Zollinger-Ellison Syndrome

Zollinger-Ellison Syndrome (ZES) is characterized by excessive production of stomach acid due to tumors called gastrinomas. Primary gastrinomas are usually found in the duodenum, pancreas, or abdominal lymph nodes. The gastrinomas produce gastrin, which causes the excess acid. This acid in turn causes peptic ulcers.

ZES was named for the two American surgeons who described two patients with severe peptic ulcer disease and pancreatic endocrine tumors in 1955. They theorized that an ulcerogenic agent originated from the pancreatic tumor, causing the increased acid.¹ Approximately one in 1,000 patients with primary duodenal ulcer disease and two in 100 patients with recurrent ulcer following ulcer surgery have a gastrinoma. ZES can occur sporadically, or may be genetic. If genetic, the syndrome is referred to as multiple endocrine neoplasia type 1 (MEN 1). The average age at which ZES begins is about 43 years, although patients with MEN 1 ZES usually present about ten years earlier.

In terms of symptoms, patients suffering from ZES usually present with abdominal pain (75 percent). Oftentimes this pain is located in the upper abdomen and is similar to that of peptic ulcer disease. Diarrhea is also a common complaint, and this symptom is most common in patients who have the genetic type of ZES and in female patients.² Other symptoms may include heartburn, nausea, vomiting, gastrointestinal bleeding, and weight loss. Reflux may cause esophagitis or stricture, and very high acid levels may induce the inactivation of pancreatic enzymes, which can lead to malabsorption.

Diagnosis of suspected ZES cases can be performed by testing fasting levels of gastrin. Because fluctuations may normally occur for these levels, multiple tests on different days are recommended.³ Esophagogastroduodenoscopy is recommended to check for duodenal ulcerations. In rare cases, thickened duodenal folds may also be noted.

ZES diagnosis can be assured when the plasma gastrin level is greater than 1,000 pg/mL and the basal acid output is greater than 15 mEq/h in patients with an intact stomach, or greater than 5 mEq/h in gastrectomized patients, or when hypergastrinemia is associated with a pH of less than 2.⁴

Imaging tests such as abdominal computed tomography (CT), ultrasound, and magnetic resonance imaging (MRI) are often helpful in locating tumors, although such tests may not always be conclusive. Opening the duodenum (duodenotomy) has shown to increase the number of duodenal tumors found, as well as the immediate and long-term rate of cure in these patients. This seems to be due to the fact that small tumors may be located in this manner, whereas similar tumors may have escaped detection previously.⁵

The diagnosis of ZES is normally delayed for about five years. With the increased use of proton pump inhibitors to control hypersecretion of acid, diagnosis may be delayed even further. Consequently, tests for tumor markers have been suggested as a means of differentiating ZES from other gastrointestinal disorders.⁶ It is suggested that duodenotomy be performed in all surgeries to find and remove gastrinomas in ZES patients.

Treatment of ulcers as a result of ZES revolves around controlling excess acid secretion, which usually means proton pump inhibitor (PPI) therapy. In the past, before the advent of today’s effective PPIs, the stomach was sometimes removed in cases of ZES. As for the tumor or tumors, surgery is usually recommended if there is only one. If surgery is not possible, other methods such as embolization, radio frequency ablation, or chemotherapy may be used. Long-term treatment with octreotide, a drug that reduces the amount of growth hormone produced by the body, may also have potential in stabilizing tumors in ZES patients.⁷ Before any form of treatment begins, however, checking for possible metastasis to surrounding areas of the body, including the liver and nearby lymph nodes, is recommended.⁸

In nearly half of ZES cases, the tumors are malignant, which creates particular concern for the possibility of spreading to other organs. Even when tumors are benign, some are aggressive and prove to be a major cause of death in MEN 1 patients. For these reasons, resection of the tumor(s) is recommended when the size is greater than 2.5 cm. When removal is successful, it is still likely that MEN 1 patients will not be cured of the syndrome. Surgical removal of all or a part of the pancreas along with the duodenum has shown to result in a higher chance of curing MEN 1 ZES.⁹

One study has shown that growth factors such as insulin-like growth factor I (IGF-I) and IGF-I receptor (IGF-IR) are usually expressed in gastrinomas. Increased levels of IGF-IR in ZES patients have been found to correlate with increased tumor growth and aggressive-ness as well as metastasis to the liver. Increased IGF-I levels showed similar results, while lower IGF-IR levels in gastrinomas were found in patients who were successfully treated.¹⁰ These results may prove valuable in determining aggressiveness of treatment in ZES patients.

Early diagnosis and intervention, while important, only results in a cure rate of about 20 to 25 for the cancerous tumors. Gastrinomas, however, are slow-growing tumors, and it is possible that patients with these tumors may live for years after their discovery. Mortality may also be related to the severity of ulcer disease present as a result of ZES.

Works Cited

1. http://pathology2.jhu.edu/pancreas/endo crineislet.cfm

2. Roy PK, et al. Zollinger-Ellison syndrome. Clinical presentation in 261 patients. Medicine (Baltimore). 2000 Nov;79(6):379-411.

3. www.emedicine.com/med/topic2437.htm

4. Campana D, et al. Zollinger-Ellison syndrome. Diagnosis and therapy. Minerva Med. 2005 Jun;96(3):187-206.

5. Norton JA. Surgical treatment and prognosis of gastrinoma. Best Pract Res Clin Gastroenterol. 2005 Oct;19(5):799-805.

6. Gibril F, Jensen RT. Zollinger-Ellison syndrome revisited: diagnosis, biologic markers, associated inherited disorders, and acid hypersecretion. Curr Gastroenterol Rep. 2004 Dec;6(6):454-63. Review.

7. Mignon M. Diagnostic and therapeutic strategies in Zollinger-Ellison syndrome associated with multiple endocrine neoplasia type I (MEN-I): experience of the Zollinger-Ellison Syndrome Research Group: Bichat 1958- 1999 Bull Acad Natl Med. 2003;187(7):1249-58; discussion 1259-60. Review. French.

8. Lee WS, et al. Zollinger-Ellison syndrome associated with neurofibromatosis type 1: a case report. BMC Cancer. 2005 Jul 21;5(1):85.

9. Tonelli F, et al. Surgery for gastroenteropancreatic tumours in multiple endocrine neoplasia type 1: review and personal experience. J Intern Med. 2005 Jan;257(1):38-49. Review.

10. Furukawa M, et al. Increased expression of insulin-like growth factor I and/or its receptor in gastrinomas is associated with low curability, increased growth, and development of metastases. Clin Cancer Res. 2005 May 1;11(9):3233-42.

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