CLASSIFICATION AND DISTRIBUTION OF GUT PEPTIDES.

Throughout the gastrointestinal tract, from the esophagus to the rectum, is found a spectrum of specialized endocrine cells that secrete peptides involved with the normal physiologic functions of the gastrointestinal tract (Table 15-1). In addition to specialized endocrine cells, gut peptides are also located in neurons widely dispersed throughout the gastrointestinal tract (Table 15-2). In enteric neurons, gut peptides probably act as neurotransmitters or neurocrine agents (Mulvihill and Debas, 2001). The bodies of enteric neurons are located within the gut wall, usually in the submucosal or myenteric plexus, from which their pathways extend to cells of the mucosa, smooth muscle, blood vessels, and other endocrine cells. This enteric nervous system is considered a division of the autonomic nervous system.

TABLE 15-1 GASTROINTESTINAL HORMONES

TABLE 15-2 DISTRIBUTION OF GASTROINTESTINAL HORMONES^*

PHYSIOLOGIC ACTIONS.

Gastrointestinal peptides regulate gastrointestinal motility as well as secretion of fluid and digestive enzymes (see Table 15-1). Gastrointestinal peptides also have several trophic actions that regulate metabolism and growth of gastrointestinal tissues by stimulating protein, RNA, and DNA synthesis; minimizing protein catabolism; and enhancing cellular uptake of amino acids (Mulvihill and Debas, 2001). The interactions between these peptides are diverse and complex, encompassing not only stimulation or repression of each other’s secretion but also potentiation or inhibition of each other’s actions on target organs within the gastrointestinal tract. These complex interactions maintain an optimal environment for efficient digestion and absorption of nutrients. As such, gastrointestinal endocrine cells must be capable of monitoring and responding to changes within the environment of the gastrointestinal tract. These responses must occur in a coordinated fashion if optimal assimilation of ingested nutrients is to be maintained.

MODES OF GUT PEPTIDE DELIVERY.

Gastrointestinal peptides are delivered to their sites of action in three main ways: some circulate in the bloodstream in order to reach the target cell (endocrine delivery); some are released into the interstitial fluid and affect nearby cells (paracrine delivery); and still others, within neurons, act as neurotransmitters or neuromodulators (neurocrine delivery; Fig. 15-1; Mulvihill and Debas, 2001). Some peptides have more than one delivery. Because of their various modes of delivery, it is preferable to refer to these substances as regulatory peptides rather than as hormones.

FIGURE 15-1 Schematic representation of the wall of the small intestine. Note the close proximity of endocrine cells and nerves to mucosal cells, blood vessels, and smooth muscle. Anatomically, local release of hormone by endocrine cells or nerves could affect secretion and absorption (mucosal cells), motility (muscle), and blood flow (blood vessels). A, Paracrine delivery—release of a messenger locally to affect adjacent cells. B, Neurocrine delivery—release of messenger by nerves to affect mucosal cells, other endocrine cells, or smooth muscle of both small intestine and blood vessels. C, Endocrine delivery—release of messenger into the blood to act as a circulating hormone.

(From Mulvihill SJ, Debas HT: In Greenspan FS, Baxter JD (eds): Basic and Clinical Endocrinology, 4th ed. Norwalk, CT, Appleton & Lange, 1994, p 551.)

BRAIN-GUT AXIS.

The discovery that many of these peptides are located in the central nervous system (CNS) and in enteric neurons—in addition to being found in specialized endocrine cells of the gastrointestinal tract—has led to the concept of the brain-gut axis. In the CNS, gut peptides are thought to be important in the regulation of bodily functions such as satiety. Furthermore, neurons of the CNS interact with those of the enteric nervous system to influence digestive processes. Many of these neurons are peptidergic. Neurons of the enteric nervous system exert local control over digestive processes, including absorption, secretion, motility, and blood flow. It is believed that some poorly understood conditions (e.g., irritable bowel syndrome in humans) are the result of abnormalities of regulation of gut function by the enteric nervous system and CNS.

ETIOLOGY.

In 1955, Zollinger and Ellison described a clinical entity in two human patients consisting of gastric hypersecretion, multiple gastrointestinal ulcers, and a non–beta-cell tumor of the pancreas. It was subsequently shown that these tumors produce gastrin (Mulvihill and Debas, 2001) and the triad of hypergastrinemia, a neuroendocrine tumor, and gastrointestinal ulceration became known as the Zollinger-Ellison syndrome (Jensen and Fraker, 1994). The main actions of gastrin are stimulation of gastric acid secretion and parietal cell growth. Hypergastrinemia induces excessive gastric secretion of hydrochloric acid, which is responsible for the development of esophageal, gastric, and duodenal ulcers, the disruption of intestinal digestive and absorptive functions, and the development of clinical signs. The first reported case of a gastrinoma in veterinary medicine resembling the Zollinger-Ellison syndrome was by Jones et al in 1976. Although sporadic case reports in dogs and cats have since appeared in the literature (Happe et al, 1980; Drazner, 1981; Middleton and Watson, 1983; Breitschwerdt et al, 1986; English et al, 1988; Eng et al, 1992; Brooks and Watson, 1997; Altschul et al, 1997; Green and Gartrell, 1997), this syndrome is still considered a rare entity.

In humans, gastrin-producing tumors are found primarily in the pancreas, proximal duodenum, and gastric antrum, although other sites have been reported (Wolfe et al, 1982; Wolfe and Jensen, 1987). These tumors tend to be small, multiple, slow-growing, and malignant. They cause clinical signs primarily as a result of excessive secretion of gastrin. Occasionally, clinical signs are related to the malignant, space-occupying nature of the multiple metastatic masses. Metastasis is primarily to the liver, lymph nodes, and adjacent omentum. Gastrinomas may also be associated with tumors in other endocrine organs, a condition known as multiple endocrine neoplasia (MEN) syndrome (see Chapter 9) (Pipeleers-Marichal et al, 1990).

Similar behavior patterns of gastrinoma are difficult to assess in dogs and cats, primarily because of the small number of affected animals that have been described to date. Nevertheless, of the 24 dogs and 4 cats with Zollinger-Ellison syndrome either reported in the literature or seen by us, 21 dogs and all cats with gastrinoma had a tumor arising from islet cells in the pancreas, with multiple pancreatic masses identified in 4 animals. The tumor was not identified in the pancreas but was identified in the regional lymph nodes in 2 dogs and at the root of the mesentery in 1 dog (Zerbe and Washabau, 2000; Brooks and Watson, 1997; Green and Gatrell, 1997). Metastatic disease involving the liver, adjacent lymph nodes, spleen, or mesentery was identified in 70% of the cases.

The cell of origin of the pancreatic gastrinoma is disputed. The normal pancreatic islets in the adult contain four cell types: A cells secrete glucagon, B cells secrete insulin, D cells secrete somatostatin, and F cells secrete pancreatic polypeptide. However, gastrin appears to be produced during fetal life by D cells. The most widely accepted current hypothesis is a reversion of D cell function back to fetal function, with subsequent secretion of gastrin instead of somatostatin (Krejs, 1998).

Gastrinomas may secrete other hormones (e.g., insulin, ACTH, pancreatic polypeptide) as well as gastrin, a phenomenon that has been documented in dogs and cats as well as in humans. A canine gastrinoma has been reported that produced gastrin and ACTH, while a gastrinoma in a cat produced gastrin, glucagon, and possibly cholecystokinin (Middleton and Watson, 1983; Feldman and Nelson, 1987). In humans, the clinical syndrome resulting from excessive hormone secretion by one of the cell types in multihormonal neoplasms may not be the result of the predominant cell type in the tumor. In addition, metastatic masses from multihormonal tumors are not necessarily composed of the cell type responsible for the clinical picture.

SIGNALMENT.

Dogs and cats with confirmed gastrinomas were 3 to 12 years old, with a median age in dogs of approximately 8 years. There does not appear to be a gender or breed predisposition, although the number of reported confirmed cases is too small for definite conclusions to be drawn.

CLINICAL SIGNS.

Almost all of the clinical signs are a result of severe gastric acid hypersecretion. The most common clinical signs are vomiting, weight loss, anorexia, and diarrhea (Table 15-4). Gastric hyperacidity eventually results in ulcer formation, most commonly involving the stomach and duodenum. Gastrointestinal ulceration was found during gastroduodenoscopy, surgery, or at necropsy in 20 (80%) of 25 dogs and cats with gastrinoma, with perforation of the ulcer identified in 4 animals (Zerbe and Washabau, 2000; Brooks and Watson, 1997; Altschul et al, 1997; Green and Gartrell, 1997). Ulcerations, in turn, may cause vomiting, hematemesis, hematochezia, melena, inappetence, weight loss, depression, and abdominal pain. Esophageal reflux of acid gastric contents may lead to esophagitis and ulceration with worsening inappetence, regurgitation, and weight loss. Diarrhea with malabsorption and steatorrhea may develop following acidification of the intestinal contents, with subsequent inactivation of lipase, precipitation of bile salts, interference with chylomicron formation, and damage to intestinal mucosal cells. Hypergastrinemia may also alter intestinal absorption of water and electrolytes.

TABLE 15-4 FREQUENCY OF OCCURRENCE OF CLINICAL SIGNS IN 24 DOGS AND 3 CATS WITH GASTRINOMA AND THE ZOLLINGER-ELLISON SYNDROME

Acidification of the intestinal lumen is a stimulant for the secretion of secretin and cholecystokinin. Secretin has been shown to stimulate the secretion of gastrin from gastrinomas, so its endogenous release may contribute to the maintenance of hypergastrinemia. Thus a cycle may develop that perpetuates the hyperacidity and resultant pathology.

PHYSICAL EXAMINATION.

Findings on the physical examination depend, in part, on the chronicity of the disorder, severity of hyperacidity and ulceration, and presence of a perforated ulcer. Findings of the physical examination can vary from relatively unremarkable to a dog or cat that is extremely sick. Animals with the Zollinger-Ellison syndrome may be lethargic, thin to emaciated, febrile, dehydrated, and in shock. Mucous membranes may appear pale as a result of anemia due to ulcer diathesis. Compensatory tachycardia and abdominal tenderness during palpation may also be present. One cat affected with gastrinoma had a palpable abdominal mass at the time of presentation (Zerbe and Washabau, 2000).

CLINICAL PATHOLOGY.

Abnormalities in the complete blood count that have been associated with the Zollinger-Ellison syndrome in dogs and cats include a neutrophilic leukocytosis, hypoproteinemia, and regenerative anemia, presumably caused by gastrointestinal inflammation and blood loss. Abnormalities identified in the serum biochemistry panel include hypoproteinemia, hypoalbuminemia, hypocalcemia, and mild increases in serum alanine aminotransferase and alkaline phosphatase activities. Hypocalcemia may be a result of concurrent hypoalbuminemia or secondary to gastrin-induced thyroid C-cell hyperplasia and increased calcitonin secretion. Hypokalemia, hypochloremia, and metabolic alkalosis may develop in those dogs and cats with frequent vomiting. Hyperglycemia and hypoglycemia have been reported in a few cases, the cause of which is unknown but may be related to tumor-associated secretion of other hormones (e.g., ACTH, insulin; Zerbe and Washabau, 2000). Results of the urinalysis are usually unremarkable. Evaluation of a fecal sample with Sudan stain may reveal steatorrhea due to both lipid and fatty acid accumulation. A positive occult blood reaction or overt melena is usually present.

DIAGNOSTIC IMAGING.

Survey abdominal radiographs are usually normal. If an ulcer has perforated through the serosal surface, radiographic signs consistent with peritonitis may be present. Contrast radiographic studies may demonstrate gastric or duodenal ulcers; thickening of the gastric rugal folds, pyloric antrum, and/or intestine; and rapid intestinal transit of barium (Zerbe and Washabau, 2000). With concurrent severe esophagitis, a secondary megaesophagus or aberrant, nonperistaltic esophageal motility may be demonstrable fluoroscopically. Potential abnormalities identified with abdominal ultrasound include thickening of the gastric and intestinal wall, gastric ulcers, and a pancreatic mass or its metastases. However, gastrinomas vary tremendously in size and may be microscopic (Roche et al, 1982). Failure to identify a pancreatic mass with ultrasonography does not rule out gastrinoma. Because a high concentration of high affinity somatostatin receptors is present in greater than 90% of tissue from human gastrinomas, the use of radiolabeled somatostatin analogues has enabled successful imaging of many gastrinomas, including previously unsuspected metastases (Schirmer et al, 1995; Gibril et al, 1996). A positive scan can also suggest whether a patient will be likely to benefit from therapy with the long-acting somatostatin analogue octreotide, which decreases gastrin release (Ellison et al, 1986). ¹¹¹Indium-pentetreotide scintigraphy successfully detected gastrinoma and its metastases in a dog with metastatic gastrinoma, and octreotide treatment was beneficial in decreasing plasma gastrin concentrations (Altschul et al, 1997).

ENDOSCOPY.

Gastroduodenoscopy in a dog or cat with the Zollinger-Ellison syndrome may reveal severe esophagitis and ulceration, especially in the vicinity of the cardia. Gastric rugal folds may be thickened and persist despite insufflation of the gastric lumen with air. Gastric and duodenal hyperemia, erosions, or ulceration is often visible (Fig. 15-2). Histologic evaluation of esophageal, gastric, and duodenal biopsies obtained during endoscopy may reveal mild to severe inflammation with infiltrates of lymphocytes, plasma cells, neutrophils and/or eosinophils, as well as gastric mucosal hypertrophy, fibrosis, and loss of the mucosal barrier.

FIGURE 15-2 Endoscopic visualization of a hemorrhagic ulcer (arrow) in the body of the stomach in a dog with Zollinger-Ellison syndrome (gastrinoma).

DIAGNOSIS.

Gastrinoma should be included in the differential diagnoses for any dog or cat presenting with severe gastrointestinal signs, especially vomiting with weight loss, melena or hematemesis, or any dog or cat in which severe gastric and duodenal ulceration is identified via gastroduodenoscopy. Identifying a pancreatic mass or metastasis with abdominal ultrasound followed by exploratory surgery, paying special attention to the pancreas and peripancreatic region, is perhaps the most cost-effective method to diagnose (and treat) gastrinoma in dogs and cats. Histologic and immunocytochemical evaluation of the mass excised at surgery confirms the diagnosis. Measurement of baseline serum gastrin concentration provides further evidence for or against gastrinoma and should be considered before surgery, especially if a mass is not identified with abdominal ultrasound. Unfortunately, gastrin-secreting tumors are often smaller than 1 cm and not discernible with routine imaging techniques, exploratory celiotomy is not typically considered unless a perforated gastric ulcer or peritonitis is suspected, and measurement of serum gastrin is not considered simply because gastrinoma is rare in dogs and cats. As such, most dogs and cats with gastrinoma are inadvertently treated for severe inflammatory bowel disease and gastroduodenal erosions/ulcers with inhibitors of gastric acid secretion, mucosal protectants, antibiotics, and diet. Presumably many of these dogs and cats respond to treatment and gastrinoma would be considered only if the dog or cat became recalcitrant to medical therapy directed at nonspecific inflammation and ulceration of the gastrointestinal tract or if clinical signs and gastrointestinal ulceration recurred after discontinuing antiulcer therapy.