What is the appropriate work‑up for a patient presenting with hypoglycemia?

Hypoglycemia Work-Up

The work-up for hypoglycemia depends critically on whether the patient has diabetes: in diabetic patients, immediately confirm the glucose level and review medications/precipitants, whereas in non-diabetic patients, you must document Whipple's triad and obtain simultaneous critical labs during a spontaneous hypoglycemic episode. 1, 2, 3

For Patients WITH Diabetes

Immediate Confirmation and Classification

• Measure capillary blood glucose immediately to confirm hypoglycemia before pursuing any further work-up. 1, 2
• Classify 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 external assistance). 4, 2, 5
• Document whether symptoms (shakiness, irritability, confusion, tachycardia, hunger, neuroglycopenic signs) were present at the time of low glucose. 2

Identify Precipitating Factors

• Review all glucose-lowering medications immediately, focusing on insulin, sulfonylureas, and meglitinides—the primary culprits. 2
• Systematically inquire about medication timing or dose changes, fasting periods (including for procedures), missed or delayed meals, recent intense physical activity, alcohol intake, and acute illness. 1
• Assess whether glycemic targets are too aggressive (HbA1c <7%) for the patient's risk profile. 2

Screen for Hypoglycemia Unawareness

• Conduct an annual assessment for impaired hypoglycemia awareness using validated questionnaires (single-question Pedersen-Bjergaard, Gold, Clarke, or HypoA-Q tools). 1
• Recognize that hypoglycemia unawareness dramatically raises the risk of severe (level 3) hypoglycemia because patients lose typical counter-regulatory hormone release and warning symptoms when glucose falls below 70 mg/dL. 1
• Ask specifically about recognition of symptoms at each encounter. 2

Assess Cognitive Function

• Evaluate cognitive function routinely, as declining cognition increases hypoglycemia risk and predicts future severe episodes. 1, 2

Consider Continuous Glucose Monitoring

• Utilize CGM to detect impending hypoglycemia patterns and evaluate the effectiveness of therapeutic adjustments, especially in patients with recurrent hypoglycemia or impaired awareness. 1, 2

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For Patients WITHOUT Diabetes (Spontaneous Hypoglycemia)

Document Whipple's Triad First

• Before pursuing any diagnostic work-up, confirm all three components of Whipple's triad: (1) low plasma glucose concentration, (2) neurogenic and neuroglycopenic symptoms/signs, and (3) resolution of symptoms with normalization of plasma glucose. 3, 6, 7
• Do not proceed with extensive testing if Whipple's triad is not documented—many patients self-diagnose hypoglycemia when symptoms occur at normal glucose levels. 3, 8

Obtain Detailed Clinical History

• Classify hypoglycemia into one of three categories based on timing: medication/toxin-induced, fasting (occurring >4 hours from last meal), or postprandial (2-4 hours after meals). 7, 9
• Review all medications (including non-diabetes medications that can cause hypoglycemia), alcohol consumption, underlying comorbid conditions (hepatic or renal dysfunction, critical illness), and any acute illness. 3, 6, 7

Critical Laboratory Evaluation During Hypoglycemia

• Measure the following simultaneously during a documented hypoglycemic episode (glucose typically <55 mg/dL): plasma glucose, insulin level, C-peptide level, proinsulin level, beta-hydroxybutyrate, and circulating oral hypoglycemic agents (sulfonylurea screen). 1, 2, 7
• Interpret results to distinguish endogenous hyperinsulinism (insulinoma, post-bariatric hypoglycemia, non-insulinoma pancreatogenous hypoglycemia syndrome) from exogenous insulin, sulfonylurea use, or insulin autoimmune syndrome based on elevated insulin, C-peptide, and proinsulin levels with suppressed beta-hydroxybutyrate. 1, 2, 7

Supervised Provocative Testing

• If spontaneous hypoglycemia cannot be captured, perform a 72-hour supervised fast for patients with fasting symptoms—this is diagnostic in nearly 100% of cases and requires measurement of plasma insulin, C-peptide, proinsulin, and beta-hydroxybutyrate when glucose falls below 55 mg/dL. 1, 3, 7, 9
• For patients with predominantly postprandial symptoms, perform a mixed-meal test instead of a 72-hour fast to recreate the situation under which symptoms occur. 3, 7
• Check glucose every 15-30 minutes initially during acute management, then every 1-2 hours until stable. 2

Diagnostic Criteria for Endogenous Hyperinsulinism

• Confirm hyperinsulinism with: hypoglycemia <2.2 mmol/L (approximately 40 mg/dL), neuroglycopenic symptoms, and inappropriately elevated plasma insulin (>30-40 pmol/L) and C-peptide levels (>200 pmol/L) to document endogenous insulin release. 9

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Common Pitfalls to Avoid

• Do not pursue extensive work-up in diabetic patients without first reviewing medications and precipitants—the vast majority of cases are iatrogenic. 1, 2
• Do not diagnose hypoglycemia in non-diabetic patients based on symptoms alone—plasma glucose nadirs overlap significantly between symptomatic and asymptomatic individuals, and 10% of asymptomatic people have nadirs ≤47 mg/dL during glucose tolerance testing. 8
• Do not rely on capillary glucose in critically ill or poorly perfused patients—use arterial blood glucose measurements for accuracy. 2
• Do not overlook factitious hypoglycemia from extrinsic insulin use or ingestion of oral hypoglycemic agents in patients with mental health issues. 7