Zollinger-Ellison Zollinger-Ellison SyndromeSyndrome

History:History:

This syndrome was first described in This syndrome was first described in 1955 by Robert Zollinger and Edwin 1955 by Robert Zollinger and Edwin Ellison, surgeons at the Ohio State Ellison, surgeons at the Ohio State University.University.

DefinitionDefinition

Zollinger-Ellison syndrome (ZES) is a Zollinger-Ellison syndrome (ZES) is a rare condition caused by a gastrin-rare condition caused by a gastrin-secreting tumour that causes secreting tumour that causes hypersecretion of gastric acid hypersecretion of gastric acid leading to ulcer disease.leading to ulcer disease.

Pathogenesis:-Pathogenesis:-√ Gastrin works on stomach parietal cells Gastrin works on stomach parietal cells

causing them to secrete more hydrogen ions causing them to secrete more hydrogen ions into the stomach lumen.into the stomach lumen.

√ In addition, gastrin acts as a trophic factor for In addition, gastrin acts as a trophic factor for parietal cells, causing parietal cell parietal cells, causing parietal cell hyperplasia.hyperplasia.

√ Thus there is an increase in the number of Thus there is an increase in the number of acid-secreting cells, and each of these cells acid-secreting cells, and each of these cells produces acid at a higher rate.produces acid at a higher rate.

√ The increase in acidity contributes to the The increase in acidity contributes to the development of peptic ulcers in the stomach development of peptic ulcers in the stomach and duodenum.and duodenum.

√ High acid levels lead to multiple ulcers in the High acid levels lead to multiple ulcers in the stomach and small bowel.stomach and small bowel.

Most tumors (≥80%) occur in the duodenum Most tumors (≥80%) occur in the duodenum and in the head of the pancreas.and in the head of the pancreas.

Frequently, multiple tumors are present.Frequently, multiple tumors are present.Commonly it occurs in gastrinoma triangle, Commonly it occurs in gastrinoma triangle,

also called also called PsarosPsaros triangle. triangle. Junction Of Cystic Duct With CBDJunction Of Cystic Duct With CBD Junction Between Head And Neck Of PancreasJunction Between Head And Neck Of Pancreas Junction Between 2Junction Between 2ndnd And 3 And 3rdrd Parts Of Parts Of

DuodenumDuodenum

Approximately 50-60% are malignant and Approximately 50-60% are malignant and metastasize.metastasize.

Zollinger-Ellison SyndromeZollinger-Ellison SyndromeThere are two types of ZES:There are two types of ZES:

– Sporadic Form – 80% Sporadic Form – 80%

– Associated with multiple endocrine Associated with multiple endocrine neoplasia type 1 (MEN 1). – 20%neoplasia type 1 (MEN 1). – 20%

EpidemiologyEpidemiology

√ In the U.S. 0.1-1% of patients with In the U.S. 0.1-1% of patients with duodenal ulcers have ZES.duodenal ulcers have ZES.

√ All racesAll races√ Male:Female 1.5:1Male:Female 1.5:1√ Age – diagnosis in 30s-50sAge – diagnosis in 30s-50s√ Mean age of diagnosis approximately Mean age of diagnosis approximately

40 40 yearsyears

Clinical FeaturesClinical Features

Abdominal PainAbdominal Pain 70%70%

DiarrheaDiarrhea 70%70%HeartburnHeartburn 50%50%NauseaNausea 25%25%VomitingVomiting 20%20%Weight LossWeight Loss 15%15%

Clinical FeaturesClinical Features

– Ninety percent develop peptic ulcers, Ninety percent develop peptic ulcers, leading to abdominal pain.leading to abdominal pain.

– Diarrhea is due to a) large volume of Diarrhea is due to a) large volume of acid being produced in the stomach, b) acid being produced in the stomach, b) neutralization of pancreatic bicarbonate neutralization of pancreatic bicarbonate and enzymes, c) inhibited Na and H20 and enzymes, c) inhibited Na and H20 reabsorption by small intestines due to reabsorption by small intestines due to low pHlow pH

– Often are malnourished.Often are malnourished.

Clinical FeaturesClinical Features

– IfIf MEN 1/ZES is suspected, look for MEN 1/ZES is suspected, look for a h/o nephrolithiasis, a h/o nephrolithiasis, hypercalcemia, and pituitary hypercalcemia, and pituitary disorders. A FH of nephrolithiasis, disorders. A FH of nephrolithiasis, hyperparathyroidism, and hyperparathyroidism, and gastrinoma also may be present. gastrinoma also may be present.

Diagnosis (Multi-Step Diagnosis (Multi-Step Approach)Approach)

•Step 1: Check serum gastrin level. Step 1: Check serum gastrin level. •Step 2: Perform a provocative test. (Secretin Step 2: Perform a provocative test. (Secretin

stimulation test)stimulation test)•Step 3: Perform Octreotide Scan.Step 3: Perform Octreotide Scan.•Step 4: Stage and localize the gastrinoma. Step 4: Stage and localize the gastrinoma. •Step 5: Determine if it is surgical disease.Step 5: Determine if it is surgical disease.

Step 1Step 1: Check serum gastrin levels: Check serum gastrin levelsoMust be fastingMust be fastingoSome recommend checking 3 fasting Some recommend checking 3 fasting

levels on different dayslevels on different daysoMost helpful if also check gastric pH Most helpful if also check gastric pH

to exclude secondary to exclude secondary hypergastrinemia (pernicious anemia)hypergastrinemia (pernicious anemia)oA serum gastrin level above 1000 A serum gastrin level above 1000

pg/mL with a concurrent gastric pH of pg/mL with a concurrent gastric pH of < 5.0 is virutally diagnostic.< 5.0 is virutally diagnostic.oMost ZES patients will have a value Most ZES patients will have a value

between 150 and 1000 pg/mL. between 150 and 1000 pg/mL.

Step 2Step 2: Perform a provocative : Perform a provocative testtest

– Done if serum gastrin level is non-diagnosticDone if serum gastrin level is non-diagnostic– Secretin Stimulation Test is test of choice.Secretin Stimulation Test is test of choice.– This is done to differentiate hypergastrinemia as This is done to differentiate hypergastrinemia as

a result of gastrinomas from other causes of a result of gastrinomas from other causes of elevated gastrin levels.elevated gastrin levels.

– Secretin stimulates gastrin release by Secretin stimulates gastrin release by gastrinomas, but inhibitis its release by gastric G gastrinomas, but inhibitis its release by gastric G cells (unknown mechanism)cells (unknown mechanism)

– Gastrin measurements are made pre and post Gastrin measurements are made pre and post secretin infusion and a rise by 200 pg/mL or secretin infusion and a rise by 200 pg/mL or more is greater than 90% sens and spec for ZES. more is greater than 90% sens and spec for ZES.

Step 3Step 3: Octreotide Scan: Octreotide Scan

– A nuclear medicine study A nuclear medicine study that uses 111-Indium-that uses 111-Indium-penetreotide to identify “hot penetreotide to identify “hot spots” of octreotide uptake spots” of octreotide uptake by the gastrinoma. by the gastrinoma.

– The recommended initial The recommended initial imaging modality because it imaging modality because it has the highest sensitivity has the highest sensitivity (67%)(67%)

Step 4:Step 4: Stage and localize the Stage and localize the gastrinomagastrinoma

– USUS– EndoscopyEndoscopy– CT scanCT scan– Somatostatin-receptor scintigraphySomatostatin-receptor scintigraphy– MRIMRI– Selective angiographySelective angiography

EndoscopyEndoscopy

Will reveal prominent mucosal folds and large amount of acid in stomach.Along with multiple gastric and duodenal ulcers.

Zollinger-Ellison SyndromeZollinger-Ellison SyndromeStep 5Step 5: Determine if it is : Determine if it is

surgical diseasesurgical disease– All patients with the All patients with the

sporadic form of Zollinger-sporadic form of Zollinger-Ellison syndrome and Ellison syndrome and without any metastatic without any metastatic disease should be offered disease should be offered surgical resection of the surgical resection of the primary tumor. primary tumor.

TreatmentTreatment

– Two goals of treatmentTwo goals of treatment

√Control the effects of gastrinControl the effects of gastrin

√ Control the tumorControl the tumor

TreatmentTreatment

– Prior to the advent of effective acid Prior to the advent of effective acid suppression therapy, the major suppression therapy, the major morbidity and mortality arose from morbidity and mortality arose from fulminant PUD. Total gastrectomy fulminant PUD. Total gastrectomy was the only effective therapy. was the only effective therapy.

TreatmentTreatment

Medical Management:Medical Management:√ High-dose proton pump inhibitorsHigh-dose proton pump inhibitors

oOmeprazole 60 mg dailyOmeprazole 60 mg dailyoEsomeprazole 120 mg dailyEsomeprazole 120 mg dailyoLansoprazole 45 mg dailyLansoprazole 45 mg dailyoRabeprazole 60 mg dailyRabeprazole 60 mg daily

TreatmentTreatment

– Surgical TreatmentSurgical TreatmentoOnly really effective for patients with Only really effective for patients with

sporadic disease without evidence for sporadic disease without evidence for metastasis. metastasis.

oUp to 1/3 can be cured surgically.Up to 1/3 can be cured surgically.oNot recommended for patients with ZES as a Not recommended for patients with ZES as a

part of MEN1 because of the multifocal part of MEN1 because of the multifocal nature of the tumors. nature of the tumors.

TreatmentTreatmentSurgery:Surgery:oType 1 Type 1 partial gastrectomy –to remove partial gastrectomy –to remove

G cells bearing areaG cells bearing areaoType 2 Type 2 if tumor is small, removal of if tumor is small, removal of

tumor can be done(enucleation)tumor can be done(enucleation)o If If tumor is large tumor is large , acid suppression is , acid suppression is

done by conservative method. Total done by conservative method. Total gastrectomy is the last resort.gastrectomy is the last resort.

TreatmentTreatmentfor metastatic disease is limitedfor metastatic disease is limited

– Somatastatin analogsSomatastatin analogs– Interferon alfaInterferon alfa– Cytotoxic chemotherapyCytotoxic chemotherapy– Surgical resectionSurgical resection– Hepatic arterial chemoembolizationHepatic arterial chemoembolization

SummarySummaryo Gastrin-producing neuroendocrine tumour, which Gastrin-producing neuroendocrine tumour, which

causes gastric acid hypersecretion and peptic causes gastric acid hypersecretion and peptic ulcer disease.ulcer disease.

o Can be sporadic or associated with multiple Can be sporadic or associated with multiple endocrine neoplasia syndrome type 1.endocrine neoplasia syndrome type 1.

o Common presentation includes refractory peptic Common presentation includes refractory peptic ulcer disease, abdominal pain, diarrhoea and ulcer disease, abdominal pain, diarrhoea and gastro-oesophageal disease.gastro-oesophageal disease.

o The main goal of treatment is control of gastric The main goal of treatment is control of gastric hypersecretion with proton-pump inhibitors.hypersecretion with proton-pump inhibitors.

o The most common cause of morbidity and The most common cause of morbidity and mortality is metastatic gastrinoma.mortality is metastatic gastrinoma.

Thank you!Thank you!