What is the best course of action for a 34-year-old female with a history of chronic migraines with aura, currently on amitriptyline (elavil), presenting with new hypoglycemic symptoms, neuroglycopenic episodes, elevated C-peptide levels, and a normal HbA1c level?

Evaluation and Management of Non-Diabetic Hypoglycemia with Neuroglycopenic Symptoms

Your planned approach is appropriate: admit this patient for a supervised 48-72 hour fast to document hypoglycemia and obtain critical samples when blood glucose falls below 3.0 mmol/L (54 mg/dL), then measure insulin, C-peptide, and proinsulin to differentiate endogenous hyperinsulinism from other causes. 1

Immediate Assessment and Admission Plan

Critical Diagnostic Threshold

• The diagnostic threshold for clinically significant hypoglycemia requiring immediate action is <54 mg/dL (<3.0 mmol/L), which represents Level 2 hypoglycemia where neuroglycopenic symptoms begin to occur. 2
• Her home glucose of 4.8 mmol/L (86 mg/dL) does not meet diagnostic criteria, making supervised fasting essential to capture a true hypoglycemic episode with appropriate laboratory samples 1

Supervised Fast Protocol

• During the 48-72 hour fast, obtain critical samples (insulin, C-peptide, proinsulin) when blood glucose drops below 3.0 mmol/L (54 mg/dL) and neuroglycopenic symptoms are present. 1, 3
• The elevated C-peptide you've already documented suggests endogenous insulin production, making insulinoma a primary diagnostic consideration 3
• Document all medications including over-the-counter drugs and supplements, as this is crucial for differential diagnosis 1

Key Diagnostic Considerations

Insulinoma as Primary Differential

• In a non-diabetic patient with neuroglycopenic symptoms and elevated C-peptide, insulinoma is the most common hormone-secreting islet cell tumor and must be ruled out. 3
• The diagnosis is confirmed by hypoglycemia occurring with inappropriately high insulin and C-peptide levels during a supervised fast 3
• Neuroglycopenic symptoms (fatigue, irritability, poor concentration, altered mental status) can be vague and easily overlooked, especially in young adults, potentially delaying diagnosis for months 4

Critical Sample Requirements

• When glucose reaches <3.0 mmol/L, immediately draw: serum insulin, C-peptide, and proinsulin before administering glucose. 1, 3
• If surreptitious insulin use is suspected, low plasma C-peptide with high insulin would be diagnostic, whereas insulinoma shows both elevated 3

Important Medication Consideration

Amitriptyline and Hypoglycemia Risk

• The FDA label for amitriptyline specifically warns that "both elevation and lowering of blood sugar levels have been reported." 5
• While amitriptyline is effective for chronic migraine prophylaxis 6, its potential to cause hypoglycemia must be considered in this clinical context 5
• However, given the severity and pattern of her symptoms with elevated C-peptide, amitriptyline alone is unlikely to be the sole cause—insulinoma remains the primary concern

Treatment During Hypoglycemic Episodes

Acute Management

• Glucose (15-20 g) is the preferred treatment for conscious individuals with blood glucose <70 mg/dL (3.9 mmol/L), or 50% IV glucose if unable to take oral. 2
• After treatment, recheck glucose in 15 minutes; if still low, repeat treatment 2
• Once glucose is trending up, provide a meal or snack to prevent recurrence 2

Glucagon Availability

• Glucagon should be prescribed for this patient as she is at high risk for Level 2 or 3 hypoglycemia, and caregivers/family should know how to administer it. 2

Post-Diagnostic Imaging and Localization

If Insulinoma Confirmed

• Most insulinomas are small and require invasive imaging methods for precise localization 3
• The brain MRI findings (mild CSF space prominence at cerebellopontine angle) are unrelated to her hypoglycemia and likely incidental given her chronic migraine history 7
• Abdominal MRI or endoscopic ultrasound will be needed for tumor localization if biochemical testing confirms insulinoma 4

Critical Pitfalls to Avoid

• Do not dismiss vague neuroglycopenic complaints (fatigue, irritability, concentration problems) as psychiatric or stress-related in a young adult—these are classic presentations of insulinoma that can delay diagnosis for months. 4
• Do not rely on random glucose measurements or home monitoring alone—supervised fasting with critical samples at the time of documented hypoglycemia is essential for diagnosis. 1, 3
• Do not attribute symptoms solely to medication side effects without ruling out serious endocrine pathology, especially with elevated C-peptide. 5, 3