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Usefulness of colonoscopy with biopsy in the evaluation of patients with chronic diarrhea
THE AMERICAN JOURNAL OF GASTROENTEROLOGY © 2001 by Am. Coll. of Gastroenterology Published by Elsevier Science Inc.
Vol. 96, No. 4, 2001 ISSN 0002-9270/01/$20.00 PII S0002-9270(01)02308-5
Usefulness of Colonoscopy With Biopsy in the Evaluation of Patients With Chronic Diarrhea Raj J. Shah, M.D., Cecilia Fenoglio-Preiser, M.D., Brian L. Bleau, M.D., and Ralph A. Giannella, M.D. Division of Digestive Diseases, Department of Internal Medicine and Department of Pathology, University of Cincinnati College of Medicine, Cincinnati, Ohio; and Tacoma Digestive Diseases, Tacoma, Washington
OBJECTIVE: Patients referred for chronic diarrhea frequently undergo endoscopic evaluation. There are limited data on the role for colonoscopy with biopsy and ileoscopy for patients with chronic diarrhea. METHODS: We reviewed the charts of 228 patients with chronic diarrhea evaluated by colonoscopy between November 1995 and March 1998. Chronic diarrhea was defined as loose, frequent bowel movements for a minimum of 4 wk. Patients were excluded if biopsies were not performed in normal colons, if they had undergone previous bowel surgery, a history of inflammatory bowel disease, HIV, or an inadequate colonoscopy. RESULTS: One hundred sixty-eight patients were included in the analysis, of whom 142 (85%) had ileoscopy. Colonoscopy and biopsy yielded a specific histological diagnosis in 52 (31%) patients. These included Crohn’s disease (9), ulcerative colitis (7), lymphocytic colitis (10), collagenous colitis (3), ischemic colitis (3), infectious colitis (6), and miscellaneous diseases (14). Ileoscopy yielded significant findings in 3% of patients (four with Crohn’s disease and one with infection). CONCLUSIONS: Colonoscopy and biopsy is useful in the investigation of patients with chronic diarrhea yielding a histological diagnosis in 31% of patients without a previous diagnosis. Ileoscopy complemented colonoscopy findings in a minority of patients with chronic diarrhea and was essential for a diagnosis in only two patients. (Am J Gastroenterol 2001;96:1091–1095. © 2001 by Am. Coll. of Gastroenterology)
INTRODUCTION Patients with chronic diarrhea often present a difficult diagnostic problem. Although colonoscopy is frequently performed in these patients, the usefulness of colonoscopy with biopsy in this setting is uncertain. The usefulness of endoscopy in the evaluation of diarrhea in patients with HIV has been well investigated (1–3). However, the decision to use Presented in part at Digestive Disease Week, May, 1999, Orlando, FL (Gastroenterology 1999;116:930); presented in part at the North American Conference of Gastroenterology Fellows, August, 1999, Vancouver, British Columbia; and presented in part at the Young Investigator’s Conference, April, 1999, Atlanta, GA.
endoscopy in the evaluation of non-HIV patients with chronic diarrhea is based on limited data and studies with various limitations. Colonoscopy with ileal intubation may be preferred to sigmoidoscopy for the detection of right-sided colitis, isolated ileitis, or in the case of pancolitis to distinguish Crohn’s disease from ulcerative colitis (4 – 8). However, this practice has not been prospectively evaluated (9). The available studies of endoscopy in chronic diarrhea have had variable inclusion criteria. These include the duration of the diarrhea (e.g., acute vs chronic), the extent of lower endoscopy, and in the case of microscopic or collagenous colitis whether random colonic biopsies (given the varied distribution of microscopic colitis) were performed (10 –12). The incidence of lymphocytic and collagenous colitis ranges from 5% to 9.5% of patients undergoing an evaluation for chronic diarrhea (13, 14). Such data support performing biopsies of normal mucosa when investigating chronic diarrhea (15). However, it has been suggested that biopsies of normal mucosa may be unnecessary, especially for patients who fit criteria for the irritable bowel syndrome (IBS) (12, 16). The purpose of this study was to investigate the diagnostic yield of total colonoscopy and biopsy with ileoscopy in non-HIV patients referred for unexplained chronic diarrhea.
MATERIALS AND METHODS This is a retrospective study of patients largely referred from primary care physicians and surgeons at the University of Cincinnati between November 1995 and March 1998 for an initial evaluation of chronic diarrhea. Both inpatient and outpatient evaluations were included. The endoscopy database was searched for colonoscopies performed for “unexplained” or “chronic diarrhea” and 228 such patients were found. Endoscopies were performed by fellows and attending faculty of the Division of Digestive Diseases. Colonoscopy reports included the extent of colitis (if present), associated symptoms, and the performance of random biopsies in the cases of normal mucosa. For the purposes of this study, endoscopic findings of polyps that were ⬍3 cm and without villous features were not considered causes of diarrhea. Pathology reports were reviewed. Outpatient charts
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Table 1. Associated Findings of Patients With Chronic Diarrhea Abdominal pain: 43%* Rectal bleeding: 27% Anemia: 15%† Weight loss: 9%‡ * Any location. † Defined as hemoglobin ⬍14 g/dl in men and ⬍13 g/dl in women. ‡ Weight loss reported by the patient.
were reviewed to confirm the duration of the diarrhea and to obtain final diagnoses in those patients in whom colonoscopy findings were normal or nonspecific. Stool study results were available by retrospective review in only a minority of patients. The information collected was manually recorded in a table format. Chronic diarrhea was defined as loose, frequent bowel movements of at least 4 wk duration that was a clear change from the patient’s baseline. Patients were excluded if they had 1) a prior diagnosis of idiopathic inflammatory bowel disease; 2) prior intestinal surgery; 3) known infection with the HIV type 1; 4) no random biopsies performed in a grossly normal colon; 5) an incomplete colonoscopy or inadequate prep; and 6) prior colonoscopy for diarrhea. Endoscopic examination was performed with videocolonoscopes. Biopsy specimens were collected from areas of gross endoscopic abnormalities or from areas of normalappearing mucosa in those examinations without any abnormalities. A single expert GI pathologist (CF-P) reviewed all abnormal histology in a blinded fashion. Lymphocytic colitis (microscopic colitis), collagenous colitis, melanosis coli, and acute self-limited colitis have previously been shown to have specific histological features (17–22). However, the term nonspecific colitis is used to indicate chronic inflammation of the lamina propria for which an etiology cannot be determined by histological examination. Final clinical diagnoses in these cases and in patients with normal histology were obtained from their outpatient charts.
RESULTS Between November 1995 and March 1998, a total of 228 patients underwent colonoscopy at University Hospital for an evaluation of chronic diarrhea. These records were re-
Table 2. Specific Histological Diagnoses by Colonoscopy With Biopsy and Ileoscopy Diagnosis
Number of Cases
Lymphocytic colitis Crohn’s disease Ulcerative colitis Melanosis coli Infection Collagenous colitis Ischemic colitis Acute self-limited colitis Rectal tubulovillous adenoma Radiation colitis Eosinophilic colitis NSAID-associated colitis Total
10 9 7 7 6 3 3 3 1 1 1 1 52
viewed. Sixty patients were excluded for the following reasons: 19 patients had HIV, 14 patients had normal colonoscopy without random biopsies being taken, 11 patients had prior intestinal surgery, five patients had incomplete examinations, four patients had a known diagnosis of inflammatory bowel disease, three patients had unavailable pathology results, two patients did not have chronic diarrhea (as defined above), and two patients had repeat examinations. The final study group consisted of 168 patients with an age range of 22– 86 yr, with a mean age of 51 yr. One hundred fourteen patients (68%) were women. Associated findings are recorded in Table 1. Ileal intubation was achieved in 142 patients (85%) and biopsies of the ileum were obtained in 83 patients (59% of patients who had ileal intubation). Eighty-nine patients (53%) also underwent upper endoscopy with distal duodenal biopsy. In the 168 study patients, 52 patients (31%) had a specific histological diagnosis; 15 patients (8.9%) had a histological diagnosis of nonspecific colitis, and the remaining 101 patients (60%) had normal colon histology (Fig. 1). The specific histological diagnoses are listed in Table 2. Ileal histology was helpful in five patients (or 6% of patients who had ileal biopsy). Four patients had Crohn’s disease by biopsy of the ileum, but only one had isolated ileitis. One cardiac transplant patient had cytomegalovirus (CMV) in-
Figure 1. The number of study patients with specific histological diagnoses, nonspecific colitis, and normal histology.
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Colonoscopy and Patients With Chronic Diarrhea
Table 3. Final Diagnoses for Patients With Nonspecific Colitis Diagnoses
Number of Cases
Irritable bowel syndrome Alcohol associated Chemotherapy associated NSAID associated Lactose intolerance GI sarcoid
6 1 1 1 1 1
fection diagnosed only by ileal biopsy. Infections diagnosed by endoscopy included four patients with CMV infection (all in posttransplant patients) and two patients with pseudomembranous colitis. Of the seven patients with melanosis coli, five had macroscopically abnormal endoscopies. Final diagnoses established by long-term follow-up of patients with nonspecific colitis were obtained in 11 patients (or 73% of patients with nonspecific colitis) and are listed in Table 3. One-half of these were thought to be IBS. Follow-up clinical diagnoses, or whether resolution of diarrhea occurred in those patients with normal histology, were obtained in 84 patients (or 83% of patients with normal histology). Fifty-six percent had a final diagnosis of IBS, 12% had spontaneous resolution of their diarrhea, 6% had a specific infection (two patients had Clostridium difficile, one had “chronic traveler’s diarrhea” for the lack of a better term as the patient was a frequent international traveler and whose diarrheal episodes responded to metronidazole and cipro but a specific etiological agent could not be found, one had Blastocystis hominis and the diarrhea responded to a course of metronidazole, and one posttransplant patient had presumptive CMV as the diarrhea resolved after ganciclovir therapy for CMV of the liver), and the remaining 26% had a scattering of assorted diagnoses. These are listed in Table 4. Sixty-five of the 116 patients (56%) with normal histology or nonspecific colitis on colonoscopy had distal duodenal biopsies. Two patients had mild villous atrophy. One had spontaneous resolution of diarrhea and the other was lost to follow-up. One patient with moderate villous atrophy had Table 4. Final Diagnoses for Patients With Normal Histology Follow-up
Number of Cases
Irritable bowel syndrome Spontaneous resolution Infection Diabetic diarrhea Lactose intolerance Fecal incontinence Ischemic colitis Pancreatic insufficiency Crohn’s disease Bacterial overgrowth GI sarcoid Antibiotic associated Alcohol associated Medication associated Total
47 10 5 4 3 3 2 2 2 2 1 1 1 1 84
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coexistent lymphocytic colitis and the diarrhea responded to sulfasalazine. There were no complications reported as a result of endoscopy and biopsy in the 228 records reviewed.
DISCUSSION Although routinely performed, there is little data on the usefulness of total colonoscopy in the evaluation of chronic diarrhea. In our study, a specific histological diagnosis could be made in 52 patients or 31% of the patients studied. Fourteen of these 52 patients (or 27% of patients with a diagnosis made by biopsy) had grossly normal-appearing mucosa on endoscopy but significant histopathology (Crohn’s disease [1], lymphocytic colitis [9], collagenous colitis [1], melanosis coli [2], CMV ileitis [1]). These findings emphasize the importance of performing random biopsies in macroscopically normal colons. Ileal biopsy was essential in making a diagnosis in two patients. One patient had a grossly normal ileum (CMV infection) and the other had isolated ileal Crohn’s disease. Ileoscopy complemented colonoscopy in three additional patients (pancolitis, patchy areas of colitis, and a grossly normal colon but histologically consistent with Crohn’s disease, respectively). As previously reported, ileal intubation may give clinically useful information for patients with chronic diarrhea (5, 6). After blinded review of all abnormal biopsies by our pathologist, three cases of nonspecific colitis, one case of melanosis coli, and one case of chemotherapy-associated colitis were reclassified as lymphocytic colitis. These are reflected in the data presented. Only one of the 10 patients with lymphocytic colitis had an increase in erythema described in the left colon. Two of the three patients with collagenous colitis had increased erythema in the left colon. Whether these endoscopic changes are attributable to bowel preparation is uncertain (23, 24). Those patients with melanosis coli were suspected to have surreptitious ingestion of laxatives. Although melanosis may be seen in patients with chronic constipation, our patients’ indication for endoscopy was diarrhea (20, 25). Only three of the patients admitted to laxative use, whereas two patients, who denied laxative abuse, had spontaneous resolution of their symptoms on subsequent follow-up. Prior et al. (16) reported on 100 consecutive patients with macroscopically normal colons and random biopsies and found significant pathology in 22% of the patients. Their slightly lower percentage of findings may be explained by the fact that only one-half of their patients had diarrhea. Patel et al. (11) reported the use of lower endoscopy in nonbloody diarrhea and found a diagnostic yield of 18% in 205 patients studied. This figure is much lower than our yield of 31%. Their study differed from ours in that they included patients with both acute and chronic diarrhea and excluded patients with rectal bleeding. In addition, more than one-third of their patients had sigmoidoscopy alone;
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therefore, right-sided colitis and ileitis may have been missed (4 – 6). Furthermore, patients with abdominal pain were excluded in an attempt to differentiate organic diarrhea from IBS. Although nonspecific, abdominal pain may be a significant feature of IBS and collagenous colitis, and these entities should be excluded before diagnosing a patient with IBS (26 –28). Marshall et al. (15) failed to identify any cases of lymphocytic or collagenous colitis in 111 patients with chronic diarrhea who had macroscopically normal colons with random biopsies. They concluded that biopsies be reserved for those patients with debilitating symptoms. However, approximately one-third of their patients had sigmoidoscopy alone. Given the variable distribution of microscopic colitis and collagenous colitis, some cases may have been missed with left-sided biopsy alone (17, 29). Furthermore, more recent data reveal a higher incidence of these colitides in large population studies (13, 14). As a result of the majority of the endoscopists performing colonoscopy in this study placing all specimens into one jar in an attempt to conserve costs, we cannot comment on which specimen (e.g., cecum or sigmoid colon) specifically made the diagnosis. However, we recommend obtaining two specimens from the cecum, hepatic flexure, transverse colon, sigmoid colon, and rectum. Recent data, however, suggest that left-sided sampling may be sufficient in the majority of cases (29, 30). A significant percentage (31%) of our patients with normal or nonspecific colitis were subsequently diagnosed with IBS. These findings are consistent with those of Read et al. (31) who reported that eight of 27 patients (30%) who underwent an extensive evaluation for chronic diarrhea were found to have the IBS. In our study, 10 additional patients with normal histology had spontaneous resolution of their diarrhea. Six patients with nonspecific colitis had the diagnosis of IBS on follow-up. Although colonic inflammation is contradictory to established criteria, an intercurrent illness cannot be excluded (12). The subsequent diagnosis of Crohn’s disease in two patients was discovered on repeat colonoscopy within 2 yr of the initial colonoscopy. Distal duodenal biopsies were not systematically done, only one-half of our patients underwent distal duodenal biopsy. Thus, recommendations on its routine use in evaluating patients with chronic diarrhea cannot be made. Most recently, Fine et al. (32) reported on 809 non-HIV patients at a major referral center for diarrheal illnesses who underwent colonoscopy for chronic diarrhea. This was a retrospective study, but the established biopsy protocol permitted the distinction of “left-sided” and “right-sided” specimens. Fifteen percent of the study population was found to have colonic histopathology. Sixty-six percent (80 of 122 patients with diagnoses) were found to have microscopic colitis reflecting their highly referred population. They concluded that more than 99% of all diagnoses could have been made by left-sided biopsy (e.g., within the reach of the sigmoidoscope) alone. Twenty-three patients (19% of the total patients with histopathology) had Crohn’s disease,
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which they believed could be diagnosed by left-sided biopsy alone. It is somewhat surprising that the diagnosis of Crohn’s disease could be made with certainty in all 23 cases by left-sided examination alone. The higher yield for histopathology in our study is likely a reflection of a predominantly primary care population undergoing an initial evaluation for unexplained diarrhea and our inclusion of patients with associated hematochezia. In conclusion, this study reports on the usefulness of colonoscopy with biopsy in the evaluation of non-HIV patients with chronic diarrhea. Ileoscopy may complement, or less commonly, make the diagnosis for patients with chronic diarrhea. A significant number of patients (56% of patients with final diagnoses) were determined to have IBS. It could be argued that in cases where IBS is suspected, a normal colonoscopy helps exclude organic pathology. Thus, our report of histological diagnoses is likely an underestimate of the clinically useful information obtained from colonoscopy. Our study is retrospective and the inability to have a uniform selection process for study patients could have influenced the results. Prospective studies may be necessary to assess the yield and cost-effectiveness of colonoscopy versus sigmoidoscopy in non-HIV patients with chronic diarrhea (9). Reprint requests and correspondence: Ralph A. Giannella, M.D., Division of Digestive Diseases, University of Cincinnati Medical Center, 231 Bethesda Ave., ML 0595, Cincinnati, OH 45267-0595. Received May 24, 2000; accepted Oct. 6, 2000.
REFERENCES 1. Kearney DJ, Steuerwald M, Koch J, et al. A prospective study of endoscopy in HIV-associated diarrhea. Am J Gastroenterol 1999;94:596 – 602. 2. Bini EJ, Cohen J. Diagnostic yield and cost-effectiveness of endoscopy in chronic human immunodeficiency virus-related diarrhea. Gastrointest Endosc 1998;48:354 – 61. 3. Bini EJ, Weinshel EH. Endoscopic evaluation of chronic human immunodeficiency virus-related diarrhea: Is colonoscopy superior to flexible sigmoidoscopy? Am J Gastroenterol 1998; 93:56 – 60. 4. Tanaka M, Mazzoleni G, Riddell GH. Distribution of collagenous colitis: Utility of flexible sigmoidoscopy. Gut 1992;33: 65–70. 5. Geboes K, Ectors N, D’Haens G, et al. Is ileoscopy with biopsy worthwhile in patients presenting with symptoms of inflammatory bowel disease? Am J Gastroenterol 1998;93: 201–5. 6. Coremans G, Rutgeerts P, Geboes K, et al. The value of ileoscopy with biopsy in the diagnosis of intestinal Crohn’s disease. Gastrointest Endosc 1984;30:167–72. 7. Borsch G, Schmidt G. Endoscopy of the terminal ileum: Diagnostic yield in 400 consecutive examinations. Dis Colon Rectum 1985;28:499 –501. 8. Zwas FR, Bonheim NA, Berken CA, et al. Diagnostic yield of routine ileoscopy. Am J Gastroenterol 1995;90:1441–3. 9. Fine KD, Schiller LR. AGA technical review on the evaluation
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10. 11. 12. 13. 14. 15. 16. 17.
18.
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and management of chronic diarrhea. Gastroenterology 1999; 116:1464 – 86 (review). Dickinson RJ, Gilmour HM, McClelland BL. Rectal biopsy in patients presenting to an infectious disease unit with diarrhoeal disease. Gut 1979;20:141– 8. Patel Y, Pettigrew NM, Grahame GR, et al. The diagnostic yield of lower endoscopy plus biopsy in nonbloody diarrhea. Gastrointest Endosc 1997;46:338 – 43. MacIntosh DG, Thompson WG, Patel DG, et al. Is rectal biopsy necessary in irritable bowel syndrome? Am J Gastroenterol 1992;87:1407–9. Alkhatib O, Ferrentino N, Moses PL, et al. The incidence of microscopic colitis in patients with chronic unexplained diarrhea. Am J Gastroenterol 1998;93:AB294 (abstract). Fernandez-Banares F, Salas A, Forne M, et al. Incidence of collagenous and lymphocytic colitis: A 5-year populationbased study. Am J Gastroenterol 1999;94:418 –23. Marshall JB, Singh R, Diaz-Arias AA. Chronic, unexplained diarrhea: Are biopsies necessary if colonoscopy is normal? Am J Gastroenterol 1995;90:372– 6. Prior A, Lessells AM, Whorwell PJ. Is biopsy necessary if colonoscopy is normal? Dig Dis Sci 1987;32:673– 6. Carpenter HA, Tremaine WJ, Batts KP, et al. Sequential histologic evaluations in collagenous colitis: Correlations with disease behavior and sampling strategy. Dig Dis Sci 1992;37: 1903–9. Lazenby AJ, Yardley JH, Giardiello FM, et al. Lymphocytic (microscopic) colitis: A comparative histopathologic study with particular reference to collagenous colitis. Hum Pathol 1989;20:18 –28. Jessurun J, Yardley JH, Giardiello FM, et al. Chronic colitis with thickening of the subepithelial collagen layer (collagenous colitis): Histopathologic findings in 15 patients. Hum Pathol 1987;18:839 – 48. Badiali D, Marcheggiano A, Pallone F, et al. Melanosis of the rectum in patients with chronic constipation. Dis Colon Rectum 1985;28:241–5.
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21. Surawicz CM, Belic L. Rectal biopsy helps to distinguish acute self-limiting colitis from idiopathic inflammatory bowel disease. Gastroenterology 1984;86:104 –13. 22. Bogomoletz WV. Collagenous, microscopic, and lymphocytic colitis. An evolving concept. Virchows Arch 1994;424:573–9 (review). 23. Meisel JL, Bergman D, Graney D, et al. Human rectal mucosa: Proctoscopic and morphological changes caused by laxatives. Gastroenterology 1977;72:1274 –9. 24. Giardiello FM, Lazenby AJ, Bayless TM, et al. Lymphocytic (microscopic) colitis— clinicopathological study of 18 patients, and comparison to collagenous colitis. Dig Dis Sci 1989;34:1730 – 8. 25. Steer HW, Colin-Jones DG. Melanosis coli: Studies of the toxic effects of irritant purgatives. J Pathol 1975;115:199 – 205. 26. Palmer KR, Berry H, Wheeler PJ, et al. Collagenous colitis—a relapsing and remitting disease. Gut 1986;27:578 – 80. 27. Hanauer SB, Meyers S. Management of Crohn’s disease in adults. Am J Gastroenterol 1997;92:559 – 66 (review). 28. Rubin PH, Present DH. Differential diagnosis of chronic ulcerative colitis in Crohn’s disease of the colon. In: Kirsner JB, Shorter RG, eds. Inflammatory bowel disease, 4th ed. Baltimore: Williams & Wilkins, 1995:355–79. 29. Alkhatib O, Fisher JB, Callas P, et al. Sensitivity of flexible sigmoidoscopy vs. full colonoscopy for the diagnosis of microscopic colitis (collagenous and lymphocytic colitis): Metaanalysis of all published data. Am J Gastroenterol 1998;93: AB295 (abstract). 30. Matteoni C, Goldblum J, Brzezinski A, et al. Flexible sigmoidoscopy for the detection of microscopic colitis. Am J Med 2000;108:416 – 8. 31. Read NW, Krejs GJ, Read MG, et al. Chronic diarrhea of unknown origin. Gastroenterology 1980;78:264 –71. 32. Fine KD, Seidel RH, Do K. The prevalence, anatomic distribution, and diagnosis of colonic causes of chronic diarrhea. Gastrointest Endosc 2000;51:318 –26.
Vol. 96, No. 4, 2001 ISSN 0002-9270/01/$20.00 PII S0002-9270(01)02308-5
Usefulness of Colonoscopy With Biopsy in the Evaluation of Patients With Chronic Diarrhea Raj J. Shah, M.D., Cecilia Fenoglio-Preiser, M.D., Brian L. Bleau, M.D., and Ralph A. Giannella, M.D. Division of Digestive Diseases, Department of Internal Medicine and Department of Pathology, University of Cincinnati College of Medicine, Cincinnati, Ohio; and Tacoma Digestive Diseases, Tacoma, Washington
OBJECTIVE: Patients referred for chronic diarrhea frequently undergo endoscopic evaluation. There are limited data on the role for colonoscopy with biopsy and ileoscopy for patients with chronic diarrhea. METHODS: We reviewed the charts of 228 patients with chronic diarrhea evaluated by colonoscopy between November 1995 and March 1998. Chronic diarrhea was defined as loose, frequent bowel movements for a minimum of 4 wk. Patients were excluded if biopsies were not performed in normal colons, if they had undergone previous bowel surgery, a history of inflammatory bowel disease, HIV, or an inadequate colonoscopy. RESULTS: One hundred sixty-eight patients were included in the analysis, of whom 142 (85%) had ileoscopy. Colonoscopy and biopsy yielded a specific histological diagnosis in 52 (31%) patients. These included Crohn’s disease (9), ulcerative colitis (7), lymphocytic colitis (10), collagenous colitis (3), ischemic colitis (3), infectious colitis (6), and miscellaneous diseases (14). Ileoscopy yielded significant findings in 3% of patients (four with Crohn’s disease and one with infection). CONCLUSIONS: Colonoscopy and biopsy is useful in the investigation of patients with chronic diarrhea yielding a histological diagnosis in 31% of patients without a previous diagnosis. Ileoscopy complemented colonoscopy findings in a minority of patients with chronic diarrhea and was essential for a diagnosis in only two patients. (Am J Gastroenterol 2001;96:1091–1095. © 2001 by Am. Coll. of Gastroenterology)
INTRODUCTION Patients with chronic diarrhea often present a difficult diagnostic problem. Although colonoscopy is frequently performed in these patients, the usefulness of colonoscopy with biopsy in this setting is uncertain. The usefulness of endoscopy in the evaluation of diarrhea in patients with HIV has been well investigated (1–3). However, the decision to use Presented in part at Digestive Disease Week, May, 1999, Orlando, FL (Gastroenterology 1999;116:930); presented in part at the North American Conference of Gastroenterology Fellows, August, 1999, Vancouver, British Columbia; and presented in part at the Young Investigator’s Conference, April, 1999, Atlanta, GA.
endoscopy in the evaluation of non-HIV patients with chronic diarrhea is based on limited data and studies with various limitations. Colonoscopy with ileal intubation may be preferred to sigmoidoscopy for the detection of right-sided colitis, isolated ileitis, or in the case of pancolitis to distinguish Crohn’s disease from ulcerative colitis (4 – 8). However, this practice has not been prospectively evaluated (9). The available studies of endoscopy in chronic diarrhea have had variable inclusion criteria. These include the duration of the diarrhea (e.g., acute vs chronic), the extent of lower endoscopy, and in the case of microscopic or collagenous colitis whether random colonic biopsies (given the varied distribution of microscopic colitis) were performed (10 –12). The incidence of lymphocytic and collagenous colitis ranges from 5% to 9.5% of patients undergoing an evaluation for chronic diarrhea (13, 14). Such data support performing biopsies of normal mucosa when investigating chronic diarrhea (15). However, it has been suggested that biopsies of normal mucosa may be unnecessary, especially for patients who fit criteria for the irritable bowel syndrome (IBS) (12, 16). The purpose of this study was to investigate the diagnostic yield of total colonoscopy and biopsy with ileoscopy in non-HIV patients referred for unexplained chronic diarrhea.
MATERIALS AND METHODS This is a retrospective study of patients largely referred from primary care physicians and surgeons at the University of Cincinnati between November 1995 and March 1998 for an initial evaluation of chronic diarrhea. Both inpatient and outpatient evaluations were included. The endoscopy database was searched for colonoscopies performed for “unexplained” or “chronic diarrhea” and 228 such patients were found. Endoscopies were performed by fellows and attending faculty of the Division of Digestive Diseases. Colonoscopy reports included the extent of colitis (if present), associated symptoms, and the performance of random biopsies in the cases of normal mucosa. For the purposes of this study, endoscopic findings of polyps that were ⬍3 cm and without villous features were not considered causes of diarrhea. Pathology reports were reviewed. Outpatient charts
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Table 1. Associated Findings of Patients With Chronic Diarrhea Abdominal pain: 43%* Rectal bleeding: 27% Anemia: 15%† Weight loss: 9%‡ * Any location. † Defined as hemoglobin ⬍14 g/dl in men and ⬍13 g/dl in women. ‡ Weight loss reported by the patient.
were reviewed to confirm the duration of the diarrhea and to obtain final diagnoses in those patients in whom colonoscopy findings were normal or nonspecific. Stool study results were available by retrospective review in only a minority of patients. The information collected was manually recorded in a table format. Chronic diarrhea was defined as loose, frequent bowel movements of at least 4 wk duration that was a clear change from the patient’s baseline. Patients were excluded if they had 1) a prior diagnosis of idiopathic inflammatory bowel disease; 2) prior intestinal surgery; 3) known infection with the HIV type 1; 4) no random biopsies performed in a grossly normal colon; 5) an incomplete colonoscopy or inadequate prep; and 6) prior colonoscopy for diarrhea. Endoscopic examination was performed with videocolonoscopes. Biopsy specimens were collected from areas of gross endoscopic abnormalities or from areas of normalappearing mucosa in those examinations without any abnormalities. A single expert GI pathologist (CF-P) reviewed all abnormal histology in a blinded fashion. Lymphocytic colitis (microscopic colitis), collagenous colitis, melanosis coli, and acute self-limited colitis have previously been shown to have specific histological features (17–22). However, the term nonspecific colitis is used to indicate chronic inflammation of the lamina propria for which an etiology cannot be determined by histological examination. Final clinical diagnoses in these cases and in patients with normal histology were obtained from their outpatient charts.
RESULTS Between November 1995 and March 1998, a total of 228 patients underwent colonoscopy at University Hospital for an evaluation of chronic diarrhea. These records were re-
Table 2. Specific Histological Diagnoses by Colonoscopy With Biopsy and Ileoscopy Diagnosis
Number of Cases
Lymphocytic colitis Crohn’s disease Ulcerative colitis Melanosis coli Infection Collagenous colitis Ischemic colitis Acute self-limited colitis Rectal tubulovillous adenoma Radiation colitis Eosinophilic colitis NSAID-associated colitis Total
10 9 7 7 6 3 3 3 1 1 1 1 52
viewed. Sixty patients were excluded for the following reasons: 19 patients had HIV, 14 patients had normal colonoscopy without random biopsies being taken, 11 patients had prior intestinal surgery, five patients had incomplete examinations, four patients had a known diagnosis of inflammatory bowel disease, three patients had unavailable pathology results, two patients did not have chronic diarrhea (as defined above), and two patients had repeat examinations. The final study group consisted of 168 patients with an age range of 22– 86 yr, with a mean age of 51 yr. One hundred fourteen patients (68%) were women. Associated findings are recorded in Table 1. Ileal intubation was achieved in 142 patients (85%) and biopsies of the ileum were obtained in 83 patients (59% of patients who had ileal intubation). Eighty-nine patients (53%) also underwent upper endoscopy with distal duodenal biopsy. In the 168 study patients, 52 patients (31%) had a specific histological diagnosis; 15 patients (8.9%) had a histological diagnosis of nonspecific colitis, and the remaining 101 patients (60%) had normal colon histology (Fig. 1). The specific histological diagnoses are listed in Table 2. Ileal histology was helpful in five patients (or 6% of patients who had ileal biopsy). Four patients had Crohn’s disease by biopsy of the ileum, but only one had isolated ileitis. One cardiac transplant patient had cytomegalovirus (CMV) in-
Figure 1. The number of study patients with specific histological diagnoses, nonspecific colitis, and normal histology.
AJG – April, 2001
Colonoscopy and Patients With Chronic Diarrhea
Table 3. Final Diagnoses for Patients With Nonspecific Colitis Diagnoses
Number of Cases
Irritable bowel syndrome Alcohol associated Chemotherapy associated NSAID associated Lactose intolerance GI sarcoid
6 1 1 1 1 1
fection diagnosed only by ileal biopsy. Infections diagnosed by endoscopy included four patients with CMV infection (all in posttransplant patients) and two patients with pseudomembranous colitis. Of the seven patients with melanosis coli, five had macroscopically abnormal endoscopies. Final diagnoses established by long-term follow-up of patients with nonspecific colitis were obtained in 11 patients (or 73% of patients with nonspecific colitis) and are listed in Table 3. One-half of these were thought to be IBS. Follow-up clinical diagnoses, or whether resolution of diarrhea occurred in those patients with normal histology, were obtained in 84 patients (or 83% of patients with normal histology). Fifty-six percent had a final diagnosis of IBS, 12% had spontaneous resolution of their diarrhea, 6% had a specific infection (two patients had Clostridium difficile, one had “chronic traveler’s diarrhea” for the lack of a better term as the patient was a frequent international traveler and whose diarrheal episodes responded to metronidazole and cipro but a specific etiological agent could not be found, one had Blastocystis hominis and the diarrhea responded to a course of metronidazole, and one posttransplant patient had presumptive CMV as the diarrhea resolved after ganciclovir therapy for CMV of the liver), and the remaining 26% had a scattering of assorted diagnoses. These are listed in Table 4. Sixty-five of the 116 patients (56%) with normal histology or nonspecific colitis on colonoscopy had distal duodenal biopsies. Two patients had mild villous atrophy. One had spontaneous resolution of diarrhea and the other was lost to follow-up. One patient with moderate villous atrophy had Table 4. Final Diagnoses for Patients With Normal Histology Follow-up
Number of Cases
Irritable bowel syndrome Spontaneous resolution Infection Diabetic diarrhea Lactose intolerance Fecal incontinence Ischemic colitis Pancreatic insufficiency Crohn’s disease Bacterial overgrowth GI sarcoid Antibiotic associated Alcohol associated Medication associated Total
47 10 5 4 3 3 2 2 2 2 1 1 1 1 84
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coexistent lymphocytic colitis and the diarrhea responded to sulfasalazine. There were no complications reported as a result of endoscopy and biopsy in the 228 records reviewed.
DISCUSSION Although routinely performed, there is little data on the usefulness of total colonoscopy in the evaluation of chronic diarrhea. In our study, a specific histological diagnosis could be made in 52 patients or 31% of the patients studied. Fourteen of these 52 patients (or 27% of patients with a diagnosis made by biopsy) had grossly normal-appearing mucosa on endoscopy but significant histopathology (Crohn’s disease [1], lymphocytic colitis [9], collagenous colitis [1], melanosis coli [2], CMV ileitis [1]). These findings emphasize the importance of performing random biopsies in macroscopically normal colons. Ileal biopsy was essential in making a diagnosis in two patients. One patient had a grossly normal ileum (CMV infection) and the other had isolated ileal Crohn’s disease. Ileoscopy complemented colonoscopy in three additional patients (pancolitis, patchy areas of colitis, and a grossly normal colon but histologically consistent with Crohn’s disease, respectively). As previously reported, ileal intubation may give clinically useful information for patients with chronic diarrhea (5, 6). After blinded review of all abnormal biopsies by our pathologist, three cases of nonspecific colitis, one case of melanosis coli, and one case of chemotherapy-associated colitis were reclassified as lymphocytic colitis. These are reflected in the data presented. Only one of the 10 patients with lymphocytic colitis had an increase in erythema described in the left colon. Two of the three patients with collagenous colitis had increased erythema in the left colon. Whether these endoscopic changes are attributable to bowel preparation is uncertain (23, 24). Those patients with melanosis coli were suspected to have surreptitious ingestion of laxatives. Although melanosis may be seen in patients with chronic constipation, our patients’ indication for endoscopy was diarrhea (20, 25). Only three of the patients admitted to laxative use, whereas two patients, who denied laxative abuse, had spontaneous resolution of their symptoms on subsequent follow-up. Prior et al. (16) reported on 100 consecutive patients with macroscopically normal colons and random biopsies and found significant pathology in 22% of the patients. Their slightly lower percentage of findings may be explained by the fact that only one-half of their patients had diarrhea. Patel et al. (11) reported the use of lower endoscopy in nonbloody diarrhea and found a diagnostic yield of 18% in 205 patients studied. This figure is much lower than our yield of 31%. Their study differed from ours in that they included patients with both acute and chronic diarrhea and excluded patients with rectal bleeding. In addition, more than one-third of their patients had sigmoidoscopy alone;
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therefore, right-sided colitis and ileitis may have been missed (4 – 6). Furthermore, patients with abdominal pain were excluded in an attempt to differentiate organic diarrhea from IBS. Although nonspecific, abdominal pain may be a significant feature of IBS and collagenous colitis, and these entities should be excluded before diagnosing a patient with IBS (26 –28). Marshall et al. (15) failed to identify any cases of lymphocytic or collagenous colitis in 111 patients with chronic diarrhea who had macroscopically normal colons with random biopsies. They concluded that biopsies be reserved for those patients with debilitating symptoms. However, approximately one-third of their patients had sigmoidoscopy alone. Given the variable distribution of microscopic colitis and collagenous colitis, some cases may have been missed with left-sided biopsy alone (17, 29). Furthermore, more recent data reveal a higher incidence of these colitides in large population studies (13, 14). As a result of the majority of the endoscopists performing colonoscopy in this study placing all specimens into one jar in an attempt to conserve costs, we cannot comment on which specimen (e.g., cecum or sigmoid colon) specifically made the diagnosis. However, we recommend obtaining two specimens from the cecum, hepatic flexure, transverse colon, sigmoid colon, and rectum. Recent data, however, suggest that left-sided sampling may be sufficient in the majority of cases (29, 30). A significant percentage (31%) of our patients with normal or nonspecific colitis were subsequently diagnosed with IBS. These findings are consistent with those of Read et al. (31) who reported that eight of 27 patients (30%) who underwent an extensive evaluation for chronic diarrhea were found to have the IBS. In our study, 10 additional patients with normal histology had spontaneous resolution of their diarrhea. Six patients with nonspecific colitis had the diagnosis of IBS on follow-up. Although colonic inflammation is contradictory to established criteria, an intercurrent illness cannot be excluded (12). The subsequent diagnosis of Crohn’s disease in two patients was discovered on repeat colonoscopy within 2 yr of the initial colonoscopy. Distal duodenal biopsies were not systematically done, only one-half of our patients underwent distal duodenal biopsy. Thus, recommendations on its routine use in evaluating patients with chronic diarrhea cannot be made. Most recently, Fine et al. (32) reported on 809 non-HIV patients at a major referral center for diarrheal illnesses who underwent colonoscopy for chronic diarrhea. This was a retrospective study, but the established biopsy protocol permitted the distinction of “left-sided” and “right-sided” specimens. Fifteen percent of the study population was found to have colonic histopathology. Sixty-six percent (80 of 122 patients with diagnoses) were found to have microscopic colitis reflecting their highly referred population. They concluded that more than 99% of all diagnoses could have been made by left-sided biopsy (e.g., within the reach of the sigmoidoscope) alone. Twenty-three patients (19% of the total patients with histopathology) had Crohn’s disease,
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which they believed could be diagnosed by left-sided biopsy alone. It is somewhat surprising that the diagnosis of Crohn’s disease could be made with certainty in all 23 cases by left-sided examination alone. The higher yield for histopathology in our study is likely a reflection of a predominantly primary care population undergoing an initial evaluation for unexplained diarrhea and our inclusion of patients with associated hematochezia. In conclusion, this study reports on the usefulness of colonoscopy with biopsy in the evaluation of non-HIV patients with chronic diarrhea. Ileoscopy may complement, or less commonly, make the diagnosis for patients with chronic diarrhea. A significant number of patients (56% of patients with final diagnoses) were determined to have IBS. It could be argued that in cases where IBS is suspected, a normal colonoscopy helps exclude organic pathology. Thus, our report of histological diagnoses is likely an underestimate of the clinically useful information obtained from colonoscopy. Our study is retrospective and the inability to have a uniform selection process for study patients could have influenced the results. Prospective studies may be necessary to assess the yield and cost-effectiveness of colonoscopy versus sigmoidoscopy in non-HIV patients with chronic diarrhea (9). Reprint requests and correspondence: Ralph A. Giannella, M.D., Division of Digestive Diseases, University of Cincinnati Medical Center, 231 Bethesda Ave., ML 0595, Cincinnati, OH 45267-0595. Received May 24, 2000; accepted Oct. 6, 2000.
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