A firmly established diagnosis of an insulin-secreting lesion of the pancreas is essential to successful management. Therefore, it is critically important to rule out other causes of hypoglycemia associated with fasting (252). A detailed differential diagnosis may be found in Table 8

Nonislet cell neoplasms associated with hypoglycemia are given in Table 9.

An accurate diagnosis of organic hyperinsulinism can be established with near certainty in all cases (252). The specific causes of hyperinsulinism (see Table 8) usually can be made before exploration. There are syndromes of autoimmunity that may lead to hypoglycemia that must be considered. Antireceptor antibodies usually occur in the presence of other autoimmune disease, with antireceptor antibodies mimicking the effect of insulin and reducing insulin clearance. Therefore, insulin levels may be normal or high, but C-peptide levels are low. This is because islet cells are suppressed. Titers fall with time, leading to remission, although corticosteroids have been used. Autoimmune hypoglycemic disease syndrome usually occurs in the presence of other autoimmune disorders (e.g., Graves’ disease, rheumatoid arthritis, lupus) and generally produces reactive hypoglycemia from prolongation of the half-life of circulating insulin. Insulin levels generally are extremely elevated, which may result from interference by antibodies with the particular insulin assay or, if C peptide also is increased, increased insulin secretion by the pancreas to compensate for inactivation of insulin by circulating antibodies. 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 and may be precipitated in some patients by exposure to drugs containing sulfhydryl groups that react with sulfhydroyl groups on insulin and render it immunogenic.

Diagnosis

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 (252;253). 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. This is strong evidence in favor of the diagnosis. 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 in mU/mL to the concomitant glucose level in 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:

If the value is greater than 50, then organic hyperinsulinism is certain (252). Measurements of proinsulin and C peptide also have proven to be valuable in patients suspected of having organic hypoglycemia (254). 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 (252;255;256). The C-peptide level is useful in ruling out factitious hypoglycemia from self-administration of insulin. Commercial insulin preparations contain no C peptide, and combined with high insulin levels, low C-peptide levels confirm the diagnosis of self-administration of insulin. High-performance liquid chromatography to characterize the insulin species found in the blood was useful before the advent of recombinant human insulin, which has provided the malingerer with a more powerful tool to test the resourcefulness of the physician. 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. A variety of insulin stimulation and suppression tests were once used when precise and accurate insulin measurements were not available. Each had its limitations, and all are currently considered to be obsolete (168;252). 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 (257). The normal maximal increment is 74 mU/mL, whereas in single adenomas, the rise is only 17 mU/mL, in nesidioblastosis 10 mU/mL, and in two patients with multiple B-cell adenomas and hyperplasia, 214 and 497 mU/mL. Patients with single adenomas and nesidioblastosis do not respond to secretin, whereas those with multiple adenomas or hyperplasia have an excessive insulin response to the administration of secretin.

Localization of insulinomas

Once the diagnosis of suspected hyperinsulinism is confirmed, every effort should be made to localize the source of excessive insulin production. Preoperative localization is important because approximately 30% of insulinomas are less than 1 cm in diameter, 10% are multiple, 10 to 15% are malignant, and 10% will have either islet cell hyperplasia or nesidioblastosis and no tumor at all (168;252;253;258-260;260;261;261;262). 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 little value. Until the past decade, the only study considered to be of proven value in the localization of insulinomas was selective pancreatic angiography (253;260;263;264). Highly selective injections of contrast, subtraction procedures, and magnification increase the number of insulinomas identified by this. In one large series, 90% of insulinomas were reported to be localized by angiography alone (253), however, most groups report less satisfactory results (264). A summary of all reports in the literature found that approximately 60% of insulinomas have been detected by this method (258). Selective intra-arterial injection of calcium with sampling of hepatic vein insulin appears to improve the ability to detect insulinomas, (152;265) similar to the results seen with intra-arterial secretin in gastrinoma.

PTHVS(percutaneous trans-hepatic venous sampling) of insulin from pancreatic veins has been used successfully in localizing occult sources of hyperinsulinism (260;266-269). 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 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.

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 it appears to be operator dependent in its sensitivity.

Treament of 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. Precise localization obviates blind pancreatic resection (270). The results of PTHVS are very useful in helping to plan the surgical approach, even in the absence of finding a tumor during careful surgical exploration. In patients who have been unresponsive to medical therapy and in whom PTHVS suggests diffuse or multiple sources, such as adenomatosis, nesidioblastosis, or hyperplasia, a resection of at least 80% of the pancreas is indicated after a frozen-section specimen of the pancreatic tail confirms the diagnosis. 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 may increase 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

The cornerstone of medical management of insulinoma and other forms of hyperinsulinism is the diet. Not uncommonly, patients may avoid symptoms of hypoglycemia for variable periods of time by shortening the number of hours between feedings. For some, the inclusion of a bedtime (11:00 pm) feeding is sufficient; for others, a midmorning, midafternoon, and/or a 3:00 snack are necessary. Although the tumor may be stimulated occasionally to secrete insulin by the ingestion of carbohydrates, it is inadvisable to restrict the intake of carbohydrate. More slowly absorbable forms of carbohydrates (e.g., starches, bread, potatoes, rice) generally are preferred. During hypoglycemic episodes, rapidly absorbable forms (e.g., fruit juices with added glucose or sucrose) are indicated. In patients with severe refractory hypoglycemia, use of a continuous intravenous infusion of glucose, coupled with increased dietary intake of carbohydrate, frequently alleviates hypoglycemia long enough to institute additional therapy.

Diazoxide and Natriuretic Benzothiadiazines

Diazoxide (Proglycem) owes its potent hyperglycemic properties to two effects (271;272): 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 (AMP) phosphodiesterase, 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 (273). 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 (274;275). 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 (275). Because these changes can mask the adrenergic symptoms of hyperglycemia 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 (276;277). 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, (278) and a similar experience was reported by Osei and O’Dorisio (279) 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 (263). 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.

Glucocorticoids

The use of glucocorticoids, which increase gluconeogenesis and cause insulin resistance, also can help to stabilize blood glucose at an acceptable level. Pharmacologic doses (prednisone, approximately 1 mg/kg) must be used.

Glucagon

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