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EC Feliberti, MD, Assistant Professor, Department of Surgery,Eastern Virginia Medical School,825 Fairfax Avenue, Suite 610,Norfolk, VA  23507

RR Perry, MD, Robert L. Payne, Jr. Professor,Chief, Division of Surgical Oncology
Eastern Virginia Medical School, Norfolk, VA  23507

AI Vinik, MD, PhD Professor of Medicine/Pathology/Neurobiology, Director of Research and Neuroendocrine Unit, Eastern Virginia Medical School, Strelitz Diabetes Center, 855 W Brambleton Ave, Norfolk, VA  23510

Updated December 2008

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Introduction

Insulinomas are rare and often benign gastroenteropancreatic neuroendocrine tumors. The hallmark features of fasting hypoglycemia include neuroglycopenic (e.g. confusion, visual changes, unusual behavior) and sympathoadrenal (e.g. palpitations, diaphoresis, tremulousness) symptoms. A firmly established diagnosis of an insulin-secreting lesion of the pancreas is essential for successful management. Therefore, it is critically important to rule out other causes of hypoglycemia associated with fasting (1). A detailed differential diagnosis may be found in Table 8.

An accurate diagnosis of organic hyperinsulinism can be established with certainty in nearly all cases (1). The specific cause of hyperinsulinism (see Table 8) usually can be determined before exploration. Nonislet cell neoplasms associated with hypoglycemia are given in Table 9.

There is a clinical entity referred to as autoimmune hypoglycemic disease syndrome (also referred to as insulin autoimmune hypoglycemia, or autoimmune hypoglycemia) in which hypoglycemia occurs in the setting of an autoimmune disorder (e.g. , Graves' disease, rheumatoid arthritis, lupus). Antireceptor antibodies that occur in the presence of other autoimmune disease mimic the effect of insulin and reduce insulin clearance. Therefore, insulin levels may be normal or high, but C-peptide levels are low. The syndrome may be precipitated in some patients by exposure to drugs containing sulfhydryl groups that react with sulfhydryl groups on insulin and render it immunogenic. Glucose tolerance testing reveals that plasma glucose is elevated early and reduced late because of the buffering effect of antibodies on the action of secreted insulin. The disease usually is self-limited as titers fall with time, leading to remission, although corticosteroids have been used.

With the increasing popularity of gastric bypass surgery for morbid obesity,
physicians caring for these patients need to be aware of associated hypoglycemic syndromes. Indeed, hyperinsulinemic hypoglycemia has been described in these patients, primarily due to nesidioblastosis (2).

Diagnosis

While hypoglycemia is a hallmark of insulinoma, the blood glucose level alone is not diagnostic of insulinoma, nor in general is the absolute insulin level elevated in all cases of organic hyperinsulinism. The standard test remains a 72-hour fast while the patient is closely observed (1); (3). More than 95% of cases can be diagnosed based on responses to a 72-hour fast. Serial glucose and insulin levels are obtained over the 72 hours until the patient becomes symptomatic. Because the absolute insulin level is not elevated in all patients with insulinomas, a normal level does not rule out the disease; however, a fasting insulin level of greater than 24 mU/mL is found in approximately 50% of patients with insulinoma. . Values of insulin greater than 7 mU/mL after a more prolonged fast in the presence of a blood glucose less than 40 mg/dL also are highly suggestive. A refinement in the interpretation of glucose and insulin levels has been established by determining the ratio of insulin levels (mU/mL) to the concomitant glucose level (mg/dL). An insulin/glucose ratio of greater than 0.3 has been found in virtually all patients proven to have an insulinoma or other islet cell disease causing organic hyperinsulinism. The accuracy of the test can be increased by calculating the amended insulin/glucose ratio as follows:
amended ratio = [insulin (mU/mL) x 100]/[glucose (mg/dL) - 30] Normal <50.
If the value is greater than 50, then organic hyperinsulinism is certain (1).

Measurements of proinsulin and C peptide also have proven to be valuable in patients suspected of having organic hypoglycemia (4). Normally, the circulating proinsulin concentration accounts for less than 22% of the insulin immunoreactivity but is greater than 24% in over 90% of individuals with insulinomas. Furthermore, when the proinsulin level is greater than 40%, a malignant islet cell tumor should be strongly suspected (1); (5); (6). The C-peptide level is useful in ruling out factitious hypoglycemia from self-administration of insulin. Commercial insulin preparations do not contain  C peptide and low C-peptide levels combined with high insulin levels confirm the diagnosis of self-administration of insulin. Patients who take sulfonylureas surreptitiously may have raised insulin and C-peptide values soon after ingestion, but chronic use will result in hypoglycemia without raised insulin or C-peptide levels. Only an index of suspicion and measurement of urine sulfonylureas will lead to the correct diagnosis.

The insulin response to secretin stimulation (2 U/kg intravenously; peak response in 1-5 minutes) is a valuable measure to differentiate multiple adenomas from nesidioblastosis and single adenomas (7). Patients with single adenomas and nesidioblastosis do not respond to secretin (normal maximal increment <74 mU/mL) whereas those with multiple adenomas or hyperplasia have an excessive insulin response to the administration of secretin (insulin levels of 214 and 497 mU/mL, respectively).

Further information has become available on diffuse hyperplasia in adults. Typically, these patients have postprandial neuroglycopenia, negative fasting test, negative pancreatic imaging, but positive intraarterial calcium stimulation (8). This series showed that patients with this syndrome are younger and mostly non-obese, compared to patients with insulinoma. Pathologically, these patients have beta cell hypertrophy characterized by enlarged and hyperchromatic beta-cell nuclei, similar to infants with nesidioblastosis (9).

A recent study on microRNA expression suggest a possible role in pancreatic tumorogenesis, and may have some diagnostic and prognostic value in these tumors (10). Certainly further study is required.

Localization of insulinomas

Once the diagnosis of insulinoma is confirmed, every effort should be made to localize the tumor. Preoperative localization is important because approximately 30% of insulinomas are less than 1 cm in diameter and 10% are multiple. In addition, 10 to 15% are malignant and 10% will have either islet cell hyperplasia or nesidioblastosis and no tumor at all (11); (1); (3); (12); (13); (14); (15); (16). Because of their small size, the techniques most commonly used to demonstrate tumors in the upper abdomen, including ultrasound, CT, MRI, contrast studies of the upper GI tract, and endoscopic retrograde pancreatography, are of limited value.

Until the past decade, the only study considered to be of proven value in the localization of insulinomas was selective pancreatic angiography (3); (14); (17); (18). During this procedure, highly selective injections of contrast, subtraction procedures, and magnification views increase the number of insulinomas identified. In one large series, 90% of insulinomas were reported to be localized by angiography alone (3); however, most groups report less satisfactory results (18). A summary of all reports in the literature found that approximately 60% of insulinomas have been detected by this method (12). Selective intra-arterial injection of calcium with sampling of hepatic vein insulin appears to improve the ability to detect insulinomas, (19); (20) similar to the results seen with intra-arterial secretin in gastrinoma.

Percutaneous trans-hepatic venous sampling (PTHVS) of insulin from pancreatic veins has been used successfully in localizing occult sources of hyperinsulinism (14); (21); (22); (23); (24). We now believe that the combination of a secretin test to determine the nature of the hyperinsulinism (e.g. , distinction of hyperplasia from adenoma or multiple adenomatosis) with PTHVS to localize the source provides the best means of establishing the specific cause of organic hyperinsulinism with near certainty. A skilled angiographer and careful analysis of the hormonal data in relationship to the venous anatomy in the individual case are required.

A variety of other imaging methods have been investigated. A recent study suggests that the glucagon-like peptide 1 receptor scan is useful to localize occult insulinomas that cannot be identified by other means (25). Multi modality imaging with specifically designed protocols appears to increase the yield of conventional imaging studies (26). Recently, use of [18F] fluorodopa positron emission tomography has been shown useful for diagnosing and localizing congenital hyperinsulinism in infants (27) and insulinoma or beta cell hyperplasia in adults patients (28). However further study in a larger number of patients as well as comparisons to other non invasive and invasive imaging studies will be required to more precisely define the utility of these localization methods in patients with hyperinsulinism.

If PTHVS is not available and preoperative localization by angiography or other techniques has been negative, the surgeon may use intraoperative ultrasound if a careful exploration fails to detect a tumor. Some who have used this technique routinely have reported excellent results. Ultrasound does not identify hyperplasia or nesidioblastosis, however, and its sensitivity appears to be operator dependent.

Treatment of Pancreatic Islet β-cell Disease with Hyperinsulinism

The treatment of pancreatic islet β-cell disease usually is surgical; in the great majority of cases, it provides a complete cure. It should be performed only when the diagnosis is certain, however, and only by a surgeon who is skilled in pancreatic surgery. The surgical approach to insulinoma is straightforward when the tumor is localized. Insulinomas are typically removed by enucleation of the tumor and rarely do tumors at the head of the pancreas require a pancreaticoduodenectomy (Whipple procedure). Precise localization obviates blind pancreatic resection (29).

The results of PTHVS on intra-arterial calcium stimulation with venous sampling are often very useful in helping to plan the surgical approach, especially in a patient in whom a tumor is not identified on routine imaging studies. However, the role of extensive pre-operative localization tests has recently been questioned. One study showed that intraoperative inspection and palpation localized lesions in 91% and intraoperative ultrasound in 93% of cases. Interestingly, all 5 occult tumors were palpatable at surgery. These investigators suggest that PTHVS is helpful in localizing lesions before re-operation, but question the need for extensive pre-operative localization prior to initial exploration in patients believed to have insulinoma (30). On the other hand, another experienced group has shown that since 1994, pre-operative imaging including the use of endoscopic ultrasound was able to identify the tumors 98% of the time. They also found that palpation and intraoperative ultrasound detected 92% of tumors (31).

In patients who have been unresponsive to medical therapy and in whom PTHVS or intra-arterial calcium stimulation with venous sampling suggests diffuse or multiple sources, such as adenomatosis, nesidioblastosis, or hyperplasia, a resection of at least 80% of the distal pancreas is indicated after a frozen-section specimen of the pancreatic tail confirms the diagnosis. Recent study confirms the value of intraarterial calcium stimulation with venous sampling prior to exploration in helping guide resection in patients that have hyperplasia and nesidioblastosis (32).

Similar to other types of tumors, increasingly there have been small series and case reports discussing the role of laparoscopy in the management of these tumors. Exploratory laparoscopy and intraoperative ultrasound was able to identify 12 of 14 tumors, and is felt to be equivalent to arteriography with calcium stimulation and venous sampling (33). Laparoscopic enucleation of insulinoma has been shown to be feasible, particularly if the lesion is visualized pre-operatively on CT scan or endoscopic ultrasound (34).

When hypoglycemia can be controlled with diet alone or with small, well-tolerated doses of diazoxide, and/or when the medical condition of the patient  increases the hazard of surgery sufficiently, medical management alone may be considered. Patients with diffuse hyperinsulinism for whom an operation is planned first should have a trial of treatment with diazoxide and a natriuretic benzothiadiazine. Medical treatment is required for the great majority of malignant insulinomas because only occasionally are they cured by operation. Medical treatment for benign insulinomas includes a change in meals to include "lente carbohydrate" or unrefined carbohydrate given as frequently as required to prevent hypoglycemia. Antihormonal therapy may be useful if diet is insufficient. The management of malignant insulinoma is antihormonal and antitumor therapy.

Medical Management of Benign Disease

Diet

Diazoxide and Natriuretic Benzothiadiazines

Diazoxide (Proglycem) owes its potent hyperglycemic properties to two effects (35); (36): it directly inhibits the release of insulin by β cells through stimulation of α-adrenergic receptors, and it has an extrapancreatic hyperglycemic effect, probably by inhibiting cyclic adenosine monophosphate phosphodiesterase (cyclic AMP), resulting in higher plasma levels of cyclic AMP and enhanced glycogenolysis. Because diazoxide induces the retention of sodium, edema is troublesome at higher dosages. The addition of a diuretic benzothiadiazine (e.g. , trichlormethiazide) not only corrects or prevents edema but synergizes the hyperglycemic effect of diazoxide. At the doses needed to counteract the higher doses of diazoxide (e.g. , 450-600 mg/d), natriuretic benzothiadiazines frequently induce hypokalemia. Nausea is an additional complication at higher dosages of diazoxide, and hypertrichosis may complicate long-term treatment. These compounds have been useful to elevate blood levels of glucose into the euglycemic range if operation must be delayed for weeks or months. Patients with benign insulinomas have been managed successfully for up to 16 years with diazoxide in doses of 150 to 450 mg/d in combination with trichlormethiazide in doses of 2 to 8 mg/d. If they can be tolerated, higher doses may be used in patients with malignant insulinomas.

Calcium Channel Blockers

Theoretically, calcium channel blockers are capable of inhibiting insulin secretion. Verapamil has been used successfully to alleviate the hypoglycemia caused by an insulin-secreting pancreatic tumor in a 94-year-old woman (37). Verapamil and diltiazem have been used with variable results in other patients with organic hyperinsulinism.

Propranolol

β-Adrenergic-receptor blocking drugs inhibit insulin secretion and therefore may be of value in treating organic hyperinsulin. Only a few reports of the use of propranolol have appeared (38); (39). Its use has been associated with the reduction of plasma insulin levels and with the relief of hypoglycemic attacks in patients with benign or malignant insulinoma. In a patient with a benign insulinoma, 80 mg of propranolol a day was sufficient, whereas a patient with malignant insulinoma, in whom streptozotocin was no longer effective, required 640 mg of propranolol orally per day (39). Because this drug can mask the adrenergic symptoms of hypoglycemia and inhibit muscle glycogenolysis, however, there is a risk of aggravating the clinical syndrome. The drug should be used with extreme caution and careful monitoring.

Dilantin

The anticonvulsive diphenylhydantoin (Dilantin) has been shown to inhibit the in vitro release of insulin from both the labile and storage β-cell pools. It has been used successfully to control refractory hypoglycemia, as evidenced by normal overnight fasting glucose levels and absence of hypoglycemia during total fasting of up to 24 hours (40); (41). In only one-third or less of patients with benign insulinoma, however, is the hyperglycemic effect of Dilantin of any clinical significance. Furthermore, with the dosage required, ataxia, nystagmus, hypertrophic gums, and megaloblastic anemia may be side effects. Maintenance doses range from 300 to 600 mg/d. The concurrent administration of diazoxide lowers measurable blood levels of dilantin, and their concurrent use is not recommended.

Long-acting Somatostatin Analogue.

We initially reported the successful use of octreotide (Sandostatin) in prolonging the ability to fast in a patient with a benign insulinoma, (42) and a similar experience was reported by Osei and O'Dorisio (43) in a patient with a malignant tumor. Our more recent experience has shown a variety of responses not easily predictable by the clinical or biochemical profile. We have examined the effects of a long-acting octreotide analogue in seven patients with endogenous hyperinsulinism: five with proven single adenomas, one with multiple adenomas, and one with organic hyperinsulinism associated with MEN-1 (17). In two patients, and possibly a third, octreotide prolonged the ability to fast without hypoglycemia, with variable decreases in plasma insulin concentrations. A trial of long-term administration of octreotide in one of these patients gave only short-term relief of hypoglycemia. Octreotide did not improve, or actually worsened, plasma glucose levels on fasting in the other four patients. In contrast, oral administration of diazoxide to four of these patients was effective in raising plasma glucose levels. A child treated for nesidioblastosis did well initially but subsequently required pancreatectomy and also grew at only the third percentile. It is unlikely that octreotide will be a useful addition to the therapeutic armamentarium for treatment of organic hyperinsulinism, except in familial forms of nesidioblastosis.

A study in benign and malignant insulinoma showed that somatostatin receptor subtype 4 was most frequently expressed in both benign and malignant tumors. 3 of the 6 malignant tumors, but none of the benign tumors expressed somatostatin receptor subtype 5. The other receptor subtypes were expressed in low numbers with no difference between benign and malignant tumors (44).

Glucocorticoids

Glucagon

Glucagon may help to raise blood glucose concentrations, but it may simultaneously directly stimulate the release of insulin.

Estrogen Receptor Blockers

Recent data suggest that estrogen and progesterone receptors are frequently expressed in insulinomas and that these receptors appear to be functional (45). However, whether or not estrogen receptor blockers can effectively decrease insulin levels in these patients is not known.

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