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DigestiveDiseasesandSciences(2018)63:547–548https://doi.
org/10.
1007/s10620-017-4872-8EDITORIALRevengeoftheNERDs:CadherinFragmentsDifferentiateFunctionalHeartburnfromNonerosiveRefluxDiseaseCarloCalabrese1,2·MarcoSalice1,2Publishedonline:12January2018SpringerScience+BusinessMedia,LLC,partofSpringerNature2018TotheEditor,Duetotheever-increasinguseofprotonpumpinhibitors(PPI),thetherapeuticfrontlineingastroesophagealrefluxdisease(GERD)haschanged.
Thesuccessfulhealingofesophagitis,anelusivetherapeutictargetamere25yearsago,hasbeeneclipsedbynewconsiderations,withemphasisnowbeingfocusedonsymptomresolution,inparticular,heartburn.
Moreover,patientswithheartburnareahetero-geneousgroup,includingsubpopulationswithdifferentmechanismsresponsiblefortheirsymptoms.
PatientswithGERDsymptomssuchasheartburneitherhaveincreasedesophagealacidexposurewith(erosiveesophagitis;EE)orwithout(non-erosiverefluxdisease;NERD)erosions,orwithnormalacidexposurewithacidhypersensitivity(func-tionalheartburn;FH)[1].
AlthoughEEisreadilydiagnosed,thedistinctionbetweenpatientsdiagnosedwithNERDandthosewithFHcanbedifficultdespitebeinghighlyclinicallyrelevant:thefirstgroupmostlybenefitsfrompharmacologi-calsuppressionofacidsecretionorfromsurgicalanti-refluxtherapy,whereasinthesecondgroup,prolongedtherapywithprotonpumpinhibitors(PPI)andanti-refluxsurgeryareunnecessaryandpossiblyharmfulandshouldthusbeassiduouslyavoided.
Untilnow,themissingpieceinthispuzzlehasbeentheexistenceofabiomarkerusefultodif-ferentiatepatientswithNERDfromFHandtopredicttheresponsetoPPItherapy.
PatientswithNERDhaveforlongbeenconsideredpoorresponderstoPPIs.
Nonetheless,ameta-analysisemphasizedthatthepreviouslyreportedlowresponserateinNERDwaslikelytheresultofbiasedstudiesthatincludedpatientswithnon-GERD-relateduppergastrointestinalsymptoms[2].
Twenty-four-houresophagealpHmonitoringisusefultodefinetheetiologyofheartburnsymptoms.
Recently,theadditionofimpedance,whichrecognizesfluidreflux,alongwithpHmonitoringhasenhancedtheabilitytodetectpatientswithFH[3].
Nevertheless,thesetechniqueshavesomeintrinsiclimitations:(a)esophagealacidexposuretimepresentsaphysiologicalday-to-dayvariabilityduetovariationsofdietaryhabitsandphysicalactivity;(b)symptomsreportedduringsingle-daymonitoringareoftenabsentorfew,decreasingthereliabilityofrefluxassocia-tionindexes;and(c)patientsareoftenuncomfortableandadoptamoresedentarylifestyle,reducingthefrequencyofreflux-provokingactivities.
TheselimitationscouldbeparticularlyrelevanttopatientswithNERDwhofrequentlyhaveweaklyacidic(pH4–7)refluxduring24-hpHmoni-toring,asopposedtopatientswithEEwhogenerallyhavestronglyacidic(pH<4)reflux[4].
Ultrastructuralstudies[5–7]havedemonstratedawiden-ingoftheintercellularjunctionsbetweencellsintheesopha-gealepitheliuminpatientswithNERD,withlimiteddatasupportingcorrespondingincreasedparacellularpermeabil-itytosolutes,whichwashypothesizedtobeduetoaciddam-agetotheintercellularjunctionalcomplex.
Sincethezonulaadherens,astructureintegraltomaintainingtheintegrityofthetightjunctionbetweencells,iscomposedpartlyofcadherins,thepresenceofE-cadherincleavedintocarboxy(C)-terminalfragments(CTFs)andamino(N)-terminalfragments(NTFs)islikelyassociatedwiththeincreasedjunctionaldamageandincreasedparacellularpermeabilityinpatientswithNERD[8].
InthisissueofDigestiveDiseasesandSciences,Jovovetal.
[9]reportedastudyoftwenty-nineNERDpatientswithheartburnoccurringatleast3days/week.
Esophagealbiop-siesforwesternblot(WB)analysisofCTFexpressionwereobtainedatbaseline,whereasbloodsamplesforNTFanaly-siswereacquiredbeforeandafteracourseofPPItherapy.
*CarloCalabresecarlo.
calabrese2@unibo.
it1DepartmentofMedicineandSurgery,UniversityofBologna,Bologna,Italy2AziendaOspedaliero-Universitaria,PoliclinicoS.
Orsola-Malpighi,ViaMassarenti9,40138Bologna,Italy548DigestiveDiseasesandSciences(2018)63:547–548Twodifferentcontrolgroupswereused:onewasrecruitedinordertomeasureCTFexpressioninbiopsiesoftheesopha-gealepitheliumandthesecondgroupwasrecruitedtoeval-uateserumconcentrationsofNTFsofbyenzyme-linkedimmunoabsorbentassay(ELISA).
TheauthorsreportedthatfragmentsofE-cadherinwerepresentintheesophagealmucosain93%ofpatients.
Inthetreatmentcohort,83%ofpatientswereeitherfullorpartialrespondersand17%werenon-responderstoPPI.
Yet,theonlytwopatientswithbiop-siesnegativeforCTFswerebothresponderstoPPIandthebiopsiesallnon-responderstoPPIwerepositiveforCTFs.
Althoughatbaseline,concentrationsofserumNTFsweresimilarbetweenthetreatmentcohortandthecontrolgroup,NTFconcentrationsinresponders(completeorpartial)weresignificantlyhigherthaninnon-respondersandincontrols.
Moreover,NTFconcentrationspost-treatmentdecreasedin75%ofcompleteandpartialresponders.
After4weeksofPPItherapy,NTFconcentrationsweresignificantlyreducedintheresponderswhileremainingunchangedinthenon-respondersandinthecontrols.
TheauthorsconcludedthatanabsorbancevalueforserumNTFsof≥0.
228AUmaybeusefulindifferentiatingbetweenthesepatientgroups.
Moreover,theconcentrationsofserumNTFsinPPI-responsivepatientsdeclinedaftertreatment,butremainedthesameascontrolsforthe5PPInon-respon-sivesubjects.
TheinformationofthispilotstudycouldbeusedtodeterminewhenPPItherapycouldbetaperedorstoppedinrespondersandhelppredicttheriskofsymptomrelapse.
Still,despitebeingapilotstudy,therearelimitations,asreportedbytheauthors.
Inparticular,thesamplesizewassmall,onlypre-treatmentCTFconcentrationswereobtained,andacorrelationofesophagealacidexposure(asdeterminedby24-hpHmonitoringonorofftherapy)withNTFconcen-trationswasnotused.
Thispilotstudygeneratesaninterestinghypothesis,thatifconfirmedinclinicaltrialswithlargerpatientcohorts,couldofferanappealingtranslationalpotential.
Inparticular,theputativebiomarkermayhelpdeterminewhenaPPImaybetaperedordiscontinuedwithouttheimmediateriskofrelapse.
ForthosewithheartburnnotresponsivetoempiricPPIs,particularlyatadouble/highdose,normalNTFcon-centrationswouldsupporttheconclusionthatthesymptomswereunrelatedtoacid-refluxdisease,addingconfidencethatPPItherapycouldbesafelydiscontinued.
Finally,anobjectiveserumbiomarkerthatdifferentiatesNERDfromFH,andassessestheresponsetoPPItreatmentwithhighsensitivity,couldbecomeinthefutureandinex-pensive,predictive,andrelativelysafemeanstodifferentiateNERDfromFH.
References1.
KahrilasPJ,PandolfinoJE.
Reviewarticle:oesophagealpHmon-itoring-technologies,interpretationandcorrelationwithclinicaloutcomes.
AlimentPharmacolTher.
2005;22:2–9.
2.
WeijenborgPW,CremoniniF,SmoutAJ,BredenoordAJ.
PPItherapyisequallyeffectiveinwell-definednon-erosiverefluxdiseaseandinrefluxesophagitis:ameta-analysis.
Neurogastro-enterolMotil.
2012;24:747–757,e350.
3.
SavarinoE,ZentilinP,TutuianR,etal.
TheroleofnonacidrefluxinNERD:lessonslearnedfromimpedance-pHmonitoringin150patientsofftherapy.
AmJGastroenterol.
2008;103:2685–2693.
4.
AmericanGastroenterologicalAssociation.
AmericanGastro-enterologicalAssociationmedicalpositionstatementguide-linesontheuseofesophagealpHrecording.
Gastroenterology.
1996;110:1981.
5.
TobeyNA,HosseiniSS,ArgoteCM,DobrucaliAM,AwaydaMS,OrlandoRC.
Dilatedintercellularspacesandshuntperme-abilityinnonerosiveacid-damagedesophagealepithelium.
AmJGastroenterol.
2004;99:13–22.
6.
CalabreseC,BortolottiM,FabbriA,etal.
ReversibilityofGERDultrastructuralalterationsandreliefofsymptomsafteromeprazoletreatment.
AmJGastroenterol.
2005;100:537–542.
7.
CavigliaR,RibolsiM,MaggianoN,etal.
Dilatedintercellularspacesofesophagealepitheliuminnonerosiverefluxdiseasepatientswithphysiologicalesophagealacidexposure.
AmJGas-troenterol.
2005;100:543–548.
8.
JovovB,QueJ,TobeyNA,DjukicZ,HoganBL,OrlandoRC.
RoleofE-cadherininthepathogenesisofgastroesophagealrefluxdisease.
AmJGastroenterol.
2011;106:1039–1047.
9.
JovovB,ReedCC,ShaheenNJ,PruittA,FerrellK,OrlandoGS,etal.
FragmentsofE-cadherinasbiomarkersofnon-erosiverefluxdisease.
DigDisSci.
(Epubaheadofprint).
https://doi.
org/10.
1007/s10620-017-4815-4.
org/10.
1007/s10620-017-4872-8EDITORIALRevengeoftheNERDs:CadherinFragmentsDifferentiateFunctionalHeartburnfromNonerosiveRefluxDiseaseCarloCalabrese1,2·MarcoSalice1,2Publishedonline:12January2018SpringerScience+BusinessMedia,LLC,partofSpringerNature2018TotheEditor,Duetotheever-increasinguseofprotonpumpinhibitors(PPI),thetherapeuticfrontlineingastroesophagealrefluxdisease(GERD)haschanged.
Thesuccessfulhealingofesophagitis,anelusivetherapeutictargetamere25yearsago,hasbeeneclipsedbynewconsiderations,withemphasisnowbeingfocusedonsymptomresolution,inparticular,heartburn.
Moreover,patientswithheartburnareahetero-geneousgroup,includingsubpopulationswithdifferentmechanismsresponsiblefortheirsymptoms.
PatientswithGERDsymptomssuchasheartburneitherhaveincreasedesophagealacidexposurewith(erosiveesophagitis;EE)orwithout(non-erosiverefluxdisease;NERD)erosions,orwithnormalacidexposurewithacidhypersensitivity(func-tionalheartburn;FH)[1].
AlthoughEEisreadilydiagnosed,thedistinctionbetweenpatientsdiagnosedwithNERDandthosewithFHcanbedifficultdespitebeinghighlyclinicallyrelevant:thefirstgroupmostlybenefitsfrompharmacologi-calsuppressionofacidsecretionorfromsurgicalanti-refluxtherapy,whereasinthesecondgroup,prolongedtherapywithprotonpumpinhibitors(PPI)andanti-refluxsurgeryareunnecessaryandpossiblyharmfulandshouldthusbeassiduouslyavoided.
Untilnow,themissingpieceinthispuzzlehasbeentheexistenceofabiomarkerusefultodif-ferentiatepatientswithNERDfromFHandtopredicttheresponsetoPPItherapy.
PatientswithNERDhaveforlongbeenconsideredpoorresponderstoPPIs.
Nonetheless,ameta-analysisemphasizedthatthepreviouslyreportedlowresponserateinNERDwaslikelytheresultofbiasedstudiesthatincludedpatientswithnon-GERD-relateduppergastrointestinalsymptoms[2].
Twenty-four-houresophagealpHmonitoringisusefultodefinetheetiologyofheartburnsymptoms.
Recently,theadditionofimpedance,whichrecognizesfluidreflux,alongwithpHmonitoringhasenhancedtheabilitytodetectpatientswithFH[3].
Nevertheless,thesetechniqueshavesomeintrinsiclimitations:(a)esophagealacidexposuretimepresentsaphysiologicalday-to-dayvariabilityduetovariationsofdietaryhabitsandphysicalactivity;(b)symptomsreportedduringsingle-daymonitoringareoftenabsentorfew,decreasingthereliabilityofrefluxassocia-tionindexes;and(c)patientsareoftenuncomfortableandadoptamoresedentarylifestyle,reducingthefrequencyofreflux-provokingactivities.
TheselimitationscouldbeparticularlyrelevanttopatientswithNERDwhofrequentlyhaveweaklyacidic(pH4–7)refluxduring24-hpHmoni-toring,asopposedtopatientswithEEwhogenerallyhavestronglyacidic(pH<4)reflux[4].
Ultrastructuralstudies[5–7]havedemonstratedawiden-ingoftheintercellularjunctionsbetweencellsintheesopha-gealepitheliuminpatientswithNERD,withlimiteddatasupportingcorrespondingincreasedparacellularpermeabil-itytosolutes,whichwashypothesizedtobeduetoaciddam-agetotheintercellularjunctionalcomplex.
Sincethezonulaadherens,astructureintegraltomaintainingtheintegrityofthetightjunctionbetweencells,iscomposedpartlyofcadherins,thepresenceofE-cadherincleavedintocarboxy(C)-terminalfragments(CTFs)andamino(N)-terminalfragments(NTFs)islikelyassociatedwiththeincreasedjunctionaldamageandincreasedparacellularpermeabilityinpatientswithNERD[8].
InthisissueofDigestiveDiseasesandSciences,Jovovetal.
[9]reportedastudyoftwenty-nineNERDpatientswithheartburnoccurringatleast3days/week.
Esophagealbiop-siesforwesternblot(WB)analysisofCTFexpressionwereobtainedatbaseline,whereasbloodsamplesforNTFanaly-siswereacquiredbeforeandafteracourseofPPItherapy.
*CarloCalabresecarlo.
calabrese2@unibo.
it1DepartmentofMedicineandSurgery,UniversityofBologna,Bologna,Italy2AziendaOspedaliero-Universitaria,PoliclinicoS.
Orsola-Malpighi,ViaMassarenti9,40138Bologna,Italy548DigestiveDiseasesandSciences(2018)63:547–548Twodifferentcontrolgroupswereused:onewasrecruitedinordertomeasureCTFexpressioninbiopsiesoftheesopha-gealepitheliumandthesecondgroupwasrecruitedtoeval-uateserumconcentrationsofNTFsofbyenzyme-linkedimmunoabsorbentassay(ELISA).
TheauthorsreportedthatfragmentsofE-cadherinwerepresentintheesophagealmucosain93%ofpatients.
Inthetreatmentcohort,83%ofpatientswereeitherfullorpartialrespondersand17%werenon-responderstoPPI.
Yet,theonlytwopatientswithbiop-siesnegativeforCTFswerebothresponderstoPPIandthebiopsiesallnon-responderstoPPIwerepositiveforCTFs.
Althoughatbaseline,concentrationsofserumNTFsweresimilarbetweenthetreatmentcohortandthecontrolgroup,NTFconcentrationsinresponders(completeorpartial)weresignificantlyhigherthaninnon-respondersandincontrols.
Moreover,NTFconcentrationspost-treatmentdecreasedin75%ofcompleteandpartialresponders.
After4weeksofPPItherapy,NTFconcentrationsweresignificantlyreducedintheresponderswhileremainingunchangedinthenon-respondersandinthecontrols.
TheauthorsconcludedthatanabsorbancevalueforserumNTFsof≥0.
228AUmaybeusefulindifferentiatingbetweenthesepatientgroups.
Moreover,theconcentrationsofserumNTFsinPPI-responsivepatientsdeclinedaftertreatment,butremainedthesameascontrolsforthe5PPInon-respon-sivesubjects.
TheinformationofthispilotstudycouldbeusedtodeterminewhenPPItherapycouldbetaperedorstoppedinrespondersandhelppredicttheriskofsymptomrelapse.
Still,despitebeingapilotstudy,therearelimitations,asreportedbytheauthors.
Inparticular,thesamplesizewassmall,onlypre-treatmentCTFconcentrationswereobtained,andacorrelationofesophagealacidexposure(asdeterminedby24-hpHmonitoringonorofftherapy)withNTFconcen-trationswasnotused.
Thispilotstudygeneratesaninterestinghypothesis,thatifconfirmedinclinicaltrialswithlargerpatientcohorts,couldofferanappealingtranslationalpotential.
Inparticular,theputativebiomarkermayhelpdeterminewhenaPPImaybetaperedordiscontinuedwithouttheimmediateriskofrelapse.
ForthosewithheartburnnotresponsivetoempiricPPIs,particularlyatadouble/highdose,normalNTFcon-centrationswouldsupporttheconclusionthatthesymptomswereunrelatedtoacid-refluxdisease,addingconfidencethatPPItherapycouldbesafelydiscontinued.
Finally,anobjectiveserumbiomarkerthatdifferentiatesNERDfromFH,andassessestheresponsetoPPItreatmentwithhighsensitivity,couldbecomeinthefutureandinex-pensive,predictive,andrelativelysafemeanstodifferentiateNERDfromFH.
References1.
KahrilasPJ,PandolfinoJE.
Reviewarticle:oesophagealpHmon-itoring-technologies,interpretationandcorrelationwithclinicaloutcomes.
AlimentPharmacolTher.
2005;22:2–9.
2.
WeijenborgPW,CremoniniF,SmoutAJ,BredenoordAJ.
PPItherapyisequallyeffectiveinwell-definednon-erosiverefluxdiseaseandinrefluxesophagitis:ameta-analysis.
Neurogastro-enterolMotil.
2012;24:747–757,e350.
3.
SavarinoE,ZentilinP,TutuianR,etal.
TheroleofnonacidrefluxinNERD:lessonslearnedfromimpedance-pHmonitoringin150patientsofftherapy.
AmJGastroenterol.
2008;103:2685–2693.
4.
AmericanGastroenterologicalAssociation.
AmericanGastro-enterologicalAssociationmedicalpositionstatementguide-linesontheuseofesophagealpHrecording.
Gastroenterology.
1996;110:1981.
5.
TobeyNA,HosseiniSS,ArgoteCM,DobrucaliAM,AwaydaMS,OrlandoRC.
Dilatedintercellularspacesandshuntperme-abilityinnonerosiveacid-damagedesophagealepithelium.
AmJGastroenterol.
2004;99:13–22.
6.
CalabreseC,BortolottiM,FabbriA,etal.
ReversibilityofGERDultrastructuralalterationsandreliefofsymptomsafteromeprazoletreatment.
AmJGastroenterol.
2005;100:537–542.
7.
CavigliaR,RibolsiM,MaggianoN,etal.
Dilatedintercellularspacesofesophagealepitheliuminnonerosiverefluxdiseasepatientswithphysiologicalesophagealacidexposure.
AmJGas-troenterol.
2005;100:543–548.
8.
JovovB,QueJ,TobeyNA,DjukicZ,HoganBL,OrlandoRC.
RoleofE-cadherininthepathogenesisofgastroesophagealrefluxdisease.
AmJGastroenterol.
2011;106:1039–1047.
9.
JovovB,ReedCC,ShaheenNJ,PruittA,FerrellK,OrlandoGS,etal.
FragmentsofE-cadherinasbiomarkersofnon-erosiverefluxdisease.
DigDisSci.
(Epubaheadofprint).
https://doi.
org/10.
1007/s10620-017-4815-4.
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