Abstract
Background
Gallstones may result in inflammation, altered bile flow, and changes in metabolic hormone levels, thereby increasing cancer risk. However, previous studies for gallstones and cancers of the liver, biliary tract and pancreas in the U.S. were relatively limited.
Methods
We followed 115,036 women from the Nurses’ Health Study (1982–2012) and 49,729 men from the Health Professionals Follow-up Study (1986–2012). History of gallstones, including with or without performed cholecystectomy, was reported at baseline and updated through biennial questionnaires. The Cox proportional hazard regression model was used to calculate multivariable hazard ratios (HRs) and 95% confidence intervals (95% CIs).
Results
During up to 30-year follow-up, we identified 204 incidents of liver cancer, 225 biliary tract cancer and 1147 pancreatic cancer cases. Compared to those without gallstones diagnosis, the multivariable HRs for individuals with gallstones (untreated or with cholecystectomy) were 1.60 for liver cancer (95% CI: 1.14–2.26), 4.79 for biliary tract cancer (95% CI: 3.02–7.58), and 1.13 for pancreatic cancer (95% CI: 0.96–1.32). The multivariable HRs for individuals with cholecystectomy were 1.33 for liver cancer (95% CI: 0.90–1.95) and 1.15 for pancreatic cancer (95% CI: 0.98–1.36).
Conclusions
Gallstones were associated with a higher risk of cancers of the liver, biliary tract and possibly pancreas.
Subject terms: Liver cancer, Biliary tract cancer, Pancreatic cancer, Risk factors, Cancer epidemiology
Introduction
Cancers of the liver, biliary tract, and pancreas have a poor prognosis [1], with estimated 110,000 new diagnoses and over 81,000 deaths in the U.S. in 2019 [2]. Liver cancer incidence has tripled since the early 1980s [3], and the increasing trends of pancreatic cancer cases were also observed during the most recent 10 years [4]. Pancreatic and liver cancers are estimated to become the second and third leading cause of cancer-related death in the U.S. by 2030 [5]. Similarly, rising incidence of biliary tract cancers, particularly among younger adults (25–49 years), relatively rare but highly fatal malignancies, were also reported [6, 7]. Given the increased incidence of these fatal diseases, quantifying the association with gallstones, the most common disorder affecting the biliary system, may inform new cancer prevention strategies.
As one of the most common gastrointestinal diseases, gallstones affect 10–15% of adults in the U.S. and cost ~$4 billion annually [8, 9]. Gallstones may result in inflammation [10, 11], altered bile flow [12] and changes in metabolic hormone levels [13], thereby increasing cancer risk. Previous studies reported positive associations of gallstones and cholecystectomy with liver [14, 15], biliary tract [16, 17] and pancreatic cancer risk [18, 19]. However, prior studies were from different countries with different study designs, data sources and lack of adequate confounding adjustment. For example, the vast majority of such studies on liver cancer were conducted in Europe [20–24] and Asia [25–28]. Only two case–control studies in the U.S., with one based on data from registries and another based on the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked data [29, 30]. Furthermore, these two studies did not control for important confounding factors such as obesity and alcohol consumption [14, 15]. In addition, evidence of gallstones and biliary tract cancer association is very limited in the U.S. where biliary tract cancer incidence is low. For pancreatic cancer, previous studies, including the findings from the Nurses’ Health Study (NHS) and the Health Professionals Follow-up Study (HPFS), reported gallstones and cholecystectomy with an increased risk of pancreatic cancer [22, 23, 27, 31–35]. However, whether the association of gallstones with cancer risk of auxiliary organs varied by risk factors is unclear.
To address these questions, we examined the associations of gallstones and cholecystectomy with cancers of the liver, biliary tract and pancreas in two large cohort studies, the NHS and HPFS, with biennially updated information on gallstones and lifestyle factors with up to 30 years of follow-up.
Methods
Study population
The current study pooled participants from two large ongoing prospective U.S. cohorts, the Nurses’ Health Study (NHS) and the Health Professionals Follow-up Study (HPFS). The NHS is comprised of 121,700 registered female nurses aged 30–55 years who were enrolled in 1976. The HPFS is comprised of 51,529 male health professionals aged 40–75 years who were enrolled in 1986. Participants were mailed a questionnaire at baseline, and every 2 years thereafter that inquired detailed information on demographics, lifestyle, medication use and health outcomes. The average follow-up rate exceeded 90% in each cohort. The follow-up for deaths is >98%. The study protocol was approved by the Institutional Review Board at the Harvard T.H. Chan School of Public Health and the Brigham and Women’s hospital and those of participating registries as required.
Assessment of gallstones
Information on gallstones was collected at baseline (NHS: 1982; HPFS: 1986) and updated biennially via questionnaires. We asked participants whether they had been diagnosed as having gallstones by a physician or had undergone cholecystectomy and, if so, the date of diagnosis and surgery. Participants were also asked whether the gallstones diagnosis had been confirmed by surgery or radiographic procedures and whether their gallstones were symptomatic. Of 50 randomly selected nurses in the NHS who self-reported cholecystectomy, all 43 who agreed to provide additional information on their earlier report. Cholecystectomy was confirmed in all the 36 nurses for whom medical records were available [36]. Similarly, to verify self-reports of diagnosed gallstones and surgical cholecystectomy in the HPFS, a random sample of 441 medical records of participants who reported a cholecystectomy or gallstones were reviewed, which confirmed 99% of the reported cases [37]. Medical records review confirmed all self-reported symptoms. Our primary exposure is gallstones, including with or without performed cholecystectomy. We defined gallstones without performed cholecystectomy as having had reported a diagnosis of gallstones but no report of cholecystectomy. We defined cholecystectomy as having had reported a cholecystectomy.
Assessment of covariates
In the biennial follow-up questionnaires, we inquired and updated information on age, body weight, physical activity, smoking status, aspirin use, type 2 diabetes mellitus (T2D) and hypercholesterolaemia. The race was first assessed in 1992 in the NHS and 1986 in the HPFS. Participants reported height at enrolment in each cohort. We calculated body mass index (BMI; kg/m2) in each cycle using self-reported height and weight. We calculated the metabolic equivalent of task-hours/week (MET-hours/week) for each activity by multiplying the MET score and reported hours per week; values from individual activities were summed for total physical activity MET-hours/week. We collected and derived dietary factors every 4 years using semi-quantitative food frequency questionnaires (FFQs) in each cohort, including total calorie intake (kcal/day), coffee consumption (cup/day), alcohol consumption (g/day) and Alternate Healthy Eating Index-2010 (AHEI-2010) score (as an overall measure of diet quality).
Assessment of cancers of the liver, biliary tract and pancreas
Participants who reported a diagnosis of cancers of the liver, biliary tract or pancreas on any biennial follow-up questionnaire were contacted to request permission to examine medical or pathologic reports. Considering potential unreported cancers, we further searched State Cancer Registries and the National Death Index [38]. For all deaths attributable to any of the above three cancers as the primary underlying cause of death on the death certificate, we requested permission from the next-of-kin to review the relevant medical records. Study physicians, blinded to exposure information, reviewed all records to confirm each diagnosis of liver cancer, biliary tract, and pancreatic cancer. For liver cancer, additional information was collected, such as the presence of viral hepatitis (e.g., hepatitis B virus (HBV)/hepatitis C virus (HCV) infection). HBV/HCV infection data were also available from a nested case–control study of liver cancer in the NHS and HPFS, derived from laboratory blood tests [39]. Biliary tract cancers include extrahepatic bile duct cancer, gallbladder cancer, and cancer of Ampullar of Vater. Among participants who developed pancreatic cancer over the follow-up period, over 80% of cases were confirmed to have adenocarcinoma by medical record review. We excluded pancreatic cancer cases with known histology other than adenocarcinoma. Since ~90% of the remaining cases are of adenocarcinoma histology, we included these as cases in the final analysis.
Statistical analysis
In the current study, we used 1982 as the baseline for the NHS and 1986 for the HPFS when the information on gallstones was first available. We excluded participants with missing data on gallstones, cholecystectomy, or with a history of cancer (except for non-melanoma skin cancer), leaving 164,765 participants (115,036 women and 49,729 men) in the final analyses. We calculated the person-time of follow-up from the date of return of the baseline questionnaire to the date of cancer diagnosis, death, or the end of follow-up (June 1, 2012 in the NHS and January 31, 2012 in the HPFS), whichever came first. We calculated hazard ratios (HRs) and 95% confidence intervals (CIs) of each cancer in relation to the gallstones using the Cox proportional hazards model. To maximise the statistical power, we conducted analyses using the combined dataset from the NHS and HPFS because of no significant heterogeneity by cohort (P for heterogeneity = 0.53 for liver cancer, 0.40 for biliary tract cancer, and 0.39 for pancreatic cancer). Gallstones and cholecystectomy were updated prospectively over each interval of follow-up. In the age-adjusted model, we used age (months), study period (2-year interval), and sex as the stratification variables. In the multivariable models, we further adjusted for the race (white, non-white), aspirin use (yes, no), smoking status (never, past, current), total calorie intake (kcal/day, tertiles), alcohol intake (g/day, tertiles), coffee consumption (never or 1, 2–3, 4+ cups/day), AHEI-2010 (tertiles), physical activity (MET-hours/week, tertiles), hypercholesterolaemia (yes, no) and T2D (yes, no). We used cumulative average updated variables for physical activity, diet, alcohol consumption and BMI, to better reflect the long-term pattern and to minimise measurement errors.
We first separately examined the overall association of gallstones with the risk of liver, biliary tract and pancreatic cancer. For liver and pancreatic cancer, we then assessed the associations according to gallstones subgroups with or without cholecystectomy. For biliary tract cancer, we only focused on overall gallstones because individuals with cholecystectomy are no longer at risk of developing gallbladder cancer. We also conducted exploratory subgroup analyses to assess whether the association of gallstones with liver, biliary tract cancer and pancreatic cancer varied across levels of major risk factors, including age, BMI, alcohol consumption, smoking status, aspirin use, and hypercholesterolaemia. We tested the significance of interactions using the log-likelihood ratio test. We also performed exploratory analyses by subtypes of biliary tract cancers.
We also conducted several sensitivity analyses to test the robustness of our findings. First, we performed the analysis to minimise reverse causation by excluding cancer diagnosis within 2 years after gallstones diagnosis. Second, we also excluded participants who reported a history of T2D. Third, we examined gallstones in relation to hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) risk separately in both cohorts. The associations of gallstones and cholecystectomy with each subtype of biliary tract cancer were also assessed. In addition, the main effect of cholecystectomy regardless of gallstones status on the risk of liver cancer and pancreatic cancer was examined. We performed all analyses in SAS version 9.4 (SAS Institute, Cary, NC, USA), and a P value less than 0.05 was considered to be statistically significant.
Results
Characteristics of study participants
At baseline, 11,557 out of 164,756 (7.01%) participants reported gallstones, with 9694 out of 115,036 women (8.43%) and 1865 out of 49,729 men (3.75%). Compared with participants who were not diagnosed with gallstones at baseline, those with gallstones were older and more likely to be overweight, aspirin users, current smokers, and have a history of T2D and hypercholesterolaemia, but were less like to be physically active, consume more calories and drink alcohol and coffee (Table 1). Participants with gallstones who underwent cholecystectomy were more likely to be current smokers, more often diagnosed with T2D than gallstone formers without surgery. We observed similar patterns in each cohort (Supplementary Table 1).
Table 1.
Age-standardised characteristics of participants according to gallstones status at baseline in the pooled Nurses’ Health Study (NHS) (1982) and Health Professionals Follow-up Study (HPFS) (1986)a.
| Variables | Gallstones | |||
|---|---|---|---|---|
| No (n = 153,306) | Yes (n = 11,559) | Cholecystectomy | ||
| Yes (n = 9848) | No (n = 1711) | |||
| Age, years | 50.4 (8.5) | 52.5 (8.2) | 52.5 (8.2) | 52.9 (8.3) |
| White, % | 96.3 | 97.9 | 97.9 | 97.8 |
| BMI,b kg/m2 | 24.7 (4.1) | 27.0 (5.6) | 27.0 (5.5) | 27.1 (5.9) |
| Type 2 diabetes mellitus, % | 1.4 | 4.7 | 5.0 | 3.5 |
| Hypercholesterolaemia, % | 8.3 | 11.1 | 11.0 | 11.4 |
| Aspirin use, % | 47.8 | 57.4 | 57.4 | 57.5 |
| Smoking status | ||||
| Never smoking, % | 47.5 | 41.0 | 40.7 | 43.0 |
| Past smoking, % | 31.8 | 31.2 | 31.1 | 31.8 |
| Current smoking, % | 20.7 | 27.8 | 28.2 | 25.2 |
| Coffee consumption | ||||
| Never or 1 cup/day, % | 51.6 | 52.9 | 52.8 | 53.9 |
| 2–3 cups/day, % | 22.3 | 22.5 | 22.7 | 21.9 |
| 4+ cups/day, % | 26.1 | 24.5 | 24.6 | 24.1 |
| Total calorie intake, kcal/day | 1819 (508) | 1766 (498) | 1762 (495) | 1786 (513) |
| Alcohol consumption, g/day | 6.7 (12.3) | 4.4 (9.4) | 4.2 (9.2) | 5.2 (10.3) |
| AHEI-2010 | 50.9 (10.0) | 49.4 (9.9) | 49.3 (9.9) | 49.8 (10.0) |
| Physical activity, MET-hrs/wk | 13.7 (21.1) | 10.9 (17.0) | 10.8 (16.7) | 11.7 (18.4) |
NHS Nurses’ Health Study, HPFS Health Professionals Follow-up Study, BMI body mass index, AHEI Alternative Health Eating Index, MET-hrs/wk Metabolic Equivalent of Task-hours/week, SD standard deviation.
aValues are means (SD) and percentages for categorical variables. All variables were standardised, except for age.
bBMI was calculated as weight in kilograms divided by the square of height in metres.
The overall gallstones and risks of incident liver, biliary tract and pancreatic cancer
During an average of 26 years of follow-up, we identified 204 liver cancer, 225 biliary tract cancer, and 1147 pancreatic cancer cases. Compared to participants without gallstones diagnosis, those with gallstones have a higher risk of the liver (HR: 1.86; 95% CI: 1.33–2.59), biliary tract cancer (HR: 5.34; 95% CI: 3.40–8.39), and pancreatic cancer (HR: 1.22; 95% CI: 1.04–1.42) in the age-adjusted model (Table 2). The multivariable HRs for individuals with gallstones were 1.60 for liver cancer (95% CI: 1.14–2.26), 4.79 for biliary tract cancer (95% CI: 3.02–7.58), and 1.13 for pancreatic cancer (95% CI: 0.96–1.32). The positive associations were consistent in each cohort (Supplementary Table 2). In the stratified analysis, we generally found similar associations of overall gallstones with the above cancers in subgroups defined by age, BMI, alcohol consumption, smoking status, aspirin use and hypercholesterolaemia (Table 3).
Table 2.
Gallstones, cholecystectomy, and risk of cancers of liver, biliary tract, and pancreas in the pooled Nurses’ Health Study (NHS) and Health Professionals Follow-up Study (HPFS).
| Gallstones, HRs (95% CI) | ||||
|---|---|---|---|---|
| No | Yes | Cholecystectomy | ||
| Yes | No | |||
| Liver cancer | ||||
| Number of cases (N = 204) | 156 | 48 | 35 | 13 |
| Age-adjusted model | 1 (ref) | 1.86 (1.33–2.59) | 1.56 (1.07–2.26) | 3.76 (2.11–6.72) |
| Multivariate modela | 1 (ref) | 1.60 (1.14–2.26) | 1.33 (0.90–1.95) | 3.42 (1.90–6.13) |
| Biliary tract cancer | ||||
| Number of cases (N = 225) | 203 | 22 | NA | NA |
| Age-adjusted model | 1 (ref) | 5.34 (3.40–8.39) | NA | NA |
| Multivariate modela | 1 (ref) | 4.79 (3.02–7.58) | NA | NA |
| Pancreatic cancer | ||||
| Number of cases (N = 1147) | 944 | 203 | 183 | 20 |
| Age-adjusted model | 1 (ref) | 1.22 (1.04–1.42) | 1.25 (1.07–1.47) | 0.98 (0.63–1.53) |
| Multivariate modela | 1 (ref) | 1.13 (0.96–1.32) | 1.15 (0.98–1.36) | 0.95 (0.61–1.49) |
BMI body mass index, NHS Nurses’ Health Study, HPFS Health Professionals Follow-up Study, HR hazard ratio, 95% CI 95% confidence interval, T2D type 2 diabetes mellitus.
aCox model stratified by age (in month), study period (two-year interval), cohort (NHS, HPFS, pooled analysis only), with additional adjustment for the race (white, non-white), aspirin use (yes, no), smoking status (never, past, current), total calorie intake (kcal/day, tertiles), alcohol intake (g/day, tertiles), coffee consumption (never or 1, 2–3, 4+ cups/day), physical activity (MET-hours/week, tertiles), AHEI-2010 (tertiles), BMI (kg/m2, continuous), hypercholesterolaemia (yes, no) and T2D (yes, no).
Table 3.
Stratified analyses of gallstones and risk of cancers of liver, biliary tract, and pancreas in pooled Nurses’ Health Study (NHS) and Health Professionals Follow-up Study (HPFS).
| Liver cancer (N = 204) | Biliary tract cancer (N = 225) | Pancreatic cancer (N = 1147) | ||||
|---|---|---|---|---|---|---|
| No. cases | HRs (95% CI) | No. cases | HRs (95% CI) | No. cases | HRs (95% CI) | |
| Age | ||||||
| <65 years | 43 | 1.71 (0.74–3.94) | 70 | 5.84 (2.42–14.1) | 285 | 1.51 (1.08–2.10) |
| ≥65 years | 161 | 1.57 (1.07–2.29) | 155 | 4.54 (2.64–7.79) | 862 | 1.04 (0.87–1.25) |
| P-interaction | 0.61 | 0.76 | 0.03 | |||
| BMI | ||||||
| <25 kg/m2 | 68 | 1.09 (0.51–2.35) | 94 | 3.80 (1.50–9.66) | 541 | 1.29 (1.00–1.66) |
| ≥25 kg/m2 | 136 | 1.69 (1.14–2.50) | 131 | 6.32 (3.66–10.9) | 606 | 1.03 (0.84–1.27) |
| P-interaction | 0.33 | 0.42 | 0.23 | |||
| Alcohol consumption | ||||||
| <15 g/day | 160 | 1.68 (1.16–2.44) | 188 | 5.03 (3.06–8.27) | 936 | 1.13 (0.95–1.33) |
| ≥15 g/day | 44 | 1.51 (0.60–3.82) | 37 | 8.33 (1.83–37.8) | 211 | 1.07 (0.67–1.69) |
| P-interaction | 0.84 | 0.92 | 0.77 | |||
| Smoking | ||||||
| Never | 109 | 1.82 (1.14–2.89) | 129 | 4.32 (2.32–8.05) | 680 | 1.08 (0.90–1.30) |
| Ever | 95 | 1.39 (0.83–2.35) | 96 | 5.79 (2.90–11.6) | 467 | 1.29 (0.95–1.74) |
| P-interaction | 0.42 | 0.67 | 0.55 | |||
| Aspirin use | ||||||
| No | 165 | 1.51 (1.02–2.22) | 152 | 3.18 (1.63–6.20) | 839 | 1.08 (0.89–1.30) |
| Yes | 39 | 1.77 (0.81–3.85) | 73 | 8.35 (4.14–16.9) | 308 | 1.28 (0.95–1.73) |
| P-interaction | 0.54 | 0.03 | 0.20 | |||
| Hypercholesterolaemia | ||||||
| No | 102 | 2.22 (1.36–3.61) | 101 | 6.20 (3.21–12.0) | 538 | 1.14 (0.89–1.46) |
| Yes | 102 | 1.18 (0.72–1.93) | 124 | 3.60 (1.83–7.08) | 609 | 1.13 (0.92–1.39) |
| P-interaction | 0.07 | 0.17 | 0.60 | |||
BMI body mass index, NHS Nurses’ Health Study, HPFS Health Professionals Follow-up Study, HR hazard ratio, 95% CI 95% confidence interval.
Cox model stratified by age (in month), study period (2-year interval), cohort (NHS, HPFS, pooled analysis only), with additional adjustment for the race (white, non-white), aspirin use (yes, no), smoking status (never, past, current), total calorie intake (kcal/day, tertiles), alcohol intake (g/day, tertiles), coffee consumption (never or 1, 2–3, 4+ cups/day), physical activity (MET-hours/week, tertiles), AHEI-2010 (tertiles), type 2 diabetes mellitus (yes, no), hypercholesterolaemia (yes, no) and BMI (kg/m2, continuous).
Factors used for stratification were not also adjusted as covariates in the models.
Cholecystectomy and risks of liver, biliary tract and pancreatic cancer
Participants with gallstones who underwent cholecystectomy were at a higher but nonstatistical significant risk of liver cancer (HR: 1.33; 95% CI: 0.90–1.95) and pancreatic cancer (HR: 1.15; 95% CI: 0.98–1.36) compared to participants without gallstones diagnosis (Table 2). For individuals with gallstones but no cholecystectomy, the risk for liver cancer (HR: 3.42; 95% CI: 1.90–6.13) was higher than for those without gallstones, whereas no such association was observed for pancreatic cancer (HR: 0.95; 95% CI: 0.61–1.49).
Sensitivity analyses
In the sensitivity analysis, when we exclude those developed cancers within 2 years after self-reported gallstones, the results were essentially the same (Supplementary Table 3). The positive associations did not materially change after excluding those with T2D (Supplementary Table 4). Gallstone disease was associated with a higher risk for HCC (HR: 1.69; 95% CI: 1.17–2.43), but not for ICC (HR: 1.01; 95% CI: 0.34–3.03) (Supplementary Table 5). We also evaluated the associations separately by subtypes of biliary tract cancers (Supplementary Table 6). Lastly, the associations of cholecystectomy regardless of gallstones status with the risk of liver and pancreatic cancer were 1.24 (95% CI: 0.84–1.81) and 1.15 (95% CI: 0.84–1.81), respectively (Supplementary Table 7).
Discussion
In these two large prospective U.S. cohort studies, we found that participants with gallstones were at greater risk of developing liver, biliary tract and possibly pancreatic cancer after adjustment for potential confounders. Cholecystectomy was associated with a suggestive increased risk of liver and pancreatic cancers. Our findings provide further evidence for a positive association of gallstones with the risk of cancers in the hepato–pancreato–biliary area.
The association between gallstones and cholecystectomy liver cancer risk has been examined by a number of studies [20–30]. Recently, one meta-analysis [14], based on 8 cohort and 2 case–control studies, reported that gallstones (OR: 2.66; 95% CI: 2.05–3.28) and cholecystectomy (OR: 1.47; 95% CI: 1.24–1.71) were positively associated with risk of liver cancer. Among prior studies, evidence from the U.S. is only limited to 2 case–control studies conducted among participants aged at least 66 years [29, 30]. One study, based on the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database, reported a significant positive association for gallstones (OR: 2.35; 95% CI: 2.18–2.54) and cholecystectomy (OR: 1.26; 95% CI: 1.12–1.41) [29]. Similarly, results from the same data source suggested that gallstones had an increased risk of intrahepatic cholangiocarcinoma (OR: 13.5; 95% CI: 11.3–16.1) [30]. Of note, the SEER data lacked information on important confounding factors, such as alcohol consumption and obesity. The current study represents an updated measure of gallstones as well as cholecystectomy and comprehensive information on potential confounders, including lifestyle, obesity and health conditions. In line with previous studies, our findings suggest gallstones as a potential risk factor for liver cancer in the U.S. In addition, cholecystectomy in our study was defined as due to gallstones in the current study. However, other conditions could become the candidate conditions for gallbladder removal, such as biliary dyskinesia and cholecystitis. In this context, the positive association between cholecystectomy and liver cancer risk might be underestimated.
The evidence for gallstones and biliary tract cancer is relatively limited due to the low incidence of the disease. Results from Denmark reported that gallstones were associated with an increased risk of biliary tract cancer, with standardised incidence ratios (SIRs) was 3.6 (95% CI: 2.6–4.9) for gallbladder cancer, 1.2 (95% CI: 0.8–1.7) for extrahepatic bile duct cancer, and 2.1 (95% CI: 1.3–3.1) for Ampulla of Vater cancer [23]. Similarly, the relative risk of biliary tract cancer increases consistently with gallstones in another study in Sweden [40]. Of note, that study relied on hospitalised data. Patients hospitalised for gallstones might have risk patterns that differed from those of individuals not requiring hospitalisation. Thus, the SIRs might lead to biased estimation and the results may not apply to the general population. Although three population-based case–control studies in China [41, 42] and the U.S. [29], along with one cohort study in Taiwan [27] also suggested gallstones were associated with an increased risk of biliary tract cancer, most of these studies have not adjusted for important confounders, such as smoking and alcohol consumption. In the current study, after adjusting for covariates, we observed a positive association between gallstones and biliary tract cancer. The results might be due to the effects of chronic inflammation caused by gallstones, which stimulates repair through cholangiocyte proliferation [43]. Accordingly, proliferation could lead to progressive destruction of extrahepatic bile ducts as well as Ampulla of Vater and an increased risk of gallbladder cancer [44]. Further studies with a larger sample size are needed to confirm our findings.
A meta-analysis of 22 studies (13 case–control and 9 cohort studies, including the aforementioned NHS and HPFS) reported positive associations of pancreatic cancer risk with gallstones (HR: 1.41; 95% CI: 1.24–1.61) and cholecystectomy (HR: 1.21; 95% CI: 1.09–1.33) [18]. We also found positive but nonsignificant associations of gallstones and cholecystectomy with pancreatic cancer risk that were consistent with the previous study based on follow-up through 1998 in the same NHS and HPFS cohorts [32] as well as the Cancer Prevention Study II [31] and the Oxford record-linkage study [22]. Interestingly, we observed that the risk of pancreatic cancer associated with gallstones appeared to be stronger in participants less than 65 years old. The observations might be due to chance. Alternatively, this may be explained by the genetic susceptibility to pancreatic cancer. Indeed, several important candidate genes were identified, including the cationic trypsinogen gene (PRSS1) and the serine protease inhibitor, Kazal type 1 gene (SPINK1) [45]. These mutations may increase the risk of pancreatitis diagnosis at younger ages, leading to younger ages at diagnosis of pancreatic cancer [46]. In this context, the impact effect of gallstones might be magnified by age.
A common potential link between gallstones and the development of the cancers of auxiliary organs might be through changes in the secretion of bile acids and their flow. Bile acids could facilitate fat absorption and may play a role in glucose and metabolism regulation, stimulating the secretion of gut hormones [47]. Gallstones disturbed the secretion of bile and its bioactive component. The distorted metabolism of bile acids has related many metabolic alterations, such as hypercholesterolaemia, T2D, and inflammation, which are risk factors for carcinogenesis [48–50].
Our study has several strengths, including the long-term follow-up, repeated collection of gallstone disease and lifestyle data. Several limitations of our study need to be noted. First, we could not consider undiagnosed gallstones, as gallstone cases were self-reported and most gallstones are asymptomatic. Thus, misclassification bias could not be ruled out. However, the results from analyses restricted to participants who had undergone cholecystectomy were similar to the main analyses. Future studies are needed to examine whether screen-detected gallstone disease (most asymptomatic) is related to digestive system cancers in the United States. Second, due to the limited case number, examining the relationship between gallstones and the risk of biliary tract cancer subtypes with an adequate sample size is desirable. Furthermore, our results might be influenced by detection bias due to increased surveillance and possible cancer detection around the time of the diagnosis of gallstone disease. We observed similar positive associations when we excluded cases diagnosed within 2 years since gallstone disease. Third, even though we adjusted for a variety of potential confounders, as with all observational studies, we cannot exclude the possibility of residual or unmeasured confounding. Last, the participants were predominantly whites, which may limit the generalisability of our results to other racial/ethnic populations.
In conclusion, our study suggests that gallstones were associated with a higher risk of liver and biliary tract and possibly pancreatic cancer. Cholecystectomy was associated with a suggestive increased risk of liver and pancreatic cancer. More research is needed to confirm our findings and examine the association between gallstones and other digestive system cancer risks, such as stomach and small intestine cancers. If confirmed by future studies, increased surveillance of individuals with gallstones for cancers in the hepato–pancreato–biliary area may be warranted.
Supplementary information
Acknowledgements
We would like to thank the participants and staff of the NHS and the 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 the analyses and interpretation of these data.
Author contributions
Drs. Luo and Zhang had full access to all the data in the study and took. responsibility for the integrity of the data and the accuracy of the data analysis. Acquisition of the data: KW, BMW, ATC, ELG and XZ. Analysis and interpretation of the data: XL. Drafting of the manuscript: XL. Critical revision of the manuscript for important intellectual content: all authors. Statistical analysis: XL. Obtained funding: ELG and XZ. Administrative, technical or material support: KW, BMW, ATC, ELG and XZ. Study supervision: ELG and XZ.
Funding
The HPFS and NHS were supported by the NCI at the NIH (grant numbers UM1 CA186107, P50 CA127003, P01 CA87969 and U01 CA167552). This work was supported by NIH grants (K07 CA188126 to XZ, and R21 CA238651 to XZ). XZ is also supported by the American Cancer Society Research Scholar Grant (RSG NEC-130476), NIH/NCI The Method to Extend Research in Time MERIT Award (R37 CA262299), Dana-Farber Harvard Cancer Center (DF/HCC), as well as Zhu Family Center at Harvard T.H. Chan School of Public Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of NIH. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
Data availability
Restrictions apply to the availability of these data, which were used under license for this study. Data are available [https://sites.google.com/channing.harvard.edu/cohortdocs/] with the permission of BWH and Harvard T.H. Chan School of Public Health.
Ethics approval and consent to participate
This study was approved by the Institutional Review Boards of the Brigham and Women’s Hospital and the Harvard T.H. Chan School of Public Health and of participating registries as required. Completion of the questionnaire was considered to imply informed consent.
Consent to publish
Not applicable.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
The online version contains supplementary material available at 10.1038/s41416-022-01877-5.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
Restrictions apply to the availability of these data, which were used under license for this study. Data are available [https://sites.google.com/channing.harvard.edu/cohortdocs/] with the permission of BWH and Harvard T.H. Chan School of Public Health.