overview - kssg.ch · 07/01/20 2 deﬁnions • drug-induced liver injury (dili) is deﬁned as a...

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HowtodealwithDILI:Updateondrug-inducedliverinjury

DavidSemela,MDPhDDivisionofGastroenterology&Hepatology,KSSGSt.Gallen

SANCTGALLENSymposium,05.12.2019

Overview•  DefiniJons•  Pathophysiology•  Diagnosis/Phenotypes•  Treatment•  ClinicalvigneNes

•  “Klassiker”FällebringenfürDILI(Vanishingbileduct,NRH,SOS,ReyeSyndrom)

•  Immuntherapienbringen•  LiverToxguterklären•  Herbalerklären()

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DefiniJons•  Drug-inducedliverinjury(DILI)isdefinedasaliverinjury

causedbyvariousmedica5ons,herbs,dietarysupplementsorotherxenobio5cs,leadingtoabnormali5esinlivertestsand/ortoliverdysfunc5onwiththeexclusionofothereJologies

•  DILIisoneoftheleadingcausesofacuteliverfailure

•  DILIcanbeclassifiedintothreedis5ncttypesofhepatotoxicity

Typesofdrug-inducedliverinjury

•  Directhepatotoxicity•  Idiosyncra5chepatotoxicity•  Indirecthepatotoxicity

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Directhepatotoxicity•  Mechanism:Intrinsichepatotoxicitywhenagentgiveninhighdose

•  Dose-related&predictable•  Frequency:Common

•  Latency:Typicallyrapid(days)•  Mostcommonlyimplicatedagents:Highdosesofparacetamol,niacin,

aspirin,cocaine,IVamiodarone,IVmethotrexate,anabolicsteroids,valproicacid,anJmetabolites,HAARTdrugs,cyclosporine,heparins,cholestyramine

•  Phenotypes:AcutehepaJcnecrosis,serumenzymeelevaJons,SOS,acutefaNyliver,NRH

Paracetamol(Acetaminophen)•  Safe&effec5veanalgesic

•  >1billiontablets/yearworldwide

•  Preferredtoaspirin/NSAIDsincirrhosisandchildren

•  Hepatotoxicityisdose-dependent(>4grams)

•  Accidentaloverdosing>suicidalintenJon

•  AnJdote:N-acetylcystein(oralori.v.)

•  Injuryseverity/prognosis:King’scollege&Clichycriteria,ALFSGindex

•  Leadingcauseofacuteliverfailureinmanycountries

•  TransferhighriskpaJentstoOLTcenter

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•  TwocyclesofhighdosechemoTxwithcispla5n,doxorubicin,methotrexate+ifosfamide,etoposide(EURAMOS-1protocol)forosteoblasJcosteosarcomawithmetastasis

•  DevelopedRUQpain,4-quadrantascites,jaundice,renalinsufficiency

•  Noknownpreviousliverdisease,negaJvescreeningforliverdisease

•  US:largebutnormalappearingliver,patentveins,slowportalveinflow

•  Paracentesis:SAAG12g/l,withoutinfecJon,nomalignantcellsbycytology

•  HVPG:14mmHg(normal3-5mmHg)

•  Transjugularbiopsy:Sinusoidalobstruc5onsyndrom(SOS)

Case:11y/oboywithjaundiceandascitesaierhighdosechemotherapy

EarlySOS:Dilata5onofsinusoidsandextravasa5onofredbloodcellsintothespaceofDisse

CentralveinPortalarea

Areasofnecrosis

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SOS:PathognomoniccentralveinlesionwithnarrowingbysubendothelialinfiltraJonofredbloodcells

•  Thechemotherapeu5cdrugsmostclearlyassociatedwithSOS:

•  Busulfan,cyclophosphamide,melphalan,carbopla5n,cispla5n,oxalipla5n,gemtuzumabozagamicin,ac5nomycinD,carmus5ne,dacarbazine,cytosinearabinoside,mitramycin,6-thioguanine,azathiorpine,mercaptopurineandurethane

•  ThemostcommoncauseofSOSinWesternnaJons:myeloabla5vecondi5oningtherapybeforehematopoieJcstemcelltransplantaJon(esp.withcyclophosphamide+wholebodyirradia5on)

•  Withtheadventofnon-myeloablaJvecondiJoningandtheavoidanceofcyclophosphamide,therehasbeenasignificantdeclineinincidenceofSOS

SinusoidalobstrucJonsyndrome(SOS):Causes

DeLeveLD,SeminarsinLiverDisease2007

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SOSphase3study:Improvedsurvivalindefibro5de-treatedpaJentsvs.historicalcontrolsreceivingsupporJvetreatment

RichardsonPGetal.,BloodAdv,2018RichardsonPGetal.,Blood,2016

DefibroJde(n=102)Historical(n=32)

•  DefibroJderesultedinsignificantlygreaterday+100survivalfollowingHSCT(38.2%)vscontrols(25%)

•  Mostcommonadverseeventswerehypotensionanddiarrhea

•  RatesofhemorrhagicAEsweresimilarinthedefibroJdeandhistoricalcontrolgroup(64%and75%,respecJvely).

p=0.0109

IdiosyncraJchepatotoxicity•  Mechanism:IdiosyncraJcmetabolicorimmunologicreacJon

•  Notdose-related&notpredictable•  Frequency:Rare•  Latency:Variable(daystoyears)•  Mostcommonlyimplicatedagents:Amoxicillin–clavulanate,

cephalosporins,INH,nitrofurantoin,minocycline,fluoroquino-lones,macrolideanJbioJcs

•  Phenotypes:AcutehepatocellularhepaJJs,mixedorcholestaJchepaJJs,blandcholestasis,chronichepaJJs

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IdiosyncraJchepatotoxicity

“Idiosyncrasy”Referringtoaperson'sownpeculiar(consJtuJonιδιoς(idios)one'sself,συν(syn)together,κρασις(crasis)“FüreinIndividuumspezifischesanatomisch-physischesVerhaltensmerkmal”

IdiosyncraJchepatotoxicity•  Mechanism:IdiosyncraJcmetabolicorimmunologicreacJon

•  Notdose-related&notpredictable•  Frequency:Rare•  Latency:Variable(daystoyears)•  Mostcommonlyimplicatedagents:Amoxicillin–clavulanate,

cephalosporins,INH,nitrofurantoin,minocycline,fluoroquino-lones,macrolideanJbioJcs

•  Phenotypes:AcutehepatocellularhepaJJs,mixedorcholestaJchepaJJs,blandcholestasis,chronichepaJJs

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IdiosyncraJcDILIExamples•  AugmenJn•  1xhepaJJsch•  1xcholestaJsch•  Ev.BlandeCholestasis•  Reyesyndrom???Erklären:Rvalue,acuteliverfailure/OLTSteroidewann:DRESS,ICI,AIH-like

IncidenceofidiosyncraJcDILI

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BjörnssonESetal.,Gastroenterology,2013

EpidemiologyofDILIinIceland(n=251,860)

AnnualincidenceofDILI:19.1per100’000

BjörnssonESetal.,Gastroenterology,2013

EpidemiologyofDILIinIceland(n=251,860)

Drug Pa5entstreated(n)

Prescrip5on(n) Cases(n) Propor5on Per100,000

95%CI 95%CI

Amoxicillin/clavulanate 35’252 83’379 15 2’350 43 24 70

Diclofenac 54’889 112’801 6 9’148 11 4 24

Azathioprine 532 3’054 4 133 752 205 1’914

Infliximab 593 * 4 148 675 184 1’718

Nitrofurantoin 5’476 12’034 4 1’369 73 20 187

Isotre5noin 2’169 7’978 3 732 138 29 404

Atorvasta5n 7’385 34’171 2 3’693 27 4 98

Doxycycline 32’677 54’232 2 16’339 6 1 22

*MostpaJentsoninfliximabreceivedconJnuostreatment

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MostFrequentCausesofIdiosyncraJcPrescripJonDILI(n=899)

ChalasaniNetal.,Gastroenterology,2015 HoofnagleJetal.,NEnglJMed,2019



9ofthe10toprankingdrugsarean5microbialagents/an5bio5cs

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Agentsrankingfrom14thto25thinfrequency:hydralazine,lamotrigine,mercaptopurine,atorvastaJn,moxifloxacin,allopurinol,amoxicillin,duloxeJne,rosuvastaJn,telithromycin,terbinafine,andvalproicacid

PathophysiologyofDILI•  Ev.GWAS&HLAhiernurerwähnen

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HepatocytetransportersandcellularmechanismsofDILI

AndradeRJeta

l.,NatRevDisPrim

,2019

CholestaJc

Hepatocellular

Mixed Vascular

“Phenotypes”ofDILI

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Mod

ified

from

And

rade

RJe

tal.,NatRevDisPrim

,2019

Acutehepa55sfluoroquinolones,isoniazid,lamotrigine,α-methyldopa,minocycline,pyrazinamide,sulfonamides

Chronichepa55scarbamazepine,methyldopa,minocycline,nitrofurantoin,phenytoin,sulfonamides

Acutecholestasisamoxicillin–clavulanate,chlorpromazine,erythromycin,flucloxacillin

Chroniccholestasisanabolicsteroids,cyclosporine,oestrogensCholesta5chepa55samoxicillin–clavulanate,AZA,carbamazepine,chlorpromazine,macrolides,sulfonamides,terbinafine

Granulomatousinflamma5onallopurinol,carbamazepine,phenytoin,sulfonamides

Microvesicularsteatosisamiodarone,aspirin(Reye),didanosine,stavudine,tetracycline,valproate

Macrovesicularsteatosismethotrexate,tamoxifen

Steatohepa55samiodarone,methotrexat,tamoxifen

Zonalnecrosisacetaminophen/paracetamol,halothane

Massiveorsubmassivenecrosisisoniazid,phenytoin,pyrazinamide,sulfonamides

Nodularregenera5vehyperplasiaazathioprine,bleomycin,busulfan,oxaliplaJn,6-thioguanine

Sinusoidalobstruc5onsyndromebusulfan,cyclophosphamide,melphalan,carboplaJn,cisplaJn,oxaliplaJn,dacarbazine,gemtuzumabozagamicin,acJnomycinD,carmusJne,,cytosinearabinoside,mitramycin,6-TG,AZA,mercaptopurineandurethane

Livertumors(hepatocellularadenoma&carcinoma)danazol,estrogens,methyl-testosterone,oxymethalone

HistologicalphenotypesofDILI

DiagnosJcs

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DILIshouldbeconsideredwhenanyoneofthefollowingthresholdsismet,evenintheabsenceofsymptoms:•  ALTorASTincreaseto≥5-foldtheULN

•  ALPincreasesto≥2-foldtheULN

•  TotalbilirubinconcentraJonincreases>2-foldtheULNassociatedwithALTorASTincreasesto≥3-foldtheULN

AndradeRJetal.,NatRevDisPrim,2019

Clinicalchemistrycriteria

“RraJo”forclassificaJonofidiosyncraJcDILIpaNern

Hepatocellular Cholesta5cMixed

DILIN,La5nDILI,SpanishDILIN:ca.50%hepatocellular,25%mixedand25%cholesta5c

BenichouCetal.,JHepatol,1990

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DILIseverityclassificaJon:InternaJonalDILIExpertWorkinGroup1

1  Mild

2  Moderate

3  Severe

4  Fatal/transplanta5on

ALT≥5orALP≥2andTBL<2×ULN

ALT≥5orALP≥2andTBL≥2×ULN,orsymptoma5chepa55s

ALT≥5orALP≥2andTBL≥2×ULN,orsymptoma5chepa55sandoneofthefollowingcriteria:-  INR≥1.5-  Ascitesand/orHE,duraJon<26weeks,nocirrhosis-  OtherorganfailureduetoDILI(i.erenal,pulmonary)

Deathorlivertransplanta5onduetoDILI

1AithalGPetal.,ClinPharmacolTher,2011 EASLDILICPG,JHepatol,2019

Category&Severity

StepwiseapproachtoDILIdiagnosis

EASLDILICPG,JHepatol,2019

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CausalityassessmentbyCIOMS/RUCAMscaleCIOMS:CouncilforInternaJonalOrganizaJonsofMedicalSciences

RUCAM:RousselUclafCausalityAssessmentMethod

ProbabilityofDILI:•  Highlyprobable>8•  Probable6-8•  Possible3-5•  Unlikely1-2•  Excluded≤0

DananGetal.,JClinEpidemiol,1993


CHRONOLOGICALCRITERIAFromdrugintakeunJlonseteventFromdrugwithdrawalunJlonseteventCourseofthereacJonRISKFACTORSAgeAlcoholCONCOMITANTTHERAPYEXCLUSIONNON-DRUGRELATEDBIBLIOGRAPHICALDATARECHALLENGE

+2to+1+1to0-2to+3+1to0+1to0-3to0-3to+20to+2-2to+3

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HepCalcApp



Onlinecalculator:www.pmidcalc.org



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WhatisthebestDILIreference?

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Herbalanddietarysupplementsinvolvedinhepatotoxicity

EASLCPGDILI,2019

ACH,acutecholestaJchepaJJs;AHH,acutehepatocellularhepaJJs;ALF,acuteliverfailure;HCC,hepatocellularcarcinoma;SOS,sinusoidalobstrucJonsyndrome.

Herbalsupplements Typeofliverinjury

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EASLCPGDILI,2019


Asianherbalmedicine(Chinese,Japanese,ayurvedicmedicines) Typeofliverinjury


EASLCPGDILI,2019


Dietarysupplements Typeofliverinjury

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TherapyofDILI•  StopimmediatelyanynonessenJaldrug!•  Specificifavailable(i.e.defobroJdeinSOS)•  Empirically

–  SteroidsifprominenthypersensiJvityfeatures,drug-inducedAIHorDILIduetocheckpointinhibitors

–  UDCAifprolongedcholestasis•  N-acetylcysteinhasprovedusefulinearlystages(encephalopathy

I-II)offulminanthepaJcfailureduetodrugs(non-acetaminophen)•  Ifimpendingliverfailure(encephalopathy,INR>1.5)referralfor

livertransplanta5on

OlsonKRetal.NEJM2017

Causesofacuteliverfailureinadults&children

Children>10years AdultsNote:Acetaminophen=Paracetamol

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Liverfailureduetonon-paracetamolDILIinUSA(1987-2006)

BernalWetal.,Lancet2010

DevelopmentofamodeltopredicttransplantfreesurvivalofpaJentswithacuteliverfailure

KochDGetal.,ClinGastroenterolHepatol,2016

ComparisonoftheALFSGModeltotheKing’sCollegeCriteria(APAP),theKing’sCollegeCriteria(APAP)andMELDScore,inpredicJng80%survival

n=1974paJentswithacuteliverfailure,retrospecJveanalysisfrom1998to2013DILIn=215(11%),paracetamoln=933(48%)

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DevelopmentofamodeltopredicttransplantfreesurvivalofpaJentswithacuteliverfailure

KochDGetal.,ClinGastroenterolHepatol,2016

Acuteliverfailureprognos5cmodelApp

Indirecthepatotoxicity•  Mechanism:IndirectacJonofagentonliverorimmunesystem

•  Notdose-related&parJallypredictable•  Frequency:Intermediate

•  Latency:Delayed(months)

•  Mostcommonlyimplicatedagents:AnJneoplasJcagents,glucocorJcoids,monoclonalanJbodies(anJ-TNF,anJ-CD20,checkpointinhibitors),proteinkinaseinhibitors

•  Phenotypes:AcutehepaJJs,immune-mediatedhepaJJs,faNyliver,chronichepaJJs,HBVreacJvaJon

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•  Mild-to-moderateALT&ASTeleva5onscommon(~10%)duringICI

•  LFTelevaJonsusuallyself-limited&resolveevenwithconJnuingcyclictherapy

•  ALT>5xULNoccurin0.5%to1.5%ofpaJents

•  AproporJonofthesepaJentsdevelopapparentliverinjurythatcanbesevere

•  OnsetofICIDILI:usuallyaper2to6cycles,1to3monthsaierICIstart

•  Parern:usuallyhepatocellularbutcanbemixed,parJcularlyattheonset

•  Liverhistology:acutehepa55s-likepaNernwithfocalorconfluentnecrosisandprominentlymphocy5cinfiltratesofacJvatedTcells

•  Autoan5bodiesareusuallynotpresent

•  RestarJngnivolumabcanresultinrecurrenceofinjury

•  Cor5costeroidtreatmentmayblockrecurrence

Livertoxicityfromimmunecheckpointinhibitors(ICI)

HaanenJetal.,AnnalsofOncology,2017

Managementoflivertoxicityfromimmunotherapy:ESMOClinicalPracJceGuidelinesfordiagnosis,treatmentandfollow-up

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•  Referralbyfamilydoctorofa42yoteacherforjaundice&fa5guesince10days

•  KnownB-celllymphomadiagnosedoneyearearlier;treatedwithsixcyclesofR-CHOP(rituximab,cyclophosphamid,doxorubicin,vincrisJne,prednison)

•  InclinicalremissionforB-celllymphomaandotherwisehealthy

•  Labs:Transaminases20xULN,totalbilirubin210

•  Ultrasound:Moderateascites,normalappearingliver,patentveins

Case:42y/owithjaundice&faJgue

•  ChartreviewshowspriorHBVscreening:an5-HBc+,HBsAg-,an5-HBs-

•  NoHBVprophylaxisorpre-emp5vetherapywereperformed

•  Currentlabs:ALT860U/l,HBsAg+,HBeAg+,HBVDNA75x106U/mL

•  Liverbiopsy:nolymphomainfiltraJon,largenecroJczones,minmalfibrosis,HBsAgposiJvehepatocytes

•  Diagnosis:HBVseroreversion(=re-seroconversion)aierrituximabtx

•  Treatmentwithtenofovirwasimmediatelystarted;thepaJentrecoveredwithin3monthsandremainsontenofovir

Case:42y/owithjaundice&faJgue

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Rituximab(i.e.MabThera®&biosimilars)

•  MonoclonalanJbodiesagainstCD20(B-cellmarker)

•  DepletesB-cellsandreducesan5bodylevels

•  IncreasingindicaJonsandcombinaJonsofrituximab(i.e.R-CHOP,R-EPOCH):NHL,leukemia/CLL,idiopathicthrombocytopenicpurpura,cryoglobulinemia,rheumatoidarthri5s,ANCA-associatedvasculi5s

•  IncreasedriskofHBVreacJvaJonand/orseroreversioneveninHBsAg-negaJve“resolved”paJentsleadtoexpandedboxwarningbyFDA

•  MortalityrateinjaundicedpaJentsexceeds10%YeoW,etal.Hepatology.2006

PapamichalisP,etal.ClinResHepatolGastroenterol.2012

Rituximab(i.e.MabThera®&biosimilars)

•  MonoclonalanJbodiesagainstCD20(B-cellmarker)

•  DepletesB-cellsandreducesan5bodylevels

•  IncreasingindicaJonsandcombinaJonsofrituximab(i.e.R-CHOP,R-EPOCH):NHL,leukemia/CLL,idiopathicthrombocytopenicpurpura,cryoglobulinemia,rheumatoidarthri5s,ANCA-associatedvasculi5s

•  IncreasedriskofHBVreacJvaJonand/orseroreversioneveninHBsAg-negaJve“resolved”paJentsleadtoexpandedboxwarningbyFDA

•  MortalityrateinjaundicedpaJentsexceeds10%YeoW,etal.Hepatology.2006

PapamichalisP,etal.ClinResHepatolGastroenterol.2012

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HBVreacJvaJonwithrituximab:Typicallylateandsevere!

Analysisof5B-celllymphomapts(24%)withHBVseroreversion1:

•  MedianpeakALT:809U/l(362-3499)

•  Medianpeakbilirubin:65µmol/l(19-249)

•  OnepaJentduring5thcycleofrituximabtreatment

•  Threeptswithmedianof98daysAFTERlastrituximabdose

Possibleriskfactorsforseroreversion1.  Male>>female2.  AnJ-HBsnegaJve(orlowanJ-HBsJters)3.  Higherage(>50years)

1YeoW,etal.JClinOncol.2009









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WhataretheEASLrecommenda5onsonprophylaxisinHBsAg-nega5ve,an5-HBcposi5vepaJentsundergoing

chemotherapyorimmunosuppression?

HBsAg-nega5ve,an5-HBc-posi5vesubjectsshouldreceivean5-HBVprophylaxisiftheyareathighrisk(>10%)ofHBVreacJvaJon.

EASLHBVCPG2017

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Meta-analysisofNUCsvs.noprophylaxisshowsa87%rela5veriskreduc5onofHBVreac5va5onforrituximabandotherimmunosuppressiveregimens

PerilloRPetal.,Gastro,2015

NewanJ-CD20anJbodiesandagentstargeJnglymphoidormyeloidcellsurfaceanJgens

Rituximab-biosimilarsavailableinEuropeand/orSwitzerland:•  Blitzima®,Ritemvia®,Rixathon®,Riximyo®,Truxima®,

Approvednextgenera5onan5-CD20an5bodies:•  Obinutuzumab(Gazyvaro®)•  Ocrelizumab(Ocrevus®)•  Ofatumumab(Arzerra®)•  Ibritumomab(Zevalin®)•  Tositumomab(Bexxar®)

Agentstarge5nglymphoidormyeloidcellsurfacean5gens(CD22,CD30,CD33,CD38,CD40,SLAMF-7,CCR4)1

•  i.e.Brentuximab,Mogamulizumab

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ReferencesondrugsleadingtoHBVreacJvaJon

AGAIns5tutetechnicalreviewonpreven5onandtreatmentofHBVreac5va5onduringimmunosuppressivedrugtherapy.PerilloRPetal.,Gastro,2015.

ESCMIDstudygroupforinfec5onsincompromisedhosts(ESGICH)consensusdocumentonthesafetyoftargetedandbiologicaltherapies:aninfec5ousdiseaseperspec5ve(agentstarge5nglymphoidormyeloidcellssurfacean5gens(II):CD22,CD30,CD33,CD38,CD40,SLAMF-7andCCR4).DrgonaLetal.,ClinMicrobiolInfect,2018.

NIHLiverToxdatabase:Clinicalandresearchinforma5onondrug-inducedliverinjury.www.livertox.nih.gov

Summary

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References

Appendix

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CausalityassessmentbyCIOMSscaleCIOMS:CouncilforInternaJonalOrganizaJonsofmedicalSciences1

ProbabilityofDILI:•  Highlyprobable>8•  Probable6-8•  Possible3-5•  Unlikely1-2•  Excluded≤0

1DananGetal.,JClinEpidemiol,1993


CHRONOLOGICALCRITERIAFromdrugintakeunJlonseteventFromdrugwithdrawalunJlonseteventCourseofthereacJonRISKFACTORSAgeAlcoholCONCOMITANTTHERAPYEXCLUSIONNON-DRUGRELATEDBIBLIOGRAPHICALDATARECHALLENGE

+2to+1+1to0-2to+3+1to0+1to0-3to0-3to+20to+2-2to+3


DananGetal,.IntJM

olScien

ces,2015

DananGetal.,JClinEpide

miol,1993

EASLDILICPG

,JHep

atol,2019

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SukKTeta

l.,ClinM

olHep

atol,2012

DananGetal,.IntJM

olScien

ces,2015

DananGetal.,JClinEpide

miol,1993

EASLDILICPG

,JHep

atol,2019

ThemostrepresentaJveliver-specificDILIcausalityassessmentscales

Garcia-CortesMetal.,JHepatol,2011

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RiskgradientofHBVreacJvaJonwith

differentimmunosuppressive

medicaJons

PerilloRPetal.,Gastro,2015

RiskgradientofHBVreacJvaJonwithdifferenttargetedtherapies

DrgonaLetal.,ClinMicrobiolInfect,2018

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EASLCPGDILI,2019

HaanenJetal.,AnnalsofOncology,2017

Managementoflivertoxicityfromimmunotherapy:ESMOClinicalPracJceGuidelinesfordiagnosis,treatmentandfollow-up

overview - kssg.ch · 07/01/20 2 deﬁnions • drug-induced liver injury (dili) is deﬁned as a...

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