RefractoryGastroesophagealrefluxdiseaseDefinitionofRGERDRGERD:Patientswhoareunresponsiveto4-8weeks'treatmentwithPPIstwicedailyoresophagealinjurycausedbyREcan’ttobehealing.—RichterJENatlClinGastroenterol2007;4:658OtherssuggestthatlackofsatisfactorysymptomaticresponsetoPPIonceadayissuf?cienttoconsiderpatientsasPPIfailures.Anyattempttonarrowthede?nitionofrefractoryGERDmightexcludemanytruesufferers.——HershcoviciTetal.BestPractice&ResearchClinicalGastroenterology2010(24)923-936PPIfailedinEachoftheGastrooesophagealRe?uxDisease(GERD)GroupsGERDNERD60-70%EE20-30%Barrett′soesophagus6-10%PPIfailurepatientsFailureonPPIqd40-50%FailureonPPIqd6-15%FailureonPPIqd20%——Fassetal.AlimentPharmacolTher2005;22(2):79-94.30%NERDfailtoPPItreatmentNERD-acid,visceralsensitivityPotentialcausesofPPIrefractorinessinGERDNeurogastroenterolMotil(2012)24,697–704WeaklyAcidRefluxTheprevalenceofweaklyacidicrefluxinrefractoryGERDis30-40%.WhentheesophagealpHfallsby≥1unit,butremains＞4,itisconsidered“weaklyacidicreflux”.Gut,2004,53:1024-1031EsophagealHypersensitivityAMJGastroenterol,2012,107,8-15.Esophagealreceptorupregulationand/orenhancedsignalingPhysiologicalstressors,sensitizationofspinalsensoryneurons.PotentialfactorscontributingtothespectrumofrefluxperceptioninpatientswithGERDGastroparesisDelayedgastricemptying(gastroparesis)maybeafactorassociatedwithseverereflux,dyspepsia,orboth.Gastroparesis,concomitantin25%ofpatientswithgastroesophagealrefluxdisease(GERD),hasbeenshowntoimproveafterNissenfundoplication.SURGICALENDOSCOPYANDOTHERINTERVENTIONALTECHNIQUES

，2008，22

（11）:2440-2444PoorCompliancewithPPITreatmentCompliancetotreatmentandproperdosingareimportant.Timingandfrequencyofdosingarecriticalformaximumef?cacyofthemedication.Patients

dosedoptimallythePPIs(%)Properdosingtiming46%Patients

dosedsuboptimallythePPIs(%)>60min

beforemeals39%aftermeals30%atbedtime28%as-needed4%PPIdosingsituationin100patientswithpersistentGERDsymptomsAlimentPharmacolTher2006;23:1473–7NocturnalAcidBreakthroughNAB:GastricpHbelow4over60consecutiveminutesatnight-timeinsubjectswhotakeprotonpumpinhibitorstwicedaily.AlimentPharmacolTher,2002,16()7:1309-1316.DilatedintercellularspacesThedilationofesophagealintercellularspaces(ICS)isconsideredanearlymorphologicmarkerofaciddamageinpatientswithGERD.ICSwillbedifficulttoeliminated

inRGERDpatientswhofailtoPPItreament.BileRefluxGastroenterol2009January21;15(3):334-338230patientswithheartburnandregurgitationcontinuedtoreportsymptomsafter8wkofhigh-dosePPItherapy(40mgesomeprazolebid).PsychologicalComorbiditiesALIMENTARYPHARMACOLOGY&THERAPEUTICS

,2007,26

(3):443-452.AnxietyanddepressionhavebeenshowntoincreaseGERD-relatedsymptomsreportinpopulation-basedstudies.NewMechanismAninflammatoryresponseoccursinthesquamousepithelium,inducedbythereleaseofinflammatorymediatorsLeadstothesubsequentchemoattractionandinfiltrationofimmunecellsFollowedbytheproliferativeresponseoftheratepithelium.Immunity:MucosalInflammationGastroesophagealrefluxdisease-fromrefluxepisodestomucosalinflammation.

Nat.Rev.Gastroenterol.Hepatol.2012Proteaseactivatedreceptor2(PAR2)Gastroesophagealrefluxdisease-fromrefluxepisodestomucosalinflammation.

Nat.Rev.Gastroenterol.Hepatol.2012

ActivatedbyserineproteasesUpregulatedinpatientswithGERDandinducedbyacidconditionsincellculturemodelsPAR2activation:LeadstoepithelialIL-8releaseandcontributestothepathogenesisofGERDImplicatedininflammatoryandneuroinflammatoryeffectsthemodulationofvisceralhypersensitivityandpaingenerationandincreasingepithelialpermeability.

GERDisImmune-mediatedesophagealmucosaldamage(IL-8AnewtargetsforGERDdrugdevelopment.ProinflammatoryandNeuroinflammatoryAspectsGastroenterol.Hepatol.2012TRPV1(transientreceptorpotentialcationchannelsubfamilyVmember1)TRPV1isinvolvedintheinflammatoryepithelialresponse,thatissupposedtobeinvolvedinGERD-relatedsymptomgeneration.EEorNERDpatientswithhighexpressionlevelofTRPV１．NuroinflammatoryaspectsinGERDpatientsNGF↑GNDF↑EsophagealEosinophiliaAmericanJournalofGastroenterology，2008，435-442Highintraepithelialeosinophilcountsinesophagealsquamousepitheliumarenotspecificforeosinophilicesophagitis.Eos＞20/HPFinGERDpatientssuggestitmaybeRGERD.＞20/HPFErosiveesophagitismayberelatedtosmallintestinalbacterialovergrowthScandinavianJournalofGastroenterology.2012GERDandSIBOOverlapofGERDandIBSLactulosehydrogenbreathtest（LHBT）InAbnormalLHBT,67%inEE,37%incontrol

（P=0.024）65%inEE,31%incontrol(withoutIBS)（P=0.032）SmallIntestinalBacterialOvergrowthDiagnosistestsUpperGastrointestinalEndoscopyGastrointestEndosc2007;66:219–24CommonlyusedinclinicalpracticetoevaluatepatientswithGERDwhofailedPPItreatment.ThevalueofendoscopyinpatientswithrefractoryGERDisverylow—Eosinophilicoesophagitiswasfoundinonly0.9%ofRGERDpatients,andNERDandfunctionalheartburnpatientstakeabigpart.Anewmethodinthediagnosisofrefluxesophagitis:confocallaserendomicroscopy.GIE.2012

Confocallaserendomicroscopy，CLEAnewmethodtotestGERD—Thedistancebetweenthesurfacetopapillary(S-P)tipcanbemeasuredbyusingCLE.S-Pdistance:0.19um/cminRE,0.44um/cmincontrol.黏膜表面毛細(xì)血管袢共聚焦激光顯微內(nèi)鏡診斷NERDNERDpatientshadmoreintrapapillarycapillaryloops(IPCLs)thancontrol.IPCLsnumberincreased;IPCLsdiameterbecomebigger;IPCLsextendedtomucosalsurface;Theintercellularspacesofsquamouscellswasenlarged.AmJGastroenterol.2012Mar13.

NERDdiagnosedbyCLE-DilatedDICAmJGastroenterol.2012Mar13.

;Control:figuera,b,e;NERD:figurec,d,f（DIS）EsophagealpHmonitoringallowthequanti?cationofesophagealacidexposureandtheassessmentofthetemporalrelationshipbetweensymptomsandacidre?uxevents.PHmonitoringcanbeperformedoffPPItotestiftheinitialdiagnosiswascorrect(i.e.,heartburnwasduetoacidre?ux)oronPPItotestwhetherthesymptomsareduetoresidualacidre?ux.Remote

proximalacidre?uxRemote

proximalacidre?uxAmbulatory24hEsophagealpHMonitoringAmbulatory24hEsophagealpHMonitoring-GraphsEsophagealBilitec

Bilitecdetectsbilirubininthere?uxatethatisusedasasurrogatemarkerforbilere?ux.Onehastorecallthatnon-acidicandbilere?uxaretwodistinctphenomena.Esophagealexposuretobileacidscanresultinheartburnsymptoms.DigDisSci2005;50:81–5.TreamentofRGERDTherapeuticoptionsforRGERDpatients

GastroenterologyandHepatology27(2012)Suppl.3;3–7GERDandPPIPaulMoayyedietal,Lancet,2006,June24(367):2086-2100NewPPIsDis.Eso