Zollinger-Ellison syndrome

(medicine) Gastric hypersecretion and hyperacidity, fulminating intractable atypical peptic ulceration, and hyperplasia of the islet cells of the pancreas.

Key Terms: Angiography, Computed tomography, Duodenum, Endoscopy, Gastric, Gastrin, Gastrinoma, Magnetic resonance imaging, Malignant, Metastasis, Parietal cells, Scintigraphy.

Definition

In Zollinger-Ellison syndrome (ZES), a tumor (a gastrinoma) secretes the hormone gastrin, which stimulates the secretion of gastric acid. This leads to the development of ulcers in the stomach and duodenum (the first part of the small intestine).

Description

In normal individuals, the stomach secretes the hormone gastrin after food enters the stomach. Gastrin is carried by the bloodstream to other parts of stomach. The main effect of gastrin is to stimulate the parietal cells of the stomach. Parietal cells are stomach cells that secrete gastric acid to aid in digestion. This acid plays a vital role in the digestion of food. This process is highly regulated so that the stomach produces gastrin in significant amounts only when necessary, as when there is food in the stomach.

The underlying entity of ZES is a tumor called a gastrinoma which secretes gastrin inappropriately. Marked overproduction of gastrin leads to hypersecretion of gastric acid by the parietal cells. The end result is severe ulcers of the stomach and duodenum that are more difficult to treat than common ulcers.

Gastrinomas are generally small tumors located in the pancreas or duodenum. They often occur in multiples in the same patient. More than half of all gastrinomas are malignant, with the potential to spread to nearby lymph nodes and also spread to the liver and other organs by way of metastasis. The malignant potential of gastrinoma is ultimately more life-threatening than the associated ulcers.

The ulcers in ZES are frequently located further down the gastrointestinal tract than common ulcers, and they may be multiple.

About 25% of patients with ZES also demonstrate other tumors of the endocrine system in a syndrome called Multiple Endocrine Neoplasia syndrome.

Demographics

ZES occurs slightly more frequently in males than females. The average age of onset is between 30 and 50 years of age. It is difficult to determine the prevalence of ZES, but it is not a common syndrome.

Causes and Symptoms

The symptoms of ZES are chiefly related to the ulcer disease. The main symptom is abdominal pain, present in the vast majority of patients. Ulcers can also cause nausea, vomiting, and heartburn. Compared with patients with common ulcers, patients with ZES generally have more severe and persistent symptoms that are more difficult to control. In some cases, the ulcers can bleed or actually perforate completely through the walls of the stomach or duodenum.

Many patients also suffer diarrhea in addition to ulcer pain. In fact, diarrhea is the only symptom in a small fraction of patients, and the diarrhea may precede the development of ulcers in the stomach and duodenum.

Diagnosis

A number of clinical circumstances suggest that a patient's ulcer disease may be due to ZES:

• ulcer disease resistant to conventional medical treatment
• recurrent ulcers after surgery intended to cure the ulcer disease
• ulcer disease in the absence of the usual risk factors for ulcers
• ulcers located in abnormal locations in the gastrointestinal tract
• multiple ulcers
• ulcers accompanied by diarrhea
• strong family history of ulcer disease

Diagnosis of ZES must be confirmed by observing abnormally high levels of gastrin in the blood. This is the hallmark of the disease. But it must be mentioned that the gastrinoma of ZES is not the only cause of hypersecretion of gastrin. ZES is distinguished from these other conditions by the presence of appropriate symptoms and high levels of gastrin and gastric acid. In cases where the diagnosis is not clear, several provocative tests can help determine if the patient has ZES. In the intravenous secretin injection test, a standard dose of the hormone secretin is injected intravenously. If the blood levels of gastrin respond by increasing a certain amount, the diagnosis is ZES. Similarly, in the intravenous calcium infusion test, a dose of calcium is injected and gastrin levels are measured. A substantial increase in the gastrin level points to ZES. A newer test measures the response in gastrin level to the ingestion of a standard meal. For example, the standard meal might be one slice of bread, one boiled egg, 200 mL of milk, and 50 gm of cheese.

Treatment Team

The surgeon and gastroenterologists are the chief members of the treatment team. Radiologists play a vital role in the localization of the gastrinoma before surgery. Oncologists may be involved after surgery or if surgery is not indicated.

Clinical Staging, Treatments, and Prognosis

The goal of treatment for ZES is the elimination of excess gastrin production, acid hypersecretion, ulcer disease, and malignant potential. This is achieved only by complete surgical removal of all gastrinomas. An attempt at surgical cure is offered to most patients, with the exception of those who already have widespread metastasis to the liver or who are too ill to undergo surgery. It is important to locate the gastrinoma(s) and any possible areas of metastasis before surgery. This can be accomplished with tests such as computed tomography (CT), ultrasound, magnetic resonance imaging (MRI), angiography, scintigraphy, and endoscopy. But as gastrinomas may be small, multiple, and hidden in atypical positions, finding the exact locations of all cancerous tissue can be challenging and sometimes impossible. In that case, surgeons will still proceed and attempt to find the tumor(s) at the time of operation. All identified gastrinoma should be removed if possible, including involved lymph nodes. Metastatic lesions in the liver can sometimes be safely removed, but only when they are isolated to one part of the liver.

Chemotherapy is sometimes able to reduce tumor size, which may relieve some symptoms due to local invasion or massive growth of the tumor. But it has not been shown to consistently prolong survival.

Medical therapy plays a vital role in the treatment of ZES. A group of drugs known as proton pump inhibitors, which includes omeprazole (a drug used to treat common ulcers), is effective in decreasing acid secretion and promoting ulcer healing in patients with ZES. Omeprazole acts by blocking the last biochemical step in acid production. Omeprazole should be prescribed immediately after diagnosis. If surgery is not attempted, or ultimately unsuccessful, omeprazole is also useful for long-term treatment. For reasons that are not fully known, sometimes patients still require omeprazole after successful surgery. Another drug called octreotide is also effective in reducing acid secretion.

The prognosis for ZES depends primarily on whether or not the gastrinoma can be completely removed. If the cancer has spread diffusely to the liver, surgical cure is nearly impossible. The gastrinoma tissue is completely removed in about 40% of patients, resulting in reduced acid secretion and resolution of ulcer disease or diarrhea. These patients should expect a normal life expectancy, although they should undergo regular testing thereafter and may also require long-term omeprazole treatment. The prognosis is poor for patients in whom all the gastrinoma cannot be removed.

Clinical Trials

In 2001, five clinical trials were recruiting patients with Zollinger-Ellison syndrome. These trials were studying various aspects of treatment for the syndrome, including the use of Omeprazole, interferon therapy, and combination chemotherapy. For further information about ongoing clinical trials, patients may consult the National Institutes of Health clinical trials site listed below.

Resources

Books

Thompson, James C., and Courtney M. Townsend, Jr."Endocrine Pancreas." In Sabiston Textbook of Surgery, edited by Courtney Townsend Jr. 16th ed. Philadelphia: W.B. Saunders Company, 2001, pp. 646–61.

Periodicals

Norton, J. A., D. L. Fraker, H. R. Alexander, D. J. Venzon, J. L. Doppman, et al. "Surgery to Cure the Zollinger-Ellison Syndrome." New England Journal of Medicine 341, no. 9 (August 26, 1999): 635–44.

Other

Clinical Trials. [cited July 24, 2001]. .

"Zollinger-Ellison Syndrome." National Digestive Diseases Information Clearinghouse. [cited July 24, 2001]. .

A condition characterized by severe peptic ulceration, gastric hypersecretion, elevated serum gastrin, and gastrinoma of the pancreas or the duodenum. It may occur in early childhood but is seen more frequently in people between 20 and 50 years of age. Two-thirds of the tumors are malignant. Total gastrectomy may be necessary, but the administration of ci-metidine in large doses may control gastric hypersecretion and allow the ulcers to heal.

A triad comprising intractable, sometimes fulminating, upper gastrointestinal ulceration, extreme gastric hyperacidity, and nonbeta cell, gastrin-secreting, islet cell tumors (gastrinomas) of the pancreas. Clinical signs in affected dogs include vomiting, often with blood, anemia, diarrhea, weight loss, and sometimes signs of peritonitis.

This article needs additional citations for verification. Please help improve this article by adding reliable references. Unsourced material may be challenged and removed. (October 2007)

Zollinger-Ellison syndrome
Classification and external resources
Endoscopy image of multiple small ulcers in the distal duodenum in a patient with Zollinger-Ellison syndrome
ICD-10	E16.4
ICD-9	251.5
MedlinePlus	000325
eMedicine	med/2437 ped/2472
MeSH	D015043

Zollinger-Ellison syndrome 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).

Contents 1 Pathophysiology 2 Presentation 3 Symptoms 4 Diagnosis 5 Therapy 6 History 7 References

Pathophysiology

Gastrin works on stomach parietal cells causing them to secrete more hydrogen ions into the stomach lumen. In addition, gastrin acts as a trophic factor for parietal cells, causing parietal cell hyperplasia. Thus there is an increase in the number of acid-secreting cells, and each of these cells produces acid at a higher rate. The increase in acidity contributes to the development of peptic ulcers in the stomach and duodenum. High acid levels lead to multiple ulcers in the stomach and small bowel.

Presentation

Patients with Zollinger-Ellison syndrome may experience abdominal pain and diarrhea. The diagnosis is also suspected in patients without symptoms who have severe ulceration of the stomach and small bowel, especially if they fail to respond to treatment.

Gastrinomas may occur as single tumors or as multiple, small tumors. About one-half to two-thirds of single gastrinomas are malignant tumors that most commonly spread to the liver and lymph nodes near the pancreas and small bowel. Nearly 25 percent of patients with gastrinomas have multiple tumors as part of a condition called multiple endocrine neoplasia type I (MEN I). MEN I patients have tumors in their pituitary gland and parathyroid glands in addition to tumors of the pancreas.

Symptoms

• epigastric pain (stomach ache)
• diarrhoea
• melaena
• Vomiting
• Weight loss

Diagnosis

Clinical suspicion of Zollinger-Ellison syndrome may be aroused when the above symptoms prove resistant to treatment, when the symptoms are especially suggestive of the syndrome, or endoscopy is suggestive. The diagnosis of Zollinger-Ellison syndrome is made by several laboratory tests and imaging studies.

• Secretin stimulation test, which measures evoked gastrin levels
• Fasting gastrin levels, on at least three separate occasions^[1]
• Gastric acid secretion and pH

In addition, the source of the increased gastrin production must be discovered. This is either done using MRI or somastatin receptor scintigraphy, the investigation of choice.^[2]

Therapy

Proton pump inhibitors (such as omeprazole and lansoprazole) and histamine H2-receptor antagonists (such as famotidine and ranitidine) are used to slow down acid secretion. Cure is only possible if the tumours are surgically removed, or treated with chemotherapy. Octreotide can be used to alleviate symptoms.

History

This syndrome was first described in 1955 by Robert Zollinger and Edwin Ellison, surgeons at the Ohio State University.^[3]

References

1. ^ http://www.patient.co.uk/showdoc/40001304/
2. ^ Jensen RT; Gastrinomas: advances in diagnosis and management. Neuroendocrinology. 2004;80 Suppl 1:23-7.
3. ^ Zollinger RM, Ellison EH (1955). "Primary peptic ulcerations of the jejunum associated with islet cell tumors of the pancreas". Ann. Surg. 142 (4): 709–23; discussion, 724–8. doi:10.1097/00000658-195510000-00015. PMID 13259432. 

webmd.com 2009

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