NSAID Colitis

Background

NSAIDS (non-steroidal anti-inflammatory drugs) like aspirin, have long been known to cause bleeding and symptoms of gastritis in the upper gastrointestinal tract. However, the lower gastrointestinal tract, particularly the small intestine, is also prone to injury.

OUTLINE

Epidemiology

Pathogenesis

Histopathological Features and Variants

Differential Diagnosis

Prognosis and Treatment

Commonly Used Terms

EPIDEMIOLOGY CHARACTERIZATION

INCIDENCE

Colonic inflammation and nonsteroidal anti-inflammatory drug administration. An assessment of the frequency of the problem.

Tanner AR, Raghunath AS.

Department of Medicine, North Tees General Hospital, Stockton-on-Tees, Cleveland, UK.
Digestion 1988;41(2):116-20 Abstract quote
Over an 18-month period at a single clinic, 43 new cases of colonic inflammation have been diagnosed (19 proctitis only). Crohn's colitis has been excluded from this analysis. In all these subjects a careful drug history has been taken in a prospective manner and in 4 of these 43 patients colonic inflammation appeared to be directly related to non-steroidal anti-inflammatory drug (NSAID) administration (mefenamic acid, 2; piroxicam, 2). In all 4 patients there was a time interval (mean 3 months) between initiation of treatment with NSAID and presentation with diarrhoea and weight loss.

Pathological findings were minor and biochemical changes insignificant, in contrast to the protracted troublesome symptoms. Resolution of symptoms was very rapid on discontinuation of NSAID medication but 2 patients experienced immediate return of symptoms following inadvertent rechallenge.

Approximately 10% of newly diagnosed colitis may be related to NSAID administration. Subjects taking NSAID medications appear to be five times more likely to develop colonic inflammation than the general population.

Colopathy associated with the systemic use of nonsteroidal antiinflammatory medications. An underestimated entity.

Katsinelos P, Christodoulou K, Pilpilidis I, Xiarchos P, Papagiannis A, Dimiropoulos S, Amperiadis P, Vasiliadis T, Tarpagos A, Katsos I, Eugenidis N.

Department of Gastroenterology, Theagenion Hospital, Aristotelion University, Ippokration Hospital, Thessaloniki, Greece.
Hepatogastroenterology 2002 Mar-Apr;49(44):345-8 Abstract quote
BACKGROUND/AIMS: Adverse effects of NSAIDs (nonsteroidal antiinflammatory drugs) on the upper gastrointestinal tract and small intestine are well described. Evidence is also accumulating that implicate NSAIDs in inducing and exacerbating damage in the distal gastrointestinal tract. In this article we describe eight cases of colonic inflammation associated with nonsteroidal antiinflammatory drug administration; our aim is to stress the importance of an underestimated entity by clinicians.

METHODOLOGY: Over a five-year period at two clinics, eight cases of NSAID-colopathy have been diagnosed. Crohn's disease, ulcerative and infections colitis have been excluded from this analysis. In all these subjects a careful drug history has been taken in a prospective manner and colonic inflammation appeared to be directly related to NSAID administration. There was a time interval (mean: 20 months) between initiation of treatment with NSAID and presentation with diarrhea, rectal hemorrhage and tenesmus.

RESULTS: A correct diagnosis of colopathy associated with NSAIDs administration was made on careful drug history, pathological findings, stool cultures and biochemical changes which were insignificant, in contrast to the protracted troublesome symptoms. Resolution of symptoms was observed on discontinuation of NSAID medication.

CONCLUSIONS: Our report is further evidence that NSAIDs administration is associated with significant mucosal injury in the distal gastrointestinal tract, despite is underestimated by most physicians.

PATHOGENESIS CHARACTERIZATION

PROSTAGLANDINS

Do prostaglandins cause gastrointestinal mucosal injury?

Northway MG, Castell DO.
Dig Dis Sci 1981 May;26(5):453-6 Abstract quote
We have reviewed various examples of the injurious effects of prostaglandins on the gastrointestinal tract along with evidence that, in certain disease states, nonsteroidal antiinflammatory agents may have a prophylactic or therapeutic effect.

The most important areas in which these drugs may be useful are in treatment or prevention of esophagitis, food intolerance symptoms, cholera, radiation-induced diarrhea, and ulcerative colitis. Although these two sets of facts appear to be contradictory, they may actually represent two distinct phenomena. The examples of deleterious effects of prostaglandins on gastrointestinal mucosa are all examples of inflammatory changes. Many changes occur in acute inflammation, including leukocytosis and chemotaxis of neutrophils to the area of inflammation. Release of many substances, including prostaglandins, histamine and bradykinin, occurs into the inflamed site. The prostaglandins involved in inflammation of the gastrointestinal mucosa may be quite different in source, type, and quantity from endogenous prostaglandins which play a role in cytoprotection. In addition, because other substances in addition to prostaglandins are involved in inflammation, and nonsteroidal antiinflammatory agents do not act exclusively by inhibition of prostaglandin synthesis, the therapeutic benefit of antiinflammatory agents in gastrointestinal mucosa may be due to several mechanisms.

Therefore, in spite of the strong evidence indicting nonsteroidal antiinflammatory drugs as occasionally harmful to the gastric, duodenal, and intestinal mucosa, we should not lose sight of their important potential therapeutic role in other areas of the gastrointestinal tract.

GROSS APPEARANCE/
CLINICAL VARIANTS CHARACTERIZATION

GENERAL

Colitis induced by nonsteroidal anti-inflammatory drugs. Report of four cases and review of the literature.

Gibson GR, Whitacre EB, Ricotti CA.

Department of Medicine, Trumbull Memorial Hospital, Warren, Ohio.
Arch Intern Med 1992 Mar;152(3):625-32 Abstract quote
In four patients, ulcerative disease of the colon developed while they were taking nonsteroidal anti-inflammatory drugs (NSAIDs). Clinical presentation and laboratory and colonoscopic findings were similar to those of inflammatory bowel disease. Review of the literature disclosed 74 additional cases of NSAID-induced colitis in adults. This is a rare but serious, sometimes fatal, complication of NSAID therapy. The elderly and those taking long-term NSAID therapy appear to be at highest risk.

The pathogenesis is thought to be related to inhibition of intestinal prostaglandin synthesis. Whether some NSAIDs are more likely to induce colitis than others is not known. Since NSAIDs are so widely prescribed and some are available without a prescription, heightened awareness by physicians and the lay public will be important in reducing injury from this disease, both by prevention and earlier recognition.

Toxicity of nonsteroidal anti-inflammatory drugs in the large intestine.

Davies NM.

Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.
Dis Colon Rectum 1995 Dec;38(12):1311-21 Abstract quote
PURPOSE: Adverse effects of nonsteroidal anti-inflammatory drugs (NSAIDS) on the upper gastrointestinal (GI) tract and small intestine are well described. Evidence is also accumulating that implicate NSAIDS in inducing and exacerbating damage in the distal GI tract. The purpose of this review is to identify possible adverse effects of NSAIDS on the large intestine and increase the clinical awareness of these toxicologic effects.

METHODS: A literature review identified the diversity of toxicologic effects induced by NSAIDS in the large intestine. The epidemiology, pathogenesis, and clinical implications of these adverse effects are described.

RESULTS: NSAID use has been associated with colonic bleeding, iron deficiency anemia, strictures, ulcerations, perforations, diarrhea, and death. In addition, NSAIDS can exacerbate inflammatory bowel disease and ulcerative colitis. The prevalence of NSAID-induced large intestinal damage is unknown. Diagnosis can be made by colonoscopy and barium scans. Although the clinical presentation of NSAID-induced gastropathy and enteropathy, bleeding or perforation, may be more dramatic than colonopathy, the overall clinical significance of these adverse effects of NSAIDS on the large intestine has not been fully characterized.

CONCLUSIONS: This review illustrates that NSAID-induced large bowel toxicity can cause significant morbidity in some patients, ranging from profuse diarrhea, chronic blood loss, and iron deficiency anemia to fatality. The pathogenesis is likely multifactorial and is thought to be related to inhibition of prostaglandin synthesis. Because NSAIDS are widely prescribed and some are available without a prescription, heightened awareness of these toxicologic manifestations throughout the GI tract may reduce morbidity.

Clinical, endoscopic, and histologic spectrum of nonsteroidal anti-inflammatory drug-induced lesions in the colon.

Puspok A, Kiener HP, Oberhuber G.

Clinic of Internal Medicine IV, AKH, Vienna, Austria.
Dis Colon Rectum 2000 May;43(5):685-91 Abstract quote
PURPOSE: It has become increasingly clear that nonsteroidal anti-inflammatory drugs may cause damage not only to the upper gastrointestinal tract but also to the small and large intestine. Although the colon may be readily investigated by endoscopy, drug-induced lesions are not well known, probably because they are considered to occur only rarely. In the present study we describe endoscopic, histologic, and gross characteristics of nonsteroidal anti-inflammatory drug-induced colonic damage. Furthermore, pathogenetic mechanisms and therapeutic options are discussed.

METHODS: The histories of all patients diagnosed as having nonsteroidal anti-inflammatory drug colitis during the last two years at the department of gastroenterology or the department of pathology at our hospital were reviewed. Endoscopic, histologic, and gross pathologic findings were systematically recorded. In addition, data on duration and type of nonsteroidal anti-inflammatory drug intake and time from onset of symptoms to diagnosis were collected. Therapy and outcome of our patients, if available, are reported.

RESULTS: During the study period 11 patients were diagnosed as having nonsteroidal anti-inflammatory drug colitis. Most patients presented with diarrhea with or without blood loss and complained about diffuse abdominal pain. Endoscopy revealed flat ulcers in the entire colon being more severe in the right colon in the three cases with acute onset of diarrhea. In four cases concentric "diaphragm-like" strictures were seen, all located in the right colon. In the remainder endoscopy showed nonspecific erosions and was normal in one patient. Histology revealed findings similar to ischemic colitis. Additionally, in two cases collagenous colitis was found. Diclofenac slow release was the most commonly involved drug. The median time from onset of symptoms to diagnosis was 1.8 (range, 0-11.5) years.

CONCLUSIONS: Nonsteroidal anti-inflammatory drug colitis is a clinically significant disease, which may present with diarrhea, anemia, and nonspecific abdominal complaints. Careful history taking, together with awareness of endoscopic and histologic findings, allows a timely diagnosis of this disease.

VARIANTS

DUODENUM

Duodenal mucosal injury with nonsteroidal antiinflammatory drugs.

Eliakim R, Ophir M, Rachmilewitz D.

Department of Gastroenterology, Hadassah University Hospital, Jerusalem, Israel.
J Clin Gastroenterol 1987 Aug;9(4):395-9 Abstract quote
The effect of nonsteroidal antiinflammatory drugs (NSAIDs) on duodenal mucosa was assessed both retrospectively and prospectively.

In 444 patients with duodenal ulcer, the incidence of upper gastrointestinal bleeding was five times higher in 56 patients who were treated with NSAIDs than in those who did not receive NSAIDs. Indomethacin and naproxen had the most potent damaging effects. In a control group of patients with gastric ulcer, nine out of 134 had taken NSAIDs. The incidence of bleeding in these patients was three times higher than in those who were not on NSAIDs. The effect of indomethacin, 150 mg/day, on the upper gastrointestinal tract was examined in a prospective study of 75 patients with acute musculoskeletal disorders.

Endoscopy after 1 week of therapy showed that 45% had mucosal damage in the duodenum, and this was as frequent and as severe as the gastric mucosal damage. In most instances, the duodenal damage was erosive duodenitis.

PERFORATION

Nonsteroidal antiinflammatory drug-induced small intestinal inflammation and blood loss. Effects of sulfasalazine and other disease-modifying antirheumatic drugs.

Hayllar J, Smith T, Macpherson A, Price AB, Gumpel M, Bjarnason I.

King's College School of Medicine and Dentistry, Denmark Hill, London, UK.

Arthritis Rheum 1994 Aug;37(8):1146-50 Abstract quote
OBJECTIVE. To identify the source of intestinal blood loss in rheumatoid arthritis patients being treated with nonsteroidal antiinflammatory drugs (NSAIDs) and assess the response to sulfasalazine and other disease-modifying antirheumatic drugs (DMARDs).

METHODS. Intestinal inflammation, blood loss, and gastroduodenal damage, and the response to treatment with DMARDs, were assessed in 46 patients taking NSAIDs.

RESULTS. Intestinal inflammation and blood loss correlated significantly with one another (r = 0.43, P < 0.003), but not with the macroscopic or microscopic appearance of the gastroduodenal mucosa. Sulfasalazine reduced both intestinal inflammation and blood loss, whereas the other DMARDs did not.

CONCLUSION. The small intestine is the main site of mild chronic blood loss in patients receiving NSAIDs, and this blood loss can be reduced with sulfasalazine treatment.

SEGMENTAL

Segmental ischemic colitis associated with nonsteroidal antiinflammatory drugs.

Carratu R, Parisi P, Agozzino A.

Cattedra di Gastroenterologia, Universita di Napoli, Italy.
J Clin Gastroenterol 1993 Jan;16(1):31-4 Abstract quote
We have seen two cases of a segmental ischemic colitis develop during nonsteroidal antiinflammatory drug (NSAID) treatment. No other possible etiologic factors were shown. The short-term clinical course and the follow-up were uneventful. NSAIDs have been reported to cause different lesions in the large bowel, either by worsening preexisting colonic diseases or by inducing a primary pathology.

We suggest that ischemia should be considered a possible mechanism of NSAID-associated colitis. Such ischemic colitis, not triggered by severe cardiovascular disease or operation, may be related to NSAIDs more often than currently recognized.

ULCERS

Benign colonic ulcers associated with nonsteroidal antiinflammatory drug ingestion.

Stamm C, Burkhalter CE, Pearce W, Larsen B, Willis M, Kikendall JW, Moses F, Rosen H, Wong RK.

Walter Reed Army Medical Center, Washington, D.C.
Am J Gastroenterol 1994 Dec;89(12):2230-3 Abstract quote
Nonsteroidal antiinflammatory drugs can be associated with benign colonic ulcers. The ulcers are easily diagnosed by colonoscopy, and, if uncomplicated, they are best treated by cessation of the nonsteroidal antiinflammatory drugs.

Benign colonic ulcers should be included in the differential diagnosis of any patient who presents with gastrointestinal complaints and is taking nonsteroidal antiinflammatory drugs.

HISTOLOGICAL TYPES CHARACTERIZATION

GENERAL

The histopathology of nonsteroidal anti-inflammatory drug-associated colitis.

Goldstein NS, Cinenza AN.

Department of Anatomic Pathology, William Beaumont Hospital, Royal Oak, Michigan, USA
Am J Clin Pathol 1998 Nov;110(5):622-8 Abstract quote
We describe the histologic findings of biopsies performed on specimens from 14 patients with nonsteroidal antiinflammatory drug (NSAID) associated colitis. Thirteen patients had endoscopially patchy colitis with small erosions in different parts of the colon. One patient had diffuse colitis extending from the rectum to the midtransverse colon.

Histologically, 8 patients had a mixed inflammatory infiltrate, 4 had predominantly neutrophilic inflammation, and 2 had predominantly lymphocytic inflammation. Seven patients had erosions. Eight patients had crypt architectural disarray, but none had crypt architectural distortion or granulomas. The histology of NSAID-associated colitis is similar in our experience to that of Crohn disease and infectious-type colitis. It shares no features with ulcerative colitis.

Given the widespread use of NSAIDs, pathologists should consider NSAID-associated colitis along with Crohn disease and infectious-type colitis in the histologic differential diagnosis of focal active colitis.

VARIANTS

APOPTOSIS

Importance of apoptosis in the histopathology of drug related lesions in the large intestine.

Lee FD.

Department of Pathology, Glasgow Royal Infirmary.
J Clin Pathol 1993 Feb;46(2):118-22 Abstract quote
AIM: To investigate the possibility that the incidence of apoptotic bodies in the cryptal epithelium might help to identify colonic lesions due to drugs, especially non-steroidal anti-inflammatory drugs (NSAIDs).

METHODS: The apoptotic count (AC) the number of apoptotic bodies per 100 crypts was calculated in a series of colorectal biopsy specimens, stained with haematoxylin and eosin from patients with (a) known or suspected drug induced colitis and (b) inflammatory bowel disease before or after treatment with salazopyrine or corticosteroids. These specimens were compared with normal biopsy specimens from a control group of comparable age and sex distribution.

RESULTS: Under normal conditions apoptotic bodies were seldom seen at all and the mean apoptotic count was less than 1.0. In untreated inflammatory bowel disease the mean apoptotic count was marginally increased (2.4), but when there was a partial response to drug treatment the apoptotic count rose to 13.1 (p 0.003). In colonic lesions directly attributable to drugs the apoptotic count was always increased, reaching its highest level (106) with 5-fluorouracil. In colitis related to NSAIDs apoptoses were associated with inflammation, most notably an increase in lymphocytes in both lamina propria and epithelium.

CONCLUSION: The presence of crypt apoptoses in substantial numbers (with an apoptotic count in excess of 5) should always raise the possibility of drug effect. The mechanisms involved are not clear but with NSAIDs the changes might well be immunologically mediated.

DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES

GENERAL

Biopsy diagnosis of colitis: possibilities and pitfalls.

Tsang P, Rotterdam H.

Department of Pathology, Cornell University Medical College, New York, New York, USA
Am J Surg Pathol 1999 Apr;23(4):423-30 Abstract quote
The histopathologic diagnosis of inflammation is common in colorectal biopsies but is of limited value, if not further specified.

We reviewed 280 endoscopic colorectal biopsy specimens for nonneoplastic disease from 100 consecutive patients in order to assess (a) the frequency of inflammation in excess of the physiologic infiltrate, (b) the frequency with which the cause of the inflammation could be specified, and (c) the interobserver variability in diagnosing inflammation.

Based on the reviewers' impression, each case was classified into one of three categories: (I) normal or nonspecific change, (II) nonspecific inflammation, and (III) inflammation suggestive or diagnostic of specific cause. Inflammation was diagnosed in 68% of cases.

The majority of these cases (75%) showed features typically associated with specific types of colitis, including Crohn's disease (n = 16), ulcerative colitis (n = 13), inflammatory bowel disease not otherwise specified (n = 5), infectious colitis (n = 6), ischemic colitis (n = 4), solitary rectal ulcer syndrome (n = 3), radiation colitis (n = 2), and lymphocytic colitis (n = 2). Interobserver variability was greatest in biopsy specimens interpreted by the reviewers as normal or showing nonspecific changes, most of which had been diagnosed as mild inflammation by the original pathologists. Etiologic classification of colitis was lacking in 59% of the cases interpreted by the reviewers as suggestive or diagnostic of a specific cause.

We conclude that (a) the majority of colorectal biopsy specimens from patients with nonneoplastic disease in this series show inflammation, (b) the majority of such cases allow a specific cause of colitis to be suggested or firmly diagnosed, and (c) pathologists tend to overdiagnose the physiologic inflammatory infiltrate as evidence of colitis and underdiagnose specific etiologic types of colitis.

CROHN'S DISEASE

PROGNOSIS AND TREATMENT CHARACTERIZATION

PROGNOSTIC FACTORS

Association of nonsteroidal antiinflammatory drugs with outcome in upper and lower gastrointestinal bleeding.

Wilcox CM, Clark WS.

Department of Medicine, Emory University School of Medicine, and the Medical Service of Grady Memorial Hospital, Atlanta, Georgia, USA.
Dig Dis Sci 1997 May;42(5):985-9 Abstract quote
Although nonsteroidal antiinflammatory drug (NSAID) use is strongly associated with both upper gastrointestinal bleeding (UGIB) and lower gastrointestinal bleeding (LGIB), few data exist regarding the outcome of the bleeding episode for those consuming these drugs. Consecutive patients with UGIB or LGIB evaluated during the period August 1, 1990 through September 30, 1994 at a large inner city hospital were prospectively identified.

Both prescription and over-the-counter NSAID use was specifically evaluated. Endoscopy was performed in most patients for diagnosis. Outcome measures included transfusion requirement, hospital stay, need for endoscopic therapy or surgery, and death. Over the 50-month study period, 785 patients admitted with UGIB and 161 with LGIB were studied. NSAID use was documented in 59% of patients with UGIB and 51% with LGIB. In UGIB, NSAID users were more likely to be female and older. NSAID users had a significantly shorter median hospital stay (4 vs 5 days), less rebleeding (11% vs 18%; P = 0.004) and in-hospital mortality (5% vs 13%; P = 0.001) as compared to nonusers. These differences remained significant when controlling for age, race, and gender. Similar trends in outcome were seen when evaluating ulcer- and non-ulcer-related bleeding.

NSAID users with LGIB were more likely to be female, although rebleeding (19% vs 21%), hospital stay, and in-hospital mortality (5% vs 2%) were not significantly different between users and nonusers. UGIB in NSAID users appears to have a better prognosis as compared to nonusers. In contrast, NSAID use does not appear to be associated with outcome in patients with LGIB.

Surgical complications of nonsteroidal antiinflammatory drug-induced small bowel ulceration.

Kessler WF, Shires GT 3rd, Fahey TJ 3rd.

Department of Surgery, the University of Texas Southwestern Medical Center, Dallas, USA.
J Am Coll Surg 1997 Sep;185(3):250-4 Abstract quote
BACKGROUND: The association between nonsteroidal antiinflammatory drug (NSAID) intake and gastroduodenal peptic ulceration is well recognized. Recent experimental data implicate NSAIDs in the development of a similar spectrum of pathologic lesions of the small bowel. However, clinically significant NSAID-induced small bowel ulcerations have been reported infrequently. This study sought to examine small bowel complications of NSAID use requiring surgical intervention.

STUDY DESIGN: A retrospective study of all patients (n = 283) who underwent small bowel resection on the general surgery services at the University of Texas Southwestern Medical Center during a 3-year period from 1991 to 1994 was conducted. Patients who had a history of chronic NSAID use, no other predisposing risk factors for gastrointestinal bleeding, and pathologically confirmed small bowel ulcerations complicated by hemorrhage, perforation, or obstruction were included in this study.

RESULTS: Eleven patients with 12 surgical complications of NSAID-induced small bowel ulcerations were identified. These 11 patients all underwent emergent laparotomies with small bowel resection (one patient had two separate operations, 8 months apart). Small bowel ulcerations were noted to occur in the jejunum (4) and the ileum (8) and were multiple in half of the cases. Complications included bleeding (50%), perforation (33%), and obstruction (17%).

CONCLUSIONS: This report is the first examining a series of surgical complications of NSAID-associated small bowel ulcerations. Our data suggest that small bowel complications of NSAID use requiring surgical intervention may occur more frequently than is currently recognized and, like peptic ulcer disease attributed to NSAIDs, result in significant morbidity and mortality.

Henry JB. Clinical Diagnosis and Management by Laboratory Methods. Twentieth Edition. WB Saunders. 2001.
Rosai J. Ackerman's Surgical Pathology. Eight Edition. Mosby 1996.
Sternberg S. Diagnostic Surgical Pathology. Third Edition. Lipincott Williams and Wilkins 1999.
Robbins Pathologic Basis of Disease. Sixth Edition. WB Saunders 1999.

Commonly Used Terms

Intestine

Last Updated 5/31/2002

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EPIDEMIOLOGY	CHARACTERIZATION
INCIDENCE
Colonic inflammation and nonsteroidal anti-inflammatory drug administration. An assessment of the frequency of the problem. Tanner AR, Raghunath AS. Department of Medicine, North Tees General Hospital, Stockton-on-Tees, Cleveland, UK.	Digestion 1988;41(2):116-20 Abstract quote Over an 18-month period at a single clinic, 43 new cases of colonic inflammation have been diagnosed (19 proctitis only). Crohn's colitis has been excluded from this analysis. In all these subjects a careful drug history has been taken in a prospective manner and in 4 of these 43 patients colonic inflammation appeared to be directly related to non-steroidal anti-inflammatory drug (NSAID) administration (mefenamic acid, 2; piroxicam, 2). In all 4 patients there was a time interval (mean 3 months) between initiation of treatment with NSAID and presentation with diarrhoea and weight loss. Pathological findings were minor and biochemical changes insignificant, in contrast to the protracted troublesome symptoms. Resolution of symptoms was very rapid on discontinuation of NSAID medication but 2 patients experienced immediate return of symptoms following inadvertent rechallenge. Approximately 10% of newly diagnosed colitis may be related to NSAID administration. Subjects taking NSAID medications appear to be five times more likely to develop colonic inflammation than the general population.
Colopathy associated with the systemic use of nonsteroidal antiinflammatory medications. An underestimated entity. Katsinelos P, Christodoulou K, Pilpilidis I, Xiarchos P, Papagiannis A, Dimiropoulos S, Amperiadis P, Vasiliadis T, Tarpagos A, Katsos I, Eugenidis N. Department of Gastroenterology, Theagenion Hospital, Aristotelion University, Ippokration Hospital, Thessaloniki, Greece.	Hepatogastroenterology 2002 Mar-Apr;49(44):345-8 Abstract quote BACKGROUND/AIMS: Adverse effects of NSAIDs (nonsteroidal antiinflammatory drugs) on the upper gastrointestinal tract and small intestine are well described. Evidence is also accumulating that implicate NSAIDs in inducing and exacerbating damage in the distal gastrointestinal tract. In this article we describe eight cases of colonic inflammation associated with nonsteroidal antiinflammatory drug administration; our aim is to stress the importance of an underestimated entity by clinicians. METHODOLOGY: Over a five-year period at two clinics, eight cases of NSAID-colopathy have been diagnosed. Crohn's disease, ulcerative and infections colitis have been excluded from this analysis. In all these subjects a careful drug history has been taken in a prospective manner and colonic inflammation appeared to be directly related to NSAID administration. There was a time interval (mean: 20 months) between initiation of treatment with NSAID and presentation with diarrhea, rectal hemorrhage and tenesmus. RESULTS: A correct diagnosis of colopathy associated with NSAIDs administration was made on careful drug history, pathological findings, stool cultures and biochemical changes which were insignificant, in contrast to the protracted troublesome symptoms. Resolution of symptoms was observed on discontinuation of NSAID medication. CONCLUSIONS: Our report is further evidence that NSAIDs administration is associated with significant mucosal injury in the distal gastrointestinal tract, despite is underestimated by most physicians.

GROSS APPEARANCE/ CLINICAL VARIANTS	CHARACTERIZATION
GENERAL
Colitis induced by nonsteroidal anti-inflammatory drugs. Report of four cases and review of the literature. Gibson GR, Whitacre EB, Ricotti CA. Department of Medicine, Trumbull Memorial Hospital, Warren, Ohio.	Arch Intern Med 1992 Mar;152(3):625-32 Abstract quote In four patients, ulcerative disease of the colon developed while they were taking nonsteroidal anti-inflammatory drugs (NSAIDs). Clinical presentation and laboratory and colonoscopic findings were similar to those of inflammatory bowel disease. Review of the literature disclosed 74 additional cases of NSAID-induced colitis in adults. This is a rare but serious, sometimes fatal, complication of NSAID therapy. The elderly and those taking long-term NSAID therapy appear to be at highest risk. The pathogenesis is thought to be related to inhibition of intestinal prostaglandin synthesis. Whether some NSAIDs are more likely to induce colitis than others is not known. Since NSAIDs are so widely prescribed and some are available without a prescription, heightened awareness by physicians and the lay public will be important in reducing injury from this disease, both by prevention and earlier recognition.
Toxicity of nonsteroidal anti-inflammatory drugs in the large intestine. Davies NM. Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.	Dis Colon Rectum 1995 Dec;38(12):1311-21 Abstract quote PURPOSE: Adverse effects of nonsteroidal anti-inflammatory drugs (NSAIDS) on the upper gastrointestinal (GI) tract and small intestine are well described. Evidence is also accumulating that implicate NSAIDS in inducing and exacerbating damage in the distal GI tract. The purpose of this review is to identify possible adverse effects of NSAIDS on the large intestine and increase the clinical awareness of these toxicologic effects. METHODS: A literature review identified the diversity of toxicologic effects induced by NSAIDS in the large intestine. The epidemiology, pathogenesis, and clinical implications of these adverse effects are described. RESULTS: NSAID use has been associated with colonic bleeding, iron deficiency anemia, strictures, ulcerations, perforations, diarrhea, and death. In addition, NSAIDS can exacerbate inflammatory bowel disease and ulcerative colitis. The prevalence of NSAID-induced large intestinal damage is unknown. Diagnosis can be made by colonoscopy and barium scans. Although the clinical presentation of NSAID-induced gastropathy and enteropathy, bleeding or perforation, may be more dramatic than colonopathy, the overall clinical significance of these adverse effects of NSAIDS on the large intestine has not been fully characterized. CONCLUSIONS: This review illustrates that NSAID-induced large bowel toxicity can cause significant morbidity in some patients, ranging from profuse diarrhea, chronic blood loss, and iron deficiency anemia to fatality. The pathogenesis is likely multifactorial and is thought to be related to inhibition of prostaglandin synthesis. Because NSAIDS are widely prescribed and some are available without a prescription, heightened awareness of these toxicologic manifestations throughout the GI tract may reduce morbidity.
Clinical, endoscopic, and histologic spectrum of nonsteroidal anti-inflammatory drug-induced lesions in the colon. Puspok A, Kiener HP, Oberhuber G. Clinic of Internal Medicine IV, AKH, Vienna, Austria.	Dis Colon Rectum 2000 May;43(5):685-91 Abstract quote PURPOSE: It has become increasingly clear that nonsteroidal anti-inflammatory drugs may cause damage not only to the upper gastrointestinal tract but also to the small and large intestine. Although the colon may be readily investigated by endoscopy, drug-induced lesions are not well known, probably because they are considered to occur only rarely. In the present study we describe endoscopic, histologic, and gross characteristics of nonsteroidal anti-inflammatory drug-induced colonic damage. Furthermore, pathogenetic mechanisms and therapeutic options are discussed. METHODS: The histories of all patients diagnosed as having nonsteroidal anti-inflammatory drug colitis during the last two years at the department of gastroenterology or the department of pathology at our hospital were reviewed. Endoscopic, histologic, and gross pathologic findings were systematically recorded. In addition, data on duration and type of nonsteroidal anti-inflammatory drug intake and time from onset of symptoms to diagnosis were collected. Therapy and outcome of our patients, if available, are reported. RESULTS: During the study period 11 patients were diagnosed as having nonsteroidal anti-inflammatory drug colitis. Most patients presented with diarrhea with or without blood loss and complained about diffuse abdominal pain. Endoscopy revealed flat ulcers in the entire colon being more severe in the right colon in the three cases with acute onset of diarrhea. In four cases concentric "diaphragm-like" strictures were seen, all located in the right colon. In the remainder endoscopy showed nonspecific erosions and was normal in one patient. Histology revealed findings similar to ischemic colitis. Additionally, in two cases collagenous colitis was found. Diclofenac slow release was the most commonly involved drug. The median time from onset of symptoms to diagnosis was 1.8 (range, 0-11.5) years. CONCLUSIONS: Nonsteroidal anti-inflammatory drug colitis is a clinically significant disease, which may present with diarrhea, anemia, and nonspecific abdominal complaints. Careful history taking, together with awareness of endoscopic and histologic findings, allows a timely diagnosis of this disease.
VARIANTS
DUODENUM
Duodenal mucosal injury with nonsteroidal antiinflammatory drugs. Eliakim R, Ophir M, Rachmilewitz D. Department of Gastroenterology, Hadassah University Hospital, Jerusalem, Israel.	J Clin Gastroenterol 1987 Aug;9(4):395-9 Abstract quote The effect of nonsteroidal antiinflammatory drugs (NSAIDs) on duodenal mucosa was assessed both retrospectively and prospectively. In 444 patients with duodenal ulcer, the incidence of upper gastrointestinal bleeding was five times higher in 56 patients who were treated with NSAIDs than in those who did not receive NSAIDs. Indomethacin and naproxen had the most potent damaging effects. In a control group of patients with gastric ulcer, nine out of 134 had taken NSAIDs. The incidence of bleeding in these patients was three times higher than in those who were not on NSAIDs. The effect of indomethacin, 150 mg/day, on the upper gastrointestinal tract was examined in a prospective study of 75 patients with acute musculoskeletal disorders. Endoscopy after 1 week of therapy showed that 45% had mucosal damage in the duodenum, and this was as frequent and as severe as the gastric mucosal damage. In most instances, the duodenal damage was erosive duodenitis.
PERFORATION
Nonsteroidal antiinflammatory drug-induced small intestinal inflammation and blood loss. Effects of sulfasalazine and other disease-modifying antirheumatic drugs. Hayllar J, Smith T, Macpherson A, Price AB, Gumpel M, Bjarnason I. King's College School of Medicine and Dentistry, Denmark Hill, London, UK.	Arthritis Rheum 1994 Aug;37(8):1146-50 Abstract quote OBJECTIVE. To identify the source of intestinal blood loss in rheumatoid arthritis patients being treated with nonsteroidal antiinflammatory drugs (NSAIDs) and assess the response to sulfasalazine and other disease-modifying antirheumatic drugs (DMARDs). METHODS. Intestinal inflammation, blood loss, and gastroduodenal damage, and the response to treatment with DMARDs, were assessed in 46 patients taking NSAIDs. RESULTS. Intestinal inflammation and blood loss correlated significantly with one another (r = 0.43, P < 0.003), but not with the macroscopic or microscopic appearance of the gastroduodenal mucosa. Sulfasalazine reduced both intestinal inflammation and blood loss, whereas the other DMARDs did not. CONCLUSION. The small intestine is the main site of mild chronic blood loss in patients receiving NSAIDs, and this blood loss can be reduced with sulfasalazine treatment.
SEGMENTAL
Segmental ischemic colitis associated with nonsteroidal antiinflammatory drugs. Carratu R, Parisi P, Agozzino A. Cattedra di Gastroenterologia, Universita di Napoli, Italy.	J Clin Gastroenterol 1993 Jan;16(1):31-4 Abstract quote We have seen two cases of a segmental ischemic colitis develop during nonsteroidal antiinflammatory drug (NSAID) treatment. No other possible etiologic factors were shown. The short-term clinical course and the follow-up were uneventful. NSAIDs have been reported to cause different lesions in the large bowel, either by worsening preexisting colonic diseases or by inducing a primary pathology. We suggest that ischemia should be considered a possible mechanism of NSAID-associated colitis. Such ischemic colitis, not triggered by severe cardiovascular disease or operation, may be related to NSAIDs more often than currently recognized.
ULCERS
Benign colonic ulcers associated with nonsteroidal antiinflammatory drug ingestion. Stamm C, Burkhalter CE, Pearce W, Larsen B, Willis M, Kikendall JW, Moses F, Rosen H, Wong RK. Walter Reed Army Medical Center, Washington, D.C.	Am J Gastroenterol 1994 Dec;89(12):2230-3 Abstract quote Nonsteroidal antiinflammatory drugs can be associated with benign colonic ulcers. The ulcers are easily diagnosed by colonoscopy, and, if uncomplicated, they are best treated by cessation of the nonsteroidal antiinflammatory drugs. Benign colonic ulcers should be included in the differential diagnosis of any patient who presents with gastrointestinal complaints and is taking nonsteroidal antiinflammatory drugs.

PROGNOSIS AND TREATMENT	CHARACTERIZATION
PROGNOSTIC FACTORS
Association of nonsteroidal antiinflammatory drugs with outcome in upper and lower gastrointestinal bleeding. Wilcox CM, Clark WS. Department of Medicine, Emory University School of Medicine, and the Medical Service of Grady Memorial Hospital, Atlanta, Georgia, USA.	Dig Dis Sci 1997 May;42(5):985-9 Abstract quote Although nonsteroidal antiinflammatory drug (NSAID) use is strongly associated with both upper gastrointestinal bleeding (UGIB) and lower gastrointestinal bleeding (LGIB), few data exist regarding the outcome of the bleeding episode for those consuming these drugs. Consecutive patients with UGIB or LGIB evaluated during the period August 1, 1990 through September 30, 1994 at a large inner city hospital were prospectively identified. Both prescription and over-the-counter NSAID use was specifically evaluated. Endoscopy was performed in most patients for diagnosis. Outcome measures included transfusion requirement, hospital stay, need for endoscopic therapy or surgery, and death. Over the 50-month study period, 785 patients admitted with UGIB and 161 with LGIB were studied. NSAID use was documented in 59% of patients with UGIB and 51% with LGIB. In UGIB, NSAID users were more likely to be female and older. NSAID users had a significantly shorter median hospital stay (4 vs 5 days), less rebleeding (11% vs 18%; P = 0.004) and in-hospital mortality (5% vs 13%; P = 0.001) as compared to nonusers. These differences remained significant when controlling for age, race, and gender. Similar trends in outcome were seen when evaluating ulcer- and non-ulcer-related bleeding. NSAID users with LGIB were more likely to be female, although rebleeding (19% vs 21%), hospital stay, and in-hospital mortality (5% vs 2%) were not significantly different between users and nonusers. UGIB in NSAID users appears to have a better prognosis as compared to nonusers. In contrast, NSAID use does not appear to be associated with outcome in patients with LGIB.
Surgical complications of nonsteroidal antiinflammatory drug-induced small bowel ulceration. Kessler WF, Shires GT 3rd, Fahey TJ 3rd. Department of Surgery, the University of Texas Southwestern Medical Center, Dallas, USA.	J Am Coll Surg 1997 Sep;185(3):250-4 Abstract quote BACKGROUND: The association between nonsteroidal antiinflammatory drug (NSAID) intake and gastroduodenal peptic ulceration is well recognized. Recent experimental data implicate NSAIDs in the development of a similar spectrum of pathologic lesions of the small bowel. However, clinically significant NSAID-induced small bowel ulcerations have been reported infrequently. This study sought to examine small bowel complications of NSAID use requiring surgical intervention. STUDY DESIGN: A retrospective study of all patients (n = 283) who underwent small bowel resection on the general surgery services at the University of Texas Southwestern Medical Center during a 3-year period from 1991 to 1994 was conducted. Patients who had a history of chronic NSAID use, no other predisposing risk factors for gastrointestinal bleeding, and pathologically confirmed small bowel ulcerations complicated by hemorrhage, perforation, or obstruction were included in this study. RESULTS: Eleven patients with 12 surgical complications of NSAID-induced small bowel ulcerations were identified. These 11 patients all underwent emergent laparotomies with small bowel resection (one patient had two separate operations, 8 months apart). Small bowel ulcerations were noted to occur in the jejunum (4) and the ileum (8) and were multiple in half of the cases. Complications included bleeding (50%), perforation (33%), and obstruction (17%). CONCLUSIONS: This report is the first examining a series of surgical complications of NSAID-associated small bowel ulcerations. Our data suggest that small bowel complications of NSAID use requiring surgical intervention may occur more frequently than is currently recognized and, like peptic ulcer disease attributed to NSAIDs, result in significant morbidity and mortality.

Epidemiology
Pathogenesis
Histopathological Features and Variants
Differential Diagnosis
Prognosis and Treatment
Commonly Used Terms

HISTOLOGICAL TYPES	CHARACTERIZATION
GENERAL
The histopathology of nonsteroidal anti-inflammatory drug-associated colitis. Goldstein NS, Cinenza AN. Department of Anatomic Pathology, William Beaumont Hospital, Royal Oak, Michigan, USA	Am J Clin Pathol 1998 Nov;110(5):622-8 Abstract quote We describe the histologic findings of biopsies performed on specimens from 14 patients with nonsteroidal antiinflammatory drug (NSAID) associated colitis. Thirteen patients had endoscopially patchy colitis with small erosions in different parts of the colon. One patient had diffuse colitis extending from the rectum to the midtransverse colon. Histologically, 8 patients had a mixed inflammatory infiltrate, 4 had predominantly neutrophilic inflammation, and 2 had predominantly lymphocytic inflammation. Seven patients had erosions. Eight patients had crypt architectural disarray, but none had crypt architectural distortion or granulomas. The histology of NSAID-associated colitis is similar in our experience to that of Crohn disease and infectious-type colitis. It shares no features with ulcerative colitis. Given the widespread use of NSAIDs, pathologists should consider NSAID-associated colitis along with Crohn disease and infectious-type colitis in the histologic differential diagnosis of focal active colitis.
VARIANTS
APOPTOSIS
Importance of apoptosis in the histopathology of drug related lesions in the large intestine. Lee FD. Department of Pathology, Glasgow Royal Infirmary.	J Clin Pathol 1993 Feb;46(2):118-22 Abstract quote AIM: To investigate the possibility that the incidence of apoptotic bodies in the cryptal epithelium might help to identify colonic lesions due to drugs, especially non-steroidal anti-inflammatory drugs (NSAIDs). METHODS: The apoptotic count (AC) the number of apoptotic bodies per 100 crypts was calculated in a series of colorectal biopsy specimens, stained with haematoxylin and eosin from patients with (a) known or suspected drug induced colitis and (b) inflammatory bowel disease before or after treatment with salazopyrine or corticosteroids. These specimens were compared with normal biopsy specimens from a control group of comparable age and sex distribution. RESULTS: Under normal conditions apoptotic bodies were seldom seen at all and the mean apoptotic count was less than 1.0. In untreated inflammatory bowel disease the mean apoptotic count was marginally increased (2.4), but when there was a partial response to drug treatment the apoptotic count rose to 13.1 (p 0.003). In colonic lesions directly attributable to drugs the apoptotic count was always increased, reaching its highest level (106) with 5-fluorouracil. In colitis related to NSAIDs apoptoses were associated with inflammation, most notably an increase in lymphocytes in both lamina propria and epithelium. CONCLUSION: The presence of crypt apoptoses in substantial numbers (with an apoptotic count in excess of 5) should always raise the possibility of drug effect. The mechanisms involved are not clear but with NSAIDs the changes might well be immunologically mediated.

DIFFERENTIAL DIAGNOSIS	KEY DIFFERENTIATING FEATURES
GENERAL
Biopsy diagnosis of colitis: possibilities and pitfalls. Tsang P, Rotterdam H. Department of Pathology, Cornell University Medical College, New York, New York, USA	Am J Surg Pathol 1999 Apr;23(4):423-30 Abstract quote The histopathologic diagnosis of inflammation is common in colorectal biopsies but is of limited value, if not further specified. We reviewed 280 endoscopic colorectal biopsy specimens for nonneoplastic disease from 100 consecutive patients in order to assess (a) the frequency of inflammation in excess of the physiologic infiltrate, (b) the frequency with which the cause of the inflammation could be specified, and (c) the interobserver variability in diagnosing inflammation. Based on the reviewers' impression, each case was classified into one of three categories: (I) normal or nonspecific change, (II) nonspecific inflammation, and (III) inflammation suggestive or diagnostic of specific cause. Inflammation was diagnosed in 68% of cases. The majority of these cases (75%) showed features typically associated with specific types of colitis, including Crohn's disease (n = 16), ulcerative colitis (n = 13), inflammatory bowel disease not otherwise specified (n = 5), infectious colitis (n = 6), ischemic colitis (n = 4), solitary rectal ulcer syndrome (n = 3), radiation colitis (n = 2), and lymphocytic colitis (n = 2). Interobserver variability was greatest in biopsy specimens interpreted by the reviewers as normal or showing nonspecific changes, most of which had been diagnosed as mild inflammation by the original pathologists. Etiologic classification of colitis was lacking in 59% of the cases interpreted by the reviewers as suggestive or diagnostic of a specific cause. We conclude that (a) the majority of colorectal biopsy specimens from patients with nonneoplastic disease in this series show inflammation, (b) the majority of such cases allow a specific cause of colitis to be suggested or firmly diagnosed, and (c) pathologists tend to overdiagnose the physiologic inflammatory infiltrate as evidence of colitis and underdiagnose specific etiologic types of colitis.
CROHN'S DISEASE