Overview of Water-Soluble Vitamins

Overview of water-soluble vitamins
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Official reprint from UpToDate

www.uptodate.com 2015 UpToDate

Authors
Sassan Pazirandeh, MD
Clifford W Lo, MD, MPH, ScD
David L Burns, MD
Section Editor
Timothy O Lipman, MD
Deputy Editor
Alison G Hoppin, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Feb 2015. | This topic last updated: Sep 24, 2014.
INTRODUCTION 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 to prevent disorders
of metabolism. They are divided into water-soluble and fat-soluble vitamins (table 1).
Many of the vitamin deficiency diseases, such as rickets (vitamin D), scurvy (vitamin C), beriberi (thiamine),
and pellagra (niacin), have been almost completely eliminated in developed countries. Great interest and
controversy continues into whether vitamin supplementation can prevent cancer, heart disease, upper
respiratory infections, and other common diseases. (See "Vitamin supplementation in disease prevention".)
The best dietary sources for most of the water-soluble vitamins are fruits and vegetables; these also contain
many related substances such as flavins and carotenoids which are generally not recognized as vitamins but
may have protective effects against various diseases. This topic review will focus on the water-soluble
vitamins excluding folic acid and vitamin B12, which are discussed separately. (See "Etiology and clinical
manifestations of vitamin B12 and folate deficiency".)
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
minerals".)
DEFINITIONS Several systems have been used to describe nutritional requirements of a population.
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. Under this system, requirements can be expressed
as a Recommended Dietary Allowance (RDA), which is defined as the dietary intake that is sufficient to meet
the daily nutrient requirements of 97 percent of the individuals in a specific life stage group. If there is
insufficient data to determine an RDA for a given nutrient, requirements can be expressed as an Adequate
Intake (AI), which is an estimation of the nutrient intake necessary to maintain a healthy state. 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, first named "the antiberiberi factor" in 1926, has a historical value
due to the very early description of Beriberi in the Chinese medical texts, as far back as 2697 BC [1].
Formerly known as vitamin B1, thiamine is soluble in water and partly soluble in alcohol. Thiamine consists
of a pyrimidine and a thiazole moiety, both of which are essential for its activity (figure 1).
Sources Thiamine is found in larger quantities in food products such as yeast, legumes, pork, rice, and
cereals. Milk products, fruits, and vegetables are poor sources of thiamine [1]. 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 [2].
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Metabolism Thiamine is absorbed in the small intestine via both passive diffusion and active transport.
The maximal absorption of thiamine is in the jejunum and ileum [3]. Thiamine passes through the mucosal
cells to enter the blood stream via a sodium and ATP dependent pump. Bound to albumin, it is carried by the
portal circulation to the liver. Thiamine enters the red blood cells by passive diffusion while its entry into other
cells is via an active energy requiring process [3]. 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 supplementation is required [3]. Through a series of
metabolic processes, thiamine is incorporated into many phosphorylated esters, including thiamine
pyrophosphate (TPP) and thiamine monophosphate (TMP). Thiamine and all of its metabolites are excreted
in the urine. Biliary excretion is a minor route of its homeostasis [4].
Actions Thiamine is an important cofactor for enzymes involved in amino-acid and carbohydrate
metabolism. Functioning along with many coenzymes such as flavin and NAD, thiamine 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 [3]. Thiamine has a role in the initiation of nerve impulse propagation that is
independent of its coenzyme functions [3].
Deficiency Thiamine deficiency can be assessed by measuring the blood thiamine concentration,
erythrocyte thiamine transketolase (ETKA), or transketolase urinary thiamine excretion (with or without a 5
mg thiamine load) [5]. Most laboratories now measure blood thiamine concentration directly, in preference to
the ETKA method [6]. The ETKA method is a functional test and results are influenced by the hemoglobin
concentration.
Thiamine deficiency has been associated with three disorders:
Beriberi (infantile and adult)
Wernicke-Korsakoff syndrome
Leigh's syndrome
Infantile beriberi Beriberi in infants becomes clinically apparent between the ages of two and three
months. The clinical features are variable and may include a fulminant cardiac syndrome with cardiomegaly,
tachycardia, a loud piercing cry, cyanosis, dyspnea, and vomiting [7]. A form of aseptic meningitis has also
been described in which the affected infants exhibit vomiting, nystagmus, purposeless movements, and
seizure, despite a "normal" cerebrospinal fluid [8].
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 [9]. 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 five and ten years later, and most had chronic epilepsy [10,11]. 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 revealed delays in language and motor development [12].
Adult beriberi Adult beriberi is described as dry or wet. Dry beriberi is the development of a
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symmetrical peripheral neuropathy characterized by both sensory and motor impairments, mostly of the
distal extremities. Wet beriberi includes a neuropathy, as well as signs of cardiac involvement with
cardiomegaly, cardiomyopathy, congestive heart failure, peripheral edema, and tachycardia [1].
Beriberi has been reported as a complication of weight loss surgery, presenting as a polyneuropathy with a
burning sensation in the extremities, weakness, and falls [13-15]. Several of the case reports have been in
adolescents, but whether this nutritional complication is more common in the adolescent age group as
compared to 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
supplements are not provided. 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 [16].
A number of studies have suggested that patients with heart failure, especially those treated with loop
diuretics, may be thiamine deficient and should be treated with 50 to 200 mg of thiamine per day [17-19].
However, this remains controversial because of questions involving assay validity and a lack of controlled
trials [20]. (See "Causes of dilated cardiomyopathy".)
Wernicke-Korsakoff syndrome Wernicke-Korsakoff syndrome is the best known neurologic
complication of thiamine (vitamin B1) deficiency. The term refers to two different syndromes, each
representing a different stage of the disease. Wernicke's encephalopathy (WE) is an acute syndrome
requiring emergent treatment to prevent death and neurologic morbidity. Korsakoff's syndrome (KS) 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 a triad of nystagmus, ophthalmoplegia, and ataxia, along with confusion. This combination is almost
exclusively described in chronic alcoholics with thiamine deficiency. The two entities are not separate
diseases, but a spectrum of signs and symptoms. 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 [21]. (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 to alcoholic patients until thiamine supplementation has been initiated to avoid precipitating
Wernicke's encephalopathy. (See "Wernicke encephalopathy", section on 'Treatment'.)
Leigh syndrome Thiamine deficiency has occasionally been reported in infants presenting with
features of Leigh syndrome, a progressive subacute necrotizing encephalomyopathy. This is a sporadic
mitochondrial disorder with a subacute neurologic course. It is manifested with ataxia, dysarthria, movement
disorders, areflexia, muscle atrophy, and weakness. (See "Hereditary neuropathies associated with
generalized disorders", section on 'Leigh syndrome'.)
Toxicity No real syndrome of excess thiamine exists since the kidneys can rapidly clear almost all excess
thiamine [22]. Its half-life is 9.5 to 18.5 days.
Requirements The RDA for thiamine in the United States is 1.2 mg daily for adult men and 1.1 mg daily
for adult women (about 0.5 mg/1000 kcal), and 1.4 mg/day during pregnancy and lactation (table 2) [23].
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Thiamine can be administered via intravenous and intramuscular routes. For the treatment of patients with
beriberi, the daily doses range from 50 to 100 mg for 7 to 14 days. Then an oral dose of 10 mg per day is
given until full recovery is achieved [1].
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. First identified in the early
1900s, riboflavin was isolated in 1935 [24].
Sources Riboflavin is supplied in many foods, including meats, fish, eggs and milk, green vegetables,
yeast, and enriched foods.
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 [25].
Metabolism Dietary flavins are bound to albumin and other riboflavin-specific carrier proteins and are
released from their protein-bound state via gastric acid and proteolytic enzymes [26]. 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 [27]. There also appears to
be some enterohepatic circulation for riboflavin facilitated by bile salts [26]. Riboflavin eventually reaches the
hepatocytes where its metabolism into flavin mononucleotide (FMN) and flavin-adenine dinucleotide (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 [25]. 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 [26]. Most of
the riboflavin stores in the body are in the forms of flavoproteins. Urinary levels of the vitamin only indirectly
reflect dietary intake or riboflavin catabolism [28].
Actions Riboflavin is an essential component of coenzymes involved in multiple cellular metabolic
pathways, including the energy producing respiratory pathways. Flavoproteins are catalysts in a number of
mitochondrial oxidative and reductive reactions and function as electron transporters [25].
Deficiency Riboflavin deficiency is more common than generally appreciated. Many cases are
undetected due to the mild nature and nonspecific signs and symptoms of deficiency. Plasma riboflavin
concentrations tend to reflect recent dietary intake. Urinary riboflavin excretion and the erythrocyte
glutathione reductase assay are better functional indices of riboflavin deficiency.
Significant deficiency syndromes are characterized by sore throat, hyperemia of pharyngeal mucous
membranes, edema of mucous membranes, cheilitis, stomatitis, glossitis (picture 1), normocyticnormochromic anemia, and seborrheic dermatitis [28]. 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) [29]. Pure deficiency of riboflavin is rare, although
it has been described in areas of the third world where starvation is prevalent and access to food is limited.
Other settings in which riboflavin deficiency may be noted include:
Patients with anorexia nervosa
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Individuals who avoid dairy products (such as people with lactose intolerance) since dairy products are
a good source of riboflavin
Patients with malabsorptive syndromes such as celiac sprue, malignancies, and short bowel syndrome
Rare inborn errors of metabolism in which there is a defect in riboflavin synthesis [30]
Long-term use of phenobarbital and other barbiturates, which may lead to oxidation of riboflavin and
impair its function [31]
Toxicity 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 [25].
Requirements The RDA for riboflavin is 1.3 mg daily for adult men and 1.1 mg daily for adult women
(about 0.6 mg per 1000 kcal); requirements rise to 1.4 mg daily during pregnancy and 1.6 mg daily during
lactation (table 2) [23,32].
Some intramitochondrial beta-oxidation defects 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
[33]. (See "Electrolyte disturbances with HIV infection".)
VITAMIN B3 (NIACIN) Pellagra (meaning "raw skin") was first described in Spain and Italy in the mid 18th
century. It is characterized by a photosensitive pigmented dermatitis (typically located in sun-exposed
areas), diarrhea, and dementia. During the early 1900s, pellagra was epidemic amongst the corn eating
population of southeastern United States. Pellagra is now extremely uncommon in the western world except
as a complication of alcoholism, anorexia nervosa, or malabsorptive disease. Pellagra due to dietary
deficiency can still be seen in India, in parts of China, and Africa.
For centuries since its first description in 1735 by Spanish physician Casal, it was thought to be an infectious
disease [34]. However, in 1937, Elvehjen and his colleagues discovered that nicotinic acid was effective in
the treatment of pellagra in dogs. In the 1950s, tryptophan, a precursor of niacin, replaced it in the treatment
of pellagra and research connected the low source of niacin and tryptophan in corn-containing foods to the
development of pellagra [35]. Niacin had been isolated since 1867, but it was not until 1937 that it became
known as the anti-pellagra factor [34].
Sources Niacin is widely distributed in plant and animal foods. Good sources include yeast, meats
(especially liver), cereals, legumes, and seeds. It is theoretically possible to maintain adequate niacin status
on a high protein diet of 100 g/day since tryptophan can be converted to a niacin derivative in the liver.
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.
Metabolism As the chief dietary forms of niacin, NAD and NADP are first hydrolyzed in the intestinal
lumen by enzymes leading to nicotinamide. Nicotinamide is converted by intestinal flora to nicotinic acid. The
two forms of niacin are then absorbed and released into plasma via passive and facilitated diffusion [36].
Through a passive process, niacin is rapidly taken up by the liver, kidneys, and erythrocytes. Intracellular
nicotinamide and nicotinic acid are quickly converted to coenzyme forms NAD and NADP, which are stored
in tissues with high metabolic activities (ie, muscle and liver).
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Actions Many enzymatic reactions depend upon NAD and NADP. 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 [37]. NADP is a cofactor in the reductive synthesis of the fatty acids and steroids. 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 [37].
Deficiency
Pellagra As mentioned above, pellagra is a rare entity in the United States, but is still a common
manifestation of niacin deficiency in poorer countries where the local diet consists of cereal, corn, or
sorghum. In industrialized countries, pellagra tends to occur in alcoholics, and has been reported as a
complication of bariatric surgery or anorexia nervosa [38,39].
The most characteristic finding is the presence of a symmetric hyperpigmented rash, similar in color to a
sunburn, which is present in the exposed areas of skin (picture 2) [37]. Other clinical findings are a red
tongue and many non-specific symptoms, such as diarrhea and vomiting. Neurologic symptoms include
insomnia, anxiety, disorientation, delusions, dementia, and encephalopathy.
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 the carcinoid syndrome".)
Prolonged use of isoniazid, since isoniazid depletes stores of pyridoxal phosphate, which enhances the
production of tryptophan, a precursor of niacin. Several other drugs induce niacin deficiency by
inhibiting the conversion of tryptophan to niacin, including 5-fluorouracil, pyrazinamide,
6-mercaptopurine, hydantoin, ethionamide, phenobarbital, azathioprine, and chloramphenicol [40].
Hartnup disease (MIM #234500), an autosomal recessive congenital disorder [41]. Hartnup disease is
associated with a defect of a membrane transport in the intestinal and renal cells normally responsible
for the absorption of tryptophan (one of the precursors of nicotinamide-adenine dinucleotide). Through
this pathway, around 50 percent of the daily niacin needs are synthesized. Due to the resulting niacin
deficiency, all the symptoms of pellagra can be expected. The diagnosis is made by detecting a
number of neutral amino acids in the urine, something that is not seen with dietary pellagra. The
treatment is aimed towards depleting stores and supplementing the diet with niacin as well as proteins
and amino acids [42]. (See "Overview of the hereditary ataxias", section on 'Aminoacidurias'.)
Toxicity The most documented and best known side effect of niacin is the flushing reaction associated
with the crystalline nicotinic acid and not nicotinamide [43]. 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 per
day [44]. Despite the inconvenience and the undesirability of the reactions, there are no serious sequelae
from flushing [43].
In pharmacological doses (eg, 1000 to 3000 mg/day), common side effects of niacin are flushing, nausea,
vomiting, pruritus, hives, elevation in serum aminotransferases [45], and constipation. A niacin-induced
myopathy has also been described [46]. Caution should be used in patients with a history of gout, since
niacin is also known to elevate serum uric acid concentration.
Severe toxicity reactions are reported in doses of 2 to 6 grams per day [44]. At such high doses, the hepatic
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metabolism becomes saturated, and side effects of this drug can be more frequently encountered. When
less than 1 g of nicotinic acid was ingested per day, only a handful of anecdotal cases of toxicity has been
reported in the literature [47]. One clinical trial assigned two groups of subjects to either a long or a shortacting formula of niacin, each starting at 500 mg per day [48]. Subjects were followed for several months
during which the dose of niacin was raised every six weeks by about 500 mg. There was no gastrointestinal
or liver toxicity below 1000 mg of niacin per 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 [48]. There is some speculation that the metabolites of nicotinic acid in these high
concentrations may lead to growth retardation in infants and children [49].
Therapeutic roles In moderate to high doses (1 to 3 grams a day) niacin is a well-established
antihyperlipidemic agent, decreasing total and LDL cholesterol [50]. The Cholesterol-Lowering
Atherosclerosis Study (CLAS II and II), for example, showed that a combination of niacin and colestipol
significantly reduced the progression of atherosclerotic related coronary artery complications (52 versus 15
percent in the control group). (See "Lipid lowering with drugs other than statins and fibrates".) To reduce the
flushing side effects, a sustained-release formulation is available for these purposes. However, these longer
acting forms may be associated with more gastrointestinal and hepatotoxic side effects [35]. Lower starting
doses of crystalline niacin or premedication of the patients with aspirin can attenuate these adverse effects
and side effects. A more recent clinical role for nicotinic acid given in high doses has been suggested for
delaying the onset of diabetes in children [51].
Requirements The RDA for Niacin is 16 NEs (Niacin Equivalents) daily for adult males, and 14 NEs daily
for adult females, rising to 18 NE during pregnancy, and 17 NE daily during lactation (table 2) [23]. One NE
is equal to 1 mg of niacin, which is equal to 60 mg of dietary tryptophan. These doses are far below the
anti-hyperlipidemic 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, as discussed
above).
VITAMIN B5 (PANTOTHENIC ACID) Pantothenic acid (PA) was first synthesized successfully in 1940
[52]. It was not until 1947 when its biologically active form, known as Coenzyme A (CoA), was recognized
[53]. PA is an essential cofactor in many acetylation reactions in vivo including tricarboxylic acid cycle (TCA),
fatty acid synthesis and breakdown, as well as other mitochondrial and cytosolic reactions.
Sources The major dietary sources of pantothenic acid are egg yolk, liver, kidney, broccoli, and milk [52].
Substantial concentrations of pantothenic acid are also found in chicken, beef, potatoes, and whole grains
[23]. In the diet, pantothenic acid is mainly in the form of CoA. Panthothenic acid is also produced by
bacteria in the colon [54].
Metabolism Once ingested and broken down, CoA is hydrolyzed in the small intestine to form
pantothenic acid (figure 2). It is then absorbed in the jejunum and secreted into the bloodstream via a
sodium-dependent transport system [55]. 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 [56]. Excess pantothenic acid is hydrolyzed and excreted
as cysteamine and pantothenate via the kidney [57].
Actions CoA has a crucial role in the synthesis of many molecules, including vitamins A, D, cholesterol,
steroids, heme A, fatty acids, 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 and then succinyl-CoA. Other biotindependent processes, such as beta-oxidation of fatty acids and the oxidative degradation of amino acids
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(which usually occur after mRNA translation) are important steps for stabilization and activation of many
proteins in vivo. Many peptide hormones, such as ACTH, undergo such acetylation in order to become
biologically active [58].
Deficiency Many animal models have been used to study the deficiency of panthenoic acid [52]. In rats,
growth failure, hemorrhage, and necrosis of adrenal cortex, dermatitis, and achromotrichia (gray hair) have
been described [59]. In primates, there is some evidence for impaired synthesis of heme, leading to anemia
[52]. Pantothenic acid deficiency is rare in humans. It has been noted in severely malnourished individuals,
usually in situations of famine and war. 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. Because pantothenate is
essential to most living organisms, microbiologic assays have been used to quantify concentrations in blood
and urine [60].
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 is not adequate data to specify the
percentage of individuals whose requirement is met by this intake. The AI is 5 mg daily for adult men and
women, 6 mg daily for pregnant women, and 7 mg daily during lactation (table 2) [23].
VITAMIN B6 (PYRIDOXINE) Paul Gyorgy separated a factor from the antipellagra factor in the 1930s that
he named vitamin B6, or pyridoxine. The related compounds, pyridoxal and pyridoxamine, were later shown
to have similar activity. Forms include pyridoxine, pyridoxal, and pyridoxamine, as well as 5' phosphates
(figure 1). These forms are catabolized into 4-pyridoxic acid, which is excreted in the urine and can be used
as a marker of pyridoxine sufficiency, as outlined below.
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.
Actions Pyridoxal phosphate is used for Schiff base formation during the transamination of amino acids.
Pyridoxal phosphate is also involved in decarboxylation of amino acids, gluconeogenesis, conversion of
tryptophan to niacin, sphingolipid biosynthesis, neurotransmitter synthesis, immune function [61], and steroid
hormone modulation.
Deficiency and treatment Overt deficiencies of vitamin B6 are probably rare. Marginal deficiencies may
be more common, manifested as nonspecific stomatitis, glossitis, cheilosis, irritability, confusion, and
depression. A number of genetic syndromes affecting PLP-dependent enzymes such as homocystinuria,
cystathioninuria, and xanthurenic aciduria mimic vitamin B6 deficiency.
Depressed concentrations of PLP have been reported in asthma, diabetes, alcoholism, heart disease,
pregnancy, breast cancer, Hodgkin lymphoma, and sickle-cell anemia [62]. Cystathionine synthase is a
PLP-dependent enzyme which produces cystathionine from serine and homocysteine. As a result, vitamin
B6 deficiency can lead to elevations in plasma homocysteine concentrations, a risk factor for the
development of atherosclerosis and venous thromboembolism [63]. (See "Overview of homocysteine".)
The following methods can be used to assess for vitamin B6 deficiency:
The mean plasma pyridoxal-5-phophate (PLP) concentration can be measured (this is often reported
as pyridoxine or vitamin B6). The normal ranges are from 27 to 75 nmol/L (6.7 to 18.5 ng/mL) for
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males and 26 to 93 nmol/L (6.4 to 23 ng/mL) for females.

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
[64].
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) [65].
Urinary excretion of xanthurenic acid is normally less than 65 mmol/day following a 2 g tryptophan
load.
Pyridoxine has been used to treat patients with Down's syndrome, autism, gestational diabetes, carpal
tunnel syndrome, premenstrual syndrome, depression, and diabetic neuropathy, with variable results [62].
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 [66-68].
Requirements The RDA of pyridoxine is 1.3 mg daily for younger men and women, and rises to 1.7 mg
daily for men older than 50 years, and 1.5 mg daily for women older than 50 years. The RDA is 1.9 mg daily
during pregnancy, and 2.0 mg daily during lactation (table 2) [69].
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. 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.
The characterization of biotin as a vitamin was based on its role (deficiency) in carboxylase deficiency
syndromes. Biotin functions as a cofactor to the carboxylase enzyme [70].
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 [71].
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 [71]. D-biotin is the
only biologically active isomer. Biocytin, bound with lysine, is also active. Many analogs of biotin are actually
antagonists.
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 [72].
Actions Biotin is an essential component of several enzyme complexes in mammals, all of which are
involved in carbohydrate and lipid metabolism. They include [73]:
Acetyl-CoA carboxylase (ACC)
Pyruvate carboxylase (PC)
Propionyl CoA carboxylase (PCC)
Beta-methylcrotonyl CoA carboxylase (MCC)
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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 and DNA synthesis and cell replication.
Deficiency Biotin deficiency was first noted in patients who were on long-term parenteral nutrition prior to
routine biotin supplementation [73]. It is now reported only rarely. Decreased function of the biotin-dependent
carboxylases can have a number of metabolic consequences. The enzyme pyruvate carboxylase, for
example, is involved in converting pyruvate to oxaloacetate in a number of tissues in which gluconeogenesis
occurs. Oxalate is later converted to glucose. In the setting of biotin deficiency, pyruvate levels rise and are
converted to lactic acid. Another example is the synthesis of succinyl-CoA from several amino acids (ie,
valine, isoleucine, and methionine), which requires the enzymatic action of propionyl CoA carboxylase.
Biotin deficiency leads to build up of propionyl-CoA, which gets metabolized into odd-chain fatty acids.
The clinical manifestations of biotin deficiency may not be solely due to decreased intake of biotin.
Consumption of large amounts of raw egg whites (which contain avidin, a substance that binds to biotin and
prevents its utilization), 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 recycling of biotin (see 'Multiple
carboxylase deficiency' below) [74].
Symptoms of biotin deficiency are nonspecific and may include changes in mental status, myalgia,
dysesthesias, anorexia, and nausea. Chronic deficiency can lead to a maculosquamous dermatitis of the
extremities [71]. Because of its role in lipid metabolism, biotin deficiency can lead to defects in metabolism of
long-chain fatty acids. The resulting deficiency of essential fatty acids is often manifested by dermatologic
changes such as seborrheic dermatitis and alopecia.
Normal serum biotin concentrations are around 1500 pmol/L. Normal urine biotin excretion is around 160
nmol/day, using biotin bioassays measuring growth of Lactobacillus or other microorganisms, or radioligand
assays with labeled avidin.
Multiple carboxylase deficiency Multiple carboxylase deficiency (MCD) refers to one of two inherited
defects of biotin metabolism. The infantile form is caused by a deficiency of holocarboxylase synthetase
(HCS) and presents in the first week of life with lethargy, poor muscle tone, and vomiting [75]. 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 [76]; 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'.)
MCD is diagnosed definitively by studying enzymes from lymphocytes. Screening 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 [60,76].
Toxicity No toxicity of excess biotin intake has been described.
Requirements There are still no accurate data estimating dietary requirements for biotin. Adequate
intakes are approximately 30 mcg daily for adults according to a report from the Food and Nutrition Board of
1998 (table 2) [69].
VITAMIN C (ASCORBIC ACID) Vitamin C (ascorbic acid) 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
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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 [77]. James Lind, a British naval surgeon, published his experiences and studies on scurvy
aboard ships in a book titled Treatise of the Scurvy [77]. 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 [78,79].
Sources Important food sources of vitamin C are citrus fruits, tomatoes, potatoes, brussel sprouts,
cauliflower, broccoli, strawberries, cabbage, and spinach [80].
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.
Metabolism Ascorbic acid is absorbed in the distal small intestine through an energy dependent process.
Usual dietary doses of up to 100 mg/day are almost completely absorbed [81]. As dietary concentrations
increase, a smaller fraction is absorbed; pharmacologic dosing (>1000 mg/day) can result in absorption
rates of <50 percent [82].
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 [83]. Dehydroascorbic acid, the
oxidative product of ascorbic acid metabolism, passively penetrates cellular membranes and is the preferred
form for erythrocytes and leukocytes [84]. The greatest concentrations of ascorbic acid are found in the
pituitary, adrenal, brain, leukocytes, and the eye [85].
Actions Ascorbic acid is a reversible biologic reductant, and provides reducing equivalents for a number
of biochemical reactions involving iron and copper [83]. Because of this property, it functions as a cofactor,
enzyme complement, co-substrate, or a strong antioxidant in a variety of reactions and metabolic processes.
Ascorbic acid provides electrons needed to reduce molecular oxygen. These anti-oxidant 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 [83].
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 enzymatic cofactor [86].
Collagen synthesis Formation of collagen requires enzymatic hydroxylation of two amino acids:
proline and lysine. Ascorbic acid works as a cofactor for the enzyme propyl hydroxylase, which catalyzes
formation of hydroxyproline and hydroxylysine [87]. Failure of this step in collagen synthesis results in
impaired wound healing, defective tooth formation, and deficient osteoblast and fibroblast function.
Neurotransmitters Synthesis of norepinephrine involves a hydroxylation of dopamine by the enzyme
dopamine-beta-mono-oxygenase, where ascorbic acid is a required cofactor [88].
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 [89]. A more recent area
of interest has been the relationship between ascorbic acid and nitric oxide, a potent vasodilator [90].
Deficiency In all primates, ascorbic acid is an essential nutrient derived from the diet. Scurvy is a clinical
syndrome seen with ascorbic acid deficiency largely due to impaired collagen synthesis with disordered
connective tissue. Symptoms (occurring as early as three months after deficient intake) include ecchymoses,
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bleeding gums (picture 3), petechiae, coiled hairs, hyperkeratosis (picture 4), Sjogren's syndrome,
arthralgias, and impaired wound healing. Generalized systemic symptoms are weakness, malaise, joint
swelling, arthralgias, edema, depression, neuropathy, and vasomotor instability [83].
In the United States, ascorbic acid deficiency occurs mostly in severely malnourished individuals, drug and
alcohol abusers, or those living in poverty or on diets devoid of fruits and vegetables [91,92]. In children,
breast milk provides an adequate source of ascorbic acid for newborns and infants. In the elderly,
institutionalized, or chronically ill patients, scurvy can be seen due to their poor dietary intake [93].
Symptoms of scurvy generally occur when the plasma concentration of ascorbic acid is less than 0.2 mg/dL
(11 micromol/L) [80]. 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 for one week, then once daily for several weeks until
the patient is fully recovered [94]. Adults are usually treated with 300 to 1000 mg daily for one month [95,96].
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, current evidence does not
support the use of vitamin C supplementation for disease prevention. Vitamin C may have a minor role in
preventing the common cold. (See "Vitamin supplementation in disease prevention", section on 'Cataracts
and macular degeneration'.)
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 [97] and have been associated
with diarrhea and abdominal bloating. There has been some controversy in the literature regarding high
intake and increased oxalate production. Some reports conclude that excessive use of vitamin C is a risk
factor for calcium oxalate nephrolithiasis [98]. However, a prospective epidemiologic study demonstrated
that consumption of high doses of vitamin C (1500 mg/day) lowered the relative risk of calcium oxalate
stones compared to 250 mg or less of vitamin C per day [99]. Thus, the relationship of high-dose vitamin C
ingestion and calcium oxalate stones is tentative [100,101]. Patients with a predisposition to form oxalate
stones or those on hemodialysis should avoid excessive use of 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 [102]. Thus, it may be reasonable to advise
patients to avoid ascorbic acid supplements, but there is no reason to discourage the consumption of fresh
fruits or vegetables containing vitamin C. (See "Management of patients with hereditary hemochromatosis".)
Requirements The RDA for ascorbic acid is 75 mg per day for most women and 90 mg per day for men;
pregnant or lactating women and the elderly have requirements up to 120 mg/day (table 2) [80]. This is
based upon the minimum requirement to prevent scurvy [83]. Requirements for smokers are increased by as
much as 40 percent [103].
OTHER VITAMINS AND PSEUDOVITAMINS Lecithin, choline (precursors for acetylcholine), 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
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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") [104].
VITAMIN B12 AND FOLIC ACID These water-soluble vitamins are discussed in detail in separate topic
reviews. (See "Etiology and clinical manifestations of vitamin B12 and folate deficiency" and "Diagnosis and
treatment of vitamin B12 and folate deficiency".)
SUMMARY
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 to prevent disorders of
metabolism. They are divided into water-soluble and fat-soluble vitamins (table 1). This topic review
discusses the water-soluble vitamins B1 (thiamine), B2 (riboflavin), B3 (niacin), B5 (pantothenic acid),
B6 (pyridoxine), biotin, and vitamin C. (See 'Introduction' above.)
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) is found in larger quantities in food products such as yeast, legumes, pork, rice,
and cereals. Thiamine deficiency causes each of the following disorders:
Beriberi, characterized by peripheral neuropathy, with or without edema and congestive heart
failure. (See 'Adult beriberi' above.)
Wernickes encephalopathy, characterized by nystagmus, ophthalmoplegia, and ataxia, along with
confusion, and Wernicke-Korsakoff syndrome, a chronic neurologic condition. (See 'WernickeKorsakoff syndrome' above.)
Infantile beriberi, due to dietary deficiency, or Leigh syndrome due to a sporadic mitochondrial
disorder. (See 'Infantile beriberi' above and 'Leigh syndrome' above.)
Riboflavin (vitamin B2) is supplied in meats, fish, eggs and 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 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) 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
industrialized countries, pellagra tends to occur in alcoholics and has been reported as a
complication of bariatric surgery or anorexia nervosa. (See 'Deficiency' above.)
In high doses (1 to 3 grams a day) niacin is a well-established antihyperlipidemic agent,
decreasing total and LDL cholesterol. Side effects at these doses include flushing, nausea,
vomiting, pruritus, hives, constipation, and elevation in serum aminotransferases. (See "Lipid
lowering with drugs other than statins and fibrates", section on 'Nicotinic acid (Niacin)' and
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'Toxicity' above.)
Pantothenic acid (vitamin B5) 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."
Pyridoxine (vitamin B6) 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, 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 was first noted in patients who were on long-term parenteral nutrition prior to routine
biotin supplementation. Symptoms of biotin deficiency are nonspecific and may include changes in
mental status, myalgia, dysesthesias, anorexia, and nausea. Chronic deficiency can lead to
maculosquamous dermatitis of the extremities. (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'.)
Vitamin C (ascorbic acid) is essential for a variety of processes including collagen synthesis. Vitamin C
deficiency, known as scurvy, is characterized by ecchymoses, bleeding gums (picture 3), petechiae,
coiled hairs, hyperkeratosis (picture 4), Sjogren's syndrome, arthralgias, and impaired wound healing,
as well as constitutional symptoms. However, current evidence does not support the use of vitamin C
supplementation for disease prevention. (See 'Vitamin C (ascorbic acid)' above.)
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76. Baumgartner ER, Suormala T. Multiple carboxylase deficiency: inherited and acquired disorders of
biotin metabolism. Int J Vitam Nutr Res 1997; 67:377.
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1931; 90:385.
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87. Ronchetti IP, Quaglino D Jr, Bergamini G. Ascorbic acid and connective tissue. In: Subcellular
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88. Katsuki H. Vitamin C and nervous tissue. In: Subcellular biochemistry Ascobic acid: biochemistry and
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95. Hirschmann JV, Raugi GJ. Adult scurvy. J Am Acad Dermatol 1999; 41:895.
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Pediatrics 2001; 108:E55.
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progression possibly accelerated by excessive ingestion of ascorbic acid. Aust N Z J Med 1982;
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York 1991.
Topic 5367 Version 15.0
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GRAPHICS
Clinical symptoms of selected vitamin deficiencies
Function
Deficiency syndrome
Water-soluble vitamins
Vitamin B1
(thiamine)
Thiamine
pyrophosphate
Beriberi - congestive heart failure (wet beriberi),

aphonia, peripheral neuropathy, Wernicke
encephalopathy (nystagmus, opthalmoplegia,
ataxia), confusion, or coma
Vitamin B2
(riboflavin)
Flavine adenine
dinucleotide
Nonspecific symptoms including edema of mucus

membranes, angular stomatitis, glossitis, and
seborrheic dermatitis (eg, nose, scrotum)
Niacin
(nicotinic acid)
Nicotinamide
adenine
dinucleotide
Pellagra - dermatitis on areas exposed to sunlight;

diarrhea with vomiting, dysphagia, mouth
inflammation (glossitis, angular stomatitis, cheilitis);
headache, dementia, peripheral neuropathy, loss of
memory, psychosis, delirium, catatonia
Vitamin B6
(pyroxidine,
pyridoxal)
Transaminase
cofactor
Anemia, weakness, insomnia, difficulty walking,

nasolabial seborrheic dermatitis, cheilosis, stomatitis
Vitamin B12
(cobalamin)
One carbon
transfer
Megaloblastic anemia (pernicious anemia). Peripheral

neuropathy, with impaired proprioception, and
slowed mentation.
Folate
One carbon
transfer
Megaloblastic anemia
Biotin
Pyruvate
carboxylase
cofactor
Nonspecific symptoms including altered mental

status, myalgia, dysesthesias, anorexia,
maculosquamous dermatitis
Pantothenate
Coenzyme A
Nonspecific symptoms including paresthesias,

dysesthesias ("burning feet"), anemia,
gastrointestinal symptoms
Vitamin C
(ascorbate)
Antioxidant,
collagen
synthesis
Scurvy - fatigue, petechiae, ecchymoses, bleeding

gums, depression, dry skin, impaired wound healing
Fat-soluble vitamins
Vitamin A
(retinol,
retinal, retinoic
acid)
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Vision, epithelial
differentiation
Night blindness, xerophthalmia, keratomalacia,

Bitot's spot, follicular hyperkeratosis
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Vitamin D
(cholecalciferol,
ergocalciferol)
Prohormone for
calcium
regulation
Rickets, osteomalacia, craniotabes, rachitic rosary
Vitamin E
(tocopherols)
Antioxidant
Sensory and motor neuropathy, ataxia, retinal

degeneration, hemolytic anemia
Vitamin K
(phylloquinone,
menaquinone,
menadione)
Clotting factors,
bone proteins
Hemorrhagic disease
Graphic 63827 Version 7.0
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Chemical structure of vitamins B1, B2, B6 and B12
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Dietary Reference Index (DRIs) of water soluble vitamins
Life
stage
group
Thiamin
(mg/d)
Riboflavin
(mg/d)
RDA*/
AI
UL
RDA/
AI
0 to
6 mo
0.2
ND
0.3
7 to
12
mo
0.3
ND
1 to
3y
0.5
4 to
8y
Niacin*
(mg/d)
Pantothenic
acid
(mg/d)
RDA/
AI
UL
ND
ND
1.7
0.4
ND
ND
ND
0.5
ND
0.6
ND
0.6
ND
9 to
13 y
0.9
ND
0.9
14 to
18 y
1.2
ND
19 to
30 y
1.2
31 to
50 y
(mg/d)
Biotin
(mcg/d)
RDA/
AI
UL
RDA/
AI
UL
ND
0.1
ND
ND
1.8
ND
0.3
ND
ND
10
ND
0.5
30
ND
15
ND
0.6
40
12
ND
ND
12
20
ND
1.0
60
20
ND
1.3
ND
16
30
ND
1.3
80
25
ND
ND
1.3
ND
16
35
ND
1.3
100
30
ND
1.2
ND
1.3
ND
16
35
ND
1.3
100
30
ND
51 to
70 y
1.2
ND
1.3
ND
16
35
ND
1.7
100
30
ND
>70
y
1.2
ND
1.3
ND
16
35
ND
1.7
100
30
ND
9 to
13 y
0.9
ND
0.9
ND
12
20
ND
1.0
60
20
ND
14 to
18 y
1.0
ND
1.0
ND
14
30
ND
1.2
80
25
ND
19 to
1.1
ND
1.1
ND
14
35
ND
1.3
100
30
ND
UL
RDA/
AI
Vitamin
B6
UL
Infants
Children
Males
Females
30 y
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31 to
50 y
1.1
ND
1.1
ND
14
35
ND
1.3
100
30
ND
51 to
70 y
1.1
ND
1.1
ND
14
35
ND
1.5
100
30
ND
>70
y
1.1
ND
1.1
ND
14
35
ND
1.5
100
30
ND
Pregnancy
14 to
18 y
1.4
ND
1.4
ND
18
30
ND
1.9
80
30
ND
19 to
30 y
1.4
ND
1.4
ND
18
35
ND
1.9
100
30
ND
31 to
50 y
1.4
ND
1.4
ND
18
35
ND
1.9
100
30
ND
14 to
18 y
1.4
ND
1.6
ND
17
30
ND
2.0
80
35
ND
19 to
30 y
1.4
ND
1.6
ND
17
35
ND
2.0
100
35
ND
31 to
50 y
1.4
ND
1.6
ND
17
35
ND
2.0
100
35
ND
Lactation
RDA: recommended dietary allowance; AI: adequate intake; UL: upper tolerable level; d: day; mo:
months; y: years.
* The RDA is the level of dietary intake that is sufficient to meet the daily nutrient requirements of
97 percent of the individuals in a specific life stage group.
The AI represents an approximation of the average nutrient intake that sustains a defined
nutritional state, based on observed or experimentally determined values in a defined population.
The UL is 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.
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 with
permission from the National Academies Press, Copyright 2006, National Academy of Sciences.
Sources: Dietary reference intakes for Thiamin, Riboflavin, Niacin, Vitamin B 6 , Folate, Vitamin B 12 ,
Panthothenic acid, Biotin, and Choline (1998); Dietary reference Intakes for Vitamin C, Vitamin E,
Selenium, and Carotenoids (2000). These reports may be accessed via www.nap.edu.
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Atrophic glossitis
A smooth tongue that has lost its papillae and is often sore suggest 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.
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Physical signs of selected nutritional deficiency states

Signs
Hair
Skin
Eyes
Mouth
Extremities
Deficiencies
Alopecia
Protein-energy malnutrition
Brittle
Biotin, Protein-energy malnutrition
Color change
Dryness
Vitamins E and A
Easy pluckability
Acneiform lesions
Vitamin A
Follicular keratosis
Vitamin A
Xerosis (dry skin)
Vitamin A
Ecchymosis
Vitamin C or K
Intradermal petechia
Vitamin C or K
Erythema (especially where exposed to

sunlight)
Niacin
Hyperpigmentation
Niacin
Seborrheic dermatitis (nose, eyebrows,

eyes)
Vitamin B2, Vitamin B6, Niacin
Scrotal dermatitis
Niacin, Vitamin B2, Vitamin B6
Angular palpebritis
Vitamin B2
Corneal revascularization
Vitamin B2
Bitot's spots
Vitamin A
Conjunctival xerosis, keratomalacia
Vitamin A
Angular stomatitis
Vitamin B12, Vitamin B2, Vitamin B6
Atrophic papillae
Niacin
Bleeding gums
Vitamin C
Cheilosis
Vitamin B2, Vitamin B6
Glossitis
Niacin, folate, vitamin B12, Vitamin

B2, Vitamin B6
Magenta tongue
Vitamin B2
Genu valgum or varum, metaphyseal

widening
Vitamin D
Loss of deep tendon reflexes of the

lower extremities
Vitamins B1 and B12
Vitamin B1: thiamine; Vitamin B2: riboflavin; Vitamin B3: niacin; Vitamin B6: pyridoxine; Vitamin
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B12: cyanocobalamin.
Adapted from: Bernard MA, Jacobs DO, Rombeau JL. Nutrition and Metabolic Support of
Hospitalized Patients. WB Saunders, Philadelphia 1986.
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Chemical structure of folate, vitamin C, pantothenate,

biotin and niacin
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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: www.visualdx.com. Copyright Logical
Images, Inc.
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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 neutrophilmediated 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.
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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.
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Disclosures
Disclosures: Sassan Pazirandeh, MD Nothing to disclose. Clifford W Lo, MD, MPH, ScD Nothing to disclose. David L Burns, MD
Nothing to disclose. Timothy O Lipman, MD Other Financial Interest: GI Board Review Lecturer [Clinical nutrition]; Audio Journal
Club Practice Reviews in Gastroenterology [Clinical nutrition, gut microbiome, complementary and alternative medicine, critical
reading skills]. Alison G Hoppin, MD Employee of UpToDate, Inc.
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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