Español | 日本語

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, 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. Yet, it is not known if marginal biotin deficiency during pregnancy increases the risk for congenital anomalies in humans. (More information)
• Biotin is used in the treatment of biotin-thiamin responsive basal ganglia disease, an inherited disorder of thiamin transport. (More information)
• Recent randomized controlled trials have not found high-dose biotin supplementation to be beneficial in the treatment of multiple sclerosis. Yet, results of animal studies and meta-analyses of human clinical trials are promising. (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)
• Use of high-dose biotin supplements can result in aberrant results of laboratory tests that utilize the very high affinity biotin-streptavidin (avidin) interaction. (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 non-protein cofactors are termed “prosthetic groups” and are common in water-soluble vitamins. The covalent attachment of biotin to the apocarboxylase (i.e., the carboxylase protein without the biotin prosthetic group and is catalytically inactive) is catalyzed by the enzyme, holocarboxylase synthetase (HCS). The term “biotinylation” refers to the covalent addition of biotin to any molecule, including the 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 histone that 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).

Enzyme cofactor

Five mammalian carboxylases 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; however, the two enzymes have different roles in metabolism and different intracellular locations. ACC1 is located in the cytosol, and the malonyl CoA generated by ACC1 is a rate-limiting substrate for the synthesis of fatty acids (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 located on the outer mitochondrial membrane, and the malonyl CoA generated via ACC2 inhibits CPT1, an enzyme that regulates malonyl-CoA entry into the inner mitochondria, thereby regulating fatty acid oxidation (Figure 3). ACC2 is especially abundant in skeletal muscle and heart (4).

• 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.

• Methylcrotonyl-CoA carboxylase catalyzes an essential step in the catabolism of leucine, an essential branched-chain amino acid. This 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) and the side chain of cholesterol (Figure 4a) and of the amino acids methionine and threonine (Figure 4b).

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). The H1 linker histone 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 for DNA replication and transcription. Chemical modifications of DNA and histones affect the folding of chromatin, increasing or reducing DNA accessibility to factors involved in replication and transcription. DNA methylation and 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 modifications of histone tails ("marks"), including acetylation, methylation, phosphorylation, ubiquitination, SUMOylation, ADP-ribosylation, carbonylation, deimination, hydroxylation, and biotinylation, have various 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. H4 biotinylation appears to be enriched in transposable elements known as long terminal repeats (3). These biotinylation marks also 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 down regulates hSMVT synthesis and reduces biotin uptake. Conversely, in biotin-deficient cells, biotinylation marks in the SLC5A6 promoter are removed increasing gene expression and enabling the synthesis of hSMVT and uptake of biotin (7).

Deficiency

Although clinically 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 avidin; this antimicrobial protein binds biotin with an affinity and specificity that is almost unique as a reversible binding. Because native avidin is resistant to mammalian and microbial digestion, avidin prevents biotin absorption. Cooking egg white denatures avidin, rendering it susceptible to digestion and therefore unable to block 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) that result in functional biotin deficiency often have similar physical findings, 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 for histone biotinylation; hence, the maternal 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). Moreover, certain types of liver disease may decrease biotinidase activity and theoretically increase the requirement for biotin. For example, 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. Additionally, 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

Biotinidase deficiency is an autosomal recessive inherited disorder that is often detected upon newborn screening for metabolic disorders, although late-onset forms have been recently described (15-17). Biotinidase deficiency leads to secondary biotin deficiency in several ways. Intestinal absorption is decreased because deficient biotinidase impairs release of biotin from dietary protein (18). Further, recycling of intracellular 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 responds to supplemental biotin. Oral supplementation with as much as 5 to 20 milligrams (mg) of biotin daily is sometimes required (19, 20), although smaller doses may be sufficient, especially later in childhood (reviewed in 20, 21). Prognosis is characteristically good when biotin therapy is introduced in infancy or early childhood and reliably continued for life (10).

Holocarboxylase synthetase deficiency

Holocarboxylase synthetase 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). Holocarboxylase synthetase deficiency responds to supplementation with pharmacologic doses of biotin in some cases but not others. The prognosis of holocarboxylase synthetase is usually, but not always, good if biotin therapy is introduced early (even antenatally) and continued for life (10, 22). 

Biotin transport deficiency

There has been one case report of a child with biotin transport deficiency who responded to high-dose biotin supplementation (23). Of note, the presence of a defective human sodium-dependent multivitamin transporter (hSMVT) was ruled out as a cause of biotin transport deficiency.

Markers of biotin status

Four measures of marginal biotin deficiency have been validated as indicators of biotin status: and (1) reduced levels of holo-methylcrotonyl-CoA carboxylase and holo-propionyl-CoA carboxylase in lymphocytes, the most reliable indicators of biotin status (24); (2) reduced propionyl-CoA carboxylase activity in peripheral blood lymphocytes (5); (3) high urinary excretion of an organic acid, 3-hydroxyisovaleric acid, and its derivative, 3-hydroxyisovaleryl carnitine, both of which reflect decreased activity of biotin-dependent methylcrotonyl-CoA carboxylase; (4) reduced urinary excretion of biotin and some of its catabolites. These markers have been only validated in men and nonpregnant women, and they may not accurately reflect biotin status in pregnant or breast-feeding women (12, 25).

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 of the National Academy of Medicine set recommendations for an Adequate Intake (AI; Table 1). The AI for adults (30 μg/day) was extrapolated from the AI for infants exclusively fed human milk and probably overestimates the dietary requirement for biotin for most adults. Dietary intakes of generally healthy adults have been estimated to be 40 to 60 micrograms (μg) of biotin daily (1). The requirement for biotin in pregnancy may be increased (26).

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). 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 (27, 28). 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 (29). A small cross-sectional study in 22 pregnant women reported an incidence of low lymphocyte propionyl-CoA carboxylase activity greater than 80% (13). Although these levels of biotin deficiency are 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 (30). 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 may increase genomic instability and result in chromosome anomalies and fetal malformations (13).

Analogous to pregnant women who 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-thiamin-responsive basal ganglia disease

Biotin-thiamin-responsive basal ganglia disease (also called biotin-responsive basal ganglia disease, thiamin transporter-2 deficiency, and thiamin metabolism dysfunction syndrome-2) is caused by an autosomal recessive mutation in the SLC19A3 gene that codes for thiamin transporter-2 (THTR-2). The disease usually presents around 3 to 10 years of age (31), but an early infantile form of the disease exists with onset as early as one month of age (32). Clinical features include subacute 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 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 diagnosis and immediate treatment with biotin and thiamin led to positive outcomes (33). Although the specific mechanism for therapeutic effects of biotin in biotin-thiamin-responsive basal ganglia disease remains unknown, lifelong high-dose supplementation with a combination of biotin and thiamin is the recommended treatment (31). Early diagnosis and treatment is important to ensure a better prognosis (32, 34).

Multiple sclerosis

Multiple sclerosis (MS) is an autoimmune disease characterized by progressive damage to the myelin sheath surrounding nerve fibers (axons) and neuronal loss in the brain and spinal cord of affected individuals in anatomic locations that vary widely among affected individuals producing variable signs and symptoms. 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 (35). Given its role in energy production by intermediary metabolism and fatty acid oxidation and in fatty acid synthesis (required for myelin formation) (see Function), high-dose biotin supplementation it has been hypothesized that to exert beneficial effects that would limit or reverse MS-associated functional impairments (35).

The mechanism of action of high-dose biotin has been investigated in a genetic mouse model of chronic axon injury caused by oxidative damage and bioenergetic failure. High-dose biotin restored redox homeostasis, mitochondria biogenesis, and ATP levels, and reversed axonal death and locomotor impairment. Dysregulation of the transcriptional program for lipid synthesis and degradation in the spinal cord was also normalized, possibly as the result of hyperactivation of a nutrient/energy/redox sensor that controls protein synthesis restoring lipid homeostasis.

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 five (out of five) 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 (36). Additionally, a multicenter, randomized, placebo-controlled trial in 154 subjects with progressive MS reported that 13 out of 103 patients supplemented with high-dose, pharmaceutical-grade biotin (300 mg/day) for 12 months achieved MS-related disability reversal — assessed by improved EDSS or 25-foot walk time (37). In comparison, none of the 51 patients randomized to the placebo group showed significant clinical improvements (37). However, when this regimen of high-dose biotin supplementation was examined in a larger, international cohort of patients with progressive MS (326 patients receiving biotin and 316 patients receiving placebo), no benefits on EDSS or walk time were seen after 12 months (38). Moreover, a randomized, double-blind, placebo-controlled trial in 93 MS patients with chronic visual loss found that 300 mg/day of pharmaceutical-grade biotin for six months did not improve visual acuity, but an interesting trend favoring the biotin group was observed in the subgroup of patients with progressive optic neuritis (39). Moreover, a meta-analysis of three randomized controlled trials (2 on disability; 3 on adverse effects), involving 889 individuals diagnosed with MS (the preponderance of participants [830] had progressive MS while only 59 had remitting relapsing MS) was conducted (40). Pooling results of two trials found no benefit of high-dose biotin on MS-related disability, but there was significant heterogeneity between the trials. When the subgroup progressive MS was analyzed separately, a moderate certainty of evidence suggested a potential benefit in favor of high-dose biotin for the 25-foot minute walk time (40). On balance, studies remain inconclusive but promising.

Diabetes mellitus

Overt biotin deficiency has been shown to impair glucose utilization in mice (41) 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 control subjects without the disease; an inverse relationship between fasting blood glucose and biotin concentrations was observed as well (42). 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 45% decrease in mean fasting blood glucose concentrations (42). Yet, another small study in 10 patients with type 2 diabetes and 7 controls without diabetes found no effect of biotin supplementation (15 mg/day) for 28 days on fasting blood glucose concentrations in either group (43). A more recent double-blind, placebo-controlled study by the same research group showed that the same biotin regimen lowered plasma triglyceride concentrations in patients with hypertriglyceridemia — independent of whether they had type 2 diabetes (44). 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 (45-48). For information on chromium supplementation as a monotherapy for type 2 diabetes, see the article on Chromium.

Potential mechanisms for the glucose and lipid effects have been suggested. As a cofactor of carboxylases required for fatty acid synthesis, biotin may increase the utilization of glucose for fat synthesis. Also, biotin stimulates glucokinase, a liver enzyme that increases synthesis of glycogen, the storage form of glucose. Biotin also triggers the secretion of insulin in the pancreas of rats and improves glucose homeostasis (50). Yet, reduced activity of ACC1 and ACC2 would be expected to reduce fatty acid synthesis and increase fatty acid oxidation, respectively. Hence, whether pharmacologic doses of biotin benefits the management of hyperglycemia in patients with impaired glucose tolerance remains unclear. Moreover, whether supplemental biotin lowers the risk of cardiovascular complications in patients with diabetes by reducing serum triglycerides and LDL-cholesterol remains to be proven (44-46).

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 (50-52). Three uncontrolled trials examining the effects of biotin supplementation (2.5 mg/day for several months) in women with brittle fingernails have been published (53-55). 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 (53, 54). 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 (55). 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 (56). Although preliminary evidence suggests that supplemental biotin may help strengthen fragile nails (reviewed in 57), 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 has been associated with alopecia reversal in children treated with the anticonvulsant valproic acid (see Drug interactions), as well as with hair regrowth or normal hair growth in some children with inborn errors of biotin metabolism or other genetic disorders (i.e., uncombable hair syndrome) (reviewed in 58). Yet, while 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 (59, 60). Randomized, placebo-controlled trials in healthy individuals would be needed to evaluate this claim.

Sources

Food sources

Biotin is found in many foods, either as the free (i.e., unbound) 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. (61) employed a high-performance liquid chromatography method rather than bioassays (62) 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 (61, 62)

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 (63). 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 (64), 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 (many containing 5,000 μg [5 mg] of biotin) and is often included in B-complex and multivitamin-mineral supplements. Several multivitamin supplements contain 30 μg of biotin, although the amount varies by product (65).

Safety

Toxicity

Biotin is not known to be toxic. In people without disorders of biotin metabolism, doses of up to 5 mg/day (5,000 μg) for two years were not associated with adverse effects (66). 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 (36, 67). 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 (68). Because reports of adverse events were lacking when the Dietary Reference Intakes (DRIs) for biotin were established in 1998, the Food and Nutrition Board 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) (69, 70). Biotin also shares the hSMVT with lipoic acid (71). Pharmacologic (very high) doses of 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 (72).

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, Phenytek), and carbamazepine (Carbatrol, Epitol, Equetro, Tegretol), include inhibition of biotin intestinal absorption and renal reabsorption, as well as increased biotin catabolism (73). Use of the anticonvulsant valproic acid in children has resulted in hair loss reversed by biotin supplementation (74-77). 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 (73).

Interference with lab assays

In 2017, the US Food and Drug Administration (FDA) released a safety communication regarding high-dose biotin supplementation and its potential interference with streptavidin (avidin)-biotin immunoassays, including assays of thyroid hormones, reproductive hormones, and the cardiac protein, troponin. Such interference can cause aberrant results — either falsely high or falsely low depending on the method of the particular assay — and potential misdiagnosis of disease (78-81). An updated FDA communication in 2019 focused on biotin interference in certain lab assays of troponin that have not addressed the concern of falsely low blood concentrations (82). Troponin in blood is a marker of cardiac damage and often used in the clinical diagnosis of a myocardial infarction (heart attack). When blood work is planned, patients should routinely inform their health care provider concerning supplementation of biotin at doses substantially greater than those in usual diets or in routine daily multivitamins.

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 National Academy 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

Updated in July 2022 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Reviewed in March 2023 by: 
Donald Mock, M.D., Ph.D. 
Professor Emeritus
Departments of Biochemistry and Molecular Biology and Pediatrics 
University of Arkansas for Medical Sciences

Copyright 2000-2023  Linus Pauling Institute

---

References

Español | 日本語

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."

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).

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).

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 21^st and 27^th 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 recommendations 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 socioeconomic 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 <10^th 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 USDA's FoodData Central.

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 2000-2023  Linus Pauling Institute

---

References

Español

Summary

• Dietary precursors of nicotinamide adenine dinucleotide (NAD), including nicotinic acid, nicotinamide, and nicotinamide riboside, are collectively referred to as niacin or vitamin B₃. The essential amino acid tryptophan can also be converted into NAD via the kynurenine pathway. (More information)
• NAD 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; pellagra can lead to death if left untreated. (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)
• Dietary intake requirements for niacin are based on the urinary excretion of niacin metabolites. (More information)
• NAD is the sole substrate for PARP enzymes and sirtuins involved in DNA repair activities; 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. In a recent phase III trial, a daily pharmacologic dose of nicotinamide was found to reduce the rate of premalignant skin lesions and nonmelanoma cancers in high-risk subjects. (More information)
• Despite promising initial results, nicotinamide administration has failed to prevent or delay the onset of type 1 diabetes mellitus in high-risk relatives of type 1 diabetic patients. Future research might explore the use of nicotinamide in combined therapy and evaluate activators of NAD-dependent enzymes. (More information)
• At pharmacologic doses, nicotinic acid improved lipid profiles of patients with a history of vascular disease yet failed to reduce recurrent cardiovascular events or mortality. (More information)
• Elevated tryptophan breakdown in the kynurenine pathway and niacin deficiency have been reported in HIV-positive people. However, at present, a better understanding of the role of kynurenine pathway and other NAD biosynthetic pathways during HIV infection is needed to establish whether this population could benefit from niacin supplementation. (More information)
• Most adverse effects of niacin (nicotinic acid and nicotinamide) have been reported with pharmacological doses of nicotinic acid. The tolerable upper intake level (UL) for niacin is based on preventing skin flushing, nicotinic acid’s most prominent side effect. The co-administration of laropiprant — a prostaglandin D2 receptor-1 antagonist — helps reduce nicotinic acid-induced skin flushing. (More information)

Niacin or vitamin B₃ is a water-soluble vitamin used by the body to form the nicotinamide coenzyme, NAD⁺. The term ‘niacin’ is often used to refer to nicotinic acid (pyridine-3-carboxylic acid) only, although other vitamers with a pyridine ring, including nicotinamide (pyridine-3-carboxamide) and nicotinamide riboside, also contribute to NAD⁺ formation (1). None of the vitamers are related to the nicotine found in tobacco, although their names are similar. Likewise, nicotine — but not nicotinic acid — is an agonist of the nicotinic receptors that respond to the neurotransmitter, acetylcholine.

Metabolism

Essential to all forms of life, the nicotinamide coenzyme NAD⁺ is synthesized in the body from four precursors that are provided in the diet: nicotinic acid, nicotinamide, nicotinamide riboside, and tryptophan (Figure 1).

[Figure 1 - Click to Enlarge]

Figure 2 illustrates the separate biosynthetic pathways that lead to NAD⁺ production from the various dietary precursors. NAD⁺ is synthesized from nicotinamide and nicotinamide riboside via two enzymatic reactions, while the pathway that yields NAD⁺ from nicotinic acid - known as the Preiss-Handler pathway — includes three steps. The kynurenine pathway is the longest NAD⁺ biosynthetic pathway: the catabolism of tryptophan through kynurenine produces quinolinic acid, which is then converted to nicotinic acid mononucleotide, an intermediate in NAD⁺ metabolism. NAD⁺ is then synthesized from nicotinic acid mononucleotide in the Preiss-Handler pathway (2).

All pathways generate intermediary mononucleotides — either nicotinic acid mononucleotide or nicotinamide mononucleotide. Specific enzymes, known as phosphoribosyltransferases, catalyze the addition of a phosphoribose moiety onto nicotinic acid or quinolinic acid to produce nicotinic acid mononucleotide or onto nicotinamide to generate nicotinamide mononucleotide. Nicotinamide mononucleotide is also generated by the phosphorylation of nicotinamide riboside, catalyzed by nicotinamide riboside kinases (NRKs). Further, adenylyltransferases catalyze the adenylation of these mononucleotides to form either nicotinic acid adenine dinucleotide or NAD⁺. Nicotinic acid adenine dinucleotide is then converted to NAD⁺ by glutamine-dependent NAD⁺ synthetase (NADSYN), which uses glutamine as an amide group donor (Figure 2) (2). Of note, nicotinic acid adenine dinucleotide has been reported to form following the administration of high-dose nicotinamide riboside, suggesting that a potential deamidation could occur to convert NAD⁺ to nicotinic acid adenine dinucleotide when the pool of NAD⁺ is high (1).

[Figure 2 - Click to Enlarge]

NAD kinase catalyzes the phosphorylation of NAD into NADP using adenosyl triphosphate (ATP) as the phosphoryl donor (3). The oxidation-reduction (redox) properties of the dinucleotide are not affected by the phosphorylation such that the redox pairs NAD⁺/NADH and NADP⁺/NADPH show similar redox potentials (4). Oxidation and reduction of the C-4 position of the nicotinamide moiety of NADand its phosphorylated form are essential for electron-transfer reactions supporting vital metabolic and bioenergetic functions in all cells (see Function). Thus, NAD and NADP are recycled back and forth between oxidized (NAD⁺ and NADP⁺) and reduced forms (NADH and NADPH), as shown in Figure 3.

[Figure 3 - Click to Enlarge]

Function

NAD as a coenzyme in electron-transfer reactions

Living organisms derive most of their energy from 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 (5). NAD and NADP appear to support distinct functions (Figure 4). NAD functions most often in energy-producing reactions involving the degradation (catabolism) of carbohydrates, fats, proteins, and alcohol. NADP generally serves in biosynthetic (anabolic) reactions, such as in the synthesis of fatty acids, steroids (e.g., cholesterol, bile acids, and steroid hormones), and building blocks of other macromolecules (4). NADP is also essential for the regeneration of components of detoxification and antioxidant systems (4). To support these functions, the cell maintains NAD in a largely oxidized state (NAD⁺) to serve as oxidizing agent for catabolic reactions, while NADP is kept largely in a reduced state (NADPH) to readily donate electrons for reductive cellular processes (4, 6).

[Figure 4 - Click to Enlarge]

NAD as a substrate for NAD-consuming enzymes

The niacin coenzyme, NAD, is the substrate (reactant) for at least four classes of enzymes. Two classes of enzymes with mono adenosine diphosphate (ADP)-ribosyltransferase and/or poly (ADP-ribose) polymerase activities catalyze ADP-ribosyl transfer reactions. Silent information regulator-2 (Sir2)-like proteins (sirtuins) catalyze the removal of acetyl groups from acetylated proteins, utilizing ADP-ribose from NAD as an acceptor for acetyl groups. Finally, ADP-ribosylcyclases are involved in the regulation of intracellular calcium signaling.

ADP-ribosylation

Enzymes with ADP-ribosyltransferase activities were formerly divided between mono ADP-ribosyltransferases (ARTs) and poly (ADP-ribose) polymerases (PARPs). ARTs were first discovered in certain pathogenic bacteria — like those causing cholera or diphtheria — where they mediate the actions of toxins. These enzymes transfer an ADP-ribose residue moiety from NAD to a specific amino acid of a target protein, with the creation of an ADP-ribosylated protein and the release of nicotinamide.

Because most PARPs have been found to exhibit only mono ADP-ribosyltransferase activities, a new nomenclature was proposed for enzymes catalyzing ADP-ribosylation: A family of mono ADP-ribosyltransferases with homology to bacterial diphteria toxins was named ARTD, while enzymes with either mono or poly ADP-ribosyltransferase activities and related to C2 and C3 clostridial toxins were included in the ARTC family (7, 8).

• ARTCs are extracellular enzymes that catalyze the mono ADP-ribosylation of membrane or secreted proteins involved in innate immunity and cell communication (2).

• ARTDs are intracellular enzymes with either mono or poly ADP-ribosyltransferase activities. At least 18 ARTDs have been identified. All ARTDs possess a diphtheria toxin-like catalytic domain that binds NAD⁺. Only ARTDs 1, 2, 5, and 6 catalyze poly (ADP-ribose) transfers; the others have mono ADP-ribosyltransferase activities. ARTDs were shown to be involved in DNA repair and stress responses, cell signaling, transcription regulation, apoptosis, cell differentiation, maintenance of genomic integrity, and antiviral defense (reviewed in 8).

NAD-dependent deacetylation

Seven sirtuins (SIRT 1-7) have been identified in humans. 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, the acetyl group is transferred onto the ADP-ribose moiety cleaved off NAD, producing O-acetyl-ADP-ribose. Nicotinamide can exert feedback inhibition to the deacetylation reaction (9). Like ADP-ribosylation, acetylation is a post-translational modification that affects the function of target proteins. The initial interest in sirtuins followed the discovery that their activation could mimic caloric 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 includes gene silencing, DNA damage repair, cell cycle regulation, and cell differentiation (10).

Calcium mobilization

In humans, CD38 and CD157 belong to a family of NAD⁺ glycohydrolases/ADP-ribosylcyclases. These enzymes catalyze the formation of key regulators of calcium signaling, namely (linear) ADP-ribose, cyclic ADP-ribose, and nicotinic acid adenine dinucleotide phosphate (Figure 5). Cyclic ADP-ribose and nicotinic acid adenine dinucleotide phosphate works within cells to provoke the release of calcium ions from internal storage sites (i.e., endoplasmic reticulum, lysosomes, mitochondria), whereas ADP-ribose stimulates extracellular calcium entry through cell membrane TRPM2 cation channels (2). Another TRPM2 agonist, 2’-deoxy-ADP-ribose, was recently identified in vitro. CD38 was found to catalyze the synthesis of 2’-deoxy-ADP-ribose from nicotinamide mononucleotide and 2’-deoxy-ATP (11). O-acetyl-ADP-ribose generated by the activity of sirtuins also controls calcium entry through TRPM2 channels (6). Intracellular calcium-mediated signal transduction is regulated by transient calcium entry into the cell or release of calcium from intracellular stores. Calcium signaling is critically involved in processes like neurotransmission, insulin release from pancreatic β-cells, muscle cell contraction, and T-lymphocyte activation (6).

[Figure 5 - Click to Enlarge]

NAD as a ligand

NAD⁺ has been identified as an endogenous agonist of purinergic membrane receptors of the P2Y subclass. In particular, NAD was found to bind to P2Y1 receptor and act as an inhibitory neurotransmitter at neuromuscular junctions in visceral smooth muscles (12). Extracellular NAD⁺ was also found to behave like a proinflammatory cytokine, triggering the activation of isolated granulocytes. NAD⁺ binding to the P2Y11 receptor at the granulocyte surface activated a signaling cascade involving cyclic ADP-ribose and the rise of intracellular calcium, eventually stimulating superoxide generation and chemotaxis (13). Similar observations were made with lipopolysaccharide-activated monocytes (14). Extracellular NAADP⁺ and ADP-ribose might also bind to P2Y receptors and trigger intracellular NAADP⁺- and ADP-ribose-dependent calcium mobilization (see Calcium mobilization) (15, 16).

Lipid-lowering effects with pharmacologic doses of nicotinic acid

For over half a century, pharmacologic doses of nicotinic acid, but not nicotinamide, have been known to reduce serum cholesterol (see Disease Treatment) (17). However, the exact mechanisms underlying the lipid-lowering effect of nicotinic acid remain speculative. Two G-protein-coupled membrane receptors, GPR109A and GPR109B, bind nicotinic acid with high and low affinity, respectively. These nicotinic acid receptors are primarily expressed in adipose tissue and immune cells (but not lymphocytes). They are also found in retinal pigmented and colonic epithelial cells, keratinocytes, breast cells, microglia, and possibly at low levels in the liver (18). Thus, lipid-modifying effects of nicotinic acid are likely to be mediated by receptor-independent mechanisms in major tissues of lipid metabolism like liver and skeletal muscle. Early in vitro data suggested that nicotinic acid could impair very-low-density lipoprotein (VLDL) secretion by inhibiting triglyceride synthesis and triggering ApoB lipoprotein degradation in hepatocytes (19). In another study, nicotinic acid affected the hepatic uptake of ApoAI lipoprotein, thereby reducing high-density lipoprotein (HDL) removal from the circulation (reviewed in 20). In adipocytes, the binding of nicotinic acid to GPR109A was found to initiate a signal transduction cascade resulting in reductions in free fatty acid production via the inhibition of hormone-sensitive lipase involved in triglyceride lipolysis (21). Nonetheless, recent observations have suggested that the lipid-lowering effect of nicotinic acid was not due to its anti-lipolytic activity (22). Trials showed that synthetic agonists of GPR109A acutely lowered free fatty acids yet failed to affect serum lipids (22). Aside from its impact on HDL and other plasma lipids, nicotinic acid has exhibited anti-atherosclerotic activities in cultured monocytes, macrophages, or vascular endothelial cells, by modulating inflammation and oxidative stress and regulating cell adhesion, migration, and differentiation (reviewed in 18).

Deficiency

Pellagra

Causes

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 (23). The disease is generally associated with poorer social classes whose chief dietary staple consisted of cereal 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 (24). 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, if corn contains appreciable amounts of niacin, 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 (25). Pellagra epidemics were also unknown to Native Americans who consumed immature corn that contains predominantly unbound (bioavailable) niacin (24).

Niacin deficiency or pellagra may result from inadequate dietary intake of NAD precursors, including tryptophan. 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 protein (26-29). Deficiencies of other B vitamins and some trace minerals may aggravate niacin deficiency (30, 31). Malabsorptive disorders that can lead to pellagra include Crohn’s disease and megaduodenum (32, 33). Patients with Hartnup’s disease, a hereditary disorder resulting in defective tryptophan absorption, have developed pellagra (see Niacin-responsive genetic disorders). 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 (34). Other pharmaceutical agents, including the immunosuppressive drugs azathioprine (Imuran) and 6-mercaptopurine, the anti-cancer drug 5-fluorouracil (5-FU, Adrucil), and levodopa/carbidopa (Sinemet; two drugs given to people with Parkinson’s disease), are known to increase the reliance on dietary niacin by interfering with the tryptophan-kynurenine-niacin pathway (35). Finally, other populations at risk for niacin deficiency include dialysis patients, cancer patients (36, 37), individuals suffering from chronic alcoholism (38), and people with HIV (see HIV/AIDS below). Further, chronic alcohol intake can lead to severe niacin deficiency through reducing dietary niacin intake and interfering with the tryptophan-to-NAD conversion (30).

Symptoms of deficiency

The most common symptoms of niacin deficiency involve the skin, the digestive system, and the nervous system. The symptoms of pellagra are commonly referred to as the three "Ds": sun-sensitive dermatitis, diarrhea, and dementia. A fourth "D," death, occurs if pellagra is left untreated (5). 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 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 patients. Neurologic symptoms include headache, apathy, fatigue, depression, disorientation, and memory loss and are more consistent with delirium than with the historically described dementia (38). 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

To treat pellagra, the World Health Organization (WHO) recommends administering nicotinamide to avoid the flushing commonly caused by nicotinic acid (see Safety). Treatment guidelines suggest using 300 mg/day of oral nicotinamide in divided doses, or 100 mg/day administered parenterally in divided doses, for three to four weeks (37, 39). Because patients with pellagra often display additional vitamin deficiencies, administration of a vitamin B-complex preparation is advised (39).

The Recommended Dietary Allowance (RDA)

Niacin equivalent (NE)

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. In healthy individuals, less than 2% of dietary tryptophan is converted to NAD in the kynurenine pathway (40). The synthesis of NAD from tryptophan is fairly inefficient and depends on enzymes requiring vitamin B₆ and riboflavin, as well as a heme (iron)-containing enzyme. Nonetheless, tryptophan is essential as a precursor for NAD⁺. Inherited defects in tryptophan transport and metabolism result in severe clinical disorders attributed to NAD⁺ depletion (see Niacin-responsive genetic disorders). On average, 60 milligrams (mg) of tryptophan are considered to correspond to 1 mg of niacin or 1 mg of NE.

Daily recommended intakes

The recommended dietary allowance (RDA) for niacin is based on the prevention of deficiency. Pellagra can be prevented by about 11 mg NE/day, but 12 mg to 16 mg NE/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 (41). However, it has been argued that cellular NAD and NADP content may be more relevant indicators of niacin nutritional status (24).

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	6	6
Children	4-8 years	8	8
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 (42). 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 (43). Among NAD-dependent reactions, poly ADP-ribosylations catalyzed by PARP enzymes (ARTDs) 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 (44). 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 (45). The expression of p53 was also altered by niacin deficiency in rat bone marrow cells (46). Impairment of DNA repair caused by niacin deficiency could lead to genomic instability and drive tumor development in rat models (47, 48). 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 (49, 50). Neither the cellular NAD content nor the dietary intake of NAD precursors 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 (51). Conversely, a pharmacologic dose of either nicotinic acid or nicotinamide was able to increase NAD and poly ADP-ribose in bone marrow and decrease the development of leukemia in rats (52). 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 of nicotinic acid 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 (53). However, nicotinic acid supplementation of up to 100 mg/day for 14 weeks in 21 healthy smokers failed to provide any evidence of a decrease in cigarette smoke-induced genetic damage in blood lymphocytes compared to placebo (54). 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 higher (28.4 mg/day) compared to lower (20.5 mg/day) dietary niacin intake (55). Higher availability of NAD⁺ in X-irradiated peripheral blood lymphocytes was found to favor DNA repair by enhancing survival, particularly through SIRT-mediated p53 deacetylation (56).

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 (57). 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. 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 (58, 59).

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 very 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 (60). 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 (61). The activation of the nicotinic acid 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 nicotinic acid receptors (62). 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 (63). 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 (64).

A pooled analysis of two large US prospective cohort studies that followed 41,808 men and 72,308 women for up to 26 years suggested that higher versus lower intake of niacin (from diet and supplements) might be protective against squamous-cell carcinoma but not against basal-cell carcinoma and melanoma (65). A phase III, randomized, double-blind, placebo-controlled trial in 386 subjects with a history of nonmelanoma skin cancer recently examined the effect of daily nicotinamide supplementation (1 g) for 12 months on skin cancer recurrence at three-month intervals over an 18-month period (66). Nicotinamide effectively reduced the rate of premalignant actinic keratose (-11%), squamous-cell carcinoma (-30%), and basal-cell carcinoma (-20%) compared to placebo after 12 months, yet this protection was not sustained during the six-month post-supplementation period (66). Larger trials are needed to assess whether nicotinamide could reduce the risk of melanomas, which are not as common as other skin cancer but are more deadly (67).

Type 1 diabetes mellitus

Type 1 diabetes mellitus in children is caused by the autoimmune destruction of insulin-secreting β-cells in the pancreas. Prior to the onset of symptomatic diabetes, specific antibodies, including islet cell autoantibodies (ICA), can be detected in the blood of high-risk individuals (68). In an experimental animal model of diabetes, high levels of nicotinamide are administered to protect β-cells from damage caused by streptozotocin (69).

Yet, pharmacologic doses of nicotinamide (up to 3 g/day) have not been found to be effective in delaying or preventing the onset of type 1 diabetes in at-risk subjects. An analysis of 10 trials, of which five were 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 control (70). A large, multicenter randomized controlled trial of nicotinamide in ICA-positive siblings (ages, 3-12 years) of type 1 diabetic patients also failed to find a difference in the incidence of type 1 diabetes after three years (70). A randomized, double-blind, placebo-controlled multicenter trial of nicotinamide (maximum of 3 g/day) was conducted in 552 ICA-positive relatives of patients with type 1 diabetes. The proportion of relatives who developed type 1 diabetes within five years was comparable whether they were treated with nicotinamide or placebo (71). Nicotinamide could reduce inflammation-related parameters in these high-risk subjects yet was ineffective to prevent disease onset (72). More recently, case reports of the combined use of nicotinamide (25 mg/kg/day) and acetyl-L-carnitine (50 mg/kg/day) in children at risk for type 1 diabetes showed promising results, warranting further investigation (73).

Disease Treatment

Niacin supplements at pharmacologic doses (i.e., doses much larger than those needed to prevent deficiency) have been used in an attempt to treat a range of conditions, some of which are discussed below.

Niacin-responsive genetic disorders

Congenital NAD deficiency-related disorders can result from mutations in genes involved in the uptake and transport of the various dietary NAD⁺ precursors or in the distinct metabolic pathways leading to NAD⁺ production (see Metabolism). Some of these disorders might respond to niacin supplementation. For example, defective transport of tryptophan into cells results in Hartnup disease, which features signs of severe niacin deficiency (74). Hartnup disease is due to mutations in the SLCA19 gene, which codes for a sodium-dependent neutral amino acid transporter expressed primarily in the kidneys and intestine. Disease management involves supplementation with nicotinic acid or nicotinamide (75). Recessive mutations in genes coding for enzymes of the kynurenine pathway — namely kynureninase and 3-hydroxyanthranilic-acid 3,4-dioxygenase — lead to combined vertebral, anal, cardiac, tracheo-esophageal, renal, and limb (VACTERL) congenital malformations (76). Depletion of NAD⁺, rather than accumulation of intermediate metabolites in the kynurenine pathway, was found to be responsible for these malformations. Niacin supplementation throughout pregnancy ensured adequate levels of NAD⁺ and prevented congenital anomalies in mice with kynurenine pathway mutations (76). In humans, the dose of NAD⁺ precursors necessary to avert NAD deficiency-induced congenital VACTERL malformations has yet to be defined (77).

Nicotinamide may also rescue NAD⁺ depletion secondary to an ultra-rare inborn error of glutamine metabolism (78). Glutamine is required for the conversion of nicotinic acid adenine dinucleotide to NAD⁺ catalyzed by NAD⁺ synthetase (Figure 2). Thus, inherited glutamine synthetase deficiency specifically affects the synthesis of NAD⁺ from the NAD⁺ precursors, tryptophan and nicotinic acid. If the combined deficiencies of glutamine and NAD⁺ are responsible for the severe clinical phenotype of subjects with inherited glutamine synthetase deficiency, it is likely that supplementation with both glutamine and nicotinamide would provide some relief (78).

Finally, many inborn errors of metabolism result from genetic mutations decreasing cofactor binding affinity and, subsequently, enzyme efficiency (79). In many cases, the administration of high doses of the vitamins serving as precursors of cofactors can restore enzymatic activity — at least partially — and lessen signs of the genetic diseases (79). Given the large number of enzymes requiring NAD, it is speculated that many of the conditions due to defective enzymes might be rescued by niacin supplementation (5).

Cardiovascular disease

Cardiovascular risk factors

Nicotinic acid is a well-known lipid-lowering agent: Nicotinic acid therapy markedly increases high-density lipoprotein (HDL) cholesterol concentrations, decreases serum lipoprotein(a) concentrations, and shifts small, dense low-density lipoprotein (LDL) particles to large, buoyant LDL particles. All of these changes in the blood lipid profile are considered cardioprotective. Low concentrations of HDL-cholesterol are one major risk factor for coronary heart disease (CHD), and an increase in HDL concentrations is associated with a reduction of that risk (80). Because of the adverse side effects associated with high doses of nicotinic acid (see Safety), nicotinic acid has most often been used in combination with other lipid-lowering medications at slightly lower doses (17). In particular, low-dose nicotinic acid is often co-administered with 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins), the cornerstone of treatment of hyperlipidemia, a major risk factor for CHD. A placebo-controlled study in 39 patients taking statins (cerivastatin, atorvastatin, or simvastatin) found that a very low dose of nicotinic acid (100 mg/day) increased HDL-cholesterol by only 2.1 mg/dL, and the combination had no effect on LDL-cholesterol, total cholesterol, or triglyceride concentrations (81).

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 nicotinic acid (1 g/day) to statin therapy in 167 patients with known CHD and low HDL concentrations on carotid intima-media thickness (CIMT) (82), a surrogate endpoint for the development of atherosclerosis. The addition of extended-release nicotinic acid to simvastatin 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 concentrations in patients with normal glycemic status. However, in the presence of additional risk factors, such as impaired fasting glucose or diabetes mellitus, the increase in HDL concentrations was not predictive of CIMT reduction and atherosclerotic retardation (83). A comparative efficacy trial (ARBITER6) also showed a significant reduction of baseline CIMT with extended-release nicotinic acid (2 g/day for 14 months), as opposed to ezetimibe (a cholesterol-lowering drug), in patients taking statins (84).

Additional studies have examined the impact of nicotinic acid on endothelium-dependent brachial flow-mediated dilation (FMD) in patients at risk of CHD or with established CHD. The measurement of FMD is often used as a surrogate marker of endothelial function; FMD values are inversely correlated with the risk of future cardiovascular events (85). A meta-analysis of seven randomized controlled trials, including 441 participants, showed a significant, 2% increase with nicotinic acid (1-2 g/day) administered for 12 weeks to one year (86).

Cardiovascular events

Several randomized, placebo-controlled, multicenter trials have investigated the efficacy and safety of nicotinic acid therapy, alone or in combination with other lipid-lowering agents, on outcomes of cardiovascular disease (CVD). Specifically, the Coronary Drug Project (CDP) followed over 8,000 men with a previous myocardial infarction for six years (87). Compared to the placebo group, patients who took 3 g of immediate-release nicotinic acid 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). In addition, nine-year follow-up post-trial revealed a 10% reduction in total deaths with nicotinic acid treatment.

The HDL-Atherosclerosis Treatment Study (HATS), a three-year randomized controlled trial in 160 patients with documented CHD and low HDL concentrations, found that a combination of simvastatin and nicotinic acid (2-3 g/day) increased HDL concentrations, inhibited the progression of coronary artery stenosis (narrowing), and decreased the frequency of cardiovascular events, including myocardial infarction and stroke, compared to placebo (88). 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 nicotinic acid (89). Moreover, a review of nicotinic acid 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 (90). Similarly, the cardiovascular benefit of long-term nicotinic acid therapy outweighed the modest increase in risk of newly onset type 2 diabetes in patients from the CDP study (91).

In contrast, the AIM-HIGH (Atherothrombosis intervention in metabolic syndrome with low HDL/high triglycerides: impact on global health outcomes) trial, which examined the incremental effect of extended-release nicotinic acid (1.5-2 g/day) on 3,414 patients who had established CVD and atherogenic dyslipidemia and were treated with simvastatin (+/- ezetimibe), provided disappointing results. Indeed, in these patients who had achieved target concentrations of LDL-cholesterol (<70 mg/dL) before randomization, the HDL-raising effect of nicotinic acid treatment failed to reduce the number of cardiovascular events after a mean follow-up of three years (92, 93). While some limitations, like a greater use of simvastatin and ezetimibe in the control group, may have confounded the results, it was also suggested that low HDL-cholesterol might be a marker of risk rather than a causal risk factor for predicting CVD (93). In addition, a post-hoc analysis of 505 participants with stage 3 chronic kidney disease found an increase in all-cause mortality in those randomized to nicotinic acid compared to those in the placebo group (94).

Although nicotinic acid failed to reduce the number of cardiovascular events in simvastatin-treated patients with low LDL-cholesterol, these results cannot be extrapolated to patients with higher LDL-cholesterol at baseline. A much larger multicenter, randomized, double-blind, placebo-controlled trial — the HPS2-THRIVE (Heart protection study 2: treatment of HDL to reduce the incidence of vascular events) trial — in 25,673 participants with vascular disease examined the incremental effect of extended-release nicotinic acid (2 g/day) and laropiprant (a prostaglandin D2 receptor-1 antagonist; 40 mg/day) on the incidence of vascular events. Compared to placebo, nicotinic acid/laropiprant reduced LDL-cholesterol by an average of 10 mg/dL, decreased triglycerides by 33 mg/dL, and increased HDL-cholesterol by 6 mg/dL after a median 3.9-year follow-up period. Nonetheless, nicotinic acid/laropiprant showed no effect on the incidence of major vascular events and death of any cause (95).

A recent meta-analysis of 23 randomized controlled trials — including the CDP, AIM-HIGH, and HPS2-THRIVE trials — in 39,195 subjects with a history of vascular disease compared the effect of nicotinic acid alone or as an add-on to other lipid-lowering agents. No cardiovascular benefits were associated with nicotinic acid therapy: the number of fatal and non-fatal myocardial infarctions and strokes was not decreased with nicotinic acid supplementation (median dose of 2 g/day for a median period of 11.5 months) (96).

Despite the lack of evidence for a role of nicotinic acid in CVD prevention (96, 97), the use of nicotinic acid therapy has rapidly increased over the years in the US (98).

Friedreich’s ataxia

Friedreich’s ataxia, a common form of inherited ataxia, is an early onset recessive disorder with clinical features that includes progressive ataxia, scoliosis, dysarthria, cardiomyopathy, and diabetes mellitus (99). Most affected subjects carry homozygous guanine-adenine-adenine (GAA) repeat expansions in the first intron of the gene FXN coding for the protein frataxin. These abnormal and unstable GAA repeats trigger gene silencing through heterochromatin formation, leading to significantly reduced frataxin expression (100). Frataxin is a mitochondrial protein needed for the making of iron-sulfur clusters (ISC). ISC-containing subunits are especially important for the mitochondrial respiratory chain and for the synthesis of heme-containing proteins (99).

Predominantly localized in the nucleus, SIRT1 is a NAD⁺-dependent deacetylase that promotes gene silencing through heterochromatin formation. Nicotinamide has been shown to antagonize heterochromatization of the FXN locus and upregulate frataxin expression in lymphoblastoid cells derived from Friedreich’s ataxia-affected patients, possibly through inhibiting SIRT1 activity (100). In an open-label, dose escalating pilot trial in 10 adult patients with Friedreich’s ataxia, single and repeated doses of nicotinamide (2-8 g) for up to eight weeks were found to be well tolerated (101). Repeated daily doses of 3.5 to 6 g of nicotinamide led to significant increases in frataxin concentration in peripheral white blood cells (101). Yet, no neurological improvements were reported, suggesting that the duration of the treatment was too short and/or the nervous system of the participants was unresponsive to increases in frataxin (102). To our knowledge, there is currently no ongoing trial designed to further investigate the effect of nicotinamide in Friedreich’s ataxia-affected patients.

HIV/AIDS

The first step in the kynurenine pathway 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 dietary niacin intakes, is observed with the infection of human immunodeficiency virus (HIV), the virus that causes acquired immunodeficiency syndrome (AIDS). Interferon-gamma (IFN-γ) is a cytokine produced by cells of the immune system in response to infection. Through stimulating the enzyme IDO, IFN-γ increases the breakdown of tryptophan, thus supporting the finding that the average tryptophan concentration in blood is significantly lower in HIV patients compared to uninfected subjects (40). An increased degradation of tryptophan via the kynurenine pathway appears to coexist with intracellular niacin/NAD deficiency in HIV infection (103). An explanatory model for these paradoxical observations incriminates the oxidative stress induced by multiple nutrient deficiencies in HIV patients (103). In particular, the activation of PARP enzymes (ARTDs) by oxidative damage to DNA could be responsible for inducing niacin/NAD depletion (see Function). The breakdown of tryptophan would then be a compensatory response to inadequate niacin/NAD levels.

However, 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 characterizes HIV infection (104, 105). The increased IDO activity has been linked to the altered immune response that contributes to the persistence of HIV (104). Antiretroviral therapy (ART) only partially restores normal IDO activity, without normalizing it, yet induces viral suppression and CD4 T-cell recovery (106). In a monkey model for HIV infection, a partial and transient blockade of IDO with IDO inhibitor 1-methyl tryptophan proved ineffective to reduce the viral load in plasma and intestinal tissues beyond the level achieved by ART (107). At present, a better understanding of the role of kynurenine pathway and other NAD biosynthetic pathways during HIV infection is needed before the relevance and clinical implications of niacin supplementation in HIV treatment could be considered.

Nonetheless, pharmacologic doses of nicotinic acid have been shown to be well tolerated in HIV patients with hyperlipidemia (108). Abnormal lipid profiles observed in patients have been attributed to the HIV infection and to the highly active antiretroviral treatment (HAART) (109). Moreover, insulin resistance has been detected together with dyslipidemia in ART-treated patients (110). 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. 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 ART. Other first-line treatments include lipid-lowering fibrates, which are preferred to nicotinic acid due to the increased risk of glucose intolerance and insulin resistance (111). Nevertheless, an unblinded, controlled pilot study showed that extended-release nicotinic acid (0.5-1.5 g/day for 12 weeks) could effectively improve endothelial function of the brachial artery in ART-treated HIV subjects with low HDL-cholesterol and no history of CVD (112). In addition, a combined treatment of fibrates, extended-release nicotinic acid (0.5-2 g/day), and lifestyle changes (low-fat diet and exercise) for 24 weeks was effective in normalizing lipid parameters in a cohort of 191 ART-treated patients. Increased risk of liver dysfunction was detected in subjects receiving both fibrates and niacin, but insulin sensitivity was not affected by nicotinic acid treatment given alone or when combined with fibrates (113). Another 24-week, open-label, uncontrolled trial in 99 ART-treated patients found that randomization to extended-release nicotinic acid (0.5-2 g/day) or fenofibrates increased blood HDL-cholesterol but did not reduce inflammatory markers or improve endothelial function when compared to baseline (114).

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 115). The adjunctive use of nutrients like niacin to correct deficiencies associated with neurologic symptoms is called orthomolecular psychiatry (116). 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 (117, 118).

Skin flushing is one major side effect of the therapeutic use of nicotinic acid 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 a specific lipid from the prostanoid family called prostaglandin D2. Prostaglandin D2, synthesized by antigen-presenting cells of the skin and mucosa (i.e., the Langerhans cells), can induce the dilation of blood vessels and trigger a flushing response. Interestingly, patients with schizophrenia tend not to flush following treatment with nicotinic acid. This blunted skin flushing response suggests abnormal prostanoid signaling in schizophrenic patients (119, 120). An association has been found between the altered niacin sensitivity and greater functional impairment in schizophrenic subjects (121), which supports other findings suggesting that altered lipid metabolism could critically impair brain development and contribute to the disease (122). Interestingly, blunted skin flushing responses are more prevalent in first-degree relatives of people with schizophrenia than in the general population, suggesting that reduced niacin sensitivity is a heritable trait within affected families (123).

Sources

Food sources

Good sources of niacin include yeast, meat, poultry, red fish (e.g., tuna, salmon), cereal (especially fortified cereal), legumes, and seeds. Milk, green leafy vegetables, coffee, and tea also provide some niacin (124). 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 its bioavailability (25).

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 (41). 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 USDA's FoodData Central database; data included in Table 2 are from this database (125).

Table 2. Some Food Sources of Niacin

Food	Serving	Niacin (mg)
Chicken (light meat, cooked without skin)	3 ounces*	8.9
Tuna (light, canned, packed in water)	3 ounces	8.6
Turkey (light meat, cooked without skin)	3 ounces	9.9
Salmon (chinook, cooked)	3 ounces	8.5
Beef (90% lean, cooked)	3 ounces	4.4
Cereal (unfortified)	1 cup	5-7
Cereal (fortified)	1 cup	20-27
Peanuts (dry-roasted)	1 ounce	4.1
Pasta (enriched, cooked)	1 cup	1.9-2.4
Lentils (cooked)	1 cup	2.1
Lima beans (cooked)	1 cup	0.8
Bread (whole-wheat)	1 slice	1.4
Coffee (brewed)	1 cup	2
*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. Nicotinic acid is available over the counter and with a prescription as a cholesterol-lowering agent (126). Nicotinic acid for anti-hyperlipidemic use is available in three formulations: immediate-release (crystalline) nicotinic acid (absorption time, 1-2 hrs), extended-release nicotinic acid (absorption time, 8-12 hrs), and sustained-release nicotinic acid (absorption time, >12 hrs) (127). At the pharmacologic dose required for cholesterol-lowering effects, the use of nicotinic acid should be approached as if it were a drug (see Safety). 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.

Safety

Toxicity

Nicotinic acid

Common side effects of nicotinic acid include flushing, pruritus (severe itching of the skin), skin rashes, and gastrointestinal disturbances, such as nausea and vomiting (97). Transient episodes of low blood pressure (hypotension) and headache have also been reported. Hepatotoxicity (liver cell damage), including elevated liver enzymes and jaundice, has been observed at intakes as low as 750 mg/day of nicotinic acid (128). Although hepatitis has been observed with extended-release nicotinic acid at dosages as little as 500 mg/day for two months, almost all reports of severe hepatitis have been associated with doses of 3 to 9 g/day used to treat high cholesterol for months or years (41). It is unclear whether immediate-release (crystalline) nicotinic acid is less toxic to the liver than extended-release forms (41). Yet, immediate-release nicotinic acid is often used at higher doses than extended-release forms, and severe liver toxicity has occurred in individuals who substituted extended-release nicotinic acid for immediate-release nicotinic acid at equivalent doses (126). Large doses of nicotinic acid have been observed to impair glucose tolerance, likely because of a decrease in insulin sensitivity. Impaired glucose tolerance in susceptible (pre-diabetic) individuals could result in elevated blood glucose concentrations and clinical type 2 diabetes mellitus. An analysis of the HPS2-THRIVE trial (see Cardiovascular disease), using data from 17,374 participants without type 2 diabetes at baseline, found a significantly higher proportion of newly diagnosed cases among those randomized to nicotinic acid/laropiprant than to placebo (5.7% versus 4.3%) over a 3.9 year-period (95). Likewise, randomization to nicotinic acid/laropiprant significantly increased the risk of serious disturbances in diabetes control (leading to hospitalization) compared to placebo among 8,299 participants with diabetes at baseline (95). Elevated blood concentrations of uric acid, occasionally resulting in attacks of gout in susceptible individuals, have also been observed with high-dose nicotinic acid therapy (126). Niacin at doses of 1.5 to 5 g/day has resulted in a few case reports of blurred vision and other eye problems, which have generally been reversible upon discontinuation (41). People with abnormal liver function or a history of liver disease, diabetes, active peptic ulcer disease, gout, cardiac arrhythmias, inflammatory bowel disease, migraine headaches, or alcoholism may be more susceptible to the adverse effects of excess niacin intake than the general population (41).

Nicotinamide

Nicotinamide is generally better tolerated than nicotinic acid; it does not generally cause flushing (126). However, nausea, vomiting, and signs of liver toxicity (elevated liver enzymes, jaundice) have been observed at very high doses (≥10 g/day) (126).

Nicotinamide riboside

A study in 12 healthy subjects found that nicotinamide riboside at three single doses (100 mg, 300 mg, and 1,000 mg) safely increased blood NAD⁺. Two of the participants self-reported skin flushing after taking the 300-mg dose, and two others reported feeling hot following intake of 1,000 mg of nicotinamide riboside (1). In a recent randomized, placebo-controlled trial in 120 healthy adults (ages, 60-80 years), daily supplementation with nicotinamide riboside (250 mg or 500 mg) and pterostilbene (a SIRT activator; 50 mg or 100 mg) for eight weeks showed a favorable side effect profile, with no evidence of higher incidence of adverse effects compared to placebo (129). Most recently, a randomized, placebo-controlled trial in 40 obese men (ages, 40-70 years) found that daily supplementation with nicotinamide riboside (2,000 mg/day divided into two daily dosages) for 12 weeks was associated with reports of only minor side effects, including excessive sweating, pruritus, and mild gastrointestinal symptoms like bloating (139).

The tolerable upper intake level (UL)

Flushing of the skin primarily on the face, arms, and chest is a common side effect of nicotinic acid 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 tolerable upper intake level (UL) for niacin (nicotinic acid and nicotinamide) at 35 mg/day in adults to avoid the adverse effect of flushing (41). Analysis of data from the US National Health and Nutrition Examination Survey (NHANES) 2003-2006 found that 15.8% of children and adolescents (ages 2-18 years) and 8.5% of adults (≥19 years) had total usual niacin intakes exceeding the UL (130). 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 (e.g., high-dose nicotinic acid for elevated blood cholesterol concentrations).

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 statins (HMG-CoA reductase inhibitors). 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 (131). Co-administration of nicotinic acid with a statin seems to enhance the risk of rhabdomyolosis (132). A new drug, laropiprant, blocks prostanoid receptors and reduces nicotinic acid-induced flushing (133). A randomized, placebo-controlled trial was designed to identify possible adverse effects of the niacin/laropiprant combination in over 25,000 simvastatin-treated subjects (134). When added to the statin therapy, niacin/laropiprant increased the risk of myopathy and rhabdomyolosis, particularly in Asian subjects. It is possible that the niacin/laropiprant combination further reduces the poor tolerability to statin treatment observed in certain populations (135).

In the three-year, randomized controlled HATS study, concurrent therapy with antioxidants (1,000 mg/day of vitamin C, 800 IU/day of RRR-α-tocopherol, 100 µg/day of selenium, and 25 mg/day of β-carotene) diminished the protective effects of the simvastatin-nicotinic acid combination (136). Although the mechanism for these effects is not known, the benefit of concurrent antioxidant therapy in patients on lipid-lowering agents has been questioned (137).

Adverse effects of large doses of nicotinic acid may be exacerbated by the concomitant use of certain medications. The risk of myopathy may be further increased in those taking nicotinic acid and bile acid sequestrants (e.g., cholestyramine, colestipol) or the anti-lipidemic drug, gemfibrozil (Lopid), and the risk of hepatotoxicity observed with nicotinic acid might be enhanced by drugs like paracetamol, amiodarone (Cordarone), or carbamazepine (Tegretol) (35). In addition, large doses of nicotinic acid may reduce uric acid excretion, thereby opposing the action of uricosuric agents like probenecid (Probalan) (35).  

Several other medications may interact with niacin therapy or with absorption and metabolism of the vitamin (126). Estrogen and estrogen-containing oral contraceptives increase the efficiency of niacin synthesis from tryptophan, resulting in a decreased dietary requirement for niacin (138). Long-term administration of chemotherapy agents has been reported to cause symptoms of pellagra; therefore, niacin supplementation may be needed (see Pellagra causes).

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 by consuming 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.

---

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

Updated in December 2017 by:
Barbara Delage, Ph.D.
Linus Pauling Institute
Oregon State University

Reviewed in March 2018 by:
Mirella Meyer-Ficca, Ph.D.
Research Assistant Professor
Utah State University

The 2017 update of this article was supported by a grant from ChromaDex, Inc.

Last updated 8/10/18  Copyright 2000-2023  Linus Pauling Institute

---

References

1.  Trammell SA, Schmidt MS, Weidemann BJ, et al. Nicotinamide riboside is uniquely and orally bioavailable in mice and humans. Nat Commun. 2016;7:12948.  (PubMed)

2.  Nikiforov A, Kulikova V, Ziegler M. The human NAD metabolome: functions, metabolism and compartmentalization. Crit Rev Biochem Mol Biol. 2015;50(4):284-297.  (PubMed)

3.  Kawai S, Murata K. Structure and function of NAD kinase and NADP phosphatase: key enzymes that regulate the intracellular balance of NAD(H) and NADP(H). Biosci Biotechnol Biochem. 2008;72(4):919-930.  (PubMed)

4.  Agledal L, Niere M, Ziegler M. The phosphate makes a difference: cellular functions of NADP. Redox Rep. 2010;15(1):2-10.  (PubMed)

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

6.  Kirkland JB. Niacin. In: Ross AC, Caballero B, Cousins RJ, Tucker KL, Ziegler TR, eds. Modern Nutrition in Health and Disease. 11^th ed. Baltimore: Lippincott Williams & Wilkins; 2014:331-340. 

7.  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)

8.  Liu C, Yu X. ADP-ribosyltransferases and poly ADP-ribosylation. Curr Protein Pept Sci. 2015;16(6):491-501.  (PubMed)

9.  Hwang ES, Song SB. Nicotinamide is an inhibitor of SIRT1 in vitro, but can be a stimulator in cells. Cell Mol Life Sci. 2017;74(18):3347-3362.  (PubMed)

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

11.  Fliegert R, Bauche A, Wolf Perez AM, et al. 2'-Deoxyadenosine 5'-diphosphoribose is an endogenous TRPM2 superagonist. Nat Chem Biol. 2017;13(9):1036-1044.  (PubMed)

12.  Mutafova-Yambolieva VN, Hwang SJ, Hao X, et al. Beta-nicotinamide adenine dinucleotide is an inhibitory neurotransmitter in visceral smooth muscle. Proc Natl Acad Sci U S A. 2007;104(41):16359-16364.  (PubMed)

13.  Moreschi I, Bruzzone S, Nicholas RA, et al. Extracellular NAD+ is an agonist of the human P2Y11 purinergic receptor in human granulocytes. J Biol Chem. 2006;281(42):31419-31429.  (PubMed)

14.  Klein C, Grahnert A, Abdelrahman A, Muller CE, Hauschildt S. Extracellular NAD(+) induces a rise in [Ca(2+)](i) in activated human monocytes via engagement of P2Y(1) and P2Y(11) receptors. Cell Calcium. 2009;46(4):263-272.  (PubMed)

15.  Moreschi I, Bruzzone S, Bodrato N, et al. NAADP+ is an agonist of the human P2Y11 purinergic receptor. Cell Calcium. 2008;43(4):344-355.  (PubMed)

16.  Huang C, Hu J, Subedi KP, et al. Extracellular adenosine diphosphate ribose mobilizes intracellular Ca2+ via purinergic-dependent Ca2+ pathways in rat pulmonary artery smooth muscle cells. Cell Physiol Biochem. 2015;37(5):2043-2059.  (PubMed)

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

18.  Graff EC, Fang H, Wanders D, Judd RL. Anti-inflammatory effects of the hydroxycarboxylic acid receptor 2. Metabolism. 2016;65(2):102-113.  (PubMed)

19.  Jin FY, Kamanna VS, Kashyap ML. Niacin accelerates intracellular ApoB degradation by inhibiting triacylglycerol synthesis in human hepatoblastoma (HepG2) cells. Arterioscler Thromb Vasc Biol. 1999;19(4):1051-1059.  (PubMed)

20.  Kamanna VS, Ganji SH, Kashyap ML. Recent advances in niacin and lipid metabolism. Curr Opin Lipidol. 2013;24(3):239-245.  (PubMed)

21.  Carlson LA. Studies on the effect of nicotinic acid on catecholamine stimulated lipolysis in adipose tissue in vitro. Acta Med Scand. 1963;173:719-722.  (PubMed)

22.  Lauring B, Taggart AK, Tata JR, et al. Niacin lipid efficacy is independent of both the niacin receptor GPR109A and free fatty acid suppression. Sci Transl Med. 2012;4(148):148ra115.  (PubMed)

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

24.  Kirkland JB. Niacin. In: Zempleni J, Suttie JW, Gregory III JF, Stover PJ, eds. Handbook of Vitamins. 5^th  ed. Boca Raton: CRC Press; 2013:149-190. 

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

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

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

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

29.  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)

30.  Badawy AA. Pellagra and alcoholism: a biochemical perspective. Alcohol Alcohol. 2014;49(3):238-250.  (PubMed)

31.  Majewski M, Kozlowska A, Thoene M, Lepiarczyk E, Grzegorzewski WJ. Overview of the role of vitamins and minerals on the kynurenine pathway in health and disease. J Physiol Pharmacol. 2016;67(1):3-19.  (PubMed)

32.  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)

33.  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)

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

35.  Natural Medicines. Professional Monograph - Niacin/Interactions with drugs. Available at: https://naturalmedicines.therapeuticresearch.com/. Accessed 8/2/17. 

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

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

38.  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)

39.  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.

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

41.  Food and Nutrition Board, Institute of Medicine. Niacin. Dietary Reference Intakes: Thiamin, Riboflavin, Niacin, Vitamin B-6, Vitamin B-12, Pantothenic Acid, Biotin, and Choline. Washington, D.C.: The National Academies Press; 1998:123-149.  (The National Academies Press)

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

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

44.  Burkle A. Poly(ADP-ribose). The most elaborate metabolite of NAD+. FEBS J. 2005;272(18):4576-4589.  (PubMed)

45.  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)

46.  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)

47.  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)

48.  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)

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

50.  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)

51.  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)

52.  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)

53.  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)

54.  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)

55.  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)

56.  Weidele K, Beneke S, Burkle A. The NAD+ precursor nicotinic acid improves genomic integrity in human peripheral blood mononuclear cells after X-irradiation. DNA Repair (Amst). 2017;52:12-23.  (PubMed)

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

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

59.  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)

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

61.  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)

62.  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)

63.  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)

64.  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)

65.  Park SM, Li T, Wu S, et al. Niacin intake and risk of skin cancer in US women and men. Int J Cancer. 2017;140(9):2023-2031.  (PubMed)

66.  Chen AC, Martin AJ, Choy B, et al. A phase 3 randomized trial of nicotinamide for skin-cancer chemoprevention. N Engl J Med. 2015;373(17):1618-1626.  (PubMed)

67.  Minocha R, Damian DL, Halliday GM. Melanoma and nonmelanoma skin cancer chemoprevention: A role for nicotinamide? Photodermatol Photoimmunol Photomed. 2018;34(1):5-12.  (PubMed)

68.  Orban T, Sosenko JM, Cuthbertson D, et al. Pancreatic islet autoantibodies as predictors of type 1 diabetes in the Diabetes Prevention Trial-Type 1. Diabetes Care. 2009;32(12):2269-2274.  (PubMed)

69.  Szkudelski T. Streptozotocin-nicotinamide-induced diabetes in the rat. Characteristics of the experimental model. Exp Biol Med (Maywood). 2012;237(5):481-490.  (PubMed)

70.  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)

71.  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)

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

73.  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)

74.  Patel AB, Prabhu AS. Hartnup disease. Indian J Dermatol. 2008;53(1):31-32.  (PubMed)

75.  Oakley A, Wallace J. Hartnup disease presenting in an adult. Clin Exp Dermatol. 1994;19(5):407-408.  (PubMed)

76.  Shi H, Enriquez A, Rapadas M, et al. NAD deficiency, congenital malformations, and niacin supplementation. N Engl J Med. 2017;377(6):544-552.  (PubMed)

77.  Vander Heiden MG. Metabolism and congenital malformations - NAD's effects on development. N Engl J Med. 2017;377(6):509-511.  (PubMed)

78.  Hu L, Ibrahim K, Stucki M, et al. Secondary NAD+ deficiency in the inherited defect of glutamine synthetase. J Inherit Metab Dis. 2015;38(6):1075-1083.  (PubMed)

79.  Ames BN, Elson-Schwab I, Silver EA. High-dose vitamin therapy stimulates variant enzymes with decreased coenzyme binding affinity (increased K(m)): relevance to genetic disease and polymorphisms. Am J Clin Nutr. 2002;75(4):616-658.  (PubMed)

80.  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)

81.  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)

82.  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)

83.  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)

84.  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)

85.  Ras RT, Streppel MT, Draijer R, Zock PL. Flow-mediated dilation and cardiovascular risk prediction: a systematic review with meta-analysis. Int J Cardiol. 2013;168(1):344-351.  (PubMed)

86.  Sahebkar A. Effect of niacin on endothelial function: a systematic review and meta-analysis of randomized controlled trials. Vasc Med. 2014;19(1):54-66.  (PubMed)

87.  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)

88.  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)

89.  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)

90.  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)

91.  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)

92.  Boden WE, Probstfield JL, Anderson T, et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011;365(24):2255-2267.  (PubMed)

93.  Michos ED, Sibley CT, Baer JT, Blaha MJ, Blumenthal RS. Niacin and statin combination therapy for atherosclerosis regression and prevention of cardiovascular disease events: reconciling the AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcomes) trial with previous surrogate endpoint trials. J Am Coll Cardiol. 2012;59(23):2058-2064.  (PubMed)

94.  Kalil RS, Wang JH, de Boer IH, et al. Effect of extended-release niacin on cardiovascular events and kidney function in chronic kidney disease: a post hoc analysis of the AIM-HIGH trial. Kidney Int. 2015;87(6):1250-1257.  (PubMed)

95.  Landray MJ, Haynes R, Hopewell JC, et al. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med. 2014;371(3):203-212.  (PubMed)

96.  Schandelmaier S, Briel M, Saccilotto R, et al. Niacin for primary and secondary prevention of cardiovascular events. Cochrane Database Syst Rev. 2017;6:Cd009744.  (PubMed)

97.  Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;63(25 Pt B):2889-2934.  (PubMed)

98.  Jackevicius CA, Tu JV, Ko DT, de Leon N, Krumholz HM. Use of niacin in the United States and Canada. JAMA Intern Med. 2013;173(14):1379-1381.  (PubMed)

99.  Burk K. Friedreich ataxia: current status and future prospects. Cerebellum Ataxias. 2017;4:4.  (PubMed)

100.  Chan PK, Torres R, Yandim C, et al. Heterochromatinization induced by GAA-repeat hyperexpansion in Friedreich's ataxia can be reduced upon HDAC inhibition by vitamin B3. Hum Mol Genet. 2013;22(13):2662-2675.  (PubMed)

101.  Libri V, Yandim C, Athanasopoulos S, et al. Epigenetic and neurological effects and safety of high-dose nicotinamide in patients with Friedreich's ataxia: an exploratory, open-label, dose-escalation study. Lancet. 2014;384(9942):504-513.  (PubMed)

102.  Lynch DR, Fischbeck KH. Nicotinamide in Friedreich's ataxia: useful or not? Lancet. 2014;384(9942):474-475.  (PubMed)

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

104.  Favre D, Mold J, Hunt PW, et al. Tryptophan catabolism by indoleamine 2,3-dioxygenase 1 alters the balance of TH17 to regulatory T cells in HIV disease. Sci Transl Med. 2010;2(32):32ra36.  (PubMed)

105.  Jenabian MA, Patel M, Kema I, et al. Distinct tryptophan catabolism and Th17/Treg balance in HIV progressors and elite controllers. PLoS One. 2013;8(10):e78146.  (PubMed)

106.  Chen J, Shao J, Cai R, et al. Anti-retroviral therapy decreases but does not normalize indoleamine 2,3-dioxygenase activity in HIV-infected patients. PLoS One. 2014;9(7):e100446.  (PubMed)

107.  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)

108.  Souza SA, Chow DC, Walsh EJ, Ford S, 3rd, Shikuma C. Pilot study on the safety and tolerability of extended release niacin for HIV-infected patients with hypertriglyceridemia. Hawaii Med J. 2010;69(5):122-125.  (PubMed)

109.  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)

110.  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)

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

112.  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)

113.  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)

114.  Dube MP, Komarow L, Fichtenbaum CJ, et al. Extended-release niacin versus fenofibrate in HIV-infected participants with low high-density lipoprotein cholesterol: effects on endothelial function, lipoproteins, and inflammation. Clin Infect Dis. 2015;61(5):840-849.  (PubMed)

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

116.  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)

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

118.  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)

119.  Yao JK, Dougherty GG, Jr., Gautier CH, et al. Prevalence and specificity of the abnormal niacin response: a potential endophenotype marker in schizophrenia. Schizophr Bull. 2016;42(2):369-376.  (PubMed)

120.  Sun L, Yang X, Jiang J, et al. Identification of the niacin-blunted subgroup of schizophrenia patients from mood disorders and healthy individuals in Chinese population. Schizophr Bull. 2017; doi: 10.1093/schbul/sbx150. [Epub ahead of print].  (PubMed)

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

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

123.  Messamore E. The niacin response biomarker as a schizophrenia endophenotype: A status update. Prostaglandins Leukot Essent Fatty Acids. 2017; pii: S0952-3278(16)30249-6. doi: 10.1016/j.plefa.2017.06.014. [Epub ahead of print].  (PubMed)

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

125.  US Department of Agriculture. USDA National Nutrient Database for Standard Reference, Release 25. 2012. Available at: https://ndb.nal.usda.gov/ndb/. Accessed 7/30/17. 

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

127.  Minto C, Vecchio MG, Lamprecht M, Gregori D. Definition of a tolerable upper intake level of niacin: a systematic review and meta-analysis of the dose-dependent effects of nicotinamide and nicotinic acid supplementation. Nutr Rev. 2017;75(6):471-490.  (PubMed)

128.  MacKay D, Hathcock J, Guarneri E. Niacin: chemical forms, bioavailability, and health effects. Nutr Rev. 2012;70(6):357-366.  (PubMed)

129.  Dellinger RW, Santos SR, Morris M, et al. Repeat dose NRPT (nicotinamide riboside and pterostilbene) increases NAD(+) levels in humans safely and sustainably: a randomized, double-blind, placebo-controlled study. NPJ Aging Mech Dis. 2017;3:17.  (PubMed)

130.  Fulgoni VL, 3rd, Keast DR, Bailey RL, Dwyer J. Foods, fortificants, and supplements: Where do Americans get their nutrients? J Nutr. 2011;141(10):1847-1854.  (PubMed)

131.  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)

132.  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)

133.  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)

134.  Hps 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)

135.  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)

136.  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)

137.  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)

138.  Rios-Avila L, Coats B, Chi YY, et al. Metabolite profile analysis reveals association of vitamin B-6 with metabolites related to one-carbon metabolism and tryptophan catabolism but not with biomarkers of inflammation in oral contraceptive users and reveals the effects of oral contraceptives on these processes. J Nutr. 2015;145(1):87-95.  (PubMed)

139. Dollerup OL, Christensen B,Svart M, et al. A randomized placebo-controlled clinical trial of nicotinamide riboside in obese men: safety, insulin-sensitivity, and lipid-mobilizing effects. Am J Clin Nutr. 2018;108:343-353.  (PubMed)

Español | 日本語

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).

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).

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).

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).

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 (ω-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).

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.

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 USDA's FoodData Central.

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

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 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 2000-2023  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. 11^th 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. 10^th 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. 4^th 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. 2^nd 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)

Español | 日本語

Summary

• Riboflavin is the precursor of the coenzymes flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN). FAD and FMN act as electron carriers in a number of oxidation-reduction (redox) reactions involved in energy production, cellular antioxidant function, and in numerous metabolic pathways. (More information)
• Riboflavin (as FAD or FMN) is required for the metabolism of iron and vitamin B₆, and in the synthesis of niacin from tryptophan. It also plays an essential role in folate and related one-carbon metabolism, where FAD is required as a cofactor for methylenetetrahydrofolate reductase (MTHFR), a key folate-metabolizing enzyme. (More information)
• Clinical signs of riboflavin deficiency include skin disorders, angular stomatitis, cheilosis, glossitis, and corneal vascularization. Riboflavin deficiency occurs commonly in low- and middle-income countries. (More information)
• Subclinical deficiency (low status) of riboflavin without clinical signs may be widespread, including in high-income countries, but it usually goes undetected because riboflavin biomarkers are very rarely measured in human studies. (More information)
• Low riboflavin status is associated with preeclampsia in pregnant women, a condition that may progress to eclampsia and cause severe bleeding and death (More information). It is also linked with cataracts in older individuals. (More information)
• Deficient/low status of riboflavin interferes with the metabolism of folate, particularly in individuals with the variant 677TT genotype in MTHFR. There is some evidence that these individuals exhibit a higher risk of cancer. (More information)    
• Case reports have shown that patients with autosomal recessive disorders of riboflavin metabolism may benefit from riboflavin supplementation. (More information)
• The MTHFR C677T polymorphism is associated with an increased risk of hypertension. Intervention studies have shown that supplementation with riboflavin (the MTHFR cofactor) effectively lowers blood pressure, specifically in individuals with the variant MTHFR 677TT genotype. (More information)
• Riboflavin supplementation has been evaluated as a prophylactic agent for migraine headache, but the results are conflicting. (More information) 
• Riboflavin supplementation has been studied as a potential adjunct therapy in cancer, certain eye disorders, and multiple sclerosis. (More information)
   

Riboflavin is a water-soluble B vitamin, also known as vitamin B₂. 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 a 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 requires FAD to regenerate two molecules of reduced glutathione from oxidized glutathione. Riboflavin deficiency has been associated with increased oxidative stress (4) Measurement of glutathione reductase activity in red blood cells is commonly used to assess riboflavin nutritional status (5). 

Glutathione peroxidases (GPx), 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).

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 (6).

Nutrient interactions

Riboflavin (as FAD or FMN) is required for the synthesis of niacin from tryptophan, and in the metabolism of vitamin B₆ and iron. It is also essential for folate and related one-carbon metabolism, where FAD is required as a cofactor for methylenetetrahydrofolate reductase (MTHFR), a key folate-metabolizing enzyme.

B-complex vitamins

Flavoproteins are involved in the metabolism of several other vitamins: vitamin B₆, niacin, vitamin B₁₂, and folate. Therefore, low and deficient riboflavin status can affect several enzyme systems. The conversion of vitamin B₆ to its active coenzyme form in tissues, pyridoxal 5'-phosphate (PLP), requires the FMN-dependent enzyme, pyridoxine 5'-phosphate oxidase (PPO) (7). Human studies have provided evidence of the metabolic dependency of vitamin B₆ on riboflavin status in older (8-10) and younger (10) adults. The synthesis of the niacin-containing coenzymes, NAD and NADP, from the amino acid tryptophan, requires the FAD-dependent enzyme, kynurenine 3-monooxygenase. Severe riboflavin deficiency can thus decrease the conversion of tryptophan to NAD and NADP, increasing the risk of niacin deficiency (3).

Methylenetetrahydrofolate reductase (MTHFR) is an FAD-dependent enzyme that plays a key role in one-carbon metabolism by catalyzing the reduction of 5,10 methyleneTHF to 5 methylTHF. Once formed, 5 methylTHF is used by methionine synthase for the vitamin B₁₂-dependent conversion of homocysteine to methionine and the formation of THF (Figure 2). Both FMN and FAD are coenzymes for the enzyme methionine synthase reductase, which is responsible for the regeneration of methylcobalamin, the biologically active form of vitamin B₁₂ acting as a coenzyme for methionine synthase (11). Along with other B vitamins (folate, vitamin B₁₂, and vitamin B₆), higher dietary riboflavin intakes have been associated with lower plasma concentrations of homocysteine (12). In individuals homozygous for the C677T polymorphism in the MTHFR gene, low riboflavin status is associated with elevated plasma homocysteine, and in turn linked with a higher risk of cardiovascular disease and other chronic diseases (13, 14). Furthermore, supplementation with riboflavin results in marked lowering of homocysteine concentrations specifically in individuals with the variant MTHFR 677TT genotype (15). Such results illustrate that chronic disease risk may be influenced by complex interactions between genetic and dietary factors.

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 (16). In humans, low dietary intake of riboflavin has been associated with an increased risk for anemia (17), and improving riboflavin nutritional status has been found to increase circulating hemoglobin levels (18). Correction of riboflavin deficiency in individuals who are both riboflavin and iron deficient improves the response of iron-deficiency anemia to iron therapy (19). Anemia during pregnancy, a worldwide public health problem, is responsible for considerable perinatal morbidity and mortality (20, 21). The management of maternal anemia typically involves supplementation with iron alone or iron in combination with folic acid (22). It is possible that the inclusion of riboflavin could enhance the effects of iron-folic acid supplementation in treating maternal anemia, but the evidence is limited. There are, however, randomized, double-blind intervention trials conducted in pregnant women with anemia in Southeast Asia showing that a combination of folic acid, iron, vitamin A, and riboflavin improved hemoglobin levels and decreased anemia prevalence compared to iron-folic acid supplementation alone (23, 24).

Deficiency

Ariboflavinosis is the medical name for clinical riboflavin deficiency, which occurs commonly in low- and middle-income countries. Riboflavin deficiency is rarely found in isolation; it typically occurs in combination with deficiencies of other water-soluble vitamins. Clinical signs 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 signs 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). Subclinical deficiency (low status) of riboflavin without clinical signs may be widespread, including in high-income countries, but usually goes undetected because riboflavin biomarkers are very rarely measured in human studies. Low or deficient riboflavin status may result in decreased conversion of vitamin B₆ to its active 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) (25). 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 (26). 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 (26).

A 2015 meta-analysis of 54 case-control studies found that the MTHFR C677T polymorphism was associated with an increased risk of preeclampsia, especially in Caucasian and Asian populations (27). The reduction in the flavoprotein MTHFR activity observed in individuals with the variant MTHFR 677TT genotype leads to an increase in plasma homocysteine (14); higher homocysteine concentrations have been associated with preeclampsia (28). One small randomized controlled trial in 450 pregnant women in West Africa, without specified MTHFR genotype but at high risk for preeclampsia, found that supplementation with 15 mg of riboflavin daily was not effective in preventing the condition (29), but the study was likely underpowered to detect a significant effect. Further studies are needed to assess the potential benefit of riboflavin supplementation in reducing perinatal complications generally and specifically in preeclamptic women with the MTHFR 677TT genotype.

Risk factors for riboflavin deficiency

Alcoholics are at an increased risk of riboflavin deficiency, likely due to decreased dietary intake, decreased absorption, and/or impaired utilization of riboflavin. Interestingly, the elevated blood homocysteine concentrations associated with riboflavin deficiency rapidly decline during alcohol withdrawal (30). Additionally, people with anorexia rarely consume adequate dietary riboflavin, and those who are lactose intolerant are unlikely to meet requirements due to the avoidance of dairy products, the major dietary sources of riboflavin. The conversion of riboflavin into the active cofactor forms FAD and FMN is impaired in hypothyroidism and adrenal insufficiency (3, 4). Further, people who are very active physically (athletes, laborers) may have slightly increased riboflavin requirements. However, riboflavin supplementation has not generally been found to increase exercise tolerance or performance (31) unless the individuals are riboflavin deficient (32).  

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 to 0.6 milligrams (mg)/day, and urinary excretion of riboflavin is seen at intake levels of approximately 1 mg/day (1).

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 cataracts (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) (33). Another case-control study reported that individuals in the highest quintile of riboflavin 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 (34). 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 (35). A prospective cohort 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) (36). However, the range between the highest and lowest quintiles was small, and median intake levels for both quintiles were above the 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 (37). A randomized controlled trial using a fractional factorial design showed that compared with placebo, the combined supplementation with riboflavin (3 mg/day) and niacin (40 mg/day) for five to six years reduced the prevalence of nuclear cataract but increased the progression of posterior subcapsular cataracts in population affected by multiple nutrient deficiency living in rural China (38). Of note is that the results of this trial are somewhat conflicting, and the study design does not allow the effects of riboflavin and niacin to be differentiated. In summary, there is some evidence predominantly from observational studies, that suggests higher riboflavin status might be beneficial; however, more evidence from well-designed, randomized controlled trials is needed to confirm a role for riboflavin in the prevention of cataracts. 

Cancer

The flavoprotein, methylenetetrahydrofolate reductase (MTHFR), plays a pivotal role in folate-mediated one-carbon metabolism. MTHFR converts 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, the cofactor form 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 (39). 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 (40). Subjects homozygous for this mutation (MTHFR 677TT genotype) exhibit reduced MTHFR activity and increased risk for a wide variety of cancers (41-43), but the evidence of an association between this polymorphism and cancer is inconsistent, with some reports suggesting a reduction in colorectal cancer risk with the T allele (44).

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 affecting cancer risk (43). In a randomized, double-blind, placebo-controlled study, 93 subjects with colorectal polyps and 86 healthy subjects were given a placebo, folic acid (400 or 1,200 μg/day), or folic acid (400 μg/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 μg folic acid on circulating 5-methyltetrahydrofolate (5-MTHF) specifically in the polyp patients with the C677T genetic variant (45). This suggests that riboflavin may improve the 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 (46); intake in the reference group was well above the RDA for riboflavin of 1.1 mg/day. The subjects in this study were not prescreened to identify those with the variant MTHFR 677TT genotype, and the association between this polymorphism and colorectal cancer remains unclear, with some reports suggesting a reduction in cancer risk with the T allele (44). Two meta-analyses have found inverse associations between riboflavin intake and risk of colorectal cancer (47, 48). The most recent of these was a dose-response meta-analysis that pooled results from five prospective cohort studies, nine case-control studies, and two studies reporting blood concentrations of riboflavin. This analysis found that higher intakes of riboflavin were associated with a significantly lower risk of colorectal cancer (RR=0.87; 95% CI, 0.81-0.93); inverse associations were observed for both dietary riboflavin intake and total daily intake from the diet and supplements (48).

Associations between riboflavin intake and cancer risk have also 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 (49). Additionally, a 25-year follow up of an intervention trial in patients at high risk for gastric cancer found that dietary supplementation with riboflavin (3.2 mg/day) and niacin (40 mg/day) for five years decreased the risk of mortality from esophageal cancer by 8% but had no effect on mortality from gastric cancer (50). In the Melbourne Collaborative Cohort Study, which followed 41,514 men and women over a 15-year period, weak inverse associations were found between riboflavin intake and lung cancer (51) and breast cancer (52); no association of riboflavin intake with prostate cancer was observed in this cohort (53). A 2017 meta-analysis of 10 observational studies found an overall inverse association of riboflavin intake and breast cancer incidence and reported a 6% lower risk with each 1 mg/day increment of riboflavin intake (54). Further, studies to date have not found riboflavin intake or measures of riboflavin status to be associated with renal cell carcinoma, as reviewed in a recent meta-analysis (55).

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 controlled trial examined the effect of very high dose riboflavin (400 mg/day) for three months on migraine prevention in 54 men and women with a history of recurrent migraine headaches (56). Riboflavin compared to placebo reduced attack frequency and the number of headache days, though the beneficial effect was most pronounced during the third month of treatment (56). Another study by the same investigators found that treatment with either a β-blocker drug 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 (57). 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 (58). A single-blinded, randomized, parallel group trial in 85 patients with migraine headaches (ages 15-55 years), high-dose riboflavin supplementation (400 mg/day) for 12 weeks decreased migraine frequency, duration, and severity compared to baseline and was as effective as sodium valproate (500 mg/day) (59), a medication with established efficacy in migraine preventative therapy (60). Riboflavin elicited significantly fewer adverse effects compared to the drug (59). Thus, although the available trials have been small and short term, most studies to date suggest that high-dose riboflavin supplementation might be a useful adjunct therapy in adults with migraine headaches.

A few randomized controlled trials have investigated the effect of riboflavin supplementation on the frequency and severity of headache attacks in children with migraines. An initial study evaluated riboflavin at 200 mg/day for 12 weeks in 48 children of ages 5 to 15 years old (61). A second study was a cross-over trial with half of the 42 children, ages 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 each), while the other half were first given the placebo then riboflavin (62). Neither study showed differences in the frequency, duration, or intensity of migraines between treatments. However, a more recent trial found a benefit of intervention with higher dose riboflavin: children with migraine treated with 400 mg/day of riboflavin for 12 weeks (n=30) had reductions in migraine frequency and duration, but not intensity, compared to placebo (n=30), yet no benefit was seen in children taking 200 mg/day for 12 weeks in this study (63). Additionally, a randomized controlled trial in 98 adolescents, ages 12 to 19 years, found that 400 mg/day of riboflavin for three months decreased both headache frequency and duration and improved migraine-related disability compared to placebo (64). Retrospective studies of children and adolescents suffering from migraine have also suggested some benefit associated with supplemental riboflavin (65-67). Thus, studies to date are somewhat conflicting, and more research is needed to understand whether riboflavin supplementation might have utility in the treatment of childhood migraine and the most effective dose required for any beneficial effects.

Metabolic disorders

Increasing evidence from case reports 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. MADD is classified into three separate types based on age of onset and clinical symptoms: type I MADD is evident in the neonatal period and is characterized by the presence of congenital anomalies; type II MADD is present in the neonatal period but lacks congenital defects; and type III is characterized by late onset, from infancy through adulthood (68), and even as late as the seventh decade of life (69). Clinical symptoms of type I and II MADD present shortly after birth and include hypoglycemia, hyperammonemia, metabolic acidosis, hepatomegaly, and respiratory distress (68, 70); these forms of MADD are often fatal in infancy, even if treated. Type III MADD usually presents later in life and includes milder symptoms, varying from periodic vomiting, rhabdomyolysis, muscle pain and weakness, and exercise intolerance (68, 70). Peripheral neuropathy has also recently been reported as a symptom of adult-onset MADD (71).

MADD is caused by autosomal recessive 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 the 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. 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, 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 (70, 72). Additionally, the 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 (73). Finally, secondary deficiencies in the respiratory chain are observed in MADD and appear to respond favorably to riboflavin supplementation (72, 74).

Acyl-CoA dehydrogenase 9 deficiency (ACAD9)

Acyl-CoA dehydrogenase family member 9 (ACAD9) is an FAD-dependent enzyme with important roles in both the electron transport chain and β-oxidation of fatty acids in the mitochondria. Recessive mutations in the ACAD9 gene coding for ACAD9 have been found in patients with mitochondrial complex I deficiency, a respiratory chain disorder (75). 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 clinical symptoms of complex I deficiency due to ACAD9 mutations typically include muscle weakness, exercise intolerance, lactic acidosis, and hypertrophic cardiomyopathy (76). However, symptoms can be of varying severity, likely due to the remaining functional activity of ACAD9. For example, affected patients have been reported to exhibit a spectrum of cardiac deficits, including isolated, mild ventricular hypertrophy to severe hypertrophic cardiomyopathy (77).

Riboflavin supplementation (100-300 mg/day) has been shown to increase 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 (78-80). A review of cases of ACAD9 deficiency presenting in infancy (i.e., cases with severe symptoms) found riboflavin treatment to be associated with improved survival: 7 of 22 patients treated with riboflavin succumbed to the illness compared to 16 out of 17 untreated patients (76). 

Defective riboflavin transport-associated disorders

SLC52A1, SLC52A2, and SLC52A3 genes code for the human riboflavin transporters RFVT1, RFVT2, and RFVT3, respectively. Mutations in these genes lead to riboflavin transporter deficiency, a rare neurodegenerative condition with variable age of onset, from infancy to early stages of adulthood. Autosomal recessive mutations in SLC52A2 or SLC52A3 respectively cause disorders known as riboflavin transporter deficiency type 2 (RFVT2 deficiency) and riboflavin transporter deficiency type 3 (RFVT3 deficiency). These genetic disorders were formerly called Brown-Vialetto-Van Laere syndrome and Fazio-Londe syndrome (81). Riboflavin transporter deficiency caused by mutation of SLC52A1 is exceedingly rare and has been reported in only three cases (reviewed in 82).

Clinical features of riboflavin transporter deficiency can include muscle weakness in the arms and legs, sensory ataxia, bulbar palsy with hypotonia and facial weakness, sensorineural deafness, and respiratory insufficiency (83, 84). High-dose, oral supplementation with riboflavin improves many of these symptoms in the majority of affected patients; such treatment should be given at the time of suspected riboflavin transporter deficiency for a better prognosis (84). A 2016 review of the published literature found that oral supplementation with riboflavin – at doses ranging from 7 to 60 mg/kg/day – led to improved symptoms in 71% of the patients (n=39) and to no deaths (83). In contrast, all of the untreated patients (n=31) had a progression of the disease and a mortality rate of at least 48% (83).

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 (85). 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 (86). The use of riboflavin supplements was reported in a 17-year-old female patient affected by pyridoxine non-responsive homocystinuria (87). 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 the betaine treatment-related body odor. Similar effects were seen with riboflavin supplementation in two pediatric patients (88). The data suggest that riboflavin might help maximize residual FMO3 enzyme activity in patients with primary trimethylaminuria. Moreover, a recent case report in a 35-year-old male with HIV described supplemental riboflavin as an effective treatment for secondary trimethylaminuria caused by antiretroviral therapy (89).

Hypertension

Hypertension in adulthood is recognized as the leading risk factor contributing to mortality worldwide primarily from cardiovascular disease, while hypertension in pregnancy leads to serious adverse fetal and maternal outcomes. A number of risk factors are recognized to contribute to the development of hypertension. In recent years, evidence has emerged from genetic and clinical studies pointing to the role of one-carbon metabolism in blood pressure (90). The common MTHFR C677T polymorphism, affecting 1 in 10 adults globally, is associated with higher blood pressure, although this is much less well recognized compared with the phenotype of elevated homocysteine concentrations that was established at the time of discovery of this polymorphism and its link with cardiovascular disease (91). Meta-analyses show that this polymorphism is associated with an increased risk of hypertension by up to 87% and of heart disease and stroke by up to 40% (92). The MTHFR C677T polymorphism is also associated with a significantly higher risk of hypertension in pregnancy (93) and with preeclampsia (27).

Since FAD is required as a cofactor for the MTHFR enzyme and the MTHFR C677T polymorphism results in decreased MTHFR activity, studies have investigated whether affected individuals may benefit from riboflavin supplementation. In an initial randomized controlled trial in 77 healthy young adults stratified by MTHFR genotype, riboflavin supplementation at dietary levels (1.6 mg/day for 12 weeks) resulted in marked lowering of homocysteine concentrations in the MTHFR 677TT genotype group, but not in the 677CC or 677CT genotype groups who exhibited normal plasma homocysteine at baseline (15). Three randomized controlled trials subsequently investigated the effect of riboflavin on blood pressure in patients with hypertension with or without overt cardiovascular disease (91, 94, 95). The results of these trials showed that supplementation with low-dose riboflavin (1.6 mg/day for 16 weeks) resulted in significant lowering of blood pressure and reduction in incidence of hypertension specifically in those patients with the variant MTHFR 677TT genotype. Riboflavin intervention reduced mean systolic/diastolic blood pressure in those with the TT genotype from 144/87 to 131/80 mm Hg, with no response observed in those without the genetic variant (i.e., the CT or CC genotypes) (89). Notably, the 13 mm Hg decrease in systolic blood pressure occurred even though over 80% of the patients were taking one or more antihypertensive drugs at recruitment, and the addition of supplemental riboflavin was shown to greatly enhance the achievement of goal blood pressure with routine antihypertensive drugs (89, 91). Furthermore, the magnitude of blood pressure response achieved with riboflavin in these trials compares very favorably with typical decreases from other interventions, such as dietary salt reductions of 3 g/day (3.6/1.9 mm Hg) and 6 g/day (7.1/3.9 mm Hg). The trial findings therefore suggest that the excess risk of hypertension linked to this genetic polymorphism can be overcome by low-dose riboflavin supplementation. Also, analysis of plasma samples from individuals participating in these trials showed lower concentrations of S-adenosylmethionine (SAM), an important methyl group donor for methylation reactions, in those with the MTHFR 677TT genotype versus the CC genotype (96). However, riboflavin supplementation (1.6 mg/day) for 12 weeks was shown to increase plasma concentrations of SAM and another one-carbon metabolite, cystathionine (96), and thus may have potential in correcting the altered one-carbon metabolism arising with the variant TT genotype.

Thus, studies to date indicate that riboflavin supplementation may have benefits in lowering blood pressure and reducing hypertension in individuals (and sub-populations) affected by the common MTHFR C677T polymorphism. However, the mechanisms explaining the blood pressure phenotype and its responsiveness to riboflavin remain unclear. Future studies examining the effects of riboflavin supplementation on one-carbon metabolism may help to elucidate the biological mechanisms involved. Interestingly, a recent randomized controlled trial found that riboflavin supplementation in those with the variant MTHFR 677TT genotype resulted in altered DNA methylation of certain genes known to be involved in blood pressure regulation (97).

Cancer

Anticancer 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 patients with breast cancer treated with tamoxifen for 90 days. This supplementation effectively prevented the oxidative stress associated with tamoxifen treatment (98).

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 anticancer agents. Under light exposure, riboflavin administration reduced cisplatin-induced DNA damage in the liver and kidneys (99). These results are promising, but human studies are needed to examine whether riboflavin is 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 fairly new procedure used by professionals to limit the progression of corneal damage –involves the use of topical riboflavin in conjunction with ultraviolet-A irradiation. Riboflavin functions as a photosensitizer in the reaction. Cross-linking modifies the properties of the cornea and strengthens its architecture (100, 101).

Multiple sclerosis

Multiple sclerosis (MS) is an autoimmune disease of unknown etiology that is characterized by the progressive destruction of myelin and nerve fibers in the central nervous system, causing neurological symptoms in affected individuals (102). Riboflavin appears to have a role in the formation of myelin (103), and oxidative stress has been implicated in the pathogenesis of MS; thus, riboflavin may be helpful in treatment of the disease. A strong inverse association between dietary riboflavin intake and risk for MS was initially observed in a case-control study (104). In a mouse model of MS (i.e., experimental autoimmune encephalomyelitis), riboflavin supplementation improved clinical measures of the disease (105). However, a randomized, double-blind, placebo-controlled pilot study in 29 patients with MS found that supplementation with 10 mg/day of riboflavin for six months had no effect on MS-related disability, assessed by the Expanded Disability Status Scale (106).  Large-scale randomized, placebo-controlled trials are needed to determine whether riboflavin supplementation has a beneficial effect in the treatment of MS.

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 a US national survey indicate that the average dietary intake of riboflavin is 2.5 mg/day for men and 1.8 mg/day for women (107); these intakes are well above the RDA values of 1.3 mg/day for men and 1.1 mg/day for women. Surveys of adults of ages 70 years or older showed similar intakes: 2.2 mg/day for older men and 1.8 mg day for older women (107).

Riboflavin is heat-stable, but it 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 (6). Nationally representative surveys from the US, Ireland, and the UK showed that milk and other dairy products were the main dietary contributors to riboflavin intake, followed by meat and ready-to-eat breakfast cereals (108-110). 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 USDA's FoodData Central.

The bioavailability of riboflavin from food is reported to be very high, nearly 95% (108). Limited data exist for the relative bioavailability of riboflavin from different food sources, however a cross-over study in healthy women using stable isotopes and kinetic modeling did not find significant differences in riboflavin absorption from milk and spinach (111).

Supplements

The most common forms of riboflavin available in supplements are riboflavin and riboflavin 5'-monophosphate. Riboflavin is commonly found in multivitamin and vitamin B-complex preparations (112). 

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 (113). This may be of concern to workers exposed to chrome, yet 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 had diminished riboflavin biomarker status. However, when investigators controlled for dietary riboflavin intake, no differences between users of oral contraceptives and non-users were found (1). Phenothiazine derivatives like the anti-psychotic medication, chlorpromazine (Thorazine), and tricyclic antidepressants inhibit the conversion of riboflavin to FAD and FMN, as do the anti-malarial medication, quinacrine, and the cancer chemotherapy agent, adriamycin (4). Long-term use of the anticonvulsant, 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 (114).

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 1.3 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 (115, 116). 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 (117). 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 (118), and riboflavin deficiency has been linked to a higher risk of fracture in postmenopausal women with the MTHFR 677T variant (119). 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 1.3 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

Updated in August 2021 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Reviewed in July 2022 by:
Kristina Pentieva, MD, Ph.D. and Helene McNulty, RD, Ph.D.
Nutrition Innovation Centre for Food and Health (NICHE)
Ulster University, Coleraine, Northern Ireland

Copyright 2000-2023  Linus Pauling Institute

---

References

Español | 日本語

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 patients with diabetes. Correction of thiamin deficiency may reduce the risk of vascular complications in these patients. (More information)
• Alzheimer’s disease has been associated with altered glucose metabolism and thiamin deficiency. Although some promising results have been observed in animal models, it is not known whether supplementation with thiamin or benfotiamine (a synthetic precursor of thiamin) might slow the cognitive decline in patients with Alzheimer’s disease. (More information)
• A recent study found decreased levels of thiamin in the brain of patients with Huntington’s disease. Clinical trials are needed to evaluate whether vitamin supplementation might be a potential therapy. (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)
• Intravenous thiamin has been studied as potential treatment for sepsis, either as a monotherapy or in combination with other agents like vitamin C and corticosteroids. Large-scale clinical trials are needed to determine its efficacy. (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, adenosine thiamin triphosphate, 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. In humans, TPP is required as a coenzyme in the metabolism of carbohydrates and branched-chain amino acids. Forms of thiamin are also needed for ribose synthesis and for α-oxidation of 3-methyl-branched fatty acids.

Pyruvate dehydrogenase, α-ketoglutarate dehydrogenase, 2-oxoadipate 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, 2-oxoadipate, and branched-chain amino acids (BCAA) to form acetyl-coenzyme A (CoA), succinyl-CoA, glutaryl-CoA, and derivatives of BCAA, respectively (Figure 1). All products play critical roles in the production of energy from food through their connection to the citric acid (Krebs) cycle (2). 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 g-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 (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, 5, 6).

2-Hydroxyacyl-CoA lyase is a TPP-dependent enzyme in peroxisomes that catalyzes the catabolism of 3-methyl-branched fatty acids through the process of α-oxidation, the oxidative removal of a single carbon atom from fatty acids like phytanic acid (7).

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, 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, 8).

Dry beriberi

The main feature of dry (paralytic or nervous) beriberi is peripheral 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 (9).

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” (10).

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 impairment. Due in part to an overlap of symptoms with alcoholic delirium, Wernicke’s encephalopathy is thought to be underdiagnosed (11). If left untreated, the 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 (12). 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 (13).

Gastrointestinal beriberi

TPP is critical for metabolic reactions that utilize glucose in glycolysis and the citric acid cycle (see 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 (8).

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 nervosa, bariatric surgery (weight-loss surgery), gastrointestinal malignancies, and malabsorption syndromes (14-17). Obese individuals may also be at heightened risk of thiamin deficiency (18, 19). Moreover, cases of Wernicke’s encephalopathy have been linked with hyperemesis gravidarum (severe nausea and vomiting during pregnancy) (20, 21), and with parenteral nutrition lacking vitamin supplementation (22, 23).

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 (24, 25). 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 (26). 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 (27).

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 (28, 29). The risk of thiamin deficiency is increased in diuretic-treated patients with marginal thiamin intake (30) and in individuals receiving long-term, diuretic therapy (31). Individuals with kidney failure requiring hemodialysis lose thiamin at an increased rate and are at risk for thiamin deficiency (32). 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 (33).

Anti-thiamin factors (ATF)

The presence of anti-thiamin factors (ATF) in foods contributes to the risk of thiamin deficiency. Certain plants contain ATF, which react with thiamin to form an oxidized, inactive product. Consuming very large amounts of tea or coffee (including decaffeinated), as well as chewing tea leaves and betel nuts, might lower thiamin status due to the presence of ATF (34, 35). ATF include mycotoxins (molds) and thiaminases that break down thiamin in food. Individuals who habitually eat certain raw fresh-water fish, raw shellfish, or ferns are at higher risk of thiamin deficiency because these foods contain thiaminase that normally is inactivated by heat in cooking (1, 6). 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 (36).

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 (37; Table 1).

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 (38). In addition, a study in 408 US women found that higher dietary intakes of thiamin were inversely associated with five-year change in lens opacification (39). However, these cross-sectional associations have yet to be elucidated by studies of causation.

Diabetes mellitus and vascular complications

Patients with diabetes mellitus have been reported to have low plasma concentrations and high renal clearance of thiamin (40, 41), suggesting that individuals with type 1 or type 2 diabetes 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. One study suggested that hyperglycemia in patients with diabetes could affect thiamin re-uptake by decreasing the expression of thiamin transporters in the kidneys (42). 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 (43, 44). In humans, thiamin deficiency caused by recessive mutations in the gene encoding THTR-1 leads to diabetes mellitus in the thiamin-responsive megaloblastic anemia syndrome (see Metabolic diseases below).

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 concentrations compared with placebo treatment but did not reduce the hyperglycemia (45). However, one study suggested that thiamin supplementation might improve fasting glucose concentrations in in early stages of type 2 diabetes (i.e., pre-diabetes) (46).

Disease Treatment

Alzheimer's disease

Some older adults are at increased risk for developing subclinical thiamin deficiency secondary to poor dietary intake, reduced gastrointestinal absorption, and multiple medical conditions (47, 48). 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 neurofibrillary tangles formed by hyperphosphorylated Tau protein (49).

Using positron emission tomography (PET) scanning, reduced glucose metabolism has been observed in brains of AD patients (50). A large, multicenter PET study using a radiolabeled 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 (51). 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 (52). Emerging evidence links type 2 diabetes and AD, conditions that may involve insulin resistance in the brain (reviewed in 53).

A reduction in thiamin-dependent processes in the brain appears to be related to the altered glucose metabolism in patients with AD (54-56). Case-control studies have found blood levels of thiamin, TPP, and TMP to be lower in those with dementia of Alzheimer's type (DAT) compared to control subjects (57, 58). 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 (59). The finding of decreased brain levels of TPP in the presence of normal levels of free thiamin and TMP suggests altered 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 (60, 61). 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 (62). Chronic benfotiamine administration was also shown to decrease the number of neurofibrillary tangles in certain brain regions and improve survival in a mouse model (63). In a rat model of neurodegeneration, long-term oral benfotiamine supplementation increased thiamin pyrophosphate concentrations and led to improvements in insulin signaling and cognitive deficits (64).

Thiamin deficiency has been linked to increased β-amyloid production in cultured neuronal cells and to plaque formation in animal models (65, 66). These pathological hallmarks of AD could be reversed by thiamin supplementation, suggesting that thiamin could be protective in AD. Other disorders, including mitochondrial dysfunction and chronic oxidative stress, have been linked to both thiamin deficiency and AD pathogenesis and progression (13, 55, 67). 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 (68). 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 (69). 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 (70). A 2001 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 (71). More recently, a small uncontrolled study in five patients with mild-to-moderate AD reported cognitive improvement, measured by the Mini-Mental Status Examination, following supplementation with 300 mg/day of benfotiamine for 18 months (72). In a placebo-controlled study of 70 β-amyloid positive patients with either amnestic mild cognitive impairment (a precursor to AD) or mild AD, those receiving 600 mg/day of benfotiamine for 12 months experienced less cognitive decline compared to placebo, but the differences did not reach statistical significance (p=0.125; 73). Large-scale, randomized controlled trials are needed to determine whether supplemental thiamin or benfotiamine might help slow progression of cognitive decline in those with Alzheimer’s disease.

Huntington’s disease

Huntington’s disease is an inherited neurodegenerative disorder characterized by selective degeneration of nerve cells known as striatal spiny neurons. Symptoms, such as movement disorders and impaired cognitive function, typically develop in the fourth decade of life and progressively deteriorate over time. A recent study found decreased levels of the thiamin transporter-2 (THTR-2) protein in the striatum and frontal cortex of patients with Huntington’s disease compared to age-and sex-matched healthy controls (74). Compared to control subjects, this study also found lower concentrations of TPP in the striatum and lower concentrations of TMP in the cerebrospinal fluid of patients with Huntington’s disease (74). Mutations in the SLC19A3 gene that encodes THTR-2 causes biotin-thiamin-responsive basal ganglia disease, which is treated with high-dose co-supplementation with biotin and thiamin for life (see Biotin-thiamin-responsive basal ganglia disease below). In a mouse model of Huntington’s disease, high-dose supplementation with both of these vitamins improved neuropathological and motor deficits but had no effect on lifespan (p=0.15) (74). A phase II, open-label clinical trial evaluating the effect of combined thiamin-biotin supplementation, at moderate (600 mg/day of thiamin and 150 mg/day of biotin) and high (1,200 mg/day of thiamin and 300 mg/day of biotin) dosages, in Huntington’s disease is currently underway (75).

Congestive heart failure 

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. Loop diuretics used in the treatment of CHF, notably furosemide, increase thiamin excretion, potentially leading to thiamin deficiency (76, 77). Patients with CHF might also have altered thiamin metabolism, including reduced absorption of thiamin in the small intestine (78). A 2015 meta-analysis of nine observational studies found a 2.5 times higher risk of thiamin deficiency in patients with heart failure compared to control subjects (78). As in the general population, older CHF patients were found to be at higher risk of thiamin deficiency than younger ones (79).

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 (31). 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 (80). 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 (81). However, clinical trials of oral thiamin supplementation in heart failure patients have not found any benefit. In a randomized, double-blind, placebo-controlled trial in 52 patients with systolic heart failure, 300 mg/day of supplemental thiamin for one month did not improve LVEF compared to placebo (82). A randomized, double-blind, placebo-controlled trial in 64 patients with heart failure reported that 200 mg/day or supplemental thiamin for six months did not improve LVEF (83).  

Although little evidence supports the routine use of supplemental thiamin in CHF patients, trials specifically in CHF patients with marginal thiamin status have not been done, and some suggest that it may be prudent to screen patients on long-term diuretic therapy for thiamin deficiency and treat accordingly (84).

Type 2 diabetes mellitus and vascular complications

Chronic hyperglycemia in individuals with diabetes mellitus contributes to the pathogenesis of microvascular diseases. Diabetes-related vascular damage can affect the heart (cardiomyopathy), kidneys (nephropathy), retina (retinopathy), and peripheral nervous system (neuropathy). In subjects with diabetes, hyperglycemia alters the function of bone marrow-derived endothelial progenitor cells (EPC) that are critical for the growth of blood vessels (85). 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 (86). An inverse association has also been found between plasma concentrations of thiamin and the presence of soluble vascular adhesion molecule-1 (sVCAM-1), a marker of vascular dysfunction, in patients with diabetes (40, 87). 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 (88). A randomized, double-blind, placebo-controlled study conducted in 40 patients with type 2 diabetes with microalbuminuria found that high-dose thiamin supplementation (300 mg/day) decreased excretion of urinary albumin over a three-month period (87). Since thiamin treatment has shown promising results in cultured cells and animal models (89-91), the effects of thiamin and its derivatives on vascular complications should be examined in patients with diabetes.

Cancer

Thiamin deficiency and Wernicke-Korsakoff syndrome have been observed in some cancer patients with rapidly growing tumors (92, 93). Research in cell culture and animal models indicates that rapidly dividing cancer cells have a high requirement for thiamin (94). 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. One 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 (95). Other studies have found that the gene encoding THTR-2 is downregulated in certain cancers (96). Moreover, use of the chemotherapeutic drug, 5-fluorouracil, inhibits phosphorylation of thiamin to thiamin pyrophosphate and may thus lead to thiamin deficiency (97, 98).

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 (99), 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. Intravenous, high-dose thiamin has been suggested as a treatment for cancer patients with confirmed Wernicke-Korsakoff (93).

Sepsis

Sepsis is a life-threatening critical illness caused by a dysregulated host response to an infection. The widespread inflammation can lead to tissue and organ damage and to death (100). Because thiamin deficiency is common among septic patients (101), several studies have investigated the treatment effect of intravenous thiamin – alone or in combination with other agents like vitamin C and hydrocortisone.

Observational studies examining the association of intravenous thiamin as a monotherapy have mainly looked at its association with lactic acidosis, which commonly occurs in both thiamin deficiency and sepsis, and with mortality. One retrospective study in 123 septic patients and 246 matched controls found that intravenous thiamin administration within 24 hours of hospital admission was linked to improvements in both lactate clearance and 28-day mortality (102). In a small retrospective study of 53 alcohol-use disorder patients presenting with septic shock, lower mortality was observed in the 34 patients who received intravenous thiamin compared to the 19 patients who did not (103).

A few randomized controlled trials have evaluated the effect of intravenous thiamin in the treatment of sepsis. A randomized, double-blind, placebo-controlled trial in 88 patients with sepsis and elevated blood concentrations of lactate reported that intravenous thiamin (200 mg twice daily for seven days or until discharge from the hospital) did not decrease lactate concentrations at 24 hours post initiation of treatment – the primary endpoint of the trial (104). No differences between the treatment and placebo groups were found for the secondary endpoints, which included survival (104). In a subsequent analysis of data from this trial, the septic patients that were given parenteral thiamin (n=31) had lower creatinine concentrations throughout the treatment and were less likely to need renal replacement therapy compared to placebo (n=39; 105).

A 2020 meta-analysis of four studies – one observational and three randomized controlled trials – found no benefit of intravenous thiamin for improving lactate concentrations, length of hospital stay in intensive care, or overall survival (106). Large-scale clinical trials are needed to determine whether parenteral administration of thiamin is beneficial in the treatment of sepsis. Administering thiamin in combination  with vitamin C and corticosteroids may be more efficacious to treat sepsis (107); some clinical trials of such treatments are currently underway (see clinicaltrials.gov/).

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 a few mg/day to doses above 1,000 mg/day) exhibit PDHC deficiency due to the decreased affinity of PDHC for TPP (108, 109). Although thiamin supplementation can reduce lactate accumulation and improve the clinical features in thiamin-responsive patients, it does not constitute a cure (110).

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 (111). 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 the SLC19A2 gene that encodes THTR-1 impairs intestinal thiamin uptake and causes thiamin deficiency, leading to thiamin-responsive megaloblastic anemia (112). This syndrome, which is also called thiamin metabolism dysfunction syndrome-1, is characterized by megaloblastic anemia, diabetes mellitus, and deafness. A review of 30 cases reported additional neurologic, visual, and cardiac impairments (113). High-dose oral supplementation with thiamin (up to 300 mg/day) helps to maintain health and correct hyperglycemia in prepubescent children. A recent study in 32 individuals with found no additional benefit of oral doses above 150 mg/day (114). 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 (115). Early diagnosis of the syndrome and early treatment with thiamin is important for a better prognosis (114).

Biotin-thiamin-responsive basal ganglia disease

Biotin-thiamin-responsive basal ganglia disease (also called biotin-responsive basal ganglia disease, thiamin transporter-2 deficiency, and thiamin metabolism dysfunction syndrome-2) is caused by an autosomal recessive mutation in the SLC19A3 gene that codes for THTR-2. The disease usually presents around 3 to 10 years of age (116), but an early infantile form of the disease exists with onset as early as one month of age (117). Clinical features include subacute 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 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 for a five-year follow-up period following thiamin supplementation (300-400 mg/day) – early diagnosis and immediate treatment with biotin and thiamin led to positive outcomes (118). Recent studies have found supplemental thiamin to be important in treating the condition. In an open-label study of 20 pediatric patients with the disease, supplemental thiamin alone was as effective as combined biotin-thiamin supplementation when given for 30 months (119). Lifelong high-dose supplementation with a combination of biotin and thiamin is generally the treatment for biotin-thiamin-responsive basal ganglia disease (116). Early diagnosis and treatment is important to ensure a better prognosis (117, 120).

Other thiamin metabolism dysfunction syndromes

Supplemental thiamin has limited utility in treating other inborn errors of thiamin metabolism. Mutations in the SLC25A19 gene that codes for the mitochondrial TPP transporter can result in either thiamin metabolism dysfunction syndrome-3 (THMD3) or thiamin metabolism dysfunction syndrome-4 (THMD4). Of these rare syndromes, THMD3 (also called Amish-type microcephaly or Amish lethal microcephaly) has the more severe phenotype, resulting in a congenital microcephaly, elevated concentrations of α-ketoglutarate in urine, and usually death in infancy (121). THMD4 is characterized by episodic encephalopathy and weakness, which often presents following a viral infection or febrile illness in childhood. Some patients affected with THMD4 may respond to high-dose thiamin supplementation (122).

Mutations in the TPK1 gene result in thiamin pyrophosphokinase 1 deficiency and thiamin metabolism dysfunction syndrome-5 (THMD5), which usually manifests in early childhood. While the clinical presentation of THMD5 varies, affected individuals often experience episodic ataxia, dystonia, and lactic acidosis (123). Only a few cases of THMD5 have been reported to date; two of these patients experienced limited improvement of symptoms upon supplementation with thiamin, in conjunction with adherence to a high-fat diet (124).

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 (125).

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 (37). However, institutionalization and poverty both increase the likelihood of inadequate thiamin intake in the elderly (126). 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 the table below, along with their thiamin content in milligrams (mg). For more information on the nutrient content of foods, search USDA's FoodData Central.

Supplements

Thiamin is available in dietary supplements and in fortified foods, most commonly as thiamin hydrochloride or thiamin mononitrate (127). Multivitamin supplements typically contain at least 1.2 mg of thiamin, the Daily Value (DV) for adults and children 4 years and older (128).

Benfotiamine is a synthetic, lipid-soluble precursor of thiamin that is available as a dietary supplement. It has higher bioavailability compared to thiamin (129).

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 (37).

Drug interactions

Reduced blood concentrations of thiamin have been reported in individuals with seizure disorders (epilepsy) taking the anticonvulsant medication, phenytoin, for long periods of time (130). 5-Fluorouracil, a drug used in cancer therapy, inhibits the phosphorylation of thiamin to TPP (131). Diuretics, especially furosemide, may increase the risk of thiamin deficiency in individuals with marginal thiamin intake due to increased urinary excretion of thiamin (29). 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 (132). 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 (133).

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/mineral 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 (126). 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

Updated in July 2021 by: 
Victoria J. Drake, Ph.D. 
Linus Pauling Institute 
Oregon State University

Reviewed in October 2021 by:
Lucien Bettendorff, Ph.D.
Research Director, F.R.S.-FNRS
University of Liège, Belgium

Copyright 2000-2023  Linus Pauling Institute

---

References

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

2.  Rindi G. Thiamin. In: Ziegler E, Filer L, eds. Present Knowledge in Nutrition. 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. 2^nd ed. San Diego: Academic Press; 1999.

5.  Whitfield KC, Bourassa MW, Adamolekun B, et al. Thiamine deficiency disorders: diagnosis, prevalence, and a roadmap for global control programs. Ann N Y Acad Sci. 2018;1430(1):3-43.  (PubMed)

6.  Bettendorff L. Thiamin. In: Erdman Jr. JW, Macdonald IA, Zeisel SH, eds. Present Knowledge in Nutrition. 10^th ed. Ames: Wiley-Blackwell; 2012:261-279.

7.  Foulon V, Antonenkov VD, Croes K, et al. Purification, molecular cloning, and expression of 2-hydroxyphytanoyl-CoA lyase, a peroxisomal thiamine pyrophosphate-dependent enzyme that catalyzes the carbon-carbon bond cleavage during alpha-oxidation of 3-methyl-branched fatty acids. Proc Natl Acad Sci U S A. 1999;96(18):10039-10044.  (PubMed)

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

9.  McDowell L. Thiamin. Vitamins in Animal and Human Nutrition. 2^nd ed. Ames: Iowa State University Press; 2000:265-310.

10.  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)

11.  Chandrakumar A, Bhardwaj A, t Jong GW. Review of thiamine deficiency disorders: Wernicke encephalopathy and Korsakoff psychosis. J Basic Clin Physiol Pharmacol. 2018;30(2):153-162.  (PubMed)

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

13.  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)

14.  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)

15.  Becker DA, Balcer LJ, Galetta SL. The neurological complications of nutritional deficiency following bariatric surgery. J Obes. 2012;2012:608534.  (PubMed)

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

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

18.  Nath A, Tran T, Shope TR, Koch TR. Prevalence of clinical thiamine deficiency in individuals with medically complicated obesity. Nutr Res. 2017;37:29-36.  (PubMed)

19.  Polegato BF, Pereira AG, Azevedo PS, et al. Role of thiamin in health and disease. Nutr Clin Pract. 2019;34(4):558-564.  (PubMed)

20.  Oudman E, Wijnia JW, Oey M, van Dam M, Painter RC, Postma A. Wernicke's encephalopathy in hyperemesis gravidarum: A systematic review. Eur J Obstet Gynecol Reprod Biol. 2019;236:84-93.  (PubMed)

21.  Meggs WJ, Lee SK, Parker-Cote JN. Wernicke encephalopathy associated with hyperemesis gravidarum. Am J Emerg Med. 2020;38(3):690 e693-690 e695.  (PubMed)

22.  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)

23.  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)

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

25.  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)

26.  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)

27.  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)

28.  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)

29.  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)

30.  Sica DA. Loop diuretic therapy, thiamine balance, and heart failure. Congest Heart Fail. 2007;13(4):244-247.  (PubMed)

31.  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):184-188.  (PubMed)

32.  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)

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

34.  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)

35.  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)

36.  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)

37.  Food and Nutrition Board, Institute of Medicine. Thiamin. Thiamin, Riboflavin, Niacin, Vitamin B-6, Vitamin B-12, Pantothenic Acid, Biotin, and Choline. Washington D.C.: National Academy Press; 1998:58-86.

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

39.  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)

40.  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)

41.  Rosner EA, Strezlecki KD, Clark JA, Lieh-Lai M. Low thiamine levels in children with type 1 diabetes and diabetic ketoacidosis: a pilot study. Pediatr Crit Care Med. 2015;16(2):114-118.  (PubMed)

42.  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(12):e53175.  (PubMed)

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

44.  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)

45.  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 Nutr. 2013; 52(7):1821-4.  (PubMed)

46.  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 Nutr. 2011;50(2):145-149.  (PubMed)

47.  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)

48.  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 (Tokyo). 2012;58(3):210-216.  (PubMed)

49.  Prvulovic D, Hampel H. Amyloid beta (Abeta) and phospho-tau (p-tau) as diagnostic biomarkers in Alzheimer's disease. Clin Chem Lab Med. 2011;49(3):367-374.  (PubMed)

50.  Kish SJ. Brain energy metabolizing enzymes in Alzheimer's disease: alpha-ketoglutarate dehydrogenase complex and cytochrome oxidase. Ann N Y Acad Sci. 1997;826:218-228.  (PubMed)

51.  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)

52.  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)

53.  Arnold SE, Arvanitakis Z, Macauley-Rambach SL, et al. Brain insulin resistance in type 2 diabetes and Alzheimer disease: concepts and conundrums. Nat Rev Neurol. 2018;14(3):168-181.  (PubMed)

54.  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)

55.  Butterfield DA, Halliwell B. Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease. Nat Rev Neurosci. 2019;20(3):148-160.  (PubMed)

56.  Gibson GE, Hirsch JA, Fonzetti P, Jordan BD, Cirio RT, Elder J. Vitamin B1 (thiamine) and dementia. Ann N Y Acad Sci. 2016;1367(1):21-30.  (PubMed)

57.  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)

58.  Pan X, Sang S, Fei G, et al. Enhanced activities of blood thiamine diphosphatase and monophosphatase in Alzheimer's disease. PLoS One. 2017;12(1):e0167273.  (PubMed)

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

60.  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)

61.  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)

62.  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)

63.  Tapias V, Jainuddin S, Ahuja M, et al. Benfotiamine treatment activates the Nrf2/ARE pathway and is neuroprotective in a transgenic mouse model of tauopathy. Hum Mol Genet. 2018;27(16):2874-2892.  (PubMed)

64.  Moraes RCM, Singulani MP, Goncalves AC, Portari GV, Torrao ADS. Oral benfotiamine reverts cognitive deficit and increase thiamine diphosphate levels in the brain of a rat model of neurodegeneration. Exp Gerontol. 2020;141:111097.  (PubMed)

65.  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)

66.  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)

67.  Dumont M, Beal MF. Neuroprotective strategies involving ROS in Alzheimer disease. Free Radic Biol Med. 2011;51(5):1014-1026.  (PubMed)

68.  Nolan KA, Black RS, Sheu KF, Langberg J, Blass JP. A trial of thiamine in Alzheimer's disease. Arch Neurol. 1991;48(1):81-83.  (PubMed)

69.  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)

70.  Mimori Y, Katsuoka H, Nakamura S. Thiamine therapy in Alzheimer's disease. Metab Brain Dis. 1996;11(1):89-94.  (PubMed)

71.  Rodriguez-Martin JL, Qizilbash N, Lopez-Arrieta JM. Thiamine for Alzheimer's disease (Cochrane Review). Cochrane Database Syst Rev. 2001;2:CD001498.  (PubMed)

72.  Pan X, Chen Z, Fei G, et al. Long-term cognitive improvement after benfotiamine administration in patients with Alzheimer's disease. Neurosci Bull. 2016;32(6):591-596.  (PubMed)

73.  Gibson GE, Luchsinger JA, Cirio R, et al. Benfotiamine and cognitive decline in Alzheimer's disease: results of a randomized placebo-controlled phase IIa clinical trial. J Alzheimers Dis. 2020;78(3):989-1010.  (PubMed)

74.  Pico S, Parras A, Santos-Galindo M, et al. CPEB alteration and aberrant transcriptome-polyadenylation lead to a treatable SLC19A3 deficiency in Huntington's disease. Sci Transl Med. 2021;13(613):eabe7104.  (PubMed)

75.  US National Library of Medicine. ClinicalTrials.gov. Trial of the combined use of thiamine and biotin in patients With Huntington's disease (HUNTIAM). Available at: https://clinicaltrials.gov/ct2/show/NCT04478734.

76.  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)

77.  Katta N, Balla S, Alpert MA. Does long-term furosemide therapy cause thiamine deficiency in patients with heart failure? A focused review. Am J Med. 2016;129(7):753 e757-753 e711.  (PubMed)

78.  Jain A, Mehta R, Al-Ani M, Hill JA, Winchester DE. Determining the role of thiamine deficiency in systolic heart failure: a meta-analysis and systematic review. J Card Fail. 2015;21(12):1000-1007.  (PubMed)

79.  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)

80.  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)

81.  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.  (PubMed)

82.  Thiamine supplementation in patients with chronic heart failure receiving optimum medical treatment. J Cardiol Curr Res. 2017;9(2):00316.  

83.  Keith M, Quach S, Ahmed M, et al. Thiamin supplementation does not improve left ventricular ejection fraction in ambulatory heart failure patients: a randomized controlled trial. Am J Clin Nutr. 2019;110(6):1287-1295.  (PubMed)

84.  Goel A, Kattoor AJ, Mehta JL. Thiamin therapy for chronic heart failure: is there any future for this vitamin? Am J Clin Nutr. 2019;110(6):1270-1271.  (PubMed)

85.  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)

86.  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)

87.  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)

88.  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)

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

90.  Varkonyi T, Kempler P. Diabetic neuropathy: new strategies for treatment. Diabetes Obes Metab. 2008;10(2):99-108.  (PubMed)

91.  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)

92.  Seligmann H, Levi R, Konijn AM, Prokocimer M. Thiamine deficiency in patients with B-chronic lymphocytic leukaemia: a pilot study. Postgrad Med J. 2001;77(911):582-585.  (PubMed)

93.  Isenberg-Grzeda E, Alici Y, Hatzoglou V, Nelson C, Breitbart W. Nonalcoholic thiamine-related encephalopathy (Wernicke-Korsakoff syndrome) among inpatients with cancer: a series of 18 cases. Psychosomatics. 2016;57(1):71-81.  (PubMed)

94.  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)

95.  Zastre JA, Hanberry BS, Sweet RL, et al. Up-regulation of vitamin B1 homeostasis genes in breast cancer. J Nutr Biochem. 2013;24(9):1616-24.  (PubMed)

96.  Lu'o'ng KV, Nguyen LT. The role of thiamine in cancer: possible genetic and cellular signaling mechanisms. Cancer Genomics Proteomics. 2013;10(4):169-185.  (PubMed)

97.  Aksoy M, Basu TK, Brient J, Dickerson JW. Thiamin status of patients treated with drug combinations containing 5-fluorouracil. Eur J Cancer. 1980;16(8):1041-1045.  (PubMed)

98.  Basu TK. Vitamins - cytotoxic drug interaction. Int J Vitam Nutr Res Suppl. 1983;24:225-233.  (PubMed)

99.  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)

100.  Centers for Disease Control and Prevention. What is sepsis? January 27, 2021. Available at: https://www.cdc.gov/sepsis/what-is-sepsis.html. Accessed 7/21/21.

101.  Moskowitz A, Donnino MW. Thiamine (vitamin B1) in septic shock: a targeted therapy. J Thorac Dis. 2020;12(Suppl 1):S78-S83.  (PubMed)

102.  Woolum JA, Abner EL, Kelly A, Thompson Bastin ML, Morris PE, Flannery AH. Effect of thiamine administration on lactate clearance and mortality in patients with septic shock. Crit Care Med. 2018;46(11):1747-1752.  (PubMed)

103.  Holmberg MJ, Moskowitz A, Patel PV, et al. Thiamine in septic shock patients with alcohol use disorders: An observational pilot study. J Crit Care. 2018;43:61-64.  (PubMed)

104.  Donnino MW, Andersen LW, Chase M, et al. Randomized, double-blind, placebo-controlled trial of thiamine as a metabolic resuscitator in septic shock: a pilot study. Crit Care Med. 2016;44(2):360-367.  (PubMed)

105.  Moskowitz A, Andersen LW, Cocchi MN, Karlsson M, Patel PV, Donnino MW. Thiamine as a renal protective agent in septic shock. A secondary analysis of a randomized, double-blind, placebo-controlled trial. Ann Am Thorac Soc. 2017;14(5):737-741.  (PubMed)

106.  Qian X, Zhang Z, Li F, Wu L. Intravenous thiamine for septic shock: A meta-analysis of randomized controlled trials. Am J Emerg Med. 2020;38(12):2718-2722.  (PubMed)

107.  Marik PE, Khangoora V, Rivera R, Hooper MH, Catravas J. Hydrocortisone, vitamin C, and thiamine for the treatment of severe sepsis and septic shock: A retrospective before-after study. Chest. 2017;151(6):1229-1238.  (PubMed)

108.  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 Neurol Sci. 2002;201(1-2):33-37.  (PubMed)

109.  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)

110.  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)

111.  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)

112.  Labay V, Raz T, Baron D, et al. Mutations in SLC19A2 cause thiamine-responsive megaloblastic anaemia associated with diabetes mellitus and deafness. Nat Genet. 1999;22(3):300-304.  (PubMed)

113.  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)

114.  Habeb AM, Flanagan SE, Zulali MA, et al. Pharmacogenomics in diabetes: outcomes of thiamine therapy in TRMA syndrome. Diabetologia. 2018;61(5):1027-1036.  (PubMed)

115.  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)

116.  Tabarki B, Al-Hashem A, Alfadhel M. Biotin-thiamine-responsive basal ganglia disease. In: Adam MP, Ardinger HH, Pagon RA, eds. GeneReviews [Internet]. Seattle: University of Washington,  Seattle; 1993-2021.  (PubMed)

117.  Kilic B, Topcu Y, Dursun S, et al. Single gene, two diseases, and multiple clinical presentations: Biotin-thiamine-responsive basal ganglia disease. Brain Dev. 2020;42(8):572-580.  (PubMed)

118.  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)

119.  Tabarki B, Alfadhel M, AlShahwan S, Hundallah K, AlShafi S, AlHashem A. Treatment of biotin-responsive basal ganglia disease: Open comparative study between the combination of biotin plus thiamine versus thiamine alone. Eur J Paediatr Neurol. 2015;19(5):547-552.  (PubMed)

120.  Algahtani H, Ghamdi S, Shirah B, Alharbi B, Algahtani R, Bazaid A. Biotin-thiamine-responsive basal ganglia disease: catastrophic consequences of delay in diagnosis and treatment. Neurol Res. 2017;39(2):117-125.  (PubMed)

121.  Biesecker LG. Amish Lethal Microcephaly. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews^®. Seattle (WA); 1993.  (PubMed)

122.  Chen Y, Fang B, Hu X, et al. Identification and functional analysis of novel SLC25A19 variants causing thiamine metabolism dysfunction syndrome 4. Orphanet J Rare Dis. 2021;16(1):403.  (PubMed)

123.  Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM Number: 614458: 6/8/17. Available at: https://omim.org/entry/614458.

124.  Mayr JA, Freisinger P, Schlachter K, et al. Thiamine pyrophosphokinase deficiency in encephalopathic children with defects in the pyruvate oxidation pathway. Am J Hum Genet. 2011;89(6):806-812.  (PubMed)

125.  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)

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

127.  US National Institutes of Health, Office of Dietary Supplements. Dietary Supplement Label Database, Version 7.0.12. August 2020. Available at: https://dsld.od.nih.gov/dsld/index.jsp.

128.  US Department of Health and Human Services, Food and Drug Administration, 21 CFR  Part 101 [Docket No. FDA-20120N-1210] RIN 0910-AF22. Food Labeling: Revision of the Nutrition and Supplement Fact Labels. Final rule. Federal Register. Vol. 81, No. 103. Available at: https://www.federalregister.gov/documents/2016/05/27/2016-11867/food-labeling-revision-of-the-nutrition-and-supplement-facts-labels.

129.  Volvert ML, Seyen S, Piette M, et al. Benfotiamine, a synthetic S-acyl thiamine derivative, has different mechanisms of action and a different pharmacological profile than lipid-soluble thiamine disulfide derivatives. BMC Pharmacol. 2008;8:10.  (PubMed)

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

131.  Schumann K. Interactions between drugs and vitamins at advanced age. Int J Vitam Nutr Res. 1999;69(3):173-178.  (PubMed)

132.  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):G23-31.  (PubMed)

133.  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):F28-34.  (PubMed)

Español | 日本語

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, liver, and fish oils; fortified cereals may also contain preformed vitamin A. 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.

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. 

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. 

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.

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.

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 USDA's FoodData Central 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 may still be listed on food and supplement labels in international units versus as μg RAE ('mcg' on labels). USDA's FoodData Central 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 0.3 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.

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).

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).

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 association between intakes of preformed vitamin A in excess of 1,500 μg RAE (5,000 IU)/day and increased 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

Last updated 2/25/21  Copyright 2000-2023  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)