Risk

Factors

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Primary Sclerosing Cholangitis

A condition in which inflammation of the bile duct (cholangitis) leads to the formation of scar tissue (sclerosis) and an increased risk of cholangiocarcinoma. The cause of the inflammation is not usually known. Many people with this disease also have inflammation of the large intestine called ulcerative colitis.

Liver fluke

Liver fluke infections occur in some Asian countries when people eat raw, pickled, fermented or poorly cooked fish that are infected with tiny parasitic worms.

  • In humans, these flukes live in the bile ducts and usually don’t cause any symptoms. Previous studies showed that around 10% of chronically infected patients with these parasites will develop cholangiocarcinoma.
  • There are several types of liver flukes. The ones most closely related to cholangiocarcinoma risk are called Clonorchis sinensis and Opisthorchis viverrini. 
  • Liver fluke infection is rare in the US but can affect people who travel to Asia, like Vietnam War veterans.

Visit https://www.scops.org.uk/internal-parasites/liver-fluke/ for more information.

Long term infection with either hepatitis B virus or hepatitis C virus increases the risk of intrahepatic cholangiocarcinoma.  This may be at least in part due to the fact that infections with these viruses can also lead to cirrhosis.  Learn more at https://www.epainassist.com/abdominal-pain/liver/viral-hepatitis

Cirrhosis is a condition in which the liver does not function properly due to long-term damage. This damage is characterized by the replacement of normal liver tissue by scar tissue. Typically, the disease develops slowly over months or years. Early on, there are often no symptoms.  Learn more at https://liverswithlife.com/stages-of-liver-disease-overview/

Bile duct stones are similar to, but much smaller than gallstones, which can also cause inflammation that increases the risk of cholangiocarcinoma.  Learn more at https://www.kediamd.com/everything-you-want-to-know-about-bile-duct-stones/

These abnormalities can allow digestive juices from the pancreas to reflux (flow back “upstream”) into the bile ducts. This backward flow prevents the bile from being emptied through the bile ducts as quickly as normal. People with these abnormalities are at higher risk of cholangiocarcinoma.

Choledochal cysts are bile-filled sacs that are connected to the bile duct. The cells lining the sac often have areas of pre-cancerous growth, which can increase the risk for developing cholangiocarcinoma.

  • It is a rare congenital abnormality. In the International Cholangiocarcinoma Patient Registry, only 2.2% of patients have been diagnosed with choledochal cysts.
  • It is more common in Asian females.
  • For patients with choledochal cysts, the average age at diagnosis is 32, which is much younger than the average cholangiocarcinoma patient.
  • A recent analysis of SEERs data showed that patients with choledochal cysts have approximately 16 times higher risk for intrahepatic cholangiocarcinoma and 27 times higher risk for extrahepatic cholangiocarcinoma.

Petrick JL, Yang B, Altekruse SF, et al. Risk factors for intrahepatic and extrahepatic cholangiocarcinoma in the United States: a population‐based study in SEER‐Medicare. PLoS One. 2017;12(10):e0186643.

Soreide K, Korner H, Havnen J, Soreide JA. Bile duct cysts in adults. Br J Surg. 2004;91(12):1538‐1548.

Two other rare diseases can lead to cholangioarcinoma in some cases, including polycystic liver disease and Caroli syndrome (a dilation of the intrahepatic bile ducts that is present at birth).

A recent study showed that patients with Caroli’s disease have approximately 38 times higher risk for intrahepatic cholangiocarcinoma and 97 times higher risk for extrahepatic cholangiocarcinoma compared to general population.

Other risk factors include

Older people are more likely than younger people to get cholangiocarcinoma.

Almost 2 out of 3 people with cholangiocarcinoma are 65 or older when it is found.

  • The average age of people diagnosed with cancer of the intrahepatic bile ducts is 70.
  • The average age of people diagnosed with cancer of the extrahepatic bile ducts (perihilar or distal cholangiocarcinoma) is 72.

People who drink alcohol are more likely to get intrahepatic cholangiocarcinoma.  The risk is higher in those that have liver problems from drinking alcohol.

Studies have reported that if you have more than 5-6 drinks per day, you have a 2-3 times higher risk for intrahepatic cholangiocarcinoma.  The International Cholangiocarcinoma Patients Registry shows that 65% of cholangiocarcinoma patients drink alcohol, with 7% drinking more than 3 drinks a day.

Palmer WC, Patel T. Are common factors involved in the pathogenesis of primary liver cancers? A meta‐analysis of risk factors for intrahepatic cholangiocarcinoma. J Hepatol. 2012;57(1):69‐76.

The data from many different studies show that people with diabetes have a slightly higher risk of cholangiocarcinoma than the general population.

Being overweight or obese can increase the risk of developing cancers of the gallbladder and bile ducts. This could be because obesity increases the risk of gallstones and bile duct stones. It remains unclear why obesity can increase the chance of cholangiocarcinoma developing.

A history of cholangiocarcinoma in the family seems to slightly increase a person’s chances of developing this cancer, but the risk is still extremely low. Most cholangiocarcinomas are not found in people with a family history of the disease.

Inflammatory Bowel Disease

Inflammatory Bowel Disease (IBD) includes ulcerative colitis (a chronic condition that results in inflammation and ulcers in the colon and rectum) and Crohn’s disease (a chronic condition that results in inflammation and ulcers along the gastrointestinal tract extending from the mouth to the anus).

Both conditions lead to chronic inflammation and/or changes in the intestinal microbiome and could lead to cholangiocarcinoma.

People with these diseases are around 3 times more likely to develop intrahepatic cholangiocarcinoma and 2 times more likely to develop extrahepatic cholangiocarcinoma.

A stronger association between intrahepatic cholangiocarcinoma and ulcerative colitis was reported compared to patients with Crohn’s disease.

Thorotrast

A radioactive substance called Thorotrast (thorium dioxide) was used as a contrast agent for x-rays until the 1950s and can lead to cholangiocarcinoma, as well as to some types of liver cancer.  Although it is no longer used, it has been shown to cause cancer 16-45 years after use.

After injecting Thorotrast, it is accumulated in the liver, spleen, bone marrow cells and could result into several different types of cancer including cholangiocarcinoma, as well as other cancers of the liver.

Previous studies showed that Thorotrast increases the risk of cholangiocarcinoma by 300 times more than general population.

Studies have found that several other risk factors may increase the risk of cholangiocarcinoma, but the link between these risk factors and cholangiocarcinoma is not as clear.

They include:

  • Smoking
    • The mechanisms by which smoking cause cholangiocarcinoma is unclear, however, this could be because tobacco has many substances that can cause cancer and these substances accumulated in the liver cells and secreted into the bile
    • Two previous studies showed that smoking associated with 1.5 time increase in the risk of intrahepatic cholangiocarcinoma
    • Another study reported increase in the risk of extrahepatic cholangiocarcinoma in smokers compared with non-smokers
  • Pancreatitis (inflammation of the pancreas)
    • Inflammation of the pancreas leads to narrowing of the biliary channels in 3%‐23% of patients, which in turn may increase the risk of biliary channel inflammation and stone formation that are risk factors for cholangiocarcinoma development
    • A positive association between chronic pancreatitis and CCA has been reported, with a 7 time increase risk of extrahepatic cholangiocarcinoma development and 3-times increase risk of intrahepatic cholangiocarcinoma development
  • Infection with HIV
  • Exposure to asbestos
    • Recently, two different case‐control studies reported an increase risk of intrahepatic cholangiocarcinoma with asbestos exposure. But, there is a limited evidence for extrahepatic cholangiocarcinoma. Similar results have been confirmed in a Nordic population‐based study
  • Exposure to radon or other radioactive chemicals
  • Exposure to dioxin, nitrosamines, or polychlorinated biphenyls (PCBs)
    • Although there is an association between these factors and increased risk of different types of cancer, there is a limited amount of data about the association between these factors and the risk of cholangiocarcinoma development

Petrick JL, Yang B, Altekruse SF, et al. Risk factors for intrahepatic and extrahepatic cholangiocarcinoma in the United States: a population‐based study in SEER‐Medicare. PLoS One. 2017;12(10):e0186643.

Petrick JL, Campbell PT, Koshiol J, et al. Tobacco, alcohol use and risk of hepatocellular carcinoma and intrahepatic cholangiocarcinoma: the liver cancer pooling project. Br J Cancer. 2018;118(7):1005‐1012.

Ye XH, Huai JP, Ding J, Chen YP, Sun XC. Smoking, alcohol consumption, and the risk of extrahepatic cholangiocarcinoma: a meta‐analysis. World J Gastroenterol. 2013;19(46):8780‐8788.

Petrick JL, Yang B, Altekruse SF, et al. Risk factors for intrahepatic and extrahepatic cholangiocarcinoma in the United States: a population‐based study in SEER‐Medicare. PLoS One. 2017;12(10):e0186643.

Brandi G, Di Girolamo S, Farioli A, et al. Asbestos: a hidden player behind the cholangiocarcinoma increase? Findings from a case‐control analysis. Cancer Causes Control. 2013;24(5):911‐918.

Farioli A, Straif K, Brandi G, et al. Occupational exposure to asbestos and risk of cholangiocarcinoma: a population‐based case‐control study in four Nordic countries. Occup Environ Med. 2018;75(3):191‐198.