At a Glance

Insulinomas are the most common functioning pancreatic neuroendocrine tumors (NETs) and account for 20-30% of all pancreatic NETs. Most cases are sporadic, but about 5-10% are associated with multiple endocrine neoplasia type 1 (MEN1). The tumors are usually solitary (except in patients with MEN1), small (<1 cm), and almost exclusively intrapancreatic. In contrast to all other pancreatic NETs, insulinomas are benign in more than 85% of patients, but, as in other NETs, the degree of malignancy cannot be predicted by histological appearance.

Insulinoma patients characteristically present with symptoms of recurrent hypoglycemia, especially neuroglucopenic symptoms (e.g., confusion, altered consciousness, visual changes) and symptoms due to sympathetic overdrive (e.g., tachycardia, anxiety, palpitations, weakness, diaphoresis), which are exaggerated by fasting in 73% of cases. However, postprandial hypoglycemia may accompany fasting hypoglycemia and may be the sole manifestation of hypoglycemia in some patients (21 and 6%, respectively). Hypoglycemia in insulinoma patients is primarily due to reduced hepatic output, rather than increased glucose utilization. Because symptoms are not specific, many patients are initially misdiagnosed with a neurologic (including seizure disorder) or psychiatric disorders. Some patients (18%) experience weight gain.

Differential diagnosis includes other disorders with primary insulin overproduction: familial persistent hyperinsulinemic hypoglycemia of infancy (congenital hyperinsulinism), primary islet-cell hyperplasia, noninsulinoma pancreatogenous hypoglycemia syndrome, and post gastric bypass hypoglycemia (the latter two presenting primarily with postprandial hypoglycemia). Artificially induced hypoglycemia should be excluded.

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What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

The diagnosis of insulinoma is established by demonstrating inappropriately high insulin concentrations during a spontaneous or induced episode of hypoglycemia (usually a 72-hour fast conducted under supervision). Blood glucose, insulin, C-peptide, and proinsulin measurements are used for evaluation.

Six criteria are used to diagnose an insulinoma:

  • documented blood glucose concentrations of 40 mg/dL or less

  • concomitant insulin concentrations of 6 μU/mL or greater

  • C-peptide concentrations equal to 200 pmol/L or greater

  • proinsulin concentrations of 5 pmol/L or greater

  • β-hydroxybutyrate concentrations of 2.7 mmol/L or less

  • absence of sulfonylurea (metabolites) in plasma and/or urine

About 98% of patients with insulinoma develop symptomatic hypoglycemia during a 72-hour fast. When the patient develops symptoms and blood glucose concentrations are less than or equal to 40 mg/dL, C-peptide, proinsulin, and insulin concentrations should be measured and the fast should be stopped. Failure of appropriate insulin suppression in the presence of hypoglycemia confirms the presence of autonomous insulin secretion by an insulinoma. Other causes of hypoglycemia should be excluded, including artificially induced hypoglycemia, by measuring plasma or urine sulfonylurea concentration.

Serum chromogranin A (CGA) is a nonspecific marker for well-differentiated neuroendocrine tumors that does not distinguish the various subtypes. CGA is usually elevated in gastroenteropancreatic neuroendocrine tumors (GEP-NETs), including insulinomas. Because CGA concentration correlates with tumor volume, it may be useful for staging, prognosis, and monitoring. CGA can be elevated in other conditions, including renal insufficiency or severe malabsorption syndrome.

After the diagnosis of insulinoma is established, an attempt should be made to locate and stage the tumor. (Table 1)

Table 1.
Glucose, blood Insulin, serum (concomitant)
40 mg/dL or less

6 μU/mL or greater

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?

Newer methods used to measure insulin concentration (immunochemiluminescent or specific immunoradiometric assays) do not show crossreactivity with proinsulin. This may affect the diagnostic criteria, which are based on older methods (radioimmunoassay) for insulin measurement that produced higher concentrations.

CGA levels may be elevated in patients with renal insufficiency or severe malabsorption syndrome.

What Lab Results Are Absolutely Confirmatory?

Venous glucose concentration of less than 45 mg/dL with a simultaneous serum insulin concentration greater than 6 μU/mL is diagnostic for insulinoma.

Histopathological evaluation (with the use of ancillary studies, including immunohistochemical stains for neuroendocrine markers if necessary) of the removed tumor or biopsy material (if performed) confirms diagnosis.

Additional Issues of Clinical Importance

Delayed diagnosis can lead to adverse effects, including risks related to recurrent episodes of hypoglycemia, as well as delay in treatment of the underlying condition, which is primarily surgical.

Errors in Interpretation

Other causes of hypoglycemia, including surreptitious medication use, should be excluded.