Risk factors for intrahepatic cholangiocarcinoma: a systematic review and meta-analysis

DOI: https://doi.org/10.21203/rs.2.11210/v1

Abstract

Background The incidence of intrahepatic cholangiocarcinoma (ICC) has increased worldwide in recent years, but the risk factors of ICC have not yet been clearly defined. The aim of this study was to identify risk factors for ICC. Methods A literature search was conducted in PubMed database for eligible studies published from January 2000 to November 2018. Summary odds ratio (OR) with their corresponding 95% confidence intervals (CI) were calculated using a random-effects model. Results Thirty-two studies (5 cohort, 27 case control) were included in this meta-analysis. Pooled estimates indicated that cirrhosis (OR=11.96, 95% CI 7.53-19.00), hepatitis B virus (HBV) infection (OR=4.09, 95% CI 3.13-5.34), hepatitis C virus (HCV) infection (OR=3.94, 95% CI 2.85-5.45), alcohol consumption (OR=2.68, 95% CI 1.97-3.66), hepatolithiasis (OR=14.94, 95% CI 6.41-34.83), choledochal cyst (OR=21.67, 95%CI 10.83-43.36), primary sclerosing cholangitis (PSC) (OR=93.91, 95%CI 43.99-200.47), diabetes mellitus (OR=1.82, 95% CI 1.57-2.11), non-alcoholic fatty liver disease (OR=2.23, 95% CI 1.65-3.02), liver fluke infection (OR=2.28, 95% CI 1.30-4.01) and smoking (OR=1.26, 95% CI 1.07-1.49) were significantly associated with ICC. Non-significant association was found between ICC and history of cholecystectomy, hypertension, coffee and aspirin. Conclusions Cirrhosis, HBV infection, HCV infection, alcohol consumption, hepatolithiasis, choledochal cyst, PSC, diabetes mellitus, non-alcoholic fatty liver disease, liver fluke infection and smoking are risk factors for ICC.

Background

Intrahepatic cholangiocarcinoma (ICC) is the second most common type of liver cancer next to hepatocellular carcinoma (HCC), accounting for nearly 3% of all gastrointestinal cancers in the world, and its incidence has been increasing recently in many geographic areas [1, 2]. The prognosis of ICC patients is dismal because most patients are diagnosed late, when curative treatment is not possible [3]. Therefore, early detection of ICC and recognition of risk factors are of great clinical significance.

Liver fluke infestation, primary sclerosing cholangitis (PSC) and hepatolithiasis are established risk factors for ICC [4]. Several recent studies have investigated the association of ICC with hepatitis B virus (HBV)/hepatitis C virus (HCV) infection cirrhosis, choledochal cyst, the history of cholecystectomy, diabetes mellitus (DM), non-alcoholic fatty liver disease (NAFLD) and smoking, but the results are inconclusive, partly due to the relatively low ICC incidence, making it difficult to assemble large enough cohorts to achieve adequate power for statistical analysis. We therefore conducted a systematic review and meta-analysis to identify risk factors for ICC.

Methods

Literature search

Studies were identified by carrying out a systematic review of all relevant published literatures in the PubMed database. The language of studies was limited only for English with studies published from January 2000 to November 2018. We conducted the search in November 2018 using the following key words: risk, “epidemiology, etiology and cholangiocarcinoma. In addition, we manually searched the citations of all retrieved articles for additional studies.

Criteria for inclusion and exclusion

The included studies must meet the following criteria: (a) cohort-based or case-control studies; (b) studies using the defined criteria to examine individual risk factors; and (c) studies providing adequate information for odds ratio (OR) calculation. Abstracts, reviews, expert opinions, animal studies, letters, editorials, and cohort studies involving patients with extra-hepatic cholangiocarcinoma and co-existing hepatocellular-cholangiocarcinoma were excluded.

Data extraction

Two reviewers (Shijie Wang and Zhibin Cai) independently the extracted information from each included study using the predefined criteria, including the first author, year of publication, documentation of risk factor, and numbers of individuals with ICC (cases) and without ICC (controls).

Statistical analysis

Statistical analyses were performed using Review Manager (RevMan) software 5.3 (Cochrane Collaboration). A pooled OR and 95% confidence interval (CI) were calculated for each risk factor from the crude number of study patients. Subgroup analysis was based on stratification by geographical area. Study heterogeneity was evaluated by I2, and values greater than 50% indicated considerable heterogeneity. The random-effects model was adopted regardless of heterogeneity or not, and funnel plots were used to detect potential publication bias.

Results

Study characteristics

A total of 1091 publications were identified, including 1088 from Pubmed and 3 from other sources, of which 32 met the selection criteria and were included in the analysis, including 5 cohort-based and 27 case-control studies (Fig. 1). Of the 32 included studies, nine were conducted in the United States [5-14], eight in China [15-22], four in Taiwan (China) [23-26], three in Korea [27-29], two in Italy [30, 31], three in Japan [32-34], one in Denmark [35], and one in 10 European countries [36]. The characteristics of the 32 included studies are summarized in Table 1.

Cirrhosis

Sixteen case-control studies investigated the association between cirrhosis and ICC [5, 6, 9, 10, 12, 13, 16, 18, 19, 22, 23, 25, 26, 29, 34, 35]. Of them, six studies were from the United States, four from China, three from Taiwan (China), and one each was from Japan, Denmark and Korea. These studies included a total case and control population of 801278 participants. All these 16 case-control studies showed that cirrhosis increased the ICC risk. Our meta-analysis further confirmed this significant association with a pooled OR of 11.96 (95% CI 7.53-19.00, I2=95%) (Fig. 2). The corresponding OR for studies in Eastern and Western countries was 8.97 (95% CI 4.91-16.37; I2=93%) and 16.38 (95% CI 9.12-29.42; I2=93%), respectively (Table 2).

HBV infection

Twenty-three studies including 21 case-control and 2 cohort-based studies investigated the association between HBV infection and ICC [5, 6, 9, 10, 13, 15-29, 31, 33, 34]. Of them, five studies were from the United States, weight from China, four from Taiwan (China), three from Korea, two from Japan, and one was from Italy. The research data were collected during the period from 1983 to 2014, involving a total of 2632515 participants. Six of the 23 studies reported no significant association between HBV infection and ICC [5, 10, 15, 27, 31, 34], but the remaining 17 studies showed a significant association [6, 9, 13, 16-26, 28, 29, 33]. Our meta-analysis showed that HBV infection was a risk factor for ICC with a pooled OR of 4.09 (95% CI 3.13-5.34; I2=83%) (Fig. 3). The corresponding OR for Eastern and Western countries studies was 4.56 (95% CI 3.33-6.24; I2=87%) and 2.90 (95% CI 1.70-4.97; I2=58%), respectively (Table 2).

HCV infection

Twenty-one studies including 19 case-control and 2 cohort-based studies investigated the association between HBV infection and ICC [5-7, 9-13, 15, 19-21, 23, 25-29, 31, 33, 34]. Of them, eight studies were from the United States, four from China, three from Taiwan (China), three from Korea, two from Japan, and one was from Italy. The research data were collected during the period from 1988 to 2014, involving a total of 1669223 participants. Seven studies reported no significant association between HCV infection and ICC [15, 19-21, 27-29], but the remaining 14 studies showed a significant association [5-7, 9-13, 23, 25, 26, 31, 33, 34]. Our meta-analysis showed that HCV infection was a risk factor for ICC with a pooled OR of 3.94 (95% CI 2.85-5.45; I2=80%) (Fig. 4). The corresponding OR for Eastern and Western countries studies was 3.03 (95% CI 1.80-5.10; I2=89%) and 5.13 (95% CI 3.81-6.91; I2=39%), respectively (Table 2).

Smoking

Seventeen case-control studies investigated the association between smoking and ICC [5, 6, 9-13, 15, 17, 19-21, 28-30, 32, 34]. Of them, seven studies were from the United States, five from China, two from Korea, two from Japan, and one was from Italy. The research data were collected during the period from 1991 to 2014, involving a total of 731128 participants. Ten studies reported no significant association between smoking and ICC [6, 11, 17, 20, 21, 28-30, 32, 34], but the remaining seven studies showed a significant association [5, 9, 10, 12, 13, 15, 19]. Our meta-analysis showed that smoking was a risk factor for ICC with a pooled OR of 1.26 (95% CI 1.07-1.49; I2=78%) (Fig. 5). The corresponding OR for Eastern and Western countries studies was 1.01 (95% CI 0.74-1.37; I2=74%) and 1.49 (95% CI 1.21-1.83; I2=79%), respectively (Table 2).

Alcohol consumption

Eighteen case-control studies investigated the association between alcohol consumption and ICC [9-13, 15, 17, 19-23, 25, 28, 29, 31, 34, 35]. Of them, five studies were from the United States, six from China, two from Taiwan (China) and Korea, and one each was from Denmark, Japan and Italy. The research data were collected during the period from 1978 and 2013, involving a total of 795889 participants. Six of the 18 studies reported no significant association between alcohol consumption and ICC [15, 17, 21, 28, 31, 34], but the remaining twelve studies showed a significant association [9-13, 19, 20, 22, 23, 25, 29, 35]. Our meta-analysis showed that alcohol consumption was a risk factor for ICC with a pooled OR of 2.68 (95% CI 1.97-3.66; I2=87%) (Fig. 6). The corresponding OR for Eastern and Western countries studies was 1.99 (95% CI 1.30-3.06; I2=88%) and 4.28 (95% CI 2.56-7.15; I2=83%), respectively (Table 2).

Hepatolithiasis

Six case-control studies investigated the association between hepatolithiasis and ICC [5, 16, 17, 21, 28, 29]. Of them, one study was from the United States, three were from China and two from Korea. The research data were collected during the period from 1998 to 2013, involving a total of 6560 participants. Five studies performed in Eastern countries indicated a significant association between hepatolithiasis and ICC [16, 17, 21, 28, 29], but the remaining one study performed in the United States did not find such an association [5]. Our meta-analysis showed that hepatolithiasis was a risk factor for ICC with a pooled OR of 14.94 (95% CI 6.41–34.83; I2=66%) (Fig. 7).

Choledochal cyst

Five case–control studies investigated the association between choledochal cyst and ICC [5, 9, 13, 23, 29]. Of them, three studies were from the United States, and one each was from Korea and Taiwan (China). The research data were collected during the period from 1993 to 2011, involving a total of 541645 participants. All five studies showed that choledochal cyst increased the ICC risk. Our meta-analysis further confirmed this significant association with a pooled OR of 21.67 (95% CI 10.83-43.36; I2=76%) (Fig. 8). The corresponding OR for studies in Eastern and Western countries was 13.37 (95% CI 4.31-41.50; I2=0%) and 25.61 (95% CI 11.02-59.50; I2=86%), respectively (Table 2).

History of cholecystectomy

Four case-control studies investigated the association between the history of cholecystectomy and ICC [9, 11, 16, 28]. Of them, two studies were from the United States and one each was from China and Korea. The research data were collected during the period from 1992 to 2013, involving a total of 326605 participants. Three of the four studies reported no significant association between the history of cholecystectomy and ICC [11, 16, 28], and the remaining one showed a significant association [9]. Our meta-analysis showed no significant association between the history of cholecystectomy and ICC with a pooled OR of 2.21 (95% CI 0.69–7.14; I2=87%) (Fig. 9). The corresponding OR for Eastern and Western countries studies was 1.32 (95% CI 0.60-2.91; I2=0%) and 3.15 (95% CI 0.45-22.21; I2=94%), respectively (Table 2).

PSC

Two case-control studies investigated the association between PSC and ICC, and both studies were conducted in the United States [5, 6]. The studies included a total case and control population of 7144 participants. Both studies showed that PSC increased the risk of ICC. Our meta-analysis further confirmed this significant association with a pooled OR of 93.91 (95% CI 43.99-200.47; I2=0%) (Fig. 10).

DM

Nineteen case-control studies investigated the association between DM and ICC [6, 9-13, 15-19, 21, 23, 25, 28, 29, 32, 34, 35]. Of them, six studies were from the United States and China, two each from Taiwan (China), Korea and Japan, and one each was from Denmark and other 10 European countries. The research data were collected during the period from 1978 to 2014, involving a total of 800979 participants. Eight studies reported no significant association between DM and ICC [11, 15-17, 32, 34-36], but the remaining 11 studies showed a significant association [6, 9, 10, 12, 13, 18, 19, 23, 25, 28, 29]. Our meta-analysis showed that DM was a risk factor for ICC with a pooled OR of 1.82 (95% CI 1.57-2.11; I2=86%) (Fig. 11). The corresponding OR for Eastern and Western countries studies was 1.91 (95% CI 1.44-2.54; I2=90%) and 1.71 (95% CI 1.54-1.89; I2=47%), respectively (Table 2).

NAFLD

Eight case-control studies investigated the association between NAFLD and ICC [6, 9, 12, 22, 23, 25, 32, 36]. Of them, one was from 10 European countries, three were from the United States, two from Taiwan (China), and one each was from China and Japan. The research data were collected during the period from 1992 to 2014, involving a total of 330896 participants. Two studies reported no significant association between NAFLD and ICC [22, 25], but the remaining six studies showed a significant association [6, 9, 12, 23, 32, 36]. Our meta-analysis showed that NAFLD was a risk factor for ICC with pooled OR of 2.23 (95% CI 1.65-3.02; I2=76%) (Fig. 12). The corresponding OR for Eastern and Western countries studies was 2.15 (95% CI 1.39-3.33; I2=64%) and 2.33 (95% CI 1.33-4.07; I2=86%), respectively (Table 2).

Liver fluke infection

Four case–control studies investigated the association between liver fluke infection and ICC [15, 16, 23, 28]. All the four studies were conducted in Eastern countries, including two in China, one in Taiwan (China) and one in Korea. The research data were collected during the period from 2000 to 2013, involving a total of 15568 participants. Only one of the four studies indicated a significant association [16], but our the meta-analysis indicated that liver fluke infection is a risk factor for ICC, with pooled OR of 2.28 (95% CI 1.30-4.01; I2=0%) (Fig. 13).

Hypertension

Eleven selective case-control studies investigated the association between hypertension and ICC [5, 9, 13, 15-19, 21, 28, 34]. Of them, three studies were from the United States, six from China, and one each was from Korea and Japan. The research data were collected during the period from 1991 to 2014, involving a total of 527487 participants. Seven studies reported no significant association between hypertension and ICC [15-18, 21, 28, 34], three studies showed an increased risk of ICC [9, 13, 19], and one study showed a reduced risk of ICC [5]. Our meta-analysis indicated no significant association between hypertension and ICC with the pooled OR of 1.01 (95% CI 0.75-1.36; I2=88%) (Fig. 14). Meanwhile, the corresponding OR for Eastern and Western countries studies was 1.02 (95% CI 0.75-1.38; I2=52%) and 1.03 (95% CI 0.58-1.81; I2=97%), respectively (Table 2).

Aspirin use

Three studies including two case-control studies and one cohort-based study investigated the association between aspirin use and ICC [6, 8, 25], including two in the United States and one in Taiwan (China). The research data were collected during the period from 2000 to 2014, involving a total of 1141708 participants. All the three studies reported that aspirin use did not increase ICC risk. Our meta-analysis further confirmed this finding with a pooled OR of 0.74 (95% CI 0.38-1.41; I2=98%) (Fig. 15).

Coffee consumption

Only one study investigated the association between coffee consumption and ICC [14]. The cohort study was conducted in the United States, involving a total of 694455 participants, with the data collected between 1992 and 2010. According to the study, drinking more than three cups of coffee a day could reduce the risk of HCC (HR=0.73; 95% CI 0.53-0.99), but no significant association was found between coffee consumption and ICC (HR=1.00; 95% CI 0.61-1.63).

Publication bias and sensitivity analysis

Risk factor analysis was conducted in more than 10 studies, and publication bias was investigated by funnel plots [37]. The results showed that the funnel plots were generally symmetrical, indicating the absence of publication bias (Supplementary Fig. 1). Sensitivity analysis was performed by removing one study at a time to calculate the pooled ORs of the remaining studies. No significant change was observed in the pooled OR after removing any one single study, demonstrating the reliability and stability of this meta-analysis.

Discussion

The incidence of ICC has increased progressively over the past few decades, but the risk factors for ICC have not been clearly defined. Liver fluke infection (Clonorchis sinensis or Opisthorchis viverrini) is regarded as a traditional infectious risk factor. Clonorchis sinensis and Opisthorchis viverrini infections are mainly prevalent in Southeast Asia, Far East and Eastern Europe [38]. Liver fluke infection was previously reported as a major risk affecting Eastern countries rather than Western countries [39]. The prevalence of some risk factors for ICC in these Eastern countries is the main reason for geographic disparity [40]. Risk factors for ICC differ between Eastern and Western countries [41]. It is therefore important to define risk factors for better prevention of ICC in different geographic areas.

Most studies appear to indicate HBV/HCV infection as an important risk factor for ICC, knowing that HBV/HCV infection can lead to chronic inflammation of the liver over time, while hepatolithiasis and liver fluke infection are also common causes of chronic inflammation. Similarly, our meta-analysis showed that these risk factors may increase the risk of ICC. In the 9th century, Rudolph Virchow, a Prussian scientist, first proposed the association of inflammation with the development of malignancies [42]. Molecular links between inflammation and tumors have also been reported in recent years. The expression of cycloxygenase 2 (COX2) is increased in chronic liver inflammation and found to be involved in hepatocarcinogenesis. Inflammatory mediator prostaglandin E 2 (PGE2) was found to be highly expressed in liver cancer cells. In addition, COX2 inhibitors were reported to inhibit the growth of liver cancer cells [43]. A previous study [6] reported that aspirin, as an effective non-steroidal anti-inflammatory drug (NSAID), was associated with decreased risk of ICC. However, our meta-analysis involving three relevant studies failed to find this correlation, possibly because of the limited number of the studies.

Increasing evidence has shown that cirrhosis increases the risk of ICC [44-47]. Further animal studies revealed that p53 deficiency, chronic bile duct injury and the fibrotic matrix microenvironment may work together to increase the risk of ICC [48], which is consistent with the finding of the present meta analysis. Meanwhile, our meta-analysis found that NAFLD was significantly associated with an increased risk of ICC, though the underlying mechanism remains unclear. Biologically, NAFLD promotes cholangiocarcinogenesis by inducing hepatic inflammation directly, or cirrhosis indirectly [49].

Several previous studies reported an association between choledochal cyst and cholangiocarcinoma [50, 51]. Repeated damage and restoration of the biliary epithelium by regurgitation of pancreatic juice into the biliary system is presumed to be the cause of carcinogenesis [52]. Our meta-analysis showed that choledochal cyst is a strong risk factor for ICC.

Smoking has been shown to be associated with most known malignancies, such as lung cancer [53], breast cancer [54] and colorectal cancer [55]. Our meta-analysis also showed a significant association between smoking and ICC in studies performed in Western countries, but not in studies performed in Eastern countries. The significant geographical variations may be due to differences in genes and environments. Alcohol consumption is a known risk factor for ICC, knowing that alcohol can induce oxidative stress, ultimately causing liver parenchyma damage [56]. This significant association between alcohol consumption and ICC was also observed in our meta-analysis.

DM is a chronic disease with a high prevalence and highly suspected to increase the risk of several malignancies [57]. Our meta-analysis consistently showed that DM is a risk factor for ICC. The underlying biological mechanism is probably associated with the up-regulation of insulin-like growth factor-1 (IGF-1), which is known to promote the progression of malignancies [58]. As for the common chronic disease hypertension, our analysis failed to find a significant association with the increased risk of ICC.

It was found in our meta-analysis that ICC shares certain risk factors with HCC, such as cirrhosis, HBV/HCV infection [59, 60]. In addition, bile duct cells and hepatocytes differentiate from the same hepatic progenitor cells in both HBV-associated ICC and HBV-associated HCC, which is known as a common disease process for carcinogenesis [17]. Awareness of these similar risk factors may help understand the pathogenesis of ICC and the origin of ICC cells.

This review of ICC risks included 31 studies involving a large number of cases throughout the world. However, there are still some limitations in this meta-analysis. First, we did not conduct separate analyses on liver fluke infection, PSC, hepatolithiasis, coffee and aspirin because of the limited number of studies. Second, we did not conduct separate meta-analyses for risk by gender, although there may be differences between different genders. The main reason is that most studies did not classify cases by sex. Finally, although we revealed a relationship between ICC and smoking, alcohol consumption and aspirin use, the duration of exposure to these risk factors varies with individual studies, and therefore future studies are required to focus on the association between the duration of exposure to these risk factors and ICC.

Conclusions

Our meta-analysis indicates that cirrhosis, HBV/HCV infection, alcohol consumption, hepatolithiasis, choledochal cyst, PSC, DM, NAFLD, liver fluke infection and smoking are significantly associated with the increased risk for ICC. A non-significant association was found with hypertension, the history of cholecystectomy, coffee and aspirin, which needs to be verified by further study. As for PSC, liver fluke infection and smoking, geographic and ethnic differences may play a role in the development of ICC.

Abbreviations

ICC: intrahepatic cholangiocarcinoma HCC: hepatocellular carcinoma

PRISMA: Preferred reporting items for systematic reviews and meta-analyses

OR: odds ratio CI: confidence intervals;

HBV: hepatitis B virus HCV: hepatitis C virus;

PSC: primary sclerosing cholangitis

DM: diabetes mellitus NAFLD: non-alcoholic fatty liver disease

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Availability of data and materials

Input data for the analyses are available from the corresponding author on request.

Competing interest

The authors declare that they have no competing interests.

Funding

The study design, data collection, analysis and interpretation of data, writing manuscript were funded  by the Foundation of Xiamen Science and Technology Bureau (No. 3502Z20174074) and Major Diseases Joint Research Program of Xiamen City (3502Z20170943).

Authors' contributions

WS, HB and ZY participated in the design and coordination of the study, carried out the critical appraisal of studies and wrote the manuscript. HB, LY, and CZ developed the literature search, carried out the extraction of data, assisted in the critical appraisal of included studies and assisted in writing up, WS and YZ carried out the statistical analysis of studies. All authors read and approved the final manuscript.

Acknowledgements

We thank Doctor Yanfang Zhao (Department of Health Statistics, Second Military Medical University, Shanghai, China) for her critical revision of the meta-analysis section.

Authors' Information

1 Department of Hepatobiliary & Pancreatovascular Surgery, First affiliated Hospital of Xiamen University, Xiamen, China

2 Department of Clinical Laboratory Medicine, First affiliated Hospital of Xiamen University, Xiamen, China

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Tables

Table 1: Characteristics of included trials.

Risk factor

Author/year of

publication

Region

Dates

Cases

Controls

Total

With risk factor

Total

With risk factor

HBV

Chaiteerakij, 2013

US

2000-2010

612

3

594

3

 

Chang,2013

Taiwan

2004-2008

2978

257

11912

229

 

Choi,2006

Korea

2003-2004

51

4

51

5

 

Choi,2016

US

2000-2014

1169

10

4769

8

 

Donato,2001

Italy

1995-2000

23

3

824

45

 

Huang,2017

Taiwan

2003-2009

4695

138

46942

513

 

Lee,2008

Korea

2000-2004

622

84

2488

125

 

Lee,2009

Taiwan

1991-2005

160

60

160

22

 

Lee,2015

Korea

2007-2013

83

19

166

9

 

Liu,2011

China

2000-2008

87

6

228

15

 

Peng,2011

China

2002-2009

98

31

196

25

 

Petrick,2017

US

2000-2011

2092

25

323615

1200

 

Shaib,2005

US

1993-1999

625

2

90834

182

 

Tao,2010

China

1998-2008

61

17

380

19

 

Welzel,2011

US

1993-2005

743

11

195953

442

 

Wu,2012

China

1998-2010

102

28

835

29

 

Xiong,2018

China

2002-2014

136

26

606

26

 

Yamamoto,2004

Japan

1991-2002

50

2

205

5

 

Zhang,2014

China

1993-2013

127

46

254

61

 

Zhou,2008

China

2004-2006

312

151

438

42

 

Zhou,2010

China

2003-2006

317

154

634

42

 

Tanaka,2010

Japan

1991-2000

HBV cohort 2519

Cases=2

Non-infected cohort 150368

Cases=8

 

Fwu,2011

Taiwan

1983-2000

HBV cohort 289992

Cases=9

Non-infected cohort 1492409

Cases=9

HCV

Chaiteerakij, 2013

US

2000-2010

612

13

594

2

 

Chang,2013

Taiwan

2004-2008

2978

193

11912

138

 

Choi,2006

Korea

2003-2004

51

1

51

1

 

Choi,2016

US

2000-2014

1169

23

4769

17

 

Donato,2001

Italy

1995-2000

24

6

824

50

 

Huang,2017

Taiwan

2003-2009

4695

112

46942

541

 

Lee,2008

Korea

2000-2004

622

12

2488

47

 

Lee,2009

Taiwan

1991-2005

160

21

160

10

 

Lee,2015

Korea

2007-2013

83

5

166

3

 

Liu,2011

China

2000-2008

87

1

228

3

 

Petrick,2017

US

2000-2011

2092

58

323615

2161

 

Shaib,2005

US

1993-1999

625

5

90834

161

 

Shaib,2007

US

1992-2002

83

5

236

2

 

Welzel,2007

US

1993-1999

535

5

102782

142

 

Welzel,2011

US

1993-2005

743

20

195953

616

 

Xiong,2018

China

2002-2014

136

5

606

8

 

Yamamoto,2004

Japan

1991-2002

50

18

205

7

 

Zhang,2014

China

1993-2013

127

2

254

1

 

Zhou,2008

China

2004-2006

312

9

438

6

 

El-Serag,2009

US

1988-2004

HCV cohort 146394

Cases=14

Non-infected cohort 572293

Cases=23

 

Tanaka,2010

Japan

1991-2000

HCV cohort 1927

Cases=1

Non-infected cohort 150368

Cases=8

Cirrhosis

Chaiteerakij, 2013

US

2000-2010

612

42

594

2

 

Chang,2013

Taiwan

2004-2008

2978

303

11912

160

 

Choi,2016

US

2000-2014

1169

114

4769

24

 

Huang,2017

Taiwan

2003-2009

4695

191

46942

636

 

Lee,2008

Korea

2000-2004

622

48

2488

10

 

Lee,2009

Taiwan

1991-2005

160

41

160

0

 

Peng,2011

China

2002-2009

98

25

196

4

 

Petrick,2017

US

2000-2011

2092

120

323615

2548

 

Shaib,2005

US

1993-1999

625

53

90834

325

 

Welzel,2011

US

1993-2005

743

53

195953

634

 

Welzel,2006

Denmark

1978-1991

764

19

3056

1

 

Welzel,2007

US

1993-1999

535

10

102782

359

 

Wu,2012

China

1998-2010

102

17

835

41

 

Xiong,2018

China

2002-2014

136

17

606

28

 

Yamamoto,2004

Japan

1991-2002

50

5

204

2

 

Zhou,2010

China

2003-2006

317

95

634

9

Smoking

Brandi,2013

Italy

2006-2010

41

21

149

71

 

Chaiteerakij,2013

US

2000-2010

612

308

594

255

 

Choi,2016

US

2000-2014

1169

499

4769

1929

 

Kinoshita,2016

Japan

1995-2014

34

11

69

35

 

Lee,2008

Korea

2000-2004

622

293

2488

1135

 

Lee,2015

Korea

2007-2013

83

16

116

43

 

Liu,2011

China

2000-2008

87

20

228

29

 

Petrick,2017

US

2000-2011

2092

268

323615

33789

 

Shaib,2005

US

1993-1999

625

24

90834

1927

 

Shaib,2007

US

1992-2002

83

20

236

37

 

Tao,2010

China

1998-2008

61

18

380

122

 

Welzel,2007

US

1993-1999

535

12

102782

1212

 

Welzel,2011

US

1993-2005

743

78

195953

9647

 

Xiong,2018

China

2002-2014

136

42

606

105

 

Yamamoto,2004

Japan

1991-2002

50

17

205

90

 

Zhang,2014

China

1993-2013

127

83

254

145

 

Zhou, 2008

China

2004-2006

312

43

438

67

Alcohol use

Chang,2013

Taiwan

2004-2008

2978

110

11912

121

 

Donato,2001

Italy

1995-2000

26

6

824

271

 

Huang,2017

Taiwan

2003-2009

4695

35

46942

155

 

Lee,2008

Korea

2000-2004

622

112

2488

78

 

Lee,2015

Korea

2007-2013

83

17

166

26

 

Liu,2011

China

2000-2008

87

9

228

24

 

Petrick,2017

US

2000-2011

2092

176

323615

8584

 

Shaib,2005

US

1993-1999

625

11

90834

282

 

Shaib,2007

US

1992-2002

83

18

236

9

 

Tao,2010

China

1998-2008

61

15

380

85

 

Welzel,2007

US

1993-1999

535

5

102782

310

 

Welzel,2011

US

1993-2005

743

21

195953

832

 

Welzel,2006

Denmark

1978-1991

764

15

3056

4

 

Xiong,2018

China

2002-2014

136

31

606

88

 

Yamamoto,2004

Japan

1991-2002

50

1

205

11

 

Zhang,2014

China

1993-2013

127

67

254

103

 

Zhou,2008

China

2004-2006

312

39

438

41

 

Zhou,2010

China

2003-2006

317

6

634

2

NAFLD

Welzel,2007

US

1993-1999

535

5

102782

353

 

Zhou,2010

China

2003-2006

317

6

634

8

 

Chang,2013

Taiwan

2004-2008

2978

156

11912

236

 

Kinoshita,2016

Japan

1995–2014

34

15

69

13

 

Choi,2016

US

2000–2014

1169

61

4769

181

 

Stepien,2016

10 European countries

1992–2000

34

21

67

25

 

Huang,2017

Taiwan

2003-2009

4695

25

46942

172

 

Petrick,2017

US

2000-2011

2092

100

323651

5053

Hepatolithiasis

Lee,2008

Korea

2000-2004

622

61

2488

6

 

Zhou,2008

China

2004-2006

312

17

438

5

 

Tao,2010

China

1998-2008

317

25

634

7

 

Peng,2011

China

2002-2009

98

34

196

4

 

Chaiteerakij,2012

US

2000-2010

612

4

594

0

 

Lee,2015

Korea

2007-2013

83

11

166

1

Choledochal cyst

Lee,2008

Korea

2000-2004

622

4

2488

2

 

Welzel,2011

US

1993-2005

743

32

195953

213

 

Chaiteerakij,2012

US

2000-2010

612

11

594

0

 

Chang,2013

Taiwan

2004-2008

2978

10

11912

2

 

Petrick,2017

US

2000-2011

2092

48

323651

462

History of cholecystectomy

Shaib,2007

US

1992-2002

83

12

236

28

 

Peng,2011

China

2002-2009

98

7

196

13

 

Lee,2015

Korea

2007-2013

83

4

166

4

 

Petrick,2017

US

2000-2011

2092

11

323651

221

PSC

Chaiteerakij,2012

US

2000-2010

612

60

594

1

 

Choi,2016

US

2000-2014

1169

131

4769

6

DM

Chang,2013

Taiwan

2004-2008

2978

932

11912

2296

 

Choi,2016

US

2000-2014

1169

208

4769

479

 

Huang,2017

Taiwan

2003-2009

4695

978

46942

8353

 

Kinoshita,2016

Japan

1995-2014

34

7

69

9

 

Lee,2008

Korea

2000-2004

622

96

2488

139

 

Lee,2015

Korea

2007-2013

83

21

166

15

 

Liu,2011

China

2000-2008

87

3

228

10

 

Peng,2011

China

2002-2009

98

6

196

14

 

Petrick,2017

US

2000-2011

2092

958

323615

117665

 

Shaib,2005

US

1993-1999

625

156

90834

14201

 

Shaib,2007

US

1992-2002

83

12

236

20

 

Tao,2010

China

1998-2008

61

3

380

36

 

Welzel,2006

Denmark

1978-1991

764

15

3056

43

 

Welzel,2007

US

1993-1999

535

177

102782

22764

 

Welzel,2011

US

1993-2005

743

299

195953

52691

 

Wu,2012

China

1998-2010

102

16

835

69

 

Xiong,2018

China

2002-2014

136

34

606

41

 

Yamamoto,2004

Japan

1991-2002

50

11

205

24

 

Zhou,2008

China

2004-2006

312

13

438

11

Hypertension

Chaiteerakij, 2013

US

2000-2010

612

165

594

256

 

Lee,2015

Korea

2007-2013

83

29

166

69

 

Liu,2011

China

2000-2008

87

5

228

22

 

Peng,2011

China

2002-2009

98

13

196

35

 

Petrick,2017

US

2000-2011

2092

1727

323615

249073

 

Tao,2010

China

1998-2008

61

14

380

104

 

Welzel,2011

US

1993-2005

743

570

195953

134069

 

Wu,2012

China

1998-2010

835

213

102

26

 

Xiong,2018

China

2002-2014

136

35

606

86

 

Yamamoto,2004

Japan

1991-2002

50

10

100

20

 

Zhou,2008

China

2004-2006

312

34

438

38

Liver flukes

Chang,2013

Taiwan

2004-2008

2798

2

11912

1

 

Lee,2015

Korea

2007-2013

83

3

166

2

 

Liu,2011

China

2000-2008

87

4

228

6

 

Peng,2011

China

2002-2009

98

18

196

19

Aspirin

Choi,2016

US

2000-2014

1169

276

4769

2129

 

Petrick,2015

US

2001-2013

Aspirin cohort 477470

Cases= 105

Non-use 606663

Cases= 120

 

Huang,2017

Taiwan

2003-2009

4695

954

46942

9977

Coffee

Petrick,2015

US

1992-2010

Coffee cohort 521438

Cases= 119

Non-use 172865

Cases= 85

    HBV, hepatitis B virus; HCV, hepatitis C virus; PSC, primary sclerosing cholangitis; DM, diabetes mellitus; NAFLD, non-alcoholic fatty liver disease

 

 Table 2: Subgroup meta-analyses stratified by geographical area.

Risk factor

Region

Number of

studies

Number of

participants

OR

95%CI

I2

HBV infection

East

16

2010560

4.56

3.33-6.24

87%

 

West

7

621955

2.90

1.70-4.97

58%

HCV infection

East

11

224944

3.12

1.84-5.31

86%

 

West

10

1444279

5.04

3.74-6.80

39%

Cirrhosis

East

9

73135

8.97

4.91-16.37

93%

 

West

7

728144

16.38

9.12-29.42

93%

Smoking

East

9

6296

1.01

0.74-1.37

74%

 

West

8

724832

1.49

1.21-1.83

79%

Alcohol use

East

11

73721

1.99

1.30-3.06

88%

 

West

7

722168

4.28

2.56-7.15

83%

choledochal cyst

East

2

18000

13.37

4.31-41.50

0%

 

West

3

523645

25.61

11.02-59.50

86%

History of cholecystectomy

East

2

543

1.32

0.60-2.91

0%

 

West

2

326062

3.15

0.45-22.21

94%

Diabetes mellitus

East

12

73723

1.91

1.44-2.54

90%

 

West

7

727256

1.71

1.54-1.89

47%

Hypertension

East

8

3878

1.02

0.75-1.38

52%

 

West

3

523609

1.03

0.58-1.81

97%

NAFLD

East

4

67581

2.15

1.39-3.33

64%

 

West

4

435099

2.33

1.33-4.07

86%

HBV, hepatitis B virus; HCV, hepatitis C virus; NAFLD, non-alcoholic fatty liver disease; OR, odds ratio; CI, confidence intervals