Gut, 1970, 11, 998-1000 Peptic ulceration in Crohn's disease (regional Gut: first published as 10.1136/gut.11.12.998 on 1 December 1970. Downloaded from enteritis)

J. F. FIELDING AND W. T. COOKE From the Nutritional and Intestinal Unit, The General Hospital, Birmingham 4

SUMMARY The incidence of peptic ulceration in a personal series of 300 patients with Crohn's disease was 8%. Resection of 60 or more centimetres of the small intestine was associated with significantly increased acid output, both basally and following pentagastrin stimulation. Only five (4 %) of the 124 patients who received steroid therapy developed peptic ulceration. It is suggested that resection of the distal small bowel may be a factor in the probable increase of peptic ulceration in Crohn's disease.

Peptic ulceration was observed in 4% of 600 1944 and 1969 for a mean period of 11-7 years patients with Crohn's disease by van Patter, with a mean duration of the disorder of 13.7

Bargen, Dockerty, Feldman, Mayo, and Waugh years. Fifty-one of these patients had Crohn's http://gut.bmj.com/ in 1954. Cooke (1955) stated that 11 of 90 patients colitis. Diagnosis in this series was based on with Crohn's disease had radiological evidence of macroscopic or histological criteria in 273 peptic ulceration whilst Chapin, Scudamore, patients, on clinical and radiological data in 25 Bagenstoss, and Bargen (1956) noted duodenal patients, and on clinical data together with minor ulceration in five of 39 (12.8%) successive radiological features in two patients with colonic patients with the disease who came to necropsy. disease. The presence of peptic ulceration was In 1958, Jackson found that 13% of his 126 determined by radiology in association with ulcer patients had duodenal ulcers whilst Crohn and dyspepsia and was confirmed in nine patients at on September 30, 2021 by guest. Protected copyright. Yarnis (1958) wrote 'gastric secretory changes are surgery. None of the patients had gastroduodenal unusual' and only 20 of their 542 patients had Crohn's disease. evidence of peptic ulceration. Atwell, Duthie, and Gastric secretory studies were performed on 22 Golligher (1965) reported that 11 or 8.1 % of their patients (12 men and 10 women) with regional series had previous evidence of ulceration, and in enteritis. None had any history of ulcer type 1966 Gjone, Myron, and Orning commented that dyspepsia or of treatment with corticosteroids or four of 72 newly diagnosed patients with regional ACTH within the last 12 months. Of these enteritis had similar evidence of ulceration. patients, eight men and threewomenhadhadmore This paper reports gastric secretory studies in than 60 cm of small intestine resected; four men regional enteritis and the incidence of peptic had had no resection. Basal gastric secretion was ulceration in a personal series of patients with collected for 30 minutes before the intravenous regional enteritis. infusion of 6 ,ug pentagastrin per kilogram for one hour. Four 15-minute collections were made and volumes recorded. The acid content was deter- mined by titration against N/10 sodium hydroxide Clinical Materials and Methods to end point pH 7.0 using a Radiometer pH instrument. All results were expressed as milli- Three hundred patients (143 men and 157 women) equivalents of acid per hour. Peak hour output with Crohn's disease have been followed between was determined by the sum of the two maximum outputs in 15 minutes multiplied by 2. The re- Received for publication 1 September 1970. sults were analysed as a whole and in subgroups 999 Peptic ulceration in Crohn's disease (regional enteritis) Gut: first published as 10.1136/gut.11.12.998 on 1 December 1970. Downloaded from according to disease activity, sex, age at diagnosis, was no significant difference between the acid and length of small intestine resected. production of eight men who had 60 cm or more resected and that of 20 patients (19 men and one woman)without regional enteritis but with surgic- allyproven duodenal ulcers. Also the gastric secre- Results tions of these eight patients were significantly different from those of the four males who had no The results of the gastric secretory studies are resection, P being between 0.05-0.02, 0 01-0.001, shown in Table I. There was a significant differ- and 002-0 01 respectively for the basal, post- ence in acid production between the 12 male and stimulatory, and peak hour outputs. There was no 10 female patients with regional enteritis in the relationship between gastric secretion and disease hour after stimulation (001 > p < 0.001). There activity or age at diagnosis. Amongst the patients with regional enteritis 24 (8%) had evidence of peptic ulceration: 19 men (13.3 %) andfive women (3.2 %): Since none of the patients with Crohn's colitis hadpepticulceration, Group No. of Acid Secretion (m-equiv/hr) Patients the incidence of ulceration associated with small Basal One Hour after Peak Hour intestinal involvement becomes 10%; 19 in 111 Stimulation men (17.3%) and five in 138 women (3.8%). Regional enteritis Of the 19 men, 14 had duodenal ulcers, two Males 12 3-11 ± 087 28.75 ± 257 36-80 ± 3.0 gastric ulcers, and three both gastric and duo- Reseztion (> 60 cm) 8 4-12 ± 117 33.56 ± 229 40.39 ± 226 No resection 4 1.09 ± 024 19.54 2-87 26-42 ± 354 denal ulcers. These findings are summarized in Females 10 2.05 ± 060 18.85 ± 208 27.56 + 370 Table II. The follow-up period for patients with Resection (> 60 cm) 3 1-36 ± 069 21-41 ± 367 31 36 + 8.05 peptic ulcer averaged 1 1P5 years, ranging from one Duodenal ulcer No rese-tion to 22 years. Five patients, all men, had the duodenal ulcers Females (1) 20 6-73 i 128 32-18 ± 293 42.10 ± 3.40 before and not obviously related to the onset of Table I The mean and standard error of the gastric Crohn's disease. Another eight patients (four acid secretion in m n and women with regional enteritis men and four women) had peptic ulceration and in patiLnts with surgically proven duodenal ulcer- diagnosed at the same time as the intestinal aticn disorder. Four men developed ulceration after http://gut.bmj.com/ Case Sex Age at Onset Peptic Ulceration Resected Duodenal Gastric Steroid Operation No. or Ulcer Ulcer Treatment Crohn's Peptic Before Onset At After Onset Bypassed Disease Ulceration of Croln's Disease Onset (cm) Before After resection resection 201 M 52 31 + + Gastroenter- ostomy on September 30, 2021 by guest. Protected copyright. 205 M 49 30 Billroth II 232 M 58 51 + 246 M 68 65 280 M 56 47 267 M 40 40 + 268 M 25 25 359 M 37 37 225 M 40 40 + Billroth II 326 M 23 36 + 122 M 14 20 4 Vagotomy and pyloroplasty 26 M 26 29 + 68 M 10 16 30 289 M 20 31 + 30 266 M 53 71 90 Vagotomy and pyloroplasty 108 M 45 46 + 30 +

+ 45 I- Billroth II 3 M 20 26 + 25 + 52 M 36 55 + 60 29 M 71 89 + 55 I+ BTZ 105 F 50 50 + 244 F 55 55 Billroth II 253 F 52 52 299 F 17 17 150 + Vagotomy and pyloroplasty 285 F 14 18 + 180 + Gastroenter- ostomy Table II Sex and age at onset ofCrohn's disease and ofpeptic ulcer, the relationship to resection andamount resected, the incidence ofgastric and duodenal ulcers, and the type ofoperation carried out 1000 J. F. Fielding and W. T. Cooke Gut: first published as 10.1136/gut.11.12.998 on 1 December 1970. Downloaded from the diagnosis of Crohn's disease and before ulceration in this series represents an increase as resection of the small intestine. One of these compared with the general population, for ade- (case 225) had duodenal ulceration at the time of quate representative figures are difficult to obtain. diagnosis and is included amongst the four cited Doll and Jones (1951) found the incidence of above. Twenty years later, this patient who had peptic ulceration between the ages of 15 and 65 in involvement of more than 150 cm of small a London population in men to be 5-8 % and in intestinewithfibrosingregional enteritis,developed women 1.9%. The incidence of peptic ulceration a gastric ulcer which responded to medical treat- in men before the onset of Crohn's disease was ment only to relapse following resection of small 4.9 %, so that in men of this series there may well intestine thus necessitating partial gastrectomy. have been an increased incidence later. Certainly Case 122, who had diffusejejuno-ilealinvolvement, the occurrence of peptic ulceration in a brother developed a duodenal ulcer necessitating opera- and sister both with diffuse jejuno-ileal involve- tion for its relief. Cases 26 and 326 had less ment which necessitated, in both, operation before severe involvement of the small intestine. One the age of 22 argues in favour of some influence woman, case 285, a sister of case 122, developed being exercised by Crohn's disease. In these two duodenal ulceration following bypassing 150 cm patients, asin two other patients (cases 26 and 326) of small intestine. Of theremaining seven patients, there was extreme fibrosis of the intestine all men, who developed ulceration following following diffuse jejuno-ileitis and this may well resection of varying lengths of intestine, one have had a similar effect to that of resection. Of developed gastric ulceration and severe haemor- the 22 male patients who had more than 60 rhage following the administration ofbutazolidin. cm resected, five (23 %) subsequently developed Three had received steroid therapy, two develop- duodenal ulcers. ing duodenal ulcers and one an ulcer on the Only five (4%) of the 124 patients who received greater curvature of the stomach. This latter case steroid therapy developed peptic ulcers. The had previously developed duodenal ulceration influence of this therapy was clear in two patients following his first intestinal resection. who developed ulcers on the greater curvature of the stomach. The remaining three patients developed duodenal ulcers afterresection of more than 60 cm in two of them and 40 cm in the third Discussion so that the influence of steroid therapy must remain doubtful in these patients. Resection of 60 cm of small intestine resulted in The frequency of peptic ulceration in this series the three female patients secreting the same is such that it has been of someclinical importance. amount of gastric acid as men without resection Though the increase in women was slight, http://gut.bmj.com/ and the eight men secreting comparable quantities approximately one male patient in six with small- to those encountered in patients with surgically intestinal involvement was troubled sympto- proven duodenal ulcers and significantly more matically with peptic ulceration. than the men with no resection. Such results are perhaps to be expected, for the small intestine has Referenc,s been thought to exert an influence on gastric acid Atwell, J. D., Duthie, H. L., and Goligher, J. C. (1965). The out- come of Crohn's disease. Brit. J. Surg., 52, 966-972. secretion for many years. Kosaka and Lim (1930) Chapin, L. E., Scudamore, H. H., Bagenstoss, A. H., and Bargen, on September 30, 2021 by guest. Protected copyright. showed that mucosal extracts of small intestine J. A. (1956). Regional enteritis: Associated visceral changes. to Gastroenterology, 30, 404-415. exposed oil had an inhibitory effect upon the Cooke, W. T. (1955). Nutritional and metabolic factors in the acid production of a denervated gastric pouch aetiology and treatment ofregional enteritis. Ann. ray. Col. and suggested the term'enterogastrone' todescribe Surg. Engi., 17, 137-158. Crohn, B. B., and Yarnis, H. (1958). Regional Ileitis, 2nd revised this mucosal agent. The innervated stomach may ed., p. 46. Grune and Stratton, New York. also be affected by bowel resection, for Frederick, Doll, R., and Jones, F. A. (1951). Occupational factors in the aetiology of gastric and duodenal ulcers: with an estimate Sizer, and Osborne (1965) showed that gastric of theii incidence in the general population Spec. Rep. Ser. secretion in dogs could be increased progressively med. Res. Coun. (Lond.), 276. by increasing lengths of intestinal Frederick, P. L., Sizer, J. S., and Osborne, M. P. (1965). Relation resection, 75 % of massive bowel resection to gastric secretion. New Engi. J. resection producing 176 % increase in gastric Med., 272, 509-514. secretion. Menguy (1960) demonstrated that bile Gjone, E., Myren, J., and Orning, 0. M. (1966). Crohn's disease in Norway-clinical features. Scand. J. Gastroent., 1, 101-105. salts were involved in gastric inhibition by fat and Jackson, B. B. (1958) Chronic regional enteritis. Ann. Surg., 148, speculated that this inhibition was mediated by 8 1-87. Kosaka, T., and Lim, R. K. S. (1930). Demonstration of the re-absorbed bile salts. Whether the failure of humoral agent in fat inhibition of gastric secretion. Proc. adequate bile salts re-absorption is a factor in the Soc. exp. Biol. (N. Y.), 27, 890-891. increased gastric secretion in some patients with Menguy, R. (1960). Studies on the role of pancreatic and biliary secretions in the mechanisms of gastric inhibition by fat. regional enteritis will need further investigation, Surgery, 48, 195-200. but it is clearly an attractive hypothesis. Patter, W. H. van., Bargen, J. A., Dockerty, M. B., Feldman, W. H., Mayo, C. W., and Waugh, J. M. (1954). Regional It is debatable whether the incidence of peptic enteritis Gastroenterology, 26, 347-448.