Tuesday, June 26, 2012

Liver Flukes Part 1: Clonorchis sinensis

This week at Infection Landscapes we begin to cover another group of trematodes, the liver flukes.We will cover two species separately as their life cycles and landscape epidemiology are different enough to warrant distinct entries. The first liver fluke species we will cover is Clonorchis sinensis.

The Worm. Clonorchis sinensis is a flatworm in the class Trematoda.

Clonorchis sinensis

This helminth's life cycle requires two intermediate hosts and a definitive host. This is a human parasite and humans constitute the definitive host species in its life cycle. Let's consider this life cycle.

Embryonated ova are expunged from an infected definitive host (human) and are infectious to the first intermediate host, i.e. freshwater snails, most commonly Parafossarulus spp. As the freshwater snails are the first intermediate host, the embryonated eggs must encounter a water environment to move to the next stage of development, which means that the human feces must come into contact with this water source. The eggs are eaten by the freshwater snails, and subsequently the miracidia emerge and relocate to the hepatopancreas, where they develop into sporocysts. After approximately 3 weeks of development in the hepatopancreas, cercariae are fully formed and exit the snail. These cercariae are highly motile in water, similar to the analogous stage of schistosomes. However, C. sinensis cercariae do not penetrate human skin. Rather, C. sinensis cercariae seek out a second intermediate host. When the cercariae encounter a fish of the Cyprinidae family, which are important freshwater food fish in many parts of the world, they burrow into the muscle tissue of the fish, or simply locate under the scales, and encyst. They subsequently transform into the metacercariae, which the infectious stage for humans. Alternatively, the cercariae can also encyst under the exoskeleton in the muscle tissue of freshwater crustaceans, such as crabs or crayfish. Human infection occurs following the ingestion of undercooked fish or crustaceans that harbor encysted metacercariae. These metacercariae then excyst in the small intestine and migrate up the bile duct where they will continue to develop into adult flukes over the course of several weeks. Adults live in the lumen of the bile duct in the liver and are thought to feed directly on the bile. C. sinensis adults contain both male and female reproductive organs, so no sex pairing is required of these trematodes to produce and fertilize the eggs. Embryonated eggs pass out of the common bile duct and into the small intestine and are eventually expunged in the feces of the host. The graphic below produced by the Centers for Disease Control and Prevention nicely depicts this trematode's complex life cycle:

The Snail. Freshwater snails are the first intermediate hosts of C. sinensis. There are several genera capable of filling this role, but the most common is Parafossarulus, and the most common species in endemic areas is Parafossarulus manchouricus.

Parafossarulus manchouricus

These snails are aquatic, breathe with gills, and are ciliary feeders. They are widely distributed throughout Asia.

The Fish. The Cyprinidae family of fish serve as the second intermediate hosts of C. sinensis. This fish family is the largest and is comprised of the carps and minnows. They are freshwater fish and, being toothless, primarily eat gastropods and aquatic vegetation, though some will eat algae, small fish, or other molluscs. Given their great diversity, wide geographic distribution (extensive in Europe, Asia, Africa, and North America), and preferred food, and given that these fish are one of the most important food fish for humans in much of the world, including much of Asia, these fish are an ideal intermediate host for C. sinensis.

In addition to these fish, crustaceans, such as crabs and crayfish, are also capable of serving as the second intermediate hosts.

The Disease. Most infections with C. sinensis are asymptomatic. Pathogenesis stems from this trematode locating in the bile duct:

Acute illness typically involves moderate, non-specific symptoms: abdominal pain, diarrhea, nausea. In high volume infections the proliferation of adults can progress to more severe pathology for two reasons. First, the large number of adult trematodes can consume substantive amounts of bile and subsequently disrupt the digestion and absorption of dietary nutrients. Second, in high volume infections the bile duct can become blocked usually due to the large egg volume produced by the adults, which can lead to inflammation, secondary bacterial infection (cholangitis), fibrosis, and hyperplasia.

In chronic infections, weight loss, lack of energy, and chronic diarrhea are common due to the ongoing digestive interruption, and carcinoma can develop in the bile duct due to the chronic obstruction and tissue damage.

The Epidemiology and the Landscape. C. sinensis is the most prevalent liver fluke in the world with approximately 30 million people currently infected, but it is not the most widely distributed (Fasciola hepatica is the most geographically widespread liver fluke). C. sinensis is endemic in East and Southeast Asia, particularly in Japan, Korea, China, Vietnam, Laos, and Cambodia.

We do not have good surveillance data describing concrete measures of the burden of disease. However, areas of high endemicity do correspond to a relatively high incidence of cholangiocarcinoma.

The landscape epidemiology of liver flukes in general, and C. sinensis in particular, differs from that of the schistosomes in that cercariae do not infect their definitive host directly, but rather require a second intermediate host, which transfers the metacercariae passively (through consumption) to the definitive host. This means that the point of intersection between pathogen and host in the landscape is fundamentally different and derives from a unique ecological framework. Whereas, schistosome transmission occurs simply by way of contact with cercariae-infested freshwater bodies, C. sinensis trematodes require a more nuanced and specific engagement of the human host with the aquatic environment, i.e. through the harvesting of food from the water. However this terrain, as narrowly described so far, is not sufficient by itself for infection transmission. In addition, the physical landscape that defines the geography and structure of C.sinensis ecology must intersect the uniquely human social landscape for transmission to occur and the life cycle to be completed. This is because human feces must first contaminate the same water sources that humans then subsequently harvest for food. This can happen through 1) poor sanitation and water infrastructure, 2) the use of human feces for the fertilization of crops, or 3) both. 

Moreover, eating metacercariae-infested fish (or crustaceans) need not transmit the infection to humans, but does because of the method of preparation of the fishIn many places where C. sinensis is endemic, raw fish is a key ingredient in some local delicacies, so food preparation, as determined by cultural preference, becomes another aspect of the social landscape that converges with the physical landscape to effect transmission.

Control and Prevention

Snail Control

As with the schistosomes, early (and some ongoing) attempts at liver fluke elimination focused on gastropod control in various surface water sources. Typically, these control campaigns have involved the chemical treatment of freshwater sources to eliminate the local snail population, thus blocking the transmission of C. sinensis at the intermediate host. However, two important problems make gastropod control unrealistic in many settings. 

First, the chemical treatment of water sources can have much broader ecologic impact than what is intended by the public health initiative. Introducing toxic agents into surface water may kill the snails, but it can also harm other organisms in the aquatic ecosystem and result in unanticipated and detrimental ecologic effects. Some investigations have explored the possibility of introducing biologic mechanisms of control to supplant chemical treatment with more "natural" mechanisms. However, these approaches can also be dangerous if the natural biologic mechanisms involve the introduction of non-native invasive species into the aquatic environment. Nevertheless, the use of some plants in specific aquatic environments has been quite successful. For example, planting Sarcoca dodecandra, i.e. the gopo berry shrub, in water sources kills any snails present. 

Second, whether chemical or natural, snails in most areas prove robust to elimination. Both their high reproductive capacity and diffuse distribution within the aquatic system usually allow some members of the population to survive, which can then re-populate the local environment fairly quickly.

Food Preparation

Thorough cooking of all freshwater fish and crustaceans is very important for blocking transmission of C. sinensis to humans. Cooking kills the metacercariae and, thus, directly prevents infection in humans. Cooking is probably the most effective method of control and prevention of C. sinensis infection. However, in many places where this helminth is endemic, certain local delicacies require raw fish as central ingredients. As such, consistent cooking of fish in each household becomes an individual choice that may be superseded by cultural dietary norms and preferences. 

Farming Practice

Finally, changing agricultural practices that rely on human feces for fertilization of crops could help reduce infection with C. sinensis in some agricultural subsistence communities.

Unfortunately this, too, can be a difficult practice to disengage since human feces serves as a very rich fertilizer and, thus, can form a critical component to subsistence farming in many parts of the world where other fertilizers or farming technologies are cost prohibitive. And, of course, without an affordable substitute, refraining from human feces fertilization could very well lead to starvation. As such, this may not be a viable option for some subsistence farmers.


  1. So for the liver flukes, it turns out that it can not be exclusively classified as a disease caused due to poor sanitation practices. It also depends very much on the social preferences. Well cooked fish = no schistosomiasis due to liver flukes? Which means, NO SUSHI???

    1. Stephanie SaettaJune 28, 2012 at 4:46 PM

      You make a great point that one would not only need to alter food practices, but culture! On the other hand, a lot of sushi/sashimi is made with salt water fish, which would not be a concern for this liver fluke. Another option is to freeze the fish for a certain period of time to kill the parasite. Eating different types of fish, and careful preparation, keep this dietary preference a viable option, but for who? This is certainly impractical for the masses in most endemic areas.

    2. Good point. Changing food preferences which are an important part of the culture of a people would probably be more difficult compared to changing sanitation and agricultural practices. I can imagine people agreeing to changing the latter two if the right resources are available.

  2. It can be difficult to control the spread of liver flukes because of the use of cheap fertilizers including human feces which is rich in nitrogen and it would be a major obstacle.

    1. I agree to what Jatinder has to say. Stephanie's question resonates a similar concept. Is it practically possible to eliminate a species? Well, it has happened in the past and can happen with liver flukes. I wonder if there could be any negative impacts after elimination of a species. Would it really be worth it?

  3. Stephanie SaettaJune 28, 2012 at 4:32 PM

    I am wondering if elimination of liver flukes, and similar helminths, is possible in certain areas by targeting food preparation. We discussed in class that if an organism has more than one host, it is impossible to eliminate, but in this case different hosts are required to complete different parts of the helminth life-cycle. My question is: if you eliminate the parasite in the human population, how long does it persist in the intermediate hosts? Does this make elimination impossible?

    1. Thats a really interesting idea because even though the liver fluke has multiple host, they all appear to be required for the life cycle, so eliminating one completely, in theory, would affect the total population, I guess. Its interesting to consider how evolutionarily complex the life cycle is, but definitely advantageous when considering distribution, because the infected humans can travel far and usually near to other humans and bodies of water.

    2. Stephanie, I think elimination of any organism is region specific. If it persists in intermediate hosts then there is always a risk of relapse if caution is not taken in terms of proper hygienic practices and other practices that are required to prevent the spread of organism among various hosts. Higher the number of intermediate hosts or/and reservoirs, more difficult it is to eradicate or eliminate the organism

    3. But does the organism have an unlimited lifespan, suspended in one life-cycle stage? Not that this is practical, but: If an intermediate host is eliminated then a developmental stage is prevented. Does the organism than die out? Intermediate hosts are certainly different than reservoirs.

  4. Another interesting aspect about the liver flukes is that the adult fluke has both the male and female reproductive organs. So you do not really need two to tango. Guess nature gives every living being a chance in the most real reality show-Survival of the fittest.

    1. I also found the C. sinensis adult’s reproductive system consisting of both male and female reproductive organs to be interesting. Similar to other organisms, such as insects, flukes do not require embryonic development within the mother to lay eggs. Their method of reproduction is fascinating.

  5. The message leaned from this article is that the infection by this fluke is not eradicable because of diversity and large numbers of nonhuman reservoirs. Many of the infected humans are asymptomatic and can shed eggs for decades, however; prevalence can be reduced by promotion of sanitary disposal of human feces and avoidance of raw fish

    1. i am convinced that the this infection is "not eradicable", we just need to double, tripple or quadriple our efforts. As I nurse I do champion self empowerment, teach people who are at greatest risk to be infected how to protect themselves...prevention sometimes is the best medicine

    2. I think that the likelihood of eradication is small, but Stephanie's point is interesting. Reading this article, it seems like the cultural and economic factors around C. sinesis would coalesce to make eradication unlikely. You probably could not easily remove the infection from human experience by promoting cooking and non-human fertilizer, but these factors that Jatinder and Ricardo cite as making the fluke "not eradicable" could be circumvented by targeting an intermediate host. The impact on fluke population should in theory be the same as if humans were the main point of control as they are all equally necessary.

  6. I totally agree with Zach and Ricardo sometimes prevention is the "best" medicine especially if the infection is not eradicable, by promoting safe practices like cooking and by the use of non-human fertizer.

    1. Russel Sharif (MPH)October 19, 2012 at 12:55 AM

      Hi Chawla, what I have learned is that-

      Do not eat raw or undercooked freshwater fish.

      The FDA recommends the following for fish preparation or storage to kill parasites.

      Cook fish adequately (to an internal temperature of at least 145° F [~63° C]).
      At -4°F (-20°C) or below for 7 days (total time), or
      At -31°F (-35°C) or below until solid, and storing at -31°F (-35°C) or below for 15 hours, or
      At -31°F (-35°C) or below until solid and storing at -4°F (-20°C) or below for 24 hours.

  7. this organism is believed to be one of the most prevalent trematode parasite in the world which warrants acute need of practices to prevent its transmission among various hosts and at least eliminate it from a particular region.

  8. This post was really interesting to me. I enjoy researching hepatic diseases, specifically HCV and as I read this post, I began to wonder how an ID doctor or hepatologist would differentiate between these two infections given their similar symptomatic presentation. The fact that this can lead to fibrosis was intriguing. Thinking about the different genotypes of HCV and their epidemiological landscaping, I wonder what the rate of co-infection or false positive HCV tests are in places like South East Asia where this infection is prominent and may be connected to their heavy fish/crustacean diet.

    1. Interesting questions! I feel like the physician would first order a liver panel. It sounds like the liver fluke mainly resides in the bile duct so the liver panel should be pretty normal (as long as the flukes haven’t traveled up the duct too far or completed blocked it) and bile is still produced albeit we won’t see much bile in the GI tract. With HCV, the liver panel should show some inflammation of the liver – maybe elevated AST/ALT, Alk Phos, and decreased bile production so it should be quite different? I’m not quite sure that having a liver fluke infection would cause false positive HCV tests. HCV tests are either looking at antibodies against HCV or the viral RNA so I don’t think those are connected. A co-infection though would be quite serious I would imagine. Although, I think HBV rates are much higher than HCV in that geographic part of the world so I would worry more about an HBV co-infection.


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