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Friday, February 6, 2015

Folic Acid Vitamin - Folic Acid Deficiency

What is folic acid?

Folic acid and folate (the anionic form) are forms of a water-soluble vitamin of the vitamin B complex, which is sometimes still inherits the old name vitamin B11. In Germany, France and the United States of America, this is also referred to as vitamin B9.

Folate is the (relatively unstable) form that occurs in food, and is the form of this vitamin in the body operates. In dietary supplements and enriched foods is the more stable synthetic folic acid (pteroylmonoglutamic) before, which is converted in the body into folate.

Biochemistry and naming

Folic acid is in most countries of the world also called vitamin B11 called (initially vitamin M). In Germany, France and in the United States of America, it is called vitamin B9.

In the diet comes not for folate, or folic acid, which stands for a large group of related compounds (pteroglutamaatverbindingen) with the same vitamin effect as folic acid. They consist of three main components: an aromatic pteridine ring, attached to para-aminobenzoic acid (PABA) and a residual group of one or more glutamate-units. About 90% of the folaten in the diet contains more than one glutamaatgroep and pteroylpolyglutamaten are based on 5-methyl-tetrahydrofolaat biologically. Usually involves five to seven groups, up to eleven, which are connected to each other through peptide bonds. The most common folaten in the power supply are 5, 6, 7, 8-tetrahydrofolaat (THF) as well as 7.8-dihydrofolaat (DHF). Folate in the body active as (various forms of) tetrahydrofolaat. Folate from food is therefore reduced to dihydrofolaat, and then once again reduced to tetrahydrofolaat. The enzyme dihydrofolaatreductase catalyzes both conversions.

Folic acid itself, the form found in supplements and fortified foods is pteroylmonoglutamic (PMG). Folic acid, however, is not originally found in nature and is derived from chemical synthesis.

Folic acid is the most (fully) oxidized form of folate, and therefore the most stable form. This is biologically active after converted in the body (reduced) to be to an active form, a form of tetrahydrofolate. This is a complicated process involving several enzymes play a role, as well as a sufficient presence of vitamin B2, vitamin B3, and zinc serine. The presence of specific inhibitors of this conversion, such as the drug methotrexate, folate status may have a negative effect.

Folinic acid (5-formyl-THF, citrovorum factor, leucovorin) is not the same as folic acid. It is a direct precursor (precursor chemical) of 5,10-methylene-THF, the most important of the tetrahydrofolaatverbindingen, and may therefore reduce the deconjugation and reduction steps "skip" which are necessary for the biochemical activation of folic acid. Further, it has a longer half-life in the body, and appears to metabolically active than folic acid. As a supplement it offers so many advantages over folic acid. The disadvantage is that it is more expensive than folic acid. It is available as calcium folinate (leucovorin calcium), and is, inter alia, in the cancer therapy used as an antidote if high doses are used methotrexate.

The term folacin is a term that is used for all derivatives of folic acid (including folate).

Functions in the body

In the form of various nutritional tetrahydrofolate are folate and folic acid as a co-enzyme involved in the transfer of one-carbon groups (such as methyl, methylene and formyl). Vitamin B6, vitamin B12 and betaine play a supporting role in this process. These reactions are several places in the metabolism can be found:

-Folic acid is involved in the synthesis of red blood cells.
-Folic acid is also involved in the development of the brains and spinal cord in a fetus.
-Folate has, inter alia, a role in the formation of nucleotides, building blocks of the genetic material (RNA and DNA) in the cells of the body.
*Folate is a co-enzyme in the formation of purine and pyrimidine (parts of these nucleotides). Folate is therefore important for cell division and hence for all the (fast) growth and tissue formation, for example in the growth of a fetus, or of a baby.
*Indirectly is involved in the folate synthesis of transfer RNA.
-In addition, it is also involved in folate conversions of some amino acids.
*Folate provides the methyl group that is necessary to make methylcobalamin, a substance that is required to break down the noxious and homocysteine to be converted in the amino acid methionine. A too high level of homocysteine is a major risk factor for cardiovascular diseases, among others. Although vitamin B6, vitamin B12 and betaine are needed in the homocysteine metabolism, the role of folic acid in lowering an elevated homocysteine level is by far the greatest.
*Folate in addition, functions as a methyl donor in the production of the amino acid serine from the amino acid glycine.
-In combination with vitamin B12 and folate, vitamin C is necessary for the degradation of proteins and the formation of hemoglobin, the component in red blood cells that transports oxygen and carbon dioxide.


Folic acid is an essential vitamin. Man can not produce folate or folic acid, and for its supply dependent on the supply from external sources (diet or supplements).

Folate in the diet
The best source of folate in the diet is green leafy vegetables such as spinach (Latin folium also means "leaf"). But Brussels sprouts, broccoli, cabbage, asparagus, fruits (especially in some citrus) and yeast contain folate. Further, some types of meat contain folic acid, especially the liver, and (to a lesser extent) kidney.

The natural folates such as that occur in the power supply (for example, 5-MTHF), are fairly unstable. They are sensitive to light, oxygen from the air and storage. Losses during storage, processing and food are high. Within days to weeks after harvest all available folate naturally inactivated.

However, folate is especially sensitive to temperature. It is estimated that is destroyed by cooking another 50-95% of the available folate or lost in the cooking water. In the refining of grains all folates are removed.

It is very difficult to put together a diet containing sufficient folate. Even a completely according to the guidelines of the Food Centre composed diet contains less than the recommended daily allowance of this vitamin. Partly to encourage folate intake is currently recommended to consume daily 200 grams of vegetables and two servings of fruit. This is about twice as much as the average American actually turns out to be entertained. Among young adults, in a survey among 750 subjects even one to 200 grams of vegetables per day, and only 7% ate two servings of fruit per day. Even if the fruit and vegetable intake would be doubled, 33% of adults would not have to 200 micrograms (mcg) of folate a day coming.

Food Fortification with Folic Acid
Because of the precarious folate status of large parts of the population, in some countries cereals are fortified with folic acid. Most folic acid fortified products contain between 125 and 200 micrograms of folic acid per 100 grams. In the United States it is mandatory that cereal with 25-100% of the recommended daily amount of folic acid enriched.

In the Netherlands, the addition of folic acid to breakfast cereals prohibited. The reason given by the health authorities is that folic acid can mask symptoms of a vitamin B12 deficiency, which makes such a deficiency is not noticed and permanent nerve damage may occur.

Following a judgment of the European Court of Justice dated 2 december 2004 it was possible for exemption after 2004 for producers to get on this prohibition. Several companies have used this possibility, whereby also in Netherlands folic acid to cereal can be added. Exemption is granted up to a maximum of 100 micrograms of folic acid per 100 kcal. As of 2007, it is no longer necessary to ask for exemption on adding folic acid to foods, subject to a certain maximum amount of folic acid is not exceeded. In February 2008 advised the Health Council of the Netherlands to also go in to enrich breads and cereals with folic acid standard.

Unlike folate, that pretty unstable, is folic acid in enriched nutrition completely stable for months to even years.

Folic acid in dietary supplements
Usually 400 µg folic acid supplements with folic acid without prescription for sale at pharmacies and drugstores. Folic acid also makes, usually in lower doses, part vitamin B complex formulations and of multivitamin and mineral tablets.

For some time is also the active form of folic acid in the body as a dietary supplement on the market: L-5-methyl tetrahydrofolaat biologically. This form works at least as well as folic acid itself improve the folate status.

Synthesis in the intestine
Folate is also manufactured by micro-organisms in the gastrointestinal tract, but this production does not contribute significantly to the folic acid supply to the host.


In the brush zone of the cells of the dunnedarmmucosa be folaatverbindingen in the food largely stripped of their glutamic acid chain (polyglutamylketen) and converted into the monoglutamate form. This happens especially in the first part of the small intestine (especially the jejunum) by a group of zinc-dependent enzymes in the intestinal tract intracelluliare (folyl polyglutamate hydrolases, also called folaatdeconjugases). This process can be disrupted by chronic alcohol and some foods (including oranges and legumes).

Then folate in unconjugated form via active transport - and to a lesser extent passive diffusion - absorbed. In the epithelial cells of the intestinal wall, the folate is then reduced to dihydrofolate and then reduced again to tetrahydrofolate. The enzyme dihydrofolate reductase catalyzes both conversions.

From the epithelial cells is folate in the gastro-intestinal tract as a 5-MTHF mono-glutamate released into the circulation. In normal circumstances, folate in the plasma solely as 5-MTHF, especially attached to proteins. This process has a limited capacity. When there is a relatively large amount of folic acid (as a food supplement) is received within, unmetabolized folic acid also occurs in the blood stream, there will be taken up by cells and is reduced by dihydrofolate to tetrahydrofolate.

The uptake of folic acid is dependent on the acidity (pH) in the jejunum (optimally 6). An increase of the pH to 6.3 decreases the bioavailability of more than 30%, which is relevant in connection with common pH-problems of the gastrointestinal tract in the western world.

Folate from natural sources is included less than the synthetic form found in dietary supplements and fortified foods. Folate from food is about 20% less well absorbed than folate. This difference is caused by inhibitors of the deconjugase enzyme found in some foods.

Synthetic folic acid is well absorbed and has a bioavailability of approximately 85%. In the liver is metabolized to the one of the polyglutamate forms, which are identical with the polyglutamates in the diet. A significant amount is excreted in the bile, but most of it is taken up again. This continuous enterohepatic cycle of folic acid is important for the maintenance of adequate levels in the body. Alcohol interferes with this mechanism.

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Foods with folic acid

Folic Acid Deficiency

Since there are hardly any body stocks, folic acid deficiency may develop rather quickly. Within four months after start of inadequate food folate deficiency may have developed.

To Prevent
Since there are many people who eat enough folate-rich foods folic acid deficiency is considered one of the most common nutrient deficiencies. In 2001, about half of all Dutch less than the time recommended daily intake of 200 micrograms of folate inside. Meanwhile, the recommended daily allowance in the Netherlands has been adjusted to 300 micrograms per day.

The average folate intake in the Netherlands is estimated to be 182 micrograms a day, 10% of the population will get even less than 100 micrograms per day within (the absolute minimum in order to keep the serum levels even up to standard). That this figure is higher in the past failed because the methods are now improved. Estimates in the past have been systematically 25% too excessive.

There is very little research into the biochemical folic acid status in Netherlands, but the little research that is available, weakens the conclusion that a large proportion of the Dutch population structurally receives too little folic acid, slightly off: the folic acid status may be low at 8 to 25 percent of adults and the elderly. The status of children under 19 years seems good.

Partly for the folic acid intake is recommended to promote daily fruit and two pieces of fruit to eat 200 grams. This is about twice as much as the average American actually turns out to take it. Of the young adults came in a survey of 750 subjects no one to even 200 grams of vegetables per day and only 7% at two pieces of fruit per day. Even when the fruit and vegetable intake would be doubled, it would be 33% of adults not yet to the folate 200 µg (micrograms) per day.

Risk factors
The following factors may contribute to a folic acid deficiency:

-Insufficient supply of folate from food.
-An increased need. This could include the case of
*Pregnant women; the rapid growth of the fetus draws much folic acid to the mother.
*Breastfeeding mothers
*Children in periods of rapid growth
*Cancer Patients
*Genetic differences: Individuals having a genetic polymorphism (677C → T genotype) for the enzyme MTHFR (methylene tetrahydrofolate reductase) that is necessary for the production of 5-MTHF, have a higher need for genetic reasons for folic acid. It is estimated that approximately 12% of Caucasians and Asians this polyform ism; among African Americans would prevent less.
*People with a deficiency of the enzyme 5,10-methylenetetrahydrofolaat reductase also have an increased need.
*Users of drugs that interfere with the metabolism of folic acid (folate antagonists)
-A reduced absorption from the intestine (absorption).
*In AIDS patients, the folic acid absorption is significantly reduced, independently of the stage of the disease.
*When intestinal disorders as celiac disease, ulcerative colitis and Crohn's disease, the absorption of folate and folic acid can be disturbed.
-Increased losses. This could include the case for:
*Folaatverliezen by hemodialysis
*Alcohol interferes with the uptake of folic acid from the intestine into the enterohepatic cycle.
-A disturbed activation of folic acid. This may be the case for:
*Alcoholics. Alcoholism is a common cause of folate deficiency.
*People with liver disease.
*Deficiency of the enzyme or the cofactor that is required for the production of activated folate in the body.

Since folic acid are most important physiological role plays in the DNA synthesis and in the amino acid metabolism, manifest deficits takes place comes first in tissues in which a rapid cell division (blood cells, epithelial cells in the gastrointestinal tract and in rapid growth, is happening at the fetus in the womb ).

Symptoms of folate deficiency may include:

-Megaloblastic anemia (also called macrocytic anemia). In this form of anemia, the red blood cells are too large. Each red blood cell can carry as much oxygen as normal blood cell, thus effectively too little oxygen is transported in the blood. This may include express in the following symptoms: headache, fatigue, weight loss, nausea, anorexia, diarrhea, insomnia, irritability, forgetfulness. Because the life cycle of a red blood cell is about four months, it may take months before people with a folate deficiency develop megaloblastic anemia.
-Inflammation of the tongue.
-Intestinal disorders (diarrhea, among others)
-Growth disorders
-Peripheral neuropathy
-Birth defects
-Weight loss
-Cerebral disturbances and cognitive decline
-Too little folate can also lead to a too high level of homocysteine in the blood. This may give a higher risk for cardiovascular disease. The idea behind this is that elevated homocysteine levels, to make sure, that platelets may clump more easily, and form a plug.

For the assessment of the folate status is based on the concentration of this vitamin in serum and red blood cells, as well as the concentration of homocysteine in plasma. In addition, a limit of 15 micrograms is used as the upper limit of what can still be called a normal homocysteine concentration. Homocysteine is a very sensitive indicator of folate status.

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