What blood work is necessary to diagnose an insulinoma?

Blood Work for Insulinoma Diagnosis

The essential blood work for diagnosing insulinoma requires measuring insulin, C-peptide, and proinsulin levels during a supervised 48-72 hour fast when blood glucose drops below 55 mg/dL, with diagnostic thresholds of insulin >3 mcIU/mL, C-peptide ≥0.6 ng/mL, and proinsulin ≥5 pmol/L. 1

Supervised Fast Protocol

The supervised fast remains the gold standard diagnostic test for insulinoma:

• A 48-72 hour supervised fast should be performed until hypoglycemia occurs or the time limit is reached 1
• The fast can be terminated when blood glucose falls below 55 mg/dL (some sources use 40-45 mg/dL) 1, 2
• 94.5% of insulinomas will be diagnosed within 48 hours, making the 48-hour fast sufficient for most cases 2
• Only 5.5% of patients require fasting beyond 48 hours 2

Critical Blood Tests at Fast Termination

When hypoglycemia is documented, the following must be measured simultaneously:

Insulin Level

• Diagnostic threshold: >3 mcIU/mL (typically >6 mcIU/mL) 3, 1
• Insulin >21 pmol/l (approximately 3 mcIU/mL) when glucose <45 mg/dL is diagnostic 4
• Important caveat: Insulin alone has lower diagnostic accuracy than proinsulin and may be suppressed in some insulinoma cases 5

C-Peptide Level

• Diagnostic threshold: ≥0.6 ng/mL 3, 1
• C-peptide >0.2 nmol/L is present in all insulinomas 5
• Critical function: Elevated C-peptide differentiates endogenous hyperinsulinemia (insulinoma) from exogenous insulin administration 1

Proinsulin Level

• Diagnostic threshold: ≥5 pmol/L 3, 1
• Proinsulin >5 pmol/L with glucose <45 mg/dL achieves 100% diagnostic specificity and sensitivity 5
• Proinsulin is elevated at the beginning of the fast in 90% of insulinoma patients 2
• Proinsulin is the most reliable single marker, as it can be elevated even when insulin and C-peptide are suppressed 6, 5

Additional Baseline Testing

Chromogranin A

• May be measured as a general neuroendocrine tumor marker 3
• Critical pitfall: Proton pump inhibitors cause spuriously elevated chromogranin A levels and must be discontinued at least 1 week before testing 3, 1
• Other causes of false elevation include renal/liver failure, hypertension, and chronic gastritis 3

Algorithmic Approach to Blood Work

1. Discontinue proton pump inhibitors at least 1 week before testing if chromogranin A will be measured 3

2. Initiate supervised 48-72 hour fast with serial glucose monitoring 1

3. At hypoglycemia (glucose <55 mg/dL), immediately draw:

   • Serum insulin
   • C-peptide
   • Proinsulin
   • Confirm glucose level 3, 1

4. Diagnostic criteria met when ALL of the following are present:

   • Insulin >3 mcIU/mL
   • C-peptide ≥0.6 ng/mL
   • Proinsulin ≥5 pmol/L
   • Blood glucose <55 mg/dL 3, 1

5. If proinsulin >5 pmol/L with glucose <45 mg/dL, diagnosis is confirmed with 100% accuracy 5

Common Diagnostic Pitfalls

• Never rely on insulin levels alone, as 8-35% of insulinoma patients may have insulin <21 pmol/L during hypoglycemia 5
• Proinsulin measurement is mandatory, not optional, as it may be the only elevated marker in some cases 6
• Ensure all samples are drawn simultaneously at the time of documented hypoglycemia, not at arbitrary time points 1
• Do not stop the fast prematurely—wait for clear neuroglycopenic symptoms or glucose threshold to be reached 2