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Home , Big gastrin, Gastrinoma

(Zollinger-Ellison Syndrome) in the Dog and Cat Darcy H. Shaw Abstract Tumors of -secreting cells () result gastrin-secreting cells located in gastric . in a characteristic clinical syndrome of hyper- Released acetylcholine and gastrin stimulate acid secre- gastrinemia, which leads to hypersecretion tion by the parietal cells (3); B. Gastric distension. with subsequent severe gastrointestinal ulceration. The Distension of the stomach results in gastrin and most common clinical signs are inappetance/anorexia, acetylcholine releases mediated by vagal reflexes (4); lethargy, weight loss, vomiting, , and hypo- C. Chemical stimulation. Protein is the main food albuminemia. Hypergastrinemia is also seen in other ingredient responsible for stimulating acid secretion. disorders and caution should be used in utilizing fast- In particular, peptides and especially amino acids are ing serum gastrin concentrations as the sole diagnostic the most potent stimulators and they act by stimulating criterion. gastrin release (3). Food present within the stomach and upper has a predominantly stimu- Resume latory effect on acid secretion, while more distal parts Gastrinomes (syndrome Zollinger-Eillson) chez of the intestinal tract are inhibitory. le chien et le chat The stimulation of acid secretion relies on three Les tumeurs qui secretent de la gastrine (gastrinomes) major mediators: acetylcholine, histamine, and resultent en un syndrome clinique caracteristique de gastrin. Histamine is present in high concentrations in l'hypergastrinemie. L'hypersecretion d'acide au niveau the gastric mucosa; the source of histamine in the dog de l'estomac est responsable de la formation d'ulceres appears to be from cells resembling mast cells located gastro-intestinaux serieux. L'inappetence, l'anorexie, in the lamina propria adjacent to the acid-secreting la lethargie, une perte de poids, des vomissements, de parietal cells. The mechanism for release and produc- la diarrhee et de l'hypoalbuminemie figurent parmi les tion of histamine at this site remains unknown (5). observations cliniques les plus frequemment rencon- The hormone gastrin exists primarily in two forms: trees. Puisque l'hypergastrinemie peut etre rencontrie a 17 (G17) and a 34 (G34) peptide some- dans d'autres conditions, il est important de les dis- times referred to as little and , respectively cerner si on utilise les concentrations de gastrine (6). The 17 amino acid peptide is principally found in serique a jeun comme seul moyen de diagnostic. the gastric and proximal duodenal mucosa while G34 is the predominant circulating form (6). Gastrin is pro- duced by enterochromaffin cells (G-cells) situated in Can Vet J 1988; 29: the gastric and duodenal mucosa. Gastrin release occurs following vagal stimulation, gastric distension Introduction and the presence of dietary peptides and amino acids Gastrointestinal ulceration is diagnosed infrequently in the intestinal lumen. Its release is inhibited by a in small animals. There are numerous causes of negative feedback effect of the secreted acid on G cells ulceration in the dog and cat, but few syndromes have in the gastric and duodenal mucosa (6). In addition as a predominant sign the formation of severe . to stimulating gastric acid secretion, gastrin also has Zollinger-Ellison syndrome in man and other mam- a trophic effect on the gastric mucosa (7), stimulates mals is caused by a functional tumor(s) of gastrin- gastric antral motility (8), increases the secretion of secreting cells (1,2). This results in a marked increase pancreatic enzymes (9), and increases the tone of the in serum gastrin concentration which serves as a potent lower esophageal sphincter (10). Gastrin is metabolized stimulus for gastric acid secretion. Severe gastro- in the capillary beds of most tissues (11). intestinal ulcers form secondary to the gastric acid Acetylcholine is released by the postganglionic para- hypersecretion. This article will review the physiology sympathetic fibers that innervate the gastric glands. of gastric acid secretion and summarize the reported Its release will increase acid secretion by directly cases of canine and feline Zollinger-Ellison syndrome. stimulating parietal cells or by increasing gastrin con- centrations (4). The has distinct receptors for gastrin, Acid Secretion histamine, and acetylcholine (Figure 1) (5). These three Three mechanisms contribute to stimulating acid secre- secretagogues have varying degrees of synergism with tion following ingestion of food: A. Cephalic-vagal each other and maximal acid secretion occurs when stimulation. The sight, smell and taste of food result all three are present. in stimulation of the vagal nerve. Vagal nerve fibers cells and innervate acid-secreting gastric parietal Exogenous Inhibitors of Acid Secretion Department of Companion Animals, Atlantic Veterinary Anticholinergic agents (e.g. atropine, isopropramide, College, University of Prince Edward Island, 550 University propantheline) inhibit acid production by interfering Avenue, Charlottetown, Prince Edward Island ClA 4P3. with the action of acetylcholine on parietal cells. The

448 Can Vet J Volume 29, May 1988 Ages of the dogs ranged from 3.5 to 10.5 years; the cat was 12-years-old. No breed or sex predilection was noted. The duration of illness ranged from a few weeks to four months in the dogs, and was present for two years in the cat. The most frequent clinical signs in all animals were weight loss, lethargy, dehydration, vomiting, and (Table 1). All eight animals had a primary pancreatic tumor and five of eight had hepatic and regional lymph node metastasis. The light colored, firm tumors ranged in size from 1-10 mm. The primary tumor was located in the and was single in six and multiple in two animals. Thus, the character of the tumor would appear to be similar to that in human beings in which half the gastrinomas are multiple and over two thirds are malignant (1). In man, the tumors are described as slow growing, locally invasive, and will metastasize to local lymph nodes, liver, spleen, bone, media- stinum, peritoneal surfaces, and skin (1). The histo- I& pathology of the gastrinomas in these animals varied acetyl choline gastrin histamine somewhat with the cells arranged in solid masses, ribbon, and trabecular patterns, or as acini (18,19). In human beings, tumors or hyperplasia of extrapan- Figure 1. A diagrammatic representation of a gastric creatic endocrine glands occur in 487o of patients with parietal cell demonstrating the presence of receptors for syndrome (22). Also, approximately hista- Zollinger-Ellison acetylcholine, gastrin and histamine. Acetylcholine, 2507o of human patients with Zollinger-Ellison syn- mine and gastrin have synergistic effects on the parietal cell drome are afflicted with the multiple endocrine to stimulate hydrochloric acid secretion. neoplasia syndrome, type I (MEN I tumors or hyperplasia of the pancreatic islets, parathyroids, and maximal inhibition that can be achieved with these Interestingly, three of eight animals in food- pituitary glands). agents in humans is a 30-40%Vo reduction had adrenocortical hyperplasia, while one animal had stimulated acid secretion (5). There are two types of hyperplasia of thyroid C-cells (16,18). in the body, referred to histamine receptors present Gastrointestinal ulceration was commonly reported. occur exclu- as H1 and H2 receptors. H2 receptors Proximal duodenal ulceration occurred in five of seven sively on parietal cells and their activation results in animals, while gastric and jejunal ulceration occurred H1 receptors occur in vascular as well acid secretion. only once. was present in five animals and as other tissues and are responsible for all of the other in the of two animals. that ulcers were present effects of histamine. Therefore, only those drugs The diameter, depth and number of ulcers was fre- antagonize H2 receptors will be useful in inhibiting not reported. Diameters ranged from 4-8 mm histamine. Cimetidine and quently acid secretion mediated by in two cases (15,19) and there was an equal incidence receptor antagonists, ranitidine are examples of H2 of solitary versus multiple ulcers. In human beings, and they will markedly inhibit basal plus food- solitary ulcers of small to moderate size (less than acid secretion (5).' is a stimulated 1 cm) are usually seen with gastrinomas (1). Gastric substituted benzimidazole and inhibits parietal cell H + - K + ATPase which is responsible for pumping hydrogen ion into the gastric lumen. This drug is a potent inhibitor of acid secretion and has been used Reatieincie..nce :of. Clinical Signs successfully in human patients with Zollinger-Ellison .;.1"..t~ ~ ~ ~~~~~~~~~~~~~~~~ ot MI syndrome (12). (15.15,0 an Femne (10 Zollinger-Ellison Syndrome in the Dog .ini Dogs (Ct.. and Cat ...... ~~ ~ ~~~ ~ ~ ~ ~ ~~~~~~~~~~~~~~~~~~~~~~~~~...... In 1955, Zollinger and Ellison described, in man, a Inappetance/anorexia 7 + Lethargy 7 + syndrome of marked gastric acid hypersecretion, upper 7 + cell vomiting ulceration, and non-beta islet Weight loss 6 + tumors (13). It was later demonstrated that the tumors Diafrhea 6 _ consisted of gastrin-secreting cells that liberated large Decreased serum albu5min S quantities of gastrin into the circulation resulting in Hentmaesi 3 + Anemia (mid to. moderate) 3 + hypersecretion of gastric acid (14). Meena 3 Steatoffbea 3 - Clinical and Pathological Findings Elevatd alkalin syndrome The first case resembling Zollinger-Ellison E in a dog was described in 1976 (15). To date, one feline 2 seven canine cases have been described (15-20). and -j I AA!I,*9 Can Vet J Volume 29, May 1988 rugal hypertrophy occurs frequently in man and diarrhea is thought to result from the combined effect animals secondary to the trophic effects of gastrin and of large volumes of gastric contents presented to the was observed in five of eight animals. , a gastrin-related inhibition of fluid and Fasting serum gastrin concentration was elevated in electrolyte reabsorption in the small intestine, and all animals in which it was measured and ranged from rapid intestinal transit (27). 360 to 2780 pg/mL (measured in five of seven dogs) In man, is usually less common than in affected dogs and was 1000 pg/mL in the cat. diarrhea (1). This was also the case in this group of Reported fasting gastrin values in normal dogs are animals where steatorrhea was identified in three of 65.8-76 pg/mL (18), 23-104 pg/mL (15) and eight animals. This is thought to be due to low 20-100 pg/mL (21). Fasting serum gastrin concentra- duodenal pH that renders bile acids insoluble (prevent- tion was measured in three normal cats and ranged ing them from emulsifying fats for absorption) and from 28-135 pg/mL (19). Hypergastrinemia, as in inactivates pancreatic lipase (1). of man, is not exclusive to canine Zollinger-Ellison vitamin B12 may develop in man by interfering with patients. In dogs, hypergastrinemia has been docu- the ability of (produced in the stomach) mented in gastric and intestinal ulcers without to facilitate absorption of vitamin B12 in the (1). neoplasia (20), gastric dilation complex (23), renal insufficiency (24), and in Basenji dogs with immunoproliferative (25). Hypergas- Diagnosis based trinemia may also occur secondary to drug therapy. The diagnosis of Zollinger-Ellison syndrome is Medications that increase the gastric and duodenal pH upon finding gastrointestinal ulceration, elevated and/or acid (e.g. antacids), or interfere with normal acid secretion fasting serum gastrin concentration, (e.g. H2 receptor antagonists, anticholinergics) will hypersecretion or testing the increase in serum gastrin or calcium remove the normal feedback mechanisms on gastrin induced by feeding, intravenous release and result in elevated concentrations. In addi- gluconate. Gastrinoma should be suspected if vomiting tion, hypergastrinemia has been documented in human (+ / - ), prolonged diarrhea or steat- beings associated with hypercalcemia (1), glucocor- orrhea, and the presence of gastric rugal fold hyper- on contrast (28). The ticoid excess (26), nontumorous hypergastrinemic trophy is present radiographs hyperchlorhydria (1), hypochlorhydria (1), and definitive diagnosis requires the measurement of retained gastric antrum and (1). fasting serum gastrin concentrations and values are considered (28). Basal acid secretion was measured in two dogs and was exceeding 500 pg/mL diagnostic 15 mEq/h and 3 mEg/h (16,18). Basal acid secretion Since mild to moderate hypergastrinemia can occur in than in the presence of was not detectable in nine healthy dogs (18). In man, situations other gastrinomas administra- basal acid secretion exceeds 10 mEq/h in over two- (e.g. hypercalcemia, chronic renal failure, thirds of gastrinoma patients (1). tion of cimetidine, ranitidine, or glucocorticoids) it has been suggested that a stimulation test in the form of a test meal be used to diagnose gastrinomas in dogs (21). A 24-hour fast, followed by the administration SEQUELAE OF HYPERGASTRINEMIA of a commercial diet (Prescription diet p/d, Hill's Pet Food Inc, Topeka, Kansas) and beef broth (Swanson GASTRIN SECRETING TUMOR clear beef broth, Campbell Soup Co, Camden, New Jersey) (approximately 200 grams each) has been used as a test meal (21). In a normal animal, gastric disten- GASTRIC RUGAL HYDROCHLORIC ACID FOLD HYPERTROPHY HYPERSECRETION sion and chemical stimulation by peptides and amino acids will result in a postprandial rise in gastrin con- centration. Serum gastrin values should not exceed GASTRIC AND DUODENJAL STEATORRHEA 200 pg/mL and 100 pg/mL, thirty and ninety minutes ULCERATION DIARRHEA The of a test WEIGHT LOSS after feeding, respectively (21). feeding meal was not performed in any of the reported cases. MELENA In man, normal individuals have less than a 5007o HEMATEMESIS increase over fasting concentrations while gastrinoma patients have greater than a 200% increase (1). Addi- human involve Figure 2. The sequelae of hypergastrinemia. tional tests performed in beings measuring the gastrin response to intravenous secretin or calcium gluconate. Secretin, given to normal human Except for those signs that may be associated with beings will result in little or no increase in serum gastrin widespread metastasis, the majority of the clinical (1). Secretin, at 2 units/kg body weight, is given as an manifestations are related to hypergastrinemia and intravenous infusion over thirty minutes. Samples for gastric acid hypersecretion (Figure 2). The gastro- gastrin assay are collected at five minute intervals. In intestinal ulceration caused by gastric hypersecretion human patients with gastrinomas, gastrin concentra- could be responsible for the anorexia, vomiting, hema- tions increased by more than 200 pg/mL over baseline temesis, melena, anemia, and hypoalbuminemia (due (1). The use of pure porcine GIH secretin (Kabi Group to blood loss into the gut) seen in the affected animals. Inc, Greenwich, Connecticut) has been recommended Diarrhea is a frequent sign in human beings and was in man (1). Boot's secretin should be avoided because frequently reported in these animals. In human beings, it is less potent than porcine GIH secretin and it cross-

450--uILaIn-jLvet %voiume..- - f%f%,ayh A - Wl10 450 Can Vet J Volume 29, May iguts reacts with gastrin antibodies used in the radio- Mylanta; Stuart Laboratories) (17). The dog responded immunoassay (29). This would result in spuriously high favorably initially, but signs recurred two months later gastrin values. The calcium infusion test, as performed and the dog was euthanized. The third dog was treated in man, uses calcium gluconate infused intravenously surgically to repair a perforated duodenal on two at a rate of 5 mg/kg body weight-per-hour for a three- occasions, one week apart, but died five days after the hour period (1). Gastrin concentrations are obtained second surgery due to septic (20). at thirty-minute intervals for four hours. In human With early recognition, the use of potent anti- gastrinoma patients, there is usually an increase of secretory medications and tumor excision could pro- more than 400 pg/mL over baseline values. A secretin vide a good quality of life for dogs and cats with and calcium infusion test was performed on only one gastrinomas. However, due to the malignant nature dog with a gastrinoma (16). Following an intravenous of most gastrinomas, it is likely that long-term success bolus dose of calcium gluconate (2 mg/kg body would be limited by metastatic disease. cvJ weight), gastrin concentration rose from a baseline of 400 pg/mL to a peak of 1100 pg/mL, sixty minutes References later. An intravenous bolus dose of secretin (4 units/kg 1. McGuigan JE. Zollinger-Ellison syndrome, In: Sleisenger MH, body weight), increased gastrin concentration from a Fordtran JS, eds. . 3rd ed. Vol 1. baseline of 400 pg/mL to a peak of 2400 pg/mL in Philadelphia: WB Saunders Co, 1983: 693-707. five minutes. In man, the secretin infusion test is con- 2. Drazner FH. Diseases of the pancreas. In: Jones BD, ed. Canine sidered the most reliable provocative test (12). and Feline . Philadelphia: WB Saunders Co, 1986: 295-344. 3. Feldman M. Gastric secretion, In: Sleisenger MH, Fordtran JS, eds. Gastrointestinal Disease. 3rd ed. Vol 1. Philadelphia: WB Treatment Saunders Co, 1983: 541-558. Therapeutic recommendations for animals with 4. Brooks FP. Physiology of the stomach. In: Berk JE, ed. gastrinomas have focused on medical therapy to reduce Gastroenterology. 4th ed. Vol 2. Philadelphia: WB Saunders the acid hypersecretion and surgical extirpation of the Co, 1985: 874-940. 5. Soll AH, Walsh JH. Regulation of gastric acid secretion. Ann tumor. Medical therapy rests on the use of H2 antag- Rev Physiol 1979; 41: 35-53. onists such as cimetidine (Tagamet; Smith, Kline and 6. Walsh JH, Grossman MI. Gastrin. N Engl J Med 1975; 292: French Canada Ltd, Mississauga, Ontario) at a dose 1324-1334. of 20 mg/kg body weight, given every eight hours, or 7. Willems G, Gepts W, Bremer A. Endogenous hypergastrinemia and cell proliferation in the fundic mucosa in dogs. Digest Dis ranitidine (Zantac; Glaxo Laboratories, Toronto, 1977; 22: 419-423. Ontario) at a dose of 10 mg/kg body weight, given 8. Strunz UT, Code CF, Grossman MJ. The effect of gastrin on every twelve hours, or the anticholinergic, isopro- electrical activity of antrum and duodenum of dogs. Proc Soc pramide (Darbid; Smith, Kline and French Canada Exp Biol Med 1979; 161: 25-27. Ontario), at a dose of 0.2 mg/kg 9. Schapiro H, Rosato FE, Jackson NJ, et al. Effect of gastrin Ltd, Mississauga, on the exocrine pancreas: A review. Am J Gastroenterol 1979; body weight, given every twelve hours (28). The tumor 71: 53-60. should be excised if possible. Medical therapy should 10. Strombeck DR, Harrold D. Effect of gastrin, histamine, precede attempts to excise the tumor to decrease the serotonin, and adrenergic amines on gastroesophageal sphincter clinical signs and ulcer formation. It has been recom- pressure in the dog. Am J Vet Res 1985; 46: 1684-1690. 11. Strunz UT, Walsh JH, Grossman MI. Removal of gastrin by mended that if there is a favorable response to medical various organs in dogs. Gastroenterology 1978; 74: 32-33. therapy preoperatively, only tumor excision need be 12. Wolfe MM, Jensen RT. Zollinger-Ellison syndrome: Current done. However, if the animal is refractory to medical concepts in diagnosis and management. N Engl J Med 1987; management, surgical intervention should include 317: 1200-1209. to remove the 13. Zollinger RM, Ellison EH. Primary peptic ulceration of the tumor removal and total gastrectomy associated with islet cell tumors of the pancreas. Ann target organ (28). Also, a selective vagotomy should Surg 1955; 142: 709. be done if no tumor is found or if metastasis is pres- 14. McGuigan JE, Trudeau WL. Immunochemical measurement ent (28). Due to the advent in recent years of newer of elevated levels of gastrin in the serum of patients with pan- and more potent antisecretory drugs (i.e. ranitidine, creatic tumors of the Zollinger-Ellison variety. N Engl J Med 1968; 278: 1308. omeprazole) more human gastrinoma patients are 15. Jones BR, Nicholls MR, Badman R. Peptic ulceration in a dog dying of metastatic disease rather than from complica- associated with an islet cell of the pancreas and an tions arising from gastrointestinal ulceration (12). In elevated plasma gastrin level. J Small Anim Pract 1976; 17: human beings, because of the efficacy of medical 593-598. of total 16. Straus E, Johnson GF, Yalow RS. Canine Zollinger-Ellison therapy and the uncertain effects gastrectomy, syndrome. Gastroenterology 1977; 72: 380-381. it is recommended that total gastrectomy be reserved 17. Drazner FH. Canine gastrinoma: A condition analogous to the for those patients that are noncompliant with medical Zollinger-Ellison syndrome in man. Calif Vet 1981; 11: 6-11. therapy or will not have access to routine follow-up 18. Happe RP, Van Der Gaag I, Lamers CBHW, et al. Zollinger- Ellison syndrome in three dogs. Vet Pathol 1980; 17: 177-186. (12). 19. Middleton DJ, Watson ADJ. Duodenal ulceration associated Three of eight animals were treated. One animal had with gastrin-secreting tumor in a cat. J Am Vet Med Assoc 1983; a solitary pancreatic mass resected (18). The tumor and 183: 461-462. clinical signs returned 4.5 months following surgery 20. Breitschwert EB, Turk JR, Turnwald GH, et al. Hyper- and the dog was euthanized. The second animal was gastrinemia in canine gastrointestinal disease. J Am Anim Hosp Assoc 1986; 22: 585-592. treated medically with cimetidine, propantheline 21. Gabbert NH, Nachreiner RF, Holmes-Word P, et al. Serum hydrobromide (Probanthine; Searle Laboratories, San immunoreactive gastrin concentrations in the dog. Basal and Juan, Puerto Rico), and antacids (aluminum hydroxide/ post-prandial values measured by radioimmunoassay. Am J Vet magnesium hydroxide/simethicone suspension- Res 1984; 45: 2351-2353.

Can Vet J Volume 29, May 1988 451 22. Lamers CBHW, Stadali F, Van Tongeren JH. Prevalence of 26. Straus E. The explosion of gastrointestinal hormones. Their endocrine abnormalities in patients with Zollinger-Ellison clinical significance. In: Janowitz HD, ed. Med Clin of North syndrome and their families. Am J Med 1978; 64: 607-612. America. Vol 62. Philadelphia: WB Saunders Co. 1978: 21-37. 23. Leib MS, Wingfield WE, Twedt DC, et al. Plasma gastrin 27. Walsh JH, Grossman MI. Gastrin. N Engl J Med 1975; 292: immunoreactivity in dogs with acute gastric dilation-volvulus. 1377-1384. J Am Vet Med Assoc 1984; 185: 205-208. 28. Chastain CB, Ganjam VK. The Clinical Endocrinology of 24. Jonas LD, Twedt DC. Serum gastrin concentrations in dogs Companion Animals. Philadelphia. Lea & Febiger, 1986. with acute and chronic renal failure. In: ACVIM Scientific 29. Brady CE, Johnson RC, Williams JR, et al. False positive serum Proceedings, Salt Lake City, Utah, July, 1982. gastrin stimulation due to impure secretin. Gastroenterology 25. Breitschwert EB, Ochoa R, Barta, M. et al. Clinical and 1979; 76: 1106. laboratory characterization of the Basenji dog with immuno- proliferative small intestinal disease. Am J Vet Res 1984; 45: 267-273.

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452 Can Vet J Volume 29, May 1988