Dr Mohammad Nurul HuqDr Mohammad Nurul HuqBangladesh Medical CollegeBangladesh Medical College

V I T A M I N SV I T A M I N S

Vitamins Vitamins

chemically unrelated substances not made in the chemically unrelated substances not made in the body body (except VD and K); (except VD and K); needed in small amounts needed in small amounts for metabolism. for metabolism. 13 vitamins13 vitamins– Water-soluble (WSV): B, C Water-soluble (WSV): B, C – fat-soluble (FSV): ADEKfat-soluble (FSV): ADEK

• We get We get allall V from our balanced food V from our balanced food• Vegetarians need B12Vegetarians need B12vītavīta ( (life) life)  +  + aminamin from amine from amine

DeficienciesDeficiencies• beriberi (B1), ariboflavinosis (B2), pellagra (B3)beriberi (B1), ariboflavinosis (B2), pellagra (B3)• megaloblastic anemia (B9, B12)megaloblastic anemia (B9, B12)• PNP (B1, B6, B12)PNP (B1, B6, B12)• scurvy (C)scurvy (C)• rickets (D)rickets (D)• xerophthalmia (A)xerophthalmia (A)• hemorrhage (K)hemorrhage (K)

Except B12, Except B12, WSVs have no significant storageWSVs have no significant storageSome are destroyed by cooking, sunlight, storageSome are destroyed by cooking, sunlight, storage

8 B Vitamins 8 B Vitamins • Needed for energy from food and erythropoiesis Needed for energy from food and erythropoiesis (B6, B9, (B6, B9,

B12), B12), nerve health nerve health (B1,B6,B12): (B1,B6,B12):

B1 B1 (thiamine), (thiamine), B2 B2 (riboflavin), (riboflavin), B3 B3 (niacin), (niacin), B5 B5 (pantothenic a.), (pantothenic a.), B6 B6 (pyridoxine), (pyridoxine), B7 B7 (biotin), (biotin), B9 B9 (folic a.) (folic a.) B12 B12 (cobalamine)(cobalamine)

SourcesSources: : leafy vege., fruits, fish, poultry, meat, eggs, leafy vege., fruits, fish, poultry, meat, eggs, dairies, beans, peasdairies, beans, peasMany cereals and some breads are fortified (not here)Many cereals and some breads are fortified (not here)Flavins, carotenoids have protective effectsFlavins, carotenoids have protective effects

THIAMINETHIAMINEB1, aneurin, antiberiberi factorB1, aneurin, antiberiberi factor

• Combined Combined thiazole and pyrimidinethiazole and pyrimidine• DRA: DRA: 0.5mg/1000 Kcal0.5mg/1000 Kcal

Sources: Sources: yeast, legumes, yeast, legumes, whole grain.whole grain.Dairies, fruits, vege. are poor sourcesDairies, fruits, vege. are poor sourcesLimited storage: Limited storage: daily intake. daily intake. Absorbed in small gutAbsorbed in small gut

Cooking, baking, canning, pasteurization can destroy itCooking, baking, canning, pasteurization can destroy it

FunctionsFunctions– Makes ATP from CHO for growth, function, repairMakes ATP from CHO for growth, function, repair– nerve signalsnerve signals– myocardial actionmyocardial action

Measured: Measured: RBC thiamine transketolase (ETKA: most RBC thiamine transketolase (ETKA: most reliable), blood level, urinary thiaminereliable), blood level, urinary thiamine

Causes of deficiency:Causes of deficiency:– milled ricemilled rice– alcoholismalcoholism– malabsorption, pregnancy, malabsorption, pregnancy, hyperemesis grav.hyperemesis grav.– poor diet: elderly, children, teenagers, food fadpoor diet: elderly, children, teenagers, food fad– stressed adults and womenstressed adults and women– AIDS, wide-spread CaAIDS, wide-spread Ca– long-term loop diureticslong-term loop diuretics– long periods of IVF without B1long periods of IVF without B1– long-term dialysis, thyrotoxicosislong-term dialysis, thyrotoxicosis

Deficiencies SyndromesDeficiencies Syndromes

• Beriberi: Beriberi: ac., chr. ac., chr. – infantile infantile – adult adult

• Wernicke-Korsakoff syn.Wernicke-Korsakoff syn.• Leigh syn.Leigh syn.

History of beriberi goes back to 2697 BCHistory of beriberi goes back to 2697 BC

Ac. BeriberiAc. Beriberi

• FatigueFatigue, , irritation, dementia, disorientation, insomnia, angina, irritation, dementia, disorientation, insomnia, angina, anorexia, confusion, personality changes, abdo. discomfortanorexia, confusion, personality changes, abdo. discomfort

• PNP, difficulty in rising, edema, cardiomegalyPNP, difficulty in rising, edema, cardiomegaly• Late stages: Late stages: coma and deathcoma and death

• In binge drinking In binge drinking (inhibits absorption) it can occur in a few (inhibits absorption) it can occur in a few days: staggering, eyeball flicking and above …days: staggering, eyeball flicking and above …

• Can cause Can cause Wernicke-Korsakoff Syn. ::PNP: peripheral neuropathyPNP: peripheral neuropathy

Wernicke-Korsakoff syn.Wernicke-Korsakoff syn. ((Exclusively Exclusively seen in alcoholics)seen in alcoholics)

Wernicke Encephalopathy and Korsakoff Psychosis are ac. and chr. phases, respectively, of the same d.; often occur together

• Nystagmus, ophthalmoplegia, ataxiaNystagmus, ophthalmoplegia, ataxia• Dementia, confabulation with normal cognitionDementia, confabulation with normal cognition

Always delay giving dextrose to alcoholicsAlways delay giving dextrose to alcoholics until B1 is given until B1 is given (precipitates Wernicke)(precipitates Wernicke)

Ac. infantile beriberiAc. infantile beriberi

• Ages: 2-3moAges: 2-3mo• EBFEBF babies can get it if mother is deficient: CCF, babies can get it if mother is deficient: CCF,

aphonia/dysphonia and areflexiaaphonia/dysphonia and areflexia

• Severe: Severe: cardiomegaly, tachycardia, loud piercing cry, cardiomegaly, tachycardia, loud piercing cry, cyanosis, dyspnea, NVcyanosis, dyspnea, NV

• Meningism Meningism (CSF is normal) can occur: nystagmus, (CSF is normal) can occur: nystagmus, purposeless movements, fitpurposeless movements, fit

Still common in AsiaStill common in Asia

• Dry: Dry: ANV, constipation, cramps, PNP, tachycardia, fatigue, ANV, constipation, cramps, PNP, tachycardia, fatigue, depressiondepression

• Wet (edema):Wet (edema): PNP and CCFPNP and CCF

Chr. BeriberiChr. Beriberi

DIAGNOSISDIAGNOSIS

Clinical Dx warrants Rx.Clinical Dx warrants Rx.• Full h/of, diet, recent illnesses, stress levelsFull h/of, diet, recent illnesses, stress levels• A thorough PEA thorough PE

• Lab: Lab: ECG, urine and blood B1, ETKA, urine and blood B1, ETKA

Rx.Rx.• B1: IV/IM: 50-100mg/d x7-14d; then orally 20mg/d until B1: IV/IM: 50-100mg/d x7-14d; then orally 20mg/d until

recovery; longer if neuro-symptoms are severerecovery; longer if neuro-symptoms are severe• Ensure daily intakeEnsure daily intake

OUTCOMESOUTCOMES• Curable. Permanent brain damage if Rx is delayedCurable. Permanent brain damage if Rx is delayed

PREVENTIONPREVENTION• Balance diet. For poor diet/malabsorption: MV supplementBalance diet. For poor diet/malabsorption: MV supplement• More B1 in preg. and BF, hyperthyroidism, F, severe liver DMore B1 in preg. and BF, hyperthyroidism, F, severe liver D• Avoid alcoholAvoid alcohol

Peripheral NeuropathyPeripheral NeuropathyParaesthesia, glove-sock anesthesia, tender calf; atrophy of Paraesthesia, glove-sock anesthesia, tender calf; atrophy of

calf, thigh and small musclescalf, thigh and small muscles• -/0 reflexes, foot- and toe-drop-/0 reflexes, foot- and toe-drop

CausesCauses• deficiencies (B1, B3, B5, B6, B12, E)deficiencies (B1, B3, B5, B6, B12, E)• leprosy, Lyme Dleprosy, Lyme D• Drugs: INH, hydralazine, vincristine, disulphirumDrugs: INH, hydralazine, vincristine, disulphirum• Dm, alcoholism, uremiaDm, alcoholism, uremia• arsenic, lead, mercury, gold, thallium, COarsenic, lead, mercury, gold, thallium, CO• idiopathicidiopathic

RxRx

Underlying causeUnderlying cause• NCS may be done to see extent of problem and get a NCS may be done to see extent of problem and get a

proper Dxproper Dx• Dm PNP is Rx by tight control Dm PNP is Rx by tight control

NCS: nerve conduction studyNCS: nerve conduction study

B2 (RIBOFLAVIN)B2 (RIBOFLAVIN)

is a part of flavin-adenine dinucleotide (FAD)is a part of flavin-adenine dinucleotide (FAD)• FAD + protein: flavoproteinsFAD + protein: flavoproteins

– catalysts in redox reactionscatalysts in redox reactions– transport electron in respiratory chain (electron transport transport electron in respiratory chain (electron transport

chain: ETC)chain: ETC)

Sources: Sources: meats, fish, eggs, dairies,meats, fish, eggs, dairies,

greens, yeast, enriched foodsgreens, yeast, enriched foods• Absorbed in small gutAbsorbed in small gut

Redox: reduction and oxidationRedox: reduction and oxidation

Deficiency is Deficiency is common! common!

Ariboflavinosis. Ariboflavinosis. Often undetected!Often undetected!

Causes:Causes: no dairies, rare IEM, malabsorption, chr. use of no dairies, rare IEM, malabsorption, chr. use of barbiturates (oxidation)barbiturates (oxidation)

CF: CF: hyperemic sore throat with edema, cheilitis, stomatitis, hyperemic sore throat with edema, cheilitis, stomatitis, glossitis, normocytic-normochromic a., and sebo. derma., glossitis, normocytic-normochromic a., and sebo. derma., corneal vascularisationcorneal vascularisation

Pure deficiency is rare!Pure deficiency is rare!

Corneal vascularization: from limbus. Commonly

from contact L, more with older hydarogel L. This

material has a relatively low O2 transmissibility so the

cornea is starved of O2

DxDxurinary level and RBC glutathione reductase assayurinary level and RBC glutathione reductase assay

RDA: RDA: 0.4mg for infants. 1.2 mg/d for adults0.4mg for infants. 1.2 mg/d for adults

• Some intramitochondrial beta-oxidation defects may Some intramitochondrial beta-oxidation defects may respond to B2respond to B2

• Zidovudine/stavudineZidovudine/stavudine in HIV can cause lactic acidosis that is in HIV can cause lactic acidosis that is fixed by B2fixed by B2

Angular stomatitisAngular stomatitis

• Deficiency: Deficiency: B2, B3, B6, Fe, B12, ZnB2, B3, B6, Fe, B12, Zn• Old ageOld age• DentureDenture• Cold exposureCold exposure• Drugs: isotretinoin, hypervitaminosis ADrugs: isotretinoin, hypervitaminosis A• Contact dermatitis (lip balm)Contact dermatitis (lip balm)

NIACIN NIACIN ((Nicotinic a./nicotinamide)Nicotinic a./nicotinamide)

water-soluble, need daily supplywater-soluble, need daily supply• 50% 50% from from tryptophantryptophan (60mg =1 mg B3) (60mg =1 mg B3)• Acts as coenzyme: NAD in redox reactions and HActs as coenzyme: NAD in redox reactions and H++

transport, synthesis of fatty a., steroidstransport, synthesis of fatty a., steroids• Widely distributed. Good Widely distributed. Good sourcessources: : yeast, liver, cereals, yeast, liver, cereals,

legumes, seeds, high protein diet (100 g/d) (tryptophan)legumes, seeds, high protein diet (100 g/d) (tryptophan)

NAD: nicotinamide adenine dinucleotide

RDA:RDA: 15-20mg/d15-20mg/d• This dosage is far <than lipid lowering dosesThis dosage is far <than lipid lowering doses

• Deficiency: Deficiency: pellagrapellagra

Therapeutic usesTherapeutic uses

• Lipid lowering: Lipid lowering: 1-3g/d lowers lipid (total, LDL). Niacin + 1-3g/d lowers lipid (total, LDL). Niacin + colestipol significantly lower atherosclerosis (52 vs 15%)colestipol significantly lower atherosclerosis (52 vs 15%)Lower doses with aspirin can decrease SELower doses with aspirin can decrease SE

PellagraPellagra (raw skin). (raw skin). Once epidemic amongst corn (low Once epidemic amongst corn (low niacin, tryptophan) eaters of USniacin, tryptophan) eaters of US

3Ds: 3Ds: Photo-Photo-ddermatitis ermatitis (classic rash like sunburn), (classic rash like sunburn), ddiarrhea, iarrhea, ddementia ementia (insomnia, disorientation, delusions). (insomnia, disorientation, delusions). Glossitis, VDGlossitis, VD

Causes of deficiencyCauses of deficiencyDietary: Dietary: chiefly cereals; corn eater. Common in alcoholicchiefly cereals; corn eater. Common in alcoholic

Non-dietary: Non-dietary: seen inseen in

• CCarcinoid syn.: arcinoid syn.: tryptophan is not converted to B3tryptophan is not converted to B3

• INH:INH: depletes tryptophan depletes tryptophan

• Hartnup D: Hartnup D: defect in transport of tryptophandefect in transport of tryptophan

Toxicity Toxicity • Best known: Best known: flushing flushing (nicotinic a. only)(nicotinic a. only)

• High dose:High dose:– 1-3g/d:1-3g/d: NV, constipation, pruritus, hives, rise in ALT, NV, constipation, pruritus, hives, rise in ALT,

AST, uric a. Rarely myopathyAST, uric a. Rarely myopathy– 2-6g/d:2-6g/d: Severe. May hamper growth Severe. May hamper growth

Toxic vitamins: B3, B6, VA, VDToxic vitamins: B3, B6, VA, VD

B5 (Panhothenic A.):B5 (Panhothenic A.): active form is CoAactive form is CoA

• CoA is essential for synthesis of vit. A, D, heme, cholesterol, CoA is essential for synthesis of vit. A, D, heme, cholesterol, steroids, fatty a., amino a., proteinssteroids, fatty a., amino a., proteins– CoA is converted in gut to PA. Inside cell, PA again CoA is converted in gut to PA. Inside cell, PA again

becomes CoAbecomes CoA

Sources: Sources: egg, liver, kidney, broccoli, milkegg, liver, kidney, broccoli, milkDeficiency: Deficiency: rare. Seen in severe Mn, faminerare. Seen in severe Mn, famineCF: CF: paresthesias and dysesthesias paresthesias and dysesthesias (burning feet syn.)(burning feet syn.)

PYRIDOXINE PYRIDOXINE (B6)(B6)

Function:Function: amino a. metabolism; gluconeogenesisamino a. metabolism; gluconeogenesis,, tryptophan to B3; synthesis of NT, steroid H and tryptophan to B3; synthesis of NT, steroid H and sphingolipid; erythropoiesis, immunitysphingolipid; erythropoiesis, immunity

Sources: Sources: meats, grains, vegetables, nutsmeats, grains, vegetables, nuts

Cooking, processing, storage reduce contentCooking, processing, storage reduce content

Toxicity (>250mg/d): Toxicity (>250mg/d): Long term HD: anesthesia in hands Long term HD: anesthesia in hands and feet, permanent nerve damage, dermatoses, and feet, permanent nerve damage, dermatoses, photosensitivity, dizziness, nauseaphotosensitivity, dizziness, nausea

DeficiencyDeficiency• Rarely severe. PNP, stomatitis, glossitis, cheilosis, irritability, Rarely severe. PNP, stomatitis, glossitis, cheilosis, irritability,

confusion, depression. Seizure in infantsconfusion, depression. Seizure in infants• Mimics homocystinuria, cystathionuria, xanthurenic aciduriaMimics homocystinuria, cystathionuria, xanthurenic aciduria

• B6 has been used in Down S, autism (with Mg), GDM, Carpal B6 has been used in Down S, autism (with Mg), GDM, Carpal TS, Premenstrual S, depression, Dm neuropathy, INHTS, Premenstrual S, depression, Dm neuropathy, INH

• Many people take B6 to fight stress and increase energyMany people take B6 to fight stress and increase energy

BIOTIN (B7)BIOTIN (B7)• In several enzymes for meta. of CHO, fats and amino a.In several enzymes for meta. of CHO, fats and amino a.• It is often recommended for strengthening hair and nails, It is often recommended for strengthening hair and nails,

and it's found in many cosmeticsand it's found in many cosmetics• Needs daily intakeNeeds daily intake• Bacteria in gut can synthesize itBacteria in gut can synthesize it• Absorbed in small gutAbsorbed in small gut

Deficiency.Deficiency. RareRare

• Huge raw egg white (avidin binds biotin) intake: mood Huge raw egg white (avidin binds biotin) intake: mood changes, myalgia, dysesthesias, ANVchanges, myalgia, dysesthesias, ANV

• In neonates; 1In neonates; 1stst week: week: lethargy, hypotonia, NV., acral lethargy, hypotonia, NV., acral dermatitis. Death from severe metabolic A. dermatitis. Death from severe metabolic A.

• Late onset (infants): Late onset (infants): acral D, hypotonia, myoclonus, seizureacral D, hypotonia, myoclonus, seizure• Meta. acidosis and aciduria may occurMeta. acidosis and aciduria may occur• Chr. deficiency: maculosquamous dermatitis, sebo. D, Chr. deficiency: maculosquamous dermatitis, sebo. D,

alopeciaalopecia

Folic Acid Folic Acid (B9, folacin, folate, THF, folinic a., (B9, folacin, folate, THF, folinic a., pteroylglutamic a.) pteroylglutamic a.)

• Essential Essential for making new cellsfor making new cells• B9 before and during pregnancy can prevent NTDsB9 before and during pregnancy can prevent NTDs• Sources: Sources: leafy veg., fruits, beans, peas, nuts, dairies, leafy veg., fruits, beans, peas, nuts, dairies,

poultry, meat, eggs, seafood. poultry, meat, eggs, seafood. Spinach, liver, yeast, Spinach, liver, yeast, asparagus, brussels sprouts (highest concn.).asparagus, brussels sprouts (highest concn.). Bread, cereal, Bread, cereal, flour, cornmeal, pasta, rice, other grains can be fortifiedflour, cornmeal, pasta, rice, other grains can be fortified

• Damaged by sun, boilingDamaged by sun, boiling• Stored in the liverStored in the liver

• Active form: Active form: THF (folinic acid)THF (folinic acid)

– synthesis of DNA-RNA, metabol. of amino a.synthesis of DNA-RNA, metabol. of amino a.– conversion of homocysteine to methionineconversion of homocysteine to methionine

• RBC folate is good index. Blood homocysteine is commonly RBC folate is good index. Blood homocysteine is commonly used for B9 statusused for B9 status

• RDA: RDA: 400 mcg/d400 mcg/d

DeficiencyDeficiency

• Isolated B9 deficiency is uncommonIsolated B9 deficiency is uncommon• Megaloblastic a.Megaloblastic a., , glossitis, mucositis; glossitis, mucositis; changes in skin, hair, changes in skin, hair,

fingernail pigmentationfingernail pigmentation• Large nucleated RBC, is the primary s/of B9/B12Large nucleated RBC, is the primary s/of B9/B12• NTDs, LBW, prematurity, IUGR, cleft, hypospadiusNTDs, LBW, prematurity, IUGR, cleft, hypospadius

CF of anaemiaCF of anaemiaA. GeneralA. General• Weakness, palpitation, anorexia, poor sleep and concn., Weakness, palpitation, anorexia, poor sleep and concn.,

depression, loss of initiative, excess sweats, poor exercise depression, loss of initiative, excess sweats, poor exercise tolerance, irritabilitytolerance, irritability

B. SpecificB. Specific• Iron: Iron: glossitis, angular stomatitis, dysphagia, irritability, glossitis, angular stomatitis, dysphagia, irritability,

koilonychia, micro-hypochromic a.koilonychia, micro-hypochromic a.• B12: B12: paraesthesia, loss of balance, poor concn.paraesthesia, loss of balance, poor concn.• B9: B9: glossitis, megaloblastic a.glossitis, megaloblastic a.• B6: B6: paraesthesiaparaesthesia

2 NTDs: 2 NTDs: open (commoner)open (commoner): : brain and/or SC are exposed via a brain and/or SC are exposed via a defect in skull/vertebrae: defect in skull/vertebrae: anencephaly, encephalocele, anencephaly, encephalocele, hydaranencephaly, iniencephaly, hydaranencephaly, iniencephaly, schizencephaly, spina bifida. schizencephaly, spina bifida. Closed Closed : defect is covered by : defect is covered by skin: lipomyelomeningocele, skin: lipomyelomeningocele, lipomeningocele and tethered lipomeningocele and tethered cordcord

NTDs: NTDs: the commonest the commonest major cong. defects of major cong. defects of CNS: NT fails to close at its CNS: NT fails to close at its end during 3-4w preg. end during 3-4w preg. Periconceptional B9 can Periconceptional B9 can prevent (50-60%). GDM, prevent (50-60%). GDM, obesity, B12, etc. are also obesity, B12, etc. are also believed to affect NTDsbelieved to affect NTDs

Atrophic glossitis: Atrophic glossitis: bald smooth raw tonguebald smooth raw tongue• Change in taste with pain, tenderness and burningChange in taste with pain, tenderness and burning• Causes: Causes: lack of B9, B12, niacin, IDA; typhoidlack of B9, B12, niacin, IDA; typhoid

Geographic tongue/benign migratory glossitisGeographic tongue/benign migratory glossitis• 3% popn., common in children. Idiopathic. Ulcer enlarges/ 3% popn., common in children. Idiopathic. Ulcer enlarges/

decreases and migrate. Self-limiting. decreases and migrate. Self-limiting. Leave it aloneLeave it alone

At Risk of B9 At Risk of B9 InadequacyInadequacy

• Alcoholism: Alcoholism: poor-quality diets; low absorption, poor-quality diets; low absorption, metabolism and accelerates breakdownmetabolism and accelerates breakdown

• Pregnancy and lactation: Pregnancy and lactation: additional B9 for fetusadditional B9 for fetus• Malabsorption: Malabsorption: tropical sprue, celiac, IBD, atrophic tropical sprue, celiac, IBD, atrophic

gastritis, gastric surgery, etc.gastritis, gastric surgery, etc.

Folate and HealthFolate and Health• Cancer: Cancer: inverse association with colorectal, lung, inverse association with colorectal, lung,

pancreatic, breast, esophageal, stomach, Cx, ovarian Ca. pancreatic, breast, esophageal, stomach, Cx, ovarian Ca.

• CV disease and stroke: CV disease and stroke: raised homocysteine level has raised homocysteine level has an an increased risk of CVDincreased risk of CVD

• Dementia, cognition, Alzheimer: Dementia, cognition, Alzheimer: raised homocysteine raised homocysteine has more risk of Alzheimer. Low B9 causes poor cognitive has more risk of Alzheimer. Low B9 causes poor cognitive function, dementiafunction, dementia

Depression: Depression: Low B9 lowers action of antidepressants; may Low B9 lowers action of antidepressants; may have a role as a supplement to Rx for depressionhave a role as a supplement to Rx for depression

NTDs: NTDs: Preterm, cong. HD, other anomalies:• B9 lengthen gestational age; lower the risk of preterm

birth; minimizes risk of cong. HD (24%)• B9 with MV have reduced UT anomalies, facial clefts, limb

defects, hydrocephalus

Excessive FolateExcessive Folate

can correct megaloblastic a., but not neurological damage from low B12. It might "mask” B12 deficiency until irreversible or precipitate cognitive symptoms from low B12

• HD B9 might accelerate preneoplastic lesions increasing the risk of colorectal or other Ca

• High dietary intake of B9 has no SE

Interactions withInteractions with

• Methotrexate:Methotrexate: a B9 antagonist. B9 could interfere a B9 antagonist. B9 could interfere its effects. In its low-dose (RhA/psoriasis), B9 might its effects. In its low-dose (RhA/psoriasis), B9 might reduce its GI SEreduce its GI SE

• AEDs:AEDs: phenytoin, carbamazepine, valproate can phenytoin, carbamazepine, valproate can reduce B9 level and vice versareduce B9 level and vice versa

• Sulfasalazine Sulfasalazine ( in( in UC) inhibits gut absorption of B9UC) inhibits gut absorption of B9

B12 B12 • Cobalamins Cobalamins (contains (contains cobaltcobalt))• Several forms: methylcobalamin, 5-deoxy-Several forms: methylcobalamin, 5-deoxy-

adenosylcobalamin are adenosylcobalamin are active formsactive forms• Essential Essential for for erythropoiesiserythropoiesis, , nerve functionnerve function, , DNADNA, ,

change of change of homocysteine homocysteine to methionineto methionine

• B12: B12: bound to protein in food, released by HCl and bound to protein in food, released by HCl and gastric protease. But B12 in fortified foods/ supplements is gastric protease. But B12 in fortified foods/ supplements is in free form. Free B12 joins in free form. Free B12 joins Intrinsic FactorIntrinsic Factor (glycoprotein) (glycoprotein) to be absorbed in distal ileumto be absorbed in distal ileum

• Only 2% oral dose is absorbed (capacity of Only 2% oral dose is absorbed (capacity of IFIF))• Cyano-/ hydroxocobalamin can be given IMCyano-/ hydroxocobalamin can be given IM• RDA: RDA: 6.0 mcg6.0 mcg

Maternal–Fetal B12–Bone AxisMaternal–Fetal B12–Bone Axis

““Nutrients should come mainly from foods Nutrients should come mainly from foods containing also fiber and functional substances for containing also fiber and functional substances for

positive health effects”positive health effects”

Sources: Sources: • Only Only in in food animal: food animal: fish, meat, poultry, eggs, fish, meat, poultry, eggs,

dairies; dairies; not not in food plant until fortified. Some yeast in food plant until fortified. Some yeast products contain B12products contain B12

• Strict vegans are at more risk than lacto-ovo vegansStrict vegans are at more risk than lacto-ovo vegans• Fortified breakfast cereals can be sources for themFortified breakfast cereals can be sources for them

PA: PA: Autoim. atrophic gastritis Autoim. atrophic gastritis (10–30% elderly). Destroys (10–30% elderly). Destroys parietal cells: achlorhydria, no IF. parietal cells: achlorhydria, no IF. 1% oral B12 can still be absorbed1% oral B12 can still be absorbed

CF:CF: • After age 30y (average 60y)After age 30y (average 60y)• May be May be asymptomatic asymptomatic or mildly ..or mildly ..General: General: CF of anaemia; CF of anaemia; diarrhea/constipation, light-diarrhea/constipation, light-

headedness, anorexia, glossitis, sore mouth or headedness, anorexia, glossitis, sore mouth or bleeding gumsbleeding gums

Neurological: Neurological: PNP, ataxia, depression, confusion, PNP, ataxia, depression, confusion, dementia. dementia. Anaemia may be absentAnaemia may be absent

PNP- peripheral neuropathyPNP- peripheral neuropathy

Diseases associated with PA

• Addison D• Hypopituitarism, Chr. thyroiditis, Grave D• Hypoparathyroidism, T1DM• Myasthenia gr• 2y amenorrhea, testicular dysfunction• Vitiligo

Large, dense RBCs in megaloblastic A

TestsTests

• B12 level (<170pg/mL)B12 level (<170pg/mL)• CBC: macrocytes, hypersegmented neutrophils, retic., CBC: macrocytes, hypersegmented neutrophils, retic.,

Schilling test, LDHSchilling test, LDH• Raised methylmalonic a. (MMA) and homocysteineRaised methylmalonic a. (MMA) and homocysteine

Pernicious A Pernicious A maymay affect test results of: affect test results of: • Bilirubin, cholesterol, gastrinBilirubin, cholesterol, gastrin• Leukocyte al. phos., peripheral smear, TIBCLeukocyte al. phos., peripheral smear, TIBC• May cause false positive Pap smear as the epithelial May cause false positive Pap smear as the epithelial

cells look abnormalcells look abnormal

RxRx• B12 IM once/mo. Severe D may need more shotsB12 IM once/mo. Severe D may need more shots

• Well-balanced diet. Well-balanced diet. PrognosisPrognosis: : uusually excellent. sually excellent. Nerve damage can be permanent if late (6mo)Nerve damage can be permanent if late (6mo)

ComplicationsComplications• There may be gastric polyps, more likely to have gastric Ca There may be gastric polyps, more likely to have gastric Ca

and gastric carcinoid tumorsand gastric carcinoid tumors• Permanent neuronal damagePermanent neuronal damage

PreventionPrevention: : None for autoimmune DNone for autoimmune D• Early Rx can reduce complicationsEarly Rx can reduce complications

B12 and HealthB12 and HealthCardiovascular disease: Cardiovascular disease: raisedraised HCHC promotes clotting promotes clotting

and atherosclerosisand atherosclerosis• B6, B9, B12 are involved in HC metabolismB6, B9, B12 are involved in HC metabolismDementiaDementia• High HC might decrease NT, increase risk of Alzheimer and High HC might decrease NT, increase risk of Alzheimer and

dementia. Cognitive declinedementia. Cognitive decline

IInteractionsnteractions• Chloramphenicol: Chloramphenicol: can interfere with RBC response to B12can interfere with RBC response to B12• PPI, H2B, Metformin: PPI, H2B, Metformin: can interfere with B12 absorptioncan interfere with B12 absorption

HC: homocysteineHC: homocysteine

Peculiarities of B vitaminsPeculiarities of B vitamins• All are water solubleAll are water soluble• Poor storage except B12Poor storage except B12• All are present in fruits, cereals and vege. except B12All are present in fruits, cereals and vege. except B12• Mostly destroyed by cooking, sun, storageMostly destroyed by cooking, sun, storage• All are essential for metabolismAll are essential for metabolism• Some are essential for nerve health: B1,B3, B6, B12; CV Some are essential for nerve health: B1,B3, B6, B12; CV

function (B1, B9)function (B1, B9)

Scurvy took a terrible toll in the ages of

sailing, killing more sailors than all sea battles combined

Vitamin C: Vitamin C: Ascorbic acid, ascorbateAscorbic acid, ascorbate

• ImportantImportant for con. tissue, skin, bones, immunityfor con. tissue, skin, bones, immunity• An An antioxidant. antioxidant. Helps healing, Fe absorptionHelps healing, Fe absorption• Deficiency causes Deficiency causes SCURVYSCURVY

Sources: Sources: citrus, vege., pepperscitrus, vege., peppersAbsent in grains and starchy foods; fizzy drinksAbsent in grains and starchy foods; fizzy drinksFortified to some BF cereals, fruit juicesFortified to some BF cereals, fruit juices5 varied servings 5 varied servings of fruits-vege./d provide enough VCof fruits-vege./d provide enough VC

DestroyedDestroyed by heat, air, light, alkali, storage, cookingby heat, air, light, alkali, storage, cooking

BF: breakfast BF: breakfast

Common scurvy grass

Extra VC need: Extra VC need: pregnancy/BF, smokers, healing, burn, pregnancy/BF, smokers, healing, burn, urine acidification,urine acidification, F, diarrhea, IDA, coldF, diarrhea, IDA, cold

RDA: RDA: 60mg/d; pregnancy: 80 mg, l60mg/d; pregnancy: 80 mg, lactation: 100 mgactation: 100 mg• 90% absorbed. >1 g/d: <50%; extra excreted in 90% absorbed. >1 g/d: <50%; extra excreted in urineurine

• Body: Body: 2g; highest in wbc, eyes, adrenals, pituitary, brain2g; highest in wbc, eyes, adrenals, pituitary, brain

• VC is assessed by plasma levelsVC is assessed by plasma levels

Groups at RiskGroups at Risk

• Smokers/passive “smokers”Smokers/passive “smokers”• Fed on evaporated/boiled milk Fed on evaporated/boiled milk (cow's milk: v. little VC)(cow's milk: v. little VC)

• Limited food variety: Limited food variety: lone lone elderly; alcoholic, drug user; food elderly; alcoholic, drug user; food faddists; mental illness; children; faddists; mental illness; children; malabsorptionmalabsorption

• ESRD, chr. hemodialysis, some Ca might increase riskESRD, chr. hemodialysis, some Ca might increase risk

Vitamin Vitamin C C • CCitrus fruitsitrus fruits• CConnective tissueonnective tissue• CCollagen fibre ollagen fibre

(Proline (Proline hydroxyproline) hydroxyproline)

Functions: Functions: C C C CC C C C

PathologyPathology

A. Defective collagenA. Defective collagen• Poor healing, weak capillary Poor healing, weak capillary bleed bleed• Weak dentin Weak dentin loose teeth loose teeth• ,, osteoid ,, osteoid ossificationossification• loose periosteum loose periosteum subperiosteal bleed subperiosteal bleed

B. B. Defective iron absorption: Defective iron absorption: IDAIDA

C. C. Impaired B9: Impaired B9: aanemianemia

Anemia in ScurvyAnemia in Scurvy

• Poor Fe absorptionPoor Fe absorption• Poor intake (severe anorexia in scurvy)Poor intake (severe anorexia in scurvy)• Impaired B9 metabolismImpaired B9 metabolism• HemorrhageHemorrhage

• BM depressionBM depression

CF:CF: fatigue/weakness, fatigue/weakness, ssevere anorexiaevere anorexia, wt loss, wt loss, gingivitis, , gingivitis, bleed, loose teeth, LGF, depression, irritability, apathy, bleed, loose teeth, LGF, depression, irritability, apathy, tender muscles: crying on handling, tender muscles: crying on handling, pseudoparesispseudoparesis, , subperiosteal bleedsubperiosteal bleed

Mother may bring her baby laid on pillows!Mother may bring her baby laid on pillows!

• Severe scurvy Severe scurvy degen. of sk. muscles, cardiomegaly, degen. of sk. muscles, cardiomegaly, BM depression, adrenal atrophy: BM depression, adrenal atrophy: ultimate deathultimate death

Causes of pseudoparalysisCauses of pseudoparalysis• Scurvy, fracture, rickets, osteochondritis, myositisScurvy, fracture, rickets, osteochondritis, myositis

Signs (many!)Signs (many!)

• Weak con. tissues: Weak con. tissues: miserable; purpura, bruises, joint p., miserable; purpura, bruises, joint p., poor healing, corkscrew hairs, hyperkeratosis, pallor, poor healing, corkscrew hairs, hyperkeratosis, pallor, tender all over, typical frog position, tender all over, typical frog position, pseudoparalysispseudoparalysis

• Spongy gumsSpongy gums bleed (bleed (No teeth: no gum bleed!)No teeth: no gum bleed!) • Edema: Edema: capillary leakage and hge.capillary leakage and hge.• Jerks are normalJerks are normal• Scorbutic rosaryScorbutic rosary: : tendertender beads, beads, sharp angulationsharp angulation

Rickets

Scurvy

Cork screw hairCork screw hair

Purpura

Vitamin C and HealthVitamin C and HealthCancer preventionCancer prevention

plenty of fruits, vege. lower risk of most Ca. VC can limit plenty of fruits, vege. lower risk of most Ca. VC can limit carcinogens like nitrosamines, modulate immunity; carcinogens like nitrosamines, modulate immunity; attenuate oxidative damageattenuate oxidative damage

Cancer RxCancer RxVery high Very high VC (plasma concn. 26,000 micromol/L) is VC (plasma concn. 26,000 micromol/L) is cytotoxic to tumor cellscytotoxic to tumor cells

Cardiovascular d.Cardiovascular d.• Plenty of fruits and vege. can reduce CVDPlenty of fruits and vege. can reduce CVD• Antioxidants attenuate oxidative damage and lower LDLAntioxidants attenuate oxidative damage and lower LDL• VC can prevent atherosclerosisVC can prevent atherosclerosis

AMD and cataractsAMD and cataractsare leading c/of blindness in elderly. Oxidative stress might are leading c/of blindness in elderly. Oxidative stress might

be a cause; VC might slow AMD progression and lower risk be a cause; VC might slow AMD progression and lower risk of cataract (70–75%)of cataract (70–75%)

Common coldCommon cold• VC 250mg-1g/d reduced cold incidence by 50%; by anti-VC 250mg-1g/d reduced cold incidence by 50%; by anti-

histamine effect of high-dose VChistamine effect of high-dose VC• VC after onset of cold is not beneficialVC after onset of cold is not beneficial

UTI: UTI: VC can acidify urine and can clear UTIVC can acidify urine and can clear UTI

DxDx• Typical CF and Typical CF and dietary historydietary history• X-ray findings are diagnosticX-ray findings are diagnostic• Leukocyte conc. of VC confirmsLeukocyte conc. of VC confirms

• Oral VC is very effective. Dramatic response • Excellent prognosis

RxRx

X-ray (knee)X-ray (knee)• Ground glass opacity Ground glass opacity • ‘‘Pencil point’ thin cortex Pencil point’ thin cortex • ‘‘Ringing’ of epiphysis Ringing’ of epiphysis • Frankel’s ‘white line’Frankel’s ‘white line’

(well calcified)(well calcified)• Raised periosteumRaised periosteum• Zone of rarefaction (a Zone of rarefaction (a

linear break) proximal and linear break) proximal and parallel to the white lineparallel to the white line

Excessive VCExcessive VC• Low toxicity; no serious SE. Common: D, nausea, APLow toxicity; no serious SE. Common: D, nausea, AP• Increases urinary oxalate and uric a.: Increases urinary oxalate and uric a.: renal stonesrenal stones• In hemochromatosis it can exacerbate FeIn hemochromatosis it can exacerbate Fe overload overload

InteractionsInteractions• Chemotherapy and radiation: Chemotherapy and radiation: antioxidants might protect antioxidants might protect

tumor from radio-therapy or chemotherapytumor from radio-therapy or chemotherapy• Statins:Statins: may attenuate the increase in HDL effectmay attenuate the increase in HDL effect

MCQMCQ

ScurvyScurvy • is caused by deficiency of ascorbic acidis caused by deficiency of ascorbic acid• can killcan kill• can cause hemorrhagecan cause hemorrhage• can cause bone swellingcan cause bone swelling• causes gum bleeding in neonatescauses gum bleeding in neonates• can cause pseudoparalysiscan cause pseudoparalysis

• VC can ward off cold• HD of VC can cause renal stone• B6 is potentially neurotoxic• B9 prevents birth defects• B12 is available from plant sources

MCQMCQ

Vitamin A Vitamin A

Retinoids: retinol, retinal, retinoic acid, retinylRetinoids: retinol, retinal, retinoic acid, retinyl

Active forms: Active forms: retinal and retinoic a.retinal and retinoic a.PProvitamin forms are carotenoidsrovitamin forms are carotenoidsRetinol Retinol is found in food animal. is found in food animal. -carotene -carotene changes to retinolchanges to retinolRDA: RDA: 400-1300mcg/d. 400-1300mcg/d. Plasma retinal is measuredPlasma retinal is measured

Sources: Sources: colorful fruits and vege., fish, liver, milk; fortified colorful fruits and vege., fish, liver, milk; fortified cereals. 90% is stored in liver (several months)cereals. 90% is stored in liver (several months)

Its liver is the highest source of VA. 1 oz can killIts liver is the highest source of VA. 1 oz can kill

FunctionsFunctions

• Essential part of rhodopsinEssential part of rhodopsin• Integrity of conjunctiva + corneaIntegrity of conjunctiva + cornea• AntioxidantAntioxidant• Epithelial integrity, immunityEpithelial integrity, immunity• Reproduction, fertility, embryogenesisReproduction, fertility, embryogenesis• Cell growth and communicationCell growth and communication

• Skeletal growthSkeletal growth

VA DeficiencyVA Deficiency

V. common in L&MICs V. common in L&MICs (expensive food animal and poor (expensive food animal and poor --carotene intake). Bangladesh: 28% population affectedcarotene intake). Bangladesh: 28% population affected

CausesCauses a. poor intakea. poor intake b. more loss (chr. D, RRTI, measles, malabsorption)b. more loss (chr. D, RRTI, measles, malabsorption) cc. . demand: demand: vegans, children, alcoholics; liver D, vegans, children, alcoholics; liver D, Crohn, Crohn,

CF, pregnancy, lactationCF, pregnancy, lactation

VADX: WHO: 190 million U-5; 9.1 million pregnant women• 250,000-500,000 VAD children become blind every year.

Half of them die within 12mo of blindness• >1 million U-5MR is associated with VAD

Why children are vulnerable?• Diarrhea, RRTI, poor vegetable intake• Bottle feeding, faulty feeding

• Increasing growth

Impact of VADImpact of VAD

– blindnessblindness– more child mortalitymore child mortality– more infx.: D and ARImore infx.: D and ARI

XerophthalmiaXerophthalmia: : ocular features of VADocular features of VAD

NyctalopiaNyctalopia: : poor dim light visionpoor dim light vision

KeratomalaciaKeratomalacia: : corneal softening and meltingcorneal softening and melting

XerophthalmiaXerophthalmia• body VA is nil!body VA is nil!• Night blindness, conjunctival xerosis, Bitot spots, corneal Night blindness, conjunctival xerosis, Bitot spots, corneal

xerosis and keratomalacia, photophobia, fundal xerosisxerosis and keratomalacia, photophobia, fundal xerosis

Extra-ocular featuresExtra-ocular features• Dry scaly skin, follicular keratosisDry scaly skin, follicular keratosis• More RTI, GITI. Death is more in VADMore RTI, GITI. Death is more in VAD

Dx• Ocular features are diagnosticOcular features are diagnostic• Conjunctival cytology suggestiveConjunctival cytology suggestive• Serum retinol level confirmatorySerum retinol level confirmatory

Classification of XerophthalmiaClassification of Xerophthalmia• XN : Night blindness

X1 : Conjunc. xerosis. XIB : Bitot's spots

X2 : Corneal xerosis

X3A : Corneal ulceration/KM <1/3 cornea

X3B : ‘do’ >1/3 cornea

XS : Corneal scar. XF : fundal xerosis

Bitot: from heaping up of desquamated, keratinized epithelial cells; foamy, may be solid and cheesy

PreventionPreventionShort term strategyShort term strategy• HPVAC (200,000 iu retinol, 40 iu of VE) to U-6 childrenHPVAC (200,000 iu retinol, 40 iu of VE) to U-6 children• VA rich foods (leafy veg., yellow fruits) VA rich foods (leafy veg., yellow fruits) • HPVAC to mother after delivery (within 14d). EBFHPVAC to mother after delivery (within 14d). EBF

Long term strategyLong term strategy• Immunization, Health educationImmunization, Health education• Female literacy, Family planningFemale literacy, Family planning• Production of vegetables and fruitsProduction of vegetables and fruits• Commercial fortification of foodsCommercial fortification of foods

VA and Health

Cancer: high intakes of carotenoids have lower risk of lung Ca in smokers

AMD: not conclusiveMeasles: VAD is a great risk for severe measles. VA

supplement reduces MM and blindness

Hypervitaminosis AHypervitaminosis A

AcuteAcute ((>400,000i.u. stat)>400,000i.u. stat)• ANV, HA, ANV, HA, AP, blurred vision, myalgia-weakness, fit, drying and drying and

cracking of skin, painful swelling of long bones (~Cafey cracking of skin, painful swelling of long bones (~Cafey disease), bone fragility, HSM, idisease), bone fragility, HSM, irritability, drowsiness

• Pseudotumor cerebriPseudotumor cerebri

• RetinoidsRetinoids: : used for psoriasis, skin effects of T-cell lymphoma. used for psoriasis, skin effects of T-cell lymphoma. They can raise the risk if taken with VAThey can raise the risk if taken with VA

Large amounts of carotenoids have no major SELarge amounts of carotenoids have no major SE

Chr. Hypervitaminosis A Chr. Hypervitaminosis A (>20,000 iu/d over several w)

• ANV, irritability, wt. loss/FTT, itch, alopecia, apathy, HSM, dizziness, HA, pseudotumor C, coma, even death, dry mucosae/fissured lips, F, insomnia, fatigue, hyperlipidemia, hypercalcemia, anemia, D, menstrual abnormalities, epistaxis

• Bone and joint pains, increased fracture• Liver damage. Desquamation in palms, soles, hyperostosis

on XR of several long bones

DxDx• H/of, SS, XR findings and serum retinol levelH/of, SS, XR findings and serum retinol level

RxRxStop intakeStop intake

Message!Message!• HDVA, topical retinoids are teratogenicHDVA, topical retinoids are teratogenic• Malformations of eye, skull, lungs, heartMalformations of eye, skull, lungs, heart• For adequate VA in BM give VA within 2w of birthFor adequate VA in BM give VA within 2w of birth

Pseudotumor cerebriPseudotumor cerebri• Mimics IC tumor but is not; often reversibleMimics IC tumor but is not; often reversible

CausesCauses• Women more, especially obese women near menopause. Women more, especially obese women near menopause.

Can occur in children. Cause is unknown. Can occur in children. Cause is unknown. Drugs:Drugs:– VA, VA, OCP, cyclosporine, isotretinoin, minocycline, OCP, cyclosporine, isotretinoin, minocycline, – nalidixic A, nalidixic A, nitrofurantoin, phenytoin, sulfasnitrofurantoin, phenytoin, sulfas– SteroidsSteroids– Tamoxifen, tetracyclineTamoxifen, tetracycline

Other factors related to PC:Other factors related to PC:• Addison's disease, CKD, CushingAddison's disease, CKD, Cushing• Hypoparathyroidism, IDA, obesityHypoparathyroidism, IDA, obesity• Menarche, pregnancyMenarche, pregnancy

CF: CF: Blurred vision, tinnitus, dizziness, diplopia, nauseaBlurred vision, tinnitus, dizziness, diplopia, nausea• May get worse in physical activityMay get worse in physical activity

alertalert, bulged fontanelle, , bulged fontanelle, OFC, papilledema OFC, papilledema

DxDx• Dx by exclusion (hydrocephalus, tumor venous sinus Dx by exclusion (hydrocephalus, tumor venous sinus

thrombosis)thrombosis)• CT, MRI with MR venographyCT, MRI with MR venography• Eye exam, CSFEye exam, CSF

RxRx• Aim: what is the cause. CSF to relieve pressure, fluid salt Aim: what is the cause. CSF to relieve pressure, fluid salt

restriction, steroids, acetazolamide, furosemiderestriction, steroids, acetazolamide, furosemide• Shunt, surgery to relieve pressure on optic nerve, weight Shunt, surgery to relieve pressure on optic nerve, weight

loss, vision closely monitoredloss, vision closely monitored

MCQMCQ

Vitamin AVitamin A• is essential for bright light visionis essential for bright light vision• is found in active form in plenty in vege. and fruitsis found in active form in plenty in vege. and fruits• is potentially teratogenicis potentially teratogenic• can cause hyperostosis in toxic dosagecan cause hyperostosis in toxic dosage• deficiency is more in under-5 childrendeficiency is more in under-5 children• is the greatest c/of nutritional blindnessis the greatest c/of nutritional blindness

saber

Vitamin D Vitamin D

• Group of sterols. Deficiency: Group of sterols. Deficiency: RICKETS RICKETS • 2 forms: 2 forms: VD-2VD-2 (ergocalciferol: main dietary, therapeutic (ergocalciferol: main dietary, therapeutic

source ): made from UV irradiation of source ): made from UV irradiation of ergosterolergosterol in yeast in yeast. . VD-3VD-3 (cholecalciferol): in skin from (cholecalciferol): in skin from 7-dehydrocholesterol7-dehydrocholesterol

• Stable to heat, acid, alkali, oxidationStable to heat, acid, alkali, oxidation

AActivationctivation• VD is inert and must have 2 OH: first in VD is inert and must have 2 OH: first in liverliver (25-OH-D or (25-OH-D or

calcidiol); 2calcidiol); 2ndnd in in kidneykidney (active 1,25(OH) (active 1,25(OH)22D, or calcitriol)D, or calcitriol)

Functions: Functions: at 3 sitesat 3 sites• GITGIT (helps absorb Ca, P), (helps absorb Ca, P), Kidneys Kidneys (prevents Ca, P loss), (prevents Ca, P loss),

BoneBones (bones grow and remodel)s (bones grow and remodel)Intestine is a locked door to Ca; VD is the key to open itIntestine is a locked door to Ca; VD is the key to open itAbsorption increased by 80%Absorption increased by 80%

Other rolesOther roles• cell growth, neuromuscular and immune function, cell growth, neuromuscular and immune function,

reduction of inflam., apoptosisreduction of inflam., apoptosis

SSources: ources: skin, food, supplementsskin, food, supplements– V. few foods V. few foods in nature contain VD. VD rich foods: egg in nature contain VD. VD rich foods: egg

yolks, sea fish, liver. Milk and cereals, are often fortified yolks, sea fish, liver. Milk and cereals, are often fortified (greatest source in the West)(greatest source in the West)

Too much sun exposure can cause skin aging and skin Ca. Too much sun exposure can cause skin aging and skin Ca. So many people try to get VD from other sourcesSo many people try to get VD from other sources

DeficiencyDeficiency: : rickets, -malacia, osteoporosis, tetanyrickets, -malacia, osteoporosis, tetany

Causes: Causes: – No sun exposure, malabsorption– Abnormal metabolism of VD, genetic factors– Abnormal metabolism of inorganic phosphate– Prolonged EBF may cause, in dark-skinned infants

Sun exposureSun exposure• UV B converts 7-dehydrocholesterol in skin to VDUV B converts 7-dehydrocholesterol in skin to VD33

• 5–30min exposure, 2/w to face, arms, legs, or back5–30min exposure, 2/w to face, arms, legs, or back• Season, time, length, cloud, smog, skin melanin, sunscreen Season, time, length, cloud, smog, skin melanin, sunscreen

can affect UVR. Cloud reduces UV 50%; pollution 60%. UVB can affect UVR. Cloud reduces UV 50%; pollution 60%. UVB does not penetrate glassdoes not penetrate glass

UVR is carcinogenUVR is carcinogen• RDA: 0-50 y: 5 µg (200 IU)

51-70 y: 10 µg (400 IU)71+ y: 15 µg (600 IU)

Extra VD: seniors, EBF, dark skin, liver and CKD, malabsorption, obesity, gastric bypass

• RicketsRickets is failure to mineralize is failure to mineralize growing bone growing bone or osteoid or osteoid tissuetissue

• Similar failure in Similar failure in mature bone: mature bone: osteomalaciaosteomalacia

C/by lack of VD; but disruptions in Ca and P homeostasis may C/by lack of VD; but disruptions in Ca and P homeostasis may also be responsible also be responsible

DefinitionDefinition

Groups at RiskGroups at Risk

• EBF: EBF: VD is insufficient in BM (78 IU/L)VD is insufficient in BM (78 IU/L)• Elderly: Elderly: less efficient skinless efficient skin, more indoors, less intake, more indoors, less intake• Poor sun exposure, people with dark skinPoor sun exposure, people with dark skin• Fat malabsorption: Fat malabsorption: liver and pancreatic D, Crohn, liver and pancreatic D, Crohn,

CF, UCCF, UC• Obese:Obese: Fat steals VD and resists release Fat steals VD and resists release• Gastric bypass: Gastric bypass: VDD over time if insufficient intakeVDD over time if insufficient intake

PathologyPathology

• EpiphysisEpiphysis stops growing, becomes frayed stops growing, becomes frayed• MetaphysisMetaphysis widens and bulgeswidens and bulges• DiaphysisDiaphysis rarifies; softens; deforms or break rarifies; softens; deforms or break

Clinical FeaturesClinical Features

• Age:Age: usually <2yusually <2y• Nonspecific:Nonspecific: pallor, excess sweats, poor feeding, pallor, excess sweats, poor feeding,

irritability, pot belly, RRTI, etc.irritability, pot belly, RRTI, etc.

• Early signsEarly signs: : thickened wrist-ankle, craniotabesthickened wrist-ankle, craniotabes

• DelayedDelayed (a few months): bowing of legs, rickety rosary, (a few months): bowing of legs, rickety rosary, pigeon chest, head deformities pigeon chest, head deformities

Head: Head: craniotabes in infants, asymmetry, large and lately craniotabes in infants, asymmetry, large and lately closing fontanel, frontal bossing, large head closing fontanel, frontal bossing, large head

Teeth: Teeth: delayed eruption, enamel defect (extensive caries, delayed eruption, enamel defect (extensive caries, defective permanent teeth)defective permanent teeth)

Region Based SignsRegion Based Signs

ThoraxThorax– Rachitic rosaryRachitic rosary– Pigeon chest Pigeon chest – Harrison grooveHarrison groove

Rickets

Scurvy

SpineSpine

– KyphosisKyphosis– Scoliosis Scoliosis – LordosisLordosis(may occur in combination)(may occur in combination)

Pelvis

• Narrow entrance (forwarding of sacral promontory)• Narrow outlet (forward displacement of the

sacrococcyx)These cause obstructed labor

Rickets is very dangerous for females

ExtremitiesExtremities

– Broadening of wrists and ankles– Bowlegs and knock-knees– Saber tibia

All bone deformities produce rachitic dwarfism

LigamentsLigaments– Relaxation cause

overextension

MusclesMuscles– Hypotonia and poor

development (late in standing and walking)

– Pot belly (hypotonic weak abdo. wall)

DxDx

• Dietary history, sun exposureDietary history, sun exposure• Living condition Living condition • Clinical findingsClinical findings• Lab: Lab: serum 25(OH)D is the best indicator of VD status. serum 25(OH)D is the best indicator of VD status.

Normal or low calcium, low PO4 (<4mg/dl), raised al. phos.Normal or low calcium, low PO4 (<4mg/dl), raised al. phos.

Wrist is the bestBroadening, cupping, frayingDistance between radius-ulna and metacarpals is increasedOsteopeniaInitial healing is shown by appearance of the line of preparatory calcification

DDDD• Familial bow legsFamilial bow legs• Osteogenesis imperfectaOsteogenesis imperfecta• Non-rachitic craniotabesNon-rachitic craniotabes

ComplicationsComplications• Permanent deformities, dwarfism, respiratory infx., Permanent deformities, dwarfism, respiratory infx.,

obstructed laborobstructed labor

Rx Rx • Oral VD3: 50-150mcg/d or DHCC 0.5-2mcg/d orOral VD3: 50-150mcg/d or DHCC 0.5-2mcg/d or• single dose of 200,000 i.u. VD3 (easy; rapid healing)single dose of 200,000 i.u. VD3 (easy; rapid healing)• Sun exposure, intake of CaSun exposure, intake of Ca

Prognosis: Prognosis: Good. Good. Healing over 2-4w. RHealing over 2-4w. Remodeling (several emodeling (several months)months)

Prophylaxis• Exposure to sun (15 min/d; 10% body surface)Exposure to sun (15 min/d; 10% body surface)• Fortification of foodsFortification of foods• Prophylaxis for preterm, EBF, malnourishedProphylaxis for preterm, EBF, malnourished• Supplement pregnancy and lactationSupplement pregnancy and lactation

Non-Vit D Deficiency Rickets

• VD dependent R (lack of 1 alpha hydroxylase or end organ VD dependent R (lack of 1 alpha hydroxylase or end organ response failure)response failure)

• Hypophosphatasia Hypophosphatasia • Familial hypophosphatemic RFamilial hypophosphatemic R• Renal tubular defect, CRFRenal tubular defect, CRF• AED: phenytoin, phenobarbitone, primidone x2-3yAED: phenytoin, phenobarbitone, primidone x2-3y

Hypophosphatasia

Vitamin D and HealthVitamin D and Health• Osteoporosis is Osteoporosis is low BMD with fragility. It is mostly low BMD with fragility. It is mostly

associated with low Ca intakes. Adequate VD and Ca might associated with low Ca intakes. Adequate VD and Ca might prevent it in older adults, sedentary people, menopausal prevent it in older adults, sedentary people, menopausal women, chr. steroid therapywomen, chr. steroid therapy

InteractionInteraction• Prolonged steroidsProlonged steroids can reduce Ca and impair VD meta. can reduce Ca and impair VD meta.• Orlistat, cholestyramine reduce absorption of FSVOrlistat, cholestyramine reduce absorption of FSV• AED increase hepatic metabolism of DAED increase hepatic metabolism of D

VITAMINVITAMIN EE"anti-sterility factor”, tocopherol (8 forms)"anti-sterility factor”, tocopherol (8 forms)

• An antioxidant; role in immunity, metabolismAn antioxidant; role in immunity, metabolism• Food is abundant in VE: vege. oils, margarine, nuts, seeds. It is Food is abundant in VE: vege. oils, margarine, nuts, seeds. It is

also added to cerealsalso added to cereals• RDA: 10mg/dRDA: 10mg/d

• Deficiency:Deficiency: uncommon. Raises LDL: atherogenesis. May be uncommon. Raises LDL: atherogenesis. May be subclinical, or cause subtle neurologic SSsubclinical, or cause subtle neurologic SSLiver diseases, CF, Crohn need extra VELiver diseases, CF, Crohn need extra VE

At risk: At risk: malabsorption, CLD, CF, blind loop (bacterial malabsorption, CLD, CF, blind loop (bacterial overgrowth), celiac, pancreatic D, IBDovergrowth), celiac, pancreatic D, IBD

• VE deficiency can cause neuromuscular disorders VE deficiency can cause neuromuscular disorders (spinocerebellar ataxia), hemolysis (common in (spinocerebellar ataxia), hemolysis (common in premterms), myopathy, pigmented retinopathypremterms), myopathy, pigmented retinopathy

• Thalassemia, SCD, G-6-PD, spherocytosis may have low VEThalassemia, SCD, G-6-PD, spherocytosis may have low VE

Vitamin K Vitamin K

"antihemorhagic factor”, phyloquinones (K1) "antihemorhagic factor”, phyloquinones (K1) menaquinone (K2)menaquinone (K2)

• Makes: osteocalcin and tissuesMakes: osteocalcin and tissues, F.: II, VII, IX, X, , F.: II, VII, IX, X, and and anticoagulant C, Santicoagulant C, S

• User of blood thinners should be careful about how much User of blood thinners should be careful about how much VK s/he gets. VE can interfere with VKVK s/he gets. VE can interfere with VK

• Natural anticoagulant proteins S and C require VK for their activity. S is a cofactor for C which inhibits thrombin

Sources: green vege., dark berries. Gut flora make K2: AB kill them

RDA: 80 mcg/d• Extremely HD of VE and A antagonize VK

Deficiency: easy bruising, mucosal bleeding, splinter hge, melena, hematuria, etc. TPN and long-term ABT can cause VK deficiency Prolonged fasting decreases its levels

Hemorrhagic D of the NewbornHemorrhagic D of the Newborn • VK deficiency is common in NB (VK clotting factors are 20% VK deficiency is common in NB (VK clotting factors are 20%

of adults; are normalized in a month)of adults; are normalized in a month)– immature liver, low VK in BM, sterile gutimmature liver, low VK in BM, sterile gut– poor placental transfer of VKpoor placental transfer of VK

• HDN causes skin, GI, IC hge; typically occurs within 7d of lifeHDN causes skin, GI, IC hge; typically occurs within 7d of life• Give VK at birth, on 4Give VK at birth, on 4thth and 28 and 28thth day (4h4d4w) day (4h4d4w)• Dose:Dose: 1-25mg oral/IM/SC/IV 1-25mg oral/IM/SC/IV

• In blood thinning, doses of K should be minimizedIn blood thinning, doses of K should be minimized

Vitamin toxicityVitamin toxicity

VA: VA: ac. toxicity can cause NV, HA, bone pain, IC ac. toxicity can cause NV, HA, bone pain, IC hypertension, alopeciahypertension, alopecia

• Highly teratogenic: >10,000 IU/d (first 8w preg.)Highly teratogenic: >10,000 IU/d (first 8w preg.)Give VA to mother within 2w post-partumGive VA to mother within 2w post-partum

• Isotretinoin:Isotretinoin: (acne); related to VA (teratogenic, IC (acne); related to VA (teratogenic, IC hypertension, depression, suicide)hypertension, depression, suicide)

• Carotenemia: Carotenemia: only cosmetic effectonly cosmetic effect

B-1, B-2, B-12:B-1, B-2, B-12: non-toxicnon-toxic

B-3:B-3: flushing with 50mg/dflushing with 50mg/d• 1.5-6g/d can cause liver toxicity, more in preexisting LD1.5-6g/d can cause liver toxicity, more in preexisting LD

B-6B-6• 300mg/d may be neurotoxic; more in renal damage300mg/d may be neurotoxic; more in renal damage

Vitamin C Toxicity• Upper limit is 2g• Ac. toxic dose is not estd. Chr. TD: >2g/d

– NVD, AP, HA, Heartburn, Insomnia – bloating, Kidney stones

Vitamin D Toxicity: Excessive sun exposure: no Excessive sun exposure: no toxicity. toxicity. Ac. toxic dose not estd.

• Chr. TD: >50,000 IU/d. In <6mo age: 1,000 IU/d is unsafe• Anorexia, wt. loss, arrhythmias, polyuria. HyperCa causes Anorexia, wt. loss, arrhythmias, polyuria. HyperCa causes

vascular and tissue calcification, damage to heart, BV, vascular and tissue calcification, damage to heart, BV, kidneys (stone)kidneys (stone)

Vitamin E Toxicity

• HD (>1600 IU/d) can prolong prothrombin time; reduces platelet thromboxane– with anticoagulants can raise risk of bleed– may impair hematologic response to iron– can depress WBC bactericidal activity and lymphocyte

transformation– increases risk of sepsis and NEC in preemies LBW

Vitamin K toxicity• V. rare; toxic dose not established. VK-3 (menadione) HD

supplements are banned• Hemolytic a., jaundice, kernicterus in neonates in HD

Folic a. toxicity• Toxic dose not established, generally nontoxic• >5000 mcg/d mask pernicious anemia

Points to PonderPoints to Ponder

• Sea food once/mo prevents B12 deficiencySea food once/mo prevents B12 deficiency• Prolonged ABT causes VK deficiencyProlonged ABT causes VK deficiency• VKD is more common in EBBVKD is more common in EBB• Vegetarians are prone to B12DVegetarians are prone to B12D• VC is lost on exposure to air and sunVC is lost on exposure to air and sun• VC requires daily intakeVC requires daily intake

• Measles can totally deplete VA statusMeasles can totally deplete VA status• Most VD is formed from sun exposureMost VD is formed from sun exposure• Rickets, scurvy, beriberi, pellagra: eliminated in the WestRickets, scurvy, beriberi, pellagra: eliminated in the West• Highest body storage of vitamin is that of B12Highest body storage of vitamin is that of B12• Toxic vitamins: B3, B6, A, DToxic vitamins: B3, B6, A, D

Points to Ponder …Points to Ponder …

Free Radicals Free Radicals

• ““Free" Free" as they float to bind, and as they float to bind, and "radical" "radical" as they take an as they take an electron from many molecules making that molecule electron from many molecules making that molecule another FRanother FR

• Created by pollution, cigarette, radiation, cleaners Created by pollution, cigarette, radiation, cleaners herbicides herbicides

• Responsible for aging, tissue damage, Ca, stroke, CVDResponsible for aging, tissue damage, Ca, stroke, CVD• FR have key role in FR have key role in phagocytosis; redoxphagocytosis; redox

Fly Geyser NevadaUSA

Sunrise @ Nilachol, Bandorban, Bd

• Sources of Vitamin B6Sources of Vitamin B6• FoodFood

Vitamin B6 is found in a wide variety of foods [Vitamin B6 is found in a wide variety of foods [1,,3,,4]. The richest sources of vitamin B6 include fish, beef ]. The richest sources of vitamin B6 include fish, beef liver and other organ meats, potatoes and other starchy vegetables, and fruit (other than citrus). In the liver and other organ meats, potatoes and other starchy vegetables, and fruit (other than citrus). In the United States, adults obtain most of their dietary vitamin B6 from fortified cereals, beef, poultry, starchy United States, adults obtain most of their dietary vitamin B6 from fortified cereals, beef, poultry, starchy vegetables, and some non-citrus fruits [vegetables, and some non-citrus fruits [1,,3,,5]. About 75% of vitamin B6 from a mixed diet is bioavailable []. About 75% of vitamin B6 from a mixed diet is bioavailable [1].].

• The table of selected food sources of vitamin B6 suggests many dietary sources of vitamin B6.The table of selected food sources of vitamin B6 suggests many dietary sources of vitamin B6.• Table 2: Selected Food Sources of Vitamin B6 [Table 2: Selected Food Sources of Vitamin B6 [4] Food Milligrams (mg) per serving Percent DV* Chickpeas, ] Food Milligrams (mg) per serving Percent DV* Chickpeas,

canned, 1 cup1.155 Beef liver, pan fried, 3 ounces0.945 Tuna, yellowfin, fresh, cooked, 3 ounces0.945 canned, 1 cup1.155 Beef liver, pan fried, 3 ounces0.945 Tuna, yellowfin, fresh, cooked, 3 ounces0.945 Salmon, sockeye, cooked, 3 ounces0.630 Chicken breast, roasted, 3 ounces0.525 Breakfast cereals, fortified Salmon, sockeye, cooked, 3 ounces0.630 Chicken breast, roasted, 3 ounces0.525 Breakfast cereals, fortified with 25% of the DV for vitamin B60.525 Potatoes, boiled, 1 cup0.420 Turkey, meat only, roasted, 3 with 25% of the DV for vitamin B60.525 Potatoes, boiled, 1 cup0.420 Turkey, meat only, roasted, 3 ounces0.420 Banana, 1 medium0.420 Marinara (spaghetti) sauce, ready to serve, 1 cup0.420 Ground beef, ounces0.420 Banana, 1 medium0.420 Marinara (spaghetti) sauce, ready to serve, 1 cup0.420 Ground beef, patty, 85% lean, broiled, 3 ounces0.315 Waffles, plain, ready to heat, toasted, 1 waffle0.315 Bulgur, patty, 85% lean, broiled, 3 ounces0.315 Waffles, plain, ready to heat, toasted, 1 waffle0.315 Bulgur, cooked, 1 cup0.210 Cottage cheese, 1% low-fat, 1 cup0.210 Squash, winter, baked, ½ cup0.210 Rice, white, cooked, 1 cup0.210 Cottage cheese, 1% low-fat, 1 cup0.210 Squash, winter, baked, ½ cup0.210 Rice, white, long-grain, enriched, cooked, 1 cup0.15 Nuts, mixed, dry-roasted, 1 ounce0.15 Raisins, seedless, ½ cup0.15 long-grain, enriched, cooked, 1 cup0.15 Nuts, mixed, dry-roasted, 1 ounce0.15 Raisins, seedless, ½ cup0.15 Onions, chopped, ½ cup0.15 Spinach, frozen, chopped, boiled, ½ cup0.15 Tofu, raw, firm, prepared with Onions, chopped, ½ cup0.15 Spinach, frozen, chopped, boiled, ½ cup0.15 Tofu, raw, firm, prepared with calcium sulfate, ½ cup0.15 Watermelon, raw, 1 cup0.15 *DV = Daily Value. DVs were developed by the U.S. calcium sulfate, ½ cup0.15 Watermelon, raw, 1 cup0.15 *DV = Daily Value. DVs were developed by the U.S. Food and Drug Administration (FDA) to help consumers compare the nutrient contents of products within Food and Drug Administration (FDA) to help consumers compare the nutrient contents of products within the context of a total diet. The DV for vitamin B6 is 2 mg for adults and children age 4 and older. However, the context of a total diet. The DV for vitamin B6 is 2 mg for adults and children age 4 and older. However, the FDA does not require food labels to list vitamin B6 content unless a food has been fortified with this the FDA does not require food labels to list vitamin B6 content unless a food has been fortified with this nutrient. Foods providing 20% or more of the DV are considered to be high sources of a nutrient.nutrient. Foods providing 20% or more of the DV are considered to be high sources of a nutrient.

• The U.S. Department of Agriculture's (USDA's) The U.S. Department of Agriculture's (USDA's) Nutrient Database (USDA Release 24) lists the nutrient (USDA Release 24) lists the nutrient content of many foods and provides a content of many foods and provides a comprehensive list of foods containing vitamin B6. containing vitamin B6.

• IntroductionIntroduction• B6 is water-soluble naturally present in many foods, added to others, or as dietary supplement. It is the generic name for 6 compounds: pyridoxine, an alcohol; pyridoxal, an aldehyde; and pyridoxamine, which contains an amino group; and their respective 5'-phosphate estersB6 is water-soluble naturally present in many foods, added to others, or as dietary supplement. It is the generic name for 6 compounds: pyridoxine, an alcohol; pyridoxal, an aldehyde; and pyridoxamine, which contains an amino group; and their respective 5'-phosphate esters• B6 as coenzyme performs a wide variety of functions, in >100 enzyme reactions, mostly protein metabolismB6 as coenzyme performs a wide variety of functions, in >100 enzyme reactions, mostly protein metabolism• B6 also plays a role in biosynthesis of NT and in maintaining normal homocysteineB6 also plays a role in biosynthesis of NT and in maintaining normal homocysteine• B6 is involved in gluconeogenesis and glycogenolysis, immune function and Hb formation B6 is involved in gluconeogenesis and glycogenolysis, immune function and Hb formation • Absorbed in the jejunum. Phosphorylated forms of the vitamin are dephosphorylated, and the pool of free vitamin B6 is absorbed by passive diffusion [Absorbed in the jejunum. Phosphorylated forms of the vitamin are dephosphorylated, and the pool of free vitamin B6 is absorbed by passive diffusion [2].].• Vitamin B6 concentrations can be measured directly by assessing concentrations of PLP; other vitamers; or total vitamin B6 in plasma, erythrocytes, or urine [Vitamin B6 concentrations can be measured directly by assessing concentrations of PLP; other vitamers; or total vitamin B6 in plasma, erythrocytes, or urine [1]. Vitamin B6 concentrations can also be measured indirectly by assessing either erythrocyte aminotransferase saturation by PLP or tryptophan metabolites. Plasma PLP is the most common measure of vitamin B6 status.]. Vitamin B6 concentrations can also be measured indirectly by assessing either erythrocyte aminotransferase saturation by PLP or tryptophan metabolites. Plasma PLP is the most common measure of vitamin B6 status.• PLP concentrations of more than 30 nmol/L have been traditional indicators of adequate vitamin B6 status in adults [PLP concentrations of more than 30 nmol/L have been traditional indicators of adequate vitamin B6 status in adults [3]. However, the Food and Nutrition Board (FNB) at the Institute of Medicine of the National Academies (formerly National Academy of Sciences) used a plasma PLP level of 20 nmol/L as the major indicator of adequacy to calculate the Recommended Dietary Allowances (RDAs) for adults []. However, the Food and Nutrition Board (FNB) at the Institute of Medicine of the National Academies (formerly National Academy of Sciences) used a plasma PLP level of 20 nmol/L as the major indicator of adequacy to calculate the Recommended Dietary Allowances (RDAs) for adults [ 1,,3].].• Recommended IntakesRecommended Intakes• Intake recommendations for vitamin B6 and other nutrients are provided in the Dietary Reference Intakes (DRIs) developed by the FNB [Intake recommendations for vitamin B6 and other nutrients are provided in the Dietary Reference Intakes (DRIs) developed by the FNB [1]. DRI is the general term for a set of reference values used for planning and assessing nutrient intakes of healthy people. These values, which vary by age and gender, include:]. DRI is the general term for a set of reference values used for planning and assessing nutrient intakes of healthy people. These values, which vary by age and gender, include:• Recommended Dietary Allowance (RDA): average daily level of intake sufficient to meet the nutrient requirements of nearly all (97%–98%) healthy individuals.Recommended Dietary Allowance (RDA): average daily level of intake sufficient to meet the nutrient requirements of nearly all (97%–98%) healthy individuals.• Adequate Intake (AI): established when evidence is insufficient to develop an RDA and is set at a level assumed to ensure nutritional adequacy.Adequate Intake (AI): established when evidence is insufficient to develop an RDA and is set at a level assumed to ensure nutritional adequacy.• Tolerable Upper Intake Level (UL): maximum daily intake unlikely to cause adverse health effects.Tolerable Upper Intake Level (UL): maximum daily intake unlikely to cause adverse health effects.• Table 1 lists the current RDAs for vitamin B6 [Table 1 lists the current RDAs for vitamin B6 [1]. For infants from birth to 12 months, the FNB established an AI for vitamin B6 that is equivalent to the mean intake of vitamin B6 in healthy, breastfed infants.]. For infants from birth to 12 months, the FNB established an AI for vitamin B6 that is equivalent to the mean intake of vitamin B6 in healthy, breastfed infants.• Table 1: Recommended Dietary Allowances (RDAs) for Vitamin B6 [Table 1: Recommended Dietary Allowances (RDAs) for Vitamin B6 [1] Age Male Female Pregnancy Lactation Birth to 6 months0.1 mg*0.1 mg* 7–12 months0.3 mg*0.3 mg* 1–3 years0.5 mg0.5 mg 4–8 years0.6 mg0.6 mg 9–13 years1.0 mg1.0 mg 14–18 years1.3 mg1.2 mg1.9 mg2.0 mg 19–50 years1.3 mg1.3 mg1.9 mg2.0 mg 51+ years1.7 mg1.5 mg * Adequate Intake (AI)] Age Male Female Pregnancy Lactation Birth to 6 months0.1 mg*0.1 mg* 7–12 months0.3 mg*0.3 mg* 1–3 years0.5 mg0.5 mg 4–8 years0.6 mg0.6 mg 9–13 years1.0 mg1.0 mg 14–18 years1.3 mg1.2 mg1.9 mg2.0 mg 19–50 years1.3 mg1.3 mg1.9 mg2.0 mg 51+ years1.7 mg1.5 mg * Adequate Intake (AI)• Dietary supplementsDietary supplements

Vitamin B6 is available in multivitamins, in supplements containing other B complex vitamins, and as a stand-alone supplement [Vitamin B6 is available in multivitamins, in supplements containing other B complex vitamins, and as a stand-alone supplement [6]. The most common vitamin B6 vitamer in supplements is pyridoxine (in the form of pyridoxine hydrochloride [HCl]), although some supplements contain PLP. Vitamin B6 supplements are available in oral capsules or tablets (including sublingual and chewable tablets) and liquids. Absorption of vitamin B6 from supplements is similar to that ]. The most common vitamin B6 vitamer in supplements is pyridoxine (in the form of pyridoxine hydrochloride [HCl]), although some supplements contain PLP. Vitamin B6 supplements are available in oral capsules or tablets (including sublingual and chewable tablets) and liquids. Absorption of vitamin B6 from supplements is similar to that from food sources and does not differ substantially among the various forms of supplements [from food sources and does not differ substantially among the various forms of supplements [1]. Although the body absorbs large pharmacological doses of vitamin B6 well, it quickly eliminates most of the vitamin in the urine []. Although the body absorbs large pharmacological doses of vitamin B6 well, it quickly eliminates most of the vitamin in the urine [7].].

• About 28%–36% of the general population uses supplements containing vitamin B6 [About 28%–36% of the general population uses supplements containing vitamin B6 [8,,9]. Adults aged 51 years or older and children younger than 9 are more likely than members of other age groups to take supplements containing vitamin B6.]. Adults aged 51 years or older and children younger than 9 are more likely than members of other age groups to take supplements containing vitamin B6.• Vitamin B6 Intakes and StatusVitamin B6 Intakes and Status• Most children, adolescents, and adults in the United States consume the recommended amounts of vitamin B6, according to an analysis of data from the 2003–2004 National Health and Nutrition Examination Survey (NHANES) [Most children, adolescents, and adults in the United States consume the recommended amounts of vitamin B6, according to an analysis of data from the 2003–2004 National Health and Nutrition Examination Survey (NHANES) [ 9]. The average vitamin B6 intake is about 1.5 mg/day in women and 2 mg/day in men []. The average vitamin B6 intake is about 1.5 mg/day in women and 2 mg/day in men [1].].• However, 11% of vitamin B6 supplement users and 24% of people in the United States who do not take supplements containing vitamin B6 have low plasma PLP concentrations (less than 20 nmol/L) [However, 11% of vitamin B6 supplement users and 24% of people in the United States who do not take supplements containing vitamin B6 have low plasma PLP concentrations (less than 20 nmol/L) [9]. In the 2003–2004 NHANES analysis, plasma PLP concentrations were low even in some groups that took 2.0–2.9 mg/day, which is higher than the current RDA. Among supplement users and nonusers, plasma PLP levels were much lower in women than men, non-Hispanic ]. In the 2003–2004 NHANES analysis, plasma PLP concentrations were low even in some groups that took 2.0–2.9 mg/day, which is higher than the current RDA. Among supplement users and nonusers, plasma PLP levels were much lower in women than men, non-Hispanic

blacks than non-Hispanic whites, current smokers than never smokers, and people who were underweight than those of normal weight. Teenagers had the lowest vitamin B6 concentrations, followed by adults aged 21–44 years. However, plasma PLP levels in the elderly were not particularly low, even in those who did not use supplements. Based on these data, the authors of this analysis concluded that the current RDAs might not guarantee adequate vitamin B6 status blacks than non-Hispanic whites, current smokers than never smokers, and people who were underweight than those of normal weight. Teenagers had the lowest vitamin B6 concentrations, followed by adults aged 21–44 years. However, plasma PLP levels in the elderly were not particularly low, even in those who did not use supplements. Based on these data, the authors of this analysis concluded that the current RDAs might not guarantee adequate vitamin B6 status in many population groups [in many population groups [9].].

• PLP concentrations tend to be low in people with alcohol dependence; those who are obese; and pregnant women, especially those with preeclampsia or eclampsia [PLP concentrations tend to be low in people with alcohol dependence; those who are obese; and pregnant women, especially those with preeclampsia or eclampsia [1]. They are also low in people with malabsorption syndromes such as celiac disease, Crohn's disease, and ulcerative colitis []. They are also low in people with malabsorption syndromes such as celiac disease, Crohn's disease, and ulcerative colitis [3].].• Vitamin B6 DeficiencyVitamin B6 Deficiency• Isolated vitamin B6 deficiency is uncommon; inadequate vitamin B6 status is usually associated with low concentrations of other B-complex vitamins, such as vitamin B12 and folic acid [Isolated vitamin B6 deficiency is uncommon; inadequate vitamin B6 status is usually associated with low concentrations of other B-complex vitamins, such as vitamin B12 and folic acid [2]. Vitamin B6 deficiency causes biochemical changes that become more obvious as the deficiency progresses []. Vitamin B6 deficiency causes biochemical changes that become more obvious as the deficiency progresses [2].].• Vitamin B6 deficiency is associated with microcytic anemia, electroencephalographic abnormalities, dermatitis with cheilosis (scaling on the lips and cracks at the corners of the mouth) and glossitis (swollen tongue), depression and confusion, and weakened immune function [Vitamin B6 deficiency is associated with microcytic anemia, electroencephalographic abnormalities, dermatitis with cheilosis (scaling on the lips and cracks at the corners of the mouth) and glossitis (swollen tongue), depression and confusion, and weakened immune function [ 1,,2]. Individuals with borderline vitamin B6 concentrations or mild deficiency might have no deficiency signs or symptoms for months or even years. In infants, vitamin B6 deficiency causes ]. Individuals with borderline vitamin B6 concentrations or mild deficiency might have no deficiency signs or symptoms for months or even years. In infants, vitamin B6 deficiency causes

irritability, abnormally acute hearing, and convulsive seizures [irritability, abnormally acute hearing, and convulsive seizures [2].].• End-stage renal diseases, chronic renal insufficiency, and other kidney diseases can cause vitamin B6 deficiency [End-stage renal diseases, chronic renal insufficiency, and other kidney diseases can cause vitamin B6 deficiency [3]. In addition, vitamin B6 deficiency can result from malabsorption syndromes, such as celiac disease, Crohn's disease, and ulcerative colitis. Certain genetic diseases, such as homocystinuria, can also cause vitamin B6 deficiency []. In addition, vitamin B6 deficiency can result from malabsorption syndromes, such as celiac disease, Crohn's disease, and ulcerative colitis. Certain genetic diseases, such as homocystinuria, can also cause vitamin B6 deficiency [ 2]. Some medications, such as antiepileptic drugs, can lead to deficiency over time.]. Some medications, such as antiepileptic drugs, can lead to deficiency over time.• Groups at Risk of Vitamin B6 InadequacyGroups at Risk of Vitamin B6 Inadequacy• Frank vitamin B6 deficiencies are relatively rare in the United States but some individuals might have marginal vitamin B6 status [Frank vitamin B6 deficiencies are relatively rare in the United States but some individuals might have marginal vitamin B6 status [2]. The following groups are among those most likely to have inadequate intakes of vitamin B6.]. The following groups are among those most likely to have inadequate intakes of vitamin B6.• Individuals with Impaired Renal FunctionIndividuals with Impaired Renal Function

People with poor renal function, including those with end-stage renal disease and chronic renal insufficiency, often have low vitamin B6 concentrations [People with poor renal function, including those with end-stage renal disease and chronic renal insufficiency, often have low vitamin B6 concentrations [3]. Plasma PLP concentrations are also low in patients receiving maintenance kidney dialysis or intermittent peritoneal dialysis, as well as those who have undergone a kidney transplant, perhaps due to increased metabolic clearance of PLP []. Plasma PLP concentrations are also low in patients receiving maintenance kidney dialysis or intermittent peritoneal dialysis, as well as those who have undergone a kidney transplant, perhaps due to increased metabolic clearance of PLP [ 10]. Patients with kidney disease often show clinical symptoms similar to those ]. Patients with kidney disease often show clinical symptoms similar to those of people with vitamin B6 deficiency [of people with vitamin B6 deficiency [10].].

• Individuals with Autoimmune DisordersIndividuals with Autoimmune DisordersPeople with rheumatoid arthritis often have low vitamin B6 concentrations, and vitamin B6 concentrations tend to decrease with increased disease severity [People with rheumatoid arthritis often have low vitamin B6 concentrations, and vitamin B6 concentrations tend to decrease with increased disease severity [3]. These low vitamin B6 levels are due to the inflammation caused by the disease and, in turn, increase the inflammation associated with the disease. Although vitamin B6 supplements can normalize vitamin B6 concentrations in patients with rheumatoid arthritis, they do not suppress the production of ]. These low vitamin B6 levels are due to the inflammation caused by the disease and, in turn, increase the inflammation associated with the disease. Although vitamin B6 supplements can normalize vitamin B6 concentrations in patients with rheumatoid arthritis, they do not suppress the production of inflammatory cytokines or decrease levels of inflammatory markers [inflammatory cytokines or decrease levels of inflammatory markers [3,,11].].

• Patients with celiac disease, Crohn's disease, ulcerative colitis, inflammatory bowel disease, and other malabsorptive autoimmune disorders tend to have low plasma PLP concentrations [Patients with celiac disease, Crohn's disease, ulcerative colitis, inflammatory bowel disease, and other malabsorptive autoimmune disorders tend to have low plasma PLP concentrations [3]. The mechanisms for this effect are not known. However, celiac disease is associated with lower pyridoxine absorption, and low PLP concentrations in inflammatory bowel disease could be due to the inflammatory response []. The mechanisms for this effect are not known. However, celiac disease is associated with lower pyridoxine absorption, and low PLP concentrations in inflammatory bowel disease could be due to the inflammatory response [ 3].].• People with Alcohol DependencePeople with Alcohol Dependence

Plasma PLP concentrations tend to be very low in people with alcohol dependence [Plasma PLP concentrations tend to be very low in people with alcohol dependence [1]. Alcohol produces acetaldehyde, which decreases net PLP formation by cells and competes with PLP in protein binding []. Alcohol produces acetaldehyde, which decreases net PLP formation by cells and competes with PLP in protein binding [1,,3]. As a result, the PLP in cells might be more susceptible to hydrolysis by membrane-bound phosphatase. People with alcohol dependence might benefit from pyridoxine supplementation []. As a result, the PLP in cells might be more susceptible to hydrolysis by membrane-bound phosphatase. People with alcohol dependence might benefit from pyridoxine supplementation [3].].• Vitamin B6 and HealthVitamin B6 and Health• Cardiovascular DiseaseCardiovascular Disease

Scientists have hypothesized that certain B vitamins (folic acid, vitamin B12, and vitamin B6) might reduce cardiovascular disease risk by lowering homocysteine levels [Scientists have hypothesized that certain B vitamins (folic acid, vitamin B12, and vitamin B6) might reduce cardiovascular disease risk by lowering homocysteine levels [1,,12]. Therefore, several clinical trials have assessed the safety and efficacy of supplemental doses of B vitamins to reduce heart disease risk. Evaluating the impact of vitamin B6 from many of these trials is challenging because these studies also included folic acid and vitamin B12 supplementation. For ]. Therefore, several clinical trials have assessed the safety and efficacy of supplemental doses of B vitamins to reduce heart disease risk. Evaluating the impact of vitamin B6 from many of these trials is challenging because these studies also included folic acid and vitamin B12 supplementation. For example, the Heart Outcomes Prevention Evaluation 2 (HOPE 2) trial, which included more than 5,500 adults with known cardiovascular disease, found that supplementation for 5 years with vitamin B6 (50 mg/day), vitamin B12 (1 mg/day), and folic acid (2.5 mg/day) reduced homocysteine levels and decreased stroke risk by about 25%, but the study did not include a separate vitamin B6 group [example, the Heart Outcomes Prevention Evaluation 2 (HOPE 2) trial, which included more than 5,500 adults with known cardiovascular disease, found that supplementation for 5 years with vitamin B6 (50 mg/day), vitamin B12 (1 mg/day), and folic acid (2.5 mg/day) reduced homocysteine levels and decreased stroke risk by about 25%, but the study did not include a separate vitamin B6 group [ 13].].

• Moreover, most other large clinical trials have failed to demonstrate that supplemental B vitamins actually reduce the risk of cardiovascular events, even though they lower homocysteine levels. For example, a randomized clinical trial in 5,442 women aged 42 or older found no effect of vitamin B6 supplementation (50 mg/day) in combination with 2.5 mg folic acid and 1 mg vitamin B12 on cardiovascular disease risk [Moreover, most other large clinical trials have failed to demonstrate that supplemental B vitamins actually reduce the risk of cardiovascular events, even though they lower homocysteine levels. For example, a randomized clinical trial in 5,442 women aged 42 or older found no effect of vitamin B6 supplementation (50 mg/day) in combination with 2.5 mg folic acid and 1 mg vitamin B12 on cardiovascular disease risk [ 14]. Two large randomized controlled trials, the ]. Two large randomized controlled trials, the Norwegian Vitamin Trial and the Western Norway B Vitamin Intervention Trial, did include a group that received only vitamin B6 supplements (40 mg/day). The combined analysis of data from these two trials showed no benefit of vitamin B6 supplementation, with or without folic acid (0.8 mg/day) plus vitamin B12 (0.4 mg/day), on major cardiovascular events in 6,837 patients with ischemic heart disease [Norwegian Vitamin Trial and the Western Norway B Vitamin Intervention Trial, did include a group that received only vitamin B6 supplements (40 mg/day). The combined analysis of data from these two trials showed no benefit of vitamin B6 supplementation, with or without folic acid (0.8 mg/day) plus vitamin B12 (0.4 mg/day), on major cardiovascular events in 6,837 patients with ischemic heart disease [ 12]. In a trial of adults who had suffered a nondisabling stroke, ]. In a trial of adults who had suffered a nondisabling stroke, supplementation with high or low doses of a combination of vitamins B6 and B12 and folic acid for 2 years had no effect on subsequent stroke incidence, cardiovascular events, or risk of death [supplementation with high or low doses of a combination of vitamins B6 and B12 and folic acid for 2 years had no effect on subsequent stroke incidence, cardiovascular events, or risk of death [15].].

• The research to date provides little evidence that supplemental amounts of vitamin B6, alone or with folic acid and vitamin B12, can help reduce the risk or severity of cardiovascular disease and stroke.The research to date provides little evidence that supplemental amounts of vitamin B6, alone or with folic acid and vitamin B12, can help reduce the risk or severity of cardiovascular disease and stroke.• CancerCancer

• Some research has associated low plasma vitamin B6 concentrations with an increased risk of certain kinds of cancer [Some research has associated low plasma vitamin B6 concentrations with an increased risk of certain kinds of cancer [3]. For example, a meta-analysis of prospective studies found that people with a vitamin B6 intake in the highest quintile had a 20% lower risk of colorectal cancer than those with an intake in the lowest quintile []. For example, a meta-analysis of prospective studies found that people with a vitamin B6 intake in the highest quintile had a 20% lower risk of colorectal cancer than those with an intake in the lowest quintile [ 16].].• However, the small number of clinical trials completed to date has not shown that vitamin B6 supplementation can help prevent cancer or reduce its impact on mortality. For example, an analysis of data from two large randomized, double-blind, placebo-controlled trials in Norway found no association between vitamin B6 supplementation and cancer incidence, mortality, or all-cause mortality [However, the small number of clinical trials completed to date has not shown that vitamin B6 supplementation can help prevent cancer or reduce its impact on mortality. For example, an analysis of data from two large randomized, double-blind, placebo-controlled trials in Norway found no association between vitamin B6 supplementation and cancer incidence, mortality, or all-cause mortality [ 17].].• Cognitive FunctionCognitive Function

Poor vitamin B6 status has been hypothesized to play a role in the cognitive decline that some older adults experience [Poor vitamin B6 status has been hypothesized to play a role in the cognitive decline that some older adults experience [18]. Several studies have demonstrated an association between vitamin B6 and brain function in the elderly. For example, an analysis of data from the Boston Normative Aging Study found associations between higher serum vitamin B6 concentrations and better memory test scores in 70 men aged 54–81 years []. Several studies have demonstrated an association between vitamin B6 and brain function in the elderly. For example, an analysis of data from the Boston Normative Aging Study found associations between higher serum vitamin B6 concentrations and better memory test scores in 70 men aged 54–81 years [ 19].].• However, a systematic review of 14 randomized controlled trials found insufficient evidence of an effect of vitamin B6 supplementation alone or in combination with vitamin B12 and/or folic acid on cognitive function in people with normal cognitive function, dementia, or ischemic vascular disease [However, a systematic review of 14 randomized controlled trials found insufficient evidence of an effect of vitamin B6 supplementation alone or in combination with vitamin B12 and/or folic acid on cognitive function in people with normal cognitive function, dementia, or ischemic vascular disease [ 18]. According to this review, most of the studies were of low quality and limited applicability. A Cochrane review found no evidence that short-term vitamin B6 ]. According to this review, most of the studies were of low quality and limited applicability. A Cochrane review found no evidence that short-term vitamin B6

supplementation (for 5–12 weeks) improves cognitive function or mood in the two studies that the authors evaluated [supplementation (for 5–12 weeks) improves cognitive function or mood in the two studies that the authors evaluated [20]. The review did find some evidence that daily vitamin B6 supplements (20 mg) can affect biochemical indices of vitamin B6 status in healthy older men, but these changes had no overall impact on cognition.]. The review did find some evidence that daily vitamin B6 supplements (20 mg) can affect biochemical indices of vitamin B6 status in healthy older men, but these changes had no overall impact on cognition.• More evidence is needed to determine whether vitamin B6 supplements might help prevent or treat cognitive decline in elderly people.More evidence is needed to determine whether vitamin B6 supplements might help prevent or treat cognitive decline in elderly people.• Premenstrual SyndromePremenstrual Syndrome

Some evidence suggests that vitamin B6 supplements could reduce the symptoms of premenstrual syndrome (PMS), but conclusions are limited due to the poor quality of most studies [Some evidence suggests that vitamin B6 supplements could reduce the symptoms of premenstrual syndrome (PMS), but conclusions are limited due to the poor quality of most studies [21]. A meta-analysis of nine published trials involving almost 1,000 women with PMS found that vitamin B6 is more effective in reducing PMS symptoms than placebo, but most of the studies analyzed were small and several had methodological weaknesses []. A meta-analysis of nine published trials involving almost 1,000 women with PMS found that vitamin B6 is more effective in reducing PMS symptoms than placebo, but most of the studies analyzed were small and several had methodological weaknesses [ 21]. A more recent double-]. A more recent double-blind, randomized controlled trial in 94 women found that 80 mg pyridoxine taken daily over the course of three cycles was associated with statistically significant reductions in a broad range of PMS symptoms, including moodiness, irritability, forgetfulness, bloating, and, especially, anxiety [blind, randomized controlled trial in 94 women found that 80 mg pyridoxine taken daily over the course of three cycles was associated with statistically significant reductions in a broad range of PMS symptoms, including moodiness, irritability, forgetfulness, bloating, and, especially, anxiety [ 22]. The potential effectiveness of vitamin B6 in alleviating the mood-related symptoms of PMS could be due to its role as a cofactor in neurotransmitter biosynthesis []. The potential effectiveness of vitamin B6 in alleviating the mood-related symptoms of PMS could be due to its role as a cofactor in neurotransmitter biosynthesis [23]. Although ]. Although vitamin B6 shows promise for alleviating PMS symptoms, more research is needed before drawing firm conclusions.vitamin B6 shows promise for alleviating PMS symptoms, more research is needed before drawing firm conclusions.

• Nausea and Vomiting in PregnancyNausea and Vomiting in PregnancyAbout half of all women experience nausea and vomiting in the first few months of pregnancy, and about 50%–80% experience nausea only [About half of all women experience nausea and vomiting in the first few months of pregnancy, and about 50%–80% experience nausea only [24,,25]. Although this condition is generally known as "morning sickness," it often lasts throughout the day. The condition is not life threatening and typically goes away after 12–20 weeks, but its symptoms can disrupt a woman's social and physical functioning.]. Although this condition is generally known as "morning sickness," it often lasts throughout the day. The condition is not life threatening and typically goes away after 12–20 weeks, but its symptoms can disrupt a woman's social and physical functioning.

• Prospective studies on vitamin B6 supplements to treat morning sickness have had mixed results. In two randomized, placebo-controlled trials, 30–75 mg of oral pyridoxine per day significantly decreased nausea in pregnant women who were experiencing nausea [Prospective studies on vitamin B6 supplements to treat morning sickness have had mixed results. In two randomized, placebo-controlled trials, 30–75 mg of oral pyridoxine per day significantly decreased nausea in pregnant women who were experiencing nausea [ 26,,27]. The authors of a recent Cochrane review of studies on interventions for nausea and vomiting in pregnancy could not draw firm conclusions on the value of vitamin B6 to control the symptoms of ]. The authors of a recent Cochrane review of studies on interventions for nausea and vomiting in pregnancy could not draw firm conclusions on the value of vitamin B6 to control the symptoms of morning sickness [morning sickness [25].].

• Randomized trials have shown that a combination of vitamin B6 and doxylamine (an antihistamine) is associated with a 70% reduction in nausea and vomiting in pregnant women and lower hospitalization rates for this problem [Randomized trials have shown that a combination of vitamin B6 and doxylamine (an antihistamine) is associated with a 70% reduction in nausea and vomiting in pregnant women and lower hospitalization rates for this problem [ 24,,28].].• The American Congress of Obstetrics and Gynecology (ACOG) recommends monotherapy with 10–25 mg of vitamin B6 three or four times a day to treat nausea and vomiting in pregnancy [The American Congress of Obstetrics and Gynecology (ACOG) recommends monotherapy with 10–25 mg of vitamin B6 three or four times a day to treat nausea and vomiting in pregnancy [28]. If the patient's condition does not improve, ACOG recommends adding doxylamine. Before taking a vitamin B6 supplement, pregnant women should consult a physician because doses could approach the UL.]. If the patient's condition does not improve, ACOG recommends adding doxylamine. Before taking a vitamin B6 supplement, pregnant women should consult a physician because doses could approach the UL.• Health Risks from Excessive Vitamin B6Health Risks from Excessive Vitamin B6• High intakes of vitamin B6 from food sources have not been reported to cause adverse effects [High intakes of vitamin B6 from food sources have not been reported to cause adverse effects [1]. However, chronic administration of 1–6 g oral pyridoxine per day for 12–40 months can cause severe and progressive sensory neuropathy characterized by ataxia (loss of control of bodily movements) []. However, chronic administration of 1–6 g oral pyridoxine per day for 12–40 months can cause severe and progressive sensory neuropathy characterized by ataxia (loss of control of bodily movements) [ 7,,29-32]. Symptom severity appears to be dose dependent, and the symptoms usually stop if the patient discontinues the pyridoxine supplements as soon as the neurologic ]. Symptom severity appears to be dose dependent, and the symptoms usually stop if the patient discontinues the pyridoxine supplements as soon as the neurologic

symptoms appear. Other effects of excessive vitamin B6 intakes include painful, disfiguring dermatological lesions; photosensitivity; and gastrointestinal symptoms, such as nausea and heartburn [symptoms appear. Other effects of excessive vitamin B6 intakes include painful, disfiguring dermatological lesions; photosensitivity; and gastrointestinal symptoms, such as nausea and heartburn [1,,2,,29].].• The scientific literature includes isolated case reports of congenital defects in the infants of women who took pyridoxine supplements during the first half of pregnancy [The scientific literature includes isolated case reports of congenital defects in the infants of women who took pyridoxine supplements during the first half of pregnancy [ 7]. However, a more recent observational study found no association between pyridoxine supplementation (mean dose 132.3 ± 74 mg/day) in pregnant women starting at 7 weeks gestation and continuing for 9 ± 4.2 weeks and teratogenic effects in the women's infants []. However, a more recent observational study found no association between pyridoxine supplementation (mean dose 132.3 ± 74 mg/day) in pregnant women starting at 7 weeks gestation and continuing for 9 ± 4.2 weeks and teratogenic effects in the women's infants [ 33].].• The FNB has established ULs for vitamin B6 that apply to both food and supplement intakes (Table 3) [The FNB has established ULs for vitamin B6 that apply to both food and supplement intakes (Table 3) [1]. The FNB noted that although several reports show sensory neuropathy occurring at doses lower than 500 mg/day, studies in patients treated with vitamin B6 (average dose of 200 mg/day) for up to 5 years found no evidence of this effect. Based on limitations in the data on potential harms from long-term use, the FNB halved the dose used in these studies to ]. The FNB noted that although several reports show sensory neuropathy occurring at doses lower than 500 mg/day, studies in patients treated with vitamin B6 (average dose of 200 mg/day) for up to 5 years found no evidence of this effect. Based on limitations in the data on potential harms from long-term use, the FNB halved the dose used in these studies to

establish a UL of 100 mg/day for adults. ULs are lower for children and adolescents based on body size. The ULs do not apply to individuals receiving vitamin B6 for medical treatment, but such individuals should be under the care of a physician.establish a UL of 100 mg/day for adults. ULs are lower for children and adolescents based on body size. The ULs do not apply to individuals receiving vitamin B6 for medical treatment, but such individuals should be under the care of a physician.• Table 3: Tolerable Upper Intake Levels (ULs) for Vitamin B6 [Table 3: Tolerable Upper Intake Levels (ULs) for Vitamin B6 [1] Age Male Female Pregnancy Lactation Birth to 6 monthsNot possible to establish*Not possible to establish* 7–12 monthsNot possible to establish*Not possible to establish* 1–3 years30 mg30 mg 4–8 years40 mg40 mg 9–13 years60 mg60 mg 14–18 years80 mg80 mg80 mg80 mg 19+ years100 mg100 mg100 mg100 mg *Breast milk, formula, and food should be the only sources of vitamin B6 for infants.] Age Male Female Pregnancy Lactation Birth to 6 monthsNot possible to establish*Not possible to establish* 7–12 monthsNot possible to establish*Not possible to establish* 1–3 years30 mg30 mg 4–8 years40 mg40 mg 9–13 years60 mg60 mg 14–18 years80 mg80 mg80 mg80 mg 19+ years100 mg100 mg100 mg100 mg *Breast milk, formula, and food should be the only sources of vitamin B6 for infants.• Interactions with MedicationsInteractions with Medications• Vitamin B6 can interact with certain medications, and several types of medications might adversely affect vitamin B6 levels. A few examples are provided below. Individuals taking these and other medications on a regular basis should discuss their vitamin B6 status with their health care providers.Vitamin B6 can interact with certain medications, and several types of medications might adversely affect vitamin B6 levels. A few examples are provided below. Individuals taking these and other medications on a regular basis should discuss their vitamin B6 status with their health care providers.• CycloserineCycloserine

Cycloserine (Seromycin®) is a broad-spectrum antibiotic used to treat tuberculosis. In combination with pyridoxal phosphate, cycloserine increases urinary excretion of pyridoxine [Cycloserine (Seromycin®) is a broad-spectrum antibiotic used to treat tuberculosis. In combination with pyridoxal phosphate, cycloserine increases urinary excretion of pyridoxine [6]. The urinary loss of pyridoxine might exacerbate the seizures and neurotoxicity associated with cycloserine. Pyridoxine supplements can help prevent these adverse effects.]. The urinary loss of pyridoxine might exacerbate the seizures and neurotoxicity associated with cycloserine. Pyridoxine supplements can help prevent these adverse effects.• Antiepileptic MedicationsAntiepileptic Medications

Some antiepileptic drugs, including valproic acid (Depakene®, Stavzor®), carbamazepine (Carbatrol®, Epitol®, Tegretol®, and others), and phenytoin (Dilantin®) increase the catabolism rate of vitamin B6 vitamers, resulting in low plasma PLP concentrations and hyperhomocysteinemia [Some antiepileptic drugs, including valproic acid (Depakene®, Stavzor®), carbamazepine (Carbatrol®, Epitol®, Tegretol®, and others), and phenytoin (Dilantin®) increase the catabolism rate of vitamin B6 vitamers, resulting in low plasma PLP concentrations and hyperhomocysteinemia [ 34,,35]. High homocysteine levels in antiepileptic drug users might increase the risk of epileptic seizures and systemic vascular events, including stroke, and reduce the ability to control ]. High homocysteine levels in antiepileptic drug users might increase the risk of epileptic seizures and systemic vascular events, including stroke, and reduce the ability to control seizures in patients with epilepsy. Furthermore, patients typically use antiepileptic drugs for years, increasing their risk of chronic vascular toxicity.seizures in patients with epilepsy. Furthermore, patients typically use antiepileptic drugs for years, increasing their risk of chronic vascular toxicity.

• Some research also indicates that pyridoxine supplementation (200 mg/day for 12–120 days) can reduce serum concentrations of phenytoin and phenobarbital, possibly by increasing the drugs' metabolism [Some research also indicates that pyridoxine supplementation (200 mg/day for 12–120 days) can reduce serum concentrations of phenytoin and phenobarbital, possibly by increasing the drugs' metabolism [ 32,,36]. Whether lower pyridoxine doses have any effect is not known []. Whether lower pyridoxine doses have any effect is not known [6].].• TheophyllineTheophylline

Theophylline (Aquaphyllin®, Elixophyllin®, Theolair®, Truxophyllin®, and many others) can prevent or treat shortness of breath, wheezing, and other breathing problems caused by asthma, chronic bronchitis, emphysema, and other lung diseases. Patients treated with theophylline often have low plasma PLP concentrations, which could contribute to the neurological and central nervous system side effects associated with theophylline, including seizures [Theophylline (Aquaphyllin®, Elixophyllin®, Theolair®, Truxophyllin®, and many others) can prevent or treat shortness of breath, wheezing, and other breathing problems caused by asthma, chronic bronchitis, emphysema, and other lung diseases. Patients treated with theophylline often have low plasma PLP concentrations, which could contribute to the neurological and central nervous system side effects associated with theophylline, including seizures [ 6,,32].].• Vitamin B6 and Healthful DietsVitamin B6 and Healthful Diets• The federal government's 2010 The federal government's 2010 Dietary Guidelines for AmericansDietary Guidelines for Americans notes that "nutrients should come primarily from foods. Foods in nutrient-dense, mostly intact forms contain not only the essential vitamins and minerals that are often contained in nutrient supplements, but also dietary fiber and other naturally occurring substances that may have positive health effects. … Dietary supplements…may be advantageous in specific situations to increase intake of a specific notes that "nutrients should come primarily from foods. Foods in nutrient-dense, mostly intact forms contain not only the essential vitamins and minerals that are often contained in nutrient supplements, but also dietary fiber and other naturally occurring substances that may have positive health effects. … Dietary supplements…may be advantageous in specific situations to increase intake of a specific

vitamin or mineral" [vitamin or mineral" [37].].• For more information about building a healthful diet, refer to the For more information about building a healthful diet, refer to the Dietary Guidelines for Americans and the U.S. Department of Agriculture's food guidance system, and the U.S. Department of Agriculture's food guidance system, MyPlate. . • The The Dietary Guidelines for AmericansDietary Guidelines for Americans describes a healthy diet as one that: describes a healthy diet as one that:• Emphasizes a variety of fruits, vegetables, whole grains, and fat-free or low-fat milk and milk products. Many fruits, vegetables, and whole grains are good sources of vitamin B6. Some ready-to-eat breakfast cereals are fortified with vitamin B6.Emphasizes a variety of fruits, vegetables, whole grains, and fat-free or low-fat milk and milk products. Many fruits, vegetables, and whole grains are good sources of vitamin B6. Some ready-to-eat breakfast cereals are fortified with vitamin B6.• Includes lean meats, poultry, fish, beans, eggs, and nuts. Fish, beef, and turkey contain high amounts of vitamin B6. Beans and nuts are also sources of vitamin B6.Includes lean meats, poultry, fish, beans, eggs, and nuts. Fish, beef, and turkey contain high amounts of vitamin B6. Beans and nuts are also sources of vitamin B6.• Is low in saturated fats, trans fats, cholesterol, salt (sodium), and added sugars.Is low in saturated fats, trans fats, cholesterol, salt (sodium), and added sugars.• Stays within your daily calorie needsStays within your daily calorie needs

• 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 ( show 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 folic acid deficiency" ). Minerals and fat-soluble vitamins are also reviewed elsewhere. (

See "Overview of fat-soluble vitamins").• 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. It is now essentially unheard of in the western world. However, pellagra 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 [1]. However, in 1937, Elvehjen and his colleagues discovered that nicotinic acid was effective in the Rx of pellagra in dogs. In the 1950s, tryptophan, a precursor of niacin, replaced it in the Rx of pellagra and research connected the low source of niacin and tryptophan in corn-containing foods to the development of pellagra [ 2]. Niacin had been isolated since 1867, but it was not until 1937 that it became known as the anti-pellagra factor [ 1].• Structure — Nicotinic acid and nicotinamide are the two common forms of the vitamin most often referred to as niacin. 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.• Absorption — 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 [ 3]. 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).• Activity — 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 [ 4]. 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 [4].• Deficiency — 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.• 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 [ 4]. 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 "The carcinoid syndrome"). • Prolonged use of isoniazid since isoniazid depletes stores of pyridoxal phosphate, which enhances the production of tryptophan, a precursor of niacin. • Hartnup disease, an autosomal recessive congenital disorder [5]. 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 Rx is aimed towards depleting stores and supplementing the diet with niacin as well as proteins and amino acids [ 6]. (See "Overview of the hereditary ataxias" ). • Toxicity — The most documented and best known side effect of niacin is the flushing reaction associated with the crystalline nicotinic acid and not nicotinamide [7]. 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 [ 8]. Despite the inconvenience and the undesirability of the reactions, there are no serious sequelae from flushing [ 7].• In pharmacological doses (eg, 1000 to 3000 mg/day), other common side effects of niacin are flushing, nausea, vomiting, pruritus, hives, elevation in serum aminotransferases [9], and constipation. A niacin-induced myopathy has also been described [10]. 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 [8]. At such high doses, the hepatic 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 have been reported in the literature [ 11]. 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 [12]. 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 [ 12]. There is some speculation that the metabolites of nicotinic acid in these high concentrations may lead to growth retardation in infants and children [ 13].• 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 [14]. 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 [ 2]. 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 [15].• Daily Values — The 1998 Daily Values (DVs, previously Recommended Dietary Allowances or RDAs) are 15 to 20 NEs ( Niacin Equivalents) per day for adult males, and 13 to 15 NEs for adult females (show table 2) [16]. 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.• 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.• VITAMIN B5 (PANTOTHENIC ACID) — Pantothenic acid (PA) was first synthesized successfully in 1940 [17]. It was not until 1947 when its biologically active form, known as Coenzyme A (CoA), was recognized [ 18]. 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.• Metabolism — The major dietary sources of pantothenic acid are egg yolk, liver, kidney, broccoli, and milk [17]. Once ingested and broken down, CoA is hydrolyzed in the small intestine to form pantothenic acid. It is then absorbed in the jejunum and secreted into the bloodstream via a sodium-dependent transport system [ 19]. 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 [ 20].• Excess pantothenic acid is hydrolyzed and excreted as cysteamine and pantothenate via the kidney [21]. 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 biotin-dependent processes, such as beta-oxidation of fatty acids and the oxidative degradation of amino acids (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 [ 22].• Deficiency — Many animal models have been used to study the deficiency of panthenoic acid [ 17]. In rats, growth failure, hemorrhage, and necrosis of adrenal cortex, dermatitis, and achromotrichia (gray hair) have been described [ 23]. In primates, there is some evidence for impaired synthesis of heme, leading to anemia [ 17]. 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 [ 24].• Toxicity — There is no known toxicity for pantothenic acid. Excess intake is excreted by the kidneys.• Daily Values — No actual DV has yet been determined for pantothenic acid. Since 1998, these ranges were represented as Adequate Dietary Intakes (ADI) rather than DV. The ADI is 5 mg per day for adults, 6 mg/day for pregnant women, and 1.7 to 3 mg/day for infants and children [ 16].• 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. The last factor 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 [ 25].• Structure — Biotin consists of two cyclic molecules: a ureido and a tetrahydrothiophene ring (show figure 1A-1B). In vivo, it is found in a number of different isomers, not all of which are active enzymatically [ 26]. D-biotin is the only biologically active isomer. Biocytin, bound with lysine, is also active. Many analogs of biotin are actually antagonists.• Absorption — 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 [ 27].• Actions — Biotin is an essential component of several enzyme complexes in mammals, all of which are involved in carbohydrate and lipid metabolism. They include [ 28]:• Acetyl-CoA carboxylase (ACC) • Pyruvate carboxylase (PC) • Propionyl CoA carboxylase (PCC) • Beta-methylcrotonyl CoA carboxylase (MCC) • Biotin acts as a CO2 carrier on the surface of each enzyme. As a result, it has an essential role in many processes, including protein 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 [ 28]. 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 below) [ 29].• 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 [ 26]. 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 — In addition to acquired biotin deficiency, there are two congenital disorders of biotin metabolism that lead to deficiency of the four biotin-dependent carboxylases (a condition referred to as multiple carboxylase deficiency). These two genetic disorders are essentially the result of a deficiency of biotinidase or holocarboxylase synthetase (HCS), two enzymes crucial to the biotin metabolism pathway [ 25]. Biotinidase deficiency is associated with a slow but progressive loss of biotin in the urine, leading to the typical

organic aciduria of multiple carboxylase deficiency [30].• Two main types of multiple carboxylase deficiency (MCD) have been recognized based upon the clinical presentation and serum biotin levels:• The neonatal type, which is seen in the first week of life and is manifested by lethargy, poor muscle tone, and vomiting [ 31]. Dermatological manifestations are common, but the cause of death is usually severe metabolic acidosis, which is often preceded by the dermatologic changes [ 32]. • Late onset, which is generally seen prior to age one. Clinical manifestations include dermatitis of the extremities, a range of neurologic signs, and symptoms of hypotonia, myoclonus, and seizure. Metabolic acidosis and organic aciduria may be variably present [ 30]. (See "Overview of the hereditary ataxias"). In addition, several forms of immunodeficiencies have been described in these patients [ 26]. • MCD is diagnosed definitively by studying enzymes from lymphocytes. Newborns are screened for these deficiencies since the Rx is simple and effective if oral supplementation of biotin is initiated early enough. Delayed Rx may fail to reverse the neurologic sequelae, and has been associated with neurologic and developmental delay [ 24,30].• Toxicity — No toxicity of excess biotin intake has been described.• Daily Values — There are still no accurate data estimating dietary requirements for biotin. Adequate intakes are 30 to 100 mcg/day for adults according to a report from the Food and Nutrition Board of 1998 [ 16]. Biotin can be found in a variety of plants, but is found in highest levels in the liver, egg yolk, soybean products, and yeast [ 26].• 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 [ 33].• Chemistry — Riboflavin's chemical nomenclature is 7,8-dimethyl-10 (1'-D-ribityl) isoalloxazine (show figure 2). 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 [ 34].• Absorption — Riboflavin is poorly soluble in water. 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 [ 35]. 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 [ 36]. There also appears to be some enterohepatic circulation for riboflavin facilitated by bile salts [ 35]. Riboflavin

eventually reaches the hepatocytes where its metabolism into flavin mononucleotide (FMN) and flavin-adenine dinucleotide (FAD) takes place.• Metabolism and activity — The metabolic conversions of flavin take place in the cytoplasm of cells of the body, particularly in the liver, heart, and kidney [ 34]. 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 [ 35]. 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 [ 37]. 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 [ 34].• 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, normocytic-normochromic anemia, and seborrheic dermatitis [ 37]. 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 [ 38]. 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 • 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 [39] • Long-term use of phenobarbital and other barbiturates, which may lead to oxidation of riboflavin and impair its function [ 40] • 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 [ 34].• Daily Values — The DV for riboflavin for people of all ages is calculated as 0.6 mg per 1000 kcal. According to 1998 recommendations, the range of DVs is from 0.4 mg for infants to 1.2 mg per day for adults ( show table 2) [16,41]. Riboflavin is supplied in many foods, including meats, fish, eggs and milk, green vegetables, yeast, and enriched foods.• Some intramitochondrial beta-oxidation defects may respond to riboflavin therapy. (See "Causes of metabolic myopathies"). In addition, patients with HIV infection who are treated with zidovudine or stavudine may develop lactic acidosis that is reversed by riboflavin therapy [ 42]. (See "Electrolyte disturbances with HIV infection").• 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 [ 43]. 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.• 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 [ 44]. 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 [ 44]. 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 [ 44]. 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 [ 45].• Activity — 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 [ 44]. Thiamine has a role in the initiation of nerve impulse propagation that is independent of its coenzyme functions [ 44].• Deficiency — An assessment of thiamine deficiency can be obtained by measuring erythrocyte thiamine transketolase (ETKA), the blood thiamine concentration, or transketolase urinary thiamine excretion (with or without a 5 mg thiamine load) [ 46]. The most reliable method is the measurement of ETKA and determination of the effect of thiamine pyrophosphate (TPP) on ETKA (the normal ETKA range varies depending upon the laboratory). A low ETKA, along with more than a 16 percent response to TPP, establishes the diagnosis of thiamine

deficiency [43]. 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 [ 47]. 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 [ 48].• Adult beriberi — Adult beriberi is described as dry or wet. Dry beriberi is the development of a symmetrical peripheral neuropathy characterized by both sensory and motor impairments, mostly of the distal extremities. Wet beriberi includes a neuropathy, as well as signs of cardiac involvement with cardiomegaly, cardiomyopathy, congestive heart failure, peripheral edema, and tachycardia [ 43].• 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 [49-51]. However, this remains controversial because of questions involving assay validity and a lack of controlled trials [ 52]. (See "Causes of dilated cardiomyopathy").• Wernicke-Korsakoff syndrome — Wernicke's disease is a triad of nystagmus, ophthalmoplegia, and ataxia, along with confusion. Korsakoff's psychosis is impaired short-term memory and confabulation with otherwise grossly normal cognition. 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 Wernicke-Korsakoff's syndrome 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 [ 53]. (See "Wernicke's encephalopathy").• The neurologic consequences of Wernicke's syndrome are treatable with thiamine supplementation. Intravenous thiamine administration should be initiated at 50 mg per day until the same dose is tolerated orally [ 54]. It is common practice to delay giving dextrose to alcoholic patients until thiamine supplementation has been given to avoid precipitating Wernicke's encephalopathy. However, this notion is largely unsupported. Uptake of thiamine into cells is slower than that of dextrose [ 55]. Thus, withholding dextrose until the administration of thiamine

is complete may not achieve the goal of repleting intracellular thiamine prior to exposing cells to dextrose and may prove detrimental in patients with altered mental status who are hypoglycemic.• Leigh's syndrome — Leigh's subacute necrotizing encephalomyopathy is a condition also seen in thiamine deficiency. It is a sporadic mitochondrial disorder with a subacute neurologic course, leading to symmetrical foci of spongy necrosis and demyelinating changes in the thalami, brainstem, pons, and even peripheral nerves. It is manifested with ataxia, dysarthria, movement disorders, areflexia, muscle atrophy, and weakness. Only about 100 cases of Leigh's have been reported in the literature [ 56].• Toxicity — No real syndrome of excess thiamine exists since the kidneys can rapidly clear almost all excess thiamine [ 57]. Its half-life is 9.5 to 18.5 days.• Daily Values — Thiamine is an important cofactor for enzymes involved in amino-acid and carbohydrate metabolism. Thiamine requirements are based upon the total caloric intake. Current recommendations in the United States are 0.5 mg per 1000 Kcal for children, adolescents, and adults ( show table 2) [57].• 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 [ 43]. 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 [ 58].• Thiamine can be administered via intravenous and intramuscular routes. For the Rx 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 [ 43].• 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.• Activity — 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 [ 59], and steroid hormone modulation.• Requirements — Recommended daily requirements of pyridoxine have been set at 2.0 mg for adult males, 1.6 mg for adult females, 0.3 mg for infants younger than three months of age, 0.6 mg for children, 1 to 1.7, 1.7 mg for males, 1 to 1.5 mg for females, 1.9 mg during pregnancy, and 2.0 mg during lactation ( show table 2) [60].• 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.• Deficiency and Rx — 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, cystathionuria, and xanthurenic aciduria mimic vitamin B6 deficiency.• Depressed concentrations of PLP have been reported in asthma, diabetes, alcoholism, heart disease, pregnancy, breast cancer, Hodgkin's disease, and sickle-cell anemia [ 61]. 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 [ 62]. (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; normal ranges from 27 to 75 nmol/L for males and 26 to 93 nmol/L for females. • Erythrocyte transaminase activity with and without PLP added has been used as a functional test of pyridoxine status. • Urinary 4-pyridoxic acid excretion greater than 3.0 mmol/day can be used as an indicator of adequate short-term vitamin B6 status. • Urinary excretion of xanthurenic acid is normally less than 65 mmol/day following a 2 g tryptophan load. • Pyridoxine has been used to tre

Leigh Syn.Leigh Syn.• Autosomal R; mitochondrial;Autosomal R; mitochondrial;

X-linkedX-linked• Infantile subac. necrotising Infantile subac. necrotising

encephalomyelopathy: ataxia, encephalomyelopathy: ataxia, dysarthria, areflexia, muscle atrophy, hypotonia; feeding dysarthria, areflexia, muscle atrophy, hypotonia; feeding difficulties; FTT; motor regression; brain stem signsdifficulties; FTT; motor regression; brain stem signs

• Symmetrical foci of spongy necrosis and demyelination in Symmetrical foci of spongy necrosis and demyelination in thalami, brainstem, pons, peripheral nervesthalami, brainstem, pons, peripheral nerves