zollinger-ellison%20syndrome
ZOLLINGER-ELLISON SYNDROME
Zollinger-Ellison syndrome (ZES) is a disease entity which refers to the triad of severe peptic ulcer disease (PUD), gastric acid hypersecretion and non-beta cell gastrin-secreting tumor primarily of the pancreas and duodenum (gastrinoma).
Approximately two-thirds of patients have sporadic ZES while the rest is part of multiple endocrine neoplasia type 1.
ZES should be considered in the differential diagnoses of patients who present with abdominal pain, malabsorption and chronic watery diarrhea.
A high index of clinical awareness is necessary to correctly diagnose ZES.

Diagnosis

  • A high index of clinical awareness is necessary to correctly diagnose ZES

Physical Examination

The clinical presentation of ZES may be obscure and the physical exam may be normal

  • Pallor secondary to GI bleeding
  • Epigastric tenderness
  • Dental erosions which are usually associated with symptoms of gastroesophageal reflux
  • Hepatomegaly in patients with liver metastases

Laboratory Tests

Fasting Serum Gastrin

  • Best single screening test
  • Gastric analysis performed concomitantly with serum fasting gastrin measurement increases the accuracy of the diagnosis of ZES
    • Gastric pH analysis is used to exclude hypergastrinemia resulting from achlorhydria, which may be secondary to chronic atrophic gastritis or severe H pylori-associated chronic gastritis
  • A markedly increased serum gastrin level (>1000 pg/mL or 475 pmol/L) is specific for ZES, but is not sensitive
    • Many patients with gastrinoma have gastrin levels <1000 pg/ml, but normal levels of serum gastrin are very rare in untreated ZES patients
  • However, about 2/3 of patients with ZES have serum gastrin concentrations <10 times the upper limit of normal, generally between 150 and 1000 pg/mL (or between 75 and 475 pmol/L)
    • Higher levels are more likely with pancreatic (compared with duodenal) tumors, larger tumor size, and with metastatic disease
  • Patients should be instructed to discontinue medications that may inhibit gastric acid secretion and produce false-positive gastrin results (eg proton pump inhibitors or PPIs) at least 1 week prior to serum gastrin testing
  • Serial determinations over several days should be done, because fasting gastrin levels may fluctuate from day to day
  • Physicians should be aware of other medical conditions that may give rise to increased serum gastrin levels
    • Hyperlipidemia
    • Renal failure
    • Primary hyperparathyroidism
    • Vagotomy without gastric resection
    • Massive small bowel resection
    • Gastric outlet obstruction

 Secretin Stimulation Test

  • Should be performed in all patients suspected to have ZES whose fasting serum gastrin level is nondiagnostic
  • Baseline gastrin levels are obtained twice prior to administering secretin test
  • Secretin is administered via the IV route after an overnight fast, after which serum gastrin levels are measured after 2, 5, 10, 15 and 20 minutes
  • ZES patients exhibit a rapid rise in gastrin levels; peak serum gastrin usually seen by 10 minutes
  • A positive secretin test is most commonly defined by an elevation of serum gastrin of ≥200 pg/mL (95 pmol/L) above the baseline
    • A large study done on ZES patients and literature-based cases recommends a cutoff of >120 pg/mL which was associated with the highest sensitivity and specificity
  • Proton pump-inhibiting medications should be discontinued 1 week before the test and patients placed on an H2 receptor antagonist, which should be discontinued 24 hours prior to testing
  • Contraindicated in patients with acute pancreatitis

Gastric Acid Secretory Tests

  • Although may provide an ancillary role, this test is now uncommonly performed and measured
  • ZES patients have an increased basal acid output (BAO): >10.6 meq/hr in men, >5.6 mEq/hr in women
  • A gastric pH <2 together with a basal gastric secretory volume >140 mL/hr in patients without prior gastric acid-reducing interventions is highly suggestive of ZES
  • Maximal acid output monitoring is infrequently performed
  • Elevated serum gastrin level with achlorhydria makes ZES extremely unlikely

Serum Chromogranin A (Serum CGA)

  • A general marker for well-differentiated neuroendocrine tumors but does not differentiate between the various tumor subtypes
  • Increased in most patients with gastrinomas, with the level of elevation correlating with tumor volume
  • Less sensitive and specific than measurement of serum gastrin, but it may be used as a confirmatory test in difficult cases

Calcium Infusion Study

  • Less sensitive and specific compared to the secretin stimulation test and more burdensome to perform
  • Usually reserved for patients with gastric acid hypersecretion in whom there is a strong clinical suspicion of gastrinoma despite a negative secretin test

Imaging

Imaging Exams for Localization of Gastrinoma

  • Once gastric acid hypersecretion has been controlled, imaging exams should be done to locate the tumor (gastrinoma)
  • Imaging exams to localize the gastrinoma and to determine the presence of metastases are important in planning the proper management strategy for ZES
  • Most gastrinomas are located in the “gastrinoma triangle”
    • Defined superiorly by the confluence of the cystic and common bile duct, inferiorly by the junction of the 2nd and 3rd portions of the duodenum and medially by the junction of the neck and body of the pancreas
    • 80% of the gastrinomas within the gastrinoma triangle are curable
  • Gastrinomas in patients with MEN-1 commonly develop in the duodenum, are multiple, and <2 cm, while sporadic gastrinomas are found in the pancreas, are solitary, and >2 cm

Somatostatin Receptor Scintigraphy (SRS)

  • Imaging method of choice because of its high sensitivity in detecting primary or metastatic lesions in ZES
  • Detects extrahepatic and lymph node involvement more reliably than computed tomography (CT) and magnetic resonance imaging (MRI)
  • Superior to bone scan in detecting bone metastases
  • Able to distinguish hepatic hemangiomas from metastatic gastrinomas in ZES patients seen to have hepatic masses via other imaging modalities
  • Able to differentiate between gastrinomas and coexisting carcinoid tumors of the stomach in patients with MEN-1-associated ZES
  • Disadvantage: Does not give reliable data about tumor size and exact location (eg duodenum vs pancreatic head)
    • CT scan with contrast is therefore also recommended

Computed Tomography (CT)

  • Helical CT is highly sensitive for the detection of primary pancreatic tumors and hepatic metastases
  • May provide additional information about tumor size and location

Magnetic Resonance Imaging (MRI)

  • Has a high sensitivity for detecting hepatic metastases
  • Disadvantage: Less sensitive for detection of primary pancreatic tumors

Endoscopic Ultrasound (EUS)

  • Has a sensitivity of 80-90% for the detection of pancreatic islet cell tumors
  • Allows fine needle aspiration for histological identification
  • Disadvantage: Often misses primary duodenal gastrinomas

Other Imaging Techniques

  • Useful imaging studies for small gastrinomas may include hybrid scanning with SRS and CT or MRI, and use of PET scan with somatostatin analogs labeled with gallium-68

Common Sites of Gastrinoma Tumor Metastases

  • Only the presence of metastases or gross invasion of normal tissues remains the generally accepted criterion for malignancy

Liver

  • Site of major metastases for gastrinomas
  • Pancreatic gastrinomas >3 cm in size are associated with a higher incidence of liver metastases
  • Pancreatic tumors metastasize more frequently to the liver, compared to duodenal tumors

Bone

  • Bone metastases (eg spine or sacrum) occur later in the course of illness
  • Associated with aggressive tumor growth and decreased survival

Lymph Nodes

  • Incidence of lymph node metastases is similar for pancreatic and duodenal gastrinomas

Evaluation

The presence of MEN-1 in a patient with ZES has important consequences affecting prognosis and treatment

  • MEN-1 is an autosomal dominant familial syndrome characterized by tumors in multiple endocrine organs, notably the parathyroid, pituitary and pancreas
    • Majority of MEN-1 endocrine tumors are benign, but pancreatic islet tumors and foregut carcinoids may be malignant
    • Gastrinomas develop in about 60% of MEN-1 patients
      • The presence of MEN-1 in ZES patients is associated with aggressive growth of gastrinoma
  • MEN-1 should be considered in any ZES patient who manifests with hypercalcemia or its complications eg nephrolithiasis
  • Serum calcium and parathyroid hormone measurements should be done in all ZES patients
  • The attending physician should inquire about a family history of PUD and hypercalcemia
  • Conversely, all patients diagnosed with MEN-1 should be screened for ZES using fasting serum gastrin with or without the secretin test
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