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.

Principles of Therapy

  • Aggressive control of acid hypersecretion in ZES patients is of prime importance because of the risk of peptic ulcer complications & other acid-peptic disease including esophagitis
  • Once gastric acid secretion is controlled, imaging studies can be performed to locate the tumor & to stage the disease
  • Control of acid secretion remains mandatory in patients who have undergone successful gastrinoma resection & exhibit biochemical evidence of cure
    • Parietal cell mass in the stomach has already expanded as a consequence of long-standing hypergastrinemia


Proton Pump Inhibitors (PPIs)

  • Most effective drugs for controlling gastric acid hypersecretion in ZES patients
    • PPIs have been found to be safe even at high doses
  • Act by irreversibly binding to & inhibiting the hydrogen/potassium ATPase found on the luminal surface of the parietal cells
  • Goal: To maintain basal acid output (BAO) at <10 mEq/hr & at <5 mEq/hr in patients w/ previous acid-reducing gastric surgery
  • Allow for once- to twice-daily dosing in about 95% of patients due to its long duration of action & potency
  • Once adequate control of acid secretion is achieved, the dose may be decreased over time to about half the starting dose
  • Dose reduction of PPIs should be done cautiously in the following patients since they require greater acid suppression:
    • Patients w/ MEN-1 or severe GERD
    • Patients who have previously undergone gastric surgery
  • PPIs given the IV route may also be used to achieve uninterrupted control of gastric acid secretion in ZES patients who are vomiting & have gastric outlet obstruction, & in those who are about to undergo gastrinoma resection or receive chemotherapy
  • Vit B12 levels should be monitored in patients receiving long-term PPI therapy because PPIs may lead to reduced Cobalamin absorption from food
  • Yrly acid secretory control assessment is recommended after initial PPI treatment

Histamine2-Receptor Antagonists (H2RAs)

  • May be effective for controlling gastric acid hypersecretion; however, higher-than-conventional doses are required
    • Failure to control acid hypersecretion w/ conventional doses often lead to a suspicion of ZES 


  • Limited experience w/ systemic chemotherapy for patients w/ metastases
  • Streptozocin & Doxorubicin have been the traditional treatment
    • Uncertainty w/ efficacy & associated toxicities (eg hair loss, renal dysfunction, prolonged myelosuppression, nausea) limit their use
    • Radiologic response rate is estimated to be between 10% & 40%
  • Single-agent therapy (eg Streptozocin, 5-fluorouracil, Doxorubicin alone) is associated w/ modest response rates
  • Antineoplastic agents Everolimus & Sunitinib have been demonstrated in studies to increase the progression-free survival time of patients
  • Temozolomide-based regimen has also shown antitumor activity
    • Choice of treatment regimen should be individualized

Palliative Therapy

  • For patients w/ metastases of the liver, a rapidly growing tumor, those w/ bone metastases, ectopic Cushing’s syndrome, or uncontrolled symptoms due to metastatic disease, antitumor treatment is indicated
  • Octreotide w/ or w/o Interferon alfa are recommended as therapy
    • Octreotide plus Interferon alfa is associated w/ relatively less toxicity compared to chemotherapy


  • Octreotide is a somatostatin analog that may inhibit tumor growth by binding to somatostatin type-2 receptors (SST2) expressed by pancreatic islet cell tumors
  • May be given to patients unresponsive to PPI therapy
  • Effect is less predictable in gastrinomas compared w/ other pancreatic islet cell tumor
    • Nevertheless, it is effective in controlling gastrin secretion & may slow down tumor growth
  • A long-acting preparation has largely eliminated the need for daily Octreotide inj
    • Used after a brief trial of short-acting formulation
    • Additional short-acting Octreotide may be used for breakthrough symptoms
  • Greater efficacy may be seen when combined w/ Interferon alfa
    • Effective in inhibiting further tumor growth in 50-60% of patients

Interferon alfa

  • May be used in combination w/ Octreotide
  • Based on past studies, reduces symptoms of hormonal hypersecretion in 40-50% of patients w/ neuroendocrine & carcinoid tumors
    • Induces tumor stabilization in 20-40%


  • A randomized study showed this somatostatin analog was associated w/ increased survival of patients w/ grade 1 or 2 metastatic enteropancreatic neuroendocrine tumors that are somatostatin positive

Hepatic Arterial Embolization

  • Palliative treatment for patient w/ symptomatic liver metastases who are not candidates for surgery
    • Liver metastases derive most of their blood supply from hepatic artery; therefore, embolization will cause metastatic necrosis
  • Can be done either via infusion of gel foam powder (bland embolization) or in conjunction with chemotherapy (chemoembolization)
    • Cisplatin, Doxorubicin & Streptozocin may be used as chemoembolization agents
  • A third technique (radioembolization) makes use of radioactive isotopes bound to glass or resin microspheres & selectively delivered to the tumor via hepatic artery
  • Response rates are generally above 50% & is measured by radiographic regression, decreased hormone secretion & symptomatic improvement
  • Proper patient selection must be done to minimize adverse effects which include fever, nausea, fatigue & elevated liver enzymes
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