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.