Unmetabolized folic acid in serum: acute studies in subjects consuming fortified food and supplements

Abstract

Periconceptual consumption of folic acid has been shown to decrease the incidence of neural tube defects. The strategy of universal fortification of staple foodstuffs with folic acid presents the possibility of life-long exposure to unmetabolized folic acid. Chief among the risks of exposure to folic acid in the circulation is that of masking the diagnosis of cobalamin deficiency in pernicious anemia and the progression of neurologic disease. Other effects are unknown. For instance, the effect of in vivo chronic exposure of adult and fetal cells to the synthetic form of the vitamin has never been investigated at the population level. This study examined the acute appearance of unmetabolized folic acid in serum in response to the consumption of some fortified foodstuffs by young and elderly volunteers. Subjects on a 5-d regimen of fortified ready-to-eat-cereal and bread in addition to their normal diet had a threshold intake of 266 micrograms folic acid per meal at which unaltered folic acid appeared in the serum. Subjects given folic acid in either isotonic saline, milk, or white bread also had a threshold > 200 micrograms. From patterns of food consumption in the United States, the implementation of flour fortification at 1.4 mg/kg is unlikely to lead to folic acid appearance in serum, assuming that consumption is spread throughout the day. Increasing this level of fortification, however, as has been advocated by some agencies, may result in the repeated appearance of folic acid in serum over many years, particularly in consumers in nontargeted populations of large amounts of fortified foods. The "safe level of intake" of 1 mg folate/d set by the US Food and Drug Administration may cause a serum folic acid effect. Furthermore, a repeated serum folic acid response is likely to be found in many women complying with the advice to take 400 micrograms folic acid/d to prevent the occurrence of neural tube defects.

Bioavailability of folic acid from fortified pasteurised and UHT-treated milk in humans

“…It is interesting to note that we were unable to detect any unmodified folic acid in the serum of those subjects who received milk supplemented with folic acid (o1% of total concentration; analysis carried out by RB van Breemen, University of Illinois at Chicago, personal communication, data not shown). This does not support the concern of others, who detected unmetabolised folic acid in serum of subjects consuming fortified food and supplements, and which might be an unwanted effect (Kelly et al, 1997;Lucock 2004).…”

Safety and benefits of interventions to increase folate status in malaria‐endemic areas

“…As with dietary folates, most folic acid is converted in the small intestine to 5‐methyl‐THF. With high oral doses of folic acid, however, this conversion is inefficient, leading to passive diffusion and transitory levels of unmodified folic acid in plasma (Kelly et al , 1997; Sweeney et al , 2007). The magnitude of this effect is dependent on dose and frequency of intake (Lucock et al , 1989; Powers, 2007), and unaltered folic acid persists in plasma for 6 h after ingestion of a single dose (Lucock et al , 1989).…”

L-ascorbic acid improves the serum folate response to an oral dose of [6S]-5-methyltetrahydrofolic acid in healthy men

“…Unlike other epithelial transport mechanisms, the mucosal system appears to be unique in its lack of hierarchy of transport, having a similar affinity for both oxidized (that is, PteGlu) and reduced natural folate forms (Said et al, 1987). Exposure to doses of PteGlu above 589 nmol results in occurrence of unmetabolized PteGlu in systemic circulation (Kelly et al, 1997) that can be converted to tetrahydrofolic acid (H 4 PteGlu). This would mask the hematological abnormalities related to vitamin B 12 deficiency, delaying its diagnosis and allow the associated neurological dysfunction to progress to an irreversible combined degeneration of the spinal cord.…”