J Hepatobiliary Pancreat Sci (2014) 21:301–308 DOI: 10.1002/jhbp.62
TOPIC
Roles of liver fluke infection as risk factor for cholangiocarcinoma Paiboon Sithithaworn · Puangrat Yongvanit · Kunyarat Duenngai · Nadda Kiatsopit · Chawalit Pairojkul
Published online: 10 January 2014 © 2014 Japanese Society of Hepato-Biliary-Pancreatic Surgery
Abstract Several factors are known to be associated with risk of cholangiocarcinoma (CCA) and infection with the liver flukes, Opisthorchis viverrini and Clonorchis sinensis, has often been singled out as the leading risk factor in east and southeast Asia. In this review, current knowledge of their biology, life cycle, and pathogenesis of O. viverrini, and its role as a carcinogenic parasite are presented. The trends of age-specific incidence of liver cancer in Khon Kaen, northeast Thailand are considered and compared with the prevalence profiles of O. viverrini. Potential impacts of the liver fluke control program particularly by mass drug administration (MDA) and public health education in the past and a recent drop of incidence of CCA are discussed in relation to primary prevention and control of this fatal bile duct cancer. Keywords Cholangiocarcinoma · Liver cancer · Liver fluke · Opisthorchis viverrini · Thailand
P. Sithithaworn (*) · N. Kiatsopit Department of Parasitology, Faculty of Medicine, Khon Kaen University, 123 Mitraparb Road, Khon Kaen 40002, Thailand e-mail: [email protected] P. Yongvanit Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand K. Duenngai Department of Public Health, Faculty of Science and Technology, Phetchabun Rajabhat University, Phetchabun, Thailand C. Pairojkul Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand P. Sithithaworn · P. Yongvanit · K. Duenngai · N. Kiatsopit · C. Pairojkul Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
Cholangiocarcinoma (CCA) is a malignant neoplasm of the biliary duct system and is the second most common primary hepatic malignancy, representing 30% of primary hepatic malignancies worldwide [1]. CCA has been described as a “silent killer” due to its relatively silent clinical progression and the consequent difficulty in diagnosis before it reaches an advanced stage [2]. Based on anatomical location, CCA can be classified as intrahepatic, extrahepatic and hilar CC (Klatskin tumors) which is also considered extrahepatic. The differentiation between intrahepatic cholangiocarcinoma (ICC) and extrahepatic cholangiocarcinoma (ECC) has become increasingly important, since the epidemiological and clinical features may be different [3]. Globally the incidence of CCA varies greatly in different regions but the hot spot is in northeast Thailand which has the highest incidence of CCA, as high as 115 per 100,000 in males have been recorded [4]. Geographically, high incidence of CCA is well correlated with the presence of the liver fluke, Opisthorchis viverrini. Several reviews on risk factors of CCA have often indicated that the liver flukes O. viverrini and Clonorchis sinensis play a dominant role as a risk factor of CCA in Asia, but specifically in Thailand. In addition to liver flukes, other established risk factors include primary sclerosing cholangitis, biliary-duct cysts, hepatolithiasis, and toxins. Other less-established, potential risk factors include inflammatory bowel disease (IBD), hepatitis C virus (HCV), hepatitis B virus (HBV), cirrhosis, diabetes, obesity, alcohol consumption, smoking, and host genetic polymorphisms [5, 6]. The purpose of this review is to provide updates on the biology, life cycle, epidemiology and pathogenesis of the liver flukes, particularly O. viverrini. Special consideration is placed on their roles as risk factors of CCA directly as a result of active or past experience of infection, history of drug treatment as well as other risk factors reported in the Thai population.
302
Prevalence and geographical distribution of the liver flukes Human liver flukes comprise O. viverrini, C. sinensis and Opisthorchis felineus with at least 25 million people in Asia and Europe. Of these, 10 million people are infected with O. viverrini, 1.2 million with O. felineus and 15 million with C. sinensis. As many as 700 million people worldwide are at risk of infection by the three liver flukes [7]. The major foci of O. viverrini are in northeast Thailand, Lao PDR, Cambodia, and to a lesser extent, Vietnam. Endemic areas for C. sinensis are in Korea, China, Taiwan, Vietnam and previously in Japan, while O. felineus is endemic in Poland, Germany, Russia, Federation of Kazakhstan and western Siberia [8]. A recent outbreak of O. felineus in central Italy has reiterated once again its presence in Europe [9]. To date, because of extensive traveling and importation of fresh water aquaculture products from Asia, it is now increasingly common to find infected people in nonendemic areas [10].
Biology and life cycle of O. viverrini Based on systematic analyses, O. viverrini in southeast Asia is a species complex in which adult worms show identical and indistinguishable morphologies but they are genetically different (i.e., cryptic species) with at least two cryptic species from northeast Thailand and Lao PDR based on allozyme electrophoresis and random amplified polymorphic DNA [11, 12]. Evidence of genetic variation for C. sinensis from China and Korea has also been documented [13–15]. Adult worms of O. viverrini inhabit the biliary tract (mainly intrahepatic bile ducts), gall bladder and to a lesser extent the pancreatic duct. Yellow–brown eggs are discharged with bile fluid into the intestine and the feces and passed out into the environment. In humans each worm on average produces about 50 egg/g feces and worm burden is related to fecal egg count [16]. When eggs reach a body of freshwater and are ingested by an appropriate snail, miracidium hatch and develop into sporocysts and rediae. Different species of Bithynia snails serve as the first intermediate hosts. The prevalence of O. viverrini infection in snail intermediate hosts (Bithynia sp.) is typically low (6000. A more recent study in Nakhon Phanom with 129 CCA cases and equal number of age- and sex-matched controls showed that elevated antibody levels to excretory-secretory antigen of O. viverrini were again strongly associated with CCA (OR 27.09; CI 6.30–116.57) [56]. The most recent communitybased study performed in Khon Kaen, northeast Thailand (121 CCA cases and 210 controls) showed a significant
305 Table 1 Risk factors of cholangiocarcinoma in Thailand Independent variables Intensity of Opisthorchis viverrini (egg/g feces)a 0 50 Sexa Female Male Antibody titer for OVb Negative Positive No. praziquantel treatmentsc 0 1 2–4 Plasma IL6 (pg/ml)d
TOPIC
Roles of liver fluke infection as risk factor for cholangiocarcinoma Paiboon Sithithaworn · Puangrat Yongvanit · Kunyarat Duenngai · Nadda Kiatsopit · Chawalit Pairojkul
Published online: 10 January 2014 © 2014 Japanese Society of Hepato-Biliary-Pancreatic Surgery
Abstract Several factors are known to be associated with risk of cholangiocarcinoma (CCA) and infection with the liver flukes, Opisthorchis viverrini and Clonorchis sinensis, has often been singled out as the leading risk factor in east and southeast Asia. In this review, current knowledge of their biology, life cycle, and pathogenesis of O. viverrini, and its role as a carcinogenic parasite are presented. The trends of age-specific incidence of liver cancer in Khon Kaen, northeast Thailand are considered and compared with the prevalence profiles of O. viverrini. Potential impacts of the liver fluke control program particularly by mass drug administration (MDA) and public health education in the past and a recent drop of incidence of CCA are discussed in relation to primary prevention and control of this fatal bile duct cancer. Keywords Cholangiocarcinoma · Liver cancer · Liver fluke · Opisthorchis viverrini · Thailand
P. Sithithaworn (*) · N. Kiatsopit Department of Parasitology, Faculty of Medicine, Khon Kaen University, 123 Mitraparb Road, Khon Kaen 40002, Thailand e-mail: [email protected] P. Yongvanit Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand K. Duenngai Department of Public Health, Faculty of Science and Technology, Phetchabun Rajabhat University, Phetchabun, Thailand C. Pairojkul Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand P. Sithithaworn · P. Yongvanit · K. Duenngai · N. Kiatsopit · C. Pairojkul Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
Cholangiocarcinoma (CCA) is a malignant neoplasm of the biliary duct system and is the second most common primary hepatic malignancy, representing 30% of primary hepatic malignancies worldwide [1]. CCA has been described as a “silent killer” due to its relatively silent clinical progression and the consequent difficulty in diagnosis before it reaches an advanced stage [2]. Based on anatomical location, CCA can be classified as intrahepatic, extrahepatic and hilar CC (Klatskin tumors) which is also considered extrahepatic. The differentiation between intrahepatic cholangiocarcinoma (ICC) and extrahepatic cholangiocarcinoma (ECC) has become increasingly important, since the epidemiological and clinical features may be different [3]. Globally the incidence of CCA varies greatly in different regions but the hot spot is in northeast Thailand which has the highest incidence of CCA, as high as 115 per 100,000 in males have been recorded [4]. Geographically, high incidence of CCA is well correlated with the presence of the liver fluke, Opisthorchis viverrini. Several reviews on risk factors of CCA have often indicated that the liver flukes O. viverrini and Clonorchis sinensis play a dominant role as a risk factor of CCA in Asia, but specifically in Thailand. In addition to liver flukes, other established risk factors include primary sclerosing cholangitis, biliary-duct cysts, hepatolithiasis, and toxins. Other less-established, potential risk factors include inflammatory bowel disease (IBD), hepatitis C virus (HCV), hepatitis B virus (HBV), cirrhosis, diabetes, obesity, alcohol consumption, smoking, and host genetic polymorphisms [5, 6]. The purpose of this review is to provide updates on the biology, life cycle, epidemiology and pathogenesis of the liver flukes, particularly O. viverrini. Special consideration is placed on their roles as risk factors of CCA directly as a result of active or past experience of infection, history of drug treatment as well as other risk factors reported in the Thai population.
302
Prevalence and geographical distribution of the liver flukes Human liver flukes comprise O. viverrini, C. sinensis and Opisthorchis felineus with at least 25 million people in Asia and Europe. Of these, 10 million people are infected with O. viverrini, 1.2 million with O. felineus and 15 million with C. sinensis. As many as 700 million people worldwide are at risk of infection by the three liver flukes [7]. The major foci of O. viverrini are in northeast Thailand, Lao PDR, Cambodia, and to a lesser extent, Vietnam. Endemic areas for C. sinensis are in Korea, China, Taiwan, Vietnam and previously in Japan, while O. felineus is endemic in Poland, Germany, Russia, Federation of Kazakhstan and western Siberia [8]. A recent outbreak of O. felineus in central Italy has reiterated once again its presence in Europe [9]. To date, because of extensive traveling and importation of fresh water aquaculture products from Asia, it is now increasingly common to find infected people in nonendemic areas [10].
Biology and life cycle of O. viverrini Based on systematic analyses, O. viverrini in southeast Asia is a species complex in which adult worms show identical and indistinguishable morphologies but they are genetically different (i.e., cryptic species) with at least two cryptic species from northeast Thailand and Lao PDR based on allozyme electrophoresis and random amplified polymorphic DNA [11, 12]. Evidence of genetic variation for C. sinensis from China and Korea has also been documented [13–15]. Adult worms of O. viverrini inhabit the biliary tract (mainly intrahepatic bile ducts), gall bladder and to a lesser extent the pancreatic duct. Yellow–brown eggs are discharged with bile fluid into the intestine and the feces and passed out into the environment. In humans each worm on average produces about 50 egg/g feces and worm burden is related to fecal egg count [16]. When eggs reach a body of freshwater and are ingested by an appropriate snail, miracidium hatch and develop into sporocysts and rediae. Different species of Bithynia snails serve as the first intermediate hosts. The prevalence of O. viverrini infection in snail intermediate hosts (Bithynia sp.) is typically low (6000. A more recent study in Nakhon Phanom with 129 CCA cases and equal number of age- and sex-matched controls showed that elevated antibody levels to excretory-secretory antigen of O. viverrini were again strongly associated with CCA (OR 27.09; CI 6.30–116.57) [56]. The most recent communitybased study performed in Khon Kaen, northeast Thailand (121 CCA cases and 210 controls) showed a significant
305 Table 1 Risk factors of cholangiocarcinoma in Thailand Independent variables Intensity of Opisthorchis viverrini (egg/g feces)a 0 50 Sexa Female Male Antibody titer for OVb Negative Positive No. praziquantel treatmentsc 0 1 2–4 Plasma IL6 (pg/ml)d
