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Gut,1984,25,784-791CasereportGlucagonomasyndromedemonstratinggiantduodenalvilliFIONAMSTEVENS,RWFLANAGAN,DO'GORMAN,ANDKDBUCHANANFromtheDepartmentsofGastroenterologyandDermatology,RegionalHospital,Galway,Ireland;andtheDepartmentofMedicine,Queen'sUniversity,Belfast,NorthernIrelandSUMMARYA39yearoldmandevelopedanitchybullousrashintheperineumandontheextremities.
Sixyearslater,aftergiantintestinalvillihadbeennotedatendoscopy,adiagnosisoftheglucagonomasyndromewasmade.
Investigationrevealedalargetumourofthepancreaticbodyandtail.
Themolecularspeciesofglucagonsecretedbythetumourwerecharacterisedusingthecombinedpurificationproceduresofimmunoaffinitychromatographyfollowedbygelfiltration.
Anecrolyticmigratoryerythematousskinrash,anaemia,angularstomatitiswithorwithoutdiabetesmellitusarerecognisedfeaturesofthepancreaticglucagonomasyndrome.
'Thesyndromeisassociatedwithapancreaticisletcelltumourproducingglucagon.
Removalofthetumourinsomecaseshasresultedincuringofthesymptomsandsignsofthesyndrome.
2Giantintestinalvillihavebeenfoundinapatientwitharenaltumourproducingenteroglucagon.
3Apatientwithfeaturesofbothconditions-thatis,skinrash,anaemia,angularstomatitis,diabetesmellitus,apancreatictumourandgiantduodenalvilliisreported.
CasehistoryApreviouslyhealthymaleagriculturalworkerfirstdevelopedanitchybullousskinrashintheperineum,feetandhandsinApril1969,attheageof39years.
Overthenextsixyearstheskinlesionswerevariouslydiagnosedascontactdermatitis,chronicmucocutaneouscandidiasisorseborrhoeicdermatitis.
Theskinlesionsrespondedtolargequantitiesoftopicalsteroidsorsystemicsteroids.
DiabetesmellitusdiagnosedinApril1969,originallywastreatedwithtolbutamide.
InDecember1970thetolbutamidewaswithdrawnandthediabetescontrolledwithl0kJ(2400cal)diet.
PulmonaryandAddressforcorrespondence:DrFMStevens.
Departmentof(iastro-enterology.
RegionalHospital.
Galway,Irelawnd.
Receivedforpublication1()October1983renaltuberculosiswasdiagnosedinDecember1970respondedtotreatmentwithstreptomycin,isoniazid,andethambutol.
BiopsyofaconcurrentanalfistulawasnegativeforMycobacteriumtuberculosis.
Minorrelapsesoftheskinrashoverthenextthreeyearsrespondedtotopicalsteroidswithnystatin.
From1973to1975theperiodsofremissionbecameshorterandtherelapsesmorewidespread,painful,anddifficulttocontrol.
Skinscrapingsforthetineawerenegative,butbecauseofpedalinterdigitalfissuring,griseofulvinandtopicalmiconazolenitratewerestartedwithoutbeneficialeffect.
TolbutamidewasreintroducedinMay1975.
InOctober1975,thepatienthaddevelopedrecurrentdiarrhoea,weightlossandamildnormo-chromic,normocyticanaemia(Hb11-4g/dl).
Abariummealandfollowthroughexaminationshoweddistortedantralmucosa,wideningoftheduodenalloopanddilationofthesmallintestinallumen,theseradiologicalfeaturesbeingsuggestiveofatumouroftheheadofthepancreaswithmalabsorptionsecondarytoexocrinepancreaticinsufficiency.
Thepatientwasreferredforuppergastrointestinalendoscopy.
Agastro-duodenoscopyshowednoabnormalityinthestomachnoranytumourinvasionintothewalloftheduodenum.
Giantvilli,however,werenotedthroughouttheproximalduodenumandthepossi-bilityofaglucagonomawasfirstconsidered.
Thenumberofvilliperendoscopicfieldisaboutonequarterthatseenincontrols-thatis,thepatient's784onMarch13,2021byguest.
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DownloadedfromGlucagonomasyndromedemonstratinggiantduodenalvillivilliareaboutfourtimesthecross-sectionalareaofcontrolvilli(Fig.
1).
Endoscopicbiopsyshowedsomeelongatedvilli;meanvillousheight,patient733,um:controls336,um,SD5065gm(n=6).
PancreaticjuicecollectedviaaDreilingtubecontainednomalignantcellsbutonexaminationthegastricaspiratewasfoundtocontainlargenumbersofmycobacteriatuberculosis.
Thepatientwasreferredforafurthercourseofantituberculoustherapy.
AtthistimeglucagonassaywasnotreadilyavailableonspecimensfromGalway.
Overthenextyeartheskinlesionsbecamealmostconstantandassociatedwithsevereburningpedalpainandoedema.
Relapsesoftheskinlesionswereaccompaniedbydiarrhoea.
Sigmoidoscopyrevealednoabnormalityintherectum.
InNovember1976,hewasreferredbacktotheGastroenterologyDepartment.
Fastingblooddrawnforglucagonassayshowedmassivehyperglucagon-aemia(detailsoftheassaywillbegivenlater).
ThepatientwasreadmittedinDecember1976forfurtherinvestigation.
EXAMINATIONTherashhadrecurred.
Thelesionsvariedincharacterhavingeitheracentralnecrolyticbullousareaofadryscalyareasurroundedbyerythemaandafigurateoutline.
Thelesionsweresitedaroundthemouthandnose(Fig.
2),antecubitalandpoplitealfossae,groinsandnatalcleftandoverpressureareas,ischialtuberositiesandlateralsurfacesofthelegs.
Acutelesionsonthefeetrelatedtothezippersonhisslipperswereaccompaniedbyextensiveerythemaandoedema,andhealedlesionsweredemarcatedbypigmentedareas.
Fissureswerenotedbetweenthetoesandonthesolesofhisfeet.
Thenailswerethickenedandopalescentwithlongitudinalridging,pittinganddistalsubungualhyperkeratosis.
Thebuccalmucosawasnormalalthoughangularstomatitiswaspresent.
Thetonguewasshiny,redandfissured.
Thepatientwaspaleandemaciated,withnoFig1EndoscopicphotographsofduodenalmucosaofpatientBB(AandB)andnormalsubject(CandD).
PhotographsweretakenthroughanOlympusGIF-D,panendoscope.
FiguresBandDaftersprayingthemucosalFig2PatientBB,withtypicalrashinvolvingmiddlethirdsurfacewith04%indigocarmine.
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DownloadedfromStevens,Flanagan,O'Gorman,andBuchanansubcutaneousfat.
Therewasnojaundiceorlympha-denopathy.
Theabdomenwasdistendedbutsoft.
Nohepatosplenomegaly,renalmasses,othermassesorascitesweredetected.
Bowelsoundswereactive.
Generalisedmuscleweaknessandwastingwasnoted.
Hyperaesthesiawasfoundina'gloveandstockingdistribution'.
Reflexeswerebrisk,withflexorplantarresponses.
Hismentalstatuswasvolatile,attimeshewasuncooperativeandatothertimesdocile.
ThepatientrepeatedlyrefusedsurgeryinGalwayandeventuallyalaparotomywasperformedelsewhere.
Atoperation,thepresenceofalargetumourofthepancreas(12x18cm)wasconfirmed.
Excisionwasimpossiblebecauseofextensionofthetumouraroundthesuperiormesentericaxis,theportalvein,andextendingintotheportahepatisandretroperitonealspace.
Biopsyrevealedanisletcellcarcinomaofthecvcelltype.
Tissuewasnotavailabletoextractglucagon-likeimmunoreactivespeciesforcomparisonwiththeperipheralbloodspecies.
Thepatientdiedpostoperatively.
InvestigationHAEMATOLOGYHaemoglobin11.
1g/dl,platelets379000,ESR16mm/l.
Redcellsweremildlyanisocytic,poikilocytic,andmacrocytic.
NoHowellJollybodiesweredetected.
Serumiron,folate,andvitaminB12normal.
BIOCHEMISTRYRoutinebiochemicalscreenshowedabnormalitiesofgammaglutamyltransferase34U/l(normalrange(NR)5-25U/l).
Cholesterol336mmol/l(NR337-7*0mmol/l).
Urinary5hydroxyindoleaceticacid(fourcollections)mean106mol/24h(NR30000MW)withthelatterbeingthemajorpeak.
.
E500BDccIGKCr15000203040506070Effluentvolume(ml)Fig7SephadexG-50Superfinegelchromatographyof0oplasmaduringL-arginineinfusion;plasmapreviously81000-opurifiedbyimmunoaffinitychromatographyonaC-terminalreactiveglucagonantibodySepharoseconjugate0.
.
EluateswereassayedbyanN-terminalantibodyN-GLI)andaC-terminalantibody(.
.
.
.
C-GLl).
()showspositionofGLlpeaksincontrolsubjects.
Columnmarkersareshown,BD=bluedextran,cc=cytochromeC,I=insulin,G=glucagon,K2CrO4=potassiumchromate.
5500-EDuringarginineinfusionchangesinthegelchromatographicprofileoccurred(Fig.
7).
Therewasamarkedincreaseinthe12000and35000203040506070molecularweightregionimmunoreactivity,theEffluentvolume(ml)glucagon-likeimmunoreactivityinthe3500molecularweightregionshowingastrongerreactionFig6SephadexG-50SuperfinegelchromatographyofwiththeN-terminalantibodyandthe12000fastingplasmapreviouslypurifiedbyimmunoaffinitymolecularweightpeakglucagon-likeimmuno-chromatographyonaC-terminalreactiveglucagonreactivityshowedstrongerreactionwiththeC-antibodySepharoseconjugate.
EluateswereassayedbyanN-terminaltantibody(N-GLI)andaC-terminalerminalantibody.
Nopeakwasfoundmgelantibody(.
.
.
.
C-GLI).
(,,)showspositionofGLIpeakschromatographyofeitherfastingspecimenortheincontrolsubjects.
Columnmarkersareshown,BD=bluearginineinfusionspecimenwhichcorrespondedtodextran,cc=cytochromeC,I=insulin,G=glucagon,the>30000molecularweightpeakfoundinnormalK2CrO4=potassiumchromate.
fastingsubjects.
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DownloadedfromStevens,Flanagan,O'Gorman,andBuchananDiscussionThepancreaticglucagonomasyndrome,whichischaracterisedbyatypicalskinrash,angularstomatitis,glossitis,weightloss,anaemia,diabetesmellitus,andglucagon-producingtumourofthepancreashasbeenrepeatedlydocumented.
'1314Thesimilarityoftherashtothatseeninacro-dermatitisenteropathicaanditsresponsetozincsupplementsleadtothesuggestionthattheskinlesionsandglossitisoftheglucagonomasyndromearerelatedtosequestrationofzincbytheactivelysecretingtumour.
Ithasbeensuggestedthatfattyaciddeficiencymayproducetheskinlesionbuteveninrelapsethefastingserumlipidswerenormalinourpatientapartfromminimaldepressionofcholesterol.
Spontaneousimprovementintheskinrashonwithdrawalofsulphonylureaswasnotedina38yearoldmanwithapancreaticglucagonoma.
'7Soleretalsuggestedthatthetolbutamidewasprovokingglucagonreleasefromthetumourandthusamoresevereskinrash.
17Therelativeremissionofsymptomsfrom1971-1973inourpatientwhendiabeticcontrolwasbycalorierestrictionaloneandsubsequentrelapseonre-introductionoftolbutamidesupportthistheory.
Ourpatientnotonlyhadfeaturesofthepancreaticglucagonomasyndromebutalsohadlargevilliintheproximalduodenum.
Theenlargedvilli,initiallynotedatendoscopy,wereconfirmedbymorphometricmeasurementonbiopsymaterial.
Endoscopicbiopsiesarenotidealforthisassessmentbecauseoftheirsmallsize,paucityofvilli,tendencytocurlandproblemsofoptimalorientation.
Nevertheless,themeanvillousheightincontrols(336Mm)wassimilartothatfoundbyotherauthors(393,Am).
'9Thefrequencyoftheoccurrenceoflargevilliinpancreaticglucagonomasyndromeisnotknownasthemajorityofpatientshavenotundergoneasmallintestinalbiopsy.
Giantintestinalvillihavebeenrecordedina44yearoldfemalepatient,presentingwithpolyuriaandconstipation,whowasfoundtohaveanenteroglucagonproducingtumourofthekidney.
3Thepatienthadatransienterythematousrash,howeverthedescriptioninthecasereportisnotthatoftheseverenecrolyticdermatosisofthepancreaticglucagonomasyndrome.
Themeanvillousheightinthispatient(1150,um)wasgreaterthaninourpatient(733,um)butthebiopsyintheformerwasfromthemid-jejunum3andinthelatterfromtheproximalduodenum.
Incontrolsthevilliarelongerinthejejunumthanintheduodenum.
'9Ithasbeensuggestedthattheenteroglucagonsecretedbytherenaltumourmayhaveinducedtheintestinalmorphologicalabnormalities,asthesechangesregressedafteroperativeremovalofthetumour,21'2andsalineextractsofthetumour,wheninjectedintraperitoneallyinmice,resultedinmacroscopicenlargementofthesmallbowel.
2'Inthepresentpatientanunusualhighmolecularweightglucagon(molecularweight12000)hasbeenisolated.
Itispossiblethatthisglucagoninducesvilloushypertrophyalthoughitislargerthantheenteroglucagon(molecularweight7000approxi-mately)extractedfromtherenaltumourofthepatientwiththegiantvilli.
20'Affinitychroma-tographyshowedourpatienttobedevoidofglucagon-likeimmunoreactivityreactingonlywithN-GLIantibody.
Innormalsubjectsglucagon-likeimmunoreactivityfromplasmaadherestoaC-terminalreactiveantibodycolumnbutthewashingsfromthiscolumncontainglucagon-likeimmuno-reactivitywhichadherestoanN-terminalcolumn.
ThereasonforthisabnormalityisnotclearbutitmaybeduetodegradationorconcealmentoftheN-terminalsequenceorthepossessionofasequencenotrecognisedbytheantibodies.
Experimentalstudieshaveshownvariousfactorsexhibitatrophiceffectonthesmallintestinalmucosa.
Exogenousgastrinstimulatesgrowthoftheduodenalmucosa,withoutasimilareffectbeingdemonstrabledistallyinthesmallintestine.
22Inourpatient,withnormalfastinggastrinconcentration,hypertrophicvilliwereseenthroughouttheareaexamined,whichwasconfinedtotheduodenalcapandthedescendingduodenum.
Anotherregulatorypeptide,epidermalgrowthfactor,EGF,extractedfromsalivaryandduodenalglandshasbeensuggestedasacandidatefortheroleofentero-trophin,thehormonalcontrollerofintestinalgrowth.
23Anincreaseinduodenalweight,DNAsynthesisandtotalDNAandRNAcontentoftheduodenalmucosahasbeendocumentedafterepidermalgrowthfactoradministration,butthisconflictswithapreviousreportfailingtodemon-stratesimilargrowth.
23Epidermalgrowthfactorassaywasnotavailableinourpatient.
Theeffectofluminalfactorsonintestinaladaptationaftergutresectionhasbeenstudied.
Pancreaticobiliarysecretions24andluminalnutrientsinhyperphagia-'resultedinincreasedmucosalgrowth.
Thesevereatrophyofthesmallintestineoccurringinratsontotalparenterualnutritioncanbepreventedbytheadministrationof15%oftotalcaloriesbytheenteralroute.
25Enterallipids,especiallylongchaintriglycerides,aresuperiortoglycogenandeggalbumeninmaintainingmucosalDNAandtotalproteinweight.
25Itisunclearwhethertheluminalfactorsactdirectlyorbyreleasingatrophichormone.
Inourpatientwehadnoevidenceofexcessiveexocrinepancreaticobiliarysecretionand790onMarch13,2021byguest.
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Theabnormalmentalstateofthepatientinfluencedhisinvestigationandtreatment.
Hismoodrapidlychangedfromfullcooperationtocompleteobstinacy.
Menta.
lsymptoms,usuallydepression,havebeennotedinthepancreaticglucagonomasyndrome.
1314Themetabolicbasisforthesesymptomsandtheotherneurologicalabnormalityfoundinthispatient,namelyalteredperipheralsensation,isunexplained.
ThisworkwassupportedbyagrantfromtheBritishDiabeticAssociationtooneoftheauthors(KDB).
WewishtothankProfessorCFMcCarthy,Depart-mentofMedicine,UniversityCollege,GalwayforhisencouragementandDrNinaCarson,SeniorLecturerinChildHealth,DepartmentofChildHealth,Queen'sUniversityofBelfastfortheplasmaaminogramonthepatient.
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