What is the recommended lab workup for a non-diabetic patient presenting with hypoglycemia?

Laboratory Workup for Non-Diabetic Hypoglycemia

For non-diabetic patients presenting with hypoglycemia, the essential laboratory workup should include plasma glucose, insulin, C-peptide, proinsulin, beta-hydroxybutyrate, and sulfonylurea screening, collected during a hypoglycemic episode to establish diagnosis and determine etiology. 1, 2

Initial Diagnostic Criteria: The Whipple Triad

Before proceeding with extensive laboratory testing, confirm hypoglycemia using Whipple's triad:

1. Documented low plasma glucose (<70 mg/dL)
2. Symptoms consistent with hypoglycemia
3. Resolution of symptoms when glucose is restored to normal

Critical Laboratory Tests During Hypoglycemic Episode

When the patient is experiencing hypoglycemia (glucose <70 mg/dL), collect the following samples simultaneously:

• Plasma glucose - Confirms hypoglycemia
• Insulin - ≥6 μIU/mL suggests inappropriate insulin secretion
• C-peptide - ≥200 pmol/L indicates endogenous hyperinsulinism
• Proinsulin - ≥5 pmol/L suggests insulinoma (elevated ratio of proinsulin to insulin strongly suggests islet cell tumor) 1
• Beta-hydroxybutyrate - ≤2.7 mmol/L suggests insulin-mediated hypoglycemia 3
• Sulfonylurea screen - Rules out surreptitious use or inadvertent ingestion 1, 3

Provocative Testing

If spontaneous hypoglycemia cannot be documented:

1. 72-hour supervised fast:

   • Gold standard for diagnosing insulinoma
   • Monitor glucose, insulin, C-peptide, and proinsulin at regular intervals and when glucose falls below 60 mg/dL
   • Test terminates when glucose <45 mg/dL with symptoms or <55 mg/dL with documented hyperinsulinemia 4, 2

2. Glucagon stimulation test:

   • Administer 1 mg IV glucagon during hypoglycemia
   • Glucose rise ≥25 mg/dL suggests insulin-mediated hypoglycemia 3

Additional Laboratory Tests Based on Clinical Suspicion

• Cortisol and ACTH - To rule out adrenal insufficiency
• Growth hormone and IGF-1 - For suspected growth hormone deficiency
• IGF-2/IGF-1 ratio - Elevated in non-islet cell tumors
• Liver function tests - To assess hepatic dysfunction
• Renal function tests - To evaluate renal insufficiency
• Alcohol level - When alcohol-induced hypoglycemia is suspected
• Toxicology screen - To identify medications that may cause hypoglycemia

Diagnostic Algorithm

1. Confirm hypoglycemia using Whipple's triad
2. Collect critical samples during hypoglycemic episode
3. Analyze results:
   • If insulin ≥6 μIU/mL, C-peptide ≥200 pmol/L, proinsulin ≥5 pmol/L with negative sulfonylurea screen → Endogenous hyperinsulinism (insulinoma)
   • If insulin elevated with low/suppressed C-peptide → Exogenous insulin administration
   • If insulin and C-peptide elevated with positive sulfonylurea screen → Sulfonylurea-induced hypoglycemia
   • If all insulin markers low → Consider non-insulin mediated causes (liver disease, renal failure, adrenal insufficiency, etc.)
4. If no spontaneous hypoglycemia, proceed with 72-hour supervised fast

Common Pitfalls to Avoid

• Failing to collect samples during hypoglycemia - The diagnostic value of these tests is highest when collected during an actual hypoglycemic episode 2
• Measuring glucose alone - Always measure insulin, C-peptide, and proinsulin simultaneously with glucose to determine etiology
• Improper sample handling - Separate plasma immediately and freeze samples for sulfonylurea screening
• Misinterpreting postprandial hypoglycemia - Consider mixed meal test for suspected reactive hypoglycemia or post-bariatric surgery hypoglycemia
• Overlooking medications - Many non-diabetes medications can cause hypoglycemia 5

By following this systematic approach to laboratory evaluation of non-diabetic hypoglycemia, clinicians can efficiently diagnose the underlying cause and implement appropriate treatment to reduce morbidity and mortality associated with hypoglycemic episodes.