Zollinger-Ellison Syndrome
Zollinger-Ellison syndrome
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 hyper-secretion 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
McGuigan, James E. "Zollinger-Ellison Syndrome and Other Hypersecretory States." In Sleisenger & Fordtran's Gastrointestinaland Liver Disease, 6th ed. Feldman, Mark, ed. Philadelphia: W.B. Saunders Company, 1998, pp. 679-95
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 (26 August 1999): 635-44.
OTHER
"Zollinger-Ellison Syndrome." National Digestive Diseases Infor mation Clearinghouse. 24 July 2001 <http://www.niddk.nih.gov/health/digest/summary/zolling/zolling.htm>.
Clinical Trials 24 July 2001 <http://clinicaltrials.gov/>.
Kevin O. Hwang, M.D.
KEY TERMS
Angiography
—Radiographic examination of blood vessels after injection with a special dye
Computed tomography
—A radiology test by which images of cross-sectional planes of the body are obtained
Duodenum
—The first portion of the small intestine in continuity with the stomach
Endoscopy
—Examination of the interior of a hollow part of the body by means of a special, lighted instrument
Gastric
—Of or relating to the stomach
Gastrin
—Hormone normally secreted by the stomach that stimulates secretion of gastric acid
Gastrinoma
—Tumor that secretes the hormone gastrin
Magnetic resonance imaging
—A radiology test that reconstructs images of the body based on magnetic fields
Malignant
—In reference to cancer, having the ability to invade local tissues and spread to distant tissues by metastasis
Metastasis
—The spread of tumor cells from one part of the body to another
Parietal cells
—Stomach cells that secrete gastric acid to aid in digestion
Scintigraphy
—A radiology test that involves injection and detection of radioactive substances to create images of body parts
Ultrasound
—A radiology test utilizing high frequency sound waves