Zollinger-Ellison Syndrome: Not Your Average Peptic Ulcer Disease

IN THIS ARTICLE

• Diagnostic criteria
• Pharmacologic management
• Patient education

A more severe variant of peptic ulcer disease, Zollinger-Ellison syndrome (ZES) is a rare, chronic, and potentially life-threatening ulcerative disorder. Because the syndrome can be easily misdiagnosed based on clinical presentation alone, primary care clinicians need to be aware of its diagnostic features and know when referral to a gastroenterologist is necessary. Clinicians should suspect ZES in patients with peptic ulcer disease that is refractory to traditional medications.

Caused by a gastrin-secreting neuroendocrine tumor of the pancreas or duodenum called a gastrinoma, ZES can be benign or malignant. It typically manifests in white men ages 30 to 50.¹ Due to the significant number of patients treated for a benign cause of peptic ulcer disease (eg, Helicobacter pylori or NSAID-induced ulcers) who are never tested for ZES, the exact incidence is difficult to determine.² However, it is estimated that approximately 0.1 to 3 people per million develop the disease annually.³

PATHOPHYSIOLOGY

Approximately 80% of gastrinomas occur in the “gastrinoma triangle,” outlined by the hepatic portal vein, neck and body of the pancreas, and latter two-thirds of the duodenum (see Figure).^1,4,5 Most gastrinomas involved in ZES occur sporadically, but there is a hereditary component associated with multiple endocrine neoplasia type 1 (MEN1), an autosomal dominant disorder.⁴

The overproduction and secretion of gastrin by the gastrinoma stimulates hypersecretion of hydrochloric acid.⁴ This is distinguished from high gastrin levels in the setting of fasting hypochlorhydria or achlorhydria, which may be caused by chronic atrophic gastritis, proton pump inhibitor (PPI) use, or pernicious anemia.⁵ The chronic hypersecretion of acid causes ulcerations to form. Most commonly, a single ulcer forms in the first portion of the duodenum.³

CLINICAL PRESENTATION

Patients with ZES often report vague abdominal pain that may mimic peptic ulcer disease on initial presentation. The widespread use of PPIs can mask symptoms, and one-fourth of patients present with no abdominal pain at all.⁶ Patients may also present with symptoms of GERD (ie, heartburn, chest pain, dysphagia).^1,4 Excessive acid production can lead to the development of Barrett esophagus, which can further complicate the management of ZES.⁶ Half of all patients with ZES have diarrhea, which can manifest on its own or be accompanied by other abdominal complaints, and is often attributed to lower GI problems such as Crohn disease.^1,7 Family history of MEN1 should raise suspicion for ZES; however, 80% of ZES cases occur sporadically.³

The physical exam may be within normal limits, and no physical finding is considered pathognomonic for ZES. Findings may include epigastric tenderness; pallor, due to an ulcer-related anemia or GI bleed; jaundice, if there is liver involvement; and esophageal or dental erosions, due to excessive acid.⁸

DIAGNOSIS

Patients with symptoms refractory to medical management should be referred to a specialist for further testing. Once a patient is referred, a gastroenterologist will perform lab tests and imaging studies. In order to be diagnosed with ZES, the patient must exhibit an acidic environment with a pH less than 2 and an inappropriate release of gastrin with a basal acid output greater than 15 mEq/h (or > 5 mEq/h in a patient with prior acid reduction surgery).^5,6

Fasting serum gastrin (FSG) is the initial study of choice, followed by a secretin-stimulating test when necessary.⁹ Diagnosis is established by an FSG level greater than 100 pg/mL; if more than 10-fold the normal level, no further testing is needed. However, results often range from 100 to 1,000 pg/mL.^6,10 At these values, further testing with secretin stimulation is warranted.⁹ The test is performed with an IV injection of secretin, and blood samples are obtained to measure serum gastrin levels.¹⁰ An increase greater than 100 pg/mL is considered positive; one greater than 200 pg/mL is diagnostic.³

Once lab tests have been performed, a series of imaging studies are indicated. Endoscopy is used to identify active ulcers and erosions due to long-term acid secretion.³ CT, MRI, and somatostatin receptor scintigraphy (a specialized form of imaging that is the study of choice for localizing gastrinomas) are performed to localize primary tumors and identify any metastatic disease that may be present.¹⁰ Finally, after lab tests and imaging studies have been completed, genetic screening for MEN1 is used to determine if the patient has a sporadic or hereditary gastrinoma.³