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《药物性肝损伤诊治指南》第一版解读全球首个关于DILI的临床指南颁布ACGClinicalGuideline:TheDiagnosisandManagementofIdiosyncraticDrug-InducedLiverInjury5P.OuWMRPidIlllnishLMDUfabcrtLBonimkkMtFACGWrtrI.MD\WHlioHLaMBMsadRobertJtm?皿
MIX.anbrfulfatthePnrtreParmrtm【XnmMkedthfAmenrw(lIdiosyncraticdrug-inducedliveripury(DILI)isarareadversedrugreactionanditcanleadtojaundice,liireifailureorewndeath.AntimicrobialsandhertalanddietarysupplefrentsareamongthemostcommontherapeuticclassestocauseDILIintheWesternworld.DILIisadiagnosiscfexclsocandthuscarefulhistorytakingandthroughwork-upforcompetingetiologiesareessentialforitstimelydiagnosis.InthisACGClin树Guidelire,theauthorspresentaneiidence-basedapproachtodiagnosisandmanagtmentofDILIwithspecialemphasisorDILIdue:oherbal3rddietarywpplementsandDILIoccurringinindiiidiukwithunderlyingliverdisease.poH虹yV7JumD14;4»IOI砌岫MUBl•涉及DILI的风险因素、诊断/鉴别诊断、再激发、治疗等各方面草药和膳食补充剂引起的DILIlowwgkvdthigh,moder",low.orveryk>wquality(I).Thisapnctio?f^oddinpbrdirkhasratherianjirvitwartkl/ndwtreferinterestedxadmtosevrra.caniprebcrnhYrwevpuHbhednxcndy|2-6|.慢性肝病中的DILI问题PRODUCTIONDrug-induedliveriniury(DILI)remainone<tfthemortdul%in|disordersfxeJby邱roe火应峠皿lhewi&angtpn*ieniMi(niuniculptit铲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中国首部DILI临床诊治指南颁布中华医学会肝病学分会务物性肝购学组主要包括:「HED黒;W"忠城!J7皮DKUG-INDUCFDliverinjury药输损伤诊治指南流行病学肝脏对药物毒性的耐受、适应与易感性发病机制病理临床分型和表现实验室、影像学和病理检查诊断和鉴别诊断治疗预后预防、管理和展望2015年10月25日北京正式发布指南适用范围:固有型和特异质型DILI有型DILI具有可预测性,与药物剂量密切相关,剂量越高越易导致肝损伤,潜伏期短,个体差异不显著A特异质型DILI具有不可预测下,个体差异显著,与药物剂量的关系相对不大,临床表现多样化。人群对药物的反应是不同的•(“耐受性”)-个体在药物治疗期间未出现肝损伤的生化证据。未检测到损伤。•(“适应性”)-个体在药物治疗期间出现肝损伤的生化证据,但继续用药生化指标恢复正常。轻度(短暂&选择性)损伤。•(“易感性”)-个体在药物治疗过程中甚至停药后出现DILI,且不等呈现适应性缓解。临床上显著损伤。指南采用GRADE系统表2GRADE系统证据质量及其定义证据级别定义高质量(A)非常确信估计的效应值接近真实的效应值,进一步研究也不可能改变该估计效应值的可信度中等质量(B)对估计的效应值确信程度中等,估计值有可能接近真实值.但仍存在二者不相同的可能性,进一步研究有可能改变该估计效应值的可信度低质量(C)对估计的效应值的确信程度有限:估计值与真实值可能大不相同。进一歩研究极有可能改变该估计效应值的可信度极低质量(D)对估计的效应值几乎没有信心:估计值与真实值很可能完全不同。对效应值的任何估计都很不确定•证据的推荐强度分为强推荐和弱推荐•证据质量分为高、中、低和极低不同等级•共形成16条推荐意见,除3条推荐意见为“A”级证据,其余引用证据的质量无一例外均为或级流行病学流行病学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•国外报道,普通人群:1/10万-20/10万•我国缺乏普通人群的发病数据,整体情况并不清楚,但不容乐观•我国基于住院患者中的数据缺乏系统性GASTROENTEROLOGY2013:144:1419-1425不同地域报道引起DILI的最常见药物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)上千种药物报道可引起肝损伤,LiverTox和HepaTox站可提供相应信息Hepatology2010:52:730-742中草药和膳食补充剂引起的DILI不容乐观草药和膳食补充剂逐年上升健身、减肥占据50%ReasonsforconsumingHDS■Bodybuilding■Weightloss■DepressionSexualperformance■Glupset■ImmunesupportJoints叩portChinese■MiscellaneousLiverDisease,Vol4,No1,July2014遗传背景相关的危险因素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伽网皿6.314.1-9.6)Ximelagatran*Oraldirectthrombininhibitornmmi4.4Lapatinib*Tyrosinekinaseinhibitorusedinadvancedbreastcancer9(3.2-27,4)HLA基因多态性与DILI相关能否用于临床,尚需大样本、设计良好的临床研究验证IHEPATOLOGY,Vol.53,No.1,2011非遗传背景相关的危险因素•高龄可能是易感因素HostfactorsEnvironmentalfactorsDrug-relatedfactors•女性可能对米诺环素、甲基AgeSmokingDailydose多巴易感,易于呈AIH的特点GenderAlcoholconsumptionMetabolicprofilePregnancyInfectionandinflam¬Classeffectand•有基础肝病者更易发生DILImatoryepisodescross-sensitization的证据有限。一旦发生,死MalnutritionDruginteractions亡风险更高andpolypharmacyObesity•糖尿病可能是某些药物引起Diab?t?smpllitiKDILI的易感因素OIUMV111vlllvUUComorbiditiesincludingunderlyingliverdisease•酗酒可增加个体对APAP、甲氨蝶吟、抗结核药物等引发IndicationsfortherapyDILI的易感性由于目前并无证据证明某一个因素是所有DILI的主要风险,因此,指廣未提出专门的推荐意见RUCAM表(国际共识会议标准)—RousselUclafCausalityAssessmentMethodCouxalityofcaDrug4CwreccMViitan*<lrvg(s):Non^ornoInfoemotionorcoruzomilonldruQwithincompatiblelimotoonsotConoomitonidru(>withcompatibleorsuggestive^limetoonsetConeomilcintdrv^iknownashepatotoxlnandwithcompatibleorsuggestivetim^toon*^tConcomitontwithovidonu。foritsroloIntKiscom*roc/ra//en^oorvo/Zcfafodros■丿□o□-1I1-2r~i-37项因素综合评估(分):>8:极可能;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吕了lnve«tigatorSignatureInvosti^otor*»»tgnafuro:________________________________________________________________________________________________________Dato,pnod:--/---Z----«■««#»>wrr“可能"的患者是否应纳入DILI的诊断?如何在有肝病背景的患者中建立DILI的诊断?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.)实践及专家证明:RUCAM量表仍是当前设计最合理、操作最方便、诊断准确率相对较高的DILI诊断工具HEPATOLOGY,Vol.48,No.4,2008鉴别诊断:引起肝脏生化学异常的其他疾病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)对疑似肝细胞型或混合型DILI患者Ill(c)排除急性巨细胞病毒,急性EB病毒,或急性单纯疱疹病毒感染的检测(b)排除戊型肝炎病毒感染,尤为近期到过流行区者(a)血清学检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综合征的可能性hepalilisihouldbeexdudedwilh灿M蜘邮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曲邮础ofex血飾廁血邱艸础㈣)d'oftliemlly响)komm浦tests.How,ilinjetiolojiesshouldbeexduMinaswtemafcmanner.shouldbt(owidtfdiotktrtjo(heightenedclinical•OnllietaoftheMueatpnsentaiion,DILIcanbe哪血(tptcentiravdinantntavea)(Condi*caiejonzedinlohepatocdlular,dioltJlaik,ormiiedtypes.lid【Komm岫灿wrylowlevelofe\iden(e).Ibis(呻血丽all邮teslinjforioniptlinj価郦(c)W峋俪祯teqtoi哪血恤間眦映inaiyslemaliiapproach.vm«RuleherpessimplaminiklionMdbe•Liverbiopsy伽helpionhaclinkal唧谊MDILLunder!齢ii'Mviralheptiluhbeenexdudtdprod血阿tan岫顽伽哪卿血繼歟rty仙ordinicalfealurts皿matypicallymphocjteandalsohelpeidudeiompelin^。睇offer啊,lymp峋神y嶼such。邮(蜩【颇nda灿verylo兩Mevi如dtai的仙i伽(d)WMdiseaseandBuMhiarisyndromeMd(1)Inindividualsrih岬ettoikpta峋ormixedDILI:be岫Mwhendindly啊邮蠅(i)A(ulenralhepatitis(A.WC)andautoimmune蜘miBitanlowkvtMtvitad对疑似胆汁淤积型DILI的患者(2)InindividualswthsuspectedcholestaticDILI:(a)Abdominalimaging(ultrasoundorcomputerizedtomographyscan)shouldbeperformedinallinstancestoexdudebiliarytractpathologyandinfiltrativeprocesses(StrongrecommendationJowlevelofevidence).(b)Serologicaltestingforprimarybiliarycirrhosisshouldbelimitedtothosewithnoevidenceofobviousbiliarytractpathologyonabdominalimaging(Strongrecommenda-(a)腹部影像学检查(超声或CT扫描等),排除胆道病变(b)排除PBC(c)内镜逆行胆管造影,排除嵌顿型胆总管结石、原发性硬化性胆管炎、或胰胆管恶性肿瘤的患者tionjowlevelofevidence).(c)Endoscopicretrogradecholangiographyshouldbelimitedtoinstanceswhereroutineimagingisunabletoexdudeimpactedcommonbileductstones,primarysclerosingcholangitis^orpancreatico-biliarymalignancy(Strongrecommendation,verylowlevelofevidence).对药物诱导的自身免疫性损伤*药物诱导性红斑狼疮L关节疼痛,浆膜炎,淋巴结病,亚急性&慢性皮肤系统II性红斑狼疮!。皮疹自身免疫性肝炎I©结肠炎!©内分泌病(甲状腺炎,肾上腺机能不全,垂体机能减弱)II________________________________________________________________________________________________________________________________________________________________________J对药物/生物制剂&诱导AIH*风险因果相关药物替尼酸,双醋酚丁,甲基多巴,双豚酰嗪,二甲胺四环素,吠喃妥英氯苯酰卩引酸,丙硫氧卩密呢,双氯酚酸,异烟月井,英夫利西单抗,干扰素-a,干扰素-b非诺贝特,他丁类,依那西普,阿达木单抗,卩引噪美辛,美++洛昔康,特比荼芬,伊马替尼,阿托西汀,匹莫林,苯丙香豆素,强力霉素,石蚕,诺丽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%为药物诱导性自免肝•类似的临床、组织学特征•停用激素后的反应可帮助鉴别两者NitrofurantoMinocyc1inein(吠喃妥英)(二甲胺四环素)2040-20481Hepaiology
2010:51:何时进行肝脏活检(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).,临床和实验室检查仍不能确诊,尤其AlH仍不能排除时•停药后,生化指标仍持续上升或出现肝功能恶化的其他迹象•停药1-3个月,生化指标未降至峰值的50%或更低・怀疑慢性DILI或伴其他CLD时・长期使用某些可能导致肝纤维化的药物,如甲氨蝶吟DILI诊断的基本策略ImmunoallergichepatitisAutoimmunehepatitis-likeAcutehepaticnecrosisAcuteviralhepatitis-likeALFCholestatichepatitisBlandcholestasisAcutefattyliverwithlacticacidosisNonalcoholicfattyliverSinusoidalobstructionsyndromeChronichepatitisNodularregenerationVanishingbileductsyndromeCirrhosisDILI临床表型:涉及几乎所有肝损伤类型基于详细病史、血液生化学检查、影像学检查和肝组织学检查等合理应用的排除性诊断,是目前DILI诊断的基本策略HEPATOLOGY,Vol.52,No.2,2010DILI诊断流程土沽人LT、AI_P及TBH寻步X升倉轲K[戏水.盼#曲,寻CJ原味底fK农理]♦f•ft9|.年》•用药史:时棗、的。程、8止曰以住肝晦忤俗@、再明指反应•HI住病史、CCW史、度皿号玷史•桂砍伶点.体怆所电•丈盟女惶査.B4fl.CT及MR1亏X®b性貞貞里、一餐JM玲・i]<*___、•l«AV.IIEV,IIBV.HCV.CMV、EBV♦尘等•■.性JFHM:侦;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■导•■*:
肝BfJRMW尘、全场<Mc«SE>寻〔•MIK毛力学»*「Q功能不全:W■■压、体兑〕各件馨为初怪丙奉引&的•怜校齢咔"横与»豚砰响佐的床垣咬優费零RIC7AM怦分叱整由肝活悅DILI临床分型基于损伤靶细胞分型•肝血管损伤型III不同药物可引起相同类型的肝损伤,同种药物在不同个体中也可能引起不同类型的肝损伤•混合型R值二2-5•肝细胞损伤型ALT>3N或R值>=5•胆汁淤积型ALP>2N或R值<2ALT最高实测值(首次)/正常上限她=ALP最高实测值(首次)/正常上限如:肝窦阻塞综合征/肝小静脉闭塞病等基于病程分型•急性DILI•慢性DILI・DILI发生6个月后,血清ALT、AST、ALP及TBiI仍持续异常,或存在门静脉高压或慢性肝损伤的影像学和组织学证据DILI严重程度DILI的严重程度0级(无肝损伤):患者对暴露药物可耐受,无肝毒性反应.1级(轻度肝损伤):血清ALT和/或ALP呈可恢复性升高,TBil<2.5ULN(2.5mg/dL或42.75ginol/L).且INRVL5.多数患者可适随.可有或无乏力、虚弱、恶心、厌食、右上腹痛、黄疸、瘙痒、皮疹或体质量减轻等症状叫,%2级(中度肝损伤):血洁ALT和/或ALP升高.TBil^2.5ULN.或虽无TBil升高但1NR^L5.上述症状可有加重.3级(重度肝损伤):血清ALT和/或ALP升高,TBil^5ULN(5mg/dL或85.5pmol/L),伴或不伴1NRN1.5。患者症状进一步加重,需要住院治疗,或住院时间延长。4级(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%,可同时出现(1)腹水或肝性脑病:或(2)与DILI相关的其他器官功能衰竭.5级(致命):因DILI死亡,或需接受肝移植才能存活。关于诊断、鉴别诊断的推荐意见:1-51.DILI临床诊断目前仍为排他性诊断,应绪合用药史、临床特征和肝脏生化学指标动态改变的特点、药物再刺激反应、其他肝損伤病因的排除等进行综合分析。肝活检组织学检查有助于诊断和婆别诊断。UB)2.推荐RUCAM因果关系评分量表作为临床实践中DILI临床诊断的应用量表。>8分为极可能(Highlyprobable),6-8分为很可豊(Probable),3〜5分为可能(Possible),1〜2分为不太可能(Unlikely),W0分为可排除(Excluded)。(18)3.完整的DILI临床诊断应包括诊断命名、临床类型、病程、RUCAM评分结果、严重程度分级。(18)4.在自身免疫性肝炎(A1H)基础上发生的DILk药物诱导的AIH和伴有自身免疫特征的A1H祥DILI(AL-DILI)常难以鉴别。应详细采集用药史和分析自身免疫指标,动态观察临床治疗应答及免疫抑制剂停药后的反应,必要时行肝组织学校查加以婆別。(2C)5•有基础肝楕背景或存在多种肝损伤病因的患者,应用具有潜在肝毒性的药物时应注意更密切的监测。诊断DILI时应十分慎重,需排除原有肝病的发作和加重,仔细甄别肝损伤的最可能原因,以便正确治疗O(IB)治疗基本原则•及时停用可疑药物,尽量避免再次使用可疑或同类药物•充分权衡停药引起原发病进展和继续用药导致肝损伤加重的风险•根据DILI的临床类型选用适当的药物治疗•ALF/SALF等重症患者必要时可考虑紧急肝移植关于停药的推荐意见:6-76.DILI的诚浙械备刎耕导刎椭柯剃机梱翘DIL词轴鐫艸七(")7.臓X耕舸皓劾发"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
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