Intra-hepatic and extra-hepatic cholangiocarcinoma: New insight into epidemiology and risk factors

Table 1 Summary of risk factors significantly associated to intra-hepatic cholangiocarcinoma^a and/or extra-hepatic cholangiocarcinoma^b as assessed by case control studies (Odd ratios by multivariate analyses)

Risk factors for IH-CCA (Ref.)	Odds ratios for increased risk	Risk factors for EH-CCA (Ref.)	Odds ratios for increased risk
Bile duct diseases and conditions
Choledochal cysts[35,36]	10.7-36.9	Choledochal cysts[35]	47.1
Cholangitis/PSC[35]	64.2	Cholangitis/PSC[35]	45.7
Biliary cirrhosis/PBC[35]	19.8	Biliary cirrhosis/PBC[35]	11.8
Cholelithiasis[34,39]	13.5	Cholelithiasis[34,35]	2.6-11
Choledocholithiasis[34,41]	22.5-34	Choledocholithiasis[35]	34
Cholecystitis[35]	8.5	Cholecystitis[35]	5.9
Cholecystectomy[35,38]	3.6-5.4	Cholecystectomy[34,35]	5.8-12
Hepatolithiasis[19]c,[36,38,39,41]	50.0-4.8; 6.7c
Liver flukes
Clonorchis sinensis infection[36,40]	8.6-13.6	Clonorchis sinensis infection[40]	6.5
Digestive diseases
IBD[35]	4	IBD[35]	2.1
Crohn’s disease[35]	2.4	Crohn’s disease[35]	2.8
Ulcerative colitis[35]	4.5
Duodenal ulcer[35]	3.4	Duodenal ulcer[35]	1.9
Chronic pancreatitis[35]	5.9	Chronic pancreatitis[35]	9.3
Endocrine disorders
Diabetes mellitus type II[36-38]	1.8-3.2	Diabetes mellitus type II[34,35]	1.5-3.2
Thyrotoxicosis[35]	1.5	Thyrotoxicosis[35]	1.7
Miscellaneous conditions
Alcohol intake > 80 g/d[36,37]	5.9-6.6	Alcohol intake > 80 g/d e[37]	3.6
Obesity[35]	1.7
Smoking[35]	1.8
Chronic liver diseases
Alcoholic liver disease[35]	3.1	Alcoholic liver disease[35]	4.5
Non specific cirrhosis[35,36,41]	10-16.5	Non specific cirrhosis[35]	5.4
Hemochromatosis[35]	2.6
Hepatic schistosomiasis[41]	11
Non alcoholic liver disease[35]	3
HCV infection[19]c,[35-39]	4.4-7.9; 9.7c
HCV infection plus cirrhosis[39]	8.53
HBsAg positive[34,36-39]	2.3-9.7
HBsAg positive plus cirrhosis[34,39,41]	13-18

^aHistological verified cases; ^bHistological verified cases comprise Klatskin tumour; ^cIH-CCA cases comprise 2 cases of cHCC-CCA. The table is prepared summarizing findings by case control studies investigating risk factors associated to IH-CCA and/or EH-CCA as assessed by multivariate analyses. The case-control studies are selected from the papers individuated by the follow terms 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 IH-CCA and/or EH-CCA with appropriate topographic classification (Klatskin tumours classified as EH-CCA and excluded from the IH-CCAs). In the 10 case control studies selected, several putative risk factors have been evaluated. The risk factors are collected together based on the patho-physiologic mechanisms lead to CCA (cells primarily targeted or activated by the diseases and therefore involved in the carcinogenic process) and on the homogeneity of the risk factors. IH-CCA: Intra-hepatic cholangiocarcinoma; EH-CCA: Extra-hepatic cholangiocarcinoma.