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 & the physical exam may be normal

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

Laboratory Tests

Fasting Serum Gastrin

  • Best single screening test
  • Gastric analysis performed concomitantly w/ 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 w/ 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 & 1000 pg/mL (or between 75 & 475 pmol/L)
    • Higher levels are more likely with pancreatic (compared with duodenal) tumors, larger tumor size, & with metastatic disease
  • Patients should be instructed to discontinue medications that may inhibit gastric acid secretion & produce false-positive gastrin results (eg proton pump inhibitors or PPIs) at least 1 wk 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 w/o 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 & 20 min
  • ZES patients exhibit a rapid rise in gastrin levels; peak serum gastrin usually seen by 10 min
  • 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 & literature-based cases recommends a cutoff of >120 pg/mL which was associated w/ the highest sensitivity & specificity
  • Proton pump-inhibiting medications should be discontinued 1 wk before the test & patients placed on an H2 receptor antagonist, which should be discontinued 24 hours prior to testing
  • Contraindicated in patients w/ acute pancreatitis

Gastric Acid Secretory Tests

  • Although may provide an ancillary role, this test is now uncommonly performed & 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 w/ a basal gastric secretory vol >140 mL/hr in patients w/o prior gastric acid-reducing interventions is highly suggestive of ZES
  • Maximal acid output monitoring is infrequently performed
  • Elevated serum gastrin level w/ 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, w/ the level of elevation correlating w/ tumor volume
  • Less sensitive & specific than measurement of serum gastrin, but it may be used as a confirmatory test in difficult cases

Calcium Infusion Study

  • Less sensitive & specific compared to the secretin stimulation test & more burdensome to perform
  • Usually reserved for patients w/ 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 & 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 & common bile duct, inferiorly by the junction of the 2nd & 3rd portions of the duodenum & medially by the junction of the neck & body of the pancreas

Somatostatin Receptor Scintigraphy (SRS)

  • Imaging method of choice because of its high sensitivity in detecting primary or metastatic lesions in ZES
  • Detects extrahepatic & lymph node involvement more reliably than computed tomography (CT) & 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 & coexisting carcinoid tumors of the stomach in patients w/ MEN-1-associated ZES
  • Disadvantage: Does not give reliable data about tumor size & exact location (eg duodenum vs pancreatic head)
    • CT scan w/ contrast is therefore also recommended

Computed Tomography (CT)

  • Helical CT is highly sensitive for the detection of primary pancreatic tumors & hepatic metastases
  • May provide additional information about tumor size & 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 w/ SRS & CT or MRI & use of PET scan w/ somatostatin analogs labeled w/ 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 w/ 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 w/ aggressive tumor growth & decreased survival

Lymph Nodes

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

Evaluation

The presence of MEN-1 in a patient w/ ZES has important consequences affecting prognosis & treatment

  • MEN-1 is an autosomal dominant familial syndrome characterized by tumors in multiple endocrine organs, notably the parathyroid, pituitary & pancreas
    • Majority of MEN-1 endocrine tumors are benign, but pancreatic islet tumors & foregut carcinoids may be malignant
    • Gastrinomas develop in about 60% of MEN-1 patients
  • MEN-1 should be considered in any ZES patient who manifests w/ hypercalcemia or its complications eg nephrolithiasis
  • Serum calcium & parathyroid hormone measurements should be done in all ZES patients
  • The attending physician should inquire about a family history of PUD & hypercalcemia
  • Conversely, all patients diagnosed w/ MEN-1 should be screened for ZES using fasting serum gastrin w/ or w/o the secretin test
  • The presence of MEN-1 in ZES patients is associated w/ aggressive growth of gastrinoma
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