Fundamentals of Human Nutrition/Vitamin B6

=8.6 Vitamin B6=

8.6.1 Sources
Vitamin B6 is a water-soluble vitamin that was first isolated in the 1930s. There are three traditionally considered forms of vitamin B6: pyridoxal (PL), pyridoxine (PN), pyridoxamine (PM). The phosphate ester derivative pyridoxal 5'-phosphate (PLP) is the principal coenzyme form and has the most importance in human metabolism (1-3).

Vitamin B6 must be obtained from the diet because humans cannot synthesize it. PLP plays a vital role in the function of approximately 100 enzymes that catalyze essential chemical reactions in the human body (1-5). For example, PLP functions as a coenzyme for glycogen phosphorylase, an enzyme that catalyzes the release of glucose from stored glycogen. Much of the PLP in the human body is found in muscle bound to glycogen phosphorylase. PLP is also a coenzyme for reactions used to generate glucose from amino acids, a process known as gluconeogenesis (4, 5).

Vitamin B6 can be found in various type of foods (Vanderschuren et. al., 2013). It can be found in high quantities in meat, fish, eggs, milk and milk products (Vanderschuren et. al., 2013; Ross et. al., 2014). It can also be found in some vegetables, non-citrus fruits, grain cereals and nuts (Ross et. al., 2014; Jain et. al., 2002). Since vitamin B6 can be lost during processing and storage, it is found fortified in some products such as cereals (Ross et. al., 2014; Gregory, 2006). Vitamin B6 is also available in dietary supplements, such as multivitamins and b-complex or as an isolated supplement. Normally, the supplemented form is found as pyridoxine, from which absorption is comparable with the forms obtained from food sources (Ross et. al., 2014).

Bioavailability:

It is estimated that in an assorted diet about 75% of B6 is bioavailable (Tarr et. al., 1981). However, bioavailability can be affected by food handling and the stability of the vitamin during storage. The stability of B6 in its natural form can be affected by temperature, canning, humidity and time of storage. Contrastingly, the fortified form pyridoxine hydrochloride has been found to be more stable to those changes, with an approximate retention of 90 to 100% (Gregory, 2006).

Nutrient interactions:

Metabolism of vitamin B6 is affected by the interaction with other nutrients. During the metabolic process, niacin and riboflavin coenzymes are necessary for aldehyde dehydrogenase. Furthermore, zinc will be required as a cofactor for phosphorylation of B6 (Ross et. al., 2014).

8.6.2 Functions
Nervous system function

In the brain, the synthesis of the neurotransmitter, serotonin, from the amino acid, tryptophan, is catalyzed by a PLP-dependent enzyme. Other neurotransmitters, such as dopamine, norepinephrine and gamma-aminobutyric acid (GABA), are also synthesized using PLP-dependent enzymes (4).

Red blood cell formation and function

PLP functions as a coenzyme in the synthesis of heme, an iron-containing component of hemoglobin. Hemoglobin is found in red blood cells and is critical to their ability to transport oxygen throughout the body. Both PL and PLP are able to bind to the hemoglobin molecule and affect its ability to pick up and release oxygen. However, the impact of this on normal oxygen delivery to tissues is not known (4).

Niacin formation

The human requirement for another B vitamin, niacin, can be met in part by the conversion of the essential amino acid, tryptophan, to niacin, as well as through dietary intake. PLP is a coenzyme for a critical reaction in the synthesis of niacin from tryptophan; thus, adequate vitamin B6 decreases the requirement for dietary niacin (4).

 Hormone function

Steroid hormones, such as estrogen and testosterone, exert their effects in the body by binding to steroid hormone receptors in the nucleus of the cell and altering gene transcription. PLP binds to steroid receptors in a manner that inhibits the binding of steroid hormones, thus decreasing their effects. The binding of PLP to steroid receptors for estrogen, progesterone, testosterone, and other steroid hormones suggests that the vitamin B6 status of an individual may have implications for diseases affected by steroid hormones, including breast cancer and prostate cancers (4).

Nucleic acid synthesis

PLP serves as a coenzyme for a key enzyme involved in the mobilization of single-carbon functional groups (one-carbon metabolism). Such reactions are involved in the synthesis of nucleic acids. The effect of vitamin B6 deficiency on the function of the immune system may be partly related to the role of PLP in one-carbon metabolism (see Disease Prevention).  Homocysteine and cardiovascular disease

Even moderately elevated levels of homocysteine in the blood have been associated with increased risk for cardiovascular disease, including heart disease and stroke (8). During protein digestion, amino acids, including methionine, are released. Homocysteine is an intermediate in the metabolism of methionine. Healthy individuals utilize two different pathways to metabolize homocysteine. One pathway converts homocysteine back to methionine and is dependent on folic acid and vitamin B12. The other pathway converts homocysteine to the amino acid cysteine and requires two vitamin B6(PLP)-dependent enzymes. Thus, the amount of homocysteine in the blood is regulated by at least three vitamins: folic acid, vitamin B12, and vitamin B6 (diagram). Several large observational studies have demonstrated an association between low vitamin B6 intake or status with increased blood homocysteine levels and increased risk of cardiovascular diseases. A large prospective study found the risk of heart disease in women who consumed, on average, 4.6 mg of vitamin B6 daily was only 67% of the risk in women who consumed an average of 1.1 mg daily (9). Another large prospective study found higher plasma levels of PLP were associated with a decreased risk of cardiovascular disease independent of homocysteine levels (10). Further, several studies have reported that low plasma PLP status is a risk factor for coronary artery disease (11-13). In contrast to folic acid supplementation, studies supplementing individuals with only vitamin B6 have not resulted in significant decreases in basal (fasting) levels of homocysteine. However, one study found that vitamin B6 supplementation was effective in lowering blood homocysteine levels after an oral dose of methionine (methionine load test) was given (14), suggesting vitamin B6 may play a role in the metabolism of homocysteine after meals.

 Immune function

Low vitamin B6 intake and nutritional status have been associated with impaired immune function, especially in the elderly. Decreased production of immune system cells known as lymphocytes, as well as decreased production of an important immune system protein called interleukin-2, have been reported in vitamin B6 deficient individuals (15). Restoration of vitamin B6 status has resulted in normalization of lymphocyte proliferation and interleukin-2 production, suggesting that adequate vitamin B6 intake is important for optimal immune system function in older individuals (15, 16). However, one study found that the amount of vitamin B6 required to reverse these immune system impairments in the elderly was 2.9 mg/day for men and 1.9 mg/day for women; these vitamin B6 requirements are higher than the current RDA (15).

Cognitive function

A few studies have associated cognitive decline in the elderly or Alzheimer's disease with inadequate nutritional status of folic acid, vitamin B12, and vitamin B6 and thus, elevated levels of homocysteine (17). One observational study found that higher plasma vitamin B6 levels were associated with better performance on two measures of memory, but plasma vitamin B6 levels were unrelated to performance on 18 other cognitive tests (18). Similarly, a double-blind, placebo-controlled study in 38 healthy elderly men found that vitamin B6 supplementation improved memory but had no effect on mood or mental performance (19). Further, a placebo-controlled trial in 211 healthy younger, middle-aged, and older women found that vitamin B6 supplementation (75 mg/day) for five weeks improved memory performance in some age groups but had no effect on mood (20). Recently, a systematic review of randomized trials concluded that there is inadequate evidence that supplementation with vitamin B6, vitamin B12, or folic acid improves cognition in those with normal or impaired cognitive function (21). Because of mixed findings, it is presently unclear whether supplementation with B vitamins might blunt cognitive decline in the elderly. Further, it is not known if marginal B vitamin deficiencies, which are relatively common in the elderly, even contribute to age-associated declines in cognitive function, or whether both result from processes associated with aging and/or disease.

Kidney stones

A large prospective study examined the relationship between vitamin B6 intake and the occurrence of symptomatic kidney stones in women. A group of more than 85,000 women without a prior history of kidney stones were followed over 14 years and those who consumed 40 mg or more of vitamin B6 daily had only two thirds the risk of developing kidney stones compared with those who consumed 3 mg or less (22). However, in a group of more than 45,000 men followed over six years, no association was found between vitamin B6 intake and the occurrence of kidney stones (23). Limited data have shown that supplementation of vitamin B6 at levels higher than the tolerable upper intake level (100 mg/day) decreases elevated urinary oxalate levels, an important determinant of calcium oxalate kidney stone formation in some individuals. However, it is less clear that supplementation actually resulted in decreased formation of calcium oxalate kidney stones. Presently, the relationship between vitamin B6 intake and the risk of developing kidney stones requires further study before any recommendations can be made.

Disease Treatment

Vitamin B6 supplements at pharmacologic doses (i.e., doses much larger than those needed to prevent deficiency) have been used in an attempt to treat a wide variety of conditions, some of which are discussed below. In general, well designed, placebo-controlled studies have shown little evidence that large supplemental doses of vitamin B6 are beneficial (24). Side effects of oral contraceptives Because vitamin B6 is required for the metabolism of the amino acid tryptophan, the tryptophan load test (an assay of tryptophan metabolites after an oral dose of tryptophan) was used as a functional assessment of vitamin B6 status. Abnormal tryptophan load tests in women taking high-dose oral contraceptives in the 1960s and 1970s suggested that these women were vitamin B6 deficient. Abnormal results in the tryptophan load test led a number of clinicians to prescribe high doses (100–150 mg/day) of vitamin B6 to women in order to relieve depression and other side effects sometimes experienced with oral contraceptives. However, most other indices of vitamin B6 status were normal in women on high-dose oral contraceptives, and it is unlikely that the abnormality in tryptophan metabolism was due to vitamin B6 deficiency (24). A more recent placebo-controlled study in women on the lower dose oral contraceptives, which are commonly prescribed today, found that doses up to 150 mg/day of vitamin B6 (pyridoxine) had no benefit in preventing side effects, such as nausea, vomiting, dizziness, depression, and irritability (25).

Premenstrual syndrome (PMS)

The use of vitamin B6 to relieve the side effects of high-dose oral contraceptives led to the use of vitamin B6 in the treatment of premenstrual syndrome (PMS). PMS refers to a cluster of symptoms, including but not limited to fatigue, irritability, moodiness/depression, fluid retention, and breast tenderness, that begin sometime after ovulation (mid-cycle) and subside with the onset of menstruation (the monthly period). A review of 12 placebo-controlled double-blind trials on vitamin B6 use for PMS treatment concluded that evidence for a beneficial effect was weak (26). A more recent review of 25 studies suggested that supplemental vitamin B6, up to 100 mg/day, may be of value to treat PMS; however, only limited conclusions could be drawn because most of the studies were of poor quality (27).

Depression

Because a key enzyme in the synthesis of the neurotransmitters serotonin and norepinephrine is PLP-dependent, it has been suggested that vitamin B6 deficiency may lead to depression. However, clinical trials have not provided convincing evidence that vitamin B6 supplementation is an effective treatment for depression (24, 28), though vitamin B6 may have therapeutic efficacy in premenopausal women (28). Morning sickness (nausea and vomiting in pregnancy) Vitamin B6 has been used since the 1940s to treat nausea during pregnancy. Vitamin B6 was included in the medication Bendectin, which was prescribed for the treatment of morning sickness and later withdrawn from the market due to unproven concerns that it increased the risk of birth defects. Vitamin B6 itself is considered safe during pregnancy and has been used in pregnant women without any evidence of fetal harm (29). The results of two double-blind, placebo-controlled trials that used 25 mg of pyridoxine every eight hours for three days (30) or 10 mg of pyridoxine every eight hours for five days (29) suggest that vitamin B6 may be beneficial in alleviating morning sickness. Each study found a slight but significant reduction in nausea or vomiting in pregnant women. A recent systematic review of placebo-controlled trials on nausea during early pregnancy found vitamin B6 to be somewhat effective (31). However, it should be noted that morning sickness also resolves without any treatment, making it difficult to perform well-controlled trials.

Carpal tunnel syndrome

Carpal tunnel syndrome causes numbness, pain, and weakness of the hand and fingers due to compression of the median nerve at the wrist. It may result from repetitive stress injury of the wrist or from soft tissue swelling, which sometimes occurs with pregnancy or hypothyroidism. Several early studies by the same investigator suggested that vitamin B6 status was low in individuals with carpal tunnel syndrome and that supplementation with 100–200 mg/day over several months was beneficial (32, 33). A recent study in men not taking vitamin supplements found that decreased blood levels of PLP were associated with increased pain, tingling, and nocturnal wakening, all symptoms of carpal tunnel syndrome (34). Studies using electrophysiological measurements of median nerve conduction have largely failed to find an association between vitamin B6 deficiency and carpal tunnel syndrome. While a few trials have noted some symptomatic relief with vitamin B6 supplementation, double-blind, placebo-controlled trials have not generally found vitamin B6 to be effective in treating carpal tunnel syndrome (24, 35).

Glucose metabolism:

PLP coenzymes assist the enzymatic cleavage of glycogen during glucose synthesis. PLP is also necessary for acid catalysis in glycogenesis (Ross et. al., 2014).

Lipid Metabolism:

PLP plays an important role in the biosynthetic pathway of carnitine. This process is important for transporting long chain fatty acids (Ross et. al., 2014). Also, it is important in protecting the cell from oxidative damage caused by lipid peroxidation. This could be beneficial by reducing levels of oxidative stress and preventing complications in patients with heart disease and diabetes (Jain et. al., 2002).

Amino Acid Metabolism:

Transamination reactions of amino acids leading to corresponding alpha-keto acids requires the presence of the coenzyme PLP to catalyze the required deamination and dehydration reactions in the presence of beta-hydroxyl or sulfhydryl groups (Meister, 1965). Since PLP has a major role in amino acid metabolism, studies suggest that vitamin B6 requirements are affected by protein consumption (Vit, 1998).

Cancer and Vitamin B6:

High intakes of vitamin B6 has been found to be significant at preventing cancer. Moreover, it has also been found that intakes of vitamin B6 in cancer patients could help them improve their immune system and prevent further progression to other stages (Vanderschuren et. al., 2013; Choi & Friso, 2012).

8.6.3 Requirements
Vitamin B6 requirements vary throughout the world and there are no exact amounts for these requirements. Typically, the recommended amount of pyridoxine needed by the body depends on age and also an individual’s protein intake. Requirements can be calculated using information about an individual’s age, along with using information about the protein intake. The current Recommended Daily Allowances for vitamin B6 is between 1.5 to 2.2 milligrams per day (NCBI, 1). The National Center for Biotechnology Information has discovered that to meet the minimum Recommended Daily Intake of vitamin B6, which is 1.5 milligrams per day, 11 milligrams for every one gram of protein is needed. Vitamin B6 requirements are related to protein intake because the vitamin is involved in many functions of proteins in the body, such as amino acid metabolism. It also is involved in the production of some hormones or neurotransmitters, which will incorporate protein function as well. Therefore, when calculating the required intake for vitamin B6, it is important to relate the required amount to protein intake for optimal body function. Based on an individual’s age, vitamin B6 intakes increase throughout life. The Recommended Dietary Allowance amounts of infants include: 0.1 milligrams for infants from birth to six months of age, 0.3 milligrams for infants seven to twelve months of age, 0.5 milligrams for one to three year olds, and 0.6 milligrams for children aged four to eight years of age (NIH). The Recommended Dietary Allowance amounts for children and teens include: 1.0 milligram for nine to thirteen year olds and 1.3 milligrams for males aged fourteen to eighteen and 1.2 milligrams for females aged fourteen to eighteen (NIH). The Recommended Dietary Allowance amount for adults aged nineteen to fifty is 1.3 milligrams (NIH). The requirements for vitamin B6 are higher in individuals who are pregnant, lactating, or over fifty-one years old. The Recommended Dietary Allowance amount for individuals over the age of fifty-one is 1.3 milligrams per day (NIH). For pregnant women, the Recommended Dietary Allowance amount is 1.9 milligrams, and for women who go through lactation the Recommended Dietary Allowance amount is 2.0 milligrams per day (NIH). These required amounts of vitamin B6 necessary for optimal body function can be obtained from the diet and from dietary supplements. Foods that can be incorporated into the diet to obtain vitamin B6 are chickpeas, liver, tuna, and salmon (NIH). Supplements with vitamin B6 in them can be taken orally by capsules or in a liquid form. The body absorbs supplemental vitamin B6 efficiently, however it can be quickly lost from the body through urine (NIH). Vitamin B6 should be obtained primarily through the diet and also through supplements for optimal absorption.

8.6.4 Deficiency
A deficiency in vitamin B6 is a rare occurrence. However, deficiencies do still appear in mild and high-risk forms. They can be seen in all age groups, mainly in children and the elderly. There are several symptoms associated with vitamin B6 deficiency:

•	Muscle weakness

•	Nerve damage

•	Difficulty contracting

•	Short-term memory loss

Vitamin B6 deficiency can be caused by a decrease in intake, alcohol consumption, or medications. Vitamin B6 is used in vitamin B12 absorption and the production of red blood cells as well as immune system cells (Ehlrich, 2015). Low levels of vitamin B6 can lead to death if your body is not able to produce the necessary cells to sustain life. It is very rare to see an individual with vitamin B6 deficiency caused by food consumption. The availability of abundant food sources makes it difficult for someone to consume insufficient amounts of vitamin B6. Consuming fresher and nutrient denser foods can ameliorate the situation. Alcohol consumption has a great effect on vitamin B6 levels in the body. Its main effect on vitamin B6 is the destruction or complete loss of the vitamin. Individuals with chronic alcohol abuse frequently exhibit lowered plasma levels of pyridoxal 5’-phosphate (PLP), the coenzyme form of vitamin B6 (Li, Lumeng, & Vech, 1975). Alcohol’s effect on the low level of PLP is due to the removal of PLP from its enzyme. As a result, PLP is dissolved and removed from the body. Decreased PLP concentration lowers the amount of vitamin B6 available resulting in a deficiency that can cause the several symptoms that were listed above. Certain medications can also lead to vitamin B6 deficiency. For instance, the drug isoniazid decreases levels of the vitamin dramatically. Vitamin B6 supplementation during isoniazid therapy is necessary to prevent the development of peripheral neuropathy (Snider, 1980). One who takes this medication can benefit from preventing the growth of tuberculosis bacterium. However, the same drug can interact and bind with vitamin B6 and cause inactivation. This inactivation results in an overall decrease of vitamin B6 and eventually lead to vitamin B6 deficiency symptoms such as nerve damage. One who must take this medication can simply increase their vitamin B6 level by taking supplements. It is extremely uncommon to find an individual in the United States with vitamin B6 deficiency because most Americans consume enough meals to nourish their bodies with adequate amounts of the vitamin. Most deficiency cases can be observed in developing countries. In certain parts of the world, particularly in Thailand, low intakes of vitamin B6 may be responsible for bladder stones (“Human nutrition,” n.d.). In developing nations, insufficient vitamin B6 intake is caused by the lack of nourishing foods that contain this vitamin.

8.6.5 Toxicity
Over time it has been concluded that vitamin B6 toxicity is not usually found when digested from food sources in the diet, the cases of toxicity most often stem from supplementing the vitamin B6. (LPI Outreach Education Fund, 2015) Being that vitamin B6 is a water-soluble vitamin it’s assumed that the vitamin would be excreted before having the opportunity to reach toxic levels in the body. However, through supplementation, you are able to take vitamin B6 at a frequency and quantity in dosage that does not allow your body to expel it quickly enough. Some of the symptoms that accompany vitamin B6 toxicity, include: depression, fatigue irritability, headaches, nerve damage, and skin lesions. (Whitney & Roles, 2013) Specifically, nerve damage may bring about issues such as: difficulty walking, numbness, progressive sensory ataxia, impairment of position and vibration senses, and deficiencies in the sense of touch; temperature; and pain. (Larry E. Johnson, 2015) The lowest dosage given to humans that caused damage was 10 mg per day. (Chaudary, Porter-Blake, & Holford, 2015) Also according to the Journal of Orthomolecular Medicine, sensory nerves will not be affected at a dosage of less than 200 mg per day. In ‘Understanding Nutrition,’ they state the earliest recorded case of vitamin B6 toxicity in the early 1980s. “This report described neurological damage in people who had been taking more than 2 grams of vitamin B6 daily for 2 months or longer.” (Whitney & Roles, 2013) The Food and Nutrition Board of the Institute of Medicine set the tolerable upper intake level for vitamin B6 at 100 mg/day for adults. There have been a variety of studies that show vitamin B6 being successful in treating ailments, including: morning sickness, PMS symptoms, Tardive dyskinesia, and more. (University of Maryland Medical Center, 2015) Nevertheless, according to the University of Maryland Medical Center more research is still necessary in almost each case, where some studies have shown no effect with the supplementation of B6. While supplementing vitamin B6 can be done safely, in the case of a deficiency, it is important to be sure that you are replenishing the right vitamin and talking with a physician before self-medicating.

Upper Intake Level (UL) for Vitamin B6 Age Group	UL (mg/day) 0–12 months (infants)	N/A 1–3 years (children)	30 4–8 years (children)	40 9–13 years (children)	60 14– 16 years (adolescents)	80 19+ (adults)	100

SOURCE: (Food and Nutrition Board, Institute of Medicine, National Academies, 2015)