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.