If we are to believe everything we hear about the possible causes of cancer, everything from the foods we eat to the shampoo we use is carcinogenic. Every so often, a “new” cancer risk is reported while another is debunked. This begs the question: what risk factors for cancer have been scientifically validated, and which ones are entirely bogus? 

In a study published in the Journal of Hepato-Biliary-Pancreatic Sciences, Ostaphan and colleagues conducted a review exploring the relationship between obesity and cholangiocarcinoma. Studies have repeatedly characterized obesity as a significant risk factor for both intrahepatic and extrahepatic cholangiocarcinoma. So how exactly does obesity contribute to the development of cholangiocarcinoma? 

“Recent advances in the field of obesity have begun to untangle the complex, underlying cellular biochemical alterations in the hormonal milieu that influence malignancy,” Ostaphan and colleagues wrote. 

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In obese states, altered neurohormonal statuses can predispose one to develop cholangiocarcinoma. Examples of neurohormones that are altered in an obese individual are adipokines, growth factors, pro-inflammatory cytokines, and pro-tumorigenesis metabolites. Obese states hence enhance tumorigenicity and metastatic proficiency. 

Read more about cholangiocarcinoma etiology 

Obese patients have high adiposity; normally, adipose tissue stores and releases lipids in response to energy needs. Adipose tissue also releases adipokines that regulate appetite and metabolism. However, in patients who are obese, aberrant adipokine secretion occurs. Studies have suggested that adipose tissue in an obese individual provides the nutrition needed to fuel the development of cancer, especially in carcinomas that infiltrate the adipose tissue. 

Another mechanism in which obesity leads to the development of cholangiocarcinoma is in causing fatty liver changes. A notable proportion of individuals who are obese also have nonalcoholic fatty liver disease (NAFLD), including the nonalcoholic steatohepatitis (NASH) subtype. Studies have revealed that chronic hepatitis is one of the key risk factors for the development of primary liver cancers. 

Epidemiological Differences 

“[Cholangiocarcinoma] is the second most common primary hepatic malignancy after hepatocellular carcinoma, comprising about 15% of all primary liver tumors and 3% of all gastrointestinal cancers,” Sarcognato and colleagues wrote in Pathologica. 

The global incidence of cholangiocarcinoma is around 0.3-6/100,000 individuals per year, making it an exceedingly rare disease. Some countries have particularly high incidence rates, including China, South Korea, and Thailand. 

However, there is an interesting Western/Eastern divide when it comes to the degree to which obesity correlates with an increased risk of cholangiocarcinoma. In the United States, there is some evidence indicating that having a body mass index (BMI) of 30 kg/m2 and above increases the risk of cholangiocarcinoma. However, another study shows that obesity correlates with cholangiocarcinoma in men but not in women. Overall, the medical literature on this issue suggests that obesity is correlated with cholangiocarcinoma in at least some cases in the West. 

“In contrast to the reports from Western countries, most studies in Asian countries, where the major [cholangiocarcinoma] risk factor is liver fluke infection, reported a null obesity effect on [cholangiocarcinoma] development,” Ostaphan and colleagues noted. 

Read more about cholangiocarcinoma epidemiology 

For example, large-scale studies conducted in South Korea and Japan both indicate that there is a null effect of obesity on the development of cholangiocarcinoma. Overall, the balance of evidence suggests that Western populations are more vulnerable to the development of cholangiocarcinoma when obese compared to Eastern populations. 

There are two possible reasons why this is the case. First, obesity is less prevalent in Asia and is sometimes defined at a slightly different cutoff point compared to the West. Second, studies on the relationship between obesity and cholangiocarcinoma in the East are less abundant because the main cause of cholangiocarcinoma in the East is liver fluke infection, which has an entirely different pathophysiology in driving the development of liver cancer. 

A Key Modifiable Risk Factor 

It is clear that obesity causes metabolic changes that raise the risk of cholangiocarcinoma; it is also true that obesity is a risk factor for a large number of noncancerous diseases. It is one of the great modifiable risk factors for a reduction in life expectancy, alongside cigarette smoking, physical inactivity, and hypertension. 

“Recent statistics indicate that overweight/obesity continues its relentless global rise, with the number of people with excess body weight reaching >2 billion, ∼30% of the world population,” Caballero in Advances in Nutrition wrote

Another alarming statistic is the sharp rise in childhood obesity over the last few years. One of the problems with childhood obesity is that it often carries over into adulthood. This means that, unless active intervention is introduced, a person who is obese in childhood is likely to be obese for the rest of their life. 

One of the factors that have contributed to the exponential increase in obesity is that energy-dense, unhealthy foods are becoming cheaper, while healthy, organic foods are becoming more expensive. This is a curious societal development; the opposite has been true for most of human history. In addition, the increasing use of technology means individuals can lead a relatively sedentary lifestyle without realizing it. 

However, the fight against obesity must continue, chiefly because it is linked to diseases such as cholangiocarcinoma, which imposes a high burden of care on existing healthcare infrastructures. How do we influence large-scale changes in behavior so that recent trends in obesity can be reversed? This is the billion-dollar question that demands an answer. 


Sarcognato S, Sacchi D, Fassan M, et al. CholangiocarcinomaPathologica. 2021;113(3):158-169. doi:10.32074/1591-951X-252

Osataphan S, Mahankasuwan T, Saengboonmee C. Obesity and cholangiocarcinoma: a review of epidemiological and molecular associationsJ Hepatobiliary Pancreat Sci. 2021;28(12):1047-1059. doi:10.1002/jhbp.1001

Caballero B. Humans against obesity: who will win?Adv Nutr. 2019;10(suppl_1):S4-S9. doi:10.1093/advances/nmy055