Risk Factors for Idiosyncratic Drug-Induced Liver

RiskFactorsforIdiosyncraticDrug-InducedLiverInjuryyesplatform+medliauthorauthorNagaChalasani,EinarBjörnssonReceived19February2010;accepted8April2010.publishedonline14April2010.JohnP.LynchandDavidC.Metz,SectionEditorsI.AbstractII.NongeneticRiskFactorsA.AgeB.SexC.DailyDoseD.MetabolismCharacteristicsE.Cross-SensitizationandClassEffectF.DrugInteractionsG.AlcoholConsumptionH.UnderlyingDiseaseStatesIII.GeneticRiskFactors.VariationsinPhase1Drug-MetabolizingEnzymesA.VariationsinPhase2andDetoxifyingEnzymesB.HepatobiliaryTransportersC.ImmunologicMechanismsD.AssociationBetweenDILIandSpecificHLAHaplotypesE.DysregulationofCytokinesF.MitochondrialDNAMutationsIV.FutureDirectionsV.ReferencesVI.CopyrightIdiosyncraticdrug-inducedliverinjury(DILI)isararedisorderthatisnotrelateddirectlytodosageandlittleisknownaboutindividualswhoareatincreasedrisk.TherearenosuitablepreclinicalmodelsforthestudyofidiosyncraticDILIanditspathogenesisispoorlyunderstood.Itislikelytoarisefromcomplexinteractionsamonggenetic,nongenetichostsusceptibility,andenvironmentalfactors.Nongeneticriskfactorsincludeage,sex,andotherdiseases(eg,chronicliverdiseaseorhumanimmunodeficiencyvirusinfection).Compound-specificriskfactorsincludedailydose,metabolismcharacteristics,andpropensityfordruginteractions.AlcoholconsumptionhasbeenproposedasariskfactorforDILIfrommedications,butthereisinsufficientevidencetosupportthis.Manystudieshaveexploredgeneticdefectsthatmightbeinvolvedinpathogenesisandfocusedongenesinvolvedindrugmetabolismandtheimmuneresponse.MulticenterdatabasesofpatientswithDILI(theUnitedStatesDrugInducedLiverInjuryNetwork,DILIGEN,andtheSpanishDILIregistry)areimportanttoolsforclinicalandgeneticresearch.Agenome-wideassociationstudyofflucloxacillinhepatotoxicityhasyieldedgroundbreakingresultsandmanysimilarstudiesareunderway.Nonetheless,DILIischallengingtoinvestigatebecauseofitsrarity,thelackofexperimentalmodels,thenumberofmedicationsthatmightcauseit,andchallengestodiagnosis.Keywords:HLA,Amoxicillin-Clavulanate,Hy'sLaw,DILIAbbreviationsusedinthispaper:anti-TB,antituberculosis,BSEP,bilesaltexportpump,DILI,drug-inducedliverinjury,IL,interleukin,MnSOD,manganesesuperoxidedismutase,MRP,multidrugresistanceprotein,NAT2,N-acetyltransferase2,OR,oddsratioThelivermetabolizesxenobiotics,soitisnotsurprisingthatdrug-inducedliverinjury(DILI)isapotentialcomplicationofmanydrugs.DILIbroadlyisclassifiedintointrinsicandidiosyncratictypes;intrinsicDILIgenerallyisdose-dependentandpredictable(eg,acetaminophentoxicity),whereasidiosyncraticDILIisunpredictableanddoesnotdependdirectlyondose.ThisreviewfocusesontheidiosyncratictypeofDILI,whichaccountsforthemajorityofhepatotoxicityassociatedwithmedicationuse.IdiosyncraticDILIisrareevenamongindividualswhoareexposedtodrugsthatareknowntobehepatotoxic.Itoccursin1in5000to1in100,000individualswhotakemedication;theriskislowerforsomedrugs.1,2TheepidemiologyofDILIisnotwellunderstood;moststudiesthatassessedtheriskofliverinjuryfromdifferentmedicationshavebeenretrospective.3,4TherearenosurveillancemechanismsinplacetomonitorDILI,soadversedrugreactions,includingDILI,areunder-reported.Controlledclinicaltrialsprovidereliableinformationaboutabnormallivertestresultsthatareassociatedwithspecificmedications,butthesegenerallydonotdetectrareadversedrugreactions,somostcasesofidiosyncratichepatotoxicityarenotdetected.1,2Toourknowledge,thereisonlyonepopulation-basedprospectivestudythatsystematicallyassessedtheincidenceofDILI.5TheincidenceofDILIinaFrenchpopulationwas13.9casesper100,000inhabitants,afrequencythatis16-foldhigherthanthatestimatedfromspontaneousreportingmethods.4Basedonthisincidencerate,itwasestimatedthatmorethan8000casesofDILImightoccurinFranceeachyearandleadtoapproximately500deaths.5TheUnitedStatesAcuteLiverFailureStudyGroupreportedthatacetaminophenandidiosyncraticdrugreactionscombinedaccountforapproximately50%ofcasesofacuteliverfailureintheUnitedStates.6Vuppalanchietal7reportedthatdrughepatotoxicityaccountedfor4%ofallcasesofnew-onsetjaundice,butmostcasesofdrughepatotoxicity(24patients)wereattributabletoacetaminophentoxicityandidiosyncraticDILIoccurredinonly5patients(0.7%oftotalstudypopulation).ByusingseveraldifferentInternationalClassificationofDiseases9threvisioncodesandthenamesofspecificmedications(amoxicillin/clavulanate,phenytoin,valproate,andisoniazid),Jinjuvadiaetal8identifiedanoverallDILIfrequencyof1.6%(119DILIcasesof7395totalpatients)usingthemostsensitivecombinationofanacuteliverinjuryInternationalClassificationofDiseases9threvisioncodeplusamedicalrecordsearchoftheUniversityofMichiganHealthSystemdatabase.Importantly,36oftheseDILIcases(0.5%)wereattributedtoacetaminophenoverdose,whereastheremaining83werecausedbyotheragents(1.1%).8StudiesofunselectedpatientswithDILIrevealedthattheirprognosisgenerallyisfavorable.9,10,11HymanZimmerman,12adrughepatotoxicityresearcher,observedthatmortalityofpatientswithhepatocellularinjuryaccompaniedbyjaundicewas10%–50%,dependingonthedruginvolved.Thisobservation,calledHy'srule,isusedbytheUnitedStatesFoodandDrugAdministr