Research Article: Liver Fluke Induces Cholangiocarcinoma

Date Published: July 10, 2007

Publisher: Public Library of Science

Author(s): Banchob Sripa, Sasithorn Kaewkes, Paiboon Sithithaworn, Eimorn Mairiang, Thewarach Laha, Michael Smout, Chawalit Pairojkul, Vajaraphongsa Bhudhisawasdi, Smarn Tesana, Bandit Thinkamrop, Jeffrey M Bethony, Alex Loukas, Paul J Brindley

Abstract: The authors discuss the molecular pathogenesis of opisthorchiasis and associated cholangiocarcinogenesis, particularly nitrative and oxidative DNA damage and the clinical manifestations of cholangiocarcinoma.

Partial Text: Liver fluke infection caused by Opisthorchis viverrini, O. felineus, and Clonorchis sinensis is a major public health problem in East Asia and Eastern Europe. Currently, more than 600 million people are at risk of infection with these trematodes [1]. O. viverrini is endemic in Southeast Asian countries, including Thailand, Lao People’s Democratic Republic, Vietnam, and Cambodia [2], and C. sinensis infection is common in rural areas of Korea and China. Opisthorchiasis has been extensively studied in Thailand, where an estimated 6 million people are infected with the liver fluke (calculated from overall 9.4% prevalence within the population in 2001) [3].

Second to tobacco use, infections are the most important preventable source of human malignancies [15–17] (Table 1). The association between the occurrence of CCA and the presence of liver flukes has been known for about 50 years [18].

Most primary malignant liver cancers are of two main histologic types distinguished by their cellular origin. HCC derives from hepatocytes, the main cells in the liver, and is the most common form of liver cancer throughout the world. There are several important risk factors that have been demonstrated with varied mechanisms of action; 75%–80% of cases are attributable to hepatitis B and C infection [29,30]. CCA is derived from cholangiocytes, which form the epithelial lining of both intrahepatic and extrahepatic bile ducts, except for those of the gallbladder. This form of liver cancer has a lower operable rate than HCC and most cases are currently untreatable except for complete liver transplantation [31]. Compared to HCC, CCA is a considerably less common form of liver cancer, except in regions within East Asia where infection with O. viverrini, and to a lesser extent, C. sinensis, is widespread [32].

Mechanical injury and fluke metabolic products. Mechanical injury from the activities of feeding and migrating flukes contributes to biliary damage in the human host. Both oral and ventral suckers of the fluke hook onto the biliary epithelium, resulting in tissue damage even early in infection [38]. As the parasite matures, the lesion becomes more pronounced and ulcerates. Fluke eggs become entrapped in the periductal tissue through the ulcer and induce granulomatous inflammation around the eggs. The granulomata are readily visualized in experimental hamster infections and occasionally in human cases with bile duct obstruction.

From a public health perspective, thorough cooking of the fish hosts efficiently blocks infection with these parasites. In this regard, liver fluke–associated CCA is preventable by changes in eating habits. Unfortunately, age-old culinary preferences for uncooked dishes such as koi-pla (Figure 1) do not readily allow for this possibility. Moreover, fish farming of grass carp and other susceptible species in ponds that are routinely contaminated by untreated sewage has resulted in the establishment of infection in fish populations at large, which, along with the involvement of animal reservoir hosts, makes control of liver fluke infection even more challenging [13,72]. Nonetheless, given this extraordinary linkage between a metazoan parasite and a tumour, characterisation of the nature and action of carcinogens of O. viverrini or C. sinensis may provide fundamental insights into carcinogenesis at large.



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