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

Hypoglycemia Workup

The workup for hypoglycemia begins with documenting Whipple's triad during a symptomatic episode: symptoms consistent with hypoglycemia, a measured low plasma glucose concentration, and resolution of symptoms after glucose normalization. 1

Initial Documentation and Classification

• Confirm hypoglycemia with laboratory measurement during symptoms—do not rely solely on patient report or capillary glucose readings in critically ill patients. 2 1
• Classify the severity using the three-level system: Level 1 (glucose <70 mg/dL but ≥54 mg/dL), Level 2 (glucose <54 mg/dL), or Level 3 (severe cognitive impairment requiring assistance). 3 3
• Document the exact glucose value, timing relative to meals, and associated symptoms at the time of hypoglycemia. 1

Determine Context: Diabetes vs Non-Diabetes

For Patients WITH Diabetes

The workup focuses on identifying iatrogenic causes and risk factors rather than extensive endocrine testing. 4 5

• Review all glucose-lowering medications immediately—insulin and sulfonylureas are the primary culprits. 4 6

• Assess for hypoglycemia risk factors: 5 1

  • Absolute or relative insulin excess (incorrect dosing, timing, or type)
  • Patterns of food ingestion and exercise
  • Alcohol consumption
  • Drug interactions
  • Endogenous insulin deficiency (advanced diabetes)
  • History of severe hypoglycemia or hypoglycemia unawareness
  • Aggressive glycemic targets (HbA1c <7%)
  • Renal or hepatic impairment affecting drug clearance

• Evaluate for hypoglycemia unawareness by asking about recognition of symptoms at each encounter. 3 3

• Consider continuous glucose monitoring (CGM) for patients with recurrent hypoglycemia, impaired awareness, or nocturnal episodes. 4 7

For Patients WITHOUT Diabetes

The workup follows a systematic algorithm to identify the underlying cause. 1

Step 1: Pursue Clinical Clues First

• Medication review: Check for accidental, surreptitious, or malicious use of insulin or sulfonylureas. 1
• Critical illness assessment: Evaluate for sepsis, liver failure, renal failure, cardiac failure, or malnutrition. 1
• Hormone deficiency screening: Test for cortisol deficiency (adrenal insufficiency) and growth hormone deficiency. 1
• Non-islet cell tumor evaluation: Consider large mesenchymal tumors or hepatomas that produce IGF-II. 1

Step 2: Laboratory Testing During Hypoglycemia

If the above causes are excluded, measure the following simultaneously during a documented hypoglycemic episode (glucose <55 mg/dL): 1

• Plasma glucose (laboratory measurement, not capillary)
• Insulin level
• C-peptide level
• Proinsulin level
• Beta-hydroxybutyrate
• Circulating oral hypoglycemic agents (sulfonylurea screen)
• Insulin antibodies 1

Interpretation of results: 1

• Endogenous hyperinsulinism (insulinoma or insulin secretagogue): Elevated insulin, C-peptide, and proinsulin with suppressed beta-hydroxybutyrate
• Exogenous insulin: Elevated insulin, low C-peptide, suppressed beta-hydroxybutyrate
• Sulfonylurea use: Elevated insulin and C-peptide, positive sulfonylurea screen
• Insulin autoimmune syndrome: Elevated insulin antibodies

Step 3: Provocative Testing if Needed

• 72-hour supervised fast remains the gold standard if spontaneous hypoglycemia cannot be documented and endogenous hyperinsulinism is suspected. 1
• Measure the same panel (glucose, insulin, C-peptide, proinsulin, beta-hydroxybutyrate) when glucose falls below 55 mg/dL or symptoms develop. 1

Step 4: Localization Studies for Insulinoma

If biochemical testing confirms endogenous hyperinsulinism: 7

• CT or MRI of the pancreas to identify the tumor. 7
• Selective arterial calcium stimulation with hepatic venous sampling if imaging is negative but biochemistry strongly suggests insulinoma. 7
• Endoscopic ultrasound can detect small lesions missed on cross-sectional imaging. 7

Critical Monitoring Considerations

• Use arterial blood glucose measurements rather than capillary in critically ill or poorly perfused patients for accuracy. 2
• Check glucose every 15-30 minutes initially during acute management, then every 1-2 hours until stable. 6 2
• Document glucose before treatment whenever possible to confirm the diagnosis. 6

Common Pitfalls to Avoid

• Do not pursue extensive workup without first documenting Whipple's triad—many patients report "hypoglycemia" without true low glucose. 1
• Do not rely on symptoms alone—neuroglycopenic and neurogenic symptoms are nonspecific and insensitive. 5
• Do not order random insulin or C-peptide levels—these must be measured during documented hypoglycemia to be interpretable. 1
• Do not assume all hypoglycemia in diabetic patients is iatrogenic—rarely, they can develop insulinomas or other causes. 1
• Do not use capillary glucose alone in critically ill patients—poor perfusion causes inaccurate readings. 2