ALTERED PANCREATIC AND BILIARY FUNCTION AFTER VAGOTOMY AND PYLOROPLASTY

Transcription

1 GASTROENTEROLOGY 66: 22-27, 1974 Copyright 1974 by The Williams & Wilkins Co. Vol. 66, No.1 Printed in U.S.A. ALTERED PANCREATIC AND BILIARY FUNCTION AFTER VAGOTOMY AND PYLOROPLASTY JUAN R. MALAGELADA, M.D., YAY L. W. Go, M.D., AND W. H. J. SUMMERSKILL, M.D. Gastroenterolor4Y Unit, Mayo Clinic and Mayo Foundation, Rochester, Minnesota Changes in pancreatic enzyme secretion and gallbladder contraction occurring after vagotomy and pyloroplasty were investigated and compared with findings from healthy volunteers and patients with duodenal ulcer. Total lipase and bile acid outputs were quantified, using duodenal perfusion, under basal conditions and in response to both endogenous cholecystokinin-pancreozymin (CCK-PZ) (released by intraduodenal perfusion of essential amino acids) and to exogenous (porcine) CCK-PZ given by vein. After vagotomy and pyloroplasty, basal pancreatic enzyme outputs were reduced, as were responses to both intraduodenal essential amino acid perfusion and lower doses of intravenous CCK-PZ, but the response to maximal doses of intravenous CCK-PZ was normal. By contrast, gallbladder contraction occurred at a lower dose of intravenous CCK-PZ than in healthy subjects or in patients with duodenal ulcer, although the response to intraduodenal essential amino acids was normal. Our results suggest that (a) vagal impulses contribute to pancreatic enzyme secretion in the interdigestive periods; and (b) after vagotomy and pyloroplasty, sensitivity of the pancreas to CCK-PZ decreases and that of the gallbladder increases. Postoperative diarrhea and steatorrhea frequently complicate truncal vagotomy and pyloroplasty (V and P) performed for treatment of peptic ulcer Steatorrhea may result from impaired enzymatic hydrolysis or micellar solubilization of dietary fat, since subnormal postprandial concen- Received June 8, Accepted September 6, Part of this work was presented at the Annual Meeting of the American Gastroenterological Associa tion, Dallas. Texas, in May, 1972, and reported in abstract form. I Address requests for reprints to: Dr. W. H. J. Summerskill, Gastroenterology Unit. Mayo Clinic and Mayo Foundation. Rochester, Minnesota Supported in part by Research Grant AM 6908 from the National Institutes of Health, Bethesda, Maryland. The authors wish to thank Dr. Willard S. Gamble for his help. Mrs. Judy Duenes, Miss Paulina Yu, and Mr. Richard Tucker provided valuable technical as sistance. 22 trations of lipase and bile acids have been found in the jejunum. 4 Intrinsic abnormalities of pancreatic and gallbladder function produced by vagotomy may be responsible, and changes in basal outputs or secretory responses of these organs to standard pharmacological stimuli have been reported by some investigators in man 5-7 and in the dog. s The failure of others to confirm such abnormalities after vagotomy may indicate that extrinsic mechanisms, such as rapid gastric emptying l2 with dilution of postprandial intestinal contents, may also account for abnormalities in fat digestion after V and P. We postulated earlier that reduction of cholecys tokinin -pancreozymin (C C K -PZ) secretion followed V and P.13 To investigate further intrinsic pancreatic and gallbladder functions after V and P in man, we perfused the duodenum and studied pancreatic enzyme secretion and gallbladder contraction in response to CCK-PZ, the

2 January 1974 PANCREATIC AND BILIARY FUNCTION AFTER VAGOTOMY 23 most potent known stimulus to these functions. 14 Exogenous (porcine) CCK-PZ was given by vein in different doses, whereas responses to endogenous CCK-PZ secreted from the small intestine mucosa were investigated by perfusing essential amino acids (EAA) under circumstances considered to cause liberation of the hormone. 15 Materials and Methods Three groups of individuals were studied: (1) 17 healthy male volunteers, ages 21 to 58 years (mean 33 years); (2) 9 patients with uncomplicated duodenal ulcer (DU) proved by X-ray, comprising six males and three females, ages 36 to 70 years (mean 51 years); and (3) 12 patients who had undergone truncal vagotomy and pyloroplasty for DU at least 1 year prior to the study. Ten males and two females, ages 23 to 71 years (mean 45 years), were included in this group. All patients with V and P had diarrhea, fecal water > 200 g per 24 hr 16; steatorrhea, fecal fat > 7 g per 24 hr, was present in 9. A standard Hollander test 17 was performed on all but 1 patient with V and P, and the completeness of truncal vagotomy was established by these criteria in 8 of the 11 patients. All patients had normal pancreatic function, as judged by responses to maximal doses of intravenous CCK-PZ, and none had evidence of gallbladder disease as determined by oral cholecystography. Perfusion followed an overnight fast. Individuals were intubated with a double lumen polyethylene tube under fluoroscopic control as detailed elsewhere"" Isotonic saline and/or a test solution, containing a nonabsorbable marker [polyethylene glycol (PEG) 5.0 g per liter], were infused into the second portion of the duodenum at a constant rate 00 ml per min). Duodenal contents were drained distally by siphonage from the ligament oftreitz, collected over ice, and pooled at 20-min intervals. Gastric juice was continuously aspirated through an additional tube placed in the antrum. Volume and PEG concentrations were determined from gastric and duodenal aspirates. Total outputs of lipase and bile acids were calculated from their concentrations in the duodenal samples relative to PEG under steady state conditions. Lipase, total bile acids, and PEG concentrations in duodenal aspirates were determined by standard methods in our laboratory, as described previously.18, I" Responses of the exocrine pancreas and gallbladder to exogenous CCK-PZ (batch no, 22927, kindly supplied by Dr, Eric Jorpes, Karolinska Institutet, Stockholm, Sweden) were quantified in 5 patients with V and P, 5 with DU, and five healthy volunteers. Isotonic saline was continuously perfused intra duo den ally, Basal samples were collected for 1 hr and, subsequently, CCK-PZ diluted in normal saline was given continuously by vein using a Harvard pump (Model 901). The dose was increased every hour in the following sequence: 0.004, O.OOB, 0,062, 0.125, and Crick-Harper-Raper unit per kg per min. The actions of CCK-PZ released from the upper small intestine in response to perfusion of EAA were tested in 12 patients after V and p, 4 patients with DU, and 12 healthy cont.rol subjects. The composition of this EAA solution has been published"" After preliminary washing of the bowel for 1 hr with isotonic saline, an isotonic test solution containing EAA (78 mm) was substituted for normal saline and perfused for 100 min. Total lipase output was determined from specimens collected during the last hour of perfusion. Peak bile acid output, presumed to represent gallbladder contraction in response to CCK-PZ was recorded as the highest 20-min output during the perfusion. Total bile acid output during gallbladder contraction was ~efined, in each individual, as the cumulative output measured during all periods with bile acid outputs above basal levels. Student's t-test was used for all statistical comparisons between groups. Results Pancreatic enzyme output (table 1). Basal lipa~e outp'uts during saline perfusion were significantly reduced after V and P, when compared with healthy subjects (P < 0.05), or with patients with DU (P < 0.02). After V and P, lipase outputs in response to endogenous CCK-PZ liberated by intraduodenal perfusion with EAA were also less (P < 0.01) than in health or in DU. Lipase outputs in response to sequentially increasing doses of intravenous CCK-PZ were also altered after V and P. At lower doses (0.004 and Crick Harper-Raper unit per kg per min), outputs were smaller after V and P than in health or with DU (P < 0.05). By contrast, responses to the higher doses of CCK-PZ (0.125 and Crick-Harper-Raper unit per kg per min) were similar in all three groups. No significant differences were found between lipase outputs in health and

3 24 MALAGELADA ET AL. Vol. 66, No. 1 TABLE 1. Total lipase outputs in healthy subjects, patients with duodenal ulcer (DlJ) and after vagotomy and pyloroplasty (V and Pi, under basal conditions, during intraduodenal perfusion of essential amino acids (EAA), and in response to sequentially increasing doses of intravenous cholecystokinin-pancreozymin (CCK-PZla Healthy DU VandP patients Basal 64.6 ± ± ± 3.4" EAA ± ± ± 7.0 c CCK-PZ dosed ± ± ± 3.7" ± ± ± 6.9" ± ± ± ± ± ± ± ± ± 80.8 a Lipase outputs (international units x 10 3 per hour. mean ± SE). a P < 0.05 versus health or duodenal ulcer. c P < 0.01 versus health or duodenal ulcer. d Crick-Harper-Raper units.... CCK-PZ, i.v.(chr,u/kg/min) 1~~Ir::~q Health ~., i Ctb.l!! f~"~'~; T :!!! Iii 8 Vagotomy a. pyloroplasty 6 4 Hours FIG. 1. Bile acid outputs in health, in patients with duodenal ulcer, and after vagotomy and pyloroplasty, in response to sequentially increasing doses of intravenous cholecystokinin-pancreozymin (CC K PZ). CHR, Crick-Harper-Raper units I Normal I saline Essenlial amino acids I Health n =12 Hours FIG. 2. Bile acid outputs in health and after vagotomy and pyloroplasty (V & Pl during intraduodenal perfusion of essential amino acids. DU during basal, EAA, or intravenous CCK-PZ stimulation. Bile acid output (figs. 1 and 2). Basal bile acid outputs did not differ significantly among the three groups. When intravenous CCK-PZ was given in increasing doses, gallbladder contraction (peak bile acid output) occurred after V and P at an 8-fold lower dose (0.008) than in healthy subjects or in patients with DU (0.062). These differing effects of intravenous CCK-PZ held true for all individuals in each group. Furthermore, total bile acid output during gallbladder contraction induced by intravenous CCK-PZ (fig. 1) was significantly greater after V and P than in healthy subjects (P < 0.01) or in patients with DU (P < 0.01). By contrast, gallbladder contraction and bile acid output in response to endogenous CCK-PZ liberated by intraluminal EAA did not differ between V and P and health (fig. 2). Discussion Pancreatic and biliary function differed after V and P when compared with the findings in healthy subjects or in patients with DU. Since our results are based on specimens collected by duodenal perfusion distal to the pylorus, they are thought to represent the effects of truncal vagotomy and not to be influenced by the py loroplasty. 2

4 January 1974 PANCREATIC AND BILIARY FUNCTION AFTER VAGOTOMY 25 After vagotomy, pancreatic lipase output was reduced under basal conditions and in response to both endogenous CCK-PZ and the lower doses of exogenous CCK-PZ, but was normal during "maximal" stimulation with intravenous CCK PZ Our results suggest that vagal impulses normally contribute to pancreatic enzyme secretion during interdigestive periods, and that after V and P the pancreas becomes hyposensitive to sub maximal stimulation by CCK-PZ. Decreased basal lipase outputs have also been reported in the dog after vagotomy8 and reduction of sensitivity of the exocrine pancreas to mixed hormonal stimuli after vagotomy in man was reported by W ormsley, 5 who found that pancreatic secretion in response to a combination of CCK-PZ and secretin was reduced at lower, but not maximal, dose levels. Others who measured pancreatic enzyme outputs in response to exogenous CCK-PZ in dogs have reported normal 11, 22 or increased 23 outputs after truncal vagotomy. Similar discrepancies involve the effects of secretin on pancreatic secretion after vagotomy in man 5, 9 or in the dog ,22.24 Differences in techniques, species, and/or doses of the hormone used may explain the variations in these results. After vagotomy, pancreatic enzyme secretion evoked by intraduodenal perfusion of EAA was also reduced. Konturek et a1. 22 earlier found subnormal enzyme outputs in response to intraduodenal infusion of amino acids in dogs after vagotomy and confirmed earlier studies with the same species These observations may reflect either a decreased sensitivity of the pancreas to "submaximal" 28 amounts of endogenous CCK-PZ released by EAA, as occurred with our intravenous CCK-PZ studies, or impaired secretion of CCK-PZ from the intestinal mucosa due to altered local cholinergic mechanisms after vagotomy.29 In man, addition of a topical anesthetic to a duodenal perfusion of EAA is thought to reduce pancreatic enzyme output by a mechanism involving inhibition of hormonal release at the mucosal leve1. 30 Thus, vagotomy may impair pancreatic secretion in response to EAA (or other nutrients) through mechanisms involving not only diminished target organ response, but also impaired hormonal release. The threshold response df the smooth muscle of the gallbladder to intravenous CCK-PZ, as measured by bile acid outputs due to contraction of the organ, was reduced by vagotomy. Threshold dose was defined as the smallest dose of intravenous CCK-PZ given which significantly increased bile acid output over basal levels. Peak outputs after vagotomy occurred at doses which were 8 times lower than those causing gallbladder contraction in health or with duodenal ulcer. This finding quantifies and confirms earlier observations that, after vagotomy in man, small doses of CCK-PZ cause greater reduction of the radiographic area of the gallbladder than in health. 7 A second abnormality of gallbladder response to exogenous CCK-PZ after vagotomy was the increased total bile acid output during gallbladder emptying. This was attributed to a greater gallbladder output of bile acids after V and P, since bilirubin and bile acid outputs are in close accord in health,20 and there is no evidence of abnormal bile acid metabolism after V and P. The increased gallbladder output of bile acids accords with earlier radiological studies which report that, after vagotomy in man, the size of the opacified gallbladder area increases 1o, 31, 32 and that the reduction in total volume produced by intravenous CCK-PZ is greater than in health. 10 Supersensitivity of intestinal smooth muscle occurs after vagotomy in the rat. 33 While increased sensitivity of the gallbladder to hormones after vagotomy has been explained in the context of the Cannon law of denervation supersensitivity after preganglionic interruption of the stimulatory pathway,7,34 it has also been shown that the enhanced responsiveness of the smooth muscle after denervation is due to physiological changes in target cells beyond the neural receptors. 35 Postvagotomy dilation of the organ has been interpreted as indicating that vagal influences normally contribute to the maintenance of muscle tone. Measured timing of gallbladder contraction and bile acid outputs induced by

5 26 MALAGELADA ET AL. Vol. 66, No. 1 endogenous CCK-PZ and intraduodenal EAA after vagotomy differed from those obtained by intravenous CCK-PZ and were similar to the findings in health (fig. 1 versus 2). Radiological studies also show that gallbladder contraction in response to a meal is initiated at the same time after vagotomy as in health. 36 Lack of agreement between responses to endogenous and exogenous CCK-PZ may be related to differing amounts of circulating hormone, altered responses of the gallbladder, or both. We postulate, as one explanation for this observation, that vagotomy reduces the amount of CCK-PZ released from the mucosa of the small intestine, and that the gallbladder is more sensitive to the smaller amount released. In conclusion, our results show that vagotomy alters both pancreatic secretion and gallbladder contraction in response to CCK-PZ in man. Application of these findings to symptomatology requires testing by different methods and must take into account additional factors, such as dilution of small intestinal contents by rapid gastric emptying,12 the possibility of bacterial overgrowth in the upper small intestine,37 and several other features 38 which may characterize postvagotomy (and pyloroplasty) syndromes in the clinical setting. REFERENCES 1. Malagelada JR, Go VLW, Gamble WS, et al: Pancreatic and gallbladder responses to cholecystokinin-pancreozymin (CCK-PZ) are altered by vagotomy or cholecystectomy (abstr). Gastroenterology 62: Cox AG, Bond MR: Bowel habits after vagotomy and gastrojejunostomy. Br Med J 1: , Logan H: Steatorrhea and diarrhea after vagotomy: a comparison of drainage procedures. Gut 5: , Fields M, Duthie HL: Effect of vagotomy on intraluminal digestion of fat in man. Gut 6: , Wormsley KG: The effect of vagotomy on the human pancreatic response to direct and indirect stimulation. Scand J Gastroenterol 7:85-91, Kiekens R, Van Geertruyden J: Digestion and absorption digestive apres vagotomie. Acta Gastroenterol Belg 26: , Tinker J, Cox AG: Gallbladder function after vagotomy. Br J Surg 56: , Moreland HJ, Johnson LR: Effect of vagotomy on pancreatic secretion stimulated by endogenous and exogenous secretin. Gastroenterology 60: , White TW, Lenninger SG, Elmsie RG, et al: Effect of truncal and selective vagotomy on duodenal aspirates in man. Ann Surg 164: , Fagerberg S, Grevsten S, Johansson H, et al: Vagotomy and gallbladder function. Gut 11: , Henriksen FW: Effect of vagotomy or atropine on the canine pancreatic response to secretin and pancreozymin. Scand J Gastroenterol 4: , McKelvey STD: Gastric incontinence and postvagotomy diarrhea. Br J Surg 57: , Gamble WS: Impaired pancreozymin (CCK-PZ) secretion after vagotomy and pyloroplasty (abstr). J Lab Clin Med 76:871, Lagerlof HO, Mutt V: Secretin and cholecystokinin-pancreozymin: Chemistry, physiology, pharmacology and clinical applications, Progress in Gastroenterology, vol 2. Edited by GB Jerzy Glass. New York and London, Grune and Stratton, 1970, p Go VLW, Hofmann AF, SummerskilJ WHJ: Pancreozymin bioassay in man based on pancreatic enzyme secretion: potency of specific amino acids and other digestive products. J Clin Invest 49: , Phillips SF: Diarrhea: a current view of the pathophysiology. Gastroenterology 63: , Hollander F: Laboratory procedures in the study of vagotomy. Gastroenterology 11 : , Go VLW, Hofmann AF, SummerskilJ WHJ: Simultaneous measurements of total pancreatic, biliary and gastric outputs in man using a perfusion technique. Gastroenterology 58: , Thistle JL, Schoenfield LJ: Induced alterations in composition of bile of persons having cholelithiasis. Gastroenterology 61: , Malagelada JR, Go VLW, Summerskill WHJ: Differing sensitivities of gallbladder and pancreas \0 cholecystokinin-pancreozymin (CCK-PZ) in man. Gastroenterology 64: , Banwell JG, Northam BE, 'Cooke WT: Secretory response of the human pancreas to continuous intravenous infusion of pancreozymin-cholecystokinin (Cecekin). Gut 8: Konturek SJ, Radecki T, Biernat J, et al: Effect of vagotomy on pancreatic secretion evoked by endogenous and exogenous cholecystokinin and cerulein. Gastroenterology 63: , Routley EF, Mann FC, Bollman JI, et al : Effect of vagotomy on pancreatic secretion in dogs with

6 January 1974 PANCREATIC AND BILIARY FUNCTION AFTER VAGOTOMY 27 chronic pancreatic fistulas. Surg Gynecol Obstet 95: , Magee DF, Fragola LA, White 11: Influence of parasympathetic innervation on the volume of pancreatic juice. Ann Surg 161:15-20, Crider JO, Thomas JE: Secretion of pancreatic juice after cutting the extrinsic nerves. Am J Physiol 141: , Lenninger SG, Magee DF, White TT: Effect of gastric, extra gastric and truncal vagotomy on the pancreas in the dog. Ann Surg 162: , Govaerts JP, Kiekens R: Vagal innervation on pancreatic secretion. Surgery 63: , Malagelada JR, Go VLW, DiMagno EP, et al: Interactions between bile acids and digestive products on pancreatic and gallbladder function. J Clin Invest 52: , Thomas JE: Mechanism of action of pancreatic stimuli studied by means of atropine-like drugs. Am J Physiol 206: , Ertan A, Brooks FP, Ostrow JD, et al: Release of cholecystokinin-pancreozymin (CCK-PZ) and secretin from the proximal jejunum and the effect of topical anesthetic in man (abstr). Gastroenterology 60:773, Rudick J, Hutchinson JSF: Effects of vagal-nerve section on the biliary system. Lancet 1: , Cox HT, Doherty JF, Kerr DF: Changes in the gallbladder after elective gastric surgery. Lancet 1: , Gutierrez LV, Kocak N, Cox AG: Alimentary transit and supersensitivity after vagotomy in the rat. Gut 12: , Cannon WB, Rosenblueth A: The Supersensitivity of Denervated Structures. New York, Macmillan Co, 1949, p Fleming W: Nonspecific supersensitivity of the guinea pig ileum produced by chronic ganglion blockade. J Pharmacol Exp Ther 162: , Glanville IN, Duthie HL: Contraction of the gallbladder before and after total abdominal vagotomy. Clin Radiol 15: , Dragstedt LR: Vagotomy in the surgical treatment of peptic ulcer. Surg Clin North Am 46: , Roth HP, Beams AJ: The effect of vagotomy on the motility of the small intestine. Gastroenterology 36: , 1959