Nonsteroidal Anti-Inflammatory Drug-Induced Enteropathy: Case Discussion and Review of the Literature

Abstract

The adverse effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on the upper gastrointestinal tract are well described. Evidence also shows that NSAIDs can be harmful to the small intestine. The use of NSAIDs has been associated with small intestinal strictures, ulcerations, perforations, diarrhea, and villous atrophy. Herein we present a case of NSAID-induced enteropathy with multiple diaphragmlike strictures that involved the distal 3S em of ileum and review the literature of other cases of NSAID-induced enteropathy in which biopsy specimens were obtained for histologic analysis to rule out other causes. The prevalence of NSAID-induced enteropathy is unknown. Diagnosis can be made by endoscopy or at abdominal exploration. The role of radionuclide scans for diagnosis remains unclear. The pathogenesis is likely multifactorial. Mucosal diaphragms may be specific for NSAID-related disease. Treatment options for NSAID-induced enteropathy are discussed. The adverse effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on the upper gastrointestinal tract are well described. Evidence also shows that NSAIDs can be harmful to the small intestine. The use of NSAIDs has been associated with small intestinal strictures, ulcerations, perforations, diarrhea, and villous atrophy. Herein we present a case of NSAID-induced enteropathy with multiple diaphragmlike strictures that involved the distal 3S em of ileum and review the literature of other cases of NSAID-induced enteropathy in which biopsy specimens were obtained for histologic analysis to rule out other causes. The prevalence of NSAID-induced enteropathy is unknown. Diagnosis can be made by endoscopy or at abdominal exploration. The role of radionuclide scans for diagnosis remains unclear. The pathogenesis is likely multifactorial. Mucosal diaphragms may be specific for NSAID-related disease. Treatment options for NSAID-induced enteropathy are discussed. Nonsteroidal anti-inflammatory drugs (NSAIDs) are useful in the treatment of osteoarthritis, musculoskeletal pain, rheumatoid arthritis, and other inflammatory conditions;1Aabakken L Review article: non-steroidal, anti-inflammatory drugsthe extending scope of gastrointestinal side effects.Aliment Pharmacol Ther. 1992; 6: 143-162Crossref PubMed Scopus (35) Google Scholar however, they cause increased mucosal damage to the upper gastrointestinal (GI) tract, including an increased incidence of gastric and duodenal ulcers.2Somerville K Faulkner G Langman M Non-steroidal anti-inflammatory drugs and bleeding peptic ulcer.Lancet. 1986; 1: 462-464Abstract PubMed Scopus (467) Google Scholar, 3Armstrong CP Blower AL Non-steroidal anti-inflammatory drugs and life threatening complications of peptic ulceration.Gut. 1987; 28: 527-532Crossref PubMed Scopus (605) Google Scholar During the past decade, the deleterious effects of NSAIDs on the small intestine and colon have also been recognized4Gibson GR Whitacre EB Ricotti CA Colitis induced by nonsteroidal anti-inflammatory drugs: report of four cases and review of the literature.Arch Intern Med. 1992; 152: 625-632Crossref PubMed Scopus (174) Google Scholar, 5Tanner AR Raghunath AS Colonic inflammation and non-steroidal anti-inflammatory drug administration: an assessment of the frequency of the problem.Digestion. 1988; 41: 116-120Crossref PubMed Scopus (104) Google Scholar, 6Huber T Ruchti C Halter F Nonsteroidal antiinflammatory drug-induced colonic strictures: a case report.Gastroenterology. 1991; 100: 1119-1122PubMed Google Scholar-changes in permeability, inflammation, and fibrosis with stenosis.7Bjarnason I Hayllar J MacPherson AJ Russell AS Side effects of nonsteroidal anti-inflammatory drugs on the small and large intestine in humans.Gastroenterology. 1993; 104: 1832-1847Abstract PubMed Scopus (881) Google Scholar Although the colon can be evaluated with colonoscopy, endoscopic examination of the jejunum and ileum with video enteroscopy is technically difficult and not available at most medical facilities. Two techniques have been advocated for quantification of inflammation in NSAID-induced enteropathy: the 1IIIn scan and urinary excretion of 51Cr. To date, no prospective studies have shown these methods to correlate with histologic changes.” Herein we present a case of histologically confirmed NSAID-induced enteropathy and review the literature of other such cases in which biopsy specimens were obtained for histologic examination. A 37-year-old woman was hospitalized because of nausea, vomiting, large-volume diarrhea, and hypokalemia. Three years before the current admission, she underwent antrectomy, vagotomy, and gastroduodenostomy with a Billroth I anastomosis because of a nonhealing gastric ulcer. Two years previously, malaise, diarrhea, and persistent iron deficiency anemia developed; at that time, the hemoglobin concentration was 6.0 g/dL, and the ferritin level was 3 μglL. She had been taking 800 mg of ibuprofen three times a day for pelvic pain for 2 years. A stomach roentgenogram with use of barium, esophagogastroduodenoscopy, colonoscopy, and biopsy of the small bowel showed normal findings. Results of a duodenal aspirate that was examined for Giardia and cultured for bacteria were negative. Because of recurrent anemia, she received a total of 6 U of packed red blood cells (RBCs) for 2 months, and ferrous sulfate was administered orally. Repeated colonoscopy demonstrated a nonbleeding 4-mm ulcer on the ileocecal valve. A biopsy specimen of the ulcer was cauterized, and the histologic examination revealed nonspecific ulceration. In addition, findings on a small bowel barium study, enteroclysis, and peroral small bowel biopsies were normal. Nonetheless, the anemia and diarrhea persisted. The patient continued to take ibuprofen primarily for pelvic pain until hospitalization. On admission, findings on physical examination were unremarkable except for pallor. Laboratory studies revealed hypokalemia (serum potassium, 1.9 mEqlL) and iron deficiency anemia (hemoglobin, 6.0 g/dL); the serum ferritin level was 3 ug/L, and the stool quantification of blood (HemoQuant) was 7.8 mg total hemoglobinlg of feces (normal, less than 4). Visceral angiography demonstrated angiodysplasia in the cecum and ascending and proximal transverse colon. At laparotomy, multiple strictures in the distal ileum were palpated. The terminal 35-cm ileum was resected along with the right colon, and an ileotransverse colonic anastomosis was performed. Pathologic examination demonstrated seven diaphragm-like l-cm strictures in the ileum with shallow circumferential ulcers in the area of strictures. Microscopic examination showed nonspecific ulceration. Postoperatively, the patient was instructed to discontinue use of ibuprofen. The anemia resolved, and she had no further anemia at 3-year follow-up. Twenty-five patients with NSAID-induced enteropathy have been described in the literature9Sturges HF Krone CL Ulceration and stricture of the jejunum in a patient on long-term indomethacin therapy.Am J Gastroenterol. 1973; 59: 162-169PubMed Google Scholar, 10Neoptolemos JP Locke TJ Recurrent small bowel obstruction associated with phenylbutazone.Br J Surg. 1983; 70: 244-245Crossref PubMed Scopus (34) Google Scholar, 11Saw KC Quick CR Higgins AF Ileocaecal perforation and bleeding—are non-steroidal anti-inflammatory drugs (NSAIDs) responsible?.J R Soc Med. 1990; 83: 114-115PubMed Google Scholar, 12Saverymuttu SH Thomas A Grundy A Maxwell JD Heal stricturing after long-term indomethacin treatment.Postgrad Med J. 1986; 62: 967-968Crossref PubMed Scopus (35) Google Scholar, 13Deakin M Small bowel perforation associated with an excessive dose of slow release diclofenac sodium.BMJ. 1988; 297: 488-489Crossref PubMed Scopus (19) Google Scholar, 14Day TK Intestinal perforation associated with osmotic slow release indomethacin capsules.BMJ. 1983; 287: 1671-1672Crossref PubMed Scopus (104) Google Scholar, 15Madhok R MacKenzie JA Lee FD Bruckner FE Terry TR Sturrock RD Small bowel ulceration in patients receiving non-steroidal anti-inflammatory drugs for rheumatoid arthritis.Q J Med. 1986; 58: 53-58PubMed Google Scholar, 16Isaacs PE Sladen GE Filipe I Mefenamic acid enteropathy.J Clin Pathol. 1987; 40: 1221-1227Crossref PubMed Scopus (37) Google Scholar, 17Lang J Price AB Levi AJ Burke M Gumpel JM Bjarnason I Diaphragm disease: pathology of disease of the small intestine induced by non-steroidal anti-inflammatory drugs.J Clin Pathol. 1988; 41: 516-526Crossref PubMed Scopus (289) Google Scholar, 18Bjarnason I Price AB Zanelli G Smethurst P Burke M Gumpel JM et al.Clinicopathological features of nonsteroidal antiinflammatory drug-induced small intestinal strictures.Gastroenterology. 1988; 94: 1070-1074PubMed Google Scholar, 19Matsuhashi N Yamada A Hiraishi M Konishi T Minota S Saito T et al.Multiple strictures of the small intestine after long-term nonsteroidal anti-inflammatory drug therapy.Am J Gastroenterol. 1992; 87: 1183-1186PubMed Google Scholar, 20Fellows IW Clarke JM Roberts PF Non-steroidal anti-inflammatory drug-induced jejunal and colonic diaphragm disease: a report of two cases.Gut. 1992; 33: 1424-1426Crossref PubMed Scopus (87) Google Scholar, 21Cree IA Walker MA Wright M Forrester JC Osmosin and ileal ulceration: a case report.Scott Med J. 1985; 30: 40-41PubMed Google Scholar, 22Laidler P Maslin SC Gilhome RW What's new in osmosin and intestinal perforation?.Pathol Res Pract. 1985; 180: 74-76Crossref PubMed Scopus (14) Google Scholar, 23Sukumar L Recurrent small bowel obstruction associated with piroxicam.Br J Surg. 1987; 74: 186Crossref PubMed Scopus (23) Google Scholar, 24Johnston F Recurrent small bowel obstruction associated with piroxicam [letter].Br J Surg. 1987; 74: 654Crossref PubMed Scopus (14) Google Scholar, 25Freeman HJ Sulindac-associated small bowel lesion.J Clin Gastroenterol. 1986; 8: 569-571Crossref PubMed Scopus (31) Google Scholar (Table 1). These patients, whose ages ranged from 40 to 78 years (mean, 66), were taking many types of NSAIDs for inflammatory conditions such as ankylosing spondylitis, osteoarthritis, and rheumatoid arthritis. The clinical manifestations were GI bleeding, obstruction, or diarrhea. Of the 21 patients in whom gender was reported, 14 were female, and 7 were male. Of the 16 patients in whom duration of NSAID use was reported, 11 had been taking NSAIDs for more than 1 year.9Sturges HF Krone CL Ulceration and stricture of the jejunum in a patient on long-term indomethacin therapy.Am J Gastroenterol. 1973; 59: 162-169PubMed Google Scholar, 10Neoptolemos JP Locke TJ Recurrent small bowel obstruction associated with phenylbutazone.Br J Surg. 1983; 70: 244-245Crossref PubMed Scopus (34) Google Scholar, 12Saverymuttu SH Thomas A Grundy A Maxwell JD Heal stricturing after long-term indomethacin treatment.Postgrad Med J. 1986; 62: 967-968Crossref PubMed Scopus (35) Google Scholar, 15Madhok R MacKenzie JA Lee FD Bruckner FE Terry TR Sturrock RD Small bowel ulceration in patients receiving non-steroidal anti-inflammatory drugs for rheumatoid arthritis.Q J Med. 1986; 58: 53-58PubMed Google Scholar, 16Isaacs PE Sladen GE Filipe I Mefenamic acid enteropathy.J Clin Pathol. 1987; 40: 1221-1227Crossref PubMed Scopus (37) Google Scholar, 17Lang J Price AB Levi AJ Burke M Gumpel JM Bjarnason I Diaphragm disease: pathology of disease of the small intestine induced by non-steroidal anti-inflammatory drugs.J Clin Pathol. 1988; 41: 516-526Crossref PubMed Scopus (289) Google Scholar, 23Sukumar L Recurrent small bowel obstruction associated with piroxicam.Br J Surg. 1987; 74: 186Crossref PubMed Scopus (23) Google Scholar, 24Johnston F Recurrent small bowel obstruction associated with piroxicam [letter].Br J Surg. 1987; 74: 654Crossref PubMed Scopus (14) Google ScholarTable 1Reported Cases of Nonsteroidal Anti-Inflammatory Drug-Induced Enteropathy*AS = ankylosing spondylitis; LBP = low-back pain; OA = osteoarthritis; RA = rheumatoid arthritis.DrugIndicationsHistopathologic and clinical findingsReferenceIndomethacinAS, RA, OA, Felty's syndromeJejunal stricture and ulcerations9Sturges HF Krone CL Ulceration and stricture of the jejunum in a patient on long-term indomethacin therapy.Am J Gastroenterol. 1973; 59: 162-169PubMed Google ScholarHeal stricture and ulcerations12Saverymuttu SH Thomas A Grundy A Maxwell JD Heal stricturing after long-term indomethacin treatment.Postgrad Med J. 1986; 62: 967-968Crossref PubMed Scopus (35) Google Scholar, 15Madhok R MacKenzie JA Lee FD Bruckner FE Terry TR Sturrock RD Small bowel ulceration in patients receiving non-steroidal anti-inflammatory drugs for rheumatoid arthritis.Q J Med. 1986; 58: 53-58PubMed Google Scholar, 22Laidler P Maslin SC Gilhome RW What's new in osmosin and intestinal perforation?.Pathol Res Pract. 1985; 180: 74-76Crossref PubMed Scopus (14) Google ScholarSubacute obstruction17Lang J Price AB Levi AJ Burke M Gumpel JM Bjarnason I Diaphragm disease: pathology of disease of the small intestine induced by non-steroidal anti-inflammatory drugs.J Clin Pathol. 1988; 41: 516-526Crossref PubMed Scopus (289) Google ScholarPerforation of terminal ileum14Day TK Intestinal perforation associated with osmotic slow release indomethacin capsules.BMJ. 1983; 287: 1671-1672Crossref PubMed Scopus (104) Google Scholar, 21Cree IA Walker MA Wright M Forrester JC Osmosin and ileal ulceration: a case report.Scott Med J. 1985; 30: 40-41PubMed Google ScholarPiroxicamOA, RAHeal stricture and ulcerations11Saw KC Quick CR Higgins AF Ileocaecal perforation and bleeding—are non-steroidal anti-inflammatory drugs (NSAIDs) responsible?.J R Soc Med. 1990; 83: 114-115PubMed Google Scholar, 19Matsuhashi N Yamada A Hiraishi M Konishi T Minota S Saito T et al.Multiple strictures of the small intestine after long-term nonsteroidal anti-inflammatory drug therapy.Am J Gastroenterol. 1992; 87: 1183-1186PubMed Google ScholarSubacute obstruction17Lang J Price AB Levi AJ Burke M Gumpel JM Bjarnason I Diaphragm disease: pathology of disease of the small intestine induced by non-steroidal anti-inflammatory drugs.J Clin Pathol. 1988; 41: 516-526Crossref PubMed Scopus (289) Google Scholar, 23Sukumar L Recurrent small bowel obstruction associated with piroxicam.Br J Surg. 1987; 74: 186Crossref PubMed Scopus (23) Google ScholarMefenamic acidOAVillous atrophy16Isaacs PE Sladen GE Filipe I Mefenamic acid enteropathy.J Clin Pathol. 1987; 40: 1221-1227Crossref PubMed Scopus (37) Google ScholarDiclofenac sodiumRA, LBPSmall intestinal strictures19Matsuhashi N Yamada A Hiraishi M Konishi T Minota S Saito T et al.Multiple strictures of the small intestine after long-term nonsteroidal anti-inflammatory drug therapy.Am J Gastroenterol. 1992; 87: 1183-1186PubMed Google ScholarPerforation of terminal ileum13Deakin M Small bowel perforation associated with an excessive dose of slow release diclofenac sodium.BMJ. 1988; 297: 488-489Crossref PubMed Scopus (19) Google ScholarNaproxenOA, RAHeal stricture and ulcerations Thickened folds on small bowel roentgenogram15Madhok R MacKenzie JA Lee FD Bruckner FE Terry TR Sturrock RD Small bowel ulceration in patients receiving non-steroidal anti-inflammatory drugs for rheumatoid arthritis.Q J Med. 1986; 58: 53-58PubMed Google Scholar18Bjarnason I Price AB Zanelli G Smethurst P Burke M Gumpel JM et al.Clinicopathological features of nonsteroidal antiinflammatory drug-induced small intestinal strictures.Gastroenterology. 1988; 94: 1070-1074PubMed Google ScholarAzapropazoneRASubacute obstruction Jejunoileal strictures with obstruction17Lang J Price AB Levi AJ Burke M Gumpel JM Bjarnason I Diaphragm disease: pathology of disease of the small intestine induced by non-steroidal anti-inflammatory drugs.J Clin Pathol. 1988; 41: 516-526Crossref PubMed Scopus (289) Google Scholar24Johnston F Recurrent small bowel obstruction associated with piroxicam [letter].Br J Surg. 1987; 74: 654Crossref PubMed Scopus (14) Google ScholarFlurbiprofenRAJejunal stricture and ulcerations20Fellows IW Clarke JM Roberts PF Non-steroidal anti-inflammatory drug-induced jejunal and colonic diaphragm disease: a report of two cases.Gut. 1992; 33: 1424-1426Crossref PubMed Scopus (87) Google ScholarPhenylbutazoneOAHeal stricture and ulcerations10Neoptolemos JP Locke TJ Recurrent small bowel obstruction associated with phenylbutazone.Br J Surg. 1983; 70: 244-245Crossref PubMed Scopus (34) Google ScholarSulindacOAVillous atrophy25Freeman HJ Sulindac-associated small bowel lesion.J Clin Gastroenterol. 1986; 8: 569-571Crossref PubMed Scopus (31) Google Scholar* AS = ankylosing spondylitis; LBP = low-back pain; OA = osteoarthritis; RA = rheumatoid arthritis. Open table in a new tab An autopsy study also demonstrated a higher frequency of nonspecific ulcerations and erosions in patients who had taken NSAIDs for more than 6 months in comparison with control patients who had taken no NSAIDs.26Allison MC Howatson AG Torrance CJ Lee FD Russell RI Gastrointestinal damage associated with the use of nonsteroidal antiinflammatory drugs.N Engl J Med. 1992; 327: 749-754Crossref PubMed Scopus (975) Google Scholar Nevertheless, five patients have. been described with NSAID-induced enteropathy after use of medication for less than 4 weeks.11Saw KC Quick CR Higgins AF Ileocaecal perforation and bleeding—are non-steroidal anti-inflammatory drugs (NSAIDs) responsible?.J R Soc Med. 1990; 83: 114-115PubMed Google Scholar, 13Deakin M Small bowel perforation associated with an excessive dose of slow release diclofenac sodium.BMJ. 1988; 297: 488-489Crossref PubMed Scopus (19) Google Scholar, 14Day TK Intestinal perforation associated with osmotic slow release indomethacin capsules.BMJ. 1983; 287: 1671-1672Crossref PubMed Scopus (104) Google Scholar, 21Cree IA Walker MA Wright M Forrester JC Osmosin and ileal ulceration: a case report.Scott Med J. 1985; 30: 40-41PubMed Google Scholar, 25Freeman HJ Sulindac-associated small bowel lesion.J Clin Gastroenterol. 1986; 8: 569-571Crossref PubMed Scopus (31) Google Scholar Moreover, the route of administration of NSAIDs does not seem to affect the development of enteropathy. For example, use of Osmosin, a now discontinued indomethacin rectal suppository, was associated with ileal perforations;14Day TK Intestinal perforation associated with osmotic slow release indomethacin capsules.BMJ. 1983; 287: 1671-1672Crossref PubMed Scopus (104) Google Scholar, 21Cree IA Walker MA Wright M Forrester JC Osmosin and ileal ulceration: a case report.Scott Med J. 1985; 30: 40-41PubMed Google Scholar 14 of the 25 patients with NSAID-induced enteropathy were taking either indomethacin or piroxicam preparations. Of these 25 patients, 10 had intestinal obstruction, 10 had ulceration and anemia, and 3 had intestinal perforation (Table 1). In a recent autopsy series, the cause of death in three patients who had received long-term NSAID therapy was undiagnosed small bowel perforations; no such lesions were noted in the control group.26Allison MC Howatson AG Torrance CJ Lee FD Russell RI Gastrointestinal damage associated with the use of nonsteroidal antiinflammatory drugs.N Engl J Med. 1992; 327: 749-754Crossref PubMed Scopus (975) Google Scholar Of 18 patients in whom histopathologic findings were reported, small intestinal strictures and ulcerations were noted in 12, villous atrophy in 3, and intestinal perforations in 3. Of the 25 patients, 21 underwent intestinal resection; in 4, the only treatment was discontinuation of use of NSAIDs. Of the 23 patients in whom follow-up was reported, 3 died, 2 of intestinal perforation. In a retrospective study of 268 patients who were hospitalized because of small and large bowel perforations or hemorrhage, those who were taking NSAIDs were twice as likely to have one of these complications develop in comparison with control patients.27Langman MJ Morgan L Worrall A Use of anti-inflammatory drugs by patients admitted with small or large bowel perforations and haemorrhage.BMJ. 1985; 290: 347-349Crossref PubMed Scopus (312) Google Scholar Perforations were noted intraoperatively or at autopsy, and small intestinal hemorrhage was presumed if the patient had melena and no evidence of an upper intestinal source. Although a colonic source of blood loss may have been possible in some of these patients, NSAIDs seemed to be the cause of small intestinal bleeding. Two NSAIDs have been reported to cause villous atrophy of the small intestine. Mefenamic acid apparently caused malabsorption, anemia, steatorrhea, and severe villous atrophy in two patients; resolution occurred after use of the drug was discontinued.24 Mefenamic acid can also cause diarrhea due to enteritis without villous atrophy.28Hall RI Petty AH Cobden I Lendrum R Enteritis and colitis associated with mefenamic acid.BMJ. 1983; 287: 1182Crossref PubMed Scopus (74) Google Scholar, 29Rampton DS Tapping PJ Enteritis and colitis associated with mefenamic acid [letter].BMJ. 1983; 287: 1627Crossref Google Scholar, 30Williams R Glazer G Enteritis and colitis associated with mefenamic acid [letter].BMJ. 1983; 287: 1627Crossref Google Scholar, 31Phillips MS Fehilly B Stewart S Dronfíeld MW Enteritis and colitis associated with mefenamic acid [letter].BMJ. 1983; 287: 1626PubMed Google Scholar Sulindac seemed to be the cause of diarrhea and villous atrophy in one patient.25Freeman HJ Sulindac-associated small bowel lesion.J Clin Gastroenterol. 1986; 8: 569-571Crossref PubMed Scopus (31) Google Scholar NSAIDs are among the most widely prescribed medications in the industrialized world; more than 100 million NSAID prescriptions are written annually by US physicians.32Gibson T Nonsteroidal anti-inflammatory drugs—another look.Br J Rheumatol. 1988; 27: 87-90Crossref PubMed Scopus (69) Google Scholar Long-term NSAID therapy is common for patients with either rheumatoid arthritis or osteoarthritis. Bjarnason and associates8Bjarnason I Zanelli G Smith T Prouse P Williams P Smethurst P et al.Nonsteroidal antiinflammatory drug-induced intestinal inflammation in humans.Gastroenterology. 1987; 93: 480-489PubMed Google Scholar examined 97 patients with rheumatoid arthritis and osteoarthritis who had been taking NSAIDs for more than 2 months and determined that two-thirds of these patients had intestinal inflammation, as demonstrated by indium scintiscans and 4-day quantitative fecal collection of indium. Nine of these patients underwent intestinal biopsies (all peroral jejunal biopsies), one of which detected increased intraepithelial lymphocytes, a nonspecific finding. Allison and colleagues26Allison MC Howatson AG Torrance CJ Lee FD Russell RI Gastrointestinal damage associated with the use of nonsteroidal antiinflammatory drugs.N Engl J Med. 1992; 327: 749-754Crossref PubMed Scopus (975) Google Scholar determined the prevalence and morphologic features of jejunal and ileal mucosal lesions at autopsy in 713 consecutive patients with and without a history of NSAID use. The prevalence of nonspecific jejunal and ileal ulceration in patients who had taken NSAIDs was significantly increased (8.4%) in comparison with control subjects (0.6%). Patients who had received NSAIDs regularly for more than 6 months seemed to have a high risk for the development of intestinal lesions (14%). The 8.4% prevalence rate26Allison MC Howatson AG Torrance CJ Lee FD Russell RI Gastrointestinal damage associated with the use of nonsteroidal antiinflammatory drugs.N Engl J Med. 1992; 327: 749-754Crossref PubMed Scopus (975) Google Scholar contrasts with the 66% prevalence rate of indium scan diagnosis of enteropathy reported by Bjarnason and coworkers.8Bjarnason I Zanelli G Smith T Prouse P Williams P Smethurst P et al.Nonsteroidal antiinflammatory drug-induced intestinal inflammation in humans.Gastroenterology. 1987; 93: 480-489PubMed Google Scholar This difference can be explained in part by technical factors, such as the inability to detect focal microscopic intestinal erosions in the postmortem study and the lack of specificity of the radionuclide study. In a study of 46 patients with rheumatoid arthritis who had received long-term NSAID therapy and who had iron deficiency anemia and normal findings on endoscopic examinations of the upper GI tract, total small intestinal enteroscopy was performed to determine the site of blood loss.33Morris AJ Wasson LA MacKenzie JF Small bowel enteroscopy in undiagnosed gastrointestinal blood loss.Gut. 1992; 33: 887-889Crossref PubMed Scopus (150) Google Scholar In 19 of the patients, small intestinal mucosal abnormalities including erosions, ulcers, and “red spots,” which may have been early mucosal lesions, were identified. Although active bleeding was not observed, these lesions may have accounted for the blood loss. In up to 50% of patients who take NSAIDs and have iron deficiency anemia, no identifiable source of blood loss can be detected by gastroscopy and colonoscopy.34Upadhyay R Torley HI McKinlay AW Sturrock RD Russell RI Iron deficiency anaemia in patients with rheumatic disease receiving non-steroidal anti-inflammatory drugs: the role of upper gastrointestinal lesions.Ann Rheum Dis. 1990; 49: 359-362Crossref PubMed Scopus (26) Google Scholar A small intestinal barium study may show strictures and areas of dilatation, factors that suggest focal obstruction even when a precise site is not evident. Small bowel strictures or diaphragms may be overlooked radiographically; thus, radiologists should be alerted to the possibility of these lesions before the study is performed.17Lang J Price AB Levi AJ Burke M Gumpel JM Bjarnason I Diaphragm disease: pathology of disease of the small intestine induced by non-steroidal anti-inflammatory drugs.J Clin Pathol. 1988; 41: 516-526Crossref PubMed Scopus (289) Google Scholar Nevertheless, normal findings on a small bowel barium examination do not rule out the diagnosis of NSAID-induced enteropathy. Four radiolabeled laboratory tests have been used in assessing patients with suspected NSAID-induced enteropathy.35Bjarnason I Zanelli G Prouse P Smethurst P Smith T Levi S et al.Blood and protein loss via small-intestinal inflammation induced by non-steroidal anti-inflammatory drugs.Lancet. 1987; 2: 711-714Abstract PubMed Scopus (205) Google Scholar, 36Bjarnason I Williams P So A Zanelli GD Levi AJ Gumpel JM et al.Intestinal permeability and inflammation in rheumatoid arthritis: effects of non-steroidal anti-inflammatory drugs.Lancet. 1984; 2: 1171-1174Abstract PubMed Scopus (279) Google Scholar 111In scintiscans of the abdomen may be used to localize areas of intestinal inflammation and are obtained at 1 to 4 hours and 20 hours after injection of the labeled leukocytes. For quantification of intestinal inflammation, an 111In quantitative fecal collection is performed. Stool specimens are collected in an inpatient setting to ensure accuracy and are collected during a 4-day period after injection of labeled leukocytes. Quantification of the marker is performed in a high-resolution bulk counter. As previously noted, two-thirds of patients receiving NSAIDs will have abnormal findings on scintiscans or increased fecal levels of 111In. The renal excretion of orally ingested 51Cr-labeled ethylenediaminetetraacetic acid can be used as a measure of intestinal permeability by quantification in urine collected 24 hours after ingestion. As an indirect assessment of NSAID-induced injury, 51Cr-labeled RBCs can be injected intravenously; stool specimens are collected for 4 days after injection to quantify intestinal blood loss. The high cost of an indium scan (more than $1,000 at many US hospitals) and the difficulty in obtaining 4-day fecal collections limit the clinical utility of these scans. To date, no study has compared a nuclear scan technique to histologic findings to assess the sensitivity and specificity of the scan for NSAID-induced enteropathy. As previously noted, small bowel enteroscopy has been used to investigate blood loss in patients receiving NSAIDs. The advantages include direct visualization of small bowel mucosa and the ability with some prototype enteroscopes to obtain biopsy tissue for histopathologic confirmation. With current enteroscopes, however, the tip often passes rapidly around bowel loops as the instrument is withdrawn; thus, the entire small bowel mucosa is not always examined satisfactorily. In addition, the procedure can be an ordeal for patients; up to 6 hours are needed for the instrument to advance passively into the ileocecal valve in preparation for retrograde inspection of the mucosa. Although small intestinal ulcerations and erosions are nonspecific, the presence of mucosal diaphragms is specific for intestinal damage by NSAIDs (Fig. 1). Diaphragm formation was initially described in five patients taking NSAIDs; such lesions were detected at small bowel resection.17Lang J Price AB Levi AJ Burke M Gumpel JM Bjarnason I Diaphragm disease: pathology of disease of the small intestine induced by non-steroidal anti-inflammatory drugs.J Clin Pathol. 1988; 41: 516-526Crossref PubMed Scopus (289) Google Scholar Because these diaphragms have morphologic features similar to prominent but otherwise normal mucosal folds, detection by barium examination is difficult. Histologically, the mucosa overlying the diaphragm shows submucosal fibrosis with or without ulceration. The frequency of diaphragm formation in the small intestine is unknown; however, diaphragms seem to be associated with long-term (more than 1 year) NSAID use.17Lang J Price AB Levi AJ Burke M Gumpel JM Bjarnason I Diaphragm disease: pathology of disease of the small intestine induced by non-steroidal anti-inflammatory drugs.J Clin Pathol. 1988; 41: 516-526Crossref PubMed Scopus (289) Google Scholar, 18Bjarnason I Price AB Zanelli G Smethurst P Burke M Gumpel JM et al.Clinicopathological features of nonsteroidal antiinflammatory drug-induced small intestinal strictures.Gastroenterology. 1988; 94: 1070-1074PubMed Google Scholar In a retrospective study of 25 patients with NSAID-induced enteropathy, no diaphragms were found.26Allison MC Howatson AG Torrance CJ Lee FD Russell RI Gastrointestinal damage associated with the use of nonsteroidal antiinflammatory drugs.N Engl J Med. 1992; 327: 749-754Crossref PubMed Scopus (975) Google Scholar In addition, diaphragmatic changes can occur in the colon, as were noted in the sigmoid colon of a patient with rheumatoid arthritis who was taking NSAIDs.37Hershfield NB Endoscopic description of “diaphragm disease” induced by non-steroidal anti-inflammatory drugs [abstract].Gastrointest Endosc. 1992; 38: 267Abstract Full Text PDF Scopus (24) Google Scholar The differential diagnosis of nonspecific erosions and ulcerations of the small intestine includes Crohn's disease, trauma (from ingested toothpicks or bones), infection (cytomegalovirus, tuberculosis, or Yersinia), radiation injury, vasculitis (lupus, rheumatoid, or periarteritis nodosa), ischemia, and medications including enteric-coated potassium. Several reports have described intestinal strictures and inflammation presumably due to rheumatoid vasculitis and other collagen vascular diseases; thus, patients with such diseases should be thoroughly examined because NSAIDs are commonly used to treat these disorders.38Kuehne SE Gauvin GP Shortsleeve MJ Small bowel stricture caused by rheumatoid vasculitis.Radiology. 1992; 184: 215-216PubMed Google Scholar, 39Dougados M Alemanni M Tulliez M Abadia R Kahan A Delrieu F et al.Systematic ileocolonoscopy in seronegative spondylarthropathies.Rev Rhum Mai Osteoartic. 1987; 54: 279-283PubMed Google Scholar, 40Okuda Y Takasugi K Imai A Kondo Y Hachinota M Ueda S et al.Two cases of rheumatoid arthritis complicated with vasculitis-induced ischemic enterocolitis.Ryumachi. 1990; 30: 403-407PubMed Google Scholar Potential mechanisms of NSAID-induced injury to the small intestine are as follows. 1.NSAIDs (like aspirin) inhibit cyclooxygenase and thereby inhibit formation of prostaglandins and divert arachidonic acid metabolism to the lipoxygenase pathway.41Rainsford KD Mechanisms of gastrointestinal toxicity of non-steroidal anti-inflammatory drugs.Scand J Gastroenterol Suppl. 1989; 163: 9-16Crossref PubMed Scopus (94) Google Scholar Prostaglandin inhibition by NSAIDs may predispose a patient to gastric ulcers and erosions.42Soll AH Weinstein WM Kurata J McCarthy D Nonsteroidal anti-inflammatory drugs and peptic ulcer disease.Ann Intern Med. 1991; 114: 307-319Crossref PubMed Scopus (409) Google Scholar Whether prostaglandins are necessary to protect the small intestinal mucosa is unknown. Subcutaneous administration of indomethacin caused intestinal ulceration in rats in approximately 24 to 48 hours and gastric erosions within 3 hours.43Whittle BJ Temporal relationship between cyclooxygenase inhibition, as measured by prostacyclin biosynthesis, and the gastrointestinal damage induced by indomethacin in the rat.Gastroenterology. 1981; 80: 94-98PubMed Scopus (419) Google Scholar Maximal cyclooxygenase inhibition also occurred 3 hours after administration of indomethacin, and intestinal ulceration probably occurred by a mechanism independent of cyclooxygenase activity; however, no data are available in animals or in humans to address this issue directly.2.NSAIDs and aspirin uncouple mitochondrial oxidative phosphorylation, as demonstrated in isolated animal gastric mucosa.44Jorgensen TG Weis-Fogh US Neilsen HH Olesen HP Salicylate- and aspirin-induced uncoupling of oxidative phos-phorylation in mitochondria isolated from the mucosal membrane of the stomach.Scand J Clin Lab Invest. 1976; 36: 649-654Crossref PubMed Google Scholar, 45Spenney JG Bhown M Effect of acetylsalicylic acid on gastric mucosa. II. Mucosal ATP and phosphocreatine content, and salicylate effects on mitochondrial metabolism.Gastroenterology. 1977; 73: 995-999PubMed Google Scholar This activity leads to a decrease in cellular adenosine triphosphate, and this depletion of high energy phosphate bonds may render the enterocyte vulnerable to damage by luminal substances. NSAIDs may also competitively inhibit enzymes in the glycolytic and Krebs' cycle. Coadministration of glucose and citrate with indomethacin prevented the increase in intestinal permeability that occurs when only indomethacin is given to healthy volunteers, presumably because the enterocyte has been supplied with sufficient substrate to maintain normal activity of the cycles.46Bjarnason I Smethurst P Macpherson A Walker F McElnay JC Passmore AP et al.Glucose and citrate reduce the permeability changes caused by indomethacin in humans.Gastroenterology. 1992; 102: 1546-1550PubMed Google Scholar3.The enterohepatic circulation of NSAIDs may also damage the small intestine. A direct correlation exists between the concentration of NSAIDs in bile and the degree of small intestinal damage.41Rainsford KD Mechanisms of gastrointestinal toxicity of non-steroidal anti-inflammatory drugs.Scand J Gastroenterol Suppl. 1989; 163: 9-16Crossref PubMed Scopus (94) Google Scholar Among the NSAIDs, indomethacin and piroxicam have the highest bile concentration.47Beck WS Schneider HT Dietzel K Nuernberg B Brune K Gastrointestinal ulcerations induced by anti-inflammatory drugs in rats: physicochemical and biochemical factors involved.ArchToxicol. 1990; 64: 210-217Google Scholar Indeed, 14 of the 25 patients with NSAID-induced enteropathy described in the literature were taking either indomethacin or piroxicam, an indication that patients may be at high risk when these two preparations are taken together (Table 1).4.In the stomach, disruption of the mucosal barrier by NSAIDs may lead to damage of the gastric mucosa by gastric acid. In the less acidic environment of the small intestine (pH, 4.5 to 7), disruption of the intestinal barrier may lead to bacterial invasion of the intestinal wall.48Wilson TH Intestinal Absorption. Saunders, Philadelphia1962: 130Google Scholar For example, indomethacin caused multiple intestinal ulcerations in rats in a standard environment; in rats that harbored a single bacterial species, intestinal ulcers developed at almost the same rate as in normal control rats. In contrast, germ-free rats were resistant to the development of intestinal lesions.49Robert A Asano T Resistance of germfree rats to indomethacin-induced intestinal lesions.Prostaglandins. 1977; 14: 333-341Crossref PubMed Scopus (295) Google Scholar In humans, NSAIDs also increase small intestinal permeability and allow bacterial invasion of the mucosa.50Bjarnason I Williams P Smethurst P Peters TJ Levi AJ Effect of non-steroidal anti-inflammatory drugs and prostaglandins on the permeability of the human small intestine.Gut. 1986; 27: 1292-1297Crossref PubMed Scopus (238) Google Scholar Metronidazole seemed to decrease intestinal inflammation and blood loss as measured by fecal excretion of 111In and scans of 51Cr-labeled RBCs in patients receiving NSAIDs, although intestinal permeability changes were unaffected.51Bjarnason I Hayllar J Smethurst P Price A Gumpel MJ Metronidazole reduces intestinal inflammation and blood loss in non-steroidal anti-inflammatory drug induced enter-opathy.Gut. 1992; 33: 1204-1208Crossref PubMed Scopus (168) Google Scholar This finding may be indirect evidence that neutrophils are attracted to invading bacteria sensitive to metronidazole.5.Leukocyte adhesion may also have an important role in the development of NSAID-induced enteropathy. Administering a monoclonal antibody against the leukocyte-adhesion glycoprotein or antineutrophil serum was protective against naproxen- or indomethacin-induced gastric mucosal injury in rats and rabbits.52Wallace JL Keenan CM Granger DN Gastric ulceration induced by nonsteroidal anti-inflammatory drugs is a neutrophil-dependent process.Am J Physiol. 1990; 259: G462-G467PubMed Google Scholar, 53Wallace JL Arfors KE McKnight GW A monoclonal antibody against the CD 18 leukocyte adhesion molecule prevents indomethacin-induced gastric damage in the rabbit.Gastroenterology. 1991; 100: 878-883PubMed Google Scholar Recently, aspirin was shown to promote leukocyte-endothelial cell adhesion in the microvasculature of the rat mesenteric venules, a possible initiating event in NSAID-induced mucosal damage.54Asako H Kubes P Wallace J Wolf RE Granger DN Modulation of leukocyte adhesion in rat mesenteric venules by aspirin and salicylate.Gastroenterology. 1992; 103: 146-152PubMed Google Scholar Data on the natural history of NSAID-induced enteropathy are scant; however, this situation may change with increasing awareness by clinicians. Recognizing the cause of the enteropathy and discontinuing use of the offending agent are the mainstay of treatment. These two factors have been reported to be successful in patients diagnosed with villous atrophy due to mefenamic acid and sulindac.16Isaacs PE Sladen GE Filipe I Mefenamic acid enteropathy.J Clin Pathol. 1987; 40: 1221-1227Crossref PubMed Scopus (37) Google Scholar, 25Freeman HJ Sulindac-associated small bowel lesion.J Clin Gastroenterol. 1986; 8: 569-571Crossref PubMed Scopus (31) Google Scholar Nonetheless, no data are available on the natural course of small intestinal ulcerations and diaphragms after NSAID therapy has been discontinued. In rats, pretreatment with dopamine, dimethyl sulfoxide, sucralfate, and pentagastrin may be protective against indomethacin-induced intestinal ulceration.55Sikiric P Rotkvic I Mise S Krizanac S Gjuris V Jukic J et al.The influence of dopamine agonists and antagonists on indomethacin lesions in stomach and small intestine in rats.Eur J Pharmacol. 1988; 158: 61-67Crossref PubMed Scopus (33) Google Scholar, 56Ali BH Protective effect of dimethylsulphoxide in stress-and indometacin-induced gastrointestinal ulceration in rats.Pharmacology. 1989; 39: 98-102Crossref PubMed Scopus (9) Google Scholar, 57Waisman Y Zahavi I Marcus H Ligumsky M Rosenbach Y Dinari G Sucralfate is protective against indomethacin-induced intestinal ulceration in the rat.Digestion. 1988; 41: 78-82Crossref PubMed Scopus (20) Google Scholar, 58Harel L Zahavi I Marcus H Waisman Y Ligumsky M Rosenbach Y et al.Pentagastrin protects the proximal small intestine against indomethacin-induced ulcers in the rat.Digestion. 1987; 38: 156-159Crossref PubMed Scopus (6) Google Scholar One patient with rheumatoid arthritis who had taken long-term piroxicam therapy had multiple ileal ulcers and diaphragms. At examination, use of piroxicam was discontinued, and high-dose ornoprostil (a prostaglandin E1 derivative available by prescription in Japan), sucralfate, and sulfasalazine were instituted; the intestinal bleeding and abdominal pain resolved.19Matsuhashi N Yamada A Hiraishi M Konishi T Minota S Saito T et al.Multiple strictures of the small intestine after long-term nonsteroidal anti-inflammatory drug therapy.Am J Gastroenterol. 1992; 87: 1183-1186PubMed Google Scholar In patients who took NSAIDs for rheumatoid arthritis or osteoarthritis, misoprostol decreased intestinal permeability, as measured by urine excretion of Ster-labeled ethylenediaminetetraacetic acid and L-rhamnose.59Bjarnason I Experimental evidence of the benefit of misoprostol beyond the stomach in humans.J Rheumatol Suppl. 1990; 20: 38-41PubMed Google Scholar Those doses of misoprostol were extremely high, however, and therapeutic doses of misoprostol have been unable to protect against indomethacin-induced increased intestinal permeability.60Davies GR Rampton DS Relevance of intestinal bacteria, prostaglandins, and pro-drug administration to non-steroidal anti-inflammatory drug (NSAID) induced increases in gut permeability [abstract].Gut. 1991; 32A: 1224Google Scholar Sulfasalazine and metronidazole may have a role in NSAID-induced enteropathy, inasmuch as both can decrease intestinal permeability.35Bjarnason I Zanelli G Prouse P Smethurst P Smith T Levi S et al.Blood and protein loss via small-intestinal inflammation induced by non-steroidal anti-inflammatory drugs.Lancet. 1987; 2: 711-714Abstract PubMed Scopus (205) Google Scholar, 61Bjarnason I Hopkinson N Zanelli G Prouse P Smethurst P Gumpel JM et al.Treatment of non-steroidal anti-inflammatory drug induced enteropathy.Gut. 1990; 31: 777-780Crossref PubMed Scopus (50) Google Scholar Obstruction is the most common indication for surgical treatment of NSAID-induced enteropathy. Infrequently, intestinal bleeding and perforation may also necessitate exploration. Intraoperatively, endoscopy can be performed with the endoscope placed perorally or through a surgical enterotomy. The surgeon moves the bowel over the end of the instrument-this approach allows inspection of the entire small bowel mucosa and transillumination for inspection from the serosa. Virtually all classes of NSAIDs have been implicated in the development of enteropathy with erosions, ulcerations, blood loss, villous atrophy, and strictures. The pathogenesis is unclear but likely multifactorial. In patients taking NSAIDs who have iron deficiency and normal findings on assessment of the upper and lower GI tract, discontinuation of the NSAID therapy must be considered. Because of their lack of availability and expense, radionuclide laboratory tests have limited use. Inasmuch as NSAID-induced enteropathy is a diagnosis of exclusion, histopathologic confirmation is helpful to rule out specific causes of enteropathy. Diaphragms seem to be specific for NSAID-induced enteropathy. Thus far, no medical therapy has proved effective. Although misoprostol has been used to decrease intestinal permeability, no controlled trials have assessed effectiveness in patients with anemia. Because of the widespread use of NSAIDs, clinicians must maintain a high level of awareness for the diagnosis of NSAID-induced enteropathy.