Cholelithiasis increased prostate cancer risk: evidence from a case–control study and a meta-analysis

Worldwide more than 1,275,000 men are diagnosed annually with PCa. PCa is the second most common malignancy and the leading cause of cancer-associated mortality in men [1]. PCa could be seen in America and Europe, but little is known about its etiology [2, 3]. Established risk factors for PCa include age, ethnicity, germline mutation (BRCA5.35%, ATM1.6%, and CHEK1.9%), and dietary factors [4‐7]. Due to the heterogeneity and the multiple-factor of PCa, it is crucial to identify more risk factors.

With the prevalence of about 5–15% of the western population, cholelithiasis was an important public health problem in Europe and America [8]. Cholelithiasis has many risk factors, including genetic, environmental risk factors, diabetes, and metabolic syndrome, although hypersecretion of cholesterol plays a vital role in promoting the formation of gallstones [9]. The mechanism suggested that high cholesterol or metabolic syndrome may have tumorigenesis on the digestive system neoplasm and PCa. High cholesterol is associated with the development of PCa and can play an essential role in tumorigenesis by accumulating in cancer tissues [10, 11]. Consistent with these findings, men who take statins after prostatectomy would have less possibility of becoming aggressive PCa [12, 13]. The association between metabolic syndrome and the risk of developing PCa is emerging [8, 14, 15]. In addition, men with gallstones have disorders of gut microbiota, which may lead to prostate carcinogenesis [16, 17]. Recently, emerging epidemiological evidence suggested that previous cholelithiasis was correlated with the development and procession of PCa [18‐20].

The relationship between the two diseases is still controversial. Given the potential risk factor of cholelithiasis in PCa, we assessed the relationship between PCa and cholelithiasis and conducted a hospital-based case–control study in the Second Affiliated Hospital of Chongqing Medical University Hospital, China. Furthermore, we performed a systematic meta-analysis of published studies and our case–control study to evaluate the association between cholelithiasis and the risk of PCa.

The detailed process of the literature search was showed in Fig. 1. Finally, 6 published studies were included in our analysis by evaluating full-text review (Fig. 1) [19, 20, 22‐25]. Table 3 summarized the characteristics of included studies. Among those studies, there were 3 cohort studies and 3 case–control studies. 3 came from Europe, and 3 came from the Asia region. The publication date of these studies was from 2004 to 2017. 6 studies involving 3560 cases among 79,963 individuals investigated the associations between cholelithiasis and PCa risk. The quality of studies was summarized in Table 4. All eligible studies were defined as high quality (NOS ≥ 6) (Table 4).

A total of 7 studies, including our studies and 6 published studies, were eligible in this meta-analysis. As shown in Fig. 2, the pooled RR of PCa for men with a history of cholelithiasis was 1.35(95%CI: 1.17–1.56), with moderate-quality evidence (Table 5). There was no obvious heterogeneity (I² = 32.4%, P = 0.181) using a random effects model for assessment.

To better evaluate the association between cholelithiasis and PCa risk. We conducted a subgroup analysis based on the study regions, BMI level, gallstones and cholecystectomy. The results of the subgroup analysis were shown in Table 6. Stratified analysis among European and Asian showed an increased risk of PCa for men with a history of cholelithiasis (RR = 1.24, 95%CI: 1.03–1.51), (RR = 1.32, 95%CI: 1.24–1.41), comparing to men without cholelithiasis. Besides, cholelithiasis increased PCa risk, as suggested by the pooled RR of case–control studies, but not cohort studies. Men with cholelithiasis with lower BMI had a higher risk of PCa (RR = 1.54, 95%CI: 1.16–2.06), as suggested by stratified analyses by BMI level. Moreover, we observed that cholecystectomy or gallstones was not related to the risk of PCa.

We performed a sensitivity analysis to evaluate the risk of cholelithiasis on the overall estimate by removing individual studies, and we observed the stability of the results of this meta-analysis (Fig. 3). Visual inspection of funnel plots showed no evident asymmetry (Fig. 4). Publication bias was not observed based on both Begg’s (P = 0.545) and Egger’s test (P = 0.368) for PCa risk.

This study aimed to evaluate the impact of cholelithiasis on the subsequent PCa risk. In our case–control study, our findings from 221 cases and 219 controls provided evidence that men with pre-existing cholelithiasis had an increased risk of PCa, whereas we did not observe a significant association between cholecystectomy and PCa risk. Combined with the results of our meta-analysis, the history of cholelithiasis was significantly associated with PCa risk. However, as for cholecystectomy or gallstones, no significant risk difference was observed.

Some previous studies have reported an association between a history of cholelithiasis and cardiovascular, cholangiocarcinoma and pancreatic cancer risk [18, 26, 27]. In older men, there was a higher risk of cholelithiasis. Whether cholelithiasis modified the risk of PCa is worth investigating by considerable studies. Bravi et al. [25] reported that finding from 1294 cases and 1451 controls demonstrated that men with gallstones did not seem to be associated PCa risk in a case–control study. Recently, Qiang Li et al. [20] found that men with cholelithiasis had a higher incidence of PCa compared without cholelithiasis, especially for advanced PCa in the Ohsaki cohort followed from 1995 to 2003. Due to these inconsistent findings, our study provided evidence from a case–control combined with a meta-analysis to estimate the underlying association between cholelithiasis and PCa susceptibility. The results supported that cholelithiasis is a risk factor for the development of PCa.

A total of 7 studies were included in this meta-analysis. And we found that men with a history of cholelithiasis were associated with PCa risk. The increased PCa risk was also seen for both European and Asian population, as suggested by subgroup analysis according to a different region. In addition, the increased risk of PCa was observed for cholelithiasis patients with high and low BMI, as suggested by subgroup analysis according to different BMI. In the analysis of the different study designs, cholelithiasis was associated with the risk of PCa in case–control studies but not in cohort studies. The possible reasons for these disparities may be the limited number of included studies. In the future, we need better-designed studies to confirm this association.

Cholecystectomy is mainly indicated for individuals with biliary tract infection and pancreatitis, and decreases the incidence of the biliary tract and pancreatic malignancy [26, 27]. However, we did not observe that men who received cholecystectomy therapy were not significantly related to a decreased PCa risk. It was demonstrated that cholecystectomy would impair the enterohepatic circulation of bile acids and might increase oxidative stress and oxidative damage to DNA to stimulate prostate cancer cell growth and prostate carcinogenesis. There were epidemiologic studies that provided evidence about the relationship between cholecystectomy and PCa. Chien-Hua Chen et al. [28] reported data from 72,606 gallstone cases and the investigators assessed that cholecystectomy was linked to increased risk for PCa compared with the non-cholecystectomy group were HR = 1.67(95%CI, 1.45–1.92). Therefore, more studies are worth examining whether other factors affect risk discrepancies.

The underlying mechanism of cholelithiasis might lead to malignancy development still deserves to be explored. The potential mechanisms for the association of cholelithiasis with PCa may be the following. Firstly, prostate cancer may be mediated by the cholesterol metabolism associated with cholelithiasis. Cholesterol was critical for the proliferation of cells, and its synthesis was tightly synchronized to cell cycle progression. Cholesterol-lowering may induce apoptosis in PCa cells progressing through the cell cycle [10, 29‐32]. In addition, the progress of PCa depends on the existence of androgen. Cholesterol plays a vital role in androgen synthesis; consequently, it is possible that cholesterol promotes cancer growth [33‐36]. Second, microbiota dysbiosis could result in cholelithiasis in the gut and biliary tract [37‐39]. Intestinal microbial diversity would influence the number of bacteria causing systemic inflammation and prostate tumorigenesis [40‐45]. For example, dysbiosis of the gut microbiome can promote conjugation and recycling of estrogens via secretion of the β-glucuronides enzyme, which results in cell proliferation and tumor development [41, 46]. Finally, the metabolic syndrome also can influence the incidence of PCa and cholelithiasis [8, 14]. Metabolic syndrome is associated with increased cancer mortality and tumor aggressiveness, but the specific mechanism is not well-known. It may affect the level of androgen [47‐49].

There are some following strengths: to our knowledge, we firstly comprehensively estimated the association between cholelithiasis and PCa. We rigorously used the GRADE approach to assess the quality of evidence for the main findings. However, there are also several following limitations: firstly, with regard to meta-analysis, we include studies that adjusted or controlled for various risk factors, but some unknown or unmeasured residual confounders cannot be excluded. Secondly, in subgroup analysis, there are only two studies about cholecystectomy. We should be cautious about the results of.cholecystectomy. Last, the association between cholelithiasis and differ-grade PCa may be due to the limited current studies and well-designed studies are required to explore.

In conclusion, our study supported the associations of cholelithiasis with the increased risk of PCa in European and Asian populations. There was no significant relationship between cholecystectomy therapy and PCa risk. Further cohort studies should be conducted to better identify more mechanisms in the pathogenesis of PCa.