Colonic motility and functional diarrhea

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GASTROENTEROLOGY Vol. 102, No. 4

possibility that pentane can also be formed by colonic bacterial flora, especially in patients with fat malabsorption. M. HIELE Y. GHOOS P. RUTGEERTS G. VANTRAPPEN Center for Gastrointestinal LJZ Gasthuisberg B-3000 Leuven, Belgium

Research

1. Lemoyne M, Van Gossum A, Kurian R and Jeejeeboy KN. Plasma vitamin E and selenium and breath pentane in home parenteral nutrition patients. Am J Clin Nutr 1988;48:13101315.

Azathioprine or 6-Mercaptopurine Therapy and Colon Carcinoma in Crohn’s Disease Dear Sir: We read with great interest the recent report of O’Brien et al.’ on the use of azathioprine or 6-mercaptopurine in patients with Crohn’s disease. We were intrigued by their 33-year-old patient in whom carcinoma of the cecum developed after 4.5 years of treatment with azathioprine. Only limited information is available about carcinoma of the colon in patients with Crohn’s disease,’ and even less is known about the possible association between the incidence of carcinoma of the colon and the use of azathioprine or 6-mercaptopurine. We retrospectively reviewed records of 26 patients in whom adenocarcinoma of the colon developed in association with Crohn’s disease among 3124 patients seen at the Lahey Clinic for Crohn’s disease between 1957 and 1991. Of the 26 patients, 2 were given azathioprine before carcinoma of the colon developed. A total of 5 patients had metastatic carcinoma of the colon, including these 2 patients. This finding is of interest because azathioprine and 6-mercaptopurine have been used rarely in our institution until recently. It is difficult to ascertain the role of immunosuppression in the development of carcinoma of the colon in patients with Crohn’s disease, particularly given the small number of patients and the known risk of the development of carcinoma of the colon in patients with Crohn’s disease.’ However, given the potential long term mutagenicity and carcinogenicity3 and the possible association between azathioprine or 6-mercaptopurine and extraintestinal malignant processes,4 we believe this possibility should be kept in mind when treating patients with azathioprine or 6-mercaptopurine. MICHAEL P. ZELIG, M.D. PAUL M. CHOI, M.D. Department of Gastroenterology Lahey Clinic Medical Center 41 Mall Road Burlington, Massachusetts 01805 O’Brien JJ, Bayless TM, Bayless JA. Use of azathioprine or 6-mercaptopurine in the treatment of Crohn’s disease. Gastroenterology 1991;101:39-46. Gyde SN. Cancer risk in Crohn’s disease. In: Allan RN, Keighley MRB, Alexander-Williams J, Hawkins C, eds. Inflammatory Bowel Diseases. 2nd ed. Edinburgh: Churchill Livingstone, 1990:575-580. Goldstein F. Immunosuppressant therapy of inflammatory bowel disease: pharmacologic and clinical aspects, J Clin Gastroenterol 1987;9:654-658. Present DH. 6-Mercaptopurine and other immunosuppressive agents in the treatment of Crohn’s disease and ulcerative colitis. Gastroenterol Clin North Am 1989;18:57-71.

Reply. Drs. Zeligand Choi raise several important issues in reference to Crohn’s disease and neoplasms. Our article,’ referred to a 33-year-old patient with a 30-year history of Crohn’s disease of the colon (onset age 3) who developed cancer of the cecum 4.5 years after the institution of azathioprine therapy. There was dysplasia in the right colon and cecum. Since then another patient (a 49-year-old man) who received azathioprine intermittently for 3 years developed adenocarcinoma in a perianal fistula. There was no dysplasia in the rectum or colon. He had had Crohn’s disease of the ileum since age 15. The peri-rectal disease was only known for 3 years. One issue involves the prevalence of dysplasia and cancer in the small bowel and colon of patients with Crohn’s disease.’ Presumably, if we can extrapolate from ulcerative colitis, those patients with extensive disease and with childhood onset will be at greatest risk. This is a presumption, not yet based on data. Perhaps our two patients were at already increased risk. Is dysplasia and colon cancer frequent enough to warrant surveillance for dysplasia? The second issue is factors that may increase the risk of cancer development. This question will probably require a registry of all patients at risk to separate out extent, age of onset, radiation exposure via diagnostic radiation, as well as medications and other therapeutic maneuvers. We do not, at this time, have enough data to incriminate immunomodulator medications in colon cancer development in Crohn’s disease. In terms of ulcerative colitis, some physicians including ourselves, have empirically taken the position of not starting immunomodulators for patients with unresponsive or steroid dependent disease if the duration of colitis is over 8-10 years. We do not have firm data for that position in terms of ulcerative colitis, and we have even less information on Crohn’s disease. Our experience with the two patients cited above has led me to try to minimize immunomodulator medications in patients with long duration Crohn’s disease of the colon, especially with childhood/ teenage onset. I’ve also begun to perform ileo-colonic dysplasia surveillance on a regular basis in such patients when feasible. Again, this is empiric. There is a definite need for data. It is my understanding that Burroughs-Welcome, the manufacturers of azathioprine and 6 mercaptopurine financially assist in the maintenance of a registry of patients with rheumatoid arthritis to get data on neoplasia development. Azathioprine has been approved by the FDA for use in rheumatoid arthritis. It is my understanding that no such IND has been requested for Crohn’s disease and ulcerative colitis. Perhaps the Crohn’s Colitis Foundation of America (formerly The National Foundation for Ileitis and Colitis) should assist (or lead) in the maintenance of a confidential registry of all patients with inflammatory bowel disease. This would aid in determining if very useful medicines such as azathioprine do, in fact, increase the risk for various neoplasms, including colon cancer. THEODORE M. BAYLESS,M.D. Meyerhoff Digestive Disease-InjIammatory Bowel Disease Center The Johns Hopkins University School ofMedicine Baltimore, Maryland 21205 1. O’Brien JJ, et al. Use of Azathioprine

or 6-Mercaptopurine in the Treatment of Crohn’s Disease 2. Hamilton SR. Colorectal carcinoma in patients with Crohn’s disease. Gastroenterology 1985;89:398-407.

Colonic Motility and Functional

Diarrhea

Dear Sir: We read with interest the paper by Bazzocchi et al.,’ which correlates colonic motility with transit in 8 patients with func-

April 1992

tional diarrhea compared with 12 healthy subjects. Transit of the luminal contents was measured by following the movement of gsmTC-diethylenetriaminepentaacetic acid instilled as a bolus in the splenic flexure. Intraluminal pressures were measured with perfused catheter ports. This paper suggests that in patients with diarrhea the fluctuation of marker in both transverse and sigmoid colon during fasting and postprandial periods is associated with a decrease of nonsegmenting contractions and more frequent propagating contractions. The authors conclude that a colonic disorder consisting of an increased number of propagating contractions may cause diarrhea, which does not require abnormalities of secretion and absorption, and found supporting evidences in previously reported effects of laxatives on colonic motility. Four years ago, we published* the results of a study of colonic myoelectrical activity performed in 23 patients with painless diarrhea and compared with a control group of 10 healthy subjects. We observed a striking difference in colonic response to eating, with an increased number of migrating long spike bursts (MLSB; mass movements) during the first postprandial hour in diarrhea1 patients compared with controls (P < O.OOl), while short spike bursts (SSB; segmental activity) were almost absent in the rectosigmoid area. Moreover a marked decrease in the number of retrograde LSB activity was observed in some diarrhea1 patients (8/23). Our results, similar to those recently observed by Bazzochi et al., suggest that a colonic disorder consisting of an increased number of propagating contractions and decreased segmenting contractions, involving especially the sigmoid brake, may cause diarrhea. In another study concerning the effects of sennosides on myoelectric colonic activity in man,3 we described a significant increase of peristaltic activity (MLSB) after sennosides (30 mg one day] which occurred between 6-12 hours after oral administration, the normal delay required for oro-caecal transit and metabolism of the drug.

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We wish to bring these results to the attention of Bazzocchi et al. and regret that, unfortunately, these two previous descriptions of similar results were not mentioned in their article. J. FREXINOS,

M.D.

Service of Gastroenterology and Nutrition Centre Hospitalier Universitaire Rangueil Toulouse, France L. BUENO, PH.D. J. FIORAMONTI, PH.D.

Department of Pharmacology INRA Toulouse, France Bazzocchi G, et al. Effect of eating on colonic motility and transit in patients with functional diarrhea. Gastroenterology 1991;101:1298-1306. Frexinos J, Fioramonti J, Bueno L. Colonic myoelectrical activity in IBS painless diarrhea. Gut 1987;28:1613-1618. Frexinos J, Staumont G, Fioramonti J, Bueno L. Effects of sennosides on colonic myoelectrical activity in Man. Dig Dis and Sci 1989;34:214-219. Reply. We thank the authors for their interest in our paper. Although the article on sennoside was included, we are sorry we inadvertently omitted their report from our reference list. Our study showed that propagating contractions could transport intraluminal contents, which is an extention of your earlier studies. WILLIAM J. SNAPE, JR., M.D. 2650

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