What laboratory findings and tests are characteristic of insulinoma for its diagnosis?

Laboratory Features of Insulinoma

The diagnosis of insulinoma requires demonstrating inappropriately elevated insulin (>3 mcIU/mL), C-peptide (≥0.6 ng/mL), and proinsulin (≥5 pmol/L) during documented hypoglycemia (glucose <55 mg/dL) during a supervised 48-72 hour fast. 1

Diagnostic Laboratory Criteria

The Supervised Fast (Gold Standard Test)

• Perform a supervised fast for 48-72 hours as the first-line diagnostic test, continuing until hypoglycemia occurs or the time limit is reached 1
• The test achieves 94.5% diagnostic sensitivity within 48 hours 1
• At the termination of the fast when glucose falls below 55 mg/dL, measure the following simultaneously:
  • Insulin level >3 mcIU/mL (inappropriately elevated for the degree of hypoglycemia) 1
  • C-peptide ≥0.6 ng/mL (confirms endogenous insulin production) 1
  • Proinsulin ≥5 pmol/L (90% of insulinoma patients have elevated proinsulin even at the beginning of the fast) 1
  • Insulin-to-glucose ratio ≥0.3 1

Key Biochemical Patterns

• The hallmark is persistence of inappropriately increased plasma insulin concentrations in the face of low glucose, distinguishing insulinoma from other causes of hypoglycemia 2
• An increased ratio of fasting proinsulin to insulin strongly suggests an islet cell tumor in someone with hypoglycemia 2
• The absence of these associated changes in glucose, insulin, and proinsulin makes insulinoma most unlikely, and alternative explanations should be sought 2

Critical Pitfalls and Caveats

Modern Insulin Assay Interference

• Newer highly-specific insulin assays may yield false-normal insulin values because they lack cross-reactivity with proinsulin, which insulinomas often produce disproportionately 3
• If clinical suspicion remains high despite normal insulin levels, measure proinsulin and C-peptide separately to avoid missing the diagnosis 3
• Consider repeating the test at a different laboratory if results are inconsistent with clinical presentation 3

Atypical Presentations

• Some insulinomas (approximately 10-30% based on case reports) may show normoglycemia after a 72-hour fast but demonstrate glucose-stimulated hypoglycemia during oral glucose tolerance testing 4, 5
• If the 72-hour fast is normal but clinical suspicion remains high, perform a prolonged oral glucose tolerance test looking for severe hyperinsulinemia followed by significant hypoglycemia 4
• Glucagon stimulation testing may unmask insulinomas that show suppressed insulin during fasting by provoking exaggerated insulin secretion 5

Differentiating from Factitious Hypoglycemia

• C-peptide measurement is essential to rule out hypoglycemia due to surreptitious insulin administration 2
• In exogenous insulin administration, insulin is elevated but C-peptide is suppressed (<0.6 ng/mL), whereas in insulinoma both are elevated 1

Additional Laboratory Markers

Chromogranin A

• Avoid measuring chromogranin A in patients on proton pump inhibitors, as these medications cause spuriously elevated levels 1
• Patients must be off proton pump inhibitors for at least 1 week before testing 1

Beta-Hydroxybutyrate

• During appropriate fasting hypoglycemia, beta-hydroxybutyrate should be elevated as a counterregulatory response 5
• Suppressed beta-hydroxybutyrate during hypoglycemia suggests inappropriate insulin excess 5

Algorithmic Approach to Laboratory Diagnosis

1. Begin with a supervised 48-72 hour fast in all patients with suspected insulinoma 1
2. When glucose falls below 55 mg/dL, simultaneously measure: insulin, C-peptide, proinsulin, and beta-hydroxybutyrate 1
3. If the fast is negative but clinical suspicion remains high, proceed to prolonged oral glucose tolerance test 4
4. If oral glucose tolerance test is also negative, consider glucagon stimulation testing with measurement of insulin response 5
5. Ensure C-peptide is elevated to exclude factitious hypoglycemia from exogenous insulin 2