What is Whipple's triad?

Whipple's Triad: Diagnostic Criteria for Hypoglycemia

Whipple's triad is the classic diagnostic criteria for hypoglycemia, consisting of three essential components: (1) symptoms consistent with hypoglycemia, (2) low plasma glucose measured at the time of symptoms, and (3) relief of symptoms when glucose is raised to normal levels.

Components of Whipple's Triad

Whipple's triad consists of three key elements that must be documented to confirm hypoglycemia:

1. Symptoms and signs consistent with hypoglycemia

   • Neuroglycopenic symptoms (confusion, altered mental status, seizures) 1
   • Autonomic symptoms (sweating, trembling, palpitations) 2

2. Documented low plasma glucose level during symptoms

   • Typically defined as plasma glucose <50 mg/dL 2
   • Must be measured at the time when symptoms are present 1

3. Relief of symptoms when glucose is raised to normal levels

   • Prompt resolution of symptoms after oral or intravenous glucose administration 3
   • This confirms that the symptoms were indeed caused by hypoglycemia 4

Clinical Application

Whipple's triad is most commonly used in the diagnosis of:

• Insulinoma - the most common cause of organic hypoglycemia 3

  • Insulinomas are rare pancreatic neuroendocrine tumors with an incidence of 1-4 cases per million per year 1
  • Most insulinomas present with the classic Whipple's triad 1

• Other causes of hypoglycemia where documenting the relationship between symptoms, low glucose, and symptom relief is essential for diagnosis

Diagnostic Testing

When Whipple's triad is observed, further diagnostic evaluation is warranted:

• 72-hour supervised fast - traditionally considered the gold standard test 2

  • However, newer evidence suggests a 48-hour fast may be sufficient in most cases 5
  • During the fast, measurements include glucose, insulin, C-peptide, and proinsulin 5

• Biochemical confirmation of insulin-mediated hypoglycemia

  • Elevated insulin levels with concurrent low glucose is diagnostic 4
  • Elevated C-peptide levels during hypoglycemia suggest endogenous hyperinsulinism 2
  • Suppressed beta-hydroxybutyrate during hypoglycemia 2

Clinical Pitfalls and Considerations

• Complete documentation is essential

  • All three components must be present and documented to fulfill Whipple's triad 1
  • Failure to document glucose levels during symptoms may necessitate provocative testing 5

• Timing of measurements is critical

  • Blood samples must be drawn during symptomatic episodes 1
  • Retrospective reporting of symptoms without glucose measurement is insufficient 2

• Differential diagnosis

  • Not all hypoglycemia is caused by insulinoma - other causes include factitious hypoglycemia, non-islet cell tumors, and adrenal insufficiency 1
  • Sulfonylurea screening may be necessary to rule out surreptitious use 2

By systematically documenting all three components of Whipple's triad, clinicians can establish a clear diagnosis of hypoglycemia and proceed with appropriate further testing to determine the underlying cause.