eMedicine Specialties > Pediatrics: General Medicine > Gastroenterology

Zollinger-Ellison Syndrome

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

Introduction

Background

Zollinger-Ellison syndrome (ZES) is a rare condition characterized by peptic ulcers that are refractory to conventional medical therapy. Gastrin-producing tumors or gastrinomas cause excessive gastric acid secretion, leading to ulcers of the upper GI tract, as well as diarrhea and severe abdominal pain.

The syndrome was originally described by Zollinger and Ellison in 1955.1 In 1960, Cawkwell described the first childhood case of Zollinger-Ellison syndrome in The New Zealand Medical Journal.

Pathophysiology

Gastrinomas are neuroendocrine tumors (NETs) that are usually found in the duodenum wall (approximately 50%) or in the pancreas. Approximately 85% of gastrinomas are located in the gastrinoma triangle. The triangle is superiorly bound by the confluence of the cystic and common bile duct, inferiorly bound by the second and third portions of the duodenum, and medially bound by the head and body of the pancreas. When gastrinomas are found in the pancreas, they are nonbeta islet cell tumors. However, in addition to locations in the duodenum and pancreas, gastrinomas have been described in the lymph nodes, liver/biliary tree, gastric antrum, and jejunum. Rare reports have described extra-GI gastrinomas occurring in the heart, ovaries, and lung.

Gastrinomas are the second most common NETs in the overall population, after insulinomas and before vasoactive intestinal polypeptide tumors (VIPomas) and glucagonomas. Gastrinomas may secrete not only high levels of gastrin, causing peptic ulcer disease (PUD) but also may secrete other hormones such as adrenocorticotropic hormone (ACTH), vasoactive intestinal polypeptide (VIP), and glucagon. Gastrinomas may also produce various peptides such as insulin, pancreatic polypeptide, glucagon, chromogranin A, neuron-specific enolase, and the alpha and beta subunits of human chorionic gonadotropin.

Gastric carcinoids (type 2 carcinoids) occur almost exclusively in patients with multiple endocrine neoplasia type 1 (MEN-1) with Zollinger-Ellison syndrome (21–70% of patients with MEN-1) and can be malignant in 10–30% of cases.

Frequency

United States

Childhood gastrinomas account for about 2% of all Zollinger-Ellison syndrome cases. In the United States, the overall incidence of gastrinomas occurring sporadically or in association with MEN-1 is 0.1-3 per million. The prevalence of MEN-1 is 0.2-2 cases per 100,000 population. MEN-1 is diagnosed in 30-38% of patients with gastrinomas, whereas 20-61% of patients diagnosed with MEN-1 are found to have gastrinomas associated with Zollinger-Ellison syndrome.

International

Until 1992, 60 cases of Zollinger-Ellison syndrome in children had been reported worldwide.

Mortality/Morbidity

Prior to the introduction of acid-suppressing drugs, including histamine H2-receptor antagonists and, more recently, proton pump inhibitors (PPIs), Zollinger-Ellison syndrome carried high mortality rates. Because safe control of gastric acid hypersecretion can be achieved with PPIs in virtually all patients, mortality and morbidity are now attributed to advanced disease with metastases to liver and bones. Because of small numbers, whether gastrinoma tumor growth in children is less aggressive than in adults, as previously thought, is not yet clear.

In a study from the National Institutes of Health (NIH) involving 151 patients with Zollinger-Ellison syndrome, the 10-year survival rate was 94% in the overall Zollinger-Ellison syndrome population.2 The survival rate at 10 years was slightly lower (89%) when Zollinger-Ellison syndrome was associated with MEN-1. In the latter condition, a high prevalence of gastric carcinoids has been described; these carcinoids can be malignant in 10–30% of cases, thus requiring active surveillance to prevent increased mortality.

Gastrinomas may be malignant or benign but usually slowly grow. Early studies reported malignancy rates as high as 65% in adults. More recent studies report a malignancy rate of closer to 30%. Lymph nodes, liver, and bone metastases are the most common, although occurrence rates in children are unknown. One case report described a renal gastrinoma in a 12-year-old child.3

Race

In 2004, the NIH conducted a large prospective study of 107 patients with Zollinger-Ellison syndrome associated with MEN-1.4 They reported that 78% of patients were white, 10% were African American, and 9% were Hispanic.

Sex

The male-to-female ratio in childhood Zollinger-Ellison syndrome (ZES) is 4:1. However, recent reviews in the adult literature report no gender preference.

Age

The youngest patient reported with Zollinger-Ellison syndrome was a boy aged 7 years. Gastrinomas have been found in patients aged 90 years and younger. The most common age at diagnosis is 30-50 years.

Clinical

History

The typical presentation of Zollinger-Ellison syndrome (ZES) is severe abdominal pain with or without diarrhea. Most children present with complications of peptic ulcer disease (PUD), such as bleeding from an ulcer or duodenal perforation.

  • Abdominal pain is the most common presenting symptom in Zollinger-Ellison syndrome. The pain is due to peptic ulcers, which can be found in the upper GI tract in 90-95% of patients. These ulcers are often multiple or in unusual locations. In 70% of patients, single or multiple ulcers are found in the first part of the duodenum. However, ulcers in the second or third part of the duodenum or in the jejunum are highly suggestive of Zollinger-Ellison syndrome.
  • Other characteristics of Zollinger-Ellison syndrome ulcers include a size larger than 2 cm, occurrence at multiple locations, and a refractory behavior to conventional therapy.
  • The second most common symptom of Zollinger-Ellison syndrome ulcers is diarrhea, which is seen in 50-65% of patients. Diarrhea may be the only symptom; however, it can also precede or follow the ulcer formation. The diarrhea is due to mucosal damage by activated pepsinogens that result from excessive acid secretion. The acid also damages enterocytes, inactivates pancreatic enzymes, and causes bile acid insolubility, thereby decreasing micelle formation and causing steatorrhea.
  • Zollinger-Ellison syndrome may also manifest as symptoms of gastroesophageal reflux and, in severe cases, has been associated with stenosis or Barrett mucosa in adults.

Physical

The physical examination findings are often normal. Patients may have abdominal tenderness and, in the case of perforation, they have peritoneal signs. Patients who experience anemia due to bleeding ulcers may be pale and have tachycardia.

Causes

Gastrinomas may be sporadic or may be associated with multiple endocrine neoplasia type 1 (MEN-1). Data suggest that the gene for MEN-1, called MENIN, is also involved in the pathogenesis of at least one third of sporadic neuroendocrine tumors (NETs), including gastrinomas. Therefore, all patients who are under evaluation for Zollinger-Ellison syndrome should undergo genetic testing for MEN-1.

MEN-1 causes multiple tumors in the pancreas and in the pituitary, parathyroid, and adrenal glands through an autosomal dominant pattern of inheritance. Patients with MEN-1 may also have increased risk of skin lesions and carcinoid and smooth muscle tumors. MEN-1 is due to mutations in the tumor suppressor gene MEN1, located on chromosome 11q13. MEN1 encodes a transcriptional regulator, menin. Patients with MEN-1 have one germline mutation and one somatic mutation that lead to inactivation.

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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