Zollinger-Ellison Syndrome
Zollinger-Ellison syndrome (ZES) is caused by a non–beta islet cell, gastrin-secreting tumor of the pancreas that stimulates the acid-secreting cells of the stomach to maximal activity, with consequent gastrointestinal mucosal ulceration. ZES may occur sporadically or as part of an autosomal dominant familial syndrome called multiple endocrine neoplasia type 1 (MEN 1). The primary tumor is usually located in the duodenum, the pancreas, and abdominal lymph nodes, but ectopic locations have also been described (eg, heart, ovary, gall bladder, liver, kidney).
The symptoms of ZES are secondary to hypergastrinemia, which causes hypertrophy of the gastric mucosa, leading to increased numbers of parietal cells and increased maximal acid output. Gastrin by itself also stimulates acid secretion, resulting in increased basal acid secretion. The large quantity of acid produced leads to gastrointestinal mucosal ulceration. It also leads to diarrhea and malabsorption. Malabsorption in ZES usually is multifactorial, being caused by direct mucosal damage by acid, inactivation of pancreatic enzymes, and precipitation of bile salts. ZES is sporadic in 75% of patients, while in the other 25% it is associated with MEN 1, an autosomal dominant condition characterized by hyperparathyroidism, pancreatic endocrine tumors, and pituitary tumors.
ZES occurs in approximately 0.1-1% of all patients with duodenal ulcers. Its frequency of occurrence is reported to be approximately the same as insulinoma, the most common functioning pancreatic endocrine tumor.
International
Incidence is 1-3 cases per million patients per year in Sweden, 0.5 cases per million patients per year in Ireland, and 0.1-0.2 cases per million patients per year in Denmark.
Currently, the morbidity and mortality of ZES is low because of improved medical and surgical management of the disease. Fewer than 5% of patients develop a complication, such as abdominal perforation, gastric outlet obstruction, or esophageal stricture.
All races can be affected.
A slight male predominance exists, with a male-to-female ratio of 1.3:1.
The mean age of onset of ZES is 43 years, with the patients with MEN 1/ZES presenting a decade earlier. Generally, a 5- to 7-year delay in diagnosis occurs. In a recent prospective study, fewer than 3% of patients were younger than 20 years, while 7% were older than 60 years at the time of disease onset.
A high index of clinical awareness is needed to make a diagnosis of ZES.
- Abdominal pain is the most common symptom, present in 75% of patients. Typically, it is located in the upper abdomen and mimics that of peptic ulcer disease. This symptom is reported more frequently by men and patients with the sporadic form of ZES.
- Of patients with ZES, 73% have diarrhea, and this is the most common symptom in patients who have MEN 1/ZES and in female patients.
- The combination of diarrhea and abdominal pain is present in more than half the patients.
- Heartburn is the third most common symptom, and this symptom mimics gastroesophageal reflux disease (GERD).
- Other symptoms include nausea, vomiting, gastrointestinal bleeding, and weight loss. Gastrointestinal bleeding frequently is due to ulceration in the duodenum and is the presenting symptom in 25% of patients.
- In patients in whom MEN 1/ZES is suspected, a history indicative of nephrolithiasis, hypercalcemia, and pituitary disorders should be sought. A family history of nephrolithiasis, hyperparathyroidism, and gastrinoma also may be present.
The findings of the physical examination may be normal.
- Patients may be pale if presenting with gastrointestinal bleeding.
- Jaundice may occur if the tumor compresses the common bile duct, although this presentation is very rare.
- Epigastric tenderness may be present.
- Dental erosions may be noted if symptoms consistent with GERD are present.
- The presence of hepatomegaly suggests liver metastasis.
- ZES is caused by a non–beta islet cell, gastrin-secreting tumor of the pancreas that stimulates the acid-secreting cells of the stomach to maximal activity, with consequent gastrointestinal mucosal ulceration.
- ZES may occur sporadically or as part of MEN 1.
DIFFERENTIALS
Other Problems to be Considered
Retained gastric antrum syndrome
Antral G cell hyperplasia
WORKUP
- Fasting serum gastrin
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- Fasting serum gastrin is the best single screening test.
- Preferably, patients should not be taking gastric antisecretory medications at the time of the test, but this is not essential for the initial screen.
- Because fasting gastrin levels can fluctuate from day to day and can appear to be normal, serial measurements on different days should be performed.
- Normal levels of serum gastrin in untreated ZES are extremely rare ( <1%).
- Gastric acid secretory tests
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- Basal acid output (BAO) greater than 15 mEq/h or greater than 5 mEq/h in patients with a prior vagotomy and partial gastrectomy is suggestive of ZES.
- Basal gastric secretory volume greater than 140 mL in patients with no prior gastric acid–reducing surgery has a high sensitivity and specificity.
- Gastric pH less than 2.0 in the presence of a large gastric volume (>140 mL over 1 h in patients without prior gastric acid–reducing surgery) is highly suggestive of ZES.
- Currently, maximal acid output measurement rarely is performed.
- Provocative tests
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- Various provocative diagnostic tests for ZES have been proposed, including the secretin stimulation test, calcium stimulation test, secretin-plus-calcium stimulation tests, bombesin test, and protein meal test.
- The secretin stimulation test is the provocative test of choice because of its higher sensitivity. In this test, a 2-U/kg bolus of secretin is administered intravenously after an overnight fast, and serum levels of gastrin are determined at 0, 2, 5, 10, and 15 minutes. An increase in serum gastrin of greater than 200 pg/mL is diagnostic.
- Elevated serum calcium levels should prompt a search for MEN 1 syndrome.
- A suggested algorithm for the evaluation of a patient with suspected gastrinoma is as follows:
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- Step 1: Check gastrin level. Measure at least 3 fasting levels of gastrin on different days.
- Step 2: Perform gastric acid secretory studies. A BAO value of greater than 15 mEq/h or a gastric volume of greater than 140 mL and pH of less than 2.0 are highly suggestive of gastrinoma.
- Step 3: Perform a provocative test. The secretin stimulation test is the preferred test.
- Step 4: Perform somatostatin receptor scintigraphy (SRS).
- Step 5: Perform imaging studies to stage and localize the gastrinoma.
- Step 6: Determine if patient is a surgical candidate for tumor resection.
- SRS is the most sensitive imaging modality for detection of primary or metastatic lesions in ZES and, thus, is the imaging modality of choice in ZES.
- CT scan can be performed to localize the tumor and is useful for evaluation for metastatic disease. However, its sensitivity for primary tumor localization is only 50%, and frequently, tumors smaller than 1 cm are missed.
- Other imaging studies, such as magnetic resonance imaging and abdominal ultrasound, also can be performed. However, sensitivity is lower compared to CT scan or SRS.
- Endoscopic ultrasound is one of the newer methods for localizing gastrinomas. Its sensitivity is higher for pancreatic gastrinoma (40-75%) than for duodenal gastrinoma (50%).
- Esophagogastroduodenoscopy should be performed to look for duodenal ulcerations and hypertrophy of gastric folds. Sensitivity for hypertrophic gastric folds is 94%. Rarely, thickened duodenal folds also may be present.
TREATMENT
Medical Care
- The goals of treatment are medical control of gastric acid hypersecretion and surgical resection of the tumor.
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- If the patient is acutely ill, immediate control of gastric acid hypersecretion can be achieved with intravenous proton pump inhibitors. Previously, this was accomplished with histamine 2 (H2) receptor blockers. Intravenous pantoprazole was approved recently by the US Food and Drug Administration. Proton pump inhibitors are superior to H2 blockers for the control of gastric acid hypersecretion.
- Patients who are candidates for surgical resection should be referred for resection of the tumor.
- For patients with metastatic disease, chemotherapy, interferon, and octreotide may be helpful. The response to these agents in most studies has been low. Liver transplantation for hepatic metastasis also has been reported. For patients with a single confined liver metastatic lesion, surgical resection may be attempted.
- All patients with sporadic ZES without hepatic metastases or medical contraindications to surgery are advised to undergo surgical resection of the tumor because this decreases the risk of developing liver metastases, which can decrease the survival of these patients.
- The role and timing of surgical resection in patients with MEN 1 is less clear. An attempt at surgical resection has been recommended if the tumor is larger than 2.5 cm. Cure is rarely achieved by surgical resection in patients with MEN 1; however, it may reduce the risk of subsequent metastatic disease.
- Because this is a rare tumor, surgical resection should be attempted only at centers with personnel experienced in treating patients with ZES.
- Gastroenterologist
- Surgeon
- Oncologist
- Possibly, endocrinologist
Medical therapy is aimed at control of gastric acid hypersecretion.
Drug Category: Proton pump inhibitors
Drugs of choice in ZES. Inhibit gastric acid secretion by inhibition of the H+/K+/ATP-ase enzyme system in the gastric parietal cells.
| Drug Name | Omeprazole (Prilosec) |
| Description | Decreases gastric acid secretion by inhibiting parietal cell H+/K+ ATP pump. Aim of therapy is to maintain BAO <10> |
| Adult Dose | 40 mg PO bid, titrate up prn to desired BAO |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity |
| Interactions | May decrease effects of itraconazole and ketoconazole; may increase toxicity of warfarin, digoxin, and phenytoin |
| Pregnancy | C - Safety for use during pregnancy has not been established. |
| Precautions | Bioavailability may increase in elderly patients |
| Drug Name | Lansoprazole (Prevacid) |
| Description | Decreases gastric acid secretion by inhibiting parietal cell H+/K+ ATP pump. Aim of therapy is to maintain BAO <10> |
| Adult Dose | 60 mg PO bid, titrate up prn to desired BAO |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity |
| Interactions | May decrease effects of ketoconazole and itraconazole; may increase theophylline clearance |
| Pregnancy | B - Usually safe but benefits must outweigh the risks. |
| Precautions | Consider adjusting dose in liver impairment |
| Drug Name | Pantoprazole (Protonix) |
| Description | Decreases gastric acid secretion by inhibiting parietal cell H+/K+ ATP pump. Aim of therapy is to maintain BAO <10> |
| Adult Dose | 40-160 mg PO qd; alternatively, 80 mg IV bid |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity |
| Interactions | May decrease effects of ketoconazole and iron salts |
| Pregnancy | C - Safety for use during pregnancy has not been established. |
| Precautions | Decrease dose in hepatic impairment, half-life can increase 7- to 9-fold; no dose adjustment required in patients with renal impairment |
| Drug Name | Esomeprazole magnesium (Nexium) |
| Description | S-isomer of omeprazole used for symptomatic GERD. Inhibits gastric acid secretion by inhibiting H+/K+ ATP pump at secretory surface of gastric parietal cells. |
| Adult Dose | 20-80 mg PO qd |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity |
| Interactions | Amoxicillin or clarithromycin may increase plasma levels when used concurrently; may reduce absorption of dapsone; may increase levels of diazepam and GI absorption of digoxin; may decrease absorption of iron, ketoconazole, and itraconazole |
| Pregnancy | C - Safety for use during pregnancy has not been established. |
| Precautions | Symptomatic relief with proton pump inhibitors may mask symptoms of gastric malignancy |
| Drug Name | Rabeprazole sodium (Aciphex) |
| Description | Decreases gastric acid secretion by inhibiting the parietal cell H+/K+ ATP pump. For short-term (4-8 wk) treatment and relief of symptomatic erosive or ulcerative GERD. In patients not healed after 8 wk, consider additional 8-wk course. |
| Adult Dose | 20-80 mg tab PO qd |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity |
| Interactions | May decrease effects of itraconazole and ketoconazole; may increase toxicity of warfarin, digoxin, and phenytoin |
| Pregnancy | B - Usually safe but benefits must outweigh the risks. |
| Precautions | Symptomatic relief with proton pump inhibitors may mask symptoms of gastric malignancy |
FOLLOW-UP
- Inpatient care is aimed at first controlling the gastric acid hypersecretion.
- Once gastric acid hypersecretion is controlled, imaging studies should be obtained to localize the tumor and determine tumor extent.
- After surgical resection for gastrinoma, patients should be assessed for evidence of recurrence with serum fasting gastrin levels, a secretin test, and SRS. The first evaluation should be performed at 3-6 months postresection and then, optimally, yearly thereafter.
- Proton pump inhibitors can be continued with the goal of maintaining the BAO at less than 10 mEq/h before the next dose of the proton pump inhibitors.
- Abdominal perforation secondary to ulceration (Duodenum and jejunum are the most common sites.)
- Esophageal stricture, with reflux
- Obstruction
- Gastrointestinal bleeding
- Gastric carcinoids (especially in patients with MEN 1)
- Prognosis is excellent in patients without metastatic disease.
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