王炳元-激素在治療重癥酒精性肝炎中的作用

王炳元教授中國醫(yī)大一院老年消化內(nèi)分泌科主任教授、博士生導師中國醫(yī)師協(xié)會脂肪肝專家委員會副主任委員中華消化學會老年協(xié)作組副組長中華消化學會肝膽協(xié)作組組員中華醫(yī)學會遼寧省消化分會副主任委員遼寧省中西醫(yī)結合肝病學會副主任委員遼寧省醫(yī)學會肝病分會常委遼寧省免疫學會老年免疫分會主任委員TheeffectofglucocorticoidinAlcoholichepatitisWangBingYuan(王炳元)DepartmentofGeriatricGastroenterology,TheFirstHospitalofChinaMedicalUniversity,Shenyang,CHINA（中國醫(yī)科大學附屬第一醫(yī)院老年消化科,沈陽，中國）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.抗炎保肝藥物的分類分類作用機制抗炎類抗炎：抗抑制炎癥因子、免疫性因子；免疫調(diào)節(jié)：刺激單核-巨噬細胞系統(tǒng)、誘生γ-干擾素，增強NK細胞活性；可抗過敏、抑制鈣離子內(nèi)流代表藥物異甘草酸鎂注射液（天晴甘美）、天晴甘平、其它甘草制劑、雙環(huán)醇修復肝細胞膜類與肝細胞膜及細胞器膜相結合，增加膜的完整性、穩(wěn)定性和流動性，使受損肝功能和酶活性恢復正常，調(diào)節(jié)肝臟的能量代謝，促進肝細胞再生代表藥物多烯磷脂酰膽堿解毒類參與體內(nèi)三羧酸循環(huán)及糖代謝，激活多種酶，促進糖、脂肪及蛋白質(zhì)代謝，減輕組織損傷，促進修復代表藥物為GSH（還原型谷胱甘肽）、硫普羅寧抗氧化類抗脂質(zhì)過氧化，增強肝細胞膜對多種損傷因素的抵抗力代表藥物為水飛薊素類利膽類促進膽汁酸轉(zhuǎn)運，達到退黃，降酶的作用代表藥物為熊去氧膽酸（UDCA）、S-腺苷蛋氨酸.王宇明.抗炎保肝藥物的作用機制及地位.中華肝臟病雜志,2011,19(1):76-77.ROS啟動Caspase（8）LOX前列腺素白三烯血栓素NF-kBTNFα/FasSOD異甘草酸鎂易善復谷胱甘肽NADPHII氧化酶ONOO-iNOS溶血磷脂膽堿LPC脂質(zhì)神經(jīng)酰胺3種抗炎保肝藥物的作用靶點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