What Is Zollinger-Ellison Syndrome?

Zollinger–Ellison syndrome (ZES) is a disease in which tumors cause the stomach to produce too much acid, resulting in peptic ulcers. Symptoms include abdominal pain and diarrhea. The syndrome is caused by a gastrinoma, a neuroendocrine tumor that secretes a hormone called gastrin. The tumor causes excessive production of gastric acid, which leads to the growth of gastric mucosa and proliferation of parietal and ECL cells.

Zollinger-Ellison syndrome (ZES) is a disease of the gastrointestinal system. People who have ZES develop tumors known as gastrinomas in the pancreas and duodenum (the first section of the small intestine). The gastrinomascaused by ZES secrete the hormone gastrin. Because gastrin creates excessive stomach acid, 90 percent of patients with ZES develop stomach and duodenal ulcers.

ZES may occur on its own or as part of an autosomal dominant syndrome called multiple endocrine neoplasia type 1 (MEN 1). The primary tumor is usually located in the pancreas, duodenum or abdominal lymph nodes, but ectopic locations (e.g., heart, ovary, gallbladder, liver, and kidney) have also been described.

Clinical Features of ZES

The estimated incidence of ZES in the United States is about 1 case per million individuals per year and about 0.1%-1% among patients with peptic ulcer disease. The mean age at presentation is 45-50 years, and men are affected more often than women. Because of the rarity of the disease, the average interval between onset of symptoms and diagnosis is about 6 years. Most gastrinomas are malignant; therefore, a high index of suspicion remains key to proper and prompt management of the disease. Management is aimed at cure.

 ZES may present in one of several ways:

Peptic ulcer disease: This disease is present in 90%-95% of patients with gastrinomas. Patients who are Helicobacter pylori infection-negative and have no history of nonsteroidal anti-inflammatory drug use may have ZES. Peptic ulcers associated with ZES tend to be more persistent and less responsive to therapy than those not associated with ZES. Ulcers occurring in the second, third, or fourth portions of the duodenum or the jejunum should alert one to the possibility of ZES, although a single ulcer in the duodenal bulb is the most common presentation. Gastroesophageal reflux disease complicated by ulcerations and strictures of the esophagus also tends to be more prevalent and more severe in patients with ZES.

Diarrhea: This symptom may precede ulcer symptoms and is seen in over 30% of patients with gastrinoma. Diarrhea results not only from gastric acid hypersecretion and subsequent activation of pepsinogens by the acid (which causes mucosal injury of the small intestine), but also from acid inactivation of pancreatic enzymes and the acid damage to enterocytes.

Steatorrhea: This defect occurs in part because inactivation of pancreatic lipase by intraluminal acid in the upper small intestine and the low pH environment render some primary bile acids insoluble, and thereby reduce the formation of micelles (which are necessary for fatty acid and monoglyceride absorption). In addition, patients often have blunted villi and, in rare cases, totally flat mucosa with resultant malabsorption.

What Are the Complications of Zollinger-Ellison Syndrome?

A person who has Zollinger-Ellison syndrome may have only one gastrinoma or may have several. Approximately 25% to 30% of ZES patients also have a genetic (inherited) disorder known as “multiple endocrine neoplasia type 1,” which causes tumors in the pituitary and parathyroid glands.

Zollinger-Ellison syndrome (ZES) is an endocrinopathy characterised by gastrin-secreting tumours, which cause multiple, refractory and recurrent peptic ulcers in the distal duodenum and proximal jejunum.

There are two main variants:

• Sporadic (isolated).
• Associated with parathyroid and pituitary tumours as part of the genetic disorder multiple endocrine neoplasia type 1 (MEN1).

The tumour (gastrinoma) is usually in the duodenum (60-65%) or the pancreas (30%).See also the separate article on Pancreatic Endocrine Tumours. In rare cases, gastrinomas occur in other abdominal locations (eg, the stomach, liver, bile duct, ovary) and also extra-abdominal locations (eg, the heart, lung – small cell lung cancer).

Another complication of ZES is that more than half of single gastrinomas are malignant (cancerous). These malignant gastrinomas can spread to other parts of the body, including the liver, lymph nodes, spleen, bones, or skin.

What Are the Symptoms of Zollinger-Ellison Syndrome?

People who have Zollinger-Ellison syndrome don’t always have symptoms. When symptoms do occur, they include:

• Abdominal pain
• Burning pain in the abdomen
• Nausea
• Diarrhea
• Weight loss
• Vomiting
• Bleeding from the stomach
• Weakness
• Fatigue

How Is Zollinger-Ellison Syndrome Diagnosed?

If your doctor suspects that you have ZES, he or she will perform a blood test to look for high levels of gastrin (the hormone secreted by gastrinomas). They may also perform tests to measure how much acid your stomach is producing.

Your doctor may examine you for gastrinomas by performing an endoscopy. This procedure is done with a flexible, lighted tube (an endoscope) that looks at your esophagus, stomach and duodenum. This is often done with endoscopic ultrasound to see the tumor.

Other tests your doctor might perform include a CT scan, a special type of X-ray that provides cross-sectional images of the body, a PET scan to locate tumors, and an octreotide scan to look for neuroendocrine tumor cells.

In addition, what follow-up tests might be useful?

Fasting serum gastrin, secretin stimulation test, and gastric acid secretion (basal acid output) studies have been used for diagnosis of ZES. The gastric acid secretion test is no longer used routinely.

Fasting serum gastrin should be performed in any patient suspected of having ZES. The combination of a fasting serum gastrin concentration higher than 1000 pg/mL (about 10 times the upper limit of normal) and an intragastric pH below 2.5 is virtually diagnostic of the disease. Measurement of gastric pH on a single specimen is important to exclude secondary hypergastrinemia due to achlorhydria. About two-thirds of patients with ZES have serum gastrin concentrations between 150 and 1000 pg/mL (mildly to moderately elevated). The secretin stimulation test should be used to evaluate these patients.

If fasting serum gastrin is not diagnostic, the secretin stimulation test should be used to differentiate patients with ZES from those with other causes of hypergastrinemia (G-cell hyperplasia, gastric outlet obstruction, antisecretory drug therapy, renal insufficiency, and massive small bowel resection). Secretin administration stimulates the release of gastrin from tumor cells (gastrinomas express secretin receptors) but not from normal gastric G-cells. Serial measurements are taken before (-5 and 0 minutes) and after (2,5,10,15, and 20 or 30 minutes) intravenous (IV) secretin administration.

Several criteria have been proposed to define a positive test. Two criteria commonly used are a rise of at least 200 pg/mL in serum gastrin and an increase over baseline of at least 50%. Antacid medications (H₂-blockers and proton pump inhibitors (PPI)) should be discontinued when feasible for at least 1 week prior to testing.

Gastric acid secretion studies are primarily of historical value; rarely, they may have an ancillary role in diagnosis.

Serum chromogranin A (CGA) is a non-specific marker for well-differentiated neuroendocrine tumors that does not distinguish the various tumor subtypes. CGA is usually elevated in patients with ZES, and the degree of increase tends to correlate with tumor volume, which may be useful for staging, prognosis, and monitoring. CGA can be increased in other conditions. Serum CGA is less sensitive and specific than fasting serum gastrin, but it may be used as a confirmatory test in difficult cases. CGA concentrations are usually normal or near normal in patients with high gastrin concentrations secondary to pernicious anemia and enterochromaffin-like cell (i.e., type I) carcinoid tumors. Falsely high values may be found in patients with renal insufficiency or severe malabsorption syndrome.

The calcium infusion study is considerably less sensitive and specific compared to the secretin stimulation test and is more difficult to perform. It is usually reserved for patients with gastric acid hypersecretion for whom there is strong clinical suspicion of gastrinoma despite a negative secretin stimulation test. The test is performed by infusing calcium gluconate and determining serum gastrin and calcium concentrations every 30 minutes. Infusion is associated with an increase in serum gastrin and calcium concentrations in patients with gastrinoma. Positive responses are usually observed between 120 and 180 minutes. A change of at least 395 pg/mL or 50% from baseline is a positive test.

How Is Zollinger-Ellison Syndrome Treated?

ZES is treated by reducing the amount of acid your stomach produces. Medications called proton pump inhibitors are usually prescribed. These drugs, which include lansoprazole (Prevacid), omeprazole (Prilosec, Zegerid), pantoprazole (Protonix), dexlansoprazole (Dexilant ), esomeprazole (Nexium), and rabeprazole (Aciphex), curb the production of stomach acid and allow the ulcers to heal.

Drug treatment

• Oral PPIs will be effective in maintaining acid secretion at an acceptable level but a higher dose than usual, such as omeprazole 40 mg daily, is required.
• Oral doses of histamine H₂ receptor antagonists (eg, ranitidine) can also be effective, but high, frequent dosing is required.
• Medical therapy with PPIs has virtually eliminated the need for acid-reducing surgical procedures.
• Chemotherapy may be tried for metastatic disease.

Surgical treatment

• Due to the efficacy of PPIs, total or partial gastrectomy is no longer indicated.
• For sporadic gastrinomas, surgery, including complete resection of the primary and involved lymph nodes, is the only curative treatment.
• Laparoscopic resection of gastrinomas is controversial and not generally recommended.
• Patients with sporadic ZES without metastases should have surgical resection of the tumour, as this decreases the risk of liver metastases.
• Surgery in MEN1 is more contentious, as it rarely achieves cure but it may reduce the risk of metastasis. It is recommended for tumours over 2.5 cm.
• A single liver metastasis may be resected.

Postoperative surveillance involves measurement of gastrin level, with imaging if an elevation of gastrin levels is detected. Re-excision of recurrent or resection of metastatic disease is controversial but aggressive excision is usually considered if feasible.

Epidemiology

• The incidence of gastrinomas is 0.5-2/million population/year.
• 20-30% of patients have ZES as part of MEN1, an autosomal dominant disorder.
• Mean age of presentation is around 40, being younger in MEN1 patients than sporadic cases. Only about 3% present before age 20 and 7% after age 60.
• Gastrinomas are the most common functioning tumour of the pancreas. In addition to secreting high levels of gastrin, these tumours may produce other hormones such as adrenocorticotrophic hormone (ACTH), vasoactive intestinal polypeptide (VIP), and glucagon.
• They can also produce various peptides, such as insulin, pancreatic polypeptide, glucagon, chromogranin A, neuron-specific enolase, and the alpha and beta subunits of human chorionic gonadotrophin (hCG).

What Is Zollinger-Ellison Syndrome?

Treatment of ZES depends on whether the gastrinoma is sporadic or part of the inherited MEN I syndrome. While the latter is usually treated with acid suppression alone, sporadic gastrinomas are treated with acid suppression and surgical removal of the tumor. Somatostatin analogs such as octreotide, which suppresses hormone production, are also very good at controlling symptoms.

If there is metastatic disease, you may be offered a combination of therapies including surgery, chemotherapy, or targeted drug therapy or radiation.

What Is the Outlook for People with Zollinger-Ellison Syndrome?

Gastrinomas tend to grow slowly and are not always malignant. The five-year survival rate depends on whether tumors are cancerous and if they’ve spread. If they have not spread to the liver, the 5-year survival rate may be 90%. If surgery removes the gastrinoma, 20%-25% of patients are completely cured.

Treatment Follow-up for ZES

If you have been treated for ZES, you should see your doctor on a regular basis to determine if the gastrinomas recur.

Interpretation

Negative fasting serum gastrin and secretin stimulation tests do not exclude ZES if clinical suspicion is high.

The diagnosis of ZES in patients with MEN1 can be complicated by hyperparathyroidism (and resultant hypercalcemia) that affects fasting serum gastrin concentration, basal acid output, and secretin stimulation. Each of these parameters can be markedly decreased after correction of hyperparathyroidism (parathyroidectomy) and, thus, can mask ZES.

Presentation

Patients with ZES as part of the MEN1 syndrome present at an earlier age (approximately 10 years earlier) and may have relatively mild symptoms which can be overlooked.

• Epigastric pain suggestive of peptic ulceration is common, especially in men and in sporadic cases of ZES.
• The other major feature is diarrhoea and this particularly occurs in MEN1 and in women.
• There is often both abdominal pain and diarrhoea.
• Pain of gastro-oesophageal reflux, nausea, vomiting and weight loss may also occur.
• Gastrointestinal (GI) bleeding is the presenting symptom in about 25% of patients.
• Most children with the disease present with complications such as perforation or bleeding.

Other features suggestive of MEN1 should be sought.

If there is hepatomegaly, this suggests liver metastasis. Liver metastases occur much more frequently with pancreatic gastrinomas than with duodenal gastrinomas.

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