What is Whipple's triad?

Whipple's Triad

Whipple's triad is the classic diagnostic criteria for insulinoma, consisting of: (1) symptoms consistent with hypoglycemia, (2) documented low blood glucose level at the time of symptoms, and (3) relief of symptoms when glucose is raised to normal levels. 1, 2

Components of Whipple's Triad

1. Hypoglycemic symptoms:

   • Adrenergic symptoms: Palpitations, diaphoresis (sweating), tremors, anxiety, hunger
   • Neuroglycopenic symptoms: Confusion, altered mental status, dizziness, blurred vision, seizures, loss of consciousness

2. Low plasma glucose measurement:

   • Typically below 50 mg/dL (2.8 mmol/L) when symptoms occur
   • Often in the range of 27-40 mg/dL during symptomatic episodes 3

3. Resolution of symptoms after glucose administration:

   • Prompt relief of symptoms following oral or intravenous glucose administration
   • This confirms that hypoglycemia was the cause of symptoms

Clinical Significance

Whipple's triad is primarily used in the diagnosis of insulinoma, which is the most common cause of organic hypoglycemia 4. However, it can be applied to any hypoglycemic disorder.

• Diagnostic challenges: Despite the clear criteria, diagnosis is often delayed because:

  • Symptoms may be nonspecific and intermittent
  • Symptoms might be misattributed to neurological or psychiatric conditions
  • Hypoglycemic episodes may not be captured during routine clinical visits 3

• Potential consequences: Undiagnosed hypoglycemic disorders can lead to serious outcomes:

  • Traffic accidents and other injuries due to loss of consciousness 5
  • Permanent neurological damage from recurrent severe hypoglycemia
  • Reduced quality of life from chronic symptoms

Diagnostic Approach

When Whipple's triad is suspected:

1. Document hypoglycemia during symptoms:

   • Measure plasma glucose when symptoms occur
   • If possible, obtain simultaneous insulin, C-peptide, and proinsulin levels

2. Supervised fasting test:

   • Gold standard for confirming endogenous hyperinsulinemic hypoglycemia
   • Monitor for up to 72 hours with regular glucose measurements
   • Terminate when hypoglycemia occurs with symptoms

3. Biochemical confirmation:

   • Elevated insulin (>3 μU/mL) with concurrent hypoglycemia
   • Elevated C-peptide levels (>0.6 ng/mL)
   • Absence of sulfonylurea in plasma/urine

Common Pitfalls

• Misdiagnosis: Symptoms may be attributed to cardiac, neurological, or psychiatric disorders 3
• Factitious hypoglycemia: Consider surreptitious insulin or sulfonylurea use
• Reactive hypoglycemia: Post-prandial symptoms that may mimic insulinoma but occur after meals
• Incomplete evaluation: Failure to document all three components of the triad simultaneously

Management Implications

Once Whipple's triad is confirmed and insulinoma diagnosed:

• Surgical resection is the definitive treatment for insulinoma, with excellent outcomes and symptom resolution 3
• Localization studies including CT, MRI, endoscopic ultrasound, and specialized nuclear imaging are essential before surgery 2
• Medical management with diazoxide or somatostatin analogs may be used temporarily or in inoperable cases

Whipple's triad remains the cornerstone of diagnosing hypoglycemic disorders, particularly insulinoma, and its proper application leads to timely diagnosis and effective treatment of these potentially dangerous conditions.