VitaminsVitamins andand MineralsMinerals forfor thethe GastroenterologistGastroenterologist

AmyAmy Tiu,Tiu, MDMD Feb.Feb. 9,9, 20062006 7:00AM7:00AM conferenceconference ObjectivesObjectives

„„DescriptionDescription fatfat--solublesoluble andand waterwater solublesoluble vitaminsvitamins „„TraceTrace mineralsminerals (zinc,(zinc, selenium,selenium, iodide,iodide, copper,copper, chromium)chromium) „„DeficiencyDeficiency andand ToxicityToxicity „„SourcesSources andand RecommendationsRecommendations „„ClinicalClinical implicationimplication HistoryHistory

„ 18351835 BritishBritish ParliamentParliament passedpassed thethe MerchantMerchant SeamanSeaman’’ss ActAct thatthat requiredrequired lemonlemon juicejuice toto bebe includedincluded inin thethe rationsrations ofof sailorssailors toto preventprevent scurvyscurvy „ 19121912 CasimirCasimir FunkFunk coinedcoined thethe termterm vitaminevitamine „ DailyDaily ValuesValues (DV(DV waswas RDA)RDA) establishedestablished byby thethe NationalNational AcademyAcademy ofof SciencesSciences andand NationalNational ResearchResearch CouncilCouncil asas thethe amountamount toto preventprevent grossgross deficiencydeficiency syndromessyndromes WhichWhich foodfood hashas thethe mostmost vitaminvitamin A?A?

Sweet potatoes Beef liver Cantoloupe 1 RE = 10 IU MVI = 3500 IU TPN = 3300 IU VitaminVitamin AA

„ Prevents xerophthalmia (abnormalities in corneal and conjunctival development) „ Phototransduction „ Cellular differentiation and integrity of the eye „ Ancient Egyptians used liver to treat night blindness VitaminVitamin AA DeficiencyDeficiency

„„ MainMain featurefeature (nyctalopia)(nyctalopia) Vitamin NightNight blindnessblindness A „„ IssuesIssues RetinalRetinal formationformation ofof rhodopsinrhodopsin

„„ OtherOther featuresfeatures Corneal,Corneal, conjunctivaconjunctiva Dermatitis,Dermatitis, keratomalaciakeratomalacia PhrynodermaPhrynoderma (follicular(follicular hyperkeratosis)hyperkeratosis)

„ BlockageBlockage ofof hairhair folliclesfollicles withwith plugsplugs ofof keratinkeratin „ Dry,Dry, scaly,scaly, roughrough „ ForearmsForearms andand thighsthighs GIGI patientspatients atat riskrisk ofof VitaminVitamin AA deficiencydeficiency „ CrohnCrohn’’ss (small(small bowel)bowel) „ CeliacCeliac spruesprue „ CholestaticCholestatic liverliver diseasedisease „ PancreaticPancreatic deficiencydeficiency „ ShortShort gutgut „ CysticCystic fibrosisfibrosis VitaminVitamin AA toxicitytoxicity

„ Arctic explorers who feasted on polar bear liver (10 million IU/lb) acute overdose with n/v; fatigue, weakness, headache, anorexia „ Dermatitis, xerosis, hair loss, joint pain, hyperostosis, hepatomegaly, pseudotumor VitaminVitamin AA toxicity:toxicity: 33 syndromessyndromes

„ AcuteAcute (>660,000(>660,000 units):units): n/v;n/v; vertigo;vertigo; blurryblurry vision;vision; drowsiness,drowsiness, malaisemalaise „ ChronicChronic (higher(higher thanthan 10X10X dailydaily values):values): ataxia;ataxia; alopecia;alopecia; hyperlipidemia;hyperlipidemia; hepatotoxicity,hepatotoxicity, bonebone andand mskmsk pain;pain; visualvisual impairments;impairments; increaseincrease riskrisk osteoporoticosteoporotic fracturesfractures (need(need toto avoidavoid >5000>5000 units)units) „ TeratogenicTeratogenic:: firstfirst trimester;trimester; spontaneousspontaneous abortion;abortion; fetalfetal anomaliesanomalies WhatWhat vitaminvitamin waswas addedadded inin thisthis experimentexperiment toto makemake thethe ratsrats fertile?fertile?

„ 19221922 EvansEvans andand BishopBishop discovereddiscovered aa substancesubstance thatthat waswas deficientdeficient inin ratsrats fedfed aa dietdiet thatthat containedcontained lardlard andand thatthat resultedresulted inin infertilityinfertility „ WhenWhen theythey addedadded aa lipidlipid extractextract thethe ratsrats becamebecame sterile.sterile. VitaminVitamin EE (Tocopherol)(Tocopherol)

„ EightEight naturallynaturally occurringoccurring compoundscompounds (alpha,(alpha, beta,beta, gamma,gamma, andand delta)delta) „ FreeFree radicalradical scavenger,scavenger, protectingprotecting polyunsaturatedpolyunsaturated fattyfatty acidsacids (PUFA),(PUFA), aa majormajor structuralstructural componentcomponent ofof cellcell membranesmembranes fromfrom peroxidationperoxidation

VitaminVitamin EE ••ReducedReduced plasmaplasma andand hepatichepatic vitaminvitamin EE levelslevels havehave beenbeen reportedreported inin liverliver diseasedisease ••VitaminVitamin EE hashas antioxidant/antioxidant/ antianti--inflammatoryinflammatory propertiesproperties VitaminVitamin EE 10000 protectsprotects againstagainst 9000 8000 CClCCl44 7000 6000 hepatotoxicityhepatotoxicity T 5000 AL 4000 3000 2000 1000 0 CCl4 None 1 mg 3 mg Treatment

Zern’s lab, Am. J Physiol 267, 1994 VitaminVitamin EE deficiency:deficiency: RARERARE

„ AtAt risk:risk: cirrhosis,cirrhosis, cholestaticcholestatic liverliver disease,disease, cysticcystic fibrosis,fibrosis, smallsmall bowelbowel bacterialbacterial overgrowth,overgrowth, pancreaticpancreatic insufficiency,insufficiency, glutengluten sensitivesensitive enteropathy,enteropathy, regionalregional enteritisenteritis „ DeficiencyDeficiency proportionalproportional toto magnitudemagnitude andand durationduration ofof steatorrheasteatorrhea „ SkeletalSkeletal myopathy,myopathy, spinocerebellarspinocerebellar ataxia,ataxia, pigmentedpigmented retinopathy;retinopathy; hemolytichemolytic anemiaanemia (G(G--66--PD)PD) deficiency;deficiency; areflexiaareflexia VitaminVitamin EE toxicity:toxicity: UnusualUnusual

„ MayMay interfereinterfere withwith vitaminvitamin K,K, arachidonicarachidonic acidacid metabolismmetabolism „ LargeLarge oraloral supplementssupplements associatedassociated withwith necrotizingnecrotizing enterocolitisenterocolitis inin infantsinfants „ Headache,Headache, MyopathyMyopathy VitaminVitamin EE

„ VitaminVitamin EE supplementationsupplementation withwith aa dosedose >> 400400 IU/dayIU/day waswas associatedassociated withwith aa significantlysignificantly increasedincreased riskrisk ofof allall--causecause mortalitymortality (95%(95% CICI 33--7474 perper 10,00010,000 persons);persons); (meta(meta analysisanalysis ofof 1919 RCTsRCTs)) „ NoteNote 11 mgmg (alpha(alpha tocopheroltocopherol equivalent)equivalent) equalsequals 1.491.49 IUIU „ RecRec:: 1010 mg/daymg/day forfor men;men; 88 mg/daymg/day forfor womenwomen „ MVIMVI == 3030 IU;IU; TPNTPN == 1010 IUIU VitaminVitamin KK

„ 19301930 IsolatedIsolated byby DoisyDoisy andand colleaguescolleagues „ ““antihemorrhagicantihemorrhagic factorfactor”” „ HenrickHenrick DamDam foundfound itit capablecapable ofof reversingreversing dietarydietary inducedinduced bleedingbleeding disordersdisorders inin chickschicks VitaminVitamin K:K: 33 formsforms

„ PhylloquinonePhylloquinone:: greengreen plantsplants „ MenaquinoneMenaquinone:: formedformed asas thethe resultsresults ofof bacterialbacterial actionaction inin thethe intestinalintestinal tracttract „ WaterWater--solublesoluble formform (K1(K1 andand K2)K2) „ NoneNone ofof thethe formsforms areare storedstored inin appreciableappreciable amountsamounts „ DestroyedDestroyed byby alkalialkali andand lightlight VitaminVitamin KK metabolismmetabolism

„„RequiresRequires pancreaticpancreatic andand biliarybiliary functionfunction forfor intactintact absorptionabsorption „„ProteinProtein boundbound andand requiresrequires pancreaticpancreatic enzymesenzymes inin thethe smallsmall intestineintestine forfor liberationliberation VitaminVitamin KK functionfunction

„ CofactorCofactor forfor carboxylasecarboxylase „ VitaminVitamin KK essentialessential forfor activityactivity ofof clottingclotting factorsfactors 7,9,107,9,10 prothrombin,prothrombin, andand anticoagulantanticoagulant proteinprotein CC andand SS VitaminVitamin KK deficiencydeficiency

„ Risk:Risk: TPN,TPN, longlong termterm antibioticsantibiotics „ EasyEasy bruisabilitybruisability,, mucosalmucosal bleeding,bleeding, splintersplinter hemorrhages,hemorrhages, melena,melena, hematuriahematuria „ HemorrhagicHemorrhagic diseasedisease ofof thethe newborn:newborn: developsdevelops withinwithin thethe firstfirst weekweek ofof lifelife „ DVDV isis 6565 toto 8080 micrograms/daymicrograms/day whichwhich cancan bebe achievedachieved withwith dietarydietary intakeintake „ TPNTPN == 150150 microgramsmicrograms „ MVIMVI == 2525 microgramsmicrograms VitaminVitamin KK ToxicityToxicity

„ Infants:Infants: hemolytichemolytic anemia;anemia; hyperbilirubinemia,hyperbilirubinemia, jaundice,jaundice, andand kernicteruskernicterus „ WithWith rapidrapid IVIV infusioninfusion possiblepossible flushingflushing andand cardiovascularcardiovascular collapsecollapse VitaminVitamin DD (calciferol)(calciferol)

„ FirstFirst recognizedrecognized byby McCollumMcCollum asas thethe componentcomponent ofof codcod liverliver oiloil thatthat waswas cablecable ofof curingcuring ricketsrickets „ RoleRole inin calciumcalcium homeostasishomeostasis andand bonebone metabolismmetabolism „ MayMay havehave aa rolerole inin inhibitinginhibiting thethe carcinogeniccarcinogenic effectseffects ofof bilebile acidsacids throughthrough calciumcalcium bindingbinding inin thethe bowelbowel lumenlumen MetabolismMetabolism Skin photoisomerization from D to D3

Liver hydroxylates vitamin D

Kidney further hydroxylates

Active form

CausesCauses ofof VitaminVitamin DD deficiencydeficiency

„ DecreasedDecreased intake/intake/ InsufficiencyInsufficiency sunlightsunlight „ FatFat malabsorptionmalabsorption (celiac(celiac disease,disease, pancreaticpancreatic insufficiency,insufficiency, IBD,IBD, cysticcystic fibrosis,fibrosis, postpost-- gastrectomygastrectomy states,states, andand smallsmall bowelbowel resectionresection „ ImpairedImpaired liver/kidneyliver/kidney „ SymtomsSymtoms:: Rickets,Rickets, osteomalacia,osteomalacia, hypophosphatemiahypophosphatemia (more(more thanthan hypocaclemiahypocaclemia),), musclemuscle weakness,weakness, phosphaturiaphosphaturia BoneBone MineralMineral AbnormalitiesAbnormalities inin IBDIBD „ StudiesStudies estimatingestimating BMDBMD prevalenceprevalence varyvary widelywidely „ 45%45% IBDIBD patientspatients havehave decreaseddecreased BMDBMD » 40% increase risk of fracture in IBD pts1 » 2.5 fold increased risk in women with CD2

„ MultipleMultiple factorsfactors contributecontribute toto increasedincreased riskrisk » Lifetime steroid use » BMI » Calcium/vitamin D deficiency 1. Bernstein Ann Int Med 2000; 133: 795-9 2. Verstergaard Gut 2000; 46:176-81 VitaminVitamin DD ToxicityToxicity

„ MinimumMinimum 200200 IU/day;IU/day; PregnancyPregnancy 400400 IU/day;IU/day; MustMust bebe withwith calciumcalcium toto preventprevent fracturefracture „ IfIf childrenchildren >1,800>1,800 IUIU oror adultsadults >2,000>2,000 IUIU toxictoxic „ ExcesiveExcesive calcificationcalcification ofof bone,bone, kidneykidney stones,stones, metastaticmetastatic calcificationcalcification ofof softsoft tissuestissues (kidney(kidney andand lung)lung) headache,headache, weakness,weakness, n/v,n/v, constipation,constipation, polyuria,polyuria, polydipsiapolydipsia „ TPNTPN == 200200 IUIU „ MVIMVI == 400400 IUIU WhatWhat isis thisthis vitamin?vitamin?

„ EpidemicEpidemic amongstamongst corncorn eatingeating populationpopulation ofof thethe UnitedUnited StatesStates „ HopiHopi IndiansIndians werewere sparedspared ofof thisthis becausebecause theythey wouldwould cookcook thethe maturemature corncorn inin alkalinealkaline woodwood ashash thatthat wouldwould releaserelease thisthis substancesubstance

Deficiency causes this

NiacinNiacin deficiencydeficiency (B3)(B3)

„ CarcinoidCarcinoid syndromesyndrome becausebecause tryptophantryptophan isis metabolizedmetabolized toto 55--OHOH tryptophantryptophan andand serotoninserotonin ratherrather thanthan toto nicotinicnicotinic acidacid

„ ProlongedProlonged useuse ofof isoniazidisoniazid sincesince isoniazidisoniazid depletesdepletes storesstores ofof pyridoxalpyridoxal phosphate,phosphate, whichwhich enhancesenhances thethe productionproduction ofof tryptophan,tryptophan, aa precursorprecursor ofof niacinniacin HartnupHartnup diseasedisease

„ AutosomoalAutosomoal recessiverecessive congenitalcongenital disorderdisorder „ DefectDefect inin transporttransport ofof tryptophantryptophan „ DiagnosisDiagnosis byby detectingdetecting aa numbernumber ofof neutralneutral aminoamino acidsacids inin thethe urineurine (not(not seenseen withwith dietarydietary pellagra)pellagra) NiacinNiacin toxicitytoxicity

„ Flushing,Flushing, n/v/pruritusn/v/pruritus,, hives,hives, elevationelevation inin serumserum aminotranferasesaminotranferases andand constipation;constipation; myopathymyopathy (doses(doses ofof 10001000--30003000 mg/day)mg/day) Note:Note: toto treattreat dyslipidemiadyslipidemia 11 toto 33 grams/daygrams/day „ Hyperglycemia,Hyperglycemia, hyperuricemiahyperuricemia (caution(caution inin thosethose withwith gout)gout) „ DV:DV: 1515--2020 NENE males;males; 1313--1515 NENE forfor femalesfemales „ 6060 mgmg tryptophantryptophan == 11 mgmg niacinniacin „ TPNTPN == 4040 mgmg „ MVIMVI == 2020 mgmg WhatWhat vitaminvitamin causescauses ““burningburning feetfeet syndromesyndrome””?? „ HumanHuman volunteersvolunteers fedfed anan antimetaboliteantimetabolite forfor threethree monthsmonths developeddeveloped burning,burning, distaldistal paresthesias,paresthesias, andand gastrointestinalgastrointestinal distressdistress

„ FoundFound inin eggegg yolk,yolk, liver,liver, kidney,kidney, brocoolibrocooli,, andand milkmilk VitaminVitamin B5B5 (Pantothenic(Pantothenic Acid)Acid)

„ 1947,1947, CoenzymeCoenzyme AA (CoA)(CoA) „ EssentialEssential inin firstfirst stepstep ofof thethe tricarboxylictricarboxylic acidacid cycle,cycle, crucialcrucial rolerole inin thethe synthesissynthesis ofof manymany moleculesmolecules (A,D,(A,D, cholesterol,cholesterol, steroids,steroids, hemeheme A,A, FA,FA, AA,AA, andand proteins)proteins) „ NoNo knownknown toxicitytoxicity „ NoNo DVDV butbut 1010 mgmg consideredconsidered 100100 %% DVDV „ TPNTPN == 1515 mgmg „ MVIMVI == 1010 mgmg BiotinBiotin

„ 19421942 SydenstricketerSydenstricketer etet alal firstfirst inducedinduced deficiencydeficiency inin adultadult volunteersvolunteers byby feedingfeeding themthem aa dietdiet toto whichwhich 200200 gg ofof dehydrateddehydrated eggegg white.white. „ BiotinBiotin actsacts asas CO2CO2 carreircarreir onon thethe surfacesurface ofof enzymesenzymes (carboxylases);(carboxylases); essentialessential rolerole inin proteinprotein inin DNADNA synthesissynthesis andand cellcell replicationreplication „ GutGut bacteriabacteria producesproduces it;it; mostlymostly absorbedabsorbed inin smallsmall intestineintestine „ MVIMVI == 3030 microgramsmicrograms (10%(10% ofof DV)DV) „ TPNTPN == 6060 microgramsmicrograms BiotinBiotin DeficiencyDeficiency „ MayMay occuroccur inin patientspatients onon ChronicChronic TPNTPN „ Conjunctivitis, Dermatitis around the eyes, nose and mouth, alopecia with loss of normal hair coloring, skin infections, and neurologic symptoms such as ataxia, hypotonia, increase Before After cholesterol, and severe lethargy, depression, and possibly parasthesia and hallucinations

VitaminVitamin B2B2 (Riboflavin)(Riboflavin)

„ PrimarilyPrimarily asas aa componentcomponent ofof coenzymescoenzymes flavinflavin adenineadenine dinucleotidedinucleotide (FAD)(FAD) andand flavinflavin adenineadenine mononucleotidemononucleotide (FMN)(FMN) „ CatalyzeCatalyze oxidationoxidation--reductionreduction reactionsreactions inin cellscells andand areare hydrogenhydrogen carrierscarriers inin thethe mitochondrialmitochondrial systemsystem „ ActivelyActively absorbedabsorbed fromfrom thethe proximalproximal smallsmall intestine;intestine; absorptionabsorption increasedincreased byby thethe presencepresence ofof foodfood VitaminVitamin B2B2 RiboflavinRiboflavin deficiencydeficiency

„ Intake must be low for several months to develop „ Photphobia, lacrimation, eye irritation, loss of visual acuity, sore lips, mouth, tongu „ Ariboflavinosis „ Seborrheic dermatitis „ Angular stomatitis; cheilosis (may be in naicin, folic acid, thiamin, B6, B12 deficiency too) RiboflavinRiboflavin deficiencydeficiency

„ More common than generally appreciated „ Urinary riboflavin excretion and the erythrocyte glutathione reductase assay are better functional indices of riboflavin deficiency „ At risk: anorexia; lactose intolerant, celiec sprue, short bowel, rare inborn errors of metabolism, long term use of phenobarbital and other barbiturates (these oxidate riboflavin na dimpair function) „ DV: 0.6 mg per 1000 kcal „ MVI = 1.7 mg „ TPN = 3.6 mg RiboflavinRiboflavin andand HIVHIV

„ PatientsPatients withwith HIVHIV whowho developdevelop lacticlactic acidosisacidosis (zidovudine(zidovudine oror stavudine)stavudine) maymay bebe treatedtreated withwith riboflavin.riboflavin.

„ SomeSome intramitchondrialintramitchondrial betabeta--oxidationoxidation defectsdefects maymay respondrespond toto riboflavinriboflavin therapytherapy VitaminVitamin B1B1 (thiamine)(thiamine)

„ Antiberiberi factor „ Absorption is in the small intestine „ Pyrophosphate (TPP) or the triphosphate (TTP) „ Catalyst for conversion of pyruvate to acetyl CoA „ Involved in initiation of nerve impulse „ Transketolation of the pentose phosphate pathway ThiamineThiamine DeficiencyDeficiency

„„ MainMain featuresfeatures BeriberiBeriberi (peripheral(peripheral neuropathy,neuropathy, CHF,CHF, musclemuscle weakness)weakness) WernickeWernicke’s’s EncephalopathyEncephalopathy (ataxia,(ataxia, nystagmus,nystagmus, confusion)confusion) KorsakoffKorsakoff’s’s SyndromeSyndrome (loss(loss ofof memory,memory, confabulation)confabulation) „„ IssuesIssues ChronicChronic EtoHEtoH abuseabuse GlucoseGlucose infusioninfusion precipitatesprecipitates deficiencydeficiency DifferentiatingDifferentiating EtoHEtoH relatedrelated problems,problems, traumatrauma „„ DiagnosisDiagnosis -- clinicalclinical suspicionsuspicion „„ TreatmentTreatment -- Intravenous,Intravenous, intramuscular,intramuscular, thenthen oraloral OftenOften empiric.empiric. NeedNeed 0.50.5 mgmg perper 10001000 KcalKcal TPNTPN == 66 mg;mg; MVIMVI == 1.51.5 mgmg WetWet BerberiBerberi

„ PrecipitatedPrecipitated byby aa highhigh carbohydratecarbohydrate intakeintake alongalong withwith strenuousstrenuous physicalphysical exertionexertion withwith edemaedema duedue toto biventricularbiventricular heartheart failurefailure andand pulmonarypulmonary congestioncongestion „ TenseTense calfcalf muscles,muscles, fastfast pulse,pulse, distendeddistended neckneck veins,veins, increasedincreased BP,BP, decreasedecrease UOPUOP „ AdministrationAdministration ofof glucoseglucose inin TPNTPN withwith lessless thanthan thethe requirementrequirement ofof thiaminethiamine cancan resultresult inin thethe rapidrapid developmentdevelopment ofof wetwet beriberiberiberi DryDry BeriberiBeriberi

„ WorseningWorsening ofof polyneuritispolyneuritis ofof earlyearly stagestage „ LossLoss ofof functionfunction oror paralysisparalysis ofof lowerlower extremitiesextremities „ WernickeWernicke--KorsakoffKorsakoff (need(need 5050 mgmg perper dayday toto treat)treat) „ ToTo treattreat berberiberberi (50(50--100100 mgmg IVIV perper dayday forfor 77--1414 days)days) oror popo 1010 mgmg perper dayday WhatWhat isis LeighLeigh’’ss syndrome?syndrome?

„ ConditionCondition seenseen inin thiaminethiamine deficiencydeficiency „ SubacuteSubacute necrotizingnecrotizing encephalomyopathyencephalomyopathy „ SporadicSporadic mitochondrialmitochondrial disorderdisorder „ Ataxia,Ataxia, dysarthria,dysarthria, movementmovement disorders,disorders, areflexia,areflexia, musclemuscle atrophy,atrophy, andand weaknessweakness NameName thethe vitaminvitamin

„ 1515 toto 20%20% ofof womenwomen takingtaking oraloral steroidsteroid contraceptivescontraceptives maymay havehave thisthis deficiencydeficiency „ InfantsInfants whowho werewere fedfed formulaformula missingmissing thisthis vitaminvitamin developeddeveloped convulsionsconvulsions „ ChildrenChildren withwith anan inborninborn errorerror ofof metabolismmetabolism ofof thisthis vitaminvitamin requirerequire largeslarges dosedose inin thethe neonatalneonatal periodperiod toto avoidavoid convulsionsconvulsions andand MRMR „ PatientsPatients treatedtreated withwith isoniazidisoniazid developdevelop peripheralperipheral neuritisneuritis Not found in typical MVI (centrum) TPN = 6 mg

VitaminVitamin B6B6 deficiencydeficiency

„ NonspecificNonspecific stomatitis,stomatitis, glossitis,glossitis, cheiolosischeiolosis,, irritability,irritability, confusion,confusion, andand depressiondepression „ GeneticGenetic syndromessyndromes affectingaffecting PLPPLP dependentdependent enzymeenzyme mimicmimic deficiencydeficiency ((homocysinuriahomocysinuria,, cystathionuriacystathionuria)) VitaminVitamin B6B6 toxicitytoxicity

„ RequiresRequires longlong termterm megadosesmegadoses 250250 mg/daymg/day „ PeripheralPeripheral neuropathyneuropathy „ DermatosesDermatoses „ PhotosensitivityPhotosensitivity „ DizzinessDizziness „ NauseaNausea WhatWhat vitaminvitamin deficiencydeficiency waswas thethe majormajor causecause ofof deathdeath duringduring thethe greatgreat potatopotato famine?famine? VitaminVitamin CC

„ AscorbicAscorbic acidacid absorbedabsorbed inin thethe distaldistal smallsmall intestineintestine „ ProvidesProvides electronselectrons neededneeded toto reducereduce molecularmolecular oxygenoxygen „ GreatestGreatest concentrationsconcentrations areare foundfound inin thethe pituitary,pituitary, adrenal,adrenal, brain,brain, leukocytes,leukocytes, andand thethe eyeeye VitaminVitamin CC

„ FattyFatty acidacid transporttransport (long(long chainchain fattyfatty acids)acids) „ CollagenCollagen synthesissynthesis „ NeurotransmittersNeurotransmitters „ ProstaglandinProstaglandin metabolismmetabolism ScurvyScurvy

„ Impaired collagen „ ImpairedImpaired woundwound synthesis healinghealing „ Occur as early as three „ WeaknessWeakness months „ „ Ecchymoses „ JointJoint swellingswelling „ Bleeding gums „ CoiledCoiled hairhair „ Petechiae „ NeuropathyNeuropathy „ Hyperkeratosis Hyperkeratosis „ VasomotorVasomotor instabilityinstability „ Sjogren’s syndrome „ NeedNeed 1010 mgmg toto preventprevent „ Arthralgias VitaminVitamin CC

Scurvy VitaminVitamin CC deficiencydeficiency

„ DrugDrug andand alcoholalcohol abusersabusers „ LowLow intakeintake associatedassociated withwith gastricgastric cancer;cancer; butbut supplementationsupplementation hashas notnot beenbeen studiedstudied „ NoteNote breastbreast milkmilk providesprovides ADEQUATEADEQUATE sourcesource „ Elderly,Elderly, institutionalized,institutionalized, oror chronicallychronically illill patientspatients atat riskrisk „ DV:DV: 6060 mg/daymg/day nonnon pregnant;pregnant; 125125 mg/daymg/day inin elderlyelderly „ MVIMVI == 6060 mgmg „ TPNTPN == 200200 mgmg ascorbicascorbic acidacid VitaminVitamin CC ToxicityToxicity

„ RequiresRequires oneone gramgram quantitiesquantities „ FalseFalse negativenegative stoolstool guaiacguaiac „ DiarrheaDiarrhea andand abdominalabdominal bloatingbloating „ FatalFatal cardiaccardiac arrhythmiasarrhythmias inin patientspatients withwith ironiron overloadoverload (due(due toto oxidativeoxidative injury)injury) „ Controversy:Controversy: riskrisk factorfactor forfor calciumcalcium oxalateoxalate stonesstones (patients(patients whowho predispositionpredisposition oror onon hemodialysishemodialysis shouldshould avoidavoid excessive)excessive)

VitaminVitamin B12B12

„ IsolatedIsolated inin 19481948 „ RequiredRequired forfor DNADNA synthesissynthesis (transfers(transfers methylmethyl group)group) „ MeatMeat andand dairydairy productsproducts areare thethe onlyonly sourcesource forfor humanshumans VitaminVitamin B12B12 absorptionabsorption

„ GastricGastric acid/pepsinacid/pepsin releasesreleases itit fromfrom foodfood proteinprotein „ B12B12 bindsbinds toto RR proteinprotein (from(from salivarysalivary glandgland andand gastricgastric mucosa)mucosa) „ B12B12--RR requiresrequires pancreaticpancreatic proteasesproteases toto releaserelease B12;B12; needneed acidacid environmentenvironment „ B12B12 thenthen bindsbinds toto intrinsicintrinsic factorfactor (parietal(parietal cells)cells) toto facilitatefacilitate absorptionabsorption inin thethe ileumileum CausesCauses ofof B12B12 deficiencydeficiency „ GastricGastric abnormalitiesabnormalities (gastrectomy)(gastrectomy) „ PerniciusPernicius anemiaanemia (autoimmune(autoimmune attackattack onon IF)IF) „ H.PyloriH.Pylori infectioninfection „ SmallSmall bowelbowel diseasedisease (ileal(ileal resection/bypass;resection/bypass; crohncrohn’’ss)) „ PancreatitisPancreatitis (pancreatic(pancreatic insufficiency)insufficiency) „ DietDiet (vegan,(vegan, chronicchronic alcoholism)alcoholism) „ AgentsAgents thatthat blockblock absorptionabsorption – Neomycin – Biguanides (eg, metformin) – PPI – N20 anesthesia inhibits methionin synthase CausesCauses ofof vitaminvitamin B12B12 deficiencydeficiency

„ DiphllobothriumDiphllobothrium LatumLatum „ 1010 toto 20%20% ofof peoplepeople takingtaking metforminmetformin (reversed(reversed withwith calcium)calcium) „ ImerslundImerslund GrasbeckGrasbeck’’ss diseasedisease oror juvenilejuvenile megaloblasticmegaloblastic anemiaanemia VitaminVitamin B12B12 deficiencydeficiency

„ Megaloblastic anemia „ Neurologic abnormalities „ Demyelinating disorder „ Painful parasthesias and loss of proprioception (symmetrical Legs > arms) „ Hypospermia „ Glossitis „ DV 2 microgram per day (western diet 5-7) Body store (2,000 micrograms) may take 5-6 years for deficiency to appear if from restriction alone_ „ TPN = 5 mcg „ MVI = 6 mcg FolicFolic acidacid

„ EstablishedEstablished asas essentialessential inin 19461946 „ NursesNurses’’ HealthHealth StudyStudy foundfound thatthat womenwomen whowho consumedconsumed folatefolate--containingcontaining supplementssupplements dailydaily forfor 1515 yearsyears werewere 75%75% lessless likelylikely toto developdevelop colorectalcolorectal cancercancer „ TheThe HealthHealth ProfessionalsProfessionals FollowFollow--upup studystudy showedshowed aa moderatemoderate riskrisk reductionreduction inin menmen receivingreceiving folatefolate forfor moremore thanthan 1010 yearsyears

CausesCauses ofof FolateFolate DeficiencyDeficiency

„ Nutritional deficiency (substance abuse, etoh, poor diet, overcooked foods, depressed patient, nursing home) „ Malabsorption (sprue, IBD, infiltrative bowel disease, short bowel syndrome) „ Drugs (methotrexate, trimethoprim, ethanol, phenytoin, sulfasaslazine) „ Increased requirements (pregnancy, lactation, chronic hemolysis, exfoliative dermatitis) „ Need: 200-400 micrograms/day „ TPN = 600 „ MVI = 400 FolateFolate deficiencydeficiency

„ AlcoholAlcohol abuseabuse onon lowlow folatefolate intakeintake cancan developdevelop megaloblastosismegaloblastosis withinwithin 55 toto 1010 weeksweeks (impairs(impairs enterohepaticenterohepatic cyclecycle andand inhibitsinhibits itsits absorption)absorption) „ Glossitis,Glossitis, intestinalintestinal mucosalmucosal dysfunction,dysfunction, megaloblasticmegaloblastic anemiaanemia (no(no neurologicneurologic abnormalities)abnormalities) SelectedSelected TraceTrace MicromineralsMicrominerals

Zinc,Zinc, Copper,Copper, Selenium,Selenium, Iodide,Iodide, Chromium,Chromium, Manganese,Manganese, MolybdenumMolybdenum ZincZinc

„ RequiredRequired forfor zinczinc metalloenzymesmetalloenzymes andand zinczinc fingerfinger proteinsproteins „ 1/31/3 ofof ingestedingested zinczinc absorbedabsorbed „ AcrodermatitisAcrodermatitis enteropathica:enteropathica: hereditaryhereditary diseasedisease ofof impairedimpaired zinczinc absorptionabsorption „ TPNTPN == 2.52.5 toto 44 mgmg „ MVIMVI == 1515 mgmg ZincZinc

Zinc supplementation tightens "leaky gut" in Crohn's disease. Sturniolo GC, Di Leo V, Ferronato A, D'Odorico A, D'Inca R. Inflamm Bowel Dis 2001 May;7(2):94-8

Intestinal Permeability before and after 8 weeks zinc therapy ConditionsConditions thatthat alteralter ZincZinc MetabolismMetabolism

„ IntestinalIntestinal ProcessesProcesses „ LiverLiver diseasedisease – IBD – ETOH – Short bowel – PBC – Jejunoileal bypass – Jejunoileal bypass – Viral hepatitis – Sprue „ TPN – Diarrhea TPN „ PancreaticPancreatic diseasedisease „ Sepsis/traumaSepsis/trauma – Schwachman’s „ EatingEating disordersdisorders syndrome „ AgingAging – CF ZincZinc deficiency:deficiency: TwoTwo categoriescategories

„ TrueTrue deficiencydeficiency –– PoorPoor intakeintake –– MucosalMucosal problemsproblems leadingleading toto decreaseddecreased absorptionabsorption –– DietaryDietary phytatephytate inhibitioninhibition (vegetarians)(vegetarians) –– DietaryDietary fiberfiber andand oxalateoxalate (vegetarians)(vegetarians) „ RedistributionRedistribution –– MediatedMediated byby ILIL--1,1, TNF,TNF, ILIL--6,6, ZincZinc DeficiencyDeficiency

„ SkinSkin lesionslesions „ AnorexiaAnorexia (alter(alter tastetaste andand smellsmell acuity)acuity) „ GrowthGrowth retardationretardation „ DepressedDepressed woundwound helainghelaing „ HypogonadismHypogonadism „ AlteredAltered immuneimmune functionfunction „ ImpairedImpaired nightnight vision,vision, alteredaltered vitaminvitamin AA metabolismmetabolism „ DiarrheaDiarrhea „ DepressedDepressed mentalmental functionfunction „ TeratogenesisTeratogenesis CopperCopper

„ CofactorCofactor forfor severalseveral oxidoreducteasesoxidoreducteases „ AceruloplamsinemiaAceruloplamsinemia:: lowlow plasmaplasma copper;copper; increasedincreased ironiron depsositsdepsosits inin thethe liver,liver, pancreas,pancreas, andand brain;brain; dementia,dementia, neurologicneurologic problems,problems, typetype II diabetesdiabetes „ RiskRisk ofof deficiency:deficiency: CF;CF; CrohnCrohn’’ss disease,disease, malabsorptivemalabsorptive disorders;disorders; patientspatients takingtaking excessexcess zinczinc „ WasWas notnot inin TPNTPN formulasformulas priorprior toto 1979;1979; TPNTPN == 0.30.3 –– 1.21.2 mgmg „ MVIMVI == 22 mgmg CopperCopper DeficiencyDeficiency

„„ MainMain featurefeature IronIron deficiencydeficiency anemiaanemia „„ IssuesIssues CoenzymeCoenzyme forfor oxidationoxidation ofof ferrousferrous →→ ferricferric ironiron ImpairedImpaired ironiron absorbtionabsorbtion,, marrowmarrow utilizationutilization „„ OtherOther featuresfeatures -- leukopenialeukopenia ageusiaageusia (taste)(taste) „„ DiagnosisDiagnosis -- clinicalclinical suspicion,suspicion, serumserum copper,copper, ceruloplasminceruloplasmin „„ ToxicityToxicity –– hepatichepatic necrosis,necrosis, coma,coma, ARF;ARF; hypotensionhypotension CopperCopper

„ ZincZinc inducesinduces metallothioneinmetallothionein andand IMPAIRSIMPAIRS coppercopper absorption;absorption; excessexcess zinczinc maymay leadlead toto deficiencydeficiency „ CopperCopper deficiencydeficiency resultsresults inin anemiaanemia NOTNOT responsiveresponsive toto ironiron supplementation,supplementation, neutropenia,neutropenia, andand lessless oftenoften hypopigmentationhypopigmentation,, immuneimmune dysfunctiondysfunction andand skeletalskeletal abnormalitiesabnormalities SeleniumSelenium DeficiencyDeficiency WhoWho isis atat risk?risk?

South Dakota Keshan China Hawaii SeleniumSelenium

„ SelenomethionineSelenomethionine „ KeshanKeshan diseasedisease:: „ RequiredRequired cofactorcofactor forfor endemicendemic proteinprotein andand DNADNA cardiomyopathycardiomyopathy thatthat synthesissynthesis effectseffects childrenchildren andand womenwomen ofof „ DeficiencyDeficiency waswas seenseen inin childbearing age in chronicchronic TPNTPN usersusers childbearing age in areas of China withwith cardiomyopathycardiomyopathy areas of China andand skeletalskeletal musclemuscle „ MVIMVI == 2020 mcgmcg dysfunctiondysfunction „ TPNTPN == 2020 toto 8080 mcgmcg SeleniumSelenium DeficiencyDeficiency

„„ MainMain featuresfeatures CongestiveCongestive heartheart failfailureure (Keshan(Keshan syndrome)syndrome) MuscleMuscle weaknessweakness „„ IssuesIssues RelatedRelated toto soilsoil contentcontent (mainland)(mainland) NotNot includedincluded inin mostmost MVIMVI KeyKey componentcomponent ofof glutathioneglutathione peroxidaseperoxidase (anti(anti-oxidant-oxidant freefree radicalradical scavenger)scavenger) ComplementsComplements antianti-oxidant-oxidant propertiesproperties ofof VitVit EE „„ DiagnosisDiagnosis -- clinicalclinical suspicionsuspicion onlyonly „„ TreatmentTreatment -- ReportedReported inin U.S.U.S. fromfrom supplementsupplement 180180 foldfold thethe amountamount labeled:labeled: nausea,nausea, emesis,emesis, hairhair lossloss,, nailnail changes,changes, mentalmental statusstatus changes,changes, andand peripheralperipheral neuropathyneuropathy IodineIodine

„ Used for synthesis of „ Toxicity:Toxicity: Goiter,Goiter, hypohypo triiodotyrosine (T3) and thyroxine (T4) oror hyperthyroidismhyperthyroidism „ Deficiency: Goiter and „ TPNTPN == 7070--140140 mcgmcg hypothyroidism „ MVIMVI == 150150 mcgmcg „ Cretinism: mental deficiency, spastic diplegia or quadriplegia, deaf mutism, dysarthria, shuffling giat, shortened stature, and hypothyroidism ChromiumChromium

„ 19571957 extractedextracted fromfrom porkpork kidneykidney termedtermed ““glucoseglucose tolerancetolerance factor")factor") correctedcorrected hyperglycemiahyperglycemia inin ratsrats „ InIn patientspatients withwith diabetesdiabetes requiringrequiring TPN,TPN, chromiumchromium deficiencydeficiency waswas indicatedindicated byby increasedincreased insulininsulin requirementsrequirements „ RequiredRequired forfor normalnormal lipidlipid andand carbohydratecarbohydrate metabolismmetabolism „ TPNTPN == 1010--2020 mcgmcg „ MVIMVI == 120120 mcgmcg ChromiumChromium DeficiencyDeficiency

„„ MainMain featurefeature -- GlucoseGlucoseGlucose intoleranceintolerance InsulinInsulin resistenceresistence „„ IssuesIssues CofactorCofactor toto insulininsulin forfor cellularcellular glucoseglucose absorptionabsorption GlucoseGlucose ToleranceTolerance FactorFactor (GTF)(GTF) „„ OtherOther featuresfeatures PoorPoor woundwound healinghealing NeurologicNeurologic -- peripheralperipheralperipheral neuropathy,neuropathy, ataxiaataxia ManganeseManganese

„ DeficiencyDeficiency firstfirst reportedreported 19721972 „ ComponentComponent ofof severalseveral enzymes;enzymes; requiresrequires bilebile forfor absorptionabsorption „ Deficiency:Deficiency: weightweight loss,loss, transienttransient dermatitis,dermatitis, n/v;n/v; changeschanges inin colorcolor,, andand slowslow growthgrowth ofof hair;hair; sterilitysterility „ StrikingStriking skeletalskeletal abnormalitiesabnormalities andand ataxiaataxia inin offspringoffspring inin deficientdeficient mothersmothers ManganeseManganese toxicitytoxicity

„ MinersMiners „ AccumulatesAccumulates inin liverliver „ AccumulatesAccumulates inin CNSCNS „ ParkinsonParkinson--likelike symptomssymptoms „ IronIron deficiencydeficiency enhancesenhances absorptionabsorption „ InIn TPNTPN (0.2(0.2--0.80.8 mg)mg) butbut reportedreported toxicitytoxicity withwith longlong termterm useuse soso nownow somesome cliniciansclinicians << 0.10.1 mgmg oror eliminateeliminate itit „ MVIMVI == 22 mgmg MolybdenumMolybdenum

„ RequiredRequired forfor severalseveral enzymesenzymes (xanthine(xanthine oxidaseoxidase andand flavoproteins)flavoproteins) „ DeficiencyDeficiency inin longlong termterm TPN:TPN: mentalmental changeschanges andand abnormalitiesabnormalities inin sulfursulfur andand purinepurine metabolismmetabolism „ Toxicity:Toxicity: goutgout likelike syndromesyndrome „ TPNTPN == 100100 –– 200200 mcgmcg „ MVIMVI == 7575 mcgmcg WhatWhat vitaminsvitamins areare inin TPN?TPN?

„ VitaminVitamin A,A, D,D, EE „ AscorbicAscorbic acid,acid, folacin,folacin, niacin,niacin, riboflavin,riboflavin, thiamin,thiamin, pyridoxine,pyridoxine, B12,B12, pantothenicpantothenic acid,acid, biotinbiotin „ TraceTrace minerals:minerals: zinc,zinc, copper,copper, chromium,chromium, andand manganesemanganese „ SingleSingle minerals:minerals: seleniumselenium andand molybdenummolybdenum separateseparate BariatricBariatric surgerysurgery

„ RYGB:RYGB: iron,iron, B12,B12, vitaminvitamin D,D, CalciumCalcium „ BiliopancreaticBiliopancreatic diversion:diversion: proteinprotein andand fatfat solublesoluble vitaminsvitamins „ 44 yearsyears postpost op:op: 44%44% hadhad lowlow hemoglobin,hemoglobin, iron,iron, andand ferritin;ferritin; 33%33% hadhad B12B12 deficiencydeficiency „ 44 yearsyears afterafter diversiondiversion deficiency:deficiency: 69%69% vitaminvitamin K;K; 63%63% vitaminvitamin D;D; 4%4% vitaminvitamin EE „ ThiamineThiamine alsoalso deficientdeficient (hyperemesis)(hyperemesis) BariatricBariatric surgerysurgery

„ Monitor:Monitor: calcium,calcium, phosphorus,phosphorus, alkalinealkaline phosphatase,phosphatase, parathyroidparathyroid hormone,hormone, andand 2525 hydroxyvitaminhydroxyvitamin DD „ UseUse CalciumCalcium citratecitrate (need(need lowlow acidacid forfor carbonate)carbonate) „ NeedNeed 20002000 mgmg ofof calciumcalcium andand 400400 IUIU vitaminvitamin DD „ NeedNeed 350350 microgramsmicrograms B12/dayB12/day (note(note DV=2);DV=2); FewFew requirerequire monthlymonthly parenteralparenteral administrationadministration „ ThiamineThiamine 5050--100100 mg/daymg/day ConclusionsConclusions

„ RDARDA nownow DVDV (Daily(Daily Values)Values) „ NeedNeed toto bebe awareaware ofof increasedincreased needsneeds inin patientspatients onon chronicchronic TPNTPN oror changeschanges inin gutgut anatomyanatomy „ IncreasedIncreased rolerole inin vitaminsvitamins andand mineralsminerals inin alteringaltering diseasedisease processprocess andand immuneimmune systemsystem (another(another talktalk allall together)together) ratherrather thanthan sustainingsustaining dailydaily metabolismmetabolism SpecialSpecial thanksthanks

„ Dr.Dr. McClainMcClain andand SteveSteve MahanesMahanes „ Dr.Dr. DrydenDryden „ Dr.Dr. McClaveMcClave „ Dr.Dr. JabbarJabbar