Cholangiocarcinoma is a malignancy arising from the bile ducts, both inside and outside the liver. Despite its relative anonymity outside specialist medical circles, we have good reason to be concerned – it is showing worrying increases in incidence across all continents and is one of few cancers where technological advance has offered little improvement in prognosis over the last few decades. Widespread in South-East Asia due to parasitic infection, it is now also the most common cause of primary liver cancer mortality in the UK largely due to the fact current treatment options are so ineffective.
New award-winning work at Imperial College, however, shows promise for the development of simple, low-cost urinary markers that could revolutionise early detection of this disease and thus significantly improve survival prospects for patients.
Cholangiocarcinoma of the liver is on the rise, with worrying increases in incidence across all continents, and a 15-fold increase in the UK alone since 1968. Currently the only hope of a cure is early detection followed by surgical removal. However, the disease normally presents too late for this to be possible and mortality rates are extremely high, which means that incidence almost equals mortality; i.e. nearly everyone who contracts this cancer will be killed by it (in very few other cancers is this true). This bleak situation becomes worse when one considers the extremely large disease burden in South-East Asia. Mainly due to parasitic infestation, this cancer is overwhelmingly common in areas like Khon Kaen in rural Thailand.
The development of simple,
low-cost urinary markers
... could revolutionise early
detection of this disease
In Khon Kaen, incidence rates have reached over 300 per 100,000 and it is not an uncommon sight to see an entire ward of young men and women jaundiced and cachectic, close to death. Quite apart from the staggering disease burden, it also presents a large development hurdle, often tearing families apart and leaving single parents to care for large families or even orphaning entire groups of siblings.
South-East Asian hill tribes and rural communities are often impoverished, isolated, and have significant cultural barriers that might limit the social acceptability of invasive testing. Although there is infrastructure in place to treat the disease (albeit often basic), these centres are often too far for communities to bother with routine screening or even to arrange consultations for non-severe symptoms.
Thus, there is an urgent need to find an accurate, cost-effective, transportable, non-perishable, and culturally permissible way to screen for this cancer in these communities, and worldwide.
Our hope was that we would be able to achieve this through urine analysis, particularly a simple urine dipstick – the kind of test that is currently used to detect blood, sugar and infections in urine as well as diagnose pregnancy. It could also be used to follow up patients and detect recurrences after treatment.
The reason cholangiocarcinoma research efforts have previously had such little effect on survival is due to the cancer’s unique characteristics (see box next page). We hope that the emerging field of metabolomics could hold the key to a new method of cholangiocarcinoma detection.
Metabolomics is the comprehensive quantitative analysis of metabolites in a biological system1. This work is increasingly popular at Imperial College especially in gastroenterological and hepatological fields where other investigative modalities may lack accuracy or be extremely invasive. This seemed to be a good starting point given this modality’s success in isolating detectable markers in other cancers, including a urinary marker for another liver cancer (hepatocellular carcinoma), and the fact that previous work had identified metabolite changes inside people with cholangiocarcinoma.
Given Imperial College’s other success with urinary metabolomics, a developed dipstick for cholangiocarcinoma could also potentially incorporate markers for other diseases such as hepatitis C and hepatocellular carcinoma – to give a much more throrough screening of isolated communities. Furthermore such work has the opportunity to illuminate the way such a poorly understood cancer arises, which may have preventative and treatment-target ramifications.
In Khon Kaen, incidence rates
have reached over 300 per 100,000
and it is not an uncommon sight
to see an entire ward of young
men and women jaundiced
and cachectic, close to death
The Patients and Profiles
Blood and urine samples were collected from cancer patients and healthy controls in Khon Kaen, Thailand. These samples were brought back to MRC Harwell, Oxfordshire for analysis in an 11.7 NMRS machine. As a pilot study with significant logistical, time and financial constraints, the project was limited to recruiting five cancer patients and 20 healthy controls.
Intelligent computer software was used to firstly look at the ‘multivariate’ profiles – i.e. all the metabolites present and their respective concentrations. Using two different statistical techniques, the computer was able to separate cancer from healthy controls with an extremely high degree of accuracy. Individual metabolites were then looked at which showed three significant individual metabolite alterations in our small study alone, as well as many others that didn’t reach significance (perhaps due to sample size).
This is extremely exciting preliminary work that now needs further validation. These results show strong evidence to support further work on such urinary diagnostics, but as a pilot study our work suffers from two main limitations. Firstly, this original study had a sample size that limits our ability to draw conclusive observations and, secondly, we cannot completely discount the fact that parasites may have been interacting with the urinary metabolites. No urinary metabolic assessment with any parasites has ever been shown to show suppressions in some of the metabolites that we observed, however no previous work has looked at these parasites so we cannot discount their influence.
To correct these study limitations more cancer and control patients are being recruited in Thailand, alongside a third cohort of people infested with parasites but without cancer. Further work will compare their profiles to non-malignant pathology of the bile ducts, and compare our alterations with other documented cancers. By combining this urinary test with other markers for hepatocellular carcinoma and viral hepatitis we hope to develop a simple screening test for multiple liver pathologies, with the ultimate of of screening large populations for different liver pathologies with one simple and cheap modality. In this way we hope to be able to move tangibly closer to the exciting dream of diagnosis of serious pathology by urinary assessment.
There are still barriers to be overcome outside technical development – mainly the logistics of screening rural communities, and capacity-building of healthcare services in response to a waft of new diagnoses that screening would likely present; however we feel these issues could be addressed and therefore not significantly limit efforts to improve this disease’s prognosis.
Although it is still very early days in this research, we are hoping this is a significant step towards finding an innovative way of alleviating a major disease burden in isolated and impoverished communities, which may also have relevance in more developed countries.
John would like to thank everyone who made this work possible, especially for the enthusiasm of Prof. Simon Taylor-Robinson, Dr. Shahid Khan, and to IGHI for their kind contribution and support for the ongoing research.
John Chetwood is a 5th year medical student studying at Imperial College London. His cholangiocarcinoma project was recent winner of the Institute of Global Health Innovation (IGHI) ‘Next Generation: Global Health Innovators’ award which included £2000 for further research.
 Khan, S. A., Davidson, B. R., Goldin, R., et al. (2002) Guidelines for the diagnosis and treatment of cholangiocarcinoma: consensus document. Gut. 51(Suppl 6): VI1-9.