王炳元-激素在治疗重症酒精性肝炎中的作用

王炳元教授中国医大一院老年消化内分泌科主任教授、博士生导师中国医师协会脂肪肝专家委员会副主任委员中华消化学会老年协作组副组长中华消化学会肝胆协作组组员中华医学会辽宁省消化分会副主任委员辽宁省中西医结合肝病学会副主任委员辽宁省医学会肝病分会常委辽宁省免疫学会老年免疫分会主任委员TheeffectofglucocorticoidinAlcoholichepatitisWangBingYuan(王炳元)DepartmentofGeriatricGastroenterology,TheFirstHospitalofChinaMedicalUniversity,Shenyang,CHINA（中国医科大学附属第一医院老年消化科,沈阳，中国）wangby@

Heavydrinkersareatriskforaspectrumofhistologicalcohol-relatedliverinjury:Steatosis,Alcoholicsteatohepatitis(ASH),alcohol-relatedfibrosis,andcirrhosis.Alcoholichepatitis(AH),theclinicalentityassociatedwithsevereASH,hashighshort-termmortality.IntroductionPathogenesisofAHBerndSchnabl.Hepatology2016.ClinicalandLaboratoryFeaturesofAHYeluru,etal.AlcoholClinExpRes,2016:pp246–255CommonClinicalandLaboratoryFeaturesofAHIntrahepaticcholestasis,IHCHistologicalcharacteristicsofAHYeluru,etal.AlcoholClinExpRes,2016:pp246–255Anintegratedapproachtotreatingalcoholichepatitis.antioxidantMetadoxinebaclofenThemanagementofliverdiseasecomplicationsandsupportivecare1.57.10.4.3.2.9.6.8.抗炎保肝药物的分类分类作用机制抗炎类抗炎：抗抑制炎症因子、免疫性因子；免疫调节：刺激单核-巨噬细胞系统、诱生γ-干扰素，增强NK细胞活性；可抗过敏、抑制钙离子内流代表药物异甘草酸镁注射液（天晴甘美）、天晴甘平、其它甘草制剂、双环醇修复肝细胞膜类与肝细胞膜及细胞器膜相结合，增加膜的完整性、稳定性和流动性，使受损肝功能和酶活性恢复正常，调节肝脏的能量代谢，促进肝细胞再生代表药物多烯磷脂酰胆碱解毒类参与体内三羧酸循环及糖代谢，激活多种酶，促进糖、脂肪及蛋白质代谢，减轻组织损伤，促进修复代表药物为GSH（还原型谷胱甘肽）、硫普罗宁抗氧化类抗脂质过氧化，增强肝细胞膜对多种损伤因素的抵抗力代表药物为水飞蓟素类利胆类促进胆汁酸转运，达到退黄，降酶的作用代表药物为熊去氧胆酸（UDCA）、S-腺苷蛋氨酸.王宇明.抗炎保肝药物的作用机制及地位.中华肝脏病杂志,2011,19(1):76-77.ROS启动Caspase（8）LOX前列腺素白三烯血栓素NF-kBTNFα/FasSOD异甘草酸镁易善复谷胱甘肽NADPHII氧化酶ONOO-iNOS溶血磷脂胆碱LPC脂质神经酰胺3种抗炎保肝药物的作用靶点Yeluru,etal.AlcoholClinExpRes,2016:pp246–255Anintegratedapproachtotreatingalcoholichepatitis.Europe:methylprednisolone40mg,iv,qd,28dourexperience:methylprednisolone120mg,iv,3dand7d.TBiL:decreasedby10%ondays3ordecreasedby30%ondays7,continuetoDFdownto32orless,graduallydecreasethedosageorstop.Lillescore<0.4510.TheeffectofglucocorticoidPrognosticscoringsystemsofalcoholichepatitisPleaseremember：From1971through2014,13randomizedtrialsand4meta-analysesinvestigatedthe

effectsofcorticosteroidsinpatientswithAH.Althoughthesestudiesproducedmany

results,controversypersistedovertheuseofcorticosteroidtherapyinthesepatients.Advocatescitereductionsinshort-tomedium-termmortality,whereasdetractorsraise

concernsaboutrisksofsepsisandgastrointestinalhemorrhage.Thelargestplacebo-controlledstudyoftheeffectsofcorticosteroids,in90patientswith

AH,foundprednisolonetoprovidenobenefitcomparedwithplacebo.Thisstudywas

hamperedbyitsinclusionofpatientswithmoderateandsevereAHorend-stage

alcoholicliverdisease.InstudiesthatrequiredhistologicalconfirmationofAH,

prednisolonewasassociatedwithashort-termdecreaseinmortality,buttherewasno

reductioninmortalityover6monthsN.Engl.J.Med.

184，311Systematicreviewsoftheseclinicaltrials

generatedconflictingresults.ACochranemeta-analysisreportedatrendtoward,butnot

anotstatisticallysignificant,increaseinsurvival.Howeverare-analysisofthe3largest

studiesindicatedthatcorticosteroidssignificantlyincreasedsurvivalofpatientswithAH.Inthisstudy,15%ofpatientswithDFvaluesof32ormoregivenprednisolonediedwithin28days,comparedto35%ofpatientsgivenplacebo.Gut.2011;60:255-260.Inanattempttoresolvethecontroversyovertheuseofsteroidsorpentoxifylline,a

doubleblind,factorial2x2,multicentertrialwasconductedintheUnitedKingdom

between2011and2014inpatientswithadiagnosisofAH(theSTOPAHtrial).This

studyreportedaborderlinereductioninmortalityat28daysforpatientsgiven

prednisolone40mgdailyfor28dayscomparedwithcontrolpatients.NEnglJMed.2015;372:1619-28.However,

survivalcurvesconvergedafter28dayssuchthatprednisolonetherapyprovidedno

benefittopatientsafter90daysor1year.Datafromthistrialandpreviousstudieswere

incorporatedintoanetworkmeta-analysis,whichconfirmedthatcorticosteroidsdonot

benefitpatientsbeyondthefirstmonthoftreatment.Gastroenterology.2015;149:958Twofactorspotentiallylimittheefficacyofcorticosteroiduse:increasedsusceptibilityto

infectionandrecidivism.IntheSTOPAHtrial,incidentinfectionsclassifiedasserious

adverseeventsweremorecommonamongsubjectsgivenprednisolonethancontrols.Infectionsoftherespiratorytractwereparticularlymorecommon.However,inthemetaanalysis

ofSinghetal,infectionwasnotanymorecommonamongpatientstreatedwith

vswithoutcorticosteroids.Thisapparentdiscrepancycouldhavebeencausedby

differentmethodsoftrialreporting.Gastroenterology.2015;149:958Ontheotherhand,astudycomparingcorticosteroids

withintensiveenteralnutritionfoundthattheshort-termgainsinsurvivalinthesteroid

groupwerelostafterthefirstmonthduetoanincreasedincidenceofinfections,which

resultedinpatientdeaths.Hepatology2000;32:36-42SIRS？Infections？Chronicliverfailure？Fig.3.Ninety-daymortalityaccordingto(A)thepresenceofMOF,(B)thepresenceofSIRS,and(C)theSIRS-associatedconditions.MICHELENAETAL.HEPATOLOGY2015;Causativepathogens:atotalnumberof89pathogenscouldbeidentifiedin34patients.BeiselC,

ScandJGastroenterol.2016Mar22:1-7.Chronicliverfailuresequentialorganfailureassessmentscore（SOFA）MoreauR.Acute-on-chronicliverfailure:anewsyndromeincirrhosis.ClinMolHepatol.2016Mar;22(1):1-6.

DefinitionsofSingleOrganFailureOrganDefini