World J. Surg. 3, 539-544, 1979
Hyperacidity and Hypergastrinemia Following Extensive Intestinal Resection William C. Meyers, M.D. and R. Scott Jones, M.D. Departments of Surgery and Physiology, Duke University Medical Center, Durham, North Carolina, U.S.A.
tion will be reviewed. Then some possible explanations for these effects will be presented.
Increased gastric acid secretion occurs after extensive intestinal resection in man, dog, rat, and monkey. Hypergastrinemia has been observed in patients with short gut syndrome and appears to accompany the hyperacidity after intestinal resection in dog, rat, and monkey. Postresectional hypergastrinemia is caused by increased release of gastrin and/or decreased degradation of the hormone. Other hormonal changes after extensive resection include increased insulin, GIP, pancreatic glucagon, and decreased enteroglucagon.
Hyperacidity
Shortening of the intestine has been known to be associated with increased acid production for most of this century. Stassoff [4] in 1914 first described increased gastric acid secretion in dogs following massive intestinal resection. The first suggestion in the literature of a clinically significant syndrome was in 1954 by Shelton and Blaine [5] who reported a patient dying from a marginal ulcer after loss of about 3/4 of his bowel. In 1964, Frederick, Sizer, and Osborne [6, 7] provided the first description of a patient with increased acidity associated with extensive intestinal loss. The gastric hyperacidity following bowel resection subsequently has been confirmed in dogs, rats, and monkeys [8-17]. The same species have been used to characterize the acid hypersecretion after resection. In monkeys the hyperacidity occurs early after intestinal resection and persists for at least 6 months [16, 18]. Both basal and maximal histamine stimulated acid outputs (BAO, MAO) were greater than in control monkeys and the BAO:MAO ratio increased from 0.2 to 0.5 [16]. In dogs it is difficult to achieve normal basal acid output ranges after resection, except by prolonged fasting of the animal or administration of atropine [12]. The timing of the acid response to histamine is normal. Food-stimulated gastric acid secretion is increased in dogs, rats, and monkeys
The cause of the gastric hyperacidity occurring after massive small bowel resection is not known, but is most likely explained by the loss or inactivation of an inhibitor of gastric acid secretion or by increased activity of a secretagogue from the remaining portion of the gastrointestinal (GI) tract. Regulation of gastric secretion by GI hormones is incompletely understood, although many hormones and candidate hormones have been demonstrated to stimulate or inhibit gastric acid secretion. For example, gastrin, cholecystokinin (CCK), bombesin, and entero-oxyntin all can stimulate acid secretion; while secretin, glucagon, GIP, VIP, somatostatin, and serotonin all can inhibit [1-3]. Whether or not any of these substances plays an important part in postresectional hyperacidity is not known. This review attempts to outline succinctly the evidence for the participation of GI hormones in the increased gastric acid production following extensive intestinal resection. First, the evidence for hyperacidity and hypergastrinemia occurring after resec-
Reprint requests: R. Scott Jones, M.D., Department of Surgery, Box 3815, Duke University Medical Center, Durham, North Carolina 27710, U.S.A.
0364-2313/79/0003-0539 $01.20 9 1979 Soci6t6 Internationale de Chirurgie 539
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[14-16]. Gastric stasis or altered gastric emptying does not account for the hyperacidity [19, 20]. Antrectomy reduces or abolishes the hyperacidity in dogs and monkeys [15, 18, 21], while vagotomy increases both fasting and food-stimulated acid outputs from Heidenhain pouches of awake dogs following intestinal resection [ 15]. Parenteral administration of extracts from the resected jejunum of rats also reduces the basal acid levels [14]. Strong evidence for participation of GI hormones in postresectional hyperacidity is that increased acid production occurs in vagally denervated gastric pouches following small bowel resection [8]. In man, the syndrome of gastric hyperacidity after resection is not well characterized. Intermittent gastric acid hypersecretion [22] and acidic jejunal contents [23] have been reported many months following intestinal removal. Both gastric resection, and vagotomy and pyloroplasty, have been reported to improve patient survival [24-26]. However, there is also evidence that gastric acid hypersecretion occurs early following extensive intestinal resection, but is not usually a problem months later [27]. Both small intestinal resection and bypass produce hyperacidity in dogs and rats, and the amount and location of intestine removed or bypassed appear to be important [28-34]. Ileal-ileal bypass for patients with hypercholesterolemia does not produce hyperacidity [35], but whether or not jejunalileal bypass does has not been conclusively determined [36-41]. The extent of intestinal resection necessary to cause increased acid secretion in man has not been determined [27].
World J. Surg. Vol. 3, No. 5, 1979
scending slopes of the meal-stimulated gastrin response of resected patients were similar to controls, Straus and associates postulated that elevated gastrin levels after intestinal resection are more likely due to loss of inhibition of gastrin release than to decreased degradation of gastrin. The hypergastrinemia following small bowel resection was confirmed in animal studies [3 l, 43, 44]. Wickbom and associates [17, 43] measured both Heidenhain pouch acid secretion and serum gastrin concentration in dogs before and after intestinal resection, and found elevated postprandial gastric acid secretion and increased gastrin, although fasting gastrin was unchanged. In addition, there was a high degree of correlation between increases in acid outputs and serum gastrin after feeding. The failure to observe increased gastrin levels and gastric hypersecretion in the basal state in these dogs is probably explained by the prolonged period of fasting that preceded the experiments. Fasting serum gastrin concentrations in monkeys were observed to increase significantly 6 weeks after resection and to return to normal after 6 months or after antrectomy [16, 44]. Because those monkeys also had lower esophageal pressure changes that persisted after antrectomy, the authors speculated that a substance produced in the distal small intestine that inhibited antral secretion of gastrin and directly altered esophageal motility had been lost with the resected segment [44].
Possible Explanations for the Hyperacidity and Hypergastrinemia Loss o f an Inhibitor
Hypergastrinemia Hypergastrinemia in patients with short bowel syndrome was first reported in 1974 by Straus, Gerson and Yalow [42]. They measured total and fractionated plasma gastrin concentrations in 4 patients who had extensive resections, and in 1 who had a jejunal-ileal bypass for obesity. The 4 patients with resections, including 1 patient who had had a previous vagotomy and Billroth I gastrectomy, all had fasting and postprandial gastrin levels 3-20 times higher than mean gastrin levels of a control group of patients. In contrast, the jejunal-ileal bypass patient did not demonstrate these elevations. We have recently observed an interesting patient with short gut syndrome and a previous 50% Billroth II gastrectomy with barely detectable basal serum gastrin, and low meal-stimulated levels. The elevated gastrin in the patients of Straus et al. was predominantly "big" gastrin, a biologically active form of the hormone. Because the ascending and de-
Some circumstantial evidence suggests that the distal small intestine produces a gastric acid inhibitor which is lost following resection and, therefore, causes the hyperacidity. That evidence is: (a) in patients after resection, the slope of the disappearance from plasma of meal-stimulated gastrin is more compatible with increased secretion of gastrin than decreased degradation [42]; (b) antrectomy abolishes hyperacidity without affecting lower esophageal pressure changes in monkeys [44]; (c) injection of extracts from the resected bowel of rats abolishes the hyperacidity [14]; (d) there is no evidence for increased production of a secretagogue other than gastrin by the remaining GI tract; and (e) some GI hormones known to inhibit gastrin secretion under various conditions are produced in small bowel mucosa.
Nonetheless, loss of a GI hormone that is a gastric acid inhibitor is a plausible explanation, so it is important to consider the known inhibitors of gas-
W.C. Meyers and R.S. Jones: Hyperacidity after Bowel Resection
541
Table 1. Observed hormonal changes after extensive intestinal resection.
Man Dog Monkey
Gastrin
Secretin
GIP
Insulin
Glucagon
Enteroglucagon
T
NT 0 NT
NT NT I'
NT 1' NT
NT 1' NT
NT J, NT
T I'
T increased; ~ decreased; 0 no change; NT not tested.
tric acid secretion that normally reside in the small bowel. Secretin, CCK, and GIP concentrations are greatest in the proximal small intestine and, therefore, are unlikely candidates to account for the hyperacidity observed after bowel resection in man [ l, 2], because proximal jejunum and duodenum usually remain intact in patients undergoing massive resection. In addition, serum GIP concentrations were found to be elevated in monkeys after resection [16, 18] and secretin levels were unchanged in dogs [45]. Similarly, serotonin [46], insulin [3, 45], and pancreatic glucagon [45], are not likely candidates because they have other principal sites of production and are not decreased after resection in dogs. Both fasting and stimulated levels of glucagon-like reactivity, however, were found to be profoundly diminished in one study on greyhounds, while pancreatic glucagon levels were not decreased [45]. In addition, there is a large concentration of glucagon-like reactivity in the distal small bowel [47]. These data suggested that a glucagonlike substance produced in the distal small bowel might be the important inhibitor. Further study is necessary to determine the meaning of these findings. histaminase have not yet been studied, so they also cannot be ruled out as candidates for the implicated inhibitor.
Impaired Degradation An alternative explanation for the hypergastrinemia that occurs after extensive bowel resection is a decrease in the capability for metabolic disposal of gastrin. There is evidence that the small bowel participates in the metabolism of gastrin [48, 49]. During endogenous release of gastrin, a 43% diminution in the integrated gastrin response across the small bowel circulation was reported in dogs [49]. The removal of gastrin in the fasted, anesthetized dog is apparently about the same for all the major vascular beds [50]. Impaired degradation of gastrin might account for the apparent prolongation of meal-stimulated gastric acid secretion after resection. If decreased intestinal degradation were the mechanism,
intestinal hyperplasia could explain the normal fasting gastrin levels seen in monkeys at 6 months after intestinal resection and not at 6 weeks [16, 18].
Conclusion
In summary, extensive intestinal resection causes both gastric acid hypersecretion and hypergastrinemia in man and experimental animals. Because there is a high degree of correlation between increases in acid outputs and serum gastrin levels in dogs, it seems reasonable to think that the hypergastrinemia is somehow causally related to the hyperacidity. In addition, no experimental evidence has yet been presented to suggest increased activity of another secretagogue, or that increased responsiveness of parietal cells to a secretagogue might be responsible. Although parietal cell hyperplasia has been observed in rats 9 months after resection [51], there is no evidence that this was associated with increased acid production; and parietal cell hyperplasia was not seen in dogs with hyperacidity in 2 studies [12, 27]. A loss of a gastric acid inhibitor that normally resides in the small intestine, impaired degradation of gastrin, or a combination of these 2 mechanisms are, therefore, the most likely explanations. Loss of an inhibitor must somehow permit increased release or decreased metabolism of gastrin. For a hormone to be the proposed inhibitor, it would have to satisfy the following requirements: (a) it would have to reside normally in the portion of bowel that is resected and be capable of inhibiting acid production; (b) levels of that hormone would have to be decreased after resection, and this decrease would have to permit hyperacidity and elevation of serum gastrin concentration to the degree seen clinically and experimentally. No hormone studied so far has satisfied all these requirements. For example, secretin, GIP, and pancreatic glucagon all are present under normal conditions in small bowel mucosa [l, 2]. All 3 have been demonstrated to inhibit gastric acid production and gastrin release under nonphysiologic conditions only, and none has been shown to be decreased significantly after bowel resection. Of considerable interest, however, was
542
the observation that glucagon-like reactivity was decreased and pancreatic glucagon increased after bowel resection, suggesting that a glucagon-like substance from the distal small bowel was lost. The validity of the lost inhibitor hypothesis will be determined by further study. The gastric acid hypersecretion consequent to extensive small intestinal resection may be very important clinically, particularly in the early period following loss of the intestine. It is possible that increased acid secretion may contribute to maldigestion and, consequently, to malabsorption. In addition, the development of duodenal ulcer and its complications is a risk following small bowel resection. Fortunately, it appears in humans that the hyperacidity following small bowel resection is not permanent, but improves during the several months after resection in most patients. With the availability of cimetidine to manage acid hypersecretion, increased acid secretion following small bowel resection can be prevented. We recommend that any patient undergoing extensive intestinal resection should have gastric acid secretion, as well as serum gastrin concentration, measured and, if high acid secretory rates are documented, the patient should receive cimetidine until acid secretion returns to normal levels.
R6sum6
Chez l'homme, le chien, le rat et le singe, la rrsection intestinale 6tendue augmente la s6crrtion gastrique d'acide. Une hypergastrin6mie a 6t6 mise en 6vidence chez les malades avec rrsection grrle large et semble accompagner l'hyperchlorydrie de la r6section intestinale chez le chien, le rat et le singe. Cette hypergastrinrmie est due ~ une librration accrue de gastrine et/ou h une drgradation moins importante de l'hormone. Les autres modifications hormonales observres aprrs rrsection intestinale 6tendue sont une augmentation de l'insuline, du GIP et du glucagon pancrratique, et une rrduction de l'entrroglucagon. References 1. Rayford, P.L., Miller, T.A., Thompson, J.C.: Secretin, cholecystokinin and newer gastrointestinal hormones. N. Engl. J. Med. 294:1093, 1157, 1976 2. Walsh, J., Grossman, M.I.: Gastrin. N. Engl. J. Med. 292:1324, 1377, 1975 3. Johnson, L.R., Grossman, M.I.: Intestinal hormones as inhibitors of gastric secretion. Gastroenterology 60:120, 1971 4. Stassoff, B.: Experiementalle untersuchurgen uber die kompensatorischen Vorgange bei Dermiesktionen. Beitr. Klin. Chir. 89:527, 1914 5. Shelton, E.L., Blaine, M.H.: Massive small bowel resection in a postgastrectomy patient. Texas J. Med. 50:96, 1954
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6. Frederick, P.L., Sizer, J.S., Osborne, M.P.: Relation of massive bowel resection to gastric secretion. Trans. N.E. Surg. Assoc. 45:89, 1964 7. Frederick, P.L., Sizer, J.S., Osborne, M.P.: Relation of massive bowel resection to gastric secretion. N. Engl. J. Med. 272:509, 1965 8. Sabsai, B.I.: The effect of the small intestine on canine gastric secretion. Bull. Exp. Biol. Med. 55:387, 1963 9. Landor, J.H., Baker, W.R.: Gastric hypersecretion produced by massive small bowel resection in dogs. J. Surg. Res. 4:518, 1964 10. Westerheide, R.L., EUiott, D.W., Hardacre, J.M.: The potential of the upper small bowel in regulating acid secretion. Surgery 58:73, 1965 11. Osborne, M.P., Frederick, P.L., Sizer, J.S., Blair, D., Cole, P., Thum, W.: Mechanism of gastric hypersecretion following massive intestinal resection: clinical and experimental observations. Ann. Surg. 164:622, 1966 12. Reul, G.J., EUison, E.H.: Effect of 75% distal small bowel resection on gastric secretion. Am. J. Surg. 111:772, 1966 13. Caridis, D.T., Roberts, M., Smith, G.: The effect of small bowel resection on gastric acid secretion in the rat. Surgery 65:292, 1969 14. Ruderman, R., Kamel, I.: The effect of intestinal resection on gastric acidity in the rat. Surg. Forum 21:312, 1970 15. Wiens, E., Bondar, G.F.: Control of gastric hypersecretion following massive small intestinal resection. Surg. Forum 21:310, 1970 16. Moosa, A.R., Hall, A.W., Clark, J., Skinner, D.B.: Effect of 50% small bowel resection on gastric secretory function in Rhesus monkeys. Surgery 80:208, 1976 17. Wickbom, G., Landor, J.H., Bushkin, R., McGuigan, J.E.: Changes in canine gastric acid output and serum gastrin levels following massive small intestinal resection. Gastroenterology 69:448, 1975 18. Hall, A.W., Moosa, A.R., Wood, R.A.B., Block, G.E., Skinner, D.B.: Effect of antrectomy on gastric hypersecretion induced by distal small bowel resection. Ann. Surg. 186:83, 1977 19. Nylander, G.: Gastric evacuation and propulsive intestinal motility following resection of the small intestine in the rat. Acta Chir. Scand. t33:131, 1967 20. Hall, A.W., Moosa, A.R., Skinner, D.B.: The effect of distal small bowel resection on gastric emptying. Ann. Surg. 185:214, 1977 21. Landor, J.H.: Intestinal resection and gastric secretion in dogs with antrectomy. Arch. Surg. 98:645, 1969 22. Klein, M.S., Winawer, S.J.: Intermittent basal gastric hypersecretion following small bowel resection. Am. J. Gastroenterol. 61:470, 1974 23. Krone, C.L., Theodor, E., Sleisinger, M.H., Jeffries, G.H.: Studies on the pathogenesis of malabsorption. Lipid hydrolysis and micelle formation in the intestinal lumen. Medicine (Baltimore) 47:89, 1968 24. Frederick, P.L., Craig, T.V.: Effect of vagotomy and pyloroplasty on weight loss and survival of dogs after massive intestinal resection. Surgery 56:135, 1964 25. Winawer, S.J., Broitman, S.A., Wolochow, D.A., Osborne, M.P., Zamcheck, N.: Successful management of massive small bowel resection based on assessment of absorption defects and nutritional needs. N. Engl. J. Med. 274:72, 1966 26. Osborne, M.P., Sizer, J., Frederick, P.L., Zancheck, N.: Massive bowel resection and gastric hypersecretion: its mechanisms and a plan for clinical study and management. Am. J. Surg. 114:393, 1967 27. Windsor, C.W.O., Fejfor, T., Woodward, D.A.: Gastric secretion after massive small bowel resection. Gut 10:779, 1969 28. Copeland, E.M., Miller, L.D., Smith, G.P.: The complex nature of small bowel control of gastric secretion. Ann. Surg. 168:36, 1968 29. Kerr, G., Elliot, D.W., Endahl, G.L.: Effect of antrectomy on gastric acid hypersecretion induced by isolation of the
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proximal small bowel. Am. J. Surg. 115:157, 1968 30. Goldman, L.I., Dorn, B., Weinberger, M., Bralow, S.P., Gruenstein, M.: The small intestine and gastric secretion in the rat. The effects of intestinal bypass, resection, and supplemental hydration on interdigestive gastric secretion. Arch. Surg. 104:73, 1972 31. Bowen, J.C., Paddack, G.L., Bush, J.C., Wilson, R.J., Johnson, L.R.: Comparison of gastric responses in small intestinal resection and bypass in rats. Surgery 83:402, 1978 32. Saik, R.K., Copeland, E.M., Miller, L.D., Smith, G.P.: Effect of ileal exclusion on the Heidenhain pouch acid response to histamine in dogs. Ann. Surg. 173:67, 1971 33. Santillana, M., Wise, L., Schuck, M., Ballinger, W.F.: Changes in gastric acid secretion following resection or exclusion of different segments of the small intestine. Surgery 65:777, 1969 34. Landor, J.M., Behringer, B.R., Wild, R.A.: Postenterectomy gastric hypersecretion in dogs. The relative importance of proximal vs. distal resection. J. Surg. Res. 11:238, 1971 35. Buchwald, H., Varco, R.L.: Human gastric secretory studies following distal small bowel bypass. Gastroenterology 58: 931, 1976 36. Salmon, P.A., Wright, W.J.: Effect of small bowel bypass on gastric secretion in obese patients. Can. J. Surg. 11:365, 1968 37. Buchwald, H., Coyle, J.J., Varco, R.L.: Effect of small bowel bypass surgery on gastric secretory function: postintestinal exclusion hypersection, a phenomenon in search of a syndrome. Surgery 75:821, 1974 38. Coutsofides, T., Barakowski, J., Himal, H.S.: Gastric acid and serum gastric secretion before and after bypass of the small intestine for morbid obesity. Surg. Gynecol. Obstet. 142:521, 1976 39. Buchwald, H., Coyle, J.J., Varco, R.L.: Gastric hypersecretion and jejunal-ileal bypass [Letter]. Ann. Surg.
184:654, 1976 40. Wise, L., Vaughan, R., Stein, T.: Studies on the effect of small bowel bypass for massive obesity on gastric secretory function. Ann. Surg. 183:259, 1976 41. Scopinaro, N., Gianetta, E., Civalleri, D.: Small bowel bypass for obesity [Letter]. Ann. Surg. 186:776, 1977 42. Straus, E., Gerson, C.D., Yalow, R.S.: Hypersecretion of gastrin associated with the short bowel syndrome. Gastroenterology 66:175, 1974 43. Wickbom, G., McGuigan, J.E., Landor, J.H.: Role of gastrin in small bowel gastric hypersecretion. Surg. Forum 24:353, 1973 44. Hall, A.W., Moosa, A.R., Pelligrini, C., Clark, J., Skinner, D.B.: The effect of small bowel resection and subsequent precise antrectomy on lower esophageal function in Rhesus monkeys. Am. J. Surg. 133:544, 1977 45. Barros D'sa, A.A.B., Buchanan, K.D.: Role of GI hormones in the response to massive resection on the small bowel. Gut 18:877, 1977 46. Rosenberg, J.C.: Distribution of serotonin in the GI tract: effect of intestinal obstruction and resection on circulating serotonin. Surgery 56:388, 1964 47. Bloom, S.R., Polak, J.M., Pearse, A.G.E.: Endocrinology. London, Heine Mann, 1973, p. 91 48. Temperly, J.M., Stagg, B.H., Wyllie, J.H.: Disappearance of gastrin and pentagastrin in the portal circulation. Gut 12:372, 1971 49. Becker, H.D., Reeder, D.D., Thompson, J.C.: Extraction of circulating endogenous gastrin by the small bowel. Gastroenterology 65:903, 1973 50. Strunz, U.T., Walsh, J.H., Grossman, M.I.: Removal of gastrin by various organs in dogs. Gastroenterology 74:32, 1978 51. Seelig, L.L., Jr., Winborn, W.B., Weser, E.: Effect of small bowel resection on the gastric mucosa in the rat. Gastroenterology 72:421, 1977
Invited Commentary
tion of circulating gastrin concentrations can be s e e n b e s t in t e r m s o f a b a s i c f e e d b a c k - i n h i b i t i o n l o o p ( F i g . 1). W h e n c i r c u l a t i n g g a s t r i n c o n c e n t r a tions r i s e (Fig. 1, t o p ) , t h e g a s t r i c p a r i e t a l cells a r e s t i m u l a t e d t o s e c r e t e a c i d ( F i g . 1, right). W h e n t h e g a s t r i n - c o n t a i n i n g a n t r a l m u c o s a is b a t h e d in a c i d , f u r t h e r r e l e a s e o f g a s t r i n is i n h i b i t e d (Fig. l , b o t t o m ) . T h i s is t h e c r u c i a l f e e d b a c k - i n h i b i t i o n a s p e c t o f t h e c y c l e t h a t is a b s e n t w h e n g a s t r i c a t r o p h y h a s reduced or eliminated the acid-secreting capacity of t h e s t o m a c h . It is t h e a b s e n c e o f this m e c h a n i s m which accounts for the markedly elevated circulating g a s t r i n c o n c e n t r a t i o n s f o u n d in p a t i e n t s w i t h p e r n i c i o u s a n e m i a . P l a s m a g a s t r i n l e v e l s fall p r o m p t l y w h e n h y d r o c h l o r i c a c i d is i n s t i l l e d i n t o the stomach of a patient with pernicious anemia. It is a l s o this a s p e c t o f t h e c y c l e w h i c h is b y p a s s e d o r is f u n c t i o n i n g i m p e r f e c t l y w h e n h y p e r g a s t r i n e m i a and hyperchlorhydria coexist. Reduced circulating g a s t r i n (Fig. 1, b o t t o m ) r e s u l t s in r e d u c i n g g a s t r i c a c i d i t y (Fig. l , left), a n d t h e i n t r a g a s t r i c m i l i e u is a g a i n a p p r o p r i a t e f o r r e l e a s e o f g a s t r i n . I t is c l e a r
Eugene W. Straus, M.D. Solomon A. Berson Research Laboratory, Veterans Administration Hospital, Bronx, New York, U.S.A. M e y e r s a n d J o n e s h a v e w r i t t e n an e x c e l l e n t r e v i e w of the hypergastrinemic-hyperchlorhydric state that c a n c o m p l i c a t e t h e s h o r t - b o w e l s y n d r o m e . T h e inappropriate hypergastrinemia observed under these c i r c u m s t a n c e s is a s p e c i a l c a s e o f a c o m m o n d e f e c t in f e e d b a c k i n h i b i t i o n o f i n t e s t i n a l g a s t r i n r e l e a s e k n o w n to o c c u r in m o s t p a t i e n t s w i t h d u o d e n a l ulc e r a t i o n a n d , m o r e s t r i k i n g l y , in t h o s e w i t h n o n - t u morous hypergastrinemic hyperchlorhydria (NTH H ) [I]. In man the mucosa of the gastric antrum and duod e n u m c o n t a i n s cells w h i c h s y n t h e s i z e g a s t r i n p e p t i d e s (G cells) a n d r e l e a s e t h e h o r m o n e s into t h e circulation when stimulated appropriately. The regula-
Hyperacidity and Hypergastrinemia Following Extensive Intestinal Resection William C. Meyers, M.D. and R. Scott Jones, M.D. Departments of Surgery and Physiology, Duke University Medical Center, Durham, North Carolina, U.S.A.
tion will be reviewed. Then some possible explanations for these effects will be presented.
Increased gastric acid secretion occurs after extensive intestinal resection in man, dog, rat, and monkey. Hypergastrinemia has been observed in patients with short gut syndrome and appears to accompany the hyperacidity after intestinal resection in dog, rat, and monkey. Postresectional hypergastrinemia is caused by increased release of gastrin and/or decreased degradation of the hormone. Other hormonal changes after extensive resection include increased insulin, GIP, pancreatic glucagon, and decreased enteroglucagon.
Hyperacidity
Shortening of the intestine has been known to be associated with increased acid production for most of this century. Stassoff [4] in 1914 first described increased gastric acid secretion in dogs following massive intestinal resection. The first suggestion in the literature of a clinically significant syndrome was in 1954 by Shelton and Blaine [5] who reported a patient dying from a marginal ulcer after loss of about 3/4 of his bowel. In 1964, Frederick, Sizer, and Osborne [6, 7] provided the first description of a patient with increased acidity associated with extensive intestinal loss. The gastric hyperacidity following bowel resection subsequently has been confirmed in dogs, rats, and monkeys [8-17]. The same species have been used to characterize the acid hypersecretion after resection. In monkeys the hyperacidity occurs early after intestinal resection and persists for at least 6 months [16, 18]. Both basal and maximal histamine stimulated acid outputs (BAO, MAO) were greater than in control monkeys and the BAO:MAO ratio increased from 0.2 to 0.5 [16]. In dogs it is difficult to achieve normal basal acid output ranges after resection, except by prolonged fasting of the animal or administration of atropine [12]. The timing of the acid response to histamine is normal. Food-stimulated gastric acid secretion is increased in dogs, rats, and monkeys
The cause of the gastric hyperacidity occurring after massive small bowel resection is not known, but is most likely explained by the loss or inactivation of an inhibitor of gastric acid secretion or by increased activity of a secretagogue from the remaining portion of the gastrointestinal (GI) tract. Regulation of gastric secretion by GI hormones is incompletely understood, although many hormones and candidate hormones have been demonstrated to stimulate or inhibit gastric acid secretion. For example, gastrin, cholecystokinin (CCK), bombesin, and entero-oxyntin all can stimulate acid secretion; while secretin, glucagon, GIP, VIP, somatostatin, and serotonin all can inhibit [1-3]. Whether or not any of these substances plays an important part in postresectional hyperacidity is not known. This review attempts to outline succinctly the evidence for the participation of GI hormones in the increased gastric acid production following extensive intestinal resection. First, the evidence for hyperacidity and hypergastrinemia occurring after resec-
Reprint requests: R. Scott Jones, M.D., Department of Surgery, Box 3815, Duke University Medical Center, Durham, North Carolina 27710, U.S.A.
0364-2313/79/0003-0539 $01.20 9 1979 Soci6t6 Internationale de Chirurgie 539
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[14-16]. Gastric stasis or altered gastric emptying does not account for the hyperacidity [19, 20]. Antrectomy reduces or abolishes the hyperacidity in dogs and monkeys [15, 18, 21], while vagotomy increases both fasting and food-stimulated acid outputs from Heidenhain pouches of awake dogs following intestinal resection [ 15]. Parenteral administration of extracts from the resected jejunum of rats also reduces the basal acid levels [14]. Strong evidence for participation of GI hormones in postresectional hyperacidity is that increased acid production occurs in vagally denervated gastric pouches following small bowel resection [8]. In man, the syndrome of gastric hyperacidity after resection is not well characterized. Intermittent gastric acid hypersecretion [22] and acidic jejunal contents [23] have been reported many months following intestinal removal. Both gastric resection, and vagotomy and pyloroplasty, have been reported to improve patient survival [24-26]. However, there is also evidence that gastric acid hypersecretion occurs early following extensive intestinal resection, but is not usually a problem months later [27]. Both small intestinal resection and bypass produce hyperacidity in dogs and rats, and the amount and location of intestine removed or bypassed appear to be important [28-34]. Ileal-ileal bypass for patients with hypercholesterolemia does not produce hyperacidity [35], but whether or not jejunalileal bypass does has not been conclusively determined [36-41]. The extent of intestinal resection necessary to cause increased acid secretion in man has not been determined [27].
World J. Surg. Vol. 3, No. 5, 1979
scending slopes of the meal-stimulated gastrin response of resected patients were similar to controls, Straus and associates postulated that elevated gastrin levels after intestinal resection are more likely due to loss of inhibition of gastrin release than to decreased degradation of gastrin. The hypergastrinemia following small bowel resection was confirmed in animal studies [3 l, 43, 44]. Wickbom and associates [17, 43] measured both Heidenhain pouch acid secretion and serum gastrin concentration in dogs before and after intestinal resection, and found elevated postprandial gastric acid secretion and increased gastrin, although fasting gastrin was unchanged. In addition, there was a high degree of correlation between increases in acid outputs and serum gastrin after feeding. The failure to observe increased gastrin levels and gastric hypersecretion in the basal state in these dogs is probably explained by the prolonged period of fasting that preceded the experiments. Fasting serum gastrin concentrations in monkeys were observed to increase significantly 6 weeks after resection and to return to normal after 6 months or after antrectomy [16, 44]. Because those monkeys also had lower esophageal pressure changes that persisted after antrectomy, the authors speculated that a substance produced in the distal small intestine that inhibited antral secretion of gastrin and directly altered esophageal motility had been lost with the resected segment [44].
Possible Explanations for the Hyperacidity and Hypergastrinemia Loss o f an Inhibitor
Hypergastrinemia Hypergastrinemia in patients with short bowel syndrome was first reported in 1974 by Straus, Gerson and Yalow [42]. They measured total and fractionated plasma gastrin concentrations in 4 patients who had extensive resections, and in 1 who had a jejunal-ileal bypass for obesity. The 4 patients with resections, including 1 patient who had had a previous vagotomy and Billroth I gastrectomy, all had fasting and postprandial gastrin levels 3-20 times higher than mean gastrin levels of a control group of patients. In contrast, the jejunal-ileal bypass patient did not demonstrate these elevations. We have recently observed an interesting patient with short gut syndrome and a previous 50% Billroth II gastrectomy with barely detectable basal serum gastrin, and low meal-stimulated levels. The elevated gastrin in the patients of Straus et al. was predominantly "big" gastrin, a biologically active form of the hormone. Because the ascending and de-
Some circumstantial evidence suggests that the distal small intestine produces a gastric acid inhibitor which is lost following resection and, therefore, causes the hyperacidity. That evidence is: (a) in patients after resection, the slope of the disappearance from plasma of meal-stimulated gastrin is more compatible with increased secretion of gastrin than decreased degradation [42]; (b) antrectomy abolishes hyperacidity without affecting lower esophageal pressure changes in monkeys [44]; (c) injection of extracts from the resected bowel of rats abolishes the hyperacidity [14]; (d) there is no evidence for increased production of a secretagogue other than gastrin by the remaining GI tract; and (e) some GI hormones known to inhibit gastrin secretion under various conditions are produced in small bowel mucosa.
Nonetheless, loss of a GI hormone that is a gastric acid inhibitor is a plausible explanation, so it is important to consider the known inhibitors of gas-
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Table 1. Observed hormonal changes after extensive intestinal resection.
Man Dog Monkey
Gastrin
Secretin
GIP
Insulin
Glucagon
Enteroglucagon
T
NT 0 NT
NT NT I'
NT 1' NT
NT 1' NT
NT J, NT
T I'
T increased; ~ decreased; 0 no change; NT not tested.
tric acid secretion that normally reside in the small bowel. Secretin, CCK, and GIP concentrations are greatest in the proximal small intestine and, therefore, are unlikely candidates to account for the hyperacidity observed after bowel resection in man [ l, 2], because proximal jejunum and duodenum usually remain intact in patients undergoing massive resection. In addition, serum GIP concentrations were found to be elevated in monkeys after resection [16, 18] and secretin levels were unchanged in dogs [45]. Similarly, serotonin [46], insulin [3, 45], and pancreatic glucagon [45], are not likely candidates because they have other principal sites of production and are not decreased after resection in dogs. Both fasting and stimulated levels of glucagon-like reactivity, however, were found to be profoundly diminished in one study on greyhounds, while pancreatic glucagon levels were not decreased [45]. In addition, there is a large concentration of glucagon-like reactivity in the distal small bowel [47]. These data suggested that a glucagonlike substance produced in the distal small bowel might be the important inhibitor. Further study is necessary to determine the meaning of these findings. histaminase have not yet been studied, so they also cannot be ruled out as candidates for the implicated inhibitor.
Impaired Degradation An alternative explanation for the hypergastrinemia that occurs after extensive bowel resection is a decrease in the capability for metabolic disposal of gastrin. There is evidence that the small bowel participates in the metabolism of gastrin [48, 49]. During endogenous release of gastrin, a 43% diminution in the integrated gastrin response across the small bowel circulation was reported in dogs [49]. The removal of gastrin in the fasted, anesthetized dog is apparently about the same for all the major vascular beds [50]. Impaired degradation of gastrin might account for the apparent prolongation of meal-stimulated gastric acid secretion after resection. If decreased intestinal degradation were the mechanism,
intestinal hyperplasia could explain the normal fasting gastrin levels seen in monkeys at 6 months after intestinal resection and not at 6 weeks [16, 18].
Conclusion
In summary, extensive intestinal resection causes both gastric acid hypersecretion and hypergastrinemia in man and experimental animals. Because there is a high degree of correlation between increases in acid outputs and serum gastrin levels in dogs, it seems reasonable to think that the hypergastrinemia is somehow causally related to the hyperacidity. In addition, no experimental evidence has yet been presented to suggest increased activity of another secretagogue, or that increased responsiveness of parietal cells to a secretagogue might be responsible. Although parietal cell hyperplasia has been observed in rats 9 months after resection [51], there is no evidence that this was associated with increased acid production; and parietal cell hyperplasia was not seen in dogs with hyperacidity in 2 studies [12, 27]. A loss of a gastric acid inhibitor that normally resides in the small intestine, impaired degradation of gastrin, or a combination of these 2 mechanisms are, therefore, the most likely explanations. Loss of an inhibitor must somehow permit increased release or decreased metabolism of gastrin. For a hormone to be the proposed inhibitor, it would have to satisfy the following requirements: (a) it would have to reside normally in the portion of bowel that is resected and be capable of inhibiting acid production; (b) levels of that hormone would have to be decreased after resection, and this decrease would have to permit hyperacidity and elevation of serum gastrin concentration to the degree seen clinically and experimentally. No hormone studied so far has satisfied all these requirements. For example, secretin, GIP, and pancreatic glucagon all are present under normal conditions in small bowel mucosa [l, 2]. All 3 have been demonstrated to inhibit gastric acid production and gastrin release under nonphysiologic conditions only, and none has been shown to be decreased significantly after bowel resection. Of considerable interest, however, was
542
the observation that glucagon-like reactivity was decreased and pancreatic glucagon increased after bowel resection, suggesting that a glucagon-like substance from the distal small bowel was lost. The validity of the lost inhibitor hypothesis will be determined by further study. The gastric acid hypersecretion consequent to extensive small intestinal resection may be very important clinically, particularly in the early period following loss of the intestine. It is possible that increased acid secretion may contribute to maldigestion and, consequently, to malabsorption. In addition, the development of duodenal ulcer and its complications is a risk following small bowel resection. Fortunately, it appears in humans that the hyperacidity following small bowel resection is not permanent, but improves during the several months after resection in most patients. With the availability of cimetidine to manage acid hypersecretion, increased acid secretion following small bowel resection can be prevented. We recommend that any patient undergoing extensive intestinal resection should have gastric acid secretion, as well as serum gastrin concentration, measured and, if high acid secretory rates are documented, the patient should receive cimetidine until acid secretion returns to normal levels.
R6sum6
Chez l'homme, le chien, le rat et le singe, la rrsection intestinale 6tendue augmente la s6crrtion gastrique d'acide. Une hypergastrin6mie a 6t6 mise en 6vidence chez les malades avec rrsection grrle large et semble accompagner l'hyperchlorydrie de la r6section intestinale chez le chien, le rat et le singe. Cette hypergastrinrmie est due ~ une librration accrue de gastrine et/ou h une drgradation moins importante de l'hormone. Les autres modifications hormonales observres aprrs rrsection intestinale 6tendue sont une augmentation de l'insuline, du GIP et du glucagon pancrratique, et une rrduction de l'entrroglucagon. References 1. Rayford, P.L., Miller, T.A., Thompson, J.C.: Secretin, cholecystokinin and newer gastrointestinal hormones. N. Engl. J. Med. 294:1093, 1157, 1976 2. Walsh, J., Grossman, M.I.: Gastrin. N. Engl. J. Med. 292:1324, 1377, 1975 3. Johnson, L.R., Grossman, M.I.: Intestinal hormones as inhibitors of gastric secretion. Gastroenterology 60:120, 1971 4. Stassoff, B.: Experiementalle untersuchurgen uber die kompensatorischen Vorgange bei Dermiesktionen. Beitr. Klin. Chir. 89:527, 1914 5. Shelton, E.L., Blaine, M.H.: Massive small bowel resection in a postgastrectomy patient. Texas J. Med. 50:96, 1954
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6. Frederick, P.L., Sizer, J.S., Osborne, M.P.: Relation of massive bowel resection to gastric secretion. Trans. N.E. Surg. Assoc. 45:89, 1964 7. Frederick, P.L., Sizer, J.S., Osborne, M.P.: Relation of massive bowel resection to gastric secretion. N. Engl. J. Med. 272:509, 1965 8. Sabsai, B.I.: The effect of the small intestine on canine gastric secretion. Bull. Exp. Biol. Med. 55:387, 1963 9. Landor, J.H., Baker, W.R.: Gastric hypersecretion produced by massive small bowel resection in dogs. J. Surg. Res. 4:518, 1964 10. Westerheide, R.L., EUiott, D.W., Hardacre, J.M.: The potential of the upper small bowel in regulating acid secretion. Surgery 58:73, 1965 11. Osborne, M.P., Frederick, P.L., Sizer, J.S., Blair, D., Cole, P., Thum, W.: Mechanism of gastric hypersecretion following massive intestinal resection: clinical and experimental observations. Ann. Surg. 164:622, 1966 12. Reul, G.J., EUison, E.H.: Effect of 75% distal small bowel resection on gastric secretion. Am. J. Surg. 111:772, 1966 13. Caridis, D.T., Roberts, M., Smith, G.: The effect of small bowel resection on gastric acid secretion in the rat. Surgery 65:292, 1969 14. Ruderman, R., Kamel, I.: The effect of intestinal resection on gastric acidity in the rat. Surg. Forum 21:312, 1970 15. Wiens, E., Bondar, G.F.: Control of gastric hypersecretion following massive small intestinal resection. Surg. Forum 21:310, 1970 16. Moosa, A.R., Hall, A.W., Clark, J., Skinner, D.B.: Effect of 50% small bowel resection on gastric secretory function in Rhesus monkeys. Surgery 80:208, 1976 17. Wickbom, G., Landor, J.H., Bushkin, R., McGuigan, J.E.: Changes in canine gastric acid output and serum gastrin levels following massive small intestinal resection. Gastroenterology 69:448, 1975 18. Hall, A.W., Moosa, A.R., Wood, R.A.B., Block, G.E., Skinner, D.B.: Effect of antrectomy on gastric hypersecretion induced by distal small bowel resection. Ann. Surg. 186:83, 1977 19. Nylander, G.: Gastric evacuation and propulsive intestinal motility following resection of the small intestine in the rat. Acta Chir. Scand. t33:131, 1967 20. Hall, A.W., Moosa, A.R., Skinner, D.B.: The effect of distal small bowel resection on gastric emptying. Ann. Surg. 185:214, 1977 21. Landor, J.H.: Intestinal resection and gastric secretion in dogs with antrectomy. Arch. Surg. 98:645, 1969 22. Klein, M.S., Winawer, S.J.: Intermittent basal gastric hypersecretion following small bowel resection. Am. J. Gastroenterol. 61:470, 1974 23. Krone, C.L., Theodor, E., Sleisinger, M.H., Jeffries, G.H.: Studies on the pathogenesis of malabsorption. Lipid hydrolysis and micelle formation in the intestinal lumen. Medicine (Baltimore) 47:89, 1968 24. Frederick, P.L., Craig, T.V.: Effect of vagotomy and pyloroplasty on weight loss and survival of dogs after massive intestinal resection. Surgery 56:135, 1964 25. Winawer, S.J., Broitman, S.A., Wolochow, D.A., Osborne, M.P., Zamcheck, N.: Successful management of massive small bowel resection based on assessment of absorption defects and nutritional needs. N. Engl. J. Med. 274:72, 1966 26. Osborne, M.P., Sizer, J., Frederick, P.L., Zancheck, N.: Massive bowel resection and gastric hypersecretion: its mechanisms and a plan for clinical study and management. Am. J. Surg. 114:393, 1967 27. Windsor, C.W.O., Fejfor, T., Woodward, D.A.: Gastric secretion after massive small bowel resection. Gut 10:779, 1969 28. Copeland, E.M., Miller, L.D., Smith, G.P.: The complex nature of small bowel control of gastric secretion. Ann. Surg. 168:36, 1968 29. Kerr, G., Elliot, D.W., Endahl, G.L.: Effect of antrectomy on gastric acid hypersecretion induced by isolation of the
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543
proximal small bowel. Am. J. Surg. 115:157, 1968 30. Goldman, L.I., Dorn, B., Weinberger, M., Bralow, S.P., Gruenstein, M.: The small intestine and gastric secretion in the rat. The effects of intestinal bypass, resection, and supplemental hydration on interdigestive gastric secretion. Arch. Surg. 104:73, 1972 31. Bowen, J.C., Paddack, G.L., Bush, J.C., Wilson, R.J., Johnson, L.R.: Comparison of gastric responses in small intestinal resection and bypass in rats. Surgery 83:402, 1978 32. Saik, R.K., Copeland, E.M., Miller, L.D., Smith, G.P.: Effect of ileal exclusion on the Heidenhain pouch acid response to histamine in dogs. Ann. Surg. 173:67, 1971 33. Santillana, M., Wise, L., Schuck, M., Ballinger, W.F.: Changes in gastric acid secretion following resection or exclusion of different segments of the small intestine. Surgery 65:777, 1969 34. Landor, J.M., Behringer, B.R., Wild, R.A.: Postenterectomy gastric hypersecretion in dogs. The relative importance of proximal vs. distal resection. J. Surg. Res. 11:238, 1971 35. Buchwald, H., Varco, R.L.: Human gastric secretory studies following distal small bowel bypass. Gastroenterology 58: 931, 1976 36. Salmon, P.A., Wright, W.J.: Effect of small bowel bypass on gastric secretion in obese patients. Can. J. Surg. 11:365, 1968 37. Buchwald, H., Coyle, J.J., Varco, R.L.: Effect of small bowel bypass surgery on gastric secretory function: postintestinal exclusion hypersection, a phenomenon in search of a syndrome. Surgery 75:821, 1974 38. Coutsofides, T., Barakowski, J., Himal, H.S.: Gastric acid and serum gastric secretion before and after bypass of the small intestine for morbid obesity. Surg. Gynecol. Obstet. 142:521, 1976 39. Buchwald, H., Coyle, J.J., Varco, R.L.: Gastric hypersecretion and jejunal-ileal bypass [Letter]. Ann. Surg.
184:654, 1976 40. Wise, L., Vaughan, R., Stein, T.: Studies on the effect of small bowel bypass for massive obesity on gastric secretory function. Ann. Surg. 183:259, 1976 41. Scopinaro, N., Gianetta, E., Civalleri, D.: Small bowel bypass for obesity [Letter]. Ann. Surg. 186:776, 1977 42. Straus, E., Gerson, C.D., Yalow, R.S.: Hypersecretion of gastrin associated with the short bowel syndrome. Gastroenterology 66:175, 1974 43. Wickbom, G., McGuigan, J.E., Landor, J.H.: Role of gastrin in small bowel gastric hypersecretion. Surg. Forum 24:353, 1973 44. Hall, A.W., Moosa, A.R., Pelligrini, C., Clark, J., Skinner, D.B.: The effect of small bowel resection and subsequent precise antrectomy on lower esophageal function in Rhesus monkeys. Am. J. Surg. 133:544, 1977 45. Barros D'sa, A.A.B., Buchanan, K.D.: Role of GI hormones in the response to massive resection on the small bowel. Gut 18:877, 1977 46. Rosenberg, J.C.: Distribution of serotonin in the GI tract: effect of intestinal obstruction and resection on circulating serotonin. Surgery 56:388, 1964 47. Bloom, S.R., Polak, J.M., Pearse, A.G.E.: Endocrinology. London, Heine Mann, 1973, p. 91 48. Temperly, J.M., Stagg, B.H., Wyllie, J.H.: Disappearance of gastrin and pentagastrin in the portal circulation. Gut 12:372, 1971 49. Becker, H.D., Reeder, D.D., Thompson, J.C.: Extraction of circulating endogenous gastrin by the small bowel. Gastroenterology 65:903, 1973 50. Strunz, U.T., Walsh, J.H., Grossman, M.I.: Removal of gastrin by various organs in dogs. Gastroenterology 74:32, 1978 51. Seelig, L.L., Jr., Winborn, W.B., Weser, E.: Effect of small bowel resection on the gastric mucosa in the rat. Gastroenterology 72:421, 1977
Invited Commentary
tion of circulating gastrin concentrations can be s e e n b e s t in t e r m s o f a b a s i c f e e d b a c k - i n h i b i t i o n l o o p ( F i g . 1). W h e n c i r c u l a t i n g g a s t r i n c o n c e n t r a tions r i s e (Fig. 1, t o p ) , t h e g a s t r i c p a r i e t a l cells a r e s t i m u l a t e d t o s e c r e t e a c i d ( F i g . 1, right). W h e n t h e g a s t r i n - c o n t a i n i n g a n t r a l m u c o s a is b a t h e d in a c i d , f u r t h e r r e l e a s e o f g a s t r i n is i n h i b i t e d (Fig. l , b o t t o m ) . T h i s is t h e c r u c i a l f e e d b a c k - i n h i b i t i o n a s p e c t o f t h e c y c l e t h a t is a b s e n t w h e n g a s t r i c a t r o p h y h a s reduced or eliminated the acid-secreting capacity of t h e s t o m a c h . It is t h e a b s e n c e o f this m e c h a n i s m which accounts for the markedly elevated circulating g a s t r i n c o n c e n t r a t i o n s f o u n d in p a t i e n t s w i t h p e r n i c i o u s a n e m i a . P l a s m a g a s t r i n l e v e l s fall p r o m p t l y w h e n h y d r o c h l o r i c a c i d is i n s t i l l e d i n t o the stomach of a patient with pernicious anemia. It is a l s o this a s p e c t o f t h e c y c l e w h i c h is b y p a s s e d o r is f u n c t i o n i n g i m p e r f e c t l y w h e n h y p e r g a s t r i n e m i a and hyperchlorhydria coexist. Reduced circulating g a s t r i n (Fig. 1, b o t t o m ) r e s u l t s in r e d u c i n g g a s t r i c a c i d i t y (Fig. l , left), a n d t h e i n t r a g a s t r i c m i l i e u is a g a i n a p p r o p r i a t e f o r r e l e a s e o f g a s t r i n . I t is c l e a r
Eugene W. Straus, M.D. Solomon A. Berson Research Laboratory, Veterans Administration Hospital, Bronx, New York, U.S.A. M e y e r s a n d J o n e s h a v e w r i t t e n an e x c e l l e n t r e v i e w of the hypergastrinemic-hyperchlorhydric state that c a n c o m p l i c a t e t h e s h o r t - b o w e l s y n d r o m e . T h e inappropriate hypergastrinemia observed under these c i r c u m s t a n c e s is a s p e c i a l c a s e o f a c o m m o n d e f e c t in f e e d b a c k i n h i b i t i o n o f i n t e s t i n a l g a s t r i n r e l e a s e k n o w n to o c c u r in m o s t p a t i e n t s w i t h d u o d e n a l ulc e r a t i o n a n d , m o r e s t r i k i n g l y , in t h o s e w i t h n o n - t u morous hypergastrinemic hyperchlorhydria (NTH H ) [I]. In man the mucosa of the gastric antrum and duod e n u m c o n t a i n s cells w h i c h s y n t h e s i z e g a s t r i n p e p t i d e s (G cells) a n d r e l e a s e t h e h o r m o n e s into t h e circulation when stimulated appropriately. The regula-
