What is the appropriate workup for a patient presenting with hypoglycemia (low blood sugar)?

Appropriate Workup for Hypoglycemia

The appropriate workup for hypoglycemia must include documentation of Whipple's triad: symptoms of hypoglycemia, low plasma glucose concentration, and resolution of symptoms after glucose administration. 1

Initial Assessment

Immediate Actions

• Check blood glucose levels immediately in all patients with suspected hypoglycemia, especially those with altered mental status 2, 3
• If blood glucose measurement is not immediately available in a patient with altered mental status, administer glucose empirically 2
• Document presence of Whipple's triad:
  1. Symptoms consistent with hypoglycemia
  2. Low blood glucose (<70 mg/dL)
  3. Resolution of symptoms after glucose administration

Classification of Hypoglycemia

• Level 1: 54-70 mg/dL (3.0-3.9 mmol/L) - Hypoglycemia alert value
• Level 2: <54 mg/dL (<3.0 mmol/L) - Clinically significant hypoglycemia
• Level 3: Severe event - Altered mental/physical status requiring assistance 3, 2

Diagnostic Workup

History

• Medication history (insulin, sulfonylureas, other glucose-lowering medications)
• Timing of symptoms (fasting, postprandial, post-exercise)
• Meal patterns and alcohol consumption
• History of diabetes and its treatment regimen
• Previous episodes of hypoglycemia or hypoglycemia unawareness 2, 3
• Recent changes in medication, diet, or activity level

Physical Examination

• Assess for adrenergic symptoms: tremor, palpitations, anxiety, sweating
• Assess for neuroglycopenic symptoms: confusion, altered mental status, seizures, loss of consciousness
• Evaluate for signs of underlying endocrine disorders (thyroid disease, adrenal insufficiency)
• Look for evidence of liver disease or malnutrition

Laboratory Evaluation

For patients with diabetes:

• Review recent HbA1c levels
• Assess kidney function (creatinine, eGFR)
• Evaluate for potential medication interactions

For non-diabetic patients or unexplained hypoglycemia:

1. Critical samples (obtain during hypoglycemic episode):

   • Plasma glucose
   • Insulin
   • C-peptide
   • Proinsulin
   • Beta-hydroxybutyrate
   • Sulfonylurea and meglitinide screen
   • Insulin antibodies

2. Additional tests based on clinical suspicion:

   • Cortisol and ACTH (for adrenal insufficiency)
   • Growth hormone and IGF-1 (for growth hormone deficiency)
   • IGF-2 (for non-islet cell tumor hypoglycemia) 4
   • Liver function tests
   • Glucagon stimulation test (can help distinguish between different causes of hypoglycemia) 4

Provocative Testing

• If spontaneous hypoglycemia cannot be documented, consider:
  • 72-hour supervised fast (gold standard for evaluation of fasting hypoglycemia)
  • Mixed meal test (for postprandial hypoglycemia)
  • Glucagon stimulation test (1 mg IV) to assess glycogen stores and help differentiate causes 4

Special Considerations

Diabetic Patients

• Review insulin regimen and dosing
• Assess for hypoglycemia unawareness
• Evaluate for changes in insulin sensitivity (weight loss, improved fitness, reduced insulin resistance)
• Consider continuous glucose monitoring for patients with recurrent hypoglycemia 2

Non-Diabetic Patients

• Consider insulinoma, non-islet cell tumors, autoimmune hypoglycemia
• Evaluate for factitious hypoglycemia (surreptitious insulin or sulfonylurea use)
• Assess for alcohol-related hypoglycemia
• Consider post-bariatric surgery hypoglycemia 1

Critical Illness

• Monitor glucose levels frequently in critically ill patients
• Target blood glucose levels should not be below 70 mg/dL (3.9 mmol/L) 2
• Do not target upper blood glucose levels <150 mg/dL (<8.3 mmol/L) in critically ill patients 2, 5

Common Pitfalls to Avoid

1. Failing to document Whipple's triad - Confirm hypoglycemia with laboratory measurement during symptoms
2. Premature diagnosis - Non-specific symptoms may not be due to hypoglycemia
3. Missing factitious hypoglycemia - Consider this in healthcare workers or patients with access to insulin/sulfonylureas
4. Overlooking medication interactions - Many medications can potentiate hypoglycemic effects of insulin or sulfonylureas
5. Inadequate follow-up - Patients with unexplained hypoglycemia require close monitoring and follow-up
6. Not addressing hypoglycemia unawareness - This requires temporary raising of glycemic targets to restore awareness 2, 6

By following this systematic approach to hypoglycemia evaluation, clinicians can identify the underlying cause and implement appropriate treatment strategies to prevent recurrent episodes and their associated morbidity and mortality.