meat, milk and poultry and even supplements if necessary," he said.


"The combination of high blood folate and normal vitamin B12 status is actually beneficial to health." This study was supported by the U.S. Department of Agriculture's Agricultural Research Service (ARS). Source: Proceedings of the National Academy of Sciences Volume 104, Pages 19995-20000, doi: 10.1073/pnas.0709487104 "In vitamin B12 deficiency, higher serum folate is associated with increased total homocysteine and methylmalonic acid concentrations"


Authors: Jacob Selhub, M.S. Morris, and P.F. Jacques

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