Cholangiocarcinoma (CCA)


Several factors are known to increase the risk of developing cholangiocarcinoma (CCA).1 These include diseases of the liver and bile ducts, and diseases affecting the digestive and endocrine systems. Lifestyle choices are less evident risk factors but have also been attracting attention as potential triggers for CCA development. Host genetic polymorphisms also have an important role in carcinogenesis.1

Even though studies show multiple established risk factors for CCA, it is not always possible to identify any of these in most patients.2 Additionally, the same risk factor may have a different impact on the development of intrahepatic (iCCA) and extrahepatic (eCCA) tumors.3

Primary Sclerosing Cholangitis

Primary sclerosing cholangitis (PSC) is an autoimmune disease that leads to inflammation, proliferation of the biliary epithelial cells, obstruction of the bile ducts and to the production of endogenous bile mutagens.3 The risk of PSC patients in developing CCA is augmented 400-fold,4 however, only up to 10% of CCA cases have been correlated with the presence of PSC.5

Bile Duct Cysts

Bile duct cysts are a congenital disorder that result from a defect in the pancreatic-biliary junction. This defect promotes the reflux of pancreatic enzymes that go into the biliary system leading to inflammation and to a dilatation of the biliary tree.6 Cysts can be divided into 5 types, with types I (solitary extrahepatic cyst) and IV (extrahepatic and intrahepatic cyst) having the highest CCA incidence.7 

Patients with bile duct cysts have been reported to develop CCA at an average age of 32, which is a younger age than the normal onset age of presentation.7,8 

Hepatolithiasis, Cholelithiasis and Choledocholithiasis

The presence of calculi in the biliary tree, hepatolithiasis, is common in East Asia and rare in Western countries.9 Patients with hepatolithiasis show an incidence of iCCA up to 13%.9,10 These calculi lead to chronic inflammation, bile stasis and to bacterial infections, which may be related to CCA development.9

Cirrhosis and Viral Hepatitis

Cirrhosis has been identified as a risk factor for developing iCCA and eCCA.11,12 In this condition, pro-inflammatory cytokines are released, cellular proliferation is enhanced, and the liver parenchyma turns fibrotic. Liver function is also compromised.13

Epidemiological studies point also to the role of Hepatitis B (HBV) and C (HCV) virus infection in CCA development.14 CCA incidence once patients are infected is different when comparing Western and Asian countries.11,15,16 Different studies show a strong association of iCCA to HBV.16,17 In HBV and HCV infections, cirrhosis occurs but there is also a carcinogenic effect of the virus at the cellular level. Cellular proliferation resulting from liver inflammation occurs, which in turn predisposes cells to malignancy.18

Inflammatory Bowel Disease

There are studies relating inflammatory bowel disease (IBD) with the risk of CCA development.19,20 Ulcerative colitis and Crohn’s disease induce chronic inflammation and microbiome changes that may set conditions for tumor formation.21

Chronic Pancreatitis and Duodenal/Gastric Ulcer

Chronic pancreatitis and ulcers of the digestive system associated with Helicobacter Pylori (H. Pylori) infection have been related to increased risk of CCA development.22 Pancreatitis causes biliary stricture resulting in cholangitis and cholelithiasis, which promote tumorigenesis.23 H. Pylori is responsible for increased cellular kinetics of the biliary system and for leading to the formation of stones.24

Parasitic Infections

Parasitic infections caused by Opisthorchis viverrini and Clonorchis sinensis liver flukes are important risk factors in CCA. These worms colonize the bile ducts and may infest humans via ingestion of raw or undercooked fish.1 In Eastern Asia, CCA is mainly associated with these infections, as the relevant parasites are endemic in the region.25 Estimates point that up to 10% of infected individuals will develop CCA.26 The parasites lead to chronic inflammation, cholangitis and fibrosis,27 and multiple infections can promote carcinogenesis.28,29 Cholangiocytes are also more susceptible to the impact of carcinogens.30 

Type 2 Diabetes and Obesity

In type 2 diabetic patients, a compensatory hyperinsulinemia is observed, and insulin has potential to induce malignant growth.31 Studies have shown an association between type 2 diabetes and CCA, particularly with iCCA.22 This association may be also mediated by other conditions such as obesity. However, data on this subject is  limited.12

Tobacco Smoking and Alcohol Consumption

Heavy consumption of alcohol can be a risk factor for CCA.3 Alcohol induces CYP2E1 with consequent increase in reactive oxygen-species, lipid peroxidation and DNA damage.32 The mechanism that leads to carcinogenesis is, however, not clear. 

Data on tobacco smoking and its impact on CCA is also not consistent.11 There are, however, carcinogenic components that are metabolized by hepatic microsomes and further excreted to bile that might contribute to carcinogenesis.33


The radiographic contrast agent Thorotrast that was used between 1930 and 1960 is associated with the development of CCA.34 Patients show a 300-fold increase in CCA risk after contact with Thorotrast.35 There is also a lag time of 16 to 45 years between exposure and tumor formation due to the lifetime of the contrast agent.34

Exposure to asbestos can also contribute to increasing the risk of CCA formation.36

Genetic Polymorphisms

Gene polymorphisms have been related to both increased and decreased risk of CCA, whether there are or not environmental factors associated.1 Polymorphism of genes that encode for enzymes that have a role in DNA repair or de immune response may lead to CCA development. Few of the polymorphisms that have been observed occur in genes coding for glutathione 5-transferases (GSTs), in carcinogen detoxification enzymes GSTM1 and GSTT1 and in oxoguanine glycosylase 1.37,38


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Reviewed by Kyle Habet, MD, on 7/1/2021.