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

In order to review literature on risk factors associated with iCCA we have searched for case series of iCCA
or case series with appropriate topographic classification of histologically verified iCCA. The risk factors
of iCCA (diagnosed according the current recognized criteria, i.e. European RARECARE ) could be
[33]
classified on the basis of the tissue or the cell which is primarily targeted by diseases or conditions and
therefore likely involved in the carcinogenic process as cell or tissue of origin. For instance, biliary diseases
as cholangitis/PSC, secondary biliary cirrhosis, choledocholithiasis, hepatolithiasis, cholecystitis, and liver
flukes are pathologic conditions primarily affecting large intra-hepatic bile ducts [Table 1] [34-46] , and are risk
factors for both iCCA and p/dCCA. Parenchymal liver diseases include chronic viral and non-viral liver
diseases, recognize the interlobular bile ducts, bile ductules and the canals of Hering as the primary targets.
Accordingly, these conditions are specific risk factors for iCCA [Table 1].

Other risk factors, like several toxic and environmental factors; amongst them nitrosamine-contaminated
food, asbestos, dioxins, vinychlorides, and thorotrast as was always the case in the past , which hit multiple
[47]
cellular targets, are considered risk factors associated to all CCA subtypes.

PSC, a disease affecting both intra-hepatic and extra-hepatic bile ducts, represents the strongest independent
risk factor both for iCCA and for pCCA [Table 1]. Most of the studies evaluated the cumulative risk of CCA
in PSC patients, but not the discrete risk of iCCA and/or pCCA to PSC [48-51] . The cumulative incidence of
CCA in PSC patients ranges from 5% to 10% [52-55] . Clinical and pathological observations suggested that
PSC is specifically associated with the development of bile duct (mucinous) type CCA [4,56] . Data on the role
of inflammatory bowel diseases (IBD), associated with or preceding PSC, in affecting the risk of CCA are
controversial. The coexistence and duration of IBD significantly increased the risk of CCA in PSC patients .
[51]
In IBD patients the RR estimated was 2.61 for iCCA vs. 1.47 for pCCA . Crohn’s disease (CD) seemed to
[57]
have a lower risk of CCA than ulcerative cholitis (UC) [57,58] . In contrast, in a study carried out in the USA,
neither IBD nor its duration confers additional risk of CCA in PSC patients .
[59]
In a study, Welzel et al. described that duodenal ulcer disease was significantly more common among pCCA
[36]
and iCCA cases than controls. Many studies have demonstrated associations between CCA and H. pylori but
the correlation remains controversial and a direct cause-and-effect relationship has not been established [60-66] . In
particular, in East-Asia, where iCCA represents a large proportion of primitive liver cancers, a strong association
exists between liver fluke infestation (Ophistorchis viverrini and Clonorchis sinensis) and the development of
CCA [Table 1] [67,68] . Several epidemiological studies estimated the relationship between type II diabetes and
CCA [Table 1] [36,69-71] . Notably, a possible explanation of this association is attributable to a recent demonstration
that in a diabetes model and in human subjects affected by type II diabetes, PBGs underwent proliferation
and expansion in relation to hyperglycemia . It’s worthy to note that metformin reduced the risk of iCCA in
[72]
diabetic patients by a significant margin up to 60% [73,74] . A recent meta-analysis confirmed that, in addition to
type II diabetes, even obesity, alcohol use and smoking, have an association with iCCA .
[75]

It is becoming increasingly evident that metabolic conditions predispose to the development of primary liver
cancers [3,44,76] . Nonalcoholic fatty liver disease/non alcoholic steato-hepatitis (NAFLD/NASH) resulted in
independent predictors of iCCA (not of pCCA development), even if with a less strong association compared
with other risk factors (viral hepatitis, cirrhosis) [Table 1] . Hemochromatosis resulted in an independent
[76]
predictor of iCCA development, and it failed to predict pCCA [Table 1].

It has long been known that the presence of cirrhosis increases the risk of iCCA [36,37,40,44,75] . HBV- and HCV-
related liver diseases have been identified as definitive risk factors for CCA, with a stronger association for
iCCA than pCCA [77,78] . A meta-analysis by Palmer and Patel concerning 8 case control studies indicated
[75]
that HCV was associated with an overall OR of 4.84 for iCCA. Where the prevalence of the HBV infection
is higher, the association with iCCA and HBV is more significant (e.g. Asian countries) [79,80] . The range of the