What is the next step in managing a patient with Zollinger Ellison syndrome (ZES) who is not responding to standard treatment, presenting with epigastric pain, diarrhea, multiple gastroduodenal ulcers, upper Gastrointestinal (GI) bleeding, and elevated gastrin levels?

Management of Zollinger-Ellison Syndrome Not Responding to Standard Treatment

The secretin stimulation test is the next appropriate step in managing a patient with suspected Zollinger-Ellison syndrome who is not responding to standard treatment. 1

Diagnostic Confirmation

When faced with a patient presenting with one month of epigastric pain, diarrhea, multiple gastroduodenal ulcers with upper GI bleeding, and elevated gastrin levels (120), who is not responding to standard treatment, the first priority is to confirm the diagnosis of ZES:

• The secretin stimulation test is considered the best test to distinguish ZES from other conditions resulting in elevated gastrin levels 2
• This test offers a safe, expeditious, and reliable means of evaluating patients with hypergastrinemia 1
• A positive secretin test shows a paradoxical increase in serum gastrin levels (typically >200 pg/mL from baseline) within 2-10 minutes after secretin administration, which is pathognomonic for gastrinoma

Imaging Considerations

After confirming the diagnosis with secretin stimulation, localization studies should be performed:

• Somatostatin receptor scintigraphy (SRS) is the initial localization study of choice 3
• Endoscopic ultrasound (EUS) may have similar sensitivity for identifying primary tumors 3
• A combination of SRS and EUS detects greater than 90% of gastrinomas 3

Treatment Approach

For a patient with confirmed ZES not responding to standard treatment:

1. Optimize acid suppression therapy:

   • High-dose proton pump inhibitors (PPIs) are the mainstay of treatment 4
   • For Zollinger-Ellison syndrome, the starting dose is 60 mg once daily, with dosages up to 120 mg three times daily as needed 4
   • Patients with ZES should not be considered for PPI de-prescribing due to high risk of complications 5

2. Consider surgical options:

   • All patients with sporadic gastrinoma who do not have unresectable metastatic disease should undergo exploratory laparotomy for potential curative resection 2
   • In patients with MEN1 and ZES, surgery should be pursued only if there is an identifiable tumor larger than 2 cm 6

3. For refractory symptoms:

   • Consider somatostatin analogs (lanreotide or octreotide) for symptom control 5
   • Peptide receptor radionuclide therapy (PRRT) may be considered for progressive disease to improve symptoms 5

Common Pitfalls and Caveats

• Diagnostic challenges: The average time between symptom onset and final diagnosis of ZES is often longer than 5 years 7
• Medication interference: PPIs and H2 antagonists raise both circulating chromogranin A and gastrin levels, potentially confounding diagnostic tests 5
• MEN1 association: Always evaluate for Multiple Endocrine Neoplasia type 1 by checking calcium, parathyroid hormone, and prolactin levels 5
• Treatment resistance: If standard PPI therapy is not controlling symptoms, consider:
  • Inadequate dosing (may need much higher doses than standard therapy)
  • Incorrect diagnosis (hence the need for secretin stimulation test)
  • Presence of metastatic disease requiring additional treatment modalities

In this case, the secretin stimulation test is essential to confirm the diagnosis of ZES before proceeding with further management decisions, especially given the non-response to standard treatment.