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Zollinger-Ellison Syndrome
Douglas S. Parks, MD
image BASICS
DESCRIPTION
  • Zollinger-Ellison syndrome (ZES) triad
    • Markedly elevated gastric acid secretion
    • Peptic ulcer disease
    • A gastrinoma or non-&bgr; islet cell tumor of the pancreas or duodenal wall that produces gastrin
      • Gastrinomas (at the time of diagnosis) may be single or multiple (1/2 to 2/3), large or small, benign or malignant (2/3), sporadic (70-75%) or associated with multiple endocrine neoplasia type 1 (MEN1) (25-30%).
  • System(s) affected: endocrine/metabolic, gastrointestinal
  • Synonym(s): Z-E syndrome; pancreatic ulcerogenic tumor syndrome; multiple endocrine neoplasia, partial; ulcerogenic islet cell tumor
EPIDEMIOLOGY
Incidence
  • 1 to 3 per million per year in the United States
  • Predominant age: middle age (30 to 65 years). Mean age of onset is 43 years. Presents a decade earlier in patients with ZES/MEN1.
  • Predominant sex: male > female (1.3:1)
Pediatric Considerations
Aggressive cases have been reported in teenagers.
Pregnancy Considerations
Rare, pregnancy alters medication choices and surgical timing.
ETIOLOGY AND PATHOPHYSIOLOGY
  • Gastrinoma is equally distributed between the head of the pancreas and the first or second portion of the duodenum; if in the pancreas, the lesion is more likely to metastasize to the liver.
  • Hypergastrinemia results in gastric mucosal hypertrophy and increased acid production. Increased acid production causes mucosal ulceration. Diarrhea and malabsorption are also common in ZES.
  • Also may be found rarely in the mesentery, peritoneum, spleen, skin, or mediastinum (possibly metastasis with primary not identified)
Genetics
˜25-30% of cases occur in association with the MEN1 syndrome—tumors of pancreas, pituitary, and parathyroid.
RISK FACTORS
  • MEN1
  • Family history of ulcer disease
GENERAL PREVENTION
Screen first-degree relatives of patients with MEN1.
COMMONLY ASSOCIATED CONDITIONS
  • MEN1
  • Insulinoma
  • Carcinoid tumors
image DIAGNOSIS
PHYSICAL EXAM
  • Hepatomegaly with metastasis
  • Conjunctival pallor if anemic
  • Jaundice (tumor compressing common bile duct)
  • Epigastric tenderness
  • Dental erosions
  • Heme + stools on rectal exam
  • Complications of severe peptic ulcer disease, including hemorrhage, perforation, and obstruction
  • Signs of MEN1 are hypercalcemia, hyperparathyroidism, and Cushing syndrome.
Geriatric Considerations
Consider the diagnosis in a patient with persistent or recurring peptic ulcer disease; it is a less aggressive disease if it appears after 65 years.
DIFFERENTIAL DIAGNOSIS
  • Elevated serum gastrin with hypochlorhydria/achlorhydria
    • Atrophic gastritis
    • Drug-induced (associated with proton pump inhibitors [PPIs])
    • Gastric cancer
    • Pernicious anemia
    • Postvagotomy
  • Elevated serum gastrin with normal or increased gastric acid
    • Antral G-cell hyperfunction
    • Chronic renal failure
    • Helicobacter pylori infection
    • Gastric outlet obstruction
    • Retained gastric antrum
  • Consider gastrinoma in all patients with the following symptoms:
    • Recurrent or refractory ulcer disease
    • Gastric hypertrophy and ulcers
    • Duodenal and jejunal ulcers
    • Ulcers and diarrhea
    • Ulcers and kidney stones
    • Hypercalcemia and ulcers
    • Pituitary disease
    • Family history of ulcer disease or endocrine tumors suggestive of MEN1
DIAGNOSTIC TESTS & INTERPRETATION
  • Preferred test is secretion stimulation test: gastrin level >100 pg/mL (>100 ng/L) (1,2)[A].
  • Some gastrin assays undermeasure serum gastrin. If have strong index of suspicion but gastrin levels low, may need to repeat with a different lab (3)[B].
  • Gastric secretory studies: basal acid output
  • Alternative test is calcium infusion test: gastrin level >400 pg/mL (test is less specific and more dangerous because of IV calcium infusion).
  • Elevated serum gastrin fasting level: >1,000 pg/mL with ulcers diagnostic; >200 pg/mL with ulcers is suggestive.
  • Elevated basal gastric acid output: >15 mEq/hr (>15 mmol/hr)
  • Gastric pH <2 with elevated gastrin
  • Check serum calcium, phosphorus, cortisol, and prolactin to rule out MEN1.
  • Drugs may alter lab results:
    • Histamine (H2) blockers and PPIs may increase gastric pH and serum gastrin.
    • Hold PPIs 7 days and H2 blockers 2 days prior to drawing gastrin level.
  • Endoscopic US: finds 24-38% of primary tumors
  • Endoscopic findings include esophagitis, duodenal ulceration with multiple ulcers, and prominent gastric and duodenal folds.
  • Used to localize tumor for possible resection
  • Much more likely to find tumors >3 cm (95%) than <1 cm (<15%) (4)[B]
  • Abdominal CT scan: most useful for pancreatic tumors and metastasis >3 cm
  • Abdominal US, MRI, and angiography are not typically useful except in large tumors.
  • Somatostatin receptor scintigraphy (SRS): more sensitive than radiologic studies, still only finds 30% of small tumors
  • Portal venous sampling and selective venous sampling for gastrin can localize the area of tumor and metastasis (80-90% sensitivity).
  • Brain imaging (MRI) and serum calcium are useful if MEN1 is suspected.
  • Because pancreatic tumors are most likely to be large and to metastasize to the liver (worse prognosis), SRS and an abdominal CT scan are suggested to look for resectable tumors. Surgical resection may improve prognosis (5)[B].
Diagnostic Procedures/Other
Endoscopy may reveal tumors in the duodenal wall; multiple ulcers, including jejunal ulcers; and prominent gastric and duodenal folds.
Test Interpretation
  • 90% of gastrinomas are found in the gastric triangle (the borders are the bile duct, the junction of second and third portions of the duodenum, and the junction of the head and body of pancreas).
  • ˜50% of gastrinomas are in the head of the pancreas (more likely >3 cm, metastasis to liver).
  • ˜50% of gastrinomas are in the wall of the first or second portion of duodenum (more likely to be small, solitary).
  • 2/3 of gastrinomas are malignant.
  • 50% of gastrinomas stain positive for adrenocorticotropic hormone (ACTH), vasoactive intestinal polypeptide, insulin, or neurotensin.
  • 1/3 of patients have metastasis on presentation: regional nodes > liver > bone, > peritoneum, spleen, skin, and mediastinum.
  • Biopsy shows hyperplasia of antral gastrin-producing cells, and histology is similar in appearance to carcinoid.
P.1145

image TREATMENT
GENERAL MEASURES
  • Goals are to control acid hypersecretion and resect the tumor.
  • Advanced imaging initially to evaluate for resection
  • Surgical removal when primary tumor can be identified and as adjunct to control symptoms
  • Medical treatment for symptom control when primary tumor is not found or metastasis on initial diagnosis
MEDICATION
  • PPIs are the first-line treatment; add H2 blockers.
  • Medications heal 80-85% of ulcers, most of which recur. Lifelong medication use should be anticipated.
  • 4- to 8-fold higher PPI dose often necessary
    • Start at a lower dose, and titrate to symptoms (or maximum recommended dosage).
  • If hyperparathyroidism is present (MEN1), correct hypercalcemia.
First Line
  • PPIs
    • Omeprazole 60 to 120 mg/day
    • Lansoprazole 60 to 180 mg/day (doses >120 mg need to be divided BID)
    • Rabeprazole 60 to 100 mg/day up to 60 mg BID
    • Pantoprazole 40 to 240 mg/day PO; 80 to 120 mg q12h IV
  • H2 blockers
    • Cimetidine 300 mg q6h up to 2.4 g/day
    • Ranitidine 150 mg q12h up to 6 g/day
    • Famotidine 20 mg q6h; up to 640 mg/day
  • Contraindications
    • Known hypersensitivity to the drug
    • H2 blockers: antiandrogen effects, drug interactions due to cytochrome P450 inhibition
    • PPIs: none
  • Precautions
    • Adjust doses for geriatric patients and patients with renal insufficiency.
    • Gynecomastia has been reported with high-dose cimetidine (>2.4 g/day).
    • PPIs may induce a profound and long-lasting effect on gastric acid secretion, thereby affecting the bioavailability of drugs depending on low gastric pH (e.g., ketoconazole, ampicillin, iron).
  • Significant possible interactions: Consider drug-drug interactions and consult prescribing materials accordingly.
Second Line
  • Octreotide may slow growth of liver metastases, or (occasionally) promote regression. Octreotide LAR can be given every 28 days (4)[B].
  • Chemotherapy regimens using streptozocin, 5-fluorouracil, and doxorubicin shows limited response.
  • Interferon shows a limited response but may be useful in combination with octreotide.
SURGERY/OTHER PROCEDURES
  • Laparotomy may be necessary to search for resectable tumors unless patient has liver metastasis on presentation or MEN1; surgery improves outcomes (6)[B].
  • Definitive therapy: removal of identifiable gastrinomas (95% of tumors are found at the time of surgery; 5-year cure is 40% when all are removed)
  • Total gastrectomy is rarely indicated.
  • In MEN1, parathyroidectomy, by lowering calcium, may also decrease acid production and decrease antisecretory drug use. Gastrinomas in MEN1 are generally small, benign, and multiple, and surgery is not usually curative in this situation.
INPATIENT CONSIDERATIONS
Admission Criteria/Initial Stabilization
  • Titrate medication to symptom control
  • Appropriate surveillance postoperatively to look for metastasis
image ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
  • Longitudinal follow-up to evaluate for metastases
  • Titrate medical therapy to control symptoms.
  • Advise patients of potential danger of stopping antisecretory treatment. Rare cases have been reported of severe adverse outcomes within 2 days of stopping PPIs (7)[B]. Gastric acid analysis can help guide medical therapy to maintain basal gastric acid output at <10 mEq/hr (<2 mEq/hr if patient has complications such as perforation or esophagitis).
DIET
Restrict foods that aggravate symptoms.
PATIENT EDUCATION
Inform patients as to the nature of disease and prognosis.
PROGNOSIS
  • Overall survival rate: 5 to 10 years: 69-94%
  • The prognosis improves with complete surgical removal of the tumor.
  • If liver metastasis is present on initial surgery, 5-year survival is 30-40%; 10-year survival is 25%.
  • Mortality is directly related to liver metastasis tumor size and presence of pancreatic tumors (4,5)[B].
REFERENCES
1. Berna MJ, Hoffmann KM, Long SH, et al. Serum gastrin in Zollinger-Ellison syndrome: II. Prospective study of gastrin provocative testing in 293 patients from the National Institutes of Health and comparison with 537 cases from the literature. Evaluation of diagnostic criteria, proposal of new criteria, and correlations with clinical and tumoral features. Medicine (Baltimore). 2006;85(6):331-364.
2. Kuiper P, Biemond I, Masclee AA, et al. Diagnostic efficacy of the secretin stimulation test for the Zollinger-Ellison syndrome: an intra-individual comparison using different dosages in patients and controls. Pancreatology. 2010;10(1):14-18.
3. Rehfeld JF, Bardram L, Hilsted L, et al. Pitfalls in diagnostic gastrin measurements. Clin Chem. 2012;58(5):831-836.
4. Hoffmann KM, Furukawa M, Jensen RT. Duodenal neuroendocrine tumors: classification, functional syndromes, diagnosis and medical treatment. Best Pract Res Clin Gastroenterol. 2005;19(5):675-697.
5. Jensen RT. Gastrinomas: advances in diagnosis and management. Neuroendocrinology. 2004;80(Suppl 1): 23-27.
6. Morrow EH, Norton JA. Surgical management of Zollinger-Ellison syndrome; state of the art. Surg Clin North Am. 2009;89(5):1091-1103.
7. Poitras P, Gingras MH, Rehfeld JF. The Zollinger-Ellison syndrome: dangers and consequences of interrupting antisecretory treatment. Clin Gastroenterol Hepatol. 2012;10(2):199-202.
8. Thomson AB, Sauve MD, Kassam N, et al. Safety of the long-term use of proton pump inhibitors. World J Gastroenterol. 2010;16(19):2323-2330.
Additional Reading
&NA;
  • Hirschowitz BI, Fineberg N, Wilcox CM, et al. Costs and risks in the management of patients with gastric acid hypersecretion. J Clin Gastroenterol. 2010;44(1):28-33.
  • Mortellaro VE, Hochwald SN, McGuigan JE, et al. Long-term results of a selective surgical approach to management of Zollinger-Ellison syndrome in patients with MEN-1. Am Surg. 2009;75(8):730-733.
  • Smallfield GB, Allison J, Wilcox CM. Prospective evaluation of quality of life in patients with Zollinger-Ellison syndrome. Dig Dis Sci. 2010;55(11):3108-3112.
Codes
&NA;
ICD10
E16.4 Increased secretion of gastrin
Clinical Pearls
&NA;
  • Consider ZES if peptic ulcers recur or if high doses of PPI are needed to control symptoms/ulcers.
  • ˜25-30% of cases of ZES occur in association with MEN1.
  • Once ZES is diagnosed, it is important to search for gastrinomas in the head of the pancreas and the first or second portion of the duodenum.
  • PPIs heal ZES ulcers. Patients should anticipate lifelong therapy.