What is the appropriate workup for a 14-year-old female with normal Hemoglobin A1c (HbA1c) levels but intermittent measured hypoglycemia?

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

This patient requires immediate evaluation to exclude hyperinsulinism and other causes of non-diabetic hypoglycemia, as the normal HbA1c effectively rules out diabetes-related hypoglycemia and suggests an alternative pathophysiology.

Initial Diagnostic Approach

Confirm True Hypoglycemia

• Document hypoglycemia with simultaneous plasma glucose measurement during symptomatic episodes, as symptoms alone are nonspecific and insensitive for diagnosing hypoglycemia 1
• Plasma glucose <70 mg/dL (3.9 mmol/L) during symptoms confirms true hypoglycemia 2
• Consider continuous glucose monitoring to capture intermittent episodes that may be missed with fingerstick testing 2

Critical Laboratory Evaluation During Hypoglycemic Episode

When hypoglycemia is documented, obtain the following critical sample (ideally when glucose <55 mg/dL):

• Plasma glucose (laboratory confirmation, not just fingerstick)
• Insulin level - elevated insulin during hypoglycemia suggests hyperinsulinism 3
• C-peptide - elevated C-peptide with elevated insulin indicates endogenous insulin production 3
• Proinsulin
• Beta-hydroxybutyrate - should be suppressed if hyperinsulinism is present
• Plasma free fatty acids - should be suppressed if hyperinsulinism is present
• Sulfonylurea/meglitinide screen - to exclude factitious hypoglycemia 4

Differential Diagnosis to Evaluate

Hyperinsulinism (Most Critical to Exclude)

• Insulinoma - rare in adolescents but must be excluded with elevated insulin and C-peptide during documented hypoglycemia 3
• Nesidioblastosis or islet cell hyperplasia - more common in infants but can occur in adolescents 3
• Factitious hypoglycemia - from exogenous insulin (elevated insulin, low C-peptide) or sulfonylureas (elevated insulin and C-peptide with positive drug screen) 3, 4

Other Endocrine Causes

• Adrenal insufficiency (Addison disease) - screen with morning cortisol and ACTH, as this is more common in patients with other autoimmune conditions 2
• Growth hormone deficiency - consider IGF-1 and growth hormone stimulation testing if growth velocity is abnormal
• Hypothyroidism - check TSH and free T4, as thyroid dysfunction is common in adolescents 2

Metabolic/Genetic Causes

• Glycogen storage diseases - consider if hypoglycemia is fasting-related
• Fatty acid oxidation disorders - evaluate with acylcarnitine profile if fasting hypoglycemia
• Hereditary fructose intolerance - if symptoms relate to fructose ingestion

Reactive/Postprandial Hypoglycemia

• Post-gastric surgery dumping syndrome - unlikely without surgical history
• Early type 1 diabetes - test pancreatic autoantibodies (GAD65, IA-2, ZnT8, insulin autoantibodies) to exclude evolving autoimmune diabetes 2
• Insulin autoimmune syndrome - rare but check insulin antibodies

Key Clinical Pitfalls to Avoid

HbA1c Interpretation Caveats

• Hemoglobin variants can falsely elevate or lower HbA1c, making it unreliable for excluding diabetes in certain populations 2, 5
• Conditions affecting red blood cell turnover (hemolytic anemia, recent blood loss) can falsely lower HbA1c 6, 5
• If there is any suspicion of diabetes despite normal HbA1c, obtain fasting glucose and consider oral glucose tolerance test 2, 6

Timing of Hypoglycemia Matters

• Fasting hypoglycemia (>8 hours without food) suggests hyperinsulinism, adrenal insufficiency, or metabolic disorders
• Postprandial/reactive hypoglycemia (2-5 hours after meals) suggests early diabetes, dumping syndrome, or idiopathic reactive hypoglycemia
• Exercise-related hypoglycemia without diabetes is unusual and warrants endocrine evaluation

Structured Diagnostic Algorithm

Step 1: Document hypoglycemia with plasma glucose <70 mg/dL during symptoms 1

Step 2: If hypoglycemia confirmed, obtain critical sample during next episode (insulin, C-peptide, proinsulin, beta-hydroxybutyrate, sulfonylurea screen) 3

Step 3: Based on critical sample results:

• Elevated insulin + elevated C-peptide + negative drug screen → Imaging for insulinoma (CT/MRI pancreas, endoscopic ultrasound) 3
• Elevated insulin + low C-peptide → Factitious hypoglycemia from exogenous insulin
• Elevated insulin + elevated C-peptide + positive sulfonylurea screen → Factitious hypoglycemia from oral agents 4
• Low insulin + low C-peptide → Evaluate for adrenal insufficiency, growth hormone deficiency 2

Step 4: Screen for autoimmune conditions given age and sex:

• Pancreatic autoantibodies (to exclude evolving type 1 diabetes) 2
• Thyroid function and antibodies 2
• Morning cortisol and ACTH 2
• Consider 21-hydroxylase antibodies if Addison disease suspected 2

Step 5: If all above negative, consider supervised fast (up to 72 hours) in monitored setting to provoke hypoglycemia and obtain diagnostic samples 3

Management Pending Diagnosis

• Frequent small meals with complex carbohydrates to prevent fasting hypoglycemia
• Avoid simple sugars that may provoke reactive hypoglycemia
• Patient and family education on recognizing and treating hypoglycemia with 15-20g fast-acting carbohydrate 2
• Glucagon emergency kit prescription for severe episodes 2
• Avoid activities where hypoglycemia could be dangerous (driving, swimming alone) until diagnosis established 2

When to Refer

Immediate endocrinology referral is warranted for any adolescent with documented recurrent hypoglycemia and normal HbA1c, as this suggests non-diabetic hypoglycemia requiring specialized evaluation 3. If hyperinsulinism is confirmed, surgical consultation may be necessary for insulinoma resection 3.