What is the most appropriate diagnostic test for a 40-year-old woman with recurrent hypoglycemia (low blood sugar) and a history of syncopal (fainting) episodes?

Diagnostic Approach for Recurrent Hypoglycemia with Syncope

The most appropriate diagnostic test for this 40-year-old woman with recurrent hypoglycemia and syncope is a 72-hour supervised fast with simultaneous measurement of plasma glucose, insulin, C-peptide, and proinsulin levels.

Clinical Assessment of the Case

This patient presents with:

• Syncopal episode
• Documented hypoglycemia with confusion that resolved with dextrose administration
• Multiple episodes of hypoglycemia over several months

These features strongly suggest inappropriate insulin secretion, which requires specific diagnostic testing to determine the underlying cause.

Diagnostic Testing Algorithm

First-Line Testing:

1. 72-hour supervised fast with measurements of:

   • Plasma glucose
   • Insulin
   • C-peptide
   • Proinsulin

   This is the gold standard test for diagnosing insulinoma and other causes of fasting hypoglycemia 1, 2.

2. Timing considerations:

   • While traditionally performed for 72 hours, evidence suggests that 48 hours may be sufficient in most cases 2
   • The fast should continue until hypoglycemia occurs (glucose ≤45 mg/dL) or the full duration is completed

3. Interpretation of results:

   • Diagnostic criteria for insulinoma during hypoglycemia:
     • Glucose ≤45 mg/dL (2.5 mmol/L)
     • Insulin ≥3 μU/mL (inappropriate for hypoglycemia)
     • C-peptide ≥0.2 nmol/L (indicating endogenous insulin production)
     • Elevated proinsulin (>90% of patients with insulinoma have elevated proinsulin at the beginning of the fast) 2

Additional Testing Based on Initial Results:

If the 72-hour fast is negative but clinical suspicion remains high:

• Oral glucose tolerance test - Some insulinomas may present with glucose-stimulated hypoglycemia rather than fasting hypoglycemia 3
• Glucagon stimulation test - May provoke hypoglycemia in some insulinoma cases that don't manifest during prolonged fasting 4

Differential Diagnosis to Consider

1. Insulinoma - Most common cause of endogenous hyperinsulinemic hypoglycemia in adults
2. Factitious hypoglycemia - Surreptitious insulin or sulfonylurea use (check sulfonylurea levels)
3. Autoimmune hypoglycemia - Anti-insulin antibodies or anti-insulin receptor antibodies
4. Post-gastric bypass hypoglycemia
5. Adrenal insufficiency
6. Non-islet cell tumor hypoglycemia
7. Medication-induced hypoglycemia (sulfonylureas, insulin, etc.)

Clinical Pearls and Pitfalls

Important Considerations:

• C-peptide is crucial for distinguishing between endogenous and exogenous insulin sources 1
• Proinsulin levels >22% of total immunoreactive insulin strongly suggest insulinoma 1
• Some insulinomas may only manifest hypoglycemia after meals rather than during fasting 3

Pitfalls to Avoid:

• Relying solely on a single fasting glucose measurement
• Failing to measure insulin and C-peptide simultaneously with hypoglycemia
• Terminating the fast too early before hypoglycemia develops
• Overlooking reactive hypoglycemia if the fasting test is negative

Management Considerations

While awaiting diagnostic results:

• Educate the patient about hypoglycemia symptoms and management
• Provide glucose tablets or equivalent for emergency treatment
• Consider small, frequent meals to prevent hypoglycemia
• Avoid prolonged fasting

Follow-up Testing

If the 72-hour fast confirms hyperinsulinemic hypoglycemia:

• Imaging studies to localize a potential insulinoma (CT, MRI, endoscopic ultrasound)
• Genetic testing if multiple endocrine neoplasia type 1 (MEN1) is suspected

The 72-hour supervised fast remains the cornerstone diagnostic test for evaluating recurrent hypoglycemia, with the highest diagnostic yield for detecting insulinoma and other causes of inappropriate insulin secretion.