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      Thinking beyond Opisthorchis viverrini for risk of cholangiocarcinoma in the lower Mekong region: a systematic review and meta-analysis

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          Cholangiocarcinoma (CCA) is a fatal bile duct cancer associated with infection by the liver fluke, Opisthorchis viverrini, in the lower Mekong region. Numerous public health interventions have focused on reducing exposure to O. viverrini, but incidence of CCA in the region remains high. While this may indicate the inefficacy of public health interventions due to complex social and cultural factors, it may further indicate other risk factors or interactions with the parasite are important in pathogenesis of CCA. This systematic review aims to provide a comprehensive analysis of described risk factors for CCA in addition to O. viverrini to guide future integrative interventions.

          Main body

          We searched five international and seven Thai research databases to identify studies relevant to risk factors for CCA in the lower Mekong region. Selected studies were assessed for risk of bias and quality in terms of study design, population, CCA diagnostic methods, and statistical methods. The final 18 included studies reported numerous risk factors which were grouped into behaviors, socioeconomics, diet, genetics, gender, immune response, other infections, and treatment for O. viverrini. Seventeen risk factors were reported by two or more studies and were assessed with random effects models during meta-analysis. This meta-analysis indicates that the combination of alcohol and smoking ( OR = 11.1, 95% CI: 5.63–21.92, P <  0.0001) is most significantly associated with increased risk for CCA and is an even greater risk factor than O. viverrini exposure. This analysis also suggests that family history of cancer, consumption of raw cyprinoid fish, consumption of high nitrate foods, and praziquantel treatment are associated with significantly increased risk. These risk factors may have complex relationships with the host, parasite, or pathogenesis of CCA, and many of these risk factors were found to interact with each other in one or more studies.


          Our findings suggest that a complex variety of risk factors in addition to O. viverrini infection should be addressed in future public health interventions to reduce CCA in affected regions. In particular, smoking and alcohol use, dietary patterns, and socioeconomic factors should be considered when developing intervention programs to reduce CCA.

          Electronic supplementary material

          The online version of this article (10.1186/s40249-018-0434-3) contains supplementary material, which is available to authorized users.

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          Most cited references 39

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          Carcinogenicity of tetrachlorvinphos, parathion, malathion, diazinon, and glyphosate.

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            The tumorigenic liver fluke Opisthorchis viverrini--multiple pathways to cancer.

            Liver fluke infection caused by Opisthorchis viverrini is a major public health problem in Thailand and adjacent countries. In addition to infection-associated morbidity, infection with O. viverrini and the related Clonorchis sinensis are unarguable risk factors for cholangiocarcinoma (CAA, bile-duct cancer). Here we review the pathogenesis of opisthorchiasis and the association between O. viverrini infection and bile-duct cancer, focusing on the molecular parallels between wound healing, chronic inflammation, and cancer development. We review a schema for human disease progression from fluke infection, chronic opisthorchiasis, advanced periductal fibrosis, and cholangiocarcinogenesis, and present a rationale for biomarker discovery to facilitate early intervention. We conclude by addressing post-genomic advances with a view to developing new control strategies to combat this infectious cancer. Copyright © 2012 Elsevier Ltd. All rights reserved.
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              The current status of opisthorchiasis and clonorchiasis in the Mekong Basin.

              This review highlights the current status and control of liver fluke infections in the Mekong Basin countries where Opisthorchis and Clonorchis are highly endemic. Updated data on prevalence and distribution have been summarized from presentations in the "96 Years of Opisthorchiasis. International Congress of Liver Flukes". It is disturbing that despite treatment and control programs have been in place for decades, all countries of the Lower Mekong Basin are still highly endemic with O. viverrini and/or C. sinensis as well as alarmingly high levels of CCA incidence. A common pattern that is emerging in each country is the difference in transmission of O. viverrini between lowlands which have high prevalence versus highlands which have low prevalence. This seems to be associated with wetlands, flooding patterns and human movement and settlement. A more concerted effort from all community, educational, public health and government sectors is necessary to successfully combat this fatal liver disease of the poor. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

                Author and article information

                +1 508-494-3104 , jasteele1@gmail.com
                Infect Dis Poverty
                Infect Dis Poverty
                Infectious Diseases of Poverty
                BioMed Central (London )
                17 May 2018
                17 May 2018
                : 7
                [1 ]ISNI 0000 0004 1936 7531, GRID grid.429997.8, Department of Infectious Disease and Global Health, , Tufts University, Cummings School of Veterinary Medicine, ; North Grafton, MA USA
                [2 ]Global Health Asia, Integrative Education and Research Programme, Faculty of Public Health, Faculty of Public Health Studies, Bangkok, Thailand
                [3 ]ISNI 0000 0004 1764 155X, GRID grid.458460.b, Center for Mountain Ecosystem Studies, , Kunming Institute of Botany, Chinese Academy of Sciences, ; Kunming, China
                [4 ]ISNI 0000 0004 0469 5874, GRID grid.258970.1, Department of Biology, , Laurentian University, ; Greater Sudbury, ON Canada
                [5 ]ISNI 0000 0004 0470 0856, GRID grid.9786.0, Department of Science Education, , Khon Kaen University, Faculty of Education, ; Khon Kaen, Thailand
                [6 ]ISNI 0000 0004 0470 0856, GRID grid.9786.0, Department of Parasitology, , Khon Kaen University, Faculty of Medicine, ; Khon Kaen, Thailand
                © The Author(s). 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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