UCLA CONFERENCE

Gastrointestinal Hormones in Clinical Disease: Recent Developments Moderator: JOHN H. WALSH, M.D. Discussants: RONALD K. TOMPKINS, M.D.; IAN L. TAYLOR, Ph.D.; JUAN LECHAGO, M.D., Ph.D.; and JACK HANSKY, M.D.; Los Angeles, California

With the advent of radioimmunoassay and immunocytochemical methods, the peptides of the gastrointestinal tract have been identified and measured. Gastrinoma and insulinoma syndromes have been well characterized. The pancreatic cholera syndrome and some of the evidence that the major manifestations of this disease may be mediated by vasoactive intestinal peptide have been re-examined. Pancreatic polypeptide seems to be an ideal peptide for study of vagal-cholinergic mechanisms that regulate hormone release; it also appears to be a tumor marker for several types of pancreatic endocrine tumors, particularly those of pancreatic cholera. Secretin and cholecystokinin are important regulators of pancreatic exocrine secretion and have been used to test pancreatic function, but there is little evidence that they account for clinical disease. Glucagon-secreting tumors produce a clinical syndrome of diabetes mellitus and distinctive skin lesions, which can be cured by tumor resection. Hormone-secreting tumors may provide insight into normal gut physiology. DR.

J O H N H. W A L S H (Department of Medicine, U C L A

School of Medicine): T h e gut has proved to be a rich source of biologically active peptides. The major hormones of the digestive tract (gastrin, secretin, and cholecystokinin) and the hormones of the pancreatic islets (insulin and glucagon) have been studied for more than half a century. New fields of investigation have developed around the hormonal regulation of gastric and pancreatic secretion and of glucose homeostasis. The advent of radioimmunoassay—first developed by Yalow and Berson for measurement of insulin—has made it possible to measure these substances in blood. It seemed that many of the mysteries of the hormonal regulation of gut function would rapidly be solved by this powerful tool. The age of innocence of the 1960s was forced to yield to further complexities in the 1970s. Hormones were found to exist in multiple molecular forms. Biochemists discovered a host of new peptides, previously undescribed, and elucidated the amino acid sequence of many of them. Immunochemists discovered the cellular localization of these peptides in specific cell types. Peptides first identified in the brain were found in the gut, and vice versa. Peptides were identified not only in endocrine cells but also in nerves. The clinical relevance of some of these peptides • An edited transcription of an Interdepartmental Clinical Case Conference arranged by the Department of Medicine of the UCLA School of Medicine, Los Angeles, California. • Authors who wish to cite a section of this conference and specifically indicate its author can use this example for the form of reference: TOMPKINS RK: Pancreatic cholera syndrome, pp. 817-819 in WALSH JH (moderator): Gastrointestinal hormones in clinical disease: recent developments. Ann Intern Med 90:817-828, 1979 Annals of Internal Medicine 9 0 : 8 1 7 - 8 2 8 , 1 9 7 9

became apparent when specific clinical syndromes could be identified as being due to overproduction of one or more of these peptides by gut endocrine tumors. Other peptides were found for which no specific function could be assigned. We shall focus here on some of the more recent work in this field. We shall not devote much attention to the best-known syndromes produced by gut and pancreatic hormones—the Zollinger-Ellison or gastrinoma and the insulinoma syndromes. Instead we shall look at one syndrome that seems to have found a new pathogenic agent, the pancreatic cholera syndrome, and a new peptide with interesting properties but unknown function, pancreatic polypeptide. Most of the diseases known to be caused by gut peptides are produced by hypersecretion from tumors made up of one or more of these cell types. Many of these tumors seem to develop in the pancreas and are known as A P U D o m a s ( A P U D = amine precursor uptake and decarboxylation). The most common and best described tumor syndromes are caused by insulinomas and gastrinomas, but recently a distinctive glucagonoma syndrome was found; this will be discussed by Dr. Hansky. The possible association between the Verner-Morrison or pancreatic cholera syndrome and VIPoma (VIP = vasoactive intestinal polypeptide) will be discussed by Dr. Tompkins. Recently, two other peptides have been identified in the pancreas: pancreatic polypeptide and somatostatin. Pancreatic endocrine tumors may produce either of these substances, as we shall learn from Drs. Taylor and Hansky. Pancreatic Cholera Syndrome

Dr. Ronald K. Tompkins (Department of Surgery, U C L A School of Medicine): The syndrome of massive, watery diarrhea (leading to hypokalemia, renal failure, and often death) in a patient with non-alpha, non-beta islet-cell tumor of the pancreas has been given various names: Verner-Morrison syndrome; W D H A (watery diarrhea, hypokalemia, achlorhydria); W D H H (watery diarrhea, hypokalemia, hypochlorhydria); diarrheogenic syndrome; and, recently, VIPoma. At an Interdepartmental Conference such as this one 12 years ago, Dean Sherman Mellinkoff coined the term "pancreatic cholera," which vividly portrays the most prominent clinical feature while linking it to a pancreatic origin (1). Within 2 years after the description of the ulcerogenic tumor by Zollinger and Ellison (2), reports describing © 1 9 7 9 American College of Physicians

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non-beta islet-cell tumors associated with diarrhea and hypokalemia, both with (3) and without (4) peptic ulceration, appeared. In 1961, Murray, Paton, and Pope (5) showed that achlorhydria was associated with such tumors. In 1967, Marks, Bank, and Louw (6) reviewed published cases and reported the beneficial use of steroids in such patients with metastases. This group coined the term W D H A for this syndrome. Based on findings in clinical and bioassay studies, Zollinger and associates (7) reported in 1968 that secretin-like activity was present in one of these tumors. Said and Mutt (8) discovered vasoactive intestinal polypeptide in 1970, and subsequently this hormone has been found in the serum or tumor, or both, of many (but not all) patients with pancreatic cholera. Vasoactive intestinal peptide is a member of the "secretin family" of polypeptide hormones and has actions similar to secretin in the gastrointestinal tract, as well as possessing vasodilator and inotropic actions (9). Although pancreatic tumors are most commonly associated with pancreatic cholera, extrapancreatic tumors of neural crest origin (APUDomas) may produce the watery diarrhea syndrome (10). Thus the term "pancreatic cholera" may not be universally applicable, and the possibility of tumors appearing ectopically, as in other endocrinopathies, must be recognized. The most profound symptom (and the one that brings the patient to the physician) is that of profuse, watery diarrhea often occurring in explosive bursts but with remarkably little cramping or hyperperistalsis. In one series of patients (11), the volume of diarrhea averaged 6 litres a day. The stool characteristically contains little fat, much bicarbonate, and has a high K + concentration. This results in the patient becoming hypokalemic and acidotic. If nasogastric tubes are placed in such patients and gastric analyses done, two thirds will have basal achlorhydria and the rest, either low or normal acid production. Gastric hypersecretion does not occur. If gastric acid production is stimulated by pentagastrin, the rise is small. Histamine stimulation, however, causes more acid to be produced; this differential reponse points to an inhibitory substance from the tumor that is more effective against gastrin than histamine (9). Malignant tumors are found in 5 6 % of these patients (11). If left untreated, or inadequately treated, the severe electrolyte and fluid shifts that occur in these patients lead to acidosis, dehydration, kidney failure, and death. In an early series (11), the mortality in 12 patients with benign tumors was 4 2 % because of failure to diagnose and surgically excise the lesion. For reasons as yet unknown, about two thirds of patients will have hypercalcemia at presentation. In patients with cyclical diarrhea caused by these tumors, serum calcium concentration has been found to be elevated during attacks and normal in the interim (11). Parathormone levels have been normal in many of these patients. About one third of patients will have hyperglycemia associated with this syndrome. Both hyperglycemia and hypercalcemia are often relieved by resection of benign tumors. At present, there is no universally applicable diagnos818

tic test for all patients with this syndrome. The documentation of the watery diarrhea, hypokalemia, and absence of gastric hypersecretion are initial diagnostic requirements. The association of hypercalcemia or hyperglycemia, or both, is an additionally helpful finding. Intestinal perfusion studies, which document active secretion of electrolytes and water by the small bowel, are difficult to obtain in many institutions but are important confirmatory findings when available. Serum radioimmunoassays for vasoactive intestinal peptide are becoming more available, and a positive test in such a patient should lead to early surgical exploration. A negative test, however, should not unduly delay operation. The most definitive diagnostic test is the finding of an islet-cell tumor of the pancreas or other neural crest tissue at surgical operation. The removal of such a tumor, if it is benign, should cure the patient. If the patient has metastatic disease at the time of exploration (as more than half of those reported do), the surgeon should place a catheter in the hepatic artery via the gastroduodenal artery and infuse streptozocin after the operation (12). Corticosteroids may also be beneficial in ameliorating the diarrhea (6). Nutmeg (13) and indomethacin (14), both inhibitors of prostaglandins, have also been used to slow the diarrhea in inoperable cases. In some patients with all of the clinical features and normal plasma vasoactive intestinal peptide levels, operations have been done and no gross tumor found. Pancreatic resection has shown diffuse microadenomatosis (15, 16), and symptoms of diarrhea have abated or disappeared in some patients after the operation. The significance of this type of abnormality is unknown. Until careful immunoassays of serum hormones and immunohistochemistry of tumor tissue are available on large series of patients, the exact nature of the hormonal agent will remain unknown. At present, the secretin-like hormone vasoactive intestinal peptide has been associated with more of these tumors than any other single agent. However, elevated levels of prostaglandin E in plasma of some patients with this syndrome have been reported (17). Because these tumors are members of the A P U D system, it is likely (as has frequently been reported) that several hormones will be found in them by immunohistochemical examination. Some of these hormones have been found to act locally (paracrine) rather than by way of the general bloodstream and hence may not be associated with high plasma levels (18). The diarrhea may be a generalized response to various endocrine and paracrine substances, which may be elaborated by histologically similar tumors and act through a common final pathway. If this is found to be true, then a panel of plasma hormone assays would need to be done to establish the presumptive diagnosis. The future of research in this area will be bright and interesting as interrelationships of gut hormones and clinical syndromes such as "pancreatic cholera" are defined. Dr. Walsh: As noted by Dr. Tompkins, vasoactive intestinal peptide is the peptide identified most closely with the watery diarrhea syndromes. This peptide is related

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structurally to other peptides found in the gut and pancreas: glucagon, secretin, and gastric inhibitory peptide (Table 1). All of these peptides share the pharmacologic features of inhibiting gastric acid secretion and stimulating water and electrolyte secretion by the small intestinal mucosa (19). With the possible exception of a secretinsecreting tumor, none of these other peptides has been shown to produce a convincing pattern of watery diarrhea in patients with hormone-producing tumors. Other substances also produce similar effects on gut secretion, and two of them, prostaglandins and calcitonin, may be involved in production of diarrhea in certain patients, especially patients with medullary carcinoma of the thyroid. The specific diagnosis of the pancreatic cholera syndrome has been difficult. In most institutions, the most common cause of watery diarrhea associated with hypokalemia is surruptitious laxative or diuretic abuse (20). This possibility must be evaluated thoroughly in each patient before surgical exploration is considered. The presence of a secretory diarrhea should be confirmed in the hospital by showing that the stool electrolytes are responsible for essentially all of the fecal osmolality (excluding the presence of some osmotic agent) and by showing that stool volumes in excess of 0.5 to 1 L / d are maintained during fasting. Where intestinal perfusion studies are available, it should be possible to show net secretion of water, sodium, and chloride by the jejunum, a rare finding in diseases other than cholera. The role of vasoactive intestinal peptide measurement before surgical exploration is still debatable and confusing. One source of difficulty is that the radioimmunoassay for vasoactive intestinal peptide is a difficult procedure, and results are not easily reproducible in various laboratories. Another is that some patients seem to have a similar syndrome, sometimes called "pseudo VernerMorrison syndrome," with normal plasma vasoactive intestinal peptide and no pancreatic tumor. However, there have been several reports of clinical improvement in such patients after partial or total pancreatic resection, although no endocrine tumor could be identified. In most patients with diarrheogenic tumors of the pancreas or neural crest tissue, vasoactive intestinal peptide can be identified in the tumors by immunocytochemistry and by extraction combined with radioimmunoassay; in addition, plasma vasoactive intestinal peptide concentrations are increased (21). Another peptide, which will be described next, has been found in the plasma and tumors of several of these patients. This peptide, pancreatic polypeptide, is not known to have any signficant effect on intestinal secretion but may be a useful tumor marker for identification of some of these patients. Pancreatic Polypeptide

Dr. Ian L. Taylor (Division of Gastroenterology, Veterans Administration, Wadsworth Hospital Center, Los Angeles, California): In 1902 Bayliss and Starling (22) discovered secretin when they showed a non-nervous mechanism of stimulation of pancreatic secretion. It was to be nearly 60 years before secretin was isolated and its

Table 1 . Structure of Porcine Gastric Inhibitory Peptide Glucagon, Secretin, and Vasoactive Intestinal Peptide (VIP)

GIP Amino acid residues, no. 43 Molecular weight 5104 Tyr Ala Glu Gly Thr Phe He Ser Asp Tyr Ser He Ala Met Asp Lys He Arg Gin Gin Asp Phe Val Asn Trp Leu Leu Ala Gin Gin Lys Gly Lys Lys Ser Asp Trp Lys His Asn He Thr Gin

(GIP) f

Glucagon

Secretin

VIP

29 3484 His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asp Thr

27 3055 His* Ser Asp Gly Thr Phe Thr Ser Glu Leu Ser Arg Leu Arg Asp Ser Ala Arg Leu Gin Arg Leu Leu Gin Gly Leu Val-NHj

28 3326 His* Ser Asp Ala Val Phe Thr Asp Asn Tyr Thr Arg Leu Arg Lys Gin Met Ala Val Lys Lys Tyr Leu Asn Ser He Leu Asn-NH2

* Italicized residues are identical to those in the peptides to the left.

chemical structure ascertained (23). In contrast, pancreatic polypeptide has only recently been identified as an apparent impurity in insulin preparations from chicken (24) and bovine (25) pancreas, and physiologic studies to determine its function have had to follow its initial chemical identification. Immunohistochemical studies have shown a cell of origin, the pancreatic polypeptide cell, to have endocrine characteristics and to be distinct from the A, B, D, and Ul cell (26) (see footnote to Table 2). This cell has a unique distribution in the pancreas, since it is found not only in the islets of Langerhans but also in the acinar tissue and duct epithelium. In humans, total pancreatectomy abolishes the pancreatic polypeptide response to a meal, suggesting that there are only insignificant amounts of pancreatic polypeptide outside the pancreas, a possibilWalsh eta/.

• Gastrointestinal Hormones

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Figure 1 . Human pancreatic polypeptide (HPP) response to minutes of sham feeding (MSF) or tube chewing (A/ = 6).

ity that is supported by tissue extraction studies in primates (27). Lin and colleagues (28) have shown that pancreatic polypeptide has potent biological effects on the stomach, pancreas, and biliary tree of the dog. Pancreatic polypeptide stimulates basal acid secretion but inhibits gastric secretion stimulated by pentagastrin. This peptide also inhibits pancreatic secretion stimulated by secretin and cholecystokinin and relaxes the gallbladder while stimulating the choledochus. It has recently been shown that pancreatic polypeptide is capable of inhibiting secretinand caerulein-stimulated pancreatic secretion in dogs at blood concentrations considered physiologic in that they are lower than those seen after a meal (29). A postprandial increase in serum pancreatic polypeptide concentrations can be readily measured by radioimmunoassay (30). However, the importance of neural and hormonal mechanisms in this release is debatable. Schwartz and co-workers (30) have shown that in man truncal vagotomy virtually abolishes the pancreatic polypeptide response to a meal. We have reported similar findings in the dog (31) and have shown that the pancreatic polypeptide response to a meal is markedly diminished by the intravenous injection of atropine sulphate. Schwartz and associates (32) have shown that electrical stimulation of the vagus in the anesthetized pig produces an increase in pancreatic polypeptide concentrations in the portal vein, which can be blocked by atropine; they have also shown that acetylcholine stimulates the release of pancreatic polypeptide from the isolated perfused porcine pancreas. Cholinomimetics also release pancreatic polypeptide in the intact dog (31). These findings all support the hypothesis that release of pancreatic polypeptide is vagal-cholinergic dependent. In contrast, Adrian and colleagues (33) found that truncal vagotomy did not alter the human pancreatic polypeptide response to a meal. They suggested that gastrointestinal hormones such as secretin and cholecystokinin were the major mechanisms of pancreatic polypeptide release in response to food. Their hypothesis is supported 820

May 1979 • Annals of Internal Medicine • Volume 90 •

by their finding that caerulein, a cholecystokinin-like peptide, and secretin (from Boots' Limited, Nottingham, England) both release human pancreatic polypeptide (33). In addition, Floyd and co-workers (34) have shown that pentagastrin releases human pancreatic polypeptide. They do not, however, establish the physiologic significance of these findings. We have shown that gastrin and cholecystokinin, given alone or in combination in physiologic doses, do not cause a significant increase in serum human pancreatic polypeptide concentrations (35). Other workers have also shown that the purer gastrointestinal hormone (GIH) secretin (from the Gastrointestinal Hormone Research Laboratory, Karolinska Institute, Stockholm, Sweden) does not release pancreatic polypeptide (36). These two theories of pancreatic polypeptide release, that is, vagal-cholinergic and hormonal, are not necessarily mutually exclusive. They can be reconciled by the discovery of a hormone whose release or action on the pancreatic polypeptide cell is vagal-cholinergically dependent. A possible candidate is bombesin, a tetradecapeptide extracted from the skin of the frog Bombina bombina (see Addendum for full reference citation). Bombesin has been shown to be a potent stimulus of pancreatic polypeptide release in dogs. This response is inhibited by atropine (37). Recently, bombesin-like immunoreactivity has been shown in extracts from the

Figure 2. Human pancreatic polypeptide (HPP) response to minutes of sham feeding*(/WSO and the intragastric instillation of food, glucose, or saline.

Numbers

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mammalian small intestine (38). Additional studies in humans (39) have shown that pancreatic polypeptide response to a meal is complex and has at least three different components: cephalic-vagal stimulation; simple gastric distention, presumably via gastropancreatic neural reflexes; and an unknown components) dependent on the presence of food in the stomach and small intestine. Figure 1 shows the effect of sham feeding on serum pancreatic polypeptide concentrations in six healthy volunteers. Sham feeding increased basal serum concentrations of pancreatic polypeptide appreciably (P < 0.05). Chewing plastic tubing for the same time period as a control subject did not alter serum pancreatic polypeptide concentrations. Figure 2 shows human pancreatic polypeptide responses to sham feeding combined with the intragastric instillation of 600 mL of saline, glucose, or homogenized food. Cephalic-vagal stimulation and gastric distention with either saline or glucose caused a rapid short-lived increase in serum pancreatic polypeptide release. However, the presence of food in the stomach and small intestine is needed for the characteristically prolonged pancreatic polypeptide response to food. In contrast to our finding in the dog (31) in which the pancreatic polypeptide response to food was virtually abolished 4 to 6 weeks after truncal vagotomy, we found that patients with duodenal ulcer disease who had undergone truncal vagotomy several years before still had a response to food (39). However, the pancreatic polypeptide response to sham feeding was abolished. Truncal vagotomy probably abolishes the pancreatic polypeptide response to food in the immediate postoperative period, but the response returns towards normal with time. Clinical interest in pancreatic polypeptide has been increased by the claim that an elevated basal serum human pancreatic polypeptide concentration ( > 240 pmol/L) is an important tumor marker for pancreatic APUDomas (40). To confirm this finding for pancreatic gastrinomas, we measured basal serum pancreatic polypeptide concentrations in 41 patients with the Zollinger-Ellison syndrome and in 100 control subjects (comprising healthy subjects and patients with duodenal ulceration) (41). Four of the patients with the Zollinger-Ellison syndrome had pancreatic polypeptide concentrations greater than 240 pmol/L. However, three of the normal subjects also had basal concentrations of pancreatic polypeptide above 240 pmol/L (Figure 3). Three of the four patients with the Zollinger-Ellison syndrome had elevated pancreatic polypeptide level concentrations obviously outside the normal range; extraction of tumor tissue showed these to be mixed tumors with high concentrations of both gastrin and pancreatic polypeptide. In the study of Polak and associates (40) none of the control subjects had pancreatic polypeptide concentrations greater than 240 pmol/L, a finding that differs from our own. In our study, there was a highly significant correlation between basal pancreatic polypeptide concentrations and age in the control group (Figure 4). Thus, a difference in age between the patients and control subjects in Polak's study must be considered as a possible explanation for the apparent discrepancy.

Bloom and associates (42) recently re-examined the incidence of elevated serum human pancreatic polypeptide concentrations in gastrinomas and insulinomas using a higher upper limit of normal (300 pmol/L) and reported incidences of 26% and 22%, respectively. However, they found a 77% incidence of elevated pancreatic polypeptide concentration in 22 patients with VIPomas. Larsson and coworkers (43) found that three of four patients with the W D H A syndrome, which included VIPomas, had elevated serum pancreatic polypeptide concentrations. Three of the four tumors contained both pancreatic polypeptide and vasoactive intestinal peptide cells. These workers checked a total of 18 APUDomas and found that 10 contained more than one cell type. With the possible exception of tumors associated with the W D H A syndrome, human pancreatic polypeptide cells were no

Figure 3. Basal serum human pancreatic polypeptide (JHPP) concentrations in 4 1 patients with the Zollinger-Ellison syndrome (ZES) and 1 0 0 control subjects. Walsh eta/.

• Gastrointestinal Hormones

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Figure 4. Correlation between age and basal serum concentrations of human pancreatic polypeptide (JHPP) in 1 0 0 control subjects.

more frequently found as the second cell in mixed tumors than were gastrin, insulin, and glucagon cells. Apparently for A P U D o m a s other than VIPomas, elevated serum human pancreatic polypeptide concentrations are no more a tumor marker than are elevated concentrations of insulin, gastrin, or glucagon. A possible role for human pancreatic polypeptide as a marker for VIPomas needs further evaluation. Pancreatic polypeptide may play a role in the diagnosis of pancreatic disease. Its unique distribution in both exocrine and endocrine pancreas, along with the observation that total pancreatectomy in humans abolishes the pancreatic polypeptide response to food, suggests that the study of pancreatic polypeptide release in chronic pancreatitis may be of some interest. Provisional studies suggest that the pancreatic polypeptide response to food is abolished in severe chronic pancreatitis but that the results are unpredictable in milder forms of the disease (44). Further studies are needed to ascertain if the study of pancreatic polypeptide release gives a more reliable and sensitive index of pancreatic damage than does the study of exocrine secretion or insulin and glucagon release. Gastro-Entero-Pancreatic Endocrine Cells in Digestive Disease

Dr. Juan Lechago (Department of Pathology, Los Angeles County Harbor-UCLA Medical Center, Torrance, California): The endocrine cells of the gut, first described by Heidenhain in 1870, have been intensively studied during the last decade by means of histochemistry, immunohistochemistry, and electron microscopy (45). Consequently, 16 endocrine cell types have been identified in the mucosa of the gastrointestinal tract (46). Similar studies on the endocrine cells of the pancreas have resulted in six different cell types being recognized in the islets of Langerhans and exocrine structures (47). 322

Early observations on morphologic similarities between the endocrine cells of the pancreas and those of the gut (48) led to the concept of the endocrine pancreas and gut as one functional unit (49), also referred to as gastroentero-pancreatic endocrine system (50). This concept found support in and was expanded by Pearse's A P U D cell theory (51), which included the endocrine cells of the gut, pancreas, tracheobronchial tree, pituitary, thyroid Ccells, chromaffin system, and others. This theory predicates common functional characteristics of these cells, for example, their capacity to transform amino acids into biogenic amines, and their common embryologic origin from neuroectodermal structures. This proposed common embryologic origin would explain the common morphologic and functional features between normal neural and endocrine structures, as well as in some digestive endocrine tumors. A comparable expansion took place in the field of the gastrointestinal hormones. Since the discovery of secretin, the event that gave birth to endocrinology in 1902 (22), an increasing number of peptides and biogenic amines have been identified in gastrointestinal structures. Thus, as many as 27 putative gastrointestinal hormones, some well-established, some candidates, have been currently characterized (52). A fascinating finding that lends support to the proposed neuroectodermal origin of the digestive endocrine cells is the presence of multiple biogenic amines and polypeptidic hormones, for example, serotonin, histamine, vasoactive intestinal peptide, somatostatin, and others, both in brain tissues and in endocrine cells of the gut (52). During the last few years, efforts have been directed towards identifying the cells of origin of the different digestive hormones. Correlations between structure and function have been successfully achieved in several cases, and the current status is shown in Table 2. This is a modification of the classification of the gastro-enteropancreatic endocrine cells agreed on at the meeting in Lausanne in 1977 (46). It is primarily based on ultrastructural and immunohistochemical information. The knowledge gained about the gastro-entero-pancreatic endocrine cells and their products has reached a stage where it can be applied towards a better understanding of some digestive diseases. Some quantitative results have appeared on the gastrin cells in some digestive diseases (53), but most of the current knowledge on gastro-entero-pancreatic endocrine pathology still deals with its tumors. The main gastro-entero-pancreatic endocrine tumors (with the exclusion of insulinomas) are reviewed below. Since Oberndorfer's first report in 1907, the definition of carcinoid tumor has expanded considerably (54, 55). For some investigators, the term carcinoid tumor should be restricted to the classic argentaffin neoplasm of the intestine; for others, carcinoid tumor in digestive and respiratory systems is practically synonymous with endocrine tumor derived from A P U D cells. Carcinoid syndrome, in contrast, is reserved for functional manifestations of the metastasizing argentaffinoma, which commonly arises from the midgut (54). Ultrastructural stud-

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Table 2. Endocrine Cell Types of the Gastro-Entero-Pancreatic System*

Stomach Oxyntic

Pyloric

Upper

Lower

Large Intestine

P EC

P EC

P EC

EC

EC

Dx (PP) D

D1 (PP) D

Di

Dx (PP)

Di

(A) X ECL

(X)

Pancreas

1P] EC D2 PP D B A [(G)]

Small Intestine

G

(PP) D

G S I K L

S I K N L

(PP)

L

Function: Ascertained or Proposed Product (Bombesin?) Serotonin plus: ECi substance P EC2 (motilin?) ECn (others?) (VIP f-Uke? Disputed) Pancreatic polypeptide Somatostatin Insulin Pancreatic glucagon Unknown Unknown (histamine or 5-hydroxytryptophan?) Gastrin Secretin Cholecystokinin Gastric inhibitory peptide (Neurotensin?) Enteroglucagon-glycentin ?

* Adapted from Solcia and colleagues (46). Parentheses indicate only in lower animals, not in humans; brackets indicate only in fetus or newborn, not in adults. P = pulmonary cells (small granular cells originally seen in the lung); EC = enterochromaffin cells; ECi and EC2 = subdivisions of enterochromaffin cells; ECn = cells that are neither ECi or EC2 (probably represents a heterogenous group of cells with chromaffin characteristics, including gastric EC cells); D = D cells, found in pancreas, stomach; and small intestine; Di = variants of D cells; PP = pancreatic polypeptide cells; B = beta-cells; A = alpha-cells; X = cells of unknown nature; ECL = enterochromaffin-like cells; G = gastrin cells; S = secretin cells; I = intermediate cells (in the dog the size of the granule is intermediate between small and large granules); K = K cells; N = theorized to be neutrotensin cells; L = large granules (originally described in the dog). t VIP = vasoactive intestinal polypeptide.

ies have shown that the cells of most midgut carcinoids have granules identical with those of the enterochromaffin cells (54). These cells normally contain serotonin, a substance that is increased in circulation in many patients with the carcinoid syndrome. Gastrinomas have rarely been found in the stomach (56), have a somewhat higher frequency in the duodenum (57), and appear most frequently in the pancreas (58). Immunofluorescent studies have shown variable patterns of gastrin localization in the cells of these tumors. Electron microscopic studies have shown the presence of cells containing granules identical to those of the antral Gcells in many, but not all, gastrinomas. In addition, cells with granules of varying structure have been seen in most gastrinomas when studied in detail (58, 59). The VIPomas seem, at times, to re-enact the postulated neuroectodermal genesis of the digestive endocrine cells. Sometimes they arise in the pancreas where they have the appearance of the typical islet cell tumors (Figure 5A). They are usually associated with the W D H A syndrome, first described in 1958 by Verner and Morrison (4), and also known as pancreatic cholera (1). Immunofluorescence showed vasoactive intestinal peptide in their cells, and radioimmunoassay often confirmed the presence of large quantities of this hormone, both in circulation and in tumor tissue (20). The presence of prostaglandin E has been recently documented in some VIPomas, further complicating the functional picture (60). On occasions, the pancreatic cholera syndrome has been associated with the presence of extrapancreatic tumors, which are often ganglioneuromas. These may show areas with neurons next to areas resembling an islet cell tumor (Figure 5B). Electron microscopic studies have shown the presence of small granules, similar to those of the

vasoactive intestinal peptide-producing D{ -cells, in some of the cells of pancreatic VIPomas (Figures 6A, B), as well as in some neurons, nerve processes, and other less well-defined cells of vasoactive intestinal peptide-producing ganglioneuromas (Figure 6C). In addition to these relatively common tumors, other neoplasms such as glucagonomas (61) and somatostatinomas (62) have been reported in pancreas and digestive tract. Of particular interest are malignant endocrine digestive tumors that produce more than one hormone (63, 64). These were believed to be rare but are now being reported with increasing frequency. Perhaps, when exhaustively investigated, many gastro-entero-pancreatic endocrine tumors, heretofore simply referred to as gastrinomas, VIPomas, insulinomas, and so forth, may prove to be multihormonal tumors also. Possibly, the cells of malignant gastro-entero-pancreatic endocrine tumors may reach a state of dedifFerentiation to the point where their progenies become capable of producing a multiplicity of polypeptides, either simultaneously or sequentially. Gastrointestinal Hormones and Clinical Disease: Other Hormones

Dr. Jack Hansky (Center for Ulcer Research and Education, Wadsworth Hospital Center, Los Angeles, California): Except for gastrinoma, most of the syndromes associated with excessive secretion of gastrointestinal hormones have been discussed. I shall briefly consider some of the other gastrointestinal hormones and their measurement and role in clinical medicine. Most have not been implicated in any syndromes of deficiency or excess, some have been difficult to measure, and the roles of many have yet to be fully defined. The first hormone discovered was secretin (22), a 27 Walsh et a/. • Gastrointestinal Hormones

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Figure 5. Photomicrographs of two VIPomas (VIP = vasoactive intestinal polypeptide). A. A pancreatic tumor, with a " t y p i c a l " islet-cell tumor appearance. B. A retroperitoneal ganglioneuroma: large neurons are seen at the top, while islet-like cells are present at the bottom. (Original magnification, x 160.)

amino acid peptide that stimulates the pancreas to produce bicarbonate and water. It is elaborated by the S cell of the duodenum and jejunum and is structurally related to vasoactive intestinal peptide, gastric inhibitory peptide, and glucagon with which it shares some actions (65). Despite the absence of a tyrosine residue, radioimmunoassays for measurement of secretin in tissues and plasma have been developed by several investigators (6668). Recently, SchafFalitzky de Muckadell and colleagues (69) found that the lowest dose of exogenous secretin to increase plasma immunoreactive secretin appreciably is 0.03 clinical units per kilogram of body weight per hour. This is subthreshold for pancreatic exocrine secretion, which makes the assay very sensitive. Despite this apparent sensitivity, only acid in the duodenum has been found to increase plasma secretin significantly, although other reports have suggested that alcohol and glucose stimulate immunoreactive secretin release (70, 71). No known syndromes of secretin excess or deficiency have been described except for one report implicating the hormone in the Verner-Morrison syndrome (7). Secretin is used in the diagnosis of pancreatic exocrine insufficiency (72) and aids in the diagnosis of gastrinoma where it increases serum gastrin appreciably (73). Because of its property of gastric acid inhibition, it has been used in the treatment of duodenal ulcer with inconclusive results. Further elucidation of its biologic versus immunologic activity is eagerly awaited. Cholecystokinin has proved to be a difficult hormone to assay, partly because it is not very immunogenic and partly because the 33 amino acid hormone has its tyrosine esterified with sulfuric acid, which prevents iodination. Despite these difficulties, several groups (74-76) g24

have described radioimmunoassays for cholecystokinin and have found high circulating levels in celiac syndrome and pancreatic insufficiency. However, from our preliminary studies with an octapeptide assay, it would seem that circulating levels of cholecystokinin are actually lower than described. Cholecystokinin has been extracted from gut mucosa as a small octapeptide and as two large forms, cholecystokinin 33 and cholecystokinin 39, designating the number of amino acid residues (77). It is not known which form(s) predominantly circulates. The octapeptide is more potent on a molar basis in stimulating pancreatic secretion and gallbladder contraction than are the large molecules. Assays have been developed for measurement of octapeptide, but it takes a dose of at least 32 pmol/kg body weight • h to produce detectable blood levels. Cholecystokinin stimulates gallbladder contraction and pancreatic protein secretion. It is an excellent stimulant of the transplanted pancreas, but endogenous release indicates a poorer response of this preparation than the innervated organ (78). This suggests that for pancreatic secretion a concerted action of nerves, secretin, and cholecystokinin is needed. The elucidation of these factors awaits the development of sensitive modes of measuring circulating hormone levels. Clinically, cholecystokinin is used in tests of gallbladder and pancreatic function. N o syndromes of cholecystokinin deficiency or excess have been described. Cholecystokinin is one of the peptides found in both brain and gut and shares this trait with substance P, neurotensin, vasoactive intestinal peptide, motilin, somatostatin, enkaphaline, thyrotrophin-releasing hormone, and bombesin. The physiologic significance of this fascinating finding is not known. Gastric inhibitory polypeptide is a 43 amino acid pep-

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tide whose role in gastrointestinal physiology is less clear than its role in glucose metabolism. Certainly it is an inhibitor of gastric acid secretion (79), but its major effect is an insulinotropic one. The time-course release of gastric inhibitory peptide after oral glucose supports the role for gastric inhibitory peptide in the control of insulin release and has been implicated in the enteroinsular axis (80). High circulating levels of gastric inhibitory peptide have been reported in obesity and diabetes mellitus (81) and in one case of the Verner-Morrison syndrome, subsequently refuted. The amount of gastric inhibitory polypeptide increases in patients with duodenal ulcer who have abnormal glucose tolerance (82). Glucagon, a 29 amino acid peptide found in the A cell of the pancreatic islet, is of interest to gastroenterologists because several patients have been identified with the glucagonoma syndrome and glucagon immunoreactivity, enteroglucagon, has been found in the gut. The physiology of glucagon has been well studied, and immunoassays for its measurement in plasma have been described. A distinctive syndrome associated with an alpha cell islet-cell tumor and increased circulating levels of glucagon has recently been recognized. In 1974, Mallinson and colleagues (83) described nine patients with pancreatic tumors who had diabetes mellitus, stomatitis, anemia, and a distinctive skin lesion—necrolytic migratory erythema. In four patients further studied, plasma amino acid was low and circulating plasma glucagon levels high. Gluca-

gon also has effects on the gastrointestinal tract, including inhibition of gastric and pancreatic secretion, stimulation of fluid secretion from the intestine, and suppression of gastrin release. Glucagon has been implicated as a candidate in the Verner-Morrison syndrome and has been used in the treatment of acute pancreatitis. Glucagon-like activity, or enteroglucagon, has been found in enteroglucagon cells of the intestine and has been detected in pancreas, stomach, and small intestine (84), with the highest levels being in the colon. There are at least two molecular forms, one of which has 100 amino acid residues. Plasma enteroglucagon is released by food, probably carbohydrate and fats (85). Blood concentrations are increased in the dumping syndrome (86). One patient was reported to have an enteroglucagon-producing tumor, associated with gross intestinal stasis and massive intestinal hypertrophy (87). Its role in physiology is unknown. Somatostatin, or growth-hormone-inhibitory-hormone, has been found throughout the gastrointestinal tract, and the cells containing immunoreactive somatostatin have been identified as D cells (88). These cells are most abundant in the pancreas but have also been found in fundus and antrum of stomach and, to a lesser extent, lower down the gut. Somatostatin inhibits gastrin, insulin, glucagon, secretin, and cholecystokinin (89-91). It also inhibits motilin release, to delay gastric emptying (92), and inhibits vasoactive intestinal peptide release from a hor-

Figure 6. Electron micrographs of the tumors shown in Figure 5 by light microscopy. A. Low magnification of the pancreatic VIPoma (VIP = vasoactive intestinal polypeptide) depicted in Figure 5A showing a cluster of small cytoplasmic granules in cells that are poorly granulated. (Original magnification, x 5 0 0 0 . ) B. Higher magnification of the granules shown in Figure 6A. (Original magnification, X 14 0 0 0 . ) C. High-power view of a nerve cell process from the VIPoma shown in Figure 5B. Granules very similar to those of the pancreatic VIPoma fill the cytoplasm. (Original magnification, x 14 0 0 0 . ) Walsh et al. • Gastrointestinal Hormones

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mone-producing tumor (93); in addition it suppresses gastric acid secretion (94), gallbladder contraction, and pancreatic enzyme secretion (95). Although assays for its measurement in plasma are now available, somatostatin is thought to act predominantly as a local hormone (paracrine effect). Somatostatin-containing D cells and gastrin G cells have been counted in antral tissue of duodenal ulcer patients, and a 7:1 G to D cell ratio was found in most patients. In a few subjects with G cell hyperplasia, there was a 70:1 G to D cell ratio, suggesting a deficiency of somatostatin in this disease (96). Creutzfeldt (personal communication) found that, compared with normal subjects, patients with duodenal ulcer diseases do not have an altered gastrin: somatostatin ratio; we, however, have found an increased ratio (unpublished observations). Recently, two patients have been described with pancreatic islet cell carcinomas that contained a large amount of somatostatin. One patient, studied by Larsson and co-workers (97), had hypochlorhydria, steatorrhea, and diabetes; the other, studied by Ganda and associates (62), had diabetes, polydipsia, and weight loss. In both patients the glucagon levels were low and cholecystectomy had been done for gallbladder disease, which may be related to diminished gallbladder contraction with somatostatin. The whole question of somatostatinomas and the relation of somatostatin to insulin and glucagon have been discussed by Unger (98). There are several other gastrointestinal hormones that have not been presented in this conference, including motilin, bombesin, substance P, chymodenin, and enkephalin. As these are increasingly studied, we may find them to be of importance in gastrointestinal physiology and pathophysiology.

tissues; however, we do not yet have direct proof of this hypothesis. Another strong possibility is that some peptides in the gut act as neurotransmitters. Substance P and vasoactive intestinal peptide have been seen in nerve endings. If they are released by nervous stimulation, and there is evidence that they are, a unique type of delivery system—neurocrine transmission—can be conceived. There is evidence that some peptides have a neurocrine function in the brain. If we can understand their function in one location, perhaps we may be able to understand their function in other places. Research in this area is in its infancy. In future years we may be able to present evidence that the gut and brain are connected by more than the sympathetic and parasympathetic nerves. These questions can be answered only by continued investigation. ACKNOWLEDGMENTS: This study was supported by grants AM 17328 and AM 17294 from the National Institutes of Health. • Requests for reprints should be addressed to John H. Walsh, M.D.; Division of Gastroenterology, Department of Medicine, UCLA School of Medicine; Los Angeles, CA 90024. Received 4 December 1978; accepted 14 December 1978.

Addendum

The original reference on bombesin, a peptide extracted from the skin of the frog Bombina bombina, is ANASTASI A, ERSPAMER V, Bucci M: Isolation and structure of bombesin and alytesin, two analogous active peptides from the skin of the European amphibians Bombina and Alytes. Experientia 27:166167, 1971. References 1. M A T S U M O T O K K , P E T E R JB, S C H U L T Z E R G , H A K I M AA, F R A N C K

2.

Summary

Dr. Walsh: We have heard about some of the syndromes produced by excess secretion of gut peptides, about the cells that produce these peptides, and about an interesting peptide that is looking for a clinical or physiologic role. Probably many other associations will be found between gut peptides and clinical disease. Before we understand the importance of peptide hormones in the pathogenesis of other disorders, we shall have to define their role in normal gastrointestinal function. The radioimmunoassay technique, for which Dr. Rosalyn Yalow received the Nobel Prize in medicine last year, will be instrumental in defining the role of circulating peptides in the regulation of gut function. However, we must also consider the concept of local or paracrine action of some of these peptides. One way peptides act as chemical messengers is by passing from their cell of origin through the blood to target cells. This is the typical route for endocrine transmission of messages. Two other possible modes of delivery should also be considered: One of these has been termed paracrine and refers to action of peptides on cells adjacent to the cells that produce and release these peptides where they reach the target cells by local diffusion in tissues. Somatostatin may possibly have a paracrine function in the pancreatic islets and in other 826

3. 4. 5. 6.

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15. VERNER JV, MORRISON AB: Endocrine pancreatic islet disease with diarrhea. Report of a case due to diffuse hyperplasia of nonbeta islet tissue with a review of 54 additional cases. Arch Intern Med 133:492500, 1974 16. BLOOM SR, POLAK JM: The role of VIP in pancreatic cholera, See Reference 9, pp. 635-642 17. JAFFE BM, CONDON S: Prostaglandins E and F in endocrine diarrheogenic syndromes. Ann Surg 184:516-524, 1976 18. PEARSE AGE, POLAK JM, BLOOM SR: The newer gut hormones. Cellular sources, physiology, pathology, and clinical aspects. Gastroenterology 72:746-761, 1977 19. W A L S H JH: Gastrointestinal peptide hormones and other biologically active peptides; duodenal ulcer; pancreatic cholera; and related syndromes, in Gastrointestinal Disease. Pathophysiology, Diagnosis, and Management, 2nd ed., edited by SLEISENGER MH, FORDTRAN JS. Philadelphia, W.B. Saunders, 1978, pp. 107-155

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AMJ, BLOOM SR, GROSSMAN MI: Lausanne 1977 classification of gastroenteropancreatic endocrine cells. See Reference 21, pp. 40-46

arrhea: intestinal perfusion studies and plasma VIP concentrations in patients with pancreatic cholera syndrome and surreptitious ingestion of laxatives and diuretics. Am J Dig Dis 22:280-292, 1977 21. BLOOM SR: VIP and watery diarrhea VI, in Gut Hormones, edited by BLOOM SR. Edinburgh, Churchill Livingstone, 1978, pp. 583-588 22. BAYLISS WM, STARLING EH: The mechanism of pancreatic secretion. / Physiol (Lond) 28:325-353, 1902 23. JORPES E, M U T T V: On the biological activity and the amino acid composition of secretin. Acta Chem Scand 15:1790-1791, 1961

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AJ: Distribution and release of human pancreatic polypeptide. Gut 17:940-944, 1976 28. LIN T-M, EVANS DC, C H A N C E RE, SPRAY GF: Bovine pancreatic peptide: action on gastric and pancreatic secretion in dogs. Am J Physiol 232:E311-E315, 1977 29. T A Y L O R IL, SOLOMON TE, W A L S H JH, GROSSMAN MI: Pancreatic

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RE, MOON N: Pancreatic-polypeptide response to food in duodenal-ulcer patients before and after vagotomy. Lancet 1:1102-1105, 1976 31. T A Y L O R IL, IMPICCIATORE M, C A R T E R DC, W A L S H J H : Effect of atro-

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localization of secretin and enteroglucagon in human intestinal mucosa.

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Gastrointestinal hormones in clinical disease: recent developments.

UCLA CONFERENCE Gastrointestinal Hormones in Clinical Disease: Recent Developments Moderator: JOHN H. WALSH, M.D. Discussants: RONALD K. TOMPKINS, M...
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