《藥物性肝損傷診治指南》第一版解讀

《藥物性肝損傷診治指南》第一版解讀全球首個關于DILI的臨床指南頒布ACGClinicalGuideline：TheDiagnosisandManagementofIdiosyncraticDrug-InducedLiverInjury5P.OuWMRPidIlllnishLMDUfabcrtLBonimkkMtFACGWrtrI.MD\WHlioHLaMBMsadRobertJtm?皿

MIX.anbrfulfatthePnrtreParmrtm【XnmMkedthfAmenrw(lIdiosyncraticdrug-inducedliveripury(DILI)isarareadversedrugreactionanditcanleadtojaundice,liireifailureorewndeath.AntimicrobialsandhertalanddietarysupplefrentsareamongthemostcommontherapeuticclassestocauseDILIintheWesternworld.DILIisadiagnosiscfexclsocandthuscarefulhistorytakingandthroughwork-upforcompetingetiologiesareessentialforitstimelydiagnosis.InthisACGClin樹Guidelire,theauthorspresentaneiidence-basedapproachtodiagnosisandmanagtmentofDILIwithspecialemphasisorDILIdue：oherbal3rddietarywpplementsandDILIoccurringinindiiidiukwithunderlyingliverdisease.poH虹yV7JumD14；4?IOI砌岫MUBl?涉及DILI的風險因素、診斷/鑒別診斷、再激發(fā)、治療等各方面草藥和膳食補充劑引起的DILIlowwgkvdthigh,moder",low.orveryk>wquality(I).Thisapnctio?f^oddinpbrdirkhasratherianjirvitwartkl/ndwtreferinterestedxadmtosevrra.caniprebcrnhYrwevpuHbhednxcndy|2-6|.慢性肝病中的DILI問題PRODUCTIONDrug-induedliveriniury(DILI)remainone<tfthemortdul%in|disordersfxeJby邱roe火應峠皿lhewi&angtpn*ieniMi(niuniculptit鏟band&kofobgwdjgtstestsmakritsdiagnoihudlorupffnenipartkularl}'difirnD?sp?tfiUlawinckieaainthegenna!popubticn,psToenkobpstsmus:dwayscaisidnthepoBitalityofDILlinpdie<withunaplauudacmeandchroniclireirjury.aswellaswh；prtKrblng?rttin臾troinifiMlrndkitiotu(eg.a?thi<prue.uu-tjmofnciiusbfuioiigcntxsulfuuiiuila)(7iMaarhttbaluddirjrywplcnunts(HDS)tinamDllzedthuithevmastbeconsidereduacausefoiDILLForl!PREAMBLEThewritinggrujpwuinvitedbrtheBoardallheTrusieesandthePracticeParametenCommitteeofLwAmericoaCdxgeofGaitrofrlewiogyljderdopapnclk:guidelineregardingth*diagnosisandmaa站anenlofdiosyncratkdrug-inducedliwfinjury(DILI)Tkurtki呼group<kwlopedthHpnakeguidelineusingancviiknicbaxdapptuiih.Wtuxdthefoklowingrtsourcecti)atomialreview血mmIvsBotthetwcntlypubluhedworldlitetaureontheto?c(Medline“mhuploMayiOBl;(U)theAnenanColle新ofPhyucUafSmHjarAht?峋HeubhPndknandDnijninjPmikrGuitlrlmm(tii)guidelinepoliciesoflbeAnxiicaoCdlegeofGastroenterology;and：w)theexperienceoftheauthorsandindependentreviewerswithlegaidtoidjosyntratcDHJ.H?ewrftomreenditioMirterdedfor?wbypbysiciimanduthcrhcalla<afrpnnidn.preferred明5dnlotheiagaafliuuimia^etiKncofCLLTheyarcintendedlo中國首部DILI臨床診治指南頒布中華醫(yī)學會肝病學分會務物性肝購學組主要包括:「HED黒;W"忠城!J7皮DKUG-INDUCFDliverinjury藥輸損傷診治指南流行病學肝臟對藥物毒性的耐受、適應與易感性發(fā)病機制病理臨床分型和表現(xiàn)實驗室、影像學和病理檢查診斷和鑒別診斷治療預后預防、管理和展望2015年10月25日北京正式發(fā)布指南適用范圍：固有型和特異質(zhì)型DILI有型DILI具有可預測性，與藥物劑量密切相關,劑量越高越易導致肝損傷，潛伏期短，個體差異不顯著A特異質(zhì)型DILI具有不可預測下，個體差異顯著，與藥物劑量的關系相對不大，臨床表現(xiàn)多樣化。人群對藥物的反應是不同的?（“耐受性”）-個體在藥物治療期間未出現(xiàn)肝損傷的生化證據(jù)。未檢測到損傷。?（“適應性”）-個體在藥物治療期間出現(xiàn)肝損傷的生化證據(jù)，但繼續(xù)用藥生化指標恢復正常。輕度（短暫&選擇性）損傷。?（“易感性”）-個體在藥物治療過程中甚至停藥后出現(xiàn)DILI,且不等呈現(xiàn)適應性緩解。臨床上顯著損傷。指南采用GRADE系統(tǒng)表2GRADE系統(tǒng)證據(jù)質(zhì)量及其定義證據(jù)級別定義高質(zhì)量（A）非常確信估計的效應值接近真實的效應值，進一步研究也不可能改變該估計效應值的可信度中等質(zhì)量（B）對估計的效應值確信程度中等，估計值有可能接近真實值.但仍存在二者不相同的可能性，進一步研究有可能改變該估計效應值的可信度低質(zhì)量（C）對估計的效應值的確信程度有限：估計值與真實值可能大不相同。進一歩研究極有可能改變該估計效應值的可信度極低質(zhì)量（D）對估計的效應值幾乎沒有信心：估計值與真實值很可能完全不同。對效應值的任何估計都很不確定?證據(jù)的推薦強度分為強推薦和弱推薦?證據(jù)質(zhì)量分為高、中、低和極低不同等級?共形成16條推薦意見，除3條推薦意見為“A”級證據(jù)，其余引用證據(jù)的質(zhì)量無一例外均為或級流行病學流行病學CLINICAL——LIVERIncidence,Presentation,andOutcomesinPatientsWithDrug-InducedLiverInjuryintheGeneralPopulationofIcelandEINARS.BJORNSSON.1-2OTTARM.BERGMANN?HELGIK.BJORNSSON.2RUNARB.KVARAN.2andSIGURDUROLAFSSON1Table1.TheCrudeAnnualIncidenceDuringtheStudyPeriodandtheAge-StandardizedIncidenceDuringthe2-YearStudyPeriodNumberofindividualsinN=96Per100,000eachagegroup95%Cl95%ClMeanprescriptionrateIncidenceofDILI19.1251.86015.423.3Age-standardizedincidencebyagegroups15-24(n=8)8.546,8313.716.80.925-39(n=17)12.667,6007.320.11.240-59(n=31)18.882,54612.826.72.460-69(n=18)32.627,62218.751.54.870-79(n=13)39.916,28221.368.37.380-106(n=9)41.010,97918.777.893?國外報道，普通人群：1/10萬-20/10萬?我國缺乏普通人群的發(fā)病數(shù)據(jù)，整體情況并不清楚，但不容樂觀?我國基于住院患者中的數(shù)據(jù)缺乏系統(tǒng)性GASTROENTEROLOGY2013:144:1419-1425不同地域報道引起DILI的最常見藥物CountrySwedenSpain-UnitedStates(DILIN)KoreaJapanSingaporeYears1975-20051994-20082004-20072005-20071997-20062004-2006n784603300371167631CaseascertainmentGovernmentregistry45centersProspective,5centersProspective,17centersRetrospective,multicenterProspective,population-basedHC/mixed/choles-52/21/2955/21/2556/20/24NA59/20/2174/6/19tatic(%)Meanage(years)58(42-74)54(13-88)48±1849.0±14.55551Female(%)57496063.35745Hospitalized(%)NA5454100NADiedortrans-9.25.49.6planted(%)ChronicDILI(%)1RQMostfrequentAntibiotics(27)AntibioticsAntimicrobials||Herbaldrugs|I

Antibiotics|liaditionaiCM|a^nts(%)Analgesicsinj(MJDisulfiram(3.4)CNSagents(15)CNSa^ntsPrescriptiondrugsCNSagentsPrescriptiondrugCarbamazepineAnalgesics(11)(15)(20.8)(10)(26)(22)Lipid-loweringagents(1)Lipid-loweringagents(5)H2blocksis(5)Endocrineagents(4)Hertoals(9)Immunomodulator(5.5)Analgesics(5)Antihypertensives(5)Antineoplasties(4)Lipid-loweringagents(3.4)Healthanddietarysupplements(13.7)Medicinalherbsorplants(9.4)Folkremedies(8.6)OTCdrugs(6.5)Dietarysupplements(10)Analgesics(9.9)Chineseherbals(7-1)Malayherb(16)上千種藥物報道可引起肝損傷，LiverTox和HepaTox站可提供相應信息Hepatology2010:52:730-742中草藥和膳食補充劑引起的DILI不容樂觀草藥和膳食補充劑逐年上升健身、減肥占據(jù)50%ReasonsforconsumingHDS■Bodybuilding■Weightloss■DepressionSexualperformance■Glupset■ImmunesupportJoints叩portChinese■MiscellaneousLiverDisease,Vol4,No1,July2014遺傳背景相關的危險因素DrugBierape血GroupHLAAlleleOddsRatioforDevelopingDILI隅Cl)lidopidineAntiplateletagent36,5(7.3-184)Rucloxacillin*AntibioticHUfi*570180,6(22.8-284.9)Amoxicillin-davulanateAntibiotic2.3(1.0-5,26)Lumiracoxib*NSW伽網(wǎng)皿6.314.1-9.6)Ximelagatran*Oraldirectthrombininhibitornmmi4.4Lapatinib*Tyrosinekinaseinhibitorusedinadvancedbreastcancer9(3.2-27,4)HLA基因多態(tài)性與DILI相關能否用于臨床，尚需大樣本、設計良好的臨床研究驗證IHEPATOLOGY,Vol.53,No.1,2011非遺傳背景相關的危險因素?高齡可能是易感因素HostfactorsEnvironmentalfactorsDrug-relatedfactors?女性可能對米諾環(huán)素、甲基AgeSmokingDailydose多巴易感，易于呈AIH的特點GenderAlcoholconsumptionMetabolicprofilePregnancyInfectionandinflam?Classeffectand?有基礎肝病者更易發(fā)生DILImatoryepisodescross-sensitization的證據(jù)有限。一旦發(fā)生，死MalnutritionDruginteractions亡風險更高andpolypharmacyObesity?糖尿病可能是某些藥物引起Diab?t?smpllitiKDILI的易感因素OIUMV111vlllvUUComorbiditiesincludingunderlyingliverdisease?酗酒可增加個體對APAP、甲氨蝶吟、抗結核藥物等引發(fā)IndicationsfortherapyDILI的易感性由于目前并無證據(jù)證明某一個因素是所有DILI的主要風險,因此，指廣未提出專門的推薦意見RUCAM表（國際共識會議標準）—RousselUclafCausalityAssessmentMethodCouxalityofcaDrug4CwreccMViitan*<lrvg(s):Non^ornoInfoemotionorcoruzomilonldruQwithincompatiblelimotoonsotConoomitonidru(>withcompatibleorsuggestive^limetoonsetConeomilcintdrv^iknownashepatotoxlnandwithcompatibleorsuggestivetim^toon*^tConcomitontwithovidonu。foritsroloIntKiscom*roc/ra//en^oorvo/Zcfafodros■丿□o□-1I1-2r~i-37項因素綜合評估(分):>8：極可能；6-8：很可能；3-5：可能；1—2：不太可能；W0：可排除Roocfionlobvlodintheproductcbaracf^ristk;bIR^octionpublishedbutonlabeledR?odlonunknownl—J*2CompatibleNegativeNotdoneornotirrterpeetableDoublinyofALTwith，h。dtuyolotwDoublingofALTwiththedrugsolreodyyivenatattFwtim?oftHoFir&trooctionIncreoseofALTbutle&stbonZinsamecondition*osforth?flr*tadmlnUtrationOther9ituatk>n&DoublingofAP(or

河wll>ithedruyciloneDoublingofAPfor7B)withrhedropsalreadyat，h。offhofirstraocrionIncreaMofAPforTB)bu，lesathanZinrhesom?conciltion&asfortH?firstadministrationOthersituations□*1呂了lnve?tigatorSignatureInvosti^otor*??tgnafuro:________________________________________________________________________________________________________Dato,pnod:--/---Z----?■??#?>wrr“可能"的患者是否應納入DILI的診斷？如何在有肝病背景的患者中建立DILI的診斷?ReliabilityoftheRousselUclafCausalityAssessmentMethodforAssessingCausalityinDrug-InducedLiverInjury*JamesRochon.1PetrProtivaCLeonardB.Seeff.1RobertJ.Fontana/SuthaiLiangpunsakul.'PaulB.Watkins.”TimodiyDavem,"andJohnG.McHuicliison,1foriheDrug-InducedLiverinjunNetwork(DILIN)TheRousselUclafCausalityAssessmentMethod(RUCAM)wasdevelopedtoquantifythestrengthofassociationbetweenaliverinjuryandthemedicationimplicatedascausingtheinjury.However,itsreliabilityinaresearchsettinghasneverbeenfiillyexplored.Theaimofthisstudywastodeterminetest-retestandinterraterreliabilitiesofRUCAMinretrospectively-identifiedcasesofdruginducedliverinjury.TheDrug-InducedLiverInjuryNetworkisenrollingwell-definedcasesofhepatotoxicitycausedbyisoniazid,phenytoin,clavulanate/amoxicillin,orvalproateoccurringsince1994.Eachcasewasadjudicatedbythreereviewersworkingindependently;afteranintervalofatleast5months,caseswerereadjudicatedbythesamereviewers.Atotalof40drug-inducedliverinjurycaseswereenrolledincludingindividualstreatedwithisoniazid(nine),phenytoin(five),clavulanate/amoxicillin(15),andvalproate(11).Mean±standarddeviationageatprotocol-definedonsetwas44.8±19.5years;patientswere68%femaleand78%Caucasian.Caseswereclassifiedashepatocellular(44%),mixed(28%),orcholestatic(28%).Test-retestdiHerencesrangedfrom—7to+8withcompleteagreementinonly26%ofcases.Onaverage,themaximumabsolutedifferenceamongthethreereviewerswas3.1onthefirstadjudicationand2.7onthesecond,althoughmuchofthisvariabilitycouldbeattributedtodifferencesbetweentheenrollinginvestigatorandtheexternalreviewers.Thetest-retestreliabilitybythesameassessorswas0.54(upper95%confidencelimit=0.77);theinterraterreliabilitywas0.45(upper95%confidencelimit=0.58).CategorizingtheRUCAMtoafive-categoryscaleimprovedthesereliabilitiesbutonlymarginally.Conclusion:ThemediocrereliabilityoftheRUCAMisproblematicforfuturestudiesofdrug-inducedliveriniurv,Alternativemethods、includingmodifyingtheRUCAM,developingdrug-specificinstruments,orcausalityassessmentbasedonexpertoDinion,maybemoreaDDioDriate.(Hepatology2008；48：1175-1183.)實踐及專家證明：RUCAM量表仍是當前設計最合理、操作最方便、診斷準確率相對較高的DILI診斷工具HEPATOLOGY,Vol.48,No.4,2008鑒別診斷：引起肝臟生化學異常的其他疾病HepatitisvirusesA,B,C,D,E(CanmimicacutehepatocellularDILI)Otherinfectiousagents(CMV,EBV,HSV)(TypicallymildATelevations,butmaybesevereinimmunesuppressedpatients)Nonalcoholicfattyliverdisease(NAFLD)(UsuallymildlomoderateelevationsinATwithmildelevationsinALP)Alcoholicliverdisease(TypicallyATlevels<300U/L,AST>ALT,bilirubinlevelmaybeelevated)Autoimmunehepatitis(CanmimicacutehepatocellularDILI)Congestiveheartfailure(MayleadtoelevatedbilirubinandprolongedINRinadditiontoelevatedAT)Hypotension/cardiacarrhythmia(UsuallyveryhighandrapidlyreversedATspike,ofteninlhepresenceofheartfailureand/orhypoxia)Systemicinfection/sepsis(GenerallymildATelevation;bilirubinmaybeelevatedparticularlywithgramnegativeinfection)Wilson'sdisease(CanmimicacutehepatocellularDILI-hemolysisoftenpresent)Hemochromatosis(ChroniclowlevelATelevation.TypicallywouldnotresembleahepatocellularDILIepisode)Primaryorsecondaryhepatictumors(TypicallypredominantlyALPelevation)Gallstonedisease(PassingastonecancauseaveryhighALTspikewilharapidresolution.ALPisgenerallyelevated,andabdominalpainisexpected)Vasculardisorder(BuddChiari,portalveinthrombosis)(Liverenzymesvary.Maybeacute,subacuteorchronicpresentation)對疑似肝細胞型或混合型DILI患者Ill(c)排除急性巨細胞病毒，急性EB病毒，或急性單純皰疹病毒感染的檢測(b)排除戊型肝炎病毒感染,尤為近期到過流行區(qū)者(a)血清學檢查排除急性病毒性肝炎(A,B,C)和自身免疫性肝炎(d)排除Wilson's病和Budd-Chiari綜合征的可能性hepalilisihouldbeexdudedwilh燦M蜘郵andHCVRNAleslinj(Strongrtcommtndalion,叫?kurltdindbutoiyrelatedlon)edi(aliootipojiifedlowMevideiKe).theon姐ofhleslabimaliliesMdbeobtainedAn(b)剛血血h甲恤E恤炒1關昭剛血苗DILIk耶測ommiied岫lounclearptrforocedmlerislks?DILI曲郵礎ofex血飾廁血邱艸礎㈣)d'oftliemlly響)komm浦tests.How,ilinjetiolojiesshouldbeexduMinaswtemafcmanner.shouldbt(owidtfdiotktrtjo(heightenedclinical?OnllietaoftheMueatpnsentaiion,DILIcanbe哪血(tptcentiravdinantntavea)(Condi*caiejonzedinlohepatocdlular,dioltJlaik,ormiiedtypes.lid【Komm岫燦wrylowlevelofe\iden(e).Ibis(呻血麗all郵teslinjforioniptlinj価酈(c)W峋儷禎teqtoi哪血恤間眥映inaiyslemaliiapproach.vm?RuleherpessimplaminiklionMdbe?Liverbiopsy伽helpionhaclinkal唧誼MDILLunder!齢ii'Mviralheptiluhbeenexdudtdprod血阿tan岫頑伽哪卿血繼歟rty仙ordinicalfealurts皿matypicallymphocjteandalsohelpeidudeiompelin^。睇offer啊，lymp峋神y嶼such。郵(蜩【頗nda燦verylo兩Mevi如dtai的仙i伽(d)WMdiseaseandBuMhiarisyndromeMd(1)Inindividualsrih岬ettoikpta峋ormixedDILI:be岫Mwhendindly啊郵蠅(i)A(ulenralhepatitis(A.WC)andautoimmune蜘miBitanlowkvtMtvitad對疑似膽汁淤積型DILI的患者(2)InindividualswthsuspectedcholestaticDILI：(a)Abdominalimaging(ultrasoundorcomputerizedtomographyscan)shouldbeperformedinallinstancestoexdudebiliarytractpathologyandinfiltrativeprocesses(StrongrecommendationJowlevelofevidence).(b)Serologicaltestingforprimarybiliarycirrhosisshouldbelimitedtothosewithnoevidenceofobviousbiliarytractpathologyonabdominalimaging(Strongrecommenda-(a)腹部影像學檢查(超聲或CT掃描等)，排除膽道病變(b)排除PBC(c)內(nèi)鏡逆行膽管造影，排除嵌頓型膽總管結石、原發(fā)性硬化性膽管炎、或胰膽管惡性腫瘤的患者tionjowlevelofevidence).(c)Endoscopicretrogradecholangiographyshouldbelimitedtoinstanceswhereroutineimagingisunabletoexdudeimpactedcommonbileductstones,primarysclerosingcholangitis^orpancreatico-biliarymalignancy(Strongrecommendation,verylowlevelofevidence).對藥物誘導的自身免疫性損傷*藥物誘導性紅斑狼瘡L關節(jié)疼痛，漿膜炎，淋巴結病，亞急性&慢性皮膚系統(tǒng)II性紅斑狼瘡!。皮疹自身免疫性肝炎I?結腸炎!?內(nèi)分泌?。谞钕傺?，腎上腺機能不全，垂體機能減弱）II________________________________________________________________________________________________________________________________________________________________________J對藥物/生物制劑&誘導AIH*風險因果相關藥物替尼酸，雙醋酚丁，甲基多巴，雙豚酰嗪,二甲胺四環(huán)素，吠喃妥英氯苯酰卩引酸，丙硫氧卩密呢，雙氯酚酸，異煙月井，英夫利西單抗，干擾素-a,干擾素-b非諾貝特，他丁類，依那西普，阿達木單抗，卩引噪美辛，美++洛昔康，特比荼芬，伊馬替尼，阿托西汀，匹莫林，苯丙香豆素，強力霉素，石蠶，諾麗Representative(Incomplete)List;X.Xiao&C.Chang,JAutoimm.2014;RL__________Drug-InducedAutoimmuneHepatitis:ClinicalCharacteristicsandPrognosisEinarBjornsson,12JayantTidwidkar,2SombatTreepnisemsuk,2

PatrickS.Kiuiiath,2NaokiTakahashi,'SchuvlerSanderson,MatthiasNenhauser,2

andKeithLindor2■%9J??■9AIHPatients(n=237)DIAIH(n=24)PValueAge52(37-62)53(24-61)NSSex,females(%)184(78%)20(92%)NSANApositive(%)165/237(70%)20(83%)NSSMApositive(%)106/237(45%)12/24(50%)NSBothANAandSMA(%)69/237(29%)9/24(38%)NSSeronegative(%)29/237(12%)1/24(4%)NSSimplifiedAIHscore:Probableordefinite(%)181/237(76%)19/21(90.5%)NSinuiiuriusuppressiveuierapy(%)222/237(94%)21/24(88%)NSSteroidsandazathioprine(%)191/222(86%)12/21(57%)0.0024Steroidsalone(%)31/222(14%)9(43%)0.0024Trialofdiscontinuationsuccessful(%)ia/52(35%)14/14(100%)<0.0001AST?48U/L)392(154-1031)679(291-956)NSALT?55U/L)480(185-1141)728(255-1141)NSALP(115U/L)241(138-350)376(229-514)0.0166TB(<1.0mg/dL)2.0(1.0-8.0)4.0(1.0-12.0)NSAlbumin(>3.5g/dL)3.4(2.95-3.7)3.1(2.6-3.6)NSINR(<1.2)1.1(1.0-1.3)1.1(1.0-1.3)NSIgG(<1500g/dL)2020(1618-2702)1905(1600-2455)NSGammagobulins(<1.7g/dL)2.5(2.0-3.2)2.55(2.2-3.1)NSJaundiceatpresentation110/237(46%)12/24(50%)NS?9.2%為藥物誘導性自免肝?類似的臨床、組織學特征?停用激素后的反應可幫助鑒別兩者NitrofurantoMinocyc1inein（吠喃妥英）（二甲胺四環(huán)素）2040-20481Hepaiology

2010:51：何時進行肝臟活檢(3)Whentoconsideraliverbiopsy?(a)Aliverbiopsyshouldbeconsideredifautoimmunehepatitisremainsacompetingetiologyandifimmuno-suppressivetherapyiscontemplated(Strongrecommendation,lowlevelofevidence).(b)Aliverbiopsymaybeconsideredinthefollowingsituations:(i)Ifthereisunrelentingriseinliverbiochemistriesorsignsofworseningliverfunctiondespitestoppingthesuspectedoffendingagent(Strongrecommendation.verylowlevelofevidence).(ii)Ifthepeakalanineaminotransferaselevelhasnotdecreasedby>50%at30-60daysaftertheonsetincasesofhepatocellularDILI,orifthepeakalkalinephosphatasehasnotfidlenby>50%at180daysincasesofcholestaticDILIdespitestoppingthesuspectedoffendingagent(Conditionalrecommendation.verylowlevelofevidence),(iii)IncasesofDILIwherecontinueduseorre-expo-suretotheimplicatedagentisexpected(Strongrecommendation,verylowlevelofevidence).(iv)Ifliverbiochemistryabnormalitiespersistbeyond180daystoevaluateforthepresenceofchronicliverdiseases(CLDs)andchronicDILI(Conditionalrecommendation,verylowlevelofevidence).，臨床和實驗室檢查仍不能確診，尤其AlH仍不能排除時?停藥后，生化指標仍持續(xù)上升或出現(xiàn)肝功能惡化的其他跡象?停藥1-3個月，生化指標未降至峰值的50%或更低?懷疑慢性DILI或伴其他CLD時?長期使用某些可能導致肝纖維化的藥物，如甲氨蝶吟DILI診斷的基本策略ImmunoallergichepatitisAutoimmunehepatitis-likeAcutehepaticnecrosisAcuteviralhepatitis-likeALFCholestatichepatitisBlandcholestasisAcutefattyliverwithlacticacidosisNonalcoholicfattyliverSinusoidalobstructionsyndromeChronichepatitisNodularregenerationVanishingbileductsyndromeCirrhosisDILI臨床表型：涉及幾乎所有肝損傷類型基于詳細病史、血液生化學檢查、影像學檢查和肝組織學檢查等合理應用的排除性診斷，是目前DILI診斷的基本策略HEPATOLOGY,Vol.52,No.2,2010DILI診斷流程土沽人LT、AI_P及TBH尋步X升倉軻K［戲水.盼#曲，尋CJ原味底fK農(nóng)理］?f?ft9|.年》?用藥史：時棗、的。程、8止曰以住肝晦忤俗@、再明指反應?HI住病史、CCW史、度皿號玷史?桂砍伶點.體愴所電?丈盟女惶査.B4fl.CT及MR1虧X?b性貞貞里、一餐JM玲?i］<*___、?l?AV.IIEV,IIBV.HCV.CMV、EBV?塵等?■.性JFHM：偵;M??弱I#-年岐.ASTVALT?比他?8T等BMURMBts.定W?M*AftttJHMAMA-AMA,SMA,y■璋歩白、!gC5??*5■tf**Sltt0EWCT,MRI.MRCT?.ER<TP等?iftieftWttlFWVrtHRWfiSa.映裏臼■導?■*：

肝BfJRMW塵、全場<Mc?SE>尋〔?MIK毛力學?*「Q功能不全：W■■壓、體兌〕各件馨為初怪丙奉引&的?憐校齢咔"橫與?豚砰響佐的床垣咬優(yōu)費零RIC7AM怦分叱整由肝活悅DILI臨床分型基于損傷靶細胞分型?肝血管損傷型III不同藥物可引起相同類型的肝損傷，同種藥物在不同個體中也可能引起不同類型的肝損傷?混合型R值二2-5?肝細胞損傷型ALT>3N或R值>=5?膽汁淤積型ALP>2N或R值<2ALT最高實測值（首次）/正常上限她=ALP最高實測值（首次）/正常上限如：肝竇阻塞綜合征/肝小靜脈閉塞病等基于病程分型?急性DILI?慢性DILI?DILI發(fā)生6個月后，血清ALT、AST、ALP及TBiI仍持續(xù)異常，或存在門靜脈高壓或慢性肝損傷的影像學和組織學證據(jù)DILI嚴重程度DILI的嚴重程度0級（無肝損傷）：患者對暴露藥物可耐受，無肝毒性反應.1級（輕度肝損傷）：血清ALT和/或ALP呈可恢復性升高，TBil<2.5ULN（2.5mg/dL或42.75ginol/L）.且INRVL5.多數(shù)患者可適隨.可有或無乏力、虛弱、惡心、厭食、右上腹痛、黃疸、瘙癢、皮疹或體質(zhì)量減輕等癥狀叫，％2級（中度肝損傷）：血潔ALT和/或ALP升高.TBil^2.5ULN.或雖無TBil升高但1NR^L5.上述癥狀可有加重.3級（重度肝損傷）：血清ALT和/或ALP升高，TBil^5ULN（5mg/dL或85.5pmol/L）,伴或不伴1NRN1.5。患者癥狀進一步加重，需要住院治療，或住院時間延長。4級（ALF）：血清ALT和/或ALP水平升高，TBil^lOULN（10mg/dL或171jimol/L）或每日上升Nl.Omg/dL（17.1gmol/L）卩叫INRN2.0或PTA<40%,可同時出現(xiàn)（1）腹水或肝性腦病：或（2）與DILI相關的其他器官功能衰竭.5級（致命）：因DILI死亡，或需接受肝移植才能存活。關于診斷、鑒別診斷的推薦意見：1-51.DILI臨床診斷目前仍為排他性診斷，應緒合用藥史、臨床特征和肝臟生化學指標動態(tài)改變的特點、藥物再刺激反應、其他肝損傷病因的排除等進行綜合分析。肝活檢組織學檢查有助于診斷和婆別診斷。UB)2.推薦RUCAM因果關系評分量表作為臨床實踐中DILI臨床診斷的應用量表。＞8分為極可能(Highlyprobable),6-8分為很可豊(Probable),3?5分為可能(Possible),1?2分為不太可能(Unlikely),W0分為可排除(Excluded)。(18)3.完整的DILI臨床診斷應包括診斷命名、臨床類型、病程、RUCAM評分結果、嚴重程度分級。(18)4.在自身免疫性肝炎(A1H)基礎上發(fā)生的DILk藥物誘導的AIH和伴有自身免疫特征的A1H祥DILI(AL-DILI)常難以鑒別。應詳細采集用藥史和分析自身免疫指標，動態(tài)觀察臨床治療應答及免疫抑制劑停藥后的反應，必要時行肝組織學校查加以婆別。(2C)5?有基礎肝楕背景或存在多種肝損傷病因的患者，應用具有潛在肝毒性的藥物時應注意更密切的監(jiān)測。診斷DILI時應十分慎重，需排除原有肝病的發(fā)作和加重，仔細甄別肝損傷的最可能原因，以便正確治療O(IB)治療基本原則?及時停用可疑藥物，盡量避免再次使用可疑或同類藥物?充分權衡停藥引起原發(fā)病進展和繼續(xù)用藥導致肝損傷加重的風險?根據(jù)DILI的臨床類型選用適當?shù)乃幬镏委?ALF/SALF等重癥患者必要時可考慮緊急肝移植關于停藥的推薦意見：6-76.DILI的誠浙械備刎耕導刎橢柯剃機梱翹DIL詞軸鐫艸七(")7.臓X耕舸皓劾發(fā)"加直版ItFDA找缺蟠中始楠的鮮考(峨下雅肱~)：(1)1於ALT或ASD8ULN;(2)ALT或ASD5ULN,梢2月；(3)ALT*AST>3