Whipple's Triad
Whipple's triad consists of three essential criteria that must all be present to confirm true hypoglycemia: (1) symptoms and/or signs consistent with hypoglycemia, (2) a documented low plasma glucose concentration, and (3) resolution of those symptoms after the plasma glucose is raised. 1, 2
The Three Components
1. Clinical Symptoms and Signs of Hypoglycemia
- Autonomic/adrenergic symptoms include shakiness, tremors, sweating, palpitations, tachycardia, pallor, and hunger 3, 4
- Neuroglycopenic symptoms include confusion, drowsiness, altered mental status, irritability, and headache—these result from direct cerebral glucose deprivation 3, 5
- Symptoms typically begin when plasma glucose falls to approximately 70 mg/dL (3.9 mmol/L), which triggers neuroendocrine counterregulatory responses 3, 5
- More severe neuroglycopenic symptoms appear at 54 mg/dL (3.0 mmol/L) when cerebral glucose delivery becomes insufficient for normal neuronal function 5
2. Low Plasma Glucose Concentration
- A documented low glucose level must be measured during the symptomatic episode 4, 2
- The diagnostic threshold is <70 mg/dL (<3.9 mmol/L) for the alert value 3, 4
- Clinically significant hypoglycemia is defined as glucose <54 mg/dL (<3.0 mmol/L), representing Level 2 hypoglycemia where neuroglycopenic symptoms typically occur 3, 4
- Blood glucose should be measured immediately when hypoglycemia is suspected; treatment should not be delayed awaiting laboratory confirmation if point-of-care testing shows values <70 mg/dL 6, 3
3. Resolution of Symptoms After Glucose Correction
- Symptoms and signs must resolve after plasma glucose is raised to normal levels 1, 2
- This confirms that the symptoms were indeed caused by hypoglycemia rather than another condition 7, 8
- For conscious patients, administer 15-20 g of fast-acting carbohydrate (glucose preferred) and recheck glucose after 15 minutes 3, 4
- If glucose remains low after 15 minutes, repeat carbohydrate administration 3, 4
Clinical Application
Why All Three Criteria Matter
- All three components must be present to diagnose true hypoglycemia and avoid misdiagnosis 2
- Symptoms alone are insufficient, as many conditions can mimic hypoglycemia without actual low glucose 7, 8
- A low glucose reading without symptoms may represent laboratory error or physiologic variation 2
- Failure of symptom resolution after glucose correction suggests an alternative diagnosis 8
Diagnostic Approach
- Document Whipple's triad during a spontaneous symptomatic episode before pursuing extensive workup 4, 2
- In patients without diabetes, obtain plasma insulin, C-peptide, proinsulin, beta-hydroxybutyrate, and screen for oral hypoglycemic agents during the hypoglycemic episode 4, 2
- For predominantly postprandial symptoms, a mixed meal test is preferable to a 72-hour fast 8
Common Pitfalls to Avoid
- Do not diagnose hypoglycemia without documenting all three components of Whipple's triad—this leads to unnecessary testing and misdiagnosis 2
- Do not rely on patient-reported glucose values alone; confirm with simultaneous symptom documentation and response to treatment 7, 8
- Do not dismiss glucose values between 54-70 mg/dL as insignificant; this Level 1 range still requires intervention and medication adjustment 3
- Do not wait for laboratory confirmation before treating when point-of-care glucose is <70 mg/dL 6, 3