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

Hypoglycemia Workup

The workup for hypoglycemia depends critically on whether the patient has diabetes or presents with spontaneous hypoglycemia without diabetes—these require fundamentally different diagnostic approaches.

For Patients WITH Diabetes

Initial Assessment

In diabetic patients presenting with hypoglycemia, the workup focuses on identifying precipitating factors and assessing for hypoglycemia unawareness rather than extensive laboratory investigation. 1

• Confirm hypoglycemia immediately with capillary blood glucose measurement—this is the first diagnostic step before any other workup 2
• Document the glucose level: Level 1 (<70 mg/dL), Level 2 (<54 mg/dL), or Level 3 (severe cognitive impairment requiring assistance) 1
• Assess for symptoms: shakiness, irritability, confusion, tachycardia, hunger, or neuroglycopenic symptoms 1

Clinical History to Obtain

• Ask about symptomatic and asymptomatic hypoglycemia at each encounter—this is a guideline recommendation for all at-risk patients 1
• Identify precipitating factors: 1, 3
  • Medication timing, dose, and recent changes (especially insulin, sulfonylureas, meglitinides)
  • Patterns of food intake (missed meals, delayed meals, fasting for procedures)
  • Exercise timing and intensity
  • Alcohol consumption
  • Concurrent illness or vomiting
• Screen for hypoglycemia unawareness—loss of warning symptoms that normally occur at glucose <70 mg/dL 1, 4
• Document history of severe hypoglycemia episodes requiring assistance 1

Medication Review

• Review all glucose-lowering medications: insulin regimen (type, dose, timing), sulfonylureas, meglitinides 3, 4
• Assess for drug interactions that may increase hypoglycemia risk 4
• Evaluate appropriateness of current glycemic targets given patient's risk profile 1

Additional Workup for Recurrent Episodes

• If hypoglycemia unawareness or recurrent severe hypoglycemia is present, trigger immediate reevaluation of the entire treatment regimen—this is mandatory 1
• Consider continuous glucose monitoring (CGM) for patients with frequent episodes, nocturnal hypoglycemia, or impaired awareness 3
• Assess cognitive function, as declining cognition increases hypoglycemia risk 1

No Extensive Laboratory Testing Needed

• In diabetic patients on glucose-lowering medications, extensive endocrine workup (insulin levels, C-peptide, imaging) is not indicated unless factitious hypoglycemia from exogenous insulin or oral agents is suspected 5, 4

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For Patients WITHOUT Diabetes (Spontaneous Hypoglycemia)

Initial Confirmation

Spontaneous hypoglycemia requires documentation of Whipple's triad: symptoms/signs of hypoglycemia, low plasma glucose, and resolution after glucose correction. 5

Diagnostic Testing Algorithm

First-Line Test: 72-Hour Supervised Fast

• The 72-hour supervised fast is the gold standard for evaluating spontaneous hypoglycemia 5
• During documented hypoglycemia (glucose typically <55 mg/dL), measure simultaneously: 5
  • Plasma glucose
  • Plasma insulin
  • C-peptide
  • Proinsulin
  • Beta-hydroxybutyrate
  • Plasma/urine sulfonylurea screen (to exclude factitious hypoglycemia)

Interpretation of 72-Hour Fast Results

• Elevated insulin with elevated C-peptide: suggests insulinoma or non-insulinoma pancreatogenous hypoglycemia syndrome 5
• Elevated insulin with suppressed C-peptide: indicates exogenous insulin administration (factitious) 5
• Suppressed insulin with elevated C-peptide: consider insulin autoimmune syndrome 5
• Suppressed insulin and C-peptide with suppressed beta-hydroxybutyrate: suggests non-islet cell tumor hypoglycemia 5
• Positive sulfonylurea screen: confirms factitious hypoglycemia from oral agents 5

Alternative Test: Mixed Meal Test

• For patients with predominantly postprandial symptoms, a mixed meal test is preferable to the 72-hour fast 5
• Measure glucose, insulin, and C-peptide at baseline and serially after a standardized meal 5

Additional Diagnostic Evaluation Based on Initial Results

If Insulinoma Suspected

• Proceed with imaging: CT, MRI, or endoscopic ultrasound to localize tumor 5
• Glucagon stimulation test (1 mg IV push with serial glucose measurements) can help confirm adequate glycogen stores and predict response to glucagon therapy 6

If Non-Islet Cell Tumor Hypoglycemia Suspected

• Evaluate for large mesenchymal tumors, hepatocellular carcinoma, or other malignancies 5, 6
• Measure IGF-II levels if available 5
• Glucagon stimulation test helps distinguish insulin-mediated hypoglycemia from hepatic glycogen depletion 6

If Hormonal Deficiency Suspected

• Evaluate for primary adrenal insufficiency: morning cortisol, ACTH stimulation test 5
• Assess for hypopituitarism: TSH, free T4, cortisol, growth hormone axis 5

Critical Illness Consideration

• In hospitalized or critically ill patients, hypoglycemia may result from sepsis, liver failure, renal failure, or malnutrition 5
• Workup should focus on identifying and treating the underlying critical illness 5

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Common Pitfalls to Avoid

• Do not perform extensive endocrine workup in diabetic patients on glucose-lowering medications—the cause is usually medication-related 5, 4
• Do not rely on random glucose measurements—hypoglycemia must be documented during symptomatic episodes 5
• Do not miss factitious hypoglycemia—always screen for sulfonylureas and assess insulin/C-peptide relationship 5
• Do not overlook hypoglycemia unawareness in diabetic patients—this requires immediate intervention with raised glycemic targets for 2-3 weeks 1, 4
• In patients with liver metastases and tumor hypoglycemia, glucagon stimulation testing rapidly distinguishes insulin-mediated hypoglycemia from hepatic failure, guiding appropriate therapy 6