What are the causes of cholangiocarcinoma?

Causes of Cholangiocarcinoma

Cholangiocarcinoma (CCA) is primarily caused by chronic biliary inflammation, with specific risk factors varying by geographical region and subtype, including hepatobiliary flukes, primary sclerosing cholangitis, biliary cystic diseases, hepatolithiasis, cirrhosis, and viral hepatitis. 1

Major Risk Factors by Geographic Region

Global Risk Factors

• Primary sclerosing cholangitis (PSC)

  • Lifetime risk of 5-15% and annual risk of 0.5-1.0% 2
  • More common in Western countries 1
  • Primarily associated with perihilar and distal CCA 1

• Biliary cystic diseases

  • Choledochal cysts (especially types I and IV): lifetime risk 5-30% 1
  • Caroli's disease: significantly increases risk of intrahepatic CCA 1
  • Higher prevalence in Asian populations (18% lifetime risk) compared to Western populations (5% lifetime risk) 1

• Hepatolithiasis/Biliary stones

  • Strong association with odds ratios up to 50 in some Asian countries 1
  • More common in Southeast Asia (20%) than Western countries (2%) 1

• Liver cirrhosis

  • Particularly associated with intrahepatic CCA 1
  • Similar risk factor as for hepatocellular carcinoma 1

Region-Specific Risk Factors

• Southeast Asia (particularly Northeast Thailand)

  • Hepatobiliary flukes (Opisthorchis viverrini, Clonorchis sinensis)
  • Classified as Group 1 human carcinogens by WHO 1
  • Infection occurs via consumption of raw/undercooked freshwater fish 1
  • Associated with odds ratios up to 27 for CCA development 1
  • Approximately 40% of fluke-associated CCAs are intrahepatic 1

• Western Countries

  • Increasing incidence related to metabolic factors 1, 2
  • Inflammatory bowel disease 1, 3

Additional Risk Factors

Infectious Causes

• Viral hepatitis

  • Hepatitis B and C infections 1, 3
  • More strongly associated with intrahepatic CCA 1

• Chronic bacterial infections

  • Chronic typhoid carriers 2

Metabolic and Lifestyle Factors

• Diabetes: 81% increased risk 2
• Obesity: 62% increased risk 2
• Alcohol consumption 1
• Tobacco use 1
• Non-alcoholic fatty liver disease 4

Genetic Factors

• Lynch syndrome 1
• BRCA1/2 mutations: relative risk of 5 for BRCA2 mutation carriers 1
• Mismatch repair deficiency: present in <1.5% of intrahepatic CCAs 1

Chemical/Toxin Exposure

• Thorotrast (previously used contrast agent) 5
• Nitrosamines 1

Pathogenesis Mechanisms

Regardless of the specific risk factor, most causes lead to CCA through two primary mechanisms:

1. Chronic inflammation 4

   • Increased exposure to inflammatory mediators (IL-6, TNF-α, COX-2)
   • Progressive mutations in tumor suppressor genes and proto-oncogenes
   • DNA mismatch-repair gene alterations

2. Cholestasis 4

   • Accumulation of bile acids
   • Reduced pH and increased apoptosis
   • Activation of ERK1/2, Akt, and NF-κB pathways
   • Promotion of cell proliferation, migration, and survival

Clinical Implications

• The majority of CCAs (approximately 70%) are sporadic with no identifiable risk factors 1

• Screening is recommended for high-risk groups:

  • Patients with PSC should undergo regular screening 1
  • Patients with Caroli's disease should receive yearly MRI screening 1
  • Screening is not recommended for patients with biliary hamartomas or LPAC syndrome without macrolithiasis 1

• When CCA is suspected, a systematic investigation of risk factors should include:

  • Biliary cystic and lithiasic pathologies
  • PSC
  • Cirrhosis
  • HBV/HCV infection
  • Alcohol use
  • Diabetes
  • Smoking history 1

Understanding these risk factors is crucial for early detection in high-risk populations and may inform prevention strategies, particularly in regions with high prevalence of modifiable risk factors.