What is the initial workup for a patient suspected of having an insulinoma?

Insulinoma Workup

The initial workup for suspected insulinoma requires a supervised 48-72 hour fast as the first-line diagnostic test, followed by biochemical confirmation and systematic imaging to localize the tumor. 1

Clinical Presentation

Patients typically present with neuroglycopenic symptoms including confusion, lethargy, and seizures, particularly during fasting or in the morning. 1 Weight gain is common (occurring in 72% of patients) due to frequent eating to avoid hypoglycemia. 1, 2 Symptoms must meet Whipple's triad: hypoglycemic symptoms, documented low plasma glucose at the time of symptoms, and relief when glucose is normalized. 3

Important caveat: While rare (approximately 6% of cases), some insulinomas present exclusively with postprandial hypoglycemia rather than fasting hypoglycemia, which can lead to misdiagnosis as reactive hypoglycemia. 4

Biochemical Diagnosis

Supervised Fast (First-Line Test)

A supervised 48-72 hour fast is the diagnostic standard, with most cases (94.5%) diagnosed within 48 hours. 1, 5 The fast should continue until hypoglycemia occurs (blood glucose <40-45 mg/dL) or the time limit is reached. 1

At the termination of the fast, measure: 6, 1

• Insulin level >3 mcIU/mL (usually >6 mcIU/mL)
• C-peptide ≥0.6 ng/mL
• Proinsulin ≥5 pmol/L
• Blood glucose <55 mg/dL

Key diagnostic point: Proinsulin is elevated at the beginning of the fast in 90% of insulinoma patients and is essential for diagnosis, particularly in cases with postprandial hypoglycemia. 5, 4 Elevated C-peptide differentiates endogenous hyperinsulinemia (insulinoma) from exogenous insulin administration. 1

Tumor Localization

Initial Non-Invasive Imaging

Start with multiphasic CT or MRI to rule out metastatic disease and attempt initial localization. 6, 1

• Multiphasic CT has 57-94% sensitivity; insulinomas appear hypervascular in the arterial phase. 1, 7
• MRI has comparable sensitivity (74-94%); tumors appear hypointense on T1 and isointense to slightly hyperintense on T2. 1, 7

Endoscopic Ultrasound (EUS)

EUS should be performed in all cases, as it has the highest sensitivity (82-93%) for detecting small pancreatic tumors and allows tissue sampling. 6, 1, 7 This is particularly valuable when cross-sectional imaging is negative or equivocal, and helps determine surgical approach (enucleation vs. formal resection). 1, 7

Advanced Localization for Occult Tumors

If non-invasive imaging is negative or equivocal:

Selective arterial calcium stimulation with hepatic venous sampling (Imamura-Doppman procedure) achieves up to 90% success in localizing occult insulinomas. 6, 1, 7 This test should be reserved for persistent/recurrent insulinoma or when other localization tests fail. 6, 1

68Ga-DOTATOC/DOTATATE PET/CT has the highest sensitivity (87-96%) for pancreatic NETs and should be considered when conventional imaging is negative. 1

Critical pitfall: Somatostatin receptor scintigraphy (SSRS) has limited utility for insulinomas specifically, with only 50-60% sensitivity compared to 75% for other pancreatic NETs. 6, 1, 7 SSRS should only be performed if octreotide or lanreotide treatment is being considered for metastatic disease. 6

Intraoperative Localization

Intraoperative ultrasound (IOUS) is mandatory during surgery regardless of preoperative imaging success, with 92-97% sensitivity for identifying small lesions. 1, 7

Additional Laboratory Testing

Chromogranin A levels may be measured but must be interpreted cautiously. 6 Spuriously elevated levels occur with proton pump inhibitor use, renal or liver failure, hypertension, and chronic gastritis. 6, 1

Recommended Diagnostic Algorithm

1. Clinical suspicion based on Whipple's triad 3
2. Supervised 48-72 hour fast with biochemical confirmation (insulin >3 mcIU/mL, C-peptide ≥0.6 ng/mL, proinsulin ≥5 pmol/L when glucose <55 mg/dL) 6, 1, 5
3. Multiphasic CT or MRI to assess for metastatic disease 6, 1
4. EUS for all patients to improve detection and obtain tissue diagnosis 1, 7
5. Selective arterial calcium stimulation for truly occult cases where non-invasive studies are negative 6, 1, 7
6. Plan for mandatory IOUS at time of surgery 1, 7

Common Pitfalls

• Do not rely on somatostatin receptor scintigraphy as primary imaging—sensitivity is only 50-60% for insulinomas. 1, 7
• Stop proton pump inhibitors at least 1 week before measuring gastrin or chromogranin A levels to avoid spurious elevations. 6, 1
• Consider insulinoma even with exclusively postprandial hypoglycemia if reactive hypoglycemia treatment fails. 4
• Always measure proinsulin levels—they are elevated in 90% of cases and critical for diagnosis. 5, 4