Helicobacter Species are Possible Risk Factors of Cholangiocarcinoma

  • Kaewpitoon, Soraya J (School of Family Medicine and Community Medicine, Suranaree University of Technology) ;
  • Loyd, Ryan A (School of Family Medicine and Community Medicine, Suranaree University of Technology) ;
  • Rujirakul, Ratana (Suranaree University of Technology Hospital) ;
  • Panpimanmas, Sukij (Suranaree University of Technology Hospital) ;
  • Matrakool, Likit (Suranaree University of Technology Hospital) ;
  • Tongtawee, Taweesak (Suranaree University of Technology Hospital) ;
  • Kootanavanichpong, Nusorn (Faculty of Public Health, Vongchavalitkul University) ;
  • Pengsaa, Prasit (Faculty of Public Health, Vongchavalitkul University) ;
  • Kompor, Ponthip (Faculty of Public Health, Vongchavalitkul University) ;
  • Chavengkun, Wasugree (Faculty of Public Health, Vongchavalitkul University) ;
  • Kujapun, Jirawoot (Faculty of Public Health, Vongchavalitkul University) ;
  • Norkaew, Jun (Faculty of Public Health, Vongchavalitkul University) ;
  • Ponphimai, Sukanya (Faculty of Public Health, Vongchavalitkul University) ;
  • Padchasuwan, Natnapa (Faculty of Public Health, Khon Kaen University) ;
  • Polsripradist, Poowadol (Provincial Public Health Office of Nakhon Ratchasima) ;
  • Eksanti, Thawatchai (Nakhon Ratchasima Rajabhat University) ;
  • Phatisena, Tanida (Nakhon Ratchasima Rajabhat University) ;
  • Kaewpitoon, Natthawut (Parasitic Disease Research Unit, Suranaree University of Technology)
  • Published : 2016.02.05


Several infectious agents are considered to be causes of cancer in human, mainly hepatitis B and C viruses, high-risk human pailloma viruses, Helicobacter pylori, Clonorchis sinensis, and Opisthorchis viverrini. Here we described the evident research and the association between Helicobacter spp. and biliary tract cancer particularly cholangiocarcinoma (CCA). Global epidemiological studies have suggested that Helicobacter spp. are possible risk factors for biliary tract diseases. Molecular studies support a linkage of Helicobacter spp. with CCA development. H. pylori, H. bilis, and H. hepaticus, are found in CCA, but the most common species are H. pylori and H. bilis. The type of CCA are associated with Helicobacter spp. include extrahepatic CCA, and common bile duct cancer. Up to the present, however, the results from different regions, materials and methods, sub-sites of cancer, and controls have not been consistent, thus introducing heterogeneity. Therefore, a comparison between co-Helicobacter spp.-CCA in the countries with low and high incident of CCA is required to settle the question. Furthermore, clarifying variation in the role of Helicobacter species in this CCA, including pathogenesis of CCA through enhanced biliary cell inflammation and proliferation, is necessary.


Helicobacter;cholangiocarcinoma;biliary tract cancer;possible risk


  1. Akamatsu N, Sugawara Y, Hashimoto D. (2011). Surgical strategy for bile duct cancer: Advances and current limitations. World J Clin Oncol, 10, 94-107.
  2. Abu Al-Soud W, Stenram U, Ljungh A, et al (2008). DNA of Helicobacter spp. and common gut bacteria in primary liver carcinoma. Dig Liver Dis, 40, 126-31.
  3. Bohr UR, Kuester D, Meyer F, et al (2007). Low prevalence of Helicobacteraceae in gall-stone disease and gall-bladder carcinoma in German population. Clin Microb Infect, 13, 525-31.
  4. Boonyanugomol W, Chomvarin C, Sripa B, et al (2012). Molecular analysis of Helicobacter pylori virulentassociated genes in hepatobiliary patient. HPB (Oxford), 14, 754-63.
  5. Boonyanugomol W, Chomvarin C, Sripa B, et al (2012). Helicobacter pylori in Thai patients with cholangiocarcinoma and its association with biliary inflammation and proliferation. HPB (Oxford), 14, 177-84.
  6. Boonyanugomol W, Chomvarin C, Baik SC, et al (2011). Role of cagA-positive Helicobacter pylori on cell proliferation, apoptosis, and inflammation in biliary cells. Dig Dis Sci, 56, 1682-92.
  7. Boyanova, L (2011). Helicobacter pylori. Caister Academic Press, Norfolk, England.
  8. Bulajic M, Maisonneuve P, Schneider-Brachert W, et al (2002). Helicobacter pylori and the risk of benign and malignant biliary tract disease. Cancer, 95, 1946-53.
  9. Bulajic M, Panic N, Stimec B, et al (2012). PCR in Helicobacter spp. diagnostic in extragastric malignancies of digestive system. Eur J Gastroenterol Hepatol, 24, 117-25.
  10. Casswall TH, Nemeth A, Nilsson I, et al (2010). Helicobacter species DNA in liver and gastric tissues in children and adolescents with chronic liver disease. Scand J Gastroenterol, 45, 160-7.
  11. Chang AH.; Parsonnet, J. (2010). Role of Bacteria in Oncogenesis. Clin Microb Rev, 23, 837-7.
  12. Chang JS, Tsai CR, Chen LT (2013). Medical risk factors associated with cholangiocarcinoma in Taiwan: a populationbased case-control study. PLoS One, 8, 69981.
  13. Chen H, Chen Y (2003). Helicobacter-specific 16S ribosomal DNA identified from patients with cholangiocarcinoma. Chin J Gen Surg, 12, 27-9.
  14. Coppola N, De Stefano G, Marrocco C, et al (2003). Helicobacter spp. and liver diseases. Infez Med, 11, 201-7.
  15. Dayton M, Longmire W, Tompkins R (1983). Caroli's Disease: a premalignant condition?. Am J Surg, 145, 41-8.
  16. Deenonpoe R, Chomvarin C, Pairojkul C, et al (2015). The carcinogenic liver fluke Opisthorchis viverrini is a reservoir for species of Helicobacter. Asian Pac J Cancer Prev, 16, 1751-8.
  17. Dore MP, Realdi G, Mura D, et al (2002). Helicobacter infection in patients with HCV-related chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Dig Dis Sci, 47, 1638-43.
  18. Donato F, Gelatti U, Tagger A, et al (2001). Intrahepatic cholangiocarcinoma and hepatitis C and B virus infection, alcohol intake, and hepatolithiasis: a case-control study in Italy. Cancer Causes Control, 12, 959-64.
  19. Fox JG, Dewhirst FE, Tully JG, et al (1994). Helicobacter hepaticus sp. nov., a microaerophilic bacterium isolated from livers and intestinal mucosal scrapings from mice. J Clin Microbiol, 32, 1238-45.
  20. Fox JG, Lee A (1997). The role of Helicobacter species in newly recognized gastrointestinal tract diseases of animals. Lab Anim Sci, 47, 222-55.
  21. Fox JG, Rogers AB, Whary MT, (2004). Helicobacter bilisassociated hepatitis in outbred mice. Comp Med, 54, 571-7.
  22. Fox JG, Shen Z, Muthupalani S, et al (2009). Chronic hepatitis, hepatic dysplasia, fibrosis, and biliary hyperplasia in hamsters naturally infected with a novel Helicobacter classified in the H. bilis cluster. J Clin Microbiol, 47, 3673-81.
  23. Foster JR (1984). Bacterial infection of the common bile duct in chronic fascioliasis in the rat. J Comp Pathol, 94, 175-81.
  24. Fowsantear W, Argo E, Pattinson C, et al (2014). Comparative proteomics of Helicobacter species: the discrimination of gastric and enterohepatic Helicobacter species. J Proteomics, 97, 245-5.
  25. Fukuda K, Kuroki T, Tajima Y, et al (2002). Comparative analysis of Helicobacter DNAs and biliary pathology in patients with and without hepatobiliary cancer. Carcinogenesis, 23, 1927-31.
  26. Goodwin CS, Armstrong JA, Chilvers T, et al (1989). Transfer of Campylobacter pylori and Campylobacter mustelae to Helicobacter gen. nov. as Helicobacter pylori comb. nov. and Helicobacter mustelae comb. nov., respectively. Int J Syst Bacteriol, 39, 397-405.
  27. Green A, Uttaravichien T, Bhudhisawasdi V, et al. (1991). Cholangiocarcinoma in northeast Thailand. A hospital-based study. Trop Geogr Med, 43, 193-8.
  28. Herrold KM (1967). Histogenesis of malignant liver tumors induced by dimethylnitrosamine. An experimental study in Syrian hamsters. J Natl Cancer Inst, 39, 1099-111.
  29. Hua JS, Zheng PY, Ho B (1999). Species differentiation and identification in the genus of helicobacter. World J Gastroenterol, 5, 7-9.
  30. Huang Y, Fan XG, Zhou JH (2004). Immunohistochemistry of Helicobacter pylori in primary liver carcinoma tissues. Zhong Nan Da Xue Xue Bao Yi Xue Ban, 29, 15-7.
  31. IARC. (1994). Infection with liver flukes (Opisthorchis viverrini, Opisthorchis felineus and Clonrochis sinensis). IARC Monogr Eval Carcinog Risks of Hum, 61, 121-75.
  32. Ito K, Nakamura M, Toda G, et al (2004). Potential role of Helicobacter pylori in hepatocarcinogenesis. Int J Mol Med, 13, 221-7.
  33. Jing W, Jin G, Zhou X, et al (2012). Diabetes mellitus and increased risk of cholangiocarcinoma: a meta-analysis. Eur J Cancer Prev, 21, 24-31.
  34. Kobayashi T, Harada K, Miwa K, et al (2005). Helicobacter genus DNA fragments are commonly detectable in bile from patients with extrahepatic biliar diseases and associated with their pathogenesis. Dig Dis Sci, 39, 862-7.
  35. Kosaka T, Tajima Y, Kuroki T, et al (2010). Helicobacter bilis colonization of the biliary system in patients with pancreaticobiliary maljunction. Br J Surg, 97, 544-9.
  36. Kuroki T, Fukuda K, Yamanouchi K, (2002). Helicobacter pylori accelerates the biliary epithelial cell proliferation activity in hepatolithiasis. Hepatogastroenterol, 49, 648-51.
  37. Landis S, Murray T, Bolden S, et al(1998). Cancer statistics, 1998. CA Cancer J Clin, 48, 6-29.
  38. Lee S, Kim M, Lee S, et al (2004). Clinicopathologic review of 58 patients with biliary papillomatosis. Cancer, 100, 783-93.
  39. Lee C, Wu C, Chen G (2002). What is the impact of coexistence of hepatolithiasis on cholangiocarcinoma?. J Gastroenterol Hepatol, 17, 1015-20.
  40. Li N, Zhang SH, Xuan SY, et al (2006). Study on Helicobacter infection in liver tissue from hepatocellular carcinoma. Zhonghua Liusingbingxue Zazhi, 27, 894-6.
  41. Lipsett P, Pitt H, Colombani P, et al (1994). Choledochal cyst disease. A changing pattern of presentation. Ann Surg, 220, 644-52.
  42. Maksimova GA, Zhukova NA, Kashina EV, et al (2015). Role of Opisthorchis felineus on induction of bile duct cancer. Parazitologiia, 49, 3-11.
  43. Mateos-Munoz B, Perez-de-la-Serna J, Ruiz-de-Leon A, et al (2013). Enterohepatic Helicobacter other than Helicobacter pylori. Rev Esp Enferm Dig, 105, 477-84.
  44. Matsukura N, Yokomuro S, Yamada S, et al (2002). Association between Helicobacter bilis in bile and biliary tract malignancies: H. bilis in bile from Japanese and Thai patients with benign and malignant diseases in the biliary tract. Jpn J Cancer Res, 93, 842-7.
  45. Mecklin J, Jarvinen H, Virolainen M (1992). The association between cholangiocarcinoma and hereditary nonpolyposis colorectal carcinoma. Cancer, 69, 1112-4.
  46. Migasena P, Changbumrung S (1974). The role of nitrosamines in the cause of primary carcinoma. J Med Assoc Thai, 57, 175-8.
  47. Migasena P, Reaunsuwan W, Changbumrung S (1980). Nitrates and nitrites in local Thai preserved protein foods. J Med Assoc Thai, 63, 500-5.
  48. Mera R, Fontham ET, Bravo LE, et al (2005). Long term follow up of patients treated for Helicobacter pylori infection. Gut, 54, 1536-40.
  49. Mitacek EJ, Brunnemann KD, Hoffmann D, et al (1999). Volatile nitrosamines and tobacco- specific nitrosamines in the smoke of Thai cigarettes: a risk factor for lung cancer and a suspected risk factor for liver cancer in Thailand. Carcinogenesis, 20, 133-7.
  50. Murata H, Tsuji S, Tsuji M, et al (2004). Helicobacter bilis infection in biliary tract cancer. Aliment Pharmacol Ther, 20, 90-4.
  51. Nilsson HO, Mulchandani R, Tranberg KG, et al (2001). Helicobacter species identified in liver from patients with cholangiocarcinoma and hepatocellular carcinoma. Gastroenterol, 120, 323-4.
  52. Oh JK, Weiderpass E (2014). Infection and Cancer: Global Distribution and Burden of Diseases. Ann Glob Health, 80, 384-92.
  53. Pandey M, Shukla M (2009). Helicobacter species are associated with possible increase in risk of hepatobiliary tract cancers. Surg Oncol, 18, 51-6.
  54. Parkin DM (2006). The global health burden of infectionassociated cancers in the year 2002. Int J Cancer, 118, 3030-44.
  55. Palmer WC, Patel T (2012). Are common factors involved in the pathogenesis of primary liver cancers? A meta-analysis of risk factors for intrahepatic cholangiocarcinoma. J Hepatol, 57, 69-76.
  56. Park J, Oh S, Kim S, et al (2005). Single-agent gemcitabine in the treatment of advanced biliary tract cancers: a phase II study. Jpn J Clin Oncol, 35, 68-73.
  57. Patel T (2002). Worldwide trends in mortality from biliary tract malignancies. BMC Cancer, 2, 10.
  58. Pellicano R, Mazzaferro V, Grigioni WF, et al (2004). Helicobacter species sequences in liver samples from patients with and without hepatocellular carcinoma. World J Gastroenterol, 10, 598-601.
  59. Pellicano R, Meard A, Rizzetto M, et al (2008). Helicobacter species and liver diseases: Association or causation?. Lancet Infect Dis, 8, 254-60.
  60. Philip P, Mahoney M, Allmer C, et al (2006). Phase II study of erlotinib in patients with advanced biliary cancer. J Clin Oncol, 24, 3069-74.
  61. Pradhan SB, Dali S (2004). Relation between gallbladder neoplasm and Helicobacter hepaticus infection. Kathmandu Univ Med J, 2, 331-5.
  62. Ryan KJ, Ray CG (2004). Sherris Medical Microbiology (4th ed.). McGraw Hill.
  63. Roe IH, Kim JT, Lee HS, et al (1999). Detection of Helicobacter DNA in bile from bile duct diseases. J Korean Med Sci, 14, 182-6.
  64. Ren HB, Yu T, Liu C, et al (2011). Diabetes mellitus and increased risk of biliary tract cancer: systematic review and meta-analysis. Cancer Causes Control, 22, 837-47.
  65. Rocha M, Avenaud P, Menard A, et al (2005). Association of Helicobacter species with hepatitis C cirrhosis with or without hepatocellular carcinoma. Gut, 54, 396-401.
  66. Rosen CB, Heimbach JK, Gores GJ (2008). Surgery for cholangiocarcinoma: the role of liver transplantation. Official J Inter Hepato Pancreato Biliary Assoc, 10, 186-9.
  67. Saengboonmee C, Seubwai W, Wongkham C, et al (2015). Diabetes mellitus: Possible risk and promoting factors of cholangiocarcinoma Association of diabetes mellitus and cholangiocarcinoma. Cancer Epidemiol, 39, 274-8.
  68. Sahani D, Prasad S, Tannabe K, et al (2003). Thorotrast-induced cholangiocarcinoma: case report. Abdom Imaging, 28, 72-4.
  69. Segura-Lopez FK, Aviles-Jimenez F, Guitron-Cantu A, et al (2015). Infection with Helicobacter bilis but not Helicobacter hepaticus was Associated with Extrahepatic Cholangiocarcinoma. Helicobacter, 20, 223-30.
  70. Segura-Lopez FK, Guitron-Cantu A, Torres J (2015). Association between Helicobacter spp. infections and hepatobiliary malignancies: A review. World J Gastroenterol, 21, 1414-23.
  71. Shaib Y, El-Serag H, Davila J, (2005). Risk factors of intrahepatic cholangiocarcinoma in the United States: a case-control study. Gastroenterology, 128, 620-6.
  72. Shin HR, Oh JK, Masuyer E, et al. (2010). Epidemiology of cholangiocarcinoma: an update focusing on risk factors. Cancer Sci, 101, 579-85.
  73. Shimoyama T, Takahashi R, Abe D, et al (2010). Serological analysis of Helicobacter hepaticus infection in patients with biliary and pan- creatic diseases. J Gastroenterol Hepatol, 25, 86-9.
  74. Shomer NH, Dangler CA, Schrenzel MD, et al (1997). Helicobacter bilis-induced inflammatory bowel disease in scid mice with defined flora. Infect Immun, 65, 4858-64.
  75. Sorensen H, Friis S, Olsen J, et al (1998). Risk of liver and other types of cancer in patients with cirrhosis: a nationwide cohort study in Denmark. Hepatology, 28, 921-5.
  76. Sripa B, Yongvanit P, Pairojkul C (2005). Etiology and pathogenesis of cholangiocarcinoma: introduction to the association with liver fluke infection. Srinagarind Med J, 20, 123-34
  77. Sripa B, Kaewkes S, Sithithaworn P, Met al. (2007). Liver fluke induces cholangiocarcinoma. PLoS Med, 4, 201.
  78. Sripa B, Kaewkes S, Intapan PM, et al (2010). Food-borne trematodiases in Southeast Asia epidemiology, pathology, clinical manifestation and control. Adv Parasitol, 72, 305-350.
  79. Su C, Shyr Y, Lui W, et al (1997). Hepatolithiasis associated with cholangiocarcinoma. Br J Surg, 84, 969-73.
  80. Thamavit W, Bhamarapravati N, Sahaphong S, et al. (1978). Effects of dimethylnitrosamine on induction of cholangiocarcinoma in Opisthorchis viverrini-infected Syrian golden hamsters. Cancer Res, 38, 4634-9.
  81. Thunyaharn N, Promthet S, Wiangnon SS, et al (2013). Survival of cholangiocarcinoma patients in northeastern Thailand after supportive treatment. Asian Pac J Cancer Prev, 14, 7029-32.
  82. Uemura N., Okamoto S, Yamamoto S, et al (2001). Helicobacter pylori infection and the development of gastric cancer. N Engl J Med, 345, 784-9.
  83. Vandamme P, Falsen E, Rossaq R, et al (1991). Revision of Campylobacter, Helicobacter, and Wolinella taxonomy: emendation of generic descriptions and proposal of Arcobacter gen. nov. Int J Syst Bacteriol, 41, 88-103.
  84. Watanapa P, Watanapa W (2002). Liver fluke-associated cholangiocarcinoma. Br J Surg, 89, 962-70.
  85. Wroblewski LE, Peek RM, Wilson KT (2010). Helicobacter pylori and gastric cancer: factors that modulate disease risk. Clin Microbiol Rev, 23, 713-39.
  86. Xiao M, Gao Y, Wang Y (2014). Helicobacter species infection may be associated with cholangiocarcinoma: a metaanalysis. Int J Clin Pract, 68, 262-70.
  87. Yamaoka Y (2008). Helicobacter pylori: molecular genetics and cellular biology. caister academic press, Norfolk, England.
  88. Yeo CJ, Pitt HA, Cameron JL (1990). Cholangiocarcinoma. Surg Clin North Am, 70, 1429-47.
  89. Young VB, Knox KA, Schauer DB (2000). Cytolethal distending toxin sequence and activity in the enterohepatic pathogen Helicobacter hepaticus. Infect Immun, 68, 184-91.
  90. Zhang LF, Zhao HX (2013). Diabetes mellitus and increased risk of extrahepatic cholangiocarcinoma: a meta-analysis. Hepatogastroenterol, 60, 684-7.
  91. Zhang SQ, Bao Y, Zu MH (2004). The correlation between Helicobacter infection and hepatocellular carcinoma. Zhongguo Zhongliu Linchuang, 31, 761-4.
  92. Zhou D, Wang JD, Weng MZ, et al (2013). Infections of Helicobacter spp. in the biliary system are associated with biliary tract cancer: a meta-analysis. Eur J Gastroenterol Hepatol, 25, 447-54.
  93. Zhu A, Lauwers G, Tanabe K (2004). Cholangiocarcinoma in association with Thorotrast exposure. J Hepatobiliary Pancreat Surg, 11, 430-3.

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