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|An insulinoma is a
neuroendocrine tumor deriving mainly from pancreatic islet
cells that produce excessive amounts of insulin. About 90%
of insulinomas are benign. In healthy individuals, insulin
and C-peptide are secreted in equimolar quantities because
they derive from the same inactive precursor, proinsulin.
Normally, less than 20% of proinsulin is released directly
into the circulation.
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
Insulinomas are the most common pancreatic
endocrine tumor. The incidence is 4 cases per
million people per year. These make up 55% of
neuroendocrine tumors, as stated above in Background
The male-to-female ratio is 2:3.
- The median age at diagnosis is about 47
years, except in insulinoma patients with MEN 1,
in whom the median age is the mid 20s.
- In one series, patients with benign disease
were younger (mean age of 38 y) than those with
metastases (mean age of 52 y).
- Symptoms caused by effects of local tumor mass are
- 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
- Hypoglycemia usually occurs several hours after a
- In severe cases, symptoms may develop in the
postprandial period. Symptoms can be aggravated by
exercise, alcohol, hypocaloric diet, and treatment with
- Weight gain occurs in 20-40% of patients.
Insulinomas are characterized clinically by the Whipple
triad (which occurred in 75% of 67 insulinoma patients as
- Episodic hypoglycemia
- Central nervous system (CNS) dysfunction temporally
related to hypoglycemia (confusion, anxiety, stupor,
- Dramatic reversal of CNS abnormalities by glucose
Other Problems to be Considered
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
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
- 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 ľU/mL or more (normal
- Glucose levels of less than 40 mg/dL
- C-peptide levels exceeding 2.5 ng/mL (normal <2
- 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
- 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 (ľU/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
- In patients with insulinoma, the ratio rises
- The presence of MEN 1 must be evaluated by excluding
- Hyperprolactinemia due to a pituitary adenoma
- Hyperparathyroidism due to parathyroid
- Hypergastrinemia due to a gastrinoma
- 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%
- 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
- 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%
- 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.
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