American Journal of Gastroenterology ISSN by Am - PDF document

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GuidelinesfortheManagementofDyspepsia2333Gradeofevidence:CAbdominalwallpaincanbeconfusedwithfunctionaldys-pepsia;physicalexaminationhereisdiagnostic(increasedratherthanreducedtendernessontensingtheabdominalwallmuscles)(130).Biliarypainischaracteristicanddifferentfromdyspepsia;ultrasoundusuallyisunhelpfulintheab-senceoftypicalbiliarypain.ExclusionofatypicalGERDwithesophagealpHtestingmayaltermanagement;atleast20%ofpatientswithdiagnosedfunctionaldyspepsiaclini-callyturnouttohaveGERDonesophagealpHstudies(23Ð25,131).Thus,evenifatrialofPPItherapyhasfailed,pHtestingmaybeconsideredofftherapy,althoughtheyieldinthisparticularsettingisnotdeÞned.Abdominalimagingtouleoutchronicpancreatitisorsmallbowelpathologymaybeworthconsideringtoobutusuallyhasalowyield;cap-suleendoscopydoesnotyethaveanestablishedrolehere.Gastricfunctiontesting(gastricemptying;gastricaccommo-dation;responsetoanutrientorwaterload)maynotchangemanagementevenifabnormalitiesaredetected,although,ifthereisgastricdysaccomodation,trialsofvariousdrugstorelaxthefundusmaybeworthtryingempirically(123,132).QuestionsaboutsymptomsconsistentwithIBSmayleadtochangeinthediagnosis.Colonicevaluationmaybeconsid-eredeveniftherearenoboweldisturbancesbecausediseaseinthetransversecolonorelsewherecanoccasionallypresentwithreferredsymptomslabeleddyspepsia.AdrughistoryishelpfulbutasidefromNSAIDs,drugsarerarelymajorcontributorstochronicdyspepsiaaccordingtotheavailablevidence(133).Diabeticradiculopathycancauseupperab-dominalpainandEMGisdiagnostic.EvaluationforreferredpainfromthechestorbackshouldbeconsideredindifÞ-cultcases.Finally,considerlookingforraremetabolicorothercausesofupperabdominalpainincludingthyroiddis-ease,electrolyteabnormalities,hypercalcemia,heavymetals,acuteintermittentporphyria,angioneuroticedema,famil-ialmediterraneanfever,chronicintestinalangina,superiormesentericarterysyndrome,liverdisease(hepatoma,steato-hepatitis),eosinophilicgastroenteritis,orconnectivetissuePracticeParameterCommitteeChair:RonnieFass,M.D. UpperGutLiver&Pancreas Chair:WilliamD.Chey,M.D.Chair:DanielPratt,M.D.Sub-Chair:RichardSub-Chair:JohnSampliner,M.D.Cunningham,M.D.EceA.Mutlu,M.D.WilliamBrugge,M.D.NimishVakil,M.D.WilliamCarey,M.D.MiguelA.Valdovinos,M.D.MatthewCohen,M.D.BenjaminWong,M.D.DavidBernstein,M.D. FunctionalBowelandLowerGutGIMotility Chair:TimKoch,M.D.Chair:HenryParkman,M.D.Sub-Chair:StevenSub-Chair:LinChang,M.D.Edmundowicz,M.D.AlvinZfass,M.D.CharlenePrather,M.D.DarrenBaroni,M.D.AdilE.Bharucha,M.D.SubbaramiahSridhar,M.D. Reprintrequestsandcorrespondence:NicholasJ.Talley,M.D.,Ph.D.,MayoClinicCollegeofMedicine,200FirstStreetS.W.,PL-6Ð56,Rochester,MN55905.ReceivedFebruary18,2005;acceptedMay23,2005. 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2332Talleyetal.Hypnotherapy,Psychotherapy,Cognitive-behavioraltherapy:BMANAGEMENTOFDOCUMENTEDFUNCTIONALDYSPEPSIAOnceadiagnosisoffunctionaldyspepsiaisconÞrmedbyanegativeendoscopy,anempirictrialoftherapyiscommonlyprescribed.However,thebeneÞtsofalltherapiesinthiscon-ditionhavebeenquestioned.Manypatientsdonotrequiremedicationfordyspepsiaaftertheyhavehadreassuranceandeducation.Itisthere-foreimportantforthecliniciantoexplainthemeaningofthesymptomsandtheirbenignnature.Ascertainingwhyapatientwithlong-standingsymptomshaspresentedonthisoccasionforcarecanbehelpful,asthismayidentifythosefearsofanunderlyingseriousdiseaseorspeciÞcpsychologicaldistressthatcanbeaddressed.Potentialprecip-itatingfactorsindyspepsiaremainpoorlydeÞned.High-fatmealsshouldbeavoided;eatingfrequentandsmallermealsthroughoutthedaycansometimesbehelpful.SpeciÞcfoodsthatprecipitatesymptomscanbeavoided.Foodintoleranceisuncommon,however,andfoodallergyveryrare.Follow-upofthepatienthelpsdeterminethenaturalhistoryandallowsfurthercorrectionoffaultyideasandprovidesreassurancethatcanbeveryhelpfulinlong-termmanagement.AntacidsandsucralfatewerenotsuperiortoplaceboinfunctionaldyspepsiabasedonaCochranereview(98).How-er,arecenttrialofsimethiconehassuggestedpotentialbeneÞtcomparedwithplacebo,andinanotherstudyequiv-alencewithcisapride(110,111).ACochranereviewof8trialsofHreceptorantagonistswith1,125patientsshowedrelativeriskreductionof30%butthequalityofthetrialsgenerallypoor(98).PPIsinthisreviewalsoproducedarelativeriskreductionofapproximately30%andthequalityofthetrialswasbetter(98).AneconomicmodelsuggestedthatPPItherapywascost-effectiveforfunctionaldyspepsiaintheUnitedStates(108).However,inarecentrandomizedtrialof453patientsfromHongKong,theproportionofpatientsachievingcompletereliefofdyspepsiawithlansoprazole30and60mgwas23%and23%,respectively,comparedwith30%onplacebo(112).Incontrast,anotherrecenttrialre-portedsigniÞcantbeneÞtwithlansoprazoleinaU.S.popula-tion(113).H.pyloristatusisunlikelytoaffectthetherapeuticoutcomeofacidsuppressiontherapyinfunctionaldyspepsia(108).LargetrialshavefailedtoidentifyanydifferenceintherapeuticoutcomeinH.pylori-positiveversusnegativepa-tients,althoughBlumetal.dididentifyasuperiorresponsetoPPItherapyinH.pylori-positivepatients(114,115).Eradicationofinfunctionaldyspepsiaiscontro-ersial.Twohigh-qualitymeta-analyseshavereacheddiffer-entconclusionsbutthismaybelikelyexplainedbywhichtrialswereincludedandexcludedineachsystematicreview(116,117).Updatingthesemeta-analysesnowsuggeststhathenallappropriatetrialsareconsidered,thereisasmallbutsigniÞcanttherapeuticgainachievedwithicationinfunctionaldyspepsia,withthenumberneededtotreatbeing15(118).Whilelongerthan1-yrfollow-updataaregenerallylacking,one5-yrstudysuggestsanybeneÞtwillpersist(119).Onthebasisoftheevidence,itisaccept-abletooffereradicationtherapytoinfectedpa-tientswithfunctionaldyspepsia.TheresultsalsoimplythatofferingH.pylorieradicationtherapyempiricallytothosewithotherwiseuninvestigateddyspepsiawhoareinfectedisreasonableevenifulcerdiseaseisunlikely.Moreover,H.pylorieradicationinthosewithdocumentedfunctionaldyspepsiamayhelppreventulcerdisease,althoughconvinc-ingevidenceisnotavailable.Hsuetal.observedduring1yroffollow-upinarandomizedcontrolledtrialcompris-ing161patientswithfunctionaldyspepsia,2patientsintheH.pylorieradicationtreatmentgroup(3%)and6patientsintheplacebogroup(8%)developedpepticulcersatrepeatendoscopy(120).ThebeneÞtofothertreatmentsremainsuncertain.ACochranereviewincluded12trialswithprokineticscom-prising829patientsandshowedthattherewasarelativeriskreductionof50%,comparedwithplacebo,butmostofthestudieswerewithcisapride(98).Moreover,analysisofthestudiessuggestedthatpublicationbiasatleastpartlyex-plainstheapparentbeneÞtsofprokinetictherapy.ProkineticsshouldbereservedfordifÞcultcasesasoptionsintheUnitedStatesarefewandcurrentagents(e.g.metoclopramide,ery-thromycin,tegaserod)havelimitedorpoorlyestablishedef-Þcacy,orside-effectsarecommon(121).Routineuseofgas-tricemptyingstudiesisnotrecommendedasimprovementsingastricemptyingdonotcorrelatewellwithsymptomim-provement(31,122).Drugsthatrelaxthegastricfundus(e.g.tegaserod,cisapride,sumatriptan,buspirone,clonidine,someSSRIs,nitricoxidedonors)maytheoreticallyimprovesomedysmotility-likedyspepsia(e.g.earlysatiety)butadequaterandomizedcontrolledtrialsarelacking(123).Antidepres-santsarealsoofuncertainefÞcacyinfunctionaldyspepsiabutareoftenprescribed(121,124).ThereareinsufÞcientdataontheuseoftricyclicantidepressantssuchasamitryptylineindyspepsia,butsmallstudieshavesuggestedbeneÞt;how-er,thebeneÞcialeffectoflow-doseamitryptylineseeninfunctionaldyspepsiawasnotrelatedtochangesinperceptionofgastricdistension(125).Anincreasedtolerancetoaver-sivevisceralsensationsmayplayaroleinthetherapeuticeffect.TherearelimiteddatawiththeSSRIs.Psychologicaltherapiesarepromising,particularlyhypnotherapy,butmoredataareneededinlargerpatientpopulationsbeforethesecanberecommendedforroutineuse(126,127).Otheralterna-tivetherapiessuchasherbalpreparationsremainofunprovenalue(128,129).ADDITIONALDIAGNOSESANDTESTINGINREFRACTORYCASESInpatientswithresistantsymptoms,itisworthreevaluatingthediagnosis. GuidelinesfortheManagementofDyspepsia2331Obviousdisadvantagesofempiricantisecretorytherapyincludetheconcernthatpepticulcerdiseasewillbeinappro-priatelyandinadequatelytreated,andpatientssubsequentlymaypresentwithcomplicatedulcerdiseaseifforanyreasonthetherapyisceased.Antisecretorytherapycanalsoleadtomisdiagnosisofpepticulcerdiseaseatsubsequentendoscopy,astheulcerwillmorelikelyhealandbemissed.Theimpactofacidreboundindyspepsiaremainsunclear(102).Em-piricantisecretorytherapymayleadtolong-terminappropri-atemaintenancetherapythatthepatientdoesnotrequire.Itisunclearwhetherantisecretorytherapypostponeseventualinvestigationornot,whichinturnimpactsonitspotentialcost-effectiveness.H.pyloriTEST-AND-TREATANTISECRETORYTHERAPYThereareonlyverylimiteddatacomparingempiricH.pyloriversusempiricPPItherapy.Manesetal.test-and-treatwithPPItherapyforamonthwith12monthsoffollow-upinasecondarycaresettinginItaly(103).Inthetest-and-treatarm,56%wereeventuallyendoscopedbecauseofpoorsymptomcontrol,butnonehadapepticulcer;inthePPIarm,88%wereendoscopedand17%hadapepticulcer,butmost(88%)wereinfectedwithH.pyloristudiesareneeded,butthesedatasuggestthatinH.pyloripositivedyspepticpatients,empiricPPItherapyisnotthemanagementoptionofchoiceinareaswheretheprevalenceH.pyloriishigh.ECONOMICMODELSOFDYSPEPSIAMANAGEMENTetal.undertookeconomicmodelingofmanage-mentstrategiesinpatientwithsuspectedpepticulcerdisease,hichpresumablyappliestothemajorityofpatientswithuninvestigateddyspepsia(104).TheyfoundthataninitialstrategyofH.pyloritestingandtreatmentwascost-effective,unlessthecostofendoscopyfelltolessthan$500whenpromptendoscopybecamemorecost-effective.Sonnenbergnotedthatiftheulcerdiseaseprevalencerateexceeded10%H.pylori-infectedsubjects,thenanoninvasivestrategybasedonserologicaltestingbecamecost-effective(105).Sil-elal.concludedthattherewasatossupbetweenH.pyloritest-and-treatcomparedwithotherstrategies,butreevaluationofthismodelapplyingtheassumptionsmadebyetal.conÞrmedtheirresults,supportingtest-and-treat(106).Ofmanetal.concludedthattest-and-treatwascost-saving;thecostofendoscopywouldneedtodropfrom$740by96%foraninitialendoscopystrategytobecomeequallycost-effectiveintheirmodel(107).Spiegeletal.testedfourdifferentmanagementstrategiesindecisionanalysis(59).ThisanalysiswasconÞnedtopatientsoungerthan45yrofagepresentinginprimarycare.TheyidentiÞedinitialantisecretorytherapyfollowedbyendoscopyastheleastcostlytherapyperpatienttreated.However,thisrenderedfewerpatientssymptom-freeat1yrthanstrategieshichcombinedempiricPPItherapywithtest-and-treat.Inthismodel,themostcostlyapproachwastest-and-treatfol-lowedbyendoscopyforfailures.ThismodelalsosuggestedthatempiricalPPItherapybecamecost-effectiveifthepreva-lenceofH.pyloriinfectionwas12%orlessinthedyspepticpopulation.Ladabaumetal.observedthatasthelikelihoodH.pylori(andulcerdisease)decreasesbelow20%,em-piricPPItherapystartstodominatetest-and-treatinunin-estigateddyspepsia(60).Therefore,recommendationsforthetest-and-treatstrategymayneedtobemodiÞedwhentheprevalenceofH.pyloriinfectionislow,andwerecommendonthebasisofexpertopinionconsideringaPPIinthesettingofaH.pyloriprevalencebelow10%inthelocalcommu-nity.Arecentsystematicreviewandeconomicanalysisusinggeneric/over-the-countercostsforPPIsfoundthattheywerecost-effectiveintheUnitedStatesprovidedgenericcostsofaPPIwereusedintheanalysis(108).UpperGIradiologywasnotacost-effectivealternativetoH.pyloritest-and-treatinanotherU.S.model(109).WEIGHINGTHEOPTIONSCochranereviewhasbeenconductedofavailablemanage-mentstrategiesfordyspepsia(70).TheyidentiÞed18pub-lishedpapersthathad20comparisonsincluded.Inapooledanalysis,PPIsweresigniÞcantlymoreeffectivethanbothreceptorantagonistsandantacidsinuninvestigateddys-pepsia.AsigniÞcantlimitationofthestudiesisthattheyincludedbroadgroupsofpatientsincludingthosewithobvi-ousreßuxdisease.TherewasinsufÞcientdatatodeterminehetherempiricprokinetictherapywasbeneÞcial.TheyalsoconcludedaH.pyloritest-and-treatstrategymaybeaseffec-tiveasendoscopy-basedmanagementwithreducedcostsbe-causeofthedecreasednumbersofpatientsthatsubsequentlyrequireEGD,butitwasunclearwhethertest-and-treatcom-paredtoempiricalacidsuppressionwasequivalentornotbecauseofthelackofdata.ENDOSCOPY-NEGATIVEDYSPEPSIA(FUNCTIONALYSPEPSIA,NONULCERDYSPEPSIA)Themanagementofendoscopy-provenfunctionaldyspep-siaisparticularlychallengingwheninitialantisecretorytherapyandH.pylorieradicationfails.Patientswhofailtorespondtosimplemeasuresneedtohavetheirdiagnosiseconsidered.DietarytherapyhasnoestablishedefÞcacyhelpsomeindividuals.Thereareverylimiteddatatosupporttheuseofherbalpreparations,simethicone,andlow-dosetricyclicantidepressantsinfunctionaldyspepsia.Bismuth,sucralfate,andantispasmodicsarenotestablishedtobeofbeneÞtoverplaceboinfunctionaldyspepsia.Hyp-notherapy,psychotherapy,andcognitive-behavioralther-apyaresupportedbylimitedstudiesbutcannotbegenerallyecommendedatthepresenttime.Gradesofevidence:DietarymodiÞcation:CSimethicone:B 2330Talleyetal.dyspepsia.Bytzerelal.conductedarandomizedtrialcom-paringpromptendoscopywithempiricH-receptiveblockertherapyindyspepsia(88).TheyfoundtherewassigniÞcantimprovementinsatisfactionscoresatonemonthafteren-doscopycomparedtotheempiricantisecretorytherapyarm.Inaddition,66%ofthepatientsintheempirictherapyarmentuallyunderwentendoscopyduringthe12monthsoffollow-up.However,thisunblindedstudymayhavebeenbi-asedbypatientandphysicianexpectationthatendoscopyisthepreferredmanagementstrategy,andH.pyloristatuswasnotconsidered.OtherstudieshavesuggestedthatpatientswithdyspepsiaarereassuredbyEGDandmayrequirefewerprescriptions,althoughthedurationofreassuranceisnotes-tablished(89Ð91).Dyspepticpatientswhoseekmedicalattentionaremoreconcernedaboutthepossibleseriousnessoftheirsymptomsandaremorelikelytobeconcernedaboutunderlyingcancer(92).Healthanxietyhasbeenshowntoleadtoacycleofrepeatedmedicalconsultations.Inastudyofprimarycarepatientsundergoingopen-accessendoscopy,Hunginetal.demonstratedthatconsultationsfordyspepsiafellby57%inpatientswithnormalendoscopyandby37%inpatientswithminorabnormalitiesatendoscopy.In60%ofpatientswithnormalendoscopy,medicationusewasterminatedordecreased(93).QuadriandVakildemonstratedthatonethirdofpatientsreferredforopen-accessendoscopyfordyspepsiaintheUnitedStateshadhighlevelsofhealthrelatedanxiety;followinganormalendoscopyorthedemonstrationofmi-norabnormalities,andreassurancebytheendoscopist,scalesforpreoccupationwithhealthandfearofillnessanddeathshowedsigniÞcantimprovementafterendoscopy,andtheef-fectswerepreservedfor6months(86).DisadvantagesofEndoscopyThereareseveralpotentialdisadvantagesofprompten-doscopyforalldyspepticpatientsthatneedtobecarefullyconsidered.Endoscopyisinvasiveandalthoughtherisksofthisprocedureinrelativelyhealthypatientsareverylow,theissueoftherisk-beneÞtrationeedscarefulweighing,par-ticularlyastheprocedureisveryunlikelytoidentifyanun-xpectedstructuralcauseinayoungpatientwithnoalarmfeatures.Findingesophagitis,themostlikelystructuralab-normality,mayoftennotleadtoachangeinmanagement(94,95).Moreover,thehighprevalenceofdyspepsiameansthatageneralrecommendationtoperformendoscopiesonallpatientswouldbeverycostlyandwouldoverwhelmen-doscopyservices.Furthermore,itiscontentiousthatpromptEGDprovidesanydirectbeneÞtsdespitesomepositivestud-iesquotedabove.Onestudyevaluatedmanagementstrategiesin326primarycarepatientswithdyspepsia;endoscopywasnotsuperiortoanyoftheempiricaltreatmentstrategiesuti-lizedinthisstudy(96).Asystematicreviewconcludedthatmostdatafailedtosupporttheviewthatendoscopyaloneimprovespatientoutcomeindyspepsiacomparedwithotherempiricstrategies(97).EMPIRICANTISECRETORYTHERAPYINUNINVESTIGATEDInH.pylori-negativecaseswithuninvestigateddyspepsiaandnoalarmfeatures,anempirictrialofacidsuppression4Ð8wkisrecommendedÞrst-linetherapy(Fig.1).Gradeofevidence:AIfinitialacidsuppressionfailsafter2Ð4wk,itisrea-sonabletostepuptherapy,althoughthisisbasedonex-pertopiniononly;thismayrequirechangingdrugclassordosing.IntheabsenceofestablishedprokineticdrugsfordyspepsiaintheUnitedStates,thisdrugclassisnotcur-entlyrecommendedasÞrst-linetherapyfordyspepsiaintheUnitedStates.Gradeofevidence:CInpatientswhodorespondtoinitialtherapy,itisrecom-mendedthattreatmentbestoppedafter4Ð8wkandifsymp-tomsrecur,anothercourseofthesametreatmentisjustiÞed.Therearenodataonlong-termself-directedtherapyinthiscondition,althoughthismaybeworthconsideringinsomeGradeofevidence:CTheAmericanCollegeofPhysiciansin1985recom-mendedanempirictrialofanHreceptorantagonistfor6Ð8wk;thosewhorelapsedaftertherapyorthosewhofailedtorespondtotherapyin7Ð10daysweretobereferredforendoscopy(44).ThewidespreadavailabilityofPPIshasre-sultedinthisclassofagentsfrequentlybeingprescribedasinitialempirictherapyinuninvestigateddyspepsiainplaceofHreceptorantagonists(98).meta-analysisofseverallargestudieshasdemonstratedshortcourseofPPItherapycomparedwithaHantagonist,alginate,orplaceboinprimarycareprovidesbettersymptomaticoutcomes(70).However,thesestud-iesfrequentlyincludedpatientswithsymptomaticreßuxdiseaseanddidnotexcludepepticulcer.ItisunknownhetherGERDorulcerdisease,orboth,accountsfortheapparentshort-termbeneÞtsofempirictherapyinthesereports.TherearelimiteddatathatprokinetictherapyemployedasanempiricstrategymaybeefÞcaciousinuninvestigateddys-pepsia.Kearneyetal.notednosigniÞcantdifferenceintheseverityofdyspepticsymptomsamong60patientsrandom-izedtoreceivecisaprideascomparedtoplacebointhesettingofuninvestigateddyspepsiaandnegativeH.pylori-serology(99).Quarteroetal.conductedatrialinprimarycareof563patientswhowererandomizedtoranitidineorcisapride;treatmentsuccesswassimilarinbothgroupsbutwasun-der50%,andtherelapse-freeperiodswerealsosimilarwithbothdrugs(100).ArandomizedtrialinH.pylori-negativedyspepsiafromCanadademonstratedthatcisapridehadlowefÞcacyandwasinferiortoacidsuppression(101).More-er,cisaprideisnolongeravailablebecauseofraretoxicityfromQTprolongationandsuddendeath.Therehavebeennotrialsofmetoclopramide,tegaserodordomperidoneinthemanagementofuninvestigateddyspepsia. AmericanJournalofGastroenterologyISSN0002-92702005byAm.Coll.ofGastroenterologydoi:10.1111/j.1572-0241.2005.00225.xPublishedbyBlackwellPublishing PRACTICEGUIDELINESGuidelinesfortheManagementofDyspepsia NicholasJ.Talley,M.D.,Ph.D.,F.A.C.G.,NimishVakil,M.D.,F.A.C.G.,andthePracticeParametersCommitteeoftheAmericanCollegeofGastroenterology GuidelinesfortheManagementofDyspepsia2329ofquestionableclinicalsigniÞcance.Theauthorsalsoiden-tiÞedareductioninthenumberofendoscopicproceduresperformedinthetest-and-treatarm.Heaneyetal.inIrelandaluateddyspepsiapatientslessthan45yroldreferredtoanopen-accessendoscopyunitwhowereH.pylori-positiveonnoninvasivetesting(66).PatientsherewererandomizedtoeitherempiricH.pyloritherapyorimmediateEGD.Theyfoundthatmorepatientsbecamesymptomfreeintheeradicationarmthaninthepromptendoscopyarm.etal.aluated708patientsunderage55yrreferredforendoscopy;thesepatientswererandomizedtoeithertest-and-treatorendoscopyincludingH.pylori(67).TheyfoundnosigniÞcantdifferenceindyspepsiascoreatthe12monthsfollow-upinthetwogroups.Furthermore,only8%ofpatientswhohadtestingandtreatmenteventuallyunderwentendoscopy;overallpatientsatisfactionandqualityoflifewassimilarinbothgroups.Jonesetal.aluated232patientsinprimarycare,ofwhom141underwenttestingandtreatmentforH.pylorihohadpreviouslyundergoneendoscopycomprisedthecontrolgroup(68).Althoughnotrandomizedcontrolledtrial,theyidentiÞedsimilarclini-caloutcomesbutlowercostsinthetest-and-treatgroupatBecausethiswasaretrospective,unmatchednoncon-secutivecontrolledstudy,theresultsaredifÞculttointerpret.Additionalrandomizedtrialdata(69)andaCochranemeta-analysis(70)suggestoverallthatpromptEGDandtest-and-treathavesimilarefÞcacy.OtherevidencesupportstheviewthatH.pylorimayprovideadequatepatientreassurance.Pateletal.uated193dyspepsiapatientsundertheageof45yr(71).SeventyofthesepatientswereH.pylori-seronegativewith-outalarmfeatures,90wereseropositiveforH.pyloriand23hadalarmfeatures;theH.pylori-positivepatientsandthosewithalarmfeaturesunderwentpromptendoscopy.Nodif-ferenceinoutcomeorsatisfactionwasdetectedbetweentheroupsinfollowupafterreferralbacktotheirprimarycarephysician.DisadvantagesofTest-and-Treatnotabledisadvantageoftest-and-treatisthatcureofinfectionwillonlyleadtoaminorityreportingsymp-tomimprovement,asdemonstratedintheabovemanagementtrials,andthiscanbeconfusingtotheclinician(60Ð65).How-er,endoscopyandtargetedmedicaltherapydoesnobetter.Indeed,eradicationofH.pyloriinfectiondoesnotrelievesymptomsinallpatientswithpepticulcerdisease,withatleastonethirdcontinuingtobesymptomatic(72,73).ThechoiceoftheH.pyloritestiscritical.Manyserologi-caltestshavenotbeenlocallyvalidated,andhavesuboptimalsensitivityandspeciÞcityinpractice(74).Theureabreathtestandstoolantigentestarecurrentlythemostaccuratenonin-asivediagnostictoolsandcanbeusedwithconÞdence(75,76).ThevalueofnoninvasiveH.pyloritesting,evenifalocalevaluatedtestisapplied,stilldependsonthepositiveandnegativepredictivevalue,whichinturnisrelatedtothebackgroundprevalenceofH.pyloriinfection.WhenH.py-isveryuncommon,apositivetestismorelikelytobeaalsepositive.WhereH.pyloriinfectionishighlyprevalent,ativeresultismorelikelytobeafalsenegative(77).Cost-effectivenessstudiessuggestthatthestooltestandtheureabreathtestthatdetectactiveinfectionarepreferabletoserologicaltestsintheUnitedStates(78,79).ThecurrenttreatmentofchoiceforH.pyloriinfectedpa-tientsisacombinationofPPI(standarddosetwicedaily)withamoxicillin(1gtwicedaily)andclarithromycin(500mgtwicedaily)administeredfor7Ð10days(7-daytherapyisapprovedwithrabeprazole;10-daytherapyisapprovedwithlansoprazole,omeprazole,pantoprazole,andesomepra-zole).Metronidazole(400mgtwicedaily)maybesubsti-tutedforamoxicillininthisregimenifthepatientisallergictopenicillin.AnalternativestrategyisthecombinationofBismuth,metronidazole,andtetracycline(Bismuthsubsal-icylate[PeptoBismol525mgQIDmetronidazole250mgQIDtetracycline500mgQID)combinedwithaPPIfor14days(80,81).Þnalissuerelatestopotentialcomplicationsoftherapy.Antibioticallergiesandsuper-infectioncanoccur.Itiscon-troversialwhethereradicationofH.pyloriinfectionincreasestheriskofdevelopmentofreßuxesophagitisorreßuxsymp-toms(82,83).However,itappearslikelythatthisriskisonlypresentinthosewithapredispositiontoGERDwhoalsohaveseveregastritisinthebodyorfundusthatimpairsacidsecretion,whichisreversedwithH.pylorithisislikelytobeuncommoninmostoftheUnitedStates(84).Hence,thisissuewhilemuchdiscussedshouldnotbemajorclinicalconcernwhencontemplatingtest-and-treat,unlessconvincingdatatothecontraryarise.ProgressionofH.pylorigastritismayoccuronacidsuppression,andsomehavesuggestedH.pylorieradicationshouldbeconsideredforallpatientsrequiringlong-termacidsuppression,whichseemsreasonable(85,86).Anunresolvedissueiswhethertest-and-treatwillwidentheproblemofcommunityacquiredantibioticresistance.PROMPTENDOSCOPYAdvantagesofPromptEndoscopyThereisempiricevidencefromamanagementtrialofpromptendoscopyinolderpatientsthatthisisthestrategyofÞrstchoice.Delaneyetal.aluatedthecost-effectivenessofaninitialendoscopycomparedwithusualmanagementinpa-tientswithdyspepsiaovertheageof50presentinginprimarycare(87).Atotalof422patientswererandomlyassignedtoeitherusualcareorinitialendoscopy;theinitialendoscopyarmshowedsigniÞcantimprovementinsymptomscoresandqualityoflifeaswellasa48%reductionintheuseofPPIs.Hence,initialendoscopyinolderpatientswithdyspepsiaatleastinthisU.K.studywaspotentiallycost-effectiveprovidedthecostofEGDwaslow.Thecost-effectivenessofendoscopyinolderpeopleintheU.S.settingneedsinvestigation.Thereisonlylimitedandunconvincingevidencethatendoscopyleadstoimprovedpatientsatisfactionscoresin 2328Talleyetal.reassuranceandeducation,withuseofover-the-counterantacids,H-blockers,orPPIsandreevaluationcanbecon-sidered,particularlyinprimarycare.Anotherstrategyworthconsideringisprescriptionofempiricalfull-doseorhigh-doseantisecretorytherapy,reservingfurtherevaluationforthosewhoareeitherunresponsiveorhaveanearlysymp-tomaticrelapseafterceasingmedication.Empiricantisecre-torytherapywasthebackboneoftheguidelineproposedbytheAmericanCollegeofPhysiciansandisstillwidelyap-pliedinpractice(44).AthirdapproachappliesH.pyloriand-treatastheinitialstrategy,currentlymostwidelyrec-ommendedaroundtheworld(54,55).Here,youngpatientswithoutalarmfeaturesaretestedforH.pyloriinfection.IfH.pyloriisdetected,empiricantibiotictherapyisprescribedinanattempttoeradicatetheinfection;H.pylori-negativepatientsaretreatedwithempiricantisecretorytherapyini-tially.AmodiÞcationoftheH.pyloritest-and-treatstrategyistoeitherprescribeempiricantisecretorytherapyÞrstandreserveH.pyloritestinglaterforfailures,orapplyempiricantisecretorytherapyafterH.pylorieradicationfailstore-lievesymptoms.AÞnalapproachistoperformpromptEGDforallpatientswithdyspepsia.Thebestoptionremainsun-derdebate,butnewdataareavailabletohelpguidearationalTEST-AND-TREATH.pyloriTheapplicationofatest-and-treatstrategyforH.pylorishouldbebasedonthepracticesetting(Fig.1).High-prevalencepopulationsintheUnitedStates(e.g.,recentimmigrantsfromdevelopingcountries)shouldundergotest-and-treatasthepreferablenonendoscopicstrategy.Conversely,incommunitieswheregastricoresophagealcancerhasahighincidence,promptendoscopyshouldbeconsideredearlybutthiswouldnotapplytomostofthecountry.Inlow-prevalencepopulations(e.g.,highsocioe-conomicareas,wherethebackgroundprevalenceofulcerorH.pyloriinfectionislow),analternativestrategyistoprescribeÞrstacourseofantisecretorytherapyempirically4Ð8wk.Ifthepatientfailstorespondorrelapsesrapidlyonstoppingantisecretorytherapy,thenthetest-and-treatstrategyisbestappliedbeforeconsiderationofreferralforEGD.EGDisnotmandatoryinthosewhoremainsymp-tomaticastheyieldislow;thedecisiontoendoscopeornotustbebasedonclinicaljudgement.Gradeofevidencefortest-and-treatoracidsuppr-ession:AGradeofevidenceforaH.pyloriprevalenceoflessthan10%inthelocalcommunityasthecutofffordecidingtouseempiricacidsuppressionratherthantest-and-treat:CTherationalefornoninvasiveH.pyloritestingistheiden-tiÞcationofunderlyingpepticulcerdisease.Forexample,inScotlandwheretheincidenceofpepticulcerishigh,McColletal.showedthatinpatientswithdyspepsiaandapositiveureabreathtesthadaduodenalulcer(DU)in40%andgastriculcer(GU)in13%;thosewhowerebreathtestnega-tivehadaDUin2%andGUin3%(56).Otherstudiessuggestthatbetween20%and60%ofpatientswithdyspepsiawhoH.pyloriinfectedwillhaveunderlyingpepticulcerdis-ease,butthisvarieswidelydependinguponthebackgroundincidenceofpepticulcer(57,58).Cost-effectivenessstud-iesintheUnitedStatessuggestthatwhentheprevalenceofH.pyloriinfectioninpatientswithfunctionaldyspepsiaislessthan12%orwhentheprevalenceofH.pyloriinpatientswithpepticulcerdiseaseislessthan48%,ini-tialempiricaltreatmentwithaPPIispreferable(59).OthershavesuggestedthatwhenH.pyloriinfectiondecreasesbelow20%,empiricPPItherapystartstodominatetest-and-treatinuninvestigateddyspepsia(60).est-and-TreatH.pyloriersusPlaceboinDyspepsiaintheCommunityTherearedataindicatingasmallbeneÞtfortreatingH.pyloriempiricallyinthosewiththeinfectioninthecommunity(nonpatients).InaU.K.communitytrial,32,929individu-alswereinvitedand8,455attendedandwereeligible;2,329erepositiveforH.pyloriandwereassignedactivetreatmentorplacebo,with1,773(76%)returningat2yr(61).Thereabsoluteriskreductionof5%forupperGIsymptomsonactivetherapyversusplacebo,althoughqualityoflifewasunchanged.PresumablymuchofthisbeneÞtisexplainedbythetreatmentofundiagnosedpepticulcerdisease.est-and-TreatH.pyloriersusUsualManagementofUninvestigatedDyspepsiainPrimaryCareetal.conductedarandomizedplacebo-controlledtrialin36familypracticesinCanada;theyrandomized294H.pylori-positivepatientstoomeprazoleplusantibioticsoromeprazoleplusplacebofor1wk,andthenarrangedfollow-upbyfamilyphysiciansforusualcare(62).Theyfounderadi-cationresultedinnoorminimalsymptomsin50%ofpatientscomparedto36%intheplacebo-therapyarmattheendof12months.ItisofinterestthatthisbeneÞtwasobserveddespiteincludingsomeGERDpatientsinthistrial.TheeradicationtherapyarmalsoreducedcostsbyCan$53perpatient.Al-etal.inastudyinprimarycareintheUnitedStatesobservednocostbeneÞtoftest-and-treatoverusualcareal-thoughsymptomsweresigniÞcantlyreducedinthetest-and-treatarm(63).AnunderpoweredU.S.studyfailedtodetectdifferencebetweentest-and-treatandusualcare(64).est-and-TreatH.pyloriersusPromptEGDinPrimaryandSecondaryCareThereisconsistentempiricevidencethatatest-and-treatstrat-leastequivalenttopromptendoscopyintermsofoutcomes.Lassenetal.randomized500patients(includingolderpatients)inprimarycarewithdyspepsiatoeithertest-and-treatorpromptendoscopy(65).Theyfoundthattherewerenodifferencesinsymptomaticoutcomesorqualityoflifebetweenthegroupsat1yr,althoughtheen-doscopygrouphadaslightlyhigherpatientsatisfactionscore GuidelinesfortheManagementofDyspepsia2327Newclinicaltestsofgastricfunctionareunderevaluation.Thewater-loadtestandnutrient-loadtestmayhelpidentifygastricdysfunctioninclinicalpractice(40,41).Theserep-resentsimpletestsoftheabilityofapatienttodrinkwateroranutrientloadsuchasEnsureuntiltheyfeelcompletelyfull.Dyspepsiapatientstoleratelowervolumesthancontrolsforexample,andhavemoresymptoms30minafterreach-ingsatiation.Hence,thisisastomachÒstresstestÓandcanobjectivelyquantifypostprandialdistress.However,normalcutoffsvarybylaboratory(asdotestprotocols),andtherateofgastricemptyingofthenutrientmealaswellasrelaxationofthefundussecondarytomealingestioncanpotentiallymodulatethetestresults.Somehavefoundthatthedrinktestscorrelatewithfundicdysaccommodationratherthanvisceralhypersensitivity(42).Othershavefailedtodemon-stratearelationshiptogastricdysfunctionwhilesomedatasuggestthesetestscorrelatewithpsychologicaldisturbances(40,41).Currently,patientswithgastroduodenalmotilitydis-turbances,gastroduodenalhypersensitivity,orotherpatho-physiologicalabnormalitiesofuncertainrelevancearenotxcludedfromthefunctionaldyspepsiaumbrella.SYMPTOMSANDSYMPTOMSUBGROUPSThereisconvincingevidencethatapatientssymptomscannotbeusedtoidentifystructuraldiseaseinuninvestigateddys-pepsia(15,43).Workingteamshavesuggestedsubdividingdyspepsiaintoulcer-likeordysmotility-likedyspepsiabasedonsymptompatternsorpredominance;itwaspostulatedthatsymptomsubgroupscouldidentifymorehomogenouspop-ulationsthatwouldrespondtotargetedmedicaltherapy(1,7).However,individualsymptoms,symptomsubgroups,andscoringsystemshaveallfailedtobeusefulinidentifyingun-derlyingpepticulcerdisease,ordistinguishingorganicfromfunctionaldyspepsia.AstudyfromCanadareportedthatthepatientÕsdominantsymptom(includingheartburn)failedtopredictendoscopicÞndingsinaprimarycarepopulation(15).Itisthuscontroversialwhethersubdividingdyspepsiaintosymptomsubgroupsaidsmanagementindocumentedfunc-tionaldyspepsia.ALARMFEATURESANDIDENTIFICATIONOFSTRUCTURALDISEASEINUNINVESTIGATEDDYSPEPSIATheriskofmalignancyincreaseswithageandthereforeempiricaltherapyisnotcurrentlyrecommendedinindivid-ualsover55yrofagewhodevelopnewdyspepticsymptoms.Gradeofevidence:CNew-onsetdyspepsiainolderageisanalarmfeatureorredßag.TheAmericanCollegeofPhysiciansin1985publishedguidelinerecommendingthatpatientswhowereovertheageof45deservedreferralforpromptendoscopytoruleoutunderlyingmalignancy,asgastriccancerisveryrareintheUnitedStatesbelowtheageof45yralthoughitincreasesthereafter(44).Somestudieshavereportedthatolderageisanindependentriskfactorforidentifyingunderlyingstructuralabnormalities,buttheresultshavebeeninconsistent(45,46).Theoptimalagethresholdforendoscopyisunclearbut55yr(ratherthan45yr)seemsareasonablecut-offbecausecancerisrareinyoungerpatientsintheUnitedStates,butnoagethresholdisabsolute(47).Severalotheralarmfeatureshavebeentraditionallyap-pliedtotryandidentifyseriousunderlyingdiseaseindyspep-sia,especiallymalignancy.Theseincludeunexplainedweightloss,anorexia,earlysatiety,vomiting,progressivedyspha-gia,odynophagia,bleeding,anemia,jaundice,anabdominalmass,lymphadenopathy,afamilyhistoryofuppergastroin-testinaltractcancer,orahistoryofpepticulcer,previousgastricsurgeryormalignancy.Uppergastrointestinalma-lignancyisrarelypresentinyoungpatientswithoutalarmfeatures,butthepositivepredictivevalueofalarmfeaturesremainsverypoor(47,48).Alonghistoryofsymptomsinpatientsshouldmakecancerunlikelybutasymptomdura-tionthresholdhasnotbeendeÞnedintheliterature.Useofantisecretorytherapycanmaskacanceratendoscopy(49)butdoesnotappeartoaltertheoutcome(50).AlthoughalarmsymptomsarenotspeciÞcforaseriousunderlyingdisorder,fewpatientsyoungerthan55yrofagewithanuppergastrointestinalmalignancypresentwithoutalarmsymptoms.Inpatientswithalarmfeatures,andinolder55yrofagewithnewsymptoms,promptEGDisconsideredthegoldstandardtoensurethatmalignancyhasnotbeenmissed.ThereareregionsintheUnitedStatesofhighcancerincidencewhereloweragethresholdsmayneedtobeconsideredsuchasAlaska(51).Onthebasisofexpertopinion,ifanEGDhasalreadybeendonerecently,repeatingthistestishighlyunlikelytoaltermanagement.Thepatientwhopresentswithnewonsetdyspepsiaorbe-causeofchronicsymptomsneedsanappropriate,evidence-basedclinicalevaluation.Thephysiciangenerallywishestoascertainthelikelycauseofthesymptomsandexcludeunder-yingseriousstructuraldisease.However,thepatientmayac-tuallybepresentingnotnecessarilybecauseofthesymptomspersebutbecauseofafearofseriousdiseaseorrecentpsy-chologicaldistress.Itisreasonablethatthephysicianidentifyandaddresssuchissuesasfearofcancerorunderlyingheartdiseaseinordertooptimizemanagement(52).Thepatientrequiringmajorreassuranceneedstobedif-ferentlymanagedthanonewhodoesnothavesuchconcerns,butfearofseriousdiseaseprobablyexplainsonlysomehealthcareseekingbehavior(53).Thephysicianalsoneedstode-cidewhetherpharmacologicaltherapyisrequired,includ-ingwhichdrugandforhowlong.Thisinturndependsontheunderlyingprovisionaldiagnosis,whichmayneedtobereÞnedafterthepatienthasinitiallyhadatrialoftherapy.MANAGEMENTOPTIONSINYOUNGERPATIENTSWITHNOALARMFEATURESnumberofmanagementoptionsareavailabletotheclin-icianinyoungerpatientswithnoalarmfeatureswithun-investigateddyspepsia.Await-and-seestrategyofpatient INTRODUCTION 2326Talleyetal. Dyspepsia (uninvestigated) �Age 55 or alarm features EGD alarm features HP prevalence PPI trial HP prevalence st and treatpylori st and treatH pylori PPI trial Consider EGD Consider EGD igure1.Algorithmforthemanagementofuninvestigatedsubjectshadpepticulceroresophagitis,although32%withesophagitiswereasymptomatic(14).Manypeoplewithdys-pepsiapresentingtoprimarycarehavenoobviouscausefortheirsymptomsbasedonEGD.ThemostcommonÞndinginNorthAmericaisprobablyesophagitis;inaCanadianstudyofuninvestigateddyspepsiainprimarycare,43%of1,040pa-tientshaderosiveesophagitisandonly5%apepticulcer,butthisstudydidincludepatientswithheartburn(15).Studiesfromopen-accessendoscopypracticesandoutpatientseriessupporttheviewthatonlyaminorityofpatientspresentingwithdyspepsiahavepepticulcerdiseaseorreßuxesophagi-tis,andgastriccancerisrelativelyrareinwesternpopulations(16,17).AdditionaldiagnostictestingoverandaboveEGDhasalowyieldindyspepsia,atleastinprimarycare.Studiesapply-ingabdominalultrasonographyindyspepsiahavereportedfewabnormalitiesasidefromasymptomaticcholelithiasisthatneedsnointervention(18,19).Endoscopicultrasonog-raphy(EUS)hasbeenreportedtohaveahigheryieldofidentifyingpancreatico-biliarypathologybutselectionbiasmayexplaintheobservationandmuchofthepathologyiden-tiÞedisofquestionablesigniÞcance(20,21).Twenty-fourhouresophagealpHtestingcanidentifypathologicalacidreßuxinapproximately20%ofpatientswithaclinicalandendoscopicdiagnosisoffunctionaldyspepsia(22Ð25).How-er,thesymptomcriteriausedtodeÞnefunctionaldyspep-siainthesestudieshavegenerallybeenbroaderthanrecom-mendedbytheRomeCommittees,andhencepatientswithtypicalreßuxsymptomscontaminatedthestudies.Klauserxtensivelyevaluatedagroupofpatientswithfunctionaldyspepsia;theyreportedthat47%hadabnormalÞndingsonadditionaltestingbutthesigniÞcanceofthevariousabnor-malitiesidentiÞed,includingminordelaysingastricempty-ingandlactoseintoleranceremainsquestionable(22).De-pendingonthebackgroundprevalenceofH.pylorithisin-fectionwillbeidentiÞedin20Ð60%ofpatientswithfunc-tionaldyspepsia,buttheclinicalrelevanceinmostcasesisuncertain;hence,thesepatientsarenotexcludedfromthefunctionaldyspepsiadiagnosiscategory(26).THOPHYSIOLOGICALDISTURBANCESINENDOSCOPY-NEGATIVE(FUNCTIONAL)DYSPEPSIAApproximately40%ofpatientswithfunctionaldyspepsiahavedelayedgastricemptying(27).However,itiscontrover-sialwhetheraspeciÞcsymptomproÞleisassociatedwithdelayedgastricemptying,andwhetherchangesingastricemptyingcanpredictsymptomimprovementinfunctionaldyspepsia.Stanghellinietal.in343ItalianpatientsreportedthatdelayedgastricemptyingwassigniÞcantlymorefrequentinpatientscharacterizedbyfemalesex,lowbodyweight,presenceofrelevantandseverepostprandialfullness,nausea,omiting,andabsenceofsevereepigastricpain;femalesex,relevantandseverepostprandialfullness,andseverevomitingereindependentlyassociatedwithdelayedgastricemptyingofsolids(28).Inaseparatestudyof483patients,thesameItaliangroupidentiÞeddistinctsubgroupsbasedonpredom-inantsymptomsandgastricemptying;onewascharacter-izedbypredominantepigastricpain,malegenderandnormalgastricemptying,andasecondbypredominantnonpainfulsymptoms,femalegender,andahighfrequencyofassoci-atedirritablebowelsyndromeanddelayedgastricemptying(29).Sarnellietal.alsoreportedthatdelayedgastricempty-ingwasassociatedwithpostprandialfullnessandvomiting(30).Otherstudies,however,havefailedtoidentifyadeÞnitesymptomproÞleassociatedwithdelayedgastricemptyingsuggestingthereisnotasimpleassociation(31).Moreover,videncethatagastricemptyingtestcost-effectivelyaltersmanagementisnotavailable.Thereisevidencethatthestomachandotherregionsofthegutincludingtheduodenumandesophagusarehyper-sensitivetodistentioninfunctionaldyspepsia,althoughthisappliesonlyinasubgroup(32Ð36).Tacketal.recentlyre-portedin160patientswithfunctionaldyspepsiathatonethirdhadgastrichypersensitivityandthisabnormalitywasassoci-atedwithincreasedpostprandialpainaswellasbelchingandeightloss,butconÞrmatorydataareneededonthesymptomassociations(35).Inabarostatstudy,Tacketal.studiedpatientswithfunc-tionaldyspepsia;impairedgastricaccommodationtoameal(aÒstifffundusÓ)wasfoundin40%,andthisabnormalityassociatedwithearlysatietyandweightlossbutnotwithypersensitivitytogastricdistention,presenceofH.pyloriordelayedgastricemptying(37).However,Boeckxstaensetal.ailedtoreplicatetheseÞndings;whilepostprandialsymptomsweremoreoftenevokedwithamealinfunctionaldyspepsia,therewasnoclearsymptomproÞlethatwasasso-ciatedwithafailureoffundicrelaxation(38).Noninvasivetestingisavailabletoassessabnormalfundicaccommoda-tionincludinggastricultrasound,SPECT,andMRI,buttheclinicalrelevanceofidentifyingthisabnormalityremainsinsomedisputeintermsofdeÞningtherapeuticinterventions GuidelinesfortheManagementofDyspepsia2325able1.LevelsofEvidence Level EvidencefromRCTswithlowfalsepositiverates(i.e.alues),adequatesamplesizes(lowlikelihoodoftypeIIerrors)andappropriatemethodology(lowlikelihoodoftypeIerrors)IIEvidencefromRCTswithhighfalsepositiverates,inadequatesamplesizes,orinappropriatemethodologyIIIEvidencefromnonrandomizedtrialsusingacontemporaneouscohortofcontrolsIVEvidencefromnonrandomizedtrialsusingahistoricalcohortofcontrolsEvidencefromcaseserieswithoutcontrols Note:AdaptedfromCookDetal.Chest1992;102:305S.includingearlysatiety,bloating,upperabdominalfullness,ornausea(1).However,bloatingismosttypicallyasymptomofIBSandmaynotbelocatedintheupperabdomenexclusively.Nauseacanbesecondarytoavarietyofnonabdominalcon-ditions.Hence,neitherbloatingnornauseaaloneshouldbeconsideredtoidentifydyspepsia.BelchingaloneisalsoaninsufÞcientsymptomtoidentifydyspepsiaandcanbesec-ondarytoairswallowing,althoughitiscommonlypresentwithepigastricpainordiscomfort.Acuteself-limiteddys-pepsiagenerallyrequiresnoinvestigationandwillnotbefurtherconsideredhereinthesemanagementguidelines.EPIDEMIOLOGYOFDYSPEPSIAItisestablishedthatdyspepsiaisacommonproblemworld-wide.IntheUnitedStates,thepointprevalenceisapproxi-mately25%,excludingthosepeoplewhohavetypicalGERDsymptoms(7).Theprevalenceislowerifpatientswithanysymptomsofheartburnandregurgitationareexcluded(8).Theincidenceismorepoorlydocumented.IntheUnitedStates,approximately9%ofpeoplewhohadnosymptomsofdyspepsiaanuallyintheprioryearreportednewsymptomsonfollow-up;however,thosewithapasthistoryofdyspepsiaorpepticulcerwerenotexcludedandhencetheonset-ratemaybeexaggerated(9).InScandinavia,anincidencerateoflessthan1%over3monthshasbeenreported(10).Whatevertheincidence,thenumberofsubjectswhodevelopdyspepsiaismatchedbyasimilarnumberofsubjectswholosetheirable2.GradedRecommendationsforClinicalPractice GradeStrengthofEvidencetoGuideClinicalPractice SupportedbytwoormorelevelIstudieswithoutconßictingevidencefromotherlevelIstudiesSupportedbytwoormorelevelIstudieswithconßictingvidencefromotherlevelIstudiesorsupportedbyonlyonelevelIortwoormorelevelIIstudiesSupportedbylevelIIIÐVevidence Note:AdaptedfromGuyattGHetal.AMA1995;274:1800Ð1804;UsersGuidestotheMedicalLiterature,JAMAPress2001;andCookDetal.Chest1992;102:305S.symptoms,explainingtheobservationthattheprevalencere-mainsstable.NATURALHISTORYANDCOSTSOFDYSPEPSIADyspepsiaisusuallyachronicconditioninprimaryandsec-ondarycare.ThecostsintheUnitedStatesremainpoorlydoc-umented,butinSwedenatotalsocietalcostof$63peradultcalculatedfordyspepsia(includingreßuxdisease)(11).Inanotherstudy,288adultprimarycarepatientswithdys-pepsiawerefollowedupfor1yr;dyspepsiapatientstendedtoremainsymptomaticwith61%usingdrugsand43%hav-inggastrointestinalprocedures,indicatingintensiveuseofmedicalresources(12).DIAGNOSTICTESTINGDyspepticpatientsmorethan55yrold,orthosewithalarmfeatures(bleeding,anemia,earlysatiety,unexplainedeightloss(10%bodyweight),progressivedysphagia,odynophagia,persistentvomiting,afamilyhistoryofgas-trointestinalcancer,previousesophastricmalignancy,previousdocumentedpepticulcer,lymphadenopathy,oranabdominalmass)shouldundergopromptendoscopytoruleoutpepticulcerdisease,esophastricmalignancy,andotherrareuppergastrointestinaltractdisease.Inpatientsaged55yroryoungerwithnoalarmfeatures,theclinicianmayconsidertwoapproximatelyequivalentmanagementoptions:(i)testandtreatforH.pyloriusingalidatednoninvasivetestandatrialofacidsuppressioniferadicationissuccessfulbutsymptomsdonotresolveor(ii)anempirictrialofacidsuppressionwithaprotonpumpinhibitor(PPI)for4Ð8wk.Thetest-and-treatoptionispreferableinpopulationswithamoderatetohighpreva-lenceofH.pyloriinfection(10%),whereastheempiricalPPIstrategyispreferableinlowprevalencesituations.Someanxiouspatientsmayneedthereassuranceaf-dedbyendoscopy.Ontheotherhand,repeatEGDisnotrecommendedonceaÞrmdiagnosisoffunctionaldys-pepsiahasbeenmade,unlesscompletelynewsymptomsoralarmfeaturesdevelop.RepeatEGDisotherwiseunlikelytoeverbecost-effective.Gradesofevidence:Earlyendoscopyforalarmsymptoms:Cest-and-treatstrategyforH.pylori:AAcidsuppressiontherapy:AReassuranceafterendoscopy:Cfewstudieshaveinvestigateddyspepsiasubjectsfromthecommunitybyesophagogastroduodenoscopy(EGD)andothertests,todeterminetheunderlyingcausesofthesymp-toms.Inapopulation-basedstudyfromnorthernNorway,amongstthosewithepigastricpainonly9%hadapepticulcerand14%hadreßuxesophagitis,buthowmanyhaden-doscopynegativereßuxdiseaseisuncertain(13).Inacom-parablestudyfromnorthernSweden,asimilarproportionof Dyspepsiaisachronicorrecurrentpainordiscomfortcenteredintheupperabdomen;patientswithpredominantorfrequent(morethanonceaweek)heartburnoracidregurgitation,shouldbeconsideredtohavegastroesophagealreßuxdisease(GERD)untilprovenotherwise.Dyspepticpatientsover55yrofage,orthosewithalarmfeaturesshouldundergopromptesophagogastroduodenoscopy(EGD).Inallotherpatients,therearetwo