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Overviewofthenaturalhistoryandtreatmentofpepticulcerdisease

Officialreprintfrom UpToDate
www.uptodate.com 2015UpToDate

Overviewofthenaturalhistoryandtreatmentofpepticulcerdisease
Authors
AndrewHSoll,MD
NimishBVakil,MD,AGAF,
FACP,FACG,FASGE

SectionEditor
MarkFeldman,MD,MACP,
AGAF,FACG

DeputyEditor
ShilpaGrover,MD,MPH

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Jan2015.|Thistopiclastupdated:Dec02,2013.
INTRODUCTIONPepticulcerdisease(PUD)isacommonproblem.Thenaturalhistoryandanoverviewofthe
treatmentofpepticulcerdiseasewillbereviewedhere.IssuesrelatedtothetreatmentofHelicobacterpylori
infection,treatmentofcomplicationsofpepticulcerdisease,andtheroleofsurgeryarediscussedseparately.(See
"ManagementofduodenalulcersinpatientsinfectedwithHelicobacterpylori"and"Treatmentregimensfor
Helicobacterpylori"and"Overviewofthecomplicationsofpepticulcerdisease"and"Surgicalmanagementof
pepticulcerdisease".)
NATURALHISTORYDatafromthepreH.pylori,preprotonpumpinhibitor(PPI)eraprovideimportantto
insightsintothenaturalhistoryofPUD.Untreated,pepticulcershaveawidelyvariablenaturalhistory[17].Some
healspontaneously,butrecurwithinmonthsorsometimeswithinayearortwo.Anillustrativereportdescribed
patientswhowerefollowedfor12monthsafterdocumentedhealingofduodenalulcers.Relapseoccurredin74
percentofcases33percenthadonerecurrence,24percenttworecurrences,and17percentexperiencedthreeor
morerecurrences[1].Otherreportshaveconfirmeda50to80percentrecurrencerateduringthe6to12months
followinginitialulcerhealing,althoughrelapsesarenotalwayssymptomatic[2,3].
Otherulcerscausecomplicationsorremainrefractorydespiteantisecretorytherapy.Thepatient'spriorulcer
historytendstopredictfuturebehaviorthosewithahistoryofcomplicationshaveanincreasedriskoffuture
complications.Ulcersthattakelongertohealinitiallyaremorelikelytorecurrapidlyandulcersthathaverecurred
frequentlyarelikelytocontinuetodoso,unlesstheunderlyingcause(eg,H.pyloriornonsteroidalanti
inflammatorydrugs[NSAIDs])isremoved.Alongdurationofsymptomspriortopresentationismorelikelytobe
associatedwithapoorresponsetomedicaltherapy.(See"Refractoryorrecurrentpepticulcerdisease".)
Distalantralulcers,especiallyprepyloriculcers(within2to3cmofthepylorus),mayhaveadifferentpatternof
healingthanulcersatorproximaltotheincisurabecauseofdifferentlevelsofacidsecretionandthedistributionof
gastritis[8].Manystudiesdidnotanalyzegastriculcersbylocation,andavailabledataareconflicting.
Nevertheless,prepyloriculcersappeartohealmoreslowlyandmaybemorelikelytorecur[9,10].
TreatmentofH.pyloriininfectedindividualsdramaticallyalterstheincidenceofulcerrelapse[11,12].Inameta
analysisthatincluded14studies,duodenalulcersrecurredinfewerthan10percentofpatientssuccessfullytreated
forH.pyloricomparedwith65to95percentofthosewhoremainedinfected[11].However,newerdatafromthe
UnitedStatessuggestthatrecurrencesaftersuccessfulH.pyloriantibiotictreatmentmaybemorefrequent[13].
Bycontrast,relapseistheruleintheabsenceofsuccessfulantiH.pyloritherapy.(See"Managementofduodenal
ulcersinpatientsinfectedwithHelicobacterpylori".)
Whenthecauseoftheulcercannotbeidentifiedorremoved(eg,continuedNSAIDuse,ornonH.pylori,non
NSAIDulcers),recurrencesarefrequent[14].(See"Refractoryorrecurrentpepticulcerdisease"and"Unusual
causesofpepticulcerdisease".)
TREATMENT
GeneralapproachThefollowingpointsshouldbeconsideredwhentreatingpepticulcerdisease(PUD):
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AllpatientswithPUDshouldreceiveantisecretorytherapy.InpatientswithuncomplicatedH.pyloriulcers,
theprotonpumpinhibitor(PPI)givenalongwiththeantibioticregimenisusuallyadequatetoinducehealing.
(See'AntisecretorytherapyafterH.pylorieradication'below.)
PatientswithPUDshouldbetestedforH.pylori,keepinginmindthatPPIs,bismuth,manyantibiotics,as
wellasupperGIbleeding,mayleadtofalsenegativetestresults.Inthefaceofaknownulcer(highpretest
prevalence),H.pyloriisonlyconfidentlyexcludediftwoappropriatelyperformedtestsarenegative,withno
exposuretotheabovementionedfoursuppressivefactorsinthetwoweeksbeforetesting.(See"Indications
anddiagnostictestsforHelicobacterpyloriinfection".)
PatientswithH.pylorishouldbetreatedwithagoalofH.pylorieradication.(See"Treatmentregimensfor
Helicobacterpylori".)
Antisecretorytherapyisthemainstayoftherapyinuninfectedpatients,andisappropriateformaintenance
therapyinselectedcases.
Itisessentialtowithdrawpotentialoffendingorcontributingagentssuchasnonsteroidalantiinflammatory
drugs(NSAIDs),cigarettes,andexcessalcohol.(See"Pepticulcerdisease:Genetic,environmental,and
psychologicalriskfactorsandpathogenesis".)
InnonH.pylori,nonNSAIDulcers,everyeffortshouldbemadetoaddressothercontributingfactorswhenever
possible,suchastreatingmedicalcomorbidities,poornutritionalstatus,ischemia,andacidhypersecretion
(table1andtable2andtable3).(See"Unusualcausesofpepticulcerdisease".)
Thereisnoevidencethataddressingstressfulpsychosocialsituationsandpsychologicalcomorbiditybenefits
treatmentoutcomesinfact,oneolderstudysuggestedthatcognitivepsychotherapyincreasedrelapserates
[15].Ontheotherhand,itisimportanttokeepinmindthatpatientswithactivepsychosocialissuesmaybe
predisposedtorecurrenceorpersistenceofsymptomsandulcers.Epidemiologicstudiesshowanincreasein
theincidenceofpepticulcerdiseaseaftereventsthatcausepsychologicaltrauma(eg,terroristattacks,
naturaldisasters).Furthermore,psychosocialissuesshouldbeaddressedsincetheycanhaveother
deleterioushealthconsequences.(See"Pepticulcerdisease:Genetic,environmental,andpsychologicalrisk
factorsandpathogenesis".)
Nofirmdietaryrecommendationsarenecessary,thoughpatientsshouldavoidanyfoodsthatprecipitate
symptoms.(See"Pepticulcerdisease:Genetic,environmental,andpsychologicalriskfactorsand
pathogenesis".)
EradicationofH.pyloriAllpatientswithpepticulcerswhoareinfectedwithH.pylorishouldundergotherapy
toeradicatetheorganism[16,17].ThisrecommendationisbaseduponoverwhelmingdataindicatingthatH.pylori
eradicationreducesulcerrecurrence[12,18].(See"TreatmentregimensforHelicobacterpylori"and"Association
betweenHelicobacterpyloriinfectionandduodenalulcer"and"Managementofduodenalulcersinpatientsinfected
withHelicobacterpylori".)
InsettingswheretheprevalenceofH.pyloriinduodenalulcersisgreaterthan90percent[19,20],empirictherapy
fortheinfectionisreasonableforuncomplicatedcasesintheabsenceofNSAIDuse[21].However,inmostareas
inthewesternworldwheretheprevalenceofH.pyloriinduodenalulcersisconsiderablylessthan90percent
[13,18],documentinginfectionisanessentialsteppriortoinitiatingantimicrobialtherapy.ThepresenceofH.pylori
shouldalwaysbeconfirmedinpatientswithgastriculcerspriortoinitiatingantibacterialtherapyatleast30percent
ofsuchpatientswillnotbeinfected[22].(See"IndicationsanddiagnostictestsforHelicobacterpyloriinfection"
and"Unusualcausesofpepticulcerdisease".)
Inmostregions,thelargemajorityofcomplicatedulcersareduetoH.pyloriorNSAIDuse[23].Theprevalenceof
H.pyloriinpatientswithcomplicatedpepticulceration(eg,bleedingandperforation)wasinitiallyreportedtobe
somewhatlowerthanthatseeninpatientswithuncomplicateddisease[24,25].However,someoftheapparent
differenceisduetoreducedsensitivityfordetectionofH.pyloriinthefaceofactivebleeding[26,27].(See"Overview
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ofthecomplicationsofpepticulcerdisease"and"NSAIDs(includingaspirin):Secondarypreventionof
gastroduodenaltoxicity".)
TreatmentofH.pyloriinpatientsonNSAIDsTherelationshipbetweenH.pyloriandNSAIDsis
controversialandcomplexandmayberelatedtowhetherthepatientisanew("nave")orachronicuserofNSAIDs
[28,29].InnaveNSAIDusers,H.pyloriappearstobeasignificantriskfactorforcomplicatedulcers[29,30].
Furthermore,thereappearstobeabenefitfromscreeningnaveNSAIDusersatthestartoftherapyforH.pylori
anderadicatingtheorganismbeforestartingNSAIDtreatment[28,29].Bycontrast,withestablishedNSAIDusers
whopresentwithulcercomplicationsandevidenceofH.pyloriinfection,eradicatingH.pyloriinfectiondoesnot
appeartoreducethehighriskofulcercomplicationsifNSAIDsarecontinued[29].
EradicatingH.pyloriinfectionmayalsolowertheriskofulcerrecurrenceinpatientsonlowdoseaspirin[31].
However,treatmentofsuchpatientswithaPPIinadditiontotheeradicationofH.pyloricansignificantlyreducethe
riskofrecurrentulcercomplications[32].
Thus,theavailabledatasupportH.pyloritestingandtreatmentpriortostartingNSAIDs.Itisappropriatetolookfor
H.pylorianderadicateitfollowingpresentationofanyclinicalulcer.However,ifpatientsaregoingtocontinue
NSAIDsoraspirin,theymustbetreatedwitharegimenthatreducestheriskoffurtherulcercomplications,suchas
PPIs.(See"NSAIDs(includingaspirin):Secondarypreventionofgastroduodenaltoxicity".)
AntisecretorytherapyafterH.pylorieradicationPatientswithuncomplicated,small(<1cm)duodenal
ulcersorgastriculcerswhohavereceivedadequatetreatmentforH.pyloriprobablydonotneedanyfurthertherapy
directedatulcerhealing,aslongastheyareasymptomaticfollowingtherapy[2].Thisrecommendationisbased
upondataindicatingthateradicationofH.pyloriwithoutconcurrentacidsuppressiontherapyhealsmostduodenal
ulcersandgastriculcers[33,34].Thiswasillustratedinatrialwith81patientswithanendoscopicallydiagnosed
duodenalulcerwhowererandomizedtoeitherplacebooranantiH.pyloriregimen(300mgmetronidazole,500mg
amoxicillin,and250mgclarithromycin,eachgivenfourtimesdailyfortwoweeks)[33].Patientinbothgroupswere
givenantacidsforsymptomcontrol.Treatmentwithantibioticsresultedinhigherulcerhealingratescomparedwith
placeboatfour(93versus37percentwithplacebo)andeightweeks(100versus63percent).
TherearenofirmguidelinesregardingthecontinuationofantisecretorymedicationafterH.pylorieradicationin
patientswhohadcomplicationsduetoPUD.ThereisevidencesuggestingthateliminationofH.pylorialoneis
sufficient[23,35]However,thisonlyappliestocompliantpatientswithconfirmedH.pylorieradication,inthe
absenceofcontinuedNSAIDuse.Inaddition,treatmentwithH.pylorieradicationaloneshouldonlybeconsidered
forpatientswithsmallormoderatesizeulcersthatcanbeexpectedtohealrapidly.
TwoconsensuspanelshaverecommendedmaintenanceacidsuppressionfollowingH.pylorieradicationinpatients
withcomplicatedduodenalulcers[36,37].
Patientswithoutcomplicatedulcerswhohaveothermarkersofincreasedrisk(suchasgiantulcers>2cm,densely
fibrosedulcerbeds,oraprotractedpriorhistory)alsowarranttreatmentwithantisecretoryagents,atleastuntil
bothcureofH.pyloriinfectionandulcerhealinghavebeenconfirmed.Prolongedantisecretorytherapycancertainly
bejustifiedinpatientswhoareconsideredtobeathighrisk,sincenostudieshavehadthepowertodefinethe
optimalmanagementinthesepatients.Patientswithintermediatesizedulcers(1to2cm)areprobablyatsome
increasedriskforslowhealing,asnotedpreviously.
Someriskofrecurrenceorexacerbationmaybeduetothereboundacidhypersecretionthataccompanies
discontinuationofpotentantisecretoryagents,especiallyafteraprolongedcourseoftreatment[38,39].Although
themagnitudevariesandtheclinicalsignificancehasnotbeenfirmlyestablished,taperingthePPIandthen
steppingdowntoanH2receptorantagonist(H2RA)fortwotothreemonthsdeservesconsiderationinhighrisk
patients.
InitialapproachtoulcersnotduetoH.pyloriCommoncausesofH.pylorinegativeulcersarefalsenegative
testingforH.pyloriandundiscoveredconsumptionofNSAIDs.However,somepatientswillhaveulcersthatarenot
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relatedtoH.pyloriorNSAIDS(table1andtable2andtable3).(See"Unusualcausesofpepticulcerdisease".)
ConfirmH.pylorinegativityInthefaceofaknownpepticulcer,asinglepositivetest(invasiveor
noninvasive)issufficienttodiagnoseH.pyloriinfection.However,withaknownulcerasinglenegativetestisnot
sufficienttoexcludeit,soadditionalH.pyloritestingisnecessaryinpatientswithPUDandnegativeH.pylori
testing.(See"IndicationsanddiagnostictestsforHelicobacterpyloriinfection".)
Forexample,intheUnitedStatesandpartsofEurope,theprevalenceofH.pyloriinpatientswithduodenalulcers
isintherangeof50to75percent.Assumingaprevalenceof75percent,anH.pyloritestwithsensitivityand
specificityof90percentwouldhaveanegativepredictivevalue(NPV)of75percent(ie,25percentofnegative
resultswouldbefalsenegatives).(See"AssociationbetweenHelicobacterpyloriinfectionandduodenalulcer",
sectionon'IncidenceofH.pyloriinpatientswithduodenalulcer'.)
ThepretestprobabilityofH.pyloriinpatientswithgastriculcersis60to80percent,soasinglenegativetestforH.
pylorihasaboutan80percentNPV(ie,20percentofnegativeresultswouldbefalsenegatives).Inpatientswith
gastriculcers,multiplebiopsiesoftheulcermarginaregenerallyindicatedtoexcludemalignancy.Inaddition,at
leastthreebiopsiesoftheantrumarejustifiedforureasetestingforH.pylori,and,ifnegative,histology.The
absenceofinflammationprovidessolidevidenceforthetrueabsenceofH.pylori.
IfagastriculcerwerediscoveredonradiographyorfoundatendoscopybutH.pyloristatuswasnotdetermined,
noninvasivetestingforH.pyloriisappropriate.However,ifadequatebiopsiesofagastriculcerwerenotobtained,
endoscopyisindicatedtoexcludemalignancy.(See'Antisecretorytherapy'below.)
AntisecretorytherapyAntisecretorytherapyiswarrantedinpatientswithPUDwhoaretrulynotinfected
withH.pylori.ProtonpumpinhibitorsaremoreeffectivethanH2RAs.
Althoughtherearedifferencesbetweentherapies,theyareoflittleclinicalimportanceinuncomplicatedulcers
costhasbecomeanimportantfactorinchoosingatherapeuticregimen.Combiningconventionalantiulceragents
(eg,PPIsandH2RAs)addstocostwithoutenhancinghealingandisnotrecommendedtakingtheseclassesof
agentsatthesametimemayactuallyattenuatePPIaction.(See"Pharmacologyofantiulcermedications".)
Studiesofthevariousagentsusedtotreatulcershaveshownthefollowing:
AllfourH2receptorantagonists(cimetidine,ranitidine,famotidine,andnizatidine)areassociatedwithhealing
ratesof70to80percentforduodenalulcersafterfourweeks,and87to94percentaftereightweeksof
therapy[6].Splitdose,evening,andnighttimetherapyarealleffective.Cimetidine,ranitidine,andfamotidine
areapprovedforgastriculcerhealingintheUnitedStates[5].
Protonpumpinhibitors,includingomeprazole,esomeprazole,lansoprazole,dexlansoprazole,pantoprazole,
andrabeprazole,areeffectiveininducingulcerhealing[4043].Dailydosesofomeprazolefrom20to40mg
producedduodenalulcerhealingratesof63to93percentattwoweeks,andof80to100percentatfour
weeks.Omeprazole(20mgdaily)producesmorerapidhealingthanstandarddosesofH2RAsinmost,but
notallstudies.Combiningdatafromeighttrialscomparing20mgofomeprazoleto300mgofranitidine,
omeprazolehada14percentadvantageattwoweeksanda9percentadvantageatfourweeks[41].Thus,
omeprazolehealsduodenalulcersmorerapidlythanstandarddosesofH2RAs,buttheadvantageafterfour
weeksoftherapyissmall.
Omeprazoleatdosesof20to40mgdailyproducesnumericallygreatergastriculcerhealingthanH2RAs,but
therateofearlyhealingofgastriculcersisnotacceleratedbyomeprazoletothesameextentasthatfound
withduodenalulcers[41].
Althoughantacids[44]andsucralfate[45]areingeneralsuperiortoplaceboinhealingduodenalulcers,
efficacyhasnotbeenestablishedforgastriculcersorforeitherNSAIDulcersornonH.pylori,nonNSAID
ulcers.
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Misoprostolenhancesduodenalulcerhealingcomparedwithplaceboatdosesof400to800mcgdaily
[45,46].However,prostaglandinanalogshavenoadvantageoverantisecretoryagentsforulcerhealingandare
notindicatedforthispurpose.
Antisecretorydrugscanbediscontinuedafterfourtosixweeksinpatientswithuncomplicatedulcerswhoare
asymptomatic.Althoughsomeprogressivehealingoccurswithlongertreatmentperiods,theadvantagesrelativeto
furtherincreasingtreatmentcostsinpatientswhoareasymptomaticanduncomplicatedaredebatable.Some
patientsareatincreasedriskforrecurrence,especiallythoseinwhomtheunderlyingcauseoftheulcercannotbe
reversed.Suchpatientsmaybenefitfrommaintenancetherapywithanantisecretorydrug.(See'Maintenance
therapy'below.)
GiantulcersMedicalmanagementofgiantulcersismoredifficultthanordinaryulcers,althoughno
controlledtrialshaveaddressedthetreatmentofgiantulcersorcomparedoptions.Aswithotherpepticulcers,the
roleofNSAIDsandH.pylorimustbeassessed.TherapeuticresponsestoH2RAsoccur,butslowhealingand
recurrences,evenonmaintenanceorfulldosetherapy,arecommon[4749].
Protonpumpinhibitorsarethedrugsofchoiceforgiantpepticulcers.Twelveweeksoftherapyiseffectiveinthe
majorityofcases.Patientsshouldbereevaluatedendoscopicallyafteracourseofmedicaltherapytoensure
healingandbecausethereisa10percentincidenceofmalignancywithgiantgastriculcers.
FOLLOWUPAFTERINITIALTHERAPYFORPEPTICULCER
DuodenalulcersPatientswithuncomplicatedduodenalulcerswhohavebeentreateddonotneedfurther
endoscopyorradiographyunlesssymptomspersistorrecur.However,patientswithgiantduodenalulcersshould
undergorepeatendoscopytoconfirmhealing.ThenecessityforfollowuptestingofH.pyloriisdiscussed
separately.(See"IndicationsanddiagnostictestsforHelicobacterpyloriinfection".)
GastriculcersTherearenoprospectiveoutcomedataandnoclearconsensustoguidemanagementwith
respecttoappropriatefollowupinpatientswithgastriculcersandtheliteratureisfilledwithdivergentviewsand
recommendations.Repeatendoscopywithbiopsyhasbeenadvocatedtoconfirmgastriculcerhealingasameans
ofensuringthatthelesionsarebenign.However,withthedecreasingincidenceofgastriccancerindeveloped
countries,theincreaseduseofnonsteroidalantiinflammatorydrugs(NSAIDs),andtheconcernoverthecostsof
care,thispracticestandardhasbeenquestioned.
Overall,theriskoffindinggastriccanceronfollowupendoscopyofanapparentlybenigngastriculcervariesfrom
about0.8to4.3percent.However,ifanexperiencedendoscopistjudgesthegastriculcertobebenignandifinitial
biopsiesareadequateandnegativeformalignancyanddysplasia,theyieldoffollowupstudiesislowandthe
costofeverycancerdiscoveredwillbehigh.Manycasesofcarcinomamasqueradingasbenignulcersoccur
becausebiopsieswereinadequateordysplasiaorneoplasiawasmissedintheinitialbiopsy[50,51].(See
"Diagnosisofpepticulcerdisease".)
Itmustbeemphasizedthatan"adequate"approachistoobtainatleastfourjumbobiopsiesfromtheulcermargin
orsevenregularbiopsiesandonefromthebase,iftheulcerisnottoodeep.Thesebiopsiesmustcontainadequate
tissueforthepathologistmanybiopsiestakenevenbyexperiencedendoscopistscontainonlymucusorblood,
whichofcoursedonotruleoutmalignancy.
Intheabsenceofguidingdataorconsensus,thereisawiderangeofstandardpractice.Ourapproachistonot
repeatanupperendoscopyonpatientswithbenignappearinggastriculcersthathavebeenadequatelybiopsied
withnoevidenceofmalignancyordysplasiaonbiopsies.Inpatientsathighriskformalignancyweperformafollow
upendoscopy(withbiopsiesoftheulcerifstillpresent)aftersixweeksoftherapy.Highriskgastriculcersinclude
thefollowing:
Occurrenceinethnicgroupsraisedinendemicareas(eg,Asians,Latinos),orafamilyhistoryofgastric
cancer
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TheabsenceofrecentNSAIDuse
ThepresenceofH.pylori,particularlyifassociatedwithgastricatrophy
Agegreaterthan50years
Theabsenceofeitheraconcomitantduodenalulcerorapriorhistoryofduodenalulcer(duodenalulcers
requirehigheracidsecretion,whichisincompatiblewiththepangastritistypicalofmostgastriccancers)
Giantulcers(>2to3cm)
Theabsenceofaprotractedulcerhistory.Althoughtherewillbeexceptions,thelongertheulcerhistory,the
lowertheriskthatagastriculceriscancer.Gastriculcersrequireacidandgastriccancerusuallydevelopsin
thesettingofatrophicpangastritis.
MAINTENANCETHERAPYMaintenancetherapyshouldbeconsideredtopreventrecurrenceinhighrisk
subgroups,definedbyahistoryofcomplications,frequentrecurrences,orrefractory,giant,orseverelyfibrosed
ulcers.InsuchpatientswhoarealsoinfectedwithH.pylori,maintenancetherapyshouldbecontinuedatleastuntil
cureoftheinfectionhasbeenconfirmed,andpossiblylonger.Longtermmaintenancetherapyisindicatedinhigh
riskpatientswhofailH.pylorieradicationorwhohaveH.pylorinegativeulcers.
DuodenalulcersMaintenanceantisecretorytherapyiseffectiveinreducingduodenalulcerrecurrencesand
complications[52].Typicalrecurrenceratesare20to25percentovera12monthperiodinpatientswhotakeH2
receptorantagonists(H2RAs)versus60to90percentforplacebo.
Protonpumpinhibitors(PPIs)alsopreventduodenalulcerrecurrencesifusedinadequatedoses.Theantisecretory
responsetolowdosesofomeprazole(5to20mg)isvariablesomepatientsshowminimalresponse,whileothers
experiencemarkedsecretoryinhibition.Onestudyfoundthata20mgdosetakenthreedaysperweekreduced
recurrencesto23percentatsixmonthscomparedwith67percentforplacebo[53].Wegenerallysuggestthat
PPIsbeusedformaintenanceonlywhenH2RAshavefailedorwhendealingwithalarge,severelyfibrosedor
refractoryulcerorahistoryofulcercomplications.ThereasonforstilladvisinguseofH2RAs,ifeffective,isthat
costswillbelowerandH2RAswillhavefewerconsequencesrelatedtoprolongedacidinhibitionthanPPIs.IfaPPI
isnecessary,thelowesteffectivedoseofPPIshouldbeused,suchas20mgdailyofomeprazole(oranequivalent
doseofanotherPPI).Althoughthesupportingdataremainlimited,adverseeffectsofprolongedPPIuse,suchas
decreasedcalciumabsorptionandincreasedriskofbonefracturesandcertaininfections(eg,C.difficile),and
hypomagnesemiaareaconsideration[54].(See"Overviewandcomparisonoftheprotonpumpinhibitorsforthe
treatmentofacidrelateddisorders",sectionon'Safety'.)
GastriculcersThelargemajorityofdataforrecurrenceareavailableforduodenalulcers.However,thepattern
withgastriculcersappearscomparable.Thehighestriskofrecurrenceoccursinthefirstthreetosixmonthsof
maintenancetherapy[52,55].Antisecretorytherapyappearstoremaineffectiveformorethanfiveyearsrecurrence
ratesafterthistimeperiodarelowerthaninthefirstyearoftherapy[47,49].Patientsfollowedfortheseprolonged
periodsonH2receptorantagonistsincludemanyindividualswithahistoryofcomplicationsorthoseinitially
referredforulcersurgery.Approximatelythreequartersofthesepatientsdidwellclinicallyonmaintenancedosesin
onereport:onequarterremainedasymptomaticandulcerfree,andonehalfhadoneormorerelapsesthat
respondedtofulldoseH2receptorantagonisttherapy[56].
Ifmaintenancetherapyisstoppedafteroneyear,ulcerrecurrenceissimilartothatforpatientsplacedonplacebo
afterinitialulcerhealing[57].Thereisdebateastowhetherrecurrenceratessubsequentlydropafterprolonged
medicaltherapy[52,56].However,thesedataaredrawnfromalargelyH.pyloripositivepatientpopulation,which
maynotbepredictiveoftreatmentofnonH.pylori,nonNSAIDulcers.
Therearenodatafromcontrolledtrialsregardingtheappropriatedurationofmaintenancetherapy.Wesuggestthat
thelengthoftherapyvarywiththeindication.Foruncomplicatedrecurrentdisease,stoppingtherapyaftertwoyears
isreasonable,whileafiveyearcoursemaybemoreappropriateforcomplicateddisease.Ifthecausalfactorcanbe
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confidentlyreversed(eg,H.pyloriinfectioneradicatedorNSAIDsdiscontinued),thenrequirementsformaintenance
aremarkedlyreduced[35].
DISCONTINUINGPPIsReboundacidhypersecretionisanimportantconsiderationfollowingabruptcessationof
prolongedtreatmentwithprotonpumpinhibitors(PPIs).Asaresult,treatmentshouldbetaperedfollowing
prolongedorhigherdosetreatmentwithaPPI.(See"Overviewandcomparisonoftheprotonpumpinhibitorsforthe
treatmentofacidrelateddisorders",sectionon'Discontinuingprotonpumpinhibitors'.)
TREATMENTDURINGPREGNANCYANDLACTATIONWhenpepticulcerdiseaseisdiagnosedinawoman
whoispregnant,thefocusoftreatmentistypicallyacidsuppression[58].AllofthePPIsareconsideredlowriskin
pregnancy,whereasmisoprostoliscontraindicatedinpregnancyasitcanprecipitateabortion.Although
confirmationisrequired,alargeSwedishstudyassociatedgastricacidsuppressors(H2receptorantagonists,
PPIs,prostaglandins,combinationsforH.pylorieradication,anddrugsforpepticulcerandgastroesophagealreflux
disease[GERD])withasignificant,butlow,absoluteriskofallergicdiseaseandasthmainchildrenexposedin
utero[59].Theoddsratiosforallergyandasthmawere1.43and1.51,respectively.
IfH.pyloriispresent,treatmentistypicallydeferreduntilafterdelivery.However,withtheexceptionofbismuthand
tetracycline,theothermedicationsusedforH.pylorieradicationarelowriskinpregnancy,especiallyafter14
weeks.Thisincludesclarithromycin,amoxicillin,andprobablymetronidazole.Moreover,thereissomeevidence
thatH.pyloricancauseseverenausea/vomitinginpregnancy,includinghyperemesisgravidarum[60,61].Thus,if
indicated,H.pyloritreatmentshouldbeconsideredinpregnancy.Inaddition,someofthemedicationstypically
usedforthetreatmentofH.pyloriareconsideredpossiblyunsafefornursinginfants(eg,bismuth,metronidazole).
(See"Medicalmanagementofgastroesophagealrefluxdiseaseinadults",sectionon'Pregnancyandlactation'and
"Initialprenatalassessmentandfirsttrimesterprenatalcare",sectionon'Antibiotictherapy'.)
REFRACTORYULCERSThetreatmentofrefractoryulcersisdiscussedelsewhere.(See"Refractoryor
recurrentpepticulcerdisease".)
INFORMATIONFORPATIENTSUpToDateofferstwotypesofpatienteducationmaterials,"TheBasics"and
"BeyondtheBasics."TheBasicspatienteducationpiecesarewritteninplainlanguage,atthe5thto6thgrade
readinglevel,andtheyanswerthefourorfivekeyquestionsapatientmighthaveaboutagivencondition.These
articlesarebestforpatientswhowantageneraloverviewandwhoprefershort,easytoreadmaterials.Beyondthe
Basicspatienteducationpiecesarelonger,moresophisticated,andmoredetailed.Thesearticlesarewrittenatthe
10thto12thgradereadinglevelandarebestforpatientswhowantindepthinformationandarecomfortablewith
somemedicaljargon.
Herearethepatienteducationarticlesthatarerelevanttothistopic.Weencourageyoutoprintoremailthese
topicstoyourpatients.(Youcanalsolocatepatienteducationarticlesonavarietyofsubjectsbysearchingon
"patientinfo"andthekeyword(s)ofinterest.)
Basicstopics(see"Patientinformation:Pepticulcers(TheBasics)"and"Patientinformation:H.pylori
infection(TheBasics)"and"Patientinformation:Gastritis(TheBasics)")
BeyondtheBasicstopics(see"Patientinformation:Pepticulcerdisease(BeyondtheBasics)"and"Patient
information:Helicobacterpyloriinfectionandtreatment(BeyondtheBasics)")
SUMMARYANDRECOMMENDATIONSThemanagementofpatientswithpepticulcerdisease(PUD)needsto
beadaptedtothespecificclinicalsituation,etiology,andanticipatednaturalhistory.Thefollowingpointsshouldbe
consideredwhentreatingPUD:
AllpatientswithPUDshouldreceiveantisecretorytherapy.InpatientswithuncomplicatedH.pyloriulcers,
theprotonpumpinhibitorgivenalongwiththeantibioticregimenisusuallyadequatetoinducehealing.(See
"TreatmentregimensforHelicobacterpylori"and'InitialapproachtoulcersnotduetoH.pylori'above.)
PatientswithPUDshouldbetestedforH.pylori,keepinginmindthatupperGIbleedingandmedications
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usedforthetreatmentofmayleadtofalsenegativetestresults.(See"Indicationsanddiagnostictestsfor
Helicobacterpyloriinfection".)
PatientswithH.pylorishouldbetreatedwithagoalofH.pylorieradication.(See'TreatmentofH.pyloriin
patientsonNSAIDs'aboveand"TreatmentregimensforHelicobacterpylori"and"Indicationsanddiagnostic
testsforHelicobacterpyloriinfection",sectionon'Confirmationoferadication'.)
ThemanagementofH.pyloripositiveulcersafterantibiotictreatmentdependsupontheclinicalsituationand
thepresenceofriskfactors.Forsmall(<about1cm),uncomplicatedulcersintheabsenceofongoing
symptomsandmarkersofincreasedrisk,thereisnoclearindicationforcontinuingantisecretorytherapyafter
completionofthecourseofantibiotics.Bycontrast,continuingantisecretorytherapyuntilthecureofH.pylori
isconfirmedisimportantforcomplicatedulcers.(See'AntisecretorytherapyafterH.pylorieradication'above.)
ForallpatientswithPUD,itisessentialtowithdrawpotentialoffendingorcontributingagentssuchas
NSAIDs,cigarettes,andexcessalcohol.Inaddition,fornonH.pylori,nonNSAIDulcers,everyeffortshould
bemadetoaddressothercontributingfactors,suchastreatingmedicalcomorbidities,poornutritionalstatus,
ischemia,andacidhypersecretion(table1andtable2andtable3).(See"Pepticulcerdisease:Genetic,
environmental,andpsychologicalriskfactorsandpathogenesis"and"Unusualcausesofpepticulcer
disease".)
Patientswithuncomplicatedduodenalulcerswhohavebeentreateddonotneedfurtherendoscopyor
radiographyunlesssymptomspersistorrecur.(See'Duodenalulcers'above.)
Repeatendoscopywithbiopsyhasbeenadvocatedtoconfirmgastriculcerhealingasameansofensuring
thatthelesionsarebenign.However,withthedecreasingincidenceofgastriccancerindevelopedcountries,
theincreaseduseofNSAIDs,andtheconcernoverthecostsofcare,thispracticestandardhasbeen
questioned.Ourapproachistonotrepeatanupperendoscopyonpatientswithbenignappearinggastric
ulcersthathavebeenadequatelybiopsiedwithnoevidenceofmalignancyordysplasiaonbiopsies.In
patientsathighriskformalignancyweperformafollowupendoscopy(withbiopsiesoftheulcerifstill
present)aftersixweeksoftherapy.(See'Gastriculcers'above.)
Reboundacidhypersecretionisanimportantconsiderationfollowingabruptcessationofprolongedtreatment
withPPIs.Asaresult,treatmentshouldbetaperedfollowingprolongedorhigherdosetreatmentwithaPPI.
(See"Overviewandcomparisonoftheprotonpumpinhibitorsforthetreatmentofacidrelateddisorders",
sectionon'Discontinuingprotonpumpinhibitors'.)
Maintenancetherapyshouldbeconsideredtopreventrecurrenceinhighrisksubgroups.(See'Maintenance
therapy'above.)
Highriskpatientsincludethosewith:
Ahistoryofcomplications
Frequentrecurrences
Refractory,giant,orseverelyfibrosedulcers.
Thetreatmentofpatientswithrefractoryulcersisdiscussedelsewhere.(See"Refractoryorrecurrentpeptic
ulcerdisease".)
UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.
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GRAPHICS
WorkupforapparentlyH.pylorinegative,NSAIDnegativeulcers
Etiologicfactor

Action

Smoking

Carefulhistory

Comorbiddisease

Clinicalevaluation

H.pylorithathasescaped
detection

PerformatleasttwotestsforH.pylori
EnsuretestingisperformedwhilethepatientisoffofPPIs,
antibiotics,bismuth
Considerfourduodenalmucosalbiopsiestodetect
isolatedduodenalcolonization

NSAIDs,aspirin,other
potentiallyulcerogenicdrugs

Carefulhistory

Neoplasia,infection,

Biopsyulcersandsurroundingmucosa,includinginthe

infiltrativedisease

duodenum

Acidhypersecretion

MeasureserumgastrinlevelsoffofPPIs

Considerobtainingurinesalicylatelevelsorplatelet
functionteststoexcludesurreptitiousNSAIDuse

Measurebasalacidoutput
Considersecretinstimulationinpatientswithnormal
serumgastrinlevels
Ischemicmechanisms

Excludeuseofcrackcocaineandmethamphetamine

H.pylori:HelicobacterpyloriNSAID:nonsteroidalantiinflammatorydrugPPI:protonpumpinhibitor.
Adaptedfrom:GisbertJP,CalvetX.Reviewarticle:Helicobacterpylorinegativeduodenalulcerdisease.
AlimentPharmacolTher200930:791.
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Etiologiesanddiseaseassociationsforpepticulcer
Ulcersduetodefinedmechanisms
Infection
Helicobacterpylori
HSV
C MV
Helicobacterheilmannii
Otherrareinfections:TB,syphilis,mucormycosis,etc

Drugexposure(allprobablyworsewhencombinedwithNSAIDsorinhighrisksubjects)
NSAIDsandaspirinincludinglowdoseaspirin
Bisphosphonates(probablywhencombinedwithNSAIDs)
C lopidogrel(whencombinedwithNSAIDsorinhighrisksubjects)
C orticosteroids(whencombinedwithNSAIDs)
Sirolimus
Spironolactone(probable,nodatawithNSAIDcotherapy)
Mycophenolatemofetil
Potassiumchloride
C hemotherapy(eg,hepaticinfusionwith5fluorouracil)

Hormonalormediatorinduced,includingacidhypersecretorystates
Gastrinoma(ZollingerEllisonsyndrome)
Systemicmastocytosis
Basophiliainmyeloproliferativedisease
AntralGcellhyperfunction(existenceindependentofH.pyloriisdebatable)

Postsurgical
Antralexclusion
Postgastricbypass

Vascularinsufficiencyincludingcrackcocaineuse
Mechanical:Duodenalobstruction(eg,annularpancreas)
Radiationtherapy
Infiltratingdisease
Sarcoidosis
C rohndisease

Idiopathicpepticulcer
NonHelicobacterpylori,nonNSAIDpepticulcer

Comorbidulcersassociatedwithdecompensatedchronicdiseaseoracute
multisystemfailure
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Stressintensivecareunitulcers
Cirrhosis
Organtransplantation
Renalfailure
Chronicobstructivepulmonarydisease(secondarytosmoking)
HSV:herpessimplexvirusCMV:cytomegalovirusNSAID:nonsteroidalantiinflammatorydrugTB:
tuberculosis.
CourtesyofAndrewHSoll,MD.
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Causesofrefractoryorrecurrentpepticulcerdisease
PersistingH.pyloriinfection
Poorcompliancewithtreatment
Resistantorganism
InadequateH.pyloriregimen
UnrecognizedH.pyloriinfection:
FalsenegativeH.pyloritesting
Skippedorinadequatetesting

Ulcersrelatedtononsteroidalantiinflammatorydrugs(NSAIDs)
ContinuedNSAIDuse
UndiscoveredNSAIDuse
PoorresponsetoPPIcotherapy

Othermechanisms
Impairedhealing:
Densefibrosis
C igarettesmoking,especiallyheavy
Giantulcer

Inadequateinhibitionofacidsecretion:
Noncompliance
Pharmacologicresistancetohistaminetype2receptorantagonists(H2RAs)orPPIs
RapidPPImetabolizers
TolerancetoH2RAs

Hypersecretorystates:
Gastrinoma
AntralGcellhyperfunction
Idiopathichypersecretoryduodenalulcer

Comorbidconditions:
Uremia
C irrhosis
C atabolicstate
Pulmonaryormultisystemfailure

Cotherapies:
Glucocorticoids
C ytotoxicdrugs
Otherdrugs,suchasmethamphetamineorcocaineuse

Uncommoncauses:
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C ancer
C rohndisease
InfectionsotherthanH.pylori
Eosinophilicandotherinflammatoryconditions

H.pylori:HelicobacterpyloriPPI:protonpumpinhibitor.
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Disclosures
Disclosures:Andrew HSoll,MDNothingtodisclose.Nim ishBVakil,MD,AGAF,FACP,FACG,
FASGEConsultant/AdvisoryBoards:AstraZeneca[GERD(Esomeprazole)]Baxter[Probiotics].Other
FinancialInterest:Salix[GERD(w ebbasedreview article)].MarkFeldm an,MD,MACP,AGAF,FACG
Nothingtodisclose.ShilpaGrover,MD,MPHEmployeeofUpToDate,Inc.
Contributordisclosuresarereview edforconflictsofinterestbytheeditorialgroup.Whenfound,these
areaddressedbyvettingthroughamultilevelreview process,andthroughrequirementsforreferences
tobeprovidedtosupportthecontent.Appropriatelyreferencedcontentisrequiredofallauthorsand
mustconformtoUpToDatestandardsofevidence.
Conflictofinterestpolicy

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