Zollinger-Ellison Syndrome

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Background

Zollinger-Ellison syndrome (ZES) is caused by a non–beta islet cell, gastrin-secreting tumor of the pancreas that stimulates the acid-secreting cells of the stomach to maximal activity, with consequent gastrointestinal mucosal ulceration.[1, 2, 3] ZES may occur sporadically or as part of an autosomal dominant familial syndrome, multiple endocrine neoplasia type 1 (MEN 1). The primary tumor is usually located in the duodenum, the pancreas, and abdominal lymph nodes, but ectopic locations have also been described (eg, heart, ovary, gall bladder, liver, kidney).

Pathophysiology

The symptoms of Zollinger-Ellison syndrome (ZES) are secondary to hypergastrinemia, which causes hypertrophy of the gastric mucosa, leading to increased numbers of parietal cells and increased maximal acid output. Gastrin by itself also stimulates acid secretion, resulting in increased basal acid secretion. The large quantity of acid produced leads to gastrointestinal mucosal ulceration. It also leads to diarrhea and malabsorption.

Malabsorption in ZES usually is multifactorial, being caused by direct mucosal damage by acid, inactivation of pancreatic enzymes, and precipitation of bile salts. ZES is sporadic in 75% of patients, whereas in the other 25% it is associated with MEN 1, an autosomal dominant condition characterized by hyperparathyroidism, pancreatic endocrine tumors, and pituitary tumors.

Etiology

Zollinger-Ellison syndrome (ZES) is caused by a non–beta islet cell, gastrin-secreting tumor of the pancreas that stimulates the acid-secreting cells of the stomach to maximal activity, with consequent gastrointestinal mucosal ulceration.

ZES may occur sporadically or as part of multiple endocrine neoplasia-type 1 (MEN 1).

Epidemiology

Frequency

United States statistics

Zollinger-Ellison syndrome (ZES) occurs in approximately 0.1-1% of all patients with duodenal ulcers. Its frequency of occurrence is reported to be approximately the same as insulinoma, the most common functioning pancreatic endocrine tumor.

Race-, sex-, and age-related demographics

All races can be affected.

A slight male predominance exists, with a male-to-female ratio of 1.3:1.

The mean age of onset of ZES is 43 years; however, patients with multiple endocrine neoplasia-type 1 and ZES (MEN 1/ZES) present a decade earlier. Generally, a 5- to 7-year delay in diagnosis occurs. In a prospective study, fewer than 3% of patients were younger than 20 years, whereas 7% were older than 60 years at the time of disease onset.

International statistics

Incidence is 1-3 cases per million patients per year in Sweden, 0.5 cases per million patients per year in Ireland, and 0.1-0.2 cases per million patients per year in Denmark.

Prognosis

Prognosis is excellent in patients with Zollinger-Ellison syndrome (ZES) without metastatic disease. Early recognition generally results in more than 80% survival at 15 years.[1]

Morbidity/mortality

In general, the morbidity and mortality of ZES is low because of improved medical and surgical management of the disease. Fewer than 5% of patients develop a complication, such as abdominal perforation, gastric outlet obstruction, or esophageal stricture.

Complications

The following complications may arise in patients with ZES:

History

A high index of clinical awareness is needed to make a diagnosis of Zollinger-Ellison syndrome (ZES), as its signs/symptoms are generally nonspecific.[1, 2]

Abdominal pain is the most common symptom, present in 75% of patients. Typically, it is located in the upper abdomen and mimics that of peptic ulcer disease. This symptom is reported more frequently by men and patients with the sporadic form of ZES.

Of patients with ZES, 73% have diarrhea; this is the most common symptom in patients who have multiple endocrine neoplasia-type 1 and ZES (MEN 1/ZES) as well as in female patients. The combination of diarrhea and abdominal pain is present in more than half the patients.

Heartburn is the third most common symptom, and this symptom mimics gastroesophageal reflux disease (GERD).

Other symptoms include nausea, vomiting, gastrointestinal bleeding, and weight loss. Gastrointestinal bleeding frequently is due to ulceration in the duodenum and is the presenting symptom in 25% of patients.

In patients in whom MEN 1/ZES is suspected, a history indicative of nephrolithiasis, hypercalcemia, and pituitary disorders should be sought. A family history of nephrolithiasis, hyperparathyroidism, and gastrinoma also may be present.

Physical Examination

The findings of the physical examination may be normal. Note the following:

Laboratory Studies

Diagnostic laboratory studies include measurement of gastric pH and levels of fasting gastrin and chromogranin A, as well as secretin stimulation.[1, 3]

Fasting serum gastrin levels

Fasting serum gastrin is the best single screening test for Zollinger-Ellison syndrome (ZES). Preferably, patients should not be taking gastric antisecretory medications at the time of the test, but this is not essential for the initial screen.

Because fasting gastrin levels can fluctuate from day to day and can appear to be normal, serial measurements on different days should be performed.

Normal levels of serum gastrin in untreated ZES are extremely rare (< 1%).

Serum calcium levels

Elevated serum calcium levels should prompt a search for multiple endocrine neoplasia-type 1 (MEN 1) syndrome.

Gastric acid secretory tests

Basal acid output (BAO) greater than 15 mEq/h or greater than 5 mEq/h in patients with a prior vagotomy and partial gastrectomy is suggestive of ZES.

Basal gastric secretory volume greater than 140 mL in patients with no prior gastric acid–reducing surgery has a high sensitivity and specificity.

Gastric pH less than 2.0 in the presence of a large gastric volume (>140 mL over 1 h in patients without prior gastric acid–reducing surgery) is highly suggestive of ZES.

Currently, maximal acid output measurement is rarely performed.

Provocative tests

Various provocative diagnostic tests for ZES have been proposed, including the secretin stimulation test, calcium stimulation test, secretin-plus-calcium stimulation tests, bombesin test, and protein meal test.

The secretin stimulation test is the provocative test of choice because of its higher sensitivity. In this test, a 2-U/kg bolus of secretin is administered intravenously after an overnight fast, and serum levels of gastrin are determined at 0, 2, 5, 10, and 15 minutes. An increase in serum gastrin of greater than 200 pg/mL is diagnostic.

Potential algorithm for suspected gastrinoma

A suggested algorithm for the evaluation of a patient with suspected gastrinoma is as follows:

Imaging Studies

Somatostatin receptor scintigraphy

Somatostatin receptor scintigraphy (SRS) is the most sensitive imaging modality for detection of primary or metastatic lesions in Zollinger-Ellison syndrome (ZES); thus, is the imaging modality of choice in ZES.

Computed tomography scanning

Computed tomography (CT) scanning can be performed to localize the tumor and is useful for evaluation for metastatic disease. However, its sensitivity for primary tumor localization is only 50%, and frequently, tumors smaller than 1 cm are missed.

Positron-emission tomography/CT scanning in conjunction with 68gallium (68Ga)-labeled somatostatin radiotracers (ie,68Ga-DOTATOC, 68Ga-DOTANOC, 68Ga-DOTATATE) yields particularly good results.[1]

Other imaging studies

Magnetic resonance imaging (MRI) and abdominal ultrasonography also can be performed. However, the sensitivity of these modalities is lower than that of CT scanning and SRS.

Endoscopic ultrasonography is one of the relatively newer methods for localizing gastrinomas. Its sensitivity is higher for pancreatic gastrinoma (40-75%) than for duodenal gastrinoma (50%). This imaging modality may be particularly useful in those with ZES and multiple endocrine neoplasia (MEN) type 1.[1]

Procedures

Esophagogastroduodenoscopy

Esophagogastroduodenoscopy should be performed to look for duodenal ulcerations and hypertrophy of gastric folds. Sensitivity for hypertrophic gastric folds is 94%. Rarely, thickened duodenal folds also may be present.

Medical Care

The goals of treatment in patients with Zollinger-Ellison syndrome (ZES) are medical control of gastric acid hypersecretion and surgical resection of the tumor. Inpatient care is aimed at first controlling the gastric acid hypersecretion. Once gastric acid hypersecretion is controlled, imaging studies should be obtained to localize the tumor and determine tumor extent.

If the patient is acutely ill, immediate control of gastric acid hypersecretion can be achieved with intravenous proton pump inhibitors. Previously, this was accomplished with histamine 2 (H2) receptor blockers. Intravenous pantoprazole was approved recently by the US Food and Drug Administration. Proton pump inhibitors are superior to H2 blockers for the control of gastric acid hypersecretion.

Patients who are candidates for surgical resection should be referred for resection of the tumor.

For patients with metastatic disease, chemotherapy, interferon, and octreotide may be helpful. The response to these agents in most studies has been low. Liver transplantation for hepatic metastasis also has been reported. For patients with a single confined liver metastatic lesion, surgical resection may be attempted.

Consultations

Consider consultation with a gastroenterologist, surgeon, oncologist, and/or an endocrinologist.

Surgical Care

All patients with sporadic Zollinger-Ellison syndrome (ZES) without hepatic metastases or medical contraindications to surgery are advised to undergo surgical resection of the tumor because this decreases the risk of developing liver metastases, which can decrease the survival of these patients.

The role and timing of surgical resection in patients with multiple endocrine neoplasia-type 1 (MEN 1) is less clear. An attempt at surgical resection has been recommended if the tumor is larger than 2.5 cm. Cure is rarely achieved by surgical resection in patients with MEN 1; however, it may reduce the risk of subsequent metastatic disease.

In a single-institution retrospective study with a median follow-up of 18 years from the time of the diagnosis of ZES, Mortellaro et al examined the long-term outcomes in 12 patients with MEN 1 and ZES from 1970 to the present.[4] The pancreas (n = 10), duodenum (n = 4), lymph nodes (n = 3), and liver (n = 1) were the most commonly identified gastrinoma sites. A total of 15 celiotomies were performed, and surgeries included 4 each of distal pancreatectomies and acid-reducing procedures, 3 each of enucleation of pancreatic gastrinoma and duodenal resection, 1 pancreaticoduodenectomy, and 7 noted as other.[4] There was 1 each of a patient with transient (3 y) biochemical postsurgical cure and liver metastasis of gastrinoma (but no deaths from metastatic gastrinoma).[4]

Deaths included causes such as respiratory arrest (n = 1), possibly due to aspiration or pulmonary embolus, and nondisease related (n = 3). At the last follow-up, 7 patients were alive. The investigators observed patients with MEN 1 and ZES rarely achieve biochemical cures with surgery; however, extended surgical resection was not only not needed in resection of localized gastrinomas, but it was also associated with excellent long-term outcomes.[4]

There is a case report of a young adolescent male with primary lymph node gastrinoma and liver metastasis that caused ZES. This patient was successfully managed with preoperative cytoreduction followed by surgical resection of the residual mass, which had a 100% response and 4-year followup.[5]

Because gastrinoma is a rare tumor, surgical resection should be attempted only at centers with personnel experienced in treating affected patients.

Outpatient postoperative care

After surgical resection of a gastrinoma, patients should be assessed for evidence of recurrence with serum fasting gastrin levels, a secretin test, and SRS. The first evaluation should be performed at 3-6 months postresection and then, optimally, yearly thereafter.

Proton pump inhibitors can be continued with the goal of maintaining the basal acid output (BAO) below 10 mEq/h before the next dose of the proton pump inhibitors.

Medication Summary

Medical therapy is aimed at control of gastric acid hypersecretion. Proton-pump inhibitors (PPIs) have been the medications of choice in managing patients with Zollinger-Ellison syndrome (ZES).

Omeprazole (Prilosec)

Clinical Context:  Decreases gastric acid secretion by inhibiting parietal cell H+/K+ ATP pump. Aim of therapy is to maintain BAO < 10 mmol 1 h prior to next dose.

Lansoprazole (Prevacid)

Clinical Context:  Decreases gastric acid secretion by inhibiting parietal cell H+/K+ ATP pump. Aim of therapy is to maintain BAO < 10 mmol 1 h prior to next dose.

Pantoprazole (Protonix)

Clinical Context:  Decreases gastric acid secretion by inhibiting parietal cell H+/K+ ATP pump. Aim of therapy is to maintain BAO < 10 mmol 1 h prior to next dose.

Esomeprazole magnesium (Nexium)

Clinical Context:  S-isomer of omeprazole used for symptomatic GERD. Inhibits gastric acid secretion by inhibiting H+/K+ ATP pump at secretory surface of gastric parietal cells.

Rabeprazole sodium (Aciphex)

Clinical Context:  Decreases gastric acid secretion by inhibiting the parietal cell H+/K+ ATP pump. For short-term (4-8 wk) treatment and relief of symptomatic erosive or ulcerative GERD. In patients not healed after 8 wk, consider an additional 8-wk course.

Class Summary

Drugs of choice in ZES. Inhibit gastric acid secretion by inhibition of the H+/K+/ATP-ase enzyme system in the gastric parietal cells.

What is Zollinger-Ellison syndrome (ZES)?What is the pathophysiology of Zollinger-Ellison syndrome (ZES)?What causes Zollinger-Ellison syndrome (ZES)?What is the prevalence of Zollinger-Ellison syndrome (ZES) in the US?Which patient groups have the highest prevalence of Zollinger-Ellison syndrome (ZES)?What is the global prevalence of Zollinger-Ellison syndrome (ZES)?What is the prognosis of Zollinger-Ellison syndrome (ZES)?What are the possible complications of Zollinger-Ellison syndrome (ZES)?Which clinical history findings are characteristic of Zollinger-Ellison syndrome (ZES)?Which physical findings are characteristic of Zollinger-Ellison syndrome (ZES)?Which conditions are included in the differential diagnoses of Zollinger-Ellison syndrome (ZES)?What are the differential diagnoses for Zollinger-Ellison Syndrome?Which lab tests are performed in the workup of Zollinger-Ellison syndrome (ZES)?What is the role of fasting serum gastrin levels in the workup of Zollinger-Ellison syndrome (ZES)?What is the role of serum calcium levels in the workup of Zollinger-Ellison syndrome (ZES)?What is the role of gastric acid secretory tests in the workup of Zollinger-Ellison syndrome (ZES)?What is the role of provocative tests in the workup of Zollinger-Ellison syndrome (ZES)?How is suspected gastrinoma evaluated in the workup of Zollinger-Ellison syndrome (ZES)?What is the role of SRS in the workup of Zollinger-Ellison syndrome (ZES)?What is the role of CT scanning in the workup of Zollinger-Ellison syndrome (ZES)?What is the role of MRI in the workup of Zollinger-Ellison syndrome (ZES)?What is the role of ultrasonography in the workup of Zollinger-Ellison syndrome (ZES)?What is the role of esophagogastroduodenoscopy in the workup of Zollinger-Ellison syndrome (ZES)?How is Zollinger-Ellison syndrome (ZES) treated?Which specialist consultations are beneficial to patients with Zollinger-Ellison syndrome (ZES)?What is the role of surgery in the treatment of Zollinger-Ellison syndrome (ZES)?What is included in the long-term monitoring of Zollinger-Ellison syndrome (ZES)?What is the role of medical therapy in the treatment of Zollinger-Ellison syndrome (ZES)?Which medications in the drug class Proton pump inhibitors are used in the treatment of Zollinger-Ellison Syndrome?

Author

Praveen K Roy, MD, AGAF, Clinical Assistant Professor of Medicine, University of New Mexico School of Medicine

Disclosure: Nothing to disclose.

Coauthor(s)

Homayoun Shojamanesh, MD, Former Fellow, Digestive Diseases Branch, National Institutes of Health

Disclosure: Nothing to disclose.

Sarah D Komanapalli, MBBS, Resident Physician in Internal Medicine, Marshfield Clinic

Disclosure: Nothing to disclose.

Showkat Bashir, MD, Assistant Professor, Department of Medicine, Division of Gastroenterology, George Washington University, Washington, DC

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

BS Anand, MD, Professor, Department of Internal Medicine, Division of Gastroenterology, Baylor College of Medicine

Disclosure: Nothing to disclose.

Chief Editor

Philip O Katz, MD, FACP, FACG, Chairman, Division of Gastroenterology, Albert Einstein Medical Center; Clinical Professor of Medicine, Jefferson Medical College of Thomas Jefferson University

Disclosure: Serve(d) as a speaker or a member of a speakers bureau for: Medtronic<br/>Received income in an amount equal to or greater than $250 from: Torax medical: pfizer consumer, .

Additional Contributors

Anil Minocha, MD, FACP, FACG, AGAF, CPNSS, Professor of Medicine, Director of Digestive Diseases, Medical Director of Nutrition Support, Medical Director of Gastrointestinal Endoscopy, Internal Medicine Department, University of Mississippi Medical Center; Clinical Professor, University of Mississippi School of Pharmacy

Disclosure: Nothing to disclose.

Acknowledgements

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous coauthor, Jehad Barakat, MD, to the development and writing of this article.

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