Risk Factors for Cholangiocarcinoma

The following is a brief summary of Tyson and El-Serag’s paper reviewing scientific literature up to and including March 2011, entitled “Risk Factors for Cholangiocarcinoma”, which was recently published in the journal Hepatology.

(The following technical translation of the published paper has been prepared for us by Dr Ruth Corrigan MA (Cantab), and a link to download the full paper can be found below the summary.)

Cholangiocarcinoma (CC) is the second most common primary hepatic malignancy after hepatocellular cancer. People below the age of 40 are rarely affected, and most people are diagnosed in their 60s. Worldwide, CC accounts for approximately 10%-25% of all hepatobiliary worldwide, although there are considerable geographic variations in the incidence of CC, largely attributed to geographical variations in known CC risk factors (particularly parasitic infections, see below). However it is important to note that for the majority of CC cases in the Western world no risk factors are evident, and thus these cases are classified as “sporadic” cholangiocarcinoma. Much research is still required in order to find out more about why CC develops. This paper aims to summarise what is known about CC risk factors to date.

In this paper the authors review 63 scientific articles relating to risk factors for the development of CC. In general, risk factors for diseases are identified using one of two methods: either by comparing people with and without the disease of interest and looking for any differences between the groups which may be linked to the development of the disease in question, or by looking at people with and without proposed risk factors and comparing how many from each group develop the disease of interest. This paper looks at the conclusions of many of these studies to provide an overview of our current knowledge of risk factors for CC.

Initially this paper reviews the evidence for known CC risk factors, for example parasitic infection of the biliary tree (prevalent in South East Asia) and the autoimmune disease primary sclerosing cholangitis. Next the paper highlights possible CC risk factors such as inflammatory bowel disease, diabetes and obesity and summarises the evidence for each.

It is important to note that although risk factors can be identified at a population level, that is to say “people with primary sclerosing cholangitis are more likely to develop CC than those without”, it remains almost impossible to identify individual risk factors in patients diagnosed with CC, that is to say “this patient developed CC because..”.

Known Risk Factors For CC

The following risk factors are all accepted by scientists to increase the likelihood of developing CC:
Parasitic infections

Biliary tree disorders including bile duct cysts

Primary sclerosing cholangitis

Bile duct stones

Toxins

Conditions are considered risk factors for a disease if numerous studies by different groups of scientists have come to this conclusion. Some examples of such work in relation to CC are described below.

Firstly, studies from Thailand have found that people with CC were between 5 and 27 times as likely to have antibodies indicating infection with the parasite Opisthorchis viverrini than similar people without CC. Similarly, patients with bile duct cysts (arising due to a developmental abnormality of their bile duct anatomy) are reported as having a 50 fold increased risk of developing CC compared to those with normal bile duct anatomy. Equally a study of Chinese patients found that those with gallstones high up in the billiary tree (before the left and right hepatic ducts join) were also 50 times more likely to get CC compared to those without. Furthermore a Japanese study found that people exposed to the radiographic contrast agent Thorotrast were 300 times more likely to get CC than those who were not exposed, strongly implicating this toxin in the development of CC.

However, it is important to note that although such conditions are consistently linked to a high risk of CC, the percentage of CC cases which can be attributed to each of these known factors is unknown, and likely to be low. For example, it has been estimated that only 10% of CC can be attributed to primary sclerosing cholangitis, even though up to one in three of these patients will develop CC.  In practical terms this means that many risk factors are yet to be identified.

Possible Risk Factors For CC

The involvement of some factors in the development of CC is currently unclear, as the conclusions from studies are either conflicting or there are too few studies to be certain. Such factors include:

Inflammatory bowel disease

Choledocholithiasis and cholangitis

Hepatitis B or C and cirrhosis

Diabetes and obesity

Alcohol use

Smoking

Genetic factors

Before discussing these potential risk factors the authors of this review suggest that CC ought to be considered as two entities; intrahepatic and extrahepatic CC, based on whether the cancer affects bile ducts inside, or outside of the liver. This is because they suggest that some less well established risk factors can be more strongly associated with a particular subtype of CC.

With regard to the proposed risk factors listed above, current research as included in the review is summarised below.

Inflammatory bowel disease (IBD). Several studies have investigated the link between IBD and either or both intra- and extrahepatic CC, with mixed results. Conclusions are further complicated by the fact that primary sclerosing cholangitis is itself more likely in people with IBD and it remains unclear whether any link between IBD and CC is in fact due to the increased risk of primary sclerosing cholangitis in IBD patients.

Choledocholithiasis and Cholangitis. In a similar vein, although both the presence of gall stones in the common bile duct (choledocholithiasis) and infection of the common bile duct (cholangitis) have also been associated with increased risk of CC in at least 3 studies it is unclear how much this is due to an increased risk of primary sclerosing cholangitis in these patients.

Hepatitis B or C and Cirrhosis. The link between hepatitis B or C with CC is equally unclear. Conflicting studies from Asia find that hepatitis B (but not C) is associated with CC, also that hepatitis C (but not B) is associated with CC, and that infection with either virus is not associated with CC. However, in European studies both hepatitis C infection and liver cirrhosis have been linked to an increased risk of developing CC, but hepatis B has not. Finally, three studies from the United States find that hepatitis C infection is associated with an increased risk of intrahepatic CC, whereas no studies have implicated hepatitis B in the development of either subtype.

Diabetes and Obesity. With regard to diabetes, the field is split, with four studies (including two large American studies) finding a potential link between diabetes and CC, but at least four finding no significant association. Again, there are studies suggesting both that obesity is and is not linked to the development of CC, but the evidence to date is too sparse to be suggestive one way or the other.

Alcohol Use. The role of alcohol use in the development of cholangiocarcinoma is similarly disputed by several studies. However, since some studies reviewed find a significantly increased CC risk of 2-15 fold in those who drink heavily compared to those who do not, the authors of this review consider it likely that heavy alcohol use is associated with an increased risk of CC.

Smoking. Interestingly, at best, smoking is only a weak risk factor for CC, but again, conflicting data from a variety of studies, some of which failed to quantify the amount of tobacco smoked mean that no firm conclusions can be made.

Genetic Factors. Finally, numerous studies have implicated many different genes involving enzymes responsible for the disposal of waste products, DNA and the immune response in the development of CC, however more work is needed to draw out consistent findings from such studies.

Summary:

In summary, with the exception of CC in countries where liver flukes are common, most cases of CC are not associated with one of the established risk factors for the disease. This is especially true in the Western world where the majority of cases of cholangiocarcinoma are classified as “sporadic”, that is to say that the causal factor is unknown. This suggests that other risk factors must exist and raises the possibility that some of these could be associated with particular disease cases. To date, data regarding the role of IBD, obesity, smoking and genetic variations is not strong enough to prove or disprove an association with CC. However, current evidence is suggestive that diabetes, heavy alcohol intake and HCV (in Western countries) may be associated with increased risk of developing CC. Given that CC in different parts of the biliary tree may have different risk factors the authors of this review also emphasize the need for a clear and consistent method of classifying cancers of the liver and biliary tree system.

El Serag CC risk factors review