Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Drug-induced injury in the gastrointestinal tract: clinical and pathologic considerations

Nature Clinical Practice Gastroenterology & Hepatology volume 4, pages 442–453 (2007)Cite this article

Abstract

Drug toxicity in the gastrointestinal tract is a common and serious medical problem; the number of drugs that can harm the gastrointestinal tract is impressive. The morbidity, mortality, and medical costs associated with drug toxicity, even when restricted to the gastrointestinal tract, are probably underestimated. Drug-induced gastrointestinal tract pathology is very diverse and can mimic many non-drug-related conditions. Drug toxicity, whether direct or indirect, can be restricted to a segment of the gastrointestinal tract or affect the entire gastrointestinal tract. The consequences of drug toxicity are also quite variable and can range from unimportant pathology (e.g. the relatively common and usually benign drug-induced diarrhea) at one end of the spectrum, to fatal gastrointestinal tract hemorrhage or perforation at the other end of the spectrum. Better awareness of the possibility of drug-induced gastrointestinal tract pathology, by both gastroenterologists and pathologists, and better communication between gastroenterologists, pathologists and other specialists will improve the recognition of drug-induced gastrointestinal tract pathology, and, ultimately, improve patient care. This Review focuses on the most common and well-described drug-related clinicopathologic conditions of the gastrointestinal tract. Much discussion is, therefore, dedicated to NSAIDs—the most commonly prescribed drugs and consequently the drugs most commonly associated with gastrointestinal tract toxicity.

Key Points

  • Drug-induced gastrointestinal injury is common and occurs throughout the gastrointestinal tract

  • The class of drugs most commonly associated with gastrointestinal injury are the nonsteroidal anti-inflammatory drugs (NSAIDs)

  • Elimination of medications and medication avoidance in patients at highest risk for the development of drug-induced gastrointestinal injury will reduce the incidence of injury

  • Better awareness of the possibility of drug-induced gastrointestinal injury and better communication among gastroenterologists, pathologists and other specialists will ultimately improve patient care

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Distribution of medications associated with drug-induced esophageal injury
Figure 2: Chemical or reactive gastropathy
Figure 3: Effects of proton pump inhibitors on the stomach
Figure 4: An NSAID-induced colonic diaphragm
Figure 5: NSAID-induced colitis
Figure 6: Iron-induced mucosal ulceration

Similar content being viewed by others

References

  1. Fennerty MB (2001) NSAID-related gastrointestinal injury. Evidence-based approach to a preventable complication. Postgrad Med 110: 87–88, 91–94

    CAS  PubMed  Google Scholar 

  2. Singh G (1998) Recent considerations in nonsteroidal anti-inflammatory drug gastropathy. Am J Med 105: 31S–38S

    CAS  PubMed  Google Scholar 

  3. Abid S et al. (2005) Pill-induced esophageal injury: endoscopic features and clinical outcomes. Endoscopy 37: 740–744

    CAS  PubMed  Google Scholar 

  4. Kikendall JW (1999) Pill esophagitis. J Clin Gastroenterol 28: 298–305

    CAS  PubMed  Google Scholar 

  5. Kikendall JW (1999) Pill-induced esophageal injury. In The Esophagus, edn 3, 527–537 (Eds Castell DO and Richter JE) Philadelphia: Lippincott Williams & Wilkins

    Google Scholar 

  6. Cameron RB (1997) Esophagitis dissecans superficialis and alendronate: case report. Gastrointest Endosc 46: 562–563

    CAS  PubMed  Google Scholar 

  7. Adachi W et al. (1998) A case of pill-induced esophagitis with mucosal dissection. Diagn Ther Endosc 4: 149–153

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Semble EL et al. (1989) Nonsteroidal anti-inflammatory drugs and esophageal injury. Semin Arthritis Rheum 19: 99–109

    CAS  PubMed  Google Scholar 

  9. Gulsen MT et al. (2005) Cyproterone acetate and ethinylestradiol-induced pill oesophagitis: a case report. Int J Clin Pract Suppl 147: 79–81

    Google Scholar 

  10. D'Agostino L et al. (2004) A life-threatening case of stenosing pill hypopharynx-oesophagitis caused by a tamsulosin capsule. Dig Liver Dis 36: 632–634

    CAS  PubMed  Google Scholar 

  11. Maekawa T et al. (2001) Pill-induced esophagitis caused by lansoprazole. J Gastroenterol 36: 790–791

    CAS  PubMed  Google Scholar 

  12. Abraham SC et al. (1999) Alendronate associated esophageal injury: pathologic and endoscopic features. Mod Pathol 12: 1152–1157

    CAS  PubMed  Google Scholar 

  13. de Groen PC et al. (1996) Esophagitis associated with the use of alendronate. N Engl J Med 335: 1016–1021

    CAS  PubMed  Google Scholar 

  14. Lufkin EG et al. (1994) Pamidronate: an unrecognized problem in gastrointestinal tolerability. Osteoporos Int 4: 320–322

    CAS  PubMed  Google Scholar 

  15. Quinn CM et al. (1993) Gastritis in patients on non-steroidal anti-inflammatory drugs. Histopathology 23: 341–348

    CAS  PubMed  Google Scholar 

  16. Sobala GM et al. (1990) Reflux gastritis in the intact stomach. J Clin Pathol 43: 303–306

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Graham DY and Smith JL (1988) Gastroduodenal complications of chronic NSAID therapy. Am J Gastroenterol 83: 1081–1084

    CAS  PubMed  Google Scholar 

  18. Schoenfeld P et al. (1999) Nonsteroidal anti-inflammatory drug-associated gastrointestinal complications—guidelines for prevention and treatment. Aliment Pharmacol Ther 13: 1273–1285

    CAS  PubMed  Google Scholar 

  19. Cryer B (2001) Nonsteroidal anti-inflammatory drug gastrointestinal toxicity. Curr Opin Gastroenterol 17: 503–512

    CAS  PubMed  Google Scholar 

  20. Jones R (2002) Efficacy and safety of COX 2 inhibitors. BMJ 325: 607–608

    PubMed  PubMed Central  Google Scholar 

  21. Deeks JJ et al. (2002) Efficacy, tolerability, and upper gastrointestinal safety of celecoxib for treatment of osteoarthritis and rheumatoid arthritis: systematic review of randomised controlled trials. BMJ 325: 619

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Bombardier C et al. (2000) Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N Engl J Med 343: 1520–1528

    CAS  PubMed  Google Scholar 

  23. Mamdani M et al. (2002) Observational study of upper gastrointestinal haemorrhage in elderly patients given selective cyclo-oxygenase-2 inhibitors or conventional non-steroidal anti-inflammatory drugs. BMJ 325: 624

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Silverstein FE et al. (1995) Misoprostol reduces serious gastrointestinal complications in patients with rheumatoid arthritis receiving nonsteroidal anti-inflammatory drugs. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 123: 241–249

    CAS  PubMed  Google Scholar 

  25. Chan FK et al. (2002) Celecoxib versus diclofenac and omeprazole in reducing the risk of recurrent ulcer bleeding in patients with arthritis. N Engl J Med 347: 2104–2110

    CAS  PubMed  Google Scholar 

  26. Scheiman JM et al. (2006) Prevention of ulcers by esomeprazole in at-risk patients using non-selective NSAIDs and COX-2 inhibitors. Am J Gastroenterol 101: 701–710

    CAS  PubMed  Google Scholar 

  27. Driman DK et al. (1996) Omeprazole produces parietal cell hypertrophy and hyperplasia in humans. Dig Dis Sci 41: 2039–2047

    CAS  PubMed  Google Scholar 

  28. Rindi G et al. (2005) European Rabeprazole Study Group. Effects of 5 years of treatment with rabeprazole or omeprazole on the gastric mucosa. Eur J Gastroenterol Hepatol 17: 559–566

    CAS  PubMed  Google Scholar 

  29. Choudhry U and Boyce HW Jr (1998) Proton pump inhibitor-associated gastric polyps: a retrospective analysis of their frequency, and endoscopic, histologic, and ultrastructural characteristics. Am J Clin Pathol 110: 615–621

    CAS  PubMed  Google Scholar 

  30. Sapoznikov B et al. (2005) Minidose aspirin and gastrointestinal bleeding—a retrospective, case–control study in hospitalized patients. Dig Dis Sci 50: 1621–1624

    CAS  PubMed  Google Scholar 

  31. Cryer B et al. (1995) Effects of very low doses of aspirin on gastric, duodenal and rectal prostaglandins and mucosal injury. Gastroenterology 108: A77

    Google Scholar 

  32. Reuter BK et al. (1997) Nonsteroidal anti-inflammatory drug enteropathy in rats: role of permeability, bacteria, and enterohepatic circulation. Gastroenterology 112: 109–117

    CAS  PubMed  Google Scholar 

  33. Somasundaram S et al. (2000) Uncoupling of intestinal mitochondrial oxidative phosphorylation and inhibition of cyclooxygenase are required for the development of NSAID-enteropathy in the rat. Aliment Pharmacol Ther 14: 639–650

    CAS  PubMed  Google Scholar 

  34. Bjarnason I et al. (1984) Intestinal permeability and inflammation in rheumatoid arthritis: effects of non-steroidal anti-inflammatory drugs. Lancet 2: 1171–1174

    CAS  PubMed  Google Scholar 

  35. Bjarnason I et al. (1987) Blood and protein loss via small-intestinal inflammation induced by non-steroidal anti-inflammatory drugs. Lancet 2: 711–714

    CAS  PubMed  Google Scholar 

  36. Bjarnason I et al. (1987) Nonsteroidal antiinflammatory drug-induced intestinal inflammation in humans. Gastroenterology 93: 480–489

    CAS  PubMed  Google Scholar 

  37. Morris AJ et al. (1992) Small bowel enteroscopy in undiagnosed gastrointestinal blood loss. Gut 33: 887–889

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Kepczyk T and Kadakia SC (1995) Prospective evaluation of gastrointestinal tract in patients with iron-deficiency anemia. Dig Dis Sci 40: 1283–1289

    CAS  PubMed  Google Scholar 

  39. Lee FD (1994) Drug related pathological lesions of the intestinal tract. Histopathology 24: 303–308

    Google Scholar 

  40. Thiéfin G et al. (2000) Diaphragme duodénal induit par la prise d'aspirine [French]. Presse Med 29: 1351–1352

    PubMed  Google Scholar 

  41. Cortina G et al. (1999) Clinical and pathologic overlap in nonsteroidal anti-inflammatory drug-related small bowel diaphragm disease and the neuromuscular and vascular hamartoma of the small bowel. Am J Surg Pathol 23: 1414–1417

    CAS  PubMed  Google Scholar 

  42. Isaacs PE et al. (1987) Mefenamic acid enteropathy. J Clin Pathol 40: 1221–1227

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Freeman HJ (1986) Sulindac-associated small bowel lesion. J Clin Gastroenterol 8: 569–571

    CAS  PubMed  Google Scholar 

  44. Gibson GR et al. (1992) Colitis induced by nonsteroidal anti-inflammatory drugs. Report of four cases and review of the literature. Arch Intern Med 152: 625–632

    CAS  PubMed  Google Scholar 

  45. Kaufman JH and Taubin HL (1987) NSAID activate quiescent inflammatory bowel disease. Ann Intern Med 107: 513–516

    Google Scholar 

  46. Stamm C et al. (1994) Benign colonic ulcers associated with nonsteroidal antiinflammatory drug ingestion. Am J Gastroenterol 89: 2230–2233

    CAS  PubMed  Google Scholar 

  47. Halter F et al. (1993) Diaphragm disease of the ascending colon. Association with sustained-release diclofenac. J Clin Gastroenterol 16: 74–80

    CAS  PubMed  Google Scholar 

  48. Bridges AJ et al. (1990) Acute eosinophilic colitis and hypersensitivity reaction associated with naproxen therapy. Am J Med 89: 526–527

    CAS  PubMed  Google Scholar 

  49. Hall RI et al. (1983) Enteritis and colitis associated with mefenamic acid. BMJ 287: 1182

    CAS  PubMed  Google Scholar 

  50. Beaugerie L et al. (1994) Drug induced lymphocytic colitis. Gut 35: 426–428

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Giardiello FM et al. (1990) Collagenous colitis in setting of nonsteroidal anti-inflammatory drugs and antibiotics. Dig Dis Sci 35: 257–260

    CAS  PubMed  Google Scholar 

  52. Campbell KL and de Baux AC (1992) Non-steroidal anti-inflammatory drugs and appendicitis in patients over 50 years. Br J Surg 79: 967–968

    CAS  PubMed  Google Scholar 

  53. Wilson RG et al. (1990) Complications of diverticular disease & non-steroidal anti-inflammatory drugs: a prospective study. Br J Surg 77: 1103–1104

    CAS  PubMed  Google Scholar 

  54. D'Halluin PN et al. (2003) Selective COX-2 inhibitor-associated colitis: two case reports. Gastroenterol Clin Biol 27: 932–935

    PubMed  Google Scholar 

  55. Ghadially FN and Walley VM (1994) Melanoses of the gastrointestinal tract. Histopathology 25: 197–207

    CAS  PubMed  Google Scholar 

  56. Byers RJ et al. (1997) Melanosis coli is associated with an increase in colonic epithelial apoptosis and not with laxative use. Histopathology 30: 160–164

    CAS  PubMed  Google Scholar 

  57. Biggar WD et al. (1985) Malakoplakia and immunosuppressive therapy: Reversal of clinical and leukocyte abnormalities after withdrawal of prednisone and azathioprine. Am J Pathol 119: 5–11

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Guinaudeau E et al. (2002) Colonic malacoplakia and ulcerative colitis: report of a case. Gastroenterol Clin Biol 26: 174–177

    PubMed  Google Scholar 

  59. Jackson CW et al. (1986) Gold induced enterocolitis. Gut 27: 452–456

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Thomson RD et al. (2002) Lansoprazole-associated microscopic colitis: a case series. Am J Gastroenterol 97: 2908–2913

    PubMed  Google Scholar 

  61. Beaugerie L et al. (1995) Ranitidine, diarrhoea, and lymphocytic colitis. Gut 37: 708–711

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Feurle GE et al. (1999) Lymphocytic colitis, induced by ticlopidine. Z Gastroenterol 37: 1105–1108

    CAS  PubMed  Google Scholar 

  63. Fernandez-Banares F et al. (2003) Collagenous and lymphocytic colitis: evaluation of clinical and histological features, response to treatment, and long-term follow-up. Am J Gastroenterol 98: 340–347

    PubMed  Google Scholar 

  64. Cappell MS (2004) Colonic toxicity of administered drugs and chemicals. Am J Gastroenterol 99: 1175–1190

    CAS  PubMed  Google Scholar 

  65. Freudenberger RS et al. (1990) Intestinal infarction after intravenous cocaine administration. Ann Intern Med 113: 715–716

    CAS  PubMed  Google Scholar 

  66. Linder JD et al. (2000) Cocaine-associated ischemic colitis. South Med J 93: 909–913

    CAS  PubMed  Google Scholar 

  67. Stillman AE et al. (1977) Ischemic bowel disease attributable to ergot. Gastroenterology 72: 1336–1337

    CAS  PubMed  Google Scholar 

  68. McClennan BL (1976) Ischemic colitis secondary to premarin: report of a case. Dis Colon Rectum 19: 618–620

    CAS  PubMed  Google Scholar 

  69. Friedel D et al. (2001) Ischemic colitis during treatment with alosetron. Gastroenterology 120: 557–560

    CAS  PubMed  Google Scholar 

  70. Beyer KL et al. (1991) Ischemic colitis associated with dextroamphetamine use. J Clin Gastroenterol 13: 198–201

    CAS  PubMed  Google Scholar 

  71. Rashid A and Hamilton SR (1997) Necrosis of the gastrointestinal tract in uremic patients as a result of sodium polystyrene sulfonate (Kayexalate) in sorbitol: an underrecognized condition. Am J Surg Pathol 21: 60–69

    CAS  PubMed  Google Scholar 

  72. Kato S et al. (1995) Antibiotic-associated hemorrhagic colitis without Clostridium difficile toxin in children. J Pediatr 126: 1008–1010

    CAS  PubMed  Google Scholar 

  73. Kronawitter U et al. (1997) Neutropenic enterocolitis in a patient with colorectal carcinoma: unusual course after treatment with 5-fluorouracil and leucovorin—a case report. Cancer 80: 656–660

    CAS  PubMed  Google Scholar 

  74. Petruzelli GJ et al. (1990) Neutropenic enterocolitis: a new complication of head and neck cancer chemotherapy. Arch Otolaryngol Head Neck Surg 116: 209–211

    Google Scholar 

  75. Eckardt VF et al. (1986) Anorectal ergotism: another cause of solitary rectal ulcers. Gastroenterology 91: 1123–1127

    CAS  PubMed  Google Scholar 

  76. Gizzi G et al. (1990) Ano-rectal lesions in patients taking suppositories containing non-steroidal anti-inflammatory drugs (NSAID). Endoscopy 22: 146–148

    CAS  PubMed  Google Scholar 

  77. Van Gossum A et al. (1993) Anorectal stenosis in patients with prolonged use of suppositories containing paracetamol and acetylsalicylic acid. Dig Dis Sci 38: 1970–1977

    CAS  PubMed  Google Scholar 

  78. de Parades V et al. (1996) Complications anorectales et coliques des suppositoires et des lavements [French]. Gastroenterol Clin Biol 20: 446–452

    CAS  PubMed  Google Scholar 

  79. Eckstein RP and Symons P (1996) Iron tablets cause histopathologically distinctive lesions in mucosal biopsies of the stomach and oesophagus. Pathology 28: 142–145

    CAS  PubMed  Google Scholar 

  80. Hruban RH et al. (1989) Taxol toxicity: epithelial necrosis in the gastrointestinal tract associated with polymerized microtubule accumulation and mitotic arrest. Cancer 15: 1944–1950

    Google Scholar 

  81. Finger JE and Headington JT (1963) Colchicine-induced epithelial atypia. Am J Clin Pathol 40: 605–609

    CAS  PubMed  Google Scholar 

  82. Iacobuzio-Donahue CA et al. (2001) Colchicine toxicity: distinct morphologic findings in gastrointestinal biopsies. Am J Surg Pathol 25: 1067–1073

    CAS  PubMed  Google Scholar 

  83. Gibson RJ et al. (2003) Irinotecan causes severe small intestinal damage, as well as colonic damage, in the rat with implanted breast cancer. J Gastroenterol Hepatol 18: 1095–1100

    CAS  PubMed  Google Scholar 

  84. Sandmeier D et al. (2005) Irinotecan-induced colitis. Int J Surg Pathol 13: 215–218

    CAS  PubMed  Google Scholar 

  85. Sears S et al. (1999) Irinotecan (CPT-11) induced colitis: report of a case and review of Food and Drug Administration MEDWATCH reporting. Gastrointest Endosc 50: 841–844

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. MP Pusztaszeri is a Pathologist at the Institute of Pathology, CHUV, Lausanne, Switzerland.,

    Marc P Pusztaszeri

  2. RM Genta is Chief of Pathology and Laboratory Service and Professor of Pathology and Medicine (Gastroenterology) in the Departments of Medicine and Pathology, and BL Cryer is Associate Professor of Medicine in the Department of Medicine, University of Texas Southwestern Medical Center and VA North Texas Health Care System, Dallas, TX, USA.,

    Robert M Genta & Byron L Cryer

Authors
  1. Marc P Pusztaszeri
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Robert M Genta
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Byron L Cryer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Robert M Genta.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pusztaszeri, M., Genta, R. & Cryer, B. Drug-induced injury in the gastrointestinal tract: clinical and pathologic considerations. Nat Rev Gastroenterol Hepatol 4, 442–453 (2007). https://doi.org/10.1038/ncpgasthep0896

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncpgasthep0896

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing