ZollingerZollinger--EllisonEllison SyndromeSyndrome andand AcidAcid HypersecretionHypersecretion

CoreCore CurriculumCurriculum ConferenceConference SeptemberSeptember 3,3, 20092009 GarrettGarrett OggOgg ZollingerZollinger--EllisonEllison SyndromeSyndrome

„ First described by Robert Zollinger and Edwin Ellison in the Annals of Surgery, October 1955.

„ Presented 2 cases with jejunal ulcers demonstrating marked gastric hypersecretion and hyperacidity.

„ Refractory to surgical therapy necessitating total gastrectomy.

„ In 1968, McGuigan and Trudeau showed elevated gastrin levels in patients with ZES. ZollingerZollinger--EllisonEllison SyndromeSyndrome

„ ClassicClassic TriadTriad ofof ZES:ZES: „ SevereSevere pepticpeptic ulcerulcer diseasedisease „ GastricGastric acidacid hypersecretionhypersecretion „ NonbetaNonbeta cellcell gastringastrin producingproducing tumortumor ofof pancreaspancreas GastrinGastrin PhysiologyPhysiology GastrinGastrin PhysiologyPhysiology

„ StimulantsStimulants ofof Gastrin:Gastrin: „ Luminal amino acids „ Elevated gastric pH GastrinGastrin PhysiologyPhysiology

„ GastrinGastrin stimulatesstimulates fundicfundic enterochromafinenterochromafin likelike (ECL)(ECL) cellscells toto secretesecrete histamine.histamine.

„ HistamineHistamine actsacts onon parietalparietal cellscells toto releaserelease HH+.. Acidic Gastric pH Negative Feedback to Gastrin

D‐cell CGRP Enteric Nerves

Somatostatin

G‐cell X Gastrin

CGNP=Calcitonin gene‐related peptide PathologyPathology

„ Gastrinomas are derived from multipotential stem cells of endodermal origin.

„ Like other neuroendocrine tumors, typically stain positive for chromogranins, neuron specific enolase, and synaptophysins.

„ Expanded glandular compartment do to excess parietal cells PathologyPathology

„ Most gastrinomas occur in the pancreas and duodenum in “Gastrinoma Triangle”.

„ Duodenum (50-70%) „ Often multiple, < 2cm, and less malignant st nd „ More than 90% in 1st or 2nd portion

„ Pancreas (25%) „ Solitary, >2 cm, and more malignant

„ Lymph node adjacent to the pancreas (5%) GastrinomaGastrinoma TriangleTriangle

EpidemiologyEpidemiology

„ 0.10.1 toto 33 patientspatients perper millionmillion „ MeanMean ageage atat timetime ofof diagnosisdiagnosis isis 4141 yrs.yrs. „ 1.5:11.5:1 toto 2:12:1 -- Male:FemaleMale:Female „ SporadicSporadic 78%,78%, MENMEN--II 22%22% „ H.H. pyloripylori (+)(+) –– 1010--50%50% „ LocalizedLocalized diseasedisease –– 70%70% „ MeanMean delaydelay ofof diagnosisdiagnosis –– 5.25.2 yrs.yrs.

Roy P, Venzon DJ, Shojamanesh H, et al. Medicine 2000; 79:379. Jensen et al. Lippincott Williams and Wilkins;2001:291

Berna MJ; Hoffmann KM; et al. Medicine. 2006 Nov;85(6):295-330. PresentationPresentation

Data from Roy, PK, Venzon, DJ, Shojamenesh, H, et al, Medicine (Baltimore) 2000; 79:379 PresentationPresentation

„ ClinicalClinical featuresfeatures suspicioussuspicious forfor ZESZES „ Postbulbar duodenal ulcer „ Multiple duodenal or jejunal ulcers „ PUD with chronic diarrhea „ PUD refractory to medical therapy „ History of PUD and nephrolithiasis „ Recurrent PUD in absence of H.pylori or NSAIDS „ Family history of PUD and hypercalcemia

Feldman: Sleisenger & Fordtran's GI and Liver Disease, 8th ed. DiagnosisDiagnosis

„ FastingFasting serumserum gastringastrin concentrationconcentration

„ SecretinSecretin stimulationstimulation testtest

„ GastricGastric acidacid secretionsecretion studiesstudies FastingFasting SerumSerum GastrinGastrin

„ UpperUpper limitlimit ofof normalnormal isis 110110 pg/mlpg/ml „ GastrinGastrin ofof >> 10001000 inin settingsetting ofof gastricgastric pHpH ofof lessless thanthan 55 isis highlyhighly specificspecific forfor ZES.ZES. „ 2/32/3 havehave gastringastrin levelslevels 150150--10001000 pg/mlpg/ml „ FalseFalse positivepositive withwith PPIPPI’’ss -- mustmust bebe offoff moremore thanthan oneone week.week. „ ChronicChronic atrophicatrophic gastritisgastritis oror severesevere H.H. pyloripylori cancan givegive falsefalse positivepositive SecretinSecretin StimulationStimulation TestTest

„ UsefulUseful forfor confirmationconfirmation ofof ZESZES inin patientspatients withwith indeterminateindeterminate gastringastrin levelslevels

„ SecretinSecretin stimulatesstimulates gastringastrin releaserelease fromfrom gastrinomasgastrinomas

„ SecretinSecretin inhibitsinhibits normalnormal GG--cellscells SecretinSecretin StimulationStimulation TestTest

„ SecretinSecretin 0.40.4 µµg/kgg/kg IVIV overover 11 minuteminute „ MeasureMeasure baselinebaseline gastringastrin twicetwice andand thenthen 2,2, 5,5, 10,10, 15,15, andand 2020 minutesminutes postpost infusioninfusion „ TraditionallyTraditionally -- positivepositive ifif gastringastrin increasesincreases byby 200pg/mL200pg/mL oror moremore „ Sens 83%, Spec 100% „ UsingUsing aa cutcut offoff ofof 120pg/mL120pg/mL increasesincreases „ Sens 94%, Spec 100% (1) „ PeakPeak atat aboutabout 55--1010 minutesminutes

(1) Berna et al. Medicine (Baltimore) 2006;85,331 SecretinSecretin StimulationStimulation TestTest OtherOther TestsTests

„ ChromograninChromogranin AA „ GeneralGeneral markermarker forfor neuroendocrineneuroendocrine tumorstumors „ LevelLevel correlatescorrelates withwith tumortumor volumevolume „ LessLess sensitivesensitive andand specificspecific thanthan secretin,secretin, butbut cancan bebe usedused forfor confirmationconfirmation EndoscopicEndoscopic FindingsFindings EndoscopicEndoscopic FindingsFindings DifferentialDifferential DiagnosisDiagnosis ofof HypergastrenemiaHypergastrenemia

„ Acid-suppressive „ Massive small bowel medications resection „ Chronic atrophic gastritis „ Ovarian cancer „ Diabetes mellitus „ Pernicious Anemia „ Foregut carcinoid „ Pheochromocytoma (histamine) „ Renal insufficiency „ Gastrin cell „ Retained gastric antrum hyperplasia/hyperfunction „ Rheumatoid arthritis „ Gastric outlet obstruction „ Systemic mastocytosis „ H. pylori infection „ Vitiligo „ Idiopathic „ ZE „ Increased intracranial pressure

TumorTumor LocalizationLocalization

„ TwoTwo mainmain modalitiesmodalities areare octreotideoctreotide scanscan andand EUSEUS „ >90%>90% ofof tumorstumors areare identifiedidentified ifif bothboth modalitiesmodalities areare usedused „ Alternatives:Alternatives: „ HelicHelicaall CT,CT, MRI,MRI, angiography,angiography, arterialarterial stimulation,stimulation, venousvenous sampling,sampling, andand laparotomylaparotomy TumorTumor LocalizationLocalization

Gastrinoma ZESZES AlgorithmAlgorithm PrognosisPrognosis ofof ZESZES

„ MostMost importantimportant factorfactor isis presencepresence oror absenceabsence ofof liverliver metastasismetastasis „ Patients with liver metastases had a 10-year survival of only 30 percent compared to a 15-year survival of 83 percent in those without liver metastases

„ LowerLower curecure ratesrates withwith MENMEN II

„ CushingCushing’’ss syndromesyndrome fromfrom ectopicectopic ACTHACTH releaserelease byby gastrinomagastrinoma associatedassociated withwith aggressiveaggressive diseasedisease ManagementManagement

ZES Confirmed

PPI

Tumor Evaluation

No Liver Metastases Liver Metastases

Men I Status Evaluation Octreotide

If response, surgical If no response, consider adding resection, RFA, or Positive Negative Chemotherapy or interferon chemoembolization

Tumor > 2 cm Tumor < 2 cm Exploratory Laparotomy

Consider Exploratory Follow Laparotomy Tumor Status (+) (-)

Resection Parietal Cell Vagotomy MedicalMedical ManagementManagement

„ Goal:Goal: LimitLimit complicationscomplications ofof diseasedisease „ ProtonProton pumppump inhibitorsinhibitors „ OmeprazOmeprazoolele 6060 mgmg QDQD –– BIDBID (or(or itsits equivalent)equivalent) isis sufficientsufficient inin 95%95% ofof patientspatients „ EsomeprazoleEsomeprazole 120120 mgmg QDQD--BIDBID „ LansoprazoleLansoprazole 4545 mgmg QDQD--BIDBID „ RabeprazoleRabeprazole 6060 mgmg QDQD--BIDBID „ PantoprazolePantoprazole 120120 mgmg QDQD--BIDBID MedicalMedical ManagementManagement

„ HistamineHistamine 22 receptorreceptor antagonistsantagonists (also(also effective)effective) „ Require higher dosing „ Cimetidine – 3.6 g/day „ Ranitidine - 1.2 g/day „ Famotidine – 0.25 g/day

„ MENMEN--11 patientspatients seemseem toto bebe moremore resistantresistant toto medicalmedical treatmenttreatment SurgicalSurgical ManagementManagement

„ AcidAcid reducingreducing surgerysurgery suchsuch asas gastrectomygastrectomy andand vagotomyvagotomy areare rarerare sincesince thethe introductionintroduction ofof PPIPPI’’s.s.

„ ConsiderConsider curativecurative surgerysurgery ifif tumortumor sizesize isis lessless thanthan 22 cm.cm. MetastaticMetastatic DiseaseDisease

„ TumorsTumors spreadspread toto liverliver first,first, thenthen bonebone (spine(spine andand sacrum)sacrum)

„ TreatmentTreatment optionsoptions „ Octreotide can decrease fasting serum gastrin levels „ Hepatic lobectomy in the absence of bilobar disease „ Hepatic arterial embolization „ Radiofrequency ablation, cyroablation „ Liver transplant (investigational) „ Chemotherapy – response rate 10-40% MENMEN II (Wermer(Wermer’’ss Syndrome)Syndrome)

„ PrimaryPrimary hyperparathyroidismhyperparathyroidism

„ PituitaryPituitary adenomasadenomas

„ PancreaticPancreatic isletislet cell/gastrointestinalcell/gastrointestinal adenomasadenomas (ZE,(ZE, insulinomas,insulinomas, nonnon--functioningfunctioning pancreaticpancreatic tumors)tumors) MKSAPMKSAP 1414

„ AA 3333--yearyear--oldold womanwoman hashas aa 33--weekweek historyhistory ofof burningburning epigastricepigastric pain,pain, nausea,nausea, intermittentintermittent vomitingvomiting ofof partiallypartially digesteddigested food,food, andand earlyearly satiety.satiety. TheThe painpain improvesimproves slightlyslightly withwith antacids.antacids. MedicalMedical historyhistory includesincludes aa duodenalduodenal ulcerulcer thatthat waswas treatedtreated

withwith anan HH2--receptorreceptor antagonist.antagonist. SheShe isis otherwiseotherwise healthyhealthy andand takestakes nono medications.medications. MKSAPMKSAP 1414

„ PhysicalPhysical examinationexamination isis normalnormal exceptexcept forfor midmid--epigastricepigastric tendernesstenderness toto palpation.palpation. UpperUpper endoscopyendoscopy showsshows severalseveral gastricgastric antralantral ulcersulcers withwith somesome narrowingnarrowing ofof thethe pyloricpyloric channelchannel andand aa moderatemoderate amountamount ofof retainedretained food.food. TheThe fastingfasting serumserum gastringastrin levellevel isis 420420 pg/mLpg/mL (420(420 ng/L).ng/L). MKSAPMKSAP 1414

„ WhichWhich ofof thethe followingfollowing isis thethe mostmost appropriateappropriate nextnext stepstep inin managingmanaging thisthis patient?patient? „ A. Endoscopic ultrasonography of the pancreas „ B. Fasting serum gastrin measurement after pyloric dilation „ C. Helical CT scan of the abdomen „ D. Somatostatin receptor scintigraphy „ E. Surgical exploration for a primary tumor Questions?