What is the appropriate workup and management for a 14-year-old patient with intermittent hypoglycemia confirmed via Continuous Glucose Monitoring (CGM) and a normal Hemoglobin A1c (HbA1c) level?

Workup for a 14-Year-Old with Intermittent Hypoglycemia and Normal HbA1c

This adolescent requires a comprehensive evaluation to identify the underlying cause of hypoglycemia, focusing on obtaining a critical sample during a symptomatic episode to measure plasma glucose, insulin, C-peptide, proinsulin, and beta-hydroxybutyrate, while simultaneously screening for endocrine disorders and considering early autoimmune type 1 diabetes. 1

Confirm True Hypoglycemia

• Verify that plasma glucose is <70 mg/dL during symptomatic episodes, as this threshold confirms true hypoglycemia rather than CGM artifact or normal glycemic variability 1
• The CGM data should be correlated with fingerstick or laboratory glucose measurements, as CGM accuracy can vary particularly in the hypoglycemic range (MARD up to 31.9% for glucose <70 mg/dL in some systems) 2
• Document the timing of hypoglycemic episodes (fasting vs. postprandial) as this guides differential diagnosis 1

Obtain Critical Sample During Hypoglycemia

The most diagnostically valuable step is obtaining blood work during an actual hypoglycemic episode (plasma glucose <70 mg/dL), which should include: 1

• Plasma glucose (laboratory confirmation, not just CGM or fingerstick)
• Insulin level
• C-peptide
• Proinsulin
• Beta-hydroxybutyrate (ketones)

This "critical sample" distinguishes between hyperinsulinemic causes (elevated insulin/C-peptide with suppressed ketones) versus counter-regulatory hormone deficiencies (low insulin with elevated ketones) 1

Screen for Endocrine Disorders

Evaluate for hormonal deficiencies that impair glucose counter-regulation: 1

• Morning cortisol and ACTH to screen for adrenal insufficiency (Addison disease), which is a life-threatening cause of hypoglycemia 1
• TSH and free T4 to exclude hypothyroidism, which can contribute to hypoglycemia 1
• IGF-1 level if growth velocity is abnormal or if there are other signs suggesting growth hormone deficiency 1

Evaluate for Early Type 1 Diabetes

Test pancreatic autoantibodies (GAD65, IA-2, ZnT8, insulin autoantibodies) to exclude evolving autoimmune type 1 diabetes, as intermittent hypoglycemia can occur in the early stages before overt hyperglycemia develops 1

• Early type 1 diabetes can present with reactive or postprandial hypoglycemia due to dysregulated insulin secretion 1
• A normal HbA1c does not exclude early-stage type 1 diabetes, as HbA1c reflects average glucose over 2-3 months and may miss intermittent patterns 2

Consider Metabolic/Genetic Causes

If hypoglycemia occurs primarily with fasting, obtain an acylcarnitine profile to screen for fatty acid oxidation disorders, which prevent appropriate ketone production during fasting 1

• Hereditary fructose intolerance should be considered if symptoms correlate with fructose ingestion 1

Immediate Safety Measures

Prescribe a glucagon emergency kit (1 mg dose for patients >25 kg or ≥6 years old) for severe hypoglycemic episodes, to be administered subcutaneously or intramuscularly by caregivers 3

• Educate the patient and family on recognizing hypoglycemia symptoms and treating with 15-20 grams of fast-acting carbohydrate 1
• Instruct caregivers to call emergency services immediately after administering glucagon 3

Ongoing Monitoring Strategy

• Continue CGM use to capture patterns and frequency of hypoglycemia, as this technology helps identify episodes that might otherwise be missed 2, 1
• Review CGM data for patterns: nocturnal hypoglycemia, exercise-related hypoglycemia, or postprandial reactive hypoglycemia 1
• Document any triggers such as prolonged fasting, specific foods, or physical activity 1

Critical Pitfall to Avoid

Do not assume this is benign reactive hypoglycemia without completing the diagnostic workup, as serious underlying conditions (adrenal insufficiency, insulinoma, early type 1 diabetes) can present with intermittent hypoglycemia and normal HbA1c 1

• The normal HbA1c indicates average glucose is not elevated, but does not exclude significant glycemic variability or intermittent hypoglycemia 2, 4
• HbA1c and CGM-derived metrics can be discordant, particularly in conditions with high glycemic variability 4