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Official reprint from UpToDate®

[Link] © 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Overview of water-soluble vitamins

Authors: Sassan Pazirandeh, MD, David L Burns, MD
Section Editor: David Seres, MD
Deputy Editor: Jane Givens, MD, MSCE

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Feb 2023. | This topic last updated: Feb 03, 2023.

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

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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.

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● 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

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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
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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.

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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
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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.

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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".)

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● 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)

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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

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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).

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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'.)

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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)

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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].

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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
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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].
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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.

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● 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
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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'.)

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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.

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● 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].

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• 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 3A-B) [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. Pediatric case series and reports have described acute limp as a presenting
symptom of scurvy (vitamin C deficiency) in children with severe malnutrition caused by food
insecurity, neglect, or eating disorders (eg, avoidant/restrictive food intake disorder or anorexia
nervosa) [156-160]. In a systematic review, musculoskeletal complaints (lower limb pain, limp,
arthritis, or refusal to walk) were reported in over 90 percent of 86 children with scurvy, and
approximately one-third had a limp [160]. 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 [161].

In the United States, ascorbic acid deficiency occurs mostly in severely malnourished
individuals, those with drug and alcohol use disorders, those who have had bariatric surgery, or
those living in poverty or on diets devoid of fruits and vegetables [162-164]. In older adult,
institutionalized, or chronically ill patients, scurvy can be seen due to their poor dietary intake
[165]. Scurvy has also been described in children with autism spectrum disorder who habitually

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ate a highly selective diet that was devoid of fruits and vegetables (often associated with autism
spectrum disorder) [156,166-168], in residents in a refugee camp [169], and in children with iron
overload due to medical conditions, such as sickle cell disease or thalassemia, or a history of
bone marrow transplantation [161]. Iron overload can precipitate scurvy because ferric deposits
accelerate the catabolism of ascorbic acid [170].

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 [171]. Adults are usually treated with 300 to 1000 mg/day for one month [155,172].

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 [173] 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 [174,175]. 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 [176]. Thus, it
may be reasonable to advise patients to avoid taking pharmacologic doses of ascorbic acid
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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 [177]. 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
[178]. In one of the included studies, which randomized 7627 females, there was an increased
risk of lung cancer in those randomized to vitamin C [179]. 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
[180]. 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 [181] and possibly neural tube defects [182],
neurologic disorders, and fatty liver disease [183,184], 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") [185].

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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

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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
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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 3A-B), 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.

Use of UpToDate is subject to the Terms of Use.

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Topic 5367 Version 56.0

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GRAPHICS

Clinical symptoms of selected vitamin deficiencies

Vitamin Deficiency syndrome

Water-soluble vitamins

Vitamin B1 Beriberi – Congestive heart failure (wet beriberi), aphonia, peripheral

(thiamine) neuropathy, Wernicke encephalopathy (nystagmus, ophthalmoplegia, ataxia),
confusion, or coma

Vitamin B2 Nonspecific symptoms including edema of mucous membranes, angular

(riboflavin) stomatitis, glossitis, and seborrheic dermatitis (eg, nose, scrotum)

Niacin Pellagra – Dermatitis on areas exposed to sunlight; diarrhea with vomiting,

(nicotinic acid) dysphagia, mouth inflammation (glossitis, angular stomatitis, cheilitis);
headache, dementia, peripheral neuropathy, loss of memory, psychosis,
delirium, catatonia

Vitamin B6 Anemia, weakness, insomnia, difficulty walking, peripheral neuropathy,

(pyridoxine, nasolabial seborrheic dermatitis, cheilosis, stomatitis
pyridoxal)

Vitamin B12 Megaloblastic anemia (pernicious anemia), peripheral neuropathy with impaired
(cobalamin) proprioception; may include axonal or optic neuropathy and slowed mentation

Folate Megaloblastic anemia; may include sensory predominant neuropathy

Biotin Nonspecific symptoms including altered mental status, myalgia, dysesthesias,

anorexia, maculosquamous dermatitis

Pantothenate Nonspecific symptoms including paresthesias, dysesthesias ("burning feet"),

anemia, gastrointestinal symptoms

Vitamin C Scurvy – Fatigue, petechiae, ecchymoses, bleeding gums, depression, dry skin,
(ascorbate) impaired wound healing

Fat-soluble vitamins

Vitamin A Night blindness, xerophthalmia, keratomalacia, Bitot spot, follicular

(retinol, retinal, hyperkeratosis
retinoic acid)

Vitamin D Rickets, osteomalacia, craniotabes, rachitic rosary

(cholecalciferol,
ergocalciferol)

Vitamin E Sensory and motor neuropathy, ataxia, retinal degeneration, hemolytic anemia
(tocopherols)

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Vitamin K Hemorrhagic disease

(phylloquinone,
menaquinone,
menadione)

Graphic 63827 Version 14.0

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Chemical structure of vitamins B1, B2, B6 and B12

Graphic 77100 Version 3.0

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Dietary reference intake (DRI) for water-soluble vitamins

Pantothenic
Life Thiamine Riboflavin Niacin Vitamin B6 Bio
acid
stage (mg/day) (mg/day) (mg/day)* (mg/day) (mcg
(mg/day)
group
RDA/AI UL RDA/AI UL RDA/AI UL RDA/AI UL RDA/AI UL RDA/A

Infants

0 to 6 0.2 ¶ ND 0.3 ¶ ND 2¶ ND 1.7 ¶ ND 0.1 ¶ ND 5¶

months

7 to 12 0.3 ¶ ND 0.4 ¶ ND 4¶ ND 1.8 ¶ ND 0.3 ¶ ND 6¶

months

Children

1 to 3 0.5 ND 0.5 ND 6 10 2¶ ND 0.5 30 8¶

years

4 to 8 0.6 ND 0.6 ND 8 15 3¶ ND 0.6 40 12 ¶

years

Males

9 to 13 0.9 ND 0.9 ND 12 20 4¶ ND 1 60 20 ¶
years

14 to 1.2 ND 1.3 ND 16 30 5¶ ND 1.3 80 25 ¶

18
years

19 to 1.2 ND 1.3 ND 16 35 5¶ ND 1.3 100 30 ¶

30
years

31 to 1.2 ND 1.3 ND 16 35 5¶ ND 1.3 100 30 ¶

50
years

51 to 1.2 ND RDA ND 16 35 5¶ ND 1.7 100 30 ¶

70
years

>70 1.2 ND 1.3 ND 16 35 5¶ ND 1.7 100 30 ¶

years

Females

9 to 13 0.9 ND 0.9 ND 12 20 4¶ ND 1 60 20 ¶
years

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14 to 1 ND 1 ND 14 30 5¶ ND 1.2 80 25 ¶
18
years

19 to 1.1 ND 1.1 ND 14 35 5¶ ND 1.3 100 30 ¶

30
years

31 to 1.1 ND 1.1 ND 14 35 5¶ ND 1.3 100 30 ¶

50
years

51 to 1.1 ND 1.1 ND 14 35 5¶ ND 1.5 100 30 ¶

70
years

>70 1.1 ND 1.1 ND 14 35 5¶ ND 1.5 100 30 ¶

years

Pregnancy

14 to 1.4 ND 1.4 ND 18 30 6¶ ND 1.9 80 30 ¶

18
years

19 to 1.4 ND 1.4 ND 18 35 6¶ ND 1.9 100 30 ¶

30
years

31 to 1.4 ND 1.4 ND 18 35 6¶ ND 1.9 100 30 ¶

50
years

Lactation

14 to 1.4 ND 1.6 ND 17 30 7¶ ND 2 80 35 ¶
18
years

19 to 1.4 ND 1.6 ND 17 35 7¶ ND 2 100 35 ¶

30
years

31 to 1.4 ND 1.6 ND 17 35 7¶ ND 2 100 35 ¶

50
years

Dietary reference intakes (DRIs) include the following measures describing optimal nutrient intake:
Recommended dietary allowance (RDA) – The level of dietary intake that is sufficient to meet
the daily nutrient requirements of 97% of the individuals in a specific life stage group.
Adequate intake (AI) – An approximation of the average nutrient intake that sustains a
defined nutritional state, based on observed or experimentally determined values in a defined

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population.
Upper tolerable level (UL) – The maximum level of daily nutrient intake that is likely to pose
no risk of adverse health effects in almost all individuals in the specified life stage or gender
group.

RDAs and AIs may both be used as goals for individual intake. The AI is used when there are
insufficient data to determine the RDA for a given nutrient.

* Niacin is dosed as niacin equivalents (NE), where 1 mg niacin = 60 mg of tryptophan. Infants 0 to 6

months: only preformed niacin (not NE).

¶ As AI.

Dietary Reference Intakes: The Essential Guide to Nutrient Requirements. Otten JJ, Hellwig JP, Meyers LD (Eds), The National
Academies Press, Washington, DC 2006. pp.530-541. Reprinted and expanded with permission from the National Academies
Press, Copyright © 2006, National Academy of Sciences.

Sources: Dietary reference intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Panthothenic acid, Biotin,
and Choline (1998); Dietary reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids (2000). These reports may
be accessed via [Link].

Graphic 69963 Version 22.0

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Atrophic glossitis

A smooth tongue that has lost its papillae and is often sore suggests
a deficiency in riboflavin, niacin, folic acid, vitamin B12, or iron. This
patient had vitamin B12 deficiency.

Reproduced with permission from: Berg D, Worzala K. Atlas of Adult Physical

Diagnosis. Philadelphia: Lippincott Williams & Wilkins, 2006. Copyright © 2006
Lippincott Williams & Wilkins.

Graphic 54472 Version 6.0

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Physical signs of selected nutritional deficiency states

Signs Deficiencies

Hair Alopecia Severe undernutrition, zinc deficiency

Brittle Biotin, severe undernutrition

Color change Severe undernutrition

Dryness Vitamins E and A

Easy pluckability Severe undernutrition

Skin Acneiform lesions Vitamin A

Follicular keratosis Vitamin A

Xerosis (dry skin) Vitamin A

Perioral and perianal bullous dermatitis (wet, Zinc

flaming-red plaques)

Ecchymosis Vitamin C or K

Intradermal petechiae Vitamin C or K

Erythema (especially where exposed to Niacin

sunlight)

Hyperpigmentation Niacin

Seborrheic dermatitis (nose, eyebrows, eyes) Vitamin B2, vitamin B6, niacin

Scrotal dermatitis Niacin, vitamin B2, vitamin B6

Eyes Angular palpebritis Vitamin B2

Corneal revascularization Vitamin B2

Bitot spots Vitamin A

Conjunctival xerosis, keratomalacia Vitamin A

Mouth Angular stomatitis Vitamin B2, vitamin B6, vitamin B12

Atrophic papillae Niacin

Bleeding gums Vitamin C

Cheilosis Vitamin B2, vitamin B6

Glossitis Niacin, folate, vitamin B1, vitamin B2,

vitamin B6, vitamin B12

Magenta tongue Vitamin B2

Extremities Genu valgum or varum, metaphyseal Vitamin D

widening

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Loss of deep tendon reflexes of the lower Vitamins B1 and B12

extremities

Vitamin B1: thiamine; vitamin B2: riboflavin; vitamin B3: niacin; vitamin B6: pyridoxine; vitamin B12:
cyanocobalamin.

Adapted from: Bernard MA, Jacobs DO, Rombeau JL. Nutrition and Metabolic Support of Hospitalized Patients. WB Saunders,
Philadelphia 1986.

Graphic 78426 Version 8.0

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Chemical structure of folate, vitamin C, pantothenate,

biotin and niacin

Graphic 57133 Version 5.0

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Pellagra dermatitis

Dermatitis due to niacin deficiency (pellagra). The term "pellagra"

derives from the Italian words for "rough skin." The condition is
characterized by an erythematous, blistering rash that may be
pruritic or painful. The rash occurs in areas of sun exposure and is
therefore often seen around the neck ("Casal's necklace"), arms,
hands, or malar area.

Reproduced with permission from: [Link]. Copyright VisualDx. All rights

reserved.

Graphic 69889 Version 8.0

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Perifollicular abnormalities in scurvy

In this example, the perifollicular hyperkeratotic papules are quite

prominent, with surrounding hemorrhage. These lesions have been
misinterpreted as "palpable purpura," leading to the mistaken
clinical diagnosis of vasculitis.

Reproduced with permission from: Hirschmann JV, Raugi GJ. Adult scurvy. J Am Acad
Dermatol 1999; 41:895. Copyright © 1999 Elsevier.

Graphic 64172 Version 2.0

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Scurvy

Perifollicular, purpuric macules are present in this patient with

scurvy.

Graphic 51219 Version 2.0

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Gingival abnormalities in scurvy

The gingival swelling and dusky color just above two of the teeth
indicate hemorrhage into the gums of this patient with poor
dentition. The gingival abnormalities of scurvy occur only in the
presence of teeth, which presumably provide portals of entry for
microbes into the gums. One hypothesis suggests that vitamin C
deficiency impairs neutrophil-mediated killing of bacteria, leading to
chronic gingivitis, which is then complicated by bleeding from the
fragile vessels characteristic of scurvy.

Reproduced with permission from: Hirschmann JV, Raugi GJ. Adult scurvy. J Am Acad
Dermatol 1999; 41:895. Copyright ©1999 Elsevier.

Graphic 76282 Version 3.0

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Contributor Disclosures
Sassan Pazirandeh, MD No relevant financial relationship(s) with ineligible companies to disclose. David
L Burns, MD No relevant financial relationship(s) with ineligible companies to disclose. David Seres,
MD Equity Ownership/Stock Options: Medaware Systems [Biomedical informatics]. Consultant/Advisory
Boards: Community Surgical Supply [Home nutrition support]. All of the relevant financial relationships
listed have been mitigated. Jane Givens, MD, MSCE No relevant financial relationship(s) with ineligible
companies to disclose.

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must
conform to UpToDate standards of evidence.

Conflict of interest policy

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