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Keywords:

  • cholelithiasis;
  • Japan;
  • prospective studies;
  • prostatic neoplasms;
  • incidence

Abstract

  1. Top of page
  2. Abstract
  3. Material and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

An association between cholelithiasis and prostate cancer has been reported sporadically in previous case-control and experimental studies, suggesting that cholesterol may play a promotional role in prostate cancer development and progression. However, this relationship remains poorly understood, and population evidence based on a strict study design is needed. The authors examined the history of cholelithiasis and the development of prostate cancer in the Ohsaki cohort followed from 1995 to 2003, in which 230 new cases of prostate cancer were ascertained among 22,458 Japanese men. Baseline information, including history of cholelithiasis, was collected using a self-administered questionnaire. The Cox proportional hazards regression model was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). The results showed that patients with a history of cholelithiasis had a higher risk of prostate cancer with a multivariate adjusted HR of 1.72 (95% CI: 1.12–2.66), and especially for advanced prostate cancer, the corresponding value was 2.29 (95% CI: 1.21–4.35). The associations were robust after adjustment for different potential confounders. This population-based prospective cohort study indicates that a history of cholelithiasis is associated with an increased incidence of prostate cancer.

The incidence and mortality of prostate cancer has been increasing rapidly and is one of the major cancers affecting men, both in Japan and worldwide.1–4 However, its etiology and pathogenesis remain poorly understood.5 Previous studies have suggested that cholesterol may play a signal transduction role that promotes tumor cell growth during the development and progression of prostate cancer,6 and that use of statin is associated with a decreased risk of advanced prostate cancer.7 As cholelithiasis (gallstone disease) is related to cholesterol metabolism, it may further impact the carcinogenesis of prostate cells. Regarding the association between cholelithiasis and prostate cancer, one ecological study and one case-control study have been reported.8, 9 Both studies suggested such an association, but it needs to be further verified using a prospective designed study. Therefore, we examined the association between history of cholelithiasis and the risk of prostate cancer to further clarify this association using data from a population-based cohort study conducted in Japan.

Material and Methods

  1. Top of page
  2. Abstract
  3. Material and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

Study population

The Ohsaki National Health Insurance (NHI) cohort study was a population-based prospective study conducted in Miyagi Prefecture, northeastern Japan. A detailed description of the design and methods is available elsewhere.10–12 Briefly, all NHI beneficiaries aged 40–79 years living in the catchment area of the Ohsaki Public Health Center were involved in 1995, when baseline characteristics (such as basic information, history of cholelithiasis, and health-related lifestyle factors) were collected through a self-administered questionnaire. The Ohsaki Public Health Center, a local government agency, provides preventive health services to the residents of 14 municipalities in Miyagi Prefecture. Among 26,481 eligible involved individuals, a total of 24,895 men (94%) responded. We considered the return of self-administered questionnaires signed by the participants to imply their consent to participate in the study. The study protocol was approved by the institutional review board of Tohoku University School of Medicine.

We excluded subjects (n = 322) who had withdrawn before the start of follow-up from January 1, 1995, subjects with a history of cancer (n = 1,558), and subjects who reported extreme daily energy intake (upper 1% and lower 1%) or with missing data for diet (n = 557). Finally, 22,458 subjects remained for analysis. During 9 years of follow-up (from January 1, 1995 to December 31, 2003), 230 incident cases of prostate cancer were identified.

Measurement

In the baseline survey, a self-administered structured questionnaire was used, which contained items on history of 14 listed diseases during the subjects' lifetime up to the baseline (1 being history of cholelithiasis) and the treatment status (finished treatment, in treatment and without treatment), items of basic individual information (such as age, body weight and height, time spent walking per day, smoking and alcohol drinking status, family history of cancer and so on), and items on general diet consumption during the previous year (based on a 40-item food frequency questionnaire). The food frequency questionnaire was subsequently assessed, and the results showed a reasonably high level of validity and reproducibility in assessing the intake of nutrients, foods and food groups among our study population.13

Follow-up and case ascertainment

We followed the diagnosis of prostate cancer through a computerized record linkage to the Miyagi Prefecture Cancer Registry, one of the oldest and most accurate population-based cancer registries in Japan.14 We ascertained the death, emigration or loss of NHI qualification of each study subject from the NHI withdrawal history files kept by Miyagi NHI Association. Prostate cancer incidence was set as our end point, which was defined as code C61.9 according to the International Classification of Diseases for Oncology, second edition (ICD-O-2).15 Clinical stage was classified as localized (cancer confined within the prostate, n = 45), advanced (extraprostatic or metastatic cancer involving lymph nodes or other organs, n = 66) or unknown. If the clinical stage information was not available, a Gleason score of less than or equal to 7 was considered to indicate localized cases (n = 23) and 1 of more than 7 was considered to indicate advanced cases (n = 18). Follow-up of the subjects who had withdrawn from the NHI was discontinued because of logistic limitations. The date and reasons for withdrawal were obtained from the records of the NHI withdrawal history files. We obtained the baseline information, the NHI claim and withdrawal history in individual files and connected them with the unique ID number of each beneficiary.

Statistical analysis

We counted the person-years of follow-up for each subject from January 1, 1995, until the date of diagnosis of prostate cancer, date of withdrawal from the NHI, date of death or the end of the study period (December 31, 2003), whichever occurred first. A total of 174,097 person-years were accumulated. We used the Cox proportional hazards regression model to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) of prostate cancer incidence according to the history of cholelithiasis and the different treatment categories, using the SAS version 9.1 statistical software package (SAS Institute, Cary, NC). The p values for the test of linear trend according to the different treatment categories of cholelithiasis were calculated by treating the category as a continuous variable. We conducted further analysis excluding cases of prostate cancer diagnosed in the first 2 years to minimize any potentially chance association within a relatively short time period. We also conducted stratified analysis according to the main confounders (such as age, BMI and smoking status) to lessen the possible influence of convincing covariates. All reported p values are two-sided, and the cut-off point for statistical significance was 0.05.

We considered the following variables to be potential confounders a priori: age at the baseline (continuous variable), family history of cancer (yes or no), BMI (calculated as weight in kilograms divided by height in meters squared; <18.5, 18.5–24.99 or ≥ 25.0), smoking status (never, former, currently smoking <20 cigarettes/day, or currently smoking ≥20 cigarettes/day) and daily total energy intake (continuous variable). Other confounders were also considered, such as history of hypertension (yes or no), education level (junior high school or lower, high school or college/university or higher), time spent walking (<1 or ≥1 hr/day), marital status (married or widowed/divorced/single), alcohol drinking (never, former or currently drinking), consumption of green tea (never or occasionally, 1–2 cups/day, 3–4 cups/day or ≥5 cups/day), daily consumption of calcium (divided continuous variable to 3 equal proportion as low, middle, or high) and daily consumption of fish and diary products (continuous variables). To consider the possibility that some factors might be collinear, we put together all these potential risk factors to evaluate multicollinearity by computing the variance inflation factors but found no possible collinearities (with a variance inflation factor of less then 10). The age-adjusted model, and the age and BMI-adjusted model were also computed and compared with the multivariate-adjusted model. The interactions between confounders were tested through the addition of cross-product terms to the multivariate-adjusted model.

Results

  1. Top of page
  2. Abstract
  3. Material and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

A total of 1,096 men (4.9%) reported that they had been previously diagnosed as having cholelithiasis at the baseline survey. The detailed characteristics of those with or without cholelithiasis are shown in Table 1. Men with a history of cholelithiasis tended to be older, with less energy intake and higher BMI than men without, and a lower proportion were current smokers and current drinkers. Subjects with cholelithiasis also tended to be more physically active than those without, showing a higher percentage of walking more than 1 hr daily and a higher percentage with a family history of cancer. The distributions of education level and marital status were similar.

Table 1. Selected characteristics of men according to history of cholelithiasis, the Ohsaki Cohort Study, 1995-2003 (n = 22,458)
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Table 2 shows the association between a history of cholelithiasis and the risk of prostate cancer incidence. The results showed that subjects with a history of cholelithiasis were associated with a higher risk of prostate cancer, with a multivariate adjusted HR of 1.72 (95% CI: 1.12–2.66), and especially for advanced prostate cancer, the corresponding value was 2.29 (95% CI: 1.21–4.35). The significant positive association was robust when adjusted for different confounders such as age (HR = 1.77, 95% CI: 1.15, 2.72), both the age- and BMI-adjusted (HR = 1.74, 95% CI: 1.13, 2.68) for all prostate cancer and the positive association was also stable for advanced prostate cancer. Although the association with localized prostate cancer was not significant at the limited set for our study, the HR indicated a trend toward a positive relationship.

Table 2. Hazard ratios and 95% confidence intervals for prostate cancer incidence according to history of cholelithiasis, the Ohsaki Cohort Study, 1995–2003 (n = 22,458)
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HRs were recalculated after the data had been stratified according to age, BMI level and smoking status. Subjects with a history of cholelithiasis were consistently more likely to develope prostate cancer than those without in all strata, with HRs greater than unity. The HR was highest for subjects who were overweight (BMI ≥ 25) as 2.89 (95% CI: 1.44, 5.81) in all categories (Table 3).

Table 3. Hazard ratios and 95% confidence intervals for prostate cancer incidence according to history of cholelithiasis, stratified by age, body mass index and smoking status, the Ohsaki Cohort Study, 1995–2003 (n = 22,458)
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Discussion

  1. Top of page
  2. Abstract
  3. Material and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

In this large population-based prospective cohort study conducted in Japan, we observed that 2% of subjects with cholelithiasis developed prostate cancer compared to less than 1% in the non-cholelithiasis group. History of cholelithiasis was significantly associated with a higher risk of prostate cancer incidence. This association was robust when different potential confounders were adjusted, and higher HRs were observed for advanced prostate cancer and for subjects with higher BMI.

To our knowledge, no previous cohort study and only 1 case-control study on this relationship has been conducted.9 The case-control study, conducted in Italy between 1991 and 2002, observed a nonsignificant excess risk of prostate cancer for patients with gallstones.9 Furthermore, an ecological study also suggested possible positive correlations between gallstones and prostate cancer across 15 countries.8 Evidences suggest that cholesterol is associated with cholelithiasis16–18 and also with advanced prostate cancer, although the data have been inconsistent.19–21 Our prospective observation of a population-based cohort (n = 22,458) confirmed these previous findings.

The possible biological mechanisms responsible for the association between cholelithiasis and prostate cancer may be mediated by the cholesterol metabolism associated with cholelithiasis. Cholesterol may play a promotional role in prostate cancer development and progression. Abnormal cholesterol metabolism influences signal transduction events at the membrane in a manner that promotes tumor cell growth, inhibits apoptotic signals and potentially stimulates other malignant cellular behaviors.6, 22–24 Cholesterol is one of the composition in making androgens and other steroid hormones, and androgens can stimulate the growth of prostate cancer cell. This implies high circulating cholesterol levels may promote the growth of prostate cancer. Previous meta-analysis of 6 randomized controlled trials and 13 observational studies indicated that use of cholesterol-lowering drugs had a protective effect against advanced prostate cancer,7 although no effect on total prostate cancer.7, 25 All these findings indicate that cholelithiasis may be a potential risk factor for the incidence of prostate cancer or that they may share the same causal factors.

High BMI is a crucial risk factor for some common cancers,26 but may not be a risk factor for prostate cancer. Some evidence indicates that BMI is positively associated with the incidence of gallstone disease,27–29 suggesting an important role in the relationship between history of cholelithiasis and the risk of prostate cancer. The HR was increased in the category of subjects with higher BMI (≥25 kg/m2), indicating an intensified risk for the subjects with both history of cholelithiasis and higher BMI. BMI has been shown to be directly associated with total cholesterol and low-density lipoprotein cholesterol,30 which may exacerbate cholelithiasis and thus increase the risk of prostate cancer.

Prostate specific antigen (PSA) mass screening has been introduced to detect prostate cancer at an early stage. In Japan, PSA mass screening has been provided free (or at low charge) during annual health check-ups by public health care facilities to all men aged 40 or elder once in every 5 years. In our study, the rate of participation in annual health check-ups did not differ between subjects with and without cholelithiasis. Moreover, we found that history of cholelithiasis was significantly associated with advanced prostate cancer as well as overall prostate cancer, which was more likely to be detected on the basis of symptoms. Therefore, our results were less likely to be influenced by PSA mass screening.

Our study had several strengths. To our knowledge, the Ohsaki Cohort Study is the first prospective cohort study to have tested the association between history of cholelithiasis and subsequent incidence of prostate cancer. Our subjects were recruited from the general population, the participation rate of 94% was high, and we excluded some subjects to avoid the possible potential bias. We analyzed the data according to the clinical stages of prostate cancer and further stratified our analysis by age, BMI and smoking status.

Our study also had some limitations. First, the history of cholelithiasis was self-reported and not confirmed by laboratory or imaging tests, and thus some asymptomatic patients may have been missed. Furthermore, we did not inquire about the duration of cholelithiasis, which prevented us from analyzing the time–response relationship. However, after we had excluded the cases of prostate cancer occurring during the first 2 years of follow-up to avoid any possible diagnosis of cholelithiasis been triggered by early symptoms associated with prostate cancer, the observed associations maintained statistical significant for total prostate cancer and advanced prostate cancer. Moreover, we listed a number of diseases in the baseline questionnaire, and, thus, we were confident that the participants would not concentrate on history of cholelithiasis.

Second, we excluded 557 subjects who had reported extreme daily energy intake (upper 1% and lower 1%), or for whom data were missing. Five cases (0.9%) of prostate cancer were diagnosed in this group, which was close to the percentage in our analysis database (1.0%). The characteristics of these subjects with missing or extreme energy consumption were similar to those of the other subjects in terms of mean age (59.5 vs. 59.3) and mean BMI (23.8 vs. 23.4). There was no difference in prostate cancer incidence between the subjects included in the analysis (n = 22,458) and those who were excluded (n = 557), and the multivariate-adjusted HR of prostate cancer risk was 0.64 (95% CI: 0.26–1.57; p = 0.33). At the same time, 2,506 (11.2%) of the participants were lost to follow-up. The basic characteristics of those who were fully followed-up (n = 19,952) and those who were lost (n = 2,506) were similar in terms of mean age (59.4 vs. 57.7), mean BMI (23.38 vs. 23.34) and the proportion with a self-reported history of cholelithiasis (4.9% vs. 4.7%, p = 0.67). Thus, our results would not have been markedly biased by exclusion of the subjects with extremely high or low diet consumption or who were lost to follow-up.

Third, we lacked stage information for some cases of prostate cancer, and thus the stratified result may have been biased. In spite of this, the HRs for prostate cancer overall, localized stage and advanced stage were close to each other, with HRs greater than unity. Although that for localized-stage prostate cancer did not reach statistical significance, we consider that the HRs would not have been affected much if stage information had been fully available.

In conclusion, this large population-based prospective cohort study carried out in Japan indicated a significantly higher risk of prostate cancer in men with a history of cholelithiasis. This association was more evident for advanced prostate cancers and for subjects who were overweight. These results suggest that cholelithiasis and prostate cancer may share the same causal factors, and that further research is warranted to explore the pathogenesis and prevention of prostate cancer.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Material and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

We thank Takeda Science Foundation offering scholarship to Qiang Li to conduct this research in Japan.

References

  1. Top of page
  2. Abstract
  3. Material and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References