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Folic acid, folinic acid, and calcium folinate
See also Vitamins
General information
Folic acid (pteroylglutamic acid) is a vitamin of the B group, whose Average Dietary Requirement in adults has been set at 140 micrograms/day, with a Population Reference Intake of 200 micrograms/day. Red cell folate concentrations above 150 ng/ml indicate sufficiency [ ]. However, higher doses are used for specific purposes, including in pregnancy, apparently without ill effects. Neural tube defects can be prevented in offspring by periconceptual ingestion of 400 micrograms/day [ ]. One aspect of folate metabolism concerns the recycling of the putatively atherogenic amino acid, homocysteine [ ]. For reasons that are not clear, homocysteine accumulates in the blood of dialysis patients, and this accumulation is inversely related to folate status. Because of the association of folate with a risk factor for atherosclerosis—it is the major cause of morbidity and mortality in dialysis patients—folate supplementation has been widely recommended as a strategy to reduce homocysteine concentrations, and a daily dose of 800 micrograms has been proposed as part of a mass strategy to reduce the risk of heart attacks and strokes by over 80% [ ].
Folinic acid is a reduced form of folic acid. Adverse reactions to antifolate drugs that are tetrahydrofolate reductase inhibitors, such as methotrexate, cannot be prevented by giving folic acid, since antifolate drugs inhibit the conversion of folic acid to folinic acid. Folinic acid is therefore given instead, as calcium folinate (leucovorin). However, in patients who take antifolate drugs intermittently (for example methotrexate once a week in psoriasis or rheumatoid arthritis) folic acid taken on another day is adequate.
Recommendations that women who plan to become or have just become pregnant should take daily oral folic acid supplements in order to prevent neural tube defects were issued by health authorities in several European countries from 1991 onwards [ ]. The recommendations generally follow the lead of the US Public Health authorities which recommended a supplementation dose of 400 micrograms/day [ ]. This is what a woman would consume if she followed the US Dietary Guidelines and Dietary Pyramid [ ]. The etiology of neural tube defects is not entirely clear; the condition may have several different causes, only some of which may be responsive to folate [ , ]. Rates of neural tube defects vary considerably between countries; in the USA rates of neural tube defects isolated from other birth anomalies fell over the period 1968–89 [ ]. The justification for a recommendation for general high-dose supplementation or food fortification is still under discussion [ ]. The debate elicited by this recommendation has spurred interest in possible adverse reactions, and a thorough review published in 1998 [ ] identified the following potential safety issues of folic acid supplementation in addition to those mentioned above: folate neurotoxicity, reduced zinc absorption, association with malignant neoplasms, hypersensitivity reactions, and increased susceptibility to malaria. However, the data are weak and consist predominantly of case series and individual reports. Furthermore, it is likely that even if such adverse reactions did occur, the benefit to harm balance would still be highly favorable.
The main argument against an increase in folic acid supply to the population as a whole is the possible masking of vitamin B 12 deficiency by normalization of the blood count (see the section Does folic acid mask vitamin B 12 deficiency? in this monograph). However, while certain animal findings and some case reports have actually suggested worsening of the neurological effects of vitamin B 12 deficiency when patients are treated with folic acid, these do not prove a causal relation (see the section Does folic acid enhance the neurological symptoms of vitamin B 12 deficiency? in this monograph). Nevertheless, because the available data do not exclude such an effect, in the US-Canadian “Dietary Reference Intakes” in adults the upper limit has been set at 1000 micrograms/day folic acid in supplements or enriched food preparations and in children (1–18 years of age) the upper limit has been set at 300–800 micrograms. At doses of 5 mg/day in more than 100 patients there was progression of neurological complications, but there have only been eight case reports of the effect of lower doses of folic acid. Because there is no NOAEL (no observed adverse effect level), a LOAEL (lowest observed adverse effect level) of 5 mg/day had to be used for the upper limit. In contrast, in 1996 the FDA fixed an upper limit of 1000 micrograms/day folic acid (natural and synthetic preparations) [ , ]. It was also argued that in children of vegetarians natural folate had masked vitamin B 12 deficiency. These previous values have now been re-evaluated by the FDA. Dietary supplementation with both folic acid and vitamin B 12 offers a solution to this problem. No risks of increasing the supply of vitamin B 12 are expected, but the dosage that would correct vitamin B 12 deficiency remains to be defined [ , ].
General adverse effects and adverse reactions
Negative effects resulting from dietary intake of high concentrations of folic acid have only rarely been documented in some older case reports and uncontrolled intervention studies. Some of these negative effects were not confirmed in subsequent randomized, controlled intervention studies [ ].
In humans the toxicity of folic acid is low, even after long-term use [ , , ]. Only in one trial in 14 volunteers (six women, eight men, aged 22–57 years) were there adverse reactions, such as gastrointestinal disturbances, insomnia, irritability, or depressive states [ ]. As a possible cause the authors suggested a high folic acid concentration in the cerebrospinal fluid (5–10 times higher than that in serum). However, these findings were not confirmed in subsequent trials with high-dose folic acid supplementation.
Does folic acid mask vitamin B 12 deficiency?
Vitamin B 12 deficiency most frequently is seen in people over 60 years of age [ ]. Deficiency of vitamin B 12 in younger adults is rare, but can occur as a result of reduced absorption of vitamin B 12 , for example in pernicious anemia, atrophic gastritis type B, long-term use of blockers of acid secretion, or short bowel syndrome after resection of the terminal ileum [ , ]. Vitamin B 12 deficiency in children usually depends on inborn defects of vitamin B 12 metabolism or on insufficient support during pregnancy and breastfeeding.
Vitamin B 12 deficiency can present as hematological, gastrointestinal, and neurological disturbances. The anemia of B 12 deficiency is actually due to functional deficiency of folic acid, and results from accumulation of folic acid derivatives in the form of 5-methyltetrahydrofolate, which prevents regeneration of tetrahydrofolic acid and consequently, by interfering with the synthesis of purines and DNA, reduces cell proliferation. Therefore, giving folic acid to patients with vitamin B 12 deficiency can abolish the hematological effects but will not affect the neurological symptoms. Normalization of the blood count requires high doses of folic acid in the absence of B 12 replacement therapy. Treatment with folic acid 0.3–1 mg/day normalizes the blood count in 50% of patients with B 12 deficiency, while at doses over 5 mg/day the hematological changes are normalized in most patients [ ]. However, the hematological effects can recur, even after treatment with high doses of folic acid (5–500 mg/day), if the vitamin B 12 deficiency is not treated.
Concerning possible masking of vitamin B 12 deficiency by folic acid, blood counts in 11–33% of the patients with neurological symptoms of vitamin B 12 deficiency are in the reference range. That means that in patients with severe funicular myelosis, a vitamin B 12 deficiency psychosis, changes in the blood count may not occur, while on the other hand in patients with severe pernicious anemia neurological symptoms are not inevitably present.
Organs and systems
Nervous system
Does folic acid enhance the neurological symptoms of vitamin B 12 deficiency?
The results of some animal experiments and case reports have suggested that high doses of folic acid can enhance or worsen the neurological effects of vitamin B 12 deficiency. Thus, in animals with vitamin B 12 deficiency being treated with folic acid, neurotoxicity developed more rapidly than in the untreated controls [ , ]. Some unproven hypotheses about how folic acid could enhance the neurological symptoms of vitamin B 12 deficiency have been discussed, for example redistribution of B 12 from the nervous system into the bone marrow, accompanied by a fall in serum concentration and reticulocytosis [ ]. There have also been some reports that in patients with vitamin B 12 deficiency neurological complications occurred for the first time or increased in severity when folic acid was given, the severity and onset of the complications correlating with the dose of folic acid.
Whether folic acid is responsible for these observations or whether the neuropathy depends on progressive vitamin B 12 deficiency and simply coincides with the administration of high doses of folic acid cannot be determined from these reports. In patients who were treated beforehand with liver extracts the neurological changes were weaker and occurred later than in patients who were treated with folic acid exclusively [ ]. This suggests that progressive reduction in cobalamin pools is as important for the development of the neurological complications as the supply of folic acid. Furthermore, rapid worsening of neurological changes in patients with cobalamin deficiency has also been seen in patients who have not received folic acid.
Because there have been no double-blind, placebo-controlled intervention studies of the effect of folic acid, the question of whether folic acid in patients with vitamin B 12 deficiency aggravates the neurological complications cannot be answered definitively. From the data at hand we cannot exclude the possibility that folic acid may exacerbate the effects of vitamin B 12 deficiency. For that reason an upper limit of 1 mg/day folic acid (in supplements or a vitamin-enriched diet) has been set in the “Dietary Reference Intakes” [ ].
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