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Obesity and Hepatocarcinogenesis

  • Yoshio SumidaEmail author
  • Yuya Seko
  • Tasuku Hara
  • Akihiko Ohashi
  • Yukiomi Nakade
  • Kiyoaki Ito
  • Haruhisa Nakao
  • Yoshitaka Fukuzawa
  • Yoshito Itoh
  • Takeshi Okanoue
  • Masashi Yoneda
Chapter

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.

Keywords

NAFLD Hepatic fibrosis PNPLA3 Type 2 diabetes 

References

  1. 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.CrossRefGoogle Scholar
  2. 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.CrossRefGoogle Scholar
  3. 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.CrossRefGoogle Scholar
  4. 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.CrossRefGoogle Scholar
  5. 5.
    Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. N Engl J Med. 2003;348:1625–38.CrossRefGoogle Scholar
  6. 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.CrossRefGoogle Scholar
  7. 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.CrossRefPubMedGoogle Scholar
  8. 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.CrossRefGoogle Scholar
  9. 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.CrossRefGoogle Scholar
  10. 10.
    Eslam M, Valenti L, Romeo S. Genetics and epigenetics of NAFLD and NASH: clinical impact. J Hepatol. 2018;68(2):268–79.CrossRefGoogle Scholar
  11. 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.CrossRefGoogle Scholar
  12. 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.CrossRefGoogle Scholar
  13. 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.CrossRefGoogle Scholar
  14. 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 26CrossRefPubMedGoogle Scholar
  15. 15.
    Neuschwander-Tetri BA. Non-alcoholic fatty liver disease. BMC Med. 2017;15:45.CrossRefGoogle Scholar
  16. 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.CrossRefGoogle Scholar
  17. 17.
    Tilg H, Hotamisligil GS. Nonalcoholic fatty liver disease: cytokine-adipokine interplay and regulation of insulin resistance. Gastroenterology. 2006;131:934–45.CrossRefGoogle Scholar
  18. 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.CrossRefGoogle Scholar
  19. 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.CrossRefGoogle Scholar
  20. 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].CrossRefGoogle Scholar
  21. 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.CrossRefGoogle Scholar
  22. 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.CrossRefGoogle Scholar
  23. 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.CrossRefGoogle Scholar
  24. 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.CrossRefGoogle Scholar
  25. 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.CrossRefGoogle Scholar
  26. 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.CrossRefGoogle Scholar
  27. 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.CrossRefGoogle Scholar
  28. 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.CrossRefGoogle Scholar
  29. 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.CrossRefGoogle Scholar
  30. 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.CrossRefGoogle Scholar
  31. 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.CrossRefGoogle Scholar
  32. 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.CrossRefGoogle Scholar
  33. 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.CrossRefGoogle Scholar
  34. 34.
    Baffy G, Brunt EM, Caldwell SH. Hepatocellular carcinoma in non-alcoholic fatty liver disease: an emerging menace. J Hepatol. 2012;56:1384–91.CrossRefGoogle Scholar
  35. 35.
    Michelotti GA, Machado MV, Diehl AM. NAFLD, NASH and liver cancer. Nat Rev Gastroenterol Hepatol. 2013;10:656–65.CrossRefGoogle Scholar
  36. 36.
    Kettner NM, Voicu H, Finegold MJ, et al. Circadian homeostasis of liver metabolism suppresses hepatocarcinogenesis. Cancer Cell. 2016;30:909–24.CrossRefGoogle Scholar
  37. 37.
    Ma C, Kesarwala AH, Eggert T, et al. NAFLD causes selective CD4(+) T lymphocyte loss and promotes hepatocarcinogenesis. Nature. 2016;531:253–7.CrossRefGoogle Scholar
  38. 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.CrossRefGoogle Scholar
  39. 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.CrossRefGoogle Scholar
  40. 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.CrossRefGoogle Scholar
  41. 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.CrossRefGoogle Scholar
  42. 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.CrossRefGoogle Scholar
  43. 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.CrossRefGoogle Scholar
  44. 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 29CrossRefPubMedGoogle Scholar
  45. 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.CrossRefGoogle Scholar
  46. 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.CrossRefGoogle Scholar
  47. 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. 48.
    Younes R, Bugianesi E. Should we undertake surveillance for HCC in patients with NAFLD? J Hepatol. 2018;68:326–34.CrossRefGoogle Scholar
  49. 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.CrossRefGoogle Scholar
  50. 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.CrossRefGoogle Scholar
  51. 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.CrossRefGoogle Scholar
  52. 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.CrossRefGoogle Scholar
  53. 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]CrossRefPubMedGoogle Scholar
  54. 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.CrossRefGoogle Scholar
  55. 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.CrossRefGoogle Scholar
  56. 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.CrossRefGoogle Scholar
  57. 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.CrossRefGoogle Scholar
  58. 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.CrossRefGoogle Scholar
  59. 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.CrossRefGoogle Scholar
  60. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 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.CrossRefGoogle Scholar
  62. 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.CrossRefGoogle Scholar
  63. 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.CrossRefGoogle Scholar
  64. 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 892CrossRefGoogle Scholar
  65. 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.CrossRefGoogle Scholar
  66. 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.CrossRefGoogle Scholar
  67. 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.CrossRefGoogle Scholar
  68. 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].CrossRefPubMedGoogle Scholar
  69. 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.CrossRefGoogle Scholar
  70. 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.CrossRefGoogle Scholar
  71. 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.CrossRefGoogle Scholar
  72. 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.CrossRefGoogle Scholar
  73. 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.CrossRefGoogle Scholar
  74. 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.CrossRefGoogle Scholar
  75. 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.CrossRefGoogle Scholar
  76. 76.
    Katsiki N, Athyros VG, Karagiannis A, Mikhailidis DP. Semaglutide, lipid-lowering drugs, and NAFLD. Lancet Diabetes Endocrinol. 2017;5(5):329–30.CrossRefGoogle Scholar
  77. 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.CrossRefGoogle Scholar
  78. 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. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  80. 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.PubMedGoogle Scholar
  81. 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.CrossRefGoogle Scholar
  82. 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.CrossRefGoogle Scholar
  83. 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.CrossRefGoogle Scholar
  84. 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.CrossRefGoogle Scholar
  85. 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].CrossRefPubMedGoogle Scholar
  86. 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

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  • Yoshio Sumida
    • 1
    Email author
  • Yuya Seko
    • 2
  • Tasuku Hara
    • 2
  • Akihiko Ohashi
    • 1
  • Yukiomi Nakade
    • 1
  • Kiyoaki Ito
    • 1
  • Haruhisa Nakao
    • 1
  • Yoshitaka Fukuzawa
    • 1
  • Yoshito Itoh
    • 2
  • Takeshi Okanoue
    • 3
  • Masashi Yoneda
    • 1
  1. 1.Division of Hepatology and Pancreatology, Department of Internal MedicineAichi Medical UniversityNagakuteJapan
  2. 2.Department of Gastroenterology and HepatologyKyoto Prefectural University of MedicineKyotoJapan
  3. 3.Hepatology CenterSaiseikai Suita HospitalSuitaJapan

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