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Diagnosis of Insulinoma Experts in this field emphasize that the most important prerequisite to diagnosing an insulinoma is simply to consider

it, particularly when facing a clinical presentation of fasting hypoglycemia with symptoms of central nervous system dysfunction such as confusion or abnormal behavior. cell tumors do not reduce secretion in the presence of hypoglycemia,

and a serum insulin level of 6 U/mL or more with concomitant plasma glucose values below 45 mg/dL (2.5 mmol/L) suggests an insulinoma. Other causes of hyperinsulinemic hypoglycemia must be considered, however, such as surreptitious administration of insulin or sulfonylureas. Insulin Assays Because insulin assays are crucial in diagnosing insulin-secreting tumors, it is important to be aware of certain limitations in their use. When radioimmunoassays (RIAs) with a sensitivity of 5 U/mL are used, patients with insulinomas have plasma insulin concentrations of 6 U/mL or more. Immunochemiluminometric assays (ICMA) have sensitivities of less than 1 U/mL, and with these assays, the cutoff for insulinomas is 3 U/mL or higher. Previous treatment with insulin may lead to development of autoantibodies to insulin that interfere with the assays, leading to falsely low or elevated values depending on the method used. Proper collection of samples is also important: If the serum is not separated and then frozen within 12 hours, falsely low values result, because the insulin molecule undergoes proteolytic degradation. Suppression Tests Failure of suppression of endogenous insulin secretion in the presence of hypoglycemia is the hallmark of an insulin-secreting tumor. The most reliable suppression test is the prolonged supervised fast in hospitalized subjects, and this remains the preferred diagnostic maneuver in the workup of suspected insulinomas. A suggested protocol for the supervised fast is set forth in Table 194. Table 194. Suggested Hospital Protocol for Supervised Rapid Diagnosis of Insulinoma.

(1) Obtain baseline serum glucose, insulin, proinsulin, and C-peptide measurements at onset of fast and place intravenous cannula. (2) Permit only calorie-free and caffeine-free fluids and encourage supervised activity (such as walking). (3) Measure urine for ketones at the beginning and every 12 hours and at end of fast. (4) Obtain capillary glucose measurements with a reflectance meter every 4 hours until values < 60 mg/dL are obtained. Then increase the frequency of fingersticks to each hour, and when capillary glucose value is < 49 mg/dL, send a venous blood sample to the

laboratory for serum glucose, insulin, proinsulin, and C-peptide measurements. Check frequently for manifestations of neuroglycopenia. (5) If symptoms of hypoglycemia occur or if a laboratory value of serum glucose is <45 mg/dL or if 72 hours have elapsed, then conclude the fast with a final blood sample for serum glucose, insulin, proinsulin, C-peptide, betahydroxybutyrate or acetone, and sulfonylurea measurements. Then give oral fast acting carbohydrate followed by a meal. If the patient is confused or unable to take oral agents, administer 50 mL of 50% dextrose intravenously over 35 minutes. Do not conclude a fast based simply on basis of a capillary blood glucose measurementwait for the laboratory glucose value. In normal men, the blood glucose value does not fall below 55 mg/dL (3.1 mmol/L) during a 72-hour fast, whereas insulin levels fall below 10 U/mL; in some normal women, however, plasma glucose may fall below 30 mg/dL (1.7 mmol/L) (lower limits have not been established), but serum insulin levels also fall appropriately to less than 5 U/mL. These women remain asymptomatic despite this degree of hypoglycemia, presumably because ketogenesis is able to provide sufficient fuel for the central nervous system. Calculation of ratios of insulin (in U/mL) to plasma glucose (in mg/dL) can be useful diagnostically. Nonobese normal subjects maintain a ratio of less than 0.25; obese subjects may have an elevated ratio, but hypoglycemia does not occur with fasting. However, most centers no longer calculate this ratio and rely only on the absolute concentrations of insulin. Virtually all patients with insulin-secreting islet cell tumors fail to suppress their insulin secretion appropriately and maintain serum insulin concentrations of 6 U/mL or more using a RIA

assay or more than 3 U/mL using an ICMA assay despite a fall in plasma glucose below 45 mg/dL. The C-peptide and proinsulin levels (by ICMA) are typically 200 pmol/L or more and pmol/L or more in these patients, respectively. The term "72-hour fast" is actually a misnomer in most cases, because the fast should be immediately terminated as soon as symptoms and laboratory confirmation of hypoglycemia are evident. Most patients with insulinomas experience progressive and symptomatic fasting hypoglycemia with associated elevated insulin levels and no evidence of ketonuria within 2436 hours. Consequently, one group has recommended reducing the duration of the supervised diagnostic fast to no more than 48 hours for cost considerations as well as patient convenience. However, an occasional patient does not demonstrate hypoglycemia until 72 hours have elapsed, and most centers therefore prefer the fast to be supervised for up to 72 hours. Brisk exercise during the fast may help precipitate hypoglycemia. Once symptoms of hypoglycemia occur, plasma glucose should be obtained and the fast immediately terminated if plasma glucose is below 45 mg/dL (2.5 mmol/L). Stimulation Tests A variety of stimulation tests with intravenous tolbutamide, glucagon, or calcium have been devised to demonstrate exaggerated and prolonged insulin secretion. However, because insulin-secreting tumors have a wide range of granule content and degrees of differentiation, they are variably responsive to these secretagogues. Thus, absence of an excessive insulin secretory response during any of these stimulation tests does not rule out the presence of an insulinoma. In addition, the tolbutamide stimulation test was extremely hazardous to patients

with responsive tumors because it induced prolonged and refractory hypoglycemia. For that reason, it is no longer recommended for diagnosis of insulinoma. The glucagon stimulation test is performed as follows: One milligram of glucagon is given intravenously, and serum insulin levels are measured every 5 minutes for 15 minutes. A level exceeding 130 U/mL suggests an insulin-secreting tumor. However, only about half of patients with insulinomas demonstrate this hyperinsulinism, and false-positive results may occur. When an exaggerated increase in serum insulin occurs, the hyperglycemic effect of glucagon may be subnormal, and profound hypoglycemia may subsequently develop by 60 minutes. To prevent this, the patient is fed and may require intravenous glucose after the 15-minute serum sample is obtained. Nausea is an unpleasant side effect, often occurring several minutes after administration of intravenous glucagon. Oral Glucose Tolerance Test The oral glucose tolerance test is of no value in the diagnosis of insulin-secreting tumors. A common misconception is that patients with insulinomas have flat glucose tolerance curves, because the tumors discharge insulin in response to oral glucose. In fact, most insulinomas respond poorly, and curves typical of diabetes are more common. In those rare tumors that do release insulin in response to glucose, a flat curve may result; however, this also can be seen occasionally in normal subjects. Proinsulin Measurements Insulinoma cells are poorly differentiated, which affects their ability to process proinsulin to insulin. Thus, in contrast to normal subjects, whose proinsulin concentration is less than 20% of the total immunoreactive insulin, most patients with insulinoma have elevated levels of proinsulin, representing as much as 3090% of total immunoreactive insulin. Although absolute proinsulin measurements may be elevated in other conditions besides insulinoma (such as in insulin-resistant states), an increased percentage of proinsulin-like components in relation to total insulin immunoreactivity is more specific for insulinoma. However, because this assay of the "percent proinsulin" requires laborious methodology with columns to separate serum protein components, its usefulness is limited. Absolute serum proinsulin measurements are more readily available in commercial laboratories, and their specificity increases considerably if hypoglycemia is achieved during a prolonged supervised fast. In cases in which serum insulin measurements are at borderline levels during a fast in a patient with suspected insulinoma, a serum proinsulin greater than 5 pmol/L in the presence of hypoglycemia is suggestive of the diagnosis. Glycohemoglobin Measurements Low glycohemoglobin values have been reported in occasional cases of insulinoma, reflecting the presence of chronic hypoglycemia. However, the diagnostic usefulness of glycohemoglobin measurements is limited by the relatively low sensitivity of this test as well as poor accuracy at the lower range of normal in many of the assays. In addition, it is nonspecific for hypoglycemia, with low levels being found in certain hemoglobinopathies and hemolytic states. Tumor Localization Studies

It is imperative that both the endocrinologist and the surgeon be convinced that the diagnosis of insulinoma has been unequivocally made by clinical and laboratory findings. Only then should surgery be considered; there is no justification for the use of surgery for diagnostic purposes. The focus of attention should be directed at the pancreas only, because virtually all insulinomas originate from this tissue; ectopic cancers secreting insulin are unknown in the experience of all major centers, with only one published report describing an atypical insulinproducing tumor believed to have originated from a small cell carcinoma of the cervix. Once the biochemical diagnosis has been established, spiral computed tomography angiography of the pancreas should be performed to rule out a large tumor of the pancreas or hepatic metastases from a malignant islet cell tumor. Endoscopic ultrasound examination of the pancreas can also be helpful in identifying the pancreatic lesions. Because of the small size of these tumors (average diameter of 1.5 cm in one large series), imaging studies do not necessarily identify all tumors. Patients who do not have an obvious tumor on imaging (but have a definite biochemical diagnosis) should undergo selective angiography with calcium stimulation. In this test, angiography is combined with injections of calcium gluconate into the gastroduodenal, splenic, and superior mesenteric arteries, and insulin levels are measured in the hepatic vein effluent. Calcium stimulates insulin release from insulinomas but not normal islets, and so a step-up in insulin levels regionalizes the source of the hyperinsulinism to the head of the pancreas for the gastroduodenal artery, the uncinate process for the superior mesenteric artery, and the body and tail of the pancreas for the splenic artery. This technique may also provide data that are particularly helpful when multiple insulinomas are suspected (multiple endocrine neoplasia type 1), and it has become a major tool in confirming the diagnosis of diffuse islet hyperplasia in the recently described noninsulinoma pancreatogenous hypoglycemia syndrome (NIPHS) (see below). Because diazoxide may interfere with this test, it should be discontinued for at least 4872 hours before sampling. Patients should be closely monitored during the procedure to avoid hypoglycemia (as well as hyperglycemia, which could affect insulin gradients). These studies combined with careful intraoperative ultrasonography and palpation by a surgeon experienced in insulinoma surgery identifies the vast majority (up to 98 %) of tumors.