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Cardinale et al. Hepatoma Res 2018;4:20 I http://dx.doi.org/10.20517/2394-5079.2018.46 Page 5 of 16

Table 1. Summary of risk factors significantly associated to iCCA* as assessed by case control studies (odd ratios by multivariate
analyses)
Risk factors for iCCA Odds ratios for increased risk
Bile duct diseases and conditions
Cholecystitis [36] 8.5
Cholelithiasis [35,40] 10.23-13.5
Hepatolithiasis [37,39,40,43,77§] 50.0-4.8; 6.7§
Choledochal cysts [36,37,44,59] 10.7-43.03; 36.9
Choledocholithiasis [35,43] 4.17-33.35
Cholangitis/primary sclerosing cholangitis [36,44] 64.2-75.23
Biliary cirrhosis/PBC [36,44] 17.08-19.8
Cholecystectomy [36,39] 3.6-5.4
Digestive diseases
Inflammatory bowel diseases [36,58] 1.72-3.95
Crohn’s disease [36,44] 1.68-2.4
Ulcerative colitis [36,44] 3.3-4.5
Duodenal ulcer [36] 3.4
Chronic pancreatitis [36] 5.9
Liver flukes
Clonorchis sinensis infection [38,42] 8.6-13.6
Endocrine disorders
Thyrotoxicosis [36] 1.5
Diabetes mellitus type II [37-39,43,75,86] 1.8-3.2
Metabolic conditions and general risks
Obesity [36,44] 1.7-1.71
Alcohol intake > 80 g/day [37,39,75] 1.52-5.21
Smoking [36,44] 1.3-2.1
Metabolic syndrome [44#] 1.32-1.83
Dyslipoproteinemia [44] 1.65
Hypertension [44] 1.63
Chronic liver diseases
Alcoholic liver disease [36,44] 3.1-5.69
Non specific cirrhosis [36,37,43,44,75] 18.24-28.79
Hemochromatosis [36] 2.6
Hepatic schitsomias [43] 11
Non alcoholic liver disease [36] 3
Unspecified viral hepatitis [44] 7.66
HCV infection [36-40,44,75,77§] 2.41-9.71; 9.7§
HCV infection plus cirrhosis [40] 8.53
HBsAg positive [35,37-40,44,75,81°] 2.3-9.7; °2.35-4.3
HBsAg positive plus cirrhosis [35,40,41] 13-18
HBsAg negative/HBcAb positive [45,81°] 1.09-1.81°
Occupational exposure
Occupational exposure to asbestos [46] 4.81
*Histological verified cases; §iCCA cases comprise 2 cases of cHCC-CCA; #according the 2001 U.S. NCEP-ATP III definition; °Risk of
CCA only in Asia. The table was prepared summarizing findings by case control studies investigating risk factors associated to iCCA
as assessed by multivariate analyses. The case-control studies were selected from the papers individuated by the following terms, that
were searched on PubMed: ("cholangiocarcinoma"[MeSH Terms] OR "cholangiocarcinoma"[All Fields]) AND ("risk factors"[MeSH
Terms] OR ("risk"[All Fields] AND "factors"[All Fields]) OR "risk factors"[All Fields] OR ("risk"[All Fields] AND "factor"[All Fields]) OR
"risk factor"[All Fields])) NOT ("review"[Publication Type] OR "review literature as topic"[MeSH Terms] OR "review"[All Fields]) AND
English[lang]. The criteria selections of the works comprise moreover the case definition of CCA: histological verified cases series of
iCCA with appropriate topographic classification (Klatskin tumours classified as pCCA and excluded from the iCCAs)

OR in the HbsAg positive subjects goes from 2.3 to 9.7 [Table 1] . The presence of cirrhosis increases the risk
[81]
of CCA [Table 1] even more by 2.5 fold (95% CI: 1.2-5.1; P = 0.02) in HBV, and 3.2 fold (95% CI: 1.231-8.148,
[41]
P = 0.017) in HCV patients .

The burden of HCV in the last decades has been associated with the specific increase of the iCCA as well as
the HCC . Accordingly, clinical and pathological observations suggested that liver cirrhosis is specifically
[81]