Digestive Diseases and Sciences, Vol. 40, No. 2 (Februa~ 1995), pp. 315-319

C A S E R E P O R T

Nonsteroidal Antiinflammatory Drug-Induced Colonic Stricture

An Unusual Cause of Large Bowel Obstruction and Perforation

M I C H A E L H.E . R O B I N S O N , FRCS, T I M O T H Y W H E A T L E Y , FRCS, and IAN H. L E A C H , MB, BS

KEY WORDS: nonsteroidal antiinflammatory drugs; colonic diseases; intestinal perforation; large bowel obstruction.

Over 100 million prescriptions for nonsteroidal anti- inflammatory drugs (NSAIDs) are written annually in the United States (1) and more than 20 million in the U.K. (2). Gastroduodenal mucosal injury is a widely recognized side effect, up to 22% of patients on N S A I D treatment having peptic ulceration (2). More recently, inflammation and ulceration affect- ing both small and large intestine have been recog- nized as adverse effects (3-5). Of particular interest have been the reports of strictures, both broad and "d iaphragml ike , " involving jejunum and ileum as- sociated with the long-term usage of these drugs (6-8). A similar NSAID- induced colonic stricture was first reported in 1989 (9). Subsequent reports of colonic diaphragms have usually been in patients being investigated for iron-deficiency anemia (10- 15). Emergency presentat ion with large bowel ob- struction and perforation secondary to an NSAID- induced colonic stricture is previously unreported. We present such a case and review the literature.

CASE REPORT

A 53-year old white female with a seven-year history of rheumatoid arthritis was admitted as an emergency. She complained of a three-day history of lower abdominal pain, suddenly becoming severe 3 hr before admission with radiation to the right shoulder. She was taking di- clofenac (slow release), aspirin, ranitidine, and coprox-

Manuscript received March 3, 1994; revised manuscript re- ceived July 26, 1994; accepted July 28, 1994.

From the Departments of Surgery and Histopathology, Uni- versity Hospital, Nottingham NG7 2UH, U.K.

Address for reprint requests: Mr. M.H.E. Robinson, Depart- ment of Surgery, University Hospital, Nottingham NG7 2UH, U,K.

amol. Diclofenac had been regularly prescribed for the last five years.

She was distressed, pale, and sweaty. Pulse was 78 beats per minute, blood pressure 78/50, and temperature 36.8°C. Her abdomen was rigid and bowel sounds scanty. Serum amylase was normal and erect chest x-ray re- vealed free gas under the right hemidiaphragm. Following fluid resuscitation, surgical exploration was undertaken.

At laparotomy, she was found to have a l-cm perforation in a grossly distended and thinned cecum. The cause of obstruction was a tight stricture of the ascending colon, but the remaining small and large bowel appeared normal. A right hemicolectomy was performed. Pathologic evaluation of the resected specimen showed two separate similar areas of circumferential mucosal ulceration with stenosis second- ary to extensive submucosal fibrosis and hypertrophy of the muscularis propria; prominent lymphoid follicles were pres- ent through the bowel wall (Figures la,b and 2). One stric- ture was located in the ascending colon and the other at the ileocaecal valve involving the root of the appendix. Be- tween these strictures the cecum was distended and thinned, leading to perforation. The remaining resected small and large bowel was grossly and microscopically normal. There was not evidence of Crohn's disease and the mesenteric blood vessels were unremarkable without evi- dence of occlusion, vasculitis or amyloid.

The patient made an uneventful recovery.

DISCUSSION

The most widely recognized complicat ions of N S A I D therapy are the consequences of gastroduo- denal inflammation and ulcerat ion--pain , bleeding, and perforation. The first report of N S A I D damage in the more distal gastrointestinal tract was in 1966, cecal ulceration occurr ing in association with oxy- phenbutazone and indomethacin therapy (3). In a comprehensive review of the literature, Bjarnason et al (5) summarize a number of adverse effects of

Digestive Diseases and Sciences, VoL 40, No. 2 (February 1995) 0163-2116/95/0200-0315507.5(110 ,© 1995 Plenum Publishing Corporalion

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ROBINSON ET AL

Fig 1.(a) Photograph of the opened resected specimen demonstrating obstructing stenoses proximal and distal to the perforated caecum, and (b) line drawing.

ingested NSAIDs on the small and large intestine, but do not include colonic stricture and obstruction. Small intestinal stricture associated with NSAID ingestion was described in 1973 (6), but obstruction due to "diaphragm disease" (multiple, 2- to 4-mm- thick concentric diaphragrnlike septa that narrow the lumen to a pinhole) was not recognized until

1987 (7). This unusual condition was identified in five separate cases by Lang et al (8) in a retrospec- tive review of 576 small bowel resections for ob- struction over a 16-year period. In this series, they also recognized broad-based stenoses associated with NSAID ingestion. They hypothesized an evo- lution of pathological changes in which tall, thin

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terminal ileum mucosa

Stenosis at ileocaecal valve

Grossly distended & thinned caecum with central perforation

Stenosis in ascending colon

Normal distal ascending colon mucosa

Fig 1. Continued.

mucosal diaphragms become broader-based humps or ridges and eventually short, fiat strictures due to the increasing fibrous obliteration of the segment of submucosa (8). It is conceivable that a similar pro- cess also occurs in the large bowel.

The first report of a colonic stricture caused by ingestion of NSAIDs was a letter by Sheers and Williams (9). They described two patients being investigated for " 'microscopic gastrointest inal blood loss" in whom colonoscopy revealed circum- ferential colonic scars with a "thin rim of erosion on the edge of each scar" leading to stricturing (9). Since then, a total of 10 more completely docu- mented cases have been reported (10-15), six from a single center in Switzerland (10, 15). Among these, there are several common themes relating to presentation, site of damage, implicated NSAID and method of delivery, and finally microscopic features. In all, histological examination of the strictures were consistent with NSAID-induced damage, the dominant feature being submucosal

fibrosis. The colonic stricture(s) have all occurred in the proximal transverse or right colon (apart from one of the originally described cases in the sig- moid). Third, eight of the 10 patients had an iron- deficiency anemia (10-15); in all but one of these (13), the strictures were associated with ulceration, restricted to the haustral folds (15). Finally, di- clofenac was an implicated drug in eight cases, all but one of the patients (12) taking a slow-release preparation. One of the two not on diclofenac was taking slow-release indomethacin.

The introduction of slow-release preparations may be moving the site of NSAID-induced gut dam- age more distally and suggests that its effect is local rather than systemic. Further evidence for a local effect is the observation that active NSAIDs in- crease intestinal permeability, while prodrugs, acti- vated after absorption, do not (16). The frequency with which diclofenac is implicated suggests the possibility of an idiosyncratic reaction. However, this is a commonly prescribed slow-release NSAID,

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Fig. 2. Mucosal ulcertion and conspicuous submucosal fibrosis (hematoxylin and eosin, x23),

and this drug is manufactured and widely pre- scribed in Switzerland (15), from where the major- ity of the reports have come.

The pathogenesis of the condition is uncertain, but it is possible that "'diaphragm disease" and longer intestinal strictures are a sequel to the preceding ul- ceration. This causality is suggested by two of the reports. In one patient (11), a diaphragm (attributed to

sulindac) in the transverse colon was segmentally resected. Four months later, having restarted sunlin- dac against medical advice, she presented again with anemia. Colonoscopy showed extensive ulceration proximal to the anastomosis. Repeat examination one month later showed four tight weblike strictures at the site of the ulceration, which had healed. In the second patient (10), colonoscopy revealed confluent ulcer-

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ation of the ascending colon which, at colonoscopy two years later, had healed to multiple diaphragmlike rigid circumferential septa. NSAIDs increase intesti- nal permeability and, in the face of a reduced mucosal barrier, intestinal contents may produce ulceration (5). Going et al (17) described narrow circumferential ulcers in the ileum of a woman on long-standing indo- methacin therapy and suggested that these may be the precursor of diaphragm disease. However, if ulcer- ation does progress to diaphragm disease, it probably happens infrequently. A postmortem study found small bowel ulceration in 21 of 74 subjects who had regularly taken NSAIDs in the six-month period prior to death, while no diaphragms were found (18).

Although the scale and significance of the problem, in terms of morbidity and mortality, is still poorly understood, various therapeutic options have been suggested. Withdrawal of NSAIDs is often not prac- tical since many patients would suffer intolerable symptoms. Prevention of enteropathy in those taking NSAIDs may be possible by the addition of misopros- toi, although the importance of enteropathy in causing strictures is unclear. Substitution of NSAID pro- drugs, like sulindac, has been suggested (5), but this was an implicated drug on two occasions (11, 12).

We are unaware of any other reported cases of NSAID-induced colonic stricture and believe that this report is the first to describe large bowel obstruction with subsequent cecal perforation caused by NSAIDs.

SUMMARY

Nonsteroidal antiinflammatory drugs (NSAIDs) are widely prescribed drugs that can result in gas- troduodenal ulceration. Adverse effects upon the small and large intestine are now more often recog- nized. Small intestinal obstruction secondary to both mucosal diaphragms and broad-based stenoses is reported, but colonic strictures appear to be less common. A case of NSAID-induced colonic stric- ture leading to large bowel obstruction and second- ary cecal perforation (previously unreported) is pre- sented. Twelve additional cases of NSAID-induced colonic stricture are reviewed from the literature and its possible pathogenesis is discussed.

ACKNOWLEDGMENTS

The authors thank Mr. C.A.S. Pegg, FRCS, for per- mission to report his patient and Dr. I. Talbot, FRCPath, for review of the pathology of this case.

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