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 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 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 cholecystec- tomy 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. The same criticism could little to settle this important issue. Perhaps much of the conflict be applied to the smaller studies by Preitner rf and is artificial as many of the studies have serious limitations in Machnik rt ~1.~~.The case control studies by Vobecky et design, size and make-up of subject groups and controls. Of Preitner rt u/.~’,Simi et ~1.~’and Spitz er ~1.~~are similar to the those studies not demonstrating an association between case control studies cited in favour of an association. The same cholecystectomy and bowel cancer, only that from Adami rt shortcomings of this type of study therefore apply but perhaps stands up to criticism. However, a geographical factor may more so in view of the comparatively small numbers included have to be considered with their results. The incidence of colon in each. In a second part of their study Simi et ~11.~’made an and rectal cancer in Sweden has been reported as 16 and 12.8 per attempt to follow up 200 post-cholecystectomy patients. Unfor- 100 000 re~pectively~~.In Northern Ireland, where an associ- tunately endoscopic or X-ray examinations were performed in ation between cholecystectomy and large bowel cancer has been only a few. Their results are therefore of limited value. demonstrated, the incidence of colon and rectal cancer is Abrams er ~1.~~did investigate a large number of both considerably higher at 21.9 and 18.7 per 100000 respectively. cholecystectomy and cancer cases. However, no matched con- This regional variation in the incidence of colorectal cancer may trols were used thereby casting doubts over the validity of any be an important factor to be taken into account when comparing conclusions. In the population study by Blanco et ~1.~’the the different results from Sweden and Northern Ireland. This

251 Br. J. Surg., Vol. 76, No. 3, March 1989 Cholecystectomy and colorectal cancer: R. J. Moorehead and S. T. D. McKelvey does not necessarily reduce the case against an association as 2. Moorehead RJ, Campbell GR, Donaldson JD, McKelvey STD. much of the evidence for an association is derived from The relationship between duodenal bile acids and colorectal unsatisfactory studies. However, as was the case with the study neoplasia. Gut 1987; 28: 1454-9. 3. Van der Werf SDJ, Nagenast FM, Van Berge Henegouwen GP, of Adami et al.*’, the findings of the prospective study by Linos Huijbregts AWN, Van Tongeren JHM. Colonic absorption of et ~1.’~cannot be simply dismissed. Indeed, the reported secondary bile acids in patients with adenomatous polyps and in increased incidence of right-sided colonic cancer in post- matched controls. Lancet 1982; i: 759-62. cholecystectomy women from some of the retrospective studies 4. Reddy BS, Wynder EL. Metabolic epidemiology of colon cancer. adds weight to their conclusions. Faecal bile acids and neutral sterols in colon cancer patients and In most of the papers mentioned, the selection of suitable patients with adenomatous polyps. Cancer 1977; 39: 2533-9. controls has been a major problem. Theoretically post-cholecys- 5. Low-Beer TS. The physiology of enterohepatic circulation of bile tectomy cases should be compared with age- and sex-matched acids. In: Proceedings ofthe First International Symposium on Bile controls known to have asymptomatic cholelithiasis. The task of Acids in Hepatobifiary and . Oxford: IRL obtaining such a group from the general population would be Press, 19841 1-8. 6. Van Der Linden W. Katzenstein B, Nakayama F. The possible virtually impossible. Most authors have therefore had to carcinogenic effect of cholecystectomy. No postoperative increase compromise and use the best available group of controls. It is in the proportion of secondary bile acids. Cancer 1983; 52: possible that most of these controls did not have biliary tract 1265-8. disease. As a result the comparison that has been made in many 7. Almond HR, Vlachevic ZR, Bell CC, Gregory DH, Swell L. Bile of the papers does not address the effect of cholecystectomy as acid pool kinetics and biliary lipid composition before and after such but the effect of symptomatic gallstones requiring cholecys- cholecystectomy. N Engl J Med 1973; 289: 1213-16. tectomy versus disease-free controls. 8. Malagelada JR, Go VLW, Summerskill WHJ, Gamble WS. Bile Downloaded from https://academic.oup.com/bjs/article/76/3/250/6171337 by guest on 29 September 2021 The only paper that has managed to make a direct compari- acid secretion and biliary bile acid composition altered by son between cholecystectomy cases and those with asympto- cholecystectomy. Am J Digest Dis 1973; 18: 455-9. 9. Pomare EW, Heaton KW. The effect of cholecystectomy on bile al.”. matic gallstones is that by Mannes et Although they found salt metabolism. Gut 1973; 14: 753-62. an increased risk of adenomas and carcinomas in cholecystec- 10. Hepner GW, Hofmann AF, Malagelada JR, Szcepanik PA, Klein tomy cases, their study was biased in that all cases and controls PD. Increased bacterial degradation of bile acids in cholecys- were undergoing investigative . tectomized patients. Gastroenterology 1974; 16: 556-64. If one thing is clear it is that further retrospective studies will 11. Kuniyasu T, Tanaka T, Shima H, Sugie S, Mori H, Takahashi M. not clarify this important issue. The question will only be finally Enhancing effect of cholecystectomy on colon carcinogenesis resolved by prospective studies following up post-cholecystec- induced by methylazoxymethanol acetate in hamsters. Dis Colon tomy patients, with colonoscopy or barium enema, to determine 1986; 29: 4924. whether the incidence of tumours is really increased. We have 12. Vernick LJ, Kuller LH, Lohsoonthorn P, Rycheck RR, Redmond CK. Relationship between cholecystectomy and ascending colon begun such a study based on the observations of Mannes et ~1.’~. cancer. Cancer 1980; 45: 392-5. In an attempt to maximize the yield from screening cholecystec- 13. Vernick LJ, Kuller LH. Cholecystectomy and right-sided colon tomy patients we are following up those over 60 years of age with cancer: an epidemiological study. Lancet 1981; ii: 381-3. 10 years or more having elapsed since surgery with double 14. Linos LDA, Beard LC, O’Fallon WM, Dockerty MB, Beart RW, contrast barium enemas and . The selection of Kurland LT. Cholecystectomy and carcinoma of the colon. controls for this study has proved to be a major problem as it Lancet 1981; ii: 379-81. was impracticable to submit a control group to the same 15. Turunen MJ, Kivilaakso EO. Increased risk of colorectal cancer investigations. A compromise had to be made and post-mortem after cholecystectomy. Ann Surg 1981; 194: 63941. patients were used. In an attempt to try to reduce any hospital 16. Turnbull PR, Smith AH, Isbister WH. Cholecystectomy and bias an equal number of cases undergoing non-hospital post cancer of the large bowel. Br J Sury 1981; 68: 551-3. 17. mortems were used. Obviously this is an area for potential Mannes AG, Weinzierl M, Stellard F, Thieme C, Wiebecke B, Paumgartner G. Adenomas of the after cholecys- criticism but nevertheless our preliminary results have shown tectomy. Gut 1984; 25: 863-6. a fourfold increase in the incidence of adenomas and carcinomas 18. Regula J, Bartnik W, Ostrowski J, Butruk E. Czy cholecystek- following chole~ystectomy~~. tomia zwieksza ryzyko rozwoju raka jelita grubego? Pol Tyg Lek Some groups have reported an increased incidence of large 1985; 40: 954-6. bowel cancer in those with a history of cholelithiasis rather than 19. Giordano M, Di Bella F. Colecistectomia e carcinoma del colon, chole~ystectomy~~~~~.However, even if an association between Minerua Chir 1986; 41: 35-7. colorectal cancer and biliary tract disease were supported by all, 20. Moorehead RJ, Kernohan RM, Patterson CC, McKelvey STD, it is possible that there is no direct link between either Parks TG. Does cholecystectomy predispose to colorectal cancer? cholecystectomy or cholelithiasis and large bowel cancer. It may Dis Colon Rectum 1986; 29: 3&8. 21. Llamas KJ, Torlach LG, Ward M, Bain C. Cholecystectomy and be that the appearance of an association in some reports is adenomatous polyps of the large bowel. Gut 1986; 27: 1181-5. because those whose diet predisposed to one disease may well 22. Barker WH. Cholecystectomy and colon cancer. Lancet 1981; ii: have increased their risk of developing the other. Whether this 986 (Letter). possible relationship is directly causal or not, those with 23. Hoare AM. Carcinoma of the colon and cholecystectomy. Lancet a history of previous cholecystectomy are readily identifiable. 1974; ii: 1395-6. Epidemiologists might suggest that such a group could be worth 24. Weiss NS, Darling JR, Chow WH. Cholecystectomy and the screening for both colorectal adenomas and carcinomas. How- incidence ofcancer of the large bowel. Cancer 1982; 49: 1713-15. ever, even if the evidence supporting an association with 25. Abrams JS, Anton JR, Dreyfuss DC. The absence ofa relationship colorectal cancer were universally supported in absolute terms, between cholecystectomy and the subsequent occurrence of cholecystectomy patients may not constitute such a high-risk cancer of the proximal colon. Dis Colon Rectum 1983; 26: 1414. 26. Vobecky J, Car0 J, Devroede G. A case control study of risk group to necessitate screening. The reported overall risks of factors for large bowel carcinoma. Cancer 1983; 51: 1958-63. between 1.59 and 2.27 would support this contention. 27. Adami H-0, Meirik 0, Gustavsson S, Nyren 0, Krusemo U-B. If such a screening programme were carried out it would have Colorectal cancer after cholecystectomy : absence of risk increase two obvious benefits: first, it would give valuable information on within 11-14 years. Gastroenterology 1983; 85: 859-65. the pathogenesis of large bowel cancer and, secondly, it would 28. Blanco D, Ross RK, Paganini-Hill A, Henderson BE. Cholecys- determine conclusively whether there is a relationship between tectomy and colonic cancer. Dis Colon Rectum 1984; 27: 290-2. cholecystectomy and the subsequent development of colorectal 29. Eriksson SG, Lindstrom CG. Lack of relationship between tumours. cholecystectomy and colorectal cancer. A case control autopsy study in a defined population. Scand J Gastroenterol 1984; 19: 977782. References 30. Preitner J, Mosimann F, Chastonay PH. Le risque de cancer 1. Zaridze DG. Environmental aetiology of large bowel cancer. colo-rectal apres cholecystectomie. 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31. Simi M, Leardi S, Siciliano R, Scappaticci G, Constantini FM, 35. Moorehead RJ, Mills JOM, Wilson HK, McKelvey STD. The Speranza V. Cancer of the large intestine and previous cholecys- value of screening post cholecystectomy patients for colorectal tectomy: does a relationship really exist? ltal J Surg Sci 1985; 15: cancer. Gut 1986; 27: A1268. 175--80. 36. Bundred NJ, Whitfield BSC, Stanton E, Prescott RJ, Davies GC, 32. Spitz MR, Russell NC, Guinee VF, Newell GR. Questionable Kingsnorth AN. Cholecystectomy, cholelithiasis and colorectal relationship between cholecystectomy and colon cancer. J Surg carcinoma. J R Coll Surg Edinb 1985; 30: 115-17. Oncol 1985; 30: 6-9. 37. Gafa M, Sarli L, Sansebastiano G et al. Prevention of colorectal 33. Machnik Von G, Fuller C, Fuller J, Kunath H. Explorative cancer: role of association between gallstones and colorectal untersuchungen zum gemeinsamen vorkommen von cancer. Dis Colon Rectum 1987: 30: 692-6. cholelithiasis, zustand nach cholezystektomie und kolonkar- zinom. Dtsch Z Verdau Stoffwechselkr 1986; 46: 22-9. 34. Doll R. The geographical distribution of cancer. Br J Cancer 1969; 23: 1-8. Paper accepted 25 October 1988 Downloaded from https://academic.oup.com/bjs/article/76/3/250/6171337 by guest on 29 September 2021

253 Br. J. Surg., Vol. 76, No. 3, March 1989