Whipple triad

**Components of the triad** 1. Symptoms and/or signs consistent with hypoglycemia. Adrenergic (autonomic) symptoms include tremor, palpitations, sweating, anxiety, and hunger. Neuroglycopenic symptoms include confusion, behavioral change, blurred vision, seizures, and coma. 2. Low plasma glucose measured at the time of symptoms. Glucose is typically <55 mg/dL (3.0 mmol/L) in nondiabetic patients. Use a lab-measured plasma glucose rather than a fingerstick if possible. 3. Relief of symptoms after glucose is raised (carbohydrate or dextrose administration).

**Physiology and glucose thresholds** - Counterregulatory response (decreased insulin, increased glucagon, epinephrine, then cortisol and GH) begins at about 80 mg/dL of glucose (insulin suppression) and about 65-70 mg/dL (glucagon and epinephrine). - Autonomic symptoms appear at about 50-55 mg/dL. Neuroglycopenic symptoms appear at lower glucose levels. - Hypoglycemia unawareness occurs in long-standing diabetes and with recurrent hypoglycemia, because the autonomic response is blunted.

**Clinical significance** - Confirming the triad establishes true hypoglycemia, so the cause can then be sought. - In a patient who meets the triad but is not on insulin or a sulfonylurea, obtain labs during the hypoglycemic episode: glucose, insulin, C-peptide, proinsulin, beta-hydroxybutyrate, and a sulfonylurea/meglitinide screen. A 72-hour fast is the classic provocative test for suspected insulinoma.

**Interpreting the labs in hypoglycemia** - Insulinoma (endogenous hyperinsulinism): high insulin, high C-peptide, high proinsulin, low beta-hydroxybutyrate. - Exogenous insulin: high insulin, **low** C-peptide. - Sulfonylurea or meglitinide: high insulin, high C-peptide, positive drug screen. - Non-islet-cell tumor hypoglycemia (IGF-2 secretion, e.g., large mesenchymal tumors): low insulin and low C-peptide. - Other causes: adrenal insufficiency, severe liver disease, sepsis, starvation, alcohol (inhibits gluconeogenesis), and glycogen storage or other inborn errors.

**Eponym note and buzzword trap** - The triad is named for Allen Whipple, the surgeon who described it for insulin-secreting pancreatic tumors. - Do not confuse it with Whipple disease (*Tropheryma whipplei*: diarrhea, arthralgia, weight loss, foamy PAS-positive macrophages) or the Whipple procedure (pancreaticoduodenectomy). - Do not confuse it with Beck triad (cardiac tamponade) or Charcot triad (cholangitis).

**Management** - Treat acute hypoglycemia with oral glucose if the patient can swallow. Otherwise give IV dextrose, or IM/SC glucagon if there is no IV access. - Definitive treatment depends on the cause. For insulinoma, surgical resection is curative in most cases.

**High-yield associations** - Insulinoma is the most common functional pancreatic neuroendocrine tumor. It is associated with MEN1 (pituitary, parathyroid, pancreas). - A classic vignette is a patient with episodic fasting confusion or sweating that resolves with eating, and weight gain from frequent eating.