Pathophysiology.docx
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Pathophysiology.docx
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Pathophysiology
GIMotilityonline(2006)doi:
10.1038/gimo22
Published16May2006
Pathophysiologyofachalasiaanddiffuseesophagealspasm
IkuoHirano,M.D.
KeyPoints
∙Achalasiaisthebestunderstoodexampleofanesophagealmotilitydisorderandcharacterizedbyesophagealaperistalsisandimpairedrelaxationoftheloweresophagealsphincter.
∙Thehistopathologyofachalasiainvolvesinflammationofthemyentericplexusoftheesophaguswithdiminutionofganglioncells.Significantreductioninnitricoxidesynthasecontainingneuronshasbeendemonstratedusingimmunohistochemicalstaining.
∙Autoimmune,neurodegenerative,andviraletiologieshavebeenimplicatedinthepathogenesisofachalasia.However,theexactcausehasyettobeelucidated.
∙Pharmacologicstudiesinachalasiapatientssupporttheselectivelossofinhibitory,nitrergicneuronswithpreservationofcholinergicinnervation.
∙Animalmodelsthatincludegeneticallyengineeredmicewithtargeteddisruptionofthegeneencodingfortheneuronalformofnitricoxidesynthaseandpharmacologicadministrationofinhibitorsofnitricoxidesubstantiatetheroleofnitrergicdenervationinachalasia.
∙Achalasiamaybesecondarytoawiderangeofsecondarydisordersincludinggeneticsyndromes,infectiousdiseases,neoplasm,andchronicinflammatoryconditions.
Introduction
SirThomasWillisiscreditedwiththefirstreportofapatientwithachalasiain1674.VonMikuliczin1882andEinhornin1888hypothesizedthatthediseasewasduetotheabsenceofopeningofthecardiaor"cardiospasm."Overthepastthreecenturies,achalasiahasemergedasanimportantmodelbywhichtounderstandthepathophysiologyandtherapyofmotilitydisordersemanatingfromadefectintheentericnervoussystem.Itisthemostextensivelystudiedandreadilytreatablegastrointestinalmotordisorder.Thisreviewdiscussescurrentconceptsinachalasiawithanemphasisonthepathophysiologyandetiologyofthedisease.Specificsecondaryetiologiesofachalasiaarediscussedthatprovideinsightintomechanismsresponsiblefortheneurodegenerationthatcharacterizesthedisorder.Diffuseesophagealspasmisalsodiscussed,althoughthereisapaucityofdataregardingthiscondition.
ClinicalFeaturesofAchalasia
Achalasiaoccurswithanincidenceofapproximately1:
100,000withanequalgenderdistribution.1Itoccursatallageswithanincreaseinincidenceobservedaftertheseventhdecade.Dysphagiaisthepredominantsymptomanditistypicallyaccompaniedbyregurgitation.Upperendoscopyisoftenthefirsttestusedtoevaluatepatientswithsuspectedachalasiaandmaydetectesophagealdilatationwithretainedsalivaorfood.Abariumesophagramcanbehighlysuggestiveofthediagnosisofachalasia,particularlywhenthereisthecombinationofesophagealdilatationwithretainedfoodandbariumandasmooth,taperedconstrictionofthegastroesophagealjunction.Quantitativeassessmentofthedegreeofesophagealemptyingofbariumovertimemayincreasethediagnosticsensitivityoftheesophagramforachalasiaandservesasavaluablemeansbywhichtofollowpatientsresponsetotherapy(Figure1).2,3Thetestwiththehighestsensitivityinthediagnosisofachalasiaisesophagealmanometry.Thedefiningmanometricfeaturesofachalasiaareaperistalsisofthedistalesophagusandincompleteorabsentloweresophagealsphincter(LES)relaxation(Figure2).Additionalsupportivefeaturesincludeahypertensiveloweresophagealsphincterandlow-amplitudeesophagealbodycontractions.Preservationofproximalesophagealperistalsiscanbeseeninsomecaseswithoutesophagealdilation(Figure3a)butapatternofcompleteesophagealaperistalsisismorecommon(Figure3b).
Figure1:
Timedbariumswallow.
Followingtheingestionofafixedvolumeofbarium,sequentialradiographsaretakenat1,2,and5minutes.Thethreepanelsdemonstratealackofemptyingwithafixedcolumnofbariumpersistingat5minutes.
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Figure2:
Esophagealmanometricfindingsinachalasia.
Thetracingillustratesthefindingsinclassicachalasiawithesophagealbodyaperistalsiswithlow-amplitudesimultaneousesophagealbodycontractionsandfailedrelaxationoftheloweresophagealsphincter.
∙Fullsizeimage(69KB)
∙DownloadPowerPointslide(494KB)
Figure3:
Contourplottopographicanalysisofesophagealmotilityinachalasia.
Topographicanalysisisamethodofaxialdatainterpolationderivedfromcomputerizedplottingofdatafrommultiple,closelyspaced,solid-staterecordingtransducers.Theinterpolatedpressureinformationisplottedasatwo-dimensionalcontourplotinwhichpressureamplitudeiscodedbycolor.a:
Anormalesophagealstudywithpropagationoftheperistalticwaveandrelaxationoftheloweresophagealsphincter(LES).Theupperesophagealsphincterisalsodepictedatthetopofthepanel,demonstratingahigherbasalpressureandshorterrelaxationphase.b:
Studyforapatientwithachalasiademonstratingintegrityofproximalesophagealperistalsiswithmidanddistalesophagealbodyaperistalsis(simultaneouscontractions).IncompleterelaxationoftheLESandelevatedesophagastricpressuregradientarealsodemonstrated.c:
AstudyfromapatientwithachalasiawithcompleteesophagealaperistalsisandincompleterelaxationofthehypertensiveLES.AlthoughthereispartialinhibitionoftheLES,therelaxationpressuresexceed40mmHg.Anesophagogastricpressuregradientisevidentinthedistalesophagus.
∙Fullsizeimage(82KB)
∙DownloadPowerPointslide(1,546KB)
High-resolutionmanometrycombinedwithtopographicanalysisisanemergingtechniquethatofferspotentialadvantagesoverconventionalesophagealmanometry.4Usingthistechnique,athresholdvalueof8to10mmHgforthemeanresidualpressureina3-secondpostdeglutitiveintervaldistinguishedachalasiapatientsfromcontrols.5Greateraccuracywasachievedutilizingthetranssphinctericpressuregradientduringthe2-to6-secondpost-swallowinterval.Pressuregradientsexceeding5mmHghadasensitivityof94%andspecificityof98%fordetectingachalasia.Althoughanemergingmethodologyforinvestigativepurposes,theadvantagesofhigh-resolutionmanometrywithtopographyoverconventionalmanometryforclinicalpracticearestillbeingestablished.Figure3illustratesacontourplottopographicanalysisoftwopatientswithachalasia.
Althoughmanometryisacceptedasthe"goldstandard"formakingthediagnosisofachalasia,heterogeneitydoesexistinthemanometricpresentation.6Themostcommonlyrecognizedvariantofachalasiaisknownas"vigorousachalasia,"variablydefinedbythepresenceofnormaltohigh-amplitudesimultaneousesophagealbodycontractionsinthepresenceofanonrelaxingLES(Figure4).Theamplitudesofpreservedesophagealbodycontractionsusedtodefinevigorousachalasiahaverangedfrom37mmHgto60mmHg.High-amplitudeandlong-durationesophagealbodycontractionshavealsobeenreported.Thesemanometricfeaturesofvigorousachalasiaoverlapwithdiffuseesophagealspasm.Althoughvigorousachalasiamayrepresentanearlystageofachalasia,studieshavefailedtodemonstratedifferencesintermsofclinicalpresentationinsuchpatientsincludingdurationofdiseaseortheoccurrenceofchestpain.Additionalmanometricvariantsofachalasiaincluderarepatientswithintactperistalsisthroughthemorethan50%ofthedistalesophagealbodyandotherswithpreservationofeitherdeglutitiveortransientLESrelaxation(Figure5).6,7Inthesereports,thediagnosisofachalasiawassubstantiatedbydemonstratingdegenerationofmyentericneuronsaswellastheclinicalresponsetodisruptionoftheLES.Theclinicalsignificanceofdefiningthesevariantsofachalasialiesintherecognitionthatthesesometimesconfusingmanometricfindingsarestillconsistentwithachalasiawhencombinedwithadditionaldatasupportiveofthediagnosis.Thevariantsalsoprovidecluestothepathophysiologyofthedisease.
Figure4:
Esophagealmanometricfindingsinvigorousachalasia.
Therecordingisfromapatientwithvigorousachalasiademonstratingrobust,simultaneousesophagealbodycontractionsandfailedrelaxationofahypertensiveloweresophagealsphincter.
∙Fullsizeimage(71KB)
∙DownloadPowerPointslide(531KB)
Figure5:
EsophagealmanometricfindingsinachalasiavariantwithpreservedLESrelaxation.
Thepanelillustratesthefindingsinclassicachalasiawithesophagealbodyaperistalsiswithlow-amplitudesimultaneousesophagealbodycontractionsandapparentrelaxationoftheloweresophagealsphincter.
∙Fullsizeimage(69KB)
∙DownloadPowerPointslide(538KB)
Inadditiontolimitationsinthesensitivityofthemanometricfeaturesofachalasia,therealsoexistlimitationsintheirspecificity.SclerodermasharesmanyofthemanometricfeaturesofachalasiawiththeexceptionoffaileddeglutitiverelaxationofahypertensiveLES.Thisdistinctionbecomesblurredinthesettingofidiopathicachalasiawithalow-normalLESbasalpressureortreatedachalasia.Inaddition,aprominentcruraldiaphragmcontributiontoLESbasalpressurecanbemisinterpretedastheintrinsicbasalLESpressure,andwhencombinedwiththepresenceofesophagealbodyaperistalsisofsclerodermaesophagus,leadstoamisdiagnosisofachalasia.Complicatingmatters,theesophagealmanifestationsofsclerodermamaybetheinitialpresentationinsomepatientswithscleroderma.Asmentioned,diffuseesophagealspasmhasseveralmanometricfeaturesthatoverlapwiththevigorousformofachalasia.Thisoverlap,combinedwithreportsofprogressionofpatientsfromesophage
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