GASTROENTEROLOGY. Official Publication of the American Gastroenterological Association. COPYRIGHT 1974 THE \VILLlAMS & WILKINS Co.

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1 GASTROENTEROLOGY Official Publication of the American Gastroenterological Association COPYRIGHT 1974 THE \VILLlAMS & WILKINS Co. Vol. 66 February 1974 Number 2 HYPERSECRETION OF GASTRIN ASSOCIATED WITH THE SHORT BOWEL SYNDROME EUGENE STRAUS, M.D., CHARLES D. GERSON, M.D., AND ROSALYN S. YALOW, PH.D. Solomon A. Berson Research Laboratory, Veterans Administration Hospital, Bronx, New York, and Department of Medicine, Mount Sinai School of Medicine. The City University of New York, New York, New York Marked hypergastrinemia characterized by high fasting levels and a prompt sharp response to a standard test meal was observed in a group of 4 patients with short bowel syndrome, but not in a patient with jejunoileal bypass. In keeping with the findings in other gastrin hypersecreters, the predominant form of circulating gastrin in the patients with short bowel syndrome was big gastrin. The possibility that hypergastrinemia might result from the absence of a factor in the distal small intestine that inhibits gastrin release is considered. Massive resection of the small intestine may result from surgical therapy during the.course of a variety of conditions including Crohn's disease, mesenteric vascular occlusion, and midgut volvulus. After resection, the patient is deprived of a vast absorptive surface, and possibly of tissue with endocrine function. A number of subsequent metabolic abnormalities may attend this situation; included among these is gastric acid hypersecretion. Gastric acid hypersecretion as a complication of massive small bowel resection has been well documented in man,1-3 and can be easily reproduced in dogs '" 5 It has been Received August 3, Accepted September 19, Address requests for reprints to: Rosalyn S. Yalow, Ph.D., Solomon A. Berson Research Laboratory. Veterans Administration Hospital, Bronx. New York This work was supported by project no from the Veterans Administration Hospital. Dr. Ger Son was supported by a grant from the National Foundation for Ileitis and Colitis, Incorporated. 175 suggested that the hypersecretory state may adversely affect the function of the remaining small bowel by contributing to diarrhea,6 reducing intestinal absorption,7, 8 disrupting the anastomosis,3 and provoking mucosal ulceration. A number of investigators have proposed that vagotomy and pyloroplasty be performed to effect control of acid hypersecretion. 1-3 This suggestion has not met with uniform approval,8. 9 and it is clear that improved therapeutic approaches await better understanding of the pathophysiologic mechanism. This study was undertaken to assess the possible role of gastrin in the acid hypersecretory state which is associated with the short bowel syndrome. Materials and Methods Plasma gastrin responses to a standard test meal were studied in 4 consecutive patients with short bowel syndrome, in 1 patient after jejunoileal bypass surgery for obesity, and in 8 normal subjects. Fractionation of plasma gas-

2 176 STRAUS ETAL. Vol. 66,No.2 trin samples on Sephadex G-50 gel filtration was also performed. Brief case summaries follow. Case 1. B. M. is an IB-year-old female with a history of regional enteritis since age 6. At the age of 12, she had extensive intestinal resection because of obstruction, inflammation, and severe growth retardation. She now has evidence of recurrent disease. An upper gastrointestinal series with follow-through pictures of the small bowel showed a normal stomach and duodenum, but there were multiple strictures and areas of dilation in the small bowel which is only 3 feet in length. Laboratory data: hemoglobin 12 g per 100 ml; prothrombin time 16.2 sec with control of l1.b sec; potassium 3.3 meq per liter; calcium 7.5 mg per 100 ml; magnesium 1.2 mg per 100 ml; carotene 0 international unit per 100 ml; albumin 1.7 g per 100 m!. On a 72-hr fecal fat determination, daily excretion is 56.4 g on BO-g intake. After 25 g of d-xylose ingestion, urinary excretion was only 1.25 g. Case 2. R. S., a 54-year-old male with a 31-year history of regional enteritis, has had multiple surgical procedures over the past 21 years. His most recent operation was 2 years ago when he underwent resection of diseased segments of small bowel and cholecystectomy. Postoperative intussusception then occurred requiring reoperation and further resection. He was left with approximately 1 foot of jejunum and 2 feet of ileum. He is presently suffering with weakness, dyspepsia. and perianal disease. On recent upper gastrointestinal series, duodenal bulb deformity consistent with chronic peptic ulcer disease was seen. Laboratory data: hemoglobin 10.2 g per 100 m!; prothrombin time 13.4 sec with a control of 11.5 sec; calcium 8.9 mg per 100 ml; potassium 3.1 meq per liter; carotene 0 international unit per 100 ml; 72-hr fecal fat daily excretion 44.5 g on 80-g intake; d-xylose excretion after 25-g ingestion was 2.66 g. Case 3. A. K. is a 56-year-old female who has only 3 feet of small intestine as a result of surgery after segmental infarction. Her recovery has included a long period of parenteral hyperalimentation. Laboratory data: hemoglobin B.9 g per 100 ml; calcium B.O mg per 100 ml; magnesium 1.1 mg per 100 ml; basal acid output. 1.3 meq per hr; ph, 2.4. Maximal acid output after subcutaneous injection of 50 mg of betazole hydrochloride was 10.8 meq per hr; ph Case 4. D. H. is a 75-year-old female with a history of regional enteritis for the past 20 years. During the first 10 years of her illness she had multiple small bowel resections. Three years ago, 60 to 75% gastrectomy was necessitated by an intractable gastric ulcer. At present, she has severe burning epigastric pain relieved by food and antacids. Upper gastrointestinal series now shows a subtotal gastrectomy with a gastroduodenal anastomosis (Billroth I) and a giant duodenal ulcer. The small intestine is seen to be approximately 16 inches in length. Laboratory data: hemoglobin 11.0 g per 100 ml; calcium 8.9 mg per 100 ml; albumin 3.4 g per 100 m!. Case 5. W. A. is a 41-year-old male who B months ago underwent jejunoileal bypass surgery for control of obesity. He has lost approximately 100 Ib in the past 8 months. He is presently on a 2,000-cal diet and has only mild diarrhea. Laboratory data: hemoglobin 15.2 g per 100 ml; potassium 4.5 meq per liter; magnesium LOB meq per liter; calcium 9.5 mg per 100 ml; albumin 5.0 g per 100 ml; wet weight of stool, 343.B g per day; d-xylose excretion after 25-g ingestion was 3.2 g. After an overnight fast, all subjects received a standard test meal consisting of two hard-boiled eggs, one slice of dry white toast, and 120 ml of orange juice totaling 16 g of protein. 13 g of fat, and 36 g of carbohydrate. Plasma samples were obt8ined at 15, 10, and 5 min prior to feeding, and at 5, 10, 15, 20, 30, 40, 60, 90, and 120 min after completion of the meal. Plasma gastrin concentrations were measured by previously described radioimmunoassay techniques. lo Fasting and peak-stimulated plasma samples were fortified with marker molecules (NalalI and lali_human serum albumin) and were then fractionated by gel filtration on Sephadex G-50 fine columns (1 by 50 cm) eluted with 0.02 M barbital buffer fortified with 2.5 mg of salt-poor human serum albumin per m\. Successive 1-ml eluates were collected. counted for radioactivity. and their immunoreactive gastrin content determined by radioimmunoassay. Results The mean values for basal and peak postprandial gastrin concentrations in a group of 8 normal subjects used as control subjects for this study were 43 ± 7 pg per ml and 96 ± 20 pg per ml, respectively. These do not differ significantly from the basal values of 35 pg per ml and peak values of 100 pg per ml with a control group of 25 subjects previously studied in this laboratory (fig. 1). II

3 February 1974 GASTRIN IN SHORT BOWEL SYNDROME 177 TEST MEAL - j ' c Z a:: I en (3 <3: en <3:..J a TIME IN MINUTES FIG. l. Plasma gastrin concentrations in the fasting state and in response to a test meal of 8 control subjects for the experimental group, compared with 25 control subjects previously reported from this laboratory." In all 4 patients with the short bowel syndrome, marked hypergastrinemia, characterized by high fasting levels, and a prompt sharp response to a standard test meal were observed (fig. 2). Fasting gastrin concentrations ranged from a low of 96 pg per ml (A. K.) to a high of610 pg per ml (R. S.) and peak-stimulated levels ranged from 310 pg per ml (D. H.) to 1600 pg per ml (B. M.). Thus, both in the fasting and stimulated states the gastrin concentrations ranged from 3 to almost 20 times the levels found in control subjects. In the 3 subjects without gastrectomy (B. M., R. S., and A. K.), the times of the peak gastrin levels were achieved between 15 and 40 min, coinciding with the times of peak concentrations observed in the control group. In addition, the subsequent rate of fall after the peak appeared to be even more rapid in these 3 subjects than in the control group. Patient D. H., with a 60 to 75% gastrectomy and a gastroduodenal anastomoses (Billroth I), had a fasting level of 190 pg per ml, and, 2 hr after completion of the test, meal gastrin levels were still elevated to a level of 265 pg per ml. In the patient, W. A., with jejunoileal bypass, normal fasting levels with a poor response to the test meal were seen (fig. 2). Results of Sephadex fractionation of plasma samples are shown in figure 3. Both in the fasting and stimulated states in all patients with short bowel syndrome, the predominant form of circulating gastrin Was the big gastrin component. 12, 13 How- TEST MEAL 1.6 I TIME IN MINUTES FIG. 2. Plasma gastrin concentrations in the fasting state and in response to a test meal in 4 patients with short bowel syndrome, and in 1 patient with a jejunoileal bypass. The mean value for the 8 control subjects is reproduced from figure 1 and shown in the stippled area. ever, in 1 of the patients, R. S., about one-third the immunoreactive gastrin in the fasting state was in the big big form (big big gastrin).14 Big big gastrin is designated as that component of immunoreactivity eluting in the void volume on Sephadex G-50 gel filtration. Big big gastrin was not stimulated after feeding, although there was an increase in the smaller forms. Discussion Previous studies have demonstrated gastric acid hypersecretion in patients with regional enteritis both with and without resection of portions of the ileum In one of these reports,15 gastrin levels were measured in some of the patients with regional enteritis and were found to be normal. It is not clear from this abstract l5 whether the patients in whom gastrin studies were performed had had ileal resection. In any case, none of the patients in these groups had undergone massive intestinal resection. Gastric analyses performed before and after small bowel bypass have demonstrated no increase in acid output subsequent to the surgery.17, 18 This study demonstrates that all 4 patients with short bowel syndrome manifest

4 178 STRAUS ET AL. Vol. 66, No.2 em. FASTING R, FASTING '" a., en w w z Q!;:( 10 0: t- Z w o u z a: to <3 8m. 15 MIN. POST FEEDING MIN. POST FEEC1N3 R 40 MIN POST FEE[w:; "". 120 MIN. POST FEEDNG PERCENT OF ELUTION VOLUME BETWEEN 13II-ALBUMIN AND 131r FIG. 3. Sephadex G-50 gel filtration of immunoreactive gastrin in the fasting and peak post-feeding plasma specimens of the patients with short bowel syndrome. Big big gastrin is that component of immunoreactivity eluting in the void volume (less than 20%). Big gastrin has an elution volume between 30 and 50%. Heptadecapeptide gastrin has an elution volume between 60 and 80%. hypergastrinemia; i.e., both fasting concentrations and integrated gastrin responses to a test meal are markedly elevated. In contrast, the patient with jejunoileal bypass had normal fasting gastrin levels and poor response to the test meal. Hypergastrinemia has not previously been shown to be associated with the short bowel syndrome. The question as to whether the hypergastrinemia is due to augmented release or diminished catabolism has been raised. Consideration of the absolute concentrations of gastrin reached in the fasting and peak-stimulated state, and the time course of appearance and disappearance of plasma gastrin unequivocally militate against the hypothesis of a significant role for decreased catabolism. Assuming that the gastrin secretory rates remained unchanged, then the degradation rates would have had to decrease by a factor of 3 to almost 20 to account for the observed hypergastrinemia. If there were a decreased degradation rate there would be a prolonged delay in achieving the peak gastrin concentration and in its return towards basal levels. Yet the peak gastrin concentrations were achieved at the same time as in the control group and the subsequent fall-off appeared even more rapid. These observations are consistent only with the hypothesis that the primary reason for the hypergastrinemia is hypersecretion of gastrin. Gastrin hypersecretion was demonstrated in the patient (D. H.) who had a 60 to 75% gastrectomy with gastroduodenal anastomosis (Billroth I). The postprandial release of duodenal gastrin was first hypothesized 19 and later was demonstrated in patients having undergone Billroth I. type subtotal gastrectomy for peptic ulcer disease. 2o In the latter report, gastrin responses in Billroth I patients were found to be similar to those found in nonulcer and unoperated duodenal ulcer patients. The high levels found in patient D. H. are.

5 February 1974 GASTRIN IN SHORT BOWEL SYNDROME 179 additional evidence that a significant proportion of the circulating gastrin in both basal and postprandial states may be of duodenal origin. In each case, fractionation of plasma gastrin revealed that the predominant form of circulating gastrin was big gastrin. This is in agreement with previous reports in which big gastrin has been shown to be the predominant form of circulating gastrin in gastrin hypersecretory states!2'14 In the 1 patient, R. S., in whose plasma big big gastrin was a significant component in the fasting state, there was no increase in this component after stimulation. Thus, the pattern of immunoreactive gastrin components in patients with short bowel syndrome resembles that of other hypersecretors, i.e., patients with Zollinger-Ellison syndrome, pernicious anemia, etc., and differs from that of normal subjects. In the latter group, the predominant form in the fasting state is big big gastrin. 14 Elevated gastrin levels are known to occur in association with both hypo- and hyperchlorhydria. In pernicious anemia, and other achlorhydric and hypochlorhydric states, hypergastrinemia is considered to result from the absence of feedback inhibition normally provided by an acidified antrum. IO II Hyperchlorhydric hypergastrinemia has been well demonstrated both in the presence and in the absence of gastrin-producing tumors. II In both situations, hypergastrinemia in the presence of hyperchlorhydria suggests that gastrin secretion is not normally responsive to inhibitory mechanisms. In the Zollinger Ellison syndrome, the gastrin-producing tumor is not responsive to feedback inhibition and is autonomous in its release of gastrin. In the absence of a gastrin-producing tumor, hyperchlorhydric hypergastrinemia in patients with and without mucosal ulceration might result from an insensitive acid feedback mechanism, or the lack of a substance which inhibits gastrin release. In the patients with short bowel syndrome presented here, it is rea Sonable to assume that the hypergastrinemia is not the result of hypochlorhydria. Two of the patients (D. H., R. S.) have developed acid peptic disease since their intestinal surgery. A 3rd (A. K.) has a gastric acid output that is within the normal range. It is tempting to speculate that the hypergastrinemia demonstrated in these short bowel patients may be due to the absence of some factor from the small intestine. Evidence for the inhibition of gastric acid secretion by hormones of intestinal origin has accumulated slowly since the early observations of Farrell and Ivy.21 It is presently thought that the intestinal hormones, secretin and cholecystokinin, playa significant role in inhibiting gastric acid secretion. 22 More recently, a polypeptide with gastric inhibitory activity, "gastric inhibitory polypeptide," has been extracted from a partially purified preparation of cholecystokinin 23 and from hog duodenal mucosa. 24 With regard to the short bowel syndrome, however, it is difficult to ascribe gastric acid hypersecretion or gastrin hypersecretion to diminished secretion of these polypeptides since they have maximal concentrations in the mucosa of the duodenum and upper small intestine. 25 The patients presented here, like most patients with the short bowel syndrome, have an intact duodenum and proximal jejunum. However, in the absence of adequate assay information regarding the distribution of these intestinal hormones in the more distal segments of the small intestine, one cannot rule out the possibility that distal resection might remove a significant portion of their secretory potential. Additional studies in patients with short bowel syndrome are needed to confirm the ubiquitous presence of gastrin hypersecretion and to correlate gastrin levels with gastric acid secretion in such patients. Nonetheless, these studies are consistent with the possible existence of a factor in the distal small intestine that may playa role in inhibiting gastrin release. REFERENCES 1. Osborne MP, Sizer J, Frederick PL. et al: Massive bowel resection and gastric hypersecretion. Am J Surg 114: , 1967

6 180 STRAUS ET AL. Vol. 66, No.2 2. Frederick PL, Sizer JS, Osborne MP: Relation of massive bowel resection to gastric secretion. N Engl J Med 272: , Winawer SJ, Broitman SA, Wolochow DA, et al: Successful management of massive small-bowel resection based on assessment of absorption defects and nutritional needs. N Engl J Med 274:72-78, Reul GJ, Ellison EH: Effect of seventy-five per cent distal small bowel resection on gastric secretion. Am J Surg 111: , Landor JH, Baker WK: Gastric hypersecretion produced by massive small bowel resection in dogs. J Surg Res 4: , Parker PE, Soergel K, Ellison EH: Effects of excessive hydrochloric acid on canine gastrointestinal tract. Surg Forum 14: , Goldenberg J, Cummins AJ: Effect of ph on absorption rate of glucose in the small intestine of humans. Gastroenterology 45: , Bochenck W, Rodgers JB, Balint JA: Effects of changes in dietary lipids on intestinal f1uid loss in the short-bowel syndrome. Ann Intern Med 72 : , Windsor CWO, Fejfar J, Woodward DAK: Gastric secretion after massive small bowel resection. Gut 10: , Yalow RS, Berson SA: Radioimmunoassay of gastrin. Gastroenterology 58: 1-14, Berson SA, Yalow RS: Radioimmunoassay in gastroenterology. Gastroenterology 62: , Yalow RS, Berson SA: Size and charge distinctions between endogenous human plasma gastrin in peripheral blood and heptadecapeptide gastrins. Gastroenterology 58: , Yalow RS, Berson SA: Further studies on the nature of immunoreactive gastrin in human plasma. Gastroenterology 60: , Yalow RS, Wu N: Additional studies on the nature of big big gastrin. Gastroenterology 65: 19-27, Earnest DL, Briggs, FT, Walsh JH, et al: Gastric acid hypersecretion (GAH) in patients with ileal regional enteritis (RE) (abstr). Gastroenterology 64:723, Fielding JF, Cooke WT, Williams JA: Gastric acid secretion in Crohn's disease in relation to disease activity and bowel resection. Lancet 1: , Salmon PA, Wright WJ: Effect of small-bowel bypass on gastric secretion in obese patients. Can J Surg 11: , Shibata HR. MacKenze JR. Long RC: Metabolic effects of controlled jejunocolic bypass. Arch Surg 95: , Berson SA, Yalow RS: Nature of immunoreactive gastrin extracted from tissues of gastrointestinal tract. Gastroenterology 60: , Stern DH, Walsh JH: Gastrin release in postoperative ulcer patients: evidence for release of duodenal gastrin. Gastroenterology 64: , Farrell JI. Ivy AC: Studies on the motility of the transplanted gastrin pouch. Am J Physiol 46: , Johnson LR, Grossman ML: Intestinal hormones as inhibitors of gastric secretion. Gastroenterology 60: , Pederson RA, Brown JC: Inhibition of histamine, pentagastrin, and insulin-stimulated canine gastric secretion by pure "gastric inhibitory polypeptide." Gastroenterology 67 : , Brown JC, Mutt V, Pederson RA: Further purification of a polypeptide demonstrating enterogastrone activity. J Physiol 209:57-64, Meyer JH, Grossman MI: Release of secretin and cholecystokinin, Gastrointestinal Hormones. International Symposium at Erlangen, August Edited by L. Demling. Stuttgart, Georg Thieme Verlag, 1972, p 43-55