INTRODUCTION — Vitamins are a number of chemically unrelated families of organic substances that cannot be synthesized by humans and are essential in small amounts for normal metabolism. A few are conditionally essential, meaning that they are essential under certain conditions (such as vitamin D, which is thought to be conditionally essential in the absence of adequate sun exposure) [1]. Vitamins are divided into water-soluble and fat-soluble vitamins (table 1).
Many of the vitamin deficiency diseases, such as scurvy (vitamin C), beriberi (thiamine), and pellagra (niacin), have been almost completely eliminated in resource-rich countries except in occasional patients with underlying medical disorders or highly restricted diets. Great interest and controversy continues into whether vitamin supplementation in pharmacologic doses can prevent cancer, heart disease, upper respiratory infections, and other common diseases. (See "Vitamin intake and disease prevention".)
This topic review will focus on the water-soluble vitamins excluding folic acid and vitamin B12, which are discussed separately. (See "Treatment of vitamin B12 and folate deficiencies".)
Minerals and fat-soluble vitamins are also reviewed elsewhere. (See "Overview of vitamin A" and "Overview of vitamin D" and "Overview of vitamin E" and "Overview of vitamin K" and "Overview of dietary trace elements".)
TERMINOLOGY FOR DIETARY STANDARDS — Dietary reference intakes (DRIs) were developed by the Food and Nutrition Board of the Institute of Medicine to guide nutrient intake in a variety of settings [2]. DRIs are comprised of:
●Recommended dietary allowance (RDA) – The dietary intake that is sufficient to meet the daily nutrient requirements of 98 percent of the individuals in a specific life-stage group and with specific physiologic conditions, such as pregnancy.
●Adequate intake (AI) – An estimate of the nutrient intake necessary to maintain a healthy state. The AI is used when there are insufficient data to determine the RDA.
●Tolerable upper intake level (UL) – The maximum level of intake that is likely to pose no risk of adverse health effects.
These terms are described in greater detail in a separate topic review. (See "Dietary history and recommended dietary intake in children".)
VITAMIN B1 (THIAMINE) — Thiamine (also written as thiamin, and also known as vitamin B1) serves as a catalyst (coenzyme required for the catalysis) in the conversion of pyruvate to acetyl coenzyme A (CoA) and is involved in many other cellular metabolic activities, including the tricarboxylic acid (TCA) cycle [3]. In addition, it participates in initiation of nerve impulse propagation. Thiamine deficiency causes clinical phenotypes of beriberi and Wernicke-Korsakoff syndrome.
Sources — Thiamine is primarily found in foods such as yeast, legumes, pork, brown rice, and cereals made from whole grains. However, thiamine is very low in white ("polished" rice) or milled white cereals including wheat flour because the processing removes thiamine [4]. The thiamine molecule is denatured at high pH and high temperatures. Hence, cooking, baking, and canning of some foods as well as pasteurization can destroy thiamine. Milk products, fruits, and vegetables are poor sources of thiamine. Thiamine deficiency is most commonly reported in populations in which the diet consists mainly of polished rice or milled white cereals, including some refugee populations [5].
Biochemistry
●Chemistry – Thiamine consists of a pyrimidine and a thiazole moiety, both of which are essential for its activity (figure 1) [3]. The main active form of thiamine is a phosphorylated ester, pyrophosphate (TPP). Thiamine is soluble in water and partly soluble in alcohol.
●Metabolism – Thiamine is absorbed in the small intestine via both active transport and passive diffusion. The maximal absorption of thiamine is in the jejunum and ileum [3]. Thiamine is dephosphorylated to pass through the mucosal cells to enter the blood stream via a sodium and ATP-dependent pump (ie, active transport), then phosphorylated intracellularly to the active form. Thiamine enters most cells via active transport and enters red blood cells by passive diffusion [2]. The highest concentrations are found in the skeletal muscles, the liver, the heart, the kidneys, and the brain. Thiamine's biologic half-life is approximately 10 to 20 days; due to limited tissue storage, continuous intake is required to maintain normal markers for thiamine sufficiency [6-9]. Thiamine and all of its metabolites are primarily excreted in the urine and a small proportion is excreted in bile [10].
●Actions – The phosphorylated form (TPP) is an important cofactor for enzymes involved in metabolism of carbohydrates and branched-chain amino acids [4,11].
In the TCA cycle, TPP serves as a catalyst in the conversion of pyruvate to acetyl CoA, an oxidative decarboxylation reaction mediated by pyruvate dehydrogenase:
Pyruvate + CoA + NAD → Acetyl CoA + CO2 + NADH + H
Thiamine is also involved in many other cellular metabolic activities such as the transketolation of the pentose phosphate pathway [12,13]. Thiamine has an unidentified role in the initiation of nerve impulse propagation that is independent of its coenzyme functions. Accordingly, thiamine deficiency is associated with neuropathy, known as beriberi neuropathy, or dry beriberi. There are several proposed mechanisms. Thiamine has an important role in synthesis of glutamate and γ-aminobutyric acid as well as myelin sheath maintenance [14]. Thiamine also appears to promote cholinergic and serotonergic nerve conduction and synaptic axonal transmission [15,16]. Mechanism of thiamine deficiency-induced neuropathy is likely in part related to impairment of these processes.
Measurement — Thiamine status can be assessed by the following tests, each of which has limitations:
●Thiamine or TPP in blood – Most laboratories now measure blood thiamine concentration directly, in preference to the erythrocyte thiamine transketolase activity (ETKA) method described below [17]. However, this has limited sensitivity and specificity in severe acute conditions because it may be falsely reduced during systemic inflammation [18]. The normal range for blood thiamine concentration varies somewhat among laboratories but is approximately 70 to 180 nmol/L (3.0 to 7.7 mcg/dL) [19,20]. Interpretation of thiamine levels may be further confounded in the presence of hypoalbuminemia. This has not been well studied.
●ETKA – This is a functional test and results are influenced by the hemoglobin concentration. In patients with subclinical thiamine deficiency, ETKA levels are low and increase by 10 to 25 percent when stimulated in vitro with TPP [3,7]. This test is not widely available outside of research settings; therefore, when the suspicion for thiamine deficiency is high, one should consider empiric therapy.
●Urinary thiamine excretion – Urinary thiamine levels provide information about the adequacy of recent dietary intakes and are useful for determining the thiamine intake of a population, but they are less useful for identifying individual patients with clinically significant thiamine deficiency [3,5,21]. Measuring urinary thiamine before and after a 5 mg test load of thiamine may help distinguish between extremes of thiamine status [3].
Deficiency — Thiamine deficiency in the diet causes two clinical phenotypes:
●Beriberi (infantile and adult)
●Wernicke-Korsakoff syndrome
In addition, case reports describe several inborn errors of thiamine metabolism and transport that respond to thiamine supplementation. (See 'Thiamine metabolism dysfunction syndromes' below.)
Infantile beriberi — Beriberi in infants becomes clinically apparent between the ages of two and three months and mainly affects infants who are breastfed by mothers with a thiamine-deficient diet [5]. The clinical features are variable and may include a fulminant cardiac syndrome with cardiomegaly, tachycardia, a loud piercing cry, cyanosis, dyspnea, vomiting and pulmonary hypertension [22-24]. Older infants may have neurologic symptoms resembling aseptic meningitis, including agitation, an aphonic (soundless) cry, vomiting, nystagmus, purposeless movements, altered consciousness, and seizure, with no abnormalities on cerebrospinal fluid analysis [18,25,26]. Treatment for acute forms is with parenterally administered thiamine, using doses in infants of 100 to 150 mg, typically leading to rapid improvement of symptoms [27].
In 2003, infantile beriberi was discovered in a series of infants in Israel, due to feeding with a soy-based formula that was inadvertently deficient in thiamine [28]. Most of the infants with severe symptoms at the time of diagnosis, which included cardiomyopathy and seizures, had severe permanent disabilities even after thiamine was replaced. Among infants with apnea or seizures at presentation, all had moderate or severe intellectual disability when reevaluated 5 and 10 years later, and most had chronic epilepsy [29,30]. A few of the severely affected infants died. Many other infants were asymptomatic or had nonspecific symptoms while being fed the thiamine-deficient diet (eg, vomiting, irritability, or failure to thrive). However, follow-up testing of these mildly affected infants revealed delays in language and motor development [31]. Similar patterns are seen in other populations of infants with mild chronic thiamine deficiency [18].
Adult beriberi — Beriberi in adults has two clinical phenotypes, described as "dry" or "wet." Dry beriberi is the development of a symmetrical peripheral neuropathy characterized by both sensory and motor impairments, mostly of the distal extremities. Wet beriberi includes signs of cardiac involvement with cardiomegaly, cardiomyopathy, heart failure, peripheral edema, and tachycardia, in addition to neuropathy [4].
Beriberi and Wernicke-Korsakoff syndrome have been reported as acute and chronic complications of weight loss surgery [32]. Several of the case reports have been in adolescents, but whether this nutritional complication is more common in the adolescent age group as compared with adults undergoing weight loss surgery has not been established. (See "Surgical management of severe obesity in adolescents".)
Thiamine deficiency can occur as a complication of total parenteral nutrition if adequate thiamine is not provided in the formulation. As an example, during the late 1990s, there were multiple reports of symptomatic thiamine deficiency among recipients of parenteral nutrition during a widespread shortage of parenteral multivitamins in the United States [33].
A number of studies have suggested that subclinical thiamine deficiency is common among hospitalized patients with heart failure, especially if they are treated with loop diuretics; some of these studies also report improvement in left ventricular function after thiamine supplementation [34-38]. However, this remains controversial because of subsequent studies suggesting lower frequencies of subnormal thiamine levels among stable patients with heart failure [39,40] as well as questions involving assay validity [41]. (See "Causes of dilated cardiomyopathy", section on 'Trace elements'.)
Treatment for beriberi in adults typically starts with parenteral administration of thiamine if the patient is critically ill (eg, 100 to 200 mg three times daily for two to three days), followed by oral thiamine, 5 to 30 mg/day [42]. Higher doses of thiamine (similar to those used for Wernicke-Korsakoff syndrome) may be used and are safe but do not appear to provide additional benefit. An oral maintenance dose of 50 or 100 mg/day is often used for convenience, as these are the lowest doses available as a single formulation, but lower doses contained in a multivitamin supplement are also sufficient.
The duration of maintenance supplementation is not well studied, and most patients with thiamine deficiency are at risk for recurrence. Unless the cause of deficiency is confirmed and corrected, thiamine should be continued indefinitely.
Wernicke-Korsakoff syndrome — Wernicke-Korsakoff syndrome is a devastating neurologic complication of thiamine deficiency. The term refers to two different syndromes, each representing a different stage of the disease. The two entities are not separate diseases but a spectrum of signs and symptoms. Wernicke encephalopathy (WE) is an acute syndrome requiring emergency treatment to prevent death and neurologic morbidity. Korsakoff syndrome refers to a chronic neurologic condition that usually occurs as a consequence of WE. It is characterized by impaired short-term memory and confabulation with otherwise grossly normal cognition. (See "Overview of the chronic neurologic complications of alcohol", section on 'Korsakoff syndrome'.)
WE is characterized by nystagmus, ophthalmoplegia, ataxia, and confusion. It has been particularly reported in those with chronic alcohol use disorder and as a consequence of bariatric surgery [43]. There may be a genetic predisposition for the development of WE since not all thiamine-deficient patients are affected. Impairment in the synthesis of one of the important enzymes of the pentose phosphate pathway (erythrocyte transketolase) may explain such a predisposition [44]. (See "Wernicke encephalopathy".)
WE is treated with thiamine supplementation. A range of replacement doses have been used successfully, but large doses are typically used because they appear to be safe. It is common practice to delay giving dextrose until thiamine supplementation has been initiated to avoid precipitating WE in patients with alcohol use disorder, prolonged starvation, or other predispositions to WE. (See "Wernicke encephalopathy", section on 'Treatment'.)
Thiamine metabolism dysfunction syndromes
●Thiamine-responsive megaloblastic anemia (MIM #249270) – Mutations in the SLC19A2 gene, which encodes a thiamine transporter, are responsible for a syndrome of megaloblastic anemia, diabetes mellitus, and sensorineural deafness. The disorder tends to present clinically between infancy and adolescence and responds to high doses of thiamine. (See "Causes and pathophysiology of the sideroblastic anemias", section on 'Thiamine-responsive megaloblastic anemia (SLC19A2 mutation)'.)
●Thiamine metabolism dysfunction syndrome type 2 (MIM #607483) – Mutations in the SLC19A3 gene, which encodes a different thiamine transporter, have been reported in a few individuals with episodic encephalopathy. The encephalopathy is often triggered by febrile illness and responds clinically to high doses of biotin or thiamine [45,46]. The clinical phenotype is similar to Leigh syndrome, which is a progressive subacute necrotizing encephalomyopathy [47,48].
Toxicity — No syndrome of excess thiamine has been identified. It is believed that toxic levels are unlikely because the kidneys can rapidly clear almost all excess thiamine and because (like most water-soluble vitamins) thiamine is not stored [2]. The biologic half-life of thiamine in humans is approximately 10 to 20 days [6].
Requirements — The United States recommended dietary allowance (RDA) for thiamine for different life-stage groups is 0.5 to 0.9 mg/day for children, 1.2 mg/day for adult males, and 1.1 mg/day for nonpregnant adult females (approximately 0.5 mg/1000 kcal) (table 2) [3].
VITAMIN B2 (RIBOFLAVIN) — Vitamin B2, or riboflavin, is a member of naturally occurring compounds known as flavins. Flavins have a critical role in numerous biochemical reactions, primarily those that are classified as oxidation-reduction reactions, otherwise referred to as redox reactions.
Sources — Riboflavin is supplied in many foods, including milk, eggs, meats, fish, green vegetables, yeast, and enriched foods (fortified cereals and breads).
Biochemistry
●Chemistry – Riboflavin's chemical nomenclature is 7,8-dimethyl-10 (1'-D-ribityl) isoalloxazine (figure 1). In the free form it is a base, but in nature and in vivo it is mostly found as a component of flavin-adenine dinucleotide (FAD). The 5'-hydroxymethyl terminus of the vitamin is phosphorylated to form a phosphate ester, allowing it to be incorporated into a different coenzyme [49].
●Metabolism – Flavins in food are present as derivatives of FAD, flavin mononucleotide (FMN), and to less extent as free flavins. The first step in the absorption of dietary riboflavin involves hydrolysis of FAD and FMN into free riboflavin by gastric acid and proteolytic enzymes [50-52]. Free riboflavin in plasma is bound to albumin and certain immunoglobulins [53]. In the proximal small intestine, riboflavin is absorbed passively along its concentration gradient across the intestinal mucosa. This involves a saturable transport system that is passive and not sodium dependent [54]. There also appears to be some enterohepatic circulation for riboflavin facilitated by bile salts [50]. Riboflavin eventually reaches the hepatocytes, where its metabolism into FMN and FAD takes place.
The metabolic conversions of flavin take place in the cytoplasm of cells of the body, particularly in the liver, heart, and kidney [49]. Riboflavin is first phosphorylated to form FMN, which can either be further phosphorylated into FAD or become incorporated as part of a certain coenzyme-flavin complex. Both of the phosphorylation reactions are ATP dependent. As the more common form of flavin in humans, FAD is often complexed with other proteins to form flavoproteins with oxidizing and hydrogenating abilities [50]. Most of the riboflavin stores in the body are in the forms of flavoproteins.
●Actions – Riboflavin is an essential component of coenzymes involved in multiple cellular metabolic pathways, including the energy-producing respiratory pathways. This includes a reaction in the tricarboxylic acid (TCA) cycle and beta-oxidation of fatty acids for energy. Flavoproteins are catalysts in a number of mitochondrial oxidative and reductive reactions and function as electron transporters [49].
Measurement — Plasma riboflavin concentrations tend to reflect recent dietary intake. The erythrocyte glutathione reductase assay is a better functional index of insufficient riboflavin intake [55,56]. The results are expressed as an activity coefficient; a coefficient >1.4 indicates riboflavin insufficiency [3]. Urinary riboflavin excretion is used primarily as a test for determining dietary intake in a population, rather than for identifying individuals with riboflavin insufficiency or deficiency, because urinary levels of the vitamin only indirectly reflect dietary intake or riboflavin catabolism [57].
Deficiency — Riboflavin deficiency is more common than generally appreciated and is referred to as ariboflavinosis. Many cases are undetected due to the mild nature and nonspecific signs and symptoms.
Clinical manifestations of riboflavin deficiency include sore throat, hyperemia of pharyngeal mucous membranes, edema of mucous membranes, cheilitis, stomatitis, glossitis (picture 1), normocytic-normochromic anemia, and seborrheic dermatitis [51]. Whether all these changes are due to riboflavin deficiency is not always clear, since riboflavin deficiency is often accompanied by other water-soluble vitamin deficiencies, which can cause similar symptoms (table 3) [58]. Pure deficiency of riboflavin is rare, although it has been described in resource-limited countries where starvation is prevalent and access to food is limited.
Other settings in which riboflavin insufficiency or deficiency may be noted include:
●Patients with anorexia nervosa. (See "Anorexia nervosa in adults and adolescents: Medical complications and their management".)
●Patients with malabsorptive syndromes such as active celiac disease, malignancies, and short bowel syndrome. (See "Chronic complications of short bowel syndrome in children", section on 'Nutritional complications'.)
●Rare inborn errors of metabolism in which there is a defect in formation of riboflavin-dependent enzymes, such as glutaric acidemia type 1 or multiple acyl-coenzyme A (CoA) dehydrogenase deficiency (MADD), or a riboflavin transporter (Brown-Vialetto-Van Laere syndrome) [59-65]. (See "Organic acidemias: An overview and specific defects", section on 'Glutaric acidemia type 1' and "Specific fatty acid oxidation disorders", section on 'Multiple acyl-CoA dehydrogenase deficiency'.)
●Long-term use of phenobarbital and other barbiturates, which may lead to oxidation of riboflavin and impair its function [66].
Individuals who avoid dairy products (such as people with lactose intolerance) are more likely to have suboptimal riboflavin intake since dairy products are a good source of riboflavin. Because exposure of dairy products to sunlight can destroy the riboflavin content, opaque containers are often used to protect this nutrient.
Therapeutic roles — Some intramitochondrial beta-oxidation defects such as MADD may respond to riboflavin therapy (see "Metabolic myopathies caused by disorders of lipid and purine metabolism"). In addition, patients with HIV infection who are treated with zidovudine or stavudine may develop lactic acidosis that is reversed by riboflavin therapy [67]. (See "Electrolyte disturbances with HIV infection".)
Limited evidence suggests a possible role for riboflavin supplementation in prevention of migraine headaches. (See "Preventive treatment of migraine in children", section on 'Nutraceuticals' and "Preventive treatment of episodic migraine in adults".)
Toxicity — No adverse effects have been reported after ingestion of high doses of riboflavin [2,68]. This may be because excessive amounts of riboflavin are usually not absorbed due to the limited water-solubility and the inability of the human gastrointestinal tract to absorb toxic doses of the compound [49].
Requirements — The United States recommended dietary allowance (RDA) for riboflavin is 0.5 to 0.9 mg/day in children, 1.3 mg/day for adult males, and 1.1 mg/day for nonpregnant adult females (approximately 0.6 mg per 1000 kcal) (table 2) [3].
VITAMIN B3 (NIACIN) — Niacin (nicotinic acid and nicotinamide) is an essential nutrient involved in the synthesis and metabolism of carbohydrates, fatty acids, and proteins. Niacin deficiency causes pellagra, which is characterized by a photosensitive pigmented dermatitis (typically located in sun-exposed areas), diarrhea, and dementia, and may progress to death; the "4 Ds" serves as a mnemonic for the manifestations of niacin deficiency [69,70].
Sources — Niacin is widely distributed in plant and animal foods. Good sources include yeast, meats (especially liver), grains, legumes, corn treated with alkali (as in corn used in tortillas), and seeds [3]. It is possible to maintain adequate niacin status on a high-protein diet (eg, protein intake of 100 g/day) since tryptophan can be converted to a niacin derivative in the liver. However, it requires approximately 60 mg of tryptophan to produce 1 mg of niacin, and this process requires vitamin B6 (pyridoxine), with significant individual variation [3,71].
Niacytin is the primary form of niacin found in mature grains, and it is nutritionally unavailable because it is bound in a complex with hemicellulose. The niacin can be released from the grain by soaking and cooking in an alkaline solution, known as nixtamalization [72].
Biochemistry
●Chemistry – Nicotinic acid and nicotinamide are the two common forms of the vitamin most often referred to as niacin (figure 2). Through a series of biochemical reactions in the mitochondria, niacin, nicotinamide, and tryptophan form nicotinamide adenine dinucleotide (NAD) and NAD phosphate (NADP). NAD and NADP are the active forms of niacin. In general, NAD(H) participates in catabolic redox reactions, whereas NADP(H) is a cofactor in anabolic redox reactions.
●Metabolism – Niacin metabolism involves conversion of dietary NAD and NADP to nicotinamide and nicotinic acid for intestinal absorption, and then back into NAD and NADP for use in cellular functions. NAD and NADP are the chief dietary forms of niacin. These are first hydrolyzed by enzymes in the intestinal lumen to nicotinamide. Nicotinamide is converted by intestinal microbiota to nicotinic acid. The two forms of niacin are then absorbed and released into plasma via passive and facilitated diffusion [73]. Through a passive process, niacin is rapidly taken up by the liver, kidneys, and erythrocytes. Additionally, a portion of dietary tryptophan can be converted into nicotinamide in the liver. This conversion, which is widely variable in humans, provides a significant portion of niacin needs [71,74]. Interruptions in this conversion, such as medications, may cause overt pellagra (see 'Deficiency (pellagra)' below). Intracellular nicotinamide and nicotinic acid are quickly converted to the coenzyme forms NAD and NADP, which are concentrated most in tissues with high metabolic activities (ie, muscle and liver).
●Actions – Many enzymatic redox reactions depend upon NAD and NADP as a cofactor. The role of the niacin moiety is to accept electrons or to donate hydrogen ions. The majority of these NAD-dependent enzymes are involved in reactions such as oxidation of fatty acids and other reactions that yield chemical structures containing high-energy bonds, including the generation of NADH by glycolysis and the tricarboxylic acid (TCA) cycle [75,76]. NADP is a cofactor in the reductive synthesis of the fatty acids and steroids; NADPH is generated by the hexose monophosphate shunt. As essential components of redox reactions and hydrogen transport, NAD and NADP are crucial in the synthesis and metabolism of carbohydrates, fatty acids, and proteins [3].
Measurement — Niacin status can be assessed by measuring urinary N-methylnicotinamide or by measuring the erythrocyte NAD:NADP (ratio). However, these tests are not widely available [77]. High levels of a metabolic product of a vitamin, such as N-methylnicotinamide, reflect adequate concentrations of intracellular niacin.
Deficiency (pellagra) — Pellagra (meaning "raw skin") is characterized by a photosensitive pigmented dermatitis (typically located in sun-exposed areas), diarrhea, and dementia. In the United States and other resource-rich countries, pellagra tends to occur in those with alcohol use disorder and has been reported as a complication of bariatric surgery, anorexia nervosa, or malabsorptive disease [78,79]. Pellagra due to dietary deficiency can still be seen in resource-limited countries where the bulk of the local diet consists of untreated corn or sorghum. This is because niacin bioavailability, and therefore its absorption, is poor unless corn is treated with alkali, as in the process of preparing tortillas (nixtamalization) (see 'Sources' above). These diet characteristics are found in India, parts of China, and Africa. In Central America and Mexico, where treated corn in the form of tortillas is a staple of the local diet, pellagra is rare. Pellagra was widespread in areas of southern United States in which the diet was predominantly based on corn. The technique of enriching processed flour with niacin, along with the other B-vitamins, effectively eradicated pellagra in the United States.
The most characteristic finding of pellagra is the presence of a symmetric hyperpigmented rash, similar in color and distribution to a sunburn, which is present in the exposed areas of skin. Dermatitis in the sun-exposed area of the neck gives a characteristic appearance that has been called "Casal necklace" (picture 2) [80]. Other clinical findings are a red tongue and many nonspecific symptoms, such as diarrhea and vomiting. Neurologic symptoms include insomnia, anxiety, disorientation, delusions, dementia, and encephalopathy (table 3).
Niacin deficiency can also be seen in three other settings:
●Carcinoid syndrome, in which metabolism of tryptophan is to 5-OH tryptophan and serotonin rather than to nicotinic acid. This leads to the deficiency of active forms of niacin and the development of pellagra. (See "Clinical features of carcinoid syndrome".)
●Prolonged use of isoniazid since isoniazid depletes stores of pyridoxal phosphate, which enhances the metabolism of tryptophan into niacin. Several other drugs induce niacin deficiency by inhibiting the conversion of tryptophan to niacin, including fluorouracil, pyrazinamide, 6-mercaptopurine, hydantoin, ethionamide, phenobarbital, azathioprine, and chloramphenicol [81].
●Hartnup disease (MIM #234500) is an autosomal recessive congenital disorder caused by a defect of a membrane transport in intestinal and renal cells that are normally responsible for the absorption of tryptophan, a precursor for niacin [74,82]. The diagnosis is made by detecting a number of neutral amino acids in the urine, which are not found in patients with dietary pellagra. The treatment is aimed towards depleting stores and supplementing the diet with niacin as well as proteins and amino acids [83]. (See "Overview of the hereditary ataxias", section on 'Aminoacidurias'.)
Toxicity — The best established side effect of niacin is the flushing reaction associated with the crystalline nicotinic acid and not nicotinamide [84]. Symptoms are dose-dependent yet variable from person to person. The flushing can be experienced in a mild form while taking doses as small as 10 mg/day [85]. Despite the inconvenience and the undesirability of the reactions, there are no serious sequelae from flushing [84].
In pharmacologic doses (eg, 1000 to 3000 mg/day), common side effects of niacin are flushing, nausea, vomiting, pruritus, hives, elevation in serum aminotransferases [86], and constipation. Only a handful of cases of toxicity have been reported in the literature when less than 1000 mg of nicotinic acid was ingested per day [87]. One clinical trial assigned two groups of subjects to either a long or a short-acting formula of niacin, each starting at 500 mg/day [88]. Subjects were followed for several months during which the dose of niacin was gradually raised to a maximum dose of 3000 mg/day. There was no gastrointestinal or liver toxicity below 1000 mg of niacin/day. The extent of the toxicity was minimal and mostly gastrointestinal in the immediate release group, while mild liver enzyme elevation was noticed only in the slow release group. Caution should be used in patients with a history of gout since niacin is also known to elevate serum uric acid concentration. (See "Low-density lipoprotein cholesterol lowering with drugs other than statins and PCSK9 inhibitors", section on 'Side effects'.)
The above side effects are most common and severe when niacin is administered in doses of 2000 to 6000 mg/day [85]. At such high doses, the hepatic metabolism becomes saturated and side effects of this drug can be more frequently encountered. A niacin-induced myopathy has also been described in a patient taking doses of 3000 mg/day [89]. Liver dysfunction and fulminant hepatitis also have been reported [2,88,90,91].
Therapeutic roles — Niacin in moderate to high doses (1000 to 3000 mg/day) is a well-established antihyperlipidemic agent, decreasing total and low-density lipoprotein cholesterol [92]. Nicotinamide is a related form that does not have lipid-lowering properties. The use of nicotinic acid is often limited by poor tolerability (flushing, pruritus, paresthesias, and nausea, as described above), and there are concerns about the safety of niacin as well as its efficacy for clinical endpoints. (See "Low-density lipoprotein cholesterol lowering with drugs other than statins and PCSK9 inhibitors", section on 'Nicotinic acid (niacin)'.)
Nicotinamide does not appear to be effective for delaying or preventing the onset of type 1 diabetes mellitus in children.
Requirements — Niacin is dosed as a "niacin equivalent" (NE), in which 1 NE is equal to 1 mg of niacin, or 60 mg of dietary tryptophan [71]. The United States recommended dietary allowance (RDA) for niacin is 6 to 12 mg/day in children, 16 mg/day for adult males, and 14 mg/day for nonpregnant adult females (table 2) [3]. These doses are far below the antihyperlipidemic doses of niacin and are not associated with toxicity. Requirements may be increased for individuals on dialysis or for those with malabsorptive processes (eg, after bariatric surgery).
VITAMIN B5 (PANTOTHENIC ACID) — Pantothenic acid is an essential nutrient. Clinical deficiency is rare, likely because it is available from many dietary sources and also from colonic bacteria. When it does occur, it is characterized by paresthesias and dysesthesias, referred to as "burning feet syndrome."
Sources — The major dietary sources of pantothenic acid are egg yolk, liver, kidney, broccoli, and milk [3,93]. Substantial concentrations of pantothenic acid are also found in chicken, beef, potatoes, and whole grains. The main dietary source of pantothenic acid is in the form of coenzyme A (CoA). Pantothenic acid is also produced by bacteria in the colon [94].
Biochemistry
●Chemistry – The biologically active form of pantothenic acid is CoA [95], which is an essential cofactor in many acetylation reactions in vivo, including tricarboxylic acid (TCA) cycle, fatty acid synthesis and breakdown, posttranslational modification of histones, and other mitochondrial, nuclear, and cytosolic reactions.
●Metabolism – CoA is hydrolyzed in the small intestine to form pantothenic acid (figure 2). Pantothenic acid, from this hydrolysis and from bacterial production, is then absorbed in the jejunum and secreted into the bloodstream via a sodium-dependent transport system [96]. Most cells of the body take up pantothenic acid via the same sodium-dependent mechanism. Once inside the cell, pantothenic acid undergoes a number of ATP-dependent phosphorylations to become CoA [97]. Excess pantothenic acid is hydrolyzed and excreted as cysteamine and pantothenate via the kidney [98].
●Actions – CoA has a crucial role in the synthesis and degradation of many molecules, including vitamins A, D, cholesterol, steroids, heme A, fatty acids, carbohydrates, amino acids, and proteins. Coenzyme A also has an essential role in the first step of the TCA cycle by binding with oxaloacetate to form citrate. Other CoA-dependent processes, such as the oxidative degradation of amino acids (which usually occur after mRNA translation), are important steps for stabilization and activation of many proteins in vivo. CoA is also required for the activation and inactivation of many peptide hormones, such as adrenocorticotropic hormone [95].
Measurement — Various laboratory techniques are employed to measure pantothenic acid levels in blood, plasma, and urine. Those include microbiologic assays, radioimmunoassays, and gas chromatography. However, since pantothenic deficiency is rare, there has not been great need or interest in developing widely available testing.
Measuring blood pantothenic acid concentrations through testing serum, plasma, or erythrocyte often lead to different results, and so these are not reliable indicators of the nutritional status of this vitamin [99,100]. Urinary excretion of pantothenic acid seems to correlate most closely to the dietary intake and is therefore a better indicator of pantothenic acid sufficiency than blood levels. Urinary excretion below 1 mg/day generally indicates low dietary intake [101].
Deficiency — Pantothenic acid deficiency is rare in humans. It has been noted in severely malnourished individuals, usually in situations of famine and war [102]. Clinical manifestations can include paresthesias and dysesthesias, referred to as "burning feet syndrome." Human volunteers who were fed a pantothenate antimetabolite for three months developed burning, distal paresthesias, and gastrointestinal distress [103]. Because pantothenate is essential to most living organisms, microbiologic assays have been used to quantify concentrations in blood and urine [104].
Several animal models have been used to study the deficiency of pantothenic acid. In rats, growth failure, hemorrhage, and necrosis of adrenal cortex, dermatitis, and achromotrichia (gray hair) have been described [103]. In primates, there is some evidence for impaired synthesis of heme, leading to anemia [105].
Toxicity — There is no known toxicity for pantothenic acid. Excess intake is excreted by the kidneys.
Requirements — The recommended intake for pantothenic acid is expressed as adequate intake (AI) rather than recommended dietary allowance (RDA), indicating that there are not adequate data to specify the percentage of individuals whose requirement is met by this intake. This is also the result of the variability between humans on the extent to which the intestinal microbiota contribute to meeting pantothenic acid needs. The AI is 2 to 4 mg/day for children and 5 mg/day for adults (table 2) [3].
VITAMIN B6 (PYRIDOXINE) — Vitamin B6 consists of pyridoxine, pyridoxamine, pyridoxal, and the phosphorylated derivative of each of these compounds. Overt deficiency of vitamin B6 is probably rare, and the primary manifestations are dermatitis, glossitis, and microcytic anemia. Vitamin B6 toxicity manifests with a peripheral neuropathy, dermatoses, photosensitivity, dizziness, and nausea.
Sources — Pyridoxine and pyridoxamine are predominantly found in plant foods; pyridoxal is most commonly derived from animal foods. Meats, whole grains, vegetables, and nuts are the best sources. Cooking, food processing, and storage can reduce vitamin B6 availability by 10 to 50 percent [106,107].
Biochemistry
●Chemistry – Forms of vitamin B6 include pyridoxine, pyridoxal, and pyridoxamine, as well as 5' phosphates, which are the active metabolites (figure 1). These forms have similar biologic activities once they are converted into pyridoxine 5-phosphate by a hepatic-dependent process.
●Metabolism – Pyridoxine is converted in the liver to its active form, pyridoxine 5-phosphate. This is then catabolized into 4-pyridoxic acid, which is excreted in the urine and can be used as a marker of pyridoxine sufficiency, as outlined below.
●Actions – Pyridoxal phosphate is used for Schiff base formation during the transamination of amino acids, a key step in gluconeogenesis. Pyridoxal phosphate is also involved in decarboxylation of amino acids, a key reaction in the conversion of tryptophan to niacin, heme synthesis, sphingolipid biosynthesis, neurotransmitter synthesis, immune function [108], and steroid hormone modulation. It is also a key enzyme cofactor in the transsulfuration pathway by which homocysteine is converted into cystathionine and its subsequent conversion to cysteine [109].
Measurement — The following methods can be used to assess for vitamin B6 insufficiency:
●The mean plasma pyridoxal-5-phosphate (PLP) concentration can be measured (this is often reported as "pyridoxine" or "vitamin B6"). PLP concentrations 20 to 30 nmol/L (4.9 to 7.4 ng/mL) are generally considered marginal and >30 nmol/L (>7.4 ng/mL) are sufficient [3,110].
●Erythrocyte transaminase activity, with and without PLP added, has been used as a functional test of pyridoxine status and may be a more accurate reflection of vitamin B6 status in critically ill patients [110].
●Urinary 4-pyridoxic acid excretion greater than 3.0 mmol/day can be used as an indicator of adequate short-term vitamin B6 status (this is often reported as "urinary pyridoxic acid") [110].
●Xanthurenic acid is a metabolite of tryptophan, and is elevated in the setting of vitamin B6 insufficiency. Urinary excretion of xanthurenic acid is normally less than 65 mmol/day following a 2 g tryptophan load [110]. Excretion of xanthurenic acid above this threshold suggests abnormal tryptophan metabolism due to vitamin B6 insufficiency.
Deficiency — Overt deficiencies of vitamin B6 are probably rare. Marginal deficiencies may be more common, manifested as nonspecific stomatitis, glossitis, cheilosis, irritability, confusion, and depression, and possibly peripheral neuropathy (table 3) [3,111]. Severe deficiency is associated with seborrheic dermatitis, microcytic anemia, and seizures [3]. A number of genetic syndromes affecting PLP-dependent enzymes such as homocystinuria, cystathioninuria, and xanthurenic aciduria mimic vitamin B6 deficiency. An inborn error of pyridoxine metabolism is responsible for pyridoxine-dependent epilepsy, which presents with medically refractory neonatal seizures. (See "Treatment of neonatal seizures", section on 'Pyridoxine or PLP responsive seizures'.)
Depressed concentrations of PLP have been reported in asthma, diabetes, alcoholism, heart disease, pregnancy, breast cancer, Hodgkin lymphoma, and sickle-cell anemia [112]. Certain drugs are associated with vitamin B6 insufficiency because they interfere with pyridoxine metabolism, including isoniazid, penicillamine, hydralazine, and levodopa/carbidopa [111,113]. Cystathionine synthase is a PLP-dependent enzyme, which produces cystathionine from serine and homocysteine. As a result, vitamin B6 insufficiency can lead to elevations in plasma homocysteine concentrations, a risk factor for the development of atherosclerosis and venous thromboembolism [114]. (See "Overview of homocysteine".)
Toxicity — Cases of peripheral neuropathy, dermatoses, photosensitivity, dizziness, and nausea have been reported with long-term megadoses of pyridoxine over 250 mg/day; a few cases of neuropathy appear to have been caused by chronic intake of 100 to 200 mg/day [115-117]. (See "Overview of acquired peripheral neuropathies in children", section on 'Vitamin deficiency or excess'.)
Requirements — The recommended dietary allowance (RDA) of vitamin B6 ranges from 0.5 to 1 mg/day in children to 1.3 mg/day for young males and females, then rises to 1.7 mg/day for males older than 50 years, and 1.5 mg/day for females older than 50 years (table 2) [3].
BIOTIN — A number of growth factors found in yeast, originally called "bios," were separated early in the 20th century and eventually identified as myoinositol, pantothenate, and biotin [118]. Biotin was also found in liver and variously called vitamin H, coenzyme R, factor S, factor W, vitamin Bw, and protective factor X because it protected against a type of dermatosis and loss of hair in animals that was associated with the intake of raw egg whites (which impair biotin absorption).
The characterization of biotin as a vitamin was based on the discovery that biotin deficiency causes a clinical syndrome, which is mediated by deficiencies of several carboxylase enzymes [119,120].
Sources — Biotin can be found in a variety of plants but is found in highest levels in the liver, egg yolk, soybean products, and yeast [121]. It is bound to proteins in foods and becomes bioavailable after it is released through the action of the enzyme biotinidase.
Biochemistry
●Chemistry – Biotin consists of two cyclic molecules: a ureido and a tetrahydro-thiophene ring (figure 2). In vivo, it is found in a number of different isomers, not all of which are active enzymatically [121]. D-biotin is the only biologically active isomer. Biotin-containing enzymes are degraded to biocytin (biotin bound with lysine), which can be converted back to biotin through the action of biotinidase.
●Metabolism – Other than the ingested forms of biotin, a number of bacteria in the gut synthesize biotin as a by-product of their proteolytic actions. Biotin is mostly absorbed in the proximal small intestine and to a lesser degree in the cecum. Unabsorbed gut biotin is excreted in the feces. Excess serum biotin is excreted via the kidney [122].
●Actions – Biotin is an essential cofactor for several carboxylase enzyme complexes in mammals, all of which are involved in carbohydrate, amino acid, and lipid metabolism. They include [123]:
•Acetyl coenzyme A (CoA) carboxylase (ACC)
•Pyruvate carboxylase (PC)
•Propionyl CoA carboxylase (PCC)
•Methylcrotonyl CoA carboxylase (MCC)
Biotin acts as a CO2 carrier on the surface of each enzyme. As a result, it has an essential role in many processes, including protein synthesis and cell replication.
Measurement — Serum biotin concentrations are not a sensitive measure of intake or sufficiency. Normal urine biotin excretion is around 75 to 195 micromol/day [124,125].
Deficiency
Nutritional deficiency — Biotin deficiency was first noted in patients who were on long-term parenteral nutrition prior to routine biotin supplementation [120]. It is now reported only rarely. Consumption of large amounts of raw egg whites (which contain avidin, a substance that binds to biotin and prevents its absorption) can also lead to biotin deficiency. In addition, secondary biotin deficiency can occur due to lack of a specific enzyme (biotinidase), which is required for release of protein-bound biotin to make it bioavailable [126]. (See 'Multiple carboxylase deficiency' below.)
The classic clinical manifestations of biotin deficiency include dermatitis around the eyes, nose, and mouth; conjunctivitis; alopecia; and neurologic symptoms, including changes in mental status, lethargy, hallucinations, and paresthesias [3,119,121,127]. Other manifestations may include myalgia, anorexia, and nausea.
The clinical manifestations of biotin deficiency are explained by the many functions of the four biotin-dependent carboxylases (ACC, PC, PCC, and MCC) [3].
PC and PCC are involved in the tricarboxylic acid (TCA) cycle in mitochondria, which is essential for metabolism of odd-chain fatty acids and proteins (3-carbon non-carbohydrate precursors for gluconeogenesis), which provides oxaloacetate as a substrate for gluconeogenesis. In the setting of biotin insufficiency, gluconeogenesis is impaired in the liver and kidney. In addition, fatty acid catabolism is impaired, causing a buildup of propionyl CoA. Fatty acid synthesis is also affected by deficiency of ACC, which is required for fatty acid elongation. The disruption in fatty acid synthesis leads to the dermatologic manifestations of biotin deficiency (seborrheic dermatitis and alopecia). MCC is required for metabolism of leucine.
Multiple carboxylase deficiency — Multiple carboxylase deficiency refers to one of two inherited defects of biotin metabolism. The infantile form is caused by a deficiency of holocarboxylase synthetase and presents in the first week of life with lethargy, poor muscle tone, and vomiting [128,129]. A later-onset form is caused by biotinidase deficiency and is associated with a slow but progressive loss of biotin in the urine, leading to organic aciduria [130]; it is characterized by ataxia, ketoacidosis, dermatitis, seizures, myoclonus, and nystagmus. (See "Overview of the hereditary ataxias", section on 'Disorders of pyruvate and lactate metabolism'.)
Multiple carboxylase deficiency is diagnosed definitively by studying enzymes from lymphocytes. Testing for these deficiencies is included in the newborn screen in most states (see "Newborn screening", section on 'Programs throughout the world'). Both infantile and late-onset multiple carboxylase deficiency can be treated with pharmacologic doses of biotin. Delayed treatment may fail to reverse the neurologic sequelae and has been associated with neurologic and developmental delay [104,130].
Toxicity — No toxicity of excess biotin intake has been described.
Interference with laboratory assays — Pharmacologic levels of biotin may interfere with laboratory tests of thyroid function and artifactually cause a laboratory pattern that mimics Graves’ disease [131,132]. This is because biotin can interfere with commonly used assays for thyroid-stimulating hormone (TSH) and thyroid hormone (T4), as well as detection of anti-TSH receptor antibodies. The pattern of abnormalities depends on the specific laboratory techniques used for the T4 assays. (See "Laboratory assessment of thyroid function", section on 'Assay interference with biotin ingestion'.)
Similarly, high doses of biotin may interfere with common laboratory immunoassays for other tests, including troponin, digoxin, ferritin, testosterone, brain natriuretic peptide, and progesterone, depending upon the analytic platform used [133-138]. Although the precise amount of time needed to excrete excess biotin is unknown, avoidance of biotin supplements for 48 to 72 hours prior to laboratory blood testing may eliminate this potential interference. (See "Troponin testing: Analytical considerations", section on 'Assay false positives and false negatives'.)
Requirements — The recommended intake for biotin is expressed as adequate intake (AI) rather than recommended dietary allowance (RDA), indicating that there are not adequate data to specify the percentage of individuals whose requirement is met by this intake. The AI is 8 to 12 mcg/day for children and 30 mcg/day for adults (table 2) [3].
VITAMIN C (ASCORBIC ACID) — Vitamin C (ascorbic acid) deficiency is responsible for scurvy, which is characterized by prominent cutaneous signs (petechiae, perifollicular hemorrhage, and bruising), gingivitis, arthralgias, and impaired wound healing, appearing within a few months of a vitamin C-deficient diet.
Scurvy has a prominent role in history. The clinical manifestations of scurvy were well described in ancient Egyptian, Greek, and Roman literature. British and European explorers of the Renaissance era were ravaged by scurvy. Scurvy was a major cause of morbidity and death amongst much of Europe during the great potato famine, the United States Civil War, the exploration of the North Pole, and the California gold rush. Captain James Cook was one of the first to demonstrate that sailors who spent months at sea could avoid scurvy by maintaining a diet rich in vegetables [139]. James Lind, a British naval surgeon, published his experiences and studies on scurvy aboard ships in a book titled Treatise of the Scurvy [139]. During 1928 to 1931, Szent-Gyorgyi isolated hexuronic acid from cabbage, oranges, paprika, and adrenal glands. Hexuronic acid was subsequently termed vitamin C and found to prevent the development of scurvy [140,141].
Sources — Important food sources of vitamin C are citrus fruits, tomatoes, potatoes, brussels sprouts, cauliflower, broccoli, strawberries, cabbage, and spinach [142]. The provision of dietary vitamin C is highly dependent on food preparation because oxidative conditions can destroy active vitamin C in foods. In children, breast milk provides an adequate source of ascorbic acid for newborns and infants.
Biochemistry
●Chemistry – Ascorbic acid is the enolic form of an alpha-ketolactone and is closely akin to the glucose structure (figure 2). A number of compounds that exhibit the biologic activities of ascorbic acid are generally referred to as vitamin C. Most mammals can synthesize vitamin C from glucose, with the exception of primates, guinea pigs, and fruit bats.
●Metabolism – Ascorbic acid is absorbed in the distal small intestine through an energy-dependent active transport process. Usual dietary doses of up to 100 mg/day are almost completely absorbed [143]. As dietary concentrations increase, a smaller fraction is absorbed; pharmacologic dosing (>1000 mg/day) can result in absorption rates of <50 percent [144].
Blood concentrations of ascorbic acid are regulated by renal excretion. Excess amounts are filtered by renal glomeruli and reabsorbed via the tubules to a predetermined threshold [145]. Dehydroascorbic acid, the oxidative product of ascorbic acid metabolism, passively penetrates cellular membranes and is the preferred form for erythrocytes and leukocytes [146]. The greatest concentrations of ascorbic acid are found in the pituitary, adrenal, brain, leukocytes, and the eye [147].
●Actions – Ascorbic acid is a reversible biologic reducing agent (electron donor), which is important to maintain the activity of several enzymes that include iron and copper [145].
Ascorbic acid provides electrons needed to reduce molecular oxygen. These antioxidant capabilities also stabilize a number of other compounds, including vitamin E and folic acid. It is a cofactor for reduction of folate to dihydro-and-tetrahydrofolate [145].
Ascorbic acid is involved in each of the following biologic processes:
•Fatty acid transport – The transport of long-chain fatty acids across the mitochondrial membrane is a carnitine-dependent process. Carnitine synthesis requires ascorbic acid as an electron donor [148].
•Collagen synthesis – Formation of collagen requires enzymatic hydroxylation of two amino acids: proline and lysine residues within the structure of collagen. Ascorbic acid is an electron donor in reactions catalyzed by the enzymes prolyl hydroxylase and lysyl hydroxylase, which form hydroxyproline and hydroxylysine, respectively [149]. Failure of this step in collagen synthesis results in impaired wound healing, defective tooth formation, and deficient osteoblast and fibroblast function.
•Neurotransmitter synthesis – Synthesis of norepinephrine involves a hydroxylation of dopamine by the enzyme dopamine-beta-mono-oxygenase, where ascorbic acid is a required cofactor [150].
•Prostaglandin metabolism – Ascorbic acid has a role in prostaglandin and prostacyclin metabolism. It may be capable of attenuating the inflammatory response or even sepsis syndrome [151].
•Nitric oxide synthesis – Ascorbic acid may promote synthesis of nitric oxide, a potent vasodilator [152,153].
Measurement — There are no reliable determinants of functional vitamin C status. However, plasma and leukocyte vitamin C levels are the mainstay for assessment and are reasonably well correlated with vitamin C intake. High-performance liquid chromatography can evaluate both reduced ascorbic acid and oxidized DHA levels [154].
Deficiency — Ascorbic acid is an essential dietary nutrient in all primates. The clinical deficiency syndrome known as scurvy is largely due to impaired collagen synthesis and disordered connective tissue. The diagnosis can be made clinically, based upon a history of insufficient vitamin C intake and typical clinical symptoms.
The most specific symptoms (occurring as early as three months after deficient intake) are follicular hyperkeratosis and perifollicular hemorrhage, with petechiae and coiled hairs (picture 3) [155]. Other common symptoms include ecchymoses, gingivitis (with bleeding and receding gums and dental caries) (picture 4), Sjögren's syndrome, arthralgias, edema, anemia, and impaired wound healing [155]. The hemorrhagic skin lesions are initially flat but may coalesce and become palpable, especially on the lower extremities. This finding may resemble a systemic vasculitis. Musculoskeletal pain, which may be severe, may be caused by hemorrhage into the muscles or periosteum. A limp may be the presenting symptom, particularly in nonverbal children [156,157]. Generalized systemic symptoms are weakness, malaise, joint swelling, arthralgias, anorexia, depression, neuropathy, and vasomotor instability [145]. Cardiorespiratory symptoms, including dyspnea, hypotension, and sudden death have been reported and are thought to be caused by impaired vasomotor response [155]. Characteristic findings on magnetic resonance imaging are sclerotic and lucent metaphyseal bands, with periosteal reaction and adjacent soft-tissue edema [158].
In the United States, ascorbic acid deficiency occurs mostly in severely malnourished individuals, those with drug and alcohol use disorders, or those living in poverty or on diets devoid of fruits and vegetables [159,160]. In older adult, institutionalized, or chronically ill patients, scurvy can be seen due to their poor dietary intake [161]. Scurvy has also been described in children with autism spectrum disorder who habitually ate a highly selective diet that was devoid of fruits and vegetables (often associated with autism spectrum disorder) [156,157,162,163], in residents in a refugee camp [164], and in children with iron overload due to medical conditions, such as sickle cell disease or thalassemia, or a history of bone marrow transplantation [158]. Iron overload can precipitate scurvy because ferric deposits accelerate the catabolism of ascorbic acid [165].
Symptoms of scurvy generally occur when the plasma concentration of ascorbic acid is less than 0.2 mg/dL (11 micromol/L) [142]. Recent vitamin C intake can normalize plasma ascorbic acid concentrations even if tissue levels are still deficient. Measurement of ascorbic acid in leukocytes is a better measure of body stores, but this test is not widely available.
The treatment for scurvy is vitamin C supplementation and reversal of the conditions that led to the deficiency. A wide range of replacement doses have been used successfully. For children, recommended doses are 100 mg ascorbic acid given three times daily (orally, intramuscularly, or intravenously) for one week, then once daily for several weeks until the patient is fully recovered [166]. Adults are usually treated with 300 to 1000 mg/day for one month [155,167].
Many of the constitutional symptoms improve within 24 hours of treatment; bruising and gingival bleeding resolve within a few weeks.
Therapeutic and prophylactic roles — Several therapeutic and prophylactic roles have been described for vitamin C, including prevention of cardiovascular disease and cancer. However, evidence does not support the use of vitamin C supplementation for disease prevention. Vitamin C has little or no role in preventing the common cold. (See "Vitamin intake and disease prevention", section on 'Vitamin C' and "The common cold in adults: Treatment and prevention", section on 'Vitamins'.)
Toxicity — A number of side effects of ascorbic acid have been reported in the literature. Large doses of vitamin C (in gram quantities) can give false-negative stool guaiac results [168] and have been associated with diarrhea and abdominal bloating. Epidemiologic data have shown a correlation between vitamin C intake (dietary and supplemental) and oxalate kidney stones in males, especially at very high doses [169,170]. Therefore, we do not support routine supplementation in males and, particularly, in any patients with a predisposition to form oxalate stones. Those at risk should limit their intake of vitamin C to the United States recommended dietary allowance (RDA). (See "Kidney stones in adults: Epidemiology and risk factors", section on 'Vitamin C'.)
Ingestion of large quantities of ascorbic acid has been rarely associated with fatal cardiac arrhythmias in patients with iron overload, presumably due to oxidative injury [171]. Thus, it may be reasonable to advise patients to avoid taking pharmacologic doses of ascorbic acid supplements, but there is no identifiable reason to discourage the consumption of fresh fruits or vegetables containing vitamin C. (See "Management and prognosis of hereditary hemochromatosis".)
Requirements — The United States RDA for vitamin C is shown in the table (table 2). It ranges from 15 to 45 mg/day in children to 75 mg/day for most females and 90 mg/day for males; pregnant or lactating females and older adults have requirements up to 120 mg/day [142]. This is based upon the minimum requirement to prevent scurvy [145].
Some studies report low blood levels of vitamin C in smokers, which results in recommendations for supplementation in this group [172]. However, in the aggregate, the data suggest that this is inappropriate. A meta-analysis concluded that supplemental vitamin C no positive impact on lung cancer incidence or mortality in either normal- or high-risk individuals [173]. In one of the included studies, which randomized 7627 females, there was an increased risk of lung cancer in those randomized to vitamin C [174]. As stated above, supplementation of vitamin C is not recommended for disease prevention. (See "Vitamin intake and disease prevention", section on 'Vitamin C'.)
OTHER VITAMINS AND PSEUDOVITAMINS — The intake of choline is below estimated requirements (adequate intake [AI]) for many groups in the Unites States population, including older children, pregnant individuals, and older adults [175]. Choline is a precursor for acetylcholine and has a role in neurotransmitter synthesis, homocysteine metabolism, and many other metabolic processes. Low choline intake is thought to be associated with accelerated atherosclerosis [176] and possibly neural tube defects [177], neurologic disorders, and fatty liver disease [178,179], although clinically apparent deficiencies are rare. Egg yolks, soy flour, and salmon are good sources of concentrated choline. (See "Nutrition in pregnancy: Dietary requirements and supplements", section on 'Choline'.)
Inositol, carnitine (long-chain fatty acid transporter), lipoic acid, lutein, zeaxanthin, other flavonoids, and carotenoids probably could be classed as vitamins because humans cannot synthesize them, but dietary sources usually provide ample amounts and clinical deficiencies are extremely rare.
In addition, there are many substances that have been promoted as vitamins in the popular press but have little support in the scientific literature, including laetrile ("vitamin B17," amygdalin), pangamic acid ("vitamin B15," diisopropylamine dichloroacetate), and gerovital ("vitamin H3") [180].
VITAMIN B12 AND FOLIC ACID — These water-soluble vitamins are discussed in detail in separate topic reviews. (See "Treatment of vitamin B12 and folate deficiencies" and "Clinical manifestations and diagnosis of vitamin B12 and folate deficiency".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Vitamin deficiencies".)
SUMMARY AND RECOMMENDATIONS
●Definition – Vitamins are a number of chemically unrelated families of organic substances that cannot be synthesized by humans but need to be ingested in the diet in small quantities for optimal health. They are divided into water-soluble and fat-soluble vitamins (table 1). (See 'Introduction' above.)
●Requirements – The following tables outline the requirements for each of the water-soluble vitamins (table 2) and typical symptoms of their deficiency (table 3).
●Thiamine – Vitamin B1 (thiamine) is found in larger quantities in foods such as yeast, legumes, pork, rice, and cereals made from whole grains. Thiamin deficiency causes each of the following disorders:
•Beriberi, characterized by peripheral neuropathy, with or without edema and heart failure. (See 'Adult beriberi' above.)
•Wernicke encephalopathy (WE; characterized by nystagmus, ophthalmoplegia, and ataxia), along with confusion and Korsakoff syndrome, a chronic neurologic condition. (See 'Wernicke-Korsakoff syndrome' above.)
•Infantile beriberi, due to dietary deficiency. (See 'Infantile beriberi' above.)
●Riboflavin – Vitamin B2 (riboflavin) is supplied in meats, fish, eggs, milk, green vegetables, yeast, and enriched foods. Mild deficiency is often undetected due to the mild nature and nonspecific signs and symptoms of deficiency. Riboflavin deficiency (ariboflavinosis) is characterized by sore throat, hyperemia of pharyngeal mucous membranes, edema of mucous membranes, cheilitis, stomatitis, glossitis, normocytic-normochromic anemia, and seborrheic dermatitis. Risk factors for riboflavin deficiency include anorexia nervosa, malabsorptive syndromes, and chronic use of phenobarbital and other barbiturates. (See 'Vitamin B2 (riboflavin)' above.)
●Niacin – Vitamin B3 (niacin) is widely distributed in plant and animal foods.
•Niacin deficiency causes pellagra, which is characterized by a photosensitive pigmented dermatitis (typically located in sun-exposed areas (picture 2)), diarrhea, and dementia. In resource-rich countries, pellagra tends to occur in those with alcohol use disorder and has been reported as a complication of bariatric surgery or anorexia nervosa. (See 'Deficiency (pellagra)' above.)
•In high doses (1000 to 3000 mg/day), niacin is a well-established antihyperlipidemic agent, decreasing total and low-density lipoprotein cholesterol. Side effects at these doses include flushing, nausea, vomiting, pruritus, hives, constipation, and elevation in serum aminotransferases. (See 'Toxicity' above and "Low-density lipoprotein cholesterol lowering with drugs other than statins and PCSK9 inhibitors", section on 'Nicotinic acid (niacin)'.)
●Pantothenic acid – Vitamin B5 (pantothenic acid) in the diet is mainly in the form of coenzyme A (CoA) and is supplied in egg yolk, liver, kidney, broccoli, and milk. Pantothenic acid deficiency is rare in humans but has been noted in severely malnourished individuals. Clinical manifestations can include paresthesias and dysesthesias, known as "burning feet syndrome." (See 'Vitamin B5 (pantothenic acid)' above.)
●Pyridoxine – Vitamin B6 (pyridoxine) is found in the diet in several forms, including pyridoxine and pyridoxamine (from plants) and pyridoxal (from animal foods). Meats, whole grains, vegetables, and nuts are the best sources. Overt deficiencies of vitamin B6 are probably rare. Marginal deficiencies may be more common. Deficiency is manifested as nonspecific stomatitis, glossitis, cheilosis, irritability, confusion, and depression. Toxicity has been reported with long-term use of megadoses of pyridoxine (over 250 mg/day), characterized by peripheral neuropathy, dermatoses, photosensitivity, dizziness, and nausea. (See 'Vitamin B6 (pyridoxine)' above.)
●Biotin deficiency – Biotin deficiency is seen clinically in the setting of severe dietary deficiency or a congenital disorder of biotin metabolism:
•Biotin deficiency was first noted in patients who were on long-term parenteral nutrition prior to routine biotin supplementation. Symptoms of biotin deficiency may include a dermatitis around the eyes, nose, and mouth; conjunctivitis; alopecia; and neurologic symptoms. Consumption of large amounts of raw egg whites can lead to biotin deficiency because the egg white impairs absorption of biotin. (See 'Deficiency' above.)
•Multiple carboxylase deficiency is a congenital disorder of biotin metabolism caused by deficiency of biotinidase or holocarboxylase synthetase, enzymes crucial to the biotin metabolism pathway. These disorders are included in newborn screening programs in the United States and can be treated with pharmacologic doses of biotin. (See 'Multiple carboxylase deficiency' above and "Overview of the hereditary ataxias", section on 'Disorders of pyruvate and lactate metabolism'.)
High doses of supplemental biotin may interfere with common laboratory immunoassays tests, including tests of thyroid function. Although the precise amount of time needed to excrete excess biotin is unknown, avoidance of biotin supplements for 48 to 72 hours prior to laboratory blood testing may eliminate this potential interference. (See 'Interference with laboratory assays' above.)
●Ascorbic acid – Vitamin C (ascorbic acid) is essential for a variety of processes including collagen synthesis, where it serves as a reducing agent. Vitamin C deficiency, known as scurvy, is characterized by ecchymoses, bleeding gums (picture 4), petechiae, coiled hairs, hyperkeratosis (picture 3), Sjögren's syndrome, arthralgias, and impaired wound healing, as well as constitutional symptoms. Evidence does not support the use of vitamin C supplementation for disease prevention. (See 'Vitamin C (ascorbic acid)' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Clifford W Lo, MD, MPH, ScD, who contributed to an earlier version of this topic review.
