NutritionNutrition andand PrimaryPrimary SclerosingSclerosing CholangitisCholangitis (PSC)(PSC)

JaimeJaime ArandaAranda--Michel,Michel, M.D.M.D. AssociateAssociate ProfessorProfessor ofof MedicineMedicine DivisionDivision ofof Gastroenterology,Gastroenterology, hepatologyhepatology andand transplantationtransplantation MayoMayo ClinicClinic JacksonvilleJacksonville

PrimaryPrimary SclerosingSclerosing CholangitisCholangitis ChronicChronic LiverLiver DiseaseDisease

ComplicationsComplications FluidFluid retentionretention –– ascitesascites andand peripheralperipheral edemaedema EncephalopathyEncephalopathy -- confusionconfusion GastrointestinalGastrointestinal bleedingbleeding –– varicesvarices CholangiocarcinomaCholangiocarcinoma andand HepatocellularHepatocellular carcinomacarcinoma MalnutritionMalnutrition MalnutritionMalnutrition isis commoncommon inin cirrhosiscirrhosis

DeficienciesDeficiencies ofof vitaminsvitamins andand mineralsminerals maymay developdevelop inin chronicchronic liverliver diseasedisease withoutwithout cirrhosiscirrhosis –– PrimaryPrimary BiliaryBiliary CirrhosisCirrhosis andand PrimaryPrimary SclerosingSclerosing CholangitisCholangitis

OtherOther deficienciesdeficiencies cancan bebe presentpresent ifif InflammatoryInflammatory BowelBowel DiseaseDisease isis presentpresent –– CrohnCrohn’’ss DiseaseDisease MalnutritionMalnutrition

99GeneralGeneral risksrisks forfor malnutritionmalnutrition inin chronicchronic liverliver diseasedisease 99SpecificSpecific risksrisks forfor malnutritionmalnutrition inin primaryprimary sclerosingsclerosing cholangitischolangitis ƒƒLipidsLipids –– fatfat metabolismmetabolism ƒƒVitaminsVitamins --A,D,E,KA,D,E,K ƒƒBoneBone diseasedisease inin chronicchronic liverliver diseasedisease NutritionNutrition inin LiverLiver DiseaseDisease ““FactsFacts”” ●● MalnutritionMalnutrition isis commoncommon butbut frequentlyfrequently ““underdiagnosedunderdiagnosed”” ●● MalnutritionMalnutrition isis multifactorialmultifactorial ●● DegreeDegree ofof malnutritionmalnutrition correlatescorrelates toto thethe severityseverity ofof liverliver diseasedisease ●● MalnutritionMalnutrition isis universaluniversal inin patientspatients withwith endend--stagestage liverliver diseasedisease waitingwaiting forfor liverliver transplantationtransplantation regardlessregardless ofof thethe etiologyetiology ●● MalnutritionMalnutrition cancan bebe diagnoseddiagnosed inin 25%25% inin patientspatients withwith cirrhosis.cirrhosis.

●● MalnutritionMalnutrition isis presentpresent inin >> 6060 %% inin patientspatients withwith complicationscomplications ofof cirrhosis.cirrhosis.

●● ModerateModerate toto severesevere malnutritionmalnutrition isis foundfound inin >> 80%80% ofof liverliver transplanttransplant patients.patients.

Campillo B Nutrition 2003 *Alvares-da-Silva MR Nutrition 2005 ““MultifactorialMultifactorial””

PoorPoor dietarydietary intakeintake

● Anorexia, hospitalization

● Dietary restrictions (Na and protein)

● Ascites / encephalopathy

● Increased in inflammation

““MultifactorialMultifactorial”” continue..continue..

Nutrient malabsorption ● Cholestatic liver disease ● Excessive protein losses Medications ● Neomycin, lactulose, cholestyramine, prednisone Iatrogenic ● Large volume paracentesis ● Sodium and protein restriction

PSCPSC -- CholestasisCholestasis ““lacklack ofof bilebile flowflow”” ●● FatigueFatigue ●● PruritusPruritus –– itchingitching ●● DiarrheaDiarrhea -- looseloose fattyfatty stoolsstools (Steatorrhea)(Steatorrhea) 99FoulFoul smelling,smelling, flatulenceflatulence ●● FatFat--solublesoluble vitaminvitamin deficienciesdeficiencies (A,D,E,K)(A,D,E,K) ●● HyperlipidemiaHyperlipidemia ●● MetabolicMetabolic bonebone diseasedisease 99BoneBone painpain 99BoneBone fracturesfractures HyperlipidemiaHyperlipidemia inin PSCPSC

●● TriglycerideTriglyceride levelslevels

●● CholesterolCholesterol levelslevels

●● MayMay developdevelop xanthomasxanthomas andand xanthelasmaxanthelasma

●● NotNot associatedassociated withwith CardiovascularCardiovascular mortalitymortality

VitaminsVitamins VitaminVitamin AA VitaminVitamin AA

●●AbsorptionAbsorption requiresrequires fatfat andand bilebile acidsacids ●●SerumSerum levelslevels areare frequentlyfrequently lowlow -- 82% ●Antioxidant ●●OccasionallyOccasionally symptomaticsymptomatic 9 Eye 9 Skin 9 Bone 9 Immune system VitaminVitamin AA

●●EyeEye –– xerophthalmiaxerophthalmia

●●SkinSkin -- hyperkeratosishyperkeratosis

VitaminVitamin EE

●Absorption requires fat and bile acids ●Prevalence is 17% ●Antioxidant ●Significance in PSC is unknown ●Symptoms are rare 9 Neurological 9 Eye muscles 9 Muscle VitaminVitamin KK

●Absorption requires fat and bile acids

●Required for clotting factors 9 Prothrombin time (INR)

●Bone metabolism - osteocalcin

VitaminVitamin KK

●Easy bruising

●Mucosal bleeding VitaminVitamin DD Vitamin D Metabolism

DietDiet Skin/UVBSkin/UVB Ca,Ca, PO4PO4

VitaminVitamin D3D3

Resorption & Mineralization

2525--OHOH--VitVit--DD 1,25(OH)2Vit1,25(OH)2Vit--D3D3 MoreMore ThanThan 1.51.5 MillionMillion FracturesFractures YearlyYearly Vertebral 46% (700,000)

Wrist Hip 16% 19% (250,000) (300,000)

Other 19% NIH/ORBD National Resource Center, October 2000 (300,000) CommonCommon CausesCauses ofof Vit.DVit.D DeficiencyDeficiency

●●DecreasedDecreased intakeintake ●●DefectDefect inin liverliver 99PoorPoor oraloral intakeintake 9 Liver disease 99↓↓ uVuV lightlight ●●DefectiveDefective activationactivation inin KidneyKidney ●●Impaired gut absorption Impaired gut absorption 9 Aging 99MalabsorptionMalabsorption (short(short 9 Renal failure (GFR < 60 bowel,bowel, pancreatitis,pancreatitis, IBD,IBD, ml/min) celiacceliac spruesprue,, cholestaischolestais))

DHC: dihydro-cholesterol. VDB: vitamin D binding. GFR: glomerular filtration rate. BONE QUANTITY BONE QUALITY

BONE STRENGHT

Trauma

OsteoporosisOsteoporosis TrabecularTrabecular MicroMicro--architecturalarchitectural ChangeChange Normal Osteoporosis

Dempster, 2000 Horizontal Perforations Micro-callous DiagnosticDiagnostic toolstools

OsteoporosisOsteoporosis CentralCentral DualDual--EnergyEnergy--XrayXray-- AbsorptiometryAbsorptiometry (DXA)(DXA) MeasurementMeasurement

● Measures multiple skeletal sites

9 Spine 9 Hip 9 Forearm 9 Total body ● Office based ● DXA bone density measurement

considered the clinical standard

WorldWorld HealthHealth OrganizationOrganization (WHO)(WHO) DiagnosticDiagnostic CriteriaCriteria forfor OsteoporosisOsteoporosis

T-Score

The WHO criteria were established for use in a postmenopausal female population

HepaticHepatic OsteodystrophyOsteodystrophy (Metabolic(Metabolic BoneBone Disease)Disease)

●● MostMost ofof thethe patientspatients havehave osteopeniaosteopenia // osteoporosisosteoporosis regardlessregardless ofof thethe causecause ofof liverliver diseasedisease ●● FrequentlyFrequently foundfound inin patientspatients withwith PSCPSC andand PBCPBC ●● FracturesFractures priorprior toto transplantationtransplantation --35%35% ●● EndEnd--StageStage LiverLiver DiseaseDisease isis consideredconsidered anan independentindependent factorfactor forfor bonebone diseasedisease RisksRisks factorsfactors

●● AgeAge ●● BMDBMD -- DEXADEXA ●● AlcoholismAlcoholism ●● SmokingSmoking ●● HypogonadismHypogonadism-- postpost--menopausalmenopausal ●● AbnormalAbnormal VitaminVitamin DD metabolismmetabolism ●● MalabsorptionMalabsorption -- malnutritionmalnutrition ●● Medication:Medication: steroids,steroids, looploop diureticsdiuretics ((lasixlasix))

TreatmentTreatment

●● BeginBegin calciumcalcium supplementationsupplementation ●● MultivitaminsMultivitamins ●● VitaminVitamin DD supplementationsupplementation ●● WeightWeight bearingbearing andand exerciseexercise ●● SmokeSmoke cessationcessation ●● ConsiderConsider antianti--resorptiveresorptive agentsagents

GeneralGeneral GuidelinesGuidelines Patients with cirrhosis have malnutrition until proven otherwise Anorexia is a major problem – calorie counts, frequent meals – snack at bedtime – early feeding tube placement

Do not restrict protein even in the presence of encephalopathy Look for malabsorption– fat soluble vitamins (ADEK) and replace if deficient

Physical activity very important and more aggressive in patients awaiting liver transplantation All patients with cirrhosis should receive multivitamins DEXA scan to assess bone density DiscussionDiscussion

Kanis JA, et al. Osteoporosis Int 2008;19:385-397.

FRAXFRAXTMTM CalculatorCalculator ●● WHOWHO 1010--yearyear fracturefracture riskrisk assessmentassessment tooltool 99RiskRisk factors:factors: age,age, BMD,BMD, priorprior fracture,fracture, steroids,steroids, etc.etc. ●● TreatmentTreatment guidelinesguidelines:: 99HipHip fracturefracture riskrisk >> 3%3% 99MajorMajor osteoporoticosteoporotic fracturefracture >> 20%20%

Kanis JA, et al. Osteoporosis Int 2008;19:385-397. http://www.shef.ac.uk/FRAX/

OsteoporosisOsteoporosis TherapyTherapy ●● BoneBone AntiAnti--resorptiveresorptive AgentsAgents 99CalciumCalcium andand VitaminVitamin--DD 99BisphosphonatesBisphosphonates (several(several oraloral andand intravenousintravenous drugs)drugs) 99EstrogenEstrogen (oral(oral oror skinskin patch)patch) 99SERMsSERMs (Evista® - raloxifene) 99CalcitoninCalcitonin (Miacalcin®) ●● BoneBone FormativeFormative (Anabolic)(Anabolic) AgentsAgents 99ParathyroidParathyroid hormonehormone (Forteo®, teriparatide - rhPTH) 99SodiumSodium FluorideFluoride (controversial,(controversial, notnot FDAFDA approved)approved) 99TiboloneTibolone andand StrontiumStrontium (not(not FDAFDA approved)approved) 99TestosteroneTestosterone (hypogonadal(hypogonadal men)men) Vit.DVit.D DeficiencyDeficiency LabLab AssessmentAssessment ofof TotalTotal 25(OH)D25(OH)D LevelsLevels

●● MayoMayo MedicalMedical LabLab,, ng/mLng/mL (1.0(1.0 ng/mLng/mL == 2.52.5 nmol/L)nmol/L) LiquidLiquid chromatographychromatography tandemtandem massmass spectrometryspectrometry << 1010 severesevere deficiencydeficiency 1010--2525 mildmild toto moderatemoderate deficiencydeficiency 2525--8080 ““optimaloptimal”” levelslevels >> 8080 toxicitytoxicity ““possiblepossible”” >> 150150 toxicitytoxicity likelylikely

A.A. NutritionalNutritional VitaminVitamin DD DeficiencyDeficiency ●● VitaminVitamin DD deficiencydeficiency isis notnot uncommonuncommon 99TheThe presentpresent ““usualusual”” practicepractice forfor vitaminvitamin DD 400400 I.U.I.U. dailydaily (RDI)(RDI) prophylaxisprophylaxis isis inadequateinadequate ●● VitaminVitamin DD deficiencydeficiency isis underunder recognizedrecognized 99ClinicalClinical symptomssymptoms oror signssigns oftenoften attributedattributed toto anotheranother diseasedisease processprocess ƒƒ Osteoporosis,Osteoporosis, ““normalnormal--calcemiccalcemic”” HPT,HPT, chronicchronic painpain syndromesyndrome ((notnot fibromyalgia),fibromyalgia), ageage--relatedrelated weaknessweakness ●● ClinicalClinical awarenessawareness && appropriateappropriate testingtesting neededneeded

SubclinicalSubclinical OsteomalaciaOsteomalacia NotNot UncommonUncommon ●● 2525--50%50% ifif inin elderlyelderly nursingnursing homehome oror houseboundhousebound 99MeanMean ageage 8181 yearsyears Gloth, JAMA 1995;274:1683 and McKenna, Am J Med 1992;93:69 ●● 23%23% ofof elderlyelderly presentingpresenting withwith hiphip fracturesfractures 99MeanMean ageage 7777 yearsyears Dirschl et al, Bone 1997;21:97 ●● 57%57% ofof adultadult generalgeneral medicinemedicine hospitalizedhospitalized patientspatients 99MeanMean ageage 6262 yearsyears

Thomas M, NEJM 1998;338:777 PrevalencePrevalence Vit.DVit.D ““InsufficiencyInsufficiency”” << 3030 ng/mlng/ml

WhiteWhite elderlyelderly 30%30% Curr Opin Endocrinol Diabetes 2002;9:87

HispanicHispanic elderlyelderly 42%42% (ibid)

BlackBlack elderlyelderly 84%84% (Ibid)

HospitalizedHospitalized ptspts 57%57% NEJM 1998;338:777

AdolescentsAdolescents 24%24% Arch Ped Adoles Med 2004;158:531

YoungYoung adultsadults 32%32% Am J Med 2002;112:659

NHANESNHANES 2525--57%57% Bone 2002;30:771

LowLow backback painpain 83%83% Spine 2003;28:177

PrevalencePrevalence Vit.DVit.D ““DeficiencyDeficiency”” << 1515 ng/mlng/ml 2525--50%50% ofof nursingnursing homehome oror houseboundhousebound residentsresidentsºº,, meanmean ageage 8181 44%44% ofof elderlyelderly ambulatoryambulatory womenwomen¹¹,, >> 8080 yrsyrs 30%30% ofof womenwomen withwith osteoporosisosteoporosis¹¹,, ageage 7070--7979 23%23% ofof patientspatients withwith hiphip fracturesfractures²²,, meanmean ageage 7777 42%42% ofof AfricanAfrican AmericanAmerican womenwomen³³,, 1515--4949 yrsyrs 57%57% ofof adultadult hospitalizedhospitalized patientspatients4,, meanmean ageage 6262

ºJAMA 1995;274:1683, ºAm J Med 1992;93:69, ¹McClung, NEJM 2001;344:333, ²Bone 1997;21:97, ³Am J Clin Nutr 2002;76:187, 4NEJM 1998;338:777

PrevalencePrevalence ofof Vit.DVit.D DeficiencyDeficiency << 1515 ng/mlng/ml

●● Thomas,Thomas, NEJMNEJM 1998;338:7771998;338:777 9957%57% ofof 290290 men/women,men/women, meanmean ageage 6262 yrsyrs,, admittedadmitted toto hospitalhospital inin MarchMarch (n=150,(n=150, 63%)63%) andand SeptSept (n=140,(n=140, 49%)49%) ƒƒ 23%23% withwith severesevere deficiencydeficiency ofof vitvit DD (<8(<8 ng/ml)ng/ml) ƒƒ 60%60% ofof thosethose notnot takingtaking aa multivitaminmultivitamin ƒƒ 46%46% ofof thosethose reportedlyreportedly takingtaking aa multivitaminmultivitamin PrevalencePrevalence ofof HypovitaminosisHypovitaminosis DD HospitalizedHospitalized MedicalMedical PatientsPatients (n=290,(n=290, meanmean 6262 yr)yr) ThomasThomas M,M, NEJMNEJM 19981998;338:777;338:777 % of Patients 43 80 82 45 PTH (nl 20-50 pg/ml) 70 40 34 60 55 35 50 44 30 40 39 40 23 33 25 30 32 20 20 <5 <10 <15 <20 <25 <30 >30 <8 8 to 15 >15 25(OH)vitamin D (ng/ml) 25(OH)vitamin D (ng/ml) B.B. DrugDrug InducedInduced VitaminVitamin DD DeficiencyDeficiency

●● InhibitorsInhibitors ofof vit.Dvit.D formationformation oror GIGI absorptionabsorption 99SunscreensSunscreens >> factorfactor 8,8, blocksblocks 90%90% ofof vit.Dvit.D formationformation 99CholestyramineCholestyramine (binding(binding ofof BABA saltssalts inin shortshort bowel)bowel) ●● IncreasedIncreased metabolismmetabolism ofof vit.Dvit.D 99AntiepilepticsAntiepileptics (induced(induced cytochromecytochrome P450P450 enzymes)enzymes) Calcium Recommendations

Optimal: Dairy products Some greens, crustaceans Fortified foods (OJ) Practical: Calcium salts: most exhibit similar bioavailability Ca-Carbonate or Ca-phosphate: take with food Brand name or chewable products likely best VitaminVitamin DD RecommendationsRecommendations

PresentPresent RDIRDI treatmenttreatment guidelines:guidelines: AgeAge RDI,RDI, IU/dIU/d BirthBirth--5050 200200 5151--7070 400400 (40(40 IUIU == 11 µµg)g) >> 7070 600600 OsteoporosisOsteoporosis 800800

3737--46%46% ofof vit.Dvit.D deficientdeficient individualsindividuals meetmeet thethe RDIRDI !!

SourcesSources ofof VitaminVitamin DD ●● NutritionalNutritional vitaminvitamin DD deficiencydeficiency 99VitaminVitamin DD isis rarerare inin foods...foods... ƒ D2 from plants and yeast ƒ D3 from fatty fish (cod liver oil, salmon, mackerel) 99...and...and possiblypossibly eveneven whenwhen ““fortifiedfortified”” ƒ 400 IU vitamin D per quart of fortified milk (100 IU/cup)… ƒ …but, almost 50% of school skim milk carton samples found to contain <50% of stated vitamin D content, and almost 15% of skim milk cartons without any vitamin D (USA/Canada)¹ 99DailyDaily multivitaminmultivitamin (400(400 IU)IU) recommendedrecommended asas aa minimumminimum RDIRDI dailydaily intakeintake ¹Holick et al, NEJM 1992;326:1178 SourcesSources ofof VitaminVitamin DD ●● FoodFood sourcessources generallygenerally poorpoor;; includesincludes fish,fish, fishfish oil,oil, eggegg yolks,yolks, andand fortifiedfortified milkmilk andand foodsfoods Food Source Serving I.U. Pink salmon, canned 3 ounces 530 Fortified instant oatmeal 1 packet 140 Fortified cow's milk 8 ounces 100 Fortified orange juice 8 ounces 100 Fortified cereal 1 serving 40 Egg yolk medium 25

●● SunlightSunlight vitaminvitamin DD provisionprovision dependsdepends uponupon exposureexposure

Vitamin D Deficiency Effect of Sunlight

Exposed 25 er 2 ft A 20 0 0 6 12 -2 e 15 e r r o f

o % Change BMD f e % Change BMD -4 e B B 10 -6 r Deprived e t f 5 A Fractures 25 OH D Level ng/ml 25 OH 25 OH D Level ng/ml 25 OH D Level 0 11-sunlight deprived 3-sunlight exposed (p=0.03) Deprived Exposed

JBMR 20:1327, 2005 VitaminVitamin DD RequirementsRequirements TreatmentTreatment forfor OsteoporosisOsteoporosis CalciumCalcium:: 12001200--15001500 mgmg totaltotal elementalelemental calciumcalcium dailydaily PhosphatePhosphate:: 22--44 gramsgrams dailydaily (supplied(supplied byby usualusual--normalnormal dietdiet intake)intake) VitaminVitamin DD (D2(D2 ergocalciferol,ergocalciferol, oror D3D3 cholecalciferol)cholecalciferol) 99>> 10001000 IU/dayIU/day vitaminvitamin DD neededneeded forfor bodilybodily needs*needs* 99>> 20002000 IU/dayIU/day totaltotal intakeintake reportedreported asas safesafe ƒƒ Milk,Milk, yogurtyogurt oror cheesecheese << 100100 IU/servingIU/serving ƒ DailyDaily multivitamin:multivitamin: 400400 IUIU (daily)(daily)

ƒ VitaminVitamin DD2 oror DD3:: 1,0001,000 IUIU (daily)(daily) ƒ VitaminVitamin DD2 oror DD3:: 50,00050,000 IUIU (1/mos.(1/mos. toto 1/wk.)1/wk.) Vieth R. Am J Clin Nutr 1999;69:842 1 mcg = 40 International Units

VitaminVitamin DD FunctionsFunctions (1,25(1,25--dihydroxydihydroxy D)D) ●● GastrointestinalGastrointestinal absorptionabsorption ofof calciumcalcium 99PreventsPrevents secondarysecondary HPTHPT 99PreventsPrevents osteoporosisosteoporosis ●● MineralizationMineralization ofof bonebone collagencollagen matrixmatrix 99PreventsPrevents osteomalaciaosteomalacia ƒ Maximizes bone mineral density & increases bone strength VitaminVitamin DD DeficiencyDeficiency MusculoskeletalMusculoskeletal AssociationsAssociations

SkeletalSkeletal MuscleMuscle ●● 22ºº HPTHPT ●● MyopathyMyopathy ●● OsteoporosisOsteoporosis 9 WeaknessWeakness ●● MineralizationMineralization defectdefect 9 PainPain 99Rickets:Rickets: childrenchildren 99Osteomalacia:Osteomalacia: adultsadults NutritionNutrition andand LiverLiver DiseaseDisease

●● MalnutritionMalnutrition adverselyadversely affectsaffects prognosisprognosis inin cirrhosiscirrhosis ●● IncreaseIncrease OralOral supplementssupplements ●● NasoNaso--entericenteric feedingfeeding tubestubes areare wellwell toleratedtolerated ●● NutritionNutrition cancan improveimprove proteinprotein balancebalance

MostMost AmericansAmericans AreAre NotNot ReceivingReceiving AdequateAdequate VitaminVitamin DD

NHANES III survey: 3,444 Vitamin D Intake women > 51 years old (Review of Diet + Supplements) 100 • Over 70% of women 51-70 yrs 90 old were estimated not to meet 80

adequate intake for vit.D (RDI 70 60 = 400 IU), based on daily diet 50 & vit.D supplements 40 30 • Nearly 90% of women > 70 yrs 20 Percent Not Consuming were estimated not to meet Percent Not Consuming 10 Adequate Intake (AI) Vitamin D Adequate Intake (AI) Vitamin D 0 NOF vit.D guidelines (600 IU) Females Females 51-70 yr >70 yr NHANES = National Health and Nutrition Examination Survey; NOF = National Moore C. J Am Diet Assoc. 2004;104(6):980 Osteoporosis Foundation OptimalOptimal Vit.DVit.D Status?Status? TheThe 25(OH)D25(OH)D ContinuumContinuum ControversyControversy

““deficiencydeficiency”” ““insufficiencyinsufficiency”” ““normalnormal””

ng/mL 0 10 20 30 40 50 60 nmol/L(ng/mL) 0 25 50 75 100 125 150

* modified after RP Heaney (10 ng/mL = 25 nmol/L) Vit D Deficiency In North America An Endemic Problem

n= 1536 community-dwelling, postmenopausal women treated for osteoporosis (61 US sites) 60 52% 50 JCEM 90:3215, 2005

40 35.5% 30

20 18.2% Prevalence Prevalence 8.1% 10 1.1% 0 < 9 < 15 < 20 < 25 < 30 25-OH Vitamin D level (ng/ml)