InteractiveCasePresentation#3:ACaseofAcute-on-ChronicLiver

Disease

Moderator:AngieCoste,MSN,CRM,FNP-C

TexasLiverInstituteSanAntonio,Texas

Case:Jocelyn

• A55yearoldHispanicfemalepresentsonaroutinephysicalexamwithlabswiththefollowingfindings

• Herexamisnormal,withBMIof28• Shehasmildfatigue,nootherssymptoms• Labs:

– WBC:4.6,Hb 13.8g/dL,platelets240k– Tbili:1.0mg/dL,alk phosphatase128U/L,AST78U/L,ALT84U/L

– BUN:38mg/dL;Creatinine:0.8mg/dL

Case:Jocelyn

• Sheisreferredtoyouforevaluation• HerhistoryisnegativeforprescribedorOTCmedications

• HerPSHincludesTAH/BSO• HerPMHispositiveforshinglesatage45,occasionalurinarytractinfections,andinfluenzaatage48

• Iwaswasthefirstconsultanttoseethispatient…..

Biochemicalmarkers,imaging,andpatientpresentationinacutehepatic

injury

AngieCoste,MSN,CRM,FNP-CTexasLiverInstituteSanAntonio,Texas

AcuteHepaticInjury:PatientPresentation

• Symptoms:– Fatigue/Malaise– Lethargy– Anorexia– Nausea/Vomiting– Pruritus– Abdominaldistentionfromascites

– Hypotensionandtachycardia

• PEfindings:– HepaticEncephalopathy

– Jaundice– RUQpainandHMG– Ascites– RenalFailure

Biochemicaltestsinliverdisease• Thetruetestofliverfunction

– INR,PT,albumin,bilirubin(direct)• Testsofhepaticinjury/inflammation

– Transaminases• Aspartateaminotransferase (AST): liver,heart, kidneys,brain,skeletalmuscle

• Alanineaminotransferase (ALT): liver specific?(heart, kidney,skeletalmuscle)

– Alkalinephosphatase(ALP)– Gamma-glutamyl transpeptidase (GGT)– Lacticdehydrogenase(LDH)

• Hepatocellular:AST/ALTelevationtwicethatofALP• Cholestatic – AST/ALTelevationlessthantwiceofALP

Whatmainlabstolookforinacutehepaticinjury?

• ElevatedAST/ALT– Canbeelevatedmildlytoseverely

• Bilirubin– Elevationmeansseriousliverinjuryanddysfunction

• ProlongationofINR/prothrombintime(PT)– Helpdetermineseverityandprognosis

ImagingandPathology

• Ultrasound– Inexpensive,readilyavailable,andnoninvasive– Bestplacetostart

• CT/MRI– MoresensitivethanU/S– Cautioninrenalpatients

• LiverBiopsy– Almostalwaysnecessaryincasesnotleadingtoliverfailure,exceptforacutehepatitisAandB

AcuteliverinjuryiscommonAcuteliverfailureisnot

AcuteLiverFailure

• Acuteliverfailurereferstothedevelopmentofsevereacuteliverinjurywithencephalopathyandimpairedsyntheticfunction(jaundice)inapatientwithoutpreexistingliverdisease.

• Acuteliverfailurecanbesubcategorizedbaseduponhowlongthepatienthasbeenill.– Hyperacute (<7days)– Acute(7to21days)– Subacute (>21daysand<26weeks)

TakeHomeMessage

• Manythingscancauseacutehepaticinjury• DoagoodhistoryandPEtohelpdetermineriskfactors– viral?Recentmeds?

• Eliminatecausativefactorforacutehepaticinjury!– toxins,medications

• Doimagingtoruleoutobstructivecauses• MonitorLFTstolookforimprovement!

BacktoAngie

Jocelyn:AnotherConsultant

• Aseniorcolleagueisaskedtoadviseonthecase.

• Averydetailedhistoryistakenandanewbitofevidencecomestolight.

• Thepatienthadaurinarytractinfection6weekspriortopresentationanditwastreatedfor5dayswithanantibiotic.

AcuteDrugInducedLiverInjury(DILI)

DawnPease,MSN,RN,ANP-BCSetonHealthcare Family

UniversityMedicalCenterBrackenridgeBrackenridge SpecialtyClinics- Gastroenterologyand

EndocrinologyAustin,Texas

AcuteDrugInducedLiverInjury(DILI)

• Drug-inducedliverinjury(DILI)hasanestimatedannualincidencebetween10-15per10,000to100,000personsexposedtoprescriptionmedications.

• DILIaccountsforapproximately10%ofallcasesofacutehepatitis,anditisthemostcommoncauseofacuteliverfailureintheUS.

• DILIisalsothemostfrequentlycitedreasonforwithdrawalofmedicationsfromthemarketplace.1

1LarsonAM.Drug-inducedliver injury.UpToDate.https://www.uptodate.com.Topiclastupdated: May29,2015

DILI:IntrinsicorIdiosyncratic

IntrinsicDILI• Hepatotoxicityw/potential

toaffectallindividualstovaryingdegrees.

• Typicallystereotypiccourse,presentation,latency

• Typicallydosedependent(e.g.APAP)

IdiosyncraticDILI• Unpredictably affectsonlyrare

susceptible individuals• Lessdosedependent• Morevaried incourseand

presentation• Variesgreatlyinseverity• Varyinglatency(daystoyear)• Mostreactionstoprescription

drugsorHDSareconsideredidiosyncratic2

2ChalasaniNP,etal.,ACGClinical Guideline:TheDiagnosisandManagementofIdiosyncraticDrug-InducedLiver Injury.Am JGastroenterol. 2014Jul;109(7):950-66

IdiosyncraticDILI:WhoGetsIt?Hostfactors: Age,pregnancy,gender,obesity,DM,malnutrition,co-morbiditiesincludingunderlyingliverdisease,indicationsfortherapy.MaybegeneticfactorsaffectingDILIsusceptibilityw/certainagents:ongoingresearch

Environmentalfactors: Smoking,ETOH,infectionandinflammatoryepisodes

Drugfactors: Dailydose,metabolicprofile(includinghepaticclearance,lipophilicity),classeffectandcross-sensitization,drug-druginteractions,polypharmacy

DILI:Howbadisit?Ingeneral,outcomesofidiosyncraticDILIaregood:90%recoverfromtheaverageinstanceofDILI• ~10%developALF(coagulopathyandencephalopathy)

• Thosewithcholestatic injurygenerallyfarebetterthanthosewithhepatocellularinjury

• DILI-ALFcarriespoorprognosis:40%requirelivertransplantation;42%dieoftheepisode.AdvancedcomagradeandhighMELDscoresareassociatedwithbadoutcomes1,2

1LarsonAM.Drug-inducedliver injury.UpToDate.https://www.uptodate.com.Topiclastupdated: May29,2015.2ChalasaniNP,etal.,ACGClinical Guideline: TheDiagnosisandManagementofIdiosyncraticDrug-InducedLiverInjury.Am JGastroenterol. 2014Jul;109(7):950-66

DILI:CommonCulprits• Acetaminophen(intrinsicDILI),amoxicillin/clavulanate,

isoniazid,NSAIDs,antiepilepticmedications(AEDs)• AntibioticsandAEDsaremostcommonlyreportedand

accountformorethan60%ofDILIoverall2

• Antibiotics:themostcommonclassofdrugresponsibleforacuteliverfailure(ALF)inDILI.

• Mostcommonindividualdrugs:3– Isoniazid– Sulfurantibiotics (TMP-SMX)– Nitrofurantoin

2ChalasaniNP,etal.,ACGClinical Guideline:TheDiagnosisandManagementofIdiosyncraticDrug-InducedLiver Injury.Am JGastroenterol. 2014Jul;109(7):950-66.3Leise,MD,etal.,Drug-InducedLiverInjury.MayoClin Proc.2014;89(1):95-106

DILIPatternsandAssociatedDrugs

• Don’tforget:Certainherbalanddietarysupplements(HDS)canbehepatotoxic,andacauseofDILI– ThisisincreasinglyaconcerngivenHDSproliferationinalargelyunregulatedmarketwithoutstandardization.

– Useofsuchsubstancesmustbeinvestigatedinhistory-taking.

DILIPatternsandAssociatedDrugs

“LIVERTOX® providesup-to-date,accurate,andeasilyaccessedinformationonthediagnosis,cause,frequency,patterns,andmanagementofliverinjuryattributabletoprescriptionandnonprescriptionmedications,herbalsanddietarysupplements. LIVERTOX alsoincludesacaseregistrythatwillenablescientificanalysisandbettercharacterizationoftheclinicalpatternsofliverinjury. TheLIVERTOXwebsiteprovidesacomprehensiveresourceforphysiciansandtheirpatients,andforclinicalacademiciansandresearcherswhospecializeinidiosyncraticdruginducedhepatotoxicity.”5

http://www.livertox.nih.gov/

DILITreatmentStopoffendingdrug(ifnotalreadydone!)

Supportivemeasuresforcomplications/symptoms,butno“silverbullet”orcurativeintervention.• SomeevidenceforN-acetylcystine inadultswith

idiosyncraticDILIandearlyALF• DI-AIHcanbetreatedwithsteroids

Avoidre-exposuretooffendingdrug:• Consideronlyifsuspecteddrugwasalifesavingmedication

forwhichtherearenootheralternatives• Proceedwithcautionunderstrictsurveillance

BacktoAngie

Jocelynrecovers

• Thispatientwasprescribednitrofurantoin,anantibioticthatcanleadtoliverinjury,particularlyinolderpatients

• Itcanbetheenvironmentaltriggertoalsoleadtoautoimmunehepatitis

• Jocelyndidwellandwasinstructedtonottakethatantibioticagain

• Herliverenzymesnormalizedafterafewweeksandshewasnotheardofagainuntil…..

Jocelyn

• 5yearslateratage60,Jocelynisdivorced,hashadaboutofdepression,andhasgainedweight,withaBMIof33

• Shehasdevelopedearlysignsofdiabetes,withfastingglucoseof120mg/dL

• Shealsohasstarteddrinkingwineeverynightwithherdinner,andoccasionalgirlsnightout

• SheisonceagainreferredforelevatedALTof109U/L,ASTof108U/L

AlcoholicHepatitis

Rossalynn Salcido,MPAS,PA-CTexasLiverInstituteSanAntonio,Texas

AlcoholicLiverDisease

• AmajorcauseofmorbidityandmortalityintheUnitedStates

• Encompassesaclinico-histologicalspectrumincluding

• Fattyliver

• Alcoholichepatitis

• Alcoholiccirrhosis

• Themajorityofpeoplewhoabusealcoholforanextendedduration,DONOTdevelopadvancedalcoholicliverdisease

• 15-20%developalcoholichepatitisand/orcirrhosis

WhyDon’tAllDrinkersDevelopSerious

AlcoholLiverDisease?

• Women>men• Familyhistory• >6-8drinks/day• Continuousdrinking/binging• Overweight/poornutrition• Geneticfactors

HowDoesAlcoholDamageTheLiver?

• Alcoholbrokendownintheliver• Breakdownproductsleadtofattyliver,inflammationandscarring

FattyLiver

CirrhoticLiver

NormalLiver

ProgressionofAlcoholicLiverInjury

“Safe”LimitofAlcoholIntake

• Women=14unitsperweek=8drinksperweek• Men=21unitsperweek=12drinksperweek

• SignificantAlcoholConsumption(2012Guidelines)– Women:>140 gofalcohol/wk =>10drinks/week– Men:>210 gofalcohol/wk =>15drinks/week

WhatIsAUnitEquivalentTo?

1standarddrink=14gramsofalcohol1unit=8gramsofalcohol

CAGEQuestionnaire• Mostwidelyused,easytoimplement,short,simpleand

canbeeasilyincorporatedintoclinicalpractice• Asks4questions

– Haveyoueverfeltyoushould cutdownonyourdrinking?– Havepeople annoyedyoubycriticizingyourdrinking?– Haveyoueverfeltbadorguiltyaboutyourdrinking?– Haveyoueverhadadrinkfirstthinginthemorning tosteady

yournervesortogetrideofahangover (eye-opener)?• ItemresponsesontheCAGEarescored0or1,witha

higherscoreanindicationofalcoholproblems• Atotalscoreof2orgreaterisconsideredclinically

significant

PhysicalExamFindings

Ascites ScleralIcterus

JaundiceSpider telangiectasia

LongTermManagementStrategies

• Alwaysadvocateabstinence fromalcoholforthesepatients

• Monitor closelyforrecidivismandsupportcounselingandbehavioralchanges

• Addressnutritional issues,considerdietaryconsult• Livertransplantation

– Alcoholicliverdiseaseis2nd mostcommonindicationfortransplantationinWesternWorld

– Majorityneverreferredduetoconcernfornoncompliance,recidivism

– Alwayssafertoreferandletprogramdecideifeligible

AlgorithmfortheManagementofAlcoholicHepatitis

ConsiderLiverBiopsy ifDiagnosis isuncertain

Establish Disease Severity

Nutritional Assessment /Intervention

HighRisk:MDF≥32,presence ofHE,or

MELD≥18

LowRisk:MDF<32and1stweekdecrease inbilirubin,orMELD<18and1stweekdecrease inMELD

by2points

Prednisolone Pentoxifylline

SupportiveCare&Closefollow-up

Ifsteroidcontraindicationsorearlyrenalfailure

Nutritional Assessment /Intervention

Response byLillemodel?

Yes

No

Continue

Stop

AlcoholicLiverDiseaseAlmostAlwaysEndsinDeathifNotTreated

BacktoAngie

Jocelyn• Jocelynundergoesaliverbiopsysinceshenowhaspossiblefeaturesofalcoholliverinjury

• Thepathologistreviewstheslidesandsaysthereisatremendousamountofsteatosis,butnoevidenceofinflammationorotherfeaturesofalcoholinjury

• Jocelynswearssheisdrinkingmaximumof2drinkspernight,andonly4-5timesperweek

• SomaybeshehasanotherconditionwhichcanlooklikeASH….

Non-Alcoholic FattyLiverDisease(NAFLD):Non-AlcoholicFattyLiver(NAFL)

andNon-AlcoholicSteatohepatitis(NASH)

AngieCoste,MSN,CRM,FNP-CTexasLiverInstituteSanAntonio,Texas

ClinicalCluesofFattyLiverDisease

• Rightupperquadrantpain• Obesity(mostpatientswhoareobesehaveNAFLD)

• Hepatomegaly• Diabetesorsignsofinsulinresistance• ElevatedALT• Hepaticsteatosisonanultrasound• Classicfindingsonliverbiopsy

VisceralObesity

Non-alcoholicFattyLiverDisease

(NAFLD)

EndothelialDysfunctionAtherosclerosis

InsulinResistanceType2Diabetes

DyslipidemiaHypertension

PolycysticOvarianSyndrome(PCOS)

CoronaryArteryDisease

(CAD)

NAFLDisCloselyAssociatedwithVisceralObesityandInsulinResistance

DiseasesAssociatedwithVisceralObesity

HowCanFatAffecttheLiver?

NASHPathogenesis:APerfectStorm

*NotallpatientswithNASHdemonstrateinsulinresistance.

InsulinResistance

HighTriglycerides

ImpairedVLDLSecretion

Obesity

NASH

FatFilledHepatocyte

2nd HIT

EvolutionofNAFLDintheUS

YounossiZetal.ClinGastroandHep2011

0

2

4

6

8

10

12

ALD CH-B HCV(+) NAFLD

1988-1994(N=15,855) 1999-2004(N=13,970) 2005-2008(N=9670)

NHANESCycles

Prevalen

cera

tes(%)

• NAFLD:Mostcommoncauseofchronicliverdisease• DiseaseburdenfromNAFLDwillcontinuetoincrease• RiseduetoobesityorbetteridentificationbyHCP

IncreasingBurdenofNAFLDAmongYoungAdultsintheU.S.

• Prevalencerosefrom9.6%in1988-94to24%2005-10

• HighestamongMexicanAmericansandthosewithBMI>40kg/m2

• TrueprevalenceofNAFLDprobablyhigherthanreportedhere(lowBMI,normalALT)

• Criticaltotargetyoungadultsforscreeningtopreventthedevelopmentofcirrhosisatayoungage.

Mrad,etal,Hepatology13May2016

WhichpatientswithNAFLDareathighestriskforNASHandhowdo

wemonitor?

No lab test or imaging study will be able to predict with 100% accuracy

The more risk factors… the more concerned you should become

RedFlagsforNASH

• Age• Gender• Hispanic• HT• Obesity• Diabetes• ALTandASTlevel• AST/ALT ratio• Insulinlevel• PNPLA3

DiagnosisofNASH

• ScreeningforNAFLDisnotrecommended– Butshoulditbe?– Whomwouldbescreened?

• IncasesofelevatedALT,exclusionofotherliverdiseasemustbedone

• WhenNAFLDissuspected,liverbiopsyisthegoldstandardfordistinguishingNASH– ShouldbeperformedinthosewiththehighestriskfactorsforNASH

WhatOptionsAvailableNow?WeightLoss

HistologicalImproveme

nt

DecreaseinALT Major Concern

Orlistat Yes1/No2 No2 Yes1/No2 Few studies

Metformin Yes4 No4 No4 Limited Efficacy

Pio/Rosiglitazone No-ñ4,5 Yes4,5 Yes4 Safety

Vitamin E No5,6 Yes5,6 Yes5,6 ñ mortality &Pr Ca

Ursodiol No No Yes/No Limited Efficacy

Omega-3FA No No Yes Variable dosing&source

>5-7%Wt loss Yes2,3 Yes2,3 Yes2,3 Lowcompliance

BariatricSurgery Yes Yes Yes Surgicalmorbidity,weightregainYes/No=Conflictingstudies.

1.Clin Gastroenterol Hepatol.2006;4:639–44.2.Hepatology 2009;49:80–86.3.Clin Gastroenterol Hepatol.2006;4:639–44. 4. AlimentPharmacol Ther 2011;34:274–285.5.NEngl JMed2010;362:1675–1685.6.JAMA.2011;305:1659–68.

EmergingSmallMoleculesinNASHCompany Product Mechanism ofAction Phase Endpoint

GENFIT GFT-505(Elafibranor) PPARα/δ agonist 2,completed Reversal of

NASH histologyIntercept Obeticholic acid FXRagonist 3 NASScoreGilead Simtuzumab Anti-LOXL2Mab 2 CollagenRAPTOR RP-103 Cysteine-depletingagent 2, completed NASscoreTobira Cenicriviroc CCR2/5 inhibitor 2 NASScore

Conatus Emricasan Caspase proteaseinhibitor 2, completedALT

Fibrosis(≥1stage)

Galmed Aramchol SyntheticFattyAcid/bileacidconjugate

2a,completed

Triglyceridelevel

2b/3 Triglyceridelevel/Safety

Galectin GR-MD-02 galectin-3inhibitor1, completed Safety/ALT

2 Portalhypertension

Source:clinicaltrials.gov.AccessedFeb18,2016

FinalThoughts:NAFLD

• Complexdiseasetiedcloselytoinsulinresistance,obesityandmetabolicsyndrome

• Geneticpredispositions

• NAFLDcanprogresstoNASH/cirrhosis

• Personalized treatmentmaybethebestfutureoptiontotreatNASH

Jocelyn

• BiopsywasconsistentwithNAFLDandshewasenrolledinaclinicaltrial

• Willupdatehercasenextyear……

TexasLiverInstitute&UTHealthScienceCenter

Adult/PediatricLiverTransplant

Livingdonortransplantprogram

LiverCancerCenter

ClinicsinAustin,CorpusChristi,ElPaso,McAllen

Largestclinical liverresearchunitintheUS

Phase1-3studies

Earlyphase testinggroundforHCV,fattyliverandantifibrotic therapies

National CancerInstitute (NCI)designation

RoundtableDiscussion/Q&A