- Email: [email protected]
Colorectal Cancer in Patients With Ulcerative Colitis
GASTROENTEROLOGY 1988;95:1692-700
CORRESPONDENCE Readers are encouraged to write Letters to the Editor concerning articles that have been published in GASTROENTEROLOGY. Short, general comments are also considered, but use of the Correspondence Section for publication of original data in preliminary form is not encouraged. Letters should be typewritten double-spaced and submitted in triplicate.
Sphincterotomy and Passage of Glass Beads Dear Sir: The recent excellent paper by Hutton et al. (1) shows that eliminating the sphincter of Oddi in dogs facilitates the passage of prosthetic gallstones (glass beads) and increases gallbladder emptying. It is unclear whether these results can be expected if extrapolated to cholesterol gallstone disease. In the Richardson ground squirrel fed a 1% cholesterol diet, gallbladder contractility decreases 44% as cholesterol saturation rises and is inhibited 62% once cholesterol stones develop (2). The additional decrease in contractility of 18% with the appearance of gallstones is quite similar to the 20% inhibition of gallbladder motility produced by implanting three 3-mm glass beads in the gallbladder of guinea pigs (3). Although no inflammatory changes occurred in these animal models, chronic inflammation is characteristic of the dog gallbladder after sphincterotomy, (4) and would likely impair gallbladder contractility. In humans with cholelithiasis, gallbladder emptying is frequently abnormal (5-9). As for patients undergoing gallstone dissolution with bile acids, gallbladder emptying increases 36% once dissolution is complete (10). Even bile acid administration per se depresses gallbladder function (7,10). Thus cholesterol gallstone disease, the physical presence of the stones, and therapy with bile acids all impair gallbladder contractility and emptying. Although sphincterotomy will probably enhance gallbladder emptying even under conditions of decreased contractility, eliminating sphincteric resistance also decreases the proportion of hepatic bile that fills the gallbladder during fasting (11). Which will be of greater importance in dictating eventual gallstone formation/dissolution is unknown. A knowledge of the effect(s) of sphincterotomy and altered gallbladder emptying also relates to the further improvement of the novel regimens being developed for treating cholesterol gallstones: fragmentation by biliary lithotripsy and rapid dissolution with contact solvents frequently leave fragments and residue behind. The impact of these nonsurgical approaches on gallbladder function also needs urgent assessment. Their evaluation should provide patients with a new site of passage, safely ridding the body of gallstones. ELDON A. SHAFFER, M.D.
Department of Medicine Gastrointestinal Research Group University of Calgary Health Sciences Centre 3330 Hospital Drive N.W. Calgary, Alberta, Canada T2N 4Nl 1. Hutton SW, Sievert CE, Vennes JA, Shaffer RB, Duane WC. Spontaneous passage of glass beads from the canine gallbladder: facilitation by sphincterotomy. Gastroenterology 1988; 94:1031-5. 2. Fridhandler TM, Davison JS, Shaffer EA. Defective gallbladder contractility in the ground squirrel and prairie dog during the early stages of cholesterol gallstone formation. Gastroenterology 1983;85:830-6. 3. Pomeranz IS, Davison JS, Shaffer EA. The effects of prosthetic gallstones on gallbladder function and bile composition. J Surg Res 1986;41:47-52.
4. Cohn MS, Schwartz SI, Faloon WW, Adams JT. Effect of sphincteroplasty on gallbladder function and bile composition. Ann Surg 1979;189:317-21. 5. Shaffer EA, McOrmond P, Duggan H. Quantitative cholescintigraphy: assessment of gallbladder filling and emptying and duodenogastric reflux. Gastroenterology 1980;79:899-906. 6. Fisher RS, Stelzer F, Rock E, Malmud LS. Abnormal gallbladder emptying in patients with gallstones. Dig Dis Sci 1982;27: 1019-24. 7. Forgacs IC, Maisey MN, Murphy GM, Dowling RH. Influence of gallstones and ursodeoxycholic acid therapy on gallbladder emptying. Gastroenterology 1984;87:299-307. 8. Pomeranz IS, Shaffer EA. Abnormal gallbladder emptying in a subgroup of patients with gallstones. Gastroenterology 1985; 88:787-91. 9. Thompson JC, Fried GM, Ogden WD, et al. Correlation between the release of cholecystokinin and contraction of the gallbladder in patients with gallstones. Ann Surg 1982;195: 670-6. 10. Sylwestrowicz TA, Shaffer EA. Gallbladder function during gallstone dissolution. Effect of bile acid therapy in patients with gallstones. Gastroenterology 1988;95:740-8. 11. Scott RB, Eidt PB, Shaffer EA. Regulation of fasting duodenal bile acid delivery by sphincter of Oddi and gallbladder. Am J Physiol 1985;249:G622-33.
Colorectal Cancer in Patients With Ulcerative Colitis Dear Sir: Gilat et al. (1) have to be congratulated for adding an important piece of information about colorectal cancer in ulcerative colitis in the population of central Israel. The figures differ among populations and have to be investigated, as suggested by the authors, in each country separately, and compared with the expected risk in that population. We, as others, showed (2,3) that the extent of the inflammatory process in ulcerative colitis cannot be assessed accurately with barium enema, and that the macroscopic view in colonoscopy is somewhat inferior to the microscopic evaluation. In a recent paper (4) we demonstrated significant change of the disease extent in 77% of our patients. The histologic extent exceeded the macroscopic extent in 28%. In 45% of the patients with proctitis we found extension (in 18% to the right colon!). The results of Gilat et al. for all cases are valid, and may represent faithfully the cancer risk in Jewish patients with ulcerative colitis in central Israel; but separation according to disease extent is probably inaccurate and nonrevealing because of the following points. 1. In only 400 patients (of 1035) was colonoscopy performed. In the other 635 patients disease extent was demonstrated by sigmoidoscopy and barium enema, which are not satisfying in most of the cases. To my best knowledge most of the barium enemas performed in Israel during the study period (19701980) were single contrast, which is a poor and inaccurate method for extent evaluation (2). 2. The extent of disease was not confirmed histologically.
December 1988
3. "If the extent of disease varied during follow-up, the greatest observed extent was used .... " It must be noted that significant variations of disease extent are frequently met during the follow-up period. Thus, in my opinion, the statement by Gilat et al. that "The cancer incidence rose with ... extent of disease ... " and their recommendation that "Surveillance is not indicated in patients with proctitis ... " have to be read with caution. YARON NIV, M.D.
Gastrointestinal Research Laboratory Veterans Administration Medical Center 4150 Clement Street San Francisco, California 1. Gilat T, Fireman Z, Grossman A, et al. Colorectal cancer in patients with ulcerative colitis. A population study in central Israel. Gastroenterology 1988;94:870-7. 2. Niv y, Bat L, Hurwitz A, et al. The role of colonoscopy in diagnosis of the inflammatory process in ulcerative colitis. Harefuah 1981;101:355-6. 3. Gabrielsson N, Granquist S, Sundelin P, et al. Extent of inflammatory lesions in ulcerative colitis assessed by radiology, colonoscopy and endoscopic biopsy. Gastrointest Radiol 1979;4:395-400. 4. Niv Y, Bat L, Theodor E. Change in the extent of the inflammatory extent in ulcerative colitis. Am J GastroenteroI1987;82: 1046-51. Reply. Dr. Niv draws attention to an important and little noted aspect of ulcerative colitis, namely the variations in the extent of disease with time. It used to be thought that the extent of disease remained constant or increased, and hardly ever decreased (1). In the colonoscopic era it became apparent that changes in extent occur rather frequently and in both directions. Dr. Niv and coworkers (2) have shown changes in the extent of disease in 77% of 33 patients studied by repeated colonoscopies and biopsies. We evaluated this problem using the 1035 patients with ulcerative colitis included in our population study in central Israel (3). In 157 patients two or more colonoscopies were performed at least 1 yr apart during active stages of the disease (Grossman A, unpublished results). Changes in extent were found in 61% of the patients. In 40% the extent increased and in 21 % it decreased. We thus agree with Dr. Niv that the extent of inflamed mucosa in ulcerative colitis is not constant and has to be periodically reevaluated, preferably by colonoscopy. Nevertheless, we feel quite confident about our findings that the risk of colorectal cancer increases with the extent of inflamed mucosa (3). The risk is minimal in patients with proctitis and maximal in patients with total colitis. This has been found in almost all investigations, both in major medical centers (4) and population studies (5). As far as population studies are concerned, ours is one of the few in which a considerable proportion of the patients had colonoscopies (400 of 1035). In most studies, including recent ones (5), the extent of disease was based on barium enema findings. Despite these reservations, the general conclusion that the cancer risk in patients with ulcerative colitis increases with extent (and duration) of disease seems valid. T. GILAT, M.D. A. GROSSMAN, M.D. Z. FIREMAN, M.D.
Department of Gastroenterology Ichilov Hospital and Tel Aviv University Tel Aviv, Israel
CORRESPONDENCE
1693
1. Goligher JC, de Dombal ET, Watts J McK, Watkinson G. Ulcerative colitis. London: Balliere Tindall & Cassell, 1969. 2. Niv Y, Bat L, Theodor E. Change in the extent of the inflammatory extent in ulcerative colitis. Am J GastroenteroI1987;82: 1046-51. 3. Gilat T, Fireman Z, Grossman A, et al. Colorectal cancer in patients with ulcerative colitis. A population study in central Israel. Gastroenterology 1988;94:870-7. 4. Devroede G. Risk of cancer in inflammatory bowel disease. In: Winawer S, Schottenfeld D, Sherlock p, eds. Colorectal cancer: prevention, epidemiology, and screening. New York: Raven, 1980:325-34. 5. Brostrom 0, Lofberg R, Nordenval B, Ost A, Hellers G. An epidemiological study of the risk for development of colorectal cancer in patients with ulcerative colitis. Scand J Gastroenterol (in press).
Should We Let Sleeping PEGs Lie? Dear Sir: The article by Schiller et al. (1) is most interesting and provocative, as it shows how little we know about commonly used preparations. Most lavage bowel preparation compounds based on a balance of polyethylene glycol (PEG) and electrolytes are considered to be isotonic (2). In their article, Schiller et al. have demonstrated that the measurement of osmolality by currently available methods is inaccurate in vitro, and in vivo can only be drawn by inference when PEG is present in solution. While investigating intraluminal colonic antigens we became interested in the effect of PEG in colonic effluent on enzymelinked immunosorbent. assay using antibodies against tumorassociated antigens. The in vitro addition of PEG to colonic effluent, collected by a laxative-purge method, reduces the sensitivity of the enzyme-linked immunosorbent assay (unpublished results). When we sought to confirm that colonic effluent collected after administration of a PEG-electrolyte solution contains similar amounts of PEG to that added in vitro, we were puzzled to find higher than expected values. The PEG estimations were performed according to the method of Malawer (3). To further clarify this question, we performed the following in vivo experiments. Three patients with a defunctioned distal loop colonostomy routinely underwent colonoscopy before surgical reconstitution. A precolostomy infusate of a conventional PEGelectrolyte solution was administered (PEG concentration 59 giL) and the resultant rectal lavage fluid was aspirated. The mean PEG concentration so measured was 46.8 giL. However, the mean PEG concentration from rectal effluent in 6 patients prepared orally by a PEG-electrolyte solution was 122.4 giL, an almost threefold difference. The reasons for this finding still await elucidation. It would be interesting to know what concentration of PEG Schiller et al. found in their study when using a PEG-electrolyte solution containing 105 g of PEG per liter. In addition to its effect on electrolytes and osmolality, PEG has a plethora of actions on proteins. These include stabilization (4), alteration of immunologic properties (5), activation of a prosthetic enzyme moiety (6), and an effect on binding to plastic plates (7). The mechanisms of these interactions have been discussed (8) and seem to have their basis in PEG acting as a salting-out agent, causing preferential hydration of the protein. As colonic effluent may contain significant amounts of protein (9), which also contribute to osmolality, the effects on effluent osmolality due to PEG might be compounded. The failure to demonstrate appreciable toxicity of PEGelectrolyte solution preparations should not exclude research efforts to delineate the enigmatic actions of PEG on osmolality,
CORRESPONDENCE Readers are encouraged to write Letters to the Editor concerning articles that have been published in GASTROENTEROLOGY. Short, general comments are also considered, but use of the Correspondence Section for publication of original data in preliminary form is not encouraged. Letters should be typewritten double-spaced and submitted in triplicate.
Sphincterotomy and Passage of Glass Beads Dear Sir: The recent excellent paper by Hutton et al. (1) shows that eliminating the sphincter of Oddi in dogs facilitates the passage of prosthetic gallstones (glass beads) and increases gallbladder emptying. It is unclear whether these results can be expected if extrapolated to cholesterol gallstone disease. In the Richardson ground squirrel fed a 1% cholesterol diet, gallbladder contractility decreases 44% as cholesterol saturation rises and is inhibited 62% once cholesterol stones develop (2). The additional decrease in contractility of 18% with the appearance of gallstones is quite similar to the 20% inhibition of gallbladder motility produced by implanting three 3-mm glass beads in the gallbladder of guinea pigs (3). Although no inflammatory changes occurred in these animal models, chronic inflammation is characteristic of the dog gallbladder after sphincterotomy, (4) and would likely impair gallbladder contractility. In humans with cholelithiasis, gallbladder emptying is frequently abnormal (5-9). As for patients undergoing gallstone dissolution with bile acids, gallbladder emptying increases 36% once dissolution is complete (10). Even bile acid administration per se depresses gallbladder function (7,10). Thus cholesterol gallstone disease, the physical presence of the stones, and therapy with bile acids all impair gallbladder contractility and emptying. Although sphincterotomy will probably enhance gallbladder emptying even under conditions of decreased contractility, eliminating sphincteric resistance also decreases the proportion of hepatic bile that fills the gallbladder during fasting (11). Which will be of greater importance in dictating eventual gallstone formation/dissolution is unknown. A knowledge of the effect(s) of sphincterotomy and altered gallbladder emptying also relates to the further improvement of the novel regimens being developed for treating cholesterol gallstones: fragmentation by biliary lithotripsy and rapid dissolution with contact solvents frequently leave fragments and residue behind. The impact of these nonsurgical approaches on gallbladder function also needs urgent assessment. Their evaluation should provide patients with a new site of passage, safely ridding the body of gallstones. ELDON A. SHAFFER, M.D.
Department of Medicine Gastrointestinal Research Group University of Calgary Health Sciences Centre 3330 Hospital Drive N.W. Calgary, Alberta, Canada T2N 4Nl 1. Hutton SW, Sievert CE, Vennes JA, Shaffer RB, Duane WC. Spontaneous passage of glass beads from the canine gallbladder: facilitation by sphincterotomy. Gastroenterology 1988; 94:1031-5. 2. Fridhandler TM, Davison JS, Shaffer EA. Defective gallbladder contractility in the ground squirrel and prairie dog during the early stages of cholesterol gallstone formation. Gastroenterology 1983;85:830-6. 3. Pomeranz IS, Davison JS, Shaffer EA. The effects of prosthetic gallstones on gallbladder function and bile composition. J Surg Res 1986;41:47-52.
4. Cohn MS, Schwartz SI, Faloon WW, Adams JT. Effect of sphincteroplasty on gallbladder function and bile composition. Ann Surg 1979;189:317-21. 5. Shaffer EA, McOrmond P, Duggan H. Quantitative cholescintigraphy: assessment of gallbladder filling and emptying and duodenogastric reflux. Gastroenterology 1980;79:899-906. 6. Fisher RS, Stelzer F, Rock E, Malmud LS. Abnormal gallbladder emptying in patients with gallstones. Dig Dis Sci 1982;27: 1019-24. 7. Forgacs IC, Maisey MN, Murphy GM, Dowling RH. Influence of gallstones and ursodeoxycholic acid therapy on gallbladder emptying. Gastroenterology 1984;87:299-307. 8. Pomeranz IS, Shaffer EA. Abnormal gallbladder emptying in a subgroup of patients with gallstones. Gastroenterology 1985; 88:787-91. 9. Thompson JC, Fried GM, Ogden WD, et al. Correlation between the release of cholecystokinin and contraction of the gallbladder in patients with gallstones. Ann Surg 1982;195: 670-6. 10. Sylwestrowicz TA, Shaffer EA. Gallbladder function during gallstone dissolution. Effect of bile acid therapy in patients with gallstones. Gastroenterology 1988;95:740-8. 11. Scott RB, Eidt PB, Shaffer EA. Regulation of fasting duodenal bile acid delivery by sphincter of Oddi and gallbladder. Am J Physiol 1985;249:G622-33.
Colorectal Cancer in Patients With Ulcerative Colitis Dear Sir: Gilat et al. (1) have to be congratulated for adding an important piece of information about colorectal cancer in ulcerative colitis in the population of central Israel. The figures differ among populations and have to be investigated, as suggested by the authors, in each country separately, and compared with the expected risk in that population. We, as others, showed (2,3) that the extent of the inflammatory process in ulcerative colitis cannot be assessed accurately with barium enema, and that the macroscopic view in colonoscopy is somewhat inferior to the microscopic evaluation. In a recent paper (4) we demonstrated significant change of the disease extent in 77% of our patients. The histologic extent exceeded the macroscopic extent in 28%. In 45% of the patients with proctitis we found extension (in 18% to the right colon!). The results of Gilat et al. for all cases are valid, and may represent faithfully the cancer risk in Jewish patients with ulcerative colitis in central Israel; but separation according to disease extent is probably inaccurate and nonrevealing because of the following points. 1. In only 400 patients (of 1035) was colonoscopy performed. In the other 635 patients disease extent was demonstrated by sigmoidoscopy and barium enema, which are not satisfying in most of the cases. To my best knowledge most of the barium enemas performed in Israel during the study period (19701980) were single contrast, which is a poor and inaccurate method for extent evaluation (2). 2. The extent of disease was not confirmed histologically.
December 1988
3. "If the extent of disease varied during follow-up, the greatest observed extent was used .... " It must be noted that significant variations of disease extent are frequently met during the follow-up period. Thus, in my opinion, the statement by Gilat et al. that "The cancer incidence rose with ... extent of disease ... " and their recommendation that "Surveillance is not indicated in patients with proctitis ... " have to be read with caution. YARON NIV, M.D.
Gastrointestinal Research Laboratory Veterans Administration Medical Center 4150 Clement Street San Francisco, California 1. Gilat T, Fireman Z, Grossman A, et al. Colorectal cancer in patients with ulcerative colitis. A population study in central Israel. Gastroenterology 1988;94:870-7. 2. Niv y, Bat L, Hurwitz A, et al. The role of colonoscopy in diagnosis of the inflammatory process in ulcerative colitis. Harefuah 1981;101:355-6. 3. Gabrielsson N, Granquist S, Sundelin P, et al. Extent of inflammatory lesions in ulcerative colitis assessed by radiology, colonoscopy and endoscopic biopsy. Gastrointest Radiol 1979;4:395-400. 4. Niv Y, Bat L, Theodor E. Change in the extent of the inflammatory extent in ulcerative colitis. Am J GastroenteroI1987;82: 1046-51. Reply. Dr. Niv draws attention to an important and little noted aspect of ulcerative colitis, namely the variations in the extent of disease with time. It used to be thought that the extent of disease remained constant or increased, and hardly ever decreased (1). In the colonoscopic era it became apparent that changes in extent occur rather frequently and in both directions. Dr. Niv and coworkers (2) have shown changes in the extent of disease in 77% of 33 patients studied by repeated colonoscopies and biopsies. We evaluated this problem using the 1035 patients with ulcerative colitis included in our population study in central Israel (3). In 157 patients two or more colonoscopies were performed at least 1 yr apart during active stages of the disease (Grossman A, unpublished results). Changes in extent were found in 61% of the patients. In 40% the extent increased and in 21 % it decreased. We thus agree with Dr. Niv that the extent of inflamed mucosa in ulcerative colitis is not constant and has to be periodically reevaluated, preferably by colonoscopy. Nevertheless, we feel quite confident about our findings that the risk of colorectal cancer increases with the extent of inflamed mucosa (3). The risk is minimal in patients with proctitis and maximal in patients with total colitis. This has been found in almost all investigations, both in major medical centers (4) and population studies (5). As far as population studies are concerned, ours is one of the few in which a considerable proportion of the patients had colonoscopies (400 of 1035). In most studies, including recent ones (5), the extent of disease was based on barium enema findings. Despite these reservations, the general conclusion that the cancer risk in patients with ulcerative colitis increases with extent (and duration) of disease seems valid. T. GILAT, M.D. A. GROSSMAN, M.D. Z. FIREMAN, M.D.
Department of Gastroenterology Ichilov Hospital and Tel Aviv University Tel Aviv, Israel
CORRESPONDENCE
1693
1. Goligher JC, de Dombal ET, Watts J McK, Watkinson G. Ulcerative colitis. London: Balliere Tindall & Cassell, 1969. 2. Niv Y, Bat L, Theodor E. Change in the extent of the inflammatory extent in ulcerative colitis. Am J GastroenteroI1987;82: 1046-51. 3. Gilat T, Fireman Z, Grossman A, et al. Colorectal cancer in patients with ulcerative colitis. A population study in central Israel. Gastroenterology 1988;94:870-7. 4. Devroede G. Risk of cancer in inflammatory bowel disease. In: Winawer S, Schottenfeld D, Sherlock p, eds. Colorectal cancer: prevention, epidemiology, and screening. New York: Raven, 1980:325-34. 5. Brostrom 0, Lofberg R, Nordenval B, Ost A, Hellers G. An epidemiological study of the risk for development of colorectal cancer in patients with ulcerative colitis. Scand J Gastroenterol (in press).
Should We Let Sleeping PEGs Lie? Dear Sir: The article by Schiller et al. (1) is most interesting and provocative, as it shows how little we know about commonly used preparations. Most lavage bowel preparation compounds based on a balance of polyethylene glycol (PEG) and electrolytes are considered to be isotonic (2). In their article, Schiller et al. have demonstrated that the measurement of osmolality by currently available methods is inaccurate in vitro, and in vivo can only be drawn by inference when PEG is present in solution. While investigating intraluminal colonic antigens we became interested in the effect of PEG in colonic effluent on enzymelinked immunosorbent. assay using antibodies against tumorassociated antigens. The in vitro addition of PEG to colonic effluent, collected by a laxative-purge method, reduces the sensitivity of the enzyme-linked immunosorbent assay (unpublished results). When we sought to confirm that colonic effluent collected after administration of a PEG-electrolyte solution contains similar amounts of PEG to that added in vitro, we were puzzled to find higher than expected values. The PEG estimations were performed according to the method of Malawer (3). To further clarify this question, we performed the following in vivo experiments. Three patients with a defunctioned distal loop colonostomy routinely underwent colonoscopy before surgical reconstitution. A precolostomy infusate of a conventional PEGelectrolyte solution was administered (PEG concentration 59 giL) and the resultant rectal lavage fluid was aspirated. The mean PEG concentration so measured was 46.8 giL. However, the mean PEG concentration from rectal effluent in 6 patients prepared orally by a PEG-electrolyte solution was 122.4 giL, an almost threefold difference. The reasons for this finding still await elucidation. It would be interesting to know what concentration of PEG Schiller et al. found in their study when using a PEG-electrolyte solution containing 105 g of PEG per liter. In addition to its effect on electrolytes and osmolality, PEG has a plethora of actions on proteins. These include stabilization (4), alteration of immunologic properties (5), activation of a prosthetic enzyme moiety (6), and an effect on binding to plastic plates (7). The mechanisms of these interactions have been discussed (8) and seem to have their basis in PEG acting as a salting-out agent, causing preferential hydration of the protein. As colonic effluent may contain significant amounts of protein (9), which also contribute to osmolality, the effects on effluent osmolality due to PEG might be compounded. The failure to demonstrate appreciable toxicity of PEGelectrolyte solution preparations should not exclude research efforts to delineate the enigmatic actions of PEG on osmolality,