Liver Flukes: the Malady Neglected

The general term 'fluke' refers to flat fish, for example, rays in the sea or leeches in fresh-water. Like leeches, liver flukes are flat helminthes or platyhelminth, of the class trematoda, and they reside in the human bile ducts (Fig. 1). Infection occurs through ingestion of fluke-infested, fresh-water raw fish. It is one of the most important food-borne diseases. Throughout the world, particularly in South-East Asia, China, Manchuria, the former USSR and northern Siberia, more than 35 million people including 15 million Chinese (1) are infected. The epidemiology of the infections is determined by food and ecological factors and it is strongly influenced by poverty and pollution in some areas and by the traditions of food intake in other areas.

Fig. 1
Adult Clonorchis sinensis within intrahepatic bile duct.

Endoscopy reveals "rayfish-like" or "leech-like" flat worm moving within lumen, and it has whitish-yellow ventral sucker at tapered head portion of worm. Note reddish inner surface of bile duct at background as mark of blood sucking (Courtesy of Dong Wan Seo, MD, Asan Medical Center, Seoul, Korea).

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The disease is generally dormant and the infected people are asymptomatic, except for the patients with very heavy infections. However, the long-lived flukes cause chronic inflammation of the bile ducts, leading to suppurative cholangitis, formation of bile duct stone and the development of cholangiocarcinoma.

In this article, we review the parasitology, epidemiology and the clinical findings and complications of liver fluke infection, and particularly the pathogenesis of cholangiocarcinoma in association with liver flukes.

Clonorchiasis and opisthorchiasis are trematodiases that are caused by chronic infection of the human liver flukes in the biliary tree. The three species of flukes, Clonorchis sinensis, Opisthorchis viverrini and Opisthorchis felineus are closely related trematodes that have similar life cycles and they cause the same pathophysiology to the biliary tract. The flukes differ in their geographic distribution and morphology.

The adult fluke of Clonorchis sinensis is a willow-leaflike, flat, flabby worm that lives in the biliary tree (Fig. 2). The size of the parasite ranges from 8.0 to 15.0 mm long by 1.5 to 4.0 mm wide and 1.0 mm thick (2). Humans are infected when ingesting uncooked fresh water fish infested with metacercariae. The larvae excyst in the stomach, migrate to the ampulla of Vater, ascend into the bile ducts and live there for 20-30 years. Usually they reside in the medium sized or small intrahepatic bile ducts, but they may also live in the extrahepatic duct, gallbladder and the peripheral pancreatic branch ducts. Intraductal flukes cause mechanical obstruction, inflammation, epithelial adenomatous hyperplasia and periductal fibrosis (2-5) (Fig. 2). One adult fluke lays 2000-4000 eggs each day and the eggs are excreted through the bile ducts and feces (2). The cycle recirculates via eating of raw fresh-water fish.

Fig. 2
Photomicrograph of rabbit bile duct that was experimentally infected with C. sinensis, and it shows adult fluke in bile duct. Note extensive epithelial hyperplasia of mucosa around fluke and periductal fibrosis (arrows) (Hematoxylin & Eosin staining, × 40).

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The adult fluke of Opisthorchis is very similar to C. sinensis in morphology. As compared to C. sinensis, O. viverrini and O. felineus are slightly smaller at approximately half the size and their testes are less branched (6). As the endemic areas of Opisthorchis are different from Clonorchis, the first and second intermediate hosts are slightly different. However, the pathophysiology, clinical manifestations and imaging findings of O. viverrini and O. felineus infection are the same as those of C. sinensis (7-9).

The clinical symptoms depend on the degree of infection and the presence of complications. The vast majority of patients are asymptomatic. In patients with severe infection, the clinical signs and symptoms include lassitude (Fig. 3), hepatomegaly and nonspecific abdominal complaints such as anorexia, nausea, vomiting, abdominal discomfort and indigestion (2, 8-10). Jaundice is due to the mechanical obstruction caused by a multitude of flukes in the bile ducts in patients with a heavy infection, or it is due to bile duct obstruction caused by stone, cholangitis or cholangiocarcinoma as a late complication of chronic infection. The public health impact and economic impact are considerable in terms of the morbidity, the loss of productivity and the absenteeism of heavily infected people (1).

Fig. 3
70-year-old man with clonorchiasis and he complained of lassitude.

He had been previously admitted 10 years ago because of jaundice and he was diagnosed with clonorchiasis and treated with praziquantel. Five years later, he had cholecystectomy for gallbladder stones and cholecystitis. Since then, he has been suffering from general weakness and lassitude. He has been eating raw fresh-water fish frequently for more than 12 years because he believed raw fish was helpful for his health. CT shows mild dilatation of small intrahepatic bile ducts up to periphery of liver without dilatation of large bile ducts, which is characteristic for clonorchiasis.

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The geographic distribution of liver flukes is largely in Asia and Eastern Europe. Endemic areas of Clonorchis sinensis include east Russia and Manchuria, South Korea, mainland China (except the northwest), Taiwan and northern Vietnam (1-3), whereas the endemic areas of Opisthorchis viverrini include Laos and northeast Thailand (1-4). The endemic areas of Opisthorchis felineus include Eastern Europe and the former U.S.S.R. People living along rivers are prone to infection by flukes because they have a habit of eating uncooked fresh-water fish. In southern China, eastern Manchuria and northern Thailand, millions of people are patients with liver fluke disease, and in some endemic areas, 30-75% of the inhabitants are infected (1-4). In the North American countries where many Asian immigrants are living, there are some people infected with C. sinensis and O. viverrini. It is estimated that about 35 million people are infected throughout the world (1-3).

In China, there are two principal endemic areas, namely southern China and Manchuria. Depending upon the endemic areas, the prevalence rate is variable at between 10% and 85%, and average prevalence rate in southern China is 18% (11). There are about 8.5 million people infected in the Guangdong and Guangxi areas and another several million people in Manchuria (11, 12).

In northern Thailand and low land Laos, there is a long tradition of eating raw fresh-water fish and salt-fermented fish. Cyprinoid fish, which are fresh water fish, are an important source of protein in these areas (1). It has been reported that average prevalence rate of opisthorchiasis in northern Thailand is 22% and 5 million of the 19 million people in this region are infected (13). The infection rate increases among the people who are living in endemic areas, ranging from 60 to 80% depending upon the communities (14). In a community in Khon Kaen, the overall prevalence of O. viverrini infection is 94% and it reaches 100% among the people above the age of 10 years (15). The tradition of eating raw or undercooked fish products is the reason for this high prevalence (14).

The prevalence rate of C. sinensis infection in South Korea is 3%; it is 2% in urban areas and 5% in rural areas (16). In some regions along some rivers, the prevalence rate is about 25-30%. In a hospital based controlled study, based on radiological study and a history of eating raw freshwater fish, about 30% of hospitalized adults (31-79 years old) had evidence of clonorchiasis (17). This high prevalence rate is because the patients included in the study were hospitalized, aged patients including long-lasting infection as well as healed infection.

On the basis of the high prevalence of liver fluke infection in certain endemic areas, it is recommended to do a screening test such as a stool ova test. The high risk groups for liver fluke infection are those who had a history of eating a significant amount of raw, freshwater fish in endemic areas and those who have ultrasonographic or CT images showing dilatation of the peripheral intrahepatic bile ducts, or combinations of these findings (17). When people are infected, anthelminthic drug should be prescribed.

Cholangiocarcinoma develops at an older age, namely, at the age over 50. In a hospital based control study in Korea, about 50-80% of the patients with cholangiocarcinoma had evidence of C. sinensis infection (17) and they were aged patients (average age: 64, age range: 32-79 years). Therefore, men and women older than 50 and who had history of clonorchiasis in the past, whether treated or not, should be put in a screening program for cholangiocarcinoma. Also, those people who show unexplained intrahepatic bile duct dilatation on sonography and/or CT images should be screened. The characteristic radiological finding of past/healed liver fluke infection is diffuse dilatation of the peripheral intrahepatic bile ducts without evidence of an obstructing cause (dilatation without obstruction) on ultrasound, CT or MR imaging (5). This image finding is frequently encountered in healthy looking but infected people in endemic areas.

There have been several papers regarding the usefulness of carbohydrate antigen 19-9 (CA19-9) as a marker to screen for cholangiocarcinoma. CA19-9 was useful for predicting cholangiocarcinoma in patients with primary sclerosing cholangitis, with the sensitivity being 79%, the specificity 99%, the adjusted positive predictive value 57% and the negative predictive value 99% (49). In patients without primary sclerosing cholangitis, the sensitivity of CA19-9 for diagnosing cholangiocarcinoma was 53-67% and the specificity was 76-87% (50-52). The usefulness of CA19-9 for diagnosing cholangiocarcinoma in patients with liver fluke infection has not yet been investigated. Also, the use of radiological examinations as a screening tool for making the diagnosis of cholangiocarcinoma is not known. Many patients with cholangiocarcinoma have evidence of C. sinensis infection (17) and this is the rationale for cholangiocarcinoma screening in those people who were once infected with liver flukes. There were 4% asymptomatic patients with cholangiocarcinoma detected on ultrasound screening in a rural area in Khon Kaen (Thailand) (29).

Intraductal papillary neoplasm of the bile duct is a premalignant condition that predominantly exhibits intraductal growth (23). Intraductal papillary neoplasm accounts for about 15% of all cholangiocarcinoma patients and it transforms to tubular adenocarcinoma or mucinous adenocarcinoma at a late stage (40-44). There have been a few papers revealing that this disease was related with C. sinensis infection (35, 36). Therefore, detection and resection of intraductal papillary neoplasm before transformation to malignant tumor may lead to cure of the disease. In this regard, the at-risk groups should be screened and the patients need preemptive surgical resection.

Liver fluke infection is initiated by ingestion of fluke-infested, raw, fresh-water fish and it causes chronic inflammatory bile duct disease. Once infected, the flukes reside in the bile duct for two or three decades. Though mostly dormant, longstanding infection causes unexplainable lassitude and reduces productivity, and it degrades the quality of life. The complications are bile duct stone formation, recurrent pyogenic cholangitis and bile duct cancer. More than 35 million people worldwide are infected. The exceptionally high incidence of cholangiocarcinoma in Thailand and Korea is attributed to the high prevalence of liver fluke infection in these areas. Traditional eating habits of raw fresh-water fish, which is believed to be a health-promoting food, brings about "the evils of health."

The strategy for control of foodborne infection clearly requires collaboration between the sectors of public health, the food industry as well as journalism. Consumer education is crucial and of the utmost importance. In this regard, physicians should know about the high prevalence of liver fluke infection among healthy looking people and the long term consequencies of the infection, and particularly the development of cholangiocarcinoma should be emphasized. Additionally, once it is recognized, the infected person should be monitored for the development of bile duct cancer. Physicians should change their attitude towards liver fluke infection. Liver flukes should not be neglected or abandoned as they are evils of human health.