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Sources and physiological effects

Dietary sources
Folic acid or folate refers to approximately 100 different folic acid active substances. Derived from the Latin folium, the leaf, folic acid is - abundant in green plants, especially in dark green leafy vegetables. Good sources of folic acid include broccoli, green beans and green cabbage as well as spinach, lamb's lettuce or chard. Wholemeal products, asparagus, radishes, tomatoes and egg yolk also supply folic acid. Particularly high concentrations are found in yeast, wheat germ and bran as well as poultry and veal liver. The availability of folic acid from the diet depends on its form. In a mixed diet only approx. ¼ of folic acid is present in its free form as monoglutamate, which can be absorbed almost completely. For polyglutamate, on the other hand, the absorption rate is only around 20%. It must first be broken down into monoglutamate by specific hydrolases in the gastrointestinal tract before it can be absorbed - but its activity is limited. On average, it can be expected that about half of the folate found in foods is bioavailable. Another factor that plays a role in the supply of folic acid is the high instability of the B vitamin. Storage and heating greatly reduces the folic acid content of foods. Regular consumption of alcohol also reduces folic acid supply.
Physiological effects
Homocysteine degradation	The precursor of folic acid, the coenzyme tetrahydrofolic acid (THF), is directly involved in the methylation of homocysteine to methionine.
Cell growth	Important function in cell renewal in epithelia and in the formation of new cells in the bone marrow.
Embryonic development	Participation in embryonic neural tube closure.
Protein metabolism	Folic acid is involved in the synthesis of purine bases, which is necessary for the synthesis of DNA.
Neurotransmitter metabolism	Co-factor of serotonin synthesis

EFSA Health Claims

Health Claims		EFSA Opinion
Folic acid	Contributes to growth of maternal tissue during pregnancy Contributes to normal hematopoiesis Contributes to a normal homocysteine metabolism Contributes to a normal function of the immune system Has a function in cell division Contributes to a normal amino acid synthesis Contributes to normal mental function Contributes to a reduction of fatigue and fatigue

Recommended intake

D-A-CH reference values for the intake of folic acid (Reference values EFSA and NHI )
	Age	Folic acid (µg/d)
Infants (months)
	0-4	60
	4-12	85
Children (years)
	1-4	120
	4-7	140
	7-10	180
	10-13	240
	13-15	300
Teenagers/adults (years)		Women	Men
	15-19	300	300
	19-25	300	300
	25-51	300	300
	51-65	300	300
	> 65	300	300
Pregnancy	550
Breast-feeding	450
Increased need	Pregnancy, growth, iron deficiency, alcohol abuse, smoking, malabsorption due to chronic inflammatory intestinal diseases and diarrhea, in liver and kidney diseases, reduced availability in vitamin B₁₂ deficiency, by taking certain drugs (cytostatics, antieptileptics, anti-malaria drugs);
Risk groups	Women with a desire to have children
Note	A detailed overview of the reference values and the nutritional aspects of folic acid intake is provided by the German, Austrian and Swiss Society for Nutrition.

Recommended intake according to food labelling regulations
(=100 % TB marking on label)		200 µg
Nutrient safety
UL	Long-term daily intake, for which no negative health effects are to be expected	1000 µg/d (according to EFSA)
NOAEL	Maximum intake, with no observed adverse effect	1000 µg/d

Detailed information

Folic acid - a key micronutrient for cell growth and division

Folic acid is one of the B group vitamins and is involved in many biological processes in humans. Like vitamin B₁₂, folic acid is necessary for the biosynthesis of DNA and RNA and is therefore indispensable for all growth and cell division processes. Another task of folic acid is the methylation of homocysteine to methionine and therefore the control of homocysteine levels (1). Although folic acid is found in numerous animal and plant foods, the intake in all population groups is assessed as critical. For example, women in Austria consumre an average of only 216 μg folic acid per day and men 197 μg - instead of the desired 300 μg (2). The reason for this is the high instability of folic acid against exogenous factors such as heat, light and oxygen, which causes considerable losses during the storage and preparation of food. The folic acid content of a meal is reduced considerably through warming and long heating. The average loss during food preperation is 35% (3).

Non-specific symptoms of folic acid deficiency

Folic acid deficiency is the most common vitamin deficiency in Europe and North America. Especially for pregnant women, nursing mothers and the elderly, adequate care is often not guaranteed. Since folic acid plays a major role in the structure of DNA, a deficiency manifests itself primarily in tissues with high cell division rates such as the hematopoietic cells of the bone marrow (3). A folic acid deficiency initially leads to unspecific complaints such as listlessness, depressive moods and weakness. Only after several weeks can specific symptoms appear such as wound healing disorders, depression and macrocytic hyperchromic anaemia (4).

Elevated homocysteine level

Insufficient folic acid intake correlates with the occurrence of atherosclerotic diseases. A deficiency leads to increased homocysteine levels in the blood, which in turn is considered an independent risk factor for the development of arteriosclerosis. An optimal folic acid intake is the most effective method to lower the homocysteine level (3). According to statistical calculations, a 25% reduction in homocysteine content should lead to 10% fewer cases of heart disease and 20% fewer cases of stroke(5).

Critical nutrient in pre-conception and early pregnancy

Folic acid is particularly important during pregnancy because it is needed for the development of the fetal nervous system. Insufficient intake increases the risk of damage to the neural tube (spina bifida) in the child. Since the neural tube closes between the 21st and 27th day of pregnancy, i.e. at a time when most women have not yet noticed anything about their pregnancy, folic acid supplements are strongly recommended for all women of childbearing age, but especially for those who plan to become pregnant (3). Sufficient folic acid intake must also be ensured during pregnancy. At 600 μg, the demand is almost twice as high as for non-pregnant women. This increased need is due to increased maternal erythropoiesis, growth of the fetus and placenta, and increased renal losses. Low birth weight, growth disorders, bone marrow changes as well as neurological abnormalities and neural tube defects are associated with insufficient folic acid intake during pregnancy (3). Malformations such as cleft lip and palate and jaw are also associated with a folic acid deficiency in early pregnancy (6).

Folic acid deficiency in chronic inflammatory bowel disease

Patients with chronic inflammatory bowel disease are often affected by a folic acid deficiency. In addition, ulcerative colitis and Crohn's disease patients are at increased risk of colorectal cancer. Due to its central role in chromosome repair processes and DNA production, folic acid deficiency is discussed as a risk factor in the carcinogenesis of colorectal and other tumors (1). In a recent double-blind, placebo-controlled study, high doses of folic acid (5 mg/d) significantly reduced the incidence of intestinal adenomas (7) and another study demonstrated a potential preventive effect (8).

Drug interactions with folic acid

Drugs and micronutrients use the same metabolic and transport pathways in the human organism for absorption, metabolization and elimination. The risk of interaction between drugs and micronutrients, including folic acid, increases when one or more drugs are taken (9). Taking antiepileptics, ASA, cholestyramine, diuretics, furosemide, oral contraceptives, metformin, pancreatin and sulfasalazine may interfere with folic acid absorption. Aminopterin, cotrimoxazole, MTX, pentamidine, proguanil, pyrimethamine, triamterene, trimethoprim and tetroxoprim also act as folic acid antagonists (1) (9).

Reference values

Parameters	Substrate	Reference value	Description of the parameter/method
Folic acid in blood	Serum/Plasma	2.0 - 17 µg/l limit <4	Fasted (12 h food leave). Values in serum reflect the uptake in the last hours.
	Whole blood	250 - 1000 µg/l	Whole blood hemolysate parameters for long-term status
Interpretation
Low values		Lower values in serum and erythrocytes indicate a manifest folic acid deficiency.
High values		Overdosage of folic acid preparations or multivitamin preparations.
Note on the interpretation
Determination of erythrocyte folic acid requires the prior determination of the hematocrit value. Drug impairment: In metotrexate and leukovorin therapy due to cross-reaction to the binding protein.

Nutrigenetics
Characteristic gene locations and their effects on Vitamin requirements

Gene	rsNumber	risk SNP	Description	Recommended nutrients
MTHFR	rs1801133	T	The transmethylation by this enzyme is reduced, the need for folic acid and vitamin B6 is increased This SNP is associated with increased homocysteine levels. Vitamin B2 (riboflavin) can increase the activity of the MTHFR enzyme, therefore an increased intake is recommended. Vitamin B6 and folic acid should always be taken together with vitamin B12 (10)(11)(12)(13).	B₂, B₆, B₁₂ and folic acid

MTR,
MTRR

rs1805087,
rs1801394

G

The transmethylation of this enzyme is reduced. A reduced synthesis of phosphatidylcholine and increased dependence on choline is associated with this SNP (14).

Folic acid, Methionine and Choline

Nutrigenetics and cancer

Gene/miRNA	Process	Change of activity	Prevention	Nutrient for cancer prevention
P16, P14, and hMLH1	Methylation	reduced	Prevention of colon cancer	Folic acid

Deficiency symptoms

Impact on	Symptoms
General health	Anorexia, pallor, depression, weakness, forgetfulness
Embryonic development	Folic acid deficiency during pregnancy increases the risk of neural tube defects such as spina bifida or anencephaly.
Blood	Impairment of erythropoiesis and development of pernicious anemia Thrombocytopenia, leukopenia, hyperhomocysteinemia
Cardiovascular system	Increased risk of stroke due to increase in blood homocysteine levels
Nerve system	Increased risk of dementia and polyneuropathy
Mucous membrane	Glossitis, stomatitis, mucosal atrophy in the GIT and urogenital tract

Indications

Effect	Indication	Dosage
Physiological effects at a low intake	For general prevention	0.4 - 0.8 mg/d
	For the treatment of folic acid deficiency disorders such as macrocytic hyperchromic anemia or hyperhomocysteinemia	0.8 mg/d
	To improve folic acid supply in women pre-conception and during pregnancy	0.8 mg/d
	To compensate for folic acid deficiency caused by drug interactions such as oral contraceptives or by laxative abuse	0.4 - 0.8 mg/d



Pharmacological effects at a high intake	For the treatment of folic acid deficiency due to chronic inflammatory bowel disease	1 - 10 mg/d

Administration

General mode of administration
When	Folic acid should be taken between meals.
Side effects
In very high doses itching and gastrointestinal disorders may occur in rare cases.
Contraindications
Megaloblastic anemia (vitamin B₁₂ deficiency)

Interactions

Drug interactions
Antiepileptics (e.g. carbamazepine, phenytoin)	Antiepileptics can affect folic acid levels.
Diuretics (e.g. loop diuretics, thiazides)	Impairment of absorption and increased renal excretion. Furosemide interferes with the pH gradient on the brush-border membrane of the small intestine and thus reduces the absorption of folic acid.
Oral antidiabetics (metformin)	Metformin can lower the level of folic acid.
NSAIDs (e.g. ibuprofen, ASS)	May interfere with folic acid absorption due to gastrointestinal damage. Folic acid can be displaced from its plasma protein binding by ASA and excreted more often.
Estrogen (oral contrazeptives)	Impairment of folic acid absorption (substitution of folic acid, vitamin B₆ and vitamin B₁₂ recommended).
Tetracycline antibiotics (e.g. minocycline)	Interferes with the absorption and effectiveness of medication, long-term administration impairs folic acid status
Sulfonamide antibiotics (e.g. sulfasalazine)	Inhibits the conjugate of folic acid and thus interferes with its absorption and activity.
Methotrexate	As a folic acid antagonist interferes with the folic acid metabolism of folic acid. With simultaneous administration it can cause mutual inhibition of action. Taking folic acid at spacedintervals may reduce methotrexate side effects.
Antidepressant SSRI (e.g. sertraline, fluoxetine)	Folic acid deficiency can affect the availability of serotonin in the brain. (Supplementation can improve therapy success.)
Nitrates (e.g. glycerol trinitrate, isosorbide mononitrate)	Folic acid reduces nitrate tolerance and reduces cardiovascular risk.
Nutrient interactions
Trace elements	Zinc deficiency impairs folic acid absorption.
Vitamins	Vitamin C plays an important role in the activation of folic acid. Vitamins work synergistically with all B vitamins, especially with vitamin B₆ and vitamin B₁₂.

Description and related substances

Description

Water-soluble vitamin

Related substances

Quatrefolic® (6S)-5-methyltetrahydrofolic acid glucosamine salt) is an active form patented by Gnosis with an increased bioavailability.
Metafolin® (5-methyltetrahydrofolic acid and calcium -L-methylfolate) is an active form patented by Merk.
Pteroyl monoglutamic acid = synthetic form of folic acid

References

1) Gröber, U. 2008. Orthomolekulare Medizin. Ein Leitfaden für Apotheker und Ärzte.
2) Elmadfa, I. et al. 2012. Österreichischer Ernährungsbericht.
3) Hahn, A. et al. 2006. Ernährung. Physiologische Grundlagen, Prävention, Therapie.
4) Gröber, U. 20011. Mikronährstoffe. Metabolic Tuning – Prävention – Therapie.
5) B-Vitamin Treatment Trialists’ Collaboration: Homocysteine-lowering trials for prevention of cardiovascular Events. 2006. a review of design and power of large randomized trials. Am Heart J. 151(2):282-7.
6) Wilcox, A. J. et al. 2007. Folic acid supplements and risk of facial clefts: national population based case-control study. BMJ. 334(7591):464.
7) Jaszewski, R. et al. 2010 Folic acid supplementation inhibits recurrence of colorectal adenomas: a randomized chemoprevention trial. Am J Epidemiol.
8) Gao, Q. Y. et al. 2013. Folic acid prevents the initial occurrence of sporadic colorectal adenoma in Chinese older than 50 years of age: a randomized clinical trial. Cancer Prev Res (Phila). 6(7):744-52
9) Gröber, U. 2007. Arzneimittel und Mikronährstoffe. Medikationsorientierte Supplementierung.
10) Olteanu, H. Munson, T. Banerjee, R. 2002. Differences in the efficiency of reductive activation of methionine synthase and exogenous electron acceptors between the common polymorphic variants of human methionine synthase reductase. Biochemistry. 41(45):13378-85. .
11) Wilson, A. et al. 1999. A common variant in methionine synthase reductase combined with low cobalamin (vitamin B12) increases risk for spina bifida. Mol Genet Metab. (4):317-23.
12) Seibold, P. et al. Polymorphisms in oxidative stress-related genes and postmenopausal breast cancer risk. Int J Cancer. 129(6):1467-76.
13) Jiang-Hua, Q. et al. 2014. Association of methylenetetrahydrofolate reductase and methionine synthase polymorphisms with breast cancer risk and interaction with folate, vitamin B6, and vitamin B 12 intakes. Tumour Biol. 35(12):11895-901.
14) Ganz, A.B, et al. 2016. Genetic impairments in folate enzymes increase dependence on dietary choline for phosphatidylcholine production at the expense of betaine synthesis. FASEB J. 30(10):3321-3333.

References Interactions
Stargrove, M. B. et al. Herb, Nutrient and Drug Interactions: Clinical Implications and Therapeutic Strategies, 1. Auflage. St. Louis, Missouri: Elsevier Health Sciences, 2008.
Gröber, U. Mikronährstoffe: Metabolic Tuning –Prävention –Therapie, 3. Auflage. Stuttgart: WVG Wissenschaftliche Verlagsgesellschaft Stuttgart, 2011.
Gröber, U. Arzneimittel und Mikronährstoffe: Medikationsorientierte Supplementierung, 3. aktualisierte und erweiterte Auflage. Stuttgart: WVG Wissenschaftliche Verlagsgesellschaft Stuttgart, 2014.