eMedicine Specialties > Pediatrics: General Medicine > Gastroenterology

Zollinger-Ellison Syndrome: Differential Diagnoses & Workup

Author: Stefano Guandalini, MD, Director, University of Chicago Celiac Disease Program, Section Chief of Gastroenterology, Hepatology and Nutrition; Professor, Department of Pediatrics, University of Chicago Comer Children's Hospital
Coauthor(s): Klaus Radebold, MD, PhD, Research Associate, Department of Surgery, Yale University School of Medicine
Contributor Information and Disclosures

Updated: Dec 1, 2008

Differential Diagnoses

Diarrhea
Helicobacter Pylori Infection
Esophagitis
Malabsorption Syndromes
Gastroesophageal Reflux
Multiple Endocrine Neoplasia
Gastrointestinal Bleeding: Surgical Perspective
Peptic Ulcer Disease
Gastrointestinal Neoplasms

Other Problems to Be Considered

Hypochlorhydria due to chronic atrophic gastritis
Prolonged proton pump inhibitor (PPI) use
GI bleeding
Gastric outlet obstruction

Workup

Laboratory Studies

Laboratory studies to confirm the diagnosis of Zollinger-Ellison syndrome (ZES) include the following:

  • Measurements of fasting serum gastrin levels
    • Gastrin levels higher than 100 pg/mL are highly suggestive of Zollinger-Ellison syndrome. If the gastric pH level is less than 2, a gastrin level of higher than 1000 pg/mL is diagnostic of Zollinger-Ellison syndrome.
    • If the patient is not receiving acid-suppressing medication and the gastric pH levels are higher than 2, Zollinger-Ellison syndrome can be ruled out.
  • Secretin stimulation test
    • If the gastrin level is 100-1000 pg/mL and the pH level is less than 2, a secretin stimulation test must be performed.
    • After blood to measure the basal gastrin level is obtained, 2 IU/kg of secretin is intravenously administered. Blood is obtained at 2.5 minutes, 5 minutes, 10 minutes, 15 minutes, and 30 minutes. An increase of serum gastrin levels to higher than 200 pg/mL is diagnostic of Zollinger-Ellison syndrome.
    • The physiologic mechanism of the secretin test remains unclear; however, it is the most important diagnostic test to exclude other conditions with increased acid secretion, hypergastrinemia, or both.
    • Clinical conditions in which patients present with hypergastrinemia, such as gastric outlet obstruction, pernicious anemia, renal failure, and achlorhydria due to atrophic gastritis, must be excluded with secretin provocative testing.
  • Measurement of basal acid output
    • Before measurement of the basal acid output (BAO), acid-inhibitory agents must be discontinued: 24 hours for H2-receptor antagonists and 7 days for proton pump inhibitors (PPIs).
    • In the 24 hours prior to the test, the patient receives antacids.
    • A nasogastric tube is placed into the antrum, and the stomach is emptied.
    • Four consecutive samples of gastric fluid are collected; a quadruplicate of each sample is titrated to pH 7 with 0.2 N sodium hydroxide, whereas the BAO is determined with a radiometer titrator.
    • In an unoperated stomach, a BAO of more than 15 mEq/h is diagnostic of Zollinger-Ellison syndrome. If the patient underwent gastric resection for acid reduction, a BAO of more than 10 mEq/h is diagnostic for Zollinger-Ellison syndrome.
  • If the patient has multiple endocrine neoplasia type 1 (MEN-1), other laboratory abnormalities may be suggestive of Zollinger-Ellison syndrome.
    • High plasma calcium levels
    • High parathyroid hormone (PTH) levels
    • High prolactin levels

Imaging Studies

Because most gastrinomas are smaller than 2 cm, visualizing them with conventional imaging techniques, such as CT scanning, transabdominal ultrasonography, and MRI, is difficult.

  • Somatostatin receptor scintigraphy (SRS) can reveal 57-78% of gastrinomas and has a sensitivity of 84-94%. It is currently the single most effective imaging modality for gastrinomas. SRS may not accurately reveal tumor size or location and is best used in conjunction with CT scanning with intravenous contrast. It is also useful because it allows for whole body scanning and measure of whole body tumor content during a single test.
  • CT scanning with intravenous contrast and MRI are highly specific for gastrinoma, with reports of 83-100% specificity using MRI. However, sensitivities range from 20-59%.
  • Transabdominal ultrasonography has a sensitivity of 0-28% but may be useful in screening for metastatic disease of the liver, with reported sensitivities of 14-63%. Specificity ranges from 92-100%.
  • Angiography has been used with limited success because of difficulties in discriminating between the relative vascularity of the gastrinoma lesion and the surrounding tissue. It has a sensitivity of 28-68%.
  • In one study, intra-arterial secretin stimulation with hepatic venous sampling yielded a sensitivity rate of 89%; however, because of its invasive nature, it is only used when other imaging techniques are ineffective.

Other Tests

  • Endoscopic ultrasonography (EUS) may reveal structures as small as 2 mm, mainly in the pancreas. Reported sensitivities are 58-100%. One study found a sensitivity of 93% and a specificity of 95% for pancreatic lesions. Specificity is reported to be 84-100%. EUS is limited in its ability to reveal duodenal gastrinomas and can fail to visualize up to one half of them. The successful and safe use of EUS in pediatrics, which requires special equipment, has recently been described in children aged 4-16 years.
  • Portal venous sampling has been described in adults with Zollinger-Ellison syndrome but not in children, with a positive yield of 46-90%; however, it is associated with a complication rate of 10% and is recommended only as a last resort.

Procedures

  • Endoscopy may be used to evaluate recurrent abdominal pain with or without GI bleeding. Ulcers typical of Zollinger-Ellison syndrome and biopsy findings may help to confirm the diagnosis. Endoscopy is also indicated to stage peptic ulcer disease (PUD). If findings are consistent with Zollinger-Ellison syndrome, immediate treatment with PPIs and further diagnostic studies are indicated to localize the tumor.
  • Operative techniques such as palpation, duodenal transillumination, and intraoperative ultrasonography can be used during laparotomy for the 20% of gastrinomas that SRS and other imaging studies fail to visualize.

Histologic Findings

  • Neuroendocrine tumors (NETs), including gastrinomas, are composed of homogenous sheets of cells with small compact nuclei and prominent nucleoli. The tumors can be glandular or trabecular. Gastrin-producing cells are often well differentiated.
  • Immunohistochemistry staining may be positive for chromogranin A, neuron-specific enolase, and synaptophysin, as well as for pancreatic peptide, somatostatin, adrenocorticotropic hormone (ACTH), and vasoactive intestinal polypeptide (VIP).
  • In a series of 57 patients with MEN-1 and Zollinger-Ellison syndrome, no patient had consistently normal gastric biopsy findings, and 47% had diffuse hyperplasia as the most advanced gastric enterochromaffinlike (ECL) cell changes, 25% had linear hyperplasia, 3.5% had micronodular hyperplasia, and 1.8% had dysplasia. In 23% of the patients, (average age at biopsy, 47 y) a carcinoid was found.

Staging

Staging is based on tumor size (>2-3 cm) and metastases to the lymph nodes, liver, or both. Metastases to the liver are associated with poor prognosis and have been reported to occur in roughly 60% of patients with pancreatic gastrinoma versus less than 10% in patients with duodenal gastrinoma.

  • Tumor size does not relate to serum gastrin levels or the severity of symptoms.
  • Ectopic Cushing syndrome, tumor flow cytometry features, and overexpression of certain growth factors such as human epidermal growth factor receptor 2 (HER2/neu) are associated with aggressive gastrinomas and poor prognosis.

More on Zollinger-Ellison Syndrome

Overview: Zollinger-Ellison Syndrome
Differential Diagnoses & Workup: Zollinger-Ellison Syndrome
Treatment & Medication: Zollinger-Ellison Syndrome
Follow-up: Zollinger-Ellison Syndrome
Multimedia: Zollinger-Ellison Syndrome
References
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References

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Further Reading

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Keywords

Zollinger-Ellison syndrome, gastrinoma, ZES, multiple endocrine neoplasia type 1, MEN-1, peptic ulcers, gastrin-producing tumors, gastrinomas, neuroendocrine tumor, vasoactive intestinal polypeptide tumors, VIPomas, glucagonomas, peptic ulcer disease, PUD, abdominal pain, gastroesophageal reflux, stenosis, Barrett mucosa, proton pump inhibitor, PPI

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Contributor Information and Disclosures

Author

Stefano Guandalini, MD, Director, University of Chicago Celiac Disease Program, Section Chief of Gastroenterology, Hepatology and Nutrition; Professor, Department of Pediatrics, University of Chicago Comer Children's Hospital
Stefano Guandalini, MD is a member of the following medical societies: American Gastroenterological Association, European Society for Paediatric Gastroenterology, Hepatology & Nutrition, and North American Society for Pediatric Gastroenterology and Nutrition
Disclosure: Nothing to disclose.

Coauthor(s)

Klaus Radebold, MD, PhD, Research Associate, Department of Surgery, Yale University School of Medicine
Klaus Radebold, MD, PhD is a member of the following medical societies: American Gastroenterological Association and New York Academy of Sciences
Disclosure: Nothing to disclose.

Medical Editor

Jayant Deodhar, MD, Associate Professor in Pediatrics, BJ Medical College, India; Honorary Consultant, Departments of Pediatrics and Neonatology, King Edward Memorial Hospital, India
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from broker recommendation; Avanir Pharma Stock Investment from broker recommendation

Managing Editor

David A Piccoli, MD, Chief, Division of Gastroenterology and Nutrition, Department of Pediatrics, The Children's Hospital of Philadelphia; Professor, University of Pennsylvania School of Medicine
David A Piccoli, MD is a member of the following medical societies: American Association for the Study of Liver Diseases, American Gastroenterological Association, and North American Society for Pediatric Gastroenterology and Nutrition
Disclosure: Nothing to disclose.

CME Editor

Steven M Schwarz, MD, FAAP, FACN, AGAF, Professor of Pediatrics, State University of New York, Downstate Medical Center College of Medicine; Distinguished Lecturer, New York Medical College, School of Public Health
Steven M Schwarz, MD, FAAP, FACN, AGAF is a member of the following medical societies: American Academy of Pediatrics, American College of Nutrition, American College of Physician Executives, American Gastroenterological Association, American Pediatric Society, Gastroenterology Research Group, New York Academy of Medicine, North American Society for Pediatric Gastroenterology and Nutrition, and Society for Pediatric Research
Disclosure: TAP Pharmaceuticals Honoraria Speaking and teaching; Curemark, LLC Consulting fee Board membership

Chief Editor

Carmen Cuffari, MD, Associate Professor, Department of Pediatrics, Division of Gastroenterology/Nutrition, Johns Hopkins University School of Medicine
Carmen Cuffari, MD is a member of the following medical societies: American College of Gastroenterology, American Gastroenterological Association, North American Society for Pediatric Gastroenterology, Hepatology and Nutrition, and Royal College of Physicians and Surgeons of Canada
Disclosure: Nothing to disclose.

 
 
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