Overview of Water-soluble Vitamins

Official reprint from UpToDatewww.uptodate.com 2015 UpToDate

AuthorsSassan Pazirandeh, MDClifford W Lo, MD, MPH, ScDDavid L Burns, MD

Section EditorTimothy O Lipman, MD

Deputy EditorAlison G Hoppin, MD

Overview of water-soluble vitamins

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 thatcannot be synthesized by humans but need to be ingested in the diet in small quantities to prevent disordersof 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 andcontroversy continues into whether vitamin supplementation can prevent cancer, heart disease, upperrespiratory 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 containmany related substances such as flavins and carotenoids which are generally not recognized as vitamins butmay have protective effects against various diseases. This topic review will focus on the water-solublevitamins excluding folic acid and vitamin B12, which are discussed separately. (See "Etiology and clinicalmanifestations of vitamin B12 and folate deficiency".)

Minerals and fat-soluble vitamins are also reviewed elsewhere. (See "Overview of vitamin A" and "Overviewof vitamin D" and "Overview of vitamin E" and "Overview of vitamin K" and "Overview of dietary traceminerals".)

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 ofMedicine to guide nutrient intake in a variety of settings. Under this system, requirements can be expressedas a Recommended Dietary Allowance (RDA), which is defined as the dietary intake that is sufficient to meetthe daily nutrient requirements of 97 percent of the individuals in a specific life stage group. If there isinsufficient data to determine an RDA for a given nutrient, requirements can be expressed as an AdequateIntake (AI), which is an estimation of the nutrient intake necessary to maintain a healthy state. These termsare described in greater detail in a separate topic review. (See "Dietary history and recommended dietaryintake in children".)

VITAMIN B1 (THIAMINE) Thiamine, first named "the antiberiberi factor" in 1926, has a historical valuedue 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 consistsof 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, andcereals. Milk products, fruits, and vegetables are poor sources of thiamine [1]. The thiamine molecule isdenatured at high pH and high temperatures. Hence, cooking, baking, and canning of some foods as well aspasteurization 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 mucosalcells to enter the blood stream via a sodium and ATP dependent pump. Bound to albumin, it is carried by theportal circulation to the liver. Thiamine enters the red blood cells by passive diffusion while its entry into othercells is via an active energy requiring process [3]. The highest concentrations are found in the skeletalmuscles, the liver, the heart, the kidneys, and the brain. Thiamine's biologic half-life is approximately 10 to20 days; due to limited tissue storage, continuous supplementation is required [3]. Through a series ofmetabolic processes, thiamine is incorporated into many phosphorylated esters, including thiaminepyrophosphate (TPP) and thiamine monophosphate (TMP). Thiamine and all of its metabolites are excretedin 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 carbohydratemetabolism. Functioning along with many coenzymes such as flavin and NAD, thiamine serves as a catalystin the conversion of pyruvate to acetyl CoA, an oxidative decarboxylation reaction mediated by pyruvatedehydrogenase:

Pyruvate + CoA + NAD Acetyl CoA + CO2 + NADH + H

Thiamine is also involved in many other cellular metabolic activities such as the transketolation of thepentose phosphate pathway [3]. Thiamine has a role in the initiation of nerve impulse propagation that isindependent 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 5mg thiamine load) [5]. Most laboratories now measure blood thiamine concentration directly, in preference tothe ETKA method [6]. The ETKA method is a functional test and results are influenced by the hemoglobinconcentration.

Thiamine deficiency has been associated with three disorders:

Infantile beriberi Beriberi in infants becomes clinically apparent between the ages of two and threemonths. 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 alsobeen described in which the affected infants exhibit vomiting, nystagmus, purposeless movements, andseizure, 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-basedformula that was inadvertently deficient in thiamine [9]. Most of the infants with severe symptoms at the timeof diagnosis, which included cardiomyopathy and seizures, had severe permanent disabilities even afterthiamine was replaced. Among infants with apnea or seizures at presentation, all had moderate or severeintellectual disability when reevaluated five and ten years later, and most had chronic epilepsy [10,11]. A fewof the severely affected infants died. Many other infants were asymptomatic or had nonspecific symptomswhile being fed the thiamine-deficient diet (eg, vomiting, irritability or failure to thrive). However, follow-uptesting 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

Beriberi (infantile and adult)Wernicke-Korsakoff syndromeLeigh's syndrome


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symmetrical peripheral neuropathy characterized by both sensory and motor impairments, mostly of thedistal extremities. Wet beriberi includes a neuropathy, as well as signs of cardiac involvement withcardiomegaly, 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 aburning sensation in the extremities, weakness, and falls [13-15]. Several of the case reports have been inadolescents, but whether this nutritional complication is more common in the adolescent age group ascompared to adults undergoing weight loss surgery has not been established. (See "Surgical managementof severe obesity in adolescents".)

Thiamine deficiency can occur as a complication of total parenteral nutrition if adequate thiaminesupplements are not provided. As an example, during the late 1990s, there were multiple reports ofsymptomatic thiamine deficiency among recipients of parenteral nutrition during a widespread shortage ofparenteral multivitamins in the United States [16].

A number of studies have suggested that patients with heart failure, especially those treated with loopdiuretics, 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 controlledtrials [20]. (See "Causes of dilated cardiomyopathy".)

Wernicke-Korsakoff syndrome Wernicke-Korsakoff syndrome is the best known neurologiccomplication of thiamine (vitamin B1) deficiency. The term refers to two different syndromes, eachrepresenting a different stage of the disease. Wernicke's encephalopathy (WE) is an acute syndromerequiring emergent treatment to prevent death and neurologic morbidity. Korsakoff's syndrome (KS) refers toa chronic neurologic condition that usually occurs as a consequence of WE. It is characterized by impairedshort-term memory and confabulation with otherwise grossly normal cognition. (See "Overview of the chronicneurologic complications of alcohol", section on 'Korsakoff syndrome'.)

WE is a triad of nystagmus, ophthalmoplegia, and ataxia, along with confusion. This combination is almostexclusively described in chronic alcoholics with thiamine deficiency. The two entities are not separatediseases, but a spectrum of signs and symptoms. There may be a genetic predisposition for thedevelopment of WE since not all thiamine deficient patients are affected. Impairment in the synthesis of oneof the important enzymes of the pentose phosphate pathway (erythrocyte transketolase) may explain such apredisposition [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 givingdextrose to alcoholic patients until thiamine supplementation has been initiated to avoid precipitatingWernicke's encephalopathy. (See "Wernicke encephalopathy", section on 'Treatment'.)

Leigh syndrome Thiamine deficiency has occasionally been reported in infants presenting withfeatures of Leigh syndrome, a progressive subacute necrotizing encephalomyopathy. This is a sporadicmitochondrial disorder with a subacute neurologic course. It is manifested with ataxia, dysarthria, movementdisorders, areflexia, muscle atrophy, and weakness. (See "Hereditary neuropathies associated withgeneralized disorders", section on 'Leigh syndrome'.)

Toxicity No real syndrome of excess thiamine exists since the kidneys can rapidly clear almost all excessthiamine [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 dailyfor 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 withberiberi, the daily doses range from 50 to 100 mg for 7 to 14 days. Then an oral dose of 10 mg per day isgiven until full recovery is achieved [1].

VITAMIN B2 (RIBOFLAVIN) Vitamin B2, or riboflavin, is a member of naturally occurring compoundsknown as flavins. Flavins have a critical role in numerous biochemical reactions. First identified in the early1900s, 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). Inthe free form, it is a base, but in nature and in vivo, it is mostly found as a component of flavin-adeninedinucleotide (FAD). The 5'-hydroxymethyl terminus of the vitamin is phosphorylated to form a phosphateester, allowing it to be incorporated into a different coenzyme [25].

Metabolism Dietary flavins are bound to albumin and other riboflavin-specific carrier proteins and arereleased from their protein-bound state via gastric acid and proteolytic enzymes [26]. In the proximal smallintestine, riboflavin is absorbed passively along its concentration gradient across the intestinal mucosa. Thisinvolves a saturable transport system that is passive and not sodium dependent [27]. There also appears tobe some enterohepatic circulation for riboflavin facilitated by bile salts [26]. Riboflavin eventually reaches thehepatocytes 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 furtherphosphorylated into FAD, or become incorporated as part of a certain coenzyme-flavin complex. Both of thephosphorylation reactions are ATP dependent. As the more common form of flavin in humans, FAD is oftencomplexed with other proteins to form flavoproteins with oxidizing and hydrogenating abilities [26]. Most ofthe riboflavin stores in the body are in the forms of flavoproteins. Urinary levels of the vitamin only indirectlyreflect dietary intake or riboflavin catabolism [28].

Actions Riboflavin is an essential component of coenzymes involved in multiple cellular metabolicpathways, including the energy producing respiratory pathways. Flavoproteins are catalysts in a number ofmitochondrial oxidative and reductive reactions and function as electron transporters [25].

Deficiency Riboflavin deficiency is more common than generally appreciated. Many cases areundetected due to the mild nature and nonspecific signs and symptoms of deficiency. Plasma riboflavinconcentrations tend to reflect recent dietary intake. Urinary riboflavin excretion and the erythrocyteglutathione reductase assay are better functional indices of riboflavin deficiency.

Significant deficiency syndromes are characterized by sore throat, hyperemia of pharyngeal mucousmembranes, edema of mucous membranes, cheilitis, stomatitis, glossitis (picture 1), normocytic-normochromic anemia, and seborrheic dermatitis [28]. Whether all these changes are due to riboflavindeficiency is not always clear since riboflavin deficiency is often accompanied by other water-soluble vitamindeficiencies, which can cause similar symptoms (table 3) [29]. Pure deficiency of riboflavin is rare, althoughit 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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Toxicity Excessive amounts of riboflavin are usually not absorbed due to the limited water-solubility andthe 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 duringlactation (table 2) [23,32].

Some intramitochondrial beta-oxidation defects may respond to riboflavin therapy. (See "Metabolicmyopathies caused by disorders of lipid and purine metabolism".) In addition, patients with HIV infection whoare 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 18thcentury. It is characterized by a photosensitive pigmented dermatitis (typically located in sun-exposedareas), diarrhea, and dementia. During the early 1900s, pellagra was epidemic amongst the corn eatingpopulation of southeastern United States. Pellagra is now extremely uncommon in the western world exceptas a complication of alcoholism, anorexia nervosa, or malabsorptive disease. Pellagra due to dietarydeficiency 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 infectiousdisease [34]. However, in 1937, Elvehjen and his colleagues discovered that nicotinic acid was effective inthe treatment of pellagra in dogs. In the 1950s, tryptophan, a precursor of niacin, replaced it in the treatmentof pellagra and research connected the low source of niacin and tryptophan in corn-containing foods to thedevelopment of pellagra [35]. Niacin had been isolated since 1867, but it was not until 1937 that it becameknown 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 statuson 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 referredto 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 NADPare the active forms of niacin.

Metabolism As the chief dietary forms of niacin, NAD and NADP are first hydrolyzed in the intestinallumen by enzymes leading to nicotinamide. Nicotinamide is converted by intestinal flora to nicotinic acid. Thetwo 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. Intracellularnicotinamide and nicotinic acid are quickly converted to coenzyme forms NAD and NADP, which are storedin tissues with high metabolic activities (ie, muscle and liver).

Individuals who avoid dairy products (such as people with lactose intolerance) since dairy products area 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 andimpair its function [31]


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Actions Many enzymatic reactions depend upon NAD and NADP. The role of the niacin moiety is toaccept electrons or to donate hydrogen ions. The majority of these NAD-dependent enzymes are involved inreactions such as oxidation of fatty acids and other reactions that yield chemical structures containing highenergy bonds [37]. NADP is a cofactor in the reductive synthesis of the fatty acids and steroids. As essentialcomponents of redox reactions and hydrogen transport, NAD and NADP are crucial in the synthesis andmetabolism 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 commonmanifestation of niacin deficiency in poorer countries where the local diet consists of cereal, corn, orsorghum. In industrialized countries, pellagra tends to occur in alcoholics, and has been reported as acomplication of bariatric surgery or anorexia nervosa [38,39].

The most characteristic finding is the presence of a symmetric hyperpigmented rash, similar in color to asunburn, which is present in the exposed areas of skin (picture 2) [37]. Other clinical findings are a redtongue and many non-specific symptoms, such as diarrhea and vomiting. Neurologic symptoms includeinsomnia, anxiety, disorientation, delusions, dementia, and encephalopathy.

Niacin deficiency can also be seen in three other settings:

Toxicity The most documented and best known side effect of niacin is the flushing reaction associatedwith the crystalline nicotinic acid and not nicotinamide [43]. Symptoms are dose-dependent yet variable fromperson to person. The flushing can be experienced in a mild form while taking doses as small as 10 mg perday [44]. Despite the inconvenience and the undesirability of the reactions, there are no serious sequelaefrom 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-inducedmyopathy has also been described [46]. Caution should be used in patients with a history of gout, sinceniacin 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

Carcinoid syndrome, in which metabolism of tryptophan is to 5-OH tryptophan and serotonin ratherthan to nicotinic acid. This leads to the deficiency of active forms of niacin and the development ofpellagra. (See "Clinical features of the carcinoid syndrome".)

Prolonged use of isoniazid, since isoniazid depletes stores of pyridoxal phosphate, which enhances theproduction of tryptophan, a precursor of niacin. Several other drugs induce niacin deficiency byinhibiting 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 isassociated with a defect of a membrane transport in the intestinal and renal cells normally responsiblefor the absorption of tryptophan (one of the precursors of nicotinamide-adenine dinucleotide). Throughthis pathway, around 50 percent of the daily niacin needs are synthesized. Due to the resulting niacindeficiency, all the symptoms of pellagra can be expected. The diagnosis is made by detecting anumber of neutral amino acids in the urine, something that is not seen with dietary pellagra. Thetreatment is aimed towards depleting stores and supplementing the diet with niacin as well as proteinsand amino acids [42]. (See "Overview of the hereditary ataxias", section on 'Aminoacidurias'.)


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metabolism becomes saturated, and side effects of this drug can be more frequently encountered. Whenless than 1 g of nicotinic acid was ingested per day, only a handful of anecdotal cases of toxicity has beenreported in the literature [47]. One clinical trial assigned two groups of subjects to either a long or a short-acting formula of niacin, each starting at 500 mg per day [48]. Subjects were followed for several monthsduring which the dose of niacin was raised every six weeks by about 500 mg. There was no gastrointestinalor liver toxicity below 1000 mg of niacin per day. The extent of the toxicity was minimal and mostlygastrointestinal in the immediate release group, while mild liver enzyme elevation was noticed only in theslow release group [48]. There is some speculation that the metabolites of nicotinic acid in these highconcentrations 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-establishedantihyperlipidemic agent, decreasing total and LDL cholesterol [50]. The Cholesterol-LoweringAtherosclerosis Study (CLAS II and II), for example, showed that a combination of niacin and colestipolsignificantly reduced the progression of atherosclerotic related coronary artery complications (52 versus 15percent in the control group). (See "Lipid lowering with drugs other than statins and fibrates".) To reduce theflushing side effects, a sustained-release formulation is available for these purposes. However, these longeracting forms may be associated with more gastrointestinal and hepatotoxic side effects [35]. Lower startingdoses of crystalline niacin or premedication of the patients with aspirin can attenuate these adverse effectsand side effects. A more recent clinical role for nicotinic acid given in high doses has been suggested fordelaying the onset of diabetes in children [51].

Requirements The RDA for Niacin is 16 NEs (Niacin Equivalents) daily for adult males, and 14 NEs dailyfor adult females, rising to 18 NE during pregnancy, and 17 NE daily during lactation (table 2) [23]. One NEis equal to 1 mg of niacin, which is equal to 60 mg of dietary tryptophan. These doses are far below theanti-hyperlipidemic doses of niacin and are not associated with toxicity. Requirements may be increased forindividuals on dialysis, or for those with malabsorptive processes (eg, after bariatric surgery, as discussedabove).

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 bybacteria in the colon [54].

Metabolism Once ingested and broken down, CoA is hydrolyzed in the small intestine to formpantothenic acid (figure 2). It is then absorbed in the jejunum and secreted into the bloodstream via asodium-dependent transport system [55]. Most cells of the body take up pantothenic acid via the samesodium-dependent mechanism. Once inside the cell, pantothenic acid undergoes a number ofATP-dependent phosphorylations to become CoA [56]. Excess pantothenic acid is hydrolyzed and excretedas 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 firststep of the TCA cycle, by binding with oxaloacetate to form citrate and then succinyl-CoA. Other biotin-dependent 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 manyproteins in vivo. Many peptide hormones, such as ACTH, undergo such acetylation in order to becomebiologically 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) havebeen 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 forthree months developed burning, distal paresthesias, and gastrointestinal distress. Because pantothenate isessential to most living organisms, microbiologic assays have been used to quantify concentrations in bloodand 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 thepercentage of individuals whose requirement is met by this intake. The AI is 5 mg daily for adult men andwomen, 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 thathe named vitamin B6, or pyridoxine. The related compounds, pyridoxal and pyridoxamine, were later shownto 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 usedas a marker of pyridoxine sufficiency, as outlined below.

Sources Pyridoxine and pyridoxamine are predominantly found in plant foods; pyridoxal is mostcommonly 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 oftryptophan to niacin, sphingolipid biosynthesis, neurotransmitter synthesis, immune function [61], and steroidhormone modulation.

Deficiency and treatment Overt deficiencies of vitamin B6 are probably rare. Marginal deficiencies maybe more common, manifested as nonspecific stomatitis, glossitis, cheilosis, irritability, confusion, anddepression. 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 aPLP-dependent enzyme which produces cystathionine from serine and homocysteine. As a result, vitaminB6 deficiency can lead to elevations in plasma homocysteine concentrations, a risk factor for thedevelopment 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 reportedas 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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Pyridoxine has been used to treat patients with Down's syndrome, autism, gestational diabetes, carpaltunnel syndrome, premenstrual syndrome, depression, and diabetic neuropathy, with variable results [62].

Toxicity Cases of peripheral neuropathy, dermatoses, photosensitivity, dizziness, and nausea have beenreported with long-term megadoses of pyridoxine over 250 mg/day; a few cases of neuropathy appear tohave 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 mgdaily for men older than 50 years, and 1.5 mg daily for women older than 50 years. The RDA is 1.9 mg dailyduring 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 the20th century and eventually identified as myoinositol, pantothenate, and biotin. Biotin was also found in liverand variously called vitamin H, coenzyme R, factor S, factor W, vitamin Bw, and protective factor X, becauseit protected against a type of dermatosis and loss of hair in animals that was associated with the intake ofraw egg whites.

The characterization of biotin as a vitamin was based on its role (deficiency) in carboxylase deficiencysyndromes. 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). Invivo, it is found in a number of different isomers, not all of which are active enzymatically [71]. D-biotin is theonly biologically active isomer. Biocytin, bound with lysine, is also active. Many analogs of biotin are actuallyantagonists.

Metabolism Other than the ingested forms of biotin, a number of bacteria in the gut synthesize biotin as aby-product of their proteolytic actions. Biotin is mostly absorbed in the proximal small intestine, and to alesser degree in the cecum. Unabsorbed gut biotin is excreted in the feces. Excess serum biotin is excretedvia the kidney [72].

Actions Biotin is an essential component of several enzyme complexes in mammals, all of which areinvolved in carbohydrate and lipid metabolism. They include [73]:

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 ofpyridoxine 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 adequateshort-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 tryptophanload.

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 manyprocesses, including protein and DNA synthesis and cell replication.

Deficiency Biotin deficiency was first noted in patients who were on long-term parenteral nutrition prior toroutine biotin supplementation [73]. It is now reported only rarely. Decreased function of the biotin-dependentcarboxylases can have a number of metabolic consequences. The enzyme pyruvate carboxylase, forexample, is involved in converting pyruvate to oxaloacetate in a number of tissues in which gluconeogenesisoccurs. Oxalate is later converted to glucose. In the setting of biotin deficiency, pyruvate levels rise and areconverted 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 andprevents its utilization), can also lead to biotin deficiency. In addition, secondary biotin deficiency can occurdue to lack of a specific enzyme (biotinidase), which is required for recycling of biotin (see 'Multiplecarboxylase 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 theextremities [71]. Because of its role in lipid metabolism, biotin deficiency can lead to defects in metabolism oflong-chain fatty acids. The resulting deficiency of essential fatty acids is often manifested by dermatologicchanges such as seborrheic dermatitis and alopecia.

Normal serum biotin concentrations are around 1500 pmol/L. Normal urine biotin excretion is around 160nmol/day, using biotin bioassays measuring growth of Lactobacillus or other microorganisms, or radioligandassays with labeled avidin.

Multiple carboxylase deficiency Multiple carboxylase deficiency (MCD) refers to one of two inheriteddefects 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-onsetform is caused by biotinidase deficiency and is associated with a slow but progressive loss of biotin in theurine, 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 andlactate metabolism'.)

MCD is diagnosed definitively by studying enzymes from lymphocytes. Screening for these deficiencies isincluded in the newborn screen in most states (see "Newborn screening", section on 'Programs throughoutthe world'). Both infantile and late onset multiple carboxylase deficiency can be treated with pharmacologicdoses of biotin. Delayed treatment may fail to reverse the neurologic sequelae and has been associated withneurologic 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. Adequateintakes are approximately 30 mcg daily for adults according to a report from the Food and Nutrition Board of1998 (table 2) [69].

VITAMIN C (ASCORBIC ACID) Vitamin C (ascorbic acid) has a prominent role in history. The clinicalmanifestations of scurvy were well described in ancient Egyptian, Greek, and Roman literature. British andEuropean 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, theexploration of the North Pole, and the California gold rush. Captain James Cook was one of the first todemonstrate that sailors who spent months at sea could avoid scurvy by maintaining a diet rich invegetables [77]. James Lind, a British naval surgeon, published his experiences and studies on scurvyaboard ships in a book titled Treatise of the Scurvy [77]. During 1928 to 1931, Szent-Gyorgyi isolatedhexuronic acid from cabbage, oranges, paprika, and adrenal glands. Hexuronic acid was subsequentlytermed 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 glucosestructure (figure 2). A number of compounds that exhibit the biologic activities of ascorbic acid are generallyreferred 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 concentrationsincrease, a smaller fraction is absorbed; pharmacologic dosing (>1000 mg/day) can result in absorptionrates of

bleeding gums (picture 3), petechiae, coiled hairs, hyperkeratosis (picture 4), Sjogren's syndrome,arthralgias, and impaired wound healing. Generalized systemic symptoms are weakness, malaise, jointswelling, arthralgias, edema, depression, neuropathy, and vasomotor instability [83].

In the United States, ascorbic acid deficiency occurs mostly in severely malnourished individuals, drug andalcohol 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 iftissue levels are still deficient. Measurement of ascorbic acid in leukocytes is a better measure of bodystores but this test is not widely available.

The treatment for scurvy is vitamin C supplementation and reversal of the conditions that led to thedeficiency. A wide range of replacement doses have been used successfully. For children, recommendeddoses are 100 mg ascorbic acid given three times daily for one week, then once daily for several weeks untilthe 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 bleedingresolve within a few weeks.

Therapeutic and prophylactic roles Several therapeutic and prophylactic roles have been described forvitamin C, including prevention of cardiovascular disease and cancer. However, current evidence does notsupport the use of vitamin C supplementation for disease prevention. Vitamin C may have a minor role inpreventing the common cold. (See "Vitamin supplementation in disease prevention", section on 'Cataractsand macular degeneration'.)

Toxicity A number of side effects of ascorbic acid have been reported in the literature. Large doses ofvitamin C (in gram quantities) can give false negative stool guaiac results [97] and have been associatedwith diarrhea and abdominal bloating. There has been some controversy in the literature regarding highintake and increased oxalate production. Some reports conclude that excessive use of vitamin C is a riskfactor for calcium oxalate nephrolithiasis [98]. However, a prospective epidemiologic study demonstratedthat consumption of high doses of vitamin C (1500 mg/day) lowered the relative risk of calcium oxalatestones compared to 250 mg or less of vitamin C per day [99]. Thus, the relationship of high-dose vitamin Cingestion and calcium oxalate stones is tentative [100,101]. Patients with a predisposition to form oxalatestones 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 inpatients with iron overload, presumably due to oxidative injury [102]. Thus, it may be reasonable to advisepatients to avoid ascorbic acid supplements, but there is no reason to discourage the consumption of freshfruits 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 isbased upon the minimum requirement to prevent scurvy [83]. Requirements for smokers are increased by asmuch 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 carotenoidsprobably 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 substancesthat 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," diisopropylaminedichloroacetate), and gerovital ("vitamin H3") [104].

VITAMIN B12 AND FOLIC ACID These water-soluble vitamins are discussed in detail in separate topicreviews. (See "Etiology and clinical manifestations of vitamin B12 and folate deficiency" and "Diagnosis andtreatment of vitamin B12 and folate deficiency".)

SUMMARY

Vitamins are a number of chemically unrelated families of organic substances that cannot besynthesized by humans but need to be ingested in the diet in small quantities to prevent disorders ofmetabolism. They are divided into water-soluble and fat-soluble vitamins (table 1). This topic reviewdiscusses 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) andtypical 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 heartfailure. (See 'Adult beriberi' above.)

Wernickes encephalopathy, characterized by nystagmus, ophthalmoplegia, and ataxia, along withconfusion, and Wernicke-Korsakoff syndrome, a chronic neurologic condition. (See 'Wernicke-Korsakoff syndrome' above.)

Infantile beriberi, due to dietary deficiency, or Leigh syndrome due to a sporadic mitochondrialdisorder. (See 'Infantile beriberi' above and 'Leigh syndrome' above.)

Riboflavin (vitamin B2) is supplied in meats, fish, eggs and milk, green vegetables, yeast, and enrichedfoods. Mild deficiency is often undetected due to the mild nature and nonspecific signs and symptomsof deficiency. Riboflavin deficiency is characterized by sore throat, hyperemia of pharyngeal mucousmembranes, edema of mucous membranes, cheilitis, stomatitis, glossitis, normocytic-normochromicanemia, 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 pigmenteddermatitis (typically located in sun-exposed areas (picture 2)), diarrhea, and dementia. Inindustrialized countries, pellagra tends to occur in alcoholics and has been reported as acomplication 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 "Lipidlowering with drugs other than statins and fibrates", section on 'Nicotinic acid (Niacin)' and


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Monget AL, Galan P, Preziosi P, et al. Micronutrient status in elderly people. Geriatrie/Min. Vit. AuxNetwork. Int J Vitam Nutr Res 1996; 66:71.

93.

American Academy of Pediatrics. Water-soluble vitamins. In: Pediatric Nutrition, 7th ed., Kleinman RE,Greer FR. (Eds), American Academy of Pediatrics, Elk Grove Village 2011. p.527.

94.

Hirschmann JV, Raugi GJ. Adult scurvy. J Am Acad Dermatol 1999; 41:895.95.

Weinstein M, Babyn P, Zlotkin S. An orange a day keeps the doctor away: scurvy in the year 2000.Pediatrics 2001; 108:E55.

96.

Jaffe RM, Kasten B, Young DS, MacLowry JD. False-negative stool occult blood tests caused byingestion of ascorbic acid (vitamin C). Ann Intern Med 1975; 83:824.

97.

Urivetzky M, Kessaris D, Smith AD. Ascorbic acid overdosing: a risk factor for calcium oxalatenephrolithiasis. J Urol 1992; 147:1215.

98.

Block G. Vitamin C and cancer prevention: the epidemiologic evidence. Am J Clin Nutr 1991; 53:270S.99.

Hatch GE. Asthma, inhaled oxidants, and dietary antioxidants. Am J Clin Nutr 1995; 61:625S.100.

Seddon JM, Ajani UA, Sperduto RD, et al. Dietary carotenoids, vitamins A, C, and E, and advancedage-related macular degeneration. Eye Disease Case-Control Study Group. JAMA 1994; 272:1413.

101.

McLaran CJ, Bett JH, Nye JA, Halliday JW. Congestive cardiomyopathy and haemochromatosis--rapidprogression possibly accelerated by excessive ingestion of ascorbic acid. Aust N Z J Med 1982;12:187.

102.

Smith JL, Hodges RE. Serum levels of vitamin C in relation to dietary and supplemental intake ofvitamin C in smokers and nonsmokers. Ann N Y Acad Sci 1987; 498:144.

103.

Cody MM. Substances without vitamin status. In: Handbook of Vitamins, 2nd, Marcel Dekker, NewYork 1991.

104.

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)

Thiaminepyrophosphate

Beriberi - congestive heart failure (wet beriberi),aphonia, peripheral neuropathy, Wernickeencephalopathy (nystagmus, opthalmoplegia,ataxia), confusion, or coma

Vitamin B2(riboflavin)

Flavine adeninedinucleotide

Nonspecific symptoms including edema of mucusmembranes, angular stomatitis, glossitis, andseborrheic dermatitis (eg, nose, scrotum)

Niacin(nicotinic acid)

Nicotinamideadeninedinucleotide

Pellagra - dermatitis on areas exposed to sunlight;diarrhea with vomiting, dysphagia, mouthinflammation (glossitis, angular stomatitis, cheilitis);headache, dementia, peripheral neuropathy, loss ofmemory, psychosis, delirium, catatonia

Vitamin B6(pyroxidine,pyridoxal)

Transaminasecofactor

Anemia, weakness, insomnia, difficulty walking,nasolabial seborrheic dermatitis, cheilosis, stomatitis

Vitamin B12(cobalamin)

One carbontransfer

Megaloblastic anemia (pernicious anemia). Peripheralneuropathy, with impaired proprioception, andslowed mentation.

Folate One carbontransfer

Megaloblastic anemia

Biotin Pyruvatecarboxylasecofactor

Nonspecific symptoms including altered mentalstatus, myalgia, dysesthesias, anorexia,maculosquamous dermatitis

Pantothenate Coenzyme A Nonspecific symptoms including paresthesias,dysesthesias ("burning feet"), anemia,gastrointestinal symptoms

Vitamin C(ascorbate)

Antioxidant,collagensynthesis

Scurvy - fatigue, petechiae, ecchymoses, bleedinggums, depression, dry skin, impaired wound healing

Fat-soluble vitamins

Vitamin A(retinol,retinal, retinoicacid)

Vision, epithelialdifferentiation

Night blindness, xerophthalmia, keratomalacia,Bitot's spot, follicular hyperkeratosis


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Vitamin D(cholecalciferol,ergocalciferol)

Prohormone forcalciumregulation

Rickets, osteomalacia, craniotabes, rachitic rosary

Vitamin E(tocopherols)

Antioxidant Sensory and motor neuropathy, ataxia, retinaldegeneration, 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

Lifestagegroup

Thiamin(mg/d)

Riboflavin(mg/d)

Niacin*(mg/d)

Pantothenicacid

(mg/d)

VitaminB

(mg/d)

Biotin(mcg/d)

RDA*/AI

ULRDA/

AIUL

RDA/AI

ULRDA/

AIUL

RDA/AI

ULRDA/

AIUL

Infants

0 to6 mo

0.2 ND 0.3 ND 2 ND 1.7 ND 0.1 ND 5 ND

7 to12mo

0.3 ND 0.4 ND 4 ND 1.8 ND 0.3 ND 6 ND

Children

1 to3 y

0.5 ND 0.5 ND 6 10 2 ND 0.5 30 8 ND

4 to8 y

0.6 ND 0.6 ND 8 15 3 ND 0.6 40 12 ND

Males

9 to13 y

0.9 ND 0.9 ND 12 20 4 ND 1.0 60 20 ND

14 to18 y

1.2 ND 1.3 ND 16 30 5 ND 1.3 80 25 ND

19 to30 y

1.2 ND 1.3 ND 16 35 5 ND 1.3 100 30 ND

31 to50 y

1.2 ND 1.3 ND 16 35 5 ND 1.3 100 30 ND

51 to70 y

1.2 ND 1.3 ND 16 35 5 ND 1.7 100 30 ND

>70y

1.2 ND 1.3 ND 16 35 5 ND 1.7 100 30 ND

Females

9 to13 y

0.9 ND 0.9 ND 12 20 4 ND 1.0 60 20 ND

14 to18 y

1.0 ND 1.0 ND 14 30 5 ND 1.2 80 25 ND

19 to30 y

1.1 ND 1.1 ND 14 35 5 ND 1.3 100 30 ND

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31 to50 y

1.1 ND 1.1 ND 14 35 5 ND 1.3 100 30 ND

51 to70 y

1.1 ND 1.1 ND 14 35 5 ND 1.5 100 30 ND

>70y

1.1 ND 1.1 ND 14 35 5 ND 1.5 100 30 ND

Pregnancy

14 to18 y

1.4 ND 1.4 ND 18 30 6 ND 1.9 80 30 ND

19 to30 y

1.4 ND 1.4 ND 18 35 6 ND 1.9 100 30 ND

31 to50 y

1.4 ND 1.4 ND 18 35 6 ND 1.9 100 30 ND

Lactation

14 to18 y

1.4 ND 1.6 ND 17 30 7 ND 2.0 80 35 ND

19 to30 y

1.4 ND 1.6 ND 17 35 7 ND 2.0 100 35 ND

31 to50 y

1.4 ND 1.6 ND 17 35 7 ND 2.0 100 35 ND

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 of97 percent of the individuals in a specific life stage group. The AI represents an approximation of the average nutrient intake that sustains a definednutritional 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 adversehealth 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 withpermission from the National Academies Press, Copyright 2006, National Academy of Sciences.Sources: Dietary reference intakes for Thiamin, Riboflavin, Niacin, Vitamin B , Folate, Vitamin B ,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 adeficiency in riboflavin, niacin, folic acid, vitamin B12 or iron. Thispatient had vitamin B12 deficiency.

Reproduced with permission from: Berg D, Worzala K. Atlas of Adult PhysicalDiagnosis. Philadelphia: Lippincott Williams & Wilkins, 2006. Copyright 2006 Lippincott Williams & Wilkins.



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Physical signs of selected nutritional deficiency states

Signs Deficiencies

Hair Alopecia Protein-energy malnutrition

Brittle Biotin, Protein-energy malnutrition

Color change Protein-energy malnutrition

Dryness Vitamins E and A

Easy pluckability Protein-energy malnutrition

Skin 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 tosunlight)

Niacin

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's spots Vitamin A

Conjunctival xerosis, keratomalacia Vitamin A

Mouth 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, VitaminB2, Vitamin B6

Magenta tongue Vitamin B2

Extremities Genu valgum or varum, metaphysealwidening

Vitamin D

Loss of deep tendon reflexes of thelower 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 ofHospitalized 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 ischaracterized by an erythematous, blistering rash that may be pruriticor painful. The rash occurs in areas of sun exposure, and is thereforeoften seen around the neck ("Casal's necklace"), arms, hands, or malararea.

Reproduced with permission from: www.visualdx.com. Copyright LogicalImages, Inc.



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Gingival abnormalities in scurvy

The gingival swelling and dusky color just above two of the teethindicate 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 thencomplicated by bleeding from the fragile vessels characteristic of scurvy.

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



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Perifollicular abnormalities in scurvy

In this example, the perifollicular hyperkeratotic papules are quiteprominent, with surrounding hemorrhage. These lesions have beenmisinterpreted as "palpable purpura," leading to the mistaken clinicaldiagnosis of vasculitis.

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



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Disclosures: Sassan Pazirandeh, MD Nothing to disclose. Clifford W Lo, MD, MPH, ScD Nothing to disclose. David L Burns, MDNothing to disclose. Timothy O Lipman, MD Other Financial Interest: GI Board Review Lecturer [Clinical nutrition]; Audio JournalClub Practice Reviews in Gastroenterology [Clinical nutrition, gut microbiome, complementary and alternative medicine, criticalreading 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 vettingthrough a multi-level review process, and through requirements for references to be provided to support the content. Appropriatelyreferenced content is required of all authors and must conform to UpToDate standards of evidence.Conflict of interest policy

Disclosures


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Documents

Overview of Water-soluble Vitamins