What diagnosis and management should be considered for a 32‑year‑old female with constant burning epigastric pain since age 3, worsened over the past 6 years, relieved by fasting, aggravated by meals and lying down, associated with 30‑lb weight loss, fatigue, difficulty eating, and prior endoscopy showing only mild gastritis, a small hiatal hernia, and gastro‑esophageal reflux disease?

Evaluation and Management of Chronic Epigastric Pain with Weight Loss and Functional Decline

This patient requires urgent upper endoscopy within 2 weeks because she has multiple alarm features—30-pound weight loss, age >25 years with treatment-resistant dyspepsia, and persistent symptoms since childhood—that mandate exclusion of serious organic pathology including gastrinoma (Zollinger-Ellison syndrome), peptic ulcer disease, and malignancy. 1, 2

Critical Diagnostic Considerations

Why This Is NOT Functional Dyspepsia

• Persistent vomiting (implied by "difficulty eating") is a red-flag symptom that excludes functional dyspepsia and signals another disorder requiring investigation. 1, 2
• Significant unintentional weight loss (30 pounds over 3 years) is an alarm feature that mandates urgent endoscopy regardless of age. 1, 2, 3
• Symptoms since age 3 with progressive worsening suggest an underlying organic process rather than a functional disorder. 1
• Pain relieved by fasting and worsened by eating is the classic pattern of peptic ulcer disease or gastrinoma, not functional dyspepsia. 2, 4, 5

Zollinger-Ellison Syndrome Must Be Excluded

The constellation of lifelong burning epigastric pain, severe erosive findings on prior endoscopy, refractory symptoms despite acid suppression, and food-related pain pattern raises strong suspicion for gastrinoma. 4, 6, 5

• ZES should be suspected in patients with severe erosive esophagitis, refractory peptic ulcers, peptic ulcers in unusual locations (beyond the duodenal bulb), and symptoms beginning in childhood. 4, 5, 7
• The average time from symptom onset to ZES diagnosis exceeds 5 years because symptoms overlap with common GERD and peptic ulcer disease. 7
• Patients with ZES often present with long-standing symptoms and delayed diagnosis, with chronic diarrhea occurring in 50% of cases. 6, 5, 7

Immediate Diagnostic Workup

Laboratory Testing (Order Today)

• Obtain fasting serum gastrin level after discontinuing all proton pump inhibitors for at least 1–2 weeks; gastrin levels >1000 pg/mL with gastric pH <2 are diagnostic for gastrinoma. 4, 5, 7
• Measure gastric pH or perform gastric acid analysis; a gastric pH >2 excludes ZES. 4, 5
• Order complete blood count to identify anemia, which is an alarm feature mandating urgent endoscopy. 1, 2, 3
• Check comprehensive metabolic panel, liver function tests, and serum lipase to exclude pancreatitis and hepatobiliary disease. 2, 3
• Perform non-invasive H. pylori testing using ¹³C-urea breath test or stool antigen (not serology). 1, 2, 3

If Gastrin Is Elevated but <1000 pg/mL

• Perform secretin stimulation test; a rise in gastrin >200 pg/mL above baseline is highly specific for gastrinoma. 4, 5, 8
• Measure chromogranin A as an additional neuroendocrine tumor marker. 8

Urgent Endoscopy Within 2 Weeks

• Schedule upper endoscopy with multiple biopsies from the stomach, duodenum (including descending duodenum and beyond), and any visible lesions. 1, 2, 5
• Look specifically for peptic ulcers in unusual locations (distal duodenum, jejunum), multiple ulcers, and severe erosive esophagitis. 4, 5, 7
• Obtain gastric pH measurement during endoscopy if not done separately. 5

Imaging for Tumor Localization (If Gastrinoma Confirmed)

• Somatostatin receptor scintigraphy (SRS) using ⁶⁸Ga-labeled tracers (DOTATATE, DOTATOC, DOTANOC) with PET/CT is the initial localization study of choice, detecting >90% of gastrinomas when combined with endoscopic ultrasound. 4, 8
• Endoscopic ultrasound (EUS) with high-resolution transducers has similar sensitivity for identifying primary tumors and is particularly useful for duodenal gastrinomas. 4, 5, 8
• Contrast-enhanced CT abdomen/pelvis can identify larger tumors and metastases but is less sensitive for small primary gastrinomas. 2, 6

Immediate Therapeutic Management

High-Dose Acid Suppression

• Initiate high-dose proton pump inhibitor therapy immediately: omeprazole 60 mg once daily before breakfast (or pantoprazole 80 mg daily), which is 2–3 times the standard dose required for ZES. 9, 4, 5
• The therapeutic target is to elevate gastric pH >4 and reduce basal acid output to <10 mEq H⁺/hour. 5
• Standard-dose PPI therapy is insufficient for gastrinoma; doses up to 120–160 mg omeprazole equivalents daily may be required. 5, 7

If H. pylori Positive

• Treat with standard eradication therapy (clarithromycin-based triple therapy or bismuth-based quadruple therapy) while continuing high-dose PPI. 2, 3

Definitive Treatment Algorithm

If Gastrinoma Is Confirmed and Localized

• Surgical resection of the gastrin-producing tumor with regional lymph node dissection is the only curative treatment and should be pursued in patients without distant metastases. 4, 5, 7
• Surgical cure is possible in approximately 30% of patients without metastases and without MEN-1. 4
• Gastrinomas >2.5 cm should undergo resection regardless of MEN-1 status to decrease metastasis risk. 4

If Metastatic or Unresectable Disease

• Continue high-dose PPI therapy indefinitely to control acid hypersecretion and prevent complications. 5, 7
• Somatostatin analogs (octreotide, lanreotide) have anti-proliferative effects due to high somatostatin receptor expression in gastrinomas. 7
• Total gastrectomy is rarely required in the modern era of potent acid suppression. 4

Critical Pitfalls to Avoid

• Do not attribute 30-pound weight loss and lifelong symptoms to functional dyspepsia or GERD without excluding organic disease; this delay can be fatal if malignancy or complications occur. 1, 2
• Do not continue empiric PPI therapy without endoscopy in a patient with alarm features; age >25 years with treatment-resistant dyspepsia requires endoscopic evaluation. 1, 2
• Do not measure fasting gastrin while the patient is taking PPIs; this produces false-positive hypergastrinemia due to feedback stimulation. 4, 5
• Do not assume a small hiatal hernia and mild gastritis explain severe, lifelong symptoms with weight loss; these findings are common and do not account for the clinical severity. 1
• Do not miss ZES by failing to consider it in young patients with refractory symptoms; 50% of patients have metastases by the time of diagnosis due to diagnostic delay. 5, 7

Expected Prognosis

• With early recognition and appropriate treatment, ZES has >80% survival at 15 years. 8
• Delayed diagnosis significantly worsens outcomes, particularly if liver metastases develop (present in 50% at diagnosis). 5
• Eighteen months after surgical resection of localized gastrinoma, patients typically remain symptom-free. 6