An Introduction To

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Acute-On-Chronic Liver Failure

WHATISACLF?AnyunderstandingofACLFmuststartwithanunderstandingofchronicliverfailure.Theliver,thebody’slargestabdominalorgan,carriesouthundredsofcriticalfunctions,includingdetoxifyingharmfulsubstances,cleaningtheblood,andmakingvitalproteins,amongothers.Thelivercanregeneratemostofitsowncellswhentheybecomedamaged.However,ifinjurytotheliveristoosevereorlonglasting,regenerationisincomplete,andthelivercreatesscartissue(fibrosis).Thebuildupoffibrotictissueisusuallyaslowandgradualprocess.Intheearly

stagesoffibrosis,thelivercontinuestofunction.However,asscartissuecontinuestodevelopandreplacesmorehealthytissue,theliverwillbecomecirrhotic.Cirrhosisoftheliverisapathologicaldiagnosischaracterizedbydiffusefibrosis(largeamountsofdensescartissuelaiddownintheliverbyspecializedcells),alterationofthehepaticarchitecture,anddisruptionoftheintrahepaticarterialandvenousflow(bloodflowintheliver).Withprogressivecirrhosis,patientsdevelopportalhypertension,i.e.,elevatedpressureintheveinsdrainingfromthestomach,intestine,spleen,andpancreasthatmergeintotheportalvein,comparedtopressure

Acute-on-ChronicLiverFailure(ACLF)isadevastatingcomplicationofcirrhosis,usually

EachyearintheU.S.some41,000peoplearerushedtohospitalwithACLF.Thegreaterthenumberoforganfailuresinvolved,thehigherthemortalityrateforthesecritically-illpatients–upto80%withinamonthofhospitalization.Whilemedicalmanagementcanbeabridgetotransplantation,manyACLFpatientsdonotqualifyfororlivelongenoughtoreceiveadonororgan.ThispaperexaminesACLF,itscauses,itsdevastatingeffectsonpatients,lovedonesandsocietyasawhole,andstepsbeingtakentoaddressthisserioushealthconcern.

broughtonbyaprecipitatingeventthatstressestheliver,which,inturn,triggersrapidprogressiontomulti-organfailurewithhighshort-termmortality.

inthebloodvesselsdrainingbloodfromtheliver(hepaticveins)andtakingitbacktotheheart.Thelifethreateningcomplicationsofcirrhosisoccuronceportalhypertensiondevelopsandincludevaricealbleeding(bleedingfromvaricose-typeveinsthatdevelopintheesophagusandstomach),ascites(fluidintheabdomen),hepaticencephalopathy(confusionthatoccursduetoexcessiveammonialevels)andrenalfailure(hepatorenalsyndrome).Cirrhosis,anecessaryprecursortoACLF,ishistoricallymostcommonlyfoundinpatientswithchronicviralhepatitislikehepatitisBorC,thosewithexcessivealcoholuseandthosewithfattyliverdisease.Thedemographicsareshifting,

however,withthedevelopmentofcurativeantiviraldrugsandtheobesityepidemic.Onceaminoritycauseofcirrhosis,

non-alcoholicfattyliverdisease(NALF)isgrowingrapidly,andisexpectedtobecomealeadingcause,alongwithalcoholabuse,ofcirrhosisand,therefore,ACLFwithinafewyears.AsNAFL-relatedcirrhosisincreases,itisexpectedtocompensateforthedecliningviralhepatitispopulation,expandingthesizeofthecirrhosispopulationfrompresentnumbers.Infact,theincidenceofcirrhosishasdoubledoverthelastdecade.WHENCIRRHOSISADVANCESTOACLFCirrhosisisconsideredeithercompensatedordecompensated.Compensatedpatientsdonotexhibitsymptomsoftheircirrhosis(theydonothaveclinicallysignificantportal

hypertension),whereasdecompensatedpatientsdohaveclinicallysignificantportalhypertensionwhichoccurswhenpatientsdevelopvarices.Decompensationissparked

Each year in the US, 41,000 people are hospitalized for ACLF

Mortality rates for hospitalized ACLF patients run as high as 80%

byanincidentofacutestressonthebackgroundofcirrhosis.Thismaybeanalcoholicbinge,anewviralinfectionoraflareofanoldone,orabacterialinfection—however,frequentlynoprecipitatingeventcanbeidentified.Thesymptomsofdecompensation,whichoftendrivehospitalizationofthesepatients,includejaundice(yellowingoftheskinandeyescausedbyanaccumulationofbilirubin,whichismadeduringthebreakdownofredbloodcells),presenceofascites,varicealhemorrhage(bleeding),and/orhepaticencephalopathy.Theseprocessesmayalterthebarrierfunctionofthegastrointestinaltract,makingpatientsmoresusceptibletoinfectionandotherfactorsthatcanexacerbatetheirinflammatorystate.Withinthebackgroundofcirrhosis,ACLFisbroughtonbyanincidentofacutestress,causingacutedecompensationalongwithoneormoreorganfailures.ACLFpatientsareknownbeinanelevatedinflammatorystate,whichplaysacrucialroleinthedevelopmentofthecondition.ROLEOFINFLAMMATIONINACLFDependingontheetiology,inflammationisattheheartoftheevolutionofcirrhosis.Itistypicallyinitiatedbyalcohol,aviralinfection,orfatdeposits.Thisinflammationpromotesthefibrosisthatalterstheliverarchitecturetothepointofcausingcirrhosis,ultimatelyresultinginportalhypertension.InACLF,theinflammatoryresponseisnotlimitedtotheliver;rather,itinvolvestheentirebody.Systemicinflammationisahallmarkfeatureofpatientswithacutedecompensation(AD)ofcirrhosisandplaysacrucialroleinthedevelopmentofACLF.ThewhitecellcountandplasmaC-reactive

proteinlevels,bothindicatorsofinflammation,arehigherinpatientswithACLFthaninthosewithADandnoorganfailures,thatis,thosewithoutACLF.1BacteriaareanimportanttriggerforthissystemicinflammatoryresponseinACLF.Bacteriaexpressmolecularstructuresknownaspathogen-associatedmolecularpatterns(PAMPs)thatarespecificallyrecognizedbygermline-encodedreceptorscalledpattern-recognitionreceptors(PRRs)locatedatthesurfaceorwithininnateimmunecells.23.TheengagementofPRRsresultsintheactivationofsignalingcascadesthatactivatetranscriptionfactors(e.g.,nuclearfactor(NF)-jB,AP-1,interferon(IFN)-regulatorfactor(IRF)3,amongothers).45Theseinducehundredsofgenesincludingthoseencodingmajorinflammatorycytokines.6Thisinflammatoryresponseisbeneficialinthatitplaysamajorroleinhostresistancetoinfection,i.e.thereductionofbacterialburden.However,theinflammatoryresponsetobacterialcomponentsmaybeexcessiveandassociatedwithcollateraltissuedamage(immunopathology)resultinginorganfailure(OF).

1MoreauR,JalanR,GinesP,etal;CANONICStudyInvestigatorsoftheEASL–CLIFConsortium.Acute-on-chronicliverfailureisadistinctsyndromethatdevelopsinpatientswithacutedecompensationofcirrhosis.Gastroenterology2013;144(7):1426–1437,1437.e1–1437.e92KawaiT,AkiraS.Toll-likereceptorsandtheircrosstalkwithotherinnatereceptorsininfectionandimmunity.Immunity2011;34:637–650.3FosterSL,HargreavesDC,MedzhitovR.Gene-specificcontrolofinflammationbyTLR-inducedchromatinmodifications.Nature2007;447:972–978.4GustotT,DurandF,LebrecD,VincentJL,MoreauR.Severesepsisincirrhosis.Hepatology2009;50:2022–2033.5KawaiT,AkiraS.Toll-likereceptorsandtheircrosstalkwithotherinnatereceptorsininfectionandimmunity.Immunity2011;34:637–650.6SarinSK,KumarA,AlmeidaJA,ChawlaYK,FanST,GragH,etal.Acute-on-chronicliverfailure:consensusrecommendationsoftheAsianPacificAssociationforthestudyoftheliver(APASL).HepatolInt2009;3:269–282.

SystemicinflammationandthedevelopmentofOFsareattributedtobacterialinfectioninapproximately30%ofpatientswithACLF.7Thesepatientshavesepsis-inducedACLF.Bacterialcomponentsandpro-inflammatorycytokinesareknowntoinducenitricoxide(NO)synthaseinarteriolarwallsofthesystemiccirculationandoncardiactissueresultinginincreasedproductionofthevaso-relaxantNO,impairmentincardiacinotropicfunction,arterialhypotensionanddecreasedoxygen

deliverytotissues.8Bacterialcomponentsandpro-inflammatorycytokinestargettheendotheliumofmicrovasculatureinvital

7Moreau R, Jalan R, Gines P, et al. Acute-on-chronic liverfailure isadistinctsyndromethatdevelops inpatientswithacute decompensation of cirrhosis. Gastroenterology2013;144:1426–37,1437.e1–9.8MacMickingJD,NathanC,HomG,ChartrainN,FletcherDS,TrumbauerM,etal.Alteredresponsestobacterialinfectionandendotoxicshockinmicelackinginduciblenitricoxidesynthase.Cell1995;81:641–650.

organsfavoringtheformationofmicrothrombi(andtissuehypoxia)aswellasadhesionandtransendothelialmigrationofvariouscirculatingcells.Influxofphagocytesintissuesmayinducetissuedamage(celldysfunction,apoptosisornecrosis)viareleaseofoxygenreactivespecies.9AllthesefeaturescontributetoOFs.Anotherimportanttriggerofsystemicinflammationisalcohol.Severealcoholic

hepatitis(inflammationoftheliver)(SAH)representsapproximately25%ofthecasesofACLF.10SeverityisrelatedtothedevelopmentofOFs.Systemicinflammation

9RussellJA.Managementofsepsis.NEnglJMed2006;355:1699–1713.10MoreauR,JalanR,GinesP,etal.Acute-on-chronicliverfailureisadistinctsyndromethatdevelopsinpatientswithacutedecompensationofcirrhosis.Gastroenterology2013;144:1426–37,1437.e1–9.

Half of ACLF patients eligible for a transplant die before receiving one

Each ACLF episode runs $116,000 to $180,000 just for ICU costs

developsinpatientswithSAHandcorrelateswiththeoutcomesuggestingaroleofinflammationinthedevelopmentofOFs.11Excessivealcoholconsumptionisassociatedwithintestinaldysbiosis(microbialimbalance)andincreasedintestinalpermeability,whichfavortranslocationofviablebacteria.12ThismayexplainwhyspontaneousbacterialperitonitisisthemostcommoninfectionatadmissionofpatientswithSAH.However,systemicinflammationisalsoobservedinpatientswithSAHwithoutclinicallydetectablebacterialinfection.Inabout40%–50%cases,patientswithACLFhavesystemicinflammationforwhichtherearenoclinicallyidentifiabletriggers.ACLFTOOOFTENLEADSTODEATHACLFisgradedintothreecategories(grades1–3)basedonthenumberofOFs,withhighergradesassociatedwithincreasedmortality.LiverandrenalfailuresarethemostcommonOFs,followedbycoagulation,brain,circulatoryandrespiratoryfailure.ACLF-1(oneOF)isassociatedwitha28-daymortalityrateof22%,ACLF-2(2OFs)of32%andACLF-3(3ormoreOFs)of79%.Bycomparison,themortalityrateindecompensatedcirrhoticpatientswithoutACLFis4.9%.CURRENTMANAGEMENTOFACLFMostACLFtreatmentfocusesonfactorsthatmaybeprecipitatingthefailure,andonsymptomaticrelief.Typically,patientsareadmittedtotheintensivecareunit,andif

11MichelenaJ,AltamiranoJ,AbraldesJG,etal.Systemicinflammatoryresponseandserumlipopolysaccharidelevelspredictmultipleorganfailureanddeathinalcoholichepatitis.Hepatology2015;62:762–72.12ArroyoV,MoreauR,KamathPS,etal.Acute-on-chronicliverfailureincirrhosis.NatRevDisPrimers2016;2:16041.

aninfectionissuspected,theyaretreatedimmediatelywithbroad-spectrumantibiotictherapy.StudieshaveshownthatrapidinitiationofantibiotictreatmentinACLFpatientswithsepsis(withinonehourofhypotensionandsigns/symptomsofinfection)cansignificantlyimproveoutcomeswhencomparedtoadministeringantibioticswithinsixhours.13Additionally,patientswithhepatitisBvirus-relatedACLFhavesignificantlylower3-monthmortalityiftreatedwithnucleot(s)ideanaloguescomparedtothosewhodonot(45%vs.73%).Furthermore,patientswithvaricealbleedingwhoaretreatedwithantibioticsmayhaveimprovedoutcomes.WhenACLFisassociatedwithaprecipitatingfactor(i.e.,bacterialinfections,GIbleeding,alcoholism,drugtoxicity),earlyidentificationandtreatmentoftheprecipitatingfactorareessential.However,thismaynotpreventthedevelopmentorworseningofthesyndrome.Inaddition,asstatedearlier,inupto50%ofpatientsaprecipitatingfactormaynotbeidentified.Moreover,availabledatasuggestthatalthoughtheprecipitatingfactormaybethetriggerofACLF,itmaynotbeanessentialpredictorofprognosis.Despiteallcurrentaggressivemedicalmanagement,mortalityat30and90daysinACLFremainshigh.Unfortunately,manyACLFpatientsdonotqualifyfortransplantation(advancedage,activealcoholism,concomitantdiseasesandthepresenceofassociatedfailingorgans,etc.),andeveniftheydo—giventhattransplantcandidatesfaroutnumberdonors—manydonotlivelongenoughtoreceivealiver.Infact,halfofallACLFpatientsthatqualifyfor

13YaseenM.Arabi,“AntimicrobialTherapeuticDeterminantsofOutcomesFromSepticShockAmongPatientsWithCirrhosis,”Hepatology,;JodyC.Olson,“IntensiveCareofthePatientwithCirrhosis,”Hepatology,Vol.54,No.5,2011

transplantation,diebeforeasuitabledonororganisavailable.That’sthebadnews.Thegoodnewsisthatforpatientsreceivinganewliver,one-yearsurvivalisveryhigh.Inastudy14ofpatientswithACLFgrade2and3,survivalat90days

withoutlivertransplantwasunder20%,versus80%inpatientswhoreceivedatransplant.Othertreatments,suchasextracorporealliversupport,havebeenstudiedbuthavenotdemonstratedamortalitybenefitand

14RichardMoreauetal,“Acute-on-ChronicLiverFailureIsaDistinctSyndromeThatDevelopsinPatientsWithAcuteDecompensationofCirrhosis,”Gastroenterology,2013;144:1426-1437.

sohavenotbeenestablishedasstandardofcare.15THEECONOMICBURDENOFACLFAcuteandchronicliverdiseasesaccountforsubstantialuseofhealthcareresources,and

strainfamiliesthathavelovedonessufferingfromthisdisease—whomanytimesnotonlyundergoanemotionaltoll,butareforcedtomakesacrificestobecomethecaregivers.WhileACLFaccountsforasmallpercentageofthosewithliverdisease,theirinpatienthospitalcareissointenseandtheyplaceahigherburdenon

15FrancoisDurand,“ManagementofAcute-on-ChronicLiverFailure,”SeminLiverDis2016;36:141–152.

CHARACTERISTICSOFACLFPATIENTSBYGRADE*

Grade Definition 28-DayTransplant-freeMortalityRate

AcuteDecompensationwithoutACLF

Noorganfailure 4.7%

Single-organfailure(liver,coagulation,circulation,lungs)inpatientswithserumcreatininelevels<1.5mg/dLandnohepaticencephalopathy

Singlecerebralfailureinpatientswithserumcreatininelevels<1.5mg/dL

ACLFGrade1 Singlekidneyfailure 22.1% Single-organfailure(liver,coagulation,circulation,

lungs)inpatientswithserumcreatininelevelsrangingfrom1.5–1.9mg/dLand/orgrades1–2hepaticencephalopathy

Singlecerebralfailureinpatientswithserumcreatininelevelsrangingfrom1.5–1.9mg/dL

ACLFGrade2 Twoorganfailures 32.0%

ACLFGrade3 Threeorganfailuresormore 78.6%

*ThistableisbasedontheCANONICstudyconductedin2011,whichprospectivelyenrolled1343patientswithcirrhosishospitalizedin29LiverUnitsfrom8Europeancountries.ThedefinitionofthePresenceorAbsenceofACLFandofACLFGradesBasedonResultsObtainedatEnrollmentintheCANONICStudy.ACLFwaspresentin23%ofpatientsathospitaladmissionordevelopedin11%ofpatientswhodidnothaveACLFatadmission;atotalof303patientshadACLF.Enrolledpatientswerehospitalizedforatleast1onedayandhadanacutedevelopmentoflargeascites,hepaticencephalopathy,gastrointestinalhemorrhage,bacterialinfections,oranycombinationofthese.Forthediagnosisoforganfailures,investigatorsusedamodifiedSOFAscale,calledtheCLIF-SOFAscale,whichhadbeendesignedspecificallybytheWritingCommitteeoftheCANONICstudybeforetheonsetofthisstudy.

thehealthcaresysteminhumanresourcesanddollars.Forinstance,theaveragelengthofhospitalstayforapatientsufferingwithcirrhosisissevendays,versus16daysforanACLFpatient16.Duetothehigherriskofmortality,thelevelofcaregivenneedstobemorespecializedandresourceintensive.Ineconomicterms,in-hospitalcostsare3.5timeshigherforanACLFpatientversusadecompensatedcirrhosispatientwithoutACLF.17SinceACLFoftenisaresultofacutecomplicationssuchassepsis,spontaneousbacterialperitonitis,orgastrointestinalbleedingorfromsuperimposedeventssuchasacuteviralhepatitis,drug-inducedliverinjury,alcoholconsumption,orischemichepatitis,thehighlikelihoodofdeathrequiresmoreintensivetreatment.ThemeanICUchargesperadmissioncanrangefrom$116,000to$180,000perepisode18-ormorethan$4billionannuallytotheU.S.healthcaresystem.19Obviouslythiscostburdendoesn’ttakeintoaccountotherrelatedcostsofcaringforthesepatientsortheeffectsthishasonsocietyasawhole.SincetheaverageageofACLFpatientsisonly56years,20therearethehiddencostsoflostworkerproductivity/wages,andinmanycases,thelossofabreadwinnerinthefamily.

16PatrickS.Kamath,M.D.,AcuteonChronicLiverFailure,ClincialLiverDisease,VOL9,No.4,April201717AlinaM.Allen,etal,TimeTrendsintheHealthCareBurdenandMortalityofAcuteonChronicLiverFailureintheUnitedStates,Hepatology,VOL.64,NO.6,201618JodyOlsonelal,IntensiveCareofthePatientwithCirrhosis,Hepatology,2011;1;54;1864—187219RowenK.Zetterman,UnderstandingAcute-on-ChronicLiverFailure,Medscape,Jan19,2016;$116,000X40,000.20AlinaM.Allen,etal,TimeTrendsintheHealthCareBurdenandMortalityofAcuteonChronicLiverFailureintheUnitedStates,Hepatology,VOL.64,NO.6,2016

FUTUREPROGRESSINTREATINGACLFIt’sbeenovertwodecadessincepublicationofthefirstarticleproposingthehypothesisthatacute-on-chronicliverfailurewaslikelytobeadistinctclinicalcondition,21andyet,despitealltheadvancementsinsomanyotherareasofmedicalscienceduringthatsameperiod,whenitcomestoACLF,muchresearchanddiscoveryisyettobedone.Hopefullyeffortsoccurringinthisfieldnowandofthoseinthefuturewillleadtonovelbiomarkersandtherapeuticstrategiesthatwillhelppatientssufferingfromthisdevastatingdisease.MartinPharmaceuticals,aclinicalstagepharmaceuticalcompany,ispassionateaboutbringinglife-changingadvancestopatientswithrarediseasesorchallengingmedicalconditions.WeareproudtobeactivelytakingstepstofindanswersforACLFpatients.Ourdrug,LIVANTRA®,showsgreatpromise22insavingandimprovingthelivesofthesevictims.Normalliversgetmostoftheirenergybymetabolizingfat.Ascirrhosisprogresses,thismechanismbecomesdefectiveandenergyproductionshiftstousingglucoseinstead.Thedefectivefatmetabolism,however,inhibitsthisprocessandsotheliverbeginstosufferfromenergyfailureandtoxicmolecules,calledreactiveoxygenspecies,arecreated.Ifleftunchecked,thesereactiveoxygenmoleculescandamageDNAandintracellularmembranesinanalready-injured/cirrhoticliver,initiatingcelldeathpathwaysthatleadtoapoptotichepatocytedeath(programmeddeathinlivercells).Atthemolecularlevel,LIVANTRAinhibitsβ-oxidationoffreefattyacids(FFA)by

21AzeemAlametal,Acute-on-chronicliverfailure:recentupdate,J.BiomedRes,2017;31(4):283–30022SeeMartinPharma.comforresultsfromahumanstudyofourdruginACLFpatients.

selectivelyinhibitingthelong-chain3-ketoacylcoenzymeAthiolase,whichisthefinalenzymeintheFFAβ-oxidationpathway.Byturningoffthiskeymechanism,livercellsareabletogetandusemoreglucoseforenergy,creatingmolecularbuildingblocksthatallowthelivertoagaincarryoutitsessentialfunctions.LIVANTRAshiftsthegenerationofenergyintheliverfromfattyacidoxidationtoaprocesscalledglycolysis.Thisprevents

formationoftoxicmoleculesandpreventscelldeath.Thisglycolysisstrategy,employedbyallactivelygrowingcellsinthebody,canbetemporarilyinducedbyLIVANTRAtorestoreproperenergybalanceandallowthelivertorecoverfromtheacuteinsultofACLF.LIVANTRAisaninvestigationaldrugandisnotapprovedbyFDA.FormoreinformationonLIVANTRA,pleasegotoourwebsite:MartinPharma.com.

NOTICE:Contentpresentedinthispaperdoesnotconstitutemedicaladvice,norisitintendedasaguideformakingtreatmentdecisions,andthereforeshouldnotbeinterpretedassuch.Youshouldonlyactuponthespecificadviceofyourphysicianoramedicalprofessional.ThispaperwaswrittenandproducedbyMartinPharmaceuticals,makersofLIVANTRA®,aninvestigationaldrugtargetingACLFpatients.LIVANTRAhasnotyetbeenapprovedforusebytheUSFDA.MartinPharmaceuticalshasreceivedOrphanDrugDesignationforLIVANTRAinthetreatmentofACLF.FormoreinformationonLIVANTRAandMartinPharmaceuticals,pleasevisit:MartinPharma.com©COPYRIGHT2018.MARTINPHARMACEUTICALS.ALLRIGHTSRESERVED.

MartinPharmaceuticals233BroadwaySuite1750NewYork,NY10279MartinPharma.com212.586.2226