Cholangiocarcinoma: What is it and why is it so prevalent In Thailand?

By Imperial medical students Thomas Hughes and Thomas O’Connor 

Today, 17th February 2016, marks the first ever World Cholangiocarcinoma Day.

Cholangiocarcinoma (CCA) is a primary liver cancer, usually formed from glandular structures in the epithelial tissue (adenocarcinomatous). It occurs in the bile ducts and is classed as being either intra-hepatic (IHCC) or extra-hepatic (EHCC) depending on whether the tumour forms inside or outside of the liver.

CCA is the second most common form of primary hepatic malignancies in the world, with survival beyond a year of diagnosis being <5%.[1] It represents 30% of primary hepatic malignancies with a mean survival rate of 3-6 months after diagnosis, due mostly to the late presentation of symptoms which massively reduces treatment success rates.[2],[3] In the western world the causes of CCA are not well known with 80% of cases being random with no specific risk factor. Despite this, several associations have led to risk factors being identified. The majority of risk factors are associated with chronic biliary inflammation, the most common of which is primary sclerosing cholangitis. The human pathogen Cryptosporidiosis has been associated with CCA and typhoid carriers have been found to have a six-fold increase in CCA. Aside from this, hepatitis B and C have both been found in higher proportions in the CCA population.

CCA is much more prevalent in south-east Asia, particularly north-east Thailand, than elsewhere in the world, with 80-90 cases per 100,000 people.1 The reason for the high incidence is due to biliary infestation with liver flukes, most notably Opisthorchis Viverrini (OV). OV has been recognised as a type 1 carcinogen since 1994 due to its role in causing inflammation of the bile ducts which leads to fibrogenesis and increasing tumorigenesis.3Oxidative stress has been proven to play a key role in transforming a chronic OV infection into CCA via advanced periductal fibrosis.4 OV makes it’s way into the human body via the consumption of raw or undercooked fish, a delicacy in Thailand, particularly in the Isaan region.

The eggs in the Mekong river, and its surrounding water bodies, are ingested by Bithynia snails (the primary intermediate hosts). Several species of cyprinid fish act as the secondary intermediate hosts and the worm will be come infective when it reaches an appropriate species. The definitive hosts are humans, with cats and dogs acting as reservoir hosts. When inside the human body the fluke will reach maturity and start to release eggs into the digestive tract which will be released into the faeces. The eggs will often make their way back into freshwater systems, due to poor sanitation, thus completing the cycle. With raw or fermented fish being a key ingredient in many cultural specialities in north-eastern Thailand, coming into villages and trying to prevent these dishes being made leads to a backlash and alienates the researchers from the villagers. The drug Praziquantel is used as an anti-helminth drug and following mass drug administration, whilst the number of people with OV infections has dropped, people now use it as a safeguard in order to continue eating raw fish. In actual fact, repeat infections is correlated with an increased risk of CCA, thus highlighting the need for further education on the matter.5 Therefore, a transdisciplinary approach is needed to tackle the problem of the eggs making their way back into freshwater, by dealing with improved sanitation methods, and to educate the villagers on the risks of raw fish consumption in order to allow them to make their own choices on whether to continue eating undercooked fish.6

thailand

The symptoms of CCA can vary depending on where the tumour is located within the bile duct. For example, perihilar tumours will cause biliary obstruction and so jaundice will be observed as well as pale stools due to the lack of bile salts reaching the digestive tract, along with biliary sepsis. However, intrahepatic tumours usually present general symptoms of late malignancy such as weight loss, loss of appetite and pain in the abdomen.7 Currently, detection of CCA remains reasonably poor as the lack of symptoms discourage people from looking into whether they may have early signs of CCA. The main diagnosis is medical imaging, using ultrasound, MRI, MRCP and CT scans. This can effectively detect biliary obstructions as well as any mass forming in the bile ducts but can not detect malignancy and does not necessarily diagnose for CCA. The other problem with imaging is the requirement for trained personnel to administer the procedure and interpret. The other diagnostic method is the use of biomarkers, such as carbohydrate antigen 19-9 (Ca19-9) in the serum. A biomarker can remove the need for imaging equipment to be transported from hospitals, and only requires someone capable of drawing blood to be present, or can be done alone if using a urinary biomarker. The problem with Ca19-9 is that 10% of people lack the Lewis antigen and so do not produce it and, as with many other biomarkers, it is not disease specific, and so will give a positive result for any disease which causes obstructive jaundice.1

The only curative treatment for CCA is surgical resection of the tumour. However, due to the late presentation of symptoms, surgery is often no longer a viable option. In the few cases that surgery is safe, there is often metastasis of the cancer to elsewhere in the body, leading to a 5 year survival rate of 20-30% post-resection. In the past, liver transplants were dismissed as being associated with poor survival. Recently in the US however, transplantation with carefully selected patients, along with neoadjuvant chemotherapy has seen a 5 year survival rate of 70% meaning this could become a treatment option following further investigation. Due to the problems of an asymptomatic progression of the disease in treating the cancer, research is now more heavily focused on diagnosing the CCA earlier in order to allow surgery before metastasis occurs. This involves looking for biomarkers in both the urine and the blood, trying to increase the specificity in order to prevent false positives with other hepatobiliary diseases.4,8 Biomarkers which determine whether an individual has an OV infection are also sought after as the main diagnosis to date is treatment of faeces followed by counting any eggs present which can give false negatives for light infections and allows the disease to progress unmonitored.9

In Thailand we (“The Two Toms”) are aiming to conduct some research that will aid in the push to combat CCA in the Isaan region. Research is currently being carried out to investigate possible treatments, early detection and prevention of the disease, and we hope to contribute to finding new methods of early detection of CCA, thereby helping in the fight to improve the currently extremely poor prognosis that comes with the diagnosis of the cancer. In particular, we will be working with the Cholangiocarcinoma Screening and Care Program (CASCAP) to investigate changes in levels of certain micro-RNA biomarkers within patient’s urine in response to changes in kidney function, OV infection, Periductal Fibrosis and CCA. We also aim to write an introductory review for a European medical journal, as comparatively little attention is paid to CCA in the west, even less to OV related CCA. We hope that bringing attention to the problem and its complexities will encourage a greater number of scientists to turn their minds to the problem, ultimately leading to more and better solutions being presented in a shorter space of time. More personal aims that we hope to achieve by coming here include expanding our scientific knowledge (in some areas to a post graduate level), our knowledge of medicine outside of the clinic, and our knowledge of a culture that is very different to our own. We think that because the causes of the high incidence of CCA are so complex, that we should be able to achieve all of these to a high level.

The first ever World Cholangiocarcinoma day on February 17th 2016, will, we think, mean that for at least one day Cholangiocarcinoma will be the topic of conversation worldwide. This increased attention will hopefully mean an increased international focus on combatting the disease, and hopefully produce a method for early diagnosis as soon as possible. This is vitally important for people who develop CCA, because due to diagnosis only currently being possible in later stages of the disease, the rate of survival is extremely low. World Cholangiocarcinoma day is utilising potentially the fastest method of spreading information; social media. This should both capture the attention of the generation beginning to be at risk, but also the younger generation, using World CCA Day 2016 profile pictures to make the message simple, easy and eye catching. This may also be particularly effective in Thailand, where Facebook is incredibly popular – perhaps the place where CCA awareness is most needed.

The Two Toms That Travelled To Thailand.

Get involved

To find out more about World Cholangiocarcinoma Day, visit their website here

To follow on social media, follow the official World CCA Day Twitter account @WorldCCADay and hashtag #WorldCCADay

References

[1] Zabron A, Edwards RJ, Khan SA. (2013). The challenge of cholangiocarcinoma: dissecting the molecular mechanisms of an insidious cancer. Disease Models & Mechanisms. 6 (1), p281-292.

[2] Sithithaworn P, Yongvanit P, Duenngai K, Kiatsopit N, Pairojkul C. (2014). Roles of liver fluke infection as risk factor for cholangiocarcinoma. J Hepatobiliary Pancreat Sci. 21 (1), p301–308.

[3] Andrews RH, Sithithaworn P, Petney TN. (2008). Opisthorchis viverrini: an underestimated parasite in world health. Trends in Parasitology. 24 (11), p497-501.

4 Saichua P, Yakovleva A, Kamamia C, Jariwala AR, Sithithaworn J, Sripa B, et al. (2015) Levels of 8-OxodG Predict Hepatobiliary Pathology in Opisthorchis viverrini Endemic Settings in Thailand. PLoS Negl Trop Dis 9(7): e0003949. doi:10.1371/ journal.pntd.0003949

5 Sithithaworn P, Yongvanit P, Duenngai K, Kiatsopit N, Pairojkul C. (2014). Roles of liver fluke infection as risk factor for cholangiocarcinoma. Japanese Society of Hepato-Biliary-Pancreatic Surgery. 21 (1), p301-308.

6 Ziegler AD, Echaubard P, Lee YT, Chuah CJ, Wilcox BA, Grundy-Warr C, Sithithaworn P, Petney TN, Laithevewat L, Ong X, Andrews RH, Ismail T, Sripa B, Khuntikeo N, Poonpon K. (2016). Untangling the Complexity of Liver Fluke Infection and Cholangiocarcinoma in NE Thailand Through Transdisciplinary Learning. EcoHealth. – (1), -.

7 Friman, S. (2011). CHOLANGIOCARCINOMA – CURRENT TREATMENT OPTIONS. Scandinavian Journal of Surgery . 100 (1), p30-34.

8 Silakit R, Loilome W, Yongvanit P, Chusorn P, Techasen A, Boonmars T, Khuntikeo N, Chamadol N, Pairojkul C, Namwat N. (2014). Circulating miR-192 in liver fluke-associated cholangiocarcinoma patients: a prospective prognostic indicator. J Hepatobiliary Pancreat Sci. 21 (1), p864-872.

9 Worasith C, Kamamia C, Yakovleva A, Duenngai K, Wangboon C, Sithithaworn J, et al. (2015) Advances in the Diagnosis of Human Opisthorchiasis: Development of Opisthorchis viverrini Antigen Detection in Urine. PLoS Negl Trop Dis 9(10): e0004157. doi:10.1371/journal. pntd.0004157

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