How to diagnose insulinoma?

Diagnosis of Insulinoma

The diagnosis of insulinoma requires a supervised 48-hour fast as the gold standard test, measuring insulin, C-peptide, and proinsulin levels when hypoglycemia occurs, followed by appropriate imaging studies for localization. 1

Clinical Presentation

• Patients typically present with neuroglycopenic symptoms including confusion, lethargy, and seizures, often occurring during fasting periods, particularly in the morning 1
• Weight gain is common due to frequent eating to avoid hypoglycemia 1
• Symptoms of hypoglycemia that improve after eating (Whipple's triad) should raise suspicion for insulinoma 2

Diagnostic Algorithm

Step 1: Supervised Fasting Test

• Conduct a supervised 48-hour fast (no longer requiring the traditional 72-hour fast) 1, 2
• Monitor for hypoglycemia, defined as blood glucose <40-45 mg/dL 3
• 94.5% of insulinomas can be diagnosed within 48 hours of fasting 2
• At the time of hypoglycemia, collect blood for the following measurements:
  • Insulin level >3 mcIU/mL (usually >6 mcIU/mL) 3, 1
  • C-peptide ≥0.6 ng/mL 1
  • Proinsulin levels ≥5 pmol/L 1
  • Insulin-to-glucose ratio of 0.3 or greater 3

Step 2: Rule Out Factitious Hypoglycemia

• Test for urinary sulfonylureas to exclude factitious hypoglycemia 3
• Elevated C-peptide levels help differentiate endogenous hyperinsulinemia (insulinoma) from exogenous insulin administration 3

Step 3: Tumor Localization

• Endoscopic ultrasound (EUS) is the preferred initial localization method, with approximately 82% sensitivity for detecting pancreatic endocrine tumors 3
• Multiphasic CT or MRI scans should be performed to rule out metastatic disease 3
• For difficult cases, selective arterial calcium stimulation test (Imamura-Doppman procedure) can be considered, which involves injecting calcium into selective pancreatic arteries and measuring insulin levels in the hepatic vein 3
• Octreoscan has limited utility for insulinomas and should only be performed if octreotide treatment is being considered 3

Alternative Diagnostic Approaches

• Recent research suggests that a shorter outpatient fasting test of 24 hours may be effective, with 91.7% of insulinomas being diagnosed within 24 hours 4
• Some studies suggest using insulin-to-glucose and C-peptide-to-glucose ratios during a 2-hour or 5-hour oral glucose tolerance test (OGTT) as alternative diagnostic methods for outpatient settings 5, 6

Important Caveats and Pitfalls

• Some insulinomas may present with normoglycemia after a prolonged fast but demonstrate glucose-stimulated hypoglycemia during an OGTT 7
• Proton pump inhibitors can cause spuriously elevated chromogranin A levels, which may complicate diagnosis 1
• Octreotide should be used with extreme caution in patients with suspected insulinoma, as it can suppress counterregulatory hormones and worsen hypoglycemia 1
• While 90% of insulinomas pursue an indolent course and can be cured surgically, proper diagnosis is essential for optimal outcomes 3