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REVIEW ARTICLE
Year : 2014  |  Volume : 10  |  Issue : 4  |  Page : 834-838

Cholelithiasis, cholecystectomy and risk of hepatocellular carcinoma: A meta-analysis


Department of General Surgery, Key Laboratory of Digestive System Tumors, Lanzhou University Second Hospital, Lanzhou 730000, Gansu Province, China

Date of Web Publication9-Jan-2015

Correspondence Address:
Prof. Yumin Li
Department of General Surgery, Key Laboratory of Digestive System Tumors, Lanzhou University Second Hospital, Lanzhou 730000, Gansu Province
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.135992

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 > Abstract 

Available evidence of the relationship between cholelithiasis, cholecystectomy, and risk of liver cancer and hence we conducted a meta-analysis to investigate the relationships. PubMed, EMBASE, and ISI Web of Knowledge were searched to identify all published cohort studies and case-control studies that evaluated the relationships of cholelithiasis, cholecystectomy and risk of liver cancer and single-cohort studies which evaluated the incidence of liver cancer among patients who understood cholecystectomy (up to February 2013). Comprehensive meta-analysis software was used for meta-analysis. A total of 11 observational studies (six cohort studies and five case-control studies) were included in this meta-analysis. The result from meta-analysis showed that cholecystectomy (risk ratio [RR]: 1.59, 95% confidence interval [CI]: 1.01-2.51, I2 = 72%) and cholecystolithiasis (RR: 5.40, 95% CI: 3.69-7.89, I2 = 93%) was associated with more liver cancer, especially for intrahepatic cholangiocarcinoma (ICC) (cholecystectomy: RR: 3.51, 95% CI: 1.84-6.71, I2 = 26%; cholecystolithiasis: RR: 11.06, 95% CI: 6.99-17.52, I2 = 0%). The pooled standardized incidence rates (SIR) of liver cancer in patients who understood cholecystectomy showed cholecystectomy might increase the incidence of liver cancer (SIR: 1.57, 95% CI: 1.13-2.20, I2 = 15%). Based on the results of the meta-analysis, cholecystectomy and cholecystolithiasis seemed to be involved in the development of liver cancer, especially for ICC. However, most available studies were case-control studies and short-term cohort studies, so the future studies should more long-term cohort studies should be well-conducted to evaluate the long-term relationship.

 > Abstract in Chinese 

胆结石、胆囊切除术和肝细胞癌的风险:一项荟萃分析
摘要 现有的证据证实胆石症、胆囊切除术与肝癌的风险之间的关系,因此我们进行了一项荟萃分析研究。在PubMed,EMBASE,ISI Web of Knowledge中进行检索,找出所有发表关于胆石症、胆囊切除、肝癌的关系的队列研究和病例对照研究评价,和单队列研究评估了胆囊切除术患者的肝癌的发病率(至2013年2月)。综合分析软件进行Meta分析。共有11个观察性研究(6项队列研究和5个病例对照研究)进行Meta分析。从元分析结果表明,胆囊切除术(风险比[RR]:1.59,95%可信区间[CI]:1.01-2.51,I2 = 72%)和胆囊结石(RR :5.40,95% CI:3.69-7.89,I2 = 93%)与肝癌相关,特别是肝内胆管细胞癌(ICC)(胆囊切除术:RR:3.51,95%可信区间:1.84-6.71,I2 = 26%;胆囊结石:RR: 11.06,95% CI:6.99-17.52,I2 = 0)。汇集肝癌标准化发病率(SIR)接受胆囊切除术者可能会增加肝癌的发生率(SIR:1.57,95%可信区间:1.13-2.20,I2 = 15%)。基于Meta分析的结果,胆囊切除、胆囊结石似乎在肝癌发展过程中有关,尤其是肝内胆管细胞癌。但是多数病例对照研究是短期研究,因此,未来的研究应该更多地进行长期队列研究,并行长期关系的评估。
关键词:胆囊切除术,胆囊结石,肝肿瘤,Meta分析

Keywords: Cholecystectomy, cholelithiasis, liver neoplasms, meta-analysis


How to cite this article:
Guo L, Mao J, Li Y, Jiao Z, Guo J, Zhang J, Zhao J. Cholelithiasis, cholecystectomy and risk of hepatocellular carcinoma: A meta-analysis. J Can Res Ther 2014;10:834-8

How to cite this URL:
Guo L, Mao J, Li Y, Jiao Z, Guo J, Zhang J, Zhao J. Cholelithiasis, cholecystectomy and risk of hepatocellular carcinoma: A meta-analysis. J Can Res Ther [serial online] 2014 [cited 2019 Nov 18];10:834-8. Available from: http://www.cancerjournal.net/text.asp?2014/10/4/834/135992


 > Introduction Top


Liver cancer is a common disorder worldwide, which ranks the fifth and seventh most common cancer among men and women. [1] It was considered that liver cancer comprised hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). [2],[3] Both HCC and ICC are primary epithelial malignancies of the liver and are often classified together as primary liver cancers in epidemiological reports. [4] A rise in incidence of liver cancer has been recently. [5],[6] According their studies, the rate of liver cancers doubled not only in England and Wales during 1971-2001, but also in the United States between 1976 and 2000. [5],[6] The incidence ratio of ICC increased dramatically. According to study conducted by West et al., the incidence of ICC increased with the greatest rise, around 12-fold. [5] Although it was reported the incidence rates of liver cancer (both HCC and ICC) around 2000 in most Asian populations have decreased as compared with 1985, the incidence rates of liver cancer were still high in these areas. [3]

Cholecystectomy (removal of the gallbladder) is the preferred treatment option for gallstone-associated cholecystitis. [7] Benign gallstones disease and thus cholecystectomy are extremely common in Western societies and developing countries. It was reported that the number of patients who received cholecystectomy increased rapidly in the United States after the introduction of laparoscopic cholecystectomy in 1991, with an estimated total number of 770,000 cholecystectomy done in 1996. [8] However, recent single-cohort studies [7],[9],[10] showed that cholecystectomy might be associated with an increased risk of hepatobiliary cancer, including liver cancer. But results from cohort studies [11],[12] were conflicted with them. The cohort study conducted by Chow et al. showed that cholecystectomy might be associated with a reduced risk of liver cancer, [12] and the cohort study conducted by Goldacre et al. found a short-term significant elevation of rates of cancers of the liver after cholecystectomy. [11] In order to resolve the differences among studies, we conducted a meta-analysis to investigate the relationships of cholelithiasis, cholecystectomy, and risk of liver cancer.


 > Methods Top


Search strategy

PubMed, EMBASE, and ISI Web of Knowledge were searched. Subject heading terms were also added in all searches for PubMed (MESH) and EMBASE (EMTREE) searches, search terms including: Liver Neoplasms, hepatocellular adenocarcinoma, cholecystectomy, cholelithiasis. Further, we screened the reference lists of the review articles and identified studies. All the searches were conducted independently by two reviewers in February 2013 without language restrictions; differences were resolved by discussion.

Inclusion criteria and study selection

We identified all published cohort studies and case-control studies that evaluated the relationships of cholelithiasis, cholecystectomy, and risk of liver cancer. Here, we defined liver cancer as HCC and/or ICC.

Simultaneously, we included single-cohort studies which evaluated the incidence of liver cancer among patients who understood cholecystectomy or have a history of cholecystolithiasis. The outcome was standardized incidence rates (SIR).

When many articles for the same study were published, we used the most comprehensive article. Two reviewers independently assessed potentially relevant citations for inclusion, disagreements were resolved involved with a third reviewer.

Data abstraction

Using a standardized data extraction form by two authors, we collected the following baseline characteristics for cases and control groups: lead author, publication year, sample size and outcomes. Any disagreements were resolved by a third reviewer.

Data analysis

Meta-analysis was conducted by Comprehensive Meta-analysis software. We expressed the data using risk ratio (RR) and its 95% confidence interval (95% CI). The percentage of variability across trials attributable to heterogeneity was estimated with the I2 test, which was deemed significant when P < 0.05. Data were pooled using random-effect model. Subgroup analyses of different sub-sites of liver cancer (HCC vs. ICC).


 > Results Top


Search results

After comprehensive search, 868 citations were retrieved (PubMed 526, EMBASE 232, ISI 81, reference tracking 29). After screening titles and abstracts, we excluded 115 duplicates and 562 records. And further we excluded studies that were not about liver cancer (n = 83), and not about cholecystectomy or cholecystolithiasis (n = 108). Finally, 11 studies [7],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18] were included.

Characteristics of included studies

Two studies [11],[12] were cohort studies, four studies [7],[9],[10],[17] were single-cohort studies, and the last five [13],[14],[15],[16],[18] were case-control studies. Nine studies [7],[9],[10],[11],[12],[15],[16],[17],[18] were about cholecystectomy, and four studies [10],[13],[14],[15] were about cholecystolithiasis. Seven studies [7],[9],[10],[11],[12],[13],[17] were about liver cancer (these studies did not distinguish ICC and HCC), and four studies [14],[15],[16],[18] were about ICC. The two cohort studies were from UK and Denmark, separately. The total number of cholecystectomy cohort was 81,715, and the total number of control cohort was 352,585. The four single-cohort studies [7],[9],[17] were from the USA, China, and Sweden (n = 2), separately. And the total number of cholecystectomy cohort was 410,575, and the total number of liver cancer event was 496. The five case-control studies [13],[14],[15],[16],[18] were from China (n = 2), Italy, Denmark, and the USA. The total number of the case was 2146, and the total number of control was 109,009. The other characteristics were presented in [Table 1] and [Table 2].
Table 1: Characteristics of included cohort studies

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Table 2: Characteristics of included case control studies

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Meta-analysis results

Meta-analysis showed that cholecystectomy was associated with more liver cancer (RR: 1.59, 95% CI: 1.01-2.51, I2 = 72%). When we restricted the studies that focused on ICC, the pooled results showed cholecystectomy was associated with more ICC (RR: 3.51, 95% CI: 1.84-6.71, I2 = 26%). However, when we restricted the studies that focused on liver cancer (those studies did not distinguish HCC and ICC), the pooled results showed cholecystectomy was not associated with more liver cancer (RR: 0.74, 95% CI: 0.39-1.40, I2 = 0%) [Figure 1].
Figure 1: The meta-analysis results of cholecystectomy and liver cancer

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Meta-analysis showed that cholecystolithiasis was associated with more liver cancer (RR: 5.40, 95% CI: 3.69-7.89, I2 = 93%). When we restricted the studies that focused on ICC, the pooled results showed cholecystolithiasis was associated with more ICC (RR: 11.06, 95% CI: 6.99-17.52, I2 = 0%). However, when we restricted the studies that focused on liver cancer (those studies did not distinguish HCC and ICC), the pooled results showed cholecystolithiasis was not associated with more liver cancer (RR: 1.17, 95% CI: 0.60-2.29, I2 = 0%) [Figure 2].
Figure 2: The meta-analysis results of cholecystolithiasis and liver cancer

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Meta-analysis showed that the pooled SIR in patients who understood cholecystectomy was 1.57 (95% CI: 1.13-2.20, I2 = 15%) and the pooled SIR in cholecystolithiasis patients was 2.77 (95% CI: 2.18-3.51) [Figure 3].
Figure 3: The meta-analysis results of the rates of cholecystectomy and liver cancer

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 > Discussion Top


Summary of finding

The meta-analysis indicated that cholecystectomy and cholecystolithiasis were associated with more liver cancer, especially for ICC (cholecystectomy: RR: 3.51, 95% CI: 1.84-6.71, I2 = 26%; cholecystolithiasis: RR: 11.06, 95% CI: 6.99-17.52, I2 = 0%). The pooled SIR of liver cancer in patients who understood cholecystectomy showed cholecystectomy might increase the incidence of liver cancer (SIR 1.57, 95% CI: 1.13-2.20, I2 = 15%).

According to a recent study, cholecystectomy was a predictor of the development cirrhosis and was associated with elevated serum liver enzymes. [19] In this study, cholelithiasis was not independently associated with serum liver enzyme levels, and whether cholelithiasis is associated with the development of cirrhosis was uncertain. [19] So based on this study, it was easy to explain the result of our meta-analysis. However, available evidence was conflicted, and that is why there were high heterogeneities in the pooled results. That might be because of low numbers of liver cancer and ICC cases which could introduce chance findings, short follow-up time, and differences in study design.

It is possible that the increases of HCC and ICC rates are related to common exposures. [11] A recent meta-analysis [4] showed that cirrhosis, chronic hepatitis B and C, diabetes, and obesity that were all established risk factors for HCC were also major risk factors for ICC. These data suggest a common pathogenesis of primary intrahepatic epithelial cancers. However, based on available evidence, it is hard to judge whether cholecystectomy and cholecystolithiasis involve the same pathogenesis of liver cancer, as none of included studies investigated the relationship of cholecystectomy and cholecystolithiasis in HCC.

Recent meta-analyses showed that cholecystectomy may increase esophageal adenocarcinoma risk, [20] colonic adenoma [21] and pancreatic cancer, [22] but cholecystectomy did not increase the risk of esophageal squamous cell carcinoma and gastric cancer development [6] and rectal cancer. [23] Our meta-analysis suggested that cholecystectomy was associated with increased liver cancer risk. This relationship of cholecystectomy was especially seen in ICC.

Strengths and limitations

This is the first meta-analysis that evaluated the relationships of cholelithiasis, cholecystectomy and risk of liver cancer. We used rigor meta-analysis method: two authors independently searched databases, selected studies, and abstracted data. However, there were still several limitations in this meta-analysis: first - we did not conduct subgroup analysis of study designs (cohort vs. case-control study). This was due to few studies we included. Second - the heterogeneities among studies existed. That might be because of low numbers of liver cancer and ICC cases, which could introduce chance findings, short follow-up time, and differences in study design. Third, we included both cohort and case-control studies. Case-control design is more susceptible to recall and selection biases than a cohort design. [22] Cohort studies may be affected by detection bias, and the ascertainment of liver cancer outcome was based on registry, which would introduce "misclassification bias."

Future implications

As a majority of previous studies were case-control studies, more large-scale longitudinal cohort studies should be conducted to establish a causal relationship. The follow-up time for cohort studies were short, so the long-term effect could not be well-evaluated. In the future, long follow-up cohort studies should be conducted. At the same time, the numbers of liver cancer and ICC cases in available cohort studies and case-control studies were low, hence the future cohort studies and case-control studies should include more liver cancer and ICC cases.


 > Conclusion Top


Based on the results of the meta-analysis, cholecystectomy and cholecystolithiasis seemed to be involved in the development of liver cancer, especially for ICC. However, most available studies were case-control studies and short-term cohort studies, so the future studies should more long-term cohort studies should be well-conducted to evaluate the long-term relationship.

 
 > References Top

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Gao J, Xie L, Yang WS, Zhang W, Gao S, Wang J, et al. Risk factors of hepatocellular carcinoma: Current status and perspectives. Asian Pac J Cancer Prev 2012;13:743-52.  Back to cited text no. 1
    
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Behrens G, Matthews CE, Moore SC, Freedman ND, McGlynn KA, Everhart JE, et al. The association between frequency of vigorous physical activity and hepatobiliary cancers in the NIH-AARP Diet and Health Study. Eur J Epidemiol 2013;28:55-66.  Back to cited text no. 2
    
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Shin HR, Oh JK, Masuyer E, Curado MP, Bouvard V, Fang Y, et al. Comparison of incidence of intrahepatic and extrahepatic cholangiocarcinoma: Focus on East and South-Eastern Asia. Asian Pac J Cancer Prev 2010;11:1159-66.  Back to cited text no. 3
    
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Palmer WC, Patel T. Are common factors involved in the pathogenesis of primary liver cancers? A meta-analysis of risk factors for intrahepatic cholangiocarcinoma. J Hepatol 2012;57:69-76.  Back to cited text no. 4
    
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West J, Wood H, Logan RF, Quinn M, Aithal GP. Trends in the incidence of primary liver and biliary tract cancers in England and Wales 1971-2001. Br J Cancer 2006;94:1751-8.  Back to cited text no. 5
    
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Welzel TM, Graubard BI, El-Serag HB, Shaib YH, Hsing AW, Davila JA, et al. Risk factors for intrahepatic and extrahepatic cholangiocarcinoma in the United States: A population-based case-control study. Clin Gastroenterol Hepatol 2007;5:1221-8.  Back to cited text no. 15
    
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Welzel TM, Mellemkjaer L, Gloria G, Sakoda LC, Hsing AW, El Ghormli L, et al. Risk factors for intrahepatic cholangiocarcinoma in a low-risk population: A nationwide case-control study. Int J Cancer 2007;120:638-41.  Back to cited text no. 16
    
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Ekbom A, Hsieh CC, Yuen J, Trichopoulos D, McLaughlin JK, Lan SJ, et al. Risk of extrahepatic bileduct cancer after cholecystectomy. Lancet 1993;342:1262-5.  Back to cited text no. 17
    
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Tao LY, He XD, Qu Q, Cai L, Liu W, Zhou L, et al. Risk factors for intrahepatic and extrahepatic cholangiocarcinoma: A case-control study in China. Liver Int 2010;30:215-21.  Back to cited text no. 18
    
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Ioannou GN. Cholelithiasis, cholecystectomy, and liver disease. Am J Gastroenterol 2010;105:1364-73.  Back to cited text no. 19
    
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Chiong C, Cox MR, Eslick GD. Gallstone disease is associated with rectal cancer: A meta-analysis. Scand J Gastroenterol 2012;47:553-64.  Back to cited text no. 23
    


    Figures

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