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, with biochemical confirmation at the time of hypoglycemia showing insulin >3 mcIU/mL, C-peptide ≥0.6 ng/mL, and proinsulin ≥5 pmol/L. 1

Clinical Presentation to Recognize

• Look for neuroglycopenic symptoms including confusion, lethargy, and seizures, particularly occurring during fasting states or in the morning 1
• Weight gain from frequent eating to avoid hypoglycemia is a characteristic feature that distinguishes insulinoma from other causes of hypoglycemia 1
• Symptoms that improve with food intake (part of Whipple's triad) should raise suspicion 2

Diagnostic Testing Algorithm

First-Line Test: Supervised Fast

• Perform a supervised 48-72 hour fast in the hospital setting, which remains the gold standard for diagnosis 1
• The fast can be terminated when hypoglycemia occurs (blood glucose <40-45 mg/dL) or when the time limit is reached 1
• Most patients (94.5%) will develop diagnostic hypoglycemia within 48 hours, making the 48-hour fast sufficient in the majority of cases 2
• Only 5.5% of insulinoma patients require fasting beyond 48 hours for diagnosis 2

Biochemical Criteria at Time of Hypoglycemia

At the termination of the fast, obtain the following measurements simultaneously:

• Insulin level >3 mcIU/mL 1
• C-peptide ≥0.6 ng/mL (this distinguishes endogenous hyperinsulinemia from exogenous insulin administration) 1
• Proinsulin levels ≥5 pmol/L 1
• Calculate insulin-to-glucose ratio, with a value ≥0.3 supporting the diagnosis 1
• Proinsulin is elevated at the beginning of the fast in 90% of insulinoma cases 2

Alternative Testing When Fast is Non-Diagnostic

• If the 72-hour fast is normal but clinical suspicion remains high, consider a prolonged oral glucose tolerance test (OGTT), as rare insulinomas may present with glucose-stimulated hypoglycemia rather than fasting hypoglycemia 3
• A 5-hour OGTT can identify insulinomas that are glucose-responsive, with measurements of insulin-to-glucose and C-peptide-to-glucose ratios at fasting, 4-hour, and 5-hour time points 4
• Some insulinomas demonstrate paradoxical glucose responsiveness and may require provocative testing beyond the standard fast 5

Tumor Localization After Biochemical Diagnosis

Once biochemical diagnosis is confirmed, proceed with imaging:

• Endoscopic ultrasound (EUS) is the preferred initial localization method, with approximately 82% sensitivity for detecting pancreatic endocrine tumors 1
• Perform multiphasic CT or MRI scans to rule out metastatic disease 1
• For difficult-to-localize tumors, consider selective arterial calcium stimulation test (Imamura-Doppman procedure), which involves injecting calcium into selective pancreatic arteries and measuring insulin levels in the hepatic vein 1

Critical Pitfalls to Avoid

• Do not use somatostatin analogs (octreotide, lanreotide) for symptom control, as they can suppress counterregulatory hormones and precipitously worsen hypoglycemia, potentially causing fatal complications 1
• Proton pump inhibitors can cause spuriously elevated chromogranin A levels, which may complicate the diagnostic workup if neuroendocrine tumor markers are being assessed 1
• Do not dismiss the diagnosis based solely on a negative 72-hour fast if clinical suspicion is high; proceed with OGTT testing 3
• Recognize that approximately 10% of insulinomas may be malignant, necessitating imaging to assess for metastatic disease 1

Preoperative Stabilization

Once diagnosed, stabilize the patient before surgical intervention:

• Use dietary management with frequent small meals as first-line approach 1
• Diazoxide is the first-line medical therapy for managing hypoglycemia due to hyperinsulinism 1
• Everolimus can be considered as an alternative for preoperative stabilization 1
• Avoid somatostatin analogs entirely due to risk of worsening hypoglycemia 1