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Capsule endoscopic diagnosis of nonsteroidal antiinflammatory drug-induced enteropathy

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Abstract

Background

Case reports have linked nonsteroidal antiinflammatory drugs (NSAIDs) to a variety of lesions in the small and large bowel including bleeding, protein loss, strictures, increased intestinal permeability, and NSAID enteropathy. We here review the use of wireless capsule endoscopy to quantitate and assess the nature of the small bowel damage caused by NSAIDs when taken short term and in patients on long-term NSAIDs and COX-2 inhibitors.

Methods

Forty healthy volunteers underwent a baseline capsule endoscopy. After taking diclofenac slow-release 75 mg twice a day for a total of 14 days, both investigations were repeated. A further 120 patients on long-term NSAIDs (more than 3 months) and 40 on COX-2 inhibitors underwent a capsule endoscopy study. Sixty healthy patients acted as controls. Small bowel damage was categorized and quantitated.

Results

Short-term diclofenac: Capsule endoscopy demonstrated new pathology in 27 (68%) of subjects. The most common lesions were mucosal breaks, seen in 16 (40%), which were seen to be bleeding in 2 (5%). Long-term NSAIDs: The main pathology was related to mucosal breaks (29%); 3% had free luminal blood and 2% had strictures. The damage seen in 50% of patients on selective COX-2 inhibitors did not differ significantly (P < 0.5) from that seen with NSAIDs.

Conclusions

Capsule endoscopy demonstrates evidence of macroscopic injury to the small intestine, in up to 68% of volunteers, resulting from 2 weeks ingestion of slow-release diclofenac. Long-term use of NSAIDs and COX-2 inhibitors causes comparable small bowel damage (50%–68%).

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References

  1. Stone E. An account of the success of the bark of the willow in the cure of agues. Philos Trans R Soc Lond 1763;53:195–200.

    Google Scholar 

  2. Laine L. Approaches to nonsteroidal anti-inflammatory drug use in the high-risk patient. Gastroenterology 2001;120:594–606.

    Article  PubMed  CAS  Google Scholar 

  3. Hawkey CJ. Non-steroidal anti-inflammatory drugs and peptic ulcers. BMJ 1990;300:278–284.

    Article  PubMed  CAS  Google Scholar 

  4. Raskin J. Gastrointestinal effects of nonsteroidal anti-inflammatory therapy. Am J Med 1999;106(5B):3S–12S.

    Article  PubMed  CAS  Google Scholar 

  5. Langman M, Weil J, Wainwright P, et al. Risks of bleeding peptic ulcer associated with individual nonsteroidal anti-inflammatory drugs. Lancet 1994;343:1075–1078.

    Article  PubMed  CAS  Google Scholar 

  6. Fries J, Williams C, Bloch D, Michel B. Nonsteroidal anti-inflammatory drug gastropathy: incidence and risk factors model. Am J Med 1991;91:213–222.

    Article  PubMed  CAS  Google Scholar 

  7. Raz A, Wyche A, Needleman P. Temporal and pharmacological division of fibroblast cyclooxygenase expression into transcriptional and translational phases. Proc Natl Acad Sci USA 1989;86:2076–2085.

    Article  Google Scholar 

  8. Kujubu DA, Fletcher BS, Varnum BC, et al. TIS10, a phorbol ester tumor promoter-inducible mRNA from Swiss 3T3 cells, encodes a novel prostaglandin synthase/cyclooxygenase homologue. J Biol Chem 1992;266:12866–12872.

    Google Scholar 

  9. Ferraz JG, Sharkey KA, Reuter BK, et al. Induction of cyclooxygenase 1 and 2 in rat stomach during endotoxemia: role in resistance to damage. Gastroenterology 1997;113:195–204.

    Article  PubMed  CAS  Google Scholar 

  10. Rainsford K. Gastrointestinal adaptation, gastrointestinal injury by NSAIDs. Regulation of eicosanoids and mucosal protection from NSAIDs. In: Rainsford KD, editor. Side effects of antiinflammatory drugs, vol 4. Dordrecht: Kluwer; 1997. 197–205.

    Google Scholar 

  11. Vaananen PM, Meddings JB, Wallace JL. Role of oxygen-derived free radicals in indomethacin-induced gastric injury. Am J Physiol 1991;261:G470–G475.

    PubMed  CAS  Google Scholar 

  12. Sigthorsson G, Tibble J, Mahmud T, Bjarnason I. NSAID-induced gastrointestinal damage: the biochemical consequences of the “ion trapping” hypothesis. Imflammopharmacology 2000;8:31–41.

    Article  CAS  Google Scholar 

  13. Hogben CAM, Schanker LS, Tocco DJ, et al. Absorption of drugs from the stomach. II. The human. J Pharmacol Exp Ther 1957;120:540–545.

    PubMed  CAS  Google Scholar 

  14. Somasundaram S, Macpherson AJ, Hayllar J, Saratchandra P, Bjarnason I. Enterocyte mitochondrial damage due to NSAIDs in the rat. Gut 1992;33(suppl):S5.

    Article  Google Scholar 

  15. Bjarnason I, Hayllar J, Macpherson AJ, Russell AS. Side effects of nonsteroidal anti-inflammatory drugs on the small and large intestine. Gastroenterology 1993;104:1832–1847.

    PubMed  CAS  Google Scholar 

  16. Lichtenberger LM, Wang ZM, Romero JJ, et al. Non-steroidal anti-inflammatory drugs (NSAIDs) associate with zwitterionic phospholipids: insight into the mechanism and reversal of NSAID-induced gastrointestinal injury. Nat Med 1995;1:154–158.

    Article  PubMed  CAS  Google Scholar 

  17. Mahmud T, Scott D, Bjarnason I. A unifying hypothesis for the mechanism of NSAID related gastrointestinal toxicity. Ann Rheum Dis 1996;55:211–213.

    Article  PubMed  CAS  Google Scholar 

  18. Morris AJ, Wasson LA, MacKenzie JF. Small bowel enteroscopy in undiagnosed gastrointestinal blood loss. Gut 1992;33:887–889.

    Article  PubMed  CAS  Google Scholar 

  19. Bjarnason I, Zanelli G, Prouse P, Smethurst P, Levi S, Gumpel MJ, Levi AJ. Blood and protein loss via small intestinal inflammation induced by nonsteroidal anti-inflammatory drugs. Lancet 1987;2:711–714.

    Article  PubMed  CAS  Google Scholar 

  20. Bjarnason I, Zanelli G, Smethurst P, Burke M, Gumpel MJ, Price AB, Levi AJ. Clinico-pathological features of nonsteroidal antiinflammatory drug induced small intestinal strictures. Gastroenterology 1988;94:1070–1074.

    PubMed  CAS  Google Scholar 

  21. Lang 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;41:516–526.

    Article  PubMed  CAS  Google Scholar 

  22. Bjarnason I, Williams P, So A, Zanelli G, Levi AJ, Gumpel MJ, et al. Intestinal permeability and inflammation in rheumatoid arthritis; effects of non-steroidal anti-inflammatory drugs. Lancet 1984;2:1171–1174.

    Article  PubMed  CAS  Google Scholar 

  23. Bjarnason I, Williams P, Smethurst P, Peters TJ, Levi AJ. The effect of NSAIDs and prostaglandins on the permeability of the human small intestine. Gut 1986;27:1292–1297.

    Article  PubMed  CAS  Google Scholar 

  24. Bjarnason I, Smethurst P, Fenn CG, Lee CE, Menzies IS, Levi AJ. Misoprostol reduces indomethacin-induced changes in human small intestinal permeability. Dig Dis Sci 1989;34:407–411.

    Article  PubMed  CAS  Google Scholar 

  25. Davies GR, Rampton DS. The pro-drug sulindac may reduce the risk of intestinal damage associated with the use of conventional non-steroidal anti-inflammatory drugs. Aliment Pharmacol Ther 1991;5:593–598.

    PubMed  CAS  Google Scholar 

  26. Davies GR, Rampton DS. Relevance of intestinal bacteria, prostaglandins and pro-drug administration to NSAID induced increase in gut permeability (abstract). Gut 1991;32:A1224.

    Google Scholar 

  27. Bjarnason I, Zanelli G, Smith T, Prouse P, Williams P, DeLacey G, et al. Nonsteroidal antiinflammatory drug induced intestinal inflammation in humans. Gastroenterology 1987;93:480–489.

    PubMed  CAS  Google Scholar 

  28. Segal AW, Isenberg DA, Hajirousou V, Tolfree S, Clark J, Snaith ML. Preliminary evidence for gut involvement in the pathogenesis of rheumatoid arthritis? Br J Rheumatol 1986;25:162–166.

    Article  PubMed  CAS  Google Scholar 

  29. Rooney PJ, Jenkins RT, Smith KM, Coates G. 111-Indiumlabelled polymorphonuclear leucocyte scans in rheumatoid arthritis: an important clinical cause of false positive results. Br J Rheumatol 1986;25:167–170.

    Article  PubMed  CAS  Google Scholar 

  30. Shah AA, Thjodleifsson B, Murray FE, Sigthorsson G, Oddson E, Gudjonsson H, et al. A randomised, double blind, double dummy, crossover study of the effects of nimesulide and naproxen on the gastrointestinal tract and an in vivo assessment of their selectivity for cyclooxygenase 1 and 2. Gut 2001;48:339–348.

    Article  PubMed  CAS  Google Scholar 

  31. Sturges HF, Krone CL. Ulcerations and stricture of the jejunum in a patient of long-term indomethacin therapy. Am J Gastroenterol 1973;59:162–169.

    PubMed  CAS  Google Scholar 

  32. Huber T, Ruchti C, Halter F. Non-steroidal anti-inflammatory drug-induced colonic structures: a case report. Gastroenterology 1991;100:1119–1122.

    PubMed  CAS  Google Scholar 

  33. Fellows IW, Clarke JM, Roberts PF. Non-steroidal antiinflammatory drug-induced jejunal and colonic diaphragm disease: a report of two cases. Gut 1992;33:1424–1426.

    Article  PubMed  CAS  Google Scholar 

  34. Bombardiner C, Laine L, Reicin A, Shapiro D, Burgos-Vargas R, Davis B, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med 2000;343:1520–1528.

    Article  Google Scholar 

  35. Silverstein FE, Faich G, Goldstein JL, Simon LS, Pincus T, Whelton A, et al. Gastrointestinal toxicity with celecoxib vs. nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: a randomised controlled trial. Celecoxib Long-term Arthritis Study. JAMA 2000;284:1247–1255.

    Article  PubMed  CAS  Google Scholar 

  36. Laine L, Connors LG, Reicin A, Hawkey CJ, Burgos-Vargas R, Schnitzer TJ, et al. Serious lower gastrointestinal clinical events with nonselective NSAID or coxib use. Gastroenterology 2003;124:288–292.

    Article  PubMed  CAS  Google Scholar 

  37. Goldstein JL, Eisen GM, Lewis B, Gralnek IM, Zlotnick S, Fort JG; Investigators. Video capsule endoscopy to prospectively assess small bowel injury with celecoxib, naproxen plus omeprazole and placebo. Clin Gastroenterol Hepatol 2005;3:133–141.

    Article  PubMed  Google Scholar 

  38. Silverstein FE, Graham GY, Senior JR, Davies HW, Struthers BJ, Bittman RM, Geis SG. Misoprostol reduces serious gastrointestinal complications in patients with rheumatoid arthritis receiving nonsteroidal anti-inflammatory drugs. Ann Intern Med 1995;123:241–249.

    PubMed  CAS  Google Scholar 

  39. Chan FK, Hung LC, Suen BY, Wu JC, Lee KC, Leung VK, et al. Celecoxib versus diclofenac and omeprazole in reducing the risk of recurrent ulcer bleeding in patients with arthritis. N Engl J Med 2002;347:2104–2110.

    Article  PubMed  CAS  Google Scholar 

  40. Tibble JA, Sigthorsson G, Foster R, Scott D, Fagerhol MK, Roseth A, Bjarnason I. High prevalence of NSAID enteropathy as shown by a simple faecal test. Gut 1999;45:362–366.

    Article  PubMed  CAS  Google Scholar 

  41. Aabakken L, Osnes M. 51Cr-Ethylenediaminetetraacetic acid absorption test. Effects of naproxen, a non-steroidal, antiinflammatory drug. Scand J Gastroenterol 1990;25:917–924.

    Article  PubMed  CAS  Google Scholar 

  42. Matsumoto T, Kudo T, Esaki M, Yano T, Yamamoto H, Sakamoto C, et al. Prevalence of non-steroidal anti-inflammatory drug-induced enteropathy determined by double-balloon endoscopy: a Japanese multicenter study. Scand J Gastroenterol 2008;43:490–496.

    Article  PubMed  CAS  Google Scholar 

  43. Maiden L, Thjodleifsson B, Theodors A, Gonzalez J, Bjarnason I. A quantitative analysis of NSAID-induced small bowel pathology by capsule enteroscopy. Gastroenterology 2005;128:1172–1178.

    Article  PubMed  Google Scholar 

  44. Maiden L, Thjodleifsson B, Seigal A, Bjarnason II, Scott D, Birgisson S, Bjarnason I. Long-term effects of nonsteroidal antiinflammatory drugs and cyclooxygenase-2 selective agents on the small bowel: a cross-sectional capsule enteroscopy study. Clin Gastroenterol Hepatol 2007;5:1040–1045.

    Article  PubMed  Google Scholar 

  45. Graham DY, Opekun AR, Willingham FF, Qureshi WA. Visible small-intestinal mucosal injury in chronic NSAID users. Clin Gastroenterol Hepatol 2005;3:55–59.

    Article  PubMed  Google Scholar 

  46. Gomez-Rodriguez B, Caunedo-Alvarez A, Romero-Vasquez J, et al. NSAIDs erosive enteropathy assessed by capsule endoscopy: a prospective controlled trial (abstract). Gastroenterology 2004;126:A96.

    Google Scholar 

  47. Vane JR. Towards a better aspirin. Nature (Lond) 1994;367:215–216.

    Article  CAS  Google Scholar 

  48. Schnitzer TJ, Burmester GR, Mysler E, Hochberg MC, Doherty M, Ehrsam E, et al; TARGET Study Group. Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), reduction in ulcer complications: randomised controlled trial. Lancet 2004;364:665–674.

    Article  PubMed  CAS  Google Scholar 

  49. Sigthorsson G, Crane R, Simon T, Hoover M, Quan H, Bolognese J, Bjarnason I. COX-2 inhibition with rofecoxib does not increase intestinal permeability in healthy subjects: a double blind crossover study comparing rofecoxib with placebo and indomethacin. Gut 2000;47:527–532.

    Article  PubMed  CAS  Google Scholar 

  50. Vane JR, Botting RM. Mechanism of action of anti-inflammatory drugs. Scand J Rheumatol Suppl 1996;102:9–21.

    Article  PubMed  CAS  Google Scholar 

  51. Sigthorsson G, Simpson RJ, Walley M, Anthony A, Foster R, Hotz-Behoftsitz C, et al. COX-1 and 2, intestinal integrity, and pathogenesis of nonsteroidal anti-inflammatory drug enteropathy in mice. Gastroenterology 2002;122:1913–1923.

    Article  PubMed  CAS  Google Scholar 

  52. Langenbach R, Morham SG, Tiano HF, Loftin CD, Ghanayem BI, Chulada PC, et al. Prostaglandin synthase 1 gene disruption in mice reduced arachidonic acid-induced inflammation and indomethacin-induced gastric ulceration. Cell 1995;83:483–492.

    Article  PubMed  CAS  Google Scholar 

  53. Wallace JL, McKnight W, Reuter BK, et al. NSAID-induced gastric damage in rats: requirement for inhibition of both cyclooxygenase 1 and 2. Gastroenterology 2000;119:706–714.

    Article  PubMed  CAS  Google Scholar 

  54. Mitchell J, Evans T. Cyclooxygenase-2 as a therapeutic target. Inflamm Res 1998;47(suppl 2):S88–S92.

    Article  PubMed  CAS  Google Scholar 

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  1. Department of Gastroenterology, Maidstone Hospital, Hermitage Lane, Kent, ME16 9QQ, UK

    Laurence Maiden

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Maiden, L. Capsule endoscopic diagnosis of nonsteroidal antiinflammatory drug-induced enteropathy. J Gastroenterol 44 (Suppl 19), 64–71 (2009). https://doi.org/10.1007/s00535-008-2248-8

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  • DOI: https://doi.org/10.1007/s00535-008-2248-8

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