Diffuse and focal sources of hyperinsulinism

DIFFUSE AND FOCAL SOURCES OF HYPERINSULINISM DENNIS A. RASBACH, M.D. SEUNG KEUN OH, M.D. TIMOTHY S. HARRISON, M.D.

0147-0272/84/09-001-043-$9.95 @ 1984, Year Book Medical Publishers, Inc.

TABLE OF CONTENTS CLINICAL PRESENTATION

. . . . . . . . . . . . . . . . . . . .

DIFFERENTIAL DIAGNOSIS OF HYPOGLYCEMIA

. . . . . . . . . . .

LABORATORY FEATURES . . . . . . . . . . . . . . . . . . . . . PREOPERATIVE LOCALIZATION

. . . . . . . . . . . . . . . . . .

PATHOLOGY AND PATHOPHYSIOLOGY

. . . . . . . . . . . . . . .

5 5 7 13 17

NONPANCREATIC TUMORS . . . . . . . . . . . . . . . . . . . .

28

MULTIPLE ENDOCRINE ADENOMATOSIS

30

SURGICAL MANAGEMENT

. . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . .

31

PHARMACOLOGIC CONTROL OF HYPERINSULINISM . . . . . . . . . .

35

CHEMOTHERAPY IN THE MANAGEMENT OF METASTATIC MALIGNANT INSULINOMA . . . . . . . . . . . . . . . . . . . . . . . . .

36

CONCLUSIONS

37

. . . . . . . . . . . . . . . . . . . . . . . . .

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practices general surgery in St. Joseph, Michigan. After graduating from the Johns Hopkins University School of Medicine, Dr. Rasbach completed a residency in Surgery at the Milton S. Hershey Medical Center of the Pennsylvania State University, and a fellowship in Surgical Endocrinology at the Hershey Medical Center, the Massachusetts General Hospital, and the Mayo Clinic. His investigative work has been in the field of catecholamine physiology.

is an Assistant Professor of Surgery, Seoul National University College of Medicine, Seoul, Korea, and a Visiting Scientist in Surgery with the Milton S. Hershey Medical Center, the Pennsylvania State University College of Medicine in Hershey. Dr. Oh received his M.D. degree from Seoul National University College of Medicine and completed a residency in Surgery at Seoul National University Hospital. His interests include investigative and surgical endocrinology and radical neck surgery.

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has been, since 1975, Professor of Surgery and Physiology at the Milton S. Hershey Medical Center, the Pennsylvania State University College of Medicine. After graduating from Hope College and the Johns Hopkins University School of Medicine, Dr. Harrison trained in Surgery at the Johns Hopkins Hospital and the Massachusetts General Hospital. On completing a fellowship in Physiology at the Karolinska Institute in Stockholm, he joined the faculty of the University of Michigan Medical School, interrupted by a 3-year period as Professor and Chairman of the Department of Surgery at the American University of Beirut. Dr. Harrison's research interests range broadly in surgical endocrinology and catecholamine physiology.

GLUCOSE HOMEOSTASIS is maintained by the complex interplay of insulin and several counterregulatory hormones, including glucagon, the catecholamines, growth hormone, cortisol, and thyroid hormones. The action of insulin is anabolic, increasing the transport of glucose across muscle and adipose cell membranes and promoting protein synthesis, lipogenesis, and glycogen synthesis. By these mechanisms, excess circulating levels of glucose are reduced and energy substrates are stored for future use. Injected insulin has a short half-life; approximately I0 minutes. Insulin's blood concentration is determined by alterations in its rate of secretion by the pancreatic beta cells. I Normally, hypoglycemia inhibits and hyperglycemia enhances the release of insulin. In states of endogenous hyperinsulinism, the capacity of pancreatic beta cells to limit insulin release in response to falling blood glucose levels is lost and hypoglycemia results. Spontaneous hyperinsulinism was first described by Harris 2 in 1924, 2 years after the discovery of insulin by Banting and Best. 3 In 1927, Dr. Charles Mayo operated on a hypoglycemic patient with metastatic carcinoma of the pancreatic islets. 4 Two years later, in Toronto, Dr. Roscoe Graham surgically cured a hypogl cemic patient by removing a pancreatic islet cell aden o m a . ~y The clinical triad of symptomatic fasting hypoglycemia, a blood glucose level less than 50 mg/100 mgl, and relief of symptoms following the ingestion of glucose, as set forth by Whipple, 6 soon became closely identified with the diagnosis of organic hyperinsulinism. By 1935, Whipple and Frantz 7 had collected from their own experience and review of the literature 35 patients with this diagnosis who had undergone surgical exploration. Interestingly, islet cell pathology was n o t found in 40% of these cases, which emphasizes the imprecision of diagnosis based solely on the documentation of fasting hypoglycemia. It was not until the radioimmunoassay for plasma insulin was developed in 1960 s that exact diagnostic criteria could be established. The documentation of absolute or inappropriately elevated plasma insulin levels in the face of fasting hypoglycemia, demonstrating autonomy of insulin release, has become the keystone of modern diagnosis. Five major disorders of pancreatic beta islet cells are now associated with hyperinsulinism: solitary adenoma, adenomatosis, carcinoma, hyperplasia, and nesidioblastosis. This monograph reviews current concepts in the diagnosis and management of these focal and diffuse sources of endogenous hyperinsulinism.

CLINICAL PRESENTATION

Hyperinsulinism m a y occur from infancy to senescence. The mean age of patients is 45.4 years, and females outnumber males by a ratio of 1.4:1.9-14 It is not surprising, given the brain's absolute requirement for glucose as an energy substrate, that symptoms of neuroglycopenia are the most prominent clinical manifestations of hyperinsulininemic hypoglycemia. Headache, confusion, diplopia, amnesia, bizarre behavior, slurred speech, stumbling, and seizures are common. A neuropsychiatric misdiagnosis is made initially in 2 0 % - 5 0 % of patients. 14 16 The symptoms occur episodically, characteristically at times of food deprivation or exercise, and are relieved by eating. Approximately 20% of patients gain weight by overeating to ameliorate their symptoms. 17 In adults, signs of neurologic impairment tend to be transient. However, severe, irreversible mental and motor retardation m a y result in adults and children if hypoglycemia is not recognized and treated promptly. The neurologic symptoms just described occur when there is a gradual decline in the blood glucose level over several hours. A rapidly falling blood glucose level, on the other hand, excites the release of epinephrine, resulting in tachycardia, apprehension, sweating, and tremor. These features are seen in only 17% of patients. ~ The diagnosis of hyperinsulinism is often delayed for many years because of the intermittent and nonspecific symptoms. In one large series 9 a correct diagnosis was made within a year of the onset of symptoms in 34% of cases, between 1 and 5 years in 46%, and after 5 years in 20%. Occasional patients have remained symptomatic for as long as 20 years before the true etiology of their complaints was recognized. 13 DIFFERENTIAL DIAGNOSIS OF HYPOGLYCEMIA 18"19

Hypoglycemia is not a disease, but rather a sign that something in the complex mechanism regulating glucose homeostasis has gone awry. The differential diagnostic possibilities are legion, and it is essential for the physician to have in mind an organized pathophysiologic framework to guide his or her thinking about these disorders. We find it convenient to consider first whether the hypoglycemia occurs in the fed or fasting state. Hyperinsulinism is among the causes of fasting hypoglycemia. POSTABSORPTIVE HYPOGLYCEMIA

Hypoglycemia in the fed state results from overutilization of glucose during the disposition of meals. The most common type 5

in adults is "functional" hypoglycemia, which occurs frequently in thin, young, emotionally unstable women with compulsive personality traits. Hypoglycemia occurs 2-4 hours after food ingestion. The mechanism remains obscure, although an altered neuroendocrine "set" has been postulated. Patients who have undergone gastrectomy or a gastric drainage procedure may develop symptomatic hypoglycemia from 11/2 to 3 hours postprandially due to rapid absorption of glucose, which excites an exaggerated insulin release. As blood glucose falls and the excess insulin is not buffered by continuing absorption of carbohydrate, reactive hypoglycemia ensues. Occasional patients with early diabetes mellitus have reactive hypoglycemia because of sluggish insulin release. The rise of immunoreactive insulin (IRI) levels trails behind blood glucose levels and excessive concentrations of the former are achieved 2-4 hours after meals, resulting in hypoglycemia. Infants may develop hypoglycemia after feeding because of hypersensitivity to the amino acid leucine, which causes excessive insulin release, or because of inherited enzyme defects (fructose-l-phosphate aldolase, galactose-l-phosphate uridyl transferase) which result in the accumulation of metabolites inhibitory to the resumption of glucose output by the liver after eating. The diagnosis of reactive hypoglycemia in adults is often facilitated by the oral glucose tolerance test. The oral leucine test is used to diagnose leucine hypersensitivity. Inherited enzyme defects are confirmed by assays for the appropriate enzymes. None of these postabsorptive causes of hypoglycemia should be confused with the organic causes of hyperinsulinism, which invariably cause symptoms after fasting. FASTING HYPOGLYCEMIA

Fasting hypoglycemia is much less common than reactive hypoglycemia. Mechanisms include deficient nutrient intake, deficient production of glucose, and glucose overutilization. Spontaneous hypoglycemia has been reported in chronically malnourished patients, i.e., those with kwashiorkor, marasmus, and severe anorexia nervosa. Spontaneous hypoglycemia is rarely seen in the absence of marked inanition. The capacity of the liver to produce glucose may be impaired by diffuse hepatoparenchymal disease and by inborn errors of metabolism such as glycogen storage disease, pyruvate carboxylase deficiency, fructose-l,6-diphosphatase deficiency, and phosphoenolpyruvate carboxykinase deficiency. Deficiencies of counter insulin glucoregulatory hormones (glucocorticoids, thyroid hormone, glucagon) may also contribute to impaired hepatic glucogenesis. 6

Idiopathic transient hypoglycemia is frequently seen in infants. Prematurity and low birth weight are predisposing factors, and it is thought that diminished hepatic glycogen stores from poor intrauterine nutrition may be an underlying cause. None of the disorders of glucose production listed above is associated with hyperinsulinism, which distinguishes them from the entities that are the major concern in this review. Overutilization of glucose, on the other hand, is caused by hypersecretion of insulin or by increased sensitivity to insulin. Hyperinsulinism is primarily associated with intrinsic abnormalities of the pancreatic beta islet cells--adenoma, adenomatosis, carcinoma, nesidioblastosis, and hyperplasia. Endogenous hyperinsulinism also occurs in the infants of diabetic mothers, due to fetal [~ cell stimulation by chronic exposure to hyperglycemia in utero, and in infants with erythroblastosis fetalis during exchange transfusion, presumably because of destruction of insulin by hemolyzed erythrocytes, leading to compensatory islet cell hyperplasia. In each of the latter two cases, hypoglycemia and hyperinsulinism remit spontaneously shortly after birth. Hyperinsulinism may result from exogenous insulin administration, either inadvertently or surreptitiously, or from ingestion of sulfonylureas. Patients are also described with high levels of IRI and anti-insulin antibodies, apparently an autoimmune disorder. It is postulated that the binding of insulin to antibody may be altered under certain circumstances, resulting in the excessive release of insulin at inappropriate times. Growth hormone deficiency increases the numbers and affinities of insulin receptor sites on circulating monocytes, which may be responsible for the increased glucose utilization of growth hormone deficiency. There is increased sensitivity to insulin, but plasma insulin levels are not elevated. Nonpancreatic tumors can cause hypoglycemia. Insulin levels are usually not elevated. Elaboration by the tumors of a nonsuppressible insulin-like humoral factor such as one of the somatomedins is found sometimes. LABORATORY FEATURES HYPOGLYCEMIA

The first step in the diagnosis of endogenous hyperinsulinism is documentation of fasting hypoglycemia. One way is to obtain a morning blood glucose level after an overnight fast (10 hours). In many patients with hyperinsulinism, this stimulus will provoke hypoglycemia. However, because of fluctuations in fasting glucose levels from day to day, it may be necessary to obtain several such samples. Fajans and Floyd found that in half of the patients with proved islet cell disease, overnight fasting blood

glucose levels were above 60 mg/dl on the first day of study, and in 18% of patients they continued so for 7 consecutive days, e~ In patients who do not readily develop hypoglycemia with overnight fasting, the fast should be continued for up to 72 hours, with vigorous exercise at the end if hypoglycemia has not developed. With fasting and exercise, 33% of patients with hyperinsulinism will exhibit symptomatic hypoglycemia within 12 hours, 80% within 24 hours, 90% within 48 hours, and 100% within 72 hours, 11 There is no definitely pathologic lower level of blood glucose. Whipple proposed a blood glucose level of less than 50 mg/dl as a part of the triad of features which he associated with hyperinsulinism. 6 Edis found that the glucose level at the time of hypoglycemic symptoms in his patients was invariably less than 40 mg/dl. 17 A study of healthy premenopausal women, on the other hand, has shown that 30% have glucose levels less than 40 mg/dl at some point during a 72~ fast, with occasional values dropping to as low as 30 mg/dl. 21 Interestingly, none of the healthy women was symptomatic from hypoglycemia. IMMUNOREACTIVE INSULIN

Measurement of fasting plasma insulin and blood glucose levels with calculation of fasting insulin/glucose ratios is the cornerstone of accurate diagnosis of endogenous hyperinsulinism, as it differentiates hyperinsulinism from other causes of fasting hypoglycemia. Because insulin secretion from beta islet cell lesions may be sporadic, it is often necessary to determine fasting insulin levels on several different days. Absolutely elevated insulin levels confirm the diagnosis but are not found in all patients with beta islet cell disease, owing in part to removal b~( the liver of some insulin before it appears in peripheral . blood. 2~ In patients with normally regulated insulin secretion, plasma insulin declines with plasma glucose during fasting, whereas in patients with pancreatic beta islet cell disease, insulin levels remain constant or rise in the face of hypoglycemia. Thus, plasma insulin levels can be inappropriate for prevailing plasma glucose levels without being outside the normal range. In 60 patients with insulinoma, Service et al. found that basal serum IRI levels were almost invariably greater than 6 ~U/ml in the presence of fasting hypoglycemia. 22 They found this criterion to be the single most accurate discriminant between endogenous hyperinsulinism and other types of hypoglycemia. Fajans et al. proposed using the ratio of IRI to plasma glucose (IRI/G) as a more sensitive diagnostic indicator in patients with mild abnormalities. In healthy nonobese males, the normal upper limit of the IRI/G ratio after an overnight fast was 0.3093 After 19 hours of fasting, all of 40 patients with pancreatic islet 8

cell disease developed significant and persistent elevations of the IRI/G ratio. 23 In obese subjects, the IRI/G ratio may be elevated because of hyperinsulinemia due to peripheral insulin resistance, b u t the fasting glucose remains normal. Other ratios, such as G/IR124 and the "amended insulin-glucose ratio" IRI x 100/(G - 30), e~ have been proposed. The latter decreases the number of false negative results but increases the false positives. Service has found none of the ratios to be as specific in excluding the diagnosis of endogenous hyperinsulinism as the finding of a serum insulin level of less than 6 ~U/ml during hypoglycemia (Fig 1). MEASUREMENT OF INSULIN ANTIBODIES AND C-PEPTIDE

Once the diagnosis of hyperinsulinism has been made, the diagnosis of an endogenous source, that is, beta islet cell disease, is established by ruling out factitious hyperinsulinism, which occurs from surreptitious self-administration of insulin. Longterm administration of porcine or bovine insulin can be detected by demonstrating circulating antibodies to those insulins. However, antibodies may not be detectable when insulin has been administered for less than 5 weeks, 2~ or when the new synthetic h u m a n insulin preparation (Humulin, Lilly) has been used. An alternative approach is to measure blood or urine levels of C-peptide, a 31-amino acid chain which is cleaved from proinsulin to form insulin. There is no C-peptide in the synthetic hum a n insulin preparation 26 or in the other, more conventional commercial preparations. C-peptide levels should be elevated in endogenous hyperinsulinism and suppressed in factitious hyperinsulinism. Measurement of C-peptide can also be useful in diagnosing endogenous hyperinsulinism in previously diabetic patients who

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Fig 1.--Simultaneous plasma glucose (G), mg/dl (horizontal axis), and serum immunoreactive insulin (IR), ~U/ml (vertical axis), measurements in patients with non-insulin-mediated hypoglycemia (X) and in insulinoma patients with low plasma glucose levels and normal but inappropriate levels of plasma immunoreactive insulin. Regression lines represent three G/IRI ratios considered diagnostic by others which are not sufficiently specific. (From Service et al.22 Reproduced by permission.)

have taken exogenous insulin. Circulating insulin antibodies in these patients interfere with measurement of serum insulin levels b u t have no effect on the C-peptide a s s a y Y Ingestion of sulfonylureas can produce hypoglycemia accompanied by elevated serum insulin levels. 2s Consequently, blood and urine should be screened for the presence of sulfonylureas to completely exclude factitious hyperinsulinism. PROINSULIN

Neoplastic beta islet cell tissue releases excessive proinsulin into the circulation. Elevated proinsulin levels, exceeding 25% of fasting total IRI (normal, 7.7% _+ 2.4%; range, 0%-20%) have been found in two thirds of patients with islet cell tumors. 29 Patients with islet cell carcinoma have very high proportions of proinsulin in p l a s m a - - 6 2 % and 76% of total IRI in two patients. 29 A raised proinsulin concentration has been used to establish the diagnosis of insulinoma in patients with low plasma IRI levels. 3~ PLASMA HUMAN CHORIONIC GONADOTROPIN

An elevated level of h u m a n chorionic gonadotropin (hCG) or its subunits in patients with endogenous hyperinsulinism is suggestive of the diagnosis of islet cell carcinoma. In one study elevated hCG levels were found in 63% of patients with malig~ nant islet cell tumors but in none of those with benign islet cell tumors. 31 The most useful measurement was hCG-~, which was abnormal in 57% of patients. Elevated immunoreactive hCG and hCG-~ levels were each found in approximately one fourth of the patients. 31 Stimulation and suppression tests have been devised to aid in the diagnosis of endogenous hyperinsulinism. In general, they are unnecessary if fasting hypoglycemia with relative hyperinsulinism has been demonstrated and factitious hyperinsulinism has been excluded. However, they m a y help to confirm or exclude the diagnosis in a few otherwise ambiguous cases. SUPPRESSION TESTS

In normal subjects, secretion of insulin, proinsulin, and C-peptide can be suppressed by giving animal insulin. However, patients with beta islet cell pathology produce these peptides autonomously, and there is a failure of hypoglycemia to suppress endogenous insulin release. The suppression tests are designed to be used in patients who have no diagnostic fasting hypoglycemia. 10

The C-peptide suppression test is as follows. Hypoglycemia is induced by the infusion of commercial pork insulin, 0.1 U/kg/ hour for 60 minutes or until hypoglycemic symptoms develop. Plasma C-peptide levels are measured at frequent intervals. At a glucose level of 40 mg/dl or less, normal subjects will have Cpeptide levels of 1.2 ng/ml or lower, whereas 92% of insulinoma patients have levels of 1.9 ng/ml or higher, a2 Proinsulin also provides good discrimination between hyperinsulinemic patients and control subjects. 2~ One advantage of the exogenous suppression tests over prolonged fasting is that the suppression tests may be performed on outpatients over a short time, whereas 72-hour fasting requires hospitalization. STIMULATION TESTS T o l b u t a m i d e T e s t 33

After overnight fasting, 1 gm of sodium tolbutamide dissolved in distilled water is infused intravenously over 2 minutes, provided that the plasma glucose level is above 50 mg/dl. Blood samples are taken every 15 minutes for the first hour and every 30 minutes in the second and third hours of the test. The best separation is achieved in the last hour of the test, with normal subjects showing return of plasma glucose levels to above 57 mg/ dl, whereas 97% of patients with insulinoma will have levels below 57 mg/dl (Fig 2). Discrimination using plasma insulin lev120iiiiii!i!ili!i~:.

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Fig 2.--Intravenous tolbutamide tests in 13 insulinoma patients. S h a d e d area and sofid line represent range and mean of values in normal subjects. Tolbutamide was given at time indicated by the arrow. (From Service et al.22 Reproduced by permission.)

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els is also best during the last hour of the test, with 85% of patients with hyperinsulinism showing an IRI level above 20 ~U/ml. Use of the formula G - 0.5 IRI at 150 minutes offers complete separation, beta islet cell adenoma patients having values below 43, and normal subjects values above 43. 22

Calcium Infusion Kaplan et al. ~4 developed the calcium infusion test, in which calcium gluconate (10 mg Ca + +/kg) is administered intravenously over a 2-hour period, following an overnight fast. Blood is drawn at 15-minute intervals and analyzed for glucose and IRI. In nine of ten patients with benign or malignant islet cell tumors, significant hypoglycemia (68 _+ 7 mg/dl ~ 31 __ 5 mg/ dl) and hyperinsulinism (38 -+ 8 ~tU/ml -* 87 _+ 28 ~U/ml) occurred within 60-90 minutes. Following successful removal of the islet cell tumors, the glucose and IRI levels failed to respond to calcium infusion. The one patient who failed to respond preoperatively had a basal glucose of 55 mg/dl and an IRI of 94 ~tU/ ml, which suggests that his tumor was secreting maximally at the start of calcium infusion. One patient with islet cell hyperplasia, five others with reactive, functional, or drug-induced hypoglycemia, and four healthy volunteers failed to show any change in glucose or IRI levels during calcium infusion. We used the calcium infusion test preoperatively and postoperatively to document the completeness of removal of islet cell adenomas. Most patients will fail to show calcium-stimulated insulin release after excision of an islet cell adenoma (Fig 3). However, one of our patients, whose adenoma was stellate and fragI

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Fig 3.--Plasma insulin and glucose levels after fasting and after calcium stimulation, before and after excision of a solitary islet cell adenoma. Note the normal glucose levels postoperatively and the failure of plasma insulin levels to rise with calcium stimulation postoperatively. (From Harrison et al? 5 Reproduced by permission.)

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mented on removal, had persistent release of insulin on calcium stimulation postoperatively, with no associated hypoglycemia (Fig 4). She had a normal IRI/G ratio of 0.15 after fasting 4 days. The data suggest that in her, the calcium stimulation test was a more sensitive diagnostic determinant than the fasting IRI/G ratio: 35 Recently a rapid calcium infusion test was described 36 in which 2 mg Ca + +/kg was infused over 1 minute and blood samples taken very early. Peak insulin levels occurred earlier and were higher than those reported after long calcium infusion. The total administered dose of calcium was also less. F u r t h e r investigation of this test is in progress at several centers. Glucagon and leucine have been used to provoke insulin secretion. They are generally considered less reliable than other stimulation tests, and we have no personal experience with them.

PREOPERATIVE LOCALIZATION Methods of preoperative localization of pancreatic islet cell tumors include highly selective arteriography, percutaneous transhepatic portal venous sampling at several sites with radioimmunoassay of portal venous plasma insulin, computerized tomography (CT), and ultrasound. E a c h of these techniques has

Fig 4.--Preoperative and postoperative blood glucose and plasma insulin in a 23year-old patient from whom a small beta cell adenoma was removed. Note the slight tendency to hypoglycemia postoperatively and persistence of stimulated insulin release. The patient is thought to have a diffuse islet cell dysplasia but has not required further surgery. (From Harrison et ai? ~ Reproduced by permission.) POST OP

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been used with varying degrees of effectiveness at different centers. Whether or not an insulin-secreting tumor is seen angiographically depends on the vascularity, size, and location of the lesion and the skill and experience of the angiographer. Angiographic accuracy ranges from 40% to 90% 9, 37,38; the best results have been reported by Fulton and colleagues at the Mayo Clinic. 3s The principles to which they attribute their success include demonstration of the complete blood supply to the area in question and the use of stereoscopic serial filming, magnification, and subtraction. Angiographic features suggesting insulinoma include a homogeneous vascular blush which persists into and through the venous phase, and, with large tumors, displacement of normal pancreatic vessels, vascular tortuosity, and neovascularity (Fig 5). The lower limit of resolution using this technique is approximately 1 cm. Fig 5.--A selective arteriogram showing the typical blush of a solitary islet cell adenoma. With rotation of the patient the lesion moved anteriorly and was found without trouble in the suggested location. The patient has been cured for 15 years following removal of the adenoma.

14

Transhepatic portal vein catheterization with radioimmunoassay of regionally sampled portal vein insulin levels was first described by Ingemansson et al. in 1975. 39 They subsequently reported on a series of five cases of hyperinsulinism in which the method was used successfully.4~ Angiography failed to demonstrate the lesion in three of those cases, including two with diffuse islet pathology. Cho et al. 41 recently reviewed the University of Michigan experience with transhepatic portal venous sampling. There were 12 patients, all of whom underwent arteriography, CT scanning, and transhepatic portal vein catheterization. Ten patients had solitary islet cell adenomas, one had an adenoma plus islet cell hyperplasia, and one nesidioblastosis. Arteriography and CT scanning were each successful in two cases, whereas transhepatic portal vein catheterization correctly indicated the site of the lesion in all 12. A localized step-up in insulin levels occurred at the site of the adenomas; multiple step-ups were seen in patients with diffuse disease (Fig 6). In 11 patients with adenoma, the mean insulin concentration at the t u m o r sites was 782 ~U/ ml (range, 64-2,600 ~U/ml), compared to 49 ~U/ml (range, 1655 ~U/ml) at nontumor sites. The mean insulin gradient (portal venous - arterial) was 633 IxU/ml (range, 39-2,547 ~U/ml) at tumor sites and 4.1 ~U/ml at nontumor sites. Subselective venous sampling was not required in any patient. There were no serious complications. CT scanning and ultrasound examination are much less reliable. Dunnick et al., of the NIH, 42 found the relative accuracies of the radiologic techniques to be as follows: angiography, 84%; CT, 43%; and ultrasonography, 25%. CT and ultrasound never demonstrated the lesion when angiography failed, and were ineffective with small lesions. CT scanning missed tumors 1-1.5 cm in diameter in the pancreatic head and up to 2.5 cm in diameter in the body and tail; sonography missed tumors 4 - 5 cm in diameter in the head and up to 8 cm in diameter in the body and tail. Some question the need for preoperative localization. Daggett and colleagues 43 found no technique was more t h a n 50% correct. Of 18 patients studied by angiography, which was their most accurate method of localization, lesions were correctly identified only in nine; however, all lesions were palpable at surgery. Furthermore, in his experience, 85% of insulin-secreting tumors were palpable at the first operation and an additional 11% at the second operation. They concluded t h a t present imaging techniques are not sufficiently precise to justify their routine use preoperatively. On the other hand, of the 16 patients with angiographically identified tumors studied by Fulton et al., in six the tumors were not palpable at surgery until the pancreatic capsule was incised 15

Fig 6.--A, venogram of the pancreatic head with superimposed regional superior mesenteric and portal venous insulin levels (~U/ml). A solitary adenoma was removed from the pancreatic head and the patient was cured. Concomitantly measured arterial insulin level was 206 ~U/ml. Concomitantly measured arterial insulin value was 38 ~U/mi. B, splenic venogram with superimposed plasma insulin values. A solitary adenoma was removed from the tail of the pancreas. (From Cho et al. 41 Reproduced by permission.)

16

at a site indicated by the preoperative study. 3s Four of these tumors were in the pancreatic head. We believe preoperative localization should be attempted in all cases. Selective angiography is the initial procedure of choice, and if it unequivocally demonstrates the tumor, there is probably little additional information to be gained by more tests. If the arteriogram fails to visualize the lesion, one should proceed with transhepatic portal vein catheterization, sampling for insulin levels at approximately 1-cm intervals in the splenic, superior mesenteric, and portal veins. One feature of the latter technique which might recommend its use in all cases is that it helps anticipate diffuse pathology, such as islet cell adenomatosis, hyperplasia, or nesidioblastosis. CT and ultrasound examination, at their present stages of development, are unlikely to be helpful if the other studies are negative. Mention should be made that ultrasound has been used successfully intraoperatively with small insulinomas. 44' 4~ The ultrasonic image of an insulinoma is one of a well-defined, hypoechoic mass with a smooth border which may deform, but does not infiltrate, surrounding structures. 45 The advantage of this method over the transcutaneous approach is that there are no intervening gas-filled structures, and consequently the resolution of the intraoperative ultrasound scan is better. Recently a radiolabeled murine monoclonal antibody A2B5, reacting across species lines, has been shown to bind to a membrane-associated GQ ganglioside common to peptide-secreting normal cells and tumors. ~ Radiation-induced insulinomas in rats have been imaged, and although there are major hindrances to imaging h u m a n insulinomas in vivo, this is clearly an exciting area for future investigation. PATHOLOGY AND PATHOPHYSIOLOGY The pancreatic beta islet cell disorders associated with hyperinsulinism include adenoma and carcinoma, most of which are unifocal; and adenomatosis, hyperplasia, and nesidioblastosis, which m a y involve the entire pancreas either focally or diffusely. Diffuse lesions are most common in children. Carcassone et al., reviewing 224 cases from the literature, reported an incidence of diffuse islet cell disease of 77% among infants and 26% among children over 1 year. No diffuse lesions were found in children more than 8 years o l d J v Until recently, the diffuse islet cell diseases were thought to be uncommon in adults and received little attention. We reviewed the experience with endogenous hyperinsulinism at two medical centers 4s and found diffuse islet cell disease in 17 of 77 patients (22%) (Table 1). 17

TABLE 1.--ENDOGENOUSHYPERINSULINISM* PATHOLOGY

SPORADIC

MEN-I

Solitary adenoma Diffuse Adenomatosis Nesidioblastosis Hyperplasia Islet cell carcinoma

55 13 (7) (4) (2) 3

1 4 (4) (0) (0) 1

Total

71

6

TOTAL(%) 56 (73) 17 (22) (11) (4) (2) 4 (5) 77 (100)

*From Harrison T.S., et al.: Prevalence of diffuse pancreatic beta islet cell disease with hyperinsulinism: Problems in recognition and management. World J. Surg., to be published. Reproduced by permission. SOLITARY PANCREATIC BETA CELL ADENOMA

The most common lesion associated with hyperinsulinism is solitary beta islet cell adenoma (Fig 7), which accounted for 73% of cases in our series and for 78%-84% of cases in several earlier reports.9-11, 14, 4s Adenomas are encapsulated. They range in size from 3 m m to 8 cm; most are 1.5 cm in diameter or less. l~ Solit a r y adenomas are evenly distributed in the pancreas. 9' 17, 21, 49 Some are reddish brown and soft; others are white and firm. Microscopically, islet cell adenomas are composed of small, uniformly sized cells arranged in trabecular networks, with anastomosing cords of cells separated by a b u n d a n t thin-walled vascular channels. Occasional ducts are seen. Amyloid m a y be found in the stroma. Capsular invasion, cellular pleomorphism, and the presence of mitoses do not necessarily indicate malignancy. PANCREATIC BETA CELL CARCINOMA

Malignant islet cell neoplasms account for 5%-15% of cases of hyperinsulinism.~-11, 13, 4s Insulin levels tend to be higher t h a n in patients with benign disease. 5~ Hepatic metastases are present in over 90% of patients at diagnosis, ~1 and frequently they can be detected by arteriography and confirmed by suitably directed percutaneous needle biopsy. The diagnosis is made when there are proved metastases or at least perineural invasion. 17 Sporadic islet cell carcinomas are aggressive and rarely, if ever, cured. PANCREATIC BETA CELL ADENOMATOSIS

Adenomatosis (Fig 8) was originally described by Frantz in 1944. 52 She reported on two patients in whom multiple macro78

Fig 7.--A, gross photograph of a palpable solitary hyperfunctioning beta islet cell adenoma. This lesion was removed from the pancreatic head of a 44-year-old man whose hyperinsulinism was cured. B, gross photograph of a nonpalpable solitary beta islet cell adenoma. This lesion was localized in the pancreatic neck by selective arteriography, and the patient, a woman in her 50s, was cured by excision of the adenoma without pancreatic resection. Without arteriography it would not have been possible to find the lesion so easily.

scopic adenomas coexisted with m a n y additional microscopic foci similar histologically. Frantz recognized that the residual pancreas probably was affected by this diffuse process, and that the possibility of persistent hyperinsulinism existed. Through the years, many patients have been reported with multiple adenomas. Among 951 beta islet cell tumors collected by Stefanini et al., 9 123 (13%) were multiple, and in over half of these, the number of adenomas ranged from four to eight. Simi19

Fig 8.--A typical pancreatic section showing enlarged and normal islet tissue in a patient with beta cell adenomatosis. The largest lesion was 2.2 cm in diameter. Eighty percent pancreatectomy has made adequate but not ideal control of the patient's hyperinsulinism possible. (From Harrison et al.49 Reproduced by permission.)

larly, in the Mayo Clinic experience from 1965 to 1975,17 five of 41 patients (12%) with insulinoma had multiple tumors. Two patients had multiple endocrine neoplasia type I. We believe that m a n y multiple adenoma patients in fact have adenomatosis, with macroscopic and microscopic lesions coexisting. Interestingly, microadenomatosis was said to have been absent in the Mayo Clinic patients referred to above, and it is rarely mentioned in other series. However, among our 77 hyperinsulinism patients, there were six with microadenomatosis, three in combination with macroadenomas and three with islet cell hyperplasia. Three additional patients have had multiple macroadenomas, and one has had macroadenoma with hyperplasia. Thus, over half of the patients with multiple adenomas also had diffuse microscopic disease, which would not have been adequately treated by simple excision of the macroadenomas. A case in point is that of a 34-year-old woman who developed symptoms of severe recurrent hyperinsulinism 2 weeks after removal of a 2.5-cm-diameter islet cell adenoma. At reexploration, no lesion was palpable, and 80% distal pancreatectomy was performed. On sectioning the specimen, several small adenomas were visible, and microscopic examination revealed microaden2O

omatosis. The patient's hypoglycemia has been controlled adequately on diazoxide t r e a t m e n t for 12 years postoperatively. The only certain identification of microadenomatosis is by frozen section microscopy of the resected pancreas. This is often difficult for the pathologist but should be tried in every patient in whom no lesion can be found at exploration and in those with multiple macroadenomas. BETA ISLET CELL HYPERPLASIA

An increase in both the number and size of the islets of Langerhans, with normal intralobular distribution, is the typical appearance of beta islet cell hyperplasia (Fig 9). Although the entity has been described primarily in neonates, several authors have reported adult cases. 13' 53 In the series of 1,067 patients collected from the literature by Stefanini et al., there were 70 (6.5%) with islet cell hyperplasia. Interestingly, they noted that when blind distal pancreatectomy was performed, often the only disorder recognized in the specimen was diffuse islet cell hyperplasia. 9 This supports our contention that diffuse sources o f h y perinsulinism are more prevalent than is commonly recognized. We have seen two patients with hyperinsulinism in whom the only pancreatic abnormality was islet cell hyperplasia, and four with hyperplasia in combination with adenomatosis, as previously discussed. The lesion was not recognized on frozen section microscopy in any of these patients. NESIDIOBLASTOSIS

Originally described by Laidlaw in 1938, 54 nesidioblastosis refers to a diffuse or disseminated proliferation of islet cells from pancreatic ductal epithelium. The endocrine cells are found randomly or in small clusters near ductal epithelium and within exocrine acini (Fig 10). They are best seen with immunocytochemical techniques. Nesidioblastosis is thought by many to be the normal mode of islet formation in the fetus, s5-57 Its relationship to hyperinsulinemic hypoglycemia, however, has been hotly debated. The first association was made by Brown and Young in 1970, 5s and numerous other reports have subsequently appeared. Some believe nesidioblastosis is the most frequent cause of persistent neonatal hypoglycemia, s9 It has also been reported as a cause of hyperinsulinism in adults., 6~ 61 Heitz et al. ~2 used immunocytochemistry and electron microscopy to study seven surgical specimens from infants with hyperinsulinemic hypoglycemia. They found a fivefold increase in the mean total area occupied by endocrine tissue compared to agematched control specimens. The ratio of beta cells to other en21

Fig 9.--Hyperplasia: A, low power, and B, higher power fields in a 50-year-old woman with endogenous hyperinsulinism. The islets visible are uniformly enlarged with increased numbers of islet ceils. The patient is well controlled by 85% pancreatic resection. docrine cells was the same in both groups. Budding from ductular epithelium and interposition of endocrine cells between duct u l a r epithelial cells were prominent findings in all cases. "Multifocal ductulo-insular proliferation," or infiltration of exocrine parenchyma by endocrine cells, was observed in five cases. There was one case each of focal adenomatosis and solitary ad22

Fig 10.--Nesidioblastosis. A, in a child of 9 years, islet cells are seen in increased number in close conjunction with a pancreatic duct. B, in another part of the pancreas of the same patient the islet cells are totally dispersed among exocrine pancreatic cells. Ninety percent pancreatectomy imperfectly controlled this child's hyperinsulinism.

enoma. Heitz et al. suggested that all of these patterns of endocrine proliferation were variants of nesidioblastosis, resulting from continued development of the endocrine fetal pancreas beyond birth. They considered the increased beta cell mass to be the anatomical basis of infantile hyperinsulinism. 23

Shermeta et al., 63 in a similar vein, described a hyperinsulinemic neonate in whom a combination of features of pancreatic islet hyperplasia, adenomatosis, and nesidioblastosis was observed. Drawing on the work of Liu and Potter, 56 they outlined the two generations of islet cells which evolve in the embryologic development of the endocrine pancreas (Fig 11): During the eighth week of gestation, islet cells detach from the primitive pancreatic ducts and coalesce within the connective tissue of the interlobular septum to form the primary islets, which degenerate and disappear during the fifth to seventh months. In the sixteenth week, the secondary islets, located in the center of the pancreatic lobules, arise from centroacinar ductule cells. Initially there are equal numbers of alpha and beta cells, but the former undergo degeneration during the seventh month to produce the typical adult configuration of a central core of beta cells surrounded by a mantle of alpha and delta cells. Shermeta proposed t h a t nesidioblastosis represents persistence of the differentiation of islet cells from ductal epithelium; adenomatosis is an abnormal continuation or overgrowth of prim a r y islets within the interlobular septa; and hyperplasia is an excessive growth of secondary islets in the normal intralobular distribution (Fig 12). Functionally, according to this interpretation, there is a persistence of i m m a t u r e glucose receptor sites on the beta cells which are unresponsive to changes in blood glucose concentration, a condition similar to t h a t which exists in the fetus. Fig 11,--Normal differentiation of ductal epithelium and islet cells with subsequent degeneration of islets. (From Shermeta et al. 63 Reproduced by permission.) Gestation '-8 weeks

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Hirsch et al., 64 on the other hand, finding small nests of pure beta cells arising from the pancreatic ducts, as well as single endocrine cells scattered throughout the exocrine pancreas, postulated that in nesidioblastosis, beta cells are deprived of the usual interaction which results from the normal intricate juxtaposition of alpha, beta, and delta cells within the islets of Langerhans. Thus, he reasoned, disruption of the paracrine relationship might be responsible for dysregulated insulin secretion in these patients. Polak and Bloom 6~ described a change in the ratio of insulinto somatostatin-secreting cells from 2:1 in the normal neonate to 5:1 in infants with nesidioblastosis. There was also a loss of the normal close anatomical relationship between the two cell types. The somatostatin content of the pancreas of hyperinsulinemic neonates was less than half that seen in controls, which suggests that somatostatin deficiency is a major feature of the disease. In support of this view, Hirsch et al. 64 demonstrated a dosedependent rise in blood glucose and a concomitant suppression of serum insulin in an infant with nesidioblastosis in response to continuous intravenous infusion of somatostatin. Some authors, however, discount the notion that nesidioblastosis is a morphological substrate of neonatal hyperinsulinism. Jaffe et al., 66 for instance, compared the pancreases of ten hy25

perinsulinemic infants with autopsy controls and found no increase in the total endocrine volume in the former group. Furthermore, nesidioblastosis was common to both groups and decreased with age. Similarly, Gould et al., 67 although finding an apparent increase in total endocrine volume in pancreases of hyperinsulinemic infants, noted that in at least one control case, the total endocrine cell volume was comparable to that seen in hypoglycemic infants. The ratios of insulin/somatostatin/glucagon cells were similar in both groups. Features of intermingling of endocrine with exocrine elements, maldistribution of endocrine cells, and irregularly defined islets were common to both groups. Gould et al. 67 suggested that the discrepancies among the various studies of nesidioblastosis m a y be due to inadequacy of current immunohistochemical methods to reflect faithfully the complexities of the endocrine cell populations present in the pancreases of hypoglycemic infants, or to the fact that the controls' pancreases were derived from unhealthy infants and therefore a variety of factors m a y have influenced the status of the endocrine tissue without resulting in a clinical hormonal syndrome. Further investigation is needed to clarify the problem. It is not known w h y adults develop nesidioblastosis. However, the process has been described in association with cystic fibrosis of the pancreas, 68 chronic pancreatitis, 69 and in patients with sulfonylurea-treated diabetes mellitus. ~~ Hyperplasia and neoformation of islets have been reported in association with cirrhosis and atrophy of the pancreas due to obstruction of the pancreatic duct by stones, congenital atresia, and tumors of the pancreatic head. 71 In experimental animals, nesidioblastosis has followed libation of the pancreatic duct. 72' 73 Laidlaw, 4 in his original description of nesidioblastosis, supported Bensley's view that pancreatic duct epithelium is totipotent and able to differentiate into acinar cells, islet cells, or branching ducts. He further maintained that the duct epithelium retains this totipotency throughout life, as shown by the regeneration of the complete pancreatic structure after ligation of the ducts in the rabbit: The islet tumors may be regarded as a reaction of the duct epithelium to a stimulus that has called forth its duct building and islet building potencies, leaving the acinus building potency in abeyance. This explanation remains plausible 45 years later. However, the nature of the stimulus still is not known. MIXED ENDOCRINE TUMORS OF THE PANCREAS

Until recently, most pancreatic endocrine tumors were thought to be composed of a single islet cell type, based on the 26

histologic characteristics of the tumors and the clinical symptoms. However, the introduction of radioimmunoassay techniques for measurement of various plasma hormone levels and the application of immunocytochemical methods in the analysis of tissue specimens have revealed that, in many cases, pancreatic endocrine tumors are of mixed cell types. Heitz et al. TM studied 125 pancreatic endocrine tumors using immunocytochemistry. The tumors were classified according to the clinical symptoms produced and the finding of elevated plasma levels of the hormone responsible for inducing the symptoms. In 15 of 23 cases of benign insulinoma, multiple immunoreactive peptides were identified within the tumor, glucagon and pancreatic polypeptide (PD) being the most common after insulin. Two of four malignant insulinomas were multihormonal (Table 2). Similarly, insulin immunoreactivity was found in 31 of 98 pancreatic endocrine tumors other than insulinoma. Proliferation of ductules and nesidioblastosis were regularly found in normal pancreatic tissue adjacent to the tumors. In 80% of specimens from extensive pancreatic resections, "budding off' of endocrine cells from ductules could be observed in areas distant from the tumor. Despite the presence of various peptides in pancreatic endocrine tumors, the clinical symptoms are usually attributable to the inappropriate secretion of a single hormone. However, the coexistence of two functionally distinct tumors, insulinoma and glucagonoma, has been reported, with islet cell hyperplasia and nesidioblastosis being present in the surrounding pancreas, v~ Transformation of an insulinoma syndrome into a glucagonoma after streptozocin chemotherapy of a malignant islet cell tumor has been described, v~ Larsson 7v found an increased frequency of PP cells, which he terms "pancreatic polypeptide hyperplasia," in the extratumoral pancreatic tissue of five of nine patients with insulinoma. In two cases, islets composed almost entirely of P P cells were encountered. PP cells were frequently seen in ductal epithelium, and buds of these cells were occasionally encountered, suggesting a ductal origin of the P P hyperplasia. There were no clinical symptoms associated with the hyperplasia. Hyperplasia of PP TABLE 2.--IMMUNOCYTOCHEMICALFINDINGS IN 27 CASES OF INSULINOMA* INSULINOMA

N

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23 4

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*From Heitz P.U., K a s p e r M., Polak J.M., et al.: Pancreatic endocrine tumors: I m m u n o c y t o c h e m i c a l a n a l y s i s of 125 tumors. Hum. Pathol. 13:263-271, 1982. Reproduced by permission. tSomatostatin SPancreatic Polypeptide 27

cells has also been described in juvenile-onset diabetics 7s and in alloxan diabetic rats. 79 This may be a nonspecific response occurring in various pancreatic disorders. However, because the hyperplasia is so frequently associated with endocrine pancreatic tumors, it is mandatory that the presence of such a tumor be excluded, and that the hyperplastic islets be shown by immunocytochemical staining to be composed primarily of beta cells, before hypoglycemic symptoms are ascribed to islet cell hyperplasia alone, s~ Knowledge that other pancreatic endocrine tumors frequently occur in association with islet cell tumors, suggests that the islet cell tumors and the diffuse islet cell disorders might represent different expressions of a common tendency to neoplastic proliferation by mulipotent stem cells in the pancreatic ductules. It is not known whether the finding of multicellular tumors represents a proliferation of all of the endocrine cell types, with eventual achievement of dominance by one, or whether a substance produced by a single neoplastic cell line is responsible for the stimulation of other cell types (e.g., stimulation of alpha cells by hypoglycemia induced by overproduction of insulin by an insulinoma). NONPANCREATIC TUMORS

A number of extrapancreatic tumors are associated with fasting hypoglycemia. According to Laurent et al., mesenchymal tumors, such as fibrosarcoma, rhabdomyosarcoma, leiomyosarcoma, and fibroma, are most common, accounting for approximately 45% of reported cases. Hepatoma, adrenocortical carcinoma, gastrointestinal carcinomas, lymphoma, and miscellaneous other tumors round out the list. The tumors are often of low-grade malignancy, grow slowly, and frequently achieve enormous size. Symptoms are primarily those of neuroglycopenia. Several hundred cases have been reported. Many authors believe that the hypoglycemia observed in patients with extrapancreatic tumors is due to the production of excess insulin by the tumor, a situation analogous to the ectopic production of ACTH by visceral carcinomas, or of secretion of antidiuretic hormone by oat cell carcinomas of the lung. The finding by Oleesky et al. s2 in 1962 of elevated immunoreactive insulin levels in a patient with fibrosarcoma and hypoglycemia lent support to this hypothesis. However, others have rarely been able to demonstrate elevated levels of insulin in the blood or in tissue from patients with nonpancreatic tumors. Skrabanek and Powell s3 critically reviewed the evidence for ectopic insulin production in 1978. Using five criteria of ectopic hormone production--greater concentration of hormone in the tumor than in the surrounding normal tissue, immunohisto28

chemical localization of insulin in tumor tissue, normalization of insulin and of blood glucose concentrations after removal of the tumor, arteriovenous gradient of insulin concentration across the tumor bed, and production of insulin by incubation of tumor slices in v i t r o - - t h e y were unable to find any patient among 120 reported in the literature satisfying two or more criteria. Furthermore, Skrabanck and Powell found that, of the patients reported to have hyperinsulinism associated with an extrapancreatic tumor, several were subsequently shown to have coexisting islet cell pathology or pancreatic "metastases." In other cases, no conclusions could be made about the state of the pancreas because autopsies were not performed. The authors urged that the concept of ectopic insulin production and storage by nonpancreatic tumors be discarded for lack of supporting evidence. Shetty et al. s4 tried to resurrect the idea of ectopic insulin production with his case report of a patient with pelvic sarcoma and hypoglycemia. P l a s m a insulin levels of 30 ~U/ml (normal, 6 . 5 34 ~U/ml) were inappropriate for prevailing hypoglycemia with a glucose of 18 mg/dl on an intravenous glucose infusion. Resection of the tumor resulted in hyperglycemia (568-905 mg/dl) for 21/2 hours before the patient died. Radioimmunoassayable insulin, 227 pg/gm, and proinsulin, less than 20 pg/gm, were detected in tumor tissue, and secretory granules were present in tumor cells: No islet cell histopathology was found in the pancreas at autopsy. Although this case does apparently satisfy two of the criteria listed above, we still caution that the weight of evidence is against ectopic insulin production in the majority of cases of nonpancreatic tumors with hypoglycemia. The pathogenesis of hypoglycemia associated with extrapancreatic tumors h a s not been clearly established. However, several mechanisms have been proposed. One is that glucose stores are depleted because of overutilization of the substrate by the tumor. Excessive glucose uptake by tumor tissue slices has been demonstrated in a few cases, s5 It is also known that hypoglycemia m a y occur as a terminal manifestation of malignancy, due to malabsorption, cachexia, or grossly impaired liver function. Recently, interest has focused on the secretion of hypoglycemic humoral factors other than insulin by extrapancreatic tumors. One such factor is nonsuppressible insulin-like activity (NSILA). Only about 10% of total plasma insulin-like activity is due to IRI and proinsulin. The bioactivity of insulin is suppressible with anti-insulin antibodies. That insulin bioactivity that is n o t suppressible by anti-insulin antibodies is referred to as NSILA and consists of two components, one which is soluble in acid ethanol (NSILA-s) and another which is precipitated in acid ethanol (NSILA-p). In the normal plasma, free NSILA-s exerts 29

insulin-like activity that is quantitatively similar to that of insulin itself. 86 Megyesi et al. s7 have demonstrated the presence of elevated circulating levels of NSILA-s in five of seven hypoglycemic patients with non-islet cell tumors. Plasma NSILA-s was not elevated in four patients with similar tumors but without hypoglycemia, in three patients with insulin-induced hypoglycemia, in two with acromegaly, or in three with hypopituitarism. High levels of NSILA-s have also been demonstrated in extracts of a non-islet cell tumor from one of these patients, suggesting that "' l i. ~ ss NSILA-s is produced by the tumo r lrse Skrabanek and Powell s3 suggested that some tumors might produce a growth factor with insulin-like activity, which would account for both the large size of the tumors and the hypoglycemia. In support of this, they cite the structural homology of nerve growth factor (NGF) with insulin, s9 the finding that NGF secretion may be a general property of fibroblasts, 9~ and the fact that insulin, proinsulin, NSILA-s, and somatomedin A all compete for the same receptor on the h u m a n fibroblast. 91 Smith et al. 92 reported a case of Hodgkin's disease with hyperinsulinism and hypoglycemia. Subtotal pancreatectomy with excision of adjacent Hodgkin's disease relieved the hypoglycemia and the hyperinsulinemia. They proposed that proximity of the tumor to the pancreas and negative immunoperoxidase staining of the tumor for insulin favored direct stimulation of pancreatic endocrine secretion by the adjacent tumor, possibly via autonomic nervous pathways. There was no increase in beta cell activity within the pancreatic specimen to suggest hypersecretion. Previous cases of hyperinsulinism attributed to peripancreatic disease have had histologic evidence of islet cell hyperplasia, vl MULTIPLE ENDOCRINE ADENOMATOSIS Beta islet cell disease may be a feature of multiple endocrine adenomatosis type I (MEA-I). Pancreatic islet cell tumors are present in approximately 80% of patients with MEA-I, and 40% of patients with pancreatic involvement have beta islet cell lesions. 93 Conversely, the incidence of MEA-I among 951 cases of beta islet cell tumors of the pancreas was 4% in a collected series, with parathyroid involvement in 16 patients, pituitary disease in ten, adrenocortical lesions in ten, and thyroid disorders in three. 9 Among 72 patients with hyperinsulinism at the Mayo Clinic, four (5.5%) had MEA-I. 11 Three of eight patients with multiple adenomas were in this group, as was one patient with a single adenoma. Multifocal islet cell disorders are particularly frequent in MEA-I patients. Included among six MEA-I patients with beta islet cell disease we recently reported in a combined series are 3O

one with a solitary adenoma, one with multifocal islet cell carcinoma, and four with adenomatosis (two with multiple macroadenomas, one with a single adenoma and microadenomatosis, and one with multiple adenomas and islet cell hyperplasia). 4s Nevertheless, more cases of multifocal islet cell disease occur sporadically than as part of a familial syndrome. Islet cell carcinoma associated with MEA-I is generally much more indolent than the sporadic variety. One of the University of Michigan Hospital's patients has done well for 15 years after undergoing a distal pancreatectomy and resection of a second focus of tumor from the pancreatic head. 4s Plasma levels of h u m a n pancreatic polypeptide have been found elevated in half of patients with insulinoma, either because there are hyperplastic PP cells in pancreatic tissue surrounding the beta cell adenoma, or because the tumor is a mixed cell type, composed of both beta cells and PP cells. 94 Interestingly, elevated PP levels were found in each of three patients with MEA-I. Elevated levels of PP m a y indicate the presence of MEA-I in family members who are otherwise without evidence of involvement. 2~ SURGICAL MANAGEMENT

Operative removal of the hyperfunctioning beta islet cell tissue is the treatment of choice, offering the only chance for permanent cure of hyperinsulinism. Solitary benign adenomas can be removed by enucleation, or by distal pancreatectomy when they occur in the body or tail of the pancreas. A 7 5 % - 8 5 % distal pancreatic resection is usually required to control diffuse beta islet cell lesions. Although this m a y not cure the patient, it enables satisfactory m a n a g e m e n t of hypoglycemia with a low carbohydrate diet and diazoxide. Preoperatively, dextrose should be infused intravenously to prevent hypoglycemia. We use an upper transverse incision because it provides superior exposure. The gastrocolic omentum is divided and the pancreas is mobilized by dividing the peritoneum at its inferior aspect and thorough mobilization of the duodenum. Careful bidigital palpation of the entire substance of the gland is always performed, even if preoperative studies have localized an adenoma, in order to exclude the presence of multiple lesions. When intraoperative ultrasound equipment is available, sonography m a y supplement the digital examination. If an adenoma is found in a superficial location, several capsular sutures of fine silk are placed circumferentially around the perimeter of the mass, the pancreatic capsule is incised, and the tumor is teased out using gentle blunt and sharp dissection. A small closed suction drain is placed in the vicinity of the residual crater in the pancreatic substance. 31

Alternatively, if the tumor is deeply placed within the substance of the body or tail of the pancreas, in close proximity to the main pancreatic duct, it m a y be safer to perform a distal pancreatectomy, dividing the gland j u s t to the right of the tumor. There is almost never an indication for pancreaticoduodenectomy for benign adenomas of the head of the pancreas because of the substantial morbidity and mortality associated with pancreaticoduodenectomy. If a lesion cannot be felt in the pancreas, ectopically located pancreatic tissue should be sought, Performance of a small duodenotomy permits palpation of any submucosat or periduodenal nodules which might be present. If this is unrewarding, we go ahead with 75%-85% distal pancreatectomy, with the following rationale in mind: (1) the 22% of patients with diffuse islet cell disease can be adequately diagnosed by examination of the resected pancreatic specimen and, in most cases, their symptoms are rendered more manageable on drug regimens ineffective before pancreatic resection (review of our complications does not suggest that distal pancreatic resection carries greater morbidity than does simple excision of an adenoma49); and (2) since solitary adenomas are distributed equally throughout the pancreas, theoretically there is a 75%-85% chance of finding an occult lesion. Others argue that, in reality, occult tumors are most often found in the head of the pancreas, 9' 95 probably because this region is the most difficult to examine, the tumors there tending to be more deeply situated than those in the body and t a i l For this reason, blind pancreaticoduodenectomy has been advocated by some. 9~ Others have recommended progressive resection of the pancreas beginning at the tail, with serial sectioning and histologic examination, which m a y require removal of up to 95% of the gland. 97' 9s We think blind pancreaticoduodenectomy carries unacceptably high morbidity and mortality without guarantee of success, and that progressive resection beyond 75%-85% risks serious endocrine and exocrine insufficiency, sometimes needlessly, as when diffuse islet cell disease is present but not appreciated on frozen section microscopy. If multiple adenomas are detected, we believe that a portion of the tail of the pancreas should be resected and examined microscopically for adenomatosis, which is almost always present, necessitating 75%-85% pancreatic resection. TREATMENT OF HYPERINSULINEMIC HYPOGLYCEMIA IN THE NEONATE

Hyperinsulinism accounts for approximately 60% of neonatal hypoglycemia persisting beyond the first 2 weeks of life. 99 The 32

diagnosis is made on the basis of elevated plasma IRI levels, or an IRI/G ratio greater than 0.3, as in adults. Radiographic localization procedures need not be attempted preoperatively, as they are exceedingly difficult to perform in the neonate and are unlikely to be helpful in guiding therapy. An initial attempt should be made to control the hypoglycemia pharmacologically with diazoxide. Spontaneous remissions of hyperinsulinism have been observed in infants, and the potential for remission may be indicated by the relative ease of control of hypoglycemia by diazoxide, l~176 When the patient continues to have hypoglycemia despite intensive medical therapy, prompt surgical intervention is indicated to minimize neurologic sequelae. Because of the frequency with which diffuse b e t a islet cell disease occurs in infants, a 75%-85% distal subtota~ pancreatectomy, with preservation of the spleen when possible, is sometimes recommended as the initial procedure of choice in all cases of neonatal hyperinsulinism. 1~ lo2 However, symptoms of hypoglycemia may persist in as many as half of patients subjected to this form of surgical treatment, l~ lo3 H a r k e n et al. advocate "total" pancreatectomy without duodenectomy as the definitive step in cases where there is a failure of subtotal pancreatectomy. 1~ Hypoglycemia is usually eliminated, b u t at the expense of endocrine and exocrine pancreatic insufficiency and therefore requiring insulin and pancreatic enzyme replacement, probably throughout a lifetime. Shermeta et al. 1~ studied three patients with nesidioblastosis not cured by 95% subtotal pancreatectomy. Despite persistence of hypoglycemia, none of the children had elevated serum insulin levels during fasting. There was an appropriate rise in serum insulin levels in response to hyperglycemia induced by multiple gavage feedings of glucose. Intravenous injection of glucagon (0.1 mg/kg) resulted in rapid rise in serum glucose levels in two patients. Based on these findings, Shermeta suggested that the recurrent hypoglycemia might not be due to insulin excess, but rather to an iatrogenic hypoglucagonism, in which case "total" pancreatectomy might not be appropriate. It should be noted that serum glucagon levels were not measured. Aynsley-Green et al. 1~ documented, preoperatively, low plasma glucagon levels and a hyperglycemic response to glucagon injection in a hyperinsulinemic neonate with nesidioblastosis. The patient did not respond to 95% pancreatectomy at age 3 months, and subsequently was cured by total pancreatectomy. Thus, it appears t h a t the "hypoglycagon state" in Shermeta's patients m a y not have been iatrogenically induced, but rather may be one of the features of nesidioblastosis in some neonates. Further evaluation of hormone secretion by the endocrine pancreas in these patients is clearly needed. Meanwhile, when hy33

poglycemia persists after subtotal pancreatectomy and is uncontrollable with intensive medical therapy, total pancreatectomy seems appropriate. INTRAOPERATIVE PLASMA GLUCOSE MONITORING

Some authors recommend intraoperative monitoring of plasma glucose levels to confirm removal of all hyperfunctioning islet tissue, which supposedly would be signaled by detection of Fig 13.--A, at time 0, removal of a solitary islet celt adenoma is followed by progressively increasing blood glucose levels, 29 mg/ml/hour, in 16 patients receiving no intravenous glucose. These patients were all cured of their hyperinsulinism, B, in patients with retained hyperfunctioning islet cell tissue a glucose increment, 24 mg/ml/hour, is seen following surgery. Art required continued therapy but were improved by surgery. (From Harrison et al.49 Reproduced by permission.) 250

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Post-Excision

a hyperglycemic rebound. 1~176 However, cases are described in which elevations of blood glucose levels in patients with retained hyperfunctioning islet tissue are similar to those seen after removal of solitary adenomas (Fig 13). 49 Conversely, 23% of patients in the Mayo Clinic experience registered false negative responses, in which hyperglycemic rebound was delayed more than 90 minutes after complete tumor r e m o v a l 9 9 We do not base operative decisions on the plasma glucose level. However, persistent hypoglycemia in the postoperative period usually does indicate residual hyperfunctioning islet cell tissue. BETA ISLET CELL CARCINOMA

If metastases can be documented nonoperatively, as by CT scanning and percutaneous liver biopsy, surgical intervention is not indicated, as the disease is incurable, and the patient can be medically managed with diazoxide and streptozocin. Occasionally biliary or gastrointestinal bypass will be needed when a large tumor mass causes obstruction. Metastases encountered at exploration for presumed benign disease, need only be biopsied. In the absence of metastases, appropriate resection should be done, even though it rarely cures sporadic islet cell carcinoma. Malignant islet cell tumors associated with MEA-I are more indolent, as previously mentioned, and long-term survival is not uncommon. SURGICAL COMPLICATIONS

Surgical mortality in a large combined series was 6.7% for first interventions and 18% for reinterventions. 9 There were no operative deaths in 72 patients treated at the Mayo Clinic. ~ Immediate postoperative complications occur in 1 5 % - 2 0 % of patients and include pancreatic pseudocyst, pancreatitis, intra-abdominal sepsis, pancreatic fistulas, and gastrointestinal tract obstruction.11' 49 PHARMACOLOGIC CONTROL OF HYPERINSULINISM Diazoxide (Proglycem), a nondiuretic thiazide with antihypertensive activity, induces hyperglycemia t h r o u g h direct inhibition of insulin release by pancreatic beta cells, and also decreases peripheral glucose utilization. 11~ The response is not seen in all patients, however. Berger et al. m correlated suppressibility of IRI by diazoxide with the morphological characteristics of abundant well-granulated typical beta cells, a trabecular architecture, and uniform insulin immunofluorescence. They suggest that diazoxide m a y interfere with the release of insulin 35

by exocytosis from m a t u r e beta cell granules. Because certain patients do not demonstrate suppressibility of IRI by diazoxide, some suggest that diazoxide infusion tests be performed preoperatively to assess the effectiveness of the drug in a given patient. Knowing that a patient is unresponsive, the surgeon would be inclined to be more aggressive. Side effects of diazoxide include sodium retention, with edema at higher dosages, nausea, and hirsutism. The combination of trichlormethiazide, a natriuretic benzothiadiazide, in dosages of 2-8 mg/day, helps minimize sodium retention, and also synergizes the hyperglycemic effect of diazoxide. 2~ Diazoxide, at dosages of 150-1000 mg/day, has proved the most effective agent for controlling hypoglycemic symptoms when surgical cure is not possible because of diffuse islet cell pathology or retained adenoma. Dyphenylhydantoin (Dilantin), 300-600 mg/day, inhibits insulin release from pancreatic beta cells in vitro. However, the hyperglycemic effect of this drug is clinically significant in only one third of patients. 2~ Propranolol (Inderal), chlorpromazine, and somatostatin have each been effective in relieving h y p o ~ c e m i c symptoms in case reports of hyperinsulinemic patients, o, 112 None of these drugs has been widely used. Continuous intravenous glucose is effective temporarily in checking hypoglycemia. Glucocorticoids (cortisone acetate, 100200 mg/day) may also be helpful and frequently potentiate the effectiveness of other agents, but their effect wears off in a few weeks. The long-term side effects of steroid therapy are well known. Glucagon may raise the blood sugar level, but that may stimulate further pancreatic insulin release. 2~ CHEMOTHERAPY IN THE MANAGEMENT OF METASTATIC MALIGNANT INSULINOMA

The most effective tumoricidal agent for pancreatic islet cell carcinoma is streptozocin, a broad-spectrum methyl, nitrosourea-glucosamine antibiotic with specific islet cell toxicity. Streptozocin is administered daily in doses of 1-2 gm/m 2. Among 52 patients treated with this drug in one series,Srthere was a 64% favorable biochemical response rate, with 50% of patients showing objective reduction in tumor mass and 17% showing complete remission. The median survival of responders was 3.5 years; two and one-half times that of nonresponders. The major toxicity occurred after 2-3 weeks of treatment, at a total drug dose of 2-4 gm/m 2, and consisted of renal tubular damage (65%), hepatotoxicity (67%), and bone marrow suppression (20%). Five patients died in renal failure, and nausea and vomiting were seen almost universally after treatments. 36

In another study, 113 the combination of streptozocin plus fluorouracil was found to be superior to streptozocin alone. Combination therapy produced a 63% overall response, versus the 36% response achieved when the single agent was used, and complete response rates were 33% and 12%, respectively. A surVival advantage was noted with the combination, but it was not statistically significant, A recent study of doxorubicin, 60 mg/m 2 every 3 - 4 weeks, in the t r e a t m e n t of advanced islet cell carcinoma demonstrated a 20% objective response lasting 2-301/2 months. 114 All patients had previously failed t r e a t m e n t with other chemotherapies. CONCLUSIONS

Endogenous hyperinsulinism should be recognized as a cause of fasting hypoglycemia in patients of all ages. Although the entity has been recognized for over half a century, our understanding evolves slowly, and there is still much to be learned about etiology and treatment. The diagnosis of hyperinsulinism was made more precise by radioimmunoassay of plasma insulin. The diagnosis is virtually certain when plasma IRI levels above 6 ~U/ml are observed in the presence of fasting hypoglycemia, provided that factitious and autoimmune causes of hyperinsulinism are satisfactorily excluded. Studies of glucose and insulin responses to infusions of calcium or tolbutamide m a y offer added support for the diagnosis but usually are unnecessary. Preoperative localization of islet cell adenomas or carcinomas is possible in 90% of patients if sophisticated angiographic techniques are used. Transhepatic portal venous catheterization with m e a s u r e m e n t of regional insulin levels m a y help localize focal lesions not seen angiographicalty and m a y suggest the diffuse sources of hyperinsulinism. Noninvasive techniques are generally unreliable, but ultrasound examination, when performed intraoperatively, m a y be helpful. In neonates, diffuse pancreatic islet cell processes, such as nesidioblastosis, adenomatosis, and hyperplasia, are most commonly associated with hyperinsulinism. These morphological features are reminiscent of stages in the embryologic development of the endocrine pancreas, and the theory that neonatal hyperinsulinemic hypoglycemia results from a failure of normal histologic and functional maturation of the endocrine fetal pancreas is attractive. However, several investigators, finding similar histologic features in the pancreases of patients with and without hyperinsulinism, question the validity of attributing pathologic significance to nesidioblastosis. It remains to be seen how such factors as overproduction, maldistribution, or dysregulation of the pancreatic islet cells might be interacting to pro37

duce the clinical syndrome of hyperinsulinemic hypoglycemia in the neonate. In older children and adults, hyperinsulinism is most often produced by excessive secretion of insulin by benign or malign a n t beta islet cell neoplasms. Only recently has it been recognized t h a t diffuse islet cell disease m a y be present in a sizable number of patients in this age group. The recognition of nesidioblastosis in adults was facilitated by immunoperoxidase staining and electron microscopy of pancreatic tissue specimens from patients with organic hyperinsulinism. There is still disagreement on classification of multifocal islet cell diseases. Some patients have more t h a n one beta islet cell abnormality, particularly in MEA-I kindreds. It is possible t h a t all of the pathologic entities described for hyperinsulinism have a common etiology. Practically, it is important only to realize t h a t diffuse islet cell disease is present. Diffuse islet cell disease should be suspected in neonates, in adults with multiple step-ups of insulin levels on transhepatic portal vein sampling, in MEA-I or sporadic MEA-I kindreds, in patients who have no visible or palpable pancreatic neoplasm at surgery, in those with multiple adenomas, and in patients with recurrent hyperinsulinism with hypoglycemia after excision of an apparently solitary islet cell adenoma. When multifocal disease is suspected, a segment of distal pancreas should be resected for histologic examination, and insulin granules demonstrated immunocytochemically. Currently, surgery offers the only hope for curing organic hyperinsulinism. Excision of solitary islet cell adenoma is curative. Although hyperinsulinism due to multifocal islet cell disease is occasionally controlled by 75%-85% distal pancreatic resection, more often t h a n not the condition persists after such treatment. However, patients become more manageable on drug regimens t h a t typically were ineffective before pancreatic resection. Further understanding of factors regulating differentiation of the pancreatic beta islet cells m a y some day make surgery obsolete. Clearly, this represents an exciting area for future research. REFERENCES 1. Cahill G.F.: Disorders of carbohydrate metabolism: Diabetes mellitus, in Beeson P.G., McDermott W. (eds.): Textbook of Medicine, ed. 4. Philadelphia, W.B. Saunders Co., 1975, p. 1603. 2. Harris S,: Hyperinsulinismand dysinsulinism.JAMA 83:729-733, 1924. 3. Banting F.G., Best C.H.: The internal secretion of the pancreas. J. Lab. Clin. Med. 7:251-266, 1922. 4. Wilder R.M., Allan F.N., Power M.H., et al.: Carcinoma of the islands of the pancreas: Hyperinsulinism and hypoglycemia. JAMA 89:348-355, 1927. 5. Howland G., Campbell W.R., Maltby E.J., et al.: Dysinsulinism: Convulsions and coma due to islet cell tumors of the pancreas, with operation and cure. J A M A 93:674-679, 1929. 38

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