Micronutrient Information Center

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The Linus Pauling Institute's Micronutrient Information Center is a source for scientifically accurate information regarding the roles of vitamins, minerals, phytochemicals (plant chemicals that may affect health), and other dietary factors, including some food and beverages, in preventing disease and promoting health. All of the nutrients and dietary factors included in the Micronutrient Information Center may be obtained from the diet, but many are also available as dietary supplements. 

 

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The Linus Pauling Institute's Micronutrient Information Center (MIC) is a source for scientifically accurate information on the functions and health effects of all micronutrients (vitamins and nutritionally essential minerals); other nutrients like choline and essential fatty acids; dietary factors, including many phytochemicals (non-nutritive plant chemicals that may affect health); and some food and beverages, including tea, coffee, and alcohol. All of the nutrients and dietary factors included in the MIC may be obtained from the diet, but many are also available as dietary supplements; dietary and supplemental sources are discussed in each article.

Human research is emphasized in the MIC, although cell culture or animal studies may be mentioned when human studies are lacking. Most MIC articles have summaries at the beginning and include the following subsections: Function or Biological Activities, Metabolism and Bioavailability, Deficiency, The RDA or AI (for males and females of various age groups), Disease Prevention, Disease Treatment, Sources (food and supplements), and Safety (toxicity and drug or nutrient interactions). For the micronutrients (vitamins and essential minerals), the Linus Pauling Institute provides a daily intake recommendation.

For each article, Ph.D. nutrition scientists critically review and synthesize basic, clinical, and epidemiological studies in the peer-reviewed literature and provide references throughout. Each article is then additionally reviewed by an expert in the field; the names of the authors and reviewers are listed at the bottom of each article. This multiple review process minimizes bias and presents objective information.

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Articles

Vitamins

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The term vitamin is derived from the words vital and amine, because vitamins are required for life and were originally thought to be amines. Although not all vitamins are amines, they are organic compounds required by humans in small amounts from the diet. An organic compound is considered a vitamin if a lack of that compound in the diet results in overt symptoms of deficiency.

The information from the Linus Pauling Institute's Micronutrient Information Center on vitamins and minerals is now available in a book titled, An Evidence-based Approach to Vitamins and Minerals: Health Benefits and Intake Recommendations. The book can be purchased from the Linus Pauling Institute or Thieme Medical Publishers.

Select a vitamin from the list for more information.

Biotin

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Summary

  • Water-soluble biotin is an essential cofactor to enzymes in intermediary metabolism and a key regulator of gene expression. (More information)
  • Both parenteral nutrition devoid of biotin and prolonged consumption of raw egg white have been associated with symptoms of frank biotin deficiency, including hair loss, dermatitis, and skin rash, ataxia, seizures, and other neurologic dysfunctions. (More information)
  • Biotinidase deficiency is a rare hereditary disorder that impairs biotin absorption and recycling, resulting in secondary biotin deficiency. (More information)
  • The recommended adequate intake (AI) of biotin is set at 30 micrograms (μg)/day in adults. Biotin requirements are likely increased during pregnancy and breast-feeding. (More information)
  • Animal studies have shown that biotin sufficiency is essential for normal fetal development. Whether marginal biotin deficiency during pregnancy increases the risk for congenital anomalies in humans is currently an area of concern and investigation. (More information)
  • Biotin is used in the treatment of an inherited disorder of thiamin transport, called biotin-responsive basal ganglia disease, and is currently being tested in trials to limit or reverse functional disabilities in individuals with multiple sclerosis. (More information)
  • Definitive evidence that establishes whether biotin supplementation improves glucose and lipid homeostasis in individuals with type 2 diabetes mellitus is currently lacking, but suggestive observations have been published. (More information)
  • Biotin cannot be synthesized by mammalian cells and must be obtained from exogenous sources. Biotin is widely found in food, and good dietary sources include egg yolk, liver, whole-grain cereal, and some vegetables. (More information)
  • Long-term anticonvulsant (anti-seizure) therapy may increase the dietary requirement for biotin because anticonvulsants can interfere with the intestinal absorption and renal re-absorption of biotin and likely also increase degradation of biotin to inactive metabolites. (More information)


Biotin is a water-soluble vitamin that is generally classified as a B-complex vitamin. After its initial discovery in 1927, 40 years of additional research was required to unequivocally establish biotin as a vitamin (1). Biotin is required by all organisms but can be synthesized by some strains of bacteria, yeast, mold, algae, and some plant species (2).

Function

Biotinylation

Biotin functions as a covalently bound cofactor required for the biological activity of the five known mammalian biotin-dependent carboxylases (see below). Such a non-protein cofactor is known as a "prosthetic group." The covalent attachment of biotin to the apocarboxylase (i.e., catalytically inactive carboxylase) is catalyzed by the enzyme, holocarboxylase synthetase (HCS). The term "biotinylation" refers to the covalent addition of biotin to any molecules, including apocarboxylases and histones. HCS catalyzes the post-translational biotinylation of the epsilon amino group of a lysine residue at the active site of each apocarboxylase, converting the inactive apocarboxylase into a fully active holocarboxylase (Figure 1a). Particular lysine residues within the N-terminal tail of specific histones, which help package DNA in eukaryotic nuclei, can also be biotinylated (3). Biotinidase is the enzyme that catalyzes the release of biotin from biotinylated histones and from the peptide products of holocarboxylase breakdown (Figure 1b).

Biotin Figure 1a. Biotinylation of Carboxylases. Holocarboxylase synthetase catalyzes the transfer of biotin to a specific lysine residue at the active site of apocarboxylase, converting the enzyme to a fully active holocarboxylase. Five mammalian carboxylases are known to require biotin for their biological activity: acetyl-CoA carboxylases 1 and 2, pyruvate-CoA carboxylase, propionyl-CoA carboxylase, and methylcrotonyl-CoA carboxylase. ATP, adenosine triphosphate; CoA, coenzyme A; PPi, pyrophosphate.

Biotin Figure 1b. Biotin Recycling. The biotinylation of apocarboxylase is catalyzed by holocarboxylase synthetase, while the enzyme biotinidase catalyzes the removal of biotin from the peptide products of carboxylase breakdown.

Enzyme cofactor

Five mammalian carboxylases that catalyze essential metabolic reactions:

• Both acetyl-Coenzyme A (CoA) carboxylase 1 (ACC1) and acetyl-CoA carboxylase 2 (ACC2) catalyze the conversion of acetyl-CoA to malonyl-CoA using bicarbonate and ATP; malonyl CoA generated via ACC1 is a rate-limiting substrate for the synthesis of fatty acids in the cytosol, and malonyl CoA generated via ACC2 inhibits CPT1, an outer mitochondrial membrane enzyme important in fatty acid oxidation (Figure 2). ACC1 is found in all tissues and is particularly active in lipogenic tissues (i.e., liver, white adipose tissue, and mammary gland), heart, and pancreatic islets. ACC2 is especially abundant in skeletal muscle and heart (4).

Biotin Figure 2. Acetyl-CoA Carboxylase 1 and Acetyl-CoA Carboxylase 2. In the cytosol of liver cells, fatty acids are converted to acyl-CoA, and glucose undergoes glycolysis that produces pyruvate. Acyl-CoA is shuttled into the mitochondria via CPT1-mediated transport and undergoes β-oxidation that generates acetyl-CoA. In addition, pyruvate is converted to acetyl-CoA in the mitochondria, and acetyl-CoA is condensed with oxaloacetate to form citrate. The latter can be exported to the cytosol and cleaved to oxaloacetate and acetyl-CoA. Acetyl-CoA is used to generate malonyl-CoA in a reaction catalyzed by biotin-containing acetyl-CoA carboxylase 1 (ACC1) in the presence of ATP and bicarbonate. Malonyl-CoA is an essential substrate for the biosynthesis of fatty acids and subsequent triglycerides, phospholipids, and lipoproteins. Malonyl-CoA is also a regulator of fatty acid β-oxidation. Indeed, malonyl-CoA generated from acetyl-CoA by another biotin-containing enzyme, acetyl-CoA carboxylase 2 (ACC2), localized at the outer mitochondrial membrane, has been shown to downregulate fatty acid β-oxidation in the mitochondria by inhibiting CPT1. ACC1, acetyl-coenzyme A carboxylase 1; ACC2, acetyl-coenzyme A carboxylase 2; CoA, coenzyme A; CPT1, carnitine/palmitoyl-transferase 1.

Pyruvate carboxylase is a critical enzyme in gluconeogenesis — the formation of glucose from sources other than carbohydrates, such as pyruvate, lactate, glycerol, and the glucogenic amino acids. Pyruvate carboxylase catalyzes the ATP-dependent incorporation of bicarbonate into pyruvate, producing oxaloacetate; hence, pyruvate carboxylase is anaplerotic for the citric acid cycle (Figure 3). Oxaloacetate can then be converted to phosphoenolpyruvate and eventually to glucose.

Biotin Figure 3. Pyruvate Carboxylase and Acetyl-CoA Carboxylase 1. Biotin-containing pyruvate carboxylase supplies the citric acid cycle with oxaloacetate by catalyzing the conversion of pyruvate to oxaloacetate using bicarbonate and ATP. In the liver, oxaloacetate can be used as a precursor for gluconeogenesis. It is first converted to phosphoenolpyruvate (PEP) by PEP carboxykinase and then to glucose via the reverse pathway of glycolysis. In the citric acid cycle, oxaloacetate can also be condensed with acetyl-CoA to produce citrate, which can be exported from the mitochondria. In the liver, adipose tissue, and skeletal muscle, citrate is cleaved to oxaloacetate and acetyl-CoA in the cytosol. Acetyl-CoA is converted to malonyl-CoA by another biotin-containing enzyme, acetyl-CoA carboxylase 1. Malonyl-CoA is then used by fatty acid synthase 1 to generate long-chain fatty acids. CoA, coenzyme A.

Methylcrotonyl-CoA carboxylase catalyzes an essential step in the catabolism of leucine, an essential branched-chain amino acid. This biotin-containing enzyme catalyzes the production of 3-methylglutaconyl-CoA from methylcrotonyl-CoA (Figure 4a).

Propionyl-CoA carboxylase produces D-malonylmalonyl-CoA from propionyl-CoA, a by-product in the β-oxidation of fatty acids with an odd number of carbon atoms (Figure 4a). The conversion of propionyl-CoA to D-malonylmalonyl-CoA is also required in the catabolic pathways of two branched-chain amino acids (isoleucine and valine), methionine, threonine, and the side chain of cholesterol (Figure 4a and 4b).

Biotin Figure 4a. Biotin-containing Carboxylases in the Metabolism of BCAAs, Odd Chain Fatty Acids, and Cholesterol. Two biotin-containing enzymes, namely propionyl-CoA carboxylase and methylcrotonyl-CoA carboxylase, are required in the metabolism of branched chain amino acids (leucine, valine, and isoleucine), the oxidation of odd chain fatty acids, and the degradation of cholesterol side chain. The metabolic pathways generate acetyl-CoA and succinyl-CoA, which then enter the citric acid cycle. BCAAs, branched chain amino acids; CoA, coenzyme A.

Biotin Figure 4b. Biotin-containing Propionyl-CoA Carboxylase in the Metabolism of Methionine and Threonine. Propionyl-CoA carboxylase converts propionyl-CoA to D-malonylmalonyl-CoA in the metabolism of methionine and threonine. CoA, coenzyme A; SAH, S-adenosylhomocysteine; SAM, S-adenosylmethionine.

Regulation of chromatin structure and gene expression

In eukaryotic nuclei, DNA is packaged into compact structures to form nucleosomes — fundamental units of chromatin. Each nucleosome is composed of 147 base pairs of DNA wrapped around eight histones (paired histones: H2A, H2B, H3, and H4). Another histone, called H1 linker, is located at the outer surface of each nucleosome and serves as an anchor to fix the DNA around the histone core. The compact packaging of chromatin must be relaxed from time to time to allow biological processes, such as DNA replication and transcription to occur. Chemical modifications of DNA and histones affect the folding of chromatin, increasing or reducing DNA accessibility to factors involved in the above-mentioned processes. Together with DNA methylation, a number of chemical modifications within the N-terminal tail of core histones modify their electric charge and structure, thereby changing chromatin conformation and transcriptional activity of genes.

The various modifications of histone tails, including acetylation, methylation, phosphorylation, ubiquitination, SUMOylation, ADP-ribosylation, carbonylation, deimination, hydroxylation, and biotinylation, have different regulatory functions. Several sites of biotinylation have been identified in histones H2A, H3, and H4 (5). Amongst them, histone H4 biotinylation at lysine (K) 12 (noted H4K12bio) appears to be enriched in heterochromatin, a tightly condensed chromatin associated with repeat regions in (peri)centromeres and telomeres, and with transposable elements known as long terminal repeats (3). In addition, biotinylation marks co-localize with well-known gene repression marks like methylated lysine 9 in histone H3 (H3K9me) in transcriptionally competent chromatin (6). For example, H4K12bio can be found at the promoter of the gene SLC5A6 that codes for the transporter mediating biotin uptake into cells, the human sodium-dependent multivitamin transporter (hSMVT). When biotin is abundant, HCS can biotinylate histones H4 in the SLC5A6 promoter, which halts hSMVT synthesis and reduces biotin uptake. Conversely, in biotin-deficient cells, biotinylation marks in the SLC5A6 promoter are removed such that gene expression can occur, enabling the synthesis of hSMVT and subsequently increasing the uptake of biotin (7).

Deficiency

Although overt biotin deficiency is very rare, the human requirement for dietary biotin has been demonstrated in three different situations: prolonged intravenous feeding (parenteral) without biotin supplementation, infants fed an elemental formula devoid of biotin, and consumption of raw egg white for a prolonged period (many weeks to years) (8). Raw egg white contains an antimicrobial protein known as avidin that can bind biotin and prevent its absorption. Cooking egg white denatures avidin, rendering it susceptible to digestion and therefore unable to prevent the absorption of dietary biotin (5).

Signs and symptoms of biotin deficiency

Signs of overt biotin deficiency include hair loss (alopecia) and a scaly red rash around the eyes, nose, mouth, and genital area. Neurologic symptoms in adults have included depression, lethargy, hallucinations, numbness and tingling of the extremities, ataxia, and seizures. The characteristic facial rash, together with unusual facial fat distribution, has been termed the "biotin deficient facies" by some investigators (1). Individuals with hereditary disorders of biotin metabolism (see Inborn metabolic disorders) resulting in functional biotin deficiency often have similar physical findings, as well as seizures and evidence of impaired immune system function and increased susceptibility to bacterial and fungal infections (9, 10).

Risk factors for biotin deficiency

Aside from prolonged consumption of raw egg white or total intravenous nutritional support lacking biotin, other conditions may increase the risk of biotin depletion. Smoking has been associated with increased biotin catabolism (11). The rapidly dividing cells of the developing fetus require biotin for synthesis of essential carboxylases and histone biotinylation; hence, the biotin requirement is likely increased during pregnancy. Research suggests that a substantial number of women develop marginal or subclinical biotin deficiency during normal pregnancy (see also Disease Prevention) (8, 12, 13). Additionally, certain types of liver disease may decrease biotinidase activity and theoretically increase the requirement for biotin. A study of 62 children with chronic liver disease and 27 healthy controls found serum biotinidase activity to be abnormally low in those with severely impaired liver function due to cirrhosis (14). However, this study did not provide evidence of biotin deficiency. Further, anticonvulsant medications, used to prevent seizures in individuals with epilepsy, increase the risk of biotin depletion (for more information on biotin and anticonvulsants, see Drug interactions).

Inborn metabolic disorders

Biotinidase deficiency

There are several ways in which the hereditary disorder, biotinidase deficiency, leads to secondary biotin deficiency. Intestinal absorption is decreased because a lack of biotinidase prevents the release of biotin from dietary protein (15). Recycling of one's own biotin bound to carboxylases and histones is also impaired, and urinary loss of biocytin (N-biotinyl-lysine) and biotin is increased (see Figure 1 above) (5). Biotinidase deficiency uniformly responds to supplemental biotin. Oral supplementation with as much as 5 to 10 milligrams (mg) of biotin daily is sometimes required, although smaller doses are often sufficient (reviewed in 16).

Holocarboxylase synthetase (HCS) deficiency

Some forms of HCS deficiency respond to supplementation with pharmacologic doses of biotin. HCS deficiency results in decreased formation of all holocarboxylases at physiological blood biotin concentrations; thus, high-dose biotin supplementation (10-80 mg of biotin daily) is required (10).

The prognosis of these two disorders is usually good if biotin therapy is introduced early (infancy or childhood) and continued for life (10).

Biotin transport deficiency

There has been one case report of a child with biotin transport deficiency who responded to high-dose biotin supplementation (17). Of note, the presence of a defective human sodium-dependent multivitamin transporter (hSMVT) was ruled out as a cause of biotin transport deficiency.

Phenylketonuria (PKU)

Abnormally elevated concentrations of the amino acid, phenylalanine, in the blood of PKU-affected individuals may inhibit the activity of biotinidase. Schulpis et al. speculated that the seborrheic dermatitis associated with low biotinidase activity in these patients would resolve upon compliance with a special low-protein diet but not with biotin supplementation (18).

Markers of biotin status

Four measures of marginal biotin deficiency have been validated as indicators of biotin status: (1) reduced urinary excretion of biotin and some of its catabolites; (2) high urinary excretion of an organic acid, 3-hydroxyisovaleric acid, and its derivative, carnityl-3-hydroxyisovaleric acid, both of which reflect decreased activity of biotin-dependent methylcrotonyl-CoA carboxylase; (3) reduced propionyl-CoA carboxylase activity in peripheral blood lymphocytes (5); and (4) reduced levels of holo-methylcrotonyl-CoA carboxylase and holo-propionyl-CoA carboxylase in lymphocytes — the most reliable indicators of biotin status (19). These markers have been only validated in men and nonpregnant women, and they may not accurately reflect biotin status in pregnant and breast-feeding women (12).

The Adequate Intake (AI)

Sufficient scientific evidence is lacking to estimate the dietary requirement for biotin; thus, no Recommended Dietary Allowance (RDA) for biotin has been established. Instead, the Food and Nutrition Board (FNB) of the Institute of Medicine (IOM) set recommendations for an Adequate Intake (AI; Table 1). The AI for adults (30 micrograms [μg]/day) was extrapolated from the AI for infants exclusively fed human milk and is expected to overestimate the dietary requirement for biotin in adults. Dietary intakes of generally healthy adults have been estimated to be 40-60 μg/day of biotin (1). The requirement for biotin in pregnancy may be increased (20).

Table 1. Adequate Intake (AI) for Biotin
Life Stage Age Males (μg/day) Females (μg/day)
Infants 0-6 months 5 5
Infants 7-12 months 6 6
Children 1-3 years 8 8
Children 4-8 years 12 12
Children 9-13 years 20 20
Adolescents 14-18 years 25 25
Adults 19 years and older 30 30
Pregnancy all ages - 30
Breast-feeding all ages - 35

Disease Prevention

Congenital anomalies

Current research indicates that at least one-third of women develop marginal biotin deficiency during pregnancy (8), but it is not known whether this might increase the risk of congenital anomalies. Small observational studies in pregnant women have reported an abnormally high urinary excretion of 3-hydroxyisovaleric acid in both early and late pregnancy, suggesting decreased activity of biotin-dependent methylcrotonyl-CoA carboxylase (21, 22). In a randomized, single-blinded intervention study in 26 pregnant women, supplementation with 300 μg/day of biotin for two weeks limited the excretion of 3-hydroxyisovaleric acid compared to placebo, confirming that increased 3-hydroxyisovaleric acid excretion indeed reflected marginal biotin deficiency in pregnancy (23). A small cross-sectional study in 22 pregnant women reported an incidence of low lymphocyte propionyl-CoA carboxylase activity (another marker of biotin deficiency) greater than 80% (13). Although the level of biotin deficiency is not associated with overt signs of deficiency in pregnant women, such observations are sources of concern because subclinical biotin deficiency has been shown to cause cleft palate and limb hypoplasia in several animal species (reviewed in 13). In addition, biotin depletion has been found to suppress the expression of biotin-dependent carboxylases, remove biotin marks from histones, and decrease the proliferation in human embryonic palatal mesenchymal cells in culture (24). Impaired carboxylase activity may result in alterations in lipid metabolism, which have been linked to cleft palate and skeletal abnormalities in animals. Further, biotin deficiency leading to reduced histone biotinylation at specific genomic loci could possibly increase genomic instability and result in chromosome anomalies and fetal malformations (13).

While pregnant women are advised to consume supplemental folic acid prior to and during pregnancy to prevent neural tube defects (see Folate), it would also be prudent to ensure adequate biotin intake throughout pregnancy. The current AI for pregnant women is 30 μg/day of biotin, and no toxicity has ever been reported at this level of intake (see Safety).

Disease Treatment

Biotin-responsive basal ganglia disease

Biotin-responsive basal ganglia disease, also called thiamin metabolism dysfunction syndrome-2, is caused by mutations in the gene coding for thiamin transporter-2 (THTR-2). The clinical features appear around three to four years of age and include sub-acute encephalopathy (confusion, drowsiness, and altered level of consciousness), ataxia, and seizures. A retrospective study of 18 affected individuals from the same family or the same tribe in Saudi Arabia was recently conducted. The data showed that biotin monotherapy (5-10 mg/kg/day) efficiently abolished the clinical manifestations of the disease, although one-third of the patients suffered from recurrent acute crises. Often associated with poor outcomes, acute crises were not observed after thiamin supplementation started (300-400 mg/day) and during a five-year follow-up period. Early diagnostic and immediate treatment with biotin and thiamin led to positive outcomes (25). The mechanism for the beneficial effect of biotin supplementation has yet to be elucidated.

Multiple sclerosis

Multiple sclerosis (MS) is an autoimmune disease characterized by progressive damages to the myelin sheath surrounding nerve fibers (axons) and neuronal loss in the brain and spinal cord of affected individuals. The progression of neurologic disabilities in MS patients is often assessed by the Expanded Disability Status Scale (EDSS) with scores from 1 to 10, from minimal signs of motor dysfunction (score of 1) to death by MS (score of 10). ATP deficiency due to mitochondrial dysfunction and increased oxidative stress may be partly responsible for the progressive degeneration of neurons in MS (26). Given its role in intermediary metabolism and fatty acid synthesis (required for myelin formation) (see Function), it has been hypothesized that biotin might exert beneficial effects that would limit or reverse MS-associated functional impairments (26).

A nonrandomized, uncontrolled pilot study in 23 patients with progressive MS found high doses of biotin (100-600 mg/day) to be associated with sustained clinical improvements in 5 (out of 5) patients with progressive visual loss and 16 (out of 18) patients with partial paralysis of the limbs after a mean three months following treatment onset (27). In addition, the preliminary results from a multicenter, randomized, placebo-controlled trial in 154 subjects with progressive MS indicated that 13 out of 103 patients randomized to receive daily oral biotin (300 mg) for 48 weeks achieved a composite functional endpoint that included a decrease in EDSS scores. In comparison, none of the 51 patients randomized to the placebo group showed significant clinical improvements (28). Two ongoing trials are evaluating the effect of high-dose biotin supplementation in the treatment of MS (see trials NCT02220933 and NCT02220244 at www.clinicaltrials.gov).

Diabetes mellitus

Overt biotin deficiency has been shown to impair glucose utilization in mice (29) and cause fatal hypoglycemia in chickens. Overt biotin deficiency likely also causes abnormalities in glucose regulation in humans (see Function). One early human study reported lower serum biotin concentrations in 43 patients with type 2 diabetes mellitus compared to 64 non-diabetic control subjects, as well as an inverse relationship between fasting blood glucose and biotin concentrations (30). In a small, randomized, placebo-controlled intervention study in 28 patients with type 2 diabetes, daily supplementation with 9 milligrams (mg) of biotin for one month resulted in a mean 45% decrease in fasting blood glucose concentrations (30). Yet, another small study in 10 patients with type 2 diabetes and 7 nondiabetic controls found no effect of biotin supplementation (15 mg/day) for 28 days on fasting blood glucose concentrations in either group (31). A more recent double-blind, placebo-controlled study by the same research group showed that the same biotin regimen lowered plasma triglyceride concentrations in both diabetic and nondiabetic patients with hypertriglyceridemia (32). In this study, biotin administration did not affect blood glucose concentrations in either patient group. Additionally, a few studies have shown that co-supplementation with biotin and chromium picolinate may be a beneficial adjunct therapy in patients with type 2 diabetes (33-36). However, administration of chromium picolinate alone has been shown to improve glycemic control in diabetic subjects (see the article on Chromium) (37).

As a cofactor of carboxylases required for fatty acid synthesis, biotin may increase the utilization of glucose for fat synthesis. Biotin has been found to stimulate glucokinase, a liver enzyme that increases synthesis of glycogen, the storage form of glucose. Biotin also appeared to trigger the secretion of insulin in the pancreas of rats and improve glucose homeostasis (38). Yet, reduced activity of ACC1 and ACC2 would be expected to reduce fatty acid synthesis and increase fatty acid oxidation, respectively. Not surprisingly, it is currently unclear whether pharmacologic doses of biotin could benefit the management of hyperglycemia in patients with impaired glucose tolerance. Moreover, whether supplemental biotin lowers the risk of cardiovascular complications in diabetic patients by reducing serum triglycerides and LDL-cholesterol remains to be proven (32-34).

Brittle fingernails (onychorrhexis)

The finding that biotin supplements were effective in treating hoof abnormalities in hoofed animals suggested that biotin might also be helpful in strengthening brittle fingernails in humans (39-41). Three uncontrolled trials examining the effects of biotin supplementation (2.5 mg/day for several months) in women with brittle fingernails have been published (42-44). In two of the trials, subjective evidence of clinical improvement was reported in 67%-91% of the participants available for follow-up at the end of the treatment period (42, 43). One trial that used scanning electron microscopy to assess fingernail brittleness reported less fingernail splitting and a 25% increase in the thickness of the nail plate in patients supplemented with biotin for 6 to 15 months (44). Biotin supplementation (5 mg/day) was also found to be effective in controlling unruly hair and splitting nails in two toddlers with inherited uncombable hair syndrome (45). Although preliminary evidence suggests that supplemental biotin may help strengthen fragile nails, larger placebo-controlled trials are needed to assess the efficacy of high-dose biotin supplementation for the treatment of brittle fingernails.

Hair loss (alopecia)

Biotin administration was found to reverse alopecia in children treated with the anticonvulsant, valproic acid (see Drug interactions). Yet, although hair loss is a symptom of severe biotin deficiency (see Deficiency), there are no published scientific studies that support the claim that high-dose biotin supplements are effective in preventing or treating hair loss in men or women (46).

Sources

Food sources

Biotin is found in many foods, either as the free form that is directly taken up by enterocytes or as biotin bound to dietary proteins. Egg yolk, liver, and yeast are rich sources of biotin. Estimates of average daily intakes of biotin from small studies ranged between 40 and 60 micrograms (μg) per day in adults (1). However, US national nutritional surveys have not yet been able to estimate biotin intake due to the scarcity and unreliability of data regarding biotin content of food. Food composition tables for biotin are incomplete such that dietary intakes cannot be reliably estimated in humans. A study by Staggs et al. (47) employed a high-performance liquid chromatography method rather than bioassays (48) and reported relatively different biotin content for some selected foods. Table 2 lists some food sources of biotin, along with their content in μg.

Table 2. Some Food Sources of Biotin (47, 48)
Food Serving Biotin (μg)
Yeast 1 packet (7 grams) 1.4-14
Bread, whole-wheat 1 slice 0.02-6
Egg, cooked 1 large 13-25
Cheese, cheddar 1 ounce 0.4-2
Liver, cooked 3 ounces* 27-35
Pork, cooked 3 ounces* 2-4
Salmon, cooked 3 ounces* 4-5
Avocado 1 whole 2-6
Raspberries 1 cup 0.2-2
Cauliflower, raw 1 cup 0.2-4
*A three-ounce serving of meat is about the size of a deck of cards.

Bacterial synthesis

A majority of bacteria that normally colonize the small and large intestine (colon) synthesize biotin (49). Whether the biotin is released and absorbed by humans in meaningful amounts remains unknown. The uptake of free biotin into intestinal cells via the human sodium-dependent multivitamin transporter (hSMVT) has been identified in cultured cells derived from the lining of the small intestine and colon (50), suggesting that humans may be able to absorb biotin produced by enteric bacteria — a phenomenon documented in swine.

Supplements

Biotin is available as a single-nutrient supplement in various doses and is often included in B-complex and multivitamin-mineral (MVM) supplements. Many MVM supplements contain 30 μg of biotin (51).

Safety

Toxicity

Biotin is not known to be toxic. In people without disorders of biotin metabolism, doses of up to 5 mg/day for two years were not associated with adverse effects (52). Oral biotin supplementation has been well tolerated in doses up to 200 mg/day (nearly 7,000 times the AI) in people with hereditary disorders of biotin metabolism (1). Daily supplementation with a highly concentrated formulation of biotin (100-600 mg) for several months was also found to be well tolerated in individuals with progressive multiple sclerosis (27, 28). However, there is one case report of life-threatening eosinophilic pleuropericardial effusion in an elderly woman who took a combination of 10 mg/day of biotin and 300 mg/day of pantothenic acid (vitamin B5) for two months (53). Because reports of adverse events were lacking when the Dietary Reference Intakes (DRI) for biotin were established in 1998, the Institute of Medicine did not establish a tolerable upper intake level (UL) for biotin (1).

Nutrient interactions

Large doses of pantothenic acid (vitamin B5) have the potential to compete with biotin for intestinal and cellular uptake by the human sodium-dependent multivitamin transporter (hSMVT) (54, 55). Biotin also shares the hSMVT with α-lipoic acid (56). Pharmacologic (very high) doses of α-lipoic acid have been found to decrease the activity of biotin-dependent carboxylases in rats, but such an effect has not been demonstrated in humans (57).

Drug interactions

Individuals on long-term anticonvulsant (anti-seizure) therapy reportedly have reduced blood biotin concentrations, as well as an increased urinary excretion of organic acids (e.g., 3-hydroxyisovaleric acid) that indicate decreased carboxylase activity (see Markers of biotin status) (5). Potential mechanisms of biotin depletion by the anticonvulsants, primidone (Mysoline), phenytoin (Dilantin), and carbamazepine (Carbatrol, Tegretol), include inhibition of biotin intestinal absorption and renal reabsorption, as well as increased biotin catabolism (51). Use of the anticonvulsant valproic acid in children has resulted in hair loss reversed by biotin supplementation (58-61). Long-term treatment with antibacterial sulfonamide (sulfa) drugs or other antibiotics may decrease bacterial synthesis of biotin. Yet, given that the extent to which bacterial synthesis contributes to biotin intake in humans is not known, effects of antimicrobial drugs on biotin nutritional status remain uncertain (51).

Linus Pauling Institute Recommendation

Little is known regarding the amount of dietary biotin required to promote optimal health or prevent chronic disease. The Linus Pauling Institute supports the recommendation made by the Institute of Medicine, which is 30 micrograms (μg) of biotin per day for adults. A varied diet should provide enough biotin for most people. However, following the Linus Pauling Institute recommendation to take a daily multivitamin-mineral supplement will generally provide an intake of at least 30 μg/day of biotin.

Older adults (>50 years)

Presently, there is no indication that older adults have an increased requirement for biotin. If dietary biotin intake is not sufficient, a daily multivitamin-mineral supplement will generally provide an intake of at least 30 μg of biotin per day.


Authors and Reviewers

Originally written in 2000 by: 
Jane Higdon, Ph.D. 
Linus Pauling Institute 
Oregon State University

Updated in June 2004 by: 
Jane Higdon, Ph.D. 
Linus Pauling Institute 
Oregon State University

Updated in August 2008 by: 
Victoria J. Drake, Ph.D. 
Linus Pauling Institute 
Oregon State University

Updated in July 2015 by:
Barbara Delage, Ph.D.
Linus Pauling Institute
Oregon State University

Reviewed in September 2015 by: 
Donald Mock, M.D., Ph.D. 
Professor 
Departments of Biochemistry and Molecular Biology and Pediatrics 
University of Arkansas for Medical Sciences

Last updated 10/21/15  Copyright 2000-2017  Linus Pauling Institute


References

1.  Food and Nutrition Board, Institute of Medicine. Biotin. Dietary Reference Intakes: Thiamin, Riboflavin, Niacin, Vitamin B6, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, D.C.: National Academy Press; 1998:374-389.  (National Academy Press)

2.  Mock DM. Biotin. Handbook of vitamins. 4th ed. Boca Raton, FL: CRC Press; 2007:361-383.

3.  Zempleni J, Teixeira DC, Kuroishi T, Cordonier EL, Baier S. Biotin requirements for DNA damage prevention. Mutat Res. 2012;733(1-2):58-60.  (PubMed)

4.  Saggerson D. Malonyl-CoA, a key signaling molecule in mammalian cells. Annu Rev Nutr. 2008;28:253-272.  (PubMed)

5.  Zempleni J, Wijeratne SSK, Kuroishi T. Biotin. In: Erdman JWJ, Macdonald IA, Zeisel SH, eds. Present Knowledge in Nutrition. 10th ed.: John Wiley & Sons, Inc.; 2012:359-374.

6.  Zempleni J, Li Y, Xue J, Cordonier EL. The role of holocarboxylase synthetase in genome stability is mediated partly by epigenomic synergies between methylation and biotinylation events. Epigenetics. 2011;6(7):892-894.  (PubMed)

7.  Zempleni J, Gralla M, Camporeale G, Hassan YI. Sodium-dependent multivitamin transporter gene is regulated at the chromatin level by histone biotinylation in human Jurkat lymphoblastoma cells. J Nutr. 2009;139(1):163-166.  (PubMed)

8.  Mock DM. Biotin. In: Ross AC, Caballero B, Cousins RJ, Tucker KL, Ziegler TR, eds. Modern Nutrition in Health and Disease. 11th ed.: Lippincott Williams & Wilkins; 2014:390-398.

9.  Baumgartner ER, Suormala T. Inherited defects of biotin metabolism. Biofactors. 1999;10(2-3):287-290.  (PubMed)

10.  Elrefai S, Wolf B. Disorders of biotin metabolism. In: Rosenberg RN, Pascual JM, eds. Rosenberg's Molecular and Genetic basis of Neurological and Psychiatric Disease. 5th ed. United States of America: Elsevier; 2015:531-539.

11.  Sealey WM, Teague AM, Stratton SL, Mock DM. Smoking accelerates biotin catabolism in women. Am J Clin Nutr. 2004;80(4):932-935.  (PubMed)

12.  Perry CA, West AA, Gayle A, et al. Pregnancy and lactation alter biomarkers of biotin metabolism in women consuming a controlled diet. J Nutr. 2014;144(12):1977-1984.  (PubMed)

13.  Mock DM. Marginal biotin deficiency is common in normal human pregnancy and is highly teratogenic in mice. J Nutr. 2009;139(1):154-157.  (PubMed)

14.  Pabuccuoglu A, Aydogdu S, Bas M. Serum biotinidase activity in children with chronic liver disease and its clinical significance. J Pediatr Gastroenterol Nutr. 2002;34(1):59-62.  (PubMed)

15.  Zempleni J, Hassan YI, Wijeratne SS. Biotin and biotinidase deficiency. Expert Rev Endocrinol Metab. 2008;3(6):715-724.  (PubMed)

16.  Wolf B. Biotinidase deficiency: "if you have to have an inherited metabolic disease, this is the one to have." Genet Med. 2012;14(6):565-575.  (PubMed)

17.  Mardach R, Zempleni J, Wolf B, et al. Biotin dependency due to a defect in biotin transport. J Clin Invest. 2002;109(12):1617-1623.  (PubMed)

18.  Schulpis KH, Nyalala JO, Papakonstantinou ED, et al. Biotin recycling impairment in phenylketonuric children with seborrheic dermatitis. Int J Dermatol. 1998;37(12):918-921.  (PubMed)

19.  Eng WK, Giraud D, Schlegel VL, Wang D, Lee BH, Zempleni J. Identification and assessment of markers of biotin status in healthy adults. Br J Nutr. 2013;110(2):321-329.  (PubMed)

20.  Mock DM. Adequate intake of biotin in pregnancy: why bother? J Nutr. 2014;144(12):1885-1886.  (PubMed)

21.  Mock DM, Stadler DD. Conflicting indicators of biotin status from a cross-sectional study of normal pregnancy. J Am Coll Nutr. 1997;16(3):252-257.  (PubMed)

22.  Mock DM, Stadler DD, Stratton SL, Mock NI. Biotin status assessed longitudinally in pregnant women. J Nutr. 1997;127(5):710-716.  (PubMed)

23.  Mock DM, Quirk JG, Mock NI. Marginal biotin deficiency during normal pregnancy. Am J Clin Nutr. 2002;75(2):295-299.  (PubMed)

24.  Takechi R, Taniguchi A, Ebara S, Fukui T, Watanabe T. Biotin deficiency affects the proliferation of human embryonic palatal mesenchymal cells in culture. J Nutr. 2008;138(4):680-684.  (PubMed)

25.  Alfadhel M, Almuntashri M, Jadah RH, et al. Biotin-responsive basal ganglia disease should be renamed biotin-thiamine-responsive basal ganglia disease: a retrospective review of the clinical, radiological and molecular findings of 18 new cases. Orphanet J Rare Dis. 2013;8:83.  (PubMed)

26.  Sedel F, Bernard D, Mock DM, Tourbah A. Targeting demyelination and virtual hypoxia with high-dose biotin as a treatment for progressive multiple sclerosis. Neuropharmacology. 2015.  (PubMed)

27.  Sedel F, Papeix C, Bellanger A, et al. High doses of biotin in chronic progressive multiple sclerosis: a pilot study. Mult Scler Relat Disord. 2015;4(2):159-169.  (PubMed)

28.  Tourbah A LFC, Edan G, Clanet M, Papeix C, Vukusic S, et al. Effect of MD1003 (high doses of biotin) in progressive multiple sclerosis: results of a pivotal phase III randomized double blind placebo controlled study. Paper presented at: American Association of Neurological Surgeons (AANS) Annual Scientific Meeting 2015; Washington, D.C. Available at: http://www.neurology.org/content/84/14_Supplement/PL2.002. Accessed 9/17/15.

29.  Larrieta E, Vega-Monroy ML, Vital P, et al. Effects of biotin deficiency on pancreatic islet morphology, insulin sensitivity and glucose homeostasis. J Nutr Biochem. 2012;23(4):392-399.  (PubMed)

30.  Maebashi M, Makino Y, Furukawa Y, Ohinata K, Kimura S, Sato T. Therapeutic evaluation of the effect of biotin on hyperglycemia in pateints with non-insulin dependent diabetes mellitus. J Clin Biochem Nutr. 1993;14:211-218.

31.  Baez-Saldana A, Zendejas-Ruiz I, Revilla-Monsalve C, et al. Effects of biotin on pyruvate carboxylase, acetyl-CoA carboxylase, propionyl-CoA carboxylase, and markers for glucose and lipid homeostasis in type 2 diabetic patients and nondiabetic subjects. Am J Clin Nutr. 2004;79(2):238-243.  (PubMed)

32.  Revilla-Monsalve C, Zendejas-Ruiz I, Islas-Andrade S, et al. Biotin supplementation reduces plasma triacylglycerol and VLDL in type 2 diabetic patients and in nondiabetic subjects with hypertriglyceridemia. Biomed Pharmacother. 2006;60(4):182-185.  (PubMed)

33.  Geohas J, Daly A, Juturu V, Finch M, Komorowski JR. Chromium picolinate and biotin combination reduces atherogenic index of plasma in patients with type 2 diabetes mellitus: a placebo-controlled, double-blinded, randomized clinical trial. Am J Med Sci. 2007;333(3):145-153.  (PubMed)

34.  Albarracin C, Fuqua B, Geohas J, Juturu V, Finch MR, Komorowski JR. Combination of chromium and biotin improves coronary risk factors in hypercholesterolemic type 2 diabetes mellitus: a placebo-controlled, double-blind randomized clinical trial. J Cardiometab Syndr. 2007;2(2):91-97.  (PubMed)

35.  Singer GM, Geohas J. The effect of chromium picolinate and biotin supplementation on glycemic control in poorly controlled patients with type 2 diabetes mellitus: a placebo-controlled, double-blinded, randomized trial. Diabetes Technol Ther. 2006;8(6):636-643.  (PubMed)

36.  Albarracin CA, Fuqua BC, Evans JL, Goldfine ID. Chromium picolinate and biotin combination improves glucose metabolism in treated, uncontrolled overweight to obese patients with type 2 diabetes. Diabetes Metab Res Rev. 2008;24(1):41-51.  (PubMed)

37.  Suksomboon N, Poolsup N, Yuwanakorn A. Systematic review and meta-analysis of the efficacy and safety of chromium supplementation in diabetes. J Clin Pharm Ther. 2014;39(3):292-306.  (PubMed)

38.  Lazo de la Vega-Monroy ML, Larrieta E, German MS, Baez-Saldana A, Fernandez-Mejia C. Effects of biotin supplementation in the diet on insulin secretion, islet gene expression, glucose homeostasis and beta-cell proportion. J Nutr Biochem. 2013;24(1):169-177.  (PubMed)

39.  Randhawa SS, Dua K, Randhawa CS, Randhawa SS, Munshi SK. Effect of biotin supplementation on hoof health and ceramide composition in dairy cattle. Vet Res Commun. 2008;32(8):599-608.  (PubMed)

40.  Reilly JD, Cottrell DF, Martin RJ, Cuddeford DJ. Effect of supplementary dietary biotin on hoof growth and hoof growth rate in ponies: a controlled trial. Equine Vet J Suppl. 1998(26):51-57.  (PubMed)

41.  Zenker W, Josseck H, Geyer H. Histological and physical assessment of poor hoof horn quality in Lipizzaner horses and a therapeutic trial with biotin and a placebo. Equine Vet J. 1995;27(3):183-191.  (PubMed)

42.  Romero-Navarro G, Cabrera-Valladares G, German MS, et al. Biotin regulation of pancreatic glucokinase and insulin in primary cultured rat islets and in biotin-deficient rats. Endocrinology. 1999;140(10):4595-4600.  (PubMed)

43.  Floersheim GL. [Treatment of brittle fingernails with biotin]. Z Hautkr. 1989;64(1):41-48.  (PubMed)

44.  Hochman LG, Scher RK, Meyerson MS. Brittle nails: response to daily biotin supplementation. Cutis. 1993;51(4):303-305.  (PubMed)

45.  Boccaletti V, Zendri E, Giordano G, Gnetti L, De Panfilis G. Familial Uncombable Hair Syndrome: Ultrastructural Hair Study and Response to Biotin. Pediatr Dermatol. 2007;24(3):E14-16.  (PubMed)

46.  Famenini S, Goh C. Evidence for supplemental treatments in androgenetic alopecia. J Drugs Dermatol. 2014;13(7):809-812.  (PubMed)

47.  Staggs CG, Sealey WM, McCabe BJ, Teague AM, Mock DM. Determination of the biotin content of select foods using accurate and sensitive HPLC/avidin binding. J Food Compost Anal. 2004;17(6):767-776.  (PubMed)

48.  Briggs DR, Wahlqvist ML. Food facts: the complete no-fads-plain-facts guide to healthy eating. Victoria, Australia: Penguin Books; 1988.

49.  Magnusdottir S, Ravcheev D, de Crecy-Lagard V, Thiele I. Systematic genome assessment of B-vitamin biosynthesis suggests co-operation among gut microbes. Front Genet. 2015;6:148.  (PubMed)

50.  Said HM. Cell and molecular aspects of human intestinal biotin absorption. J Nutr. 2009;139(1):158-162.  (PubMed)

51.  Natural-Medicines. Biotin/Drug interactions. http://www.naturaldatabase.com/. 2014 ed.; 2014

52.  Koutsikos D, Agroyannis B, Tzanatos-Exarchou H. Biotin for diabetic peripheral neuropathy. Biomed Pharmacother. 1990;44(10):511-514.  (PubMed)

53.  Debourdeau PM, Djezzar S, Estival JL, Zammit CM, Richard RC, Castot AC. Life-threatening eosinophilic pleuropericardial effusion related to vitamins B5 and H. Ann Pharmacother. 2001;35(4):424-426.  (PubMed)

54.  Chirapu SR, Rotter CJ, Miller EL, Varma MV, Dow RL, Finn MG. High specificity in response of the sodium-dependent multivitamin transporter to derivatives of pantothenic acid. Curr Top Med Chem. 2013;13(7):837-842.  (PubMed)

55.  Said HM, Ortiz A, McCloud E, Dyer D, Moyer MP, Rubin S. Biotin uptake by human colonic epithelial NCM460 cells: a carrier-mediated process shared with pantothenic acid. Am J Physiol. 1998;275(5 Pt 1):C1365-1371.  (PubMed)

56.  Prasad PD, Wang H, Kekuda R, et al. Cloning and functional expression of a cDNA encoding a mammalian sodium-dependent vitamin transporter mediating the uptake of pantothenate, biotin, and lipoate. J Biol Chem. 1998;273(13):7501-7506.  (PubMed)

57.  Zempleni J, Trusty TA, Mock DM. Lipoic acid reduces the activities of biotin-dependent carboxylases in rat liver. J Nutr. 1997;127(9):1776-1781.  (PubMed)

58.  Castro-Gago M, Gomez-Lado C, Eiris-Punal J, Diaz-Mayo I, Castineiras-Ramos DE. Serum biotinidase activity in children treated with valproic acid and carbamazepine. J Child Neurol. 2010;25(1):32-35.  (PubMed)

59.  Castro-Gago M, Perez-Gay L, Gomez-Lado C, Castineiras-Ramos DE, Otero-Martinez S, Rodriguez-Segade S. The influence of valproic acid and carbamazepine treatment on serum biotin and zinc levels and on biotinidase activity. J Child Neurol. 2011;26(12):1522-1524.  (PubMed)

60.  Schulpis KH, Karikas GA, Tjamouranis J, Regoutas S, Tsakiris S. Low serum biotinidase activity in children with valproic acid monotherapy. Epilepsia. 2001;42(10):1359-1362.  (PubMed)

61.  Yilmaz Y, Tasdemir HA, Paksu MS. The influence of valproic acid treatment on hair and serum zinc levels and serum biotinidase activity. Eur J Paediatr Neurol. 2009;13(5):439-443.  (PubMed)

Folate

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Summary

  • Folate is a generic term referring to both natural folates in food and folic acid, the synthetic form used in supplements and fortified food. Folate is critical in the metabolism of nucleic acid precursors and several amino acids, as well as in methylation reactions. (More information)
  • Severe deficiency in either folate or vitamin B12 can lead to megaloblastic anemia, which causes fatigue, weakness, and shortness of breath. Improper treatment of vitamin B12-dependent megaloblastic anemia with high dose supplemental folic acid can potentially delay the diagnosis of vitamin B12 deficiency and thus leave the individual at risk of developing irreversible brain damage. (More information)
  • Folate status is influenced by the presence of genetic variations in folate metabolism, particularly those found in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene. (More information)
  • Inadequate folate status during early pregnancy increases the risk of congenital anomalies. The introduction of mandatory folic acid fortification of refined grain products in the US in 1998 has reduced the prevalence of neural tube defects (NTDs) in newborns. Yet, folate status is considered inadequate in a majority of women of childbearing age worldwide. Moreover, genetic factors might modify the risk of NTDs by increasing the susceptibility to folate deficiency during pregnancy. Several studies are currently investigating the role of folic acid supplementation in the prevention of congenital anomalies other than NTDs. (More information)
  • Folate deficiency and elevated concentrations of homocysteine in the blood are associated with increased risk of cardiovascular disease (CVD). Although folic acid supplementation has been proven effective to control circulating homocysteine concentrations, the effect of homocysteine lowering on the incidence of CVD is still debated. (More information)
  • Low folate status has been linked to increased cancer risk. However, intervention trials with high doses of folic acid have not generally shown any benefit on cancer incidence. (More information)
  • Prospective cohort studies have reported an inverse association between folate status and colorectal cancer (CRC) risk, especially among men. The relationship between folate status and cancer risk is however complex and requires further research. (More information)
  • Folate is essential for brain development and function. Low folate status and/or high homocysteine concentrations are associated with cognitive dysfunction in aging (from mild impairments to dementia). Whether supplemental B-vitamins, including folic acid, will have long-term benefits in maintaining cognitive health is not yet known. (More information)
  • Several autosomal recessive disorders affecting folate transport and metabolism can be treated with high doses of folinic acid, a folate derivative. (More information)

Folate is a water-soluble B-vitamin, which is also known as vitamin B9 or folacin. Naturally occurring folates exist in many chemical forms; folates are found in food, as well as in metabolically active forms in the human body. Folic acid is the major synthetic form found in fortified foods and vitamin supplements. Other synthetic forms include folinic acid (Figure 1) and levomefolic acid. Folic acid has no biological activity unless converted into folates (1). In the following discussion, forms found in food or the body are referred to as "folates," while the form found in supplements or fortified food is referred to as "folic acid."

Folate Figure 1. Chemical Structures. Chemical structures of folic acid (C19H19N7O6), 5-methyltetrahydrofolate (C20H25N7O6), and folinic acid (C20H23N7O7)

 

Function

One-carbon metabolism

The only function of folate coenzymes in the body appears to be in mediating the transfer of one-carbon units (2). Folate coenzymes act as acceptors and donors of one-carbon units in a variety of reactions critical to the metabolism of nucleic acids and amino acids (Figure 2) (3).

Folate Figure 2. Overview of One-carbon Metabolism. 5,10-methylenetetrahydrofolate is required for the synthesis of nucleic acids, and 5-methyltetrahydrofolate is required for the formation of methionine from homocysteine. Methionine, in the form of methyl donor S-adenosylmethionine (SAM), is essential to many biological methylation reactions, including DNA methylation. Methylenetetrahydrofolate reductase (MTHFR) is a riboflavin (FAD)-dependent enzyme that catalyzes the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate. SAM, S-adenosylmethionine; SAH, S-adenosylhomocysteine; TH4-Folate, Tetrahydrofolate.

Nucleic acid metabolism

Folate coenzymes play a vital role in DNA metabolism through two different pathways. (1) The synthesis of DNA from its precursors (thymidine and purines) is dependent on folate coenzymes. (2) A folate coenzyme is required for the synthesis of methionine from homocysteine, and methionine is required for the synthesis of S-adenosylmethionine (SAM). SAM is a methyl group (one-carbon unit) donor used in most biological methylation reactions, including the methylation of a number of sites within DNA, RNA, proteins, and phospholipids. The methylation of DNA plays a role in controlling gene expression and is critical during cell differentiation. Aberrations in DNA methylation have been linked to the development of cancer (see Cancer).

Amino acid metabolism

Folate coenzymes are required for the metabolism of several important amino acids, namely methionine, cysteine, serine, glycine, and histidine. The synthesis of methionine from homocysteine is catalyzed by methionine synthase, an enzyme that requires not only folate (as 5-methyltetrahydrofolate) but also vitamin B12. Thus, folate (and/or vitamin B12) deficiency can result in decreased synthesis of methionine and an accumulation of homocysteine. Elevated blood concentrations of homocysteine have been considered for many years to be a risk factor for some chronic diseases, including cardiovascular disease and dementia (see Disease Prevention).

Nutrient interactions

Vitamin B12 and vitamin B6

The metabolism of homocysteine, an intermediate in the metabolism of sulfur-containing amino acids, provides an example of the interrelationships among nutrients necessary for optimal physiological function and health. Healthy individuals utilize two different pathways to metabolize homocysteine (Figure 3). One pathway (methionine synthase) synthesizes methionine from homocysteine and is dependent on both folate and vitamin B12 as cofactors. The other pathway converts homocysteine to another amino acid, cysteine, and requires two vitamin B6-dependent enzymes. Thus, the concentration of homocysteine in the blood is regulated by three B-vitamins: folate, vitamin B12, and vitamin B6 (4). In some individuals, riboflavin (vitamin B2) is also involved in the regulation of homocysteine concentrations (see the article on Riboflavin).

Folate Figure 3. Homocysteine Metabolism. Homocysteine is methylated to form the essential amino acid methionine in two pathways. The reaction of homocysteine remethylation catalyzed by the vitamin B12-dependent methionine synthase captures a methyl group from the folate-dependent one-carbon pool (5-methyltetrahydrofolate). A second pathway requires betaine (N,N,N-trimethylglycine) as a methyl donor for the methylation of homocysteine catalyzed by betaine homocysteine methyltransferase. The catabolic pathway of homocysteine, known as the transsulfuration pathway, converts homocysteine to the amino acid cysteine via two vitamin B6 (PLP)-dependent enzymes. Cystathionine beta synthase catalyzes the condensation of homocysteine with serine to form cystathionine, and cystathionine is then converted to cysteine, alpha-ketobutyrate, and ammonia by cystathionine gamma lyase. TH4-Folate, Tetrahydrofolate.

Riboflavin

Although less well recognized, folate has an important metabolic interaction with riboflavin. Riboflavin is a precursor of flavin adenine dinucleotide (FAD), a coenzyme required for the activity of the folate-metabolizing enzyme, 5,10-methylenetetrahydrofolate reductase (MTHFR). FAD-dependent MTHFR in turn catalyzes the reaction that generates 5-methyltetrahydrofolate (see Figure 2 above). This active form of folate is required to form methionine from homocysteine. Along with other B-vitamins, higher riboflavin intakes have been associated with decreased plasma homocysteine concentrations (5). The effects of riboflavin on folate metabolism appear to be greatest in individuals homozygous for the common c.677C>T polymorphism (i.e., TT genotype) in the MTHFR gene (see Genetic variation in folate requirements) (6). These individuals (about 10% of adults worldwide) typically present with low folate status, along with elevated homocysteine concentrations, particularly when folate and/or riboflavin intake is suboptimal. The elevated homocysteine concentration in these individuals, however, is highly responsive to lowering with riboflavin supplementation, confirming the importance of the riboflavin-MTHFR interaction (7).

Vitamin C

Vitamin C may limit degradation of natural folate coenzymes and supplemental folic acid in the stomach and thus improve folate bioavailability. A cross-over trial in nine healthy men found that oral co-administration of 5-methyltetrahydrofolic acid (343 μg) and vitamin C (289 mg or 974 mg) was associated with higher concentrations of serum folate compared to 5-methyltetrahydrofolic acid alone (8). Moreover, a recent study suggested that several genetic variations of folate metabolism might influence the effect of vitamin C on folate metabolism (9).

Bioavailability

Dietary folates exist predominantly in the polyglutamyl form (containing several glutamate residues), whereas folic acid—the synthetic vitamin form—is a monoglutamate, containing just one glutamate moiety. In addition, natural folates are reduced molecules, whereas folic acid is fully oxidized. These chemical differences have major implications for the bioavailability of the vitamin such that folic acid is considerably more bioavailable than naturally occurring food folates at equivalent intake levels.

The intestinal absorption of dietary folates is a two-step process that involves the hydrolysis of folate polyglutamates to the corresponding monoglutamyl derivatives, followed by their transport into intestinal cells. There, folic acid is converted into a naturally occurring folate, namely 5-methyltetrahydrofolate, which is the major circulating form of folate in the human body (see Figure 1 above).

The bioavailability of naturally occurring folates is inherently limited and variable. There is much variability in the ease with which folates are released from different food matrices, and the polyglutamyl "tail" is removed (de-conjugation) before uptake by intestinal cells. Also, other dietary constituents can contribute to instability of labile folates during the processes of digestion. As a result, naturally occurring folates show incomplete bioavailability compared with folic acid. The bioavailability of folic acid, in contrast, is assumed to be 100% when ingested as a supplement, while folic acid in fortified food is estimated to have about 85% the bioavailability of supplemental folic acid.

Of note, folate recommendations in the US and certain other countries are now expressed as Dietary Folate Equivalents (DFEs), a calculation that was devised to take into account the greater bioavailability of folic acid compared to naturally occurring dietary folates (see The Recommended Dietary Allowance).

Transport

Folate and its coenzymes require transporters to cross cell membranes. Folate transporters include the reduced folate carrier (RFC), the proton-coupled folate transporter (PCFT), and the folate receptor proteins, FRα and FRβ. Folate homeostasis is supported by the ubiquitous distribution of folate transporters, although abundance and importance vary among tissues (10). PCFT plays a major role in folate intestinal transport since mutations affecting the gene encoding PCFT cause hereditary folate malabsorption. Defective PCFT also leads to impaired folate transport into the brain (see Disease Treatment). FRα and RFC are also critical for folate transport across the blood-brain barrier when extracellular folate is either low or high, respectively. Folate is essential for the proper development of the embryo and the fetus. The placenta is known to concentrate folate to the fetal circulation, leading to higher folate concentrations in the fetus compared to those found in the pregnant woman. All three types of receptors have been associated with folate transport across the placenta during pregnancy (11).

Deficiency

Causes

Folate deficiency is most often caused by a dietary insufficiency; however, folate deficiency can also occur in a number of other situations. For example, chronic and heavy alcohol consumption is associated with diminished absorption of folate (in addition to low dietary intake), which can lead to folate deficiency (12). Smoking is also associated with low folate status. In one study, folate concentrations in blood were about 15% lower in smokers compared to nonsmokers (13). Additionally, impaired folate transport to the fetus has been described in pregnant women who either smoked or abused alcohol during their pregnancy (14, 15).

Pregnancy is a time when the folate requirement is greatly increased to sustain the demand for rapid cell replication and growth of fetal, placental, and maternal tissue. Conditions such as cancer or inflammation can also result in increased rates of cell division and metabolism, causing an increase in the body's demand for folate (16). Moreover, folate deficiency can result from some malabsorptive conditions, including inflammatory bowel diseases (Crohn's disease and ulcerative colitis) and celiac disease (17). Several medications may also contribute to folate deficiency (see Drug interactions). Finally, a number of genetic diseases affecting folate absorption, transport, or metabolism can cause folate deficiency or impede its metabolic functions (see Disease Treatment).

Symptoms

Clinical folate deficiency leads to megaloblastic anemia, which is reversible with folic acid treatment. Rapidly dividing cells like those derived from bone marrow are most vulnerable to the effects of folate deficiency since DNA synthesis and cell division are dependent on folate coenzymes. When folate supply to the rapidly dividing cells of the bone marrow is inadequate, blood cell division is reduced, resulting in fewer but larger red blood cells. This type of anemia is called megaloblastic or macrocytic anemia, referring to the enlarged, immature red blood cells. Neutrophils, a type of white blood cell, become hypersegmented, a change that can be found by examining a blood sample microscopically. Because normal red blood cells have a lifetime in the circulation of approximately four months, it can take months for folate-deficient individuals to develop the characteristic megaloblastic anemia. Progression of such an anemia leads to a decreased oxygen carrying capacity of the blood and may ultimately result in symptoms of fatigue, weakness, and shortness of breath (1). It is important to point out that megaloblastic anemia resulting from folate deficiency is identical to the megaloblastic anemia resulting from vitamin B12 deficiency, and further clinical testing is required to diagnose the true cause of megaloblastic anemia (see Toxicity).

Individuals in the early stages of folate deficiency may not show obvious symptoms, but blood concentrations of homocysteine may increase (see Disease Prevention). Yet, the concentration of circulating homocysteine is not a specific indicator of folate status, as elevated homocysteine can be the result of vitamin B12 and other B-vitamin deficiencies, lifestyle factors, and renal insufficiency. Subclinical deficiency is typically detected by measurement of folate concentrations in serum/plasma or in red blood cells.

The Recommended Dietary Allowance (RDA)

Determination of the RDA

Traditionally, the dietary folate requirement was defined as the amount needed to prevent a deficiency severe enough to cause symptoms like anemia. The most recent RDA (1998; Table 1) was based primarily on the adequacy of red blood cell folate concentrations at different levels of folate intake, as judged by the absence of abnormal hematological indicators. Red cell folate has been shown to correlate with liver folate stores and is used as an indicator of long-term folate status. Plasma folate reflects recent folate intake and is not a reliable biomarker for folate status. Maintenance of normal blood homocysteine concentrations, an indicator of one-carbon metabolism, was considered only as an ancillary indicator of adequate folate intake.

Because pregnancy is associated with a significant increase in cell division and other metabolic processes that require folate coenzymes, the RDA for pregnant women is considerably higher than for women who are not pregnant (3). However, the prevention of neural tube defects (NTDs) was not considered when setting the RDA for pregnant women. Rather, reducing the risk of NTDs was considered in a separate recommendation for women capable of becoming pregnant (see Disease Prevention), because the crucial events in the development of the neural tube occur before many women are aware that they are pregnant (18).

Dietary Folate Equivalents (DFEs)

When the Food and Nutrition Board of the US Institute of Medicine set the new dietary recommendation for folate, they introduced a new unit, the Dietary Folate Equivalent (DFE) (1). Use of the DFE reflects the higher bioavailability of synthetic folic acid found in supplements and fortified food compared to that of naturally occurring food folates (18).

  • 1 microgram (μg) of food folate provides 1 μg of DFEs
  • 1 μg of folic acid taken with meals or as fortified food provides 1.7 μg of DFEs
  • 1 μg of folic acid (supplement) taken on an empty stomach provides 2 μg of DFEs

For example, a serving of food containing 60 μg of folate would provide 60 μg of DFEs, while a serving of pasta fortified with 60 μg of folic acid would provide 1.7 x 60 = 102 μg of DFEs due to the higher bioavailability of folic acid. A folic acid supplement of 400 μg taken on an empty stomach would provide 800 μg of DFEs. It should be noted that DFEs were determined in studies with adults and whether folic acid in infant formula is more bioavailable than folates in mother's milk has not been studied. Use of DFEs to determine a folate requirement for the infant would not be desirable.

Table 1. Recommended Dietary Allowance for Folate in Dietary Folate Equivalents (DFEs)
Life Stage Age Males (μg/day) Females (μg/day)
Infants 0-6 months 65 (AI) 65 (AI)
Infants 7-12 months 80 (AI) 80 (AI)
Children 1-3 years 150 150
Children 4-8 years 200 200
Children 9-13 years 300 300
Adolescents 14-18 years 400 400
Adults 19 years and older 400 400
Pregnancy all ages - 600
Breast-feeding all ages - 500

Genetic variation in folate requirements

A common polymorphism or variation in the sequence of the gene for the enzyme, 5, 10-methylenetetrahydrofolate reductase (MTHFR), known as the MTHFR c.677C>T polymorphism, results in a thermolabile enzyme (19). The substitution of a cytosine (C) by a thymine (T) at nucleotide 677 in the exon 4 of MTHFR gene leads to an alanine-to-valine transition in the catalytic domain of the enzyme. Depending on the population, 20% to 53% of individuals may have inherited one T copy (677C/T genotype), and 3% to 32% of individuals may have inherited two T copies (677T/T genotype) for the MTHFR gene (20). MTHFR catalyzes the reduction of 5,10-methylenetetrahydrofolate (5,10-methylene THF) into 5-methyl tetrahydrofolate (5-MeTHF). The latter is the folate coenzyme required to form methionine from homocysteine (see Figure 2 above). MTHFR activity is greatly diminished in heterozygous 677C/T (-30%) and homozygous 677T/T (-65%) individuals compared to those with the 677C/C genotype (21). Homozygosity for the mutation (677T/T) is linked to lower concentrations of folate in red blood cells and higher blood concentrations of homocysteine (22, 23). Improving folate nutritional status in elderly women with the T allele reduced plasma homocysteine concentration (24). An important unanswered question about folate is whether the present RDA is enough to compensate for the reduced MTHFR enzyme activity in individuals with at least one T allele, or whether those individuals have a higher folate requirement than the RDA (25).

Disease Prevention

Adverse pregnancy outcomes

Neural tube defects

Fetal growth and development are characterized by widespread cell division. Adequate folate is critical for DNA and RNA synthesis. Neural tube defects (NTDs) arise from failure of embryonic neural tube closure between the 21st and 27th days after conception, a time when many women may not even realize they are pregnant (26). NTDs include various malformations, such as lesions of the brain (e.g., anencephaly, encephalocele) or lesions of the spine (spina bifida), which are devastating and life-threatening (27). The prevalence of NTDs in the United States prior to fortification of food with folic acid was estimated to be 1 per 1,000 pregnancies (1). Results of randomized trials have demonstrated 60% to 100% reductions in NTD cases when women consumed folic acid supplements in addition to a varied diet during the periconceptional period (about one month before and at least one month after conception) (28, 29). The results of these and other studies prompted the US Public Health Service to recommend that all women capable of becoming pregnant consume 400 μg of folic acid daily to prevent NTDs. Women with a previously affected pregnancy were also advised to receive 4,000 μg (4 mg) of folic acid daily in order to reduce NTD recurrence (30). These recommendation were made to all women of childbearing age because adequate folate must be available very early in pregnancy, and because many pregnancies in the US are unplanned (31).

Despite the effectiveness of folic acid supplementation in improving folate status, it appears that globally only 30% of women who become pregnant correctly follow the recommendation, and there is some concern that young women from minority ethnic groups and lower socio-economic backgrounds are the least likely to follow the recommendation (32-34). To decrease the incidence of NTDs, the US FDA implemented legislation in 1998 requiring the fortification of all enriched grain products with 1.4 mg of folic acid per kg of grain (see Sources). The required level of folic acid fortification in the US was initially estimated to provide 100 μg of additional folic acid in the average person's diet, though it probably provides even more due to overuse of folic acid by food manufacturers (25, 35). The National Birth Defects Prevention Network reported about a 30% decrease in the prevalence of NTDs in the US compared to the pre-fortification period, and the post-fortification prevalence of NTDs is 0.69 cases per 1,000 live births and fetal deaths (36).

Also, a genetic component in NTD etiology is evidenced by the increased risk in women with a family history of an NTD and also by variations in risk among ethnicities (37). Moreover, NTD occurrence can be attributed to specific folate-gene interactions. The MTHFR c.677C>T polymorphism and other genetic variations can increase the folate requirement and susceptibility for an NTD-affected pregnancy. Prior to the fortification era, a case-control study showed that both red blood cell and serum folate concentrations were significantly lower in pregnant women with the T/T and C/T variants compared to the wild-type C/C genotype (22), suggesting inadequate folate metabolism with specific maternal genotypes. A meta-analysis of 25 case-control studies, including 2,429 case mothers and 3,570 control mothers, showed a positive association between the maternal MTHFR c.677C>T polymorphism and NTDs (38). Another MTHFR variant, an A-to-C change at position 1298, has also been associated with reduced MTHFR activity and increased NTD risk (39). Individuals heterozygous for both of these MTHFR variants (677C/T + 1298A/C) exhibit lower plasma folate and higher homocysteine concentrations than individuals with 677C/T + 1298A/A (40). Combined genotypes with homozygosity G/G for the reduced folate carrier transporter (RFC-1) polymorphism (c.80A>G) could further contribute to NTD occurrence (41). The degree of NTD risk was also assessed with additional MTHFR polymorphisms (c.116C>T, c.1793G>A) (42), as well as with mutations affecting other enzymes of the one-carbon metabolism, including methionine synthase (MTR c.2756A>G) (43), methionine synthase reductase (MTRR c.66A>G) (44), and methylenetetrahydrofolate dehydrogenase (MTHFD1 c.1958G>A) (45). While maternal genotype can impact pregnancy outcome, it appears that gene-gene interactions between mother and fetus influence it further. The risk of NTD was increased by certain genetic combinations, including maternal (MTHFR c.677C>T)-fetal (MTHFR c.677C>T) and maternal (MTRR c.66A>G)-fetal (MTHFR c.677C>T) interactions (43, 44, 46). Finally, vitamin B12 status has been associated with NTD risk modification in the presence of specific polymorphisms in one-carbon metabolism (47).

Cardiovascular malformations

Congenital anomalies of the heart are a major cause of infant mortality but also cause deaths in adulthood (48). Using data from the European Registration of Congenital Anomalies and Twins (EUROCAT) database, a case-control study, involving 596 cases and 2,359 controls, found that consumption of at least 400 μg/day of folic acid during the periconceptual period (one month before conception through eight weeks' post-conception, covering the period of embryonic heart development) was associated with an 18% reduced risk of congenital heart defects (49). Recent meta-analyses of 20 to 25 case-control and family-based studies observed positive associations between maternal, fetal, or paternal MTHFR c.677C>T variant and incidence of congenital heart defects (50, 51). Additional studies are needed to elucidate the effects of gene-nutrient interactions on the risk of congenital heart defects; however, the currently available research indicates that adequate folate intake may play an important role.

Orofacial clefts

Maternal folate status during pregnancy may influence the risk of congenital anomalies called orofacial clefts, namely cleft lip with or without cleft palate (CL/P) (52). A population-based case-control study in Norway investigated the impact of folic acid supplements in mothers of 377 newborns with CL/P, 196 with cleft palate only (CPO) and 763 controls (53). Although dietary intakes or supplements (during the first three months of pregnancy) on their own did not significantly modify the risk of CL/P, the study reported a 64% lower risk among women taking multivitamin and folic acid (≥400 μg daily) supplements in addition to dietary folates. In the same population, polymorphisms in the cystathionine β-synthase (CBS) gene (c.699C>T) or MTHFR gene (c.677C>T; when folate intake was below 400 μg/day) appeared protective, while other gene variants in the folate/one-carbon metabolism could not be linked to CL/P (54, 55). However, a recent meta-analysis of 18 studies showed an elevation of CL/P risk with the maternal 677T/T homozygosity (56). Additional studies are needed to evaluate the risk of CL/P while integrating both genetic polymorphism and folate intake parameters. Epidemiological evidence supporting a role for folate in the risk of CPO is lacking.

Other adverse pregnancy outcomes

Low birth weight has been associated with increased risk of mortality during the first year of life and may also influence health outcomes during adulthood (57). A recent systematic review and meta-analysis of eight randomized controlled trials found a positive association between folic acid supplementation and birth weight; no association with length of gestation was observed (58). Additionally, a prospective cohort study of 306 pregnant adolescents associated low folate intakes and maternal folate status during the third trimester of pregnancy with higher incidence of small for gestational age births (birth weight <10th percentile) (59). Moreover, the maternal c.677C>T MTHFR genotype and increased homocysteine concentrations, considered an indicator of functional folate deficiency, have been linked to lower birth weights (60).

Elevated blood homocysteine concentrations have also been associated with increased incidence of miscarriage and other pregnancy complications, including preeclampsia and placental abruption (61). A large retrospective study showed that plasma homocysteine in Norwegian women was strongly related to adverse outcomes and complications, including preeclampsia, premature delivery, and very low birth weight, in previous pregnancies (62). A recent meta-analysis of 51 prospective cohort studies linked the c.677C>T MTHFR variant with increased risk of preeclampsia in Caucasian and East Asian populations, reinforcing the notion that folate metabolism may play a role in the condition (63). A large multicenter, randomized, controlled trial, the Folic Acid Clinical Trial (FACT), has been initiated to evaluate whether the daily supplementation of up to 5.1 mg of folic acid throughout pregnancy could prevent preeclampsia and other adverse outcomes (e.g., maternal death, placental abruption, preterm delivery) in high-risk women (64). Adequate folate intake during pregnancy protects against megaloblastic anemia (65). A recent case-control study found a reduction in risk of autism spectrum disorders with daily folic acid consumption of 600 μg or more before and during pregnancy when mother and child carried the c.677C>T MTHFR genotype (66).

Thus, it is reasonable to maintain folic acid supplementation throughout pregnancy, even after closure of the neural tube, in order to decrease the risk of other problems during pregnancy. Moreover, recent systematic reviews of observational studies found no evidence of an association between folate exposure during pregnancy and adverse health outcomes in offspring, in particular childhood asthma and allergies (67, 68).

Cardiovascular disease

Homocysteine and cardiovascular disease

The results of more than 80 studies indicate that even moderately elevated concentrations of homocysteine in the blood increase the risk of cardiovascular disease (CVD) (4). Possible predispositions to vascular accidents have also been linked to genetic deficiencies in homocysteine metabolism in certain populations (69). The mechanism by which homocysteine may increase the risk of vascular disease has been the subject of a great deal of research, but it may involve adverse effects of homocysteine on blood clotting, arterial vasodilation, and thickening of arterial walls (70). Although increased homocysteine concentrations in the blood have been consistently associated with increased risk of CVD, it is unclear whether lowering circulating homocysteine will reduce CVD risk (see Folate and homocysteine). Research had initially predicted that a prolonged decrease in serum homocysteine level of 3 micromoles/liter would lower the risk of CVD by up to 25% and be a reasonable treatment goal for individuals at high risk (71, 72). However, the analysis of recent clinical trials of B-vitamin supplementation has shown that lowering homocysteine concentrations did not prevent the occurrence of a second cardiovascular event in patients with existing CVD (73, 74). Consequently, the American Heart Association recommends screening for elevated total homocysteine concentrations only in "high risk" individuals, for example, in those with personal or family history of premature cardiovascular disease, malnutrition or malabsorption syndromes, hypothyroidism, kidney failure, lupus, or individuals taking certain medications (nicotinic acid, theophylline, bile acid-binding resins, methotrexate, and L-dopa.

Folate and homocysteine

Folate-rich diets have been associated with decreased risk of CVD, including coronary artery disease, myocardial infarction (heart attack), and stroke. A study that followed 1,980 Finnish men for 10 years found that those who consumed the most dietary folate had a 55% lower risk of an acute coronary event when compared to those who consumed the least dietary folate (75). Of the three B-vitamins that regulate homocysteine concentrations, folic acid has been shown to have the greatest effect in lowering basal concentrations of homocysteine in the blood when there is no coexisting deficiency of vitamin B12 or vitamin B6 (see Nutrient interactions) (76). Increasing folate intake through folate-rich food or supplements has been found to reduce homocysteine concentrations (77). Besides, blood homocysteine concentrations have declined since the FDA mandated folic acid fortification of the grain supply in the US (25). A meta-analysis of 25 randomized controlled trials, including almost 3,000 subjects, found that folic acid supplementation with 800 μg/day or more could achieve a maximal 25% reduction in plasma homocysteine concentrations. In this meta-analysis, daily doses of 200 μg and 400 μg of folic acid were associated with a 13% and 20% reduction in plasma homocysteine, respectively (78). A supplement regimen of 400 μg of folic acid, 2 mg of vitamin B6, and 6 μg of vitamin B12 has been advocated by the American Heart Association if an initial trial of a folate-rich diet (see Sources) is not successful in adequately lowering homocysteine concentrations (79).

Several polymorphisms in folate/one-carbon metabolism modify homocysteine concentrations in blood (80). In particular, the effect of the c.677C>T MTHFR variant has been examined in relation to folic acid fortification policies worldwide. The analysis of randomized trials, including 59,995 subjects without a history of CVD, revealed that the difference in homocysteine concentrations between T/T and C/C genotypes was greater in low-folate regions compared to regions with food fortification policy (3.12 vs. 0.13 micromoles/liter) (81). Although folic acid supplementation effectively decreases homocysteine concentrations, it is not yet clear whether it also decreases risk for CVD. A recent meta-analysis of 19 randomized clinical trials, including 47,921 subjects with preexisting cardiovascular or renal disease, found that homocysteine lowering through folic acid and other B-vitamin supplementation failed to reduce the incidence of CVD despite significant reductions in plasma homocysteine concentrations (74). Other meta-analyses have confirmed the lack of causality between the lowering of homocysteine and the risk of CVD (80-82), including the risk of stroke (83, 84). Consequently, the American Heart Association removed its recommendation for using folic acid to prevent cardiovascular disease in high-risk women (85). It should be noted that the majority of prevention trials to date have been performed in CVD patients with advanced disease. The evidence supporting a beneficial role for folate and related B-vitamins appears to be strongest for the primary prevention of stroke (86). The introduction of mandatory folic acid fortification has been associated with a decline in stroke-related mortality in North America, adding further support to the potential benefit of enhancing folate status and/or lowering homocysteine in the prevention of stroke (87).

Despite the controversy regarding the role of homocysteine lowering in CVD prevention, some studies have investigated the effect of folic acid supplementation on the development of atherosclerosis, a known risk factor for vascular accidents. The measurement of the carotid intima-media thickness (CIMT) is a surrogate endpoint for early atherosclerosis and a predictor for cardiovascular events (88). The meta-analysis of 10 randomized trials testing the effect of folic acid supplementation showed a significant reduction in CIMT in subjects with chronic kidney diseases and in those at risk for CVD, but not in healthy participants (89). Endothelial dysfunction is a common feature in atherosclerosis and vascular disease. High doses of folic acid (400-10,000 μg/day) have been associated with improvements in vascular health in both healthy and CVD subjects (90). Although recent trials failed to demonstrate any cardiovascular protection from folic acid supplementation, low folate intake is a known risk factor for vascular disease, and more research is needed to explore the role of folate in maintaining vascular health (91).

Cancer

Cancer is thought to arise from DNA damage in excess of ongoing DNA repair and/or the inappropriate expression of critical genes. Because of the important roles played by folate in DNA and RNA synthesis and methylation, it is possible that inadequate folate intake contributes to genome instability and chromosome breakage that often characterize cancer development. In particular, DNA replication and repair are critical for genome maintenance, and the shortage in nucleotides caused by folate deficiency might lead to genome instability and DNA mutations. A decrease in 5,10-methylene THF can compromise the conversion of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP) by the enzyme thymidylate synthase (TS), causing uracil accumulation and thymine depletion. This could then lead to uracil misincorporation into DNA during replication or repair, and cause DNA damage, including point mutations and strand breaks (92). Since 5,10-methylene THF is also the MTHFR enzyme substrate, it is plausible that a reduction of MTHFR activity with the c.677C>T polymorphism may increase the use of 5,10-methylene THF for thymidylate synthesis and prevent DNA damage. However, this hypothesis might only be valid in a situation of folate deficiency (93). Conversely, it was argued that folic acid supplementation could fuel DNA synthesis, therefore promoting tumor growth. This is supported by the observation that TS can function like a tumor promoter (oncogene), while a reduction in TS activity is linked to a lower risk of cancer (94, 95). Additionally, antifolate molecules that block the thymidylate synthesis pathway are successfully used in cancer therapy (96). Folate also controls the homocysteine/methionine cycle and the pool of S-adenosylmethionine (SAM), the methyl donor for methylation reactions. Thus, folate deficiency may impair DNA and protein methylation and alter the expression of genes involved in DNA repair, proliferation and cell death. Global DNA hypomethylation, a typical hallmark of cancer, causes genome instability and chromosome breaks (reviewed in 97).

The consumption of at least five servings of fruit and vegetables daily has been consistently associated with a decreased incidence of cancer (98). Fruit and vegetables are excellent sources of folate, which may play a role in their anti-carcinogenic effect. Observational studies have found diminished folate status to be associated with site-specific cancers. While food fortification is mandatory in the US (since 1998; see Sources), concerns about the impact of high folic acid intakes on health have delayed the practice in several other countries (99). However, the most recent meta-analyses of folic acid intervention trials (supplemental doses ranging from 500 to 5,000 μg/day for at least one year) did not show any specific benefit or harm regarding total and site-specific cancer incidence (100, 101).

Colorectal cancer

A pooled analysis of 13 prospective cohort studies, which followed a total of 725,134 individuals for a 7 to 20-year period, revealed a modest, inverse association between dietary and total (from food and supplements) folate intake and colon cancer risk. Specifically, a 2% decrease in colon cancer risk was estimated for every 100 μg/day increase in total folate intake (102). A large US prospective study, which followed 525,488 subjects, ages 50 to 71 years between 1995 and 2006, correlated dietary folate, supplemental folic acid, and total folate intakes with a decreased colorectal cancer (CRC) risk (103). However, when stratified by gender, there was no association between dietary folate intake and CRC risk in women (103, 104). A lack of association between CRC risk and dietary, supplemental, and total folate intakes was also reported in another prospective study that followed more than 90,000 US postmenopausal women during an 11-year period encompassing pre- and post-fortification periods (105). These data suggest the possible influence of gender over CRC risk modification by folate. In the latter study, a significant but transient risk elevation was also observed during the post-fortification era; however, some have asserted that this is unlikely to be caused by increased folate intake due to mandatory fortification (106). Finally, a meta-analysis of 18 case-control studies found a slight reduction in CRC risk with folate from food (107). However, it is important to note that the case-control studies were highly heterogeneous, and that the authors stated that dietary fiber, vitamins, and alcohol intake could have confounded their results. Moreover, the lower limit of the highest quantile of folate intake was highly variable, ranging from 270 to 1,367 μg/day (107).

While most epidemiological research shows a protective effect of folate against colorectal cancer development, it has been suggested that high doses of supplemental folic acid may actually accelerate tumor growth in cancer patients (108). Whereas higher folate status within the normal dietary range is widely considered to be protective against cancer, some investigators remain concerned that exposure to excessively high folic acid intakes may increase the growth of pre-existing neoplasms (108). Several clinical trials addressed the effect of folic acid supplementation in patients with a history of colorectal adenoma, with trials finding a risk reduction or no effect of supplemental folic acid (109-112). A recent meta-analysis of three large randomized controlled trials in high-risk subjects did not demonstrate any increase in colorectal adenoma recurrence in subjects supplemented with 500 or 1,000 μg/day of folic acid for 24 to 42 months when compared with placebo treatment (113).

As suggested earlier, the MTHFR 677T/T genotype might prevent uracil misincorporation and protect DNA integrity and stability under low-folate conditions. A meta-analysis of 62 case-control and two cohort studies revealed that while the T/T variant reduces CRC risk by 12% compared to both C/T and C/C genotypes, the risk was decreased by 30% with high (348-1,583 μg/day) versus low total folate intakes (264-450 μg/day), irrespective of the genotype (114). A common polymorphism (c.2756A>G) in the MTR gene, which codes for methionine synthase, was also examined in relation with the risk of colorectal adenoma and cancer. Methionine synthase catalyzes the simultaneous conversion of homocysteine and 5-methylene THF into methionine and TFH, respectively. The recent meta-analysis of 27 case-control studies showed no association between MTR variant and cancer risk (115).

Although alcohol consumption interferes with the absorption and metabolism of folate (16), one case-control and five prospective cohort studies have reported either reduction in CRC risk among nondrinkers compared to drinkers or a lack of association (107). However, in a large prospective study that followed more than 28,000 male health professionals for 22 years, intake of more than two alcoholic drinks (>30 grams of alcohol) per day augmented CRC risk by 42% during the pre-fortification period. CRC risk was not increased during the post-fortification period, suggesting that it is the combination of high alcohol and low folate intake that might increase CRC risk. Yet, another prospective study that followed more than 69,000 female nurses for 28 years did not report a significant increase in CRC risk with alcohol intake before and after the mandatory folic acid fortification (116). In some studies, individuals who are homozygous for the c.677C>T MTHFR polymorphism (T/T) have been found to be at decreased risk for colon cancer when folate intake is adequate. However, when folate intake is low and/or alcohol intake is high, individuals with the (T/T) genotype have been found to be at increased risk of colorectal cancer (117, 118).

Breast cancer

Several prospective cohort and case-control studies investigating whether folate intake affects breast cancer risk have reported mixed results (119). A meta-analysis of 15 prospective studies and one nested case-control study found no relationship with dietary folate intake (120). Moderate alcohol intake has been associated with increased risk of breast cancer in women (121). The results of three prospective studies suggested that increased folate intake may reduce the risk of breast cancer in women who regularly consume alcohol (122-124). Thus, high folate intake might be associated with a risk reduction only in women whose breast cancer risk is raised by alcohol consumption. A very large prospective study in more than 88,000 nurses reported that folic acid intake was not associated with breast cancer in women who consumed less than one alcoholic drink per day. However, in women consuming at least one alcoholic drink per day, folic acid intake of at least 600 μg daily resulted in about half the risk of breast cancer compared with women who consumed less than 300 μg of folic acid daily (124). Nevertheless, whether and how alcohol consumption increases breast cancer risk is still subject to discussion (125, 126). Finally, recent meta-analyses evaluating the influence of polymorphisms in one-carbon metabolism on cancer risk found that specific variants in the gene encoding thymidylate synthase increased the risk of breast cancer in certain ethnic populations (127, 128).

Childhood cancers

The incidence of Wilms' tumors (kidney cancer) and certain types of brain cancers (neuroblastoma, ganglioneuroblastoma, and ependymoma) in children has decreased since the mandatory fortification of the US grain supply in 1998 (129). However, incidence rates were unchanged between the pre- and post-fortification periods for leukemia—a predominant childhood malignancy. Despite earlier studies linking maternal folic acid supplementation during pregnancy with the reduced risk of childhood leukemia, more recent investigations have found little evidence to support a preventive effect of folic acid (130). Several meta-analyses have also found little to no protective effect with MTHFR polymorphisms; however, the most recent meta-analysis of 22 case-control studies found a reduction in the risk of acute lymphoblastic leukemia (ALL) with the c.677C>T variant in Caucasians and Asians (131).

Alzheimer's disease and cognitive impairment

Alzheimer's disease (AD) is the most common form of dementia, affecting more than 5 million individuals over 65 years old in the US (132). β-amyloid plaque deposition, Tau protein-forming tangles, and increased cell death in the brain of AD patients have been associated with cognitive decline and memory loss. One study associated increased consumption of fruit and vegetables, which are abundant sources of folate, with a reduced risk of developing dementia and AD in women (133). Through its role in nucleic acid synthesis and methyl donor provision for methylation reactions, folate is critical for normal brain development and function, not only during pregnancy and after birth, but also later in life (134). In one cross-sectional study of elderly women, AD patients had significantly higher homocysteine and lower red blood cell folate concentrations compared to healthy individuals. However, there was no difference in the level of serum folate between groups, suggesting that long-term folate status, rather than recent folate intake, may be associated with the risk of AD (135).

Several investigators have described associations between increased homocysteine concentrations and cognitive impairment in the elderly (136), but prospective cohort studies have not found higher folate intakes to be associated with improved cognition (137, 138). Higher homocysteine concentrations were found in individuals suffering from dementia, including AD and vascular dementia, compared to healthy subjects (139, 140). Although deficiencies in folate, vitamin B12, and vitamin B6 could increase homocysteine concentrations, a reduction in vitamin concentrations in the serum of AD patients compared to healthy individuals could not be attributed to decreased vitamin intakes (141). It is not presently clear whether serum homocysteine is a risk factor for developing dementia or simply associated with the cognitive decline. In the last decade, a number of clinical trials have tested the use of B-vitamins to lower homocysteine and prevent or delay cognitive decline. A meta-analysis of nine randomized, placebo-controlled trials of folic acid supplementation (0.2 to 15 mg/day for a median duration of six months) in healthy individuals over 45 years of age failed to find a short-term effect on cognitive functions, including memory, speed, language, and executive functions (142). More recently, a meta-analysis of 19 randomized, placebo-controlled trials of B-vitamin supplementation found no difference in cognitive parameters between the treatment and placebo groups, despite the treatment effectively lowering homocysteine concentrations (143). Inconsistent findings across trials may be due to differences in design and methodology (reviewed in 144).

Nevertheless, a two-year randomized, placebo-controlled trial in 168 elderly subjects with mild cognitive impairment recently described the benefits of a daily regimen of 800 μg of folic acid, 500 μg of vitamin B12, and 20 mg of vitamin B6 (145, 146). Atrophy of specific brain regions affected by AD was observed in individuals of both groups, and this atrophy correlated with cognitive decline; however, the B-vitamin treatment group experienced a smaller loss of gray matter compared to the placebo group (0.5% vs. 3.7%). A greater benefit was seen in subjects with higher baseline homocysteine concentrations, suggesting the importance of lowering circulating homocysteine in prevention of cognitive decline and dementia. Although encouraging, the effect of B-vitamin supplementation needs to be further studied in larger trials that evaluate long-term outcomes, such as the incidence of AD.

Disease Treatment

Metabolic diseases

Folinic acid (see Figure 1 above), a tetrahydrofolic acid derivative, is used in the clinical management of rare inborn errors that affect folate transport or metabolism (reviewed in 147). Such conditions are of autosomal recessive inheritance, meaning only individuals receiving two copies of the mutated gene (one from each parent) develop the disease.

Hereditary folate malabsorption

Hereditary folate malabsorption is caused by mutations in the SLC46A1 gene coding for the folate transporter PCFT and typically affects gastrointestinal folate absorption and folate transport into the brain (148). Patients present with low to undetectable concentrations of folate in serum and cerebrospinal fluid, pancytopenia (low number of all blood cells), impaired immune responses that increase susceptibility to infections, and a general failure to thrive (149). Neurologic symptoms, including seizures, have also been observed (150). Clinical improvements have been recorded following parenteral provision of folinic acid (151).

Cerebral Folate Deficiency (CFD) syndrome

CFD is characterized by low levels of folate coenzymes in cerebrospinal fluid despite normal concentrations of folate in blood. Folate transport across the blood-brain barrier is compromised in CFD and has been linked either to the presence of antibodies blocking the folate receptor FRα or to mutations in the FOLR1 gene encoding FRα (152, 153). Neurologic abnormalities, along with visual and hearing impairments, have been described in children with CFD; autism spectrum disorder (ASD) is present in some cases. Folinic acid (also known as leucovorin) can enter the brain and normalize the level of folate coenzymes and has been shown to normalize folate concentrations and improve various social interactions in CFD, including mood, behavior, and verbal communication in children with ASD (152, 154, 155).

Dihydrofolate reductase (DHFR) deficiency

DHFR is the NADPH-dependent enzyme that catalyzes the reduction of dihydrofolic acid (DHF) to tetrahydrofolic acid (THF). DHFR is also required to convert folic acid to DHF. DHFR deficiency is characterized by megaloblastic anemia and cerebral folate deficiency causing intractable seizures and mental deficits. Although folinic acid treatment can alleviate the symptoms of DHFR deficiency, early diagnosis is essential to prevent irreversible brain damage and improve clinical outcomes (156, 157).

Sources

Food sources

Green leafy vegetables (foliage) are rich sources of folate and provide the basis for its name. Citrus fruit juices, legumes, and fortified foods are also excellent sources of folate (1); the folate content of fortified cereal varies greatly. A number of folate-rich foods are listed in Table 2, along with their folate content in micrograms (μg). For more information on the nutrient content of specific foods, search the USDA food composition database.

Table 2. Some Food Sources of Folate and Folic Acid
Food Serving Folate (μg DFEs)
Lentils (mature seeds, cooked, boiled) ½ cup 179
Garbanzo beans (chickpeas, cooked, boiled) ½ cup 141
Asparagus (cooked, boiled) ½ cup (~6 spears) 134
Spinach (cooked, boiled) ½ cup 131
Lima beans (large, mature seeds, cooked, boiled) ½ cup 78
Orange juice (raw) 6 fl. oz. 56
Spaghetti (enriched, cooked) 1 cup 167*
White rice (enriched, cooked) 1 cup 153*
Bread (enriched) 1 slice 84*
*To help prevent neural tube defects, the US FDA required the addition of 1.4 milligrams (mg) of folic acid per kilogram (kg) of grain to be added to refined grain products, which are already enriched with niacin, thiamin, riboflavin, and iron, as of January 1, 1998. The addition of nutrients to food in order to prevent a nutritional deficiency or restore nutrients lost in processing is known as fortification. The FDA initially estimated that this level of fortification would increase dietary intake by an average of 100 μg folic acid/day (26). However, further evaluations based on observational studies suggested increases twice that predicted by the FDA (35). The prevalence of low folate concentrations in both serum and red blood cells is currently below 1% in the US population, compared to 24% and 3.5%, respectively, before the fortification period (158).

Supplements

The principal form of supplementary folate is folic acid. It is available in single-ingredient and combination products, such as B-complex vitamins and multivitamins. Doses of 1 mg or greater require a prescription (159). Additionally, folinic acid, a tetrahydrofolic acid derivative, is used to manage certain metabolic diseases (see Disease Treatment). Further, the US FDA has approved the supplementation of folate in oral contraceptives. The addition of levomefolate calcium (the calcium salt of MeTHF; 451 μg/tablet) to oral contraceptives is intended to raise folate status in women of childbearing age (160). According to a US national survey, only 24% of non-pregnant women aged 15-44 years are meeting the current recommendation of 400 μg/day of folic acid (161).

Safety

Toxicity

No adverse effects have been associated with the consumption of excess folate from food. Concerns regarding safety are limited to synthetic folic acid intake. Deficiency of vitamin B12, though often undiagnosed, may affect a significant number of people, especially older adults (see the article on Vitamin B12). One symptom of vitamin B12 deficiency is megaloblastic anemia, which is indistinguishable from that associated with folate deficiency (see Deficiency). Large doses of folic acid given to an individual with an undiagnosed vitamin B12 deficiency could correct megaloblastic anemia without correcting the underlying vitamin B12 deficiency, leaving the individual at risk of developing irreversible neurologic damage. Such cases of neurologic progression in vitamin B12 deficiency have been mostly seen at folic acid doses of 5,000 μg (5 mg) and above. In order to be very sure of preventing irreversible neurological damage in vitamin B12-deficient individuals, the Food and Nutrition Board of the US Institute of Medicine advises that all adults limit their intake of folic acid (supplements and fortification) to 1,000 μg (1 mg) daily (Table 3). The Board also noted that vitamin B12 deficiency is very rare in women in their childbearing years, making the consumption of folic acid at or above 1,000 μg/day unlikely to cause problems (1); however, there are limited data on the effects of large doses.

Table 3. Tolerable Upper Intake Level (UL) for Folic Acid
Age Group UL (μg/day)
Infants 0-12 months Not possible to establish*
Children 1-3 years 300
Children 4-8 years 400
Children 9-13 years 600
Adolescents 14-18 years 800
Adults 19 years and older 1,000
*Source of intake should be from food and formula only.

The saturation of DHFR metabolic capacity by oral doses of folic acid has been associated with the appearance of unmetabolized folic acid in blood (162). Hematologic abnormalities and poorer cognition have been associated with the presence of unmetabolized folic acid in vitamin B12-deficient older adults (≥60 years) (163, 164). A small study conducted in postmenopausal women also raised concerns about the effect of exposure to unmetabolized folic acid on immune function (165). In a small, randomized, open-label trial in 38 women of reproductive age receiving 30 weeks of daily multivitamin supplements, daily supplementation with either 1.1 mg or 5 mg of folic acid resulted in the transient appearance of unmetabolized folic acid in blood over the first 12 weeks of supplementation (166). However, unmetabolized folic acid concentrations returned to baseline levels at the end of the study, suggesting that adaptive mechanisms eventually converted folic acid to reduced forms of folate. Nonetheless, the use of supplemental levomefolate (5-methyl THF) may provide an alternative to prevent the potential negative effects of unconverted folic acid in older adults.

Drug interactions

When nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin or ibuprofen, are taken in very large therapeutic dosages (i.e., to treat severe arthritis), they may interfere with folate metabolism. In contrast, routine use of NSAIDs has not been found to adversely affect folate status. The anticonvulsant, phenytoin, has been shown to inhibit the intestinal absorption of folate, and several studies have associated decreased folate status with long-term use of the anticonvulsants, phenytoin, phenobarbital, and primidone (167). However, few studies controlled for differences in dietary folate intake between anticonvulsant users and nonusers. Also, taking folic acid at the same time as the cholesterol-lowering agents, cholestyramine and colestipol, may decrease the absorption of folic acid (159). Methotrexate is a folate antagonist used to treat a number of diseases, including cancer, rheumatoid arthritis, and psoriasis. Some of the side effects of methotrexate are similar to those of severe folate deficiency, and supplementation with folic or folinic acid is used to reduce antifolate toxicity. Other antifolate molecules currently used in cancer therapy include aminopterin, pemetrexed, pralatrexate, and raltitrexed (96). Further, a number of other medications have been shown to have antifolate activity, including trimethoprim (an antibiotic), pyrimethamine (an antimalarial), triamterene (a blood pressure medication), and sulfasalazine (a treatment for ulcerative colitis). Early studies of oral contraceptives (birth control pills) containing high doses of estrogen indicated adverse effects on folate status; however, this finding has not been supported in more recent studies that used low-dose oral contraceptives and controlled for dietary folate (168).

Linus Pauling Institute Recommendation

The available scientific evidence shows that adequate folate intake prevents neural tube defects and other poor outcomes of pregnancy; is helpful in lowering the risk of some forms of cancer, especially in genetically susceptible individuals; and may lower the risk of cardiovascular disease. The Linus Pauling Institute recommends that adults take a daily multivitamin/mineral supplement, which typically contains 400 μg of folic acid, the Daily Value (DV). Even with a larger than average intake of folic acid from fortified food, it is unlikely that an individual's daily folic acid intake would regularly exceed the tolerable upper intake level of 1,000 μg/day established by the Institute of Medicine (see Safety).

Older adults (>50 years)

The recommendation for 400 μg/day of supplemental folic acid as part of a daily multivitamin/mineral supplement, in addition to a folate-rich diet, is especially important for older adults because blood homocysteine concentrations tend to increase with age (see Disease Prevention).


Authors and Reviewers

Originally written in 2000 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in April 2002 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in September 2007 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in June 2014 by:
Barbara Delage, Ph.D.
Linus Pauling Institute
Oregon State University

Reviewed in December 2014 by:
Helene McNulty, Ph.D., R.D.
Professor of Human Nutrition and Dietetics
Northern Ireland Centre for Food and Health (NICHE)
University of Ulster
Coleraine, United Kingdom

The 2014 update of this article was underwritten, in part, by a grant from Bayer Consumer Care AG, Basel, Switzerland.

Copyright 2000-2017  Linus Pauling Institute


References

1. Food and Nutrition Board, Institute of Medicine. Folate. Dietary Reference Intakes: Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, D.C.: National Academy Press; 1998:196-305.  (National Academy Press)

2. Choi SW, Mason JB. Folate and carcinogenesis: an integrated scheme. J Nutr. 2000;130(2):129-132.  (PubMed)

3.  Bailey LB, Gregory JF, 3rd. Folate metabolism and requirements. J Nutr. 1999;129(4):779-782.  (PubMed)

4.  Gerhard GT, Duell PB. Homocysteine and atherosclerosis. Curr Opin Lipidol. 1999;10(5):417-428.  (PubMed)

5.  Jacques PF, Bostom AG, Wilson PW, Rich S, Rosenberg IH, Selhub J. Determinants of plasma total homocysteine concentration in the Framingham Offspring cohort. Am J Clin Nutr. 2001;73(3):613-621.  (PubMed)

6.  Jacques PF, Kalmbach R, Bagley PJ, et al. The relationship between riboflavin and plasma total homocysteine in the Framingham Offspring cohort is influenced by folate status and the C677T transition in the methylenetetrahydrofolate reductase gene. J Nutr. 2002;132(2):283-288.  (PubMed)

7.  McNulty H, Dowey le RC, Strain JJ, et al. Riboflavin lowers homocysteine in individuals homozygous for the MTHFR 677C->T polymorphism. Circulation. 2006;113(1):74-80.  (PubMed)

8.  Verlinde PH, Oey I, Hendrickx ME, Van Loey AM, Temme EH. L-ascorbic acid improves the serum folate response to an oral dose of [6S]-5-methyltetrahydrofolic acid in healthy men. Eur J Clin Nutr. 2008;62(10):1224-1230.  (PubMed)

9.  Lucock M, Yates Z, Boyd L, et al. Vitamin C-related nutrient-nutrient and nutrient-gene interactions that modify folate status. Eur J Nutr. 2013;52(2):569-582.  (PubMed)

10.  Desmoulin SK, Hou Z, Gangjee A, Matherly LH. The human proton-coupled folate transporter: Biology and therapeutic applications to cancer. Cancer Biol Ther. 2012;13(14):1355-1373.  (PubMed)

11.  Solanky N, Requena Jimenez A, D'Souza SW, Sibley CP, Glazier JD. Expression of folate transporters in human placenta and implications for homocysteine metabolism. Placenta. 2010;31(2):134-143.  (PubMed)

12.  Halsted CH, Villanueva JA, Devlin AM, Chandler CJ. Metabolic interactions of alcohol and folate. J Nutr. 2002;132(8 Suppl):2367S-2372S.  (PubMed)

13.  Pfeiffer CM, Sternberg MR, Schleicher RL, Rybak ME. Dietary supplement use and smoking are important correlates of biomarkers of water-soluble vitamin status after adjusting for sociodemographic and lifestyle variables in a representative sample of US adults. J Nutr. 2013;143(6):957S-965S.  (PubMed)

14.  Stark KD, Pawlosky RJ, Sokol RJ, Hannigan JH, Salem N, Jr. Maternal smoking is associated with decreased 5-methyltetrahydrofolate in cord plasma. Am J Clin Nutr. 2007;85(3):796-802.  (PubMed)

15.  Hutson JR, Stade B, Lehotay DC, Collier CP, Kapur BM. Folic acid transport to the human fetus is decreased in pregnancies with chronic alcohol exposure. PLoS One. 2012;7(5):e38057.  (PubMed)

16.  Herbert V. Folic acid. In: Shils M, Olson JA, Shike M, Ross AC, eds. Modern Nutrition in Health and Disease. 9th ed. Baltimore: Lippincott Williams & Wilkins; 1999:433-446.

17.  Stabler SP. Clinical folate deficiency. In: Bailey LB, ed. Folate in Health and Disease. 2nd edition ed. Boca Raton, FL: CRC press, Taylor & Francis Group; 2010:409-428.

18.  Bailey LB. Dietary reference intakes for folate: the debut of dietary folate equivalents. Nutr Rev. 1998;56(10):294-299.  (PubMed)

19. Bailey LB, Gregory JF, 3rd. Polymorphisms of methylenetetrahydrofolate reductase and other enzymes: metabolic significance, risks and impact on folate requirement. J Nutr. 1999;129(5):919-922.  (PubMed)

20.  Wilcken B, Bamforth F, Li Z, et al. Geographical and ethnic variation of the 677C>T allele of 5,10 methylenetetrahydrofolate reductase (MTHFR): findings from over 7000 newborns from 16 areas world wide. J Med Genet. 2003;40(8):619-625.  (PubMed)

21.  Guenther BD, Sheppard CA, Tran P, Rozen R, Matthews RG, Ludwig ML. The structure and properties of methylenetetrahydrofolate reductase from Escherichia coli suggest how folate ameliorates human hyperhomocysteinemia. Nat Struct Biol. 1999;6(4):359-365.  (PubMed)

22.  Molloy AM, Daly S, Mills JL, et al. Thermolabile variant of 5,10-methylenetetrahydrofolate reductase associated with low red-cell folates: implications for folate intake recommendations. Lancet. 1997;349(9065):1591-1593.  (PubMed)

23.  Rozen R. Genetic predisposition to hyperhomocysteinemia: deficiency of methylenetetrahydrofolate reductase (MTHFR). Thromb Haemost. 1997;78(1):523-526.  (PubMed)

24. Kauwell GP, Wilsky CE, Cerda JJ, et al. Methylenetetrahydrofolate reductase mutation (677C-->T) negatively influences plasma homocysteine response to marginal folate intake in elderly women. Metabolism. 2000;49(11):1440-1443.  (PubMed)

25.  Shane B. Folic acid, vitamin B-12, and vitamin B-6. In: Stipanuk M, ed. Biochemical and Physiological Aspects of Human Nutrition. Philadelphia: W.B. Saunders Co.; 2000:483-518.

26.  Eskes TK. Open or closed? A world of difference: a history of homocysteine research. Nutr Rev. 1998;56(8):236-244.  (PubMed)

27.  Czeizel AE, Dudas I, Vereczkey A, Banhidy F. Folate deficiency and folic acid supplementation: the prevention of neural-tube defects and congenital heart defects. Nutrients. 2013;5(11):4760-4775.  (PubMed)

28.  MRC Vitamin Study Research Group. Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. Lancet. 1991;338(8760):131-137.  (PubMed)

29.  Czeizel AE, Dudas I. Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation. N Engl J Med. 1992;327(26):1832-1835.  (PubMed)

30.  Talaulikar VS, Arulkumaran S. Folic acid in obstetric practice: a review. Obstet Gynecol Surv. 2011;66(4):240-247.  (PubMed)

31.  American College of Obstetricians and Gynecologists (ACOG). Neural tube defects. Washington, DC. 2003.  Available at: http://www.guideline.gov/content.aspx?id=3994. Accessed 12/19/14.

32.  McNulty B, Pentieva K, Marshall B, et al. Women's compliance with current folic acid recommendations and achievement of optimal vitamin status for preventing neural tube defects. Hum Reprod. 2011;26(6):1530-1536.  (PubMed)

33.  Nilsen RM, Vollset SE, Gjessing HK, et al. Patterns and predictors of folic acid supplement use among pregnant women: the Norwegian Mother and Child Cohort Study. Am J Clin Nutr. 2006;84(5):1134-1141.  (PubMed)

34.  Ray JG, Singh G, Burrows RF. Evidence for suboptimal use of periconceptional folic acid supplements globally. BJOG. 2004;111(5):399-408.  (PubMed)

35.  Quinlivan EP, Gregory JF, 3rd. Effect of food fortification on folic acid intake in the United States. Am J Clin Nutr. 2003;77(1):221-225.  (PubMed)

36.  National Birth Defects Prevention Network. Neural Tube Defect Ascertainment Project. Available at: http://www.nbdpn.org/ntd_folic_acid_information.php. Accessed 12/16/14.

37.  Copp AJ, Stanier P, Greene ND. Neural tube defects: recent advances, unsolved questions, and controversies. Lancet Neurol. 2013;12(8):799-810.  (PubMed)

38.  Yan L, Zhao L, Long Y, et al. Association of the maternal MTHFR C677T polymorphism with susceptibility to neural tube defects in offsprings: evidence from 25 case-control studies. PLoS One. 2012;7(10):e41689.  (PubMed)

39.  De Marco P, Calevo MG, Moroni A, et al. Study of MTHFR and MS polymorphisms as risk factors for NTD in the Italian population. J Hum Genet. 2002;47(6):319-324.  (PubMed)

40.  van der Put NM, Gabreels F, Stevens EM, et al. A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects? Am J Hum Genet. 1998;62(5):1044-1051.  (PubMed)

41.  De Marco P, Calevo MG, Moroni A, et al. Reduced folate carrier polymorphism (80A-->G) and neural tube defects. Eur J Hum Genet. 2003;11(3):245-252.  (PubMed)

42.  O'Leary VB, Mills JL, Parle-McDermott A, et al. Screening for new MTHFR polymorphisms and NTD risk. Am J Med Genet A. 2005;138A(2):99-106.  (PubMed)

43.  Christensen B, Arbour L, Tran P, et al. Genetic polymorphisms in methylenetetrahydrofolate reductase and methionine synthase, folate levels in red blood cells, and risk of neural tube defects. Am J Med Genet. 1999;84(2):151-157.  (PubMed)

44.  Relton CL, Wilding CS, Pearce MS, et al. Gene-gene interaction in folate-related genes and risk of neural tube defects in a UK population. J Med Genet. 2004;41(4):256-260.  (PubMed)

45.  Brody LC, Conley M, Cox C, et al. A polymorphism, R653Q, in the trifunctional enzyme methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase/formyltetrahydrofolate synthetase is a maternal genetic risk factor for neural tube defects: report of the Birth Defects Research Group. Am J Hum Genet. 2002;71(5):1207-1215.  (PubMed)

46.  van der Put NM, van den Heuvel LP, Steegers-Theunissen RP, et al. Decreased methylene tetrahydrofolate reductase activity due to the 677C-->T mutation in families with spina bifida offspring. J Mol Med (Berl). 1996;74(11):691-694.  (PubMed)

47.  Wilson A, Platt R, Wu Q, et al. A common variant in methionine synthase reductase combined with low cobalamin (vitamin B12) increases risk for spina bifida. Mol Genet Metab. 1999;67(4):317-323.  (PubMed)

48.  Gilboa SM, Salemi JL, Nembhard WN, Fixler DE, Correa A. Mortality resulting from congenital heart disease among children and adults in the United States, 1999 to 2006. Circulation. 2010;122(22):2254-2263.  (PubMed)

49.  van Beynum IM, Kapusta L, Bakker MK, den Heijer M, Blom HJ, de Walle HE. Protective effect of periconceptional folic acid supplements on the risk of congenital heart defects: a registry-based case-control study in the northern Netherlands. Eur Heart J. 2010;31(4):464-471.  (PubMed)

50.  Yin M, Dong L, Zheng J, Zhang H, Liu J, Xu Z. Meta analysis of the association between MTHFR C677T polymorphism and the risk of congenital heart defects. Ann Hum Genet. 2012;76(1):9-16.  (PubMed)

51.  Wang W, Wang Y, Gong F, Zhu W, Fu S. MTHFR C677T polymorphism and risk of congenital heart defects: evidence from 29 case-control and TDT studies. PLoS One. 2013;8(3):e58041.  (PubMed)

52.  Badovinac RL, Werler MM, Williams PL, Kelsey KT, Hayes C. Folic acid-containing supplement consumption during pregnancy and risk for oral clefts: a meta-analysis. Birth Defects Res A Clin Mol Teratol. 2007;79(1):8-15.  (PubMed)

53.  Wilcox AJ, Lie RT, Solvoll K, et al. Folic acid supplements and risk of facial clefts: national population based case-control study. BMJ. 2007;334(7591):464.  (PubMed)

54.  Boyles AL, Wilcox AJ, Taylor JA, et al. Folate and one-carbon metabolism gene polymorphisms and their associations with oral facial clefts. Am J Med Genet A. 2008;146A(4):440-449.  (PubMed)

55.  Boyles AL, Wilcox AJ, Taylor JA, et al. Oral facial clefts and gene polymorphisms in metabolism of folate/one-carbon and vitamin A: a pathway-wide association study. Genet Epidemiol. 2009;33(3):247-255.  (PubMed)

56.  Luo YL, Cheng YL, Ye P, Wang W, Gao XH, Chen Q. Association between MTHFR polymorphisms and orofacial clefts risk: a meta-analysis. Birth Defects Res A Clin Mol Teratol. 2012;94(4):237-244.  (PubMed)

57.  Wilcox AJ. On the importance--and the unimportance--of birthweight. Int J Epidemiol. 2001;30(6):1233-1241.  (PubMed)

58.  Fekete K, Berti C, Trovato M, et al. Effect of folate intake on health outcomes in pregnancy: a systematic review and meta-analysis on birth weight, placental weight and length of gestation. Nutr J. 2012;11:75.  (PubMed)

59.  Baker PN, Wheeler SJ, Sanders TA, et al. A prospective study of micronutrient status in adolescent pregnancy. Am J Clin Nutr. 2009;89(4):1114-1124.  (PubMed)

60.  Lee HA, Park EA, Cho SJ, et al. Mendelian randomization analysis of the effect of maternal homocysteine during pregnancy, as represented by maternal MTHFR C677T genotype, on birth weight. J Epidemiol. 2013;23(5):371-375.  (PubMed)

61.  Scholl TO, Johnson WG. Folic acid: influence on the outcome of pregnancy. Am J Clin Nutr. 2000;71(5 Suppl):1295S-1303S.  (PubMed)

62.  Vollset SE, Refsum H, Irgens LM, et al. Plasma total homocysteine, pregnancy complications, and adverse pregnancy outcomes: the Hordaland Homocysteine study. Am J Clin Nutr. 2000;71(4):962-968.  (PubMed)

63.  Wang XM, Wu HY, Qiu XJ. Methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism and risk of preeclampsia: an updated meta-analysis based on 51 studies. Arch Med Res. 2013;44(3):159-168.  (PubMed)

64.  Wen SW, Champagne J, Rennicks White R, et al. Effect of folic acid supplementation in pregnancy on preeclampsia: the folic acid clinical trial study. J Pregnancy. 2013;2013:294312.  (PubMed)

65.  Lassi ZS, Salam RA, Haider BA, Bhutta ZA. Folic acid supplementation during pregnancy for maternal health and pregnancy outcomes. Cochrane Database Syst Rev. 2013;3:CD006896.  (PubMed)

66.  Schmidt RJ, Tancredi DJ, Ozonoff S, et al. Maternal periconceptional folic acid intake and risk of autism spectrum disorders and developmental delay in the CHARGE (CHildhood Autism Risks from Genetics and Environment) case-control study. Am J Clin Nutr. 2012;96(1):80-89.  (PubMed)

67.  Crider KS, Cordero AM, Qi YP, Mulinare J, Dowling NF, Berry RJ. Prenatal folic acid and risk of asthma in children: a systematic review and meta-analysis. Am J Clin Nutr. 2013;98(5):1272-1281.  (PubMed)

68.  Brown SB, Reeves KW, Bertone-Johnson ER. Maternal folate exposure in pregnancy and childhood asthma and allergy: a systematic review. Nutr Rev. 2014;72(1):55-64.  (PubMed)

69.  Ding R, Lin S, Chen D. The association of cystathionine β synthase (CBS) T833C polymorphism and the risk of stroke: a meta-analysis. J Neurol Sci. 2012;312(1-2):26-30.  (PubMed)

70.  Seshadri N, Robinson K. Homocysteine, B vitamins, and coronary artery disease. Med Clin North Am. 2000;84(1):215-237.  (PubMed)

71.  Wald DS, Law M, Morris JK. Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. BMJ. 2002;325(7374):1202.  (PubMed)

72.  Homocysteine Studies Collaboration. Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. JAMA. 2002;288(16):2015-2022.  (PubMed)

73.  Clarke R, Halsey J, Bennett D, Lewington S. Homocysteine and vascular disease: review of published results of the homocysteine-lowering trials. J Inherit Metab Dis. 2011;34(1):83-91.  (PubMed)

74.  Huang T, Chen Y, Yang B, Yang J, Wahlqvist ML, Li D. Meta-analysis of B vitamin supplementation on plasma homocysteine, cardiovascular and all-cause mortality. Clin Nutr. 2012;31(4):448-454.  (PubMed)

75.  Voutilainen S, Rissanen TH, Virtanen J, Lakka TA, Salonen JT. Low dietary folate intake is associated with an excess incidence of acute coronary events: The Kuopio Ischemic Heart Disease Risk Factor Study. Circulation. 2001;103(22):2674-2680.  (PubMed)

76.  Brattstrom L. Vitamins as homocysteine-lowering agents. J Nutr. 1996;126(4 Suppl):1276S-1280S.  (PubMed)

77.  Rader JI. Folic acid fortification, folate status and plasma homocysteine. J Nutr. 2002;132(8 Suppl):2466S-2470S.  (PubMed)

78.  Homocysteine Lowering Trialists' Collaboration. Dose-dependent effects of folic acid on blood concentrations of homocysteine: a meta-analysis of the randomized trials. Am J Clin Nutr. 2005;82(4):806-812.  (PubMed)

79.  Malinow MR, Bostom AG, Krauss RM. Homocyst(e)ine, diet, and cardiovascular diseases: a statement for healthcare professionals from the Nutrition Committee, American Heart Association. Circulation. 1999;99(1):178-182.  (PubMed)

80.  van Meurs JB, Pare G, Schwartz SM, et al. Common genetic loci influencing plasma homocysteine concentrations and their effect on risk of coronary artery disease. Am J Clin Nutr. 2013;98(3):668-676.  (PubMed)

81.  Holmes MV, Newcombe P, Hubacek JA, et al. Effect modification by population dietary folate on the association between MTHFR genotype, homocysteine, and stroke risk: a meta-analysis of genetic studies and randomised trials. Lancet. 2011;378(9791):584-594.  (PubMed)

82.  Clarke R, Bennett DA, Parish S, et al. Homocysteine and coronary heart disease: meta-analysis of MTHFR case-control studies, avoiding publication bias. PLoS Med. 2012;9(2):e1001177.  (PubMed)

83.  Ji Y, Tan S, Xu Y, et al. Vitamin B supplementation, homocysteine levels, and the risk of cerebrovascular disease: A meta-analysis. Neurology. 2013;81(15):1298-1307.  (PubMed)

84.  Zhang C, Chi FL, Xie TH, Zhou YH. Effect of B-vitamin supplementation on stroke: a meta-analysis of randomized controlled trials. PLoS One. 2013;8(11):e81577.  (PubMed)

85.  Mosca L, Benjamin EJ, Berra K, et al. Effectiveness-based guidelines for the prevention of cardiovascular disease in women--2011 update: a guideline from the American Heart Association. J Am Coll Cardiol. 2011;57(12):1404-1423.  (PubMed)

86.  Wang X, Qin X, Demirtas H, et al. Efficacy of folic acid supplementation in stroke prevention: a meta-analysis. Lancet. 2007;369(9576):1876-1882.  (PubMed)

87.  Yang Q, Botto LD, Erickson JD, et al. Improvement in stroke mortality in Canada and the United States, 1990 to 2002. Circulation. 2006;113(10):1335-1343.  (PubMed)

88.  Lorenz MW, Markus HS, Bots ML, Rosvall M, Sitzer M. Prediction of clinical cardiovascular events with carotid intima-media thickness: a systematic review and meta-analysis. Circulation. 2007;115(4):459-467.  (PubMed)

89.  Qin X, Xu M, Zhang Y, et al. Effect of folic acid supplementation on the progression of carotid intima-media thickness: a meta-analysis of randomized controlled trials. Atherosclerosis. 2012;222(2):307-313.  (PubMed)

90.  de Bree A, van Mierlo LA, Draijer R. Folic acid improves vascular reactivity in humans: a meta-analysis of randomized controlled trials. Am J Clin Nutr. 2007;86(3):610-617.  (PubMed)

91.  McNeil CJ, Beattie JH, Gordon MJ, Pirie LP, Duthie SJ. Nutritional B vitamin deficiency disrupts lipid metabolism causing accumulation of proatherogenic lipoproteins in the aorta adventitia of ApoE null mice. Mol Nutr Food Res. 2012;56(7):1122-1130.  (PubMed)

92.  Blount BC, Mack MM, Wehr CM, et al. Folate deficiency causes uracil misincorporation into human DNA and chromosome breakage: implications for cancer and neuronal damage. Proc Natl Acad Sci U S A. 1997;94(7):3290-3295.  (PubMed)

93.  Narayanan S, McConnell J, Little J, et al. Associations between two common variants C677T and A1298C in the methylenetetrahydrofolate reductase gene and measures of folate metabolism and DNA stability (strand breaks, misincorporated uracil, and DNA methylation status) in human lymphocytes in vivo. Cancer Epidemiol Biomarkers Prev. 2004;13(9):1436-1443.  (PubMed)

94.  Rahman L, Voeller D, Rahman M, et al. Thymidylate synthase as an oncogene: a novel role for an essential DNA synthesis enzyme. Cancer Cell. 2004;5(4):341-351.  (PubMed)

95.  Hubner RA, Liu JF, Sellick GS, Logan RF, Houlston RS, Muir KR. Thymidylate synthase polymorphisms, folate and B-vitamin intake, and risk of colorectal adenoma. Br J Cancer. 2007;97(10):1449-1456.  (PubMed)

96.  Desmoulin SK, Wang L, Polin L, et al. Functional loss of the reduced folate carrier enhances the antitumor activities of novel antifolates with selective uptake by the proton-coupled folate transporter. Mol Pharmacol. 2012;82(4):591-600.  (PubMed)

97.  Crider KS, Yang TP, Berry RJ, Bailey LB. Folate and DNA methylation: a review of molecular mechanisms and the evidence for folate's role. Adv Nutr. 2012;3(1):21-38.  (PubMed)

98.  Butrum RR, Clifford CK, Lanza E. NCI dietary guidelines: rationale. Am J Clin Nutr. 1988;48(3 Suppl):888-895.  (PubMed)

99.  Crider KS, Bailey LB, Berry RJ. Folic acid food fortification-its history, effect, concerns, and future directions. Nutrients. 2011;3(3):370-384.  (PubMed)

100.  Qin X, Cui Y, Shen L, et al. Folic acid supplementation and cancer risk: A meta-analysis of randomized controlled trials. Int J Cancer. 2013;133(5):1033-1041.  (PubMed)

101.  Vollset SE, Clarke R, Lewington S, et al. Effects of folic acid supplementation on overall and site-specific cancer incidence during the randomised trials: meta-analyses of data on 50,000 individuals. Lancet. 2013;381(9871):1029-1036.  (PubMed)

102.  Kim DH, Smith-Warner SA, Spiegelman D, et al. Pooled analyses of 13 prospective cohort studies on folate intake and colon cancer. Cancer Causes Control. 2010;21(11):1919-1930.  (PubMed)

103.  Gibson TM, Weinstein SJ, Pfeiffer RM, et al. Pre- and postfortification intake of folate and risk of colorectal cancer in a large prospective cohort study in the United States. Am J Clin Nutr. 2011;94(4):1053-1062.  (PubMed)

104.  Stevens VL, McCullough ML, Sun J, Jacobs EJ, Campbell PT, Gapstur SM. High levels of folate from supplements and fortification are not associated with increased risk of colorectal cancer. Gastroenterology. 2011;141(1):98-105, 105 e101.  (PubMed)

105.  Zschabitz S, Cheng TY, Neuhouser ML, et al. B vitamin intakes and incidence of colorectal cancer: results from the Women's Health Initiative Observational Study cohort. Am J Clin Nutr. 2013;97(2):332-343.  (PubMed)

106.  Keum N, Giovannucci EL. Folic acid fortification and colorectal cancer risk. Am J Prev Med. 2014;46(3 Suppl 1):S65-72.  (PubMed)

107.  Kennedy DA, Stern SJ, Moretti M, et al. Folate intake and the risk of colorectal cancer: a systematic review and meta-analysis. Cancer Epidemiol. 2011;35(1):2-10.  (PubMed)

108.  Kim YI. Folate: a magic bullet or a double edged sword for colorectal cancer prevention? Gut. 2006;55(10):1387-1389.  (PubMed)

109.  Paspatis GA, Kalafatis E, Oros L, Xourgias V, Koutsioumpa P, Karamanolis DG. Folate status and adenomatous colonic polyps. A colonoscopically controlled study. Dis Colon Rectum. 1995;38(1):64-67; discussion 67-68.  (PubMed)

110.  Jaszewski R, Misra S, Tobi M, et al. Folic acid supplementation inhibits recurrence of colorectal adenomas: a randomized chemoprevention trial. World J Gastroenterol. 2008;14(28):4492-4498.  (PubMed)

111.  Wu K, Platz EA, Willett WC, et al. A randomized trial on folic acid supplementation and risk of recurrent colorectal adenoma. Am J Clin Nutr. 2009;90(6):1623-1631.  (PubMed)

112.  Logan RF, Grainge MJ, Shepherd VC, Armitage NC, Muir KR. Aspirin and folic acid for the prevention of recurrent colorectal adenomas. Gastroenterology. 2008;134(1):29-38.  (PubMed)

113.  Figueiredo JC, Mott LA, Giovannucci E, et al. Folic acid and prevention of colorectal adenomas: a combined analysis of randomized clinical trials. Int J Cancer. 2011;129(1):192-203.  (PubMed)

114.  Kennedy DA, Stern SJ, Matok I, et al. Folate intake, MTHFR polymorphisms, and the risk of colorectal cancer: a systematic review and meta-analysis. J Cancer Epidemiol. 2012;2012:952508.  (PubMed)

115.  Ding W, Zhou DL, Jiang X, Lu LS. Methionine synthase A2756G polymorphism and risk of colorectal adenoma and cancer: evidence based on 27 studies. PLoS One. 2013;8(4):e60508.  (PubMed)

116.  Nan H, Lee JE, Rimm EB, Fuchs CS, Giovannucci EL, Cho E. Prospective study of alcohol consumption and the risk of colorectal cancer before and after folic acid fortification in the United States. Ann Epidemiol. 2013;23(9):558-563.  (PubMed)

117.  Slattery ML, Potter JD, Samowitz W, Schaffer D, Leppert M. Methylenetetrahydrofolate reductase, diet, and risk of colon cancer. Cancer Epidemiol Biomarkers Prev. 1999;8(6):513-518.  (PubMed)

118.  Ma J, Stampfer MJ, Giovannucci E, et al. Methylenetetrahydrofolate reductase polymorphism, dietary interactions, and risk of colorectal cancer. Cancer Res. 1997;57(6):1098-1102.  (PubMed)

119.  Larsson SC, Giovannucci E, Wolk A. Folate and risk of breast cancer: a meta-analysis. J Natl Cancer Inst. 2007;99(1):64-76.  (PubMed)

120.  Liu M, Cui LH, Ma AG, Li N, Piao JM. Lack of effects of dietary folate intake on risk of breast cancer: an updated meta-analysis of prospective studies. Asian Pac J Cancer Prev. 2014;15(5):2323-2328.  (PubMed)

121.  Brooks PJ, Zakhari S. Moderate alcohol consumption and breast cancer in women: from epidemiology to mechanisms and interventions. Alcohol Clin Exp Res. 2013;37(1):23-30.  (PubMed)

122.  Rohan TE, Jain MG, Howe GR, Miller AB. Dietary folate consumption and breast cancer risk. J Natl Cancer Inst. 2000;92(3):266-269.  (PubMed)

123.  Sellers TA, Kushi LH, Cerhan JR, et al. Dietary folate intake, alcohol, and risk of breast cancer in a prospective study of postmenopausal women. Epidemiology. 2001;12(4):420-428.  (PubMed)

124.  Zhang S, Hunter DJ, Hankinson SE, et al. A prospective study of folate intake and the risk of breast cancer. JAMA. 1999;281(17):1632-1637.  (PubMed)

125.  Tjonneland A, Christensen J, Olsen A, et al. Alcohol intake and breast cancer risk: the European Prospective Investigation into Cancer and Nutrition (EPIC). Cancer Causes Control. 2007;18(4):361-373.  (PubMed)

126.  Bassett JK, Baglietto L, Hodge AM, et al. Dietary intake of B vitamins and methionine and breast cancer risk. Cancer Causes Control. 2013;24(8):1555-1563.  (PubMed)

127.  Wang J, Wang B, Bi J, Di J. The association between two polymorphisms in the TYMS gene and breast cancer risk: a meta-analysis. Breast Cancer Res Treat. 2011;128(1):203-209.  (PubMed)

128.  Weiner AS, Boyarskikh UA, Voronina EN, et al. Polymorphisms in the folate-metabolizing genes MTR, MTRR, and CBS and breast cancer risk. Cancer Epidemiol. 2012;36(2):e95-e100.  (PubMed)

129.  Linabery AM, Johnson KJ, Ross JA. Childhood cancer incidence trends in association with US folic acid fortification (1986-2008). Pediatrics. 2012;129(6):1125-1133.  (PubMed)

130.  Milne E, Royle JA, Miller M, et al. Maternal folate and other vitamin supplementation during pregnancy and risk of acute lymphoblastic leukemia in the offspring. Int J Cancer. 2010;126(11):2690-2699.  (PubMed)

131.  Yan J, Yin M, Dreyer ZE, et al. A meta-analysis of MTHFR C677T and A1298C polymorphisms and risk of acute lymphoblastic leukemia in children. Pediatr Blood Cancer. 2012;58(4):513-518.  (PubMed)

132.  Alzheimer's Association. 2013 Alzheimer's Disease Fact and Figures. Alzheimer's & Dementia. 9(2). Available at: http://www.alz.org/downloads/facts_figures_2013.pdf. Accessed 9/9/13.

133.  Hughes TF, Andel R, Small BJ, et al. Midlife fruit and vegetable consumption and risk of dementia in later life in Swedish twins. Am J Geriatr Psychiatry. 2010;18(5):413-420.  (PubMed)

134.  Weir DG, Scott JM. Brain function in the elderly: role of vitamin B12 and folate. Br Med Bull. 1999;55(3):669-682.  (PubMed)

135.  Faux NG, Ellis KA, Porter L, et al. Homocysteine, vitamin B12, and folic acid levels in Alzheimer's disease, mild cognitive impairment, and healthy elderly: baseline characteristics in subjects of the Australian Imaging Biomarker Lifestyle study. J Alzheimers Dis. 2011;27(4):909-922.  (PubMed)

136.  Van Dam F, Van Gool WA. Hyperhomocysteinemia and Alzheimer's disease: A systematic review. Arch Gerontol Geriatr. 2009;48(3):425-430.  (PubMed)

137. Morris MC, Evans DA, Bienias JL, et al. Dietary folate and vitamin B12 intake and cognitive decline among community-dwelling older persons. Arch Neurol. 2005;62(4):641-645.  (PubMed)

138.  Morris MC, Evans DA, Schneider JA, Tangney CC, Bienias JL, Aggarwal NT. Dietary folate and vitamins B-12 and B-6 not associated with incident Alzheimer's disease. J Alzheimers Dis. 2006;9(4):435-443.  (PubMed)

139.  Wald DS, Kasturiratne A, Simmonds M. Serum homocysteine and dementia: meta-analysis of eight cohort studies including 8669 participants. Alzheimers Dement. 2011;7(4):412-417.  (PubMed)

140.  Ho RC, Cheung MW, Fu E, et al. Is high homocysteine level a risk factor for cognitive decline in elderly? A systematic review, meta-analysis, and meta-regression. Am J Geriatr Psychiatry. 2011;19(7):607-617.  (PubMed)

141.  Nilforooshan R, Broadbent D, Weaving G, et al. Homocysteine in Alzheimer's disease: role of dietary folate, vitamin B6 and B12. Int J Geriatr Psychiatry. 2011;26(8):876-877.  (PubMed)

142.  Wald DS, Kasturiratne A, Simmonds M. Effect of folic acid, with or without other B vitamins, on cognitive decline: meta-analysis of randomized trials. Am J Med. 2010;123(6):522-527 e522.  (PubMed)

143.  Ford AH, Almeida OP. Effect of homocysteine lowering treatment on cognitive function: a systematic review and meta-analysis of randomized controlled trials. J Alzheimers Dis. 2012;29(1):133-149.  (PubMed)

144.  Nachum-Biala Y, Troen AM. B-vitamins for neuroprotection: narrowing the evidence gap. Biofactors. 2012;38(2):145-150.  (PubMed)

145.  Smith AD, Smith SM, de Jager CA, et al. Homocysteine-lowering by B vitamins slows the rate of accelerated brain atrophy in mild cognitive impairment: a randomized controlled trial. PLoS One. 2010;5(9):e12244.  (PubMed)

146.  Douaud G, Refsum H, de Jager CA, et al. Preventing Alzheimer's disease-related gray matter atrophy by B-vitamin treatment. Proc Natl Acad Sci U S A. 2013;110(23):9523-9528.  (PubMed)

147.  Watkins D, Rosenblatt DS. Update and new concepts in vitamin responsive disorders of folate transport and metabolism. J Inherit Metab Dis. 2012;35(4):665-670.  (PubMed)

148.  Zhao R, Min SH, Qiu A, et al. The spectrum of mutations in the PCFT gene, coding for an intestinal folate transporter, that are the basis for hereditary folate malabsorption. Blood. 2007;110(4):1147-1152.  (PubMed)

149.  Borzutzky A, Crompton B, Bergmann AK, et al. Reversible severe combined immunodeficiency phenotype secondary to a mutation of the proton-coupled folate transporter. Clin Immunol. 2009;133(3):287-294.  (PubMed)

150.  Sofer Y, Harel L, Sharkia M, Amir J, Schoenfeld T, Straussberg R. Neurological manifestations of folate transport defect: case report and review of the literature. J Child Neurol. 2007;22(6):783-786.  (PubMed)

151.  Diop-Bove N, Kronn D, Goldman ID. Hereditary folate malabsorption. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong CT, Stephens K, eds. GeneReviews™ [Internet]. Seattle, WA: University of Washington, Seattle; 2008.  (PubMed)

152.  Frye RE, Sequeira JM, Quadros EV, James SJ, Rossignol DA. Cerebral folate receptor autoantibodies in autism spectrum disorder. Mol Psychiatry. 2013;18(3):369-381.  (PubMed)

153.  Grapp M, Just IA, Linnankivi T, et al. Molecular characterization of folate receptor 1 mutations delineates cerebral folate transport deficiency. Brain. 2012;135(Pt 7):2022-2031.  (PubMed)

154.  Ramaekers VT, Blau N, Sequeira JM, Nassogne MC, Quadros EV. Folate receptor autoimmunity and cerebral folate deficiency in low-functioning autism with neurological deficits. Neuropediatrics. 2007;38(6):276-281.  (PubMed)

155.  Ramaekers VT, Hausler M, Opladen T, Heimann G, Blau N. Psychomotor retardation, spastic paraplegia, cerebellar ataxia and dyskinesia associated with low 5-methyltetrahydrofolate in cerebrospinal fluid: a novel neurometabolic condition responding to folinic acid substitution. Neuropediatrics. 2002;33(6):301-308.  (PubMed)

156.  Banka S, Blom HJ, Walter J, et al. Identification and characterization of an inborn error of metabolism caused by dihydrofolate reductase deficiency. Am J Hum Genet. 2011;88(2):216-225.  (PubMed)

157.  Cario H, Smith DE, Blom H, et al. Dihydrofolate reductase deficiency due to a homozygous DHFR mutation causes megaloblastic anemia and cerebral folate deficiency leading to severe neurologic disease. Am J Hum Genet. 2011;88(2):226-231.  (PubMed)

158.  Pfeiffer CM, Hughes JP, Lacher DA, et al. Estimation of trends in serum and RBC folate in the US population from pre- to postfortification using assay-adjusted data from the NHANES 1988-2010. J Nutr. 2012;142(5):886-893.  (PubMed)

159.  Folate. In: Hendler SS, Rorvik, D.R., ed. PDR for Nutritional Supplements. 2nd ed. Montvale: Physicians' Desk Reference Inc.; 2008.

160.  Wiesinger H, Eydeler U, Richard F, et al. Bioequivalence evaluation of a folate-supplemented oral contraceptive containing ethinylestradiol/drospirenone/levomefolate calcium versus ethinylestradiol/drospirenone and levomefolate calcium alone. Clin Drug Investig. 2012;32(10):673-684.  (PubMed)

161.  Tinker SC, Cogswell ME, Devine O, Berry RJ. Folic acid intake among US women aged 15-44 years, National Health and Nutrition Examination Survey, 2003-2006. Am J Prev Med. 2010;38(5):534-542.  (PubMed)

162.  Kelly P, McPartlin J, Goggins M, Weir DG, Scott JM. Unmetabolized folic acid in serum: acute studies in subjects consuming fortified food and supplements. Am J Clin Nutr. 1997;65(6):1790-1795.  (PubMed)

163.  Morris MS, Jacques PF, Rosenberg IH, Selhub J. Folate and vitamin B-12 status in relation to anemia, macrocytosis, and cognitive impairment in older Americans in the age of folic acid fortification. Am J Clin Nutr. 2007;85(1):193-200.  (PubMed)

164.  Morris MS, Jacques PF, Rosenberg IH, Selhub J. Circulating unmetabolized folic acid and 5-methyltetrahydrofolate in relation to anemia, macrocytosis, and cognitive test performance in American seniors. Am J Clin Nutr. 2010;91(6):1733-1744.  (PubMed)

165.  Troen AM, Mitchell B, Sorensen B, et al. Unmetabolized folic acid in plasma is associated with reduced natural killer cell cytotoxicity among postmenopausal women. J Nutr. 2006;136(1):189-194.  (PubMed)

166.  Tam C, O'Connor D, Koren G. Circulating unmetabolized folic acid: relationship to folate status and effect of supplementation. Obstet Gynecol Int. 2012;2012:485179.  (PubMed)

167.  Apeland T, Mansoor MA, Strandjord RE. Antiepileptic drugs as independent predictors of plasma total homocysteine levels. Epilepsy Res. 2001;47(1-2):27-35.  (PubMed)

168.  Wilson SM, Bivins BN, Russell KA, Bailey LB. Oral contraceptive use: impact on folate, vitamin B(6), and vitamin B(1)(2) status. Nutr Rev. 2011;69(10):572-583.  (PubMed)

Niacin

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Summary

  • Niacin and its derivative nicotinamide are dietary precursors of nicotinamide adenine dinucleotide (NAD), which can be phosphorylated (NADP) and reduced (NADH and NADPH). NAD functions in oxidation-reduction (redox) reactions and non-redox reactions. (More information)
  • Pellagra is the disease of severe niacin deficiency. It is characterized by symptoms affecting the skin, the digestive system, and the nervous system and can lead to death if left untreated. (More information)
  • Dietary tryptophan can be converted to niacin, although the efficiency of conversion is low in humans and affected by deficiencies in other nutrients. (More information)
  • Causes of niacin deficiency include inadequate oral intake, poor bioavailability from unlimed grains, defective tryptophan absorption, metabolic disorders, and the long-term use of chemotherapeutic treatments. (More information)
  • The requirements for niacin are based on the urinary excretion of niacin metabolites. (More information)
  • NAD is the sole substrate for PARP enzymes involved in DNA repair activity in response to DNA strand breaks; thus, NAD is critical for genome stability. Several studies, mostly using in vitro and animal models, suggest a possible role for niacin in cancer prevention. Nevertheless, large studies are needed to investigate the association between niacin deficiency and cancer risk in human populations. (More information)
  • Despite promising initial results, nicotinamide administration has failed to prevent or delay the onset of type 1 diabetes in high-risk relatives of type 1 diabetics. Future research might explore the use of nicotinamide in combined therapy and evaluate activators of NAD-dependent enzymes. (More information)
  • At pharmacologic doses, niacin, but not nicotinamide, improves the lipid profile and reduces coronary events and total mortality in patients at high risk for coronary heart disease. Several clinical trials have explored the cardiovascular benefit of niacin in combination with other lipid-lowering medications. (More information)
  • Elevated tryptophan breakdown and niacin deficiency have been reported in HIV-positive people. This population is also at high risk for cardiovascular disease, and current data show that they could benefit from niacin supplementation. (More information)
  • The tolerable upper intake level (UL) for niacin is based on skin flushing, niacin's most prominent side effect. A new drug, laropiprant, has been developed to reduce skin flushing. Adverse effects have also been reported with pharmacologic doses of niacin administrated alone or in combination with other lipid-lowering medications. (More information)

Niacin is a water-soluble vitamin, which is also known as nicotinic acid or vitamin B3. Nicotinamide is the derivative of niacin and used by the body to form the coenzymes nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). The chemical structures of the various forms of niacin are shown (Figure 1). None of the forms are related to the nicotine found in tobacco, although their names are similar (1).

Figure 1. Chemical Structures of Niacin and Related Compounds. Niacin is also known as nicotinic acid or vitamin B3. nicotinamide is the derivative of niacin that is used to form the coenzymes NAD and NADP.

Function

Oxidation-reduction (redox) reactions

Living organisms derive most of their energy from oxidation-reduction (redox) reactions, which are processes involving the transfer of electrons. Over 400 enzymes require the niacin coenzymes, NAD and NADP, mainly to accept or donate electrons for redox reactions (2). NAD functions most often in energy-producing reactions involving the degradation (catabolism) of carbohydrates, fats, proteins, and alcohol. NADP functions more often in biosynthetic (anabolic) reactions, such as in the synthesis of all macromolecules, including fatty acids and cholesterol (1, 3).

Non-redox reactions

The niacin coenzyme, NAD, is the substrate (reactant) for at least four classes of enzymes that separate the nicotinamide moiety from NAD and transfer ADP-ribose to acceptors.

Mono-ADP-ribosyltransferase enzymes were first discovered in certain bacteria, where they mediate the action of toxins, such as cholera and diptheria. In mammalian cells, these enzymes transfer an ADP-ribose residue from NAD to a specific amino acid of a target protein, with the creation of an ADP-ribosylated protein and the release of nicotinamide. Mono ADP-ribosylation reactions reversibly modify the activity of acceptor proteins, such as G-proteins that bind guanosine-5'-triphosphate (GTP) and act as intermediaries in a number of cell-signaling pathways (4).

Poly-ADP-ribose polymerases (PARPs) are enzymes that catalyze the transfer of polymers of ADP-ribose from NAD to acceptor proteins. PARPs appear to function in DNA repair and stress responses, cell signaling, transcription, regulation, apoptosis, chromatin structure, and cell differentiation, suggesting a role for NAD in cancer prevention (3). At least six different PARPs have been identified, and although their functions are not yet fully understood, their existence indicates a potential for considerable consumption of NAD (5, 6).

A new nomenclature has been proposed for enzymes catalyzing ADP-ribosylation: The PARP family was renamed ARTD, while ARTC designates the mono ADP-ribosyltransferase family (6).

ADP-ribosylcyclases catalyze the formation of cyclic ADP-ribose from ADP-ribose. Cyclic ADP-ribose works within cells to provoke the release of calcium ions from internal storage sites and probably also plays a role in cell signaling (1).

Sirtuins are a class of NAD-dependent deacetylase enzymes that remove acetyl groups from the acetylated lysine residues of target proteins. During the deacetylation process, an ADP-ribose is added to the acetyl group to produce O-acetyl-ADP-ribose. Both acetylation and ADP-ribosylation are known post-translational modifications that affect protein activities. The initial interest in sirtuins followed the discovery that their activation could mimic calorie restriction, which has been shown to increase lifespan in lower organisms. Such a role in mammals is controversial, although sirtuins are energy-sensing regulators involved in signaling pathways that could play important roles in delaying the onset of age-related diseases (e.g., cardiovascular disease, cancer, dementia, arthritis). To date, the spectrum of their biological functions include gene silencing, DNA damage repair, cell cycle regulation, and cell differentiation (7).

Deficiency

Pellagra

The late stage of severe niacin deficiency is known as pellagra. Early records of pellagra followed the widespread cultivation of corn in Europe in the 1700s (1). The disease is generally associated with poorer social classes whose chief dietary staple consisted of cereals like corn or sorghum. Pellagra was also common in the southern United States during the early 1900s where income was low and corn products were a major dietary staple (8). Interestingly, pellagra was not known in Mexico, where corn was also an important dietary staple and much of the population was also poor. In fact, corn contains appreciable amounts of niacin, but it is present in a bound form that is not nutritionally available to humans. The traditional preparation of corn tortillas in Mexico involves soaking the corn in a lime (calcium oxide) solution, prior to cooking. Heating the corn in an alkaline solution results in the release of bound niacin, increasing its bioavailability (9).

The most common symptoms of niacin deficiency involve the skin, the digestive system, and the nervous system (3). The symptoms of pellagra are commonly referred to as the three D's: dermatitis, diarrhea, and dementia. A fourth D, death, occurs if pellagra is left untreated (10). In the skin, a thick, scaly, darkly pigmented rash develops symmetrically in areas exposed to sunlight. In fact, the word "pellagra" comes from "pelle agra," the Italian phrase for rough or raw skin. Symptoms related to the digestive system include inflammation of the mouth and tongue ("bright red tongue"), vomiting, constipation, abdominal pain, and ultimately, diarrhea. Gastrointestinal disorders and diarrhea contribute to the ongoing malnourishment of the subjects. Neurologic symptoms include headache, apathy, fatigue, depression, disorientation, and memory loss and are more consistent with delirium than with the historically described dementia (11). Disease presentations vary in appearance since the classic triad rarely presents in its entirety. The absence of dermatitis, for example, is known as pellagra sine pellagra.

Treatment of pellagra

To treat pellagra, the World Health Organization (WHO) recommends administering nicotinamide to avoid the flushing commonly caused by niacin (see Safety). Treatment guidelines suggest using 300 mg nicotinamide per day orally in divided doses, or 100 mg per day parenterally in divided doses, for three to four weeks (12, 13). Because patients with pellagra often display additional vitamin deficiencies, administration of a vitamin B-complex preparation is advised.

Tryptophan metabolism

In addition to its synthesis from dietary niacin, NAD can be synthesized from the dietary amino acid tryptophan via the kynurenine pathway (see Figure 2 below). The relative ability to make this conversion varies greatly from mice to humans. The first step is catalyzed by the extrahepatic enzyme indoleamine 2,3-dioxygenase (IDO), which is responsible for the oxidative cleavage of tryptophan. The chronic stimulation of tryptophan oxidation, mediated by an increased activity of IDO and/or inadequate niacin levels, is observed in a number of diseases, including human immunodeficiency virus (HIV) infection (see HIV/AIDS). In healthy individuals, less than 2% of dietary tryptophan is converted to NAD by this tryptophan oxidation pathway (14). Tryptophan metabolism plays an essential regulatory role by mediating immunological tolerance of the fetus during pregnancy (15). It is now understood that tryptophan oxidation in the placenta drives a physiologic tryptophan depletion that impairs the function of nearby maternal T-lymphocytes and prevents the rejection of the fetus. However, the synthesis of niacin from tryptophan is a fairly inefficient pathway that depends on enzymes requiring vitamin B6 and riboflavin, as well as an enzyme containing heme (iron). On average, 1 milligram (mg) of niacin can be synthesized from the ingestion of 60 mg of tryptophan. The term "niacin equivalent" (NE) is used to describe the contribution to dietary intake of all the forms of niacin that are available to the body. Thus, 60 mg of tryptophan are considered to be 1 mg NE. However, studies of pellagra in the southern US during the early twentieth century indicated that the diets of many individuals who suffered from pellagra contained enough NE to prevent pellagra (10), challenging the idea that 60 mg of dietary tryptophan are equivalent to 1 mg of niacin. In particular, one study in young men found that the tryptophan content of the diet had no effect on the decrease in red blood cell niacin content that resulted from low dietary niacin (16).

Figure 2. Niacin Metabolism. As explained in the article text, NAD can be synthesized from dietary niacin or nicotinamide, in addition from the dietary amino acid, tryptophan, via the kynuremine pathway. NAD participates in redox reactions. Also explained in the text, the activation of PARP enzymes by oxidative damage to DNA could be responsible for inducing NAD/niacin depletion.

Causes of niacin deficiency

Niacin deficiency or pellagra may result from inadequate dietary intake of niacin and/or tryptophan. As mentioned above, other nutrient deficiencies may also contribute to the development of niacin deficiency. Niacin deficiency, often associated with malnutrition, is observed in the homeless population, in individuals suffering from anorexia nervosa or obesity, and in consumers of diets high in maize and poor in animal proteins (17-20). Patients with Hartnup's disease, a hereditary disorder resulting in defective tryptophan absorption, have developed pellagra (3). Other malabsorptive states that can lead to pellagra include Crohn's disease and megaduodenum (21, 22). Carcinoid syndrome, a condition of increased secretion of serotonin and other catecholamines by carcinoid tumors, may also result in pellagra due to increased utilization of dietary tryptophan for serotonin rather than niacin synthesis. Further, prolonged treatment with the anti-tuberculosis drug Isoniazid has resulted in niacin deficiency (23). Other pharmaceutical agents, including the immunosuppressive drugs Azathioprine and 6-Mercaptopurine, the anti-cancer drug 5-Fluorouracil, and Carbidopa, a drug given to people with Parkinson's disease, are known to increase the reliance on dietary niacin by interfering with the tryptophan-kynurenine-niacin pathway. Finally, other populations at risk for niacin deficiency include dialysis patients, cancer patients (13, 24), individuals suffering from chronic alcoholism (11), and people with HIV (see HIV/AIDS).

The Recommended Dietary Allowance (RDA)

The RDA for niacin, revised in 1998, is based on the prevention of deficiency (Table 1). Pellagra can be prevented by about 11 mg NE/day, but 12 mg to 16 mg/day has been found to normalize the urinary excretion of niacin metabolites (breakdown products) in healthy young adults. Because pellagra represents severe deficiency, the Food and Nutrition Board (FNB) of the US Institute of Medicine chose to use the excretion of niacin metabolites as an indicator of niacin nutritional status rather than symptoms of pellagra (25). However, some researchers feel that cellular NAD and NADP content may be more relevant indicators of niacin nutritional status (16, 26, 27).

Table 1. Recommended Dietary Allowance (RDA) for Niacin
Life Stage Age Males (mg NE*/day) Females (mg NE/day)
Infants 0-6 months 2 (AI 2 (AI) 
Infants  7-12 months  4 (AI)  4 (AI) 
Children  1-3 years 
Children  4-8 years 
Children  9-13 years  12  12 
Adolescents  14-18 years  16  14 
Adults  19 years and older  16  14 
Pregnancy  all ages  18 
Breast-feeding  all ages  17
*NE, niacin equivalent: 1 mg NE = 60 mg of tryptophan = 1 mg niacin

Disease Prevention

Cancer

Studies of cultured cells (in vitro) provide evidence that NAD content influences mechanisms that maintain genomic stability. Loss of genomic stability, characterized by a high rate of damage to DNA and chromosomes, is a hallmark of cancer (28). The current understanding is that the pool of NAD is decreased during niacin deficiency and that it affects the activity of NAD-consuming enzymes rather than redox and metabolic functions (29). Among NAD-dependent reactions, poly ADP-ribosylations catalyzed by PARP enzymes are critical for the cellular response to DNA injury. After DNA damage, PARPs are activated. The subsequent poly ADP-ribosylations of a number of signaling and structural molecules by PARPs were shown to facilitate DNA repair at DNA strand breaks. Cellular depletion of NAD has been found to decrease levels of the tumor suppressor protein p53, a target for poly ADP-ribosylation, in human breast, skin, and lung cells (27). The expression of p53 was also altered by niacin deficiency in rat bone marrow cells (30). Impairment of DNA repair caused by niacin deficiency could lead to genomic instability and drive tumor development in rat models (31, 32). Both PARPs and sirtuins have been recently involved in the maintenance of heterochromatin, a chromosomal domain associated with genome stability, as well as in transcriptional gene silencing, telomere integrity, and chromosome segregation during cell division (33, 34). Neither the cellular NAD content nor the dietary intake of NAD precursors (niacin and tryptophan) necessary for optimizing protective responses following DNA damage has been determined, but both are likely to be higher than that required for the prevention of pellagra.

Bone marrow

Cancer patients often suffer from bone marrow suppression following chemotherapy, given that bone marrow is one of the most proliferative tissues in the body and thus a primary target for chemotherapeutic agents. Niacin deficiency was found to decrease bone marrow NAD and poly-ADP-ribose levels and increase the risk of chemically induced leukemia in rats (35). Conversely, a pharmacologic dose of niacin was able to increase NAD and poly ADP-ribose in bone marrow and decrease the development of leukemia in rats (36). It has been suggested that niacin deficiency often observed in cancer patients could sensitize bone marrow tissue to the suppressive effect of chemotherapy. However, little is known regarding cellular NAD levels and the prevention of DNA damage or cancer in humans. One study in two healthy individuals involved elevating NAD levels in blood lymphocytes by supplementation with 100 mg/day niacin for eight weeks. Compared to non-supplemented individuals, the supplemented individuals had reduced DNA strand breaks in lymphocytes exposed to free radicals in a test tube assay (37). However, niacin supplementation of up to 100 mg/day in 21 healthy smokers failed to provide any evidence of a decrease in cigarette smoke-induced genetic damage in blood lymphocytes compared to placebo (38). More recently, the frequency of chromosome translocation was used to evaluate DNA damage in peripheral blood lymphocytes of 82 pilots chronically exposed to ionizing radiation, a known human carcinogen. In this observational study, the rate of chromosome aberrations was significantly lower in subjects with high (28.4 mg/day) compared to low (20.5 mg/day) dietary niacin intake (39).

Upper digestive tract

Generally, relationships between dietary factors and cancer are established first in epidemiological studies and followed up by basic cancer research at the cellular level. In the case of niacin, research on biochemical and cellular aspects of DNA repair has stimulated an interest in the relationship between niacin intake and cancer risk in human populations (40). A large case-control study found increased consumption of niacin, along with antioxidant nutrients, to be associated with decreased incidence of oral (mouth), pharyngeal (throat), and esophageal cancers in northern Italy and Switzerland (41, 42). An increase in daily niacin intake of 6.2 mg was associated with about a 40% decrease in cases of cancers of the mouth and throat, while a 5.2 mg increase in daily niacin intake was associated with a similar decrease in cases of esophageal cancer.

Skin

Niacin deficiency can lead to severe sunlight sensitivity in exposed skin. Given the implication of NAD-dependent enzymes in DNA repair, there has been some interest in the effect of niacin on skin health. In vitro and animal experiments have helped gather information, but human data on niacin/NAD status and skin cancer are severely limited. One study reported that niacin supplementation decreased the risk of ultraviolet light (UV)-induced skin cancers in mice, despite the fact that mice convert tryptophan to NAD more efficiently than rats and humans and thus do not get severely deficient (43). Hyper-proliferation and impaired differentiation of skin cells can alter the integrity of the skin barrier and increase the occurrence of pre-malignant and malignant skin conditions. A protective effect of niacin was suggested by topical application of myristyl nicotinate, a niacin derivative, which successfully increased the expression of epidermal differentiation markers in subjects with photodamaged skin (44). The activation of the "niacin receptors," GPR109A and GPR109B, by pharmacologic doses of niacin could be involved in improving skin barrier function. Conversely, differentiation defects in skin cancer cells were linked to the abnormal cellular localization of defective "niacin receptors" (45). Nicotinamide restriction with subsequent depletion of cellular NAD was shown to increase oxidative stress-induced DNA damage in a precancerous skin cell model, implying a protective role of NAD-dependent pathways in cancer (46). Altered NAD availability also affects sirtuin expression and activity in UV-exposed human skin cells. Along with PARPs, NAD-consuming sirtuins could play an important role in the cellular response to photodamage and skin homeostasis (47).

Type 1 diabetes mellitus

Type 1 (insulin-dependent) diabetes mellitus in children is known to result from the autoimmune destruction of insulin-secreting β-cells in the pancreas. Prior to the onset of symptomatic diabetes, specific antibodies, including islet cell antibodies (ICA), can be detected in the blood of high-risk individuals. The ability to detect individuals at high risk for the development of IDDM led to the enrollment of high-risk siblings of children with IDDM into trials designed to prevent its onset. Evidence from in vitro and animal research indicates that high levels of nicotinamide protect β-cells from damage by toxic chemicals, inflammatory white blood cells, and reactive oxygen species. Pharmacologic doses of nicotinamide (up to 3 grams/day) were first used to protect β-cells in patients shortly after the onset of IDDM. An analysis of 10 published trials (5 placebo-controlled) found evidence of improved β-cell function after one year of treatment with nicotinamide, but the analysis failed to find any clinical evidence of improved glycemic (blood glucose) control (48). However, high doses of nicotinamide could decrease insulin sensitivity in high-risk relatives of IDDM patients (49), which might explain the finding of improved β-cell function without concomitant improvement in glycemic control.

Several pilot studies for the prevention of IDDM in ICA-positive relatives of patients with IDDM yielded conflicting results, whereas a large randomized trial in school children that was not placebo-controlled found a significantly lower incidence of IDDM in the nicotinamide-treated group. A large, multicenter randomized controlled trial of nicotinamide in ICA-positive siblings of IDDM patients between 3 and 12 years of age also failed to find a difference in the incidence of IDDM after three years (48). A randomized, double-blind, placebo-controlled, multicenter trial of nicotinamide (maximum of 3 grams/day) was conducted in 552 ICA-positive relatives of patients with IDDM. The proportion of relatives who developed IDDM within five years was comparable whether they were treated with nicotinamide or placebo (50). Although inflammation-related parameters were decreased in high-risk subjects, nicotinamide was ineffective in the prevention of IDDM (51). Recently, preliminary data have examined the combination of nicotinamide with acetyl-L-carnitine and warrant further investigation (52). Interestingly, resveratrol, a sirtuin agonist, was shown to be more potent than nicotinamide in preventing chemically induced IDDM in a rat model (53).

Disease Treatment

High cholesterol and cardiovascular disease

Pharmacologic doses of niacin, but not nicotinamide, have been known to reduce serum cholesterol since 1955 (54). Today, niacin is commonly prescribed with other lipid-lowering medications. However, one randomized, placebo-controlled, multicenter trial examined the effect of niacin acid therapy, alone, on outcomes of cardiovascular disease. Specifically, the Coronary Drug Project (CDP) followed over 8,000 men with a previous myocardial infarction (heart attack) for six years (55). Compared to the placebo group, patients who took 3 grams of niacin daily experienced an average 10% reduction in total blood cholesterol, a 26% decrease in triglycerides, a 27% reduction in recurrent nonfatal myocardial infarction, and a 26% reduction in cerebrovascular events (stroke and transient ischemic attacks). Although niacin therapy did not decrease total deaths or deaths from cardiovascular disease during the six-year study period, post-trial follow up nine years later revealed a 10% reduction in total deaths with niacin treatment. Four out of five major cardiovascular outcome trials found niacin in combination with other therapies to be of statistically significant benefit in men and women (56). Niacin therapy markedly increases HDL-cholesterol levels, decreases serum Lp(a) (lipoprotein-a) concentrations, and shifts small, dense LDL particles to large, buoyant LDL particles. All of these changes in the blood lipid profile are considered cardioprotective. Low levels of HDL-cholesterol are one major risk factor for coronary heart disease (CHD), and an increase in HDL levels is associated with a reduction of that risk (57).

Because of the adverse side effects associated with high doses of niacin (see Safety), it has most often been used in combination with other lipid-lowering medications in slightly lower doses (54). In particular, LDL cholesterol-lowering statins like simvastatin form the cornerstone of treatment of hyperlipidemia, a major risk factor for CHD. The HDL-Atherosclerosis Treatment Study (HATS), a three-year randomized controlled trial in 160 patients with documented CHD and low HDL levels found that a combination of simvastatin and niacin (2 to 3 grams/day) increased HDL levels, inhibited the progression of coronary artery stenosis (narrowing), and decreased the frequency of cardiovascular events, including myocardial infarction and stroke (58). Patients with metabolic syndrome display a number of metabolic disorders, including dyslipidemia and insulin resistance, that put them at increased risk for type 2 diabetes mellitus, cardiovascular disease, and mortality. A subgroup analysis of the HATS patients with metabolic syndrome showed a reduction in rate of primary clinical events even though glucose and insulin metabolism were moderately impaired by niacin (59). Moreover, a review of niacin safety and tolerability among the HATS subjects showed glycemic control in diabetic patients returned to pretreatment values following eight months of disease management with medication and diet (60). Similarly, the cardiovascular benefit of long-term niacin therapy outweighed the modest increase in risk of newly onset type 2 diabetes in patients from the CDP study (61).

The Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) 2 study—a double-blind, placebo-controlled trial—investigated the incremental effect of adding niacin (1 gram daily) to statin therapy in 167 patients with known CHD and low HDL levels (62) on carotid intima-media thickness (CIMT), a surrogate endpoint for the development of atherosclerosis. The addition of extended-release niacin prevented the increase in CIMT compared to simvastatin monotherapy. A post-hoc analysis of data from ARBITER2 showed that the blockade of atherosclerotic progression was related to the increase in HDL levels in patients with normal glycemic status. However, in the presence of additional risk factors, such as impaired fasting glucose or diabetes, the increase in HDL levels was not predictive of CIMT reduction and atherosclerotic retardation (63). A comparative efficacy trial (ARBITER6) also showed a significant reduction of baseline CIMT with extended-release niacin (2 grams daily for 14 months), as opposed to ezetimibe (a cholesterol-lowering drug), in patients on statins (64). Additional studies are needed to address the impact of niacin in combination with statins on clinical outcomes.

The effects of niacin are dose-dependent (65). Doses of niacin higher than 1 gram/day are typically used to treat hyperlipidemia. A placebo-controlled study in 39 patients taking statins (cerivastatin, atorvastatin, or simvastatin) found that a very low dose of niacin, 100 mg daily, increased HDL cholesterol by only 2.1 mg/dL, and the combination had no effect on LDL cholesterol, total cholesterol, or triglyceride levels (66). At the pharmacologic dose required for cholesterol-lowering effects, the use of niacin should be approached as if it were a drug. Individuals should only undertake cholesterol-lowering therapy with niacin under the supervision of a qualified health care provider in order to minimize potentially adverse effects and maximize therapeutic benefits.

Although it is a nutrient, at the pharmacologic dose required for cholesterol-lowering effects, the use of nicotinic acid should be approached as if it were a drug. Individuals should only undertake cholesterol-lowering therapy with nicotinic acid under the supervision of a qualified health care provider in order to minimize potentially adverse effects and maximize therapeutic benefits.

HIV/AIDS

It has been hypothesized that infection with human immunodeficiency virus (HIV), the virus that causes acquired immmunodeficiency syndrome (AIDS), increases the risk of niacin deficiency. Interferon-γ (IFN-γ) is a cytokine produced by cells of the immune system in response to infection. IFN-γ levels are elevated in individuals infected with HIV, and higher IFN-γ levels have been associated with poorer prognoses. By stimulating the enzyme indoleamine 2,3-dioxygenase (IDO), IFN-γ increases the breakdown of tryptophan, thus supporting the finding that the average tryptophan levels in blood are significantly lower in HIV patients compared to uninfected subjects (14). The increase in tryptophan degradation that leads to de novo niacin synthesis and NAD production paralleled niacin deficiency in HIV infection (67). An explanatory model for these paradoxical observations incriminates the oxidative stress induced by multiple nutrient deficiencies in HIV patients (68). In particular, the activation of PARP enzymes by oxidative damage to DNA could be responsible for inducing niacin/NAD depletion (see Figure 2 above). The breakdown of tryptophan would then be a compensatory response to inadequate niacin/NAD levels.

Some metabolites derived from the oxidation of tryptophan in the kynurenine pathway regulate specific T-lymphocyte subgroups. As mentioned above, circulating IFN-γ, but also viral and bacterial products, can activate IDO during HIV infection. The overstimulation of the tryptophan pathway has been involved in the loss of normal T-lymphocyte function, which is characteristic of HIV. The increased IDO activity has been linked to the altered immune response that contributes to the persistence of HIV in patients receiving antiviral therapy. One therapeutic option consisting of blocking IDO using IDO inhibitor 1-methyl tryptophan was tested in a monkey model for HIV infection, the simian immunodeficiency virus (SIV)-infected rhesus macaque. However, a partial and transient blockade of the enzyme proved ineffective to reduce the viral load in plasma and intestinal tissues beyond the level achieved by antiretroviral therapy (69). Other molecules that inhibit the IDO pathway (e.g., INCB024360 and Indoximod) are being currently tested in oncology trials and could be of relevance against HIV.

An observational study of 281 HIV-positive men found that higher levels of niacin intake were associated with decreased progression rate to AIDS and improved survival (70). In a very small, uncontrolled study, treatment of four HIV positive individuals with 1 to 1.5 grams/day of nicotinamide for two months resulted in 40% increases in plasma tryptophan levels (71). Nicotinamide supplementation may prove to be useful adjunct to HIV treatment although the clinical implications are still poorly understood.

Cardiovascular disease (CVD) is the second most frequent cause of deaths in the HIV population, and the rate of CVD is predicted to increase further as patients are living longer due to successful antiretroviral therapies. Abnormal lipid profiles observed in patients have been attributed to the HIV infection and to the highly active antiretroviral treatment (HAART) (72). Moreover, insulin resistance was detected together with dyslipidemia in HAART-treated patients (73). As for the general population, statin-based therapy appears to benefit HIV patients in terms of atherogenic protection and CVD risk reduction, although contraindications exist due to drug interactions with HAART. Other first-line treatments include lipid-lowering fibrates, which are preferred to niacin due to the increased risk of glucose intolerance and insulin resistance (74). Nevertheless, an unblinded, controlled pilot study showed that extended-release niacin (0.5-1.5 grams/day for 12 weeks) could effectively improve endothelial function of the brachial artery in HAART-treated HIV subjects with low HDL and no history of CVD (75). Damaged endothelial function is an early sign of atherosclerosis before structural changes of the endothelial wall occur and has prognostic value in predicting adverse CVD outcomes. Finally, a combined treatment of fibrates, niacin, and lifestyle changes (low-fat diet and exercise) was effective in normalizing lipid parameters in a cohort of 191 HAART-treated patients. Increased risk of liver dysfunction was detected in subjects receiving both fibrates and niacin, but insulin sensitivity was not affected by niacin treatment given alone or when combined with fibrates (76).

Schizophrenia

Schizophrenia is a neurologic disorder with unclear etiology that is diagnosed purely from its clinical presentation. Because neurologic disorders associated with pellagra resemble acute schizophrenia, niacin-based therapy for the condition was investigated during the 1950s-70s (reviewed in 77). The adjunctive use of nutrients like niacin to correct deficiencies associated with neurologic symptoms is called orthomolecular psychiatry (78). Such an approach has not been included in psychiatric practice; practitioners have instead relied solely on antipsychotic drugs to eliminate the clinical symptoms of schizophrenia. Nevertheless, recent scientific advances and new hypotheses on the benefit of nutrient supplementation in the treatment of psychiatric disorders have suggested the re-assessment of orthomolecular medicine by the medical community (79, 80).

Skin flushing is one major side effect of the therapeutic use of niacin and the primary reason for non-adherence to treatment (see Toxicity). Flushing is caused by the activation of phospholipase A2, an enzyme that stimulates the production of specific lipids called prostanoids. These molecules can induce the dilation of blood vessels in the skin and trigger a flushing response. Interestingly, patients with schizophrenia tend not to flush following treatment with niacin. This blunted skin flushing response suggests abnormal prostanoid signaling in schizophrenic patients. An association has been found between the altered niacin sensitivity and greater functional impairment in schizophrenic subjects (81), which supports other findings that suggest altered lipid metabolism could critically impair brain development and contribute to the disease (82).

Sources

Food sources

Good sources of niacin include yeast, meat, poultry, red fish (e.g., tuna, salmon), cereals (especially fortified cereals), legumes, and seeds. Milk, green leafy vegetables, coffee, and tea also provide some niacin (10). In plants, especially mature cereal grains like corn and wheat, niacin may be bound to sugar molecules in the form of glycosides, which significantly decrease niacin bioavailability (9).

In the United States, the average dietary intake of niacin is about 30 mg/day for young adult men and 20 mg/day for young adult women. In a sample of adults over the age of 60, men and women were found to have an average dietary intake of 21 mg/day and 17 mg/day, respectively (25). Some foods with substantial amounts of niacin are listed in Table 2, along with their niacin content in milligrams (mg). Food composition tables generally list niacin content without including niacin equivalents (NE) from tryptophan, or any adjustment for niacin bioavailability. For more information on the nutrient content of specific foods, search the USDA food composition database; data included in Table 2 are from this database (83).

Table 2. Some Food Sources of Niacin
Food Serving Niacin (mg)
Chicken (light meat) 3 ounces* (cooked without skin) 7.3-11.7
Tuna (light, canned, packed in water) 3 ounces 8.6-11.3
Turkey (light meat) 3 ounces (cooked without skin) 10.0
Salmon (chinook) 3 ounces (cooked) 8.5
Beef (90% lean) 3 ounces (cooked) 4.4-5.8
Cereal (unfortified) 1 cup 5-7
Cereal (fortified) 1 cup 20-27
Peanuts 1 ounce (dry-roasted) 3.8
Pasta (enriched) 1 cup (cooked) 1.9-2.4
Lentils 1 cup (cooked) 2.1
Lima beans 1 cup (cooked) 0.8-1.8
Bread (whole-wheat) 1 slice 1.3
Coffee (brewed) 1 cup 0.5
*A three-ounce serving of meat is about the size of a deck of cards.

Supplements

Niacin supplements are available as nicotinamide or nicotinic acid. Nicotinamide is the form of niacin typically used in nutritional supplements and in food fortification. Niacin is available over the counter and with a prescription as a cholesterol-lowering agent (84). The nomenclature for niacin formulations can be confusing. Niacin is available over the counter in an "immediate-release" (crystalline), and a "slow-release" or "timed-release form." A shorter acting timed-release preparation referred to as "intermediate release" or "extended release" niacin is available by prescription (85, 86). Due to the potential for side effects, medical supervision is recommended for the use of niacin as a cholesterol-lowering agent.

Safety

Toxicity

Niacin from foods is not known to cause adverse effects. Although one study noted adverse effects following consumption of bagels with 60 times the normal amount of niacin fortification, most adverse effects have been reported with pharmacologic preparations of niacin (25).

Niacin

Common side effects of niacin include flushing, itching, and gastrointestinal disturbances, such as nausea and vomiting. Hepatotoxicity (liver cell damage), including elevated liver enzymes and jaundice, has been observed at intakes as low as 750 mg of niacin per day for less than three months (84, 85). Hepatitis has been observed with timed-release niacin at dosages as little as 500 mg/day for two months, although almost all reports of severe hepatitis have been associated with the timed-release form of niacin at doses of 3 to 9 grams per day used to treat high cholesterol for months or years (25). Immediate-release (crystalline) niacin appears to be less toxic to the liver than extended-release forms. Immediate-release niacin is often used at higher doses than timed-release forms, and severe liver toxicity has occurred in individuals who substituted timed-release niacin for immediate-release niacin at equivalent doses (84). Skin rashes and dry skin have been noted with niacin supplementation. Transient episodes of low blood pressure (hypotension) and headache have also been reported. Large doses of niacin have been observed to impair glucose tolerance, likely due to decreased insulin sensitivity. Impaired glucose-tolerance in susceptible (pre-diabetic) individuals could result in elevated blood glucose levels and clinical diabetes. Elevated blood levels of uric acid, occasionally resulting in attacks of gout in susceptible individuals, have also been observed with high-dose niacin therapy (85). Niacin at doses of 1.5 to 5 grams/day has resulted in a few case reports of blurred vision and other eye problems, which have generally been reversible upon discontinuation. People with abnormal liver function or a history of liver disease, diabetes, active peptic ulcer disease, gout, cardiac arrhythmias, inflammatory bowel disease, migraine headaches, and alcoholism may be more susceptible to the adverse effects of excess niacin intake than the general population (25).

Nicotinamide

Nicotinamide is generally better tolerated than niacin. It does not generally cause flushing. However, nausea, vomiting, and signs of liver toxicity (elevated liver enzymes, jaundice) have been observed at doses of 3 grams/day (84). Nicotinamide has resulted in decreased insulin sensitivity at doses of 2 grams/day in adults at high risk for insulin-dependent diabetes (49).

The tolerable upper intake level (UL)

Flushing of the skin primarily on the face, arms, and chest is a common side effect of niacin and may occur initially at doses as low as 30 mg/day. Although flushing from nicotinamide is rare, the Food and Nutrition Board set the UL for niacin (nicotinic acid and nicotinamide) at 35 mg/day to avoid the adverse effect of flushing (25; Table 3). The UL applies to the general population and is not meant to apply to individuals who are being treated with a nutrient under medical supervision, as should be the case with high-dose niacin for elevated blood cholesterol levels.

Table 3. Tolerable Upper Intake Level (UL) for Niacin
Age Group  UL (mg/day) 
Infants 0-12 months  Not possible to establish* 
Children 1-3 years  10
Children 4-8 years  15
Children 9-13 years  20
Adolescents 14-18 years  30
Adults 19 years and older  35
*Source of intake should be from food and formula only.

Drug interactions

The occurrence of rhabdomyolysis is increased in patients treated with HMG-CoA reductase inhibitors (statins). Rhabdomyolysis is a relatively uncommon condition in which muscle cells are broken down, releasing enzymes and electrolytes into the blood, and sometimes resulting in kidney failure (87). Co-administration of niacin with a statin seems to enhance the risk of rhabdomyolysis (88). A new drug, laropiprant, blocks prostanoid receptors and reduces niacin-induced flushing (89). A randomized, placebo-controlled trial was designed to identify possible adverse effects of the niacin/laropiprant combination in over 25,000 simvastatin-treated subjects (90). When added to the statin therapy, niacin/laropiprant increased the risk of myopathy and rhabdomyolysis, particularly in Asian subjects. It is possible that the niacin/laropiprant combination further reduces the poor tolerability to statin treatment observed in certain populations (91).

In the three-year, randomized controlled HATS study, concurrent therapy with antioxidants (1,000 mg/day of vitamin C, 800 IU/day of α-tocopherol, 100 mcg/d of selenium, and 25 mg/d of β-carotene) diminished the protective effects of the simvastatin-niacin combination (92). Although the mechanism for these effects is not known, some scientists have questioned the benefit of concurrent antioxidant therapy in patients on lipid-lowering agents (93).

Several other medications may interact with niacin therapy or with absorption and metabolism of the vitamin. Sulfinpyrazone is a medication for the treatment of gout that promotes excretion of uric acid from the blood into urine. Niacin may inhibit this "uricosuric" effect of sulfinpyrazone (84). Further, estrogen and estrogen-containing oral contraceptives increase the efficiency of niacin synthesis from tryptophan, resulting in a decreased dietary requirement for niacin (3). Long-term administration of chemotherapy agents has been reported to cause symptoms of pellagra, and thus niacin supplementation may be needed (see Causes of niacin deficiency).

Linus Pauling Institute Recommendation

The optimum intake of niacin for health promotion and chronic disease prevention is not yet known. The RDA (16 mg NE/day for men and 14 mg NE/day for women) is easily obtainable in a varied diet and should prevent deficiency in most people. Following the Linus Pauling Institute recommendation to take a daily multivitamin/mineral supplement, containing 100% of the Daily Value (DV) for niacin, will provide at least 20 mg of niacin daily.

Older adults (>50 years)

Dietary surveys indicate that 15% to 25% of older adults do not consume enough niacin in their diets to meet the RDA (16 mg NE/day for men and 14 mg NE/day for women), and that dietary intake of niacin decreases between the ages of 60 and 90 years. Thus, it is advisable for older adults to supplement their dietary intake with a multivitamin/mineral, which will generally provide at least 20 mg of niacin daily.


Authors and Reviewers

Originally written in 2000 by: 
Jane Higdon, Ph.D. 
Linus Pauling Institute 
Oregon State University

Updated in August 2002 by:
Jane Higdon, Ph.D.
Linus Pauling Institute 
Oregon State University

Updated in June 2007 by:
Victoria J. Drake, Ph.D
Linus Pauling Institute 
Oregon State University

Updated in July 2013 by: 
Barbara Delage, Ph.D. 
Linus Pauling Institute 
Oregon State University

Reviewed in July 2013 by: 
Elaine L. Jacobson, Ph.D., Professor (Retired) 
Department of Pharmacology and Toxicology 
College of Pharmacy and Arizona Cancer Center 
University of Arizona

Copyright 2000-2017  Linus Pauling Institute


References

1.  Brody T. Nutritional Biochemistry. 2nd ed. San Diego: Academic Press; 1999.

2.  Penberthy WT, Kirkland JB. Niacin. In: Erdman JW, MacDonald I, Zeisel SH, eds. Present Knowledge in Nutrition. 10th ed. Ames: International Life Sciences Institute; 2012:293-306.

3.  Cervantes-Laurean D, McElvaney NG, Moss J. Niacin. In: Shils M, Olson JA, Shike M, Ross AC, eds. Modern Nutrition in Health and Disease. 9th ed. Baltimore: Williams & Wilkins; 1999:401-411.

4.  Di Girolamo M, Dani N, Stilla A, Corda D. Physiological relevance of the endogenous mono(ADP-ribosyl)ation of cellular proteins. FEBS J. 2005;272(18):4565-4575.  (PubMed)

5.  Jacobson MK, Jacobson EL. Discovering new ADP-ribose polymer cycles: protecting the genome and more. Trends Biochem Sci. 1999;24(11):415-417.

6.  Hottiger MO, Hassa PO, Luscher B, Schuler H, Koch-Nolte F. Toward a unified nomenclature for mammalian ADP-ribosyltransferases. Trends Biochem Sci. 2010;35(4):208-219.  (PubMed)

7.  Morris BJ. Seven sirtuins for seven deadly diseases of aging. Free Radic Biol Med. 2013;56:133-171.  (PubMed)

8.  Park YK, Sempos CT, Barton CN, Vanderveen JE, Yetley EA. Effectiveness of food fortification in the United States: the case of pellagra. Am J Public Health. 2000;90(5):727-738.  (PubMed)

9.  Gregory JF, 3rd. Nutritional properties and significance of vitamin glycosides. Annu Rev Nutr. 1998;18:277-296.  (PubMed)

10.  Jacob R, Swenseid M. Niacin. In: Ziegler E, Filer L, eds. Present Knowledge in Nutrition. 7th ed. Washington D.C.: ILSI Press; 1996:185-190.

11.  Oldham MA, Ivkovic A. Pellagrous encephalopathy presenting as alcohol withdrawal delirium: a case series and literature review. Addict Sci Clin Pract. 2012;7(1):12.  (PubMed)

12.  World Health Organization, United Nations High Commissions for Refugees. Pellagra and its prevention and control in major emergencies. World Health Organization. 2000. Available at http://www.who.int/nutrition/publications/
emergencies/WHO_NHD_00.10/en/
. Accessed 6/20/13.

13. Nogueira A, Duarte AF, Magina S, Azevedo F. Pellagra associated with esophageal carcinoma and alcoholism. Dermatol Online J. 2009;15(5):8.  (PubMed)

14.  Murray MF. Tryptophan depletion and HIV infection: a metabolic link to pathogenesis. Lancet Infect Dis. 2003;3(10):644-652.  (PubMed)

15.  Hao K, Zhou Q, Chen W, et al. Possible role of the 'IDO-AhR axis' in maternal-foetal tolerance. Cell Biol Int. 2013;37(2):105-108.  (PubMed)

16.  Fu CS, Swendseid ME, Jacob RA, McKee RW. Biochemical markers for assessment of niacin status in young men: levels of erythrocyte niacin coenzymes and plasma tryptophan. J Nutr. 1989;119(12):1949-1955.  (PubMed)

17.  Dawson B, Favaloro EJ, Taylor J, Aggarwal A. Unrecognized pellagra masquerading as odynophagia. Intern Med J. 2006;36(7):472-474.  (PubMed)

18.  Jagielska G, Tomaszewicz-Libudzic EC, Brzozowska A. Pellagra: a rare complication of anorexia nervosa. Eur Child Adolesc Psychiatry. 2007;16(7):417-420.  (PubMed)

19.  Kertesz SG. Pellagra in 2 homeless men. Mayo Clin Proc. 2001;76(3):315-318.  (PubMed)

20.  Prakash R, Gandotra S, Singh LK, Das B, Lakra A. Rapid resolution of delusional parasitosis in pellagra with niacin augmentation therapy. Gen Hosp Psychiatry. 2008;30(6):581-584.  (PubMed)

21.  Rosmaninho A, Sanches M, Fernandes IC, et al. Letter: Pellagra as the initial presentation of Crohn disease. Dermatol Online J. 2012;18(4):12.  (PubMed)

22.  Zaraa I, Belghith I, El Euch D, et al. A case of pellagra associated with megaduodenum in a young woman. Nutr Clin Pract. 2013;28(2):218-222.  (PubMed)

23.  Bilgili SG, Karadag AS, Calka O, Altun F. Isoniazid-induced pellagra. Cutan Ocul Toxicol. 2011;30(4):317-319.  (PubMed)

24.  Dreizen S, McCredie KB, Keating MJ, Andersson BS. Nutritional deficiencies in patients receiving cancer chemotherapy. Postgrad Med. 1990;87(1):163-167, 170.  (PubMed)

25.  Food and Nutrition Board, Institute of Medicine. Niacin. Dietary Reference Intakes: Thiamin, Riboflavin, Niacin, Vitamin B6, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, D.C.: National Academy Press; 1998:123-149.  (National Academy Press)

26.  Jacobson EL, Jacobson MK. Tissue NAD as a biochemical measure of niacin status in humans. Methods Enzymol. 1997;280:221-230.

27.  Jacobson EL, Shieh WM, Huang AC. Mapping the role of NAD metabolism in prevention and treatment of carcinogenesis. Mol Cell Biochem. 1999;193(1-2):69-74.  (PubMed)

28.  Negrini S, Gorgoulis VG, Halazonetis TD. Genomic instability--an evolving hallmark of cancer. Nat Rev Mol Cell Biol. 2010;11(3):220-228.  (PubMed)

29.  Kirkland JB. Niacin requirements for genomic stability. Mutat Res. 2012;733(1-2):14-20.  (PubMed)

30.  Spronck JC, Nickerson JL, Kirkland JB. Niacin deficiency alters p53 expression and impairs etoposide-induced cell cycle arrest and apoptosis in rat bone marrow cells. Nutr Cancer. 2007;57(1):88-99.  (PubMed)

31.  Spronck JC, Kirkland JB. Niacin deficiency increases spontaneous and etoposide-induced chromosomal instability in rat bone marrow cells in vivo. Mutat Res. 2002;508(1-2):83-97.  (PubMed)

32.  Kostecki LM, Thomas M, Linford G, et al. Niacin deficiency delays DNA excision repair and increases spontaneous and nitrosourea-induced chromosomal instability in rat bone marrow. Mutat Res. 2007;625(1-2):50-61.  (PubMed)

33.  Dantzer F, Santoro R. The expanding role of PARPs in the establishment and maintenance of heterochromatin. FEBS J. 2013;280(15):3508-3518.  (PubMed)

34.  El Ramy R, Magroun N, Messadecq N, et al. Functional interplay between Parp-1 and SirT1 in genome integrity and chromatin-based processes. Cell Mol Life Sci. 2009;66(19):3219-3234.  (PubMed)

35.  Boyonoski AC, Spronck JC, Gallacher LM, et al. Niacin deficiency decreases bone marrow poly(ADP-ribose) and the latency of ethylnitrosourea-induced carcinogenesis in rats. J Nutr. 2002;132(1):108-114.  (PubMed)

36.  Boyonoski AC, Spronck JC, Jacobs RM, Shah GM, Poirier GG, Kirkland JB. Pharmacological intakes of niacin increase bone marrow poly(ADP-ribose) and the latency of ethylnitrosourea-induced carcinogenesis in rats. J Nutr. 2002;132(1):115-120.  (PubMed)

37.  Weitberg AB. Effect of nicotinic acid supplementation in vivo on oxygen radical-induced genetic damage in human lymphocytes. Mutat Res. 1989;216(4):197-201.  (PubMed)

38.  Hageman GJ, Stierum RH, van Herwijnen MH, van der Veer MS, Kleinjans JC. Nicotinic acid supplementation: effects on niacin status, cytogenetic damage, and poly(ADP-ribosylation) in lymphocytes of smokers. Nutr Cancer. 1998;32(2):113-120.  (PubMed)

39.  Yong LC, Petersen MR. High dietary niacin intake is associated with decreased chromosome translocation frequency in airline pilots. Br J Nutr. 2011;105(4):496-505.  (PubMed)

40.  Jacobson EL. Niacin deficiency and cancer in women. J Am Coll Nutr. 1993;12(4):412-416.  (PubMed)

41.  Negri E, Franceschi S, Bosetti C, et al. Selected micronutrients and oral and pharyngeal cancer. Int J Cancer. 2000;86(1):122-127.  (PubMed)

42.  Franceschi S, Bidoli E, Negri E, et al. Role of macronutrients, vitamins and minerals in the aetiology of squamous-cell carcinoma of the oesophagus. Int J Cancer. 2000;86(5):626-631.  (PubMed)

43.  Gensler HL, Williams T, Huang AC, Jacobson EL. Oral niacin prevents photocarcinogenesis and photoimmunosuppression in mice. Nutr Cancer. 1999;34(1):36-41.  (PubMed)

44.  Jacobson EL, Kim H, Kim M, et al. A topical lipophilic niacin derivative increases NAD, epidermal differentiation and barrier function in photodamaged skin. Exp Dermatol. 2007;16(6):490-499.  (PubMed)

45.  Bermudez Y, Benavente CA, Meyer RG, Coyle WR, Jacobson MK, Jacobson EL. Nicotinic acid receptor abnormalities in human skin cancer: implications for a role in epidermal differentiation. PLoS One. 2011;6(5):e20487.  (PubMed)

46.  Benavente CA, Jacobson EL. Niacin restriction upregulates NADPH oxidase and reactive oxygen species (ROS) in human keratinocytes. Free Radic Biol Med. 2008;44(4):527-537.  (PubMed)

47.  Benavente CA, Schnell SA, Jacobson EL. Effects of niacin restriction on sirtuin and PARP responses to photodamage in human skin. PLoS One. 2012;7(7):e42276.  (PubMed)

48  Lampeter EF, Klinghammer A, Scherbaum WA, et al. The Deutsche Nicotinamide Intervention Study: an attempt to prevent type 1 diabetes. DENIS Group. Diabetes. 1998;47(6):980-984.  (PubMed)

49.  Greenbaum CJ, Kahn SE, Palmer JP. Nicotinamide's effects on glucose metabolism in subjects at risk for IDDM. Diabetes. 1996;45(11):1631-1634.  (PubMed)

50.  Gale EA, Bingley PJ, Emmett CL, Collier T, European Nicotinamide Diabetes Intervention Trial Group. European Nicotinamide Diabetes Intervention Trial (ENDIT): a randomised controlled trial of intervention before the onset of type 1 diabetes. Lancet. 2004;363(9413):925-931.  (PubMed)

51.  Hedman M, Ludvigsson J, Faresjo MK. Nicotinamide reduces high secretion of IFN-γ in high-risk relatives even though it does not prevent type 1 diabetes. J Interferon Cytokine Res. 2006;26(4):207-213.  (PubMed)

52.  Fernandez IC, Del Carmen Camberos M, Passicot GA, Martucci LC, Cresto JC. Children at risk of diabetes type 1. Treatment with acetyl-L-carnitine plus nicotinamide - Case reports. J Pediatr Endocrinol Metab. 2013;26(3-4):347-355.  (PubMed)

53.  Ku CR, Lee HJ, Kim SK, Lee EY, Lee MK, Lee EJ. Resveratrol prevents streptozotocin-induced diabetes by inhibiting the apoptosis of pancreatic β-cell and the cleavage of poly (ADP-ribose) polymerase. Endocr J. 2012;59(2):103-109.  (PubMed)

54.  Knopp RH. Drug treatment of lipid disorders. N Engl J Med. 1999;341(7):498-511.

55.  Canner PL, Berge KG, Wenger NK, et al. Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin. J Am Coll Cardiol. 1986;8(6):1245-1255.  (PubMed)

56.  Guyton JR, Capuzzi DM. Treatment of hyperlipidemia with combined niacin-statin regimens. Am J Cardiol. 1998;82(12A):82U-84U; discussion 85-86U.  (PubMed)

57.  Bays HE, Shah A, Lin J, Sisk CM, Dong Q, Maccubbin D. Consistency of extended-release niacin/laropiprant effects on Lp(a), ApoB, non-HDL-C, Apo A1, and ApoB/ApoA1 ratio across patient subgroups. Am J Cardiovasc Drugs. 2012;12(3):197-206.  (PubMed)

58.  Brown BG, Zhao XQ, Chait A, et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med. 2001;345(22):1583-1592.  (PubMed)

59.  Vittone F, Chait A, Morse JS, Fish B, Brown BG, Zhao XQ. Niacin plus Simvastatin Reduces Coronary Stenosis Progression Among Patients with Metabolic Syndrome Despite a Modest Increase in Insulin Resistance: A Subgroup Analysis of the HDL-Atherosclerosis Treatment Study (HATS). J Clin Lipidol. 2007;1(3):203-210.  (PubMed)

60.  Zhao XQ, Morse JS, Dowdy AA, et al. Safety and tolerability of simvastatin plus niacin in patients with coronary artery disease and low high-density lipoprotein cholesterol (The HDL Atherosclerosis Treatment Study). Am J Cardiol. 2004;93(3):307-312.  (PubMed)

61.  Sazonov V, Maccubbin D, Sisk CM, Canner PL. Effects of niacin on the incidence of new onset diabetes and cardiovascular events in patients with normoglycaemia and impaired fasting glucose. Int J Clin Pract. 2013;67(4):297-302.  (PubMed)

62.  Taylor AJ, Sullenberger LE, Lee HJ, Lee JK, Grace KA. Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) 2: a double-blind, placebo-controlled study of extended-release niacin on atherosclerosis progression in secondary prevention patients treated with statins. Circulation. 2004;110(23):3512-3517.  (PubMed)

63.  Taylor AJ, Zhu D, Sullenberger LE, Lee HJ, Lee JK, Grace KA. Relationship between glycemic status and progression of carotid intima-media thickness during treatment with combined statin and extended-release niacin in ARBITER 2. Vasc Health Risk Manag. 2007;3(1):159-164.  (PubMed)

64.  Villines TC, Stanek EJ, Devine PJ, et al. The ARBITER 6-HALTS Trial (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6-HDL and LDL Treatment Strategies in Atherosclerosis): final results and the impact of medication adherence, dose, and treatment duration. J Am Coll Cardiol. 2010;55(24):2721-2726.  (PubMed)

65.  McKenney J. New perspectives on the use of niacin in the treatment of lipid disorders. Arch Intern Med. 2004;164(7):697-705.  (PubMed)

66.  Wink J, Giacoppe G, King J. Effect of very-low-dose niacin on high-density lipoprotein in patients undergoing long-term statin therapy. Am Heart J. 2002;143(3):514-518.  (PubMed)

67.  Brown RR, Ozaki Y, Datta SP, Borden EC, Sondel PM, Malone DG. Implications of interferon-induced tryptophan catabolism in cancer, auto-immune diseases and AIDS. Adv Exp Med Biol. 1991;294:425-435.  (PubMed)

68.  Taylor EW. The oxidative stress-induced niacin sink (OSINS) model for HIV pathogenesis. Toxicology. 2010;278(1):124-130.  (PubMed)

69.  Dunham RM, Gordon SN, Vaccari M, et al. Preclinical evaluation of HIV eradication strategies in the simian immunodeficiency virus-infected rhesus macaque: a pilot study testing inhibition of indoleamine 2,3-dioxygenase. AIDS Res Hum Retroviruses. 2013;29(2):207-214.  (PubMed)

70.  Tang AM, Graham NM, Saah AJ. Effects of micronutrient intake on survival in human immunodeficiency virus type 1 infection. Am J Epidemiol. 1996;143(12):1244-1256.  (PubMed)

71.  Murray MF, Langan M, MacGregor RR. Increased plasma tryptophan in HIV-infected patients treated with pharmacologic doses of nicotinamide. Nutrition. 2001;17(7-8):654-656.  (PubMed)

72.  Dube MP, Lipshultz SE, Fichtenbaum CJ, et al. Effects of HIV infection and antiretroviral therapy on the heart and vasculature. Circulation. 2008;118(2):e36-40.  (PubMed)

73.  Carr A, Samaras K, Burton S, et al. A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance in patients receiving HIV protease inhibitors. AIDS. 1998;12(7):F51-58.  (PubMed)

74.  Giannarelli C, Klein RS, Badimon JJ. Cardiovascular implications of HIV-induced dyslipidemia. Atherosclerosis. 2011;219(2):384-389.  (PubMed)

75.  Chow DC, Stein JH, Seto TB, et al. Short-term effects of extended-release niacin on endothelial function in HIV-infected patients on stable antiretroviral therapy. AIDS. 2010;24(7):1019-1023.  (PubMed)

76.  Balasubramanyam A, Coraza I, Smith EO, et al. Combination of niacin and fenofibrate with lifestyle changes improves dyslipidemia and hypoadiponectinemia in HIV patients on antiretroviral therapy: results of "heart positive," a randomized, controlled trial. J Clin Endocrinol Metab. 2011;96(7):2236-2247.  (PubMed)

77.  Hoffer LJ. Vitamin therapy in schizophrenia. Isr J Psychiatry Relat Sci. 2008;45(1):3-10.  (PubMed)

78.  Pauling L. Orthomolecular psychiatry. Varying the concentrations of substances normally present in the human body may control mental disease. Science. 1968;160(3825):265-271.  (PubMed)

79.  Seybolt SE. Is it time to reassess alpha lipoic acid and niacinamide therapy in schizophrenia? Med Hypotheses. 2010;75(6):572-575.  (PubMed)

80.  Zell M, Grundmann O. An orthomolecular approach to the prevention and treatment of psychiatric disorders. Adv Mind Body Med. 2012;26(2):14-28.  (PubMed)

81.  Messamore E. Niacin subsensitivity is associated with functional impairment in schizophrenia. Schizophr Res. 2012;137(1-3):180-184.  (PubMed)

82.  Horrobin DF. The membrane phospholipid hypothesis as a biochemical basis for the neurodevelopmental concept of schizophrenia. Schizophr Res. 1998;30(3):193-208.  (PubMed)

83.  US Department of Agriculture, Agricultural Research Service. USDA National Nutrient Database for Standard Reference, Release 25. 2012. Available at: http://ndb.nal.usda.gov/. Accessed 6/24/13.

84.  Hendler SS, Rorvik DR, eds. PDR for Nutritional Supplements. Montvale: Medical Economics Company, Inc; 2001.

85.  Vitamins. Drug Facts and Comparisons. St. Louis: Facts and Comparisons; 2000:6-33.

86.  Knopp RH. Evaluating niacin in its various forms. Am J Cardiol. 2000;86(12A):51L-56L.  (PubMed)

87.  Kar S, Chockalingam A. Statin-associated rhabdomyolysis with acute renal failure complicated by intradialytic NSTEMI: a review of lipid management considerations. Am J Ther. 2013;20(1):57-60.  (PubMed)

88.  Cziraky MJ, Willey VJ, McKenney JM, et al. Risk of hospitalized rhabdomyolysis associated with lipid-lowering drugs in a real-world clinical setting. J Clin Lipidol. 2013;7(2):102-108.  (PubMed)

89.  Maccubbin DL, Chen F, Anderson JW, et al. Effectiveness and safety of laropiprant on niacin-induced flushing. Am J Cardiol. 2012;110(6):817-822.  (PubMed)

90.  HPS2-THRIVE Collaborative Group. HPS2-THRIVE randomized placebo-controlled trial in 25 673 high-risk patients of ER niacin/laropiprant: trial design, pre-specified muscle and liver outcomes, and reasons for stopping study treatment. Eur Heart J. 2013;34(17):1279-1291.  (PubMed)

91.  Lewey J, Shrank WH, Bowry AD, Kilabuk E, Brennan TA, Choudhry NK. Gender and racial disparities in adherence to statin therapy: a meta-analysis. Am Heart J. 2013;165(5):665-678, 678 e661.  (PubMed)

92.  Cheung MC, Zhao XQ, Chait A, Albers JJ, Brown BG. Antioxidant supplements block the response of HDL to simvastatin-niacin therapy in patients with coronary artery disease and low HDL. Arterioscler Thromb Vasc Biol. 2001;21(8):1320-1326.  (PubMed)

93.  Brown BG, Cheung MC, Lee AC, Zhao XQ, Chait A. Antioxidant vitamins and lipid therapy: end of a long romance? Arterioscler Thromb Vasc Biol. 2002;22(10):1535-1546.  (PubMed)

Pantothenic Acid

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Summary

  • Pantothenic acid — also known as vitamin B5 — is a water-soluble vitamin that is a precursor in the synthesis of coenzyme A. Coenzyme A is essential to many biochemical reactions that sustain life. Also, the phosphopantetheinyl moiety of coenzyme A is required for the biological activity of several proteins, including the acyl-carrier protein involved in fatty acid synthesis. (More information)
  • Pantothenic acid is essential to all forms of life. It is ubiquitously found in foods of plant and animal origin, and dietary deficiency is very rare. (More information)
  • The Food and Nutrition Board of the US Institute of Medicine set an adequate intake (AI) of 5 milligrams (mg)/day for adults based on the estimated daily average intake of pantothenic acid. (More information)
  • Evidence from limited intervention studies suggests that pantothenic acid and/or pantothenol (alcohol analog) might improve the healing process of skin wounds. Yet, additional larger studies are warranted. (More information)
  • Treatment with high-dose pantethine — a pantothenic acid derivative — has been shown to lower serum cholesterol and lipid concentrations. Although pantethine therapy appears to be well tolerated, medical supervision is indispensable. (More information)
  • Foods rich in pantothenic acid include animal organs (liver and kidney), fish, shellfish, milk products, eggs, avocados, legumes, mushrooms, and sweet potatoes. (More information)
  • Little or no toxicity has been associated with dietary and supplemental pantothenic acid such that no tolerable upper intake level (UL) has been set. (More information)


Pantothenic acid, also known as vitamin B5, is essential to all forms of life (1). Pantothenic acid is found throughout all branches of life in the form of coenzyme A, a vital coenzyme in numerous chemical reactions (2).

Function

Synthesis of pantothenic acid cofactors

Coenzyme A

Pantothenic acid is a precursor in the biosynthesis of coenzyme A (CoA) (Figure 1), an essential coenzyme in a variety of biochemical reactions that sustain life (see below). Pantothenic acid kinase II (PANKII) catalyzes the initial step of phosphorylation of pantothenic acid to 4’-phosphopantothenic acid. Coenzyme A and its derivatives inhibit the synthesis of 4’-phosphopantothenic acid, but the inhibition can be reversed by carnitine, required for the transport of fatty acids into the mitochondria (3). The subsequent reactions in this biosynthetic pathway include the synthesis of the intermediate 4’-phosphopantetheine, as well as the recycling of coenzyme A to 4’-phosphopantetheine (Figure 1).

Figure 1. Coenzyme A Synthesis from Pantothenic Acid. Pantothenic acid is a precursor in the synthesis of coenzyme A. The initial phosphorylation reaction that converts pantothenic acid into 4'-phosphopantothenic acid is impaired in individuals with an inherited defect in the gene (PANKII) coding for pantothenic acid kinase II.

4’-phosphopantetheine

The 4’-phosphopantetheinyl moiety of coenzyme A can be transferred to enzymes in which 4’-phosphopantetheine is an essential cofactor for their biological activities (see 4’-phosphopantetheinylation).

Cofactor and co-substrate function

Coenzyme A

Coenzyme A reacts with acyl groups, giving rise to thioester derivatives, such as acetyl-CoA, succinyl-CoA, malonyl-CoA, and 3-hydroxy-3-methylglutaryl (HMG)-CoA. Coenzyme A and its acyl derivatives are required for reactions that generate energy from the degradation of dietary fat, carbohydrates, and proteins. In addition, coenzyme A in the form of acetyl-CoA and succinyl-CoA is involved in the citric acid cycle, in the synthesis of essential fats, cholesterol, steroid hormones, vitamins A and D, the neurotransmitter acetylcholine, and in the fatty acid β-oxidation pathway. Coenzyme A derivatives are also required for the synthesis of the hormone, melatonin, and for a component of hemoglobin called heme. Further, metabolism of a number of drugs and toxins by the liver requires coenzyme A (4).

Coenzyme A was named for its role in acetylation reactions. Most acetylated proteins in the body have been modified by the addition of an acetate group that was donated by the coenzyme A thioester derivative, acetyl-CoA. Protein acetylation alters the overall charge of proteins, modifying their three-dimensional structure and, potentially, their function. For example, acetylation is a mechanism that regulates the activity of peptide hormones, including those produced by the pituitary gland (5). Also, protein acetylation, like other posttranslational modifications, has been shown to regulate the subcellular localization, the function, and the half-life of many signaling molecules, transcription factors, and enzymes. Notably, the acetylation of histones plays a role in the regulation of gene expression by facilitating transcription (i.e., mRNA synthesis), while deacetylated histones are usually associated with chromatin compaction and gene silencing. The acetylation of histones was found to result in structural changes of the chromatin, which affect both DNA-protein and protein-protein interactions. Crosstalk between acetylation marks and other posttranscriptional modifications of the histones also facilitate the recruitment of transcriptional regulators to the promoter of genes that are subsequently transcribed (reviewed in 6).

Finally, a number of signaling molecules are modified by the attachment of long-chain fatty acids donated by coenzyme A. These modifications are known as protein acylation and have central roles in cell-signaling pathways (4).

4’-phosphopantetheinylation

Specific multi-enzyme complexes, which need to carry out several reactions in an orderly manner, may require the covalent attachment of a 4’-phosphopantetheine arm to a “carrier” domain (or protein). This carrier domain holds substrates or reaction intermediates during the progression through the various enzymatic reactions. In mammals, the transfer of the 4’-phosphopantetheinyl moiety from coenzyme A to a conserved serine residue of a specific carrier domain is catalyzed by one unique phosphopantetheinyl transferase (7). The 4’-phosphopantetheinylation is necessary for the conversion of apo-enzymes into fully active holo-enzymes (see below).

Acyl-carrier protein

Lipids are fat molecules essential for normal physiological function and, among other types, include sphingolipids (essential components of the myelin sheath that enhances nerve transmission), phospholipids (important structural components of cell membranes), and fatty acids. Fatty acid synthase (FAS) is a multi-enzyme complex that catalyzes the synthesis of fatty acids. Within the FAS complex, the acyl-carrier protein (ACP) requires pantothenic acid in the form of 4'-phosphopantetheine for its activity as a carrier protein (3). A group, such as the 4’-phosphopantetheinyl moiety for ACP, is called a prosthetic group; the prosthetic group is not composed of amino acids and is a tightly bound cofactor required for the biological activity of some proteins (Figure 2). Acetyl-CoA, malonyl-CoA, and ACP are all required for the synthesis of fatty acids in the cytosol. During fatty acid synthesis, the acyl groups of acetyl-CoA and malonyl-CoA are transferred to the sulfhydryl group (-SH) of the 4’-phosphopantetheinyl moiety of ACP. The prosthetic group is used as a flexible arm to transfer the growing fatty acid chain to each of the enzymatic centers of the type I FAS complex. In the mitochondria, 4'-phosphopantetheine also serves as a prosthetic group for an ACP homolog present in mitochondrial type II FAS complex (8).

Figure 2. 4'-Pantetheinylation of Acyl-Carrier Protein (ACP). A prosthetic group – in this case, a 4'-phosphopantetheinyl moiety – is required for the biological function of ACP. The addition of the prosthetic group occurs after ACP synthesis (post-translation) in a reaction catalyzed by 4'-phosphopantetheinyl transferase. The enzyme catalyzes the hydrolysis of coenzyme A to 3',5'-adenosine diphosphate and 4'-phosphopantetheine, and the transfer of the 4'-phosphopantetheinyl moiety to a serine residue at the active site of ACP. ACP, acyl-carrier protein; apo-ACP, biologically inactive ACP; holo-ACP, biologically active ACP.

10-formyltetrahydrofolate dehydrogenase

The enzyme 10-formyltetrahydrofolate dehydrogenase (FDH) catalyzes the conversion of 10-formyltetrahydrofolate to tetrahydrofolate, an essential cofactor in the metabolism of nucleic acids and amino acids (Figure 3). Similar to ACP, FDH requires a 4’-phosphopantetheine prosthetic group for its biological activity. The prosthetic group acts as a swinging arm to couple the activities of the two catalytic domains of FDH (9, 10). A homolog of FDH in mitochondria also requires 4’-phosphopantetheinylation to be biologically active (11).

Figure 3. 4'-Pantetheinylation of Formyltetrahydrofolate Dehydrogenase (FDH). (a) The generation of TH4 from 10-CHO-TH4 is catalyzed by FDH, an enzyme requiring 4'-phosphopantetheine as a prosthetic group to be biologically active. Of note, 10-CHO-TH4 can also be hydrolyzed to TH4 (and formate) in another reaction catalyzed by formyltetrahydrofolate deformylase. (b) The enzyme 4'-phosphopantetheinyl transferase catalyzes the transfer of a 4'-phosphopantetheinyl moiety from coenzyme A to a specific serine residue of FDH, converting apo-FDH to holo-FDH. FDH, formyltetrahydrofolate dehydrogenase; apo-FDH, biologically inactive FDH; holo-FDH, biologically active FDH; 10-CHO-TH4, 10-formyltetrahydrofolate; TH4, tetrahydrofolate; NADP+/NADPH, nicotinamide adenine dinucleotide phosphate oxidized/reduced.

α-Aminoadipate semialdehyde synthase

4’-phosphopantetheinylation is required for the biological activity of the apo-enzyme α-aminoadipate semialdehyde synthase (AASS). AASS catalyzes the initial reactions in the mitochondrial pathway for the degradation of lysine — an essential amino acid for humans. AASS is made of two catalytic domains. The lysine-ketoglutarate reductase domain first catalyzes the conversion of lysine to saccharopine. Saccharopine is further converted to α-aminoadipate semialdehyde in a reaction catalyzed by the saccharopine dehydrogenase domain (Figure 4).

Figure 4. 4'-Pantetheinylation of α-Aminoadipate Semialdehyde Synthase (AASS). AASS is a mitochondrial enzyme responsible for the conversions of lysine to saccharopine, and saccharopine to α-aminoadipate semialdehyde in the mitochondrial pathway for lysine degradation. The first reaction is catalyzed by the lysine-ketoglutarate reductase domain of AASS, and the saccharopine dehydrogenase domain catalyzes the second reaction. Apo-AASS requires 4'-phosphopantetheine as a prosthetic group to be biologically active. The enzyme 4'-phosphopantetheinyl transferase catalyzes the transfer of a 4'-phosphopantetheinyl moiety from coenzyme A to a specific residue of AASS, converting apo-AASS to holo-AASS. The 4'-phosphopantetheinyl arm is thought to serve as a swinging arm that couples the activities of the two enzymatic domains of AASS. AASS, α-aminoadipate semialdehyde synthase.

Deficiency

Naturally occurring pantothenic acid deficiency in humans is very rare and has been observed only in cases of severe malnutrition. World War II prisoners in the Philippines, Burma, and Japan experienced numbness and painful burning and tingling in their feet; these symptoms were relieved specifically by pantothenic acid supplementation (4). Pantothenic acid deficiency in humans has been induced experimentally by co-administering a pantothenic acid kinase inhibitor (w-methylpantothenate; see Figure 1 above) and a pantothenic acid-deficient diet. Participants in this experiment complained of headache, fatigue, insomnia, intestinal disturbances, and numbness and tingling of their hands and feet (12). In another study, participants fed only a pantothenic acid-free diet did not develop clinical signs of deficiency, although some appeared listless and complained of fatigue (13).

Calcium homopantothenate (or hopantenate) is a pantothenic acid antagonist with cholinergic effects (i.e., similar to those of the neurotransmitter, acetylcholine). This compound is used in Japan to enhance mental function, especially in Alzheimer’s disease. A rare side effect was the development of hepatic encephalopathy, a condition of abnormal brain function resulting from the failure of the liver to eliminate toxins. The encephalopathy was reversed by pantothenic acid supplementation, suggesting that it was due to homopantothenate-induced pantothenic acid deficiency (14). Of note, genetic mutations in the human gene PANKII, which codes for pantothenic acid kinase II (see Figure 1 above), result in impaired synthesis of 4'-phosphopantetheine and coenzyme A (see Function). The disorder, called pantothenate kinase-associated neurodegeneration, is characterized by visual and intellectual impairments, dystonia, speech abnormalities, behavioral difficulties, and personality disorders (15).

Yet, because pantothenic acid is widely distributed in nature and deficiency is extremely rare in humans, most information regarding the consequences of deficiency has been gathered from experimental research in animals (reviewed in 3). Pantothenic acid-deficient rats developed damage to the adrenal glands, while monkeys developed anemia due to decreased synthesis of heme, a component of hemoglobin. Dogs with pantothenic acid deficiency developed low blood glucose, rapid breathing and heart rates, and convulsions. Chickens developed skin irritation, feather abnormalities, and spinal nerve damage associated with the degeneration of the myelin sheath. Pantothenic acid-deficient mice showed decreased exercise tolerance and diminished storage of glucose (in the form of glycogen) in muscle and liver. Mice also developed skin irritation and graying of the fur, which is reversed by pantothenic acid administration.

The diversity of symptoms emphasizes the numerous functions of pantothenic acid in its coenzyme forms.

The Adequate Intake (AI)

Because there was little information on the requirements of pantothenic acid in humans, the Food and Nutrition Board of the Institute of Medicine set an adequate intake (AI) based on observed dietary intakes in healthy population groups (Table 1) (16).

Table 1. Adequate Intake (AI) for Pantothenic Acid
Life Stage  Age  Males (mg/day)  Females (mg/day) 
Infants  0-6 months  1.7  1.7 
Infants  7-12 months  1.8  1.8 
Children  1-3 years 
Children  4-8 years 
Children  9-13 years 
Adolescents  14-18 years 
Adults  19 years and older 
Pregnancy  all ages  - 
Breast-feeding  all ages 7

Disease Treatment

Wound healing

The addition of calcium D-pantothenate and/or pantothenol (Figure 5) to the medium of cultured skin fibroblasts given an artificial wound was found to increase cell proliferation and migration, thus accelerating wound healing in vitro (17, 18). Likewise, in vitro deficiency in pantothenic acid induced the expression of differentiation markers in proliferating skin fibroblasts and inhibited proliferation in human keratinocytes (19). The application of ointments containing either calcium D-pantothenate or pantothenol — also known as D-panthenol or dexpanthenol — to the skin has been shown to accelerate the closure of skin wounds and increase the strength of scar tissue in animals (3).

The effects of dexpanthenol on wound healing are unclear. In a placebo-controlled study that included 12 healthy volunteers, the application of dexpanthenol-containing ointment (every 12 hours for 1 to 6 days) in a model of skin wound healing was associated with an enhanced expression of markers of proliferation, inflammation, and tissue repair (20). However, the study failed to report whether these changes in response to topical dexpanthenol improved the wound-repair process compared to placebo (20). Some studies have shown no effects. Early randomized controlled trials in patients undergoing surgery for tattoo removal found that daily co-supplementation with 1 gram or 3 grams of vitamin C and 200 mg or 900 mg of pantothenic acid for 21 days did not significantly improve the wound-healing process (21, 22). Yet, in a recent randomized, double-blind, placebo-controlled study, the use of dexpanthenol pastilles (300 mg/day for up to 14 days post surgery) was found to accelerate mucosal healing after tonsillectomy in children (23).

High cholesterol

Early studies suggested that pharmacologic doses of pantethine, a pantothenic acid derivative, might have a cholesterol-lowering effect (24, 25). Pantethine is made of two molecules of pantetheine joined by a disulfide bond (chemical bond between two molecules of sulfur) (Figure 5). Pantethine is structurally related to coenzyme A and is found in the prosthetic group that is required for the biological function of acyl-carrier protein, formyltetrahydrofolate dehydrogenase, and α-aminoadipate semialdehyde synthase (see Function). In a 16-week, randomized, double-blind, placebo-controlled study, daily pantethine supplementation (600 mg/day for 8 weeks, followed by 900 mg/day for another 8 weeks) significantly improved the profile of lipid parameters in 120 individuals at low-to-moderate risk of cardiovascular disease (CVD). After adjusting to baseline, pantethine was found to be significantly more effective than placebo in lowering the concentrations of low-density lipoprotein-cholesterol (LDL-C) and apolipoprotein B (apoB), as well as reducing the ratio of triglycerides to high-density lipoprotein-cholesterol (TG:HDL-C) (26). Although it appears to be well tolerated and potentially beneficial in improving cholesterol metabolism, pantethine is not a vitamin, and the decision to use pharmacologic doses of pantethine to treat elevated blood cholesterol or triglycerides should only be made in collaboration with a qualified health care provider who provides appropriate follow up.

Figure 5. Chemical Structures of Some Pantothenic Acid Derivatives.

Graying of hair

Mice that are deficient in pantothenic acid developed skin irritation and graying of the fur, which is reversed by pantothenic acid administration. In humans, there is no evidence that taking pantothenic acid as supplements or using shampoos containing pantothenic acid can prevent or restore hair color.

Sources

Food sources

Pantothenic acid is available in a variety of foods, usually as a component of coenzyme A (CoA) and 4’-phosphopantetheine (see Figure 1 above). Upon ingestion, dietary coenzyme A and phosphopantetheine are hydrolyzed to pantothenic acid prior to intestinal absorption (3). Animal liver and kidney, fish, shellfish, pork, chicken, egg yolk, milk, yogurt, legumes, mushrooms, avocados, broccoli, and sweet potatoes are good sources of pantothenic acid. Whole grains are also good sources of pantothenic acid, but processing and refining grains may result in a 35 to 75% loss. Freezing and canning of foods result in similar losses (16). Large national, nutritional surveys failed to estimate pantothenic acid intake, mainly because of the scarcity of data on the pantothenic acid content of food (16). Smaller studies estimated average daily intakes of pantothenic acid to be between 4 and 7 mg/day in adults. Table 2 lists some rich sources of pantothenic acid, along with their content in milligrams (mg). For more information on the nutrient content of foods, search the USDA food composition database.

Table 2. Some Food Sources of Pantothenic Acid
Food Serving Pantothenic Acid (mg)
Beef liver (cooked, pan fried) 3 ounces* 5.6
Sunflower seed kernels (dry roasted) 1 ounce 2.0
Fish, trout (mixed species, cooked, dry heat) 3 ounces* 1.9
Yogurt (plain, nonfat) 8 ounces 1.6
Lobster (cooked) 3 ounces 1.4
Avocado (raw, California) ½ fruit 1.0
Sweet potato (cooked, with skin) 1 medium (½ cup) 1.0
Milk 1 cup (8 fluid ounces) 0.87
Pork (tenderloin, lean, cooked, roasted) 3 ounces* 0.86
Chicken (light meat, cooked, roasted) 3 ounces* 0.83
Egg (cooked, hard-boiled) 1 large 0.70
Cheese, feta ½ cup (crumbled) 0.70
Lentils (mature seeds, cooked, boiled) ½ cup 0.63
Split peas (mature seeds, cooked, boiled) ½ cup 0.58
Mushrooms (white, raw) ½ cup (chopped) 0.52
Peanuts 1 ounce 0.50
Broccoli (cooked, boiled) ½ cup (chopped) 0.48
Orange 1 whole 0.30
Whole-wheat bread 1 slice 0.21
*A three-ounce serving of meat or fish is about the size of a deck of cards.

Intestinal bacteria

The bacteria that normally colonize the colon (large intestine) are capable of synthesizing pantothenic acid. A specialized transporter for the uptake of biotin and pantothenic acid was identified in cultured cells derived from the lining of the colon, suggesting that humans may be able to absorb pantothenic acid and biotin produced by intestinal bacteria (27). However, the extent to which bacterial synthesis contributes to pantothenic acid intake in humans is not known (28).

Supplements

Pantothenol and pantothenate

Supplements commonly contain pantothenol (panthenol), a stable alcohol analog of pantothenic acid, which can be rapidly converted to pantothenic acid by humans. Calcium and sodium D-pantothenate, the calcium and sodium salts of pantothenic acid, are also available as supplements.

Pantethine

Pantethine is used as a cholesterol-lowering agent in Japan and is available in the US as a dietary supplement (29).

Safety

Toxicity

Pantothenic acid is not known to be toxic in humans. The only adverse effect noted was diarrhea resulting from very high intakes of 10 to 20 g/day of calcium D-pantothenate (30). However, there is one case report of life-threatening eosinophilic pleuropericardial effusion in an elderly woman who took a combination of 10 mg/day of biotin and 300 mg/day of pantothenic acid for two months (31). Due to the lack of reports of adverse effects when the Dietary Reference Intakes (DRI) for pantothenic acid were established in 1998, the Food and Nutrition Board of the Institute of Medicine did not establish a tolerable upper intake level (UL) for pantothenic acid (16). Pantethine is generally well tolerated in doses up to 1,200 mg/day. However, gastrointestinal side effects, such as nausea and heartburn, have been reported (29). Also, topical formulations containing up to 5% of dexpanthenol (D-panthenol) have been safely used for up to one month. Yet, a few cases of skin irritation, contact dermatitis, and eczema have been reported with the use of dexpanthenol-containing ointments (32, 33).

Nutrient interactions

Large doses of pantothenic acid have the potential to compete with biotin for intestinal and cellular uptake by the human sodium-dependent multivitamin transporter (hSMVT) (27, 34).

Drug interactions

Oral contraceptives (birth control pills) containing estrogen and progestin may increase the requirement for pantothenic acid (30). Use of pantethine in combination with cholesterol-lowering drugs called statins (HMG-CoA reductase inhibitors) or with nicotinic acid (see the article on Niacin) may produce additive effects on blood lipids (29).

Linus Pauling Institute Recommendation

More data are needed to define the amount of dietary pantothenic acid required to promote optimal health or prevent chronic disease. The Linus Pauling Institute supports the recommendation by the Food and Nutrition Board of 5 mg/day of pantothenic acid for adults. A varied diet should provide enough pantothenic acid for most people. Following the Linus Pauling Institute recommendation to take a daily multivitamin/mineral supplement that contains 100% of the Daily Value (DV) for pantothenic acid will ensure an intake of at least 5 mg/day.

Older adults (>50 years)

There is currently little evidence that older adults differ in their intake of or their requirement for pantothenic acid. Most multivitamin/mineral supplements provide at least 5 mg/day of pantothenic acid.


Authors and Reviewers

Written in May 2004 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in April 2008 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in April 2015 by:
Barbara Delage, Ph.D.
Linus Pauling Institute
Oregon State University

Reviewed in July 2015 by:
Robert B. Rucker, Ph.D.
Distinguished Professor Emeritus
Department of Nutrition and School of Medicine
University of California, Davis

Copyright 2000-2017  Linus Pauling Institute


References 

1.  Trumbo PR. Pantothenic acid. In: Ross AC, Caballero B, Cousins RJ, Tucker KL, Ziegler TR, eds. Modern Nutrition in Health and Disease. 11th ed. Baltimore: Lippincott Williams & Wilkins; 2014:351-357.

2.  Martinez DL, Tsuchiya Y, Gout I. Coenzyme A biosynthetic machinery in mammalian cells. Biochem Soc Trans. 2014;42(4):1112-1117.  (PubMed)

3.  Miller JW, Rucker RB. Pantothenic acid. In: Erdman JWJ, Macdonald IA, Zeisel SH, eds. Present Knowledge in Nutrition. 10th ed. Ames: Wiley-Blackwell; 2012:375-390.

4.  Bauerly K, Rucker RB. Pantothenic acid. In: Zempleni J, Rucker RB, McCormick DB, Suttie JW, eds. Handbook of vitamins. 4th ed. Boca Raton: CRC Press; 2007:289-314.

5.  Takahashi A, Mizusawa K. Posttranslational modifications of proopiomelanocortin in vertebrates and their biological significance. Front Endocrinol (Lausanne). 2013;4:143.  (PubMed)

6.  Choudhary C, Weinert BT, Nishida Y, Verdin E, Mann M. The growing landscape of lysine acetylation links metabolism and cell signalling. Nat Rev Mol Cell Biol. 2014;15(8):536-550.  (PubMed)

7.  Beld J, Sonnenschein EC, Vickery CR, Noel JP, Burkart MD. The phosphopantetheinyl transferases: catalysis of a post-translational modification crucial for life. Nat Prod Rep. 2014;31(1):61-108.  (PubMed)

8.  Bunkoczi G, Pasta S, Joshi A, et al. Mechanism and substrate recognition of human holo ACP synthase. Chem Biol. 2007;14(11):1243-1253.  (PubMed)

9.  Donato H, Krupenko NI, Tsybovsky Y, Krupenko SA. 10-formyltetrahydrofolate dehydrogenase requires a 4'-phosphopantetheine prosthetic group for catalysis. J Biol Chem. 2007;282(47):34159-34166.  (PubMed)

10.  Strickland KC, Hoeferlin LA, Oleinik NV, Krupenko NI, Krupenko SA. Acyl carrier protein-specific 4'-phosphopantetheinyl transferase activates 10-formyltetrahydrofolate dehydrogenase. J Biol Chem. 2010;285(3):1627-1633.  (PubMed)

11.  Strickland KC, Krupenko NI, Dubard ME, Hu CJ, Tsybovsky Y, Krupenko SA. Enzymatic properties of ALDH1L2, a mitochondrial 10-formyltetrahydrofolate dehydrogenase. Chem Biol Interact. 2011;191(1-3):129-136.  (PubMed)

12.  Hodges RE, Ohlson MA, Bean WB. Pantothenic acid deficiency in man. J Clin Invest. 1958;37(11):1642-1657.  (PubMed)

13.  Fry PC, Fox HM, Tao HG. Metabolic response to a pantothenic acid deficient diet in humans. J Nutr Sci Vitaminol (Tokyo). 1976;22(4):339-346.  (PubMed)

14.  Bender DA. Optimum nutrition: thiamin, biotin and pantothenate. Proc Nutr Soc. 1999;58(2):427-433.  (PubMed)

15.  Kurian MA, Hayflick SJ. Pantothenate kinase-associated neurodegeneration (PKAN) and PLA2G6-associated neurodegeneration (PLAN): review of two major neurodegeneration with brain iron accumulation (NBIA) phenotypes. Int Rev Neurobiol. 2013;110:49-71.  (PubMed)

16. Food and Nutrition Board, Institute of Medicine. Pantothenic acid. Dietary Reference Intakes: Thiamin, Riboflavin, Niacin, Vitamin B6, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, D.C.: National Academy Press; 1998:357-373.  (National Academy Press)

17.  Weimann BI, Hermann D. Studies on wound healing: effects of calcium D-pantothenate on the migration, proliferation and protein synthesis of human dermal fibroblasts in culture. Int J Vitam Nutr Res. 1999;69(2):113-119.  (PubMed)

18.  Wiederholt T, Heise R, Skazik C, et al. Calcium pantothenate modulates gene expression in proliferating human dermal fibroblasts. Exp Dermatol. 2009;18(11):969-978.  (PubMed)

19.  Kobayashi D, Kusama M, Onda M, Nakahata N. The effect of pantothenic acid deficiency on keratinocyte proliferation and the synthesis of keratinocyte growth factor and collagen in fibroblasts. J Pharmacol Sci. 2011;115(2):230-234.  (PubMed)

20.  Heise R, Skazik C, Marquardt Y, et al. Dexpanthenol modulates gene expression in skin wound healing in vivo. Skin Pharmacol Physiol. 2012;25(5):241-248.  (PubMed)

21.  Vaxman F, Olender S, Lambert A, et al. Effect of pantothenic acid and ascorbic acid supplementation on human skin wound healing process. A double-blind, prospective and randomized trial. Eur Surg Res. 1995;27(3):158-166.  (PubMed)

22.  Vaxman F, Olender S, Lambert A, Nisand G, Grenier JF. Can the wound healing process be improved by vitamin supplementation? Experimental study on humans. Eur Surg Res. 1996;28(4):306-314.  (PubMed)

23.  Celebi S, Tepe C, Yelken K, Celik O. Efficacy of dexpanthenol for pediatric post-tonsillectomy pain and wound healing. Ann Otol Rhinol Laryngol. 2013;122(7):464-467.  (PubMed)

24.  Coronel F, Tornero F, Torrente J, et al. Treatment of hyperlipemia in diabetic patients on dialysis with a physiological substance. Am J Nephrol. 1991;11(1):32-36.  (PubMed)

25.  Gaddi A, Descovich GC, Noseda G, et al. Controlled evaluation of pantethine, a natural hypolipidemic compound, in patients with different forms of hyperlipoproteinemia. Atherosclerosis. 1984;50(1):73-83.  (PubMed)

26.  Rumberger JA, Napolitano J, Azumano I, Kamiya T, Evans M. Pantethine, a derivative of vitamin B(5) used as a nutritional supplement, favorably alters low-density lipoprotein cholesterol metabolism in low- to moderate-cardiovascular risk North American subjects: a triple-blinded placebo and diet-controlled investigation. Nutr Res. 2011;31(8):608-615.  (PubMed)

27.  Said HM, Ortiz A, McCloud E, Dyer D, Moyer MP, Rubin S. Biotin uptake by human colonic epithelial NCM460 cells: a carrier-mediated process shared with pantothenic acid. Am J Physiol. 1998;275(5 Pt 1):C1365-1371.  (PubMed)

28.  Said HM. Intestinal absorption of water-soluble vitamins in health and disease. Biochem J. 2011;437(3):357-372.  (PubMed)

29.  Hendler SS, Rorvik DR, eds. PDR for Nutritional Supplements. 2nd ed. Montvale: Thomson Reuters; 2008.

30.  Flodin N. Pharmacology of micronutrients. New York: Alan R. Liss, Inc.; 1988. 

31.  Debourdeau PM, Djezzar S, Estival JL, Zammit CM, Richard RC, Castot AC. Life-threatening eosinophilic pleuropericardial effusion related to vitamins B5 and H. Ann Pharmacother. 2001;35(4):424-426.  (PubMed)

32.  Herbst RA, Uter W, Pirker C, Geier J, Frosch PJ. Allergic and non-allergic periorbital dermatitis: patch test results of the Information Network of the Departments of Dermatology during a 5-year period. Contact Dermatitis. 2004;51(1):13-19.  (PubMed)

33.  Schmuth M, Wimmer MA, Hofer S, et al. Topical corticosteroid therapy for acute radiation dermatitis: a prospective, randomized, double-blind study. Br J Dermatol. 2002;146(6):983-991.  (PubMed)

34. Chirapu SR, Rotter CJ, Miller EL, Varma MV, Dow RL, Finn MG. High specificity in response of the sodium-dependent multivitamin transporter to derivatives of pantothenic acid. Curr Top Med Chem. 2013;13(7):837-842.  (PubMed)

Riboflavin

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Summary

  • Riboflavin is the precursor of the coenzymes, flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN). They act as electron carriers in a number of oxidation-reduction (redox) reactions involved in energy production and in numerous metabolic pathways. (More information)
  • Riboflavin deficiency can affect multiple pathways in the metabolism of vitamin B6, folate, niacin, and iron. (More information)
  • Riboflavin deficiency has been linked to preeclampsia in pregnant women. This condition may progress to eclampsia and cause severe bleeding and death. The risk of preeclampsia has recently been associated with the presence of a genetic variant (C677T) in the methylenetetrahydrofolate reductase (MTHFR) gene. This gene codes for the MTHFR enzyme, which is FAD-dependent. (More information)
  • Oxidative stress can cause opacification of the eye lens, leading to cataracts in older individuals. While the results of some observational studies are promising, intervention studies are needed to assess a potential benefit of riboflavin in the prevention of cataracts. (More information)
  • Riboflavin (in the form, FAD) is required as a cofactor for the key folate-metabolizing enzyme, MTHFR. A low status of riboflavin status may interfere with the metabolism of folate, particularly in individuals homozygous for the MTHFR C677T gene variant; these individuals exhibit a higher risk of cardiovascular disease (CVD). Emerging evidence from intervention trials supports a protective role for riboflavin against hypertension in individuals with the MTHFR 677TT genotype. (More information)
  • Riboflavin has been evaluated as a prophylactic agent in studies with children and adults suffering from migraine headache. Riboflavin supplementation has been shown to decrease the frequency and severity of headache attacks in adults but not in children. (More information)
  • Case reports have shown that patients with autosomal recessive disorders of riboflavin metabolism may benefit from riboflavin supplementation. (More information)
  • Riboflavin has been evaluated as a potential adjunct therapy in cancer and certain eye disorders. (More information)

Riboflavin is a water-soluble B vitamin, also known as vitamin B2. In the body, riboflavin is primarily found as an integral component of the coenzymes, flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN) (1). Coenzymes derived from riboflavin are termed flavocoenzymes, and enzymes that use a flavocoenzyme are called flavoproteins (2).

Function

Oxidation-reduction (redox) reactions

Living organisms derive most of their energy from redox reactions, which are processes that involve the transfer of electrons. Flavocoenzymes participate in redox reactions in numerous metabolic pathways (3). They are critical for the metabolism of carbohydrates, lipids, and proteins. FAD is part of the electron transport (respiratory) chain, which is central to energy production. In conjunction with cytochrome P-450, flavocoenzymes also participate in the metabolism of drugs and toxins (4).

Antioxidant functions

Glutathione reductase is an FAD-dependent enzyme that participates in the redox cycle of glutathione. The glutathione redox cycle plays a major role in protecting organisms from reactive oxygen species, such as hydroperoxides. Glutathione reductase (GR) requires FAD to regenerate two molecules of reduced glutathione from oxidized glutathione. Riboflavin deficiency has been associated with increased oxidative stress (4). Measurement of GR activity in red blood cells is commonly used to assess riboflavin nutritional status (5). The erythrocyte glutathione reductase activation coefficient (EGRac) assay assesses riboflavin status by measuring the activity of GR before and after in vitro reactivation with its prosthetic group FAD; EGRac is calculated as the ratio of FAD-stimulated to unstimulated enzyme activity and indicates the degree of tissue saturation with riboflavin. EGRac is thus a functional measure of riboflavin status and has shown to be effective in reflecting biomarker status from severe deficiency to normal status (6).

Glutathione peroxidases, selenium-containing enzymes, require two molecules of reduced glutathione to break down hydroperoxides. GPx are involved in the glutathione oxidation-reduction (redox) cycle (Figure 1).

Figure 1. Glutathione Oxidation Reduction (Redox) Cycle. One molecule of hydrogen peroxide is reduced to 2 molecules of water while 2 molecules of glutathione (GSH) are oxidized in a reaction catalyzed by the selenoenzyme, glutathione peroxidase. Oxidized glutathione (GSSG) may be reduced by the flavin adenine dinucleotide (FAD)-dependent enzyme, glutathione reductase.

[Figure 1 - Click to Enlarge]

Xanthine oxidase, another FAD-dependent enzyme, catalyzes the oxidation of hypoxanthine and xanthine to uric acid. Uric acid is one of the most effective water-soluble antioxidants in the blood. Riboflavin deficiency can result in decreased xanthine oxidase activity, reducing blood uric acid levels (7).

Nutrient interactions

B-complex vitamins

Flavoproteins are involved in the metabolism of several other vitamins: (vitamin B6, niacin, and folate). Therefore, severe riboflavin deficiency may affect many enzyme systems. Conversion of most naturally available vitamin B6 to its coenzyme form, pyridoxal 5'-phosphate (PLP), requires the FMN-dependent enzyme, pyridoxine 5'-phosphate oxidase (PPO) (8). At least two studies in the elderly have documented significant interactions between indicators of vitamin B6 and riboflavin nutritional status (9, 10). The synthesis of the niacin-containing coenzymes, NAD and NADP, from the amino acid tryptophan, requires the FAD-dependent enzyme, kynurenine mono-oxygenase. Severe riboflavin deficiency can decrease the conversion of tryptophan to NAD and NADP, increasing the risk of niacin deficiency (3). 5, 10-Methylenetetrahydrofolate reductase (MTHFR) is an FAD-dependent enzyme that plays an important role in maintaining the specific folate coenzyme required to form methionine from homocysteine (Figure 2). Along with other B vitamins, higher riboflavin intakes have been associated with decreased plasma homocysteine levels (11). Increased plasma riboflavin levels have also been associated with decreased plasma homocysteine levels, mainly in individuals homozygous for the C677T polymorphism in the MTHFR gene and in individuals with low folate intake (12). Such results illustrate that chronic disease risk may be influenced by complex interactions between genetic and dietary factors (see Cardiovascular disease and Cancer).

Figure 2. Folate and Nucleic acid Metabolism. 5,10-Methylene tetrahydrofolate (TH4-folate) is required for the synthesis of nucleic acids, and 5-methyl TH4-folate is required for the formation of methionine from homocysteine. Methionine, in the form of S-adenosylmethionine, is required for many biological methylation reactions, including DNA methylation. Methylene TH4-folate reductase is a flavin-dependent enzyme required to catalyze the reduction of 5,10-methylene TH4-folate to 5-methyl TH4-folate.

[Figure 2 - Click to Enlarge]

Iron

Riboflavin deficiency alters iron metabolism. Although the mechanism is not clear, research in animals suggests that riboflavin deficiency may impair iron absorption, increase intestinal loss of iron, and/or impair iron utilization for the synthesis of hemoglobin (Hb) (13). In humans, improving riboflavin nutritional status has been found to increase circulating Hb levels (14). Correction of riboflavin deficiency in individuals who are both riboflavin and iron deficient improves the response of iron-deficiency anemia to iron therapy (15). Anemia during pregnancy, a worldwide public health problem, is responsible for considerable perinatal morbidity and mortality (16, 17). The management of maternal anemia includes the supplementation with iron alone or iron in combination with folic acid (18), and it has been considered that riboflavin supplementation could enhance the iron-folic acid supplementation. Randomized, double-blind intervention trials conducted in pregnant women with anemia in Southeast Asia showed that a combination of folic acid, iron, vitamin A, and riboflavin improved Hb levels and decreased anemia prevalence compared to the iron-folic acid supplementation alone (19, 20).

Deficiency

Ariboflavinosis is the medical name for clinical riboflavin deficiency. Riboflavin deficiency is rarely found in isolation; it occurs frequently in combination with deficiencies of other water-soluble vitamins. Symptoms of riboflavin deficiency include sore throat, redness and swelling of the lining of the mouth and throat, cracks or sores on the outsides of the lips (cheliosis) and at the corners of the mouth (angular stomatitis), inflammation and redness of the tongue (magenta tongue), and a moist, scaly skin inflammation (seborrheic dermatitis). Other symptoms may involve the formation of blood vessels in the clear covering of the eye (vascularization of the cornea) and decreased red blood cell count in which the existing red blood cells contain normal levels of hemoglobin and are of normal size (normochromic normocytic anemia) (1, 3). Severe riboflavin deficiency may result in decreased conversion of vitamin B6 to its coenzyme form (PLP) and decreased conversion of tryptophan to niacin (see Nutrient interactions).

Preeclampsia is defined as the presence of elevated blood pressure, protein in the urine, and edema (significant swelling) during pregnancy. About 5% of women with preeclampsia progress to eclampsia, a significant cause of maternal and fetal death. Eclampsia is characterized by seizures, in addition to high blood pressure and increased risk of hemorrhage (severe bleeding) (21). A study in 154 pregnant women at increased risk of preeclampsia found that those who were riboflavin deficient were 4.7 times more likely to develop preeclampsia than those who had adequate riboflavin nutritional status (22). The cause of preeclampsia-eclampsia is not known. Decreased intracellular levels of flavocoenzymes could cause mitochondrial dysfunction, increase oxidative stress, and interfere with nitric oxide release and thus blood vessel dilation — all of these changes have been associated with preeclampsia (22).

A recent meta-analysis of 51 studies found that the methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism was associated with preeclampsia in Caucasian and East Asian populations (23). However an earlier meta-analysis reported that the MTHFR 677TT genotype carried a significantly greater risk of preeclampsia among Asian women only, while in Caucasian women the increased risk was not significant (24). Such heterogeneity among studies may suggest that the effect of MTHFR 677TT genotype could be modulated by riboflavin and other relevant dietary factors that may vary considerably among different populations. The reduction in the flavoprotein MTHFR activity observed in subjects with the C677T genetic variant leads to a slight increase in plasma homocysteine concentrations; increased homocysteine levels have been associated with preeclampsia (25). One small randomized, placebo-controlled, double-blind trial in 450 pregnant women at high risk for preeclampsia found that supplementation with 15 mg of riboflavin daily did not prevent the condition (26). However, studies are needed to assess the potential benefit of riboflavin supplementation in reducing perinatal complications specifically in preeclamptic women with the C677T genotype.

Risk factors for riboflavin deficiency

Alcoholics are at increased risk for riboflavin deficiency due to decreased intake, decreased absorption, and impaired utilization of riboflavin. Interestingly, the elevated homocysteine levels associated with riboflavin deficiency rapidly decline during alcohol withdrawal (27). Additionally, anorexic individuals rarely consume adequate riboflavin, and lactose intolerant individuals may not consume milk or other dairy products that are good sources of riboflavin. The conversion of riboflavin into FAD and FMN is impaired in hypothyroidism and adrenal insufficiency (3, 4). Further, people who are very active physically (athletes, laborers) may have a slightly increased riboflavin requirement. However, riboflavin supplementation has not generally been found to increase exercise tolerance or performance (28).

Although clinical riboflavin deficiency (i.e., including signs such as angular stomatitis, cheilosis, and glossitis) is rare in the developed world, there is evidence suggesting that suboptimal riboflavin status (as determined by the functional biomarker EGRac) may be a widespread problem affecting many otherwise healthy populations within the developed world. For example, a high proportion of the British adult population was reported to have poor riboflavin status as determined from national survey data using EGRac (29). Dietary intakes however were generally found to compare favorably with recommended values, except in young women who had low intakes. The large proportion of the UK population with abnormal EGRac values, despite apparently adequate dietary intakes, requires further investigation.

The Recommended Dietary Allowance (RDA)

The RDA for riboflavin, revised in 1998, is based on the prevention of deficiency (Table 1). Clinical signs of deficiency in humans appear at intakes of less than 0.5-0.6 milligrams (mg)/day, and urinary excretion of riboflavin is seen at intake levels of approximately 1 mg/day (1).

Table 1. Recommended Dietary Allowance (RDA) for Riboflavin
Life Stage Age Males (mg/day) Females (mg/day)
Infants  0-6 months  0.3 (AI 0.3 (AI) 
Infants  7-12 months  0.4 (AI)  0.4 (AI) 
Children  1-3 years  0.5  0.5 
Children  4-8 years  0.6  0.6 
Children  9-13 years  0.9  0.9 
Adolescents  14-18 years  1.3  1.0 
Adults  19 years and older  1.3  1.1 
Pregnancy  all ages  1.4 
Breast-feeding  all ages  1.6

Disease Prevention

Cataracts

Age-related cataracts are the leading cause of visual disability in the US and other developed countries. Research has focused on the role of nutritional antioxidants because of evidence that light-induced oxidative damage of lens proteins may lead to the development of age-related cataracts. A case-control study found significantly decreased risk of age-related cataract (33 to 51%) in men and women in the highest quintile of dietary riboflavin intake (median of 1.6 to 2.2 mg/day) compared to those in the lowest quintile (median of 0.08 mg/day in both men and women) (30). Another case-control study reported that individuals in the highest quintile of riboflavin nutritional status, as measured by red blood cell glutathione reductase activity, had approximately one-half the occurrence of age-related cataract as those in the lowest quintile of riboflavin status, though the results were not statistically significant (31). A cross-sectional study of 2,900 Australian men and women, 49 years of age and older, found that those in the highest quintile of riboflavin intake were 50% less likely to have cataracts than those in the lowest quintile (32). A prospective study of more than 50,000 women did not observe a difference between rates of cataract extraction between women in the highest quintile of riboflavin intake (median of 1.5 mg/day) and women in the lowest quintile (median of 1.2 mg/day) (33). However, the range between the highest and lowest quintiles was small, and median intake levels for both quintiles were above the current RDA for riboflavin. A study in 408 women found that higher dietary intakes of riboflavin were inversely associated with a five-year change in lens opacification (34). Although these observational studies provide some support for the role of riboflavin in the prevention of cataracts, randomized, placebo-controlled intervention trials that include a response biomarker (such as EGRac) are needed to confirm the relationship.

Cardiovascular disease

For many years, elevated homocysteine levels in plasma have been considered to be a risk factor for cardiovascular disease (CVD), although this has recently become somewhat controversial (35). Plasma homocysteine is responsive to the lowering effects of interventions with folate and metabolically related B vitamins, including riboflavin. Riboflavin acts as a cofactor for MTHFR and is therefore needed to generate 5-methyltetrahydrofolate required in the remethylation of homocysteine to methionine (see Figure 2 above). These B vitamins, however, may have roles in the prevention of CVD that are independent of their effects on homocysteine.

Genetic studies provide convincing evidence to support a link between suboptimal B-vitamin status and CVD risk. A meta-analysis of such studies showed that individuals who are homozygous for the MTHFR C677T gene variant had a significantly higher risk of CVD (by 14 to 21%) compared to those without this polymorphism, but there was a large amount of geographical variation in the increased CVD risk (36), strongly suggesting that dietary factors can modulate the disease risk related to this genetic factor.

Accumulating evidence links this common folate polymorphism with hypertension (defined as a blood pressure of 140/90 mm Hg or greater), a major risk factor for CVD, particularly stroke. The emerging evidence that blood pressure in patients homozygous for this polymorphism is highly responsive to low-dose riboflavin (see Disease Treatment) raises the possibility that improving riboflavin status will have an important role in preventing hypertension. This in turn could potentially reduce the risk of stroke specifically in individuals with the relevant genotype. Notably, the reported frequency of the MTHFR 677TT genotype is 10% worldwide, ranging from 4%-26% in Europe, 20% in Northern China, and as high as 32% in Mexico (37).

Cancer

The flavoprotein, methylenetetrahydrofolate reductase (MTHFR), plays a pivotal role in folate-mediated homocysteine metabolism. MTHFR converts 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, which is necessary for the re-methylation of homocysteine to methionine (see Figure 2 above). The conversion of homocysteine to methionine is of importance for homocysteine detoxification and for the production of S-adenosylmethionine (SAM), the methyl donor for the methylation of DNA and histones. Folate deficiency and elevated homocysteine concentrations may increase cancer risk (see the article on Folate). Aberrant methylation changes are also known to alter the structure and function of DNA and histones during cancer development (38). Since MTHFR controls the detoxification of homocysteine and the supply of methyl groups for SAM synthesis, a reduction in its activity can affect homocysteine metabolism and disturb cellular methylation processes. The substitution of a cytosine by a thymine in position 677 (c.677C>T) in the MTHFR gene is a polymorphism that affects the binding of FAD and leads to an increased propensity for MTHFR to lose its flavin coenzyme (39). Individuals homozygous for this mutation (i.e., MTHFR 677TT genotype) exhibit reduced MTHFR activity, and some evidence shows that such individuals are at increased risk of cancer at various sites (40-42); however, the nature of the association between this common polymorphism and cancer risk remains unclear.

As mentioned above (see B-complex vitamins), riboflavin intake is a determinant of homocysteine concentration. This suggests that riboflavin status can influence MTHFR activity and the metabolism of folate, thereby potentially affecting cancer risk (42). In a randomized, double-blind, placebo-controlled study, 93 subjects with colorectal polyps and 86 healthy subjects were given either a placebo, folic acid (400 or 1,200 mcg/day), or folic acid (400 mcg/day) plus riboflavin (5 mg/day) for 45 days. These interventions significantly improved folate and riboflavin status in vitamin-supplemented individuals compared to those taking the placebo. Interestingly, riboflavin enhanced the effect of 400 mcg folic acid on circulating 5-methyl tetrahydrafolate (5-MeTH4) specifically in the polyp patients with the C677T genetic variant (43). This suggests that riboflavin may improve response to folic acid supplementation in individuals with a reduced MTHFR activity. Additionally, a prospective cohort study of 88,045 postmenopausal women found total (dietary plus supplemental) intake of riboflavin to be inversely correlated with colorectal cancer risk when comparing the highest (>3.97 mg) and lowest (<1.80 mg) quartiles of daily intake (44); intake in the reference group was well above the RDA of 1.1 mg/day. The subjects in this study were not prescreened to identify those with the C677T genotype, and the association between the C677T polymorphism and colorectal cancer is unclear, with reports suggesting a reduction in the risk with the T allele (45).

Associations between riboflavin intake and cancer risk have been evaluated in other types of cancer. A seven-year intervention study evaluated the use of riboflavin-fortified salt in 22,093 individuals at high risk for esophageal cancer in China. Riboflavin status and esophageal pathology (percent normal, dysplastic, and cancerous tissues) improved in the intervention group compared to the control group, but the lower incidence of esophageal cancer found in the intervention group was not statistically significant (46). Additionally, the Melbourne Collaborative Cohort Study, which followed 41,514 men and women over a 15-year period, found weak inverse associations between riboflavin intake and lung cancer (47) and breast cancer (48) and no association with prostate cancer (49). However, a 10-year follow up of an intervention trial in patients at high risk for gastric (stomach) cancer found that dietary supplementation with minerals and vitamins, including riboflavin (3.2 mg/day) and niacin (40 mg/day), for five years failed to decrease the incidence or mortality rate of gastric cancer (50).

Disease Treatment

Migraine headaches

Some evidence indicates that impaired mitochondrial oxygen metabolism in the brain may play a role in the pathology of migraine headaches. Since riboflavin is the precursor of the two flavocoenzymes (FAD and FMN) required by the flavoproteins of the mitochondrial electron transport chain, supplemental riboflavin has been investigated as a treatment for migraine. A randomized, placebo-controlled trial examined the effect of 400 mg/day of riboflavin for three months on migraine prevention in 54 men and women with a history of recurrent migraine headaches (51). Riboflavin was significantly better than placebo in reducing attack frequency and the number of headache days, though the beneficial effect was most pronounced during the third month of treatment. Another study by the same investigators found that treatment with either a medication called a β-blocker or high-dose riboflavin (400 mg/day) for four months resulted in clinical improvement, but each therapy appeared to act on a distinct pathological mechanism: β-blockers on abnormal cortical information processing and riboflavin on decreased brain mitochondrial energy reserve (52). A small study in 23 patients reported a reduction in median migraine attack frequency after supplementation with 400 mg of riboflavin daily for three months (53). However, a three-month randomized, double-blind, placebo-controlled study that administered a combination of riboflavin (400 mg/day), magnesium, and feverfew to migraine sufferers reported no therapeutic benefit beyond that associated with taking a placebo containing 25 mg/day of riboflavin (54). Compared to baseline measurements in this trial, both the placebo and treatment groups experienced some benefits with respect to the mean number of migraines, migraine days, or migraine index (54). Although these findings are preliminary, data from most studies to date suggest that riboflavin supplementation in adults might be a useful adjunct to pharmacologic therapy in migraine prevention.

Two randomized, double-blind, placebo-controlled trials investigated the effect of riboflavin supplementation on the frequency and severity of headache attacks in children with migraines. The first study evaluated riboflavin at 200 mg/day for 12 weeks in 48 children aged 5 to 15 years old (55). The second study was a cross-over trial with half of the 42 children, aged 6 to 13, receiving 50 mg/day riboflavin for 16 weeks then placebo (100 mg/day carotene) for 16 weeks with a four-week washout period in between, while the other half were first given the placebo then riboflavin (56). Both studies showed no differences in the frequency, duration, or intensity of migraines between treatments. The effectiveness of riboflavin supplementation in children with migraine is yet to be established, and future research should first determine the most appropriate riboflavin dosage for this population.

Metabolic disorders

Increasing evidence indicates that patients with autosomal recessive disorders caused by defective FAD-dependent enzymes could benefit from riboflavin supplementation.

Multiple acyl-CoA dehydrogenase deficiency (MADD)

MADD, also known as type II glutaric aciduria (or acidemia), is a fatty acid metabolism disorder characterized by the accumulation of short-, medium-, and long-chain acyl-carnitines in various tissues. Neonatal and late onset forms of MADD show a wide spectrum of clinical severity and variable presentations, including episodic encephalopathy, periodic vomiting, hepatopathy, and rhabdomyolysis (57). MADD is caused by mutations in genes that impair the activity of enzymes involved in the transfer of electrons from acyl-Coenzyme A (acyl-CoA) to Coenzyme Q10/Ubiquinone inside mitochondria (Figure 3). ETFA, ETFB, and ETFDH code for the two subunits of the electron transfer flavoprotein (ETF-A and -B), and for ETF dehydrogenase/ubiquinone oxidoreductase (ETFDH/ETFQO), respectively.

Figure 3. Fatty-Acid Beta-Oxidation and the Electron Transfer Flavoprotein System. Multiple acyl-coenzyme A dehydrogenase deficiency (MADD) is caused by mutations in the genes coding for the electron transfer flavoprotein (ETF) and the electron transfer flavoprotein-ubiquinone oxidoreductase (ETF-QO). These flavoproteins are essential for electron transfer from the fatty-acid beta-oxidation (beta-oxidation) pathway to the respiratory chain: FAD is the electron acceptor for acyl-CoA dehydrogenase (first step in fatty acid beta-oxidation), and it donates electrons to ETF-FAD, reducing it to ETF-FADH2. The flavoprotein is restored to its oxidized form by ETF-QO, which transfers the electrons to coenzyme Q10, via its iron-sulfur (Fe-S) cluster and FAD.

[Figure 3 - Click to Enlarge]

Deficiencies in these enzymes (ETF or ETFDH) lead to a decrease in oxidized FAD, which becomes unavailable for FAD-dependent dehydrogenation reactions, including the first step in β-oxidation — a major fatty acid catabolic process that takes place in the mitochondria. A defect in fatty acid β-oxidation causes lipid accumulation in skeletal muscles, leading to lipid storage myopathy characterized by muscle pain and weakness and exercise intolerance. Together with a low-fat and high-carbohydrate diet, riboflavin supplementation has led to significant clinical improvements in patients with ETFDH mutations. The specific type of the mutation in ETF/ETFDH contributes to age of onset, severity, and responsiveness to riboflavin treatment (58). Additionally, the recent report of a 20-year-old man with riboflavin-responsive MADD failed to find mutations in ETF and ETFDH genes, suggesting that other sites of mutation should not be excluded (57). Finally, secondary deficiencies in the respiratory chain are observed in MADD and appear to respond favorably to riboflavin supplementation (58, 59).

Acyl-CoA dehydrogenase 9 deficiency (ACAD9)

Recessive mutations in the ACAD9 gene coding for a FAD-dependent acyl CoA dehydrogenase were found in patients with mitochondrial complex I deficiency, a respiratory chain disorder (60). ACAD9 deficiency has not been linked to fatty acid β-oxidation defects, suggesting instead a role in complex I assembly for ACAD9 (61). Complex I carries electrons from NADH to Coenzyme Q10 in the electron transport chain. Defective oxidative phosphorylation (ATP synthesis by the respiratory chain) due to complex I deficiency has been linked to a broad variety of clinical manifestations from neonatal death to late-onset neurodegenerative diseases. The symptoms of complex I deficiency due to ACAD9 mutations include muscle weakness, exercise intolerance, lactic acidosis, encephalopathy, and cardiomyopathy. Riboflavin supplementation (100-300 mg/day) increased complex I activity in patients with childhood-onset clinical forms of ACAD9 deficiency. Improvements in muscle strength and exercise tolerance have also been associated with riboflavin supplementation (62-64).

Defective riboflavin transport-associated disorders

SLC52A1, SLC52A3, and SLC52A2 genes code for the human riboflavin transporters hRTF1, hRTF2, and hRTF3, respectively. Mutations in these genes have been linked with Brown-Vialetto-Van Laere syndrome (BVVL), a rare neurodegenerative disorder characterized by variable age onsets. The syndrome includes bulbar palsy with hypotonia and facial weakness, sensorineural deafness, and respiratory insufficiency. Lack of hearing loss in the clinical description of BVVL symptoms is known as Fazio-Londe syndrome (FL). Transient clinical and biochemical features of MADD were described in a newborn of a riboflavin-deficient mother; this mild deficiency, caused by a mutation in hRTF1, was promptly corrected by riboflavin supplementation (65, 66). A recent review of the literature, which analyzed reports of 74 patients affected by the BVVL/FL syndrome, found that 8 of the 13 patients given supplemental riboflavin (average dose of 10 mg/kg/day) experienced clinical improvements, and the treated individuals had a survival rate of 100% (67). Riboflavin also restored normal flavin and acylcarnitine levels in patients presenting abnormal profiles.

Riboflavin-responsive trimethylaminuria

Primary trimethylaminuria is caused by defective oxidation of trimethylamine by a liver flavoprotein called flavin containing mono-oxygenase 3 (FMO3). Individuals with FMO3 deficiency have increased levels of trimethylamine in urine, sweat, and breath (68). This socially distressing condition is known as "fish odor syndrome" due to the fishy odor and volatile nature of trimethylamine. FMO3 gene mutations are usually associated with mild or intermittent trimethylaminuria; the condition is sometimes limited to peri-menstrual periods in female subjects or to the consumption of trimethylamine-rich food. The clinical management of the condition includes dietary restriction of trimethylamine and its precursors, such as foods rich in choline and seafood, as well as cruciferous vegetables that contain both trimethylamine precursors and FMO3 antagonists (69). The use of riboflavin supplements was recently reported in a 17-year-old female patient affected by pyridoxine non-responsive homocystinuria (70). The disease was initially treated with betaine (a choline derivative), which caused body odor secondary to FMO3 deficiency. Riboflavin supplementation (200 mg/day) reduced trimethylamine excretion and betaine treatment-related body odor. The data suggest that riboflavin might help maximize residual FMO3 enzyme activity in patients with primary trimethylaminuria.

Hypertension

Although the etiology of hypertension is unclear, the methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism is the main determinant of homocysteine concentrations and has been related to elevated blood pressure (a marker of hypertension) (71) and increased risk of coronary heart disease and vascular accident (72-74). Since this genetic variant leads to decreased MTHFR activity, individuals with the 677TT genotype may benefit from riboflavin supplementation. In an initial randomized, double-blind, placebo-controlled trial in 77 healthy subjects who had been pre-screened for MTHFR genotype, riboflavin supplementation (1.6 mg/day for 12 weeks) lowered homocysteine levels in the MTHFR 677TT genotype group but not in the age-matched 677CC and 677CT groups that exhibited normal plasma homocysteine levels at baseline (75). Two subsequent randomized, double-blind, placebo-controlled trials investigated the possibility of riboflavin modulating hypertension in premature cardiovascular disease (CVD) patients (pre-screened for the MTHFR 677C→T polymorphism) (76, 77). Results showed a significant lowering of blood pressure only in the patients with the 677TT genotype supplemented with riboflavin (1.6 mg/day for 16 weeks) compared to placebo, both on initial examination (69) and when the same cohort of high-risk CVD patients was reinvestigated four years after the original trial (70). Another study investigated the effect of riboflavin in 88 hypertensive patients (but without overt CVD) with the MTHFR 677TT genotype, the majority of whom were being treated with antihypertensive therapy. At baseline, 60% of participants had failed to achieve target BP levels (≤140/90 mm Hg), despite taking three or more antihypertensive medications. The reduction in blood pressure following riboflavin supplementation (1.6 mg/day for 16 weeks) in these patients suggested that the excess risk of hypertension linked to this genetic variation could be overcome by optimizing riboflavin status (78).

Cancer

Anti-cancer agents often display various side effects that may force patients to limit the dose or to discontinue the treatment. The antioxidant effect of co-administering riboflavin (10 mg/day), niacin (50 mg/day), and coenzyme Q10 (100 mg/day) was evaluated in 78 postmenopausal breast cancer patients treated with Tamoxifen for 90 days. This supplementation effectively prevented the oxidative stress associated with tamoxifen treatment (79). Riboflavin can also act as a photosensitizer, and this property may have value in photodynamic therapy of cancer. A mouse model was used to assess the effect of riboflavin in combination with cisplatin, one of the most effective anti-cancer agents. Under light exposure, riboflavin administration reduced cisplatin-induced DNA damage in the liver and kidneys (80). These results are promising, but human studies are needed to examine whether riboflavin might be an effective adjunct to chemotherapy.

Corneal disorders

Corneal ectasia is an eye condition characterized by irregularities of the cornea that affect vision. Corneal cross-linking — a new procedure used by professionals to limit the progression of corneal damage — involves the use of riboflavin in conjunction with ultraviolet light irradiation. Cross-linking modifies the properties of the cornea and strengthens its architecture (81).

Sources

Food sources

Most plant- and animal-derived foods contain at least small quantities of riboflavin. In the US, wheat flour and bread have been enriched with riboflavin (as well as thiamin, niacin, and iron) since 1943. Data from large dietary surveys indicate that the average intake of riboflavin for men is about 2 mg/day and for women is about 1.5 mg/day; both intakes are well above the RDA. Intake levels were similar for a population of elderly men and women (1). Riboflavin is easily destroyed upon exposure to light. For instance, up to 50% of the riboflavin in milk contained in a clear glass bottle can be destroyed after two hours of exposure to bright sunlight (7). Some foods with substantial amounts of riboflavin are listed in Table 2, along with their riboflavin content in milligrams (mg). For more information on the nutrient content of food, search the USDA food composition database.

Table 2. Some Food Sources of Riboflavin
Food Serving Riboflavin (mg)
Fortified, wheat, puffed cereal 1 cup 0.22
Milk (nonfat) 1 cup (8 ounces) 0.45
Cheddar cheese 1 ounce 0.11
Egg (cooked, hard-boiled) 1 large 0.26
Almonds 1 ounce 0.29
Salmon (cooked) 3 ounces* 0.13
Halibut (Greenland, cooked, dry-heat) 3 ounces 0.09
Chicken, light meat (roasted) 3 ounces 0.08
Chicken, dark meat (roasted) 3 ounces 0.16
Beef (ground, cooked) 3 ounces 0.15
Broccoli (boiled) ½ cup chopped 0.10
Asparagus (boiled) 6 spears 0.13
Spinach (boiled) ½ cup 0.21
Bread, whole-wheat 1 slice 0.06
Bread, white (enriched) 1 slice 0.09
*A three-ounce serving of meat is about the size of a deck of cards.

Supplements

The most common forms of riboflavin available in supplements are riboflavin and riboflavin 5'-monophosphate. Riboflavin is most commonly found in multivitamin and vitamin B-complex preparations (82).

Safety

Toxicity

No toxic or adverse effects of high riboflavin intake in humans are known. Studies in cell culture indicate that excess riboflavin may increase the risk of DNA strand breaks in the presence of chromium (VI), a known carcinogen (83). This may be of concern to workers exposed to chrome, but no data in humans are available. High-dose riboflavin therapy has been found to intensify urine color to a bright yellow (flavinuria), but this is a harmless side effect. The Food and Nutrition Board did not establish a tolerable upper intake level (UL) when the RDA was revised in 1998 (1).

Drug interactions

Several early reports indicated that women taking high-dose oral contraceptives (OC) had diminished riboflavin nutritional status. However, when investigators controlled for dietary riboflavin intake, no differences between OC users and non-users were found (1). Phenothiazine derivatives like the anti-psychotic medication chlorpromazine and tricyclic antidepressants inhibit the incorporation of riboflavin into FAD and FMN, as do the anti-malarial medication, quinacrine, and the cancer chemotherapy agent, adriamycin (4). Long-term use of the anti-convulsant, phenobarbitol may increase destruction of riboflavin by liver enzymes, increasing the risk of deficiency (3). Additionally, chronic alcohol consumption has been associated with riboflavin deficiency. In rats chronically fed alcohol, the inhibition of riboflavin transporters caused impairment in intestinal absorption and renal re-uptake of the vitamin (84).

Linus Pauling Institute Recommendation

The RDA for riboflavin (1.3 mg/day for men and 1.1 mg/day for women), which should prevent deficiency in most individuals, is easily met by eating a varied diet. Consuming a varied diet should supply 1.5 mg to 2 mg of riboflavin a day. Following the Linus Pauling Institute recommendation to take a multivitamin/mineral supplement containing 100% of the Daily Values (DV) will ensure an intake of at least 1.7 mg/day of riboflavin.

Older adults (>50 years)

Some experts in nutrition and aging feel that the RDA (1.3 mg/day for men and 1.1 mg/day for women) leaves little margin for error in people over 50 years of age (85, 86). A study of independently living people between 65 and 90 years of age found that almost 25% consumed less than the recommended riboflavin intake, and 10% had biochemical evidence of deficiency (87). Epidemiological studies of cataract prevalence indicate that riboflavin intakes of 1.6 to 2.2 mg/day may reduce the risk of developing age-related cataracts. Additionally, older people suffering from acute ischemic stroke were found to be deficient for riboflavin (88), and riboflavin deficiency has been linked to a higher risk of fracture in postmenopausal women with the MTHFR 677T variant (89). Individuals whose diets may not supply adequate riboflavin, especially those over 50 years of age, should consider taking a multivitamin/mineral supplement, which generally provides at least 1.7 mg/day of riboflavin.


Authors and Reviewers

Originally written in 2000 by: 
Jane Higdon, Ph.D. 
Linus Pauling Institute 
Oregon State University

Updated in September 2002 by: 
Jane Higdon, Ph.D. 
Linus Pauling Institute 
Oregon State University

Updated in June 2007 by: 
Victoria J. Drake, Ph.D. 
Linus Pauling Institute 
Oregon State University

Updated in July 2013 by: 
Barbara Delage, Ph.D. 
Linus Pauling Institute 
Oregon State University

Reviewed in December 2013 by: 
Helene McNulty, Ph.D., R.D. 
Professor of Human Nutrition and Dietetics 
Northern Ireland Centre for Food and Health (NICHE) 
University of Ulster 
Coleraine, United Kingdom

Reviewed in December 2013 by: 
Adrian McCann, Ph.D. 
Research Associate 
Northern Ireland Centre for Food and Health (NICHE) 
University of Ulster 
Coleraine, United Kingdom

Copyright 2000-2017  Linus Pauling Institute


References

1.  Food and Nutrition Board, Institute of Medicine. Riboflavin. Dietary Reference Intakes: Thiamin, Riboflavin, Niacin, Vitamin B6, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington D.C.: National Academy Press; 1998:87-122.  (National Academy Press)

2.  Brody T. Nutritional Biochemistry. 2nd ed. San Diego: Academic Press; 1999.

3.  McCormick DB. Riboflavin. In: Shils M, Olson JA, Shike M, Ross AC, eds. Modern Nutrition in Health and Disease. 9th ed. Baltimore: Williams & Wilkins; 1999:391-399.

4.  Powers HJ. Current knowledge concerning optimum nutritional status of riboflavin, niacin and pyridoxine. Proc Nutr Soc. 1999;58(2):435-440.  (PubMed)

5.  Rivlin RS. Riboflavin. In: Ziegler EE, Filer LJ, eds. Present Knowledge in Nutrition. 7th ed. Washington D.C.: ILSI Press; 1996:167-173.

6.  Hoey L, McNulty H, Strain JJ. Studies of biomarker responses to intervention with riboflavin: a systematic review. Am J Clin Nutr. 2009;89(6):1960S-1980S.  (PubMed)

7.  Bohles H. Antioxidative vitamins in prematurely and maturely born infants. Int J Vitam Nutr Res. 1997;67(5):321-328.  (PubMed)

8.  McCormick DB. Two interconnected B vitamins: riboflavin and pyridoxine. Physiol Rev. 1989;69(4):1170-1198.  (PubMed)

9.  Madigan SM, Tracey F, McNulty H, et al. Riboflavin and vitamin B-6 intakes and status and biochemical response to riboflavin supplementation in free-living elderly people. Am J Clin Nutr. 1998;68(2):389-395.  (PubMed)

10.  Lowik MR, van den Berg H, Kistemaker C, Brants HA, Brussaard JH. Interrelationships between riboflavin and vitamin B6 among elderly people (Dutch Nutrition Surveillance System). Int J Vitam Nutr Res. 1994;64(3):198-203.  (PubMed)

11.  Jacques PF, Bostom AG, Wilson PW, Rich S, Rosenberg IH, Selhub J. Determinants of plasma total homocysteine concentration in the Framingham Offspring cohort. Am J Clin Nutr. 2001;73(3):613-621.  (PubMed)

12.  Jacques PF, Kalmbach R, Bagley PJ, et al. The relationship between riboflavin and plasma total homocysteine in the Framingham Offspring cohort is influenced by folate status and the C677T transition in the methylenetetrahydrofolate reductase gene. J Nutr. 2002;132(2):283-288.  (PubMed)

13.  Powers HJ, Weaver LT, Austin S, Beresford JK. A proposed intestinal mechanism for the effect of riboflavin deficiency on iron loss in the rat. Br J Nutr. 1993;69(2):553-561.  (PubMed)

14.  Powers HJ, Hill MH, Mushtaq S, Dainty JR, Majsak-Newman G, Williams EA. Correcting a marginal riboflavin deficiency improves hematologic status in young women in the United Kingdom (RIBOFEM). Am J Clin Nutr. 2011;93(6):1274-1284.  (PubMed)

15.  Powers HJ. Riboflavin-iron interactions with particular emphasis on the gastrointestinal tract. Proc Nutr Soc. 1995;54(2):509-517.  (PubMed)

16.  Kalaivani K. Prevalence & consequences of anaemia in pregnancy. Indian J Med Res. 2009;130(5):627-633.  (PubMed)

17.  Worldwide prevalence of anaemia 1993-2005: WHO global database on anaemia. de Benoist B, McLean E, Egli I, Cogswell M, eds. 2008; World Health Organization Press. Available at: http://www.who.int/nutrition/publications/
micronutrients/anaemia_iron_deficiency/9789241596657/en/
. Accessed 7/22/13.

18.  Pena-Rosas JP, Viteri FE. Effects of routine oral iron supplementation with or without folic acid for women during pregnancy. Cochrane Database Syst Rev. 2006(3):CD004736.  (PubMed)

19.  Suprapto B, Widardo, Suhanantyo. Effect of low-dosage vitamin A and riboflavin on iron-folate supplementation in anaemic pregnant women. Asia Pac J Clin Nutr. 2002;11(4):263-267.  (PubMed)

20.  Ma AG, Schouten EG, Zhang FZ, et al. Retinol and riboflavin supplementation decreases the prevalence of anemia in Chinese pregnant women taking iron and folic Acid supplements. J Nutr. 2008;138(10):1946-1950.  (PubMed)

21.  Crombleholme WR. Obstetrics. In: Tierney LM, McPhee SJ, Papadakis MA, eds. Current Medical Treatment and Diagnosis. 37th ed. Stamford: Appleton and Lange; 1998:731-734.

22. Wacker J, Fruhauf J, Schulz M, Chiwora FM, Volz J, Becker K. Riboflavin deficiency and preeclampsia. Obstet Gynecol. 2000;96(1):38-44.  (PubMed)

23.  Wang XM, Wu HY, Qiu XJ. Methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism and risk of preeclampsia: an updated meta-analysis based on 51 studies. Arch Med Res. 2013;44(3):159-168.  (PubMed)

24.  Xia XP, Chang WW, Cao YX. Meta-analysis of the methylenetetrahydrofolate reductase C677T polymorphism and susceptibility to pre-eclampsia. Hypertens Res. 2012;35(12):1129-1134.  (PubMed)

25.  Braekke K, Ueland PM, Harsem NK, Karlsen A, Blomhoff R, Staff AC. Homocysteine, cysteine, and related metabolites in maternal and fetal plasma in preeclampsia. Pediatr Res. 2007;62(3):319-324.  (PubMed)

26. Neugebauer J, Zanre Y, Wacker J. Riboflavin supplementation and preeclampsia. Int J Gynaecol Obstet. 2006;93(2):136-137.  (PubMed)

27.  Heese P, Linnebank M, Semmler A, et al. Alterations of homocysteine serum levels during alcohol withdrawal are influenced by folate and riboflavin: results from the German Investigation on Neurobiology in Alcoholism (GINA). Alcohol Alcohol. 2012;47(5):497-500.  (PubMed)

28.  Soares MJ, Satyanarayana K, Bamji MS, Jacob CM, Ramana YV, Rao SS. The effect of exercise on the riboflavin status of adult men. Br J Nutr. 1993;69(2):541-551.  (PubMed)

29.  Ruston D, Hoare J, Henderson L, et al. The National Diet & Nutrition Survey: adults aged 19 to 64 years: Nutritional status (anthropometry and blood analytes), blood pressure and physical activity. Volume 4. London: The Stationary Office; 2004.

30.  Mares-Perlman JA, Brady WE, Klein BE, et al. Diet and nuclear lens opacities. Am J Epidemiol. 1995;141(4):322-334.  (PubMed)

31.  Leske MC, Wu SY, Hyman L, et al. Biochemical factors in the lens opacities. Case-control study. The Lens Opacities Case-Control Study Group. Arch Ophthalmol. 1995;113(9):1113-1119.  (PubMed)

32.  Cumming RG, Mitchell P, Smith W. Diet and cataract: the Blue Mountains Eye Study. Ophthalmology. 2000;107(3):450-456.  (PubMed)

33.  Hankinson SE, Stampfer MJ, Seddon JM, et al. Nutrient intake and cataract extraction in women: a prospective study. BMJ. 1992;305(6849):335-339.  (PubMed)

34.  Jacques PF, Taylor A, Moeller S, et al. Long-term nutrient intake and 5-year change in nuclear lens opacities. Arch Ophthalmol. 2005;123(4):517-526.  (PubMed)

35.  McNulty H, Strain JJ, Pentieva K, Ward M. C(1) metabolism and CVD outcomes in older adults. Proc Nutr Soc. 2012;71(2):213-221.  (PubMed)

36.  Holmes MV, Newcombe P, Hubacek JA, et al. Effect modification by population dietary folate on the association between MTHFR genotype, homocysteine, and stroke risk: a meta-analysis of genetic studies and randomised trials. Lancet. 2011;378(9791):584-594.  (PubMed)

37.  Wilcken B, Bamforth F, Li Z, et al. Geographical and ethnic variation of the 677C>T allele of 5,10 methylenetetrahydrofolate reductase (MTHFR): findings from over 7000 newborns from 16 areas world wide. J Med Genet. 2003;40(8):619-625.  (PubMed)

38.  McGlynn AP, Wasson GR, O'Reilly SL, et al. Low colonocyte folate is associated with uracil misincorporation and global DNA hypomethylation in human colorectum. J Nutr. 2013;143(1):27-33.  (PubMed)

39.  Guenther BD, Sheppard CA, Tran P, Rozen R, Matthews RG, Ludwig ML. The structure and properties of methylenetetrahydrofolate reductase from Escherichia coli suggest how folate ameliorates human hyperhomocysteinemia. Nat Struct Biol. 1999;6(4):359-365.  (PubMed)

40.  Yin G, Ming H, Zheng X, Xuan Y, Liang J, Jin X. Methylenetetrahydrofolate reductase C677T gene polymorphism and colorectal cancer risk: A case-control study. Oncol Lett. 2012;4(2):365-369.  (PubMed)

41.  Gao S, Ding LH, Wang JW, Li CB, Wang ZY. Diet folate, DNA methylation and polymorphisms in methylenetetrahydrofolate reductase in association with the susceptibility to gastric cancer. Asian Pac J Cancer Prev. 2013;14(1):299-302.  (PubMed)

42.  Wen YY, Yang SJ, Zhang JX, Chen XY. Methylenetetrahydrofolate reductase genetic polymorphisms and esophageal squamous cell carcinoma susceptibility: a meta-analysis of case-control studies. Asian Pac J Cancer Prev. 2013;14(1):21-25.  (PubMed)

43.  Powers HJ, Hill MH, Welfare M, et al. Responses of biomarkers of folate and riboflavin status to folate and riboflavin supplementation in healthy and colorectal polyp patients (the FAB2 Study). Cancer Epidemiol Biomarkers Prev. 2007;16(10):2128-2135.  (PubMed)

44.  Zschabitz S, Cheng TY, Neuhouser ML, et al. B vitamin intakes and incidence of colorectal cancer: results from the Women's Health Initiative Observational Study cohort. Am J Clin Nutr. 2013;97(2):332-343.  (PubMed)

45.  Kennedy DA, Stern SJ, Matok I, et al. Folate Intake, MTHFR Polymorphisms, and the Risk of Colorectal Cancer: A Systematic Review and Meta-Analysis. J Cancer Epidemiol. 2012:952508. doi: 10.1155/2012/952508.  (PubMed)

46.  He Y, Ye L, Shan B, Song G, Meng F, Wang S. Effect of riboflavin-fortified salt nutrition intervention on esophageal squamous cell carcinoma in a high incidence area, China. Asian Pac J Cancer Prev. 2009;10(4):619-622.  (PubMed)

47.  Bassett JK, Hodge AM, English DR, et al. Dietary intake of B vitamins and methionine and risk of lung cancer. Eur J Clin Nutr. 2012;66(2):182-187.  (PubMed)

48.  Bassett JK, Baglietto L, Hodge AM, et al. Dietary intake of B vitamins and methionine and breast cancer risk. Cancer Causes Control. 2013;24(8):1555-1563.  (PubMed)

49.  Bassett JK, Severi G, Hodge AM, et al. Dietary intake of B vitamins and methionine and prostate cancer incidence and mortality. Cancer Causes Control. 2012;23(6):855-863.  (PubMed)

50.  Qiao YL, Dawsey SM, Kamangar F, et al. Total and cancer mortality after supplementation with vitamins and minerals: follow-up of the Linxian General Population Nutrition Intervention Trial. J Natl Cancer Inst. 2009;101(7):507-518.  (PubMed)

51.  Schoenen J, Jacquy J, Lenaerts M. Effectiveness of high-dose riboflavin in migraine prophylaxis. A randomized controlled trial. Neurology. 1998;50(2):466-470.  (PubMed)

52.  Sandor PS, Afra J, Ambrosini A, Schoenen J. Prophylactic treatment of migraine with β-blockers and riboflavin: differential effects on the intensity dependence of auditory evoked cortical potentials. Headache. 2000;40(1):30-35.  (PubMed)

53.  Boehnke C, Reuter U, Flach U, Schuh-Hofer S, Einhaupl KM, Arnold G. High-dose riboflavin treatment is efficacious in migraine prophylaxis: an open study in a tertiary care centre. Eur J Neurol. 2004;11(7):475-477.  (PubMed)

54.  Maizels M, Blumenfeld A, Burchette R. A combination of riboflavin, magnesium, and feverfew for migraine prophylaxis: a randomized trial. Headache. 2004;44(9):885-890.  (PubMed)

55.  MacLennan SC, Wade FM, Forrest KM, Ratanayake PD, Fagan E, Antony J. High-dose riboflavin for migraine prophylaxis in children: a double-blind, randomized, placebo-controlled trial. J Child Neurol. 2008;23(11):1300-1304.  (PubMed)

56.  Bruijn J, Duivenvoorden H, Passchier J, Locher H, Dijkstra N, Arts WF. Medium-dose riboflavin as a prophylactic agent in children with migraine: a preliminary placebo-controlled, randomised, double-blind, cross-over trial. Cephalalgia. 2010;30(12):1426-1434.  (PubMed)

57.  Cotelli MS, Vielmi V, Rimoldi M, et al. Riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency with unknown genetic defect. Neurol Sci. 2012;33(6):1383-1387.  (PubMed)

58.  Olsen RK, Olpin SE, Andresen BS, et al. ETFDH mutations as a major cause of riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency. Brain. 2007;130(Pt 8):2045-2054.  (PubMed)

59.  Liang WC, Ohkuma A, Hayashi YK, et al. ETFDH mutations, CoQ10 levels, and respiratory chain activities in patients with riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency. Neuromuscul Disord. 2009;19(3):212-216.  (PubMed)

60.  Haack TB, Danhauser K, Haberberger B, et al. Exome sequencing identifies ACAD9 mutations as a cause of complex I deficiency. Nat Genet. 2010;42(12):1131-1134.  (PubMed)

61.  Nouws J, Nijtmans L, Houten SM, et al. Acyl-CoA dehydrogenase 9 is required for the biogenesis of oxidative phosphorylation complex I. Cell Metab. 2010;12(3):283-294.  (PubMed)

62.  Scholte HR, Busch HF, Bakker HD, Bogaard JM, Luyt-Houwen IE, Kuyt LP. Riboflavin-responsive complex I deficiency. Biochim Biophys Acta. 1995;1271(1):75-83.  (PubMed)

63.  Gerards M, van den Bosch BJ, Danhauser K, et al. Riboflavin-responsive oxidative phosphorylation complex I deficiency caused by defective ACAD9: new function for an old gene. Brain. 2011;134(Pt 1):210-219.  (PubMed)

64.  Garone C, Donati MA, Sacchini M, et al. Mitochondrial Encephalomyopathy Due to a Novel Mutation in ACAD9. JAMA Neurol. 2013:1-3.  (PubMed)

65.  Chiong MA, Sim KG, Carpenter K, et al. Transient multiple acyl-CoA dehydrogenation deficiency in a newborn female caused by maternal riboflavin deficiency. Mol Genet Metab. 2007;92(1-2):109-114.  (PubMed)

66.  Ho G, Yonezawa A, Masuda S, et al. Maternal riboflavin deficiency, resulting in transient neonatal-onset glutaric aciduria Type 2, is caused by a microdeletion in the riboflavin transporter gene GPR172B. Hum Mutat. 2011;32(1):E1976-1984.  (PubMed)

67.  Bosch AM, Stroek K, Abeling NG, Waterham HR, Ijlst L, Wanders RJ. The Brown-Vialetto-Van Laere and Fazio Londe syndrome revisited: natural history, genetics, treatment and future perspectives. Orphanet J Rare Dis. 2012;7:83. doi: 10.1186/1750-1172-7-83.  (PubMed)

68.  Mackay RJ, McEntyre CJ, Henderson C, Lever M, George PM. Trimethylaminuria: causes and diagnosis of a socially distressing condition. Clin Biochem Rev. 2011;32(1):33-43.  (PubMed)

69.  Phillips IR, Shephard EA. Trimethylaminuria. 2007 Oct 8 [Updated 2011 Apr 19]. In: Pagon RA, Adam MP, Bird TD, et al., editors. GeneReviews™ [Internet]. Seattle: University of Washington, Seattle; 1993-2013. Available at: http://www.ncbi.nlm.nih.gov/books/NBK1103/.

70.  Manning NJ, Allen EK, Kirk RJ, Sharrard MJ, Smith EJ. Riboflavin-responsive trimethylaminuria in a patient with homocystinuria on betaine therapy. JIMD Rep. 2012;5:71-75.  (PubMed)

71.  Niu WQ, You YG, Qi Y. Strong association of methylenetetrahydrofolate reductase gene C677T polymorphism with hypertension and hypertension-in-pregnancy in Chinese: a meta-analysis. J Hum Hypertens. 2012;26(4):259-267.  (PubMed)

72.  Almawi WY, Khan A, Al-Othman SS, Bakhiet M. Case-control Study of methylenetetrahydrofolate reductase mutations and hyperhomocysteinemia and risk of stroke. J Stroke Cerebrovasc Dis. 2009;18(5):407-408.  (PubMed)

73.  Heux S, Morin F, Lea RA, Ovcaric M, Tajouri L, Griffiths LR. The methylentetrahydrofolate reductase gene variant (C677T) as a risk factor for essential hypertension in Caucasians. Hypertens Res. 2004;27(9):663-667.  (PubMed)

74.  Klerk M, Verhoef P, Clarke R, et al. MTHFR 677C→T polymorphism and risk of coronary heart disease: a meta-analysis. JAMA. 2002;288(16):2023-2031.  (PubMed)

75.  McNulty H, Dowey le RC, Strain JJ, et al. Riboflavin lowers homocysteine in individuals homozygous for the MTHFR 677C→T polymorphism. Circulation. 2006;113(1):74-80.  (PubMed)

76.  Horigan G, McNulty H, Ward M, Strain JJ, Purvis J, Scott JM. Riboflavin lowers blood pressure in cardiovascular disease patients homozygous for the 677C→T polymorphism in MTHFR. J Hypertens. 2010;28(3):478-486.  (PubMed)

77.  Wilson CP, Ward M, McNulty H, et al. Riboflavin offers a targeted strategy for managing hypertension in patients with the MTHFR 677TT genotype: a 4-y follow-up. Am J Clin Nutr. 2012;95(3):766-772.  (PubMed)

78.  Wilson CP, McNulty H, Ward M, et al. Blood pressure in treated hypertensive individuals with the MTHFR 677TT genotype is responsive to intervention with riboflavin: findings of a targeted randomized trial. Hypertension. 2013;61(6):1302-1308.  (PubMed)

79.  Yuvaraj S, Premkumar VG, Vijayasarathy K, Gangadaran SG, Sachdanandam P. Augmented antioxidant status in Tamoxifen treated postmenopausal women with breast cancer on co-administration with Coenzyme Q10, Niacin and Riboflavin. Cancer Chemother Pharmacol. 2008;61(6):933-941.  (PubMed)

80.  Hassan I, Chibber S, Khan AA, Naseem I. Riboflavin ameliorates cisplatin induced toxicities under photoillumination. PLoS One. 2012;7(5):e36273.  (PubMed)

81.  Raiskup F, Spoerl E. Corneal crosslinking with riboflavin and ultraviolet A. I. Principles. Ocul Surf. 2013;11(2):65-74.  (PubMed)

82.  Hendler SS, Rorvik DR, eds. PDR for Nutritional Supplements. Montvale: Medical Economics Company, Inc; 2001.

83.  Sugiyama M. Role of physiological antioxidants in chromium(VI)-induced cellular injury. Free Radic Biol Med. 1992;12(5):397-407.  (PubMed)

84.  Subramanian VS, Subramanya SB, Ghosal A, Said HM. Chronic alcohol feeding inhibits physiological and molecular parameters of intestinal and renal riboflavin transport. Am J Physiol Cell Physiol. 2013; 305(5):C539-C546.  (PubMed)

85.  Russell RM, Suter PM. Vitamin requirements of elderly people: an update. Am J Clin Nutr. 1993;58(1):4-14.  (PubMed)

86.  Blumberg J. Nutritional needs of seniors. J Am Coll Nutr. 1997;16(6):517-523.  (PubMed)

87.  Lopez-Sobaler AM, Ortega RM, Quintas ME, et al. The influence of vitamin B2 intake on the activation coefficient of erythrocyte glutation reductase in the elderly. J Nutr Health Aging. 2002;6(1):60-62.  (PubMed)

88.  Gariballa S, Ullegaddi R. Riboflavin status in acute ischaemic stroke. Eur J Clin Nutr. 2007;61(10):1237-1240.  (PubMed)

89.  Yazdanpanah N, Uitterlinden AG, Zillikens MC, et al. Low dietary riboflavin but not folate predicts increased fracture risk in postmenopausal women homozygous for the MTHFR 677 T allele. J Bone Miner Res. 2008;23(1):86-94.  (PubMed)

Thiamin

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Summary

  • Thiamin pyrophosphate (TPP), the active form of thiamin, is involved in several enzyme functions associated with the metabolism of carbohydrates, branched-chain amino acids, and fatty acids. (More information)
  • Severe thiamin deficiency leads to beriberi, a disease that affects multiple organ systems, including the central and peripheral nervous systems. (More information)
  • Wernicke's encephalopathy refers to an acute neurologic disorder secondary to thiamin deficiency. The Wernicke-Korsakoff syndrome results in persistent alterations in memory formation, along with the encephalopathy-related symptoms. (More information)
  • Thiamin deficiency can result from poor dietary intake, inadequate provision in parenteral nutrition, reduced gastrointestinal absorption, increased metabolic requirements, or excessive loss of thiamin. Chronic alcohol consumption is the primary cause of thiamin deficiency in industrialized countries. (More information)
  • Alteration in glucose metabolism has been associated with decreased plasma thiamin concentrations in diabetic patients. Correction of thiamin deficiency may reduce the risk of vascular complications in diabetic subjects. (More information)
  • Thiamin deficiency and decreased thiamin-dependent enzyme activity are associated with Alzheimer's disease. Although thiamin supplementation markedly reverses cognitive impairment in animal models of thiamin deficiency, the effect of thiamin supplementation in Alzheimer's disease patients is not yet known. (More information)
  • Diuretic-induced thiamin excretion may increase the risk of thiamin deficiency and disease severity in subjects with congestive heart failure. Further studies are needed to assess the inclusion of thiamin supplementation in the management of this disease. (More information)

Thiamin (also spelled thiamine) is a water-soluble B vitamin, also known as vitamin B1 or aneurine (1). Isolated and characterized in the 1930s, thiamin was one of the first organic compounds to be recognized as a vitamin (2). Thiamin occurs in the human body as free thiamin and as various phosphorylated forms: thiamin monophosphate (TMP), thiamin triphosphate (TTP), and thiamin pyrophosphate (TPP), which is also known as thiamin diphosphate.

Function

Coenzyme function

The synthesis of TPP from free thiamin requires magnesium, adenosine triphosphate (ATP), and the enzyme, thiamin pyrophosphokinase. TPP is required as a coenzyme for four multi-component enzyme complexes associated with the metabolism of carbohydrates and branched-chain amino acids.

Pyruvate dehydrogenase, α-ketoglutarate dehydrogenase, and branched-chain α-ketoacid dehydrogenase (BCKDH) each comprise a different enzyme complex found within cellular organelles called mitochondria. They catalyze the decarboxylation of pyruvate, α-ketoglutarate, and branched-chain amino acids to form acetyl-coenzyme A (CoA), succinyl-CoA, and derivatives of branched-chain amino acids, respectively. All products play critical roles in the production of energy from food through their connection to the citric acid (Krebs) cycle (2). Branched-chain amino acids (BCAA), including leucine, isoleucine, and valine, are eventually degraded into acetyl-CoA and succinyl-CoA to fuel the citric acid cycle. The catabolism of the three BCAAs also contributes to the production of cholesterol and donates nitrogen for the synthesis of the neurotransmitters, glutamate and γ-aminobutyric acid (GABA) (3). In addition to the thiamin coenzyme (TPP), each dehydrogenase complex requires a niacin-containing coenzyme (NAD), a riboflavin-containing coenzyme (FAD), and lipoic acid.

Transketolase catalyzes critical reactions in another metabolic pathway occurring in the cytosol, known as the pentose phosphate pathway. One of the most important intermediates of this pathway is ribose-5-phosphate, a phosphorylated 5-carbon sugar required for the synthesis of the high-energy ribonucleotides, such as ATP and guanosine triphosphate (GTP). Nucleotides are the building blocks of nucleic acids, DNA, and RNA. The pentose phosphate pathway also supplies various anabolic pathways, including fatty acid synthesis, with the niacin-containing coenzyme NADPH, which is essential for a number of biosynthetic reactions (1, 4). Because transketolase decreases early in thiamin deficiency and, unlike most thiamin-dependent enzymes, is present in red blood cells, measurement of its activity in red blood cells has been used to assess thiamin nutritional status (2).

Deficiency

Beriberi, the disease resulting from severe thiamin deficiency, was described in Chinese literature as early as 2600 B.C. Thiamin deficiency affects the cardiovascular, nervous, muscular, gastrointestinal, and central and peripheral nervous systems (2). Beriberi has been subdivided into dry, wet, cerebral, or gastrointestinal, depending on the systems affected by severe thiamin deficiency (1, 5).

Dry beriberi

The main feature of dry (paralytic or nervous) beriberi is neuropathy. Early in the course of the neuropathy, "burning feet syndrome" may occur. Other symptoms include abnormal (exaggerated) reflexes, as well as diminished sensation and weakness in the legs and arms. Muscle pain and tenderness and difficulty rising from a squatting position have also been observed (6).

Wet beriberi

In addition to neurologic symptoms, wet (cardiac) beriberi is characterized by cardiovascular manifestations of thiamin deficiency, which include rapid heart rate, enlargement of the heart, severe swelling (edema), difficulty breathing, and ultimately congestive heart failure. The Japanese literature describes the acute fulminant form of wet beriberi as "shoshin" (7).

Cerebral beriberi

Cerebral beriberi may lead to Wernicke's encephalopathy and Korsakoff's psychosis, especially in people who abuse alcohol. The diagnosis of Wernicke's encephalopathy is based on a "triad" of signs, which include abnormal eye movements, stance and gait ataxia, and cognitive impairments. If left untreated, irreversible neurologic damage can cause additional clinical manifestations known as Korsakoff's psychosis. This syndrome—also called Korsakoff's dementia, Korsakoff's amnesia, or amnestic confabulatory syndrome—involves a confused, apathetic state and a profound memory disorder, with severe amnesia and loss of recent and working memory.

Thiamin deficiency affecting the central nervous system is referred to as Wernicke's disease when the amnesic state is not present and Wernicke-Korsakoff syndrome (WKS) when the amnesic symptoms are present along with the eye-movement and gait disorders. Rarer neurologic manifestations can include seizures (8). Most WKS sufferers are alcoholics, although it has been observed in other disorders of gross malnutrition, including stomach cancer and AIDS. Administration of intravenous thiamin to WKS patients generally results in prompt improvement of the eye symptoms, but improvements in motor coordination and memory may be less, depending on how long the symptoms have been present. Evidence of increased immune cell activation and increased free radical production in the areas of the brain that are selectively damaged suggests that oxidative stress plays an important role in the neurologic pathology of thiamin deficiency (9).

Gastrointestinal beriberi

TPP is critical for metabolic reactions that utilize glucose in glycolysis and the citric acid cycle (Figure 1). A decrease in the activity of thiamin-dependent enzymes limits the conversion of pyruvate to acetyl-CoA and the utilization of the citric acid cycle, leading to accumulation of pyruvate and lactate. Lactic acidosis, a condition resulting from the accumulation of lactate, is often associated with nausea, vomiting, and severe abdominal pain in a syndrome described as gastrointestinal beriberi (5).

Figure 1. Metabolic Pathways Requiring Thiamin Pyrophosphate (TPP). As explained in the article text, TPP is critical for metabolic reactions that utilize glucose in glycolysis and the citric acid cycle. Specifically, TPP is needed for the following enzymes: transketolase in the pentose phosphate cycle, which converts ribose-5-phosphate to glyceraldehyde-3-phosphate; branched chain alpha-ketoacid dehydrogenase complex (BCKDH) in the branched amino acid catabolic pathway, which converts branched-chain alpha-ketoacids to branched chain acyl-CoA; pyruvate dehydrogenase, which converts pyruvate to acetyl-CoA (shown here, acetyl-CoA enters the citric acid cycle where it is metabolized); and alpha-ketoglutarate dehydrogenase, which coverts alpha-ketoglutarate to succinyl-CoA in the citric acid cycle.

Causes of thiamin deficiency

Thiamin deficiency may result from inadequate thiamin intake, increased requirement for thiamin, excessive loss of thiamin from the body, consumption of anti-thiamin factors in food, or a combination of these factors.

Inadequate intake

Inadequate consumption of thiamin is the main cause of thiamin deficiency in developing countries (2). Thiamin deficiency is common in low-income populations whose diets are high in carbohydrate and low in thiamin (e.g., milled or polished rice). Breast-fed infants whose mothers are thiamin deficient are vulnerable to developing infantile beriberi. Alcoholism, which is associated with low intake of thiamin among other nutrients, is the primary cause of thiamin deficiency in industrialized countries. Some of the non-alcoholic conditions associated with WKS include anorexia, bariatric surgery (weight-loss surgery), gastrointestinal malignancies, and malabsorption syndromes (10-13). Cases of Wernicke's encephalopathy have also been linked to parenteral nutrition lacking vitamin supplementation (14, 15).

Increased requirement

Conditions resulting in an increased requirement for thiamin include strenuous physical exertion, fever, pregnancy, breast-feeding, and adolescent growth. Such conditions place individuals with marginal thiamin intake at risk for developing symptomatic thiamin deficiency. Malaria patients in Southeast Asia were found to be thiamin deficient more frequently than non-infected individuals (16, 17). Malarial infection leads to a large increase in the metabolic demand for glucose. Because thiamin is required for enzymes involved in glucose metabolism, the stresses induced by malarial infection could exacerbate thiamin deficiency in predisposed individuals. HIV-infected individuals, whether or not they had developed AIDS, were also found to be at increased risk for thiamin deficiency (18). Further, chronic alcohol abuse impairs intestinal absorption and utilization of thiamin (1); thus, alcoholics have increased requirements for thiamin. Thiamin deficiency is also observed as a complication of the refeeding syndrome: the introduction of carbohydrates in severely starved individuals leads to an increased demand for thiamin in glycolysis and the citric acid cycle that precipitates thiamin deficiency (19).

Excessive loss

Excessive loss of thiamin may precipitate thiamin deficiency. By increasing urinary flow, diuretics may prevent reabsorption of thiamin by the kidneys and increase its excretion in the urine (20, 21). The risk of thiamin deficiency is increased in diuretic-treated patients with marginal thiamin intake (22) and in individuals receiving long-term, diuretic therapy (23). Individuals with kidney failure requiring hemodialysis lose thiamin at an increased rate and are at risk for thiamin deficiency (24). Alcoholics who maintain a high fluid intake and high urine flow rate may also experience increased loss of thiamin, exacerbating the effects of low thiamin intake (25).

Anti-thiamin factors (ATF)

The presence of anti-thiamin factors (ATF) in foods also contributes to the risk of thiamin deficiency. Certain plants contain ATF, which react with thiamin to form an oxidized, inactive product. Consuming large amounts of tea and coffee (including decaffeinated), as well as chewing tea leaves and betel nuts, have been associated with thiamin depletion in humans due to the presence of ATF (26, 27). ATF include mycotoxins (molds) and thiaminases that break down thiamin in food. Individuals who habitually eat certain raw, fresh-water fish; raw shellfish; and ferns are at higher risk of thiamin deficiency because these foods contain thiaminase that normally is inactivated by heat in cooking (1). In Nigeria, an acute neurologic syndrome (seasonal ataxia) has been associated with thiamin deficiency precipitated by a thiaminase in African silkworms, a traditional, high-protein food for some Nigerians (28).

The Recommended Dietary Allowance (RDA)

The RDA for thiamin, revised in 1998 by the Food and Nutrition Board of the Institute of Medicine, was based on the prevention of deficiency in generally healthy individuals (29; Table 1).

Table 1. Recommended Dietary Allowance (RDA) for Thiamin
Life Stage Age Males (mg/day) Females (mg/day)
Infants 0-6 months  0.2 (AI) 0.2 (AI)
Infants 7-12 months 0.3 (AI) 0.3 (AI)
Children 1-3 years 0.5 0.5
Children 4-8 years 0.6 0.6
Children 9-13 years 0.9 0.9
Adolescents 14-18 years 1.2 1.0
Adults 19 years and older 1.2 1.1
Pregnancy all ages - 1.4
Breast-feeding all ages  - 1.4

Disease Prevention

Cataracts

A cross-sectional study of 2,900 Australian men and women, 49 years of age and older, found that those in the highest quintile of thiamin intake were 40% less likely to have nuclear cataracts than those in the lowest quintile (30). In addition, a recent study in 408 US women found that higher dietary intakes of thiamin were inversely associated with five-year change in lens opacification (31). However, these cross-sectional associations have yet to be elucidated by studies of causation.

Diabetes mellitus and vascular complications

Low plasma concentrations and high renal clearance of thiamin have been observed in diabetic patients compared to healthy subjects (32), suggesting that individuals with type 1 or type 2 diabetes mellitus are at increased risk for thiamin deficiency. Two thiamin transporters, thiamin transporter-1 (THTR-1) and THTR-2, are involved in thiamin uptake by enterocytes in the small intestine and re-uptake in the proximal tubules of the kidneys. A recent study suggested that hyperglycemia in diabetic patients could affect thiamin re-uptake by decreasing the expression of thiamin transporters in the kidneys (33). Conversely, thiamin deficiency appears to impair the normal endocrine function of the pancreas and exacerbate hyperglycemia. Early studies showed that insulin synthesis and secretion were altered in the endocrine pancreatic cells of thiamin-deficient rats (34, 35). In humans, thiamin deficiency caused by recessive mutations in the gene coding for THTR-1 leads to diabetes mellitus in the thiamin-responsive megaloblastic anemia syndrome (see Metabolic diseases).

In a randomized, double-blind pilot study, high-dose thiamin supplements (300 mg/day) were given for six weeks to hyperglycemic individuals (either glucose intolerant or newly diagnosed with type 2 diabetes). Thiamin supplementation prevented any further increase in fasting glucose and insulin levels compared with placebo treatment but did not reduce the hyperglycemia (36). However, one study suggested that thiamin supplementation might improve fasting glucose levels in type 2 diabetics in early stages of the disease (i.e., pre-diabetes or early diabetes) (37).

Chronic hyperglycemia in individuals with diabetes mellitus contributes to the pathogenesis of micro-vascular diseases. Diabetes-related vascular damage can affect the heart (cardiomyopathy), kidneys (nephropathy), retina (retinopathy), and peripheral nervous system (neuropathy). In diabetic subjects, hyperglycemia alters the function of bone marrow-derived endothelial progenitor cells (EPC) that are critical for the growth of blood vessels (38). Interestingly, a higher daily intake of thiamin from the diet was correlated with more circulating EPC and with better vascular endothelial health in 88 individuals with type 2 diabetes (39). An inverse association has also been found between plasma concentrations of thiamin in diabetic patients and the presence of soluble vascular adhesion molecule-1 (sVCAM-1), a marker of vascular dysfunction (32, 40). Early markers of diabetic nephropathy include the presence of serum albumin in the urine, known as microalbuminuria. Administration of thiamin or benfotiamine (a thiamin derivative) prevented the development of renal complications in chemically-induced diabetic rats (41). A randomized, double-blind study conducted in 40 type 2 diabetic patients with microalbuminuria found that high-dose thiamin supplementation (300 mg/day) decreased excretion of urinary albumin compared to placebo over a three-month period (40). Since thiamin treatment has shown promising results in cultured cells and animal models (42-44), the effects of thiamin and its derivatives on vascular complications should be examined in diabetic patients.

Disease Treatment

Alzheimer's disease

Some elderly people are at increased risk for developing subclinical thiamin deficiency secondary to poor dietary intake, reduced gastrointestinal absorption, and multiple medical conditions (45, 46). Since thiamin deficiency can result in a form of dementia (Wernicke-Korsakoff syndrome), its relationship to Alzheimer's disease (AD) and other forms of dementia have been investigated. AD is characterized by a decline in cognitive function in elderly people, accompanied by pathologic features that include β-amyloid plaque deposition and tangles formed by phosphorylated Tau protein (47). Using positron emission tomography (PET) scanning, reduced glucose metabolism was observed in brains of AD patients (48). A large, multicenter PET study using a radio-labeled glucose analog, 18F-Fluoro-deoxyglucose (FDG), correlated a reduction in FDG uptake (a surrogate marker for glucose metabolism) with the extent of cognitive impairment in AD patients. This study, which included 822 subjects over 55 years of age that were cognitively normal (n=229), displayed mild cognitive impairment (n=405), or had mild AD (n=188), demonstrated that brain glucose utilization could predict the progression from mild cognitive impairment to AD (49). Interestingly, a nine-year longitudinal study associated the presence of diabetes mellitus in older people (above 55 years old) with an increased risk for developing AD (50).

A reduction in thiamin-dependent processes in the brain might be related to the altered glucose metabolism in patients with AD (51). A case-control study in 38 elderly women found that blood levels of thiamin, TPP, and TMP were lower in those with dementia of Alzheimer's type (DAT) compared to those in the control group (52). Moreover, several investigators have found evidence of decreased activity of TPP-dependent enzymes, α-ketoglutarate dehydrogenase and transketolase, in the brains of patients who died of AD (53). The finding of decreased brain levels of TPP in the presence of normal levels of free thiamin and TMP suggested alterations in TPP synthesis rather than poor thiamin bioavailability. However it is not clear whether the activities of TPP-metabolizing enzymes (including thiamin pyrophosphokinase) are altered in AD patients (54, 55). Chronic administration of the thiamin derivative benfotiamine alleviated cognitive alterations and decreased the number of β-amyloid plaques in a mouse model of AD without increasing TMP and TPP levels in the brain. This suggested that the beneficial effects of benfotiamine in the brain were likely mediated by the stimulation of TPP-independent pathways (56).

Thiamin deficiency has been linked to increased β-amyloid production in cultured neuronal cells and to plaque formation in animal models (57, 58). These pathological hallmarks of AD could be reversed by thiamin supplementation, suggesting that thiamin could be protective in AD. Moreover, other disorders including mitochondrial dysfunction and chronic oxidative stress have been linked to both thiamin deficiency and AD pathogenesis and progression (9, 59). Presently, there is only slight and inconsistent evidence that thiamin supplements are of benefit in AD. A double-blind, placebo-controlled study of 15 patients (10 completed the study) reported no beneficial effect of 3 grams/day of thiamin on cognitive decline over a 12-month period (60). A preliminary report from another study claimed a mild benefit of 3 to 8 grams of thiamin per day in DAT, but no additional data from that study are available (61). A mild beneficial effect in patients with AD was reported after 12 weeks of treatment with 100 mg/day of a thiamin derivative (thiamin tetrahydrofurfuryl disulfide), but this study was not placebo-controlled (62). A systematic review of randomized, double-blind, placebo-controlled trials of thiamin in patients with DAT found no evidence that thiamin was a useful treatment for the symptoms of Alzheimer's disease (63).

Congestive Heart Failure (CHF)

Severe thiamin deficiency (wet beriberi) can lead to impaired cardiac function and ultimately congestive heart failure (CHF). Although cardiac manifestations of beriberi are rarely encountered in industrialized countries, CHF due to other causes is common, especially in the elderly. Diuretics used in the treatment of CHF, notably furosemide, have been found to increase thiamin excretion, potentially leading to marginal thiamin deficiency (64). A number of studies have examined thiamin nutritional status in CHF patients and most found a fairly low incidence of thiamin deficiency, as measured by assays of transketolase activity. As in the general population, older CHF patients were found to be at higher risk of thiamin deficiency than younger ones (65). An important measure of cardiac function in CHF is the left ventricular ejection fraction (LVEF), which can be assessed by echocardiography. One study in 25 patients found that furosemide use, at doses of 80 mg/day or greater, was associated with a 98% prevalence of thiamin deficiency (23). In a randomized, double-blind study of 30 CHF patients, all of whom had been taking furosemide (80 mg/day) for at least three months, intravenous (IV) thiamin therapy (200 mg/day) for seven days resulted in an improved LVEF compared to IV placebo (66). When all 30 of the CHF patients in that study subsequently received six weeks of oral thiamin therapy (200 mg/day), the average LVEF improved by 22%. This finding may be relevant because improvements in LVEF have been associated with improved survival in CHF patients (67). However, conclusions from studies published to date are limited due to the small sample sizes of the studies, lack of randomization in some studies, and a need for more precise assays of thiamin nutritional status. Presently, the need for thiamin supplementation in maintaining cardiac function in CHF patients remains controversial.

Cancer

Thiamin deficiency has been observed in some cancer patients with rapidly growing tumors. Research in cell culture and animal models indicates that rapidly dividing cancer cells have a high requirement for thiamin (68). All rapidly dividing cells require nucleic acids at an increased rate, and some cancer cells appear to rely heavily on the TPP-dependent enzyme, transketolase, to provide the ribose-5-phosphate necessary for nucleic acid synthesis. A recent study found that the levels of THTR-1, transketolase, and TPP mitochondrial transporters were increased in samples of human breast cancer tissue compared to normal tissue, suggesting an adaptation in thiamin homeostasis in support of cancer metabolism (69). Thiamin supplementation in cancer patients is common to prevent thiamin deficiency, but Boros et al. caution that too much thiamin may actually fuel the growth of some malignant tumors (70), suggesting that thiamin supplementation be reserved for those cancer patients who are actually deficient in thiamin. Presently, there is no evidence available from studies in humans to support or refute this theory. However, it would be prudent for individuals with cancer who are considering thiamin supplementation to discuss it with the clinician managing their cancer therapy.

Metabolic diseases

Thiamin supplementation is included in the clinical management of genetic diseases that affect the metabolism of carbohydrates and branched-chain amino acids (BCAAs).

Thiamin-responsive pyruvate dehydrogenase complex (PDHC) deficiency

Mutations in PDHC prevent the efficient oxidation of carbohydrates in affected individuals. PDHC deficiency is commonly characterized by lactic acidosis, neurologic and neuromuscular degeneration, and death during childhood. The patients who respond to thiamin treatment (from few mg/day to doses above 1,000 mg/day) exhibit PDHC deficiency due to the decreased affinity of PDHC for TPP (71, 72). Although the vitamin supplementation can reduce lactate accumulation and improve the clinical features in thiamin-responsive patients, it does not constitute a cure (73).

Maple syrup urine disease

Inborn errors of BCAA metabolism lead to thiamin-responsive branched-chain ketoaciduria, also known as maple syrup urine disease. Alterations in the BCAA catabolic pathway result in neurologic dysfunction caused by the accumulation of BCAAs and their derivatives, branched-chain ketoacids (BCKA). The therapeutic approach includes a synthetic diet with reduced BCAA content, and thiamin (10-1,000 mg/day) is supplemented to patients with mutations in the E2 subunit of the BCKDH complex (74). In thiamin-responsive individuals, the supplementation has been proven effective to correct the phenotype without recourse to the BCAA restriction diet.

Thiamin-responsive megaloblastic anemia

Mutations in THTR-1 that impair intestinal thiamin uptake and cause thiamin deficiency have been found in patients affected by thiamin-responsive megaloblastic anemia. This syndrome is characterized by megaloblastic anemia, diabetes mellitus, and deafness. A review of 30 cases reported additional neurologic, visual, and cardiac impairments (75). Oral doses of thiamin (up to 300 mg/day) maintain health and correct hyperglycemia in prepubescent children. However, after puberty, a decline in pancreatic function results in the requirement of insulin together with thiamin to control the hyperglycemia. One study also reported that the treatment of a four-month-old girl with 100 mg/day of thiamin did not prevent hearing loss at 20 months of age (76).

Biotin-responsive basal ganglia disease

Biotin-responsive basal ganglia disease, also called thiamin metabolism dysfunction syndrome-2, is caused by mutations in the gene coding for THTR-2. The clinical features appear around three to four years of age and include sub-acute encephalopathy (confusion, drowsiness, altered level of consciousness), ataxia, and seizures. A retrospective study of 18 affected individuals from the same family or the same tribe in Saudi Arabia was recently conducted. The data showed that biotin monotherapy (5-10 mg/kg/day) efficiently abolished the clinical manifestations of the disease, although one-third of the patients suffered from recurrent acute crises. Often associated with poor outcomes, acute crises were not observed after thiamin supplementation started (300-400 mg/day) and for a five-year follow-up period. Early diagnostic and immediate treatment with biotin and thiamin led to positive outcomes (77).

Sources

Humans obtain thiamin from dietary sources and from the normal microflora of the colon, although the contribution of the latter towards the body's requirement for thiamin is not clear (78).

Food sources

A varied diet should provide most individuals with adequate thiamin to prevent deficiency. In the US the average dietary thiamin intake for young adult men is about 2 mg/day and 1.2 mg/day for young adult women. A survey of people over the age of 60 found an average dietary thiamin intake of 1.4 mg/day for men and 1.1 mg/day for women (29). However, institutionalization and poverty both increase the likelihood of inadequate thiamin intake in the elderly (79). Whole-grain cereals, legumes (e.g., beans and lentils), nuts, lean pork, and yeast are rich sources of thiamin (1). Because most of the thiamin is lost during the production of white flour and polished (milled) rice, white rice and foods made from white flour (e.g., bread and pasta) are fortified with thiamin in many Western countries. A number of thiamin-rich foods are listed in Table 2, along with their thiamin content in milligrams (mg). For more information on the nutrient content of foods, search the USDA food composition database (80).

Table 2. Some Food Sources of Thiamin
Food Serving Thiamin (mg)
Lentils (cooked, boiled) ½ cup 0.17
Green peas (cooked, boiled ½ cup 0.21
Long-grain, brown rice (cooked) 1 cup 0.19
Long-grain, white rice, enriched (cooked) 1 cup 0.26
Long-grain, white rice, unenriched (cooked) 1 cup 0.04
Whole-wheat bread 1 slice 0.10
White bread, enriched 1 slice 0.23
Fortified breakfast cereal (wheat, puffed) 1 cup 0.31
Wheat germ breakfast cereal (toasted, plain) 1 cup 1.88
Pork, lean (loin, tenderloin, cooked, roasted) 3 ounces* 0.81
Pecans 1 ounce 0.19
Spinach (cooked, boiled) ½ cup 0.09
Orange 1 fruit 0.11
Cantaloupe ½ fruit 0.11
Milk 1 cup 0.10
Egg (cooked, hard-boiled) 1 large 0.03
*Three ounces of meat is a serving about the size of a deck of cards

Supplements

Thiamin is available in nutritional supplements and for fortification as thiamin hydrochloride and thiamin nitrate (81).

Safety

Toxicity

The Food and Nutrition Board did not set a tolerable upper intake level (UL) for thiamin because there are no well-established toxic effects from consumption of excess thiamin in food or through long-term, oral supplementation (up to 200 mg/day). A small number of life-threatening anaphylactic reactions have been observed with large intravenous doses of thiamin (29).

Drug interactions

Reduced blood levels of thiamin have been reported in individuals with seizure disorders (epilepsy) taking the anticonvulsant medication, phenytoin, for long periods of time (82). 5-Fluorouracil, a drug used in cancer therapy, inhibits the phosphorylation of thiamin to TPP (83). Diuretics, especially furosemide, may increase the risk of thiamin deficiency in individuals with marginal thiamin intake due to increased urinary excretion of thiamin (21). Moreover, chronic alcohol abuse is associated with thiamin deficiency due to low dietary intake, impaired absorption and utilization, and increased excretion of the vitamin (1). Chronic alcohol feeding to rats showed a decrease in the active absorption of thiamin linked to the inhibition of thiamin membrane transporter THTR-1 in the intestinal epithelium (84). Alcohol consumption in rats also decreases the levels of THTR-1 and THTR-2 in renal epithelial cells, thus limiting thiamin re-uptake by the kidneys (85).

Linus Pauling Institute Recommendation

The Linus Pauling Institute supports the recommendation by the Food and Nutrition Board of 1.2 mg/day of thiamin for men and 1.1 mg/day for women. A varied diet should provide enough thiamin for most people. Following the Linus Pauling Institute recommendation to take a daily multivitamin/multimineral supplement, containing 100% of the Daily Values (DV), will ensure an intake of at least 1.5 mg/day of thiamin.

Older adults (>50 years)

Presently, there is no evidence that the requirement for thiamin is increased in older adults, but some studies have found inadequate dietary intake and thiamin insufficiency to be more common in elderly populations (79). Thus, it would be prudent for older adults to take a multivitamin/mineral supplement, which will generally provide at least 1.5 mg/day of thiamin.


Authors and Reviewers

Originally written in 2000 by: 
Jane Higdon, Ph.D. 
Linus Pauling Institute 
Oregon State University

Updated in September 2002 by: 
Jane Higdon, Ph.D. 
Linus Pauling Institute 
Oregon State University

Updated in June 2007 by: 
Victoria J. Drake, Ph.D. 
Linus Pauling Institute 
Oregon State University

Updated in June 2013 by: 
Barbara Delage, Ph.D. 
Linus Pauling Institute 
Oregon State University

Reviewed in July 2013 by: 
Christopher Bates, D.Phil. 
Honorary Senior Scientist 
Formerly Head of Micronutrient Status Research 
MRC Human Nutrition Research 
Elsie Widdowson Laboratory 
Cambridge, UK

Copyright 2000-2017  Linus Pauling Institute


References

1.  Tanphaichitr V. Thiamin. In: Shils M, Olson JA, Shike M, Ross AC, eds. Modern Nutrition in Health and Disease. 9th ed. Baltimore: Williams & Wilkins; 1999:381-389.

2.  Rindi G. Thiamin. In: Ziegler EE, Filer LJ, eds. Present Knowledge in Nutrition. 7th ed. Washington D.C.: ILSI Press; 1996:160-166.

3.  Hutson SM, Sweatt AJ, Lanoue KF. Branched-chain [corrected] amino acid metabolism: implications for establishing safe intakes. J Nutr. 2005;135(6 Suppl):1557S-1564S.  (PubMed)

4.  Brody T. Nutritional Biochemistry. 2nd ed. San Diego: Academic Press; 1999.

5.  Donnino M. Gastrointestinal beriberi: a previously unrecognized syndrome. Ann Intern Med. 2004;141(11):898-899.  (PubMed)

6.  McDowell L. Thiamin. In: Vitamins in Animal and Human Nutrition. 2nd ed. Ames: Iowa State University Press; 2000:265-310. Available at: http://www.ucv.ve/fileadmin/user_upload/facultad_agronomia/Producion_Animal/Vitamins_in_Animal_and_Human_Nutrition.pdf

7.  Yamasaki H, Tada H, Kawano S, Aonuma K. Reversible pulmonary hypertension, lactic acidosis, and rapidly evolving multiple organ failure as manifestations of shoshin beriberi. Circ J. 2010;74(9):1983-1985.  (PubMed)

8.  Doss A, Mahad D, Romanowski CA. Wernicke encephalopathy: unusual findings in nonalcoholic patients. J Comput Assist Tomogr. 2003;27(2):235-240.  (PubMed)

9.  Hazell AS, Faim S, Wertheimer G, Silva VR, Marques CS. The impact of oxidative stress in thiamine deficiency: a multifactorial targeting issue. Neurochem Int. 2013;62(5):796-802.  (PubMed)

10.  Saad L, Silva LF, Banzato CE, Dantas CR, Garcia C, Jr. Anorexia nervosa and Wernicke-Korsakoff syndrome: a case report. J Med Case Rep. 2010;4:217.  (PubMed)

11.  Becker DA, Balcer LJ, Galetta SL. The Neurological Complications of Nutritional Deficiency following Bariatric Surgery. J Obes. 2012;2012:608534.  (PubMed)

12.  Jung ES, Kwon O, Lee SH, et al. Wernicke's encephalopathy in advanced gastric cancer. Cancer Res Treat. 2010;42(2):77-81.  (PubMed)

13.  Greenspon J, Perrone EE, Alaish SM. Shoshin beriberi mimicking central line sepsis in a child with short bowel syndrome. World journal of pediatrics : World J Pediatr. 2010;6(4):366-368.  (PubMed)

14.  Sequeira Lopes da Silva JT, Almaraz Velarde R, Olgado Ferrero F, et al. Wernicke's encephalopathy induced by total parental nutrition. Nutr Hosp. 2010;25(6):1034-1036.  (PubMed)

15.  Francini-Pesenti F, Brocadello F, Manara R, Santelli L, Laroni A, Caregaro L. Wernicke's syndrome during parenteral feeding: not an unusual complication. Nutrition. 2009;25(2):142-146.  (PubMed)

16.  Krishna S, Taylor AM, Supanaranond W, et al. Thiamine deficiency and malaria in adults from southeast Asia. Lancet. 1999;353(9152):546-549.  (PubMed)

17.  Mayxay M, Taylor AM, Khanthavong M, et al. Thiamin deficiency and uncomplicated falciparum malaria in Laos. Trop Med Int Health. 2007;12(3):363-369.  (PubMed)

18.  Muri RM, Von Overbeck J, Furrer J, Ballmer PE. Thiamin deficiency in HIV-positive patients: evaluation by erythrocyte transketolase activity and thiamin pyrophosphate effect. Clin Nutr. 1999;18(6):375-378.  (PubMed)

19.  Stanga Z, Brunner A, Leuenberger M, et al. Nutrition in clinical practice-the refeeding syndrome: illustrative cases and guidelines for prevention and treatment. Eur J Clin Nutr. 2008;62(6):687-694.  (PubMed)

20.  Suter PM, Haller J, Hany A, Vetter W. Diuretic use: a risk for subclinical thiamine deficiency in elderly patients. J Nutr Health Aging. 2000;4(2):69-71.  (PubMed)

21.  Rieck J, Halkin H, Almog S, et al. Urinary loss of thiamine is increased by low doses of furosemide in healthy volunteers. J Lab Clin Med. 1999;134(3):238-243.  (PubMed)

22.  Sica DA. Loop diuretic therapy, thiamine balance, and heart failure. Congestive heart failure 2007;13(4):244-247.  (PubMed)

23.  Zenuk C, Healey J, Donnelly J, Vaillancourt R, Almalki Y, Smith S. Thiamine deficiency in congestive heart failure patients receiving long term furosemide therapy. Can J Clin Pharmacol. 2003;10(4):184-8.  (PubMed)

24.  Hung SC, Hung SH, Tarng DC, Yang WC, Chen TW, Huang TP. Thiamine deficiency and unexplained encephalopathy in hemodialysis and peritoneal dialysis patients. Am J Kidney Dis. 2001;38(5):941-947.  (PubMed)

25.  Wilcox CS. Do diuretics cause thiamine deficiency? J Lab Clin Med. 1999;134(3):192-193.

26.  Vimokesant SL, Hilker DM, Nakornchai S, Rungruangsak K, Dhanamitta S. Effects of betel nut and fermented fish on the thiamin status of northeastern Thais. Am J Clin Nutr. 1975;28(12):1458-1463.  (PubMed)

27.  Ventura A, Mafe MC, Bourguet M, Tornero C. Wernicke's encephalopathy secondary to hyperthyroidism and ingestion of thiaminase-rich products. Neurologia. 2013;28(4):257-259.  (PubMed)

28.  Nishimune T, Watanabe Y, Okazaki H, Akai H. Thiamin is decomposed due to Anaphe spp. entomophagy in seasonal ataxia patients in Nigeria. J Nutr. 2000;130(6):1625-1628.  (PubMed)

29.  Food and Nutrition Board, Institute of Medicine. Thiamin. Dietary Reference Intakes: Thiamin, Riboflavin, Niacin, Vitamin B6, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington D.C.: National Academy Press; 1998:58-86.  (National Academy Press)

30.  Cumming RG, Mitchell P, Smith W. Diet and cataract: the Blue Mountains Eye Study. Ophthalmology. 2000;107(3):450-456.  (PubMed)

31.  Jacques PF, Taylor A, Moeller S, et al. Long-term nutrient intake and 5-year change in nuclear lens opacities. Arch Ophthalmol. 2005;123(4):517-526.  (PubMed)

32.  Thornalley PJ, Babaei-Jadidi R, Al Ali H, et al. High prevalence of low plasma thiamine concentration in diabetes linked to a marker of vascular disease. Diabetologia. 2007;50(10):2164-2170.  (PubMed)

33.  Larkin JR, Zhang F, Godfrey L, et al. Glucose-induced down regulation of thiamine transporters in the kidney proximal tubular epithelium produces thiamine insufficiency in diabetes. PLoS One. 2012;7:e53175.  (PubMed)

34.  Rathanaswami P, Sundaresan R. Effects of thiamine deficiency on the biosynthesis of insulin in rats. Biochem Int. 1991;24(6):1057-1062.  (PubMed)

35.  Rathanaswami P, Pourany A, Sundaresan R. Effects of thiamine deficiency on the secretion of insulin and the metabolism of glucose in isolated rat pancreatic islets. Biochem Int. 1991;25(3):577-583.  (PubMed)

36.  Alaei Shahmiri F, Soares MJ, Zhao Y, Sherriff J. High-dose thiamine supplementation improves glucose tolerance in hyperglycemic individuals: a randomized, double-blind cross-over trial. Eur J Clin Nutr. 2013. May 29 [Epub ahead of print]  (PubMed)

37.  Gonzalez-Ortiz M, Martinez-Abundis E, Robles-Cervantes JA, Ramirez-Ramirez V, Ramos-Zavala MG. Effect of thiamine administration on metabolic profile, cytokines and inflammatory markers in drug-naive patients with type 2 diabetes. Eur J Clin Nutr. 2011;50(2):145-149.  (PubMed)

38.  Tepper OM, Galiano RD, Capla JM, et al. Human endothelial progenitor cells from type II diabetics exhibit impaired proliferation, adhesion, and incorporation into vascular structures. Circulation. 2002;106(22):2781-2786.  (PubMed)

39.  Wong CY, Qiuwaxi J, Chen H, et al. Daily intake of thiamine correlates with the circulating level of endothelial progenitor cells and the endothelial function in patients with type II diabetes. Mol Nutr Food Res. 2008;52(12):1421-1427.  (PubMed)

40.  Rabbani N, Alam SS, Riaz S, et al. High-dose thiamine therapy for patients with type 2 diabetes and microalbuminuria: a randomised, double-blind placebo-controlled pilot study. Diabetologia. 2009;52(2):208-212.  (PubMed)

41.  Babaei-Jadidi R, Karachalias N, Ahmed N, Battah S, Thornalley PJ. Prevention of incipient diabetic nephropathy by high-dose thiamine and benfotiamine. Diabetes. 2003;52(8):2110-2120.  (PubMed)

42.  Hammes HP, Du X, Edelstein D, et al. Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic retinopathy. Nature Med. 2003;9(3):294-299.  (PubMed)

43.  Varkonyi T, Kempler P. Diabetic neuropathy: new strategies for treatment. Diabetes Obes Metab. 2008;10(2):99-108.  (PubMed)

44.  Kohda Y, Shirakawa H, Yamane K, et al. Prevention of incipient diabetic cardiomyopathy by high-dose thiamine. J Toxicol Sci. 2008;33(4):459-472.  (PubMed)

45.  Lee DC, Chu J, Satz W, Silbergleit R. Low plasma thiamine levels in elder patients admitted through the emergency department. Acad Emerg Med. 2000;7(10):1156-1159.  (PubMed)

46.  Ito Y, Yamanaka K, Susaki H, Igata A. A cross-investigation between thiamin deficiency and the physical condition of elderly people who require nursing care. J Nutr Sci Vitaminol. 2012;58(3):210-216.  (PubMed)

47.  Prvulovic D, Hampel H. Amyloid β (A-β) and phospho-τ (p-τ) as diagnostic biomarkers in Alzheimer's disease. Clin Chem Lab Med. 2011;49:367-374.  (PubMed)

48.  Kish SJ. Brain energy metabolizing enzymes in Alzheimer's disease: α-ketoglutarate dehydrogenase complex and cytochrome oxidase. Ann N Y Acad Sci. 1997;826:218-228.  (PubMed)

49.  Langbaum JB, Chen K, Lee W, et al. Categorical and correlational analyses of baseline fluorodeoxyglucose positron emission tomography images from the Alzheimer's Disease Neuroimaging Initiative (ADNI). NeuroImage. 2009;45(4):1107-1116.  (PubMed)

50.  Arvanitakis Z, Wilson RS, Bienias JL, Evans DA, Bennett DA. Diabetes mellitus and risk of Alzheimer disease and decline in cognitive function. Arch Neurol. 2004;61(5):661-666.  (PubMed)

51.  Gibson GE, Hirsch JA, Cirio RT, Jordan BD, Fonzetti P, Elder J. Abnormal thiamine-dependent processes in Alzheimer's Disease. Lessons from diabetes. Mol Cell Neurosci. 2013;55:17-25.  (PubMed)

52.  Glaso M, Nordbo G, Diep L, Bohmer T. Reduced concentrations of several vitamins in normal weight patients with late-onset dementia of the Alzheimer type without vascular disease. J Nutr Health Aging. 2004;8(5):407-413.  (PubMed)

53.  Bender DA. Optimum nutrition: thiamin, biotin and pantothenate. Proc Nutr Soc. 1999;58(2):427-433.  (PubMed)

54.  Mastrogiacoma F, Bettendorff L, Grisar T, Kish SJ. Brain thiamine, its phosphate esters, and its metabolizing enzymes in Alzheimer's disease. Ann Neurol. 1996;39(5):585-591.  (PubMed)

55.  Heroux M, Raghavendra Rao VL, Lavoie J, Richardson JS, Butterworth RF. Alterations of thiamine phosphorylation and of thiamine-dependent enzymes in Alzheimer's disease. Metab Brain Dis. 1996;11(1):81-88.  (PubMed)

56.  Pan X, Gong N, Zhao J, et al. Powerful beneficial effects of benfotiamine on cognitive impairment and beta-amyloid deposition in amyloid precursor protein/presenilin-1 transgenic mice. Brain. 2010;133(Pt 5):1342-1351.  (PubMed)

57.  Karuppagounder SS, Xu H, Shi Q, et al. Thiamine deficiency induces oxidative stress and exacerbates the plaque pathology in Alzheimer's mouse model. Neurobiol Aging. 2009;30(10):1587-1600.  (PubMed)

58.  Zhang Q, Yang G, Li W, et al. Thiamine deficiency increases beta-secretase activity and accumulation of beta-amyloid peptides. Neurobiol Aging. 2011;32(1):42-53.  (PubMed)

59.  Dumont M, Beal MF. Neuroprotective strategies involving ROS in Alzheimer disease. Free Rad Res Med. 2011;51(5):1014-1026.  (PubMed)

60.  Nolan KA, Black RS, Sheu KF, Langberg J, Blass JP. A trial of thiamine in Alzheimer's disease. Arch Neurology. 1991;48(1):81-83.  (PubMed)

61.  Meador K, Loring D, Nichols M, et al. Preliminary findings of high-dose thiamine in dementia of Alzheimer's type. J Geriatr Psychiatry Neurol. 1993;6(4):222-229.  (PubMed)

62.  Mimori Y, Katsuoka H, Nakamura S. Thiamine therapy in Alzheimer's disease. Metab Brain Dis. 1996;11(1):89-94.  (PubMed)

63.  Rodriguez-Martin JL, Qizilbash N, Lopez-Arrieta JM. Thiamine for Alzheimer's disease (Cochrane Review). Cochrane Database Syst Rev. 2001;2:CD001498.  (PubMed)

64.  Hanninen SA, Darling PB, Sole MJ, Barr A, Keith ME. The prevalence of thiamin deficiency in hospitalized patients with congestive heart failure. J Am Coll Cardiol. 2006;47(2):354-361.  (PubMed)

65.  Wilkinson TJ, Hanger HC, George PM, Sainsbury R. Is thiamine deficiency in elderly people related to age or co-morbidity? Age Ageing. 2000;29(2):111-116.  (PubMed)

66.  Shimon I, Almog S, Vered Z, et al. Improved left ventricular function after thiamine supplementation in patients with congestive heart failure receiving long-term furosemide therapy. Am J Med. 1995;98(5):485-490.  (PubMed)

67.  Leslie D, Gheorghiade M. Is there a role for thiamine supplementation in the management of heart failure? Am Heart J. 1996;131(6):1248-1250.

68.  Comin-Anduix B, Boren J, Martinez S, et al. The effect of thiamine supplementation on tumour proliferation. A metabolic control analysis study. Eur J Biochem. 2001;268(15):4177-4182.  (PubMed)

69.  Zastre JA, Hanberry BS, Sweet RL, et al. Up-regulation of vitamin B1 homeostasis genes in breast cancer. J Nutr Biochem. 2013. May 1 [Epub ahead of print]  (PubMed)

70.  Boros LG, Brandes JL, Lee WN, et al. Thiamine supplementation to cancer patients: a double edged sword. Anticancer Res. 1998;18(1B):595-602.  (PubMed)

71.  Naito E, Ito M, Yokota I, Saijo T, Ogawa Y, Kuroda Y. Diagnosis and molecular analysis of three male patients with thiamine-responsive pyruvate dehydrogenase complex deficiency. J Neurological Sci. 2002;201(1-2):33-37.  (PubMed)

72.  Patel KP, O'Brien TW, Subramony SH, Shuster J, Stacpoole PW. The spectrum of pyruvate dehydrogenase complex deficiency: clinical, biochemical and genetic features in 371 patients. Mol Genet Metab. 2012;106(3):385-394.  (PubMed)

73.  Lee EH, Ahn MS, Hwang JS, Ryu KH, Kim SJ, Kim SH. A Korean female patient with thiamine-responsive pyruvate dehydrogenase complex deficiency due to a novel point mutation (Y161C)in the PDHA1 gene. J Korean Med Sci. 2006;21(5):800-804.  (PubMed)

74.  Chuang DT, Chuang JL, Wynn RM. Lessons from genetic disorders of branched-chain amino acid metabolism. J Nutr. 2006;136(1 Suppl):243S-249S.  (PubMed)

75.  Shaw-Smith C, Flanagan SE, Patch AM, et al. Recessive SLC19A2 mutations are a cause of neonatal diabetes mellitus in thiamine-responsive megaloblastic anaemia. Pediatr Diabetes. 2012;13(4):314-321.  (PubMed)

76.  Akin L, Kurtoglu S, Kendirci M, Akin MA, Karakukcu M. Does early treatment prevent deafness in thiamine-responsive megaloblastic anaemia syndrome? J Clin Res Pediatr Endocrinol. 2011;3(1):36-39.  (PubMed)

77.  Alfadhel M, Almuntashri M, Jadah RH, et al. Biotin-responsive basal ganglia disease should be renamed biotin-thiamine-responsive basal ganglia disease: a retrospective review of the clinical, radiological and molecular findings of 18 new cases. Orphanet J Rare Dis. 2013;8:83.  (PubMed)

78.  LeBlanc JG, Milani C, de Giori GS, Sesma F, van Sinderen D, Ventura M. Bacteria as vitamin suppliers to their host: a gut microbiota perspective. Curr Opin Biotechnol. 2013;24(2):160-168.  (PubMed)

79.  Russell RM, Suter PM. Vitamin requirements of elderly people: an update. Am J Clin Nutr. 1993;58(1):4-14.  (PubMed)

80.  US Department of Agriculture, Agricultural Research Service. USDA National Nutrient Database for Standard Reference, Release 25. 2012. Available at: http://ndb.nal.usda.gov. Accessed 6/21/13.

81.  Thiamin (vitamin B1). In: Hendler S, Rorvik D, eds. PDR for Nutritional Supplements. 2nd ed. Montvale: Physicians' Desk Reference Inc.; 2008:609-615.

82.  Flodin N. Pharmacology of micronutrients. New York: Alan R. Liss, Inc.; 1988.

83.  Schumann K. Interactions between drugs and vitamins at advanced age. Int J Vitam Nutr Res. 1999;69(3):173-178.  (PubMed)

84.  Subramanya SB, Subramanian VS, Said HM. Chronic alcohol consumption and intestinal thiamin absorption: effects on physiological and molecular parameters of the uptake process. Am J Physiol Gastrointest Liver Physiol. 2010;299(1):G23-G31.  (PubMed)

85.  Subramanian VS, Subramanya SB, Tsukamoto H, Said HM. Effect of chronic alcohol feeding on physiological and molecular parameters of renal thiamin transport. Am J Physiol Renal Physiol. 2010;299(1):F28-F34.  (PubMed) 

Vitamin A

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Summary

  • Vitamin A is a generic term that refers to fat-soluble compounds found as preformed vitamin A (retinol) in animal products and as provitamin A carotenoids in fruit and vegetables. The three active forms of vitamin A in the body are retinol, retinal, and retinoic acid. (More information)
  • Vitamin A is involved in regulating the growth and specialization (differentiation) of virtually all cells in the human body. Vitamin A has important roles in embryonic development, organ formation during fetal development, normal immune functions, and eye development and vision. (More information)
  • Vitamin A deficiency is a major cause of preventable blindness in the world. It is most prevalent among children and women of childbearing age. Vitamin A deficiency is associated with an increased susceptibility to infections, as well as to thyroid and skin disorders. (More information)
  • The recommended dietary allowance (RDA) is 700 micrograms of retinol activity equivalents (μg RAE)/day for women and 900 μg RAE/day for men. (More information)
  • Vitamin A prophylaxis appears to significantly reduce childhood mortality in regions at high risk of vitamin A deficiency. Further, high-dose vitamin A supplementation is widely recommended for children over six months of age when they are infected with measles while malnourished, immunodeficient, or are at risk of measles complications. (More information)
  • Retinoic acid and analogs are used at pharmacological doses in the treatment of acute promyelocytic leukemia and various skin diseases. (More information)
  • Animal food sources rich in preformed vitamin A include dairy products, fortified cereal, liver, and fish oils. Rich sources of provitamin A carotenoids include orange and green vegetables, such as sweet potato and spinach. (More information)
  • Overconsumption of preformed vitamin A can be highly toxic and is especially contraindicated prior to and during pregnancy as it can result in severe birth defects. The tolerable upper intake level (UL) for vitamin A in adults is set at 3,000 μg RAE/day. The UL does not apply to vitamin A derived from carotenoids. (More information)

Vitamin A is a generic term that encompasses a number of related compounds (Figure 1). Retinol and retinyl esters are often referred to as preformed vitamin A. Retinol can be converted by the body to retinal, which can be in turn be oxidized to retinoic acid, the form of vitamin A known to regulate gene transcription. Retinol, retinal, retinoic acid, and related compounds are known as retinoids. β-Carotene and other food carotenoids that can be converted by the body into retinol are referred to as provitamin A carotenoids (see the article on Carotenoids). Hundreds of different carotenoids are synthesized by plants, but only about 10% of them are capable of being converted to retinol (1). The following discussion will focus mainly on preformed vitamin A compounds and retinoic acid.

Figure 1. Chemical structures of beta-carotene, retinyl palmitate, all-trans-retinol, all-trans-retinal, 11-cis-retinal, all-trans-retinoic acid, 12-cis-retinoic acid, and 9-cis-retinoic acid.

Function

Vitamin A compounds are essential fat-soluble molecules predominantly stored in the liver in the form of retinyl esters (e.g., retinyl palmitate). When appropriate, retinyl esters are hydrolyzed to generate all-trans-retinol, which binds to retinol binding protein (RBP) before being released in the bloodstream. The all-trans-retinol/RBP complex circulates bound to the protein, transthyretin, which delivers all-trans-retinol to peripheral tissues (reviewed in 2). Vitamin A as retinyl esters in chylomicrons was also found to have an appreciable role in delivering vitamin A to extrahepatic tissues, especially in early life (3, 4)

Visual system and eyesight

Located at the back of the eye, the retina contains two main types of light-sensitive receptor cells − known as rod and cone photoreceptor cells. Photons (particles of light) that pass through the lens are sensed by the photoreceptor cells of the retina and converted to nerve impulses (electric signals) for interpretation by the brain. All-trans-retinol is transported to the retina via the circulation and accumulates in retinal pigment epithelial (RPE) cells (Figure 2) (5). Here, all-trans-retinol is esterified to form a retinyl ester, which can be stored. When needed, retinyl esters are broken apart (hydrolyzed) and isomerized to form 11-cis-retinol, which can be oxidized to form 11-cis-retinal. 11-cis-retinal can be shuttled across the interphotoreceptor space to the rod photoreceptor cell that is specialized for vision in low-light conditions and for detection of motion. In rod cells, 11-cis-retinal binds to a protein called opsin to form the visual pigment rhodopsin (also known as visual purple). Absorption of a photon of light catalyzes the isomerization of 11-cis-retinal to all-trans-retinal that is released from the opsin molecule. This photoisomerization triggers a cascade of events, leading to the generation of a nerve impulse conveyed by the optic nerve to the brain’s visual cortex. All-trans-retinal is converted to all-trans-retinol and transported across the interstitial space to the RPE cells, thereby completing the visual cycle. 

Figure 2. The Visual Cycle. Retinol is transported to the retina via the circulation, where it moves into retinal pigment epithelial cells. There, retinol is esterified to form a retinyl ester that can be stored. When needed, retinyl esters are broken apart (hydrolyzed) and isomerized to form 11-cis-retinol, which can be oxidized to form 11-cis-retinal. 11-cis-retinal can be shuttled to the rod cell, where it binds to a protein called opsin to form the visual pigment, rhodopsin (also known as visual purple). Absorption of a photon of light catalyzes the isomerization of 11-cis-retinal to all-trans-retinal and results in its release. This isomerization triggers a cascade of events, leading to the generation of an electrical signal to the optic nerve. The nerve impulse generated by the optic nerve is conveyed to the brain where it can be interpreted as vision. Once released, all-trans-retinal is converted to all-trans-retinol, which can be transported across the interphotoreceptor matrix to the retinal epithelial cell to complete the visual cycle.

A similar cycle occurs in cone cells that contain red, green, or blue opsin proteins required for the absorption of photons from the visible light spectrum (2). Vitamin A is also essential for mammalian eye development (6). Thus, because vitamin A is required for the normal functioning of the retina, dim-light vision, and color vision, inadequate retinol and retinal available to the retina result in impaired dark adaptation. In the severest cases of vitamin A deficiency, thinning and ulceration of the cornea leads to blindness (see Deficiency). 

Regulation of gene expression

Regulatory capacity of retinoic acid

In cells, all-trans-retinol can be either stored (in the form of retinyl ester) or oxidized to all-trans-retinal by alcohol dehydrogenases. In turn, retinaldehyde dehydrogenases can catalyze the conversion of all-trans-retinal into two biologically active isomers of retinoic acid (RA): all-trans-RA and 9-cis-RA. RA isomers act as hormones to affect gene expression and thereby influence numerous physiological processes. All-trans-RA and 9-cis-RA are transported to the nucleus of the cell bound to cellular retinoic acid-binding proteins (CRABP). Within the nucleus, RA isomers bind to specific nuclear receptor proteins that are ligand-dependent transcription factors (Figure 3). Both all-trans-RA and 9-cis-RA can bind to retinoic acid receptors (RARα, RARβ, and RARγ), whereas only 9-cis-RA binds to retinoid X receptors (RXRα, RXRβ, and RXRβ) (7). RAR and RXR subtypes form either complexes of two of the same protein (RAR/RAR and RXR/RXR homodimers) or complexes of two different proteins (RAR/RXR heterodimers). RAR/RXR heterodimers can bind to a regulatory DNA sequence called retinoic acid response element (RARE) located within the promoter of retinoid-responsive genes. The transcriptional activity of RAR/RXR heterodimers appears to be mainly driven by the binding of all-trans-RA to RAR. 

Figure 3. A Simplified Model of the Regulation of Gene Expression by Retinoic Acid (RA) Isomers. All-trans-RA and 9-cis-RA are transported to the nucleus of the cell bound to cytoplasmic retinoic acid-binding proteins. Within the nucleus, all-trans-RA binds to retinoic acid receptors (RAR) and 9-cis-RA binds to retinoid receptors (RXR). RAR and RXR form RAR/RXR heterodimers, which bind to regulatory regions of the chromosome called retinoic acid response elements (RARE). Binding of all-trans-RA and 9-cis-RA to RAR and RXR respectively allows the complex to regulate the rate of gene transcription.

The activation of RAR by RA binding triggers the recruitment of transcriptional coregulators to target promoters, thereby inhibiting or allowing the transcription of genes (8). RXR also forms heterodimers with several other nuclear receptors, including thyroid hormone receptor (TR), vitamin D receptor (VDR), steroid receptors, and peroxisome proliferator-activated receptor (PPAR) (9). In this way, vitamin A may interact with thyroid hormone, vitamin D, steroids (e.g., estrogen), or PPAR ligands signaling pathways and influence the transcription of a broad range of genes. 

There is also evidence that RA/RAR can affect gene expression in a RARE-independent manner. For example, it was reported that RAR could interfere with TGFβ/Smad signaling pathway through direct interaction of RAR with the heterodimeric transcription factor, Smad3/Smad4. In the absence of RA, RAR was found to act as a coactivator of Smad3/Smad4-mediated transcription, while RAR agonists repressed the transcriptional activity of Smad3/Smad4 (10). In retinoblastoma cells, RAR was also involved in RA-induced activation of signaling cascades mediated by tyrosine kinases known as phosphoinositide 3-kinase (PI3K) and leading to cell differentiation (11, 12). RA also appeared to induce neuronal differentiation by activating ERK1/2 MAP kinase signaling pathway that phosphorylated transcription factor, CREB (cyclic AMP response element binding protein). Phosphorylated CREB can subsequently bind to the CREB response element in the promoter of genes involved in cell differentiation (13). Also, independently of RAR, RA was found to inhibit ERK1/2 phosphorylation/activation and subsequent AP1-mediated expression of interleukin-6 in synovial cells (14). Hence, RA can influence the expression of genes whose promoters do not contain RARE.  

By regulating the expression of over 500 retinoid-responsive genes (including several genes involved in vitamin A metabolism itself), retinoic acid isomers play major roles in cellular proliferation and differentiation (i.e., cell commitment to highly specialized functions). 

Regulatory capacity of retinol

In the eye and tissues like white adipose and muscle, retinol plasma membrane receptor/transporter STRA6 accepts retinol from extracellular RBP and unloads it to intracellular retinol-binding protein (CRBP). STRA6 also cooperates with lecithin:retinol acyltransferase (LRAT), an enzyme that catalyzes retinol esterification and storage, to maintain an inward concentration gradient of retinol (15). Interestingly, retinol uptake by STRA6 was found to trigger the activation of a signaling cascade mediated by tyrosine kinases known as Janus kinases (JAK) and associated transcription factors (STAT). JAK/STAT signaling pathway regulates the expression of a wide range of cytokines, hormones, and growth factors (16). Animal studies have reported that an increased expression of genes, such as SOCS3 by the JAK/STAT pathway, could result in the inhibition of insulin signaling. Hence, obese mice lacking LRAT or STRA6 appear to be protected from retinol/STRA6-induced insulin resistance (17, 18).

Regulatory capacity of retinal

Apart from its role as a ligand for opsin in the visual cascade (see Visual system and eyesight), retinal has been specifically implicated in the regulation of genes important for lipid metabolism. In humans, two types of adipose tissue have been distinguished based on their respective functions: white adipose tissue (WAT) stores fatty acids as triglycerides, and brown adipose tissue (BAT) oxidizes fatty acids to generate heat (thermogenesis). In the mitochondrial respiratory chain of brown adipose cells, the processes of electron transport and ATP production are uncoupled (dissociated) to permit the rapid production of heat from fatty acid oxidation (19)

Retinaldehyde dehydrogenase 1 (RALDH1), which converts retinal to retinoic acid, is highly expressed in WAT but not in BAT. The suppression of RALDH1 expression in WAT can induce a thermogenic phenotype resembling that of BAT (20). During adipocyte differentiation, the stimulation of cells with all-trans retinal has been found to activate the UCP1 gene required for thermogenesis while inhibiting genes promoting adipogenesis, such as PPARγ (20). Retinal also appeared to regulate lipid metabolism and adiposity in bone marrow by inhibiting PPARγ/RXR heterodimer-mediated gene expression (21). In addition, retinal was found to inhibit gluconeogenic gene expression and glucose production in the liver of mice deficient in RALDH1 (22).

Immunity

Vitamin A was initially coined “the anti-infective vitamin” because of its importance in the normal functioning of the immune system (23). The skin and mucosal cells, lining the airways, digestive tract, and urinary tract function as a barrier and form the body's first line of defense against infection. Retinoic acid (RA) is produced by antigen-presenting cells (APCs), including macrophages and dendritic cells, found in these mucosal interfaces and associated lymph nodes. RA appears to act on dendritic cells themselves to regulate their differentiation, migration, and antigen-presenting capacity. In addition, the production of RA by APCs is required for the differentiation of naïve CD4 T-lymphocytes into induced regulatory T- lymphocytes (Tregs). Critical to the maintenance of mucosal integrity, the differentiation of Tregs is driven by all-trans-RA through RARα-mediated regulation of gene expression (see Regulation of gene expression). Also, during inflammation, all-trans-RA/RARα signaling pathway promotes the conversion of naïve CD4 T-lymphocytes into effector T-lymphocytes − type 1 helper T-cells (Th1) − (rather than into Tregs) and induces the production of proinflammatory cytokines by effector T-lymphocytes in response to infection. There is also substantial evidence to suggest that RA may help prevent the development of autoimmunity (reviewed in 24).

Prenatal and postnatal development

Both vitamin A excess and deficiency are known to cause birth defects. Retinoid signaling begins soon after the early phase of embryonic development known as gastrulation. During fetal development, RA is critical for the development of organs, including the heart, eyes, ears, lungs, as well as other limbs and visceral organs. Vitamin A has been implicated in fetal lung maturation (2). Vitamin A status is lower in preterm newborns than in full-term infants (25). There is some evidence to suggest that vitamin A supplementation may help reduce the incidence of chronic lung disease and mortality in preterm newborns (see Disease Prevention). Retinoid signaling is also involved in the expression of many proteins of the extracellular matrix (ECM; material surrounding cells), including collagen, laminin, and proteoglycans (26). Vitamin A deficiency may then result in alterations of the ECM composition, thus disrupting organ morphology and function (reviewed in 26). 

Red blood cell production (erythropoiesis)

Red blood cells (erythrocytes), like all blood cells, are derived from pluripotent stem cells in the bone marrow. Studies involving in vitro culture systems have suggested a role for retinoids in stem cell commitment and differentiation to the red blood cell lineage. Retinoids might also regulate apoptosis (programmed cell death) of red blood cell precursors (erythropoietic progenitor cells) (27). However, whether retinoids regulate erythropoiesis in vivo has not been established. Yet, vitamin A supplementation in vitamin A deficient-individuals has been shown to increase hemoglobin concentrations. Additionally, vitamin A appears to facilitate the mobilization of iron from storage sites to the developing red blood cell for incorporation into hemoglobin, the oxygen carrier in red blood cells (27, 28).

Nutrient interactions

Zinc

Zinc deficiency is thought to interfere with vitamin A metabolism in several ways (29): (1) zinc deficiency results in decreased synthesis of retinol-binding protein (RBP), which transports retinol through the circulation to peripheral tissues and protects the organism against potential toxicity of retinol; (2) zinc deficiency results in decreased activity of the enzyme that releases retinol from its storage form, retinyl palmitate, in the liver; and (3) zinc is required for the enzyme that converts retinol into retinal (30). The health consequences of zinc deficiency on vitamin A nutritional status in humans are yet to be defined (29)

Iron

Vitamin A deficiency often coexists with iron deficiency and may exacerbate iron deficiency anemia by altering iron metabolism (27). Vitamin A supplementation has beneficial effects on iron deficiency anemia and improves iron nutritional status among children and pregnant women (27, 28). The combination of supplemental vitamin A and iron seems to reduce anemia more effectively than either supplemental iron or vitamin A alone (31). Moreover, studies in rats have shown that iron deficiency alters plasma and liver levels of vitamin A (32, 33)

Deficiency

Vitamin A deficiency usually results from inadequate intakes of vitamin A from animal products (as preformed vitamin A) and fruit and vegetables (as provitamin A carotenoids). In developing countries, vitamin A deficiency and associated disorders predominantly affect children and women of reproductive age. Other individuals at risk of vitamin A deficiency are those with poor absorption of lipids due to impaired pancreatic or biliary secretion and those with inflammatory bowel diseases, such as Crohn’s disease and celiac disease (2). Subclinical vitamin A deficiency is often defined by serum retinol concentrations lower than 0.70 μmol/L (20 μg/dL). In severe vitamin A deficiency, vitamin A body stores are depleted and serum retinol concentrations fall below 0.35 μmol/L (10 μg/dL). Other biomarkers have been calibrated to assess vitamin A nutritional status (reviewed in 34). Of note, the World Health Organization considers vitamin A deficiency a public health problem when the prevalence of low serum retinol (<0.70 μmol/L) reaches 15% or more of a defined population. 

Vitamin A deficiency-related disorders

Disease of the eye and blindness

With an estimated 250,000 to 500,000 children becoming blind annually, vitamin A deficiency constitutes the leading preventable cause of blindness in low- and middle-income nations (35). The earliest symptom of vitamin A deficiency is impaired dark adaptation known as night blindness or nyctalopia. The next clinical stage is the occurrence of abnormal changes in the conjunctiva (corner of the eye), manifested by the presence of Bitot's spots. Severe or prolonged vitamin A deficiency eventually results in a condition called xerophthalmia (Greek for dry eye), characterized by changes in the cells of the cornea (clear covering of the eye) that ultimately result in corneal ulcers, scarring, and blindness (36). Immediate administration of 200,000 international units (IU) of vitamin A for two consecutive days is required to prevent blinding xerophthalmia (36)

There is an estimated 19.1 million pregnant women worldwide (especially in Sub-Saharan Africa, Southeast Asia, and Central America) with vitamin A deficiency and over half of them are affected by night blindness (37). The prevalence of vitamin A deficiency and night blindness is especially high during the third trimester of pregnancy due to accelerated fetal growth. Also, approximately 190 million preschool-age children have low serum retinol concentrations (<0.70 μmol/L), with 5.2 million suffering from night blindness. Moreover, half of the children affected by severe vitamin A deficiency-induced blinding xerophthalmia are estimated to die within a year of becoming blind (37). The World Health Organization (WHO) and the United Nations Children’s Fund (UNICEF) promote vitamin A supplementation as a public health intervention to reduce child mortality in areas and populations where vitamin A deficiency is prevalent (38-40).

Susceptibility to infectious diseases

Infectious diseases have been associated with depletion of vitamin A hepatic reserves (already limited in vitamin A-deficient subjects), reduced serum retinol concentrations, and increased loss of vitamin A in the urine (37). Infection with the measles virus was found to precipitate conjunctival and corneal damage, leading to blindness in children with poor vitamin A status (41). Conversely, vitamin A deficiency can be considered a nutritionally acquired immunodeficiency disease (42). Even children who are only mildly deficient in vitamin A have a higher incidence of respiratory complications and diarrhea, as well as a higher rate of mortality from measles infection compared to children consuming sufficient vitamin A (43). Because vitamin A supplementation may decrease both the severity and incidence of measles complications in developing countries (see Disease Prevention), WHO recommends that children aged at least one year receive 200,000 IU of vitamin A (60 mg RAE) for two consecutive days in addition to standard treatment when they are infected with measles virus and live in areas of vitamin A deficiency (44)

A recent prospective cohort study, conducted in 2,774 Colombian children (ages, 5-12 years old) followed for a median 128 days, also reported an inverse relationship between plasma retinol concentrations and rates of diarrhea with vomiting and cough with fever, the latter being a strong predictor of influenza infection (flu) (45). A review of five randomized, placebo-controlled studies that included 7,528 HIV-positive pregnant or breast-feeding women found no substantial benefit of vitamin A supplementation in reducing the mother-to-child transmission of HIV (46). One early observational study found that HIV-infected women who were vitamin A deficient were three to four times more likely to transmit HIV to their infants (47). Yet, no trial to date has provided any information on potential adverse effects of vitamin A supplementation on mother-to-child HIV transmission (48).

Thyroid dysfunction

In North and West Africa, vitamin A deficiency and iodine deficiency induced-goiter can coexist in up to 50% of children. The response to iodine prophylaxis in iodine-deficient populations appears to depend on various nutritional factors, including vitamin A status (49, 50). Vitamin A deficiency in animal models was found to interfere with the pituitary-thyroid axis by (1) increasing the synthesis and secretion of thyroid-stimulating hormone (TSH) by the pituitary gland, (2) increasing the size of the thyroid gland, (3) reducing iodine uptake by the thyroid gland and impairing the synthesis and iodination of thyroglobulin, and (4) increasing circulating concentrations of thyroid hormones (reviewed in 51). A cross-sectional study of 138 children with concurrent vitamin A and iodine deficiencies found that the severity of vitamin A deficiency was associated with higher risk of goiter and higher concentrations of circulating TSH and thyroid hormones (50). These children received iodine-enriched salt with either vitamin A (200,000 IU at baseline and 5 months) or placebo in a randomized, double-blind, 10-month trial. This vitamin A supplementation significantly decreased TSH concentration and thyroid volume compared to placebo (50). In another trial, supplementation of vitamin A to iodine-deficient children had no additional effect to iodine on thyroid status compared to placebo, but vitamin A supplementation alone (without iodine) reduced the volume of the thyroid gland, as well as TSH and thyroglobulin concentrations (52).

Other disorders

Phrynoderma or follicular hyperkeratosis is a skin condition characterized by an excessive production of keratin in hair follicles. The lesions first appear on the extremities, shoulders, and buttocks and may spread over the entire body in the severest cases (53). While vitamin A deficiency may contribute to the occurrence of phrynoderma, the condition has been strongly associated with multiple nutritional deficiencies and is considered a sign of general malnutrition. A rare case of esophagitis (inflammation of the esophagus) has recently been attributed to hyperkeratosis secondary to vitamin A deficiency (54).

Also, vitamin A deficiency affects iron mobilization, impairs hemoglobin synthesis, and precipitates iron deficiency anemia that is only alleviated with supplementation of both vitamin A and iron (see Nutrient interactions) (27).

The Recommended Dietary Allowance (RDA)

Retinol Activity Equivalents (RAE)

Vitamin A can be obtained from food as preformed vitamin A in animal products or as provitamin A carotenoids in fruit and vegetables (see Food sources). Yet, while preformed vitamin A is effectively absorbed, stored, and hydrolyzed to form retinol, provitamin A carotenoids like β-carotene are less easily digested and absorbed, and must be converted to retinol and other retinoids by the body after uptake into the small intestine. The efficiency of conversion of provitamin A carotenes into retinol is highly variable, depending on factors such as food matrix, food preparation, and one’s digestive and absorptive capacities (55)

The most recent international standard of measure for vitamin A is retinol activity equivalents (RAE), which represent vitamin A activity as retinol. It has been determined that 2 micrograms (μg) of β-carotene in oil provided as a supplement could be converted by the body to 1 μg of retinol giving it an RAE ratio of 2:1. However, 12 μg of β-carotene from food are required to provide the body with 1 μg of retinol, giving dietary β-carotene an RAE ratio of 12:1. Other provitamin A carotenoids in food are less easily absorbed than β-carotene, resulting in RAE ratios of 24:1. RAE ratios are shown in Table 1 (56)

Table 1. Retinol activity equivalents (RAE) Ratios for Preformed Vitamin A and Provitamin A Carotenoids
Quantity Consumed Quantity Bioconverted to Retinol RAE Ratio
1 μg of dietary or supplemental vitamin A  1 μg of retinol*  1:1 
2 μg of supplemental β-carotene  1 μg of retinol  2:1 
12 μg of dietary β-carotene  1 μg of retinol  12:1 
24 μg of dietary α-carotene  1 μg of retinol  24:1 
24 μg of dietary β-cryptoxanthin 1 μg of retinol  24:1
*1 IU is equivalent to 0.3 microgram (μg) of retinol, and 1 μg of retinol is equivalent to 3.33 IU of retinol.

Determination of the RDA

The RDA for vitamin A was revised by the Food and Nutrition Board (FNB) of the US Institute of Medicine (IOM) in 2001. The RDA is based on the Estimated Average Requirement (EAR), which is defined as the biological requirement for 50% of the population. The RDA is the recommended intake needed by nearly all of the population to ensure adequate hepatic stores of vitamin A in the body (20 μg/g for four months if the person consumes a vitamin A-deficient diet) to support normal reproductive function, immune function, gene expression, and vision (for details of calculations, see 56). Table 2 lists the RDA values in micrograms (μg) of Retinol Activity Equivalents (RAE) per day.

Table 2. Recommended Dietary Allowance (RDA) for Vitamin A as Preformed Vitamin A (micrograms [μg] of Retinol Activity Equivalents [RAE]/day)
Life Stage Age Males (μg/day) Females (μg/day)
Infants   0-6 months  400 (AI) 400 (AI)
Infants  7-12 months  500 (AI)  500 (AI)
Children  1-3 years  300 300
Children  4-8 years  400 400
Children  9-13 years  600 600
Adolescents  14-18 years  900 700
Adults  19 years and older  900 700
Pregnancy  18 years and younger  750
Pregnancy  19 years and older 770
Breast-feeding  18 years and younger  1,200
Breast-feeding  19 years and older  1,300

Disease Prevention

Bronchopulmonary dysplasia in preterm infants

Preterm infants are born with inadequate body stores of vitamin A, placing them at risk of developing diseases of the eye and the respiratory and gastrointestinal tracts. About one-third of preterm infants born between 22 and 28 weeks of gestation develop bronchopulmonary dysplasia (BPD), a chronic lung disease that can be fatal or result in life-long morbidities in survivors. A few randomized controlled studies have investigated the effect of postnatal vitamin A supplementation on the incidence of BPD and the risk of mortality in very low birth weight infants (≤1,500 g) requiring respiratory support (57-59). In the largest, multicenter, randomized, blinded, placebo-controlled trial that enrolled 807 extremely low birth weight (ELBW; ≤1,000 g) preterm newborns, the intramuscular administration of 5,000 IU of vitamin A three times a week for four weeks significantly, though modestly, reduced the risk of BPD or death at 36 weeks’ postmenstrual age (gestational age plus chronological age) (58). While vitamin A supplementation was included in some neonatal programs after this trial (60), a national shortage in vitamin A supply that has affected US neonatal intensive care units since 2010 has led to a significant reduction in the use of vitamin A supplementation in premature newborns (401-1,000 g at birth) with respiratory failure (61, 62). However, a retrospective analysis of US nationwide data from 6,210 preterm infants born between 2010 and 2012 found that a reduction in vitamin A prophylaxis from 27.2% to 2.1% during the same period had no significant impact on the incidence of BPD or death before hospital discharge (62)

In another retrospective study, the nonrandomized use of vitamin A supplementation with inhaled nitric oxide (iNO) was found to result in a lower incidence of BPD (but not mortality) compared to iNO therapy alone in preterm newborns with a birth weight of 750-999 g (63). Neurodevelopment index scores at one year of age were also improved in the vitamin A group of newborns weighing 500-749 g at birth. Yet, caution is advised with the interpretation of the results, especially because the trial was not designed to assess the effect of vitamin A. In Germany, one large, multicenter, randomized study – the NeoVitaA trial – is under way to explore the effect of high-dose oral vitamin A (5,000 IU/kg/day) for 28 days on the incidence of BPD and mortality at 36 weeks’ postmenstrual age (64)

While high doses of vitamin A during early pregnancy can cause birth defects (see Safety), vitamin A supplementation during late pregnancy may improve maternal and fetal vitamin A status (65). Although a few randomized controlled trials have failed to show an effect on maternal and neonatal mortality (66), more research is required to assess whether vitamin A supplementation during pregnancy reduces BPD incidence in infants.  

Childhood morbidity and mortality

A recent meta-analysis of randomized controlled trials evaluating the preventive effect of vitamin A on childhood mortality indicated that vitamin A supplementation (200,000 IU every 4 or 6 months) reduced all-cause mortality by 25% (13 studies) and diarrhea-specific mortality by 30% (7 studies) in children aged 6 to 59 months. However, vitamin A administration in this age group had no preventive effect on rates of pneumonia-specific mortality (7 studies), measles-specific mortality (5 studies), or meningitis-specific mortality (3 studies). Moreover, no reduction in the risk of disease-specific mortality was found in neonates (0 to 28 days of age) and infants 1 to 6 months of age supplemented with vitamin A (67). Another meta-analysis of randomized controlled trials found no evidence of a reduction in mortality risk during infancy when either breast-feeding mothers (7 studies) or infants aged less than six months (9 studies) were supplemented with vitamin A (68)

Current WHO policy recommends vitamin A supplementation at routine vaccination contacts in children after six months of age living in regions at high risk of vitamin A deficiency. Supplementation with high doses of vitamin A − 100,000 IU (30 mg RAE) for infants 6 to 11 months of age and 200,000 IU (60 mg RAE) for children 12 to 59 months of age − is thought to provide adequate protection for up to six months (38). A recent placebo-controlled trial in Guinea-Bissau, which randomized 7,587 children (ages, 6 to 23 months old) to receive vitamin A supplementation at one vaccination contact, evaluated the co-administration of vitamin A and vaccines on child mortality (69). The study found that vitamin A supplementation had no effect on overall mortality rates, although a six-month follow-up of infants given both measles and DTP (diphtheria-tetanus-pertussis) vaccinations showed a significant reduction in mortality in girls, but not in boys (69). Although neonatal vitamin A supplementation is not currently recommended, a trial assessing the benefit of early measles vaccination − at 4.5 rather than the usual 9 months of age − found no reduction in mortality rates when children had received neonatal vitamin A supplementation (70). The recent pooled analysis of previous trials of vitamin A supplementation (VITA I-III) in Guinea-Bissau confirmed that vitamin A supplementation may interfere with vaccines. Specifically, compared to placebo, neonatal vitamin A supplementation was associated with a significant increase in mortality rates in boys (but not in girls) when children had received measles virus vaccination at 4.5 months of age rather than the usual 9 months of age (71). The timing of vitamin A interventions needs to be further examined in relation to the timing of vaccinations in order to maximize their benefits.

Complications from measles infection

An earlier meta-analysis of seven randomized controlled trials examining specifically the role of vitamin A supplementation in 2,069 children with measles found no overall reduction on the risk of mortality (72). Yet, the pooled analysis of four studies that reported the age distribution of participants found an 83% lower risk of mortality with two doses of 200,000 IU of vitamin A in children younger than two years. In addition, the pooled analysis of three studies indicated a 67% reduction in the risk of pneumonia-led mortality (72). Similar to WHO and UNICEF guidelines, the American Academy of Pediatrics recommends vitamin A supplementation for children over six months of age when they are infected with measles while malnourished, immunodeficient, or are at risk of measles complications or vitamin A deficiency disorders (73). Although measles infection has been associated with vitamin A deficiency and blindness, there is currently no evidence to suggest that vitamin A supplementation reduces the risk of blindness in children infected with measles (74)

Cancer

Studies in cell culture and animal models have documented the capacity for natural and synthetic retinoids to reduce carcinogenesis significantly in skin, breast, liver, colon, prostate, and other sites. However, the results of human studies examining the relationship between the consumption of preformed vitamin A and cancer do not currently suggest that consuming vitamin A at intakes greater than the RDA benefit in the prevention of cancer (2).

Lung cancer

The results of the β-Carotene And Retinol Efficacy Trial (CARET) have suggested that high-dose supplementation of preformed vitamin A and β-carotene should be avoided in people at high risk for lung cancer (75). In the CARET study, about 9,000 people (smokers and people with asbestos exposure) were assigned a daily regimen of 25,000 IU (7,500 μg RAE) of retinyl palmitate and 30 mg of β-carotene, while a similar number of people were assigned a placebo. After four years of follow-up, the incidence of lung cancer was 28% higher in the supplemented group compared to the placebo group; however, the incidence was not different six years after the intervention ended (76). A possible explanation for an increase in lung cancer is that the oxidative environment of the lung, created by smoke or asbestos exposure, could give rise to unusual carotenoid cleavage products, which might promote carcinogenesis (77). Interestingly, a case-control study that included 749 lung cancer cases and 679 controls from the CARET trial found a significant association between lung cancer risk reduction and high vitamin D intakes (≥400 IU/day) in individuals who received the active CARET supplements or in those with vitamin A intakes equal to or greater than 1,500 μg RAE/day (78). Further, a recent meta-analysis of four randomized controlled trials, including a total of 202,924 participants at low risk of lung cancer, indicated that supplementation with retinol and/or β-carotene had no significant effect on lung cancer incidence (79). At present, it seems unlikely that increased intake of preformed vitamin A (e.g., retinol) could lower the risk of lung cancer.

Disease Treatment

Retinoids may be used at pharmacological doses to treat several conditions, including, acute promyelocytic leukemia, retinitis pigmentosa, and various skin diseases. It is important to note that treatment with high doses of natural or synthetic retinoids overrides the body's own control mechanisms; therefore, retinoid therapies are associated with potential side effects and toxicities. Additionally, all of the retinoid compounds have been found to cause fetal deformations. Thus, women who have a chance of becoming pregnant should avoid treatment with these medications. Retinoids tend to be very long acting: side effects and birth defects have been reported to occur months after discontinuing retinoid therapy (2). The retinoids discussed below are prescription drugs and should not be used without medical supervision.

Acute promyelocytic leukemia

Normal differentiation of myeloid stem cells in the bone marrow gives rise to platelets, red blood cells, and white blood cells (also called leukocytes) that are important for the immune response. Altered differentiation of myeloid cells can result in the proliferation of immature white blood cells, giving rise to leukemia. Reciprocal chromosome translocations involving the promyelocytic leukemia (PML) gene and the gene coding for retinoic acid receptor α (RARα) lead to a specific type of leukemia called acute promyelocytic leukemia (APL). The fusion protein PML/RARα represses transcription by binding to RARE in the promoter of retinoid-responsive genes involved in hematopoietic cell differentiation. Gene repression by PML/RARα is achieved by the recruitment of several chromatin modifiers, including histone deacetylases (HDACs) and DNA methyltransferases (DNMTs). Contrary to RARα wild-type receptor, PML/RARα appears to be insensitive to physiological concentrations of retinoic acid (RA) such that only treatments with high doses of all-trans-RA can restore normal differentiation and lead to significant improvements and complete remission in some APL patients (80)

More information on APL treatment programs can be found in the National Cancer Institute website.

Diseases of the skin

Both natural and synthetic retinoids have been used as pharmacologic agents to treat disorders of the skin. Acitretin is a synthetic retinoid that has been proven useful in combination treatments for psoriasis (81). Topical tretinoin (all-trans-retinoic acid) and oral isotretinoin (13-cis-retinoic acid) have been used successfully to treat mild-to-severe acne vulgaris (82, 83). Retinoids exhibit anti-inflammatory properties and regulate the proliferation and differentiation of skin epithelial cells, as well as the production of sebum. Use of pharmacological doses of retinoids (especially oral isotretinoin) by pregnant women causes birth defects and is therefore contraindicated prior to and during pregnancy (see Safety in pregnancy). 

For more information on the use of retinoids in the management of acne, see the article on Vitamin A and Skin Health

Retinitis pigmentosa

Retinitis pigmentosa (RP) affects approximately 1.5 million people worldwide and is a leading cause of inherited blindness. RP describes a broad spectrum of genetic disorders that result in the progressive loss of photoreceptor cells (rods and cones) in the retina of the eye (84). While at least 45 loci have been associated with RP, mutations in the rhodopsin gene (RHO), the usherin gene (USH2A), and the RP GTPase regulator gene (RPGR) account for about 30% of all RP cases (85)

Early symptoms of RP include impaired dark adaptation and night blindness, followed by the progressive loss of peripheral and central vision over time (85). The results of only one randomized controlled trial in 601 patients with common forms of RP indicated that supplementation with 15,000 IU/day of retinyl palmitate (4,500 μg RAE) significantly slowed the loss of retinal function over a period of four to six years (86). In contrast, supplementation with 400 IU/day of vitamin E (dl-α-tocopherol) modestly but significantly increased the loss of retinal function, suggesting that patients with common forms of RP may benefit from long-term vitamin A supplementation but should avoid high-dose vitamin E supplementation. Up to 12 years of follow-up in these patients did not reveal any signs of liver toxicity as a result of excess vitamin A intake (87). Because neither children younger than 18 years nor adults affected by less common forms of RP were included in the trial, no formal recommendation about vitamins A and E could be made (85). High-dose vitamin A supplementation to slow the course of RP requires medical supervision and must be discontinued if there is a possibility of pregnancy (see Safety).

Sources

Food sources

Free retinol is not generally found in food. Retinyl esters (including retinyl palmitate) are the storage form of retinol in animals and thus the main precursors of retinol in food from animals. Plants contain carotenoids, some of which are precursors for vitamin A (e.g., α-carotene, β-carotene, and β-cryptoxanthin). Yellow- and orange-colored vegetables contain significant quantities of carotenoids. Green vegetables also contain carotenoids, though yellow-to-red pigments are masked by the green pigment of chlorophyll (1). The table below lists a number of good food sources of vitamin A, including fruit and vegetables, along with their vitamin A content. The retinol activity is indicated in micrograms of retinol activity equivalents (μg RAE). For information on this unit of measurement, see the section on RAE. In addition, use the USDA food composition database to check foods for their content of carotenoids without vitamin A activity, such as lycopene, lutein, and zeaxanthin. 

Vitamin A international units (IUs)

Vitamin A is currently listed on food and supplement labels in international units. The USDA database also provides the vitamin A content of food sources using the vitamin A international unit (IU). Yet, contrary to RAE, the number of IUs of vitamin A does not reflect the bioavailability of vitamin A from different food sources. Conversion rates between IUs and μg RAE are set as follows:

•  1 IU of retinol is equivalent to 0.3 μg RAE
•  1 IU of supplemental β-carotene is equivalent to 0.15 μg RAE 
•  1 IU of dietary β-carotene is equivalent to 0.05 μg RAE
•  1 IU of α-carotene or β-cryptoxanthin to 0.025 μg RAE 

Thus, in Table 3, the number of IUs of vitamin A in carotenoid-containing food (numbers in italics) can be obtained by multiplying the RAE by approximately 20.

Table 3. Some Food Sources of Vitamin A
Food Serving Preformed Vitamin A (Retinol), μg Vitamin A, μg RAE Vitamin A, IU
Beef liver, cooked 1 slice (68 g) 6,421* 6,421* 21,566*
Cod liver oil 1 teaspoon 1,350 1,350 4,500
Fortified breakfast cereal (oats) 1 serving (1 oz) 216 216 721
Egg 1 large 80 80 270
Butter 1 tablespoon 95 95 355
Whole milk 1 cup (8 fl oz) 110 110 395
2% fat milk (vitamin A added) 1 cup (8 fl oz) 134 134 464
Nonfat milk (vitamin A added) 1 cup (8 fl oz) 149 149 500
Sweet potato (canned, mashed) ½ cup 0 555 11,091
Sweet potato (baked) ½ cup 0 961 19,218
Pumpkin (canned) ½ cup 0 953 19,065
Carrot (raw, chopped) ½ cup 0 534 10,692
Cantaloupe ½ medium melon 0 466 9,334
Mango 1 fruit 0 181 3,636
Spinach (cooked) ½ cup 0 472 9,433
Broccoli (cooked) ½ cup 0 60 1,207
Kale (cooked) ½ cup 0 443 8,854
Collards (cooked) ½ cup 0 361 7,220
Squash, butternut (cooked) ½ cup 0 572 11,434
*Above the tolerable upper intake level (UL) of 3,000 μg RAE (10,000 IU)/day

Supplements

The principal forms of preformed vitamin A in supplements are retinyl palmitate and retinyl acetate. β-Carotene is also a common source of vitamin A in supplements, and many supplements provide a combination of retinol and β-carotene (88). If a percentage of the total vitamin A content of a supplement comes from β-carotene, this information is included in the Supplement Facts label under vitamin A (Figure 4). Some multivitamin supplements available in the US provide up to 5,000 IU of preformed vitamin A, corresponding to 1,500 μg RAE, which is substantially more than the current RDA for vitamin A. This is due to the fact that the Daily Values (DV) used by the US Food and Drug Administration (FDA) for supplement labeling are based on the RDA established in 1968 rather than the most recent RDA, and multivitamin supplements typically provide 100% of the DV for most nutrients. Because retinol intakes of 5,000 IU/day (1,500 μg RAE) may be associated with an increased risk of osteoporosis in older adults (see Safety), some companies have reduced the retinol content in their multivitamin supplements to 2,500 IU (750 μg RAE).

Figure 4. An Example of a Multivitamin/Mineral Supplement Label. 50% (2,500 IU) of vitamin A is supplied as beta-carotene, while the rest (2,500 IU) is supplied as retinol.

Safety

Toxicity

The condition caused by vitamin A toxicity is called hypervitaminosis A. It is caused by overconsumption of preformed vitamin A, not carotenoids. Preformed vitamin A is rapidly absorbed and slowly cleared from the body. Therefore, toxicity from preformed vitamin A may result acutely from high-dose exposure over a short period of time or chronically from a much lower intake (2). Acute vitamin A toxicity is relatively rare, and symptoms include nausea, headache, fatigue, loss of appetite, dizziness, dry skin, desquamation, and cerebral edema. Signs of chronic toxicity include dry itchy skin, desquamation, anorexia, weight loss, headache, cerebral edema, enlarged liver, enlarged spleen, anemia, and bone and joint pain. Also, symptoms of vitamin A toxicity in infants include bulging fontanels. Severe cases of hypervitaminosis A may result in liver damage, hemorrhage, and coma. Generally, signs of toxicity are associated with long-term consumption of vitamin A in excess of 10 times the RDA (8,000-10,000 μg RAE/day or 25,000-33,000 IU/day). However, more research is necessary to determine if subclinical vitamin A toxicity is a concern in certain populations (89). There is evidence that some populations may be more susceptible to toxicity at lower doses, including the elderly, chronic alcohol users, and some people with a genetic predisposition to high cholesterol (90). In January 2001, the Food and Nutrition Board of the US Institute of Medicine set the tolerable upper intake level (UL) of vitamin A intake for adults at 3,000 μg RAE (10,000 IU)/day of preformed vitamin A (56).

Table 4. Tolerable Upper Intake Level (UL) for Preformed Vitamin A
Age Group μg RAE/day IU/day*
Infants 0-12 months  600 2,000
Children 1-3 years  600 2,000
Children 4-8 years  900 3,000
Children 9-13 years  1,700  5,667
Adolescents 14-18 years  2,800 9,333
Adults 19 years and older  3,000 10,000
*1 IU of preformed vitamin A is equivalent to 0.3 μg RAE, and 1 μg RAE is equivalent to 3.33 IU of preformed vitamin A

Safety in pregnancy

Although normal fetal development requires sufficient vitamin A intake, consumption of excess preformed vitamin A (such as retinol) during early pregnancy is known to cause birth defects. No increase in the risk of vitamin A-associated birth defects has been observed at doses of preformed vitamin A from supplements below 3,000 μg RAE/day (10,000 IU/day) (56). Of note, in 2011, the World Health Organization (WHO) recommended vitamin A supplementation (up to 3,000 μg RAE/day or 7,500 μg RAE/week) during pregnancy in areas with high prevalence of vitamin A deficiency for the prevention of blindness (91). In industrialized countries, pregnant or potentially pregnant women should monitor their intake of vitamin A from fortified food and food naturally high in preformed vitamin A (e.g., liver) and avoid taking daily multivitamin supplements that contain more than 1,500 μg RAE (5,000 IU) of vitamin A. There is no evidence that consumption of vitamin A from β-carotene might increase the risk of birth defects. The synthetic derivative of retinol, isotretinoin, is known to cause serious birth defects and should not be taken during pregnancy or if there is a possibility of becoming pregnant (82). Tretinoin (all-trans-retinoic acid), another retinol derivative, is prescribed as a topical preparation that is applied to the skin. Although percutaneous absorption of topical tretinoin is minimal, its use during pregnancy is not recommended (92)

Do high intakes of vitamin A increase the risk of osteoporosis?

Results from some prospective studies have suggested that long-term intakes of preformed vitamin A in excess of 1,500 μg RAE/day (equivalent to 5,000 IU/day of vitamin A as retinol) were associated with reduced bone mineral density (BMD) and increased risk of osteoporotic fracture in older adults (93-95). However, other investigators failed to observe such detrimental effects on BMD and/or fracture risk (96-98). The recent meta-analysis of four prospective studies, including nearly 183,000 participants over 40 years of age, found that highest vs. lowest quintiles of retinol (preformed vitamin A) intake significantly increased the risk of hip fracture (99). Only excess intakes of retinol, not β-carotene, were associated with adverse effects on bone health. Besides, the pooled analysis of four observational studies also indicated that a U-shaped relationship between circulating retinol and risk of hip fracture, suggesting that both elevated and reduced retinol concentrations in the blood were associated with an increased risk of hip fracture (99)

To date, limited experimental data have suggested that vitamin A (as all-trans-retinoic acid) may affect the development of bone-remodeling cells and stimulate bone matrix degradation (resorption) (reviewed in 100). Vitamin A may also interfere with the ability of vitamin D to maintain calcium balance (101). In the large Women’s Health Initiative (WHI) prospective study, the highest vs. lowest quintile of retinol intake (≥1,426 μg/day vs. <474 μg/day) was found to be significantly associated with increased risk of fracture only in women with the lowest vitamin D intakes (≤440 IU/day) (102)

Until supplements and fortified food are reformulated to reflect the current RDA for vitamin A, it is advisable for older individuals to consume multivitamin supplements that contain no more than 2,500 IU (750 μg) of preformed vitamin A (usually labeled vitamin A acetate or vitamin A palmitate) and no more than 2,500 IU of additional vitamin A as β-carotene.

Drug interactions

Chronic alcohol consumption results in depletion of liver stores of vitamin A and may contribute to alcohol-induced liver damage (cirrhosis) (103). However, the liver toxicity of preformed vitamin A (retinol) is enhanced by chronic alcohol consumption, thus narrowing the therapeutic window for vitamin A supplementation in alcoholics (103). Oral contraceptives that contain estrogen and progestin increase retinol binding protein (RBP) synthesis by the liver, increasing the export of all-trans-retinol/RBP complex to the circulation. Whether this increases the dietary requirement of vitamin A is not known. Also, the use of cholesterol-lowering medications (like cholestyramine and colestipol), as well as orlistat, mineral oil, and the fat substitute, olestra, which interfere with fat absorption, may affect the absorption of fat-soluble vitamins, including vitamin A (88). Further, intake of large doses of vitamin A may decrease the absorption of vitamin K. Retinoids or retinoid analogs, including acitretin, all-trans-retinoic acid, bexarotene, etretinate, and isotretinoin, should not be used in combination with single-nutrient vitamin A supplements, because they may increase the risk of vitamin A toxicity (88)

Linus Pauling Institute Recommendation

The RDA for vitamin A (700 μg RAE/day for women and 900 μg RAE/day for men) is sufficient to support normal gene expression, immune function, and vision. However, following the Linus Pauling Institute’s recommendation to take a multivitamin/mineral supplement daily could supply as much as 5,000 IU (1,500 μg RAE)/day of vitamin A as retinol, the amount that has been associated with adverse effects on bone health in older adults. For this reason, we recommend taking a multivitamin/mineral supplement that provides no more than 2,500 IU (750 μg) of preformed vitamin A (usually labeled vitamin A acetate or vitamin A palmitate) and no more than 2,500 IU of additional vitamin A as β-carotene. High potency vitamin A supplements should not be used without medical supervision due to the risk of toxicity.

Older adults (>50 years)

Presently, there is little evidence that the requirement for vitamin A in older adults differs from that of younger adults. Additionally, vitamin A toxicity may occur at lower doses in older adults than in younger adults. Further, data from observational studies suggested an inverse association between intakes of preformed vitamin A in excess of 1,500 μg RAE (5,000 IU)/day and risk of hip fracture in older people (see Safety). Yet, following the Linus Pauling Institute’s recommendation to take a multivitamin/mineral supplement daily could supply as much as 5,000 IU/day of retinol, the amount that has been associated with adverse effects on bone health in older adults. For this reason, we recommend taking a multivitamin/mineral supplement that provides (750 μg) of preformed vitamin A (usually labeled vitamin A acetate or vitamin A palmitate) and no more than 2,500 IU of additional vitamin A as β-carotene. As for all age groups, high potency vitamin A supplements should not be used without medical supervision due to the risk of toxicity.


Authors and Reviewers

Originally written in 2000 by: 
Jane Higdon, Ph.D. 
Linus Pauling Institute 
Oregon State University

Updated in December 2003 by: 
Jane Higdon, Ph.D. 
Linus Pauling Institute 
Oregon State University

Updated in November 2007 by: 
Victoria J. Drake, Ph.D. 
Linus Pauling Institute 
Oregon State University

Updated in January 2015:
Barbara Delage, Ph.D.
Linus Pauling Institute
Oregon State University

Reviewed in February 2015 by:
A. Catharine Ross, Ph.D.
Professor of Nutrition
Dorothy Foehr Huck Chair
Department of Nutritional Sciences
The Pennsylvania State University

Reviewed in March 2015 by:
Libo Tan, Ph.D.
Assistant Professor
Department of Human Nutrition
The University of Alabama

Copyright 2000-2017  Linus Pauling Institute


References

1.  Groff JL. Advanced Nutrition and Human Metabolism. 2nd ed. St. Paul: West Publishing; 1995.

2.  Ross AC. Vitamin A. In: Ross A, Caballero B, Cousins R, Tucker K, Ziegler T, eds. Modern Nutrition in Health and Disease. 11th ed: Lippincott Williams & Wilkins; 2014:260-277.

3.  Tan L, Green MH, Ross AC. Vitamin A Kinetics in Neonatal Rats vs. Adult Rats: Comparisons from Model-Based Compartmental Analysis. J Nutr. 2014;145(3):403-410.  (PubMed)

4.  Tan L, Wray AE, Green MH, Ross AC. Compartmental modeling of whole-body vitamin A kinetics in unsupplemented and vitamin A-retinoic acid-supplemented neonatal rats. J Lipid Res. 2014;55(8):1738-1749.  (PubMed)

5.  Zhong M, Kawaguchi R, Ter-Stepanian M, Kassai M, Sun H. Vitamin A transport and the transmembrane pore in the cell-surface receptor for plasma retinol binding protein. PLoS One. 2013;8(11):e73838.  (PubMed) 

6.  See AW, Clagett-Dame M. The temporal requirement for vitamin A in the developing eye: mechanism of action in optic fissure closure and new roles for the vitamin in regulating cell proliferation and adhesion in the embryonic retina. Dev Biol. 2009;325(1):94-105.  (PubMed)

7.  Theodosiou M, Laudet V, Schubert M. From carrot to clinic: an overview of the retinoic acid signaling pathway. Cell Mol Life Sci. 2010;67(9):1423-1445.  (PubMed)

8.  Lefebvre P, Martin PJ, Flajollet S, Dedieu S, Billaut X, Lefebvre B. Transcriptional activities of retinoic acid receptors. Vitam Horm. 2005;70:199-264.  (PubMed)

9.  Amann PM, Eichmuller SB, Schmidt J, Bazhin AV. Regulation of gene expression by retinoids. Curr Med Chem. 2011;18(9):1405-1412.  (PubMed)

10.  Pendaries V, Verrecchia F, Michel S, Mauviel A. Retinoic acid receptors interfere with the TGF-beta/Smad signaling pathway in a ligand-specific manner. Oncogene. 2003;22(50):8212-8220.  (PubMed)

11.  Masia S, Alvarez S, de Lera AR, Barettino D. Rapid, nongenomic actions of retinoic acid on phosphatidylinositol-3-kinase signaling pathway mediated by the retinoic acid receptor. Mol Endocrinol. 2007;21(10):2391-2402.  (PubMed)

12.  Qiao J, Paul P, Lee S, et al. PI3K/AKT and ERK regulate retinoic acid-induced neuroblastoma cellular differentiation. Biochem Biophys Res Commun. 2012;424(3):421-426.  (PubMed)

13.  Canon E, Cosgaya JM, Scsucova S, Aranda A. Rapid effects of retinoic acid on CREB and ERK phosphorylation in neuronal cells. Mol Biol Cell. 2004;15(12):5583-5592.  (PubMed)

14.  Kirchmeyer M, Koufany M, Sebillaud S, Netter P, Jouzeau JY, Bianchi A. All-trans retinoic acid suppresses interleukin-6 expression in interleukin-1-stimulated synovial fibroblasts by inhibition of ERK1/2 pathway independently of RAR activation. Arthritis Res Ther. 2008;10(6):R141.  (PubMed)

15.  Amengual J, Golczak M, Palczewski K, von Lintig J. Lecithin:retinol acyltransferase is critical for cellular uptake of vitamin A from serum retinol-binding protein. J Biol Chem. 2012;287(29):24216-24227.  (PubMed)

16.  Noy N. Signaling by retinol and its serum binding protein. Prostaglandins Leukot Essent Fatty Acids. 2014;93:3-7.  (PubMed)

17.  Berry DC, Jacobs H, Marwarha G, et al. The STRA6 receptor is essential for retinol-binding protein-induced insulin resistance but not for maintaining vitamin A homeostasis in tissues other than the eye. J Biol Chem. 2013;288(34):24528-24539.  (PubMed)

18.  Marwarha G, Berry DC, Croniger CM, Noy N. The retinol esterifying enzyme LRAT supports cell signaling by retinol-binding protein and its receptor STRA6. FASEB J. 2014;28(1):26-34.  (PubMed)

19.  Farmer SR. Molecular determinants of brown adipocyte formation and function. Genes Dev. 2008;22(10):1269-1275.  (PubMed)

20.  Kiefer FW, Vernochet C, O'Brien P, et al. Retinaldehyde dehydrogenase 1 regulates a thermogenic program in white adipose tissue. Nat Med. 2012;18(6):918-925.  (PubMed)

21.  Nallamshetty S, Le PT, Wang H, et al. Retinaldehyde dehydrogenase 1 deficiency inhibits PPARgamma-mediated bone loss and marrow adiposity. Bone. 2014;67:281-291.  (PubMed)

22.  Kiefer FW, Orasanu G, Nallamshetty S, et al. Retinaldehyde dehydrogenase 1 coordinates hepatic gluconeogenesis and lipid metabolism. Endocrinology. 2012;153(7):3089-3099.  (PubMed)

23.  Green HN, Mellanby E. Vitamin A as an anti-infective agent. Br Med J. 1928;2(3537):691-696.  (PubMed)

24.  Raverdeau M, Mills KH. Modulation of T cell and innate immune responses by retinoic Acid. J Immunol. 2014;192(7):2953-2958.  (PubMed)

25.  Spears K, Cheney C, Zerzan J. Low plasma retinol concentrations increase the risk of developing bronchopulmonary dysplasia and long-term respiratory disability in very-low-birth-weight infants. Am J Clin Nutr. 2004;80(6):1589-1594.  (PubMed)

26.  Barber T, Esteban-Pretel G, Marin MP, Timoneda J. Vitamin A Deficiency and Alterations in the Extracellular Matrix. Nutrients. 2014;6(11):4984-5017.  (PubMed)

27.  Semba RD, Bloem MW. The anemia of vitamin A deficiency: epidemiology and pathogenesis. Eur J Clin Nutr. 2002;56(4):271-281.  (PubMed)

28.  Allen LH. Iron supplements: scientific issues concerning efficacy and implications for research and programs. J Nutr. 2002;132(4 Suppl):813S-819S.  (PubMed)

29.  Christian P, West KP, Jr. Interactions between zinc and vitamin A: an update. Am J Clin Nutr. 1998;68(2 Suppl):435S-441S.  (PubMed)

30.  Auld DS, Bergman T. Medium- and short-chain dehydrogenase/reductase gene and protein families : The role of zinc for alcohol dehydrogenase structure and function. Cell Mol Life Sci. 2008;65(24):3961-3970.  (PubMed)

31.  Suharno D, West CE, Muhilal, Karyadi D, Hautvast JG. Supplementation with vitamin A and iron for nutritional anaemia in pregnant women in West Java, Indonesia. Lancet. 1993;342(8883):1325-1328.  (PubMed)

32.  Jang JT, Green JB, Beard JL, Green MH. Kinetic analysis shows that iron deficiency decreases liver vitamin A mobilization in rats. J Nutr. 2000;130(5):1291-1296.  (PubMed)  

33.  Rosales FJ, Jang JT, Pinero DJ, Erikson KM, Beard JL, Ross AC. Iron deficiency in young rats alters the distribution of vitamin A between plasma and liver and between hepatic retinol and retinyl esters. J Nutr. 1999;129(6):1223-1228.  (PubMed)

34.  Tanumihardjo SA. Vitamin A: biomarkers of nutrition for development. Am J Clin Nutr. 2011;94(2):658S-665S.  (PubMed)

35.  Underwood BA, Arthur P. The contribution of vitamin A to public health. Faseb J. 1996;10(9):1040-1048.  (PubMed)

36.  Solomons NW. Vitamin A. In: Erdman JJ, Macdonald I, Zeisel S, eds. Present Knowledge in Nutrition. 10th ed: John Wiley & Sons, Ltd.; 2012:149-184. 

37.  Sherwin JC, Reacher MH, Dean WH, Ngondi J. Epidemiology of vitamin A deficiency and xerophthalmia in at-risk populations. Trans R Soc Trop Med Hyg. 2012;106(4):205-214.  (PubMed)

38.  World Health Organization. Guideline - Vitamin A supplementation for infants and children 6-59 months of age - Guideline. Geneva 2011.

39.  World Health Organization. Guideline - Neonatal vitamin A supplementation Geneva 2011.

40.  World Health Organization. Guideline - Vitamin A supplementation for infants 1–5 months of age - Guideline. Geneva 2011.

41.  Gilbert C, Awan H. Blindness in children. BMJ. 2003;327(7418):760-761.  (PubMed)

42.  Semba RD. Vitamin A and human immunodeficiency virus infection. Proc Nutr Soc. 1997;56(1B):459-469.  (PubMed)

43.  Field CJ, Johnson IR, Schley PD. Nutrients and their role in host resistance to infection. J Leukoc Biol. 2002;71(1):16-32.  (PubMed)

44.  WHO, UNICEF, IVACG Task Force. Vitamin A supplements: a guide to their use in the treatment and prevention of vitamin A deficiency and xerophthalmia. Geneva: World Health Organization; 1997.

45.  Thornton KA, Mora-Plazas M, Marin C, Villamor E. Vitamin A deficiency is associated with gastrointestinal and respiratory morbidity in school-age children. J Nutr. 2014;144(4):496-503.  (PubMed)

46.  Wiysonge CS, Shey M, Kongnyuy EJ, Sterne JA, Brocklehurst P. Vitamin A supplementation for reducing the risk of mother-to-child transmission of HIV infection. Cochrane Database Syst Rev. 2011(1):CD003648.  (PubMed)

47.  Semba RD, Miotti PG, Chiphangwi JD, et al. Maternal vitamin A deficiency and mother-to-child transmission of HIV-1. Lancet. 1994;343(8913):1593-1597.  (PubMed)

48.  World Health Organization. Guideline - Vitamin A supplementation in pregnancy for reducing the risk of mother-to-child transmission of HIV. Geneva 2011.

49.  Zimmermann MB, Adou P, Torresani T, Zeder C, Hurrell RF. Effect of oral iodized oil on thyroid size and thyroid hormone metabolism in children with concurrent selenium and iodine deficiency. Eur J Clin Nutr. 2000;54(3):209-213.  (PubMed)

50.  Zimmermann MB, Wegmuller R, Zeder C, Chaouki N, Torresani T. The effects of vitamin A deficiency and vitamin A supplementation on thyroid function in goitrous children. J Clin Endocrinol Metab. 2004;89(11):5441-5447.  (PubMed)

51.  Zimmermann MB. Interactions of vitamin A and iodine deficiencies: effects on the pituitary-thyroid axis. Int J Vitam Nutr Res. 2007;77(3):236-240.  (PubMed)

52.  Zimmermann MB, Jooste PL, Mabapa NS, et al. Vitamin A supplementation in iodine-deficient African children decreases thyrotropin stimulation of the thyroid and reduces the goiter rate. Am J Clin Nutr. 2007;86(4):1040-1044.  (PubMed)

53.  Maronn M, Allen DM, Esterly NB. Phrynoderma: a manifestation of vitamin A deficiency?... The rest of the story. Pediatr Dermatol. 2005;22(1):60-63.  (PubMed)

54.  Herring W, Nowicki MJ, Jones JK. An uncommon cause of esophagitis. Answer to the clinical challenges and images in GI question: image 1: esophageal hyperkeratosis secondary to vitamin A deficiency. Gastroenterology. 2010;139(2):e6-7.  (PubMed)

55.  Weber D, Grune T. The contribution of beta-carotene to vitamin A supply of humans. Mol Nutr Food Res. 2012;56(2):251-258.  (PubMed)

56.  Food and Nutrition Board, Institute of Medicine. Vitamin A. Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. Washington, D.C.: National Academy Press; 2001:65-126.  (National Academy Press)

57.  Ravishankar C, Nafday S, Green RS, et al. A trial of vitamin A therapy to facilitate ductal closure in premature infants. J Pediatr. 2003;143(5):644-648.  (PubMed)

58.  Tyson JE, Wright LL, Oh W, et al. Vitamin A supplementation for extremely-low-birth-weight infants. National Institute of Child Health and Human Development Neonatal Research Network. N Engl J Med. 1999;340(25):1962-1968.  (PubMed)

59.  Wardle SP, Hughes A, Chen S, Shaw NJ. Randomised controlled trial of oral vitamin A supplementation in preterm infants to prevent chronic lung disease. Arch Dis Child Fetal Neonatal Ed. 2001;84(1):F9-F13.  (PubMed)

60.  Ambalavanan N, Kennedy K, Tyson J, Carlo WA. Survey of vitamin A supplementation for extremely-low-birth-weight infants: is clinical practice consistent with the evidence? J Pediatr. 2004;145(3):304-307.  (PubMed)

61.  Laughon MM. Vitamin A shortage and risk of bronchopulmonary dysplasia. JAMA Pediatr. 2014;168(11):995-996.  (PubMed)

62.  Tolia VN, Murthy K, McKinley PS, Bennett MM, Clark RH. The effect of the national shortage of vitamin A on death or chronic lung disease in extremely low-birth-weight infants. JAMA Pediatr. 2014;168(11):1039-1044.  (PubMed)

63.  Gadhia MM, Cutter GR, Abman SH, Kinsella JP. Effects of early inhaled nitric oxide therapy and vitamin A supplementation on the risk for bronchopulmonary dysplasia in premature newborns with respiratory failure. J Pediatr. 2014;164(4):744-748.  (PubMed)

64.  Meyer S, Gortner L, NeoVita ATI. Early postnatal additional high-dose oral vitamin A supplementation versus placebo for 28 days for preventing bronchopulmonary dysplasia or death in extremely low birth weight infants. Neonatology. 2014;105(3):182-188.  (PubMed)

65.  Babu TA, Sharmila V. Vitamin A supplementation in late pregnancy can decrease the incidence of bronchopulmonary dysplasia in newborns. J Matern Fetal Neonatal Med. 2010;23(12):1468-1469.  (PubMed)

66.  Thorne-Lyman AL, Fawzi WW. Vitamin A and carotenoids during pregnancy and maternal, neonatal and infant health outcomes: a systematic review and meta-analysis. Paediatr Perinat Epidemiol. 2012;26 Suppl 1:36-54.  (PubMed)

67.  Imdad A, Yakoob MY, Sudfeld C, Haider BA, Black RE, Bhutta ZA. Impact of vitamin A supplementation on infant and childhood mortality. BMC Public Health. 2011;11 Suppl 3:S20.  (PubMed)

68.  Gogia S, Sachdev HS. Vitamin A supplementation for the prevention of morbidity and mortality in infants six months of age or less. Cochrane Database Syst Rev. 2011(10):CD007480.  (PubMed)

69.  Fisker AB, Bale C, Rodrigues A, et al. High-dose vitamin A with vaccination after 6 months of age: a randomized trial. Pediatrics. 2014;134(3):e739-748.  (PubMed)

70.  Aaby P, Martins CL, Garly ML, et al. Non-specific effects of standard measles vaccine at 4.5 and 9 months of age on childhood mortality: randomised controlled trial. BMJ. 2010;341:c6495.  (PubMed)

71.  Benn CS, Martins CL, Fisker AB, et al. Interaction between neonatal vitamin A supplementation and timing of measles vaccination: a retrospective analysis of three randomized trials from Guinea-Bissau. Vaccine. 2014;32(42):5468-5474.  (PubMed)

72.  Huiming Y, Chaomin W, Meng M. Vitamin A for treating measles in children. Cochrane Database Syst Rev. 2005(4):CD001479.  (PubMed)

73.  American Academy of Pediatrics Committee on Infectious Diseases: Vitamin A treatment of measles. Pediatrics. 1993;91(5):1014-1015.  (PubMed)

74.  Bello S, Meremikwu MM, Ejemot-Nwadiaro RI, Oduwole O. Routine vitamin A supplementation for the prevention of blindness due to measles infection in children. Cochrane Database Syst Rev. 2014;1:CD007719.  (PubMed)

75.  Omenn GS, Goodman GE, Thornquist MD, et al. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med. 1996;334(18):1150-1155.  (PubMed)

76.  Goodman GE, Thornquist MD, Balmes J, et al. The Beta-Carotene and Retinol Efficacy Trial: incidence of lung cancer and cardiovascular disease mortality during 6-year follow-up after stopping beta-carotene and retinol supplements. J Natl Cancer Inst. 2004;96(23):1743-1750.  (PubMed)

77.  Palozza P, Simone R, Mele MC. Interplay of carotenoids with cigarette smoking: implications in lung cancer. Curr Med Chem. 2008;15(9):844-854.  (PubMed)

78.  Cheng TY, Goodman GE, Thornquist MD, et al. Estimated intake of vitamin D and its interaction with vitamin A on lung cancer risk among smokers. Int J Cancer. 2014;135(9):2135-2145.  (PubMed)

79.  Cortes-Jofre M, Rueda JR, Corsini-Munoz G, Fonseca-Cortes C, Caraballoso M, Bonfill Cosp X. Drugs for preventing lung cancer in healthy people. Cochrane Database Syst Rev. 2012;10:CD002141.  (PubMed)

80.  Lo-Coco F, Avvisati G, Vignetti M, et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med. 2013;369(2):111-121.  (PubMed)

81.  Booij MT, Van De Kerkhof PC. Acitretin revisited in the era of biologics. J Dermatolog Treat. 2011;22(2):86-89.  (PubMed)

82.  Orfanos CE, Zouboulis CC. Oral retinoids in the treatment of seborrhoea and acne. Dermatology. 1998;196(1):140-147.  (PubMed)

83.  Thielitz A, Gollnick H. Topical retinoids in acne vulgaris: update on efficacy and safety. Am J Clin Dermatol. 2008;9(6):369-381.  (PubMed)

84.  Vishwanathan R, Johnson EJ. Eye disease. In: Erdman JJ, Macdonald I, Zeisel S, eds. Present Knowledge in Nutrition. 10th ed: John Wiley & Sons, Ltd; 2012:939-981.

85.  Hartong DT, Berson EL, Dryja TP. Retinitis pigmentosa. Lancet. 2006;368(9549):1795-1809.  (PubMed)

86.  Berson EL, Rosner B, Sandberg MA, et al. A randomized trial of vitamin A and vitamin E supplementation for retinitis pigmentosa. Arch Ophthalmol. 1993;111(6):761-772.  (PubMed)

87.  Sibulesky L, Hayes KC, Pronczuk A, Weigel-DiFranco C, Rosner B, Berson EL. Safety of <7500 RE (<25000 IU) vitamin A daily in adults with retinitis pigmentosa. Am J Clin Nutr. 1999;69(4):656-663.  (PubMed)

88.  Hendler SS, Rorvik DR, eds. PDR for Nutritional Supplements. 2nd edition ed: Thomson Reuters; 2008.

89.  Penniston KL, Tanumihardjo SA. The acute and chronic toxic effects of vitamin A. Am J Clin Nutr. 2006;83(2):191-201.  (PubMed)

90.  Russell RM. The vitamin A spectrum: from deficiency to toxicity. Am J Clin Nutr. 2000;71(4):878-884.  (PubMed)

91.  World Health Organization. Guideline - Vitamin A supplementation in pregnant women. Geneva 2011.

92.  Bozzo P, Chua-Gocheco A, Einarson A. Safety of skin care products during pregnancy. Can Fam Physician. 2011;57(6):665-667.  (PubMed)

93.  Michaelsson K, Lithell H, Vessby B, Melhus H. Serum retinol levels and the risk of fracture. N Engl J Med. 2003;348(4):287-294.  (PubMed)

94.  Promislow JH, Goodman-Gruen D, Slymen DJ, Barrett-Connor E. Retinol intake and bone mineral density in the elderly: the Rancho Bernardo Study. J Bone Miner Res. 2002;17(8):1349-1358.  (PubMed)

95.  Feskanich D, Singh V, Willett WC, Colditz GA. Vitamin A intake and hip fractures among postmenopausal women. JAMA. 2002;287(1):47-54.  (PubMed)

96.  Rejnmark L, Vestergaard P, Charles P, et al. No effect of vitamin A intake on bone mineral density and fracture risk in perimenopausal women. Osteoporos Int. 2004;15(11):872-880.  (PubMed)

97.  Sowers MF, Wallace RB. Retinol, supplemental vitamin A and bone status. J Clin Epidemiol. 1990;43(7):693-699.  (PubMed)

98.  Ballew C, Galuska D, Gillespie C. High serum retinyl esters are not associated with reduced bone mineral density in the Third National Health And Nutrition Examination Survey, 1988-1994. J Bone Miner Res. 2001;16(12):2306-2312.  (PubMed)

99.  Wu AM, Huang CQ, Lin ZK, et al. The relationship between vitamin A and risk of fracture: meta-analysis of prospective studies. J Bone Miner Res. 2014;29(9):2032-2039.  (PubMed)

100.  Conaway HH, Henning P, Lerner UH. Vitamin a metabolism, action, and role in skeletal homeostasis. Endocr Rev. 2013;34(6):766-797.  (PubMed)

101.  Johansson S, Melhus H. Vitamin A antagonizes calcium response to vitamin D in man. J Bone Miner Res. 2001;16(10):1899-1905.  (PubMed)

102.  Caire-Juvera G, Ritenbaugh C, Wactawski-Wende J, Snetselaar LG, Chen Z. Vitamin A and retinol intakes and the risk of fractures among participants of the Women's Health Initiative Observational Study. Am J Clin Nutr. 2009;89(1):323-330.  (PubMed)

103.  Lieber CS. Relationships between nutrition, alcohol use, and liver disease. Alcohol Res Health. 2003;27(3):220-231.  (PubMed)

Vitamin B6

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Summary

  • Vitamin B6 and its derivative pyridoxal 5'-phosphate (PLP) are essential to over 100 enzymes mostly involved in protein metabolism. (More information)
  • High levels of circulating homocysteine are associated with an increased risk of cardiovascular disease. Randomized controlled trials have demonstrated that supplementation with B vitamins, including vitamin B6, could effectively reduce homocysteine levels. However, homocysteine lowering by B vitamins has failed to lower the risk of adverse cardiovascular outcomes in high-risk individuals. (More information)
  • Growing evidence from experimental and clinical studies suggests that systemic inflammation underlying most chronic diseases may impair vitamin B6 metabolism. (More information)
  • Although supplementation with vitamin B6 and other B vitamins has not been associated with improved cognitive performance or delayed cognitive deterioration in the elderly, recent studies suggest that vitamin B6 might help reduce the risk of late-life depression. (More information)
  • Pharmacologic doses of vitamin B6 are used to treat seizures in rare inborn errors of vitamin B6 metabolism. Also, randomized controlled trials support the use of vitamin B6 to treat morning sickness in pregnant women and suggest a possible benefit in the management of premenstrual syndrome and carpal tunnel syndrome. (More information)
  • Vitamin B6 is found in a variety of foods, including fish, poultry, nuts, legumes, potatoes, and bananas. (More information)
  • Several medications, including anti-tuberculosis drugs, anti-parkinsonians, nonsteroidal anti-inflammatory drugs, and oral contraceptives, may interfere with vitamin B6 metabolism. (More information)

Vitamin B6 is a water-soluble vitamin that was first isolated in the 1930s. The term vitamin B6 refers to six common forms, namely pyridoxal, pyridoxine (pyridoxol), pyridoxamine, and their phosphorylated forms. The phosphate ester derivative pyridoxal 5'-phosphate (PLP) is the bioactive coenzyme form involved in over 4% of all enzymatic reactions (Figure 1) (1-3).

Figure 1. Chemical Structures of pyridoxine, pyridoxal, pyridoxamine, and pyridoxal 5'-phosphate (PLP). Non-phosphorylated forms of vitamin B6 include pyridoxine, pyridoxal, and pyridoxamine. While all three of these variants can be phosphorylated, the phosphate ester derivative of pyridoxal, pyridoxal 5'-phosphate (PLP), is the cofactor of most vitamin B6-dependent enzymes in the body.

Function

Vitamin B6 must be obtained from the diet because humans cannot synthesize it. PLP plays a vital role in the function of over 100 enzymes that catalyze essential chemical reactions in the human body (4). PLP-dependent enzymes have been classified into five structural classes known as Fold Type I-V (5):

  • Fold Type I - aspartate aminotransferase family
  • Fold Type II - tryptophan synthase family
  • Fold Type III - alanine racemase family
  • Fold Type IV - D-amino acid aminotransferase family
  • Fold Type V - glycogen phosphorylase family

The many biochemical reactions catalyzed by PLP-dependent enzymes are involved in essential biological processes, such as hemoglobin and amino acid biosynthesis, as well as fatty acid metabolism. Of note, PLP also 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 that generate glucose from amino acids, a process known as gluconeogenesis (6).

Nervous system function

In the brain, the PLP-dependent enzyme aromatic L-amino acid decarboxylase catalyzes the synthesis of two major neurotransmitters: serotonin from the amino acid tryptophan and dopamine from L-3,4-dihydroxyphenylalanine (L-Dopa). Other neurotransmitters, including glycine, D-serine, glutamate, histamine, and γ-aminobutyric acid (GABA), are also synthesized in reactions catalyzed by PLP-dependent enzymes (7).

Hemoglobin synthesis and function

PLP functions as a coenzyme of 5-aminolevulinic acid synthase, which is involved 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 pyridoxal 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 (6, 8). Vitamin B6 deficiency may impair hemoglobin synthesis and lead to microcytic anemia (3).

Tryptophan metabolism

Deficiency in another B vitamin, niacin, is easily prevented by adequate dietary intakes. The dietary requirement for niacin and the niacin coenzyme, nicotinamide adenine dinucleotide (NAD), can be also met, though to a fairly limited extent, by the catabolism of the essential amino acid tryptophan in the tryptophan-kynurenine pathway (Figure 2). Key reactions in this pathway are PLP-dependent; in particular, PLP is the cofactor for the enzyme kynureninase, which catalyzes the conversion of 3-hydroxykynurenine to 3-hydroxyanthranilic acid. A reduction in PLP availability appears to primarily affect kynureninase activity, limiting NAD production and leading to higher concentrations of kynurenine, 3-hydroxykynurenine, and xanthurenic acid in blood and urine (Figure 2) (9). Thus, while dietary vitamin B6 restriction impairs NAD synthesis from tryptophan, adequate PLP levels help maintain NAD formation from tryptophan (10). The effect of vitamin B6 inadequacy on immune activation and inflammation may be partly related to the role of PLP in the tryptophan-kynurenine metabolism (see Disease Prevention).

Figure 2. Overview of the Tryptophan-Kynurenine Metabolic Pathway. Pyridoxal 5'-phosphate, a vitamin B6 coenzyme, is required for the activity of several key enzymes in tryptophan catabolic pathway: KAT (kynurenine aminotransferase), KMO (kynurenine 3-monooxygenase), and kynureninase. As explained in the article text, tryptophan is metabolized to kynurenine, which is further metabolized with the vitamin B6-dependent enzymes, KAT or KMO. Through metabolism with KMO, 3-hydroxykynurenine is created, which can ultimately generate NAD. Dietary restriction of vitamin B6 most prominently affects kynureninase activity and results in the shift from 3-hydroxykynurenine metabolism and NAD formation to the production of kynurenic acid and xanthurenic acid.

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 target cells. The nuclear receptors themselves bind to specific regulatory sequences in DNA and alter the transcription of target genes. Experimental studies have uncovered a mechanism by which PLP may affect the activity of steroid receptors and decrease their effects on gene expression. It was found that PLP could interact with RIP140/NRIP1, a repressor of nuclear receptors known for its role in reproductive biology (11). Yet, additional research is needed to confirm that this interaction can enhance RIP140/NRIP1 repressive activity on steroid receptor-mediated gene expression. If the activity of steroid receptors for estrogen, progesterone, testosterone, or other steroid hormones can be inhibited by PLP, it is possible that vitamin B6 status may influence one's risk of developing diseases driven by steroid hormones, such as breast and prostate cancers (6).

Nucleic acid synthesis

The synthesis of nucleic acids from precursors thymidine and purines is dependent on folate coenzymes. The de novo thymidylate (dTMP) biosynthesis pathway involves three enzymes: dihydrofolate reductase (DHFR), serine hydroxymethyltransferase (SHMT), and thymidylate synthase (TYMS) (Figure 3). PLP serves as a coenzyme for SHMT, which catalyzes the simultaneous conversions of serine to glycine and tetrahydrofolate (THF) to 5,10-methylene THF. The latter molecule is the one-carbon donor for the generation of dTMP from dUMP by TYMS.

Figure 3. De Novo Thymidylate Biosynthesis. Folate coenzymes are essential intermediates in the synthesis of nucleic acid precursors thymidine and purines. Thymidylate biosynthesis pathway involves three enzymes: dihydrofolate reductase, serine hydroxymethyltransferase, and thymidylate synthase. Pyridoxal 5'-phosphate (PLP), a vitamin B6 coenzyme, is required by serine hydroxymethyltransferase, which uses serine as a one-carbon donor for the generation of 5,10-methylenetetrahydrofolate (5,10-methylene THF) from THF. 5,10-methylene THF is then used in both methionine transmethylation cycle (not shown in the figure) and thymidylate biosynthesis.

Deficiency

Severe deficiency of vitamin B6 is uncommon. Alcoholics are thought to be most at risk of vitamin B6 deficiency due to low dietary intakes and impaired metabolism of the vitamin. In the early 1950s, seizures were observed in infants as a result of severe vitamin B6 deficiency caused by an error in the manufacture of infant formula (7). Abnormal electroencephalogram (EEG) patterns have also been reported in vitamin B6-deficient adults. Other neurologic symptoms observed in severe vitamin B6 deficiency include irritability, depression, and confusion; additional symptoms include inflammation of the tongue, sores or ulcers of the mouth, and ulcers of the skin at the corners of the mouth (12).

The Recommended Dietary Allowance (RDA)

Since vitamin B6 is involved in many aspects of metabolism, especially in amino acid metabolic pathways, an individual's protein intake is likely to influence the requirement for vitamin B6 (13). Unlike previous recommendations issued by the Food and Nutrition Board (FNB) of the Institute of Medicine, the most recent RDA for vitamin B6 was not expressed in terms of protein intake, although the relationship was considered in setting the RDA (14). The current RDA was revised by the FNB in 1998 and is presented in Table 1.

Table 1. Recommended Dietary Allowance (RDA) for Vitamin B6
Life Stage Age Males (mg/day) Females (mg/day)
Infants  0-6 months 0.1 (AI) 0.1 (AI)
Infants  7-12 months   0.3 (AI)  0.3 (AI)
Children  1-3 years  0.5  0.5 
Children 4-8 years  0.6  0.6 
Children  9-13 years  1.0  1.0 
Adolescents  14-18 years  1.3  1.2 
Adults  19-50 years  1.3  1.3 
Adults  51 years and older  1.7  1.5 
Pregnancy  all ages  1.9 
Breast-feeding  all ages  2.0

Disease Prevention

Immune dysfunction

Several enzymatic reactions in the tryptophan-kynurenine pathway are dependent on vitamin B6 coenzyme, pyridoxal 5'-phosphate (PLP) (see Figure 2 above) (see Tryptophan metabolism). This pathway is known to be activated during pro-inflammatory immune responses and plays a critical role in immune tolerance of the fetus during pregnancy (15). Key intermediates in the tryptophan-kynurenine pathway are involved in the regulation of immune responses. Several tryptophan derivatives have been found to induce the death (apoptosis) or block the proliferation of certain types of immune cells, such as lymphocytes (in particular T-helper 1). They can also inhibit the production of pro-inflammatory cytokines (reviewed in 15). There is evidence to suggest that adequate vitamin B6 intake is important for optimal immune system function, especially in older individuals (16, 17). Yet, chronic inflammation that triggers tryptophan degradation and underlies many diseases (e.g., cardiovascular disease and cancers) may precipitate the loss of PLP and increase vitamin B6 requirements. Additional research is needed to evaluate whether vitamin B6 intakes higher than the current RDA could prevent and/or reverse immune system impairments (see also Vitamin B6 and inflammation).

Cardiovascular disease

The use of multivitamin supplements (including vitamin B6) has been associated with a 24% lower risk of incidental coronary artery disease (CAD) in a large prospective study of 80,082 women from the US Nurses' Health Study cohort (18). Using food frequency questionnaires, the authors observed that women in the highest quintile of vitamin B6 intakes from both food and supplements (median, 4.6 mg/day) had a 34% lower risk of CAD compared to those in the lowest quintile (median, 1.1 mg/day). CAD is characterized by the abnormal stenosis (narrowing) of coronary arteries (generally due to atherosclerosis), which can result in a potentially fatal myocardial infarction (heart attack). More recently, a prospective study that followed a Japanese cohort of over 40,000 middle-aged individuals for 11.5 years reported a 48% lower risk of myocardial infarction in those in the highest (mean, 1.6 mg/day) versus lowest quintile (mean, 1.3 mg/day) of vitamin B6 intakes in non-supplement users (19).

Early observational studies have also demonstrated an association between suboptimal pyridoxal 5'-phosphate (PLP) plasma level, elevated homocysteine blood level, and increased risk of cardiovascular disease (20-22). More recent research has confirmed that low plasma PLP status is a risk factor for CAD. In a case-control study, which included 184 participants with CAD and 516 healthy controls, low plasma PLP levels (<30 nanomoles/liter) were associated with a near doubling of CAD risk when compared to higher PLP levels (≥30 nanomoles/liter) (23). In a nested case-control study based on the Nurses' Health Study cohort and including 144 cases of myocardial infarction (of which 21 were fatal), women in the highest quartile of blood PLP levels (≥70 nanomoles/liter) had a 79% lower risk of myocardial infarction compared to those in the lowest quartile (<27.9 nanomoles/liter) (24).

Vitamin B6 and homocysteine

Even moderately elevated levels of homocysteine in the blood have been associated with increased risk for cardiovascular disease (CVD), including cardiac insufficiency (heart failure), CAD, myocardial infarction, and cerebrovascular attack (stroke) (25). During protein digestion, amino acids, including methionine, are released. Methionine is an essential amino acid and precursor of S-adenosylmethionine (SAM), the universal methyl donor for most methylation reactions, including the methylation of DNA, RNA, proteins, and phospholipids (Figure 4). Homocysteine is an intermediate in the metabolism of methionine. Healthy individuals utilize two different pathways to regenerate methionine from homocysteine in the methionine remethylation cycle (Figure 5). One pathway relies on the vitamin B12-dependent methionine synthase and the methyl donor, 5-methyl tetrahydrofolate (a folate derivative), to convert homocysteine back to methionine. The other reaction is catalyzed by betaine homocysteine methyltransferase, which uses betaine as a source of methyl groups for the formation of methionine from homocysteine. Moreover, two PLP-dependent enzymes are required to convert homocysteine to the amino acid cysteine in homocysteine transsulfuration pathway: cystathionine β synthase and cystathionine γ lyase (Figure 5). Thus, the amount of homocysteine in the blood may be influenced by nutritional status of at least three B vitamins, namely folate, vitamin B12, and vitamin B6.

Figure 4. Overview of One-Carbon Metabolism. Methionine is an essential amino acid and precursor of S-adenosylmethionine (SAM), the universal methyl donor for most methylation reactions, including the methylation of DNA, RNA, proteins, and phospholipids. SAM is converted to S-adenosylhomocysteine (SAH) and then to homocysteine, which can be metabolized to cysteine via the vitamin-B6 dependent transsulfuration pathyway. Homocysteine can be converted to methionine with an enzyme that requires 5-methyl-tetrahydrfolate and vitamin B12.

Vitamin B Figure 5. Homocysteine Metabolism. Homocysteine is methylated to form the essential amino acid methionine in two pathways. The reaction of homocysteine remethylation catalyzed by the vitamin B12-dependent methionine synthase captures a methyl group from the folate-dependent one-carbon pool (5-methyl tetrahydrofolate). A second pathway requires betaine (N,N,N-trimethylglycine) as a methyl donor for the methylation of homocysteine catalyzed by betaine homocysteine methyltransferase. The catabolic pathway of homocysteine, known as transsulfuration pathway, converts homocysteine to the amino acid cysteine via two vitamin B6 (PLP)-dependent enzymes: cystathionine beta synthase catalyzes the condensation of homocysteine with serine to form cystathionine, and cystathionine is then converted to cysteine, alpha-ketobutyrate, and ammonia by cystathionine gamma lyase.

Deficiencies in one or all of these B vitamins may affect both remethylation and transsulfuration processes and result in abnormally elevated homocysteine levels. An early study found that vitamin B6 supplementation could lower blood homocysteine levels after an oral dose of methionine was given (i.e., a methionine load test) (26), but vitamin B6 supplementation might not be effective in decreasing fasting levels of homocysteine. In a recent study conducted in nine healthy young volunteers, the rise of homocysteine during the postprandial period (after a meal) was found to be greater with marginal vitamin B6 deficiency (mean plasma PLP level of 19 nanomoles/liter) as compared to vitamin B6 sufficiency (mean PLP level of 49 nanomoles/liter) (27). The authors reported an increased rate of cystathionine synthesis with vitamin B6 restriction, suggesting that homocysteine catabolism in the transsulfuration may be maintained or enhanced in response to a marginal reduction in PLP availability. Yet, the flux ratio between methionine cycle and transsulfuration pathway appeared to favor homocysteine clearance by remethylation rather than transsulfuration in six out of nine participants (27).

Numerous randomized controlled trials, many in subjects with existing hyperhomocysteinemia and vascular dysfunction, have demonstrated that supplementation with folic acid, alone or combined with vitamin B6 and vitamin B12, could effectively reduce fasting plasma homocysteine concentrations. In 19 intervention studies recently included in a meta-analysis, reductions in homocysteine level in the blood following B-vitamin supplementation ranged between 7.6% and 51.7% compared to baseline levels (28). In contrast, studies supplementing individuals with only vitamin B6 have usually failed to show an effect on fasting levels of homocysteine (29, 30). Of the three supplemental B vitamins, folic acid appears to be the main determinant in the regulation of fasting homocysteine levels when there is no coexisting deficiency of vitamin B12 or vitamin B6 (31). Yet, the effect of homocysteine lowering on CVD risk reduction is debated. A recent meta-analysis of nine randomized controlled trials reported a 10% reduction in stroke events with supplemental B vitamins, with greater benefits for high-risk subjects (e.g., those with kidney disease) (32). However, most systematic reviews and meta-analyses of B-vitamin intervention studies to date have indicated a lack of causality between the decrease of fasting homocysteine levels and the prevention of cardiovascular events (28, 33-35). Moreover, B-vitamin supplementation trials in high-risk subjects have not resulted in significant changes in carotid intima-media thickness (CIMT) and flow-mediated dilation (FMD) of the brachial artery, two markers of vascular health used to assess atherosclerotic progression (36). Finally, in the Western Norway B Vitamin Intervention Trial (WENBIT), a randomized, double-blind, placebo-controlled trial in 87 subjects with suspected CAD, vitamin B6 supplementation (40 mg/day of pyridoxine) for a median of 10 months had no effect on coronary stenosis progression, assessed by quantitative angiography (37).

It has been suggested that antiplatelet therapy used in the primary prevention of CVD might interfere with the effect of homocysteine lowering by B vitamins on CVD risk (38). In this context, a post-hoc subgroup analysis of the multicenter, randomized, double blind, placebo-controlled VITATOPS trial (39) proposed that the small benefit of homocysteine-lowering by B vitamins might be cancelled in patients treated with antiplatelet drugs (40). Yet, the benefit of B-vitamin supplementation in primary prevention (i.e., in non-antiplatelet users) remains to be established.

Vitamin B6 and inflammation

A growing body of evidence currently suggests that low vitamin B6 status may increase the risk of cardiovascular disease through mechanisms independent of homocysteine lowering (41-43). Markers of immune activation and inflammation have been associated with hyperhomocysteinemia (homocysteine levels >15 micromoles/liter) in individuals with coronary artery disease (CAD) (44). In fact, inflammation is involved in the early steps of atherosclerosis in which lipids deposit in plaques (known as atheromas) within arterial walls and increase the risk of CAD (45). In a case-control study that included 267 patients with CAD and 475 healthy controls, plasma PLP concentrations were inversely correlated with the levels of two markers of systemic inflammation, C-reactive protein (CRP) and fibrinogen (46). Yet, the study suggested that suboptimal PLP levels (<36.3 nanomoles/liter) might contribute to an increased risk of CAD independently of inflammation since the risk was unchanged after adjustment for inflammation markers (unadjusted odds ratio (OR): 1.71 vs. multivariate adjusted OR: 1.73). Furthermore, the analysis of inflammation markers in 2,686 participants of the US National Health and Nutrition Examination Survey (NHANES) 2003-2004 indicated that serum CRP concentrations were inversely related to total vitamin B6 intakes (from both food and supplements). Specifically, the risk of having serum CRP levels greater than 10 mg/L (corresponding to high inflammatory activity) was 57% higher in individuals with vitamin B6 intakes lower than 2 mg/day compared to those with intakes equal to and above 5 mg/day (41). In addition, the prevalence of inadequate vitamin B6 status (plasma PLP levels <20 nanomoles/liter) with intakes lower than 5 mg/day was systematically greater in individuals with high versus low serum CRP concentrations (>10 mg/L vs. ≤3 mg/L), suggesting that inflammation might impair vitamin B6 metabolism. These observations were confirmed in the study of another cohort (Framingham Offspring Study) in which vitamin B6 status was linked to an overall inflammatory score based on the levels of 13 inflammation markers (including CRP, fibrinogen, tumor necrosis factor-α, and interleukin-6) (42). Specifically, plasma PLP levels were 24% lower in individuals in the highest versus lowest tertile of inflammatory score. Moreover, the inverse correlation between PLP levels and inflammatory scores remained significant regardless of vitamin B6 intakes, questioning again the nature of this relationship. Interestingly, a recent analysis of data collected in the WENBIT study demonstrated that systemic inflammation was associated with an increased degradation of pyridoxal (PL) to 4-pyridoxic acid (PA), supporting the use of the ratio PA:(PL+PLP) as a marker of both vitamin B6 status and systemic inflammation (47). Finally, while inflammation may contribute to lower vitamin B6 status, current evidence fails to support a role for vitamin B6 in the control of inflammation in patients with cardiovascular disease (48, 49).

Cognitive decline and Alzheimer's disease

A few observational studies have linked cognitive decline and Alzheimer's disease (AD) in the elderly with inadequate status of folate, vitamin B12, and vitamin B6 (50). Yet, the relationship between B vitamins and cognitive health in aging is complicated by both the high prevalence of hyperhomocysteinemia and signs of systemic inflammation in elderly people (51). On the one hand, since inflammation may impair vitamin B6 metabolism, low serum PLP levels may well be caused by processes related to aging rather than by malnutrition. On the other hand, high serum homocysteine may possibly be a risk factor for cognitive decline in the elderly, although the matter remains under debate. Specifically, the meta-analysis of 19 randomized, placebo-controlled trials of B-vitamin supplementation failed to report any difference in several measures of cognitive function between treatment and placebo groups, despite the treatment effectively lowering homocysteine levels (52). In a recent randomized, double-blind, placebo-controlled study of 2,695 stroke survivors with or without cognitive impairments, daily supplementation with 2 mg of folic acid, 0.5 mg of vitamin B12, and 25 mg of vitamin B6 for 3.4 years resulted in significant reductions in mean homocysteine levels (by 28% and 43% in cognitively unimpaired and impaired patients, respectively) compared to placebo. Yet, the B-vitamin intervention had no effect on either the incidence of newly diagnosed cognitive impairments or on measures of cognitive performance when compared to placebo (53). In contrast, another recent placebo-controlled trial found that a daily B-vitamin regimen that led to significant homocysteine lowering in high-risk elderly individuals could limit the progressive atrophy of gray matter brain regions associated with the AD process (54). Yet, the authors attributed the changes in homocysteine levels primarily to vitamin B12. Because of mixed findings, it is presently unclear whether supplementation with B vitamins might blunt cognitive decline in the elderly. Evidence is needed to determine whether 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.

Depression

Late-life depression is a common disorder sometimes occurring after acute illnesses, such as hip fracture or stroke (55, 56). Coexistence of symptoms of depression and low vitamin B6 status (plasma PLP level ≤20 nanomoles/liter) has been reported in a few cross-sectional studies (57, 58). In a prospective study of 3,503 free-living people aged 65 and older from the Chicago Health and Aging Project, total vitamin B6 intakes (but not dietary intakes alone) were inversely correlated with the incidence of depressive symptoms during a mean follow-up period of 7.2 years (59). In a randomized, double-blind, placebo-controlled trial in 563 individuals who suffered from a recent stroke, daily supplementation of 2 mg of folic acid, 0.5 mg of vitamin B12, and 25 mg of vitamin B6 halved the risk of developing a major depressive episode during a mean follow-up period of 7.1 years (60). This reduction in risk was associated with a 25% lower level of plasma homocysteine in supplemented patients compared to controls. Additional evidence is needed to evaluate whether B vitamins could be included in the routine management of older people at high risk for depression.

Cancer

Chronic inflammation that underlies most cancers may enhance vitamin B6 degradation (see Vitamin B6 and inflammation). In addition, the requirement of PLP in the methionine cycle, homocysteine catabolism, and thymidylate synthesis that low vitamin B6 status may contribute to the onset and/or progression of tumors. The systematic review of nine prospective studies found either inverse or positive associations between vitamin B6 intakes and colorectal cancer (CRC) risk (61). Inconsistent evidence regarding the link between vitamin B6 intakes and breast cancer was also recently reported in a meta-analysis (62). Yet, a prospective study that followed nearly 500,000 older adults for nine years observed that the risk of esophageal and stomach cancers was lower in participants in the highest versus lowest quintile of total vitamin B6 intakes (median values, 2.7 mg/day vs. 1.4 mg/day) (63). Additionally, a meta-analysis of four nested case-control studies reported a 48% reduction in CRC risk in the highest versus lowest quartile of blood PLP level (61). Another meta-analysis of five nested case-control studies found higher versus lower serum PLP levels to be associated with a 29% lower risk of breast cancer in postmenopausal, but not premenopausal, women (62).

Very few randomized, placebo-controlled trials investigating the nature of the association between B vitamins and cancer risk have focused on vitamin B6. Two earlier studies conducted in subjects with coronary artery disease failed to observe any benefit of supplemental vitamin B6 (40 mg/day) on CRC risk and mortality (reviewed in 64). A recent randomized, double-blind, placebo-controlled study conducted in 1,470 women with high cardiovascular risk showed that daily supplementation with 2.5 mg of folic acid, 1 mg of vitamin B12, and 50 mg of vitamin B6 for a mean treatment period of 7.3 years had no effect on the risk of developing colorectal adenoma when compared to placebo (65).

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 (66). However, in a group of more than 45,000 men followed for 14 years, no association was found between vitamin B6 intake and the occurrence of kidney stones (67). Limited experimental data have suggested that supplementation with high doses of pyridoxamine may help decrease the formation of calcium oxalate kidney stones and reduce urinary oxalate levels, an important determinant of calcium oxalate kidney stone formation (68, 69). 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.

Metabolic diseases

A few rare inborn metabolic disorders, including pyridoxine-dependent epilepsy (PDE) and pyridox(am)ine phosphate oxidase (PNPO) deficiency, are the cause of early-onset epileptic encephalopathies that are found to be responsive to pharmacologic doses of vitamin B6. In individuals affected by PDE and PNPO deficiency, PLP bioavailability is limited, and treatment with pyridoxine and/or PLP have been used to alleviate or abolish epileptic seizures characterizing these conditions (70, 71). Pyridoxine therapy, along with dietary protein restriction, is also used in the management of vitamin B6 responsive homocystinuria caused by the deficiency of the PLP-dependent enzyme, cystathionine β synthase (72).

Morning sickness

Nausea and vomiting in pregnancy (NVP), often referred to as morning sickness, can affect up to 85% of women during early pregnancy and usually lasts between 12 and 16 weeks (73). Vitamin B6 has been used since the 1940s to treat nausea during pregnancy. Vitamin B6 was originally included in the medication Bendectin, which was prescribed for NVP treatment and later withdrawn from the market due to unproven concerns that it increased the risk for birth defects. Vitamin B6 itself is considered safe during pregnancy and has been used in pregnant women without any evidence of fetal harm (74). The results of two double-blind, placebo-controlled trials, including 401 pregnant women that used 25 mg of pyridoxine every eight hours for three days (75) or 10 mg of pyridoxine every eight hours for five days (76), suggested that vitamin B6 may be beneficial in reducing nausea. A recent systematic review of randomized controlled trials on NVP symptoms during early pregnancy found supplemental vitamin B6 to be somewhat effective (77). It should be noted that NVP usually resolves without any treatment, making it difficult to perform well-controlled trials. More recently, NVP symptoms were evaluated using Pregnancy Unique Quantification of Emesis (PUQE) scores in a randomized, double-blind, placebo-controlled study conducted in 256 pregnant women (7-14 weeks' gestation) suffering from NVP (78). Supplementation with pyridoxine and the drug doxylamine significantly improved NVP symptoms, as assessed by lower PUQE scores compared to placebo. Moreover, more women supplemented with pyridoxine-doxylamine (48.9%) than placebo-treated (32.8%) asked to continue their treatment at the end of the 15-day trial. The American and Canadian Colleges of Obstetrics and Gynecology have recommended the use of vitamin B6 (pyridoxine hydrochloride, 10 mg) and doxylamine succinate (10 mg) as first-line therapy for NVP (73).

Premenstrual syndrome

Premenstrual syndrome (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 systematic review and meta-analysis of nine randomized, placebo-controlled trials suggested that supplemental vitamin B6, up to 100 mg/day, may be of value to treat PMS, including mood symptoms; however, only limited conclusions could be drawn because most of the studies were of poor quality (79). Another more recent review of 13 randomized controlled studies also emphasized the need for conclusive evidence before recommendations can be made (80).

Depression

The importance of PLP-dependent enzymes in the synthesis of several neurotransmitters (see Nervous system function) has led researchers to consider whether vitamin B6 deficiency may contribute to the onset of depressive symptoms (see Disease Prevention). There is limited evidence suggesting that supplemental vitamin B6 may have therapeutic efficacy in the management of depression. In a randomized, placebo-controlled trial conducted in 225 elderly patients hospitalized for acute illness, a six-month intervention with daily multivitamin/mineral supplements improved nutritional B-vitamin status and decreased the number and severity of depressive symptoms when compared to placebo (81). In addition, while supplement intake effectively reduced plasma homocysteine levels compared to placebo, the effect of supplementation on depressive symptoms at the end of the trial was greater in treated subjects in the lowest versus highest quartile of homocysteine levels (≤10 micromoles/liter vs. ≥16.1 micromoles/liter) (82). Yet, the etiology of late-onset depression is unclear and evidence is currently lacking to suggest whether supplemental B vitamins (including vitamin B6) could relieve depressive symptoms.

Carpal tunnel syndrome

Carpal tunnel syndrome (CTS) 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. Early studies by the same investigator suggested that supplementation with 100-200 mg/day of vitamin B6 for several months might improve CTS symptoms in individuals with low vitamin B6 status (83, 84). In addition, a cross-sectional study in 137 men not taking vitamin supplements found that decreased blood levels of PLP were associated with increased pain, tingling, and nocturnal wakening—all symptoms of CTS (85). However, studies using electrophysiological measurements of median nerve conduction have largely failed to find an association between vitamin B6 deficiency and CTS (86). While a few studies 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 CTS (86). Yet, despite its equivocal effectiveness, vitamin B6 supplementation is sometimes used in complementary therapy in an attempt to avoid hand surgery. Patients taking high doses of vitamin B6 should be advised by a physician and monitored for vitamin B6-related toxicity symptoms (see Toxicity) (87).

Sources

Food sources

The analysis of data collected in the US NHANES 2003-2004 has indicated that vitamin B6 intakes from food only averaged about 1.9 mg/day (88). Yet, despite values well above the current RDA, total vitamin B6 intakes (combining food and supplements) below 2 mg/day appear to be associated with relatively high proportions of low vitamin B6 status in all age groups (see Supplements). Many plant foods contain a unique form of vitamin B6 called pyridoxine glucoside; this form of vitamin B6 appears to be only about half as bioavailable as vitamin B6 from other food sources or supplements (7). Vitamin B6 in a mixed diet has been found to be approximately 75% bioavailable (14). In most cases, including foods in the diet that are rich in vitamin B6 should supply enough to meet the current RDA. However, those who follow a very restricted vegetarian diet might need to increase their vitamin B6 intake by eating foods fortified with vitamin B6 or by taking a supplement. Some foods that are relatively rich in vitamin B6 and their vitamin B6 content in milligrams (mg) are listed in Table 2. For more information on the nutrient content of specific foods, search the USDA food composition database.

Table 2. Some Food Sources of Vitamin B6
Food Serving Vitamin B6 (mg)
Fortified breakfast cereal 1 cup 0.5-2.5
Salmon, wild (cooked) 3 ounces* 0.48-0.80
Potato, Russet, with skin (baked) 1 medium 0.70
Turkey, light meat (cooked) 3 ounces 0.69
Avocado 1 medium 0.52
Chicken, light meat without skin (cooked) 3 ounces 0.51
Spinach (cooked) 1 cup 0.44
Banana 1 medium 0.43
Dried plums, pitted 1 cup 0.36
Hazelnuts (dry roasted) 1 ounce 0.18
Vegetable juice cocktail 6 ounces 0.13
*A three-ounce serving of meat or fish is about the size of a deck of cards.

Supplements

Vitamin B6 is available as pyridoxine hydrochloride in multivitamin, vitamin B-complex, and vitamin B6 supplements (89). In NHANES 2003-2004, low vitamin B6 status (plasma PLP level <20 nanomoles/liter) was reported in 24% of non users of supplements and 11% of supplement users. Moreover, total vitamin B6 intakes (from food and supplements) lower than 2 mg/day were associated with high proportions of low plasma PLP levels: 16% in men aged 13-54 years, 24% in menstruating women, and 26% in individuals aged 65 years and older. Finally, the prevalence of low PLP levels was found to be greater in individuals consuming less than 2 mg/day of vitamin B6 compared to higher intakes. For example, only 14% of men and women aged 65 and older had low PLP values with total vitamin B6 intakes of 2-2.9 mg/day compared to 26% in those consuming less than 2 mg/day of vitamin B6 (88).

Safety

Toxicity

Because adverse effects have only been documented from vitamin B6 supplements and never from food sources, safety concerning only the supplemental form of vitamin B6 (pyridoxine) is discussed. Although vitamin B6 is a water-soluble vitamin and is excreted in the urine, long-term supplementation with very high doses of pyridoxine may result in painful neurological symptoms known as sensory neuropathy. Symptoms include pain and numbness of the extremities and in severe cases, difficulty walking. Sensory neuropathy typically develops at doses of pyridoxine in excess of 1,000 mg per day. However, there have been a few case reports of individuals who developed sensory neuropathies at doses of less than 500 mg daily over a period of months. Yet, none of the studies in which an objective neurological examination was performed reported evidence of sensory nerve damage at intakes below 200 mg pyridoxine daily (90). To prevent sensory neuropathy in virtually all individuals, the Food and Nutrition Board of the Institute of Medicine set the tolerable upper intake level (UL) for pyridoxine at 100 mg/day for adults (Table 3) (14). Because placebo-controlled studies have generally failed to show therapeutic benefits of high doses of pyridoxine, there is little reason to exceed the UL of 100 mg/day.

Table 3. Tolerable Upper Intake Level (UL) for Vitamin B6
Age Group UL (mg/day)
Infants 0-12 months Not possible to establish*
Children 1-3 years 30
Children 4-8 years   40
Children 9-13 years   60
Adolescents 14-18 years 80
Adults 19 years and older 100
*Source of intake should be from food and formula only.

Drug interactions

Certain medications interfere with the metabolism of vitamin B6; therefore, some individuals may be vulnerable to a vitamin B6 deficiency if supplemental vitamin B6 is not taken. In the NHANES 2003-2004 analysis, significantly more current and past users of oral contraceptives (OCs) among menstruating women had low plasma PLP levels compared to women who have never used OCs, suggesting that the estrogen content of OCs may interfere with vitamin B6 metabolism (see Side effects of oral contraceptives) (88). Anti-tuberculosis medications (e.g., isoniazid and cycloserine), the metal chelator penicillamine, and anti-parkinsonian drugs like L-Dopa can all form complexes with vitamin B6 and limit its bioavailability, thus creating a functional deficiency. PLP bioavailability may also be reduced by methylxanthines, such as theophylline used to treat certain respiratory conditions (7). The long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs; e.g. celecoxib and naproxen) may also impair vitamin B6 metabolism (91). Conversely, high doses of vitamin B6 have been found to decrease the efficacy of two anticonvulsants, phenobarbital and phenytoin, and of L-Dopa (6, 90).

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) has been used as a functional assessment of vitamin B6 status. Abnormal tryptophan load tests in women taking high-dose oral contraceptives (OCs) in the 1960s and 1970s suggested that these women were vitamin B6 deficient, which led to the prescription of high doses of vitamin B6 (100-150 mg/day) to women taking OCs. However, most other indices of vitamin B6 status were normal in women on high-dose OCs, and the estrogen content of OCs appeared to be more likely responsible for the abnormality in tryptophan metabolism (88). Yet, more recently, the use of lower dose formulations has also been associated with vitamin B6 inadequacy (88, 92). Although it is not known whether OCs actually impair vitamin B6 metabolism or merely affect the tissue distribution of PLP, the use of OCs may place women at higher risk of vitamin B6 deficiency when they discontinue OCs and become pregnant (93). Whether OC users are at higher risk of cardiovascular disease despite normal homocysteine levels also needs to be determined. Finally, although high doses of vitamin B6 (pyridoxine) have demonstrated no benefit in preventing the risk of side effects from OCs (94), the use of vitamin B6 supplements may be warranted in current and past OC users.

Linus Pauling Institute Recommendation

The Linus Pauling Institute supports the RDA for vitamin B6. LPI recommends that all adults take a daily multivitamin/mineral supplement, which usually contains at least 2 mg of vitamin B6. This amount is slightly above the RDA but still 50 times lower than the tolerable upper intake level (UL) set by the Food and Nutrition Board (see Safety).

Older adults (>50 years)

Early metabolic studies have indicated that the requirement for vitamin B6 in older adults is approximately 2 mg daily (95). Yet, the analysis of the US population survey (NHANES) 2003-2004 showed that adequate vitamin B6 status and low homocysteine levels were associated with total vitamin B6 intakes equal to and above 3 mg/day in people aged 65 years and older (88). The Linus Pauling Institute recommends that older adults take a multivitamin/mineral supplement, which provides at least 2.0 mg of vitamin B6 daily.


Authors and Reviewers

Originally written in 2000 by: 
Jane Higdon, Ph.D. 
Linus Pauling Institute 
Oregon State University

Updated in February 2002 by: 
Jane Higdon, Ph.D. 
Linus Pauling Institute 
Oregon State University

Updated in November 2007 by: 
Victoria J. Drake, Ph.D. 
Linus Pauling Institute 
Oregon State University

Updated in May 2014 by: 
Barbara Delage, Ph.D. 
Linus Pauling Institute 
Oregon State University

Reviewed in June 2014 by: 
Jesse F. Gregory, Ph.D. 
Professor, Food Science and Human Nutrition 
University of Florida

The 2014 update of this article was underwritten, in part, by a grant from Bayer Consumer Care AG, Basel, Switzerland.

Copyright 2000-2017  Linus Pauling Institute


References

1.  Dakshinamurti S, Dakshinamurti K. Vitamin B6. In: Zempleni J, Rucker RB, McCormick DB, Suttie JW, eds. Handbook of Vitamins. 4th ed. New York: CRC Press (Taylor & Fracis Group); 2007:315-359.

2.  Galluzzi L, Vacchelli E, Michels J, et al. Effects of vitamin B6 metabolism on oncogenesis, tumor progression and therapeutic responses. Oncogene. 2013;32(42):4995-5004.  (PubMed)

3.  McCormick DB. Vitamin B6. In: Bowman BA, Russell RM, eds. Present Knowledge in Nutrition. Vol. I. Washington, D.C.: International Life Sciences Institute; 2006:269-277.

4.  Da Silva VR, Russell KA, Gregory JF 3rd. Vitamin B6. In: Erdman JW Jr., Macdonald IA, Zeisel SH. Present Knowldege in Nutrition. 10th ed: Wiley-Blackwell; 2012:307-320.

5.  Eliot AC, Kirsch JF. Pyridoxal phosphate enzymes: mechanistic, structural, and evolutionary considerations. Annu Rev Biochem. 2004;73:383-415.  (PubMed)

6.  Leklem JE. Vitamin B-6. In: Shils M, Olson JA, Shike M, Ross AC, eds. Modern Nutrition in Health and Disease. 9th ed. Baltimore: Williams & Wilkins; 1999:413-422.

7.  Clayton PT. B6-responsive disorders: a model of vitamin dependency. J Inherit Metab Dis. 2006;29(2-3):317-326.  (PubMed)

8.  Schnackerz KD, Benesch RE, Kwong S, Benesch R, Helmreich EJ. Specific receptor sites for pyridoxal 5'-phosphate and pyridoxal 5'-deoxymethylenephosphonate at the α and β NH2-terminal regions of hemoglobin. J Biol Chem. 1983;258(2):872-875.  (PubMed)

9.  Rios-Avila L, Nijhout HF, Reed MC, Sitren HS, Gregory JF, 3rd. A mathematical model of tryptophan metabolism via the kynurenine pathway provides insights into the effects of vitamin B-6 deficiency, tryptophan loading, and induction of tryptophan 2,3-dioxygenase on tryptophan metabolites. J Nutr. 2013;143(9):1509-1519.  (PubMed)

10.  Oxenkrug G. Insulin resistance and dysregulation of tryptophan-kynurenine and kynurenine-nicotinamide adenine dinucleotide metabolic pathways. Mol Neurobiol. 2013;48(2):294-301.  (PubMed)

11.  Huq MD, Tsai NP, Lin YP, Higgins L, Wei LN. Vitamin B6 conjugation to nuclear corepressor RIP140 and its role in gene regulation. Nat Chem Biol. 2007;3(3):161-165.  (PubMed)

12.  Leklem JE. Vitamin B6. In: Machlin L, ed. Handbook of Vitamins. New York: Marcel Decker Inc; 1991:341-378.

13.  Hansen CM, Shultz TD, Kwak HK, Memon HS, Leklem JE. Assessment of vitamin B-6 status in young women consuming a controlled diet containing four levels of vitamin B-6 provides an estimated average requirement and recommended dietary allowance. J Nutr. 2001;131(6):1777-1786.  (PubMed)

14.  Food and Nutrition Board, Institute of Medicine. Vitamin B6. Dietary Reference Intakes: Thiamin, Riboflavin, Niacin, Vitamin B6, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington D.C.: National Academies Press; 1998:150-195.  (National Academies Press)

15.  Paul L, Ueland PM, Selhub J. Mechanistic perspective on the relationship between pyridoxal 5'-phosphate and inflammation. Nutr Rev. 2013;71(4):239-244.  (PubMed)

16.  Meydani SN, Ribaya-Mercado JD, Russell RM, Sahyoun N, Morrow FD, Gershoff SN. Vitamin B-6 deficiency impairs interleukin 2 production and lymphocyte proliferation in elderly adults. Am J Clin Nutr. 1991;53(5):1275-1280.  (PubMed)

17.  Talbott MC, Miller LT, Kerkvliet NI. Pyridoxine supplementation: effect on lymphocyte responses in elderly persons. Am J Clin Nutr. 1987;46(4):659-664.  (PubMed)

18.   Rimm EB, Willett WC, Hu FB, et al. Folate and vitamin B6 from diet and supplements in relation to risk of coronary heart disease among women. JAMA. 1998;279(5):359-364.  (PubMed)

19.  Ishihara J, Iso H, Inoue M, et al. Intake of folate, vitamin B6 and vitamin B12 and the risk of CHD: the Japan Public Health Center-Based Prospective Study Cohort I. J Am Coll Nutr. 2008;27(1):127-136.  (PubMed)

20.  Folsom AR, Nieto FJ, McGovern PG, et al. Prospective study of coronary heart disease incidence in relation to fasting total homocysteine, related genetic polymorphisms, and B vitamins: the Atherosclerosis Risk in Communities (ARIC) study. Circulation. 1998;98(3):204-210.  (PubMed)

21.  Robinson K, Arheart K, Refsum H, et al. Low circulating folate and vitamin B6 concentrations: risk factors for stroke, peripheral vascular disease, and coronary artery disease. European COMAC Group.Circulation. 1998;97(5):437-443.  (PubMed)

22.  Robinson K, Mayer EL, Miller DP, et al. Hyperhomocysteinemia and low pyridoxal phosphate. Common and independent reversible risk factors for coronary artery disease. Circulation. 1995;92(10):2825-2830.  (PubMed)

23.  Lin PT, Cheng CH, Liaw YP, Lee BJ, Lee TW, Huang YC. Low pyridoxal 5'-phosphate is associated with increased risk of coronary artery disease. Nutrition. 2006;22(11-12):1146-1151.  (PubMed)

24.  Page JH, Ma J, Chiuve SE, et al. Plasma vitamin B(6) and risk of myocardial infarction in women. Circulation. 2009;120(8):649-655.  (PubMed)

25.  Gerhard GT, Duell PB. Homocysteine and atherosclerosis. Curr Opin Lipidol. 1999;10(5):417-428.  (PubMed)

26.  Ubbink JB, Vermaak WJ, van der Merwe A, Becker PJ, Delport R, Potgieter HC. Vitamin requirements for the treatment of hyperhomocysteinemia in humans. J Nutr. 1994;124(10):1927-1933.  (PubMed)

27.  Lamers Y, Coats B, Ralat M, Quinlivan EP, Stacpoole PW, Gregory JF, 3rd. Moderate vitamin B-6 restriction does not alter postprandial methionine cycle rates of remethylation, transmethylation, and total transsulfuration but increases the fractional synthesis rate of cystathionine in healthy young men and women. J Nutr. 2011;141(5):835-842.  (PubMed)

28.  Huang T, Chen Y, Yang B, Yang J, Wahlqvist ML, Li D. Meta-analysis of B vitamin supplementation on plasma homocysteine, cardiovascular and all-cause mortality. Clin Nutr. 2012;31(4):448-454.  (PubMed)

29.  Bosy-Westphal A, Holzapfel A, Czech N, Muller MJ. Plasma folate but not vitamin B(12) or homocysteine concentrations are reduced after short-term vitamin B(6) supplementation. Ann Nutr Metab. 2001;45(6):255-258.  (PubMed)

30.  Lee BJ, Huang MC, Chung LJ, et al. Folic acid and vitamin B12 are more effective than vitamin B6 in lowering fasting plasma homocysteine concentration in patients with coronary artery disease. Eur J Clin Nutr. 2004;58(3):481-487.  (PubMed)

31.  Bostom AG, Carpenter MA, Kusek JW, et al. Homocysteine-lowering and cardiovascular disease outcomes in kidney transplant recipients: primary results from the Folic Acid for Vascular Outcome Reduction in Transplantation trial. Circulation. 2011;123(16):1763-1770.  (PubMed)

32.  Qin X, Huo Y, Xie D, Hou F, Xu X, Wang X. Homocysteine-lowering therapy with folic acid is effective in cardiovascular disease prevention in patients with kidney disease: a meta-analysis of randomized controlled trials. Clin Nutr. 2013;32(5):722-727.  (PubMed)

33.  Clarke R, Halsey J, Bennett D, Lewington S. Homocysteine and vascular disease: review of published results of the homocysteine-lowering trials. J Inherit Metab Dis. 2011;34(1):83-91.  (PubMed)

34.  Marti-Carvajal AJ, Sola I, Lathyris D, Karakitsiou DE, Simancas-Racines D. Homocysteine-lowering interventions for preventing cardiovascular events. Cochrane Database Syst Rev. 2013;1:CD006612.  (PubMed)

35.  Zhang C, Chi FL, Xie TH, Zhou YH. Effect of B-vitamin supplementation on stroke: a meta-analysis of randomized controlled trials. PLoS One. 2013;8(11):e81577.  (PubMed)

36.  Potter K, Hankey GJ, Green DJ, Eikelboom J, Jamrozik K, Arnolda LF. The effect of long-term homocysteine-lowering on carotid intima-media thickness and flow-mediated vasodilation in stroke patients: a randomized controlled trial and meta-analysis. BMC Cardiovasc Disord. 2008;8:24.  (PubMed)

37.  Loland KH, Bleie O, Blix AJ, et al. Effect of homocysteine-lowering B vitamin treatment on angiographic progression of coronary artery disease: a Western Norway B Vitamin Intervention Trial (WENBIT) substudy. Am J Cardiol. 2010;105(11):1577-1584.  (PubMed)

38.  Wang X, Qin X, Demirtas H, et al. Efficacy of folic acid supplementation in stroke prevention: a meta-analysis. Lancet. 2007;369(9576):1876-1882.  (PubMed)

39.  Vitatops Trial Study Group. B vitamins in patients with recent transient ischaemic attack or stroke in the VITAmins TO Prevent Stroke (VITATOPS) trial: a randomised, double-blind, parallel, placebo-controlled trial. Lancet Neurol. 2010;9(9):855-865.  (PubMed)

40.  Hankey GJ, Eikelboom JW, Yi Q, et al. Antiplatelet therapy and the effects of B vitamins in patients with previous stroke or transient ischaemic attack: a post-hoc subanalysis of VITATOPS, a randomised, placebo-controlled trial. Lancet Neurol. 2012;11(6):512-520.  (PubMed)

41.  Morris MS, Sakakeeny L, Jacques PF, Picciano MF, Selhub J. Vitamin B-6 intake is inversely related to, and the requirement is affected by, inflammation status. J Nutr. 2010;140(1):103-110.  (PubMed)

42.  Sakakeeny L, Roubenoff R, Obin M, et al. Plasma pyridoxal-5-phosphate is inversely associated with systemic markers of inflammation in a population of US adults. J Nutr. 2012;142(7):1280-1285.  (PubMed)

43.  Shen J, Lai CQ, Mattei J, Ordovas JM, Tucker KL. Association of vitamin B-6 status with inflammation, oxidative stress, and chronic inflammatory conditions: the Boston Puerto Rican Health Study. Am J Clin Nutr. 2010;91(2):337-342.  (PubMed)

44.  Schroecksnadel K, Grammer TB, Boehm BO, Marz W, Fuchs D. Total homocysteine in patients with angiographic coronary artery disease correlates with inflammation markers. Thromb Haemost. 2010;103(5):926-935.  (PubMed)

45.  Hartman J, Frishman WH. Inflammation and atherosclerosis: a review of the role of interleukin-6 in the development of atherosclerosis and the potential for targeted drug therapy. Cardiol Rev. 2014;22(3):147-151.  (PubMed)

46.  Friso S, Girelli D, Martinelli N, et al. Low plasma vitamin B-6 concentrations and modulation of coronary artery disease risk. Am J Clin Nutr. 2004;79(6):992-998.  (PubMed)

47.  Ulvik A, Midttun O, Pedersen ER, Eussen SJ, Nygard O, Ueland PM. Evidence for increased catabolism of vitamin B-6 during systemic inflammation. Am J Clin Nutr. 2014;100(1):250-255. [Epub ahead of print]  (PubMed)

48.  Bleie O, Semb AG, Grundt H, et al. Homocysteine-lowering therapy does not affect inflammatory markers of atherosclerosis in patients with stable coronary artery disease. J Intern Med. 2007;262(2):244-253.  (PubMed)

49.  Potter K, Lenzo N, Eikelboom JW, Arnolda LF, Beer C, Hankey GJ. Effect of long-term homocysteine reduction with B vitamins on arterial wall inflammation assessed by fluorodeoxyglucose positron emission tomography: a randomised double-blind, placebo-controlled trial. Cerebrovasc Dis. 2009;27(3):259-265.  (PubMed)

50.  Selhub J, Bagley LC, Miller J, Rosenberg IH. B vitamins, homocysteine, and neurocognitive function in the elderly. Am J Clin Nutr. 2000;71(2):614S-620S.  (PubMed)

51.  Pawelec G, Goldeck D, Derhovanessian E. Inflammation, ageing and chronic disease. Curr Opin Immunol. 2014;29C:23-28.  (PubMed)

52.  Ford AH, Almeida OP. Effect of homocysteine lowering treatment on cognitive function: a systematic review and meta-analysis of randomized controlled trials. J Alzheimers Dis. 2012;29(1):133-149.  (PubMed)

53.  Hankey GJ, Ford AH, Yi Q, et al. Effect of B vitamins and lowering homocysteine on cognitive impairment in patients with previous stroke or transient ischemic attack: a prespecified secondary analysis of a randomized, placebo-controlled trial and meta-analysis. Stroke. 2013;44(8):2232-2239.  (PubMed)

54.  Douaud G, Refsum H, de Jager CA, et al. Preventing Alzheimer's disease-related gray matter atrophy by B-vitamin treatment. Proc Natl Acad Sci U S A. 2013;110(23):9523-9528.  (PubMed)

55.  Hackett ML, Yapa C, Parag V, Anderson CS. Frequency of depression after stroke: a systematic review of observational studies. Stroke. 2005;36(6):1330-1340.  (PubMed)

56.  Lenze EJ, Munin MC, Skidmore ER, et al. Onset of depression in elderly persons after hip fracture: implications for prevention and early intervention of late-life depression. J Am Geriatr Soc. 2007;55(1):81-86.  (PubMed)

57.  Merete C, Falcon LM, Tucker KL. Vitamin B6 is associated with depressive symptomatology in Massachusetts elders. J Am Coll Nutr. 2008;27(3):421-427.  (PubMed)

58.  Pan WH, Chang YP, Yeh WT, et al. Co-occurrence of anemia, marginal vitamin B6, and folate status and depressive symptoms in older adults. J Geriatr Psychiatry Neurol. 2012;25(3):170-178.  (PubMed)

59.  Skarupski KA, Tangney C, Li H, Ouyang B, Evans DA, Morris MC. Longitudinal association of vitamin B-6, folate, and vitamin B-12 with depressive symptoms among older adults over time. Am J Clin Nutr. 2010;92(2):330-335.  (PubMed)

60.  Almeida OP, Marsh K, Alfonso H, Flicker L, Davis TM, Hankey GJ. B-vitamins reduce the long-term risk of depression after stroke: The VITATOPS-DEP trial. Ann Neurol. 2010;68(4):503-510.  (PubMed)

61.  Larsson SC, Orsini N, Wolk A. Vitamin B6 and risk of colorectal cancer: a meta-analysis of prospective studies. JAMA. 2010;303(11):1077-1083.  (PubMed)

62.  Wu W, Kang S, Zhang D. Association of vitamin B6, vitamin B12 and methionine with risk of breast cancer: a dose-response meta-analysis. Br J Cancer. 2013;109(7):1926-1944.  (PubMed)

63.  Xiao Q, Freedman ND, Ren J, Hollenbeck AR, Abnet CC, Park Y. Intakes of folate, methionine, vitamin B6, and vitamin B12 with risk of esophageal and gastric cancer in a large cohort study. Br J Cancer. 2014;110(5):1328-1333.  (PubMed)

64.  Zhang XH, Ma J, Smith-Warner SA, Lee JE, Giovannucci E. Vitamin B6 and colorectal cancer: current evidence and future directions. World J Gastroenterol. 2013;19(7):1005-1010.  (PubMed)

65.  Song Y, Manson JE, Lee IM, et al. Effect of combined folic acid, vitamin B(6), and vitamin B(12) on colorectal adenoma. J Natl Cancer Inst. 2012;104(20):1562-1575.  (PubMed)

66.  Curhan GC, Willett WC, Speizer FE, Stampfer MJ. Intake of vitamins B6 and C and the risk of kidney stones in women. J Am Soc Nephrol. 1999;10(4):840-845.  (PubMed)

67.  Taylor EN, Stampfer MJ, Curhan GC. Dietary factors and the risk of incident kidney stones in men: new insights after 14 years of follow-up. J Am Soc Nephrol. 2004;15(12):3225-3232.  (PubMed)

68.  Chetyrkin SV, Kim D, Belmont JM, Scheinman JI, Hudson BG, Voziyan PA. Pyridoxamine lowers kidney crystals in experimental hyperoxaluria: a potential therapy for primary hyperoxaluria. Kidney Int. 2005;67(1):53-60.  (PubMed)

69.  Scheinman JI, Voziyan PA, Belmont JM, Chetyrkin SV, Kim D, Hudson BG. Pyridoxamine lowers oxalate excretion and kidney crystals in experimental hyperoxaluria: a potential therapy for primary hyperoxaluria. Urol Res. 2005;33(5):368-371.  (PubMed)

70.  Pearl PL, Gospe SM, Jr. Pyridoxine or pyridoxal-5'-phosphate for neonatal epilepsy: The distinction just got murkier. Neurology. 2014;82(16):1392-1394.  (PubMed)

71.  Stockler S, Plecko B, Gospe SM, Jr., et al. Pyridoxine dependent epilepsy and antiquitin deficiency: clinical and molecular characteristics and recommendations for diagnosis, treatment and follow-up. Mol Genet Metab. 2011;104(1-2):48-60.  (PubMed)

72.  Picker JD, Levy HL. Homocystinuria caused by cystathionine β-synthase deficiency. In: Pagon RA, Adam MP, Ardinger HH, et al., eds. GeneReviews®. Seattle, Washington: University of Washington, Seattle 1993-2014.  (PubMed)

73.  Maltepe C, Koren G. The management of nausea and vomiting of pregnancy and hyperemesis gravidarum--a 2013 update. J Popul Ther Clin Pharmacol. 2013;20(2):e184-192.  (PubMed)

74.  Magee LA, Mazzotta P, Koren G. Evidence-based view of safety and effectiveness of pharmacologic therapy for nausea and vomiting of pregnancy (NVP). Am J Obstet Gynecol. 2002;186(5 Suppl Understanding):S256-261.  (PubMed)

75.  Sahakian V, Rouse D, Sipes S, Rose N, Niebyl J. Vitamin B6 is effective therapy for nausea and vomiting of pregnancy: a randomized, double-blind placebo-controlled study. Obstet Gynecol. 1991;78(1):33-36.  (PubMed)

76.  Vutyavanich T, Wongtra-ngan S, Ruangsri R. Pyridoxine for nausea and vomiting of pregnancy: a randomized, double-blind, placebo-controlled trial. Am J Obstet Gynecol. 1995;173(3 Pt 1):881-884.  (PubMed)

77.  Matthews A, Haas DM, O'Mathuna DP, Dowswell T, Doyle M. Interventions for nausea and vomiting in early pregnancy. Cochrane Database Syst Rev. 2014;3:CD007575.  (PubMed)

78.  Koren G, Clark S, Hankins GD, et al. Effectiveness of delayed-release doxylamine and pyridoxine for nausea and vomiting of pregnancy: a randomized placebo controlled trial. Am J Obstet Gynecol. 2010;203(6):571 e571-577.  (PubMed)

79.  Wyatt KM, Dimmock PW, Jones PW, Shaughn O'Brien PM. Efficacy of vitamin B-6 in the treatment of premenstrual syndrome: systematic review. BMJ. 1999;318(7195):1375-1381.  (PubMed)

80.  Whelan AM, Jurgens TM, Naylor H. Herbs, vitamins and minerals in the treatment of premenstrual syndrome: a systematic review. Can J Clin Pharmacol. 2009;16(3):e407-429.  (PubMed)

81.  Gariballa S, Forster S. Effects of dietary supplements on depressive symptoms in older patients: a randomised double-blind placebo-controlled trial. Clin Nutr. 2007;26(5):545-551.  (PubMed)

82.  Gariballa S. Testing homocysteine-induced neurotransmitter deficiency, and depression of mood hypothesis in clinical practice. Age Ageing. 2011;40(6):702-705.  (PubMed)

83.  Ellis J, Folkers K, Watanabe T, et al. Clinical results of a cross-over treatment with pyridoxine and placebo of the carpal tunnel syndrome. Am J Clin Nutr. 1979;32(10):2040-2046.  (PubMed)

84.  Ellis JM, Kishi T, Azuma J, Folkers K. Vitamin B6 deficiency in patients with a clinical syndrome including the carpal tunnel defect. Biochemical and clinical response to therapy with pyridoxine. Res Commun Chem Pathol Pharmacol. 1976;13(4):743-757.  (PubMed)

85.  Keniston RC, Nathan PA, Leklem JE, Lockwood RS. Vitamin B6, vitamin C, and carpal tunnel syndrome. A cross-sectional study of 441 adults. J Occup Environ Med. 1997;39(10):949-959.  (PubMed)

86.  Aufiero E, Stitik TP, Foye PM, Chen B. Pyridoxine hydrochloride treatment of carpal tunnel syndrome: a review. Nutr Rev. 2004;62(3):96-104.  (PubMed)

87.  Ryan-Harshman M, Aldoori W. Carpal tunnel syndrome and vitamin B6. Can Fam Physician. 2007;53(7):1161-1162.  (PubMed)

88.  Morris MS, Picciano MF, Jacques PF, Selhub J. Plasma pyridoxal 5'-phosphate in the US population: the National Health and Nutrition Examination Survey, 2003-2004. Am J Clin Nutr. 2008;87(5):1446-1454.  (PubMed)

89.  Hendler SS, Rorvik DR, eds. PDR for Nutritional Supplements. Montvale: Medical Economics Company, Inc; 2001.

90.  Bender DA. Non-nutritional uses of vitamin B6. Br J Nutr. 1999;81(1):7-20  (PubMed)

91.  Chang HY, Tang FY, Chen DY, et al. Clinical use of cyclooxygenase inhibitors impairs vitamin B-6 metabolism. Am J Clin Nutr. 2013;98(6):1440-1449.  (PubMed)

92.  Lussana F, Zighetti ML, Bucciarelli P, Cugno M, Cattaneo M. Blood levels of homocysteine, folate, vitamin B6 and B12 in women using oral contraceptives compared to non-users. Thromb Res. 2003;112(1-2):37-41.  (PubMed)

93.  Wilson SM, Bivins BN, Russell KA, Bailey LB. Oral contraceptive use: impact on folate, vitamin B(6), and vitamin B(1)(2) status. Nutr Rev. 2011;69(10):572-583.  (PubMed)

94.  Villegas-Salas E, Ponce de Leon R, Juarez-Perez MA, Grubb GS. Effect of vitamin B6 on the side effects of a low-dose combined oral contraceptive. Contraception. 1997;55(4):245-248.  (PubMed)

95.  Ribaya-Mercado JD, Russell RM, Sahyoun N, Morrow FD, Gershoff SN. Vitamin B-6 requirements of elderly men and women. J Nutr. 1991;121(7):1062-1074.  (PubMed)

Vitamin B12

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Summary

  • Vitamin B12 or cobalamin plays essential roles in folate metabolism and in the synthesis of the citric acid cycle intermediate, succinyl-CoA. (More information)
  • Vitamin B12 deficiency is commonly associated with chronic stomach inflammation, which may contribute to an autoimmune vitamin B12 malabsorption syndrome called pernicious anemia and to a food-bound vitamin B12 malabsorption syndrome. Impairment of vitamin B12 absorption can cause megaloblastic anemia and neurologic disorders in deficient subjects. (More information)
  • Normal function of the digestive system required for food-bound vitamin B12 absorption is commonly impaired in individuals over 60 years of age, placing them at risk for vitamin B12 deficiency. (More information)
  • Vitamin B12 and folate are important for homocysteine metabolism. Elevated homocysteine levels in blood are a risk factor for cardiovascular disease (CVD). Although B vitamin supplementation has been proven effective to control homocysteine levels, current data from intervention trials have not shown that lowering homocysteine levels decreases CVD risk. (More information)
  • The preservation of DNA integrity is dependent on folate and vitamin B12 availability. Poor vitamin B12 status has been linked to increased risk of breast cancer in some, but not all, observational studies. There is a need to evaluate whether supplemental vitamin B12, along with folic acid, could help reduce breast cancer incidence. (More information)
  • Low maternal vitamin B12 status has been associated with an increased risk of neural tube defects (NTD), but it is not known whether vitamin B12 supplementation could help reduce the risk of NTD. (More information)
  • Vitamin B12 is essential for the preservation of the myelin sheath around neurons and for the synthesis of neurotransmitters. While hyperhomocysteinemia may increase the risk of cognitive impairment, it is not clear whether vitamin B12 deficiency contributes to the risk of dementia in the elderly. Although B-vitamin supplementation lowers homocysteine levels in older subjects, the long-term benefit is not yet known. (More information)
  • Both depression and osteoporosis have been linked to diminished vitamin B12 status and high homocysteine levels. (More information)
  • Products of animal origin constitute the primary source of vitamin B12. Older individuals and vegans are advised to use vitamin B12 fortified foods and supplements to meet their needs. (More information)
  • The long-term use of certain medications, such as inhibitors of stomach acid secretion, can adversely affect vitamin B12 absorption. (More information)


Vitamin B12 has the largest and most complex chemical structure of all the vitamins. It is unique among vitamins in that it contains a metal ion, cobalt. For this reason cobalamin is the term used to refer to compounds having vitamin B12 activity. Methylcobalamin and 5-deoxyadenosylcobalamin are the forms of vitamin B12 used in the human body (1). The form of cobalamin used in most nutritional supplements and fortified foods, cyanocobalamin, is readily converted to 5-deoxyadenosylcobalamin and methylcobalamin in the body. In mammals, cobalamin is a cofactor for only two enzymes, methionine synthase and L-methylmalonyl-coenzyme A mutase (2).

Function

Cofactor for methionine synthase

Methylcobalamin is required for the function of the folate-dependent enzyme, methionine synthase. This enzyme is required for the synthesis of the amino acid, methionine, from homocysteine. Methionine in turn is required for the synthesis of S-adenosylmethionine, a methyl group donor used in many biological methylation reactions, including the methylation of a number of sites within DNA, RNA, and proteins (3). Aberrant methylation of DNA and proteins, which causes alterations in chromatin structure and gene expression, are a common feature of cancer cells. Inadequate function of methionine synthase can lead to an accumulation of homocysteine, which has been associated with increased risk of cardiovascular disease (Figure 1).

Figure 1. Vitamin B12 and Homocysteine Metabolism. Methionine synthase is a vitamin B12-dependent enzyme that catalyzes the formation of methionine from homocysteine using 5-methyltetrahydrofolate (5-methyl TH4), a folate derivative, as a methyl donor. Another pathway catalyzed by betaine homocysteine methyltransferase also remethylates homocysteine to methionine using betaine as a methyl donor (not shown here). Methionine, in the form of S-adenosylmethionine, is required for most biological methylation reactions, including DNA methylation.

Cofactor for L-methylmalonyl-coenzyme A mutase

5-Deoxyadenosylcobalamin is required by the enzyme that catalyzes the conversion of L-methylmalonyl-coenzyme A to succinyl-coenzyme A (succinyl-CoA), which then enters the citric acid cycle (Figure 2). Succinyl-CoA plays an important role in the production of energy from lipids and proteins and is also required for the synthesis of hemoglobin, the oxygen-carrying pigment in red blood cells (3).

Figure 2. Metabolic Pathway Requiring 5-Deoxyadenosylcobalamin. 5-deoxyadenosylcobalamin is required by L-methylmalonyl-CoA mutase, which converts L-methylmalonyl-CoA to succinyl-CoA.

Deficiency

In healthy adults, vitamin B12 deficiency is uncommon, mainly because total body stores can exceed 2,500 μg, daily turnover is slow, and dietary intake of only 2.4 μg/day is sufficient to maintain adequate vitamin B12 status (see RDA) (4). In elderly individuals, vitamin B12 deficiency is more common mainly because of impaired intestinal absorption that can result in marginal to severe vitamin B12 deficiency in this population.

Causes of vitamin B12 deficiency

Intestinal malabsorption, rather than inadequate dietary intake, can explain most cases of vitamin B12 deficiency (5). Absorption of vitamin B12 from food requires normal function of the stomach, pancreas, and small intestine. Stomach acid and enzymes free vitamin B12 from food, allowing it to bind to R-protein (also known as transcobalamin-1 or haptocorrin), found in saliva and gastric fluids. In the alkaline environment of the small intestine, R-proteins are degraded by pancreatic enzymes, freeing vitamin B12 to bind to intrinsic factor (IF), a protein secreted by specialized cells in the stomach. Receptors on the surface of the ileum (final part of the small intestine) take up the IF-B12 complex only in the presence of calcium, which is supplied by the pancreas (5). Vitamin B12 can also be absorbed by passive diffusion, but this process is very inefficient—only about 1% absorption of the vitamin B12 dose is absorbed passively (2). The prevalent causes of vitamin B12 deficiency are (1) an autoimmune condition known as pernicious anemia, and (2) a disorder called food-bound vitamin B12 malabsorption. Both conditions have been associated with a chronic inflammatory disease of the stomach known as atrophic gastritis.

Atrophic gastritis

Atrophic gastritis is thought to affect 10%-30% of people over 60 years of age (6). The condition is frequently associated with the presence of autoantibodies directed toward stomach cells (see Pernicious anemia) and/or infection by the bacteria, Helicobacter pylori (H. pylori) (7). H. pylori infection induces chronic inflammation of the stomach, which may progress to peptic ulcer disease, atrophic gastritis, and/or gastric cancer in some individuals. Diminished gastric function in individuals with atrophic gastritis can result in bacterial overgrowth in the small intestine and cause food-bound vitamin B12 malabsorption. Vitamin B12 levels in serum, plasma, and gastric fluids are significantly decreased in individuals with H. pylori infection, and eradication of the bacteria has been shown to significantly improve vitamin B12 serum concentrations (8).

Pernicious anemia

Pernicious anemia has been estimated to be present in approximately 2% of individuals over 60 years of age (9). Although anemia is often a symptom, the condition is actually the end stage of an autoimmune inflammation of the stomach known as autoimmune atrophic gastritis, resulting in destruction of stomach cells by one's own antibodies (autoantibodies). Progressive destruction of the cells that line the stomach causes decreased secretion of acid and enzymes required to release food-bound vitamin B12. Antibodies to intrinsic factor (IF) bind to IF preventing formation of the IF-B12 complex, further inhibiting vitamin B12 absorption. About 20% of the relatives of pernicious anemia patients also have the condition, suggesting a genetic predisposition. It is also thought that H. pylori infection could be involved in initiating the autoimmune response in a subset of individuals (10). Further, co-occurrence of autoimmune atrophic gastritis with other autoimmune conditions, especially autoimmune thyroiditis and type 1 diabetes mellitus, has been reported (11, 12).

Treatment of pernicious anemia generally requires injections of vitamin B12 to bypass intestinal absorption. High-dose oral supplementation is another treatment option, because consuming 1,000 μg (1 mg)/day of vitamin B12 orally should result in the absorption of about 10 μg/day (1% of dose) by passive diffusion. In fact, high-dose oral therapy is considered to be as effective as intramuscular injection (4).

Food-bound vitamin B12 malabsorption

Food-bound vitamin B12 malabsorption is defined as an impaired ability to absorb food- or protein-bound vitamin B12; individuals with this condition can fully absorb the free form (13). While the condition is the major cause of poor vitamin B12 status in the elderly population, it is usually associated with atrophic gastritis, a chronic inflammation of the lining of the stomach that ultimately results in the loss of glands in the stomach (atrophy) and decreased stomach acid production (see Atrophic gastritis). Because stomach acid is required for the release of vitamin B12 from the proteins in food, vitamin B12 absorption is diminished. Decreased stomach acid production also provides an environment conducive to the overgrowth of anaerobic bacteria in the stomach, which further interferes with vitamin B12 absorption (3). Because vitamin B12 in supplements is not bound to protein, and because intrinsic factor (IF) is still available, the absorption of supplemental vitamin B12 is not reduced as it is in pernicious anemia. Thus, individuals with food-bound vitamin B12 malabsorption do not have an increased requirement for vitamin B12; they simply need it in the crystalline form found in fortified foods and dietary supplements.

Other causes of vitamin B12 deficiency

Other causes of vitamin B12 deficiency include surgical resection of the stomach or portions of the small intestine where receptors for the IF-B12 complex are located. Conditions affecting the small intestine, such as malabsorption syndromes (celiac disease and tropical sprue), may also result in vitamin B12 deficiency. Because the pancreas provides critical enzymes, as well as calcium required for vitamin B12 absorption, pancreatic insufficiency may contribute to vitamin B12 deficiency. Since vitamin B12 is found only in foods of animal origin, a strict vegetarian (vegan) diet has resulted in cases of vitamin B12 deficiency. Moreover, alcoholics may experience reduced intestinal absorption of vitamin B12 (2), and individuals with acquired immunodeficiency syndrome (AIDS) appear to be at increased risk of deficiency, possibly related to a failure of the IF-B12 receptor to take up the IF-B12 complex (3). Further, long-term use of acid-reducing drugs has also been implicated in vitamin B12 deficiency (see Drug interactions).

Inherited disorders of vitamin B12 absorption

Rare cases of inborn errors of vitamin B12 metabolism have been reported in the literature (reviewed in 5). Imerslund-Gräsbeck syndrome is an inherited vitamin B12 malabsorption syndrome that causes megaloblastic anemia and neurologic disorders of variable severity in affected subjects. Similar clinical symptoms are found in individuals with hereditary IF deficiency (also called congenital pernicious anemia) in whom the lack of IF results in the defective absorption of vitamin B12. Additionally, mutations affecting vitamin B12 transport in the body have been identified (14).

Symptoms of vitamin B12 deficiency

Vitamin B12 deficiency results in impairment of the activities of vitamin B12-requiring enzymes. Impaired activity of methionine synthase results in elevated homocysteine levels, while impaired activity of L-methylmalonyl-CoA mutase results in increased levels of a metabolite of methylmalonyl-CoA called methylmalonic acid (MMA). While individuals with mild vitamin B12 deficiency may not experience symptoms, blood levels of homocysteine and/or MMA may be elevated (15).

Megaloblastic anemia

Diminished activity of methionine synthase in vitamin B12 deficiency inhibits the regeneration of tetrahydrofolate (THF) and traps folate in a form that is not usable by the body (Figure 3), resulting in symptoms of folate deficiency even in the presence of adequate folate levels. Thus, in both folate and vitamin B12 deficiencies, folate is unavailable to participate in DNA synthesis. This impairment of DNA synthesis affects the rapidly dividing cells of the bone marrow earlier than other cells, resulting in the production of large, immature, hemoglobin-poor red blood cells. The resulting anemia is known as megaloblastic anemia and is the symptom for which the disease, pernicious anemia, was named (3). Supplementation with folic acid will provide enough usable folate to restore normal red blood cell formation. However, if vitamin B12 deficiency is the cause, it will persist despite the resolution of the anemia. Thus, megaloblastic anemia should not be treated with folic acid until the underlying cause has been determined (16).

Figure 3. Vitamin B12 and Nucleic Acid Metabolism. 5,10-Methylene tetrahydrofolate (TH4) is required for the synthesis of nucleic acids, while 5-methyl TH4 is required for the formation of methionine from homocysteine. Methionine, in the form of S-adenosylmethionine, is required for many biological methylation reactions, including DNA methylation. Methylene TH4 reductase is a flavin-dependent enzyme required to catalyze the reduction of 5,10-methylene TH4 to 5-methyl TH4.

Neurologic symptoms

The neurologic symptoms of vitamin B12 deficiency include numbness and tingling of the hands and, more commonly, the feet; difficulty walking; memory loss; disorientation; and dementia with or without mood changes. Although the progression of neurologic complications is generally gradual, such symptoms may not be reversed with treatment of vitamin B12 deficiency, especially if they have been present for a long time. Neurologic complications are not always associated with megaloblastic anemia and are the only clinical symptom of vitamin B12 deficiency in about 25% of cases (17). Although vitamin B12 deficiency is known to damage the myelin sheath covering cranial, spinal, and peripheral nerves, the biochemical processes leading to neurological damage in vitamin B12 deficiency are not yet fully understood (18).

Gastrointestinal symptoms

Tongue soreness, appetite loss, and constipation have also been associated with vitamin B12 deficiency. The origins of these symptoms are unclear, but they may be related to the stomach inflammation underlying some cases of vitamin B12 deficiency and to the progressive destruction of the lining of the stomach (17).

The Recommended Dietary Allowance (RDA)

The RDA for vitamin B12 was revised by the Food and Nutrition Board (FNB) of the US Institute of Medicine in 1998 (Table 1). Because of the increased risk of food-bound vitamin B12 malabsorption in older adults, the FNB recommended that adults over 50 years of age get most of the RDA from fortified food or vitamin B12-containing supplements (17).

Table 1. Recommended Dietary Allowance (RDA) for Vitamin B12
Life Stage Age Males (μg/day) Females (μg/day)
Infants  0-6 months  0.4 (AI 0.4 (AI) 
Infants  7-12 months  0.5 (AI)  0.5 (AI) 
Children  1-3 years  0.9  0.9 
Children 4-8 years  1.2  1.2 
Children  9-13 years  1.8  1.8 
Adolescents  14-18 years  2.4  2.4 
Adults  19-50 years  2.4  2.4 
Adults  51 years and older  2.4*  2.4* 
Pregnancy  all ages  2.6 
Breast-feeding  all ages  2.8
*Vitamin B12 intake should be from supplements or fortified foods due to the age-related increase in food-bound malabsorption.

Disease Prevention

Cardiovascular disease

As mentioned above, chronic atrophic gastritis and infection by H. pylori can cause deficiency in vitamin B12 secondary to malabsorption disorders (see Causes of vitamin B12 deficiency). However, the occurrence of H. pylori infection and chronic atrophic gastritis did not modify the five-year incidence of cardiovascular accidents (stroke and heart attack) or mortality in a large cohort study of nearly 10,000 men and women over 50 years old (19). Yet, vitamin B12 status was not assessed in this study, despite the high prevalence of vitamin B12 deficiency in older individuals.

Homocysteine and cardiovascular disease

Epidemiological studies indicate that even moderately elevated levels of homocysteine in the blood raise the risk of cardiovascular disease (CVD) (20), though the mechanism by which homocysteine may increase the CVD risk remains the subject of a great deal of research (21). The amount of homocysteine in the blood is regulated by at least three vitamins: folate, vitamin B6, and vitamin B12 (see Figure 1 above). An early analysis of the results of 12 randomized controlled trials showed that folic acid supplementation (0.5-5 mg/day) had the greatest lowering effect on blood homocysteine levels (25% decrease); co-supplementation with folic acid and vitamin B12 (500 μg/day) provided an additional 7% reduction (32% decrease) in blood homocysteine concentrations (22). The results of a sequential supplementation trial in 53 men and women indicated that after folic acid supplementation, vitamin B12 became the major determinant of plasma homocysteine levels (23). It is thought that the elevation of homocysteine levels might be partly due to vitamin B12 deficiency in individuals over 60 years of age. Two studies found blood methylmalonic acid (MMA) levels to be elevated in more than 60% of elderly individuals with elevated homocysteine levels. In the absence of impaired kidney function, an elevated MMA level in conjunction with elevated homocysteine suggests either a vitamin B12 deficiency or a combined vitamin B12 and folate deficiency (24). Thus, it appears important to evaluate vitamin B12 status, as well as kidney function, in older individuals with elevated homocysteine levels prior to initiating homocysteine-lowering therapy. For more information regarding homocysteine and CVD, see the article on Folate.

Intervention studies

Although increased intake of folic acid and vitamin B12 is effective in decreasing homocysteine levels, the combined intervention of these B vitamins did not lower risk for CVD. Indeed, several randomized, placebo-controlled trials have been conducted to determine whether homocysteine-lowering through folic acid, vitamin B12, and vitamin B6 supplementation reduces the incidence of CVD. A recent meta-analysis of data from 11 trials, including nearly 45,000 participants at risk of CVD, showed that B-vitamin supplementation had no significant effect on risk of myocardial infarction (heart attack) or stroke, nor did it modify the risk of all-cause mortality (25). Other meta-analyses that included patients with chronic kidney disease have confirmed the lack of effect of homocysteine-lowering on risk of myocardial infarction and death. However, stroke risk was significantly reduced by 7%-12% with the B-vitamin supplementation (26, 27). Another meta-analysis of 12 clinical trials measuring flow-mediated vasodilation (FMD; a surrogate marker of vascular health) in response to homocysteine reduction revealed that B-vitamin supplementation was accompanied by an improved FMD in short-term <8 weeks) but not in long-term studies conducted in subjects with preexisting vascular diseases (28). Yet, some of the studies included in these meta-analyses did not use vitamin B12, and folate administration on its own has shown a protective role on vascular function and stroke risk (29). Besides, the high prevalence of malabsorption disorders and vitamin B12 deficiency in elderly individuals might warrant the use of higher doses of vitamin B12 than those used in these trials (30); in cases of malabsorption, only high-dose oral therapy or intramuscular injections can overcome vitamin B12 deficiency (4).

Cancer

Folate is required for synthesis of DNA, and there is evidence that decreased availability of folate results in strands of DNA that are more susceptible to damage. Deficiency of vitamin B12 traps folate in a form that is unusable by the body for DNA synthesis. Both vitamin B12 and folate deficiencies result in a diminished capacity for methylation reactions (see Figure 3 above). Thus, vitamin B12 deficiency may lead to an elevated rate of DNA damage and altered methylation of DNA, both of which are important risk factors for cancer. A series of studies in young adults and older men indicated that increased levels of homocysteine and decreased levels of vitamin B12 in the blood were associated with a biomarker of chromosome breakage in white blood cells (reviewed in 31). In a double-blind, placebo-controlled study, the same biomarker of chromosome breakage was minimized in young adults who were supplemented with 700 μg of folic acid and 7 μg of vitamin B12 daily in cereal for two months (32).

Breast cancer

A case-control study compared prediagnostic levels of serum folate, vitamin B6, and vitamin B12 in 195 women later diagnosed with breast cancer and 195 age-matched, cancer-free women. Among postmenopausal women, the association between blood levels of vitamin B12 and breast cancer suggested a threshold effect. The risk of breast cancer was more than doubled in women with serum vitamin B12 levels in the lowest quintile compared to women in the four highest quintiles (33). However, the meta-analysis of this study with three additional case-control studies found no protection associated with high compared to low vitamin B12 serum levels (34). A case-control study in Mexican women (475 cases and 1,391 controls) reported that breast cancer risk for women in the highest quartile of vitamin B12 intake (7.3-7.7 μg/day) was 68% lower than those in the lowest quartile (2.6 μg/day). Stratification of the data revealed that the inverse association between dietary vitamin B12 intake and breast cancer risk was stronger in postmenopausal women compared to premenopausal women, though both associations were statistically significant. Moreover, among postmenopausal women, the apparent protection conferred by folate was only observed in women with the highest vitamin B12 quartiles of intake (35). However, more recent case-control and prospective cohort studies have reported weak to no risk reduction with vitamin B12 intakes in different populations, including Hispanic, African American and European American women (36, 37). A meta-analysis of seven case-control and seven prospective cohort studies concluded that the risk of breast cancer was not modified by high versus low vitamin B12 intakes (34). There was no joint association between folate and vitamin B12 intakes and breast cancer risk. Presently, there is little evidence to suggest a relationship between vitamin B12 status and breast cancer. In addition, results from observational studies are not consistently in support of an association between high dietary folate intakes and reduced risk for breast cancer (see the article on Folate). There is a need to evaluate the effect of folate and vitamin B12 supplementation in well-controlled, randomized, clinical trials, while considering various factors that modify breast cancer risk, such as menopausal status, ethnicity, and alcohol intake.

Neural tube defects

Neural tube defects (NTD) may result in anencephaly or spina bifida, which are mostly fatal congenital malformations of the central nervous system. The defects arise from failure of embryonic neural tube to close, which occurs between the 21st and 28th days after conception, a time when many women are unaware of their pregnancy (38). Randomized controlled trials have demonstrated 60% to 100% reductions in NTD cases when women consumed folic acid supplements in addition to a varied diet during the month before and the month after conception. Increasing evidence indicates that the homocysteine-lowering effect of folic acid plays a critical role in reducing the risk of NTD (39). Homocysteine may accumulate in the blood when there is inadequate folate and/or vitamin B12 for effective functioning of the methionine synthase enzyme. Decreased vitamin B12 levels and elevated homocysteine concentrations have been found in the blood and amniotic fluid of pregnant women at high risk of NTD (40). The recent meta-analysis of 12 case-control studies, including 567 mothers with current or prior NTD-affected pregnancy and 1,566 unaffected mothers, showed that low maternal vitamin B12 status was associated with an increased risk of NTD (41). Yet, whether vitamin B12 supplementation may be beneficial in the prevention of NTD has not been evaluated (42).

Cognitive decline, dementia, and Alzheimer's disease

The occurrence of vitamin B12 deficiency prevails in the elderly population and has been frequently associated with Alzheimer's disease (reviewed in 43). One study found lower vitamin B12 levels in the cerebrospinal fluid of patients with Alzheimer's disease than in patients with other types of dementia, though blood levels of vitamin B12 did not differ (44). The reason for the association of low vitamin B12 status with Alzheimer's disease is not clear. Vitamin B12 deficiency, like folate deficiency, may lead to decreased synthesis of methionine and S-adenosylmethionine (SAM), thereby adversely affecting methylation reactions. Methylation reactions are essential for the metabolism of components of the myelin sheath of nerve cells as well as for synthesis of neurotransmitters (18). Other metabolic implications of vitamin B12 deficiency include the accumulation of homocysteine and methylmalonic acid, which might contribute to the neuropathologic features of dementia (43).

Observational studies

A large majority of cross-sectional and prospective cohort studies have associated elevated homocysteine concentrations with measures of poor cognitive scores and increased risk of dementia, including Alzheimer's disease (reviewed in 45). A case-control study of 164 patients with dementia of Alzheimer's type included 76 cases in which the diagnosis of Alzheimer's disease was confirmed by examination of brain cells after death. Compared to 108 control subjects without evidence of dementia, subjects with dementia of Alzheimer's type and confirmed Alzheimer's disease had higher blood homocysteine levels and lower blood levels of folate and vitamin B12. Measures of general nutritional status indicated that the association of increased homocysteine levels and diminished vitamin B12 status with Alzheimer's disease was not due to dementia-related malnutrition (46). In a sample of 1,092 men and women without dementia followed for an average of 10 years, those with higher plasma homocysteine levels at baseline had a significantly higher risk of developing Alzheimer's disease and other types of dementia. Specifically, those with plasma homocysteine levels greater than 14 μmol/L had nearly double the risk of developing Alzheimer's disease (47). A study in 650 elderly men and women reported that the risk of elevated plasma homocysteine levels was significantly higher in those with lower cognitive function scores (48). A prospective study in 816 elderly men and women reported that those with hyperhomocysteinemia (homocysteine levels >15 μmol/L) had a significantly higher risk of developing Alzheimer's disease or dementia. Although raised homocysteine levels might be partly due to a poor vitamin B12 status, the latter was not related to risk of Alzheimer's disease or dementia in this study (49).

A recent systematic review of 35 prospective cohort studies assessing the association between vitamin B12 status and cognitive deterioration in older individuals with or without dementia at baseline did not support a relationship between vitamin B12 serum concentrations and cognitive decline, dementia, or Alzheimer's disease (50). Nevertheless, studies utilizing more sensitive biomarkers of vitamin B12 status, including measures of holo-transcobalamin (holo-TC; a vitamin B12 carrier) and methylmalonic acid, showed more consistent results and a trend toward associations between poor vitamin B12 status and faster cognitive decline and risk of Alzheimer's disease (51-55). Besides, it cannot be excluded that the co-occurrence of potential confounders like elevated homocysteine level and poor folate status might mitigate the true contribution of vitamin B12 status to cognitive functioning (45).

Intervention studies

High-dose B-vitamin supplementation has been proven effective for treating hyperhomocysteinemia in elderly individuals with or without cognitive impairment. However, homocysteine-lowering trials have produced equivocal results regarding the prevention of cognitive deterioration in this population. A systematic review and meta-analysis of 18 randomizedplacebo-controlled trials examining the effect of B-vitamin supplementation did not find that the decrease in homocysteine level prevented or delayed cognitive decline among older subjects (56). A more recent randomized, double-blind, placebo-controlled clinical trial in 900 older individuals at high risk of cognitive impairment found that daily supplementation of 400 μg of folic acid and 100 μg of vitamin B12 for two years significantly improved measures of immediate and delayed memory and slowed the rise in plasma homocysteine concentrations (57). However, supplemented subjects had no reduction in homocysteine concentrations compared to baseline, nor did they perform better in processing speed tests compared to placebo. Another two-year, randomized, placebo-controlled study in elderly adults reported that a daily regimen of 800 μg of folic acid, 500 μg of vitamin B12, and 20 mg of vitamin B6 significantly reduced the rate of brain atrophy compared to placebo treatment (0.5% vs. 3.7%). Interestingly, a greater benefit was seen in those with high compared to low homocysteine concentrations at baseline, suggesting the importance of lowering homocysteine levels in prevention of brain atrophy and cognitive decline (58, 59). The authors attributed the changes in homocysteine levels primarily to vitamin B12 (59). Finally, the most recent randomized, double blind, placebo-controlled trial in over 2,500 individuals who suffered a stroke showed that the normalization of homocysteine concentrations by B-vitamin supplementation (2 mg of folic acid, 500 μg of vitamin B12, and 25 mg of vitamin B6) did not improve cognitive performance or decrease incidence of cognitive decline compared to placebo (60). Currently, there is a need for larger trials to evaluate the effect of B-vitamin supplementation on long-term outcomes, such as the incidence of Alzheimer's disease.

Depression

Observational studies have found as many as 30% of patients hospitalized for depression are deficient in vitamin B12 (61). A cross-sectional study of 700 community-living, physically disabled women over the age of 65 found that vitamin B12-deficient women were twice as likely to be severely depressed as non-deficient women (62). A population-based study in 3,884 elderly men and women with depressive disorders found that those with vitamin B12 deficiency were almost 70% more likely to experience depression than those with normal vitamin B12 status (63). The reasons for the relationship between vitamin B12 deficiency and depression are not clear but may involve a shortage in S-adenosylmethionine (SAM). SAM is a methyl group donor for numerous methylation reactions in the brain, including those involved in the metabolism of neurotransmitters whose deficiency has been related to depression (64). Severe vitamin B12 deficiency in a mouse model showed dramatic alterations in the level of DNA methylation in the brain, which might lead to neurologic impairments (65). This hypothesis is supported by several studies that have shown supplementation with SAM improves depressive symptoms (66-69).

Increased homocysteine level is another nonspecific biomarker of vitamin B12 deficiency that has been linked to depressive symptoms in the elderly (70). However, in a recent cross-sectional study conducted in 1,677 older individuals, higher vitamin B12 plasma levels, but not changes in homocysteine concentrations, were correlated with a lower prevalence of depressive symptoms (71). Few studies have examined the relationship of vitamin B12 status, homocysteine levels, and the development of depression over time. In a randomized, placebo-controlled, intervention study with over 900 older participants experiencing psychological distress, daily supplementation with folic acid (400 μg) and vitamin B12 (100 μg) for two years did not reduce the occurrence of symptoms of depression despite significantly improving blood folate, vitamin B12, and homocysteine levels compared to placebo (72). However, in a long-term randomized, double-blind, placebo-controlled study among sufferers of cerebrovascular accidents at high risk of depression, daily supplementation with 2 mg of folic acid, 25 mg of vitamin B6, and 500 μg vitamin B12 significantly lowered the risk of major depressive episodes during a seven-year follow-up period compared to placebo (73). Although it cannot yet be determined whether vitamin B12 deficiency plays a causal role in depression, it may be beneficial to screen for vitamin B12 deficiency in older individuals as part of a medical evaluation for depression.

Osteoporosis

High homocysteine levels may affect bone remodeling by increasing bone resorption (breakdown), decreasing bone formation, and reducing bone blood flow. Another proposed mechanism involves the binding of homocysteine to the collagenous matrix of bone, which may modify collagen properties and reduce bone strength (reviewed in 74). Alterations of bone biomechanical properties can contribute to osteoporosis and increase the risk of fractures in the elderly. Since vitamin B12 is a determinant of homocysteine metabolism, it was suggested that the risk of osteoporotic fractures in older subjects might be enhanced by vitamin B12 deficiency. A meta-analysis of four observational studies, following a total of 7,475 older individuals for 3 to 16 years, found a weak association between an elevation in vitamin B12 of 50 picomoles/L in blood and a reduction in fracture risk (75). A randomized, placebo-controlled trial in 559 elderly individuals with low serum levels of folate and vitamin B12 and at increased risk of fracture evaluated the combined supplementation of very high doses of folic acid (5 mg/day) and vitamin B12 (1.5 mg/day). The two-year study found that the supplementation improved B-vitamin status, decreased homocysteine concentrations, and reduced risk of total fractures compared to placebo (76). However, a multicenter study in 5,485 subjects with cardiovascular disease or diabetes mellitus showed that daily supplementation with folic acid (2.5 mg), vitamin B12 (1 mg), and vitamin B6 (50 mg) lowered homocysteine concentrations but had no effect on fracture risk compared to placebo (77). Another small, randomized, double-blind trial in 93 individuals with low vitamin D status found no additional benefit of B-vitamin supplementation (50 mg/day of vitamin B6, 0.5 mg/day of folic acid, and 0.5 mg/day of vitamin B12) on markers of bone health over a one-year period beyond that associated with vitamin D and calcium supplementation. Yet, the short-scale of the study did not permit a conclusion on whether the lowering of homocysteine through B-vitamin supplementation could have long-term benefits on bone strength and fracture risk (78). A large intervention study conducted in older people with no preexisting conditions is under way to evaluate the effect of B-vitamin supplementation on markers of bone health and incidence of fracture; this trial might clarify whether B vitamins could have a protective effect on bone health in the elderly population (79).

Sources

Food sources

Only bacteria can synthesize vitamin B12 (80). Vitamin B12 is present in animal products, such as meat, poultry, fish (including shellfish), and to a lesser extent dairy products and eggs (1). Fresh pasteurized milk contains 0.9 μg per cup and is an important source of vitamin B12 for some vegetarians (17). Those strict vegetarians who eat no animal products (vegans) need supplemental vitamin B12 to meet their requirements. Recent analyses revealed that some plant-source foods, such as certain fermented beans and vegetables and edible algae and mushrooms, contain substantial amounts of bioactive vitamin B12 (81). Together with B-vitamin fortified food and supplements, these foods may contribute, though modestly, to prevent vitamin B12 deficiency in individuals consuming vegetarian diets. Also, individuals over the age of 50 should obtain their vitamin B12 in supplements or fortified foods (e.g., fortified cereals) because of the increased likelihood of food-bound vitamin B12 malabsorption with increasing age.

Most people do not have a problem obtaining the RDA of 2.4 μg/day of vitamin B12 in food. According to a US national survey, the average dietary intake of vitamin B12 is 5.4 μg/day for adult men and 3.4 μg/day for adult women. Adults over the age of 60 had an average dietary intake of 4.8 μg/day (42). However, consumption of any type of vegetarian diet dramatically increases the prevalence of vitamin B12 deficiency in individuals across all age groups (82). Some foods with substantial amounts of vitamin B12 are listed in Table 2, along with their vitamin B12 content in micrograms (μg). For more information on the nutrient content of specific foods, search the USDA food composition database.

Table 2. Some Food Sources of Vitamin B12
Food Serving Vitamin B12 (μg)
Clams (steamed) 3 ounces 84.1
Mussels (steamed) 3 ounces 20.4
Mackerel (Atlantic, cooked, dry-heat) 3 ounces* 16.1
Crab (Alaska king, steamed) 3 ounces 9.8
Beef (lean, plate steak, cooked, grilled) 3 ounces 6.9
Salmon (chinook, cooked, dry-heat) 3 ounces 2.4
Rockfish (cooked, dry-heat) 3 ounces 1.0
Milk (skim) 8 ounces 0.9
Turkey (cooked, roasted) 3 ounces 0.8
Brie (cheese) 1 ounce 0.5
Egg (poached) 1 large 0.4
Chicken (light meat, cooked, roasted) 3 ounces 0.3
*A three-ounce serving of meat or fish is about the size of a deck of cards.

Supplements

Cyanocobalamin is the principal form of vitamin B12 used in oral supplements, but methylcobalamin is also available as a supplement. Cyanocobalamin is available by prescription in an injectable form and as a nasal gel for the treatment of pernicious anemia. Over-the-counter preparations containing cyanocobalamin include multivitamins, vitamin B-complex supplements, and single-nutrient, vitamin B12 supplements (83).

Safety

Toxicity

No toxic or adverse effects have been associated with large intakes of vitamin B12 from food or supplements in healthy people. Doses as high as 2 mg (2,000 μg) daily by mouth or 1 mg monthly by intramuscular (IM) injection have been used to treat pernicious anemia without significant side effects (84). When high doses of vitamin B12 are given orally, only a small percentage can be absorbed, which may explain the low toxicity (4). Because of the low toxicity of vitamin B12, no tolerable upper intake level (UL) has been set by the US Food and Nutrition Board (17).

Drug interactions

A number of drugs reduce the absorption of vitamin B12. Proton-pump inhibitors (e.g., omeprazole and lansoprazole), used for therapy of Zollinger-Ellison syndrome and gastroesophageal reflux disease (GERD), markedly decrease stomach acid secretion required for the release of vitamin B12 from food but not from supplements. Long-term use of proton-pump inhibitors has been found to decrease blood vitamin B12 levels. However, vitamin B12 deficiency does not generally develop until after at least three years of continuous therapy (85, 86). Another class of gastric acid inhibitors known as histamine2 (H2)-receptor antagonists (e.g., cimetidine, famotidine, and ranitidine), often used to treat peptic ulcer disease, has also been found to decrease the absorption of vitamin B12 from food. It is not clear whether the long-term use of H2-receptor antagonists could cause overt vitamin B12 deficiency (87, 88). Individuals taking drugs that inhibit gastric acid secretion should consider taking vitamin B12 in the form of a supplement because gastric acid is not required for its absorption. Other drugs found to inhibit vitamin B12 absorption from food include cholestyramine (a bile acid-binding resin used in the treatment of high cholesterol), chloramphenicol and neomycin (antibiotics), and colchicine (medicine for gout treatment). Metformin, a medication for individuals with type 2 diabetes, was found to decrease vitamin B12 absorption by tying up free calcium required for absorption of the IF-B12 complex (89). However, the clinical significance of this is unclear (90). It is not known whether calcium supplementation can reverse vitamin B12 malabsorption; therefore, calcium supplementation is not currently prescribed for the prevention or treatment of metformin-induced vitamin B12 deficiency (91). Previous reports that megadoses of vitamin C destroy vitamin B12 have not been supported (92) and may have been an artifact of the assay used to measure vitamin B12 levels (17).

Nitrous oxide, a commonly used anesthetic, oxidizes and inactivates vitamin B12, thus inhibiting both of the vitamin B12-dependent enzymes, and can produce many of the clinical features of vitamin B12 deficiency, such as megaloblastic anemia or neuropathy. Since nitrous oxide is commonly used for surgery in the elderly, some experts feel vitamin B12 deficiency should be ruled out prior to its use (6, 15).

Large doses of folic acid given to an individual with an undiagnosed vitamin B12 deficiency could correct megaloblastic anemia without correcting the underlying vitamin B12 deficiency, leaving the individual at risk of developing irreversible neurologic damage (17). For this reason, the Food and Nutrition Board of the US Institute of Medicine advises that all adults limit their intake of folic acid (supplements and fortification) to 1,000 μg (1 mg) daily.

Linus Pauling Institute Recommendation

A varied diet should provide enough vitamin B12 to prevent deficiency in most individuals 50 years of age and younger. Strict vegetarians and women planning to become pregnant should take a multivitamin supplement daily or eat fortified cereal, which would ensure a daily intake of 6 to 30 μg of vitamin B12 in a form that is easily absorbed. Higher doses of vitamin B12 supplements are recommended for patients taking medications that interfere with its absorption (see Drug interactions).

Older adults (>50 years)

Because vitamin B12 malabsorption and vitamin B12 deficiency are more common in older adults, the Linus Pauling Institute recommends that adults older than 50 years take 100 to 400 μg/day of supplemental vitamin B12.


Authors and Reviewers

Originally written in 2000 by: 
Jane Higdon, Ph.D. 
Linus Pauling Institute
Oregon State University

Updated in March 2003 by: 
Jane Higdon, Ph.D. 
Linus Pauling Institute 
Oregon State University

Updated in August 2007 by: 
Victoria J. Drake, Ph.D. 
Linus Pauling Institute 
Oregon State University

Updated in January 2014 by: 
Barbara Delage, Ph.D. 
Linus Pauling Institute 
Oregon State University

Reviewed in April 2014 by: 
Joshua W. Miller, Ph.D. 
Professor and Chair, Department of Nutritional Sciences 
Rutgers, The State University of New Jersey

Last updated 6/4/15  Copyright 2000-2017  Linus Pauling Institute


References

1.  Brody T. Nutritional Biochemistry. 2nd ed. San Diego: Academic Press; 1999.

2.  Carmel R. Cobalamin (Vitamin B-12). In: Shils ME, Shike M, Ross AC, Caballero B, Cousins RJ, eds. Modern Nutrition in Health and Disease. Philadelphia: Lippincott Williams & Wilkins; 2006:482-497.

3.  Shane B. Folic acid, vitamin B-12, and vitamin B-6. In: Stipanuk M, ed. Biochemical and Physiological Aspects of Human Nutrition. Philadelphia: W.B. Saunders Co.; 2000:483-518.

4.  Carmel R. How I treat cobalamin (vitamin B12) deficiency. Blood. 2008;112(6):2214-2221.  (PubMed)

5.  Kozyraki R, Cases O. Vitamin B12 absorption: mammalian physiology and acquired and inherited disorders. Biochimie. 2013;95(5):1002-1007.  (PubMed)

6.  Baik HW, Russell RM. Vitamin B12 deficiency in the elderly. Annu Rev Nutr. 1999;19:357-377.  (PubMed)

7.  Neumann WL, Coss E, Rugge M, Genta RM. Autoimmune atrophic gastritis--pathogenesis, pathology and management. Nat Rev Gastroenterol Hepatol. 2013;10(9):529-541.  (PubMed)

8.  Lahner E, Persechino S, Annibale B. Micronutrients (Other than iron) and Helicobacter pylori infection: a systematic review. Helicobacter. 2012;17(1):1-15.  (PubMed)

9.  Carmel R. Megaloblastic anemias. Curr Opin Hematol. 1994;1(2):107-112.  (PubMed)

10.  Banka S, Ryan K, Thomson W, Newman WG. Pernicious anemia - genetic insights. Autoimmun Rev. 2011;10(8):455-459.  (PubMed)

11.  Lam-Tse WK, Batstra MR, Koeleman BP, et al. The association between autoimmune thyroiditis, autoimmune gastritis and type 1 diabetes. Pediatr Endocrinol Rev. 2003;1(1):22-37.  (PubMed)

12.  Checchi S, Montanaro A, Ciuoli C, et al. Prevalence of parietal cell antibodies in a large cohort of patients with autoimmune thyroiditis. Thyroid. 2010;20(12):1385-1389.  (PubMed)

13.  Ho C, Kauwell GP, Bailey LB. Practitioners' guide to meeting the vitamin B-12 recommended dietary allowance for people aged 51 years and older. J Am Diet Assoc. 1999;99(6):725-727.  (PubMed)

14.  Watkins D, Rosenblatt DS. Lessons in biology from patients with inborn errors of vitamin B12 metabolism. Biochimie. 2013;95(5):1019-1022.  (PubMed)

15.  Weir DG, Scott JM. Vitamin B12 "Cobalamin." In: Shils M, ed. Nutrition in Health and Disease. 9th ed. Baltimore: Williams & Wilkins; 1999:447-458.

16.  Herbert V. Vitamin B-12. In: Ziegler EE, Filer LJ, eds. Present Knowledge in Nutrition. 7th ed. Washington D.C.: ILSI Press; 1996:191-205.

17.  Food and Nutrition Board, Institute of Medicine. Vitamin B12. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, D.C.: National Academy Press; 1998:306-356.  (National Academy Press)

18.  Scalabrino G. The multi-faceted basis of vitamin B12 (cobalamin) neurotrophism in adult central nervous system: Lessons learned from its deficiency. Prog Neurobiol. 2009;88(3):203-220.  (PubMed)

19.  Schottker B, Adamu MA, Weck MN, Muller H, Brenner H. Helicobacter pylori infection, chronic atrophic gastritis and major cardiovascular events: a population-based cohort study. Atherosclerosis. 2012;220(2):569-574.  (PubMed)

20.  Gerhard GT, Duell PB. Homocysteine and atherosclerosis. Curr Opin Lipidol. 1999;10(5):417-428.  (PubMed)

21.  Homocysteine Lowering Trialists' Collaboration. Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials. Homocysteine Lowering Trialists' Collaboration. BMJ. 1998;316(7135):894-898.  (PubMed)

22.  Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials. Homocysteine Lowering Trialists' Collaboration. Bmj. 1998;316(7135):894-898.  (PubMed)

23.  Quinlivan EP, McPartlin J, McNulty H, et al. Importance of both folic acid and vitamin B12 in reduction of risk of vascular disease. Lancet. 2002;359(9302):227-228.  (PubMed)

24.  Stabler SP, Lindenbaum J, Allen RH. Vitamin B-12 deficiency in the elderly: current dilemmas. Am J Clin Nutr. 1997;66(4):741-749.  (PubMed)

25.  Marti-Carvajal AJ, Sola I, Lathyris D, Karakitsiou DE, Simancas-Racines D. Homocysteine-lowering interventions for preventing cardiovascular events. Cochrane Database Syst Rev. 2013;1:CD006612.  (PubMed)

26.  Huang T, Chen Y, Yang B, Yang J, Wahlqvist ML, Li D. Meta-analysis of B vitamin supplementation on plasma homocysteine, cardiovascular and all-cause mortality. Clin Nutr. 2012;31(4):448-454.  (PubMed)

27.  Ji Y, Tan S, Xu Y, et al. Vitamin B supplementation, homocysteine levels, and the risk of cerebrovascular disease: A meta-analysis. Neurology. 2013;81(15):1298-1307.  (PubMed)

28.  Potter K, Hankey GJ, Green DJ, Eikelboom J, Jamrozik K, Arnolda LF. The effect of long-term homocysteine-lowering on carotid intima-media thickness and flow-mediated vasodilation in stroke patients: a randomized controlled trial and meta-analysis. BMC Cardiovasc Disord. 2008;8:24.  (PubMed)

29.  Qin X, Xu M, Zhang Y, et al. Effect of folic acid supplementation on the progression of carotid intima-media thickness: a meta-analysis of randomized controlled trials. Atherosclerosis. 2012;222(2):307-313.  (PubMed)

30.  Spence JD. B vitamin therapy for homocysteine: renal function and vitamin B12 determine cardiovascular outcomes. Clin Chem Lab Med. 2013;51(3):633-637.  (PubMed)

31.  Fenech M. Folate (vitamin B9) and vitamin B12 and their function in the maintenance of nuclear and mitochondrial genome integrity. Mutat Res. 2012;733(1-2):21-33.  (PubMed)

32.  Fenech M. Micronucleus frequency in human lymphocytes is related to plasma vitamin B12 and homocysteine. Mutat Res. 1999;428(1-2):299-304.  (PubMed)

33.  Wu K, Helzlsouer KJ, Comstock GW, Hoffman SC, Nadeau MR, Selhub J. A prospective study on folate, B12, and pyridoxal 5'-phosphate (B6) and breast cancer. Cancer Epidemiol Biomarkers Prev. 1999;8(3):209-217.  (PubMed)

34.  Wu W, Kang S, Zhang D. Association of vitamin B6, vitamin B12 and methionine with risk of breast cancer: a dose-response meta-analysis. Br J Cancer. 2013;109(7):1926-1944.  (PubMed)

35.  Lajous M, Lazcano-Ponce E, Hernandez-Avila M, Willett W, Romieu I. Folate, vitamin B(6), and vitamin B(12) intake and the risk of breast cancer among Mexican women. Cancer Epidemiol Biomarkers Prev. 2006;15(3):443-448.  (PubMed)

36.  Yang D, Baumgartner RN, Slattery ML, et al. Dietary intake of folate, B-vitamins and methionine and breast cancer risk among Hispanic and non-Hispanic white women. PLoS One. 2013;8(2):e54495.  (PubMed)

37.  Bassett JK, Baglietto L, Hodge AM, et al. Dietary intake of B vitamins and methionine and breast cancer risk. Cancer Causes Control. 2013;24(8):1555-1563.  (PubMed)

38.  Eskes TK. Open or closed? A world of difference: a history of homocysteine research. Nutr Rev. 1998;56(8):236-244.  (PubMed)

39.  Mills JL, Scott JM, Kirke PN, et al. Homocysteine and neural tube defects. J Nutr. 1996;126(3):756S-760S.  (PubMed)

40.  Imbard A, Benoist JF, Blom HJ. Neural tube defects, folic acid and methylation. Int J Environ Res Public Health. 2013;10(9):4352-4389.  (PubMed)

41.  Wang ZP, Shang XX, Zhao ZT. Low maternal vitamin B(12) is a risk factor for neural tube defects: a meta-analysis. J Matern Fetal Neonatal Med. 2012;25(4):389-394.  (PubMed)

42.  Dror DK, Allen LH. Interventions with vitamins B6, B12 and C in pregnancy. Paediatr Perinat Epidemiol. 2012;26 Suppl 1:55-74.  (PubMed)

43.  McCaddon A. Vitamin B12 in neurology and ageing; clinical and genetic aspects. Biochimie. 2013;95(5):1066-1076.  (PubMed)

44.  Nourhashemi F, Gillette-Guyonnet S, Andrieu S, et al. Alzheimer disease: protective factors. Am J Clin Nutr. 2000;71(2):643S-649S.  (PubMed)

45.  Smith AD. The worldwide challenge of the dementias: a role for B vitamins and homocysteine? Food Nutr Bull. 2008;29(2 Suppl):S143-172.  (PubMed)

46.  Clarke R, Smith AD, Jobst KA, Refsum H, Sutton L, Ueland PM. Folate, vitamin B12, and serum total homocysteine levels in confirmed Alzheimer disease. Arch Neurol. 1998;55(11):1449-1455.  (PubMed)

47.  Seshadri S, Beiser A, Selhub J, et al. Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. N Engl J Med. 2002;346(7):476-483.  (PubMed)

48.  Ravaglia G, Forti P, Maioli F, et al. Homocysteine and cognitive function in healthy elderly community dwellers in Italy. Am J Clin Nutr. 2003;77(3):668-673.  (PubMed)

49.  Ravaglia G, Forti P, Maioli F, et al. Homocysteine and folate as risk factors for dementia and Alzheimer disease. Am J Clin Nutr. 2005;82(3):636-643.  (PubMed)

50.  O'Leary F, Allman-Farinelli M, Samman S. Vitamin B(1)(2) status, cognitive decline and dementia: a systematic review of prospective cohort studies. Br J Nutr. 2012;108(11):1948-1961.  (PubMed)

51.  Clarke R, Birks J, Nexo E, et al. Low vitamin B-12 status and risk of cognitive decline in older adults. Am J Clin Nutr. 2007;86(5):1384-1391.  (PubMed)

52.  Tangney CC, Tang Y, Evans DA, Morris MC. Biochemical indicators of vitamin B12 and folate insufficiency and cognitive decline. Neurology. 2009;72(4):361-367.  (PubMed)

53.  Kivipelto M, Annerbo S, Hultdin J, et al. Homocysteine and holo-transcobalamin and the risk of dementia and Alzheimers disease: a prospective study. Eur J Neurol. 2009;16(7):808-813.  (PubMed)

54.  Hooshmand B, Solomon A, Kareholt I, et al. Homocysteine and holotranscobalamin and the risk of Alzheimer disease: a longitudinal study. Neurology. 2010;75(16):1408-1414.  (PubMed)

55.  Hooshmand B, Solomon A, Kareholt I, et al. Associations between serum homocysteine, holotranscobalamin, folate and cognition in the elderly: a longitudinal study. J Intern Med. 2012;271(2):204-212.  (PubMed)

56.  Ford AH, Almeida OP. Effect of homocysteine lowering treatment on cognitive function: a systematic review and meta-analysis of randomized controlled trials. J Alzheimers Dis. 2012;29(1):133-149.  (PubMed)

57.  Walker JG, Batterham PJ, Mackinnon AJ, et al. Oral folic acid and vitamin B-12 supplementation to prevent cognitive decline in community-dwelling older adults with depressive symptoms--the Beyond Ageing Project: a randomized controlled trial. Am J Clin Nutr. 2012;95(1):194-203.  (PubMed)

58.  Smith AD, Smith SM, de Jager CA, et al. Homocysteine-lowering by B vitamins slows the rate of accelerated brain atrophy in mild cognitive impairment: a randomized controlled trial. PLoS One. 2010;5(9):e12244.  (PubMed)

59.  Douaud G, Refsum H, de Jager CA, et al. Preventing Alzheimer's disease-related gray matter atrophy by B-vitamin treatment. Proc Natl Acad Sci U S A. 2013;110(23):9523-9528.  (PubMed)

60.  Hankey GJ, Ford AH, Yi Q, et al. Effect of B vitamins and lowering homocysteine on cognitive impairment in patients with previous stroke or transient ischemic attack: a prespecified secondary analysis of a randomized, placebo-controlled trial and meta-analysis. Stroke. 2013;44(8):2232-2239.  (PubMed)

61.  Hutto BR. Folate and cobalamin in psychiatric illness. Compr Psychiatry. 1997;38(6):305-314.  (PubMed)

62.  Penninx BW, Guralnik JM, Ferrucci L, Fried LP, Allen RH, Stabler SP. Vitamin B(12) deficiency and depression in physically disabled older women: epidemiologic evidence from the Women's Health and Aging Study. Am J Psychiatry. 2000;157(5):715-721.  (PubMed)

63.  Tiemeier H, van Tuijl HR, Hofman A, Meijer J, Kiliaan AJ, Breteler MM. Vitamin B12, folate, and homocysteine in depression: the Rotterdam Study. Am J Psychiatry. 2002;159(12):2099-2101.  (PubMed)

64.  Mischoulon D, Fava M. Role of S-adenosyl-L-methionine in the treatment of depression: a review of the evidence. Am J Clin Nutr. 2002;76(5):1158S-1161S.  (PubMed)

65.  Fernandez-Roig S, Lai SC, Murphy MM, Fernandez-Ballart J, Quadros EV. Vitamin B12 deficiency in the brain leads to DNA hypomethylation in the TCblR/CD320 knockout mouse. Nutr Metab (Lond). 2012;9:41.  (PubMed)

66.  Bressa GM. S-adenosyl-l-methionine (SAMe) as antidepressant: meta-analysis of clinical studies. Acta Neurol Scand Suppl. 1994;154:7-14.  (PubMed)

67.  Bell KM, Plon L, Bunney WE, Jr., Potkin SG. S-adenosylmethionine treatment of depression: a controlled clinical trial. Am J Psychiatry. 1988;145(9):1110-1114.  (PubMed)

68.  Delle Chiaie R, Pancheri P, Scapicchio P. Efficacy and tolerability of oral and intramuscular S-adenosyl-L-methionine 1,4-butanedisulfonate (SAMe) in the treatment of major depression: comparison with imipramine in 2 multicenter studies. Am J Clin Nutr. 2002;76(5):1172S-1176S.  (PubMed)

69.  Williams AL, Girard C, Jui D, Sabina A, Katz DL. S-adenosylmethionine (SAMe) as treatment for depression: a systematic review. Clin Invest Med. 2005;28(3):132-139.  (PubMed)

70.  Almeida OP, McCaul K, Hankey GJ, Norman P, Jamrozik K, Flicker L. Homocysteine and depression in later life. Arch Gen Psychiatry. 2008;65(11):1286-1294.  (PubMed)

71.  Moorthy D, Peter I, Scott TM, et al. Status of vitamins B-12 and B-6 but not of folate, homocysteine, and the methylenetetrahydrofolate reductase C677T polymorphism are associated with impaired cognition and depression in adults. J Nutr. 2012;142(8):1554-1560.  (PubMed)

72.  Walker JG, Mackinnon AJ, Batterham P, et al. Mental health literacy, folic acid and vitamin B12, and physical activity for the prevention of depression in older adults: randomised controlled trial. Br J Psychiatry. 2010;197(1):45-54.  (PubMed)

73.  Almeida OP, Marsh K, Alfonso H, Flicker L, Davis TM, Hankey GJ. B-vitamins reduce the long-term risk of depression after stroke: The VITATOPS-DEP trial. Ann Neurol. 2010;68(4):503-510.  (PubMed)

74.  Vacek TP, Kalani A, Voor MJ, Tyagi SC, Tyagi N. The role of homocysteine in bone remodeling. Clin Chem Lab Med. 2013;51(3):579-590.  (PubMed)

75.  van Wijngaarden JP, Doets EL, Szczecinska A, et al. Vitamin B12, folate, homocysteine, and bone health in adults and elderly people: a systematic review with meta-analyses. J Nutr Metab. 2013;2013:486186.  (PubMed)

76.  Sato Y, Honda Y, Iwamoto J, Kanoko T, Satoh K. Effect of folate and mecobalamin on hip fractures in patients with stroke: a randomized controlled trial. JAMA. 2005;293(9):1082-1088.  (PubMed)

77.  Sawka AM, Ray JG, Yi Q, Josse RG, Lonn E. Randomized clinical trial of homocysteine level lowering therapy and fractures. Arch Intern Med. 2007;167(19):2136-2139.  (PubMed)

78.  Herrmann W, Kirsch SH, Kruse V, et al. One year B and D vitamins supplementation improves metabolic bone markers. Clin Chem Lab Med. 2013;51(3):639-647.  (PubMed)

79.  van Wijngaarden JP, Dhonukshe-Rutten RA, van Schoor NM, et al. Rationale and design of the B-PROOF study, a randomized controlled trial on the effect of supplemental intake of vitamin B12 and folic acid on fracture incidence. BMC Geriatr. 2011;11:80.  (PubMed)

80.  LeBlanc JG, Milani C, de Giori GS, Sesma F, van Sinderen D, Ventura M. Bacteria as vitamin suppliers to their host: a gut microbiota perspective. Curr Opin Biotechnol. 2013;24(2):160-168.  (PubMed)

81.  Watanabe F, Yabuta Y, Tanioka Y, Bito T. Biologically active vitamin B12 compounds in foods for preventing deficiency among vegetarians and elderly subjects. J Agric Food Chem. 2013;61(28):6769-6775.  (PubMed)

82.  Pawlak R, Parrott SJ, Raj S, Cullum-Dugan D, Lucus D. How prevalent is vitamin B(12) deficiency among vegetarians? Nutr Rev. 2013;71(2):110-117.  (PubMed)

83.  Hendler SS, Rorvik DR, eds. PDR for Nutritional Supplements. Montvale: Medical Economics Company, Inc; 2001.

84.  Kuzminski AM, Del Giacco EJ, Allen RH, Stabler SP, Lindenbaum J. Effective treatment of cobalamin deficiency with oral cobalamin. Blood. 1998;92(4):1191-1198.  (PubMed)

85.  Dharmarajan TS, Kanagala MR, Murakonda P, Lebelt AS, Norkus EP. Do acid-lowering agents affect vitamin B12 status in older adults? J Am Med Dir Assoc. 2008;9(3):162-167.  (PubMed)

86.  Wilhelm SM, Rjater RG, Kale-Pradhan PB. Perils and pitfalls of long-term effects of proton pump inhibitors. Expert Rev Clin Pharmacol. 2013;6(4):443-451.  (PubMed)

87.  Valuck RJ, Ruscin JM. A case-control study on adverse effects: H2 blocker or proton pump inhibitor use and risk of vitamin B12 deficiency in older adults. J Clin Epidemiol. 2004;57(4):422-428.  (PubMed)

88. Termanini B, Gibril F, Sutliff VE, Yu F, Venzon DJ, Jensen RT. Effect of long-term gastric acid suppressive therapy on serum vitamin B12 levels in patients with Zollinger-Ellison syndrome. Am J Med. 1998;104(5):422-430.  (PubMed)

89.  Bauman WA, Shaw S, Jayatilleke E, Spungen AM, Herbert V. Increased intake of calcium reverses vitamin B12 malabsorption induced by metformin. Diabetes Care. 2000;23(9):1227-1231.  (PubMed)

90.  Obeid R. Metformin causing vitamin B12 deficiency: a guilty verdict without sufficient evidence. Diabetes Care. 2014;37(2):e22-23.  (PubMed)

91.  Mazokopakis EE, Starakis IK. Recommendations for diagnosis and management of metformin-induced vitamin B12 (Cbl) deficiency. Diabetes Res Clin Pract. 2012;97(3):359-367.  (PubMed)

92.  Simon JA, Hudes ES. Relation of serum ascorbic acid to serum vitamin B12, serum ferritin, and kidney stones in US adults. Arch Intern Med. 1999;159(6):619-624.  (PubMed) 

Vitamin C

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Summary

Function

Vitamin C is a potent reducing agent, meaning that it readily donates electrons to recipient molecules. Related to this oxidation-reduction (redox) potential, two major functions of vitamin C are as an antioxidant and as an enzyme cofactor (1, 2).

Vitamin C is the primary water-soluble, non-enzymatic antioxidant in plasma and tissues (1, 2). Even in small amounts vitamin C can protect indispensable molecules in the body, such as proteins, lipids (fats), carbohydrates, and nucleic acids (DNA and RNA), from damage by free radicals and reactive oxygen species (ROS) that are generated during normal metabolism, by active immune cells, and through exposure to toxins and pollutants (e.g., certain chemotherapy drugs and cigarette smoke). Vitamin C also participates in redox recycling of other important antioxidants; for example, vitamin C is known to regenerate vitamin E from its oxidized form (3, 4).

Vitamin C’s role as a cofactor is also related to its redox potential. By maintaining enzyme-bound metals in their reduced forms, vitamin C assists mixed-function oxidases in the synthesis of several critical biomolecules (1, 2). Symptoms of vitamin C deficiency, such as poor wound healing and lethargy, result from impairment of these enzymatic reactions and insufficient collagen, carnitine, and catecholamine synthesis (see Deficiency). Research also suggests that vitamin C is involved in the metabolism of cholesterol to bile acids, which may have implications for blood cholesterol levels and the incidence of gallstones (5).

Finally, vitamin C increases the bioavailability of iron from foods by enhancing intestinal absorption of non-heme iron (1) (see the article on Iron).

Bioavailability

Depletion-repletion pharmacokinetic experiments demonstrated that plasma vitamin C concentration is tightly controlled by three primary mechanisms: intestinal absorption, tissue transport, and renal reabsorption (6). In response to increasing oral doses of vitamin C, plasma vitamin C concentration rises steeply at doses between 30 and 100 mg/day and reaches a steady-state concentration (60 to 80 μmol/L) at doses of 200 to 400 mg/day in healthy young adults (7, 8). One hundred percent absorption efficiency is observed when ingesting vitamin C at doses up to 200 mg at a time. Once plasma ascorbic acid levels reach saturation, additional vitamin C is largely excreted in the urine. Notably, intravenous administration of vitamin C bypasses absorptive control in the intestine such that very high concentrations of ascorbic acid can be achieved in the plasma; over time, renal excretion restores vitamin C to baseline plasma levels (9) (see Cancer Treatment).

While plasma vitamin C concentration reflects recent dietary intake, leukocyte (white blood cell) vitamin C is thought to more closely reflect tissue stores. However, a recent randomized controlled trial (RCT) demonstrated that human skeletal muscle, a major body pool for vitamin C, is highly labile and more responsive to vitamin C intake than neutrophils or mononuclear cells (encompassing the major types of leukocytes) (10). Thus, leukocyte vitamin C concentration does not accurately reflect skeletal muscle ascorbic acid, and may underestimate muscle tissue ascorbic acid uptake. However, plasma concentrations of ascorbic acid ≥50 μmol/L are sufficient to saturate muscle tissue vitamin C.

Due to the pharmacokinetics and tight regulation of plasma ascorbic acid, supplementation with vitamin C will have variable effects in vitamin C-replete (plasma levels near saturation) versus sub-optimal (plasma levels <50 μmol/L), marginally deficient (plasma levels <28 μmol/L), or severely deficient (plasma levels <11 μmol/L) individuals. Scientific studies investigating vitamin C efficacy to prevent or treat disease need to assess baseline vitamin C status before embarking on an intervention or statistical analysis (6, 11-13).

For a more detailed discussion on the bioavailability of different forms of vitamin C, see the article, The Bioavailability of Different Forms of Vitamin C .

Deficiency

Severe vitamin C deficiency has been known for many centuries as the potentially fatal disease, scurvy. By the late 1700s the British navy was aware that scurvy could be cured by eating oranges or lemons, even though ascorbic acid would not be isolated until the early 1930s. Symptoms of scurvy include subcutaneous bleeding, poor wound closure, and bruising easily, hair and tooth loss, and joint pain and swelling. Such symptoms appear to be related to the weakening of blood vessels, connective tissue, and bone, which all contain collagen. Early symptoms of scurvy like fatigue may result from diminished levels of carnitine, which is needed to derive energy from fat, or from decreased synthesis of the catecholamine norepinephrine (see Function). Scurvy is rare in developed countries because it can be prevented by as little as 10 mg of vitamin C daily (14). However, cases have occurred in children and the elderly on very restricted diets (15, 16).

The Recommended Dietary Allowance (RDA)

In the US, the recommended dietary allowance (RDA) for vitamin C was revised in 2000 upward from the previous recommendation of 60 mg daily for men and women (Table 1). The RDA is based on the amount of vitamin C intake necessary to maintain neutrophil concentration with minimal urinary excretion of ascorbic acid, presumed to provide sufficient antioxidant protection (17). The recommended intake for smokers is 35 mg/day higher than for nonsmokers, because smokers are under increased oxidative stress from the toxins in cigarette smoke and generally have lower blood levels of vitamin C.

Table 1. Recommended Dietary Allowance (RDA) for Vitamin C
Life Stage Age Males (mg/day) Females (mg/day)
Infants 0-6 months 40 (AI) 40 (AI)
Infants 7-12 months 50 (AI) 50 (AI)
Children 1-3 years 15 15
Children 4-8 years 25 25
Children 9-13 years 45 45
Adolescents 14-18 years 75 65
Adults 19 years and older 90 75
Smokers 19 years and older 125 110
Pregnancy 18 years and younger - 80
Pregnancy    19 years and older - 85
Breast-feeding     18 years and younger - 115
Breast-feeding 19 years and older - 120

Disease Prevention

The amount of vitamin C required to help prevent chronic disease is higher than the amount required for prevention of scurvy. Information regarding vitamin C and the prevention of chronic disease is based on both observational prospective cohort studies and randomized controlled trials (RCTs) (3, 11). Prospective cohort studies assess vitamin C intake or body status in large numbers of people who are followed over time to determine whether they develop a specific chronic disease outcome. RCTs evaluate the effect of vitamin C supplementation on the reduction of chronic disease in participants randomly assigned to receive either vitamin C or placebo for a given length of time.

Cardiovascular disease

Coronary heart disease

Coronary heart disease (CHD) is characterized by the build-up of plaque inside the arteries that supply blood to the heart (atherosclerosis). Over years of build-up and accumulated damage to the coronary arteries, CHD may culminate in a myocardial infarction or heart attack. Many prospective cohort studies have examined the relationship between vitamin C intake from diet and supplements and CHD risk, the results of which have been pooled and analyzed in two separate studies (18, 19). In 2004, a pooled analysis of nine prospective cohort studies found that supplemental vitamin C intake (≥400 mg/day for a mean of 10 years), but not dietary vitamin C intake, was inversely associated with CHD risk (18). Conversely, a 2008 meta-analysis of 14 cohort studies concluded that dietary, but not supplemental, vitamin C intake was inversely related to CHD risk (19). The most recent large prospective cohort study found an inverse association between dietary vitamin C intake and CHD mortality in Japanese women, but not in men (20). In spite of the variable association depending on source, these analyses indicate an overall inverse association between higher vitamin C intakes and CHD risk.

Limitations inherent to dietary assessment methodology, such as recall bias, measurement error, and residual confounding, may account for some of the inconsistent associations between vitamin C intake and CHD risk. In order to overcome such limitations, some prospective studies measured plasma or serum levels of vitamin C as a more reliable index of vitamin C intake and biomarker of body vitamin C status. The European Investigation into Cancer and Nutrition (EPIC)-Norfolk prospective cohort study investigated the relationship between vitamin C status and incident heart failure in healthy adults (9,187 men and 11,112 women, aged 58.1±9.2 years) (21). After a mean follow-up of 12.8 years, plasma vitamin C was inversely associated with incident cases of heart failure. Specifically, plasma vitamin C ranged from approximately 23-70 μmol/L in men and 33-82 μmol/L in women; across this range, every 20 μmol/L increase in plasma vitamin C was associated with a 9% reduction in risk of heart failure. Self-reported consumption of fruit and vegetables assessed by food frequency questionnaire was not associated with heart failure, consistent with the notion that limitations associated with dietary assessment methods may be overcome by using biomarkers of nutrient intake (22, 23).

A meta-analysis of 13 randomized controlled trials (RCTs) assessed the effect of vitamin C supplementation on serum cholesterol and triglycerides — established risk factors for cardiovascular disease (CVD) (24). The analysis included 549 hypercholesterolemic subjects, with an age range of 48-82 years, who received vitamin C supplements or placebo at doses ranging from 500 to 2,000 mg/day for 4 to 24 weeks. Overall, vitamin C supplementation significantly reduced serum levels of low-density lipoprotein cholesterol (LDL-C) (-7.9 mg/dL, 95% Confidence Interval (CI): -12.3 to -3.5) and serum triglycerides (-20.1 mg/dL, 95% CI: -33.3 to -6.8), but had no effect on serum levels of high-density lipoprotein cholesterol (HDL-C). On the other hand, an RCT in more than 14,000 older men participating in the Physicians' Health Study II found that vitamin C supplementation (500 mg/day) for an average of eight years had no significant effect on major cardiovascular events, total myocardial infarction, or cardiovascular mortality (25). Notably, this study had several limitations (26), including no measurement of vitamin C status and the recruitment of a well-nourished study population. See the Linus Pauling Institute’s Response to the PHS II Study for a more extensive discussion.

Overall, results of individual and pooled analyses of large prospective studies in conjunction with pharmacokinetic data of vitamin C in humans (see Bioavailability) and RCTs suggest that maximal reduction of CHD risk may require vitamin C intakes of 400 mg/day or more (27).

Stroke

A cerebrovascular event, or stroke, can be classified as hemorrhagic or ischemic. Hemorrhagic stroke occurs when a weakened blood vessel ruptures and bleeds into the surrounding brain tissue. Ischemic stroke occurs when an obstruction within a blood vessel blocks blood flow to the brain. Most (~80%) cerebrovascular events are ischemic in nature and associated with atherosclerosis as an underlying condition (28).

With respect to vitamin C and cerebrovascular disease, a prospective cohort study that followed more than 2,000 residents of a rural Japanese community for 20 years found that the risk of stroke in those with the highest serum levels of vitamin C was 29% lower than in those with the lowest serum levels of vitamin C (29). Additionally, the risk of stroke in those who consumed vegetables 6-7 days of the week was 54% lower than in those who consumed vegetables 0-2 days of the week. Similarly, the EPIC-Norfolk study, a 10-year prospective cohort study in 20,649 adults, found that individuals with plasma vitamin C levels in the top quartile (25%) had a 42% lower risk of stroke compared to those in the lowest quartile (30). In both the Japanese (29) and EPIC-Norfolk (30) populations, serum levels of vitamin C were highly correlated with fruit and vegetable intake. Therefore, as in many studies of vitamin C intake and chronic disease risk, it is difficult to separate the effects of vitamin C from the effects of other components of fruit and vegetables, emphasizing the benefits of a diet rich in fruit and vegetables in reducing stroke risk. For example, potassium—found at high levels in bananas, potatoes, and other fruit and vegetables—is known to be important in blood pressure regulation, and elevated blood pressure is a major risk factor for stroke (see the article on Potassium). Hence, plasma vitamin C levels may be a good biomarker for fruit and vegetable intake and other lifestyle factors that contribute to a reduced risk of stroke.

Some studies have investigated the effect of vitamin C supplementation on specific types of stroke. A small RCT performed in 60 ischemic stroke patients demonstrated that intravenous vitamin C supplementation (500 mg/day for 10 days, initiated day 1 post-stroke) had no effect on serum markers of oxidative stress or neurological outcomes compared to placebo, which was administered to both ischemic stroke patients and healthy controls (31). A randomized, double-blind, placebo-controlled trial in more than 14,000 older men participating in the Physicians’ Health Study II (PHS II) found that vitamin C supplementation (500 mg/day) for an average of eight years had no significant effect on the incidence of or mortality from any type of stroke (25). However, this study had numerous limitations that make it difficult to draw conclusions for the general population (26); see the Linus Pauling Institute’s Response to the PHS II Study.

Hypertension

In an analysis that combined data from three, large, independent prospective cohorts: (1) Nurses' Health Study 1 (NHS1; 88,540 women, median age 49 years); (2) Nurses' Health Study 2 (NHS2; 97,315 women, median age 36 years); and (3) Health Professionals Follow-up Study (HPFS; 37,375 men, median age 52 years), higher intakes of fructose and vitamin C were not associated with the risk for developing hypertension (32). On the other hand, when plasma vitamin C concentration is measured, thus overcoming some of the limitations of dietary assessment (23), cross-sectional studies consistently indicate that plasma vitamin C concentration is inversely related to blood pressure in both men and women (33-35).

Cancer

Overall, observational prospective cohort studies report no or modest inverse associations between vitamin C intake and the risk of developing a given type of cancer (3, 36-38). Additional detail is provided below for those cancer subtypes with substantial scientific information obtained from prospective cohort studies. Randomized, double-blind, placebo-controlled trials that have tested the effect of vitamin C supplementation (alone or in combination with other antioxidant nutrients) on cancer incidence or mortality have shown no effect (39).

Breast cancer

Two large, prospective studies found dietary vitamin C intake to be inversely associated with breast cancer incidence in certain subgroups. In the Nurses' Health Study, premenopausal women with a family history of breast cancer who consumed an average of 205 mg/day of vitamin C from foods had a 63% lower risk of breast cancer than those who consumed an average of 70 mg/day (40). In the Swedish Mammography Cohort, overweight women who consumed an average of 110 mg/day of vitamin C had a 39% lower risk of breast cancer compared to overweight women who consumed an average of 31 mg/day (41). More recent prospective cohort studies have found no association between dietary and/or supplemental vitamin C intake and breast cancer (42-44).

Stomach cancer

A number of observational studies have found increased dietary vitamin C intake to be associated with decreased risk of stomach cancer, and laboratory experiments indicate that vitamin C inhibits the formation of carcinogenic N-nitroso compounds in the stomach (45-47). A nested case-control study in the EPIC study found an inverse association between plasma vitamin C and gastric cancer incidence in the highest (≥51 μmol/L) versus lowest (<29 μmol/L) quartiles of plasma vitamin C concentration (Odds Ratio (OR): 0.55, 95% CI: 0.31-0.97); no association between dietary vitamin C intake and gastric cancer risk was observed (48).

Infection with the bacteria, Helicobacter pylori (H. pylori), is known to increase the risk of stomach cancer and is associated with lower vitamin C content of stomach secretions (49, 50). Although two intervention studies did not find a decrease in the occurrence of stomach cancer with vitamin C supplementation (17), more recent research suggests that vitamin C supplementation may be a useful addition to standard H. pylori eradication therapy in reducing the risk of gastric cancer (51). Because vitamin C can inactivate urease, an enzyme that facilitates H. pylori survival and colonization of the gastric mucosa at low pH, vitamin C may be most effective as a prophylactic agent in those without achlorhydria (52).

Colon cancer

By pooling data from 13 cohort studies comprising 676,141 participants, it was determined that dietary intake of vitamin C was not associated with colon cancer, while total intake of vitamin C (i.e., from food and supplements) was associated with a modestly reduced risk of colon cancer (Relative Risk (RR): 0.81, 95% CI: 0.71-0.92, >600 vs. ≤100 mg/day) (53). Each of the cohort studies used self-administered food frequency questionnaires at baseline to assess vitamin C intake. Although the analysis adjusted for several lifestyle and known risk factors, the authors note that other healthy behaviors and/or folate intake may have confounded the association.

Non-Hodgkin lymphoma (NHL)

A population-based, prospective study, the Iowa Women’s Health Study, collected baseline data on diet and supplement use in 35,159 women (aged 55-69 years) and evaluated the risk of developing NHL after 19 years of follow-up (54). Overall, an inverse association between fruit and vegetable intake and risk of NHL was observed. Additionally, dietary, but not supplemental, intake of vitamin C and other antioxidant nutrients (carotenoids, proanthocyanidins, and manganese) was inversely associated with NHL risk, suggesting that the association of NHL with these individual antioxidants may be mediated through food sources. The Women's Health Initiative was a large, multi-center, prospective study that assessed the association between antioxidant nutrient intake and risk of NHL, among other chronic diseases, in 154,363 postmenopausal women (55). After 11 years of follow-up, dietary and supplemental vitamin C intake at baseline was inversely associated with diffuse B-cell lymphoma, a subtype of NHL.

Alzheimer's disease

The majority of large, population-based studies examining the relationship of ascorbic acid intake or supplementation with Alzheimer's disease (AD) incidence have reported null results (56). Notably, these types of studies are limited by subjective measures of ascorbic acid exposure, which may be even less reliable in cognitively impaired study participants. To overcome this study limitation, the relationship between plasma vitamin C (a marker of body vitamin C status) and cognitive function has been examined in some observational studies. Overall, higher plasma ascorbic acid is associated with better cognitive function or lower risk of cognitive impairment (56), and plasma ascorbic acid concentration tends to be lower in AD patients (57).

Few studies have measured ascorbic acid concentration in the cerebrospinal fluid (CSF), which is thought to more closely reflect the vitamin C status of the brain. Ascorbic acid is concentrated in the brain through a combination of active transport into brain tissue and retention via the blood-brain barrier (BBB) (56). Although CSF vitamin C is maintained at levels several-fold higher than plasma vitamin C, the precise function of vitamin C in cognitive function and AD etiology is not yet known. In a small, longitudinal biomarker study in 32 individuals with probable AD, a higher CSF to plasma ascorbic acid ratio at baseline was associated with a slower rate of cognitive decline at one year of follow-up (58). The strength of this relationship was modified by the CSF Albumin Index, a marker of BBB integrity; this suggests that BBB dysfunction may lead to diffusion of AA from the central nervous system and impair the brain’s ability to maintain a high CSF:plasma ascorbic acid ratio. The significance of the CSF:plasma ascorbic acid ratio in AD progression requires further study.

The effect of vitamin C supplementation, in combination with other antioxidants, on CSF biomarkers and cognitive function has been tested in two trials involving AD patients. In a small (n=23), open-label trial, combined supplementation with vitamin C (1,000 mg/day) and vitamin E (400 IU/day) to AD patients taking a cholinesterase inhibitor significantly increased antioxidant levels and decreased lipoprotein oxidation in CSF after one year, but had no effect on the clinical course of AD compared to controls (59). A similar finding was obtained in a double-blind, randomized controlled trial (RCT) in which combined supplementation with vitamin C (500 mg/day), vitamin E (800 IU/day), and alpha-lipoic acid (900 mg/day) for 16 weeks reduced lipoprotein oxidation in CSF, but elicited no clinical benefit in individuals with mild-to-moderate AD (n=78) (60). In this latter trial, a greater decline in Mini Mental State Examination (MMSE) score was observed in the supplemented group, however, the significance of this observation remains unclear.

At this time, avoidance of ascorbic acid deficiency or insufficiency, rather than supplementation in replete individuals, seems prudent for the promotion of healthy brain aging (57).

Cataracts

The lens of the eye focuses light, producing a clear, sharp image on the retina, a layer of tissue on the inside back wall of the eyeball. Age-related changes to the lens (thickening, loss of flexibility) and oxidative damage contribute to the formation of cataract, cloudiness or opacity in the lens that interferes with the clear focusing of images on the retina.

Decreased vitamin C levels in the lens of the eye have been associated with increased severity of cataracts (61). Some, but not all, observational studies have reported that increased dietary intake (62-64) or increased concentration of vitamin C in the blood (65, 66) is associated with decreased risk of cataract formation. In general, those studies that have found a relationship suggest that vitamin C intake may have to be higher than 300 mg/day for a number of years before a protective effect can be detected (3).

A 2012 Cochrane review of RCTs concluded that there is no evidence that single or mixed antioxidant vitamin supplements (beta-carotene, vitamin C, and vitamin E) influence the development or progression of age-related cataract (67). In fact, two prospective cohort studies in Swedish men (68) and women (69) reported that high-dose single nutrient supplements of vitamin C were associated with increased risk of cataract, especially in those on corticosteroid therapy.

Although RCTs have not supported the use of high-dose supplementation with vitamin C in cataract prevention, there is a consistent inverse association observed between high daily intake of fruit and/or vegetables (>5 servings/day) and risk of cataract (64).

Gout

Gout, a condition that afflicts more than 4% of US adults (70), is characterized by abnormally high blood levels of uric acid (urate) (71). Urate crystals may form in joints, resulting in inflammation and pain, as well as in the kidneys and urinary tract, resulting in kidney stones. The tendency to develop elevated blood uric acid levels and gout is often inherited; however, dietary and lifestyle modification may be helpful in both the prevention and treatment of gout (72). In an observational study that included 1,387 men, higher intakes of vitamin C were associated with lower serum levels of uric acid (73). More recently, a prospective study that followed a cohort of 46,994 men for 20 years found that total daily vitamin C intake was inversely associated with incidence of gout, with higher intakes being associated with greater risk reductions (74). The results of this study also indicated that supplemental vitamin C may be helpful in the prevention of gout (74).

A recent meta-analysis of 13 RCTs revealed that vitamin C supplementation (a median dose of 500 mg/day for a median duration of 30 days) modestly reduced serum uric acid concentrations by -0.35 mg/dL compared to placebo (95% CI: -0.66, -0.03) (75). Though lowering serum uric acid may help prevent incident and recurrent gout, more studies are needed to test this possibility.

Role in immunity

Vitamin C affects several components of the human immune system; for example, vitamin C has been shown to stimulate both the production (76-80) and function (81, 82) of leukocytes (white blood cells), especially neutrophils, lymphocytes, and phagocytes. Specific measures of functions stimulated by vitamin C include cellular motility (82), chemotaxis (81, 82), and phagocytosis (81). Neutrophils, mononuclear phagocytes, and lymphocytes accumulate vitamin C to high concentrations, which can protect these cell types from oxidative damage (80, 83, 84). In response to invading microorganisms, phagocytic leukocytes release non-specific toxins, such as superoxide radicals, hypochlorous acid ("bleach"), and peroxynitrite; these reactive oxygen species kill pathogens and, in the process, can damage the leukocytes themselves (85). Vitamin C, through its antioxidant functions, has been shown to protect leukocytes from self-inflicted oxidative damage (86). Phagocytic leukocytes also produce and release cytokines, including interferons, which have antiviral activity (87). Vitamin C has been shown to increase interferon levels in vitro (88).

It is widely thought by the general public that vitamin C boosts immune function, yet human studies published to date are conflicting. Additional controlled clinical trials are necessary to conclusively demonstrate that supplemental vitamin C enhances the function of the immune system in adequately nourished individuals.

Mortality

Two large prospective cohort studies assessed the relationship between vitamin C intake from both dietary and supplemental sources and mortality. In the Vitamins and Lifestyle Study, 55,543 men and women (aged 50-76 years) were questioned at baseline on their use of dietary supplements during the previous 10 years (89). After five years of follow-up, vitamin C supplement use was associated with a small decreased risk of total mortality, though no association was found with CVD- or cancer-specific mortality. In the second prospective cohort study, the Diet, Cancer and Health Study, 55,543 Danish adults (aged 50-64 years) were questioned at baseline about their lifestyle, diet, and supplement use during the previous 12 months (90). No association between dietary or supplemental intake of vitamin C and mortality was found after approximately 14 years of follow-up.

In contrast to these dietary assessment studies, a strong inverse association between plasma ascorbic acid and mortality from all-causes, CVD, and ischemic heart disease (and cancer in men only) was observed in the EPIC-Norfolk multicenter, prospective cohort study (91). After approximately four years of follow-up in 19,496 men and women (aged 45-79 years), a continuous relationship was observed such that each 20 μmol/L increase in plasma ascorbic acid was associated with an ~20% risk reduction in all-cause mortality. Similarly, higher serum vitamin C levels were associated with decreased risks of cancer- and all-cause mortality in 16,008 adults from NHANES III (1994-1998) (92).

Disease Treatment

Cardiovascular disease

Vasodilation

The ability of blood vessels to relax or dilate (vasodilation) is compromised in individuals with atherosclerosis. Damage to the heart muscle caused by a heart attack and damage to the brain caused by a stroke are related, in part, to the inability of blood vessels to dilate enough to allow blood flow to the affected areas. The pain of angina pectoris is also related to insufficient dilation of the coronary arteries. Impaired vasodilation has been identified as an independent risk factor for cardiovascular disease (93). Many randomized, double-blind, placebo-controlled studies have shown that treatment with vitamin C consistently results in improved vasodilation in individuals with coronary heart disease, as well as those with angina pectoris, congestive heart failure, diabetes, high cholesterol, and high blood pressure (3, 94-96). Improved vasodilation has been demonstrated at an oral dose of 500 mg of vitamin C daily (94).

Hypertension

A recent meta-analysis of 29 short-term trials (each trial included 10 to 120 participants) indicated that vitamin C supplementation at a median dose of 500 mg/day for a median duration of eight weeks reduced blood pressure in both healthy, normotensive and hypertensive adults (97). In normotensive individuals, the pooled changes in systolic and diastolic blood pressure were -3.84 mm Hg and -1.48 mm Hg, respectively; in hypertensive participants, corresponding reductions were -4.85 mm Hg and -1.67 mm Hg. The significance of the blood pressure-lowering effect of vitamin C on CVD risk has not yet been determined (98). It is important for individuals with significantly elevated blood pressure not to rely on vitamin C supplementation alone to treat their hypertension, but to seek or continue therapy with anti-hypertensive medication and through diet and lifestyle changes in consultation with their health care provider. For information on dietary and lifestyle strategies to control blood pressure, see the article in the Spring/Summer 2009 Research Newsletter.

Diabetes mellitus

A strong inverse association between plasma vitamin C and risk of diabetes mellitus has been reported in a cohort of 21,831 men and women from the EPIC study (99). Additionally, two large, population-based cross-sectional studies reported an inverse association between serum or plasma vitamin C concentration and hemoglobin A1c level, an indicator of glucose control (100, 101).

Cardiovascular disease (CVD) are the leading cause of death in individuals with diabetes. Evidence that diabetes is a condition of increased oxidative stress led to the hypothesis that higher intakes of antioxidant nutrients could help decrease CVD risk in diabetic individuals. A 16-year prospective study of 85,000 women, 2% of whom were diabetic, found that vitamin C supplement use (400 mg/day or more) was associated with significant reductions in the risk of fatal and nonfatal coronary heart disease in the entire cohort as well as in those with diabetes (102). In contrast, a 15-year prospective study of postmenopausal women found that diabetic women (N = 1,923) who reported taking at least 300 mg/day of vitamin C from supplements when the study began were at significantly higher risk of death from CVD (RR: 1.69, 95% CI: 1.09, 2.44), coronary artery disease (RR: 2.07, 95% CI: 1.27, 3.38), and stroke (RR: 2.37, 95% CI: 1.01, 5.57) than those who did not take vitamin C supplements (103). Vitamin C supplement use was not associated with a significant increase in CVD mortality in the cohort as a whole. Randomized controlled trials have not found antioxidant supplementation that included vitamin C to reduce the risk of CVD in diabetic or other high-risk individuals (101, 105).

It is possible that genetic differences may influence the effect of vitamin C supplementation on CVD risk in diabetic patients. When the results of one randomized controlled trial were reanalyzed based on haptoglobin genotype, antioxidant therapy (1,000 mg/day of vitamin C + 800 IU/day of vitamin E) was associated with improvement of coronary atherosclerosis in diabetic women with two copies of the haptoglobin 1 gene but worsening of coronary atherosclerosis in those with two copies of the haptoglobin 2 gene (106).

Cancer

Studies in the 1970s and 1980s conducted by Linus Pauling, Ewan Cameron, and colleagues suggested that very large doses of vitamin C (10 grams/day infused intravenously for 10 days followed by at least 10 grams/day orally indefinitely) were helpful in increasing the survival time and improving the quality of life of terminal cancer patients (107). Controversy surrounding the efficacy of vitamin C in cancer treatment ensued, leading to the recognition that the route of vitamin C administration is critical (6, 108). Compared to orally administered vitamin C, intravenous vitamin C can result in 30 to 70-fold higher plasma levels of vitamin C (9). The higher plasma levels achieved via intravenous ascorbic acid administration are comparable to those that are toxic to cancer cells in culture. The anticancer mechanism of intravenous vitamin C action is under investigation. It may involve the production of high levels of hydrogen peroxide, selectively toxic to cancer cells (6, 109-111), or the deactivation of hypoxia inducible factor, a prosurvival transcription factor that protects cancer cells from various forms of stress (108, 112, 113).

Currently, results from controlled clinical trials indicate that intravenous vitamin C is generally safe and well tolerated in cancer patients. Four phase I clinical trials in patients with advanced cancer found that intravenous administration of vitamin C at doses up to 1.5 g/kg of body weight and 70-80 g/m2 was well tolerated and safe in pre-screened patients (114-117). A retrospective analysis of breast cancer patients reported that complementary intravenous ascorbic acid treatment reduced quality-of-life related side effects of chemotherapy (118). A phase I study in nine patients with metastatic pancreatic cancer showed that millimolar levels of plasma ascorbic acid could be reached safely when administered in conjunction with the cancer chemotherapy drugs, gemcitabine and erlotinib (116).

In a pilot study performed in 15 patients with refractory myelodisplastic syndrome or acute myeloid leukemia, an alternating ascorbic acid depletion/intravenous repletion protocol was safe and elicited a clinical response in a subset of nine patients (119). Retrospective in vitro colony formation assays revealed that patient leukemic cells displayed variable sensitivity to ascorbic acid treatment: leukemic cells from seven out of the nine patients who experienced a significant clinical benefit were sensitive to ascorbic acid in vitro (i.e., "responders"); the leukemic cells from the remaining six patients were not sensitive to ascorbic acid (i.e., "non-responders"). Thus, in vitro ascorbic acid sensitivity assays may provide predictive value for the clinical response to intravenous vitamin C treatment. The mechanisms underlying differential sensitivity to ascorbic acid are under investigation. In vitro experiments performed using 11 different cancer cell lines demonstrated that sensitivity to ascorbic acid correlated with the expression of catalase, an enzyme involved in the decomposition of hydrogen peroxide (120). Approximately half of the cell lines tested were resistant to ascorbic acid cytotoxicity, a response associated with high levels of catalase activity. Sensitivity to ascorbic acid may also be determined by the expression of sodium-dependent vitamin C transporter-2 (SVCT-2), which transports ascorbic acid into cells (121). Higher SVCT-2 levels were associated with enhanced sensitivity to L-ascorbic acid in nine different breast cancer cell lines. Moreover, SVCT-2 was significantly expressed in 20 breast cancer tissue samples, but weakly expressed in normal tissues.

These pilot and phase I study results motivate larger, longer-duration phase II clinical trials that test the efficacy of intravenous ascorbic acid in disease progression and overall survival. Such phase II clinical trials are currently under way (122). Because different cancer subtypes may be recalcitrant or require different doses of intravenous vitamin C, phase II trials are necessary before use of intravenous vitamin C as an anti-tumor agent can be fully realized (123). For information about the use of high-dose intravenous vitamin C as an adjunct in cancer treatment, visit The University of Kansas Medical Center Program in Integrative Medicine website.

Common cold

The work of Linus Pauling stimulated public interest in the use of large doses (greater than 1 gram/day) of vitamin C to prevent the common cold (124). In the past 40 years, numerous placebo-controlled trials have examined the effect of vitamin C supplementation on the prevention and treatment of colds. A recent meta-analysis of 53 placebo-controlled trials evaluated the effect of vitamin C supplementation on the incidence, duration, or severity of the common cold when taken as a continuous daily supplement (43 trials) or as therapy upon onset of cold symptoms (10 trials) (125). Regarding the incidence of colds, a distinction was observed between two groups of participants: regular supplementation with vitamin C (0.25 to 2 grams/day) did not reduce the incidence of colds in the general population (23 trials); however, in participants undergoing heavy physical stress (e.g., marathon runners, skiers, or soldiers in subarctic conditions), vitamin C supplementation halved the incidence of colds (5 trials; RR: 0.48, 95% CI: 0.35-0.64). A benefit of regular vitamin C supplementation was also seen in the duration of colds, with a greater benefit in children than in adults: the pooled effect of vitamin C supplementation was a 14% reduction in cold duration in children and an 8% reduction in adults. Finally, no significant effect of vitamin C supplementation (1-8 grams/day) was observed in therapeutic trials in which vitamin C was administered after cold symptoms occurred.

Asthma

Evidence for an effect of vitamin C on respiratory health comes from a meta-analysis of three RCTs that evaluated the effect of vitamin C on exercise-induced bronchoconstriction (126). Exercise-induced bronchoconstriction is a transient narrowing of the airways that occurs after exercise and is indicated by a ≥10% decline in Forced Expiratory Volume in 1 second (FEV1). The trials encompassed 40 asthmatic participants who received either vitamin C (a 0.5 g dose on two subsequent days in one trial; a single dose of 2 grams in the second trial; 1.5 g daily for 2 weeks in the third trial) or placebo before exercise. Compared to placebo, vitamin C administration significantly reduced the exercise-induced decline in FEV1 by 48% (95% CI: 0.33-0.64).

Lead toxicity

Although the use of lead paint and leaded gasoline has been discontinued in the US, lead toxicity continues to be a significant health problem, especially in children living in urban areas. Abnormal growth and development have been observed in infants of women exposed to lead during pregnancy, while children who are chronically exposed to lead are more likely to develop learning disabilities, behavioral problems, and to have a low IQ. In adults, lead toxicity may result in kidney damage, high blood pressure, and anemia.

Several cross-sectional studies report an inverse association between vitamin C status and blood lead level (BLL). In a study of 747 older men, BLL was significantly higher in those who reported total dietary vitamin C intakes averaging less than 109 mg/day compared to those who reported higher vitamin C intakes (127). A much larger study of 19,578 people, including 4,214 children from 6 to 16 years of age, found higher serum vitamin C levels to be associated with significantly lower BLL (128). A US national survey of more than 10,000 adults found that BLL were inversely related to serum vitamin C levels (129).

Cigarette smoking or second-hand exposure to cigarette smoke contributes to increased BLL and a state of chronic low-level lead exposure. An intervention trial in 75 adult male smokers found that supplementation with 1,000 mg/day of vitamin C resulted in significantly lower BLL over a four-week treatment period compared to placebo (130). A lower dose of 200 mg/day did not significantly affect BLL, despite the finding that serum vitamin C levels were not different from those in the group who took 1,000 mg/day.

The mechanism for the relationship between vitamin C intake and BLL is not known, although it has been postulated that vitamin C may inhibit intestinal absorption (130) or enhance urinary excretion of lead.

Sources

Food sources

As shown in Table 2, different fruit and vegetables vary in their vitamin C content (131), but five servings (2½ cups) of fruit and vegetables should average out to about 200 mg of vitamin C. If you wish to check foods for their nutrient content, search the USDA food composition database.

Table 2. Some Food Sources of Vitamin C
Food Serving Vitamin C (mg)
Orange juice ¾ cup (6 ounces) 62-93
Grapefruit juice ¾ cup (6 ounces) 62-70
Kiwifruit, gold 1 fruit (86 g) 91
Orange 1 medium 70
Grapefruit ½ medium 38
Strawberries 1 cup, whole 85
Tomato 1 medium 16
Sweet red pepper ½ cup, raw chopped 95
Broccoli ½ cup, cooked 51
Potato 1 medium, baked 17
Spinach 1 cup, raw 8

Supplements

Vitamin C (L-ascorbic acid) is available in many forms, but there is little scientific evidence that any one form is better absorbed or more effective than another. Most experimental and clinical research uses ascorbic acid or its sodium salt, called sodium ascorbate. Natural and synthetic L-ascorbic acid are chemically identical and there are no known differences in their biological activities or bioavailabilities (132).

Mineral ascorbates

Mineral salts of ascorbic acid are buffered and, therefore, less acidic than ascorbic acid. Some people find them less irritating to the gastrointestinal tract than ascorbic acid. Sodium ascorbate and calcium ascorbate are the most common forms, although a number of other mineral ascorbates are available. Sodium ascorbate provides 111 mg of sodium (889 mg of ascorbic acid) per 1,000 mg of sodium ascorbate, and calcium ascorbate generally provides 90-110 mg of calcium (890-910 mg of ascorbic acid) per 1,000 mg of calcium ascorbate.

Vitamin C with bioflavonoids

Bioflavonoids are a class of water-soluble plant pigments that are often found in vitamin C-rich fruit and vegetables, especially citrus fruit (see the article on Flavonoids). There is little evidence that the bioflavonoids in most commercial preparations increase the bioavailability or efficacy of vitamin C (133). Studies in cell culture indicate that a number of flavonoids inhibit the transport of vitamin C into cells (134-136), and supplementation of rats with quercetin and vitamin C decreased the intestinal absorption of vitamin C (134). More research is needed to determine the significance of these findings in humans.

Ascorbic acid and vitamin C metabolites

One supplement, Ester-C®, contains mainly calcium ascorbate but also contains small amounts of the vitamin C metabolites dehydroascorbic acid (oxidized ascorbic acid), calcium threonate, and trace levels of xylonate and lyxonate. Although these metabolites are purported to increase the bioavailability of vitamin C, the only published study in humans addressing this issue found no difference between Ester-C® and commercially available ascorbic acid tablets with respect to the absorption and urinary excretion of vitamin C (133). Ester-C® should not be confused with ascorbyl palmitate, which is also marketed as "vitamin C ester." 

Ascorbyl palmitate

Ascorbyl palmitate is a vitamin C ester (i.e., ascorbic acid linked to a fatty acid). In this case, vitamin C is esterified to the saturated fatty acid, palmitic acid, resulting in a fat-soluble form of vitamin C. Ascorbyl palmitate has been added to a number of skin creams due to interest in its antioxidant properties, as well as its importance in collagen synthesis (137) (see the separate article, Vitamin C and Skin Health). Although ascorbyl palmitate is also available as an oral supplement, it is likely that most of it is hydrolyzed (broken apart) to ascorbic acid and palmitic acid in the digestive tract before it is absorbed (138). Ascorbyl palmitate is also marketed as "vitamin C ester," which should not be confused with Ester-C®.

For a more detailed review of scientific research on the bioavailability of different forms of vitamin C, see The Bioavailability of Different Forms of Vitamin C.

Safety

Toxicity

A number of possible problems with very large doses of vitamin C have been suggested, mainly based on in vitro experiments or isolated case reports, including genetic mutations, birth defects, cancer, atherosclerosis, kidney stones, "rebound scurvy," increased oxidative stress, excess iron absorption, vitamin B12 deficiency, and erosion of dental enamel. However, none of these alleged adverse health effects have been confirmed in subsequent studies, and there is no reliable scientific evidence that large amounts of vitamin C (up to 10 grams/day in adults) are toxic or detrimental to health. The concern of kidney stone formation with vitamin C supplementation is discussed below.

With the latest RDA published in 2000, a tolerable upper intake level (UL) for vitamin C was set for the first time (Table 3). A UL of 2 grams (2,000 milligrams) daily was recommended in order to prevent most adults from experiencing diarrhea and gastrointestinal disturbances (17). Such symptoms are not generally serious, especially if they resolve with temporary discontinuation or reduction of high-dose vitamin C supplementation. 

Table 3. Tolerable Upper Intake Level (UL) for Vitamin C
Age Group UL (mg/day)
Infants 0-12 months Not possible to establish*
Children 1-3 years 400
Children 4-8 years 650
Children 9-13 years  1,200
Adolescents 14-18 years 1,800
Adults 19 years and older 2,000
*Source of intake should be from foods or formula only.

Kidney stones

Because oxalate is a metabolite of vitamin C, there is some concern that high vitamin C intake could increase the risk of calcium oxalate kidney stones. Some (7, 139, 140), but not all (141-143), studies have reported that supplemental vitamin C increases urinary oxalate levels. Whether any increase in oxalate levels would translate to an elevation in risk for kidney stones has been examined in several epidemiological studies. Two large prospective cohort studies, one following 45,251 men for 6 years and the other following 85,557 women for 14 years, reported that consumption of ≥1,500 mg of vitamin C daily did not increase the risk of kidney stone formation compared to those consuming <250 mg daily (144, 145). On the other hand, two other large prospective studies reported that a high intake of ascorbic acid was associated with an increased risk of kidney stone formation in men (146, 147). Specifically, in the Health Professionals Follow-Up Study, 45,619 male health professionals (aged 40-75 years) reported vitamin C intake from food and supplemental sources every four years (146). After 14 years of follow-up, men who consumed ≥1,000 mg/day of vitamin C had a 41% higher risk of kidney stones compared to men consuming <90 mg of vitamin C daily. In the Cohort of Swedish Men study, self-reported use of single-nutrient ascorbic acid supplements (taken 7 or more times per week) at baseline was associated with a 2-fold higher risk of incident kidney stones among 48,840 men (aged 45-79 years) followed for 11 years (147). Despite conflicting results, it may be prudent for individuals predisposed to oxalate kidney stone formation to avoid high-dose vitamin C supplementation.

Drug interactions

A number of drugs are known to lower vitamin C levels, requiring an increase in its intake. Estrogen-containing contraceptives (birth control pills) are known to lower vitamin C levels in plasma and white blood cells. Aspirin can lower vitamin C levels if taken frequently. For example, taking two aspirin tablets every six hours for a week has been reported to lower vitamin C levels in white blood cells by 50%, primarily by increasing urinary excretion of vitamin C (148).

There is some evidence, though controversial, that vitamin C interacts with anticoagulant medications (blood thinners) like warfarin (Coumadin). Large doses of vitamin C may block the action of warfarin, requiring an increase in dose to maintain its effectiveness. Individuals on anticoagulants should limit their vitamin C intake to 1 gram/day and have their prothrombin time monitored by the clinician following their anticoagulant therapy. Because high doses of vitamin C have also been found to interfere with the interpretation of certain laboratory tests (e.g., serum bilirubin, serum creatinine, and the guaiac assay for occult blood), it is important to inform one's health care provider of any recent supplement use (149).

Antioxidant supplements and HMG-CoA reductase inhibitors (statins)

A three-year randomized controlled trial (RCT) in 160 patients with documented coronary heart disease and low HDL levels found that a combination of simvastatin (Zocor) and niacin increased HDL2 levels, inhibited the progression of coronary artery stenosis (narrowing), and decreased the frequency of cardiovascular events, such as myocardial infarction and stroke (150). Surprisingly, when an antioxidant combination (1,000 mg vitamin C, 800 IU alpha-tocopherol, 100 μg selenium, and 25 mg beta-carotene daily) was taken with the simvastatin-niacin combination, the protective effects were diminished. Since the antioxidants were taken together in this trial, the individual contribution of vitamin C cannot be determined. In contrast, a much larger RCT in more than 20,000 men and women with CHD or diabetes found that simvastatin and an antioxidant combination (600 mg vitamin E, 250 mg vitamin C, and 20 mg beta-carotene daily) did not diminish the cardioprotective effects of simvastatin therapy over a five-year period (151). These contradictory findings indicate that further research is needed on potential interactions between antioxidant supplements and cholesterol-lowering drugs, such as HMG-CoA reductase inhibitors (statins).

Does vitamin C promote oxidative damage under physiological conditions? Vitamin C is known to function as a highly effective antioxidant in living organisms. However, in test tube experiments, vitamin C can interact with some free metal ions to produce potentially damaging free radicals. Although free metal ions are not generally found under physiological conditions, the idea that high doses of vitamin C might be able to promote oxidative damage in vivo has received a great deal of attention. Widespread publicity has been given to a few studies suggesting a pro-oxidant effect of vitamin C (152, 153), but these studies turned out to be either flawed or of no physiological relevance. A comprehensive review of the literature found no credible scientific evidence that supplemental vitamin C promotes oxidative damage under physiological conditions or in humans (154).

Linus Pauling Institute Recommendation

Based on the combined evidence from metabolic, pharmacokinetic, and observational studies and from randomized controlled trials, it has been argued that sufficient scientific evidence exists to support an optimum, daily vitamin C intake of at least 200 mg/day, which is substantially higher than the current RDA (11). Studies conducted at the National Institutes of Health showed that plasma and circulating cells in healthy, young subjects attained near-maximal concentrations of vitamin C at a dose of 400 mg/day (11). Because of the very high benefit-to-risk ratio of vitamin C supplementation, and to ensure tissue and body saturation of vitamin C in almost all healthy people, the Linus Pauling Institute recommends a vitamin C intake of at least 400 mg daily for adult men and women. Consuming at least five servings (2½ cups) of fruit and vegetables daily provides about 200 mg of vitamin C. Most multivitamin/mineral supplements provide 60 mg of vitamin C. To make sure you meet the Institute’s recommendation, supplemental vitamin C in two separate 250-mg doses taken in the morning and evening is recommended.

Older adults (>50 years)

Although it is not yet known with certainty whether older adults have higher requirements for vitamin C, some older populations have been found to have vitamin C intakes considerably below the RDA of 75 and 90 mg/day for women and men, respectively. A vitamin C intake of at least 400 mg daily may be particularly important for older adults who are at higher risk for age-related chronic diseases. In addition, a meta-analysis of 36 publications examining the relationship between vitamin C intake and plasma concentrations of vitamin C concluded that older adults (aged 60-96 years) have considerably lower plasma levels of vitamin C following a certain intake of vitamin C compared with younger individuals (aged 15-65 years) (155), suggesting that older adults have higher vitamin C requirements. Pharmacokinetic studies in older adults have not yet been conducted, but evidence suggests that the efficiency of one of the molecular mechanisms for the cellular uptake of vitamin C declines with age (156). Because maximizing blood levels of vitamin C may be important in protection against oxidative damage to cells and biological molecules, a vitamin C intake of at least 400 mg daily is particularly important for older adults who are at higher risk for chronic diseases caused, in part, by oxidative damage, such as heart disease, stroke, certain cancers, and cataract.

For more information on the difference between Dr Linus Pauling's recommendation and the Linus Pauling Institute's recommendation for vitamin C intake, select the highlighted text.


Authors and Reviewers

Originally written in 2000 by:
Jane Higdon, Ph.D. 
Linus Pauling Institute 
Oregon State University

Updated in November 2002 by:  
Jane Higdon, Ph.D.  
Linus Pauling Institute  
Oregon State University

Updated in September 2003 by:  
Jane Higdon, Ph.D.  
Linus Pauling Institute  
Oregon State University

Updated in December 2004 by:  
Jane Higdon, Ph.D.  
Linus Pauling Institute  
Oregon State University

Updated in January 2006 by: 
Jane Higdon, Ph.D. 
Linus Pauling Institute 
Oregon State University

Updated in September 2009 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute 
Oregon State University

Updated in November 2013 by: 
Giana Angelo, Ph.D. 
Linus Pauling Institute 
Oregon State University

Reviewed in November 2013 by: 
Balz Frei, Ph.D. 
Director and Endowed Chair, Linus Pauling Institute 
Joan H. Facey Linus Pauling Institute Professor 
Distinguished Professor, Dept. of Biochemistry and Biophysics 
Oregon State University

Reviewed in November 2013 by: 
Alexander J. Michels, Ph.D. 
Research Associate, Linus Pauling Institute 
Oregon State University

The 2013 update of this article was underwritten, in part, by a grant from Bayer Consumer Care AG, Basel, Switzerland.

Last updated 1/14/14  Copyright 2000-2017  Linus Pauling Institute


References:

1.   Combs J, Gerald F. The Vitamins. 4 ed. Burlington: Elsevier Science; 2012.

2.   Erdman JW, MacDonald I, Zeisel SH, International Life Sciences Institute. Present knowledge in nutrition. 10th ed. Ames, Iowa: International Life Sciences Institute; 2012.

3.  Carr AC, Frei B. Toward a new recommended dietary allowance for vitamin C based on antioxidant and health effects in humans. Am J Clin Nutr. 1999;69(6):1086-1107.  (PubMed)

4.  Bruno RS, Leonard SW, Atkinson J, et al. Faster plasma vitamin E disappearance in smokers is normalized by vitamin C supplementation. Free Radic Biol Med. 2006;40(4):689-697.  (PubMed)

5.  Simon JA, Hudes ES. Serum ascorbic acid and gallbladder disease prevalence among US adults: the Third National Health and Nutrition Examination Survey (NHANES III). Arch Intern Med. 2000;160(7):931-936.  (PubMed)

6.  Levine M, Padayatty SJ, Espey MG. Vitamin C: a concentration-function approach yields pharmacology and therapeutic discoveries. Adv Nutr. 2011;2(2):78-88.  (PubMed)

7.  Levine M, Conry-Cantilena C, Wang Y, et al. Vitamin C pharmacokinetics in healthy volunteers: evidence for a recommended dietary allowance. Proc Natl Acad Sci U S A. 1996;93(8):3704-3709.  (PubMed)

8.  Levine M, Wang Y, Padayatty SJ, Morrow J. A new recommended dietary allowance of vitamin C for healthy young women. Proc Natl Acad Sci U S A. 2001;98(17):9842-9846.  (PubMed)

9.  Padayatty SJ, Sun H, Wang Y, et al. Vitamin C pharmacokinetics: implications for oral and intravenous use. Ann Intern Med. 2004;140(7):533-537.  (PubMed)

10.  Carr AC, Bozonet SM, Pullar JM, Simcock JW, Vissers MC. Human skeletal muscle ascorbate is highly responsive to changes in vitamin C intake and plasma concentrations. Am J Clin Nutr. 2013;97(4):800-807.  (PubMed)

11.  Frei B, Birlouez-Aragon I, Lykkesfeldt J. Authors' perspective: What is the optimum intake of vitamin C in humans? Crit Rev Food Sci Nutr. 2012;52(9):815-829.  (PubMed)

12.  Levine M, Rumsey SC, Daruwala R, Park JB, Wang Y. Criteria and recommendations for vitamin C intake. JAMA. 1999;281(15):1415-1423.  (PubMed)

13.  Lykkesfeldt J, Poulsen HE. Is vitamin C supplementation beneficial? Lessons learned from randomised controlled trials. Br J Nutr. 2010;103(9):1251-1259.  (PubMed)

14.  Sauberlich, HE. A history of scurvy and vitamin C. In Packer, L. and Fuchs, J, eds. Vitamin C in health and disease. New York: Marcel Decker Inc. 1997: pages 1-24. 

15.  Stephen R, Utecht T. Scurvy identified in the emergency department: a case report. J Emerg Med. 2001;21(3):235-237.  (PubMed)

16.  Weinstein M, Babyn P, Zlotkin S. An orange a day keeps the doctor away: scurvy in the year 2000. Pediatrics. 2001;108(3):E55.  (PubMed)

17.  Food and Nutrition Board, Institute of Medicine. Vitamin C. Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids. Washington, D.C.: National Academy Press; 2000:95-185.  (National Academy Press)

18.  Knekt P, Ritz J, Pereira MA, et al. Antioxidant vitamins and coronary heart disease risk: a pooled analysis of 9 cohorts. Am J Clin Nutr. 2004;80(6):1508-1520.  (PubMed)

19. Ye Z, Song H. Antioxidant vitamins intake and the risk of coronary heart disease: meta-analysis of cohort studies. Eur J Cardiovasc Prev Rehabil. 2008;15(1):26-34.   (PubMed)

20.   Kubota Y, Iso H, Date C, et al. Dietary intakes of antioxidant vitamins and mortality from cardiovascular disease: the Japan Collaborative Cohort Study (JACC) study. Stroke. 2011;42(6):1665-1672.  (PubMed)

21.   Pfister R, Sharp SJ, Luben R, Wareham NJ, Khaw KT. Plasma vitamin C predicts incident heart failure in men and women in European Prospective Investigation into Cancer and Nutrition-Norfolk prospective study. Am Heart J. 2011;162(2):246-253.  (PubMed)

22.   Carter P, Gray LJ, Troughton J, Khunti K, Davies MJ. Fruit and vegetable intake and incidence of type 2 diabetes mellitus: systematic review and meta-analysis. BMJ. 2010;341:c4229.  (PubMed)

23.   Dehghan M, Akhtar-Danesh N, McMillan CR, Thabane L. Is plasma vitamin C an appropriate biomarker of vitamin C intake? A systematic review and meta-analysis. Nutr J. 2007;6:41.  (PubMed)

24.   McRae MP. Vitamin C supplementation lowers serum low-density lipoprotein cholesterol and triglycerides: a meta-analysis of 13 randomized controlled trials. J Chiropr Med. 2008;7(2):48-58.  (PubMed)

25.  Sesso HD, Buring JE, Christen WG, et al. Vitamins E and C in the prevention of cardiovascular disease in men: the Physicians' Health Study II randomized controlled trial. JAMA. 2008;300(18):2123-2133.  (PubMed)

26.  Roberts LJ, 2nd, Traber MG, Frei B. Vitamins E and C in the prevention of cardiovascular disease and cancer in men. Free Radic Biol Med. 2009;46(11):1558.  (PubMed)

27.  Frei B. To C or not to C, that is the question! J Am Coll Cardiol. 2003;42(2):253-255.  (PubMed)

28.   Good DC. Cerebrovascular Disease. In: Walker HK, Hall WD, Hurst JW, eds. Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd ed. Boston; 1990.

29.  Yokoyama T, Date C, Kokubo Y, Yoshiike N, Matsumura Y, Tanaka H. Serum vitamin C concentration was inversely associated with subsequent 20-year incidence of stroke in a Japanese rural community. The Shibata study. Stroke. 2000;31(10):2287-2294.  (PubMed)

30.  Myint PK, Luben RN, Welch AA, Bingham SA, Wareham NJ, Khaw KT. Plasma vitamin C concentrations predict risk of incident stroke over 10 y in 20 649 participants of the European Prospective Investigation into Cancer Norfolk prospective population study. Am J Clin Nutr. 2008;87(1):64-69.  (PubMed)

31.  Lagowska-Lenard M, Stelmasiak Z, Bartosik-Psujek H. Influence of vitamin C on markers of oxidative stress in the earliest period of ischemic stroke. Pharmacol Rep. 2010;62(4):751-756.  (PubMed)

32.  Forman JP, Choi H, Curhan GC. Fructose and vitamin C intake do not influence risk for developing hypertension. J Am Soc Nephrol. 2009;20(4):863-871.  (PubMed)

33.  Moran JP, Cohen L, Greene JM, et al. Plasma ascorbic acid concentrations relate inversely to blood pressure in human subjects. Am J Clin Nutr. 1993;57(2):213-217.  (PubMed)

34.  Block G, Jensen CD, Norkus EP, Hudes M, Crawford PB. Vitamin C in plasma is inversely related to blood pressure and change in blood pressure during the previous year in young Black and White women. Nutr J. 2008;7:35.  (PubMed)

35.  Myint PK, Luben RN, Wareham NJ, Khaw KT. Association between plasma vitamin C concentrations and blood pressure in the European prospective investigation into cancer-Norfolk population-based study. Hypertension. 2011;58(3):372-379.  (PubMed)

36.  Bertoia M, Albanes D, Mayne ST, Mannisto S, Virtamo J, Wright ME. No association between fruit, vegetables, antioxidant nutrients and risk of renal cell carcinoma. Int J Cancer. 2010;126(6):1504-1512.  (PubMed)

37.  Heinen MM, Verhage BA, Goldbohm RA, van den Brandt PA. Intake of vegetables, fruit, carotenoids and vitamins C and E and pancreatic cancer risk in The Netherlands Cohort Study. Int J Cancer. 2012;130(1):147-158.  (PubMed)

38.  Roswall N, Olsen A, Christensen J, Dragsted LO, Overvad K, Tjonneland A. Micronutrient intake and risk of urothelial carcinoma in a prospective Danish cohort. Eur Urol. 2009;56(5):764-770.  (PubMed)

39.  Goodman M, Bostick RM, Kucuk O, Jones DP. Clinical trials of antioxidants as cancer prevention agents: past, present, and future. Free Radic Biol Med. 2011;51(5):1068-1084.  (PubMed)

40.  Zhang S, Hunter DJ, Forman MR, et al. Dietary carotenoids and vitamins A, C, and E and risk of breast cancer. J Natl Cancer Inst. 1999;91(6):547-556.  (PubMed)

41.  Michels KB, Holmberg L, Bergkvist L, Ljung H, Bruce A, Wolk A. Dietary antioxidant vitamins, retinol, and breast cancer incidence in a cohort of Swedish women. Int J Cancer. 2001;91(4):563-567.  (PubMed)

42.  Roswall N, Olsen A, Christensen J, Dragsted LO, Overvad K, Tjonneland A. Micronutrient intake and breast cancer characteristics among postmenopausal women. Eur J Cancer Prev. 2010;19(5):360-365.  (PubMed)

43.  Nagel G, Linseisen J, van Gils CH, et al. Dietary β-carotene, vitamin C and E intake and breast cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC). Breast Cancer Res Treat. 2010;119(3):753-765.  (PubMed)

44.  Hutchinson J, Lentjes MA, Greenwood DC, et al. Vitamin C intake from diary recordings and risk of breast cancer in the UK Dietary Cohort Consortium. Eur J Clin Nutr. 2012;66(5):561-568.  (PubMed)

45.  Tsugane S, Sasazuki S. Diet and the risk of gastric cancer: review of epidemiological evidence. Gastric Cancer. 2007;10(2):75-83.  (PubMed)

46.  Liu C, Russell RM. Nutrition and gastric cancer risk: an update. Nutr Rev. 2008;66(5):237-249.  (PubMed)

47.  Mirvish SS, Wallcave L, Eagen M, Shubik P. Ascorbate-nitrite reaction: possible means of blocking the formation of carcinogenic N-nitroso compounds. Science. 1972;177(4043):65-68.  (PubMed)

48.  Jenab M, Riboli E, Ferrari P, et al. Plasma and dietary vitamin C levels and risk of gastric cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC-EURGAST). Carcinogenesis. 2006;27(11):2250-2257.  (PubMed)

49.  Banerjee S, Hawksby C, Miller S, Dahill S, Beattie AD, McColl KE. Effect of Helicobacter pylori and its eradication on gastric juice ascorbic acid. Gut. 1994;35(3):317-322.  (PubMed)

50.  Zhang ZW, Patchett SE, Perrett D, Katelaris PH, Domizio P, Farthing MJ. The relation between gastric vitamin C concentrations, mucosal histology, and CagA seropositivity in the human stomach. Gut. 1998;43(3):322-326.  (PubMed)

51.  Chuang CH, Sheu BS, Kao AW, et al. Adjuvant effect of vitamin C on omeprazole-amoxicillin-clarithromycin triple therapy for Helicobacter pylori eradication. Hepatogastroenterology. 2007;54(73):320-324.  (PubMed)

52.  Pal J, Sanal MG, Gopal GJ. Vitamin-C as anti-Helicobacter pylori agent: More prophylactic than curative- Critical review. Indian J Pharmacol. 2011;43(6):624-627.  (PubMed)

53.  Park Y, Spiegelman D, Hunter DJ, et al. Intakes of vitamins A, C, and E and use of multiple vitamin supplements and risk of colon cancer: a pooled analysis of prospective cohort studies. Cancer Causes Control. 2010;21(11):1745-1757.  (PubMed)

54.  Thompson CA, Cerhan JR. Fruit and vegetable intake and survival from non-Hodgkin lymphoma: does an apple a day keep the doctor away? Leuk Lymphoma. 2010;51(6):963-964.  (PubMed)

55.  Kabat GC, Kim MY, Wactawski-Wende J, Shikany JM, Vitolins MZ, Rohan TE. Intake of antioxidant nutrients and risk of non-Hodgkin's Lymphoma in the Women's Health Initiative. Nutr Cancer. 2012;64(2):245-254.  (PubMed)

56.  Bowman GL. Ascorbic acid, cognitive function, and Alzheimer's disease: a current review and future direction. BioFactors. 2012;38(2):114-122.  (PubMed)

57. Harrison J, Rentz DM, McLaughlin T, et al. Cognition in MCI and Alzheimer's disease: baseline data from a longitudinal study of the NTB. The Clinical neuropsychologist. 2014;28(2):252-268.   (PubMed)

58.  Bowman GL, Dodge H, Frei B, et al. Ascorbic acid and rates of cognitive decline in Alzheimer's disease. Journal of Alzheimer's disease: JAD. 2009;16(1):93-98.  (PubMed)

59.  Arlt S, Muller-Thomsen T, Beisiegel U, Kontush A. Effect of one-year vitamin C- and E-supplementation on cerebrospinal fluid oxidation parameters and clinical course in Alzheimer's disease. Neurochemical research. 2012;37(12):2706-2714.  (PubMed)

60.  Galasko DR, Peskind E, Clark CM, et al. Antioxidants for Alzheimer disease: a randomized clinical trial with cerebrospinal fluid biomarker measures. Archives of neurology. 2012;69(7):836-841.  (PubMed)

61.   Tessier F, Moreaux V, Birlouez-Aragon I, Junes P, Mondon H. Decrease in vitamin C concentration in human lenses during cataract progression. Int J Vitam Nutr Res. 1998;68(5):309-315.  (PubMed)

62. Jacques PF, Chylack LT, Jr., Hankinson SE, et al. Long-term nutrient intake and early age-related nuclear lens opacities. Arch Ophthalmol. 2001;119(7):1009-1019.  (PubMed)

63.  Yoshida M, Takashima Y, Inoue M, et al. Prospective study showing that dietary vitamin C reduced the risk of age-related cataracts in a middle-aged Japanese population. Eur J Nutr. 2007;46(2):118-124.  (PubMed)

64.  Pastor-Valero M. Fruit and vegetable intake and vitamins C and E are associated with a reduced prevalence of cataract in a Spanish Mediterranean population. BMC Ophthalmol. 2013;13(1):52.  (PubMed)

65.  Simon JA, Hudes ES. Serum ascorbic acid and other correlates of self-reported cataract among older Americans. J Clin Epidemiol. 1999;52(12):1207-1211.  (PubMed)

66.  Dherani M, Murthy GV, Gupta SK, et al. Blood levels of vitamin C, carotenoids and retinol are inversely associated with cataract in a North Indian population. Invest Ophthalmol Vis Sci. 2008;49(8):3328-3335.  (PubMed)

67.  Mathew MC, Ervin AM, Tao J, Davis RM. Antioxidant vitamin supplementation for preventing and slowing the progression of age-related cataract. Cochrane Database Syst Rev. 2012;6:CD004567.  (PubMed)

68.  Zheng Selin J, Rautiainen S, Lindblad BE, Morgenstern R, Wolk A. High-dose supplements of vitamins C and E, low-dose multivitamins, and the risk of age-related cataract: a population-based prospective cohort study of men. Am J Epidemiol. 2013;177(6):548-555.  (PubMed)

69.  Rautiainen S, Lindblad BE, Morgenstern R, Wolk A. Vitamin C supplements and the risk of age-related cataract: a population-based prospective cohort study in women. Am J Clin Nutr. 2010;91(2):487-493.  (PubMed)

70.   Zhu Y, Pandya BJ, Choi HK. Prevalence of gout and hyperuricemia in the US general population: the National Health and Nutrition Examination Survey 2007-2008. Arthritis Rheum. 2011;63(10):3136-3141. (PubMed)

71.  Saag KG, Choi H. Epidemiology, risk factors, and lifestyle modifications for gout. Arthritis Res Ther. 2006;8 Suppl 1:S2.  (PubMed)

72.  Choi HK, Curhan G. Gout: epidemiology and lifestyle choices. Curr Opin Rheumatol. 2005;17(3):341-345.  (PubMed)

73.  Gao X, Curhan G, Forman JP, Ascherio A, Choi HK. Vitamin C intake and serum uric acid concentration in men. J Rheumatol. 2008;35(9):1853-1858.  (PubMed)

74.  Choi HK, Gao X, Curhan G. Vitamin C intake and the risk of gout in men: a prospective study. Arch Intern Med. 2009;169(5):502-507.  (PubMed)

75.  Juraschek SP, Miller ER, 3rd, Gelber AC. Effect of oral vitamin C supplementation on serum uric acid: a meta-analysis of randomized controlled trials. Arthritis Care Res (Hoboken). 2011;63(9):1295-1306.  (PubMed)

76.  Prinz W, Bortz R, Bregin B, Hersch M. The effect of ascorbic acid supplementation on some parameters of the human immunological defence system. Int J Vitam Nutr Res. 1977;47(3):248-257.  (PubMed)

77.  Vallance S. Relationships between ascorbic acid and serum proteins of the immune system. Br Med J. 1977;2(6084):437-438.  (PubMed)

78.  Kennes B, Dumont I, Brohee D, Hubert C, Neve P. Effect of vitamin C supplements on cell-mediated immunity in old people. Gerontology. 1983;29(5):305-310.  (PubMed)

79.  Panush RS, Delafuente JC, Katz P, Johnson J. Modulation of certain immunologic responses by vitamin C. III. Potentiation of in vitro and in vivo lymphocyte responses. Int J Vitam Nutr Res Suppl. 1982;23:35-47.  (PubMed)

80.  Jariwalla RJ, Harakeh S. Antiviral and immunomodulatory activities of ascorbic acid. In: Harris JR (ed). Subcellular Biochemistry. Vol. 25. Ascorbic Acid: Biochemistry and Biomedical Cell Biology. New York: Plenum Press; 1996:215-231.

81.  Levy R, Shriker O, Porath A, Riesenberg K, Schlaeffer F. Vitamin C for the treatment of recurrent furunculosis in patients with imparied neutrophil functions. J Infect Dis. 1996;173(6):1502-1505.  (PubMed)

82.  Anderson R, Oosthuizen R, Maritz R, Theron A, Van Rensburg AJ. The effects of increasing weekly doses of ascorbate on certain cellular and humoral immune functions in normal volunteers. Am J Clin Nutr. 1980;33(1):71-76.  (PubMed)

83.  Bergsten P, Amitai G, Kehrl J, Dhariwal KR, Klein HG, Levine M. Millimolar concentrations of ascorbic acid in purified human mononuclear leukocytes. Depletion and reaccumulation. J Biol Chem. 1990;265(5):2584-2587.  (PubMed)

84.  Evans RM, Currie L, Campbell A. The distribution of ascorbic acid between various cellular components of blood, in normal individuals, and its relation to the plasma concentration. Br J Nutr. 1982;47(3):473-482.  (PubMed)

85.  Alberts B, Bray D, Lewis J, Raff M, Roberts K, Watson JD. Differentiated cells and the maintenance of tissues. In: Molecular Biology of the Cell. 3rd ed. New York: Garland Publishing, Inc.; 1994:1139-1193.

86.  Jariwalla RJ, Harakeh S. Mechanisms underlying the action of vitamin C in viral and immunodeficiency disease. In: Packer L, Fuchs J, eds. Vitamin C in Health and Disease. New York: Marcel Dekker, Inc.; 1997:309-322.

87.  Pauling L. The immune system. How to Live Longer and Feel Better. 20th Anniversary ed. Corvallis: Oregon State University Press; 2006:105-111.

88.  Dahl H, Degre M. The effect of ascorbic acid on production of human interferon and the antiviral activity in vitro. Acta Pathol Microbiol Scand B. 1976;84B(5):280-284.  (PubMed)

89.  Pocobelli G, Peters U, Kristal AR, White E. Use of supplements of multivitamins, vitamin C, and vitamin E in relation to mortality. Am J Epidemiol. 2009;170(4):472-483.  (PubMed)

90.  Roswall N, Olsen A, Christensen J, et al. Micronutrient intake in relation to all-cause mortality in a prospective Danish cohort. Food Nutr Res. 2012;56.  (PubMed)

91.  Khaw KT, Bingham S, Welch A, et al. Relation between plasma ascorbic acid and mortality in men and women in EPIC-Norfolk prospective study: a prospective population study. European Prospective Investigation into Cancer and Nutrition. Lancet. 2001;357(9257):657-663.  (PubMed)

92.  Goyal A, Terry MB, Siegel AB. Serum Antioxidant Nutrients, Vitamin A, and Mortality in US Adults. Cancer Epidemiol Biomarkers Prev. 2013. Oct 17. [Epub ahead of print].  (PubMed)

93.  Vita JA, Keaney JF, Jr. Endothelial function: a barometer for cardiovascular risk? Circulation. 2002;106(6):640-642.  (PubMed)

94.  Gokce N, Keaney JF, Jr., Frei B, et al. Long-term ascorbic acid administration reverses endothelial vasomotor dysfunction in patients with coronary artery disease. Circulation. 1999;99(25):3234-3240.  (PubMed)

95.  Versari D, Daghini E, Virdis A, Ghiadoni L, Taddei S. Endothelium-dependent contractions and endothelial dysfunction in human hypertension. Br J Pharmacol. 2009;157(4):527-536.  (PubMed)

96.  Frikke-Schmidt H, Lykkesfeldt J. Role of marginal vitamin C deficiency in atherogenesis: in vivo models and clinical studies. Basic Clin Pharmacol Toxicol. 2009;104(6):419-433.  (PubMed)

97.  Juraschek SP, Guallar E, Appel LJ, Miller ER, 3rd. Effects of vitamin C supplementation on blood pressure: a meta-analysis of randomized controlled trials. Am J Clin Nutr. 2012;95(5):1079-1088.  (PubMed)

98.  Newberry SJ. What is the evidence that vitamin C supplements lower blood pressure? Am J Clin Nutr. 2012;95(5):997-998.  (PubMed)

99.  Harding AH, Wareham NJ, Bingham SA, et al. Plasma vitamin C level, fruit and vegetable consumption, and the risk of new-onset type 2 diabetes mellitus: the European prospective investigation of cancer--Norfolk prospective study. Arch Intern Med. 2008;168(14):1493-1499.  (PubMed)

100.  Kositsawat J, Freeman VL. Vitamin C and A1c relationship in the National Health and Nutrition Examination Survey (NHANES) 2003-2006. J Am Coll Nutr. 2011;30(6):477-483.  (PubMed)

101.  Sargeant LA, Wareham NJ, Bingham S, et al. Vitamin C and hyperglycemia in the European Prospective Investigation into Cancer--Norfolk (EPIC-Norfolk) study: a population-based study. Diabetes Care. 2000;23(6):726-732.  (PubMed)

102.  Osganian SK, Stampfer MJ, Rimm E, et al. Vitamin C and risk of coronary heart disease in women. J Am Coll Cardiol. 2003;42(2):246-252.  (PubMed)

103.  Lee DH, Folsom AR, Harnack L, Halliwell B, Jacobs DR, Jr. Does supplemental vitamin C increase cardiovascular disease risk in women with diabetes? Am J Clin Nutr. 2004;80(5):1194-1200.  (PubMed)

104.  Waters DD, Alderman EL, Hsia J, et al. Effects of hormone replacement therapy and antioxidant vitamin supplements on coronary atherosclerosis in postmenopausal women: a randomized controlled trial. JAMA. 2002;288(19):2432-2440.  (PubMed)

105.  MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360(9326):23-33.  (PubMed)

106.  Levy AP, Friedenberg P, Lotan R, et al. The effect of vitamin therapy on the progression of coronary artery atherosclerosis varies by haptoglobin type in postmenopausal women. Diabetes Care. 2004;27(4):925-930.  (PubMed)

107.  Cameron E, Pauling L. Supplemental ascorbate in the supportive treatment of cancer: Prolongation of survival times in terminal human cancer. Proc Natl Acad Sci U S A. 1976;73(10):3685-3689.

108.  Ohno S, Ohno Y, Suzuki N, Soma G, Inoue M. High-dose vitamin C (ascorbic acid) therapy in the treatment of patients with advanced cancer. Anticancer Res. 2009;29(3):809-815.  (PubMed)

109.  Chen Q, Espey MG, Krishna MC, et al. Pharmacologic ascorbic acid concentrations selectively kill cancer cells: action as a pro-drug to deliver hydrogen peroxide to tissues. Proc Natl Acad Sci U S A. 2005;102(38):13604-13609.  (PubMed)

110.  Chen Q, Espey MG, Sun AY, et al. Ascorbate in pharmacologic concentrations selectively generates ascorbate radical and hydrogen peroxide in extracellular fluid in vivo. Proc Natl Acad Sci U S A. 2007;104(21):8749-8754.  (PubMed)

111.  Chen Q, Espey MG, Sun AY, et al. Pharmacologic doses of ascorbate act as a prooxidant and decrease growth of aggressive tumor xenografts in mice. Proc Natl Acad Sci U S A. 2008;105(32):11105-11109.  (PubMed)

112.  Kuiper C, Molenaar IG, Dachs GU, Currie MJ, Sykes PH, Vissers MC. Low ascorbate levels are associated with increased hypoxia-inducible factor-1 activity and an aggressive tumor phenotype in endometrial cancer. Cancer Res. 2010;70(14):5749-5758.  (PubMed)

113.  Gao P, Zhang H, Dinavahi R, et al. HIF-dependent antitumorigenic effect of antioxidants in vivo. Cancer Cell. 2007;12(3):230-238.  (PubMed)

114.  Riordan HD, Casciari JJ, Gonzalez MJ, et al. A pilot clinical study of continuous intravenous ascorbate in terminal cancer patients. P R Health Sci J. 2005;24(4):269-276.  (PubMed)

115.  Hoffer LJ, Levine M, Assouline S, et al. Phase I clinical trial of i.v. ascorbic acid in advanced malignancy. Ann Oncol. 2008;19(11):1969-1974.  (PubMed)

116.  Monti DA, Mitchell E, Bazzan AJ, et al. Phase I evaluation of intravenous ascorbic acid in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer. PLoS One. 2012;7(1):e29794.  (PubMed)

117.  Stephenson CM, Levin RD, Spector T, Lis CG. Phase I clinical trial to evaluate the safety, tolerability, and pharmacokinetics of high-dose intravenous ascorbic acid in patients with advanced cancer. Cancer Chemother Pharmacol. 2013;72(1):139-146.  (PubMed)

118.  Vollbracht C, Schneider B, Leendert V, Weiss G, Auerbach L, Beuth J. Intravenous vitamin C administration improves quality of life in breast cancer patients during chemo-/radiotherapy and aftercare: results of a retrospective, multicentre, epidemiological cohort study in Germany. In Vivo. 2011;25(6):983-990.  (PubMed)

119.  Park CH, Kimler BF, Yi SY, et al. Depletion of L-ascorbic acid alternating with its supplementation in the treatment of patients with acute myeloid leukemia or myelodysplastic syndromes. Eur J Haematol. 2009;83(2):108-118.  (PubMed)

120.  Klingelhoeffer C, Kammerer U, Koospal M, et al. Natural resistance to ascorbic acid induced oxidative stress is mainly mediated by catalase activity in human cancer cells and catalase-silencing sensitizes to oxidative stress. BMC Complement Altern Med. 2012;12:61.  (PubMed)

121.  Hong SW, Lee SH, Moon JH, et al. SVCT-2 in breast cancer acts as an indicator for L-ascorbate treatment. Oncogene. 2013;32(12):1508-1517.  (PubMed)

122.  US National Institutes of Health. ClinicalTrials.gov [Web page]. Available at: http://www.clinicaltrials.gov/. Accessed 9/16/09.

123.  Cabanillas F. Vitamin C and cancer: what can we conclude--1,609 patients and 33 years later? P R Health Sci J. 2010;29(3):215-217.  (PubMed)

124.  Pauling LC. Vitamin C and the Common Cold. San Francisco: W. H. Freeman; 1970.

125.  Hemila H, Chalker E. Vitamin C for preventing and treating the common cold. Cochrane database of systematic reviews. 2013;1:CD000980.  (PubMed)

126.  Hemila H. Vitamin C may alleviate exercise-induced bronchoconstriction: a meta-analysis. BMJ Open. 2013;3(6).  (PubMed)

127.  Cheng Y, Willett WC, Schwartz J, Sparrow D, Weiss S, Hu H. Relation of nutrition to bone lead and blood lead levels in middle-aged to elderly men. The Normative Aging Study. Am J Epidemiol. 1998;147(12):1162-1174.  (PubMed)

128.  Simon JA, Hudes ES. Relationship of ascorbic acid to blood lead levels. JAMA. 1999;281(24):2289-2293.  (PubMed)

129.  Lee DH, Lim JS, Song K, Boo Y, Jacobs DR, Jr. Graded associations of blood lead and urinary cadmium concentrations with oxidative-stress-related markers in the U.S. population: results from the third National Health and Nutrition Examination Survey. Environ Health Perspect. 2006;114(3):350-354.  (PubMed)

130.  Dawson EB, Evans DR, Harris WA, Teter MC, McGanity WJ. The effect of ascorbic acid supplementation on the blood lead levels of smokers. J Am Coll Nutr. 1999;18(2):166-170.  (PubMed)

131.  US Department of Agriculture, Agricultural Research Service. USDA National Nutrient Database for Standard Reference, Release 22. 2009. Available at: http://www.nal.usda.gov/fnic/foodcomp/search/. Accessed 11/7/09.

132.  Gregory JF, 3rd. Ascorbic acid bioavailability in foods and supplements. Nutr Rev. 1993;51(10):301-303.

133.  Johnston CS, Luo B. Comparison of the absorption and excretion of three commercially available sources of vitamin C. J Am Diet Assoc. 1994;94(7):779-781.

134.  Song J, Kwon O, Chen S, et al. Flavonoid inhibition of sodium-dependent vitamin C transporter 1 (SVCT1) and glucose transporter isoform 2 (GLUT2), intestinal transporters for vitamin C and Glucose. J Biol Chem. 2002;277(18):15252-15260.  (PubMed)

135.  Park JB, Levine M. Intracellular accumulation of ascorbic acid is inhibited by flavonoids via blocking of dehydroascorbic acid and ascorbic acid uptakes in HL-60, U937 and Jurkat cells. J Nutr. 2000;130(5):1297-1302.  (PubMed)

136.  Kwon O, Eck P, Chen S, et al. Inhibition of the intestinal glucose transporter GLUT2 by flavonoids. FASEB J. 2007;21(2):366-377.  (PubMed)

137.  Austria R, Semenzato A, Bettero A. Stability of vitamin C derivatives in solution and topical formulations. J Pharm Biomed Anal. 1997;15(6):795-801.  (PubMed)

138.  DeRitter E. Physiologic availability of dehydro-L-ascorbic acid and palmitoyl-L-ascorbic acid. Science. 1951;113:628-631.

139.  Traxer O, Huet B, Poindexter J, Pak CY, Pearle MS. Effect of ascorbic acid consumption on urinary stone risk factors. J Urol. 2003;170(2 Pt 1):397-401.  (PubMed)

140.  Massey LK, Liebman M, Kynast-Gales SA. Ascorbate increases human oxaluria and kidney stone risk. J Nutr. 2005;135(7):1673-1677.  (PubMed)

141.  Auer BL, Auer D, Rodgers AL. The effect of ascorbic acid ingestion on the biochemical and physicochemical risk factors associated with calcium oxalate kidney stone formation. Clin Chem Lab Med. 1998;36(3):143-147.  (PubMed)

142.  Liebman M, Chai WW, Harvey E, Boenisch L. Effect of supplemental ascorbate and orange juice on urinary oxalate. Nutr Res. 1997;17(3):415-425.

143.  Wandzilak TR, D'Andre SD, Davis PA, Williams HE. Effect of high dose vitamin C on urinary oxalate levels. J Urol. 1994;151(4):834-837.  (PubMed)

144.  Curhan GC, Willett WC, Rimm EB, Stampfer MJ. A prospective study of the intake of vitamins C and B6, and the risk of kidney stones in men. J Urol. 1996;155(6):1847-1851.  (PubMed)

145.  Curhan GC, Willett WC, Speizer FE, Stampfer MJ. Intake of vitamins B6 and C and the risk of kidney stones in women. J Am Soc Nephrol. 1999;10(4):840-845.  (PubMed)

146.  Taylor EN, Stampfer MJ, Curhan GC. Dietary factors and the risk of incident kidney stones in men: new insights after 14 years of follow-up. J Am Soc Nephrol. 2004;15(12):3225-3232.  (PubMed)

147.  Thomas LD, Elinder CG, Tiselius HG, Wolk A, Akesson A. Ascorbic acid supplements and kidney stone incidence among men: a prospective study. JAMA Intern Med. 2013;173(5):386-388.  (PubMed)

148.  Basu TK. Vitamin C-aspirin interactions. Int J Vitam Nutr Res Suppl. 1982;23:83-90.  (PubMed)

149.  Hendler SS, Rorvik DR, eds. PDR for Nutritional Supplements. Montvale: Medical Economics Company, Inc; 2001.

150.  Brown BG, Zhao XQ, Chait A, et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med. 2001;345(22):1583-1592.  (PubMed)

151.  Collins R, Peto R, Armitage J. The MRC/BHF Heart Protection Study: preliminary results. Int J Clin Pract. 2002;56(1):53-56.  (PubMed)

152.  Lee SH, Oe T, Blair IA. Vitamin C-induced decomposition of lipid hydroperoxides to endogenous genotoxins. Science. 2001;292(5524):2083-2086.  (PubMed)

153.  Podmore ID, Griffiths HR, Herbert KE, Mistry N, Mistry P, Lunec J. Vitamin C exhibits pro-oxidant properties. Nature. 1998;392(6676):559.

154.  Carr A, Frei B. Does vitamin C act as a pro-oxidant under physiological conditions? FASEB J. 1999;13(9):1007-1024.  (PubMed)

155.  Brubacher D, Moser U, Jordan P. Vitamin C concentrations in plasma as a function of intake: a meta-analysis. Int J Vitam Nutr Res. 2000;70(5):226-237.  (PubMed)

156.  Michels AJ, Joisher N, Hagen TM. Age-related decline of sodium-dependent ascorbic acid transport in isolated rat hepatocytes. Arch Biochem Biophys. 2003;410(1):112-120.  (PubMed)

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The Bioavailability of Different Forms of Vitamin C (Ascorbic Acid)

In the rapidly expanding market of dietary supplements, it is possible to find vitamin C in many different forms with many claims regarding its efficacy or bioavailability. Bioavailability refers to the degree to which a nutrient (or drug) becomes available to the target tissue after it has been administered. We reviewed the literature for the results of scientific research on the bioavailability of different forms of vitamin C.

Natural vs. synthetic ascorbic acid

Natural and synthetic L-ascorbic acid are chemically identical, and there are no known differences in their biological activity. The possibility that the bioavailability of L-ascorbic acid from natural sources might differ from that of synthetic ascorbic acid was investigated in at least two human studies, and no clinically significant differences were observed. A study of 12 males (6 smokers and 6 nonsmokers) found the bioavailability of synthetic ascorbic acid (powder administered in water) to be slightly superior to that of orange juice, based on blood levels of ascorbic acid, and not different based on ascorbic acid in leukocytes (white blood cells) (1). A study in 68 male nonsmokers found that ascorbic acid consumed in cooked broccoli, orange juice, orange slices, and as synthetic ascorbic acid tablets are equally bioavailable, as measured by plasma ascorbic acid levels (2, 3).

Different forms of ascorbic acid

The gastrointestinal absorption of ascorbic acid occurs through an active transport process, as well as through passive diffusion. At low gastrointestinal concentrations of ascorbic acid active transport predominates, while at high gastrointestinal concentrations active transport becomes saturated, leaving only passive diffusion. In theory, slowing down the rate of stomach emptying (e.g., by taking ascorbic acid with food or taking a slow-release form of ascorbic acid) should increase its absorption. While the bioavailability of ascorbic acid appears equivalent whether it is in the form of powder, chewable tablets, or non-chewable tablets, the bioavailability of ascorbic acid from slow-release preparations is less certain. 

A study of three men and one woman found 1 gram of ascorbic acid to be equally well absorbed from solution, tablets, and chewable tablets, but the absorption from a timed-release capsule was 50% lower. Absorption was assessed by measuring urinary excretion of ascorbic acid after an intravenous dose of ascorbic acid and then comparing it to urinary excretion after the oral dosage forms (4).

A more recent study examined the plasma levels of ascorbic acid in 59 male smokers supplemented for t