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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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