What to do with a patient having hypergastrinemia (elevated gastrin level) without evidence of gastrinoma on positron emission tomography (PET) scan?

Management of Hypergastrinemia (2135 ng/L) Without Gastrinoma on PET Scan

Stop all proton pump inhibitors immediately for at least 1-2 weeks, then remeasure fasting gastrin and perform upper endoscopy with gastric biopsies to differentiate gastrinoma from atrophic gastritis, as PPI therapy is the most common cause of false elevation and can mask the true diagnosis. 1, 2, 3

Critical First Step: Exclude PPI-Induced Hypergastrinemia

• Discontinue PPIs for 10-14 days before any further gastrin testing, as omeprazole and other PPIs cause marked gastrin elevation through decreased gastric acidity, leading to compensatory G-cell hyperplasia 1, 2, 3
• The FDA label for omeprazole explicitly states that serum gastrin levels increase 1.3 to 3.6-fold during PPI therapy, and increased gastrin causes enterochromaffin-like cell hyperplasia with elevated chromogranin A that creates false positive results in neuroendocrine tumor investigations 3
• During the PPI washout period, substitute with H2 antagonists if acid suppression is essential, but stop these 48 hours before gastrin measurement 1
• This is the single most common diagnostic pitfall - interpreting gastrin levels while on PPIs leads to unnecessary workup for gastrinoma 2, 4

Perform Upper Endoscopy with Gastric Biopsies

• Upper gastrointestinal endoscopy with gastric biopsy is always required to differentiate gastrinoma from autoimmune atrophic gastritis, which is a far more common cause of hypergastrinemia than gastrinoma 1, 2
• Obtain biopsies from both gastric body and antrum to assess for atrophic gastritis, intestinal metaplasia, and Helicobacter pylori infection 1, 5
• Measure intragastric pH during endoscopy - achlorhydria (pH >4) strongly suggests atrophic gastritis rather than gastrinoma 1, 5
• Atrophic gastritis can produce gastrin levels as high as 2078 pg/mL (similar to your patient's 2135 ng/L), particularly when combined with H. pylori infection 5, 6

Diagnostic Algorithm After PPI Withdrawal

If fasting gastrin remains >10 times upper limit of normal (typically >1000 pg/mL) AND gastric pH <2:

• This combination is diagnostic of gastrinoma 2, 4
• Proceed to secretin stimulation test if diagnosis remains equivocal 1, 2

If gastric pH >4 (achlorhydria) with elevated gastrin:

• Diagnosis is atrophic gastritis, pernicious anemia, or chronic gastritis - NOT gastrinoma 1, 5, 7
• Check for H. pylori infection, as this significantly elevates gastrin in atrophic gastritis (median 50 pM vs 20 pM in normal patients) 6
• Measure anti-parietal cell antibodies and intrinsic factor antibodies to confirm pernicious anemia 7

Why PET Scan May Be Negative Despite True Gastrinoma

• Most gastrinomas (approximately 70%) are located in the duodenum, not the pancreas, and duodenal gastrinomas are typically very small (often <1 cm) 1, 2
• Small duodenal gastrinomas may be missed on conventional imaging including PET scans 1
• Somatostatin receptor scintigraphy (Octreoscan) should be performed if gastrinoma remains suspected after PPI withdrawal, as it may detect tumors missed by CT/MRI/PET 8
• Endoscopic ultrasound is particularly valuable for detecting small pancreatic and duodenal lesions 8

Additional Diagnostic Considerations

• Check fasting calcium, parathyroid hormone, and prolactin to screen for Multiple Endocrine Neoplasia Type 1 (MEN1) syndrome, as gastrinoma is one of the most common pancreatic neuroendocrine tumors in MEN1 patients 1, 2
• Measure basal acid output if available - values >15 mmol/h suggest gastrinoma in the presence of elevated gastrin 1
• The secretin stimulation test shows a paradoxical rise in gastrin (>200 pg/mL increase) in gastrinoma but not in atrophic gastritis 1

Common Clinical Scenarios

Atrophic gastritis with H. pylori (most likely in your patient):

• Produces hypergastrinemia due to achlorhydria 5, 6
• Gastrin levels can exceed 2000 pg/mL 5
• PET scan negative because there is no tumor 5
• Treatment: H. pylori eradication if present, vitamin B12 supplementation, endoscopic surveillance for gastric neoplasia 6, 7

True gastrinoma with negative imaging:

• Requires secretin stimulation test for confirmation 1, 2
• Consider repeat imaging with Octreoscan and endoscopic ultrasound 8
• Surgical exploration may be needed if biochemically confirmed 1

Critical Pitfall to Avoid

• Never interpret elevated gastrin or chromogranin A while the patient is on PPIs - this is explicitly warned against in FDA labeling and all major guidelines 3
• The FDA specifically states that PPIs cause "hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma" 3