Gallstone Disease and Risk of Conventional Adenomas and Serrated Polyps: A Prospective Study

Colorectal cancer is one of the leading causes of cancer-related death in the United States and the western world (1) with increasing incidence in younger adults (2, 3). Serrated polyps (SP) are a precursor lesion for colorectal cancer and contribute to colorectal cancer through the serrated pathway (4). This entails the transition of hyperplastic polyps into sessile SPs (SSP) or traditional serrated adenomas and further on to dysplasia and cancer while there is also some risk of in situ carcinomas arising directly from SSPs (5, 6). Different exposures such as dietary factors, body mass index, and smoking have a distinct association with SPs than conventional adenomas (7).

The most prominent link between colorectal cancer and gallstone disease has been the effect of secondary bile acids which are increased after cholecystectomy. However, the role of gallstone disease in the early stages of colorectal cancer development is largely unknown. A meta-analysis of six prospective cohort studies showed a null association between gallstone disease and adenoma development [OR, 1.01 (0.91–1.12)] (8). No prospective cohort studies have yet assessed SPs. Therefore, we examined the association of gallstone disease with risk of conventional adenomas and SPs in three prospective cohorts, including the Nurses’ Health Study (NHS), the NHS II, and the Health Professionals Follow-up Study (HPFS).

We utilized the NHS, an ongoing prospective cohort of 121,700 female registered nurses in the United States between the ages of 30 and 55 years at the time of enrollment in 1976, the NHS II which included 116,430 registered U.S. female nurses ages 25 to 42 years at enrollment in 1989 and the HPFS another nationwide U.S.-based prospective cohort that recruited 51,529 male health professionals ages 40 to 75 years in 1986 (9–11). Follow-up questionnaires were sent every 2 years to update information on exposures and to ascertain the occurrence of newly diagnosed illnesses, including gallstone disease (7, 12). On each biennial questionnaire, participants were asked whether they had undergone a colonoscopy or sigmoidoscopy and if any colorectal polyp had been diagnosed in the past 2 years. We linked endoscopy and pathology reports when participants reported yes to both questions. Review of records and extraction of clinicopathologic data were conducted by investigators blinded to exposure information. Because detailed histologic information of polyps was not collected until 1992 for the NHS, 1991 for the NHS II, and 1992 for the HPFS, these years were used as the baseline of the current study for each of the cohorts.

We considered three main exposures: history of gallstone disease, history of cholecystectomy, and a composite exposure of either conditions (13). Time-varying exposures were used, and participants were censored at the diagnosis of colorectal polyps, colorectal cancer, death or the end of follow-up, whichever occurred first. To capture long-term exposure, cumulative average of risk factors from preceding questionnaires up to the current cycle was calculated. Multivariable logistic regressions for clustered data were used to account for repeated observations (i.e., multiple endoscopies) and to calculate ORs and their 95% confidence intervals (CI; see details of covariates in the footnote of Table 1; ref. 10). We also performed subgroup analyses according to sex and polyp size, subsite, and adenoma risk classification (advanced conventional adenomas being defined as at least one conventional adenoma of ≥10 mm in size of the presence of advanced histology; ref. 10). Because polyp development can take several years, we also performed a lagged analysis of 6 years in the HPFS and NHS by using the gallstone disease information first reported in 1986 for polyps diagnosed in 1992 to 1994, gallstone disease reported in 1988 for polyps in 1994 to 1996, and so on.

Our study included 109,890 women from the NHS and NHS II and 23,831 men from the HPFS, who had undergone a total of 323,832 endoscopies. The baseline prevalence of gallstone disease and cholecystectomy was 16.5% and 11.3%, respectively.

We did not find any association between gallstones and risk of conventional adenomas (OR, 1.00; 95% CI, 0.95–1.06). Similar null associations were found for cholecystectomy (OR, 0.99; 95% CI, 0.93–1.06) or the composite exposure (OR, 1.00; 95% CI, 0.95–1.05). The risk of SPs was unaffected by gallstones (OR, 0.98; 95% CI, 0.92–1.04), cholecystectomy (OR, 0.99; 95% CI, 0.93–1.06) or the composite exposure (OR, 0.97; 95% CI, 0.92–1.03; Table 1).

No associations were found in subgroup analyses according to sex and polyp features (Table 2). We detected a slightly increased incidence of distal SPs in the cholecystectomy group (OR, 1.09; 95% CI, 0.98–1.20; P_{heterogeneity} = 0.02; Supplementary Tables S1–S4). The results of the lag analysis were similarly null for the NHS and HPFS (Supplementary Table S5).

In contrast with prior findings for an increased risk of colorectal cancer associated with gallstones or cholecystectomy, we did not observe higher risk for adenomas or SPs. Recent longitudinal data have shown an association between history of gallstones and colorectal cancer in women, while others have shown an association of screen-detected gallstones (but not cholecystectomy) with right-sided colorectal cancer (15, 16). Although women showed higher gallstone disease incidence, there was no association of SPs or adenomas with regard to sex in our study. A higher prevalence of colorectal cancer in women with gallstone disease may be due to detection bias, because mainly women are followed-up after cholecystectomy. Another reason why our findings might differ with previous gallstone disease/colorectal cancer literature is that gallstone disease and related changes may primarily act as a promoter rather than initiator in colorectal carcinogenesis, thus not leaving traces of effect in polyp development. Studies show increased bile secretion with gallstone disease and after cholecystectomy (17, 18). This could be facilitating the population increase of bacteria associated with production of toxic metabolites which can promote malignant transformation (18, 19).

Besides the prospective design, large sample size and long-term follow-up, our study's strengths include detailed and repeated data collection, as well as the confirmation of polyp diagnosis with detailed recording of histopathologic information based on pathology reports. Our study also has some limitations. Primarily, central pathologic review was not conducted for polyps, which may have contributed to misdiagnosis or misclassification of some polyps. Moreover, medical records were collected for individuals with self-reported polyps only. Finally, the study participants are predominantly White and may not be generalizable to other racial/ethnic groups.

In a large prospective analysis of predominantly Whites, we did not find any association of gallstones or cholecystectomy with conventional adenomas or SPs.

S. Ogino reports grants from NIH during the conduct of the study. A.T. Chan reports personal fees from Pfizer, Inc., Bayer Pharma AG, Boehringer Ingelheim, and grants from Zoe, Ltd. outside the submitted work. No disclosures were reported by the other authors.

G. Polychronidis: Conceptualization, data curation, formal analysis, funding acquisition, investigation, writing–original draft. K. Wang: Data curation, software, supervision, writing–review and editing. C.-H. Lo: Data curation, software, formal analysis, writing–review and editing. L. Wang: Data curation, validation, investigation. M. He: Resources, validation, writing–review and editing. M.D. Knudsen: Data curation, validation, visualization, writing–review and editing. K. Wu: Software, validation, methodology. A.D. Joshi: Software, methodology, writing–review and editing. S. Ogino: Supervision, validation, methodology, writing–review and editing. E.L. Giovannucci: Conceptualization, supervision, validation. A.T. Chan: Resources, supervision, writing–review and editing. M. Song: Conceptualization, resources, supervision, funding acquisition, validation, methodology, writing–original draft, project administration.

We would like to thank the participants and staff of the NHS and HPFS for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, and WY. The authors assume full responsibility for analyses and interpretation of these data.

This work was supported by the German Research Foundation [Deutsche Forschungsgemeinschaft (DFG)]—project number 426308975, the U.S. NIH (UM1 CA186107, P01 CA87969, U01 CA167552; R03 CA197879, R21 CA222940, to K. Wu; R01 CA151993, R35 CA197735, to S. Ogino; R21 CA230873, to K. Wu and S. Ogino; R35 CA253185, to A.T. Chan; R00 CA215314, to M. Song), the American Cancer Society (MRSG-17-220-01—NEC, to M. Song), the American Institute for Cancer Research (to K. Wu), the Project P Fund for Colorectal Cancer Research, the Bennett Family Foundation, and the Entertainment Industry Foundation through National Colorectal Cancer Research Alliance. The funders had no role in design and conduct of the study. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funders.

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