Introduction

Cholangiocarcinoma (CCA) is a group of rare cancers with a probability of 1.26 per 100,000 people. It majorly affects the intrahepatic or extrahepatic (perihilar ordistal) bile ducts. These types of cancers are difficult to diagnose and treat as they generally exhibit painless symptoms, such as painless jaundice, weight loss, or cholangitis, also due to their silent clinical course, lack of specific tumour markers, limited sensitivity of imaging techniques, as they tend to grow longitudinally along the bile duct rather than radially. It is therefore difficult to obtain a tissue diagnosis. The only treatment for these cancers is palliative care.¹

These are classified based on anatomical location into intrahepatic (comprising 10–20%), perihilar or Klatskin tumours (50%), and distal (30–40%) CCA, and based on aetiology into fluke-negative or fluke-positive cholangiocarcinoma.²

Risk factors

The global incidence of CCA has increased over the past decades and varies across distinct geographical areas, reflecting unique population risk factors and the evolving etiopathogenesis landscape. Intrahepatic cholangiocarcinoma has a greater incidence risk in the European and American populations.²

Risk factors in East Asian countries

The most prevalent risk factor is infection with endemic parasitic liver flukes, Opisthorchis viverrini (Ov) or Clonorchis sinensis. They are both classified as Class 1 carcinogens. Infestation with liver flukes is predominant in the northeastern region of Thailand and its neighbouring countries, Laos and Cambodia. The parasite can inhabit the biliary tract within the human host for over 10 years. OV has been suggested to induce cholangiocarcinoma (CCA) through three mechanisms: 

• Physical damage to the biliary epithelia is caused by the parasites’ feeding activities
• Immunopathology resulting from infection-related inflammation, and 
• The deleterious effect of excretory/secretory molecules released by the parasites

Risk factors in Western countries

One of the major risk factors in Western countries is a rare immune-related condition called primary sclerosing cholangitis (PSC). It is marked by chronic biliary inflammation. People suffering from Caroli disease and Caroli syndrome are at greater risk. Both these genetic conditions are defined by cystic dilation of intrahepatic bile ducts. Some other most prevalent risk factors are liver cirrhosis, cholelithiasis and choledocholithiasis. Chronic viral infections with the hepatitis B virus (HBV) and hepatitis C virus (HCV) may also represent a risk factor for CCA development. A relation between non-alcoholic fatty liver disease (NAFLD) and CCA has also been suggested. Type 2 diabetes has also been recorded to be at a higher risk. Some other factors are still under investigation, such as inflammatory bowel disease, alcohol consumption, and tobacco smoking, while obesity and hypertension.²

Environmental factors

Thorotrast, a radiographic contrast agent, was suggested to increase the probability of cholangiocarcinoma. Some incidents have shown that asbestos exposure may also result in this cancer progression. Asbestos exposure leads to a greater risk of intrahepatic CCA than extrahepatic CCA. Some traditional medicines. The compound Aristolochic acid (AA) is generally present in plants of the genera Aristolochia and Asarum. These are known for their anti-inflammatory and analgesic properties. Aristolochic acid is classified as a Class I carcinogen. They act by metabolically activating AA binds covalently to dA and dG purine residues in DNA to form aristolactam-DNA (AL-DNA) adducts, which block DNA replication eventually.²

Other risk factors

Bile-tract disorders

Bile-duct cysts

These are rare congenital disorders characterised by cystic dilatation of the extrahepatic and/or intrahepatic bile ducts. This results in pancreatic enzymes refluxing into the biliary system, resulting in increased intraductal pressure and swelling, leading to an increase in ductal size. The type I (solitary, extrahepatic) and IV (extrahepatic and intrahepatic) bile-duct cysts have a higher incidence of CC.³

Primary Sclerosing Cholangitis (PSC)

It is an autoimmune disease that results in narrowing of the extrahepatic and/or intrahepatic bile ducts. Although PSC is known to be a strong risk factor for CCA, no more than 10% of CCA is attributed to PSC. Some of the mechanisms for carcinogenesis for PSC are chronic inflammation, proliferation of biliary epithelium, production of endogenous bile mutagens, and bile stasis.

Hepatolithiasis

These are calculi or concretions located near the confluence of the right and left hepatic ducts. Infestation with parasites such as Clonorchis sinensis and Ascaris lumbricoides has been shown in up to 30% of patients with hepatolithiasis. This cause is mainly predominant in Southeast Asia (e.g. up to 20% in Taiwan) and is rare in the West (1–2%).

Inflammatory bowel disorder (IBD)

Some studies evaluate IBD, both ulcerative colitis and Crohn’s disease, as risk factors independent of PSC for CCA.

Choledocholithiasis and Cholangitis

It has been said that cholangiocarcinoma has symptoms such as chronic inflammation and bile stasis, which are also very common in choledocholithiasis and cholangitis. Therefore, choledocholithiasis and cholangitis are risk factors for CCA.

Summary

Cholangiocarcinoma (CCA) is a rare but aggressive malignancy of the biliary tract, with a challenging clinical profile due to its silent onset, nonspecific symptoms, and limited diagnostic sensitivity. The disease is anatomically classified into intrahepatic, perihilar, and distal subtypes, and etiologically into fluke-associated and non-fluke-associated types, each with distinct geographical patterns and risk profiles. In East Asia, liver fluke infestation remains a major causative factor, while in Western populations, conditions such as primary sclerosing cholangitis, biliary cysts, hepatolithiasis, chronic viral hepatitis, and metabolic diseases are more prevalent. Environmental exposures, including Thorotrast, asbestos, and aristolochic acid-containing herbal remedies, further contribute to disease risk.

Given its tendency to grow longitudinally along the bile ducts, difficulty in obtaining histological samples, and lack of specific biomarkers, CCA is often diagnosed at an advanced stage when curative interventions are rarely feasible. Consequently, treatment is frequently palliative, aiming to alleviate symptoms and improve quality of life rather than achieve a cure. The global rise in CCA incidence underscores the need for enhanced surveillance in high-risk populations, improved diagnostic modalities, and targeted prevention strategies addressing both infectious and non-infectious risk factors. Early detection remains the most critical factor for improving patient prognosis and survival outcomes.