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Zollinger Ellison syndrome

The information in NORD’s Rare Disease Database is for educational purposes only. It should never be used for diagnostic or treatment purposes. If you have questions regarding a medical condition, always seek the advice of your physician or other qualified health professional. NORD’s reports provide a brief overview of rare diseases. For more specific information, we encourage you to contact your personal physician or the agencies listed as “Resources” on this report.

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NORD is very grateful to E. Christopher Ellison, MD, Associate Vice-President Health Sciences and Vice-Dean for Clinical Affairs; Chair, The Ohio State University Physicians Board; Robert M.Zollinger Professor and Chair Department of Surgery, The Ohio State University Medical Center, for assistance in the preparation of this report.

Synonyms of Zollinger Ellison syndrome

Disorder Subdivisions

General Discussion

Zollinger-Ellison syndrome (ZES) is characterized by the development of a tumor (gastrinoma) or tumors that secrete excessive levels of gastrin, a hormone that stimulates production of acid by the stomach. Many affected individuals develop multiple gastrinomas, which are thought to have the potential to be cancerous (malignant). In most cases, the tumors arise within the pancreas and/or the upper region of the small intestine (duodenum).

Due to excessive acid production (gastric acid hypersecretion), individuals with ZES may develop peptic ulcers of the stomach, the duodenum, and/or other regions of the digestive tract. Peptic ulcers are sores or raw areas within the digestive tract where the lining has been eroded by stomach acid and digestive juices. Symptoms and findings associated with ZES may include mild to severe abdominal pain; diarrhea; increased amounts of fat in the stools (steatorrhea); and/or other abnormalities.

In most affected individuals, ZES appears to develop randomly (sporadically) for unknown reasons. In approximately 25 percent of cases, ZES occurs in association with a genetic syndrome known as multiple endocrine neoplasia type 1 (MEN-1). All of the tumors are considered to have malignant potential. Prognosis is related to tumor size and the presence of distant metastases.

Symptoms

Zollinger-Ellison syndrome (ZES) is characterized by abnormally increased acid production (gastric hypersecretion), excessively high levels of gastrin in the blood (hypergastrinemia), and ulceration of the stomach or the upper region of the small intestine (duodenum) due to gastrin-producing tumors (gastrinomas). In most cases, gastrinomas arise within the wall of the duodenum or within the pancreas. The pancreas is a gland that functions as part of the digestive and endocrine systems. Certain pancreatic cells (exocrine cells) secrete digestive juice into ducts, while clusters of other pancreatic cells (pancreatic endocrine cells known as "islet cells") secrete certain hormones directly into the bloodstream.

The gastrinomas associated with ZES are considered to have malignant potential. Evidence suggests that these malignancies are usually slow growing, although a small percentage may be rapidly invasive. The malignancies most commonly spread to regional lymph nodes and the liver. Malignant tumor growth and metastatic disease may result in potentially life-threatening complications.

In individuals with ZES, excessive acid secretion may erode the lining of the stomach, duodenum, or other regions of the digestive tract (peptic ulcers). Most affected individuals have single or, less commonly, multiple ulcers of the stomach or the upper region of the duodenum. In those with multiple ulcers, ulceration may extend to the lower duodenum or the middle region of the small intestine (jejunum). Particularly during early disease, ulcer symptoms associated with ZES are often similar to those seen in others with peptic ulcers from other causes. Such symptoms may include a "gnawing" or burning pain in the abdominal area, inflammation of the esophagus (esophagitis), appetite changes, nausea, vomiting, weight loss, and/or other abnormalities.

However, in some cases, symptoms associated with peptic ulcers may be more severe, persistent, and progressive and may be associated with potentially life-threatening complications, such as bleeding, perforation, or intestinal obstruction. Bleeding from peptic ulcers may result in vomiting of blood and/or the passage of blood in the stools. In some cases, ulcers may penetrate the wall of the digestive tract, creating an abnormal opening (perforation) into the abdominal cavity. Associated symptoms may include severe, persistent, piercing pain in the abdominal area; inflammation of the abdominal lining (peritonitis); and/or other symptoms and findings. In addition, inflammation and scarring from chronic ulceration may narrow the outlet from the stomach to the duodenum (pyloric stenosis), causing obstruction, a feeling of early fullness, lack of appetite, pain, vomiting, and/or other associated abnormalities. Such complications are considered medical emergencies that require immediate treatment.

In some individuals with ZES, diarrhea may be the initial symptom. Excessive acid levels within the digestive tract may also cause increased amounts of fat in the stools (steatorrhea).

Causes

In most individuals with Zollinger-Ellison syndrome (ZES), the condition appears to occur spontaneously for unknown reasons (sporadically). However, in approximately 25 percent of affected individuals, ZES occurs in association with the genetic syndrome known as multiple endocrine neoplasia type 1 (MEN-1). In most cases, MEN-1 is inherited as an autosomal dominant trait with high penetrance and variable expressivity. Less commonly, the disorder may appear to occur sporadically.

Human traits, including the classic genetic diseases, are the product of the interaction of two genes for that condition, one received from the father and one from the mother. In dominant disorders, a single copy of the disease gene (received from either the mother or father) will be expressed "dominating" the other normal gene and resulting in the appearance of the disease. The risk of transmitting the disorder from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child.

In most cases, individuals with a disease gene for MEN-1 will develop symptoms and findings associated with the disorder (high penetrance). However, in such cases, the characteristics that are manifested may vary greatly in range and severity from case to case (variable expressivity).

Researchers have determined that MEN-1 is caused by changes (mutations) of a gene (known as the MEN1 gene) located on the long arm (q) of chromosome 11 (11q13).* The MEN1 gene regulates production of a protein (termed "menin") that appears to play some role in preventing tumor development (tumor suppressor). (For more information on MEN-1, please see the "Related Disorders" section of this report below.)

*Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as "p" and a long arm identified by the letter "q". Chromosomes are further subdivided into bands that are numbered.

Affected Populations

ZES may become apparent at any age. However, symptom onset usually occurs between ages 30 and 60 years. The exact frequency of ZES in the general population is unknown. However, some researchers estimate that ZES represents less than one percent of peptic ulcers.

Related Disorders

As discussed above, Zollinger-Ellison syndrome may occur as a component of the following disorder:

Multiple endocrine neoplasia type 1 (MEN-1), also known as Wermer syndrome, is a genetic disorder in which tumors may arise from cells of various endocrine glands, such as the parathyroid glands, the pancreas, and the pituitary gland. Evidence suggests that individuals with Zollinger-Ellison syndrome in association with MEN-1 may tend to develop symptoms at an earlier age than those with sporadic Zollinger-Ellison syndrome. Most individuals with MEN-1 develop hyperparathyroidism or excessive secretion of parathyroid hormone, resulting in increased calcium blood levels. Associated symptoms may include kidneys tones, bone abnormalities and/or other findings. In some individuals with MEN-1, tumors may also arise within the duodenum or the pancreas causing excessive gastrin secretion and associated ZES. In addition, in some cases, other tumors may arise within the pancreas, in islet cells that secrete the hormone insulin (insulinomas), a hormone that helps to regulate levels of the sugar glucose in the blood. In individuals with insulinomas, excessive insulin secretion leads to abnormally diminished blood glucose levels (hypoglycemia). Some individuals with MEN-1 may also develop tumors of the pituitary, potentially leading to excessive production of certain pituitary hormones. Associated symptoms and findings may vary, depending upon whether the tumors secrete such hormones and which hormone is involved. Some individuals with MEN-1 may also develop tumors affecting other tissues or organs.

Standard Therapies

Diagnosis
The diagnosis of Zollinger-Ellison syndrome (ZES) is based upon a thorough clinical evaluation, a detailed patient history, and specialized tests, including certain laboratory studies and advanced imaging techniques. ZES may be suggested by various factors, including the development of frequent or multiple peptic ulcers that are resistant to certain standard ulcer treatments and/or that occur in unusual sites (e.g., the jejunum).

In individuals with suspected ZES, diagnostic studies may include blood testing to detect increased gastrin levels and evaluation of samples of gastric juice to detect increased acid levels. In some cases, additional laboratory tests may also be conducted to help confirm ZES. Such tests may include measuring levels of gastrin within the fluid portion of the blood (serum) before and after intravenous infusion of calcium; injection of the digestive hormone secretin, or feeding of a standard meal. Additional laboratory studies may also be conducted to help confirm or rule out MEN-1.

The FDA has approved the use of Synthetic Porcine Secretin for use in the diagnosis of gastrinoma associated with Zollinger-Ellison syndrome. This biological is manufactured by:

ChiRhoClin, Inc.
15500 Gallaudet Avenue
Silver Springs, MD 20905

If possible, treatment may include surgical removal of the gastrinoma (see below). Various advanced imaging techniques may be used before surgery to help localize and characterize the gastrinoma and exclude metastatic disease (e.g., endoscopic ultrasound, octreotide scans, abdominal ultrasounds, computerized tomography [CT] scanning, abdominal angiography). In addition, in some cases, certain imaging techniques (e.g., intraoperative endoscopic transillumination or ultrasound) may be used during surgical exploration to aid in the localization and possible removal of tumors.

Treatment
In October 2006 the FDA approved AstraZeneca's proton pump inhibitor Nexium for the treatment of ZES. For information, contact AstraZeneca or go to www.astrazeneca-us.com.

In individuals with Zollinger-Ellison syndrome, initial treatment commonly includes the use of certain medications called proton pump inhibitors, such as omeprazole. Such medications may reduce stomach acid production, relieve symptoms, and promote ulcer healing. In some cases, another type of acid-suppressing medication called H2 blockers may also be used, such as cimetidine or ranitidine.

The Food and Drug Administration (FDA) has approved a proton pump inhibitor called Protonix (pantoprazole sodium), in the form of delayed-release tablets, for the long-term treatment of individuals with ZES. Protonix is marketed in the United States by Wyeth Pharmaceuticals.

As noted above, when possible (e.g., if there is no evidence of metastasis of a single tumor), complete surgical removal of the gastrinoma may be considered the optimal treatment. Evidence suggests that complete and curative removal of gastrinoma is possible in approximately 20 to 30 percent of individuals with ZES.

Rarely, in severe cases in which other therapy is ineffective, surgical removal of the stomach (gastrectomy) may be considered.

Due to the effectiveness of the medications discussed above, serious complications associated with ulcers may often be prevented. However, in some cases, affected individuals may remain undiagnosed until developing such complications (e.g., perforation or obstruction). These complications are considered medical emergencies that require immediate treatment, potentially including surgery.

In some affected individuals with aggressively invasive gastrinoma, recommended treatment may include the use of certain anticancer drugs (chemotherapy) to help reduce tumor mass and blood gastrin levels.

Genetic counseling may be of benefit for affected individuals and their families. Other treatment for this disease is symptomatic and supportive.

Investigational Therapies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

Information on cancer clinical trials is available through the Internet on www.cancer.gov or by calling: 1-800-4CANCER.

In some cases, if affected individuals do not have a sufficient response to proton pump inhibitors, treatment may be recommended with synthetic somatostatin compounds (analogs), such as octreotide. (Somatostatin is a hormone that inhibits the secretion of other hormones, including gastrin.)

If metastatic disease is present in individuals with ZES, therapy with certain anticancer drugs (chemotherapy) may be beneficial in some cases. In addition, it is possible that other measures may be recommended, such as excision of all removable areas of tumor growth, therapy with somatostatin analogs, and/or other therapies as appropriate (e.g., interferon therapy, hepatic arterial embolization).

Further research is needed to determine the long-term safety and effectiveness of such therapies in the treatment of individuals with ZES.

Organizations related to Zollinger Ellison syndrome

References

JOURNAL ARTICLES
Nazir Z. Long-term follow-up of a child with primary lymph node gastrinoma and
Zollinger-Ellison syndrome. J Pediatr Surg. 2011 May;46(5):969-72. PubMed PMID:
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Pritchard DM. Zollinger-Ellison syndrome: still a diagnostic challenge in the
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PMID: 21443889.

Rehfeld JF, Gingras MH, Bardram L, Hilsted L, Goetze JP, Poitras P. The
Zollinger-Ellison syndrome and mismeasurement of gastrin. Gastroenterology. 2011
May;140(5):1444-53. Epub 2011 Mar 23. PubMed PMID: 21315717.

Wilcox CM, Seay T, Arcury JT, Mohnen J, Hirschowitz BI. Zollinger-Ellison
syndrome: presentation, response to therapy, and outcome. Dig Liver Dis. 2011
Jun;43(6):439-43. Epub 2010 Dec 30. PubMed PMID: 21193359.

Smallfield GB, Allison J, Wilcox CM. Prospective evaluation of quality of life
in patients with Zollinger-Ellison syndrome. Dig Dis Sci. 2010
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Rustagi T, Siegel RD. Zollinger-ellison syndrome with subsequent association
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Price TN, Thompson GB, Lewis JT, Lloyd RV, Young WF. Zollinger-Ellison
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reports and review of literature. Endocr Pract. 2009 Nov-Dec;15(7):737-49.
Review. PubMed PMID: 19491075.

Wilcox CM, Hirschowitz BI. Treatment strategies for Zollinger-Ellison
syndrome. Expert Opin Pharmacother. 2009 May;10(7):1145-57. Review. PubMed PMID:
19351273.

Ellison EC, Johnson JA. The Zollinger-Ellison syndrome: a comprehensive review
of historical, scientific, and clinical considerations. Curr Probl Surg. 2009
Jan;46(1):13-106. Review. PubMed PMID: 19059523.

Ellison EC. Zollinger-Ellison syndrome: a personal perspective. Am Surg. 2008
Jul;74(7):563-71. Review. PubMed PMID: 18646472.

Berna MJ, Hoffmann KM, Long SH, Serrano J, Gibril F, Jensen RT. Serum gastrin
in Zollinger-Ellison syndrome: II. Prospective study of gastrin provocative
testing in 293 patients from the National Institutes of Health and comparison
with 537 cases from the literature. evaluation of diagnostic criteria, proposal
of new criteria, and correlations with clinical and tumoral features. Medicine
(Baltimore). 2006 Nov;85(6):331-64. PubMed PMID: 17108779.

Berna MJ, Hoffmann KM, Serrano J, Gibril F, Jensen RT. Serum gastrin in
Zollinger-Ellison syndrome: I. Prospective study of fasting serum gastrin in 309
patients from the National Institutes of Health and comparison with 2229 cases
from the literature. Medicine (Baltimore). 2006 Nov;85(6):295-330. PubMed PMID:
17108778.

FROM THE INTERNET
McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore, MD: The Johns Hopkins University; Entry No: 131100; Last Update:10/11/11. http://omim.org/entry/131100
Accessed on:January 16, 2012.

Report last updated: 2012/01/20 00:00:00 GMT+0