Skip to main content
SpringerLink
Log in

Obesity and Hepatocarcinogenesis

  • Chapter
  • First Online:
Alcoholic/Non-Alcoholic Digestive Diseases

  • 325 Accesses

Abstract

Obesity has been recognized as a cluster of risk factors associated with type 2 diabetes (T2D), cardiovascular morbidity, and higher frequency of cancers in a variety of tissues including the liver. Liver cancer most often occurs as hepatocellular carcinoma (HCC) complicating cirrhosis due to chronic viral infection, heavy alcohol consumption, or non-alcoholic steatohepatitis (NASH) which is a severe form of non-alcoholic fatty liver disease (NAFLD). NAFLD is a major cause of liver disease worldwide, and is becoming the leading cause of HCC/liver transplantation. Obesity-associated HCC has recently been attributed to molecular mechanisms such as chronic inflammation due to adipose tissue remodeling and pro-inflammatory adipokine secretion, ectopic lipid accumulation and lipotoxicity, altered gut microbiota, and disrupted senescence in stellate cells, as well as insulin resistance leading to increased levels of insulin and insulin-like growth factors. Genetic polymorphism has also an important role in the development of HCC without hepatitis virus infection. PNPLA3 genotype GG is the most significant predictor for incident HCC in patients with obesity, T2D, and NAFLD. The frequency of PNPLA3 G allele is known to be more prevalent in Asians and Hispanics than other ethnics. These mechanisms synergize and accelerate the development of HCC before or after the onset of cirrhosis. Better understanding of this complex process will improve our strategies of HCC prevention, prediction, and surveillance in obesity-associated diseases.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
eBook
USD 16.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Bertuccio P, Turati F, Carioli G, Rodriguez T, La Vecchia C, Malvezzi M, Negri E. Global trends and predictions in hepatocellular carcinoma mortality. J Hepatol. 2017;67(2):302–9.

    Article  Google Scholar 

  2. Tateishi R, Okanoue T, Fujiwara N, Okita K, Kiyosawa K, Omata M, Kumada H, Hayashi N, Koike K. Clinical characteristics, treatment, and prognosis of non-B, non-C hepatocellular carcinoma: a large retrospective multicenter cohort study. J Gastroenterol. 2015;50(3):350–60.

    Article  CAS  Google Scholar 

  3. GBD 2015 Obesity Collaborators, Afshin A, Forouzanfar MH, Reitsma MB, Sur P, Estep K, Lee A, Marczak L, Mokdad AH, Moradi-Lakeh M, Naghavi M, Salama JS, Vos T, Abate KH, Abbafati C, Ahmed MB, Al-Aly Z, Alkerwi A, Al-Raddadi R, Amare AT, Amberbir A, Amegah AK, Amini E, Amrock SM, Anjana RM, Ärnlöv J, Asayesh H, Banerjee A, Barac A, Baye E, Bennett DA, Beyene AS, Biadgilign S, Biryukov S, Bjertness E, Boneya DJ, Campos-Nonato I, Carrero JJ, Cecilio P, Cercy K, Ciobanu LG, Cornaby L, Damtew SA, Dandona L, Dandona R, Dharmaratne SD, Duncan BB, Eshrati B, Esteghamati A, Feigin VL, Fernandes JC, Fürst T, Gebrehiwot TT, Gold A, Gona PN, Goto A, Habtewold TD, Hadush KT, Hafezi-Nejad N, Hay SI, Horino M, Islami F, Kamal R, Kasaeian A, Katikireddi SV, Kengne AP, Kesavachandran CN, Khader YS, Khang YH, Khubchandani J, Kim D, Kim YJ, Kinfu Y, Kosen S, Ku T, Defo BK, Kumar GA, Larson HJ, Leinsalu M, Liang X, Lim SS, Liu P, Lopez AD, Lozano R, Majeed A, Malekzadeh R, Malta DC, Mazidi M, McAlinden C, McGarvey ST, Mengistu DT, Mensah GA, Mensink GBM, Mezgebe HB, Mirrakhimov EM, Mueller UO, Noubiap JJ, Obermeyer CM, Ogbo FA, Owolabi MO, Patton GC, Pourmalek F, Qorbani M, Rafay A, Rai RK, Ranabhat CL, Reinig N, Safiri S, Salomon JA, Sanabria JR, Santos IS, Sartorius B, Sawhney M, Schmidhuber J, Schutte AE, Schmidt MI, Sepanlou SG, Shamsizadeh M, Sheikhbahaei S, Shin MJ, Shiri R, Shiue I, Roba HS, DAS S, Silverberg JI, Singh JA, Stranges S, Swaminathan S, Tabarés-Seisdedos R, Tadese F, Tedla BA, Tegegne BS, Terkawi AS, Thakur JS, Tonelli M, Topor-Madry R, Tyrovolas S, Ukwaja KN, Uthman OA, Vaezghasemi M, Vasankari T, Vlassov VV, Vollset SE, Weiderpass E, Werdecker A, Wesana J, Westerman R, Yano Y, Yonemoto N, Yonga G, Zaidi Z, Zenebe ZM, Zipkin B, Murray CJL. Health effects of overweight and obesity in 195 countries over 25 years. N Engl J Med. 2017;377(1):13–27.

    Article  Google Scholar 

  4. Bhaskaran K, Douglas I, Forbes H, dos-Santos-Silva I, Leon DA, Smeeth L. Body-mass index and risk of 22 specific cancers: a population-based cohort study of 5·24 million UK adults. Lancet. 2014;384(9945):755–65.

    Article  Google Scholar 

  5. Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. N Engl J Med. 2003;348:1625–38.

    Article  Google Scholar 

  6. Hagström H, Stål P, Hultcrantz R, Hemmingsson T, Andreasson A. Overweight in late adolescence predicts development of severe liver disease later in life: a 39years follow-up study. J Hepatol. 2016;65(2):363–8.

    Article  Google Scholar 

  7. Hagström H, Tynelius P, Rasmussen F. High BMI in late adolescence predicts future severe liver disease and hepatocellular carcinoma: a national, population-based cohort study in 1.2 million men. Gut. 2018;67:1536–42. https://doi.org/10.1136/gutjnl-2016-313622.

    Article  PubMed  Google Scholar 

  8. Muto Y, Sato S, Watanabe A, Moriwaki H, Suzuki K, Kato A, Kato M, Nakamura T, Higuchi K, Nishiguchi S, Kumada H, Long-Term Survival Study Group. Effects of oral branched-chain amino acid granules on event-free survival in patients with liver cirrhosis. Clin Gastroenterol Hepatol. 2005;3(7):705–13.

    Article  CAS  Google Scholar 

  9. Kawaguchi T, Sumida Y, Umemura A, Matsuo K, Takahashi M, Takamura T, Yasui K, Saibara T, Hashimoto E, Kawanaka M, Watanabe S, Kawata S, Imai Y, Kokubo M, Shima T, Park H, Tanaka H, Tajima K, Yamada R, Matsuda F, Okanoue T, Japan Study Group of Nonalcoholic Fatty Liver Disease. Genetic polymorphisms of the human PNPLA3 gene are strongly associated with severity of non-alcoholic fatty liver disease in Japanese. PLoS One. 2012;7(6):e38322.

    Article  CAS  Google Scholar 

  10. Eslam M, Valenti L, Romeo S. Genetics and epigenetics of NAFLD and NASH: clinical impact. J Hepatol. 2018;68(2):268–79.

    Article  CAS  Google Scholar 

  11. Singal AG, Manjunath H, Yopp AC, Beg MS, Marrero JA, Gopal P, Waljee AK. The effect of PNPLA3 on fibrosis progression and development of hepatocellular carcinoma: a meta-analysis. Am J Gastroenterol. 2014;109(3):325–34.

    Article  CAS  Google Scholar 

  12. Burza MA, Pirazzi C, Maglio C, Sjöholm K, Mancina RM, Svensson PA, Jacobson P, Adiels M, Baroni MG, Borén J, Ginanni Corradini S, Montalcini T, Sjöström L, Carlsson LM, Romeo S. PNPLA3 I148M (rs738409) genetic variant is associated with hepatocellular carcinoma in obese individuals. Dig Liver Dis. 2012;44(12):1037–41.

    Article  CAS  Google Scholar 

  13. Nakagawa H, Umemura A, Taniguchi K, Font-Burgada J, Dhar D, Ogata H, Zhong Z, Valasek MA, Seki E, Hidalgo J, Koike K, Kaufman RJ, Karin M. ER stress cooperates with hypernutrition to trigger TNF-dependent spontaneous HCC development. Cancer Cell. 2014;26(3):331–43.

    Article  CAS  Google Scholar 

  14. Yoshimoto S, Loo TM, Atarashi K, Kanda H, Sato S, Oyadomari S, Iwakura Y, Oshima K, Morita H, Hattori M, Honda K, Ishikawa Y, Hara E, Ohtani N. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature. 2013;499(7456):97–101. https://doi.org/10.1038/nature12347. Epub 2013 Jun 26

    Article  CAS  PubMed  Google Scholar 

  15. Neuschwander-Tetri BA. Non-alcoholic fatty liver disease. BMC Med. 2017;15:45.

    Article  Google Scholar 

  16. Park EJ, Lee JH, Yu GY, et al. Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell. 2010;140:197–208.

    Article  CAS  Google Scholar 

  17. Tilg H, Hotamisligil GS. Nonalcoholic fatty liver disease: cytokine-adipokine interplay and regulation of insulin resistance. Gastroenterology. 2006;131:934–45.

    Article  CAS  Google Scholar 

  18. El-Serag HB, Hampel H, Javadi F. The association between diabetes and hepatocellular carcinoma: a systematic review of epidemiologic evidence. Clin Gastroenterol Hepatol. 2006;4:369–80.

    Article  Google Scholar 

  19. Wang C, Wang X, Gong G, et al. Increased risk of hepatocellular carcinoma in patients with diabetes mellitus: a systematic review and meta-analysis of cohort studies. Int J Cancer. 2012;130:1639–48.

    Article  CAS  Google Scholar 

  20. Simon TG, King LY, Chong DQ, Nguyen L, Ma Y, VoPham T, Giovannucci EL, Fuchs CS, Meyerhardt JA, Corey KE, Khalili H, Chung RT, Zhang X, Chan AT. Diabetes, metabolic comorbidities and risk of hepatocellular carcinoma: results from two prospective cohort studies. Hepatology. 2017;67:1797. https://doi.org/10.1002/hep.29660. [Epub ahead of print].

    Article  CAS  Google Scholar 

  21. Chen Y, Wu F, Saito E, Lin Y, Song M, Luu HN, Gupta PC, Sawada N, Tamakoshi A, Shu XO, Koh WP, Xiang YB, Tomata Y, Sugiyama K, Park SK, Matsuo K, Nagata C, Sugawara Y, Qiao YL, You SL, Wang R, Shin MH, Pan WH, Pednekar MS, Tsugane S, Cai H, Yuan JM, Gao YT, Tsuji I, Kanemura S, Ito H, Wada K, Ahn YO, Yoo KY, Ahsan H, Chia KS, Boffetta P, Zheng W, Inoue M, Kang D, Potter JD. Association between type 2 diabetes and risk of cancer mortality: a pooled analysis of over 771,000 individuals in the Asia Cohort Consortium. Diabetologia. 2017;60(6):1022–32.

    Article  Google Scholar 

  22. Nakamura J, Kamiya H, Haneda M, Inagaki N, Tanizawa Y, Araki E, Ueki K, Nakayama T. Causes of death in Japanese patients with diabetes based on the results of a survey of 45,708 cases during 2001-2010: report of the Committee on Causes of Death in Diabetes Mellitus. J Diabetes Investig. 2017;8(3):397–410.

    Article  CAS  Google Scholar 

  23. Si WK, Chung JW, Cho J, Baeg JY, Jang ES, Yoon H, Kim J, Shin CM, Park YS, Hwang JH, Jeong SH, Kim N, Lee DH, Lim S, Kim JW. Predictors of Increased Risk of Hepatocellular Carcinoma in Patients with Type 2 Diabetes. PLoS One. 2016;11(6):e0158066.

    Article  Google Scholar 

  24. Ueyama M, Nishida N, Korenaga M, Korenaga K, Kumagai E, Yanai H, Adachi H, Katsuyama H, Moriyama S, Hamasaki H, Sako A, Sugiyama M, Aoki Y, Imamura M, Murata K, Masaki N, Kawaguchi T, Torimura T, Hyogo H, Aikata H, Ito K, Sumida Y, Kanazawa A, Watada H, Okamoto K, Honda K, Kon K, Kanto T, Mizokami M, Watanabe S. The impact of PNPLA3 and JAZF1 on hepatocellular carcinoma in non-viral hepatitis patients with type 2 diabetes mellitus. J Gastroenterol. 2016;51(4):370–9.

    Article  CAS  Google Scholar 

  25. Younossi ZM, Koenig AB, Abdelatif D, et al. Global epidemiology of nonalcoholic fatty liver disease—meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;64:73–84.

    Article  Google Scholar 

  26. Kawamura Y, Arase Y, Ikeda K, Seko Y, Imai N, Hosaka T, Kobayashi M, Saitoh S, Sezaki H, Akuta N, Suzuki F, Suzuki Y, Ohmoto Y, Amakawa K, Tsuji H, Kumada H. Large-scale long-term follow-up study of Japanese patients with non-alcoholic Fatty liver disease for the onset of hepatocellular carcinoma. Am J Gastroenterol. 2012;107(2):253–61.

    Article  CAS  Google Scholar 

  27. Seko Y, Sumida Y, Tanaka S, Taketani H, Kanemasa K, Ishiba H, Okajima A, Nishimura T, Yamaguchi K, Moriguchi M, Mitsuyoshi H, Yasui K, Minami M, Itoh Y. Predictors of malignancies and overall mortality in Japanese patients with biopsy-proven non-alcoholic fatty liver disease. Hepatol Res. 2015;45(7):728–38.

    Article  CAS  Google Scholar 

  28. Dulai PS, Singh S, Patel J, Soni M, Prokop LJ, Younossi Z, Sebastiani G, Ekstedt M, Hagstrom H, Nasr P, Stal P, Wong VW, Kechagias S, Hultcrantz R, Loomba R. Increased risk of mortality by fibrosis stage in nonalcoholic Fatty liver disease: systematic review and meta-analysis. Hepatology. 2017;65(5):1557–65.

    Article  CAS  Google Scholar 

  29. Nakahara T, Hyogo H, Yoneda M, Sumida Y, Eguchi Y, Fujii H, Ono M, Kawaguchi T, Imajo K, Aikata H, Tanaka S, Kanemasa K, Fujimoto K, Anzai K, Saibara T, Sata M, Nakajima A, Itoh Y, Chayama K, Okanoue T, Japan Study Group of Nonalcoholic Fatty Liver Disease. Type 2 diabetes mellitus is associated with the fibrosis severity in patients with nonalcoholic fatty liver disease in a large retrospective cohort of Japanese patients. J Gastroenterol. 2014;49(11):1477–84.

    Article  CAS  Google Scholar 

  30. Younossi Z, Anstee QM, Marietti M, Hardy T, Henry L, Eslam M, George J, Bugianesi E. Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol. 2018;15(1):11–20.

    Article  Google Scholar 

  31. Donati B, Dongiovanni P, Romeo S, Meroni M, McCain M, Miele L, et al. MBOAT7 rs641738 variant and hepatocellular carcinoma in noncirrhotic individuals. Sci Rep. 2017;7:4492.

    Article  Google Scholar 

  32. Kawaguchi T, Shima T, Mizuno M, Mitsumoto Y, Umemura A, Kanbara Y, Tanaka S, Sumida Y, Yasui K, Takahashi M, Matsuo K, ItohY TK, Hashimoto E, Kiyosawa K, Kawaguchi M, Itoh H, Uto H, Komorizono Y, Shirabe K, Takami S, Takamura T, Kawanaka M, Yamada R, Matsuda F, Okanoue T. Risk estimation model for nonalcoholic fatty liver disease in the Japanese using multiple genetic markers. PLoS One. 2018;13(1):e0185490.

    Article  Google Scholar 

  33. Tang H, Wei P, Chang P, Li Y, Yan D, Liu C, Hassan M, Li D. Genetic polymorphisms associated with pancreatic cancer survival: a genome-wide association study. Int J Cancer. 2017;141(4):678–86.

    Article  CAS  Google Scholar 

  34. Baffy G, Brunt EM, Caldwell SH. Hepatocellular carcinoma in non-alcoholic fatty liver disease: an emerging menace. J Hepatol. 2012;56:1384–91.

    Article  Google Scholar 

  35. Michelotti GA, Machado MV, Diehl AM. NAFLD, NASH and liver cancer. Nat Rev Gastroenterol Hepatol. 2013;10:656–65.

    Article  CAS  Google Scholar 

  36. Kettner NM, Voicu H, Finegold MJ, et al. Circadian homeostasis of liver metabolism suppresses hepatocarcinogenesis. Cancer Cell. 2016;30:909–24.

    Article  CAS  Google Scholar 

  37. Ma C, Kesarwala AH, Eggert T, et al. NAFLD causes selective CD4(+) T lymphocyte loss and promotes hepatocarcinogenesis. Nature. 2016;531:253–7.

    Article  CAS  Google Scholar 

  38. Gomes AL, Teijeiro A, Buren S, et al. Metabolic inflammation-associated IL-17A causes non-alcoholic steatohepatitis and hepatocellular carcinoma. Cancer Cell. 2016;30:161–75.

    Article  CAS  Google Scholar 

  39. Loo TM, Kamachi F, Watanabe Y, et al. Gut microbiota promotes obesity-associated liver cancer through PGE2-mediated suppression of antitumor immunity. Cancer Discov. 2017;7:522–38.

    Article  CAS  Google Scholar 

  40. Ong JP, Pitts A, Younossi ZM. Increased overall mortality and liver-related mortality in non-alcoholic fatty liver disease. J Hepatol. 2008;49(4):608–12.

    Article  Google Scholar 

  41. Kim GA, Lee HC, Choe J, Kim MJ, Lee MJ, Chang HS, Bae IY, Kim HK, An J, Shim JH, Kim KM, Lim YS. Association between non-alcoholic fatty liver disease and cancer incidence rate. J Hepatol. 2017; https://doi.org/10.1016/j.jhep.2017.09.012.

    Article  Google Scholar 

  42. Piscaglia F, Svegliati-Baroni G, Barchetti A. HCC-NAFLD Italian Study Group Clinical patterns of hepatocellular carcinoma in nonalcoholic fatty liver disease: a multicenter prospective study. Hepatology. 2016;63:827–38.

    Article  Google Scholar 

  43. Mittal S, Sada Y, El-Serag HB, Kanwal F, Duan Z, Temple S, et al. Temporal trends of nonalcoholic fatty liver disease-related hepatocellular carcinoma in the veteran affairs population. Clin Gastroenterol Hepatol. 2015;13:594–601.

    Article  Google Scholar 

  44. Chalasani N, Younossi Z, Lavine JE, Charlton M, Cusi K, Rinella M, Harrison SA, Brunt EM, Sanyal AJ. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2018;67(1):328–57. https://doi.org/10.1002/hep.29367. Epub 2017 Sep 29

    Article  PubMed  Google Scholar 

  45. Yasui K, Hashimoto E, Komorizono Y, Koike K, Arii S, Imai Y, Shima T, Kanbara Y, Saibara T, Mori T, Kawata S, Uto H, Takami S, Sumida Y, Takamura T, Kawanaka M, Okanoue T, Japan NASH Study Group, Ministry of Health, Labour, and Welfare of Japan. Characteristics of patients with nonalcoholic steatohepatitis who develop hepatocellular carcinoma. Clin Gastroenterol Hepatol. 2011;9(5):428–33.

    Article  Google Scholar 

  46. Seko Y, Sumida Y, Tanaka S, Mori K, Taketani H, Ishiba H, Hara T, Okajima A, Umemura A, Nishikawa T, Yamaguchi K, Moriguchi M, Kanemasa K, Yasui K, Imai S, Shimada K, Itoh Y. Development of hepatocellular carcinoma in Japanese patients with biopsy-proven non-alcoholic fatty liver disease: association between PNPLA3 genotype and hepatocarcinogenesis/fibrosis progression. Hepatol Res. 2017;47(11):1083–92.

    Article  CAS  Google Scholar 

  47. European Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD), European Association for the Study of Obesity (EASO). EASL-EASD-EASO clinical practice guidelines for the management of non-alcoholic fatty liver disease. J Hepatol. 2016;64:1388–402.

    Google Scholar 

  48. Younes R, Bugianesi E. Should we undertake surveillance for HCC in patients with NAFLD? J Hepatol. 2018;68:326–34.

    Article  Google Scholar 

  49. Johnson PJ, Pirrie SJ, Cox TF, Berhane S, Teng M, Palmer D, Morse J, Hull D, Patman G, Kagebayashi C, Hussain S, Graham J, Reeves H, Satomura S. The detection of hepatocellular carcinoma using a prospectively developed and validated model based on serological biomarkers. Cancer Epidemiol Biomark Prev. 2014;23(1):144–53.

    Article  CAS  Google Scholar 

  50. Berhane S, Toyoda H, Tada T, Kumada T, Kagebayashi C, Satomura S, Schweitzer N, Vogel A, Manns MP, Benckert J, Berg T, Ebker M, Best J, Dechêne A, Gerken G, Schlaak JF, Weinmann A, Wörns MA, Galle P, Yeo W, Mo F, Chan SL, Reeves H, Cox T, Johnson P. Role of the GALAD and BALAD-2 serologic models in diagnosis of hepatocellular carcinoma and prediction of survival in patients. Clin Gastroenterol Hepatol. 2016;14(6):875–86.

    Article  CAS  Google Scholar 

  51. Ito K, Murotani K, Nakade Y, Inoue T, Nakao H, Sumida Y, Kamada Y, Yoneda M. Serum Wisteria floribunda agglutinin-positive Mac-2-binding protein levels and liver fibrosis: a meta-analysis. J Gastroenterol Hepatol. 2017;32(12):1922–30.

    Article  CAS  Google Scholar 

  52. Abe M, Miyake T, Kuno A, Imai Y, Sawai Y, Hino K, Hara Y, Hige S, Sakamoto M, Yamada G, Kage M, Korenaga M, Hiasa Y, Mizokami M, Narimatsu H. Association between Wisteria floribunda agglutinin-positive Mac-2 binding protein and the fibrosis stage of non-alcoholic fatty liver disease. J Gastroenterol. 2015;50(7):776–84.

    Article  CAS  Google Scholar 

  53. Yoneda M, Imajo K, Takahashi H, Ogawa Y, Eguchi Y, Sumida Y, Yoneda M, Kawanaka M, Saito S, Tokushige K, Nakajima A. Clinical strategy of diagnosing and following patients with nonalcoholic fatty liver disease based on invasive and noninvasive methods. J Gastroenterol. 2018;53:181–96. https://doi.org/10.1007/s00535-017-1414-2. [Epub ahead of print]

    Article  CAS  PubMed  Google Scholar 

  54. Hiraoka A, Ochi M, Matsuda R, Aibiki T, Okudaira T, Kawamura T, Yamago H, Nakahara H, Suga Y, Azemoto N, Miyata H, Miyamoto Y, Ninomiya T, Hirooka M, Abe M, Matsuura B, Hiasa Y, Michitaka K. Ultrasonography screening for hepatocellular carcinoma in Japanese patients with diabetes mellitus. J Diabetes. 2016;8(5):640–6.

    Article  CAS  Google Scholar 

  55. Imajo K, Kessoku T, Honda Y, Tomeno W, Ogawa Y, Mawatari H, Fujita K, Yoneda M, Taguri M, Hyogo H, Sumida Y, Ono M, Eguchi Y, Inoue T, Yamanaka T, Wada K, Saito S, Nakajima A. Magnetic resonance imaging more accurately classifies steatosis and fibrosis in patients with nonalcoholic fatty liver disease than transient elastography. Gastroenterology. 2016;150(3):626–37.

    Article  Google Scholar 

  56. Motosugi U, Ichikawa T, Koshiishi T, Sano K, Morisaka H, Ichikawa S, Enomoto N, Matsuda M, Fujii H, Araki T. Liver stiffness measured by magnetic resonance elastography as a risk factor for hepatocellular carcinoma: a preliminary case-control study. Eur Radiol. 2013;23(1):156–62.

    Article  Google Scholar 

  57. Yang Y, Zhang D, Feng N, et al. Increased intake of vegetables, but not fruit, reduces risk for hepatocellular carcinoma: a meta-analysis. Gastroenterology. 2014;147:1031–42.

    Article  Google Scholar 

  58. Duarte-Salles T, Fedirko V, Stepien M, et al. Dietary fat, fat subtypes and hepatocellular carcinoma in a large European cohort. Int J Cancer. 2015;137:2715–28.

    Article  CAS  Google Scholar 

  59. Sawada N, Inoue M, Iwasaki M, et al. Consumption of n-3 fatty acids and fish reduces risk of hepatocellular carcinoma. Gastroenterology. 2012;142:1468–75.

    Article  CAS  Google Scholar 

  60. Kennedy OJ, Roderick P, Buchanan R, Fallowfield JA, Hayes PC, Parkes J. Coffee, including caffeinated and decaffeinated coffee, and the risk of hepatocellular carcinoma: a systematic review and dose-response meta-analysis. BMJ Open. 2017;7(5):e013739. https://doi.org/10.1136/bmjopen-2016-013739.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Watanabe S, Hashimoto E, Ikejima K, Uto H, Ono M, Sumida Y, Seike M, Takei Y, Takehara T, Tokushige K, Nakajima A, Yoneda M, Saibara T, Shiota G, Sakaida I, Nakamuta M, Mizuta T, Tsubouchi H, Sugano K, Shimosegawa T, Japanese Society of Gastroenterology; Japan Society of Hepatology. Evidence-based clinical practice guidelines for nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. J Gastroenterol. 2015;50(4):364–77.

    Article  Google Scholar 

  62. Hashida R, Kawaguchi T, Bekki M, Omoto M, Matsuse H, Nago T, Takano Y, Ueno T, Koga H, George J, Shiba N, Torimura T. Aerobic vs. resistance exercise in non-alcoholic fatty liver disease: a systematic review. J Hepatol. 2017;66(1):142–52.

    Article  Google Scholar 

  63. Piguet AC, Saran U, Simillion C, Keller I, Terracciano L, Reeves HL, Dufour JF. Regular exercise decreases liver tumors development in hepatocyte-specific PTEN-deficient mice independently of steatosis. J Hepatol. 2015;62(6):1296–303.

    Article  CAS  Google Scholar 

  64. Singh S, Singh PP, Singh AG, et al. Anti-diabetic medications and the risk of hepatocellular cancer: a systematic review and meta-analysis. Am J Gastroenterol. 2013;108:881–91.. quiz 892

    Article  CAS  Google Scholar 

  65. Zhou YY, Zhu GQ, Liu T, et al. Systematic review with network meta-analysis: antidiabetic medication and risk of hepatocellular carcinoma. Sci Rep. 2016;6:33743.

    Article  CAS  Google Scholar 

  66. Chitturi S, Wong VW, Chan WK, Wong GL, Wong SK, Sollano J, Ni YH, Liu CJ, Lin YC, Lesmana LA, Kim SU, Hashimoto E, Hamaguchi M, Goh KL, Fan J, Duseja A, Dan YY, Chawla Y, Farrell G, Chan HL. The Asia-Pacific working party on non-alcoholic fatty liver disease guidelines 2017-part 2: management and special groups. J Gastroenterol Hepatol. 2018;33(1):86–98.

    Article  Google Scholar 

  67. Sumida Y, Seko Y, Yoneda M, Japan Study Group of NAFLD (JSG-NAFLD). Novel antidiabetic medications for non-alcoholic fatty liver disease with type 2 diabetes mellitus. Hepatol Res. 2017;47(4):266–80.

    Article  Google Scholar 

  68. Kaji K, Nishimura N, Seki K, Sato S, Saikawa S, Nakanishi K, Furukawa M, Kawaratani H, Kitade M, Moriya K, Namisaki T, Yoshiji H. Sodium glucose cotransporter 2 inhibitor canagliflozin attenuates liver cancer cell growth and angiogenic activity by inhibiting glucose uptake. Int J Cancer. 2018;142:1712. https://doi.org/10.1002/ijc.31193. [Epub ahead of print].

    Article  CAS  PubMed  Google Scholar 

  69. Obara K, Shirakami Y, Maruta A, Ideta T, Miyazaki T, Kochi T, Sakai H, Tanaka T, Seishima M, Shimizu M. Preventive effects of the sodium glucose cotransporter 2 inhibitor tofogliflozin on diethylnitrosamine-induced liver tumorigenesis in obese and diabetic mice. Oncotarget. 2017;8(35):58353–63.

    Article  Google Scholar 

  70. Shiba K, Tsuchiya K, Komiya C, Miyachi Y, Mori K, Shimazu N, Yamaguchi S, Ogasawara N, Katoh M, Itoh M, Suganami T, Ogawa Y. Canagliflozin, an SGLT2 inhibitor, attenuates the development of hepatocellular carcinoma in a mouse model of human NASH. Sci Rep. 2018;8(1):2362.

    Article  Google Scholar 

  71. Tang H, Dai Q, Shi W, Zhai S, Song Y, Han J. SGLT2 inhibitors and risk of cancer in type 2 diabetes: a systematic review and meta-analysis of randomised controlled trials. Diabetologia. 2017;60(10):1862–72.

    Article  CAS  Google Scholar 

  72. Armstrong MJ, Gaunt P, Aithal GP, Barton D, Hull D, Parker R, Hazlehurst JM, Guo K, LEAN Trial Team, Abouda G, Aldersley MA, Stocken D, Gough SC, Tomlinson JW, Brown RM, Hübscher SG, Newsome PN, Wilku M, Russell C, Iqbal S, Corbett C, Lee MY, Keely J, Nicholls M, Henry S, Lewis M, Dixon E, Myers S, Sharman S, Bishop R. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet. 2016;387(10019):679–90.

    Article  CAS  Google Scholar 

  73. Eguchi Y, Kitajima Y, Hyogo H, Takahashi H, Kojima M, Ono M, Araki N, Tanaka K, Yamaguchi M, Matsuda Y, Ide Y, Otsuka T, Ozaki I, Ono N, Eguchi T, Anzai K, Japan Study Group for NAFLD (JSG-NAFLD). Pilot study of liraglutide effects in non-alcoholic steatohepatitis and non-alcoholic fatty liver disease with glucose intolerance in Japanese patients (LEAN-J). Hepatol Res. 2015;45(3):269–78.

    Article  CAS  Google Scholar 

  74. Seko Y, Sumida Y, Tanaka S, Mori K, Taketani H, Ishiba H, Hara T, Okajima A, Umemura A, Nishikawa T, Yamaguchi K, Moriguchi M, Kanemasa K, Yasui K, Imai S, Shimada K, Itoh Y. Effect of 12-week dulaglutide therapy in Japanese patients with biopsy-proven non-alcoholic fatty liver disease and type 2 diabetes mellitus. Hepatol Res. 2017;47(11):1206–11.

    Article  CAS  Google Scholar 

  75. Zhou M, Mok MT, Sun H, Chan AW, Huang Y, Cheng AS, Xu G. The anti-diabetic drug exenatide, a glucagon-like peptide-1 receptor agonist,counteracts hepatocarcinogenesis through cAMP-PKA-EGFR-STAT3 axis. Oncogene. 2017;36(29):4135–49.

    Article  CAS  Google Scholar 

  76. Katsiki N, Athyros VG, Karagiannis A, Mikhailidis DP. Semaglutide, lipid-lowering drugs, and NAFLD. Lancet Diabetes Endocrinol. 2017;5(5):329–30.

    Article  Google Scholar 

  77. Singh S, Singh PP, Singh AG, Murad MH, Sanchez W. Statins are associated with a reduced risk of hepatocellular cancer: a systematic review and meta-analysis. Gastroenterology. 2013;144:323–32.

    Article  CAS  Google Scholar 

  78. Kim G, Jang SY, Nam CM, Kang ES. Statin use and the risk of hepatocellular carcinoma in patients at high risk: A nationwide nested case-control study. J Hepatol. 2018;53:181–96.

    Google Scholar 

  79. Zhou YY, Zhu GQ, Wang Y, Zheng JN, Ruan LY, Cheng Z, Hu B, Fu SW, Zheng MH. Systematic review with network meta-analysis: statins and risk of hepatocellular carcinoma. Oncotarget. 2016;7(16):21753–62. https://doi.org/10.18632/oncotarget.7832.

    Article  PubMed  PubMed Central  Google Scholar 

  80. Muto Y, Sato S, Watanabe A, Moriwaki H, Suzuki K, Kato A, Kato M, Nakamura T, Higuchi K, Nishiguchi S, Kumada H, Ohashi Y, Long-Term Survival Study (LOTUS) Group. Overweight and obesity increase the risk for liver cancer in patients with liver cirrhosis and long-term oral supplementation with branched-chain amino acid granules inhibits liver carcinogenesis in heavier patients with liver cirrhosis. Hepatol Res. 2006;35(3):204–14.

    CAS  PubMed  Google Scholar 

  81. Yoshiji H, Noguchi R, Namisaki T, Moriya K, Kitade M, Aihara Y, Douhara A, Yamao J, Fujimoto M, Toyohara M, Mitoro A, Sawai M, Yoshida M, Morioka C, Uejima M, Uemura M, Fukui H. Branched-chain amino acids suppress the cumulative recurrence of hepatocellular carcinoma under conditions of insulin-resistance. Oncol Rep. 2013;30(2):545–52.

    Article  CAS  Google Scholar 

  82. Takegoshi K, Honda M, Okada H, Takabatake R, Matsuzawa-Nagata N, Campbell JS, Nishikawa M, Shimakami T, Shirasaki T, Sakai Y, Yamashita T, Takamura T, Tanaka T, Kaneko S. Branched-chain amino acids prevent hepatic fibrosis and development of hepatocellular carcinoma in a non-alcoholic steatohepatitis mouse model. Oncotarget. 2017;8(11):18191–205.

    Article  Google Scholar 

  83. Loomba R, Lawitz E, Mantry PS, et al. The ASK1 inhibitor selonsertib in patients with nonalcoholic steatohepatitis: a randomized, phase 2 trial. Hepatology. In press; https://doi.org/10.1002/hep.29514.

    Article  Google Scholar 

  84. Nakagawa H, Hirata Y, Takeda K, Hayakawa Y, Sato T, Kinoshita H, Sakamoto K, Nakata W, Hikiba Y, Omata M, Yoshida H, Koike K, Ichijo H, Maeda S. Apoptosis signal-regulating kinase 1 inhibits hepatocarcinogenesis by controlling the tumor-suppressing function of stress-activated mitogen-activated protein kinase. Hepatology. 2011;54(1):185–95.

    Article  CAS  Google Scholar 

  85. Younossi ZM, Stepanova M, Lawitz E, Charlton M, Loomba R, Myers RP, Subramanian GM, McHutchison JG, Goodman Z. Improvement of hepatic fibrosis and patient-reported outcomes in non-alcoholic steatohepatitis treated with selonsertib. Liver Int. 2018;38:1849. https://doi.org/10.1111/liv.13706. [Epub ahead of print].

    Article  CAS  PubMed  Google Scholar 

  86. Friedman SL, Ratziu V, Harrison SA, et al. A randomized, placebo-controlled trial of cenicriviroc for treatment of nonalcoholic steatohepatitis with fibrosis. Hepatology. In press;

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Hepatology and Pancreatology, Department of Internal Medicine, Aichi Medical University, Nagakute, Aichi, Japan

    Yoshio Sumida, Akihiko Ohashi, Yukiomi Nakade, Kiyoaki Ito, Haruhisa Nakao, Yoshitaka Fukuzawa & Masashi Yoneda

  2. Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan

    Yuya Seko, Tasuku Hara & Yoshito Itoh

  3. Hepatology Center, Saiseikai Suita Hospital, Suita, Japan

    Takeshi Okanoue

Authors
  1. Yoshio Sumida
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yuya Seko
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tasuku Hara
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Akihiko Ohashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yukiomi Nakade
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kiyoaki Ito
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Haruhisa Nakao
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yoshitaka Fukuzawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yoshito Itoh
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Takeshi Okanoue
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Masashi Yoneda
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yoshio Sumida .

Editor information

Editors and Affiliations

  1. Third Department of Internal Medicine, Nara Medical University, Kashihara, Japan

    Hitoshi Yoshiji

  2. Third Department of Internal Medicine, Nara Medical University, Kashihara, Japan

    Kosuke Kaji

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Singapore Pte Ltd.

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Sumida, Y. et al. (2019). Obesity and Hepatocarcinogenesis. In: Yoshiji, H., Kaji, K. (eds) Alcoholic/Non-Alcoholic Digestive Diseases. Springer, Singapore. https://doi.org/10.1007/978-981-13-1465-0_8

Download citation

  • DOI: https://doi.org/10.1007/978-981-13-1465-0_8

  • Published:

  • Publisher Name: Springer, Singapore

  • Print ISBN: 978-981-13-1464-3

  • Online ISBN: 978-981-13-1465-0

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation