NONALCOHOLIC STEATOHEPATITISAssessing Severity and Optimizing Management

Sanjiv Chopra, M.D., MACPProfessor of Medicine

Harvard Medical SchoolEditor in Chief

Hepatology Section Up to Date

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DefinitionofNASH

Nonalcoholicsteatohepatitis (NASH)isthetermusedtodescribethedistinctclinicalentityinwhichpatientslackahistoryofsignificantalcoholconsumptionbuthaveliverbiopsyfindingsindistinguishablefromalcoholichepatitits.

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30%Can progress to cirrhosis and HCC

70% Relatively benign

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CriteriaforDxofNASH

• Liverbx showsmacrovesicular fattychangewithinflammationandwithorwithoutMallorybodies,fibrosisorcirrhosis.

• Convincingevidenceofnegligiblealcoholconsumption(lessthan10g/dayofalcoholforwomenandlessthan20g/dayformen).

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Ultrasoundshowing

Brightechogenicliver

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LiverUltrasoundReport

Theliverisenlarged.Itisdiffuselyechogenicconsistentwithfatinfiltrationoftheliver.Otherformsofliverdiseaseandmoreadvancedliverdiseaseincludingearlycirrhosiscannotbeexcludedbythisstudy.

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macrovesicularsteatosis(zoneIII)

Biopsies

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lobular sinusoidal neutrophils

Ballooningdegeneration

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Sinusoidal pericellular fibrosis, trichrome stain

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NASH:LiverHistology

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ProperInterpretationoftheHistology

...thesefeaturesareconsistentwithaToxicMetabolicetiology.

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Cirrhosis,lowpower

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SignsofAdvancedFibrosis

•Physicalexam• Spiderangiomata, palmar erythema

• Terry’snails

• Gynecomastia, testicular atrophyinmen

• Caputmedusa, etc.

• LaboratoryData• Thrombocytopenia

• Elevated INR

• AST/ALTratio>1

•Radiology- splenomegaly,varices,nodularliver

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NASHisLikelyaMajorCauseofCryptogenicCirrhosis

• 74%of70consecutivepatientswithcryptogeniccirrhosishadobesityand/ordiabetes

• Thispercentageissimilartoprevalenceofobesityand/ordiabetesnotedin50consecutivepatientswithNASHCOP

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EpidemiologyofNAFLD

• Estimate:70million AmericanshaveNAFLDMorethan5million arecirrhotic

•MajorityofPtswithNASHhavemetabolic

syndrome

•Overage60years,40%havemetabolicsyndrome

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NAFLDisPartoftheMetabolicSyndromeCalledSyndromeX

Obesity Hypertriglyceridemia

Hyperinsulinemia Hypertension

InsulinResistance DiabetesCOPYRIG

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Regularsugar-sweetenedbeverageconsumptionisassociatedwithagreaterriskoffattyliverdisease

• Examinationofcross-sectionalassociation

betweenintakeofsugar-sweetenedbeveragesand

fattyliverdiseaseinFraminghamHeartStudy

cohorts

JMaetal.,JournalofHepatology2015May29

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PatientswithNASH

Normal ALT Increased ALT p.value

FibrosisStage22%34%NS2orgreater

FracanzaniAL,etal.Hepatology2008:48;792

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OtherConditions AssociatedwithNASH

•DrugsorToxins •AbdominalSurgery

• MetabolicDisorders •MiscellaneousCOPYRIG

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Onedisorderthatiscritical toexcludeinyoungindividualsisWilson’sdisease

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K-FRing

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DrugsAssociatedwithNASH

•Glucocorticoids • Tamoxifen

•Syntheticestrogens • Perhexilene maleate

•Amiodarone • Isoniazid

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ProgressiontoCirrhosis10YrSurvival

Alcoholic 38–50% 20%Hepatitis

NASH 8– 26% 60%COPYRIG

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ClinicalFeaturesofNASH

Symptoms

• Asymptomatic

• Fatigue

• RUQDiscomfortorPainCOPYRIG

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LaboratoryFeaturesofNASH

•ALTandAST2to4foldelevatedinmostpatients

•Alk phos mildlyelevatedinathirdofpatients

•Albumin,PT,bilirubinmostoftennormal

• Serumferritinelevatedinhalfthepatients

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WeneedtoThinkDifferentlyabouttheUpperNormalLimitofALT• TruenormalhealthyALT:

19to25 IU/Linfemales

29to 33IU/Linmales

•Multiplestudies:ElevatedALTassociatedwith

increasedliver-relatedmortality.

• Likely,manyofthenewlyidentifiedpatientsusing

theseparameterswillhaveNAFLD.

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PatientswithSuspectedNASHshouldUndergoLiverBiopsy

Pros Cons

hNASHisahistologicdx h Smallbutfiniteriskofcomplications

hPoorcorrelationbetweenlabh Biopsyresultsmaynotfindingsandhistologicseveritychangemanagement

hBiopsyresultsmaychangeh Limitedmanpowermanagement

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SuspectedNASH:Reasonabletoperformliverbiopsy

Ifanyoffollowingpresent

• Peripheralstigmataofchronicliverdisease

• Splenomegaly

• Cytopenia

• Abnormalironstudies

• Diabetesand/orsignificantobesityinapatientover45yearsofagewithelevatedALT

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Aretherealternativestoliverbiopsy?

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Sampling error of liver biopsyFibrosis area: 65%

Fibrosis area: 15%Courtesy of M. Pinzani, Florence

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Fibrotest(fibrosure)

Alpha2macroglobulin,haptoglobin,

gammaglobulin,GGT,totalbilirubin,apolipoprotein

A1

Theseverityofdiseasewascorrectlyidentifiedin

46%ofpatients.

AmJGastroenterol 2006

Fibrosure. I am not so sure!

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Fibroscann Fasting

n Examination time < 5 minutes

n Median value of 10 successful acquisitions

n Sampling errorq Biopsy – 1/50,000q Fibroscan – 1/500

Courtesy of N. Afdhal, MD

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Sampled volume: 1: 500

Hepatic Elastography

Courtesy N. Afdhal, MD

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Sampling

• Liverbiopsysamplesonly1/50,000th ofwholeliver.

• Fibroscan samples1/500th ofwholeliver.

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LikelyFutureScenario

Patients with suspected Liver Disease

Low likelihood of fibrosis

No liver biopsy

Follow or treat

Grey zone

Liver biopsy

High likelihood of fibrosis

No liver biopsy

Screen HCC, varices

Biomarkers and Fibroscan

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Transientelastography (Fibroscan)isaccurateinmostpatientswithNAFLD.Withhighnegativepredictivevalueandmodestpositivepredictivevalue,Fibroscan isusefulasascreeningtesttoexcludeadvancedfibrosis.

WongVW-S,etal.Hepatology2010;51:454-462

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Fibroscan- pros

• Noninvasive

• Excellent negative predictive value to exclude advanced fibrosis

• Fast- 5 minute tests

• Point of care- results immediately available

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FibroscanResult

• LiverstiffnessinkPa

• Lowriskforadvancedfibrosis<7.9kPa

• Highriskforadvancedfibrosis>9.9kPa

• CAP- fatquantification

Tapper et al. Am J Gastroenterol 2016;111:677-684.

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ProgressionofNAFLD

InitialBiopsyResultsMayBeUseful

• FatAlone5%

•BallooningDegenerationand

MalloryHyalineorFibrosis

Gastroenterology:1999;116:1413

Progression toCirrhosis

Progression toCirrhosis

25%

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PathogenesisofNASH

• Perturbationoffattyacidprocessing.

• Insulinresistance

• Lipidperoxidationandoxidativestress*

*Potentialoxidativestressorsinclude:hepaticiron,intestinalbacteria,leptinandstatescharacterizedbyanti-oxidantdeficiencies

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Definition

Theconceptofthehumanmicrobiomewasfirst

suggestedbyJoshuaLederberg,whocoinedthe

term“microbiome,tosignifytheecological

communityofcommensal,symbiotic,and

pathogenicmicroorganismsthatliterallyshare

ourbodyspace”.

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WelcometoBoston WelcometoGut

Population:667,000 Population:100trillion

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TheGutMicrobiotaandNAFLD

• Microbiotainadditiontoregulatingbodyfatgainandinsulinresistance:

• Changegeneexpression

• Increaseenergyharvestfromdiet

• Produceethanol

• Affectinflammation andimmunity

ELauetal.GutMicrobiota:AssociationwithNAFLDandMetabolicDisturbances.BiomedicalResearchInternational.2015.

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YouMayNotDrinkAlcoholbuttheK.pneumoniabacteriainyourgut…….

• 60%ofNAFLDPatientsversus6%ofhealthycontrolshadhighandmediumalcoholproducingK.pneumoniainthegut.

• GermfreemicefedalcoholproducingK.pneumoniadevelopedfatty

liverwithinamonthandwithin2monthstherewashepaticfibrosis.

• WhenthebacteriafedmiceweregivenanantibioticagainstK.

Pneumoniathehepaticdamagewasreversed.

YuanJ.etal.FattyLiverDiseaseCausedbyHigh-AlcoholProducing

Klebsiella pneumoniae.CellMetabolism2019.

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PreventionandTreatmentofNASH

•Preventionofobesityandmetabolicsyndrome

• Treatmentofmetabolicsyndrome

•Coffee?

•BariatricSurgeryifappropriate

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Pioglitazone therapyovera12monthperiodinnondiabetic NASH

patientsresultedinimprovementinbiochemical,metabolicand

histologicalparameters(includingfibrosis).

Aithal GP,etal.

Gastroenterology2008:135;1176COPYRIG

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NASH:WeightLossisBeneficial!

1.9%orgreaterweightlossresultedin:

• Biochemicalimprovement• Histologicimprovement(steatosis,ballooning,inflammn)• ImprovementinInsulinresistance• HigherAdiponectin levels

HarrisonSA,etal.Hepatology 2009;49:80

2.Followingbariatricsurgery,HepaticFibrosisimprovedorwasreversedin66%.

Furuya CKJr.,etal.JGastroHepatol 2007;22:510

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VitaminEMayHaveBenefit

• 247AdultswithNASH(withoutdiabetes)randomlyassignedtopioglitazone(30mg.daily)VitaminE(800IUdaily)orplacebofor96weeks*.

• VitaminEgrouphadsignificantimprovementinglobalhistologyscorescomparedwithplacebo(43%vs19%).

• ConcernsregardingVitaminEandincreasedmortalityhaveledmanyHepatologists tonotrecommendVitaminEortouse400IUdaily.

*Sanyal,A,etal.Pioglitazone, vitamine E,orplacebo for

nonalcoholic steatohepatitis. NEngl JMed2010

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OtherPharmacologicalTreatmentModalities

• Pioglitazone• Metformin• Liraglutide• Orlistat• Probucol• Betaine

Of limited or no proven efficacy

• Ursodeoxycholic acid(UDCA)• Omega-3FattyAcids• Losartan• Atorvastatin• Pentoxifylline

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1. Whoisthispersonandhowoldwashewhenhedied?Voltaire(1694– 1778)83years

2. Howmanycupsofcoffeedidhedrinkeveryday?50-72!

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ANewKindofCoffeeConnection!

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MechanismofProtectiveEffectofCoffeeUnknown•Caffeine,cafestol andkahweol protectiveinexperimentalstudies

•Antioxidanteffect

• Insulinsensitizingeffect

•Coffeedrinkershavehigherlevelsofplasmaadiponectin

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Morethan1BillionPeopleintheWorldHaveChronicLiverDisease

Consumingtwocupsofcoffeeperdayreduceshospitalizationrateandmortalityfromchronicliverdiseasebymorethan50%

Ruhl CE,etal.Gastroenterology2005;129:1928COPYRIG

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References:CoffeeandLiverDisease,2012SanjivChopra,MD,MACP1.Klatsky A,ArmstrongM.Alcohol,smoking,coffeeand

cirrhosis.AmJEpidemiol.1992;136:1248.

2.Casiglia E,etal.Unexpectedeffectsofcoffeeconsumption

onliverenzymes.Eur JEpidemiol.1993;9:293.

3.Tverdal A,Skurveit S.Coffeeintakeandmortalityfrom

livercirrhosis.AnnEpidemiol.2003;13:419.

4.Shimazu T,etal.Coffeeconsumptionandtheriskof

primarylivercancer;pooledanalysisoftwoprospective

studiesinJapan.Int JCancer.2005;10:150.

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5.Ruhl CE,EverhartJ.CoffeeandteaconsumptionareassociatedwithalowerincidenceofchronicliverdiseaseintheUnitedStates.Gastroenterology.2005;129:1928.

6.Klatsky AL,MortonC,UdaltsovaN,FriedmanG.Coffee,cirrhosis,andtransaminaseenzymes.ArchInternMed.2006;166:1190.

7.HuG,Tuomilehto J,Pukkala E,HakulinenT,Antikainen R,VartiainenE,Jousilahti P.Jointeffectsofcoffeeconsumptionandserumgamma-glutamyltransferase ontheriskoflivercancer.Hepatology.2008;48(1):129-36.

8.LarssonSC,Wolk A.Coffeeconsumptionandriskoflivercancer:ameta-analysis.Gastroenterology.2007;132(5):1740-5.COP

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9.Corrao G,Zambon A,Bagnardi V,D'Amicis A,Klatsky A;Collaborative

SIDECIRGroup.Coffee,caffeine,andtheriskoflivercirrhosis.AnnEpidemiol.

2001;11(7):458-65.

10.GallusS,Tavani A,Negri E,LaVecchia C.Doescoffeeprotectagainstliver

cirrhosis?AnnEpidemiol.2002;12(3):202-5.

11.Schilter B,PerrinI,Cavin C,Huggett AC.PlacentalglutathioneS-

transferase (GST-P) inductionasapotentialmechanismfortheanti-

carcinogeniceffectofthecoffee-specific componentscafestol andkahweol.

Carcinogenesis.1996;17(11):2377-84.

12.Gelatti U,Covolo L,Franceschini M,Pirali F,TaggerA,Ribero ML,Trevisi P,

Martelli C,Nardi G,Donato F;BresciaHCCStudyGroup. Coffeeconsumption

reducestheriskofhepatocellularcarcinomaindependentlyofitsaetiology:a

case-controlstudy.JHepatol.2005;42(4):528-34.

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13.Modi AA,FeldJJ,ParkY,Kleiner DE,EverhartJE,LiangTJ,Hoofnagle JH.Increasedcaffeineconsumptionisassociatedwithreducedhepaticfibrosis.

Hepatology.2010;51(1):201-9.

14.Kalthoff S,Ehmer U,FreibergN,Manns MP,Strassburg CP.Coffeeinduces

expressionofglucuronosyltransferases bythearylhydrocarbonreceptorandNrf2inliverandstomach.Gastroenterology.2010;139(5):1699-710.

15.FreedmanNDetal.Coffeeconsumptionisassociatedwithresponsetopeginterferon andribavirintherapyinpatientswithchronichepatitisC.

Gastroenterology2011; 140:161-69.

16.MolloyJW,CalcagnoCJ,WilliamsCD,JonesFJ,TorresDM,HarrisonSA.

Associationofcoffeeandcaffeineconsumptionwithfattyliverdisease,nonalcoholicsteatohepatitis,anddegreeofhepaticfibrosis.Hepatology.2012;55(2):429-36.

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Largeprospectivestudy;Coffeeconsumptioninverselyassociatedwithtotalandcause-specificmortality.

• Freedman,NDPh.D.,Park,YSc.D.,Abnet,CCPh.D.,etal.

AssociationofCoffeeDrinkingwithTotalandCause-SpecificMortalityNEngl JMed2012;366:1891-1904COP

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Twoadditonal studiespublished intheAnnalsofInternalMedicine July2017addressingcoffeedrinking andmortality.

Afourthstudypublished inJAMAInternalMedicine July2018

Naci et al. BMJ. 2013: 5577

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CoffeeDrinkingAssociatedwithReducedRiskforDeathfromvariouscauses.Thisrelationshipwasseenin10EuropeanCountries• Largecohort- morethan520,000menandwomenfrom10European

countriesaveragefollow-up16years.

• Inverserelationshipbetweencoffeeintakeandallcausemortalityin

menandwomen.

• Notethatthepopulationsindifferentcountriesusedifferentcoffeepreparationmethodsandhaddifferentdrinkingpatterns.

Gunter,M.J.etal.CoffeeDrinkingandMortality in10European Countries: A

Multinational CohortStudy

AnnInternMed.July2017

Naci et al. BMJ. 2013: 5577

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HigherConsumptionofCoffeeAssociatewithLowerRiskofDeathinAfrican-Americans,JapaneseAmericans,Latinos,andWhites• 185,855individualsages45-75yearsatrecruitment

• Coffeeconsumptionassociatedwithlowertotalmortalityafter

adjustmentforsmoking,otherpotentialconfounders.

• Inverseassociationsobservedfordeathsduetoheartdisease,cancer,diabetes,stroke,etc.

Park,S-Yetal.Association ofCoffeeConsumption With TotalandCause-Specific

Mortality AmongNonwhite Populations

AnnInternMed.July2017

Naci et al. BMJ. 2013: 5577

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InverseAssociationforCoffeeDrinkingandMortality(A2018Publication)

• UKBiobankStudy.500,000Individuals

• OnecupofCoffeeaday:8%lowerriskofprematuredeath

6cupsofCoffeeaday:16%lowerriskofprematuredeath

• SpeedofCaffeineMetabolismhadnoeffectonLongevity

AssociationofCoffeeDrinkingWithMortalitybyGeneticVariationinCaffeineMetabolismFindings FromtheUKBiobankErikka Loftfield,etal.JAMAInternalMedicine2018.

Naci et al. BMJ. 2013: 5577

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Kaldi the shepherd from Kaffa

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“Coffeeissogood,theinfidelsshouldnothaveexclusiveuseofit.”

PopeVincentIII

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LowVitaminDMayIncreaseRiskofNAFLD

• VitaminDDeficiencymaybemorecommoninpatientswithNAFLD

thancontrols.

• PatientswithlowVitaminDappeartohavehigherriskofmoderate-

severeNAFLDcomparedwithpatientswithnormallevels.

TrahanL.PharmacyTimesJuly2016.

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MyDoctorSaidICouldHaveOneGlassofWineperDay

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•HowMuchofThatBottleisintheGlass?

•A.33%

•B.50%

•C.66%

MyDoctorSaidICouldHaveOneGlassofWineperDay

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PotentialApproachestoTreatmentintheFuture

•Willlikelyincludecombination therapyandlife-stylechanges.

• ExperimentalstudyinaratmodelofNASHcombiningangiotensin IIreceptorblockerwithanoralironchelator attenuatedprogression.

•Moderateexerciseandcoffeeconsumption likelyofbenefit.

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PatientswithElevatedTransaminasesarenotatHigherRiskforStatinHepatotoxicity

Mild-ModerateSevereElevations Elevations

• 1439withnormaltransaminases 1.9%0.2%prescribedastatin

• 342with elevatedtransaminases 4.7%0.6%prescribedastatin

• 2245withelevatedtransaminasesnot 6.4%0.4%prescribedastatin

Chalasani etal:Gastroenterology2004;126

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APotentialTreatment

• ASK1 (apoptosissignal-regulatingkinase)promoteshepatic

inflammationandfibrosis.

• Selonsertib (GS-4997)isanoralsmallmoleculeASK1inhibitorthat

hasbeenshowninmousemodelstoimprovesteatosis,inflammation

andfibrosis.

• 72patientswithbiopsyprovenNASH,stage2and3fibrosis.

• Patientsachievedsignificantreductioninfatcontentandinfibrosisscores.

Loomba Retal.

AASLDNovember 2016

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CurrentLandscapeofClinicalTrials:2019

• AsperClinicalTrials.govover250StudiesOngoingintheUnitedStatesCOP

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Quiz Answer True or False

1. NAFLD is the most common hepatic disorder in the U.S.

2. Serum ferritin is elevated in 50% of pts with NASH.

3. NASH has been reported in children.

4. Progression to cirrhosis occurs in 15-20% of pts.

5. NASH is likely the leading cause of cryptogenic cirrhosis.

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6. The histologic features of NASH maybe seen in Wilson’s disease.

7. Both Amiodarone and Tamoxifen can cause NASH.

8. Primary hepatocellular carcinoma has been reported in patients with NASH and cirrhosis.

Quiz (Continued) Answer True or False

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