Cholecystectomy and Colorectal Cancer R

Review 25S253Br. J. Surg. 1989, Vol. 76, March. Cholecystectomy and colorectal cancer R. J. Moorehead and S. T. D. McKelvey This review examines the evidence for and against an association between Department of Surgery, Queen's cholecystectomy and colorectal cancer. University of Belfast, Belfast, UK Keywords: Cholecystectomy, bile acids, colorectal cancer Correspondence to: Mr R. J. Moorehead, University Department of Surgery, Queen Mary Hospital, Pokfulam Road, Hong Kong There is a considerable amount of epidemiological evidence women (Table 1). Unfortunately not all of the other studies go as suggesting that bile acids are aetiologically important in the far as reporting relative risks but those that do claim increased development of colorectal cancer'. While several clinical studies incidences for colonic cancer of between 1.59 and 2.27"~'~.Even Downloaded from https://academic.oup.com/bjs/article/76/3/250/6171337 by guest on 29 September 2021 have demonstrated abnormalities in bile acids of those with higher relative risks of up to 3.5 have been reported for adenomas and carcinomas of the large bowel' ', the precise right-sided cancer in women*", with the highest so far being 4.5 action of bile acids in tumour promotion or initiation remains to for sigmoid lesions18, though neither of these studies dem- be determined. onstrated anything more than a trend for an overall increased Certain surgical procedures can affect the size of the bile acid risk. Caution is required in accepting these increased risks at face pool with consequent changes in the proportions of bile acids value as some of the studies from which they are derived may be present in duodenal bile. Cholecystectomy is one such pro- flawed through selection of cases and controls. In our own study'" cedure. It is now generally accepted that the size of the bile acid and those from Regula et ul." and Turnbull et ~1.'~controls pool negatively correlates with the level of deoxycholic acid were all drawn from a hospital population. It could be argued present in bile, i.e. a smaller pool is associated with a greater that such a group is not representative of the general population. proportion of deoxycholic acid5.While some may argue that it is Similarly, in the study by Turunen and Kivilaakso" both cancer the presence of gallstones that produces this change in bile acid patients and controls were drawn from those undergoing metabolism6 it is generally agreed that cholecystectomy patients post-mortem examination with the obvious selection bias that have a significantly increased proportion of secondary bile acids this might entail. in bile, chiefly deoxycholic acid'-'". As a possible explanation Others have divided their cancer patients into cholecystec- for these changes it is suggested that, while before cholecystectomy and non-cholecystectomy groups and compared tumour tomy the bile acid pool circulates two or three times per meal, distribution between the two without reference to outside after cholecystectomy the pool circulates even during the fasting ~ontrols~'~'~~'~.While this may give information on any state. This enhanced circulation results in an increased exposure potential predisposition for tumour sites in cholecystectomy of bile acids to the degrading action of intestinal bacteria. As patients it does not give information on the overall risk a result there is an increased input of secondary bile acids from compared with the rest of the population. A major criticism the intestine into hepatic bile with a corresponding reduction in levelled against most of these investigations is that they are primary bile acid synthesis owing to increased feedback inhibi- retrospective case control studies. The finding of an association tion8.'. between two conditions in this type of study could well be due to Such observations on the effects of cholecystectomy on bile chance producing a Berksonian bias in the res~lt'~,~~.Therefore acid metabolism, together with epidemiological, clinical and one investigation alone suggesting an association between experimental evidence' suggesting possible carcinogenic or cholecystectomy and colonic cancer might be of interest yet not co-carcinogenic properties of bile acids have led to increased really significant. That several have observed an association speculation on the hypothesis that patients with a history of between the two conditions suggests that the result may not be cholecystectomy may have an increased risk of developing due to chance. Further, the reported increased risk of proximal colorectal cancer. colonic tumours in some of these studies" 15.20, suggests that While confirmation of such a link would give further weight the link between the two conditions may indeed be a causal one. to the argument which links bile acids with bowel cancer, it This predilection for right-sided tumours in some studies may be would also be of some clinical significance by clearly identifying explained by proposing that higher levels of these bacterially an at-risk group. There have been several studies investigating modified bile acids are absorbed more proximally in the colon. the possibility of a link between cholecystectomy and large That some have noticed this finding in women only may be bowel cancer. The findings of these studies have been varied and a reflection of the increased incidence of cholecystectomy in in some cases contradictory. In many instances differences in women compared with men. methodology and inadequacy of study group size may account There are more recent reports giving further support to the for these variations. association. In a colonoscopic study, patients over 60 years of age with more than 10 years having elapsed since their The argument for and against an association cholecystectomy were found to have an increased incidence of both adenomas and carcinomas of the colon when compared There have been many studies suggesting the existence of an with controls known to have asymptomatic gallstones". A fur- association between bowel cancer and cholecystectomy " 'I. ther similar study reported an increased incidence of adenomas Undoubtedly the best of these is the prospective study by Linos in post-cholecystectomy women with a trend for a preponder- et ~1.'~who followed up 168 1 post-cholecystectomy patients ance of proximal turnours2'. and demonstrated an increased relative risk of developing The evidence against an association between colorectal colorectal cancer of 1.7. They also reported an even more cancer and previous ch~lecystectomy'~33 is open to criticisms marked risk of 2.1 for the development of right-sided lesions in similar to those that applied to the studies reporting an ~~ ~ ~ -- 250 0007-1323/X9/030250 04$3 00 1 19x9 Rutterworth & Co (Publisher\) Ltd Cholecystectorny and colorectal cancer: R. J. Moorehead and S. T. D. McKelvey Table 1 Studies that have investigated the possibility of an association between cholecystectomy and colorectal cancer Number Relative 95% Confidence Tumour site Reference of cases Type of cases risk interval P (if applicable) ~ ~~ ~ -. Vernick et a1 ’’ 706 Cancer 2.23 (1 ‘33-3’75) * Right colon Vernick and Kuller13 150 Right colon cancer 1.87 (0.89-3.9 1) * Right colon 150 Left colon cancer Linos et 1681 Cholecystectomy 1.7 (1 ‘1-2.5) * All sites 2.1 (1.1-3‘6) * Right colon, women Turunen and Kivilaaks~’~ 304 Post-mortem cancer 1.59 * <0.05 All sites 3.0 * Right colon Turnbull et 305 Cancer 2.27 * t0.01 All sites, women Mannes et a1.” 331 Cholecystectomy * * <0.05 All sites Regula et a/.l8 200 Cancer 4.5 * <0.05 Sigmoid colon, women Giordano and Di Bella” 177 Cancer * * * All sites Moorehead et a/.*’ 598 Cancer 3.5 (1.7-7.5) t0.005 Right colon, women Llamas et al.” 72 Adenoma * (1.7-*) <0.0 1 Right colon, women (trend) Downloaded from https://academic.oup.com/bjs/article/76/3/250/6171337 by guest on 29 September 2021 Hoare” 100 Cancer * * * Weiss et 01.’~ 141 Cancer I .4 (0.8-2.5) * Abrams et a/.25 249 Cholecystectomy * * * 582 Cancer * * * Vobecky et 207 Cancer * * * Adami et a/.’’ 16 773 Cholecystectomy 0.85 (0.68-1.07) * Blanco et a/.28 * * 1.2 (0.6-2.2) * Eriksson and LindstromZ9 1061 Post-mortem cancer * * Preitner et 237 Cancer * * * 194 Post-mortem cancer Simi et a/.3’ 250 Cancer * * * 200 Cholecystectomy Spitz et a/.3z 267 Right colon cancer 1.49 (0.83-2.67) * 268 Left colon cancer Machnik et 449 Post-mortem cancer * * * * Not specitied association. Hoare’s conclusions cannot be accepted as they precise number of patients who replied to the questionnaires is came from a small retrospective case control study of only 100 not stated. It is therefore difficult to make any comment on their patients23. One would not expect significant differences from findings. a study of this size unless the incidence of cholecystectomy in Of all the papers finding no evidence of an association cancer patients compared with controls was very high (Table 1). between colorectal cancer and cholecystectomy, there is only Similarly, although Weiss er set out to study 243 cancer one that stands outz7. In an impressive follow-up of 16773 patients data were only obtained from 141. The authors accept cholecystectomy cases by Adami et al., no increased risk of large that uncertainty surrounded their results because of the small bowel cancer was observed. Clearly, findings such as this cannot number of patients studied. From their reported relative risk be simply dismissed. and confidence intervals one could speculate that had they studied a larger number of patients then evidence to support an association may have been demonstrated. Discussion The investigation by Eriksson and Lindstrom”, although The precise relationship between cholecystectomy and the large (1061 cases), involved cases and controls coming to development of large bowel cancer remains controversial. The hospital post mortem. Such groups might be considered unrep- conflicting results from the studies already outlined have done resentative of the general population.

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