Can Zollinger-Ellison Syndrome Present with Normal Duodenal Biopsies?
Yes, Zollinger-Ellison syndrome can absolutely present with normal duodenal biopsies, as the diagnosis is based on biochemical testing (hypergastrinemia and gastric acid hypersecretion) rather than specific duodenal histologic findings.
Understanding the Diagnostic Approach
The diagnosis of ZES does not rely on duodenal biopsy findings. Instead, the critical diagnostic steps include:
- Biochemical confirmation is paramount: Fasting serum gastrin levels should be measured after discontinuing proton pump inhibitors for 1-2 weeks, as PPIs can cause false elevations 1, 2, 3
- Gastrin levels >1000 pg/mL with gastric pH <2 are considered diagnostic for gastrinoma 4, 5
- The secretin stimulation test serves as the best adjuvant test to distinguish ZES from other hypergastrinemic states, with secretin stimulating gastrinoma cells to secrete gastrin while inhibiting normal G cells 4, 6, 7
Why Duodenal Biopsies May Be Normal
Standard mucosal biopsies of the duodenum are typically normal in ZES patients because:
- The pathology in ZES is related to gastric acid hypersecretion causing peptic ulceration and esophagitis, not primary duodenal mucosal disease 1, 2
- Gastrinomas themselves are subepithelial neuroendocrine tumors that arise from deeper layers, making standard mucosal biopsies non-diagnostic 8
- The majority of gastrinomas are located in the duodenum or pancreas within the "gastrinoma triangle," but they are submucosal lesions covered by normal-appearing epithelium 1, 4
Important Exception: Gastric Oxyntic Heterotopia
One notable finding that may be present (though not required for diagnosis):
- Hypertrophic gastric oxyntic heterotopia (GOH) in the proximal duodenal bulb has been described in patients with ZES, found in approximately 5 out of 7 patients in one study 9
- This represents patchy replacement of duodenal surface epithelium by gastric-type epithelium with hypertrophic oxyntic glands, likely resulting from chronic hypergastrinemia 9
- However, this finding is not necessary for diagnosis and its absence does not exclude ZES 9
Clinical Pitfalls to Avoid
Do not rely on duodenal biopsy appearance to rule out ZES. Common diagnostic errors include:
- Failing to suspect ZES in patients with refractory GERD, chronic diarrhea (50% at diagnosis), severe peptic ulceration, or epigastric pain lasting years despite acid suppression 1, 2, 4
- Not ruling out more common causes of hypergastrinemia first, particularly renal failure, atrophic gastritis, H. pylori-associated pangastritis, and PPI use 2, 4, 6
- Attempting to diagnose gastrinomas with standard forceps biopsies, which have poor yield for subepithelial lesions 8
When Endoscopy Is Indicated
Endoscopy should be performed in suspected ZES to:
- Assess for peptic ulcer disease and esophagitis, which are common manifestations 1, 4
- Evaluate for multiple, recurrent, or atypically located ulcers (including postbulbar or jejunal ulcers) 6, 7
- Endoscopic ultrasound (EUS) is recommended for tumor localization, particularly for pancreatic gastrinomas (sensitivity up to 83%), though sensitivity is lower for duodenal lesions 1, 4
Tumor Localization Strategy
Once ZES is biochemically confirmed:
- Gallium-68 radiotracers with PET (especially DOTATOC) are currently the standard for tumor localization, with high sensitivity and specificity 1, 4
- Multiphase CT and MRI scans play important roles in detecting gastrinomas 1, 3
- EUS and esophagogastroduodenoscopy are used for duodenal and gastric evaluation 1
The key message: Normal duodenal biopsies do not exclude ZES—the diagnosis rests on demonstrating hypergastrinemia with gastric acid hypersecretion, not on duodenal histology.