Some insulinomas secrete additional hormones, such as gastrin, 5-hydroxyindolic acid, adrenocorticotropic hormone (ACTH), glucagon, human chorionic gonadotropin, and somatostatin. The tumor may secrete insulin in short bursts, causing wide fluctuations in blood levels

History

• Symptoms caused by effects of local tumor mass are very rare.
• About 85% of patients present with symptoms of hypoglycemia with diplopia, blurred vision, palpitations, or weakness.
• Other symptoms include confusion, abnormal behavior, unconsciousness, or amnesia.
• About 12% of patients have grand mal seizures.
• Adrenergic symptoms (hypoglycemia causes adrenalin release) include weakness, sweating, tachycardia, palpitations, and hunger.
• Symptoms may be present from 1 week to as long as several decades prior to the diagnosis (1 mo to 30 y, median 24 mo, as found in a large series of 59 patients).
• Hypoglycemia usually occurs several hours after a meal.
• In severe cases, symptoms may develop in the postprandial period. Symptoms can be aggravated by exercise, alcohol, hypocaloric diet, and treatment with sulfonylureas.
• Weight gain occurs in 20-40% of patients.

Physical

Insulinomas are characterized clinically by the Whipple triad (which occurred in 75% of 67 insulinoma patients as reported recently).

• Episodic hypoglycemia
• Central nervous system (CNS) dysfunction temporally related to hypoglycemia (confusion, anxiety, stupor, convulsions, coma)
• Dramatic reversal of CNS abnormalities by glucose administration

Factitious hypoglycemia can occur in patients who have psychiatric disturbances or a need for attention and access to insulin or sulfonylurea drugs (eg, medical staff). The triad of hypoglycemia, high immunoreactive insulin levels, and suppressed plasma C-peptide immunoreactivity is pathognomonic of exogenous origin. Insulin-induced hypoglycemia can be detected by a ratio of insulin to C-peptide that is greater than 1.0.

Hypoglycemia can occur after inadvertent ingestion of sulfonylurea due to patient or pharmacist error.

Autoimmune hypoglycemia is a rare disorder caused by the interaction of endogenous antibodies with insulin or the insulin receptor. The condition is more common in Japan than in the United States or Europe. The syndrome may produce severe neuroglycopenic symptoms, making immunosuppressive therapy occasionally necessary.

Nesidioblastosis is defined as hyperplasia of the islet cells causing hyperinsulinemic hypoglycemia. It is a predominantly neonatal disorder, although cases in adults have been reported recently.

Noninsulinoma pancreatogenic hypoglycemia syndrome (NIPHS) is a condition in which pancreatic islet hyperplasia is present. This is manifested with postprandial neuroglycopenia, a negative normal fasting test, negative pancreatic imaging results, and positive intra-arterial calcium stimulation of serum insulin.

Familial persistent hyperinsulinemia is manifested with inappropriately high insulin secretions seen in families with mutations in the glucokinase enzymes, glutamate dehydrogenase and short-chain3-hydroxyacyl1-CoA dehydrogenase.

Other causes for hypoglycemia include liver disease, endocrine deficiencies, extrapancreatic insulin-producing tumors (an insulin-secreting small-cell carcinoma of the cervix recently has been described), and pentamidine-induced hypoglycemia.

Lab Studies

• The presence of hypoglycemia in the face of inappropriately elevated levels of insulin is the key to diagnosis. Considering the reference range, the fasting plasma levels of insulin, C-peptide, and, to a lesser degree, proinsulin need not be elevated in insulinoma patients in absolute terms.
• The biochemical diagnosis is established in 95% of patients during prolonged fasting (up to 72 h) when the following parameters are found:
• • Serum insulin levels of 10 µU/mL or more (normal <6 µU/mL)
  • Glucose levels of less than 40 mg/dL
  • C-peptide levels exceeding 2.5 ng/mL (normal <2 ng/mL)
  • Proinsulin levels greater than 25% (or up to 90%) that of immunoreactive insulin
  • Screening for sulfonylurea negative
• Stimulation tests no longer are recommended. The intravenous application of tolbutamide, glucagon, or calcium can be hazardous by inducing prolonged and refractory hypoglycemia.
• Failure of endogenous insulin secretion to be suppressed in the presence of hypoglycemia is the hallmark of an insulinoma.
• Prolonged (ie, 72 h) supervised fast in hospitalized patients provides the most reliable results.
• • The calculation of ratios of insulin (µU/mL) to plasma glucose (mg/dL) is diagnostic.
  • Healthy patients maintain a rate of less than 0.25. Obese patients may have a slightly higher rate.
  • In patients with insulinoma, the ratio rises during fasting.
• The presence of MEN 1 must be evaluated by excluding the following:
• • Hyperprolactinemia due to a pituitary adenoma
  • Hyperparathyroidism due to parathyroid hyperplasia
  • Hypergastrinemia due to a gastrinoma

Imaging Studies

• Start imaging studies only after the diagnosis has been confirmed biochemically, because 80% of insulinomas are less than 2 cm in size and may not be visible by CT scan or transabdominal ultrasonography.
• Successful preoperative tumor localization is achieved in about 60% of patients.
• • Some experienced surgeons perform only transabdominal ultrasound preoperatively.
  • Other surgeons argue that the preoperative localization of insulinomas is not necessary at all because surgical exploration and intraoperative ultrasonography identify more than 90% of tumors.
  • Thus, the extent to which one attempts to define the anatomy of the beta cell lesion before surgery is a matter of judgment.
• CT scan has 44% sensitivity.
• When performed with gadolinium, MRI has 57% sensitivity.
• The accuracy of selective arteriography is 82%, although affected by a false-positive rate of 5%. Many experts see it as the best overall preoperative localization procedure.
• Arteriography with catheterization of small arterial branches of the celiac system combined with calcium injections (which stimulate insulin release from neoplastic tissue but not from normal islets), and simultaneous measurements of hepatic vein insulin during each selective calcium injection localizes tumors in 47% of patients.
• The sensitivity of somatostatin receptor scintigraphy is 60%, although many insulinomas lack somatostatin receptor subtype 2 for successful identification. Endoscopic ultrasonography detects 77% of insulinomas in the pancreas.
• Real-time transabdominal high-resolution ultrasonography has 50% sensitivity.
• Intraoperative transabdominal high-resolution ultrasonography with the transducer wrapped in a sterile rubber glove and passed over the exposed pancreatic surface detects more than 90% of insulinomas.
• Performing a preoperative study to localize the tumor followed by intraoperative ultrasonography and a physical examination is not unreasonable.