Human Gastrin Response to Secretin after Vagotomy

Mkhsel McLsughUn, MD, San Diego, California

GeraM W. Peskln, MD, FACS, San Diio, California

Rkhard P. Salk, MD, San Diego, California

Secretin is a major enterogastrone and is thought to play a significant role in the negative feedback of the duodenum on gastric acid secretion [I]. Al- though secretin decreases basal gastrin levels and the gastrin response to feeding in both normal man and patients with duodenal ulcer [2,3], John- son and Grossman [4] have concluded that secre- tin’s major effect in decreasing acid output is me- diated through a noncompetitive inhibition of gas- trin at the parietal cell level. In certain patients with Zollinger-Ellison tumors, .however, many au- thors have demonstrated that secretin infusion causes elevation of serum gastrin levels [3,5,6]. Thus, secretin infusion is the agent of choice as a provocative test for this syndrome, particularly since it causes inhibition in normal patients and increases in patients with Zollinger-Ellison syn- drome, whereas calcium infusion increases gastrin response (to differing degrees) in both of these groups [7,8]. Since many patients with Zollinger- Ellison syndrome may elude diagnosis and be treated as ordinary ulcer patients with vagotomy (less than total gastrectomy), elevation in gastrin levels post vagotomy, associated with recurrent ulcer disease, may be a confusing situation. The ef- fect of secretin on postvagotomy hypergastrinemia has not been reported, and it has served as the stimulus for this study assessing its reliability as a

diagnostic test in this circumstance.

Nine patients scheduled to undergo vagotomy and py- loroplasty for duodenal ulcer disease were studied pre- and postoperatively. Seven underwent truncal and two selective vagotomy, all with Jaboulay pyloroplasty. After an overnight fast, each was fed a standard liquid meal containing 52 gm of protein, 7 gm of fat, and 150 gm of carbohydrate. The following day, the meal was re-

From the Department of Surgery, Unhwslty of California. San Diego. and the Veterans Adrninistratfon Hos@ial. San Diego, CaMcmia. This work was supported in Part by VA &ants MIlS 7001 and 7891 and US Public Heatth Service &ant #AM 1598604.

Reprint requests should be addressed to Rkzhard P. Wk. MD. Veter- ans AdmInistration Hospttal, 3350 La Jolla Vilege Drive. San DIego. Cali- fcmia 92161.

Presented at the Sixteentf~ Annual Meeting of the Society for Surgery of the Alimentary Tract. San Antonlo. Texas. May 20-21. 1975.

Vohnm 131. January 1976

peated with a two hour constant infusion of Boote secre- tin (2 units/kglhr) (one patient received 2 units/kg/hr of pure natural secretin [Gastrointestinal Hormone Re- search Unit (GIH), Karolinaka Institutet, Stockholm] starting 30 minutes before the meal. With each test, two basal blood samples were drawn 30 minutes apart, im- mediately after which the meal was given and further blood samples obtained at the next 15, 30, 60, 120, and 180 minute intervals as diagrammed schematically in Figure 1. Serum gastrin levels were measured using standard radioimmunoassay, and serum calcium level was determined (A.A. spectrophotometer). Two hour in- tegrated gastrin outputs were calculated after the feed- ing stimulus. Patients were restudied postoperatively on two successive days after resuming a regular diet. Inte- grated gastrin output and basal gastrins were calculated and compared using the Fisher Sign Test (median dif- ferences) 191.

Results

Fasting gastrin levels were significantly in- creased in eight of nine patients after vagotomy (p <0.0195) as shown in Table I. The integrated gas- trin response to feeding, expressed as percentage change from baseline, however, was not signifi- cantly altered by vagotomy. (Table II.) Secretin infusion did not consistently suppress the basal gastrin levels either preoperatively or after vagoto- my. Infusion of secretin,did, however, significantly lower the integrated gastrin response to feeding both pre- and postoperatively in eight of nine pa- tients as shown in Table II (p dO.0195). No signifi- cant changes in serum calcium level were observed

TABLE I Mean Basal Gamin Levels (W/ml)

Patient Before Vagotomy After Vagotomy

CD 112 177

DO 10 55

cs 52 155

EB 65 140

EE 17 125

BH 95 90

JD 75 108

SA 15 55

CM 115 135 ~-

Note: Actual p value is p < 0.0195.

69

McLaughlin, Peskin, and Salk

TABLE II Effect of Secretin on Integrated Gastrin Output be/min/ml)

Gastrin Response before Vagotomy

Patient Feeding Post Secretin Infusion

CD 30 17 DD 433 17 cs 41 37 El3 269 13 EE 1.300 94

BH 34 36 JD 89 43

SA 236 98 CM 109 16

Note: Actual p value is p < 0.0195.

Gastrin Response after Vagotomy

Feeding Post Secretin Infusion

6 4 230 470

86 62 40 13

173 32

603 49 119 61 550 100 260 125

175

150

125

100

75

50

Secre tin

MINUTES

Ftgure 1. A representative patient testtng scheme wtth each potnt representlng serum gastrln sampling. Notched bar represents period of secret/n Infuston.

Meal .

0 30 60 90 120 150

MINUTES

Figure 2. Prevagotomy gastrfn response to food atone and food pfus secret/n lnfuston In an Iltustratlve pattent.

during secretin infusion. No untoward sequelae of the testing were recognized. The gastrin response curves of an illustrative patient both before and after vagotomy are represented in Figures 2 and 3.

Comments

Unlike the results reported by some [2,3], no in- hibition of the basal gastrin levels either before or after vagotomy was demonstrated by secretin infu- sion. Although basal gastrin levels were un- changed, the integrated gastrin response to feed- ing was consistently reduced by secretin infusion. Recent information using gastrin fractionation technics suggests that most of the fasting serum gastrin in man is Big Big Gastrin (G60) [IO], whereas the major circulating gastrins in man postprandially are Big Gastrin (G34) and heptade- capeptide gastrin (Gl’?) [II]. Walsh has hypothe- sized that the gastrin response to feeding consists of an early, brief antral release of Gl7 stored in granules in the G cells followed by a more pro- longed direct synthesis and release of G34 [12]. This is also supported by recent evidence from Track, Creutzfeldt, and Arnold [I3]. Further stud- ies are needed to determine whether secretin might have differing effects on these different forms of circulating gastrin, which might explain suppression of integrated gastrin response to feed- ing without an effect on basal gastrin. It is also possible that 30 minutes of infusion was insuffi- cient time or that 2 units/kg of secretin was too small a dose to demonstrate inhibition of basal gastrin. Yet this has been described by others at this dosage and time interval [2,3]. Boots secretin also contains small amounts of cholecystokinin as contaminants, which may mask secretin inhibition of gastrin. Cholecystokinin itself, however, demon-

70 The American Journal ai Surgery

Gastrin Response t0 Secretin

&rates less than 2 per cent cross-reactivity with gastrin in our radioimmunoassay. Hansky, Soveny,

and Korman [Z] have demonstrated less inhibition with Boots secretin than with GIH secretin, yet

one patient in our group infused with GIH secretin also failed to show a decrease in fasting gastrin.

Isenberg et al [5] first reported the paradoxical increase in gastric acid secretion and serum gastrin in a patient with Zollinger-Ellison syndrome. Thompson et al f3] have confirmed this result, al- though there is disagreement whether small but significant elevations in serum calcium follow the intravenous infusion of secretin and are the re- sponsible intermediary for gastrin release. Both the mechanisms for secretin stimulation of gas- trinomas and the inhibition of the G cell in ulcer patients and normal patients are unknown. It is known, however, that the antral G cell and the pancreatic D cell do have different ultrastructure and staining characteristics [14-l 71. Whether these differences account for the differing release patterns is merely conjectural.

Although this study, like that of others [18j, demonstrates elevated fasting gastrin levels imme- diately after vagotomy, the integrated gastrin re- sponse to feeding was unchanged by vagotomy, suggesting that the initial contribution of vagally- induced gastrin release (cephalic phase) comprises an insignificant fraction of the total gastrin re- sponse to a meal. These elevated fasting gastrin levels seen after vagotomy are ascribed, in most cases, to decreased acid production by the stom- ach, although loss of vagal inhibitory fibers has been postulated [I&?]. In general, however, Tru- deau and McGuigan [19] have demonstrated that, in most clinical situations, serum gastrin levels are inversely related to the amount of intragastric acid. A potential problem exists in differentiating the patients with elevated gastrins and recurrent ulcer after vagotomy from the patient with a true Zollinger-Elliaon syndrome. Recurrent ulcer after an adequate operative procedure has always been a reason for suspicion that a Zollinger-Ellison tumor may be present. Serum gastrin levels, how- ever, will be elevated in both patients with vagoto- my and patients with Zollinger-Ellison. Therefore, secretin infusion would seem to be an ideal testing agent. Secretin has recently been shown to inhibit the hypergastrinemia seen in a patient with a re- tained antrum after Billroth II antrectomy [20]. Its effects on the postvagotomy patient with high serum gastrin has not been available. This study provides evidence that secretin infusion remains a

Meal

*O” r 4 175

150

125

100

75

25

01 ’ ’ ’ ’ ’ ’ ’ ’ ’ ’ 0 30 60 90 120 150

MINUTES

FIgwe 3. Pwtvagatomy gastrfn mspome to food &no smi foad pbs secretf.. fnhston fn saw Mustratlve pa- tient.

the gastrin response to a meal despite antral den- ervation and lowered intragastric pH, unlike its role in patients with Zollinger-Ellison syndrome.

Summary

The gastrin response to a liquid meal with and without secretin infusion was studied in nine pa- tients undergoing selective or truncal vagotomy with pyloroplasty for duodenal ulcer disease. Fast- ing gastrin levels were significantly increased in eight of nine patients after vagotomy, but secretin infusion did not consistently suppress these basal gastrin levels either pre- or postoperatively. Infu- sion of secretin did significantly lower the inte- grated gastrin response to feeding both pre- and postoperatively in eight of nine patients. Vagoto- my alone did not significantly alter the integrated gastrin response to feeding. This data gives evi- dence that secretin infusion remains a helpful di- agnostic test, differentiating those patients with recurrent ulcer and elevated gastrin levels postva- gotomy from those patients with occult Zollinger- Ellison syndrome.

References

1. Johnson L, Grossman M: Secretin: the enterogastrone re- leased bv acid in the duodenum. Am J FYwsk3~ 215: 685. 1968. .

2. Hansky J, Soveny C. Korman M: Effect of secretin on serum gastrln as measured by immunoassay. &sfrot?ntero&# 61: 62, 1971.

3. Thompson J, Reeder D, Bunchman H. Becker H, Brandt E: Effect of secretin on circulating gastrin. Ann Surg 176: 364, 1972.

4. Johnson L, Grossman M: Intestinal hormones as inhibitors of helpful tool in this clinical situation by inhibiting gastric secretiin. Gasifoc?nter0bgy 60: 120. 197 1.

Vohma 131, January 1978 71

McLaughlin, Peskin, and Saik

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Bra&y E, Galambos J. Lobley C, Yick-Kwong C: SeCretin- gastrin relationships in Zollinger-Ellison syndrome. Surgery 73: 550, 1973.

Trudeau W, McGuigan J: Effects of calcium on serum gastrin levels in the Zollinger-Ellison syndrome. N Engl J Med 281: 862.1969.

Passaro E, Basso M, Walsh J: Calcium Challenge in the Zol- Iinger-Ellison syndrome. Surgev 72: 60, 1972.

Hollander M, Wolfe DA: Nonparametric Statistical Methods. New York, John Wiley 8 Sons, 1973, p 39.

Yalow RS, Wu N: Additional studies on the nature of big big gastrin. G9stroenterObgy65: 79. 7973.

Rehfeld J, Stadil, F, Vikelse J: lmmunoreactive gastrin com- ponents in human serum. Gut 15: 102, 1974.

Dockray GJ: Aminoterminal gastrin fragment in serum of Zollinger-Ellison patients. Gasfroenterology 68: 222, 1975.

Track N, Creutzfe!& C, Arnold R: The Effect of Feeding upon the Biosynthesis and Release of lmmunoreactivs Gastrin and the Ultrastructural Appearance of the G-Cell Gran- ules. Fifth World Congress of Gastroenterology Abstracts. October 1974, p 288.

McGuigan J, Greider M. Grawe L: Staining characteristics of the gastrin cell. Gastroenterology 62: 959, 1972.

Greider M, Steinberg V, McGuigan J: Electron microscopic identification of the gastrin cell of the human a&al muco- sa by means of immunocytochemistry. Gastroenterology 63: 572, 1972.

Solcia E, Sempietco R: Cytology observations on the pan- creatic Islets with reference to some endocrine-like cells of the gastrointestinal tract. Zelrforsch 68: 689, 1965.

Creutzfeldt W. Arnold R, Feurle G, Ketteren H: Gastrin and Gcells in the antral mucosa of patients with pernicious anemia, acromegaly and hyperparathyroidism and in a Zollinger-Ellison tumor of the pancreas. Eur J C/in invest 1: 461, 1971.

Stedil F, Rehfeld J: Gastrin response to insulin after selective highly selective and truncal vagotomy. Gastroenterology 68: 7, 1974.

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Dlscussion

Edward L. Bradley, III (Atlanta, GA): We have been interested in using the secretin inhibition test as a means of differentiating patients with gastrinoma from those cases of functional hypergastrinemia. In ten pa- tients with histologically proved gastrinomas, the per- centage increase in serum gastrin ranged from 22 to 11 per cent. We do not feel, however, that it is necessary for gastrin to increase after exogenous secretin to confirm

the diagnosis of gastrinoma. Rather, we believe a posi- tive secretin test is one that lacks the normally occurring inhibition of gastrin levels. In three additional patients with mild hypergastrinemia, hyperchlorhydria, and se- cretin-induced gastrin inhibition, the diagnosis remains questionable. Whether these patients represent unusual examples of Zollinger-Ellison syndrome and reflect false-negative results from secretin inhibition or wheth-

er they could be classified as pseudogastrinomas cannot be determined at present. We plan to continue following their course.

We are also in complete agreement with the authors that secretin at these dosage levels does not increase the serum calcium level in most patients. It is doubtful whether secretin-induced augmentation of gastrin in pa- tients with gastrinoma can be attributed to concommi- tant hypercalcemia.

James C. Thompson (Galveston, TX): These are in- stances in which this test is not infallible. We now have had three patients who did not have the Zollinger-Elli- son syndrome whose gastrin levels decreased. Nonethe- less, it is far and away the best test that we have. Secre- tin releases gastrin from tumor tissue, so if there is an increase in gastrin, we are fairly secure in diagnosing Zollinger-Ellison syndrome. If we have no changes, I would still say that we are very secure in diagnosing Zol- linger-Ellison syndrome. If gastrin levels decrease, I think we can almost rule out the Zollinger-Ellison syn- drome, but there seem to be rare exceptions, and like any other test, if we do not believe the results, we need to repeat the test. As far as this study is concerned, the cases in which the reported or putative confusion might exist must be very rare, because certainly in our hands, those patients who have recurrent ulcers after vagotomy and pyloroplasty, who turn out to have the Zollinger- Ellison syndrome, also have massive gastric hypersecre- tion, and it would’be on that basis that my suspicions of the Zollinger-Ellison syndrome would be raised rather than on a borderline elevation of serum gastrin.

Chairman William Silen (Boston, MA): We have one patient who retained the antrum after a distal resec- tion in whom the serum gastrin level increased after se- cretin infusion and such increase was inhibited by infus- ing acid into the stomach. I think there is no test in the world that is going to be absolute. It is interesting to note, however, that the vagotomy itself will result in this. Is there any difference or was there any difference between your selective and truncal vagotomy group?

Richard P. Saik (closing): No, there was no differ- ence.

72 The American Journal of Surgery