We usually associate cancer with environmental determinants, such as gamma ray or bisphenol A exposure, but two parasitic flukes that have been implicated in more than two-thirds of cases of a rare liver cancer in Southeast Asia and parts of East Asia may change how we think about carcinogens. The most fascinating aspect of these two parasites, Opisthorchis viverrini and Clonorchis senensis, is that human infection is directly associated with a culturally-specific method of cooking food, or in this case, not cooking it.
A labeled diagram of a speciman of the liver fluke Clonorchis sinensis. Image: Unknown. Click for source.
Clonorchis sinesis is endemic in Japan, Korea, Cambodia, Laos, Vietnam and China. Opisthorichis felineus may be found in the Philippines, India, Japan, Vietnam and eastern Europe, whereas O. viverrini is localized to Northern Thailand and Laos (a). The three species share nearly identical biology, pathogenesis and clinical pathology.
The flukes have a life cycle typical of parasitic helminths - complicated with many intermediate hosts for various life stages before reaching its intended location in the human biliary tract that supplies the liver. The larval form, known as metacercariae, hatch in the human small intestine following consumption of raw freshwater fish in the Cyprinidae family, such as carp, minnow and salmon. The larvae travel from the small intestine to their final destination in the biliary duct where they mature into adults and reproduce.
The life cycle of C. sinensis. Image: CDC. Click for source.
In chronic infections, flukes really start tinkering with the cellular state of things, causing serious inflammation and fibrosis of the biliary duct, as well as epithelia hyperplasia (abnormal cell growth and proliferation) and metaplasia (cell differentiation) of the mucin-producing cells in the mucosa (d). The parasitic load, time span of infection as well as the host's immune status all determine pathology and symptom intensity. Over time, these pathologies can lead to obstruction of the biliary duct with adult worms or calcium bilirubinate stones, and predispose the host to bacterial superinfection, liver abscesses and hepatitis (d). Unlucky individuals may also suffer from cholangiocarcinoma, cancer of bile duct epithelia. Really nasty stuff.
In Northeast Thailand, outrageous rates of O. viverrini infection have been definitively linked to carp consumption, specifically that of a regional delicacy known as pla-ra in which the fish are fermented for three months to a year. The resulting fish sauce is served over sticky rice (b)(c). A local delicacy, it is traditionally served during festivals for guests and consumed with vodka. Those who are aware of the relation between the fluke and liver cancer regrettably believe that both the short fermentation process and vodka are capable of killing the organisms (b). It always seems to be the finer things in life, like alcohol, cigarettes and pla-ra, that are the latest public health scourge, isn't it?
The Thai delicacy pla-ra, a dish of fermented fish. Image: Unknown. Click for source.
A study conducted in 2004 in the the Khon Kaen province of Northeast Thailand examining O. viverrini infection and cholangiocarcinoma found that incidence of the malignancy was a startling 24% for male residents. Prevalence of infection is equivalent in males and females though heavy infection is more common in men and the elderly due to their higher levels of pla-ra consumption (a, c). High levels of N-nitrosamines in their diet, a side-product of the use of nitrites for pickling and salting fish, have also been implicated (a). In the same study, the authors found that the incidence of primary liver cancer in the region was found to be the highest in the world.
Luckily O. viverrini infection can be treated with a relatively cheap and accessible anti-helmintic drug praziquantel that is frequently used to treat schistosomiasis, tapeworm and other flatworms. As long as the acute infection is targeted quickly before the parasite starts feeling at home in the biliary ducts and causing cellular pathology, chronic infection and its grisly side effects can be averted.
I find these cases to be particularly interesting because there has been a recent trend of public awareness in non-environmental determinants in causing cancer. Viruses and parasites are indeed capable of causing oncogenic infection, whether through their own virulence or as a result of the body’s immunological response. Viral examples include human papillomavirus (HPV), hepatitis B and C, human T-lymphotropic virus Type I (HTLV-1) and Epstein-Barr virus (EBV), responsible for causing a smorgasbord of carcinomas, leukemias and lymphomas. These tumor-associated viruses are estimated to account for 10% to 15% of cancers worldwide, earning the moniker “oncovirus” (e). On the other side are the parasitic helminth worms, particularly the schistosomes and flukes. These guys usually bring about pathological changes through physical obstruction, as well as the host’s inflammatory and immune responses (a).
So add flukes to the list of carcinogenic substances and stay away from that pla-ra on your next trip to Northern Thailand!
(a) Despommier, D, Gwadz RW, Hotez PJ and Knirsch CA. Parasitic Diseases. 5th ed. New York: Apple Trees Production, LLC. 2006 (b) The George Washington University Medical Center “Stopping the Worm that's Devastating Thailand”. Accessed: April 9, 2011. http://smhs.gwumc.edu/newsevents/notjustafluke (c) Sriamporn S, Pisani P, Pipitgool V, Suwanrungruang K, Kamsa-ard S, Parkin DM. (2004) Prevalence of Opisthorchis viverrini infection and incidence of cholangiocarcinoma in Khon Kaen, Northeast Thailand. Trop Med Int Health. 9(5): 588-94. (d) Byung Ihn Choi, Joon Koo Han, Sung Tae Hong, and Kyoung Ho Lee. (2004) Clonorchiasis and Cholangiocarcinoma: Etiologic Relationship and Imaging Diagnosis. Clin Microbiol Rev.17(3): 540–552 (e) Martin D and Gutkind JS. (2008) Human tumor-associated viruses and new insights into the molecular mechanisms of cancer. Oncogene. 27 Suppl 2: S31-42
Sriamporn, S., Pisani, P., Pipitgool, V., Suwanrungruang, K., Kamsa-ard, S., & Parkin, D. (2004). Prevalence of Opisthorchis viverrini infection and incidence of cholangiocarcinoma in Khon Kaen, Northeast Thailand Tropical Medicine and International Health, 9 (5), 588-594 DOI: 10.1111/j.1365-3156.2004.01234.x