When I was in medical school, one of my professors said, “In your exams, just remember – smoking increases the risk of everything.” This sounds almost sarcastic at first, but if we look closely at the known risk factors for many diseases, we will be hard-pressed to find one that does not include smoking. 

The same can be said about obesity, which predisposes a person to a number of diseases, especially those of a cardiovascular nature. Indeed, most lifestyle choices have an unseen metabolic impact; they can trigger a number of pathways that ultimately result in a particular disease. 

Cholangiocarcinoma (CCA) is a rare cancer that arises from the biliary epithelium. Studies have attributed the global incidence of CCA to a combination of genetic, metabolic, and lifestyle risk factors. A team of researchers identified a few key metabolic disorders associated with CCA and published their findings in Expert Review of Gastroenterology & Hepatology. We will discuss some of their findings in this article. 

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Metabolic Changes in CCA

Let us begin by examining what happens metabolically when CCA occurs. A common feature of CCA is the uptake of glucose and activation of glycolysis. Pyruvate is the main metabolic product of glycolysis, and instead of being oxidized in the mitochondria, it is used in lactate production through the activation of lactate dehydrogenase (LDH) and is secreted out of the cells. 

Read more about CCA etiology

This process is known as aerobic glycolysis since it occurs even when oxygen is adequately produced through mitochondrial respiration – a process known as the “Warburg effect.” The altered expression of glucose transporter 1 (GLUT-1) has been linked to both non-fluke and fluke-related CCA. Indeed, high GLUT-1 expression is associated with a poorer prognosis, especially in patients with aggressive liver fluke-related CCA. 

The gut microbiome has also been associated with CCA carcinogenesis. Pathologies such as inflammatory bowel disease, cirrhosis, and primary sclerosing cholangitis are all known risk factors for the development of CCA. In the case of dysbiosis and the impairment of the gastrointestinal barrier, chemotactic processes may result in the accumulation of polymorphonuclear myeloid-derived suppressor cells, which can cause an immunosuppressive environment that promotes the development of CCA. 

Metabolic Risk Factors 

In this section, we will explore some of the common risk factors for CCA. One such risk factor is diabetes mellitus (DM), which is increasingly associated with cancers of any type. In the context of CCA, DM increases the risk of biliary stones, which, in turn, is a risk factor for the development of extrahepatic CCA. 

In type 2 DM, the body is in a hyperinsulinemic state, which supports the cellular proliferation of cholestatic cells. Studies have found that consistent insulin stimulation increases the levels of insulin-like growth factor 1 (IGF-1), as well as insulin receptors in tumor cells within the gallbladder; the same is true in CCA. 

Read more about CCA comorbidities

Obesity has also been implicated as a risk factor for the development of CCA. It is important to remember that adipose tissue is a biologically active entity. Adipose tissue is capable of secreting several key mediators, such as leptin, adiponectin (APN), and proinflammatory molecules. Leptin, for example, is a hormone most commonly known for inhibiting hunger drive in the brain. Additionally, studies have shown that leptin can stimulate the growth, migration, and antiapoptotic effect observed in intrahepatic CCA cells. We also know that normal and malignant cholangiocytes can secrete leptin and that the disruption of leptin-dependent pathways can inhibit cancer growth. 

As for APN, it is recognized to possess antioncogenic properties, and it has an inverse relationship with CCA. However, studies have shown that obese patients are likely to have less than adequate quantities of APN for its antioncogenic properties to take effect. Lastly, proinflammatory cytokines secreted by adipose tissue can create generalized inflammation in the body and thus produce a pro-oncogenic environment. 

Another risk factor for the development of CCA that is closely linked to obesity is metabolic syndrome. Metabolic syndrome consists of a triad of conditions: obesity, hyperglycemia, and dyslipidemia. A study showed that metabolic syndrome significantly increased the risk of developing CCA: patients with metabolic syndrome were 2.68 times more likely to develop intrahepatic CCA and 1.79 times more likely to develop extrahepatic CCA than those without. In addition, dyslipidemia in itself is associated with a high risk of developing intrahepatic CCA. 

Some risk factors for the development of CCA are inherited. For example, genetic hemochromatosis, which causes an excessive accumulation of iron in the body, is associated with a significantly increased risk of developing intrahepatic CCA. Wilson’s disease, on the other hand, is associated with excessive accumulation of copper in the body. Statistics show that around 0.5% of patients with Wilson’s disease will develop CCA; this is because Wilson’s disease causes generalized liver inflammation, which creates an environment that encourages oncogenesis. 

Directions for Future Research

It is clear from this article that a number of metabolic conditions can contribute to the development of CCA. These metabolic conditions can either be inherited or driven by lifestyle choices or environmental exposures. As much as we currently know about the metabolic foundations underpinning CCA, we still have much to learn about how exactly they cause CCA to develop. 

As the authors of the study observed, “While our understanding of CCA has evolved over the past decades, the majority of CCA cases are still diagnosed in the absence of recognizable risk factors.” More research needs to be conducted to cement the link between what we know about the metabolic aspects of CCA and the development of new, more targeted CCA therapies.


Ghidini M, Ramai D, Facciorusso A, et al. Metabolic disorders and the risk of cholangiocarcinoma. Expert Rev Gastroenterol Hepatol. 2021;15(9):999-1007. doi:10.1080/17474124.2021.1946393

Wu HJ, Chu PY. Role of cancer stem cells in cholangiocarcinoma and therapeutic implicationsInt J Mol Sci. 2019;20(17):4154. doi:10.3390/ijms20174154