What labs are needed to rule out the cause of hypoglycemia?

Laboratory Tests to Rule Out Causes of Hypoglycemia

The diagnostic workup for hypoglycemia should include critical samples during a hypoglycemic episode with glucose <54 mg/dL, including insulin, C-peptide, proinsulin, beta-hydroxybutyrate, and screening for sulfonylurea use, as these are essential to determine the etiology and guide appropriate treatment. 1

Initial Laboratory Evaluation

When evaluating hypoglycemia, laboratory tests should be obtained during a symptomatic episode whenever possible:

• Critical samples (ideally when glucose <54 mg/dL):

  • Plasma glucose (to document hypoglycemia)
  • Insulin level
  • C-peptide level
  • Proinsulin level
  • Beta-hydroxybutyrate
  • Sulfonylurea screen (to rule out surreptitious use)
  • IGF-1 and IGF-2 (to evaluate for non-islet cell tumor hypoglycemia)
  • Cortisol and ACTH (to assess adrenal function)

• Additional baseline laboratory tests:

  • Complete blood count
  • Basic metabolic panel (electrolytes, renal function)
  • Liver function tests
  • Thyroid-stimulating hormone
  • HbA1c (to assess overall glycemic control)

Diagnostic Algorithm Based on Insulin and C-peptide Results

The pattern of insulin and C-peptide levels during hypoglycemia provides crucial diagnostic information:

1. High insulin with high C-peptide:

   • Suggests endogenous hyperinsulinism
   • Consider insulinoma, nesidioblastosis, or sulfonylurea use
   • Additional test: sulfonylurea screen

2. High insulin with low/suppressed C-peptide:

   • Suggests exogenous insulin administration
   • Consider factitious hypoglycemia or insulin abuse
   • Insulin:C-peptide ratio >1.0 strongly suggests exogenous insulin 2

3. Low insulin with low C-peptide:

   • Consider non-insulin mediated causes:
     • Non-islet cell tumor hypoglycemia (check IGF-2)
     • Adrenal insufficiency (check cortisol)
     • Liver failure (check liver function)
     • Sepsis or critical illness
     • Alcohol-induced hypoglycemia

Timing-Based Approach to Hypoglycemia Evaluation

The timing of hypoglycemic episodes provides important diagnostic clues:

• Fasting hypoglycemia:

  • Consider insulinoma, adrenal insufficiency, liver disease, or medication effect
  • Perform a supervised 72-hour fast if spontaneous episodes cannot be captured 3
  • Monitor glucose, insulin, C-peptide, and beta-hydroxybutyrate during the fast

• Postprandial hypoglycemia:

  • Consider reactive hypoglycemia, post-bariatric surgery hypoglycemia, or early diabetes
  • Perform a mixed meal test with glucose, insulin, and C-peptide measurements at baseline, 30,60,120, and 180 minutes 3

• Exercise-induced hypoglycemia:

  • Consider genetic disorders of metabolism
  • Evaluate with exercise testing and genetic testing as appropriate 4

Special Considerations

• Medication-induced hypoglycemia:

  • Obtain detailed medication history, including insulin, sulfonylureas, and other medications that can cause hypoglycemia
  • Consider drug screen in cases of unexplained hypoglycemia

• Autoimmune hypoglycemia:

  • Test for insulin antibodies and insulin receptor antibodies, especially in patients with other autoimmune disorders 4

• Genetic causes:

  • Consider in patients with family history of hypoglycemia or systemic involvement
  • Genetic testing may be indicated for suspected monogenic disorders 4

Common Pitfalls to Avoid

• Failing to obtain critical samples during an actual hypoglycemic episode
• Misinterpreting laboratory results without considering the clinical context
• Not screening for surreptitious use of insulin or sulfonylureas in unexplained cases
• Overlooking non-diabetic medications that can cause hypoglycemia
• Diagnosing reactive hypoglycemia without documented low glucose during symptoms

The diagnostic approach to hypoglycemia requires careful documentation of symptoms in relation to glucose levels (Whipple's triad) and systematic laboratory evaluation to determine the underlying cause, which is essential for appropriate treatment and prevention of recurrent episodes.