Mechanisms and clinical behavior of hepatocellular carcinoma in HBV and HCV infection and alcoholic and non-alcoholic fatty liver disease

Abstract

Hepatocellular carcinoma (HCC) is the main tumor of the liver and is the sixth most frequently diagnosed tumor in the world. It is the evolution of chronic hepatic injury secondary to different etiologies. Chronic hepatitis B virus and hepatitis C virus infection, chronic alcoholic hepatitis, as well as non-alcoholic fatty liver disease are the most common causes behind the development of HCC. The introduction of effective prophylaxis and treatment against hepatitis B, the recent use of highly effective hepatitis C treatments, as well as lifestyle changes observed in recent decades in the general population causing an increase in obesity and metabolic syndrome have led to significant epidemiological change in HCC in relation to the changed etiologic prevalence of liver injury. Increasing evidence was emerging, emphasizing how the development of HCC is a complex and multifactorial process. The knowledge of the molecular mechanisms involved is important for the understanding of the basic factors of the development of hepatocarcinogenesis and of possible therapeutic approaches. Several pathogenic mechanisms and clinical expression of HCC occur in relation to the different etiologies of the underlying liver disease. The different clinical behavior of HCC often makes diagnosis difficult at an early stage, that is necessary for an effective therapeutic approach. This review analyzes the possible different pathogenic mechanisms involved in the development of HCC and emphasizes the different epidemiological and clinical aspects of HCC observed in the most common forms of liver diseases of viral and non-viral origin.

Keywords

Hepatocellular carcinoma / hepatitis C virus / hepatitis B virus / alcohol hepatitis / non-alcoholic fatty liver disease

References

[1] Collaboration Global Burden of Disease Liver Cancer.The burden of primary liver cancer and underlying etiologies from 1990 to 2015 at the global, regional, and national level: results from the Global Burden of Disease Study 2015.JAMA Oncol2017;3:1683-91

[2] Ferlay J,Dikshit R,Mathers C,Parkin DM,Bray F.Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012.Int J Cancer2015;136:E359-86

[3] Siegel RL,Jemal A.Cancer statistics, 2018.CA Cancer J Clin2018;68:7-30

[4] Petrick JL,Laversanne M,Bray F.International trends in liver cancer incidence, overall and by histologic subtype, 1978-2007.Int J Cancer2016;139:1534-45 PMCID:PMC5310166

[5] Younossi ZM,Abdelatif D,Henry L.Global epidemiology of nonalcoholic fatty liver diasease – meta-analytic assessment of prevalence, incidence, and outcomes.Hepatology2016;64:73-84

[6] Younossi ZM,Henry L,Mishra A,Hunt S.Association of nonalcoholic fatty liver disease (NAFLD) with hepatocellular carcinoma (HCC) in the United States from 2004 to 2009.Hepatology2015;62:1723-30

[7] Yang JD,Coelho R,Benson JT,Therneau TM,Roberts LR.Cirrhosis is present in most patients with hepatitis B and hepatocellular carcinoma.Clin Gastroenterol Hepatol2011;9:64-70 PMCID:PMC3951426

[8] Parkin DM.The global health burden of infection-associated cancers in the years 2002.Int J Cancer2006;118:3030-44

[9] El-Serag HB.Epidemiology of viral hepatitis and hepatocellular carcinoma.Gastroenterology2012;142:1264-73.el PMCID:PMC3338949

[10] Lozano R,Foreman K,Shibuya K,Abraham J,Aggarwal R,Alvarado M,Anderson LM,Atkinson C,Barker-Collo S,Bell ML,Bennett D,Bikbov B,Birbeck G,Bolliger I,Bucello C,Burney P,Chen H,Chugh SS,Colan SD,Colson KE,Connor MD,Corriere M,de Vaccaro KC,Cowie BC,Cross M,Dahodwala N,Degenhardt L,Denenberg J,Dharmaratne SD,Driscoll T,Ebel B,Espindola P,Feigin V,Forouzanfar MH,Franklin R,Freeman MK,Gakidou E,Gillum RF,Halasa YA,Harrison JE,Hay RJ,Hotez PJ,Jacobsen KH,Jasrasaria R,Johns N,Kassebaum N,Khoo JP,Kobusingye O,Krishnamurthi R,Lipshultz SE,Mabweijano J,Mallinger L,Marks GB,Matsumori A,Mayosi BM,McDermott MM,Mensah GA,Michaud C,Miller TR,Mocumbi AO,Moran A,Nair MN,Narayan KM,Norman P,Omer SB,Osborne R,Pahari B,Rivero AP,Perez-Ruiz F,Phillips D,Pope CA3rd,Pourmalek F,Ranganathan D,Rein DB,Rivara FP,De León FR,Rushton L,Salomon JA,Sanman E,Segui-Gomez M,Singh D,Sliwa K,Steer A,Thomas B,Towbin JA,Undurraga EA,Vijayakumar L,Wagner GR,Wang W,Weinstock MA,Wilkinson JD,Wulf S,Yip P,Zheng ZJ,Murray CJ,Memish ZA.Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010.Lancet2012;380:2095-128

[11] Venook AP,Furuse J.The incidence and epidemiology of hepatocellular carcinoma: a global and regional perspective.Oncologist2010;15 Suppl 4:5-13

[12] Levrero M.Mechanisms of HBV-induced hepatocellular carcinoma.J Hepatol2016;64:S84-101

[13] Wang SH,Lin WH,Chen DS.Identification of androgen response elements in the enhancer I of hepatitis B virus: a mechanism for sex disparity in chronic hepatitis B.Hepatology2009;50:1392-402

[14] Chen X,Liu Y,Zhu B,Chen W,Wang Y.The contribution of serum hepatitis B virus load in the carcinogenesis and prognosis of hepatocellular carcinoma: evidence from two meta-analyses.Oncotarget2016;7:49299-309

[15] Wang SH,Lin WH,Yuan Q,Chen DS.Estrogen receptor α represses transcription of HBV genes via interaction with hepatocyte nuclearfactor 4α.Gastroenterology2012;142:989-998.e4

[16] Xie Y.Hepatitis B virus-associated hepatocellular carcinoma.Adv Exp Med Biol2017;1018:11-21

[17] Plentz RR,Lechel A,Nellessen F,Wilkens L,Fiamengo B,Roncalli M.Telomere shortening and inactivation of cell cycle checkpoints characterize human hepatocarcinogenesis.Hepatology2007;45:968-76

[18] Kojima H,Imazeki F,Omata M.Telomerase activity and telomere length in hepatocellular carcinoma and chronic liver disease.Gastroenterology1997;112:493-500

[19] El-Serag HB,Everhart JE.Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma.Gastroenterology2004;126:460-8

[20] Yu MC,Lu SC.Alcohol, cofactors and the genetics of hepatocellular carcinoma.J Gastroenterol Hepatol2008;23 Suppl 1:S92-7 PMCID:PMC2391242

[21] Marrero JA,Fu S,Su GL.Alcohol, tobacco and obesity are synergistic risk factors for hepatocellular carcinoma.J Hepatol2005;42:218-24

[22] Zampino R,Cirillo G,Macera M,Stanzione M,Gentile I,Signoriello G,Adinolfi LE.Hepatocellular carcinoma in chronic HBV-HCV co-infection is correlated to fibrosis and disease duration.Ann Hepatol2015;14:75-82

[23] Brau N,Xiao P,Naqvi Z,Trikha A,Sulkowski MS,Rigsby MO,Hernandez MD,Khatri GK,Bonacini M,Aytaman A,Brown ST.Presentation and outcome of hepatocellular carcinoma in HIV-infected patients: a U.S.-Canadian multicenter study. J Hepatol2007;47:527-37

[24] Chan HL,Wong ML,Hung LC,Sung JJ.Genotype C hepatitis B virus infection is associated with an increased risk of hepatocellular carcinoma.Gut2004;53:1494-8 PMCID:PMC1774221

[25] Lin CL.Natural history of acute and chronic hepatitis B: the role of HBV genotypes and mutants.Best Pract Res Clin Gastroenterol2017;31:249-55

[26] Datta S,Ghosh A,Ghosh A,Ray S,Santra AK,Das K,Chowdhury A.Distinct distribution pattern of hepatitis B virus genotype C and D in liver tissue and serum of dual genotype infected liver cirrhosis and hepatocellular carcinoma patients.PLoS One2014;9:e102573 PMCID:PMC4102524

[27] Yang HI,Liaw YF,Sun CA,Hsiao CK,Chen DS.Hepatitis B e antigen and the risk of hepatocellular carcinoma.N Engl J Med2002;347:168-74

[28] Chen CJ,Su J,You SL,Huang GT.Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level.JAMA295:65-73

[29] Chan KY,Kwan JS,Cheung KW,Lai CL,Sham PC.Genome-wide association study of hepatocellular carcinoma in Southern Chinese patients with chronic hepatitis B virus infection.PLoS One2011;6:e28798 PMCID:PMC3234276

[30] Migita K,Maeda Y,Abiru S,Yano K,Matsumoto T,Hamasaki K,Ishibashi H.Cytokine gene polymorphisms in Japanese patients with hepatitis B virus infection--association between TGF-beta1 polymorphisms and hepatocellular carcinoma.J Hepatol2005;42:505-10

[31] Jiang DK,Cao G,Lin D,Ren WH,Zhang H,Wang Z,Chen TY,Sun LD,Huang HX,Yu H,Tang LS,Cai H,Zhou P,Lin X,Wan B,Qin LX,Liu L,Pei Y,Zhai Y,Tan A,Fan J,Gu X,Li Y,Zhai K,Hu Z,Yi Q,Shi R,Zheng W,Mo Z,Zhang XJ,Shen H,Xu J.Genetic variants in STAT4 and HLA-DQ genes confer risk of hepatitis B virus-related hepatocellular carcinoma.Nat Genet2013;45:72-5 PMCID:PMC4105840

[32] Gu X,Zhou F,Wang H,Zhao Y.+49G > A polymorphism in the cytotoxic T-lymphocyte antigen-4 gene increases susceptibility to hepatitis B-related hepatocellular carcinoma in a male Chinese population.Hum Immunol2010;71:83-7

[33] Yoon YJ,Ahn SH,Park YK,Park JY,Kim DY,Han KH.MDM2 and p53 polymorphisms are associated with the development of hepatocellular carcinoma in patients with chronic hepatitis B virus infection.Carcinogenesis2008;29:1192-6

[34] Levrero M,Petersen J,Raimondo G.Control of cccDNA function in hepatitis B virus infection.J Hepatol2009;51:581-92

[35] Xie Y.Hepatitis B virus-associated hepatocellular carcinoma.Adv Exp Med Biol2017;1018:11-21

[36] Ding D,Hua D,Li L,Gao F,Ren G,Lin B.Recurrent targeted genes of hepatitis B virus in the liver cancer genomes identified by a next-generation sequencing-based approach.PLoS Genet2012;8:e1003065 PMCID:PMC3516541

[37] Sung WK,Li S,Liu X,Lee NP,Ariyaratne PN,Mulawadi FH,Liu AM,Fan ST,Gong Z,Lin Z,Zhang Q,Chou WC,Hao K,Zhang C,Buser C,Kan Z,Mao M,Wang J.Genome-wide survey of recurrent HBV integration in hepatocellular carcinoma.Nat Genet2012;44:765-9

[38] Lau CC,Ching AK,Li JW,Co NN,Li PS,Tong JH,Chan HL,Chan TF.Viral-human chimeric transcript predisposes risk to liver cancer development and progression.Cancer Cell2014;25:335-49

[39] Chotiyaputta W.Hepatitis B virus variants.Nat Rev Gastroenterol Hepatol2009;6:453-62

[40] Liu WC,Lee YC,Cheng JH,Yen CJ,Li PF,Cheng PW,Yan SL,Yang JC,Ho CH,Chang BC,Chang TT.Hepatocellular carcinoma-associated single-nucleotide variants and deletions identified by the use of genome-wide high-throughput analysis of hepatitis B virus.J Pathol2017;243:176-92

[41] Kuang SY,Wang JB,Mu-oz A,Kensler TW.Specific mutations of hepatitis B virus in plasma predict liver cancer development.Proc Natl Acad Sci U S A2004;101:3575-80 PMCID:PMC373504

[42] Liu S,Gu C,He Y,Cao G.Associations between hepatitis B virus mutations and the risk of hepatocellular carcinoma: a meta-analysis.J Natl Cancer Inst2009;101:1066-82 PMCID:PMC2720989

[43] Wang HC,Lai MD.Hepatitis B virus pre-S mutants, endoplasmic reticulum stress and hepatocarcinogenesis.Cancer Sci2006;97:683-8

[44] Chen CH,Lee CM,Wang JH,Lu SN.Pre-S deletion and complex mutations of hepatitis B virus related to advanced liver disease in HBeAg-negative patients.Gastroenterology2007;133:1466-74

[45] Pollicino T,Saffioti F.Hepatitis B virus PreS/S gene variants: pathobiology and clinical implications.J Hepatol2014;61:408-17

[46] Lee SA,Kim H.Nucleotide change of codon 182 in the surface gene of hepatitis B virus genotype C leading to truncated surface protein is associated with progression of liver diseases.J Hepatol2012;56:63-9

[47] Lucifora J,Durantel D,Strubin M,Zoulim F,Protzer U.Hepatitis B virus X protein is essential to initiate and maintain virus replication after infection.J Hepatol2011;55:996-1003

[48] Belloni L,De Nicola F,Raffa G,Raimondo G.Nuclear HBx binds the HBV minichromosome and modifies the epigenetic regulation of cccDNA function.Proc Natl Acad Sci U S A2009;106:19975-9 PMCID:PMC2775998

[49] Forgues M,Linke SP,Nagashima K,Valerie K,Wang XW.Involvement of Crm1 in hepatitis B virus X protein-induced aberrant centriole replication and abnormal mitotic spindles.Mol Cell Biol2003;23:5282-92 PMCID:PMC165739

[50] Sanz-Cameno P,Lara-Pezzi E,Salmerón J,Solís JA,Moreno-Otero R.Hepatitis B virus promotes angiopoietin-2 expression in liver tissue: role of HBV x protein.Am J Pathol2006;169:1215-22 PMCID:PMC1698851

[51] Park SH,Lim JS,Jang KL.Hepatitis B virus X protein overcomes all-trans retinoic acid-induced cellular senescence by downregulating levels of p16 and p21 via DNA methylation.J Gen Virol2011;92:1309-17

[52] Levrero M.Mechanisms of HBV-induced hepatocellular carcinoma.J Hepatol2016;64:S84-S101

[53] Khalaf AM,Morshid AI,Kaseb AO,Hazle JD.Role of Wnt/β-catenin signaling in hepatocellular carcinoma, pathogenesis, and clinical significance.J Hepatocell Carcinoma2018;5:61-73 PMCID:PMC6027703

[54] European Association for the Study of the Liver.Electronic address: [e-mail]; European Association for the Study of the Liver. EASL2017;67:370-98

[55] Guidelines Approved by the Guidelines Review Committee WHO.Guidelines for the prevention, care and treatment of persons with chronic hepatitis B infection.Geneva: World Health Organization;2015;

[56] Mason WS,Litwin S,Peri S,Hong ML,Quaglia A,Kennedy PT.HBV-DNA integration and clonal hepatocyte expansion in chronic hepatitis b patients considered immune tolerant.Gastroenterology2016;151:986-98.e4. d

[57] Kim GA,Han S,Shim JH,Lee HC.High risk of hepatocellular carcinoma and death in patients with immune-tolerant-phase chronic hepatitis B.Gut2017;pii:gutjnl-2017-314904

[58] Chang Y,Sinn DH,Ahn SH,Shim JJ,Park SY,Yu SJ,Lee JM,Kwon SY,Yoon JH.Nucleos(t)ide analogue treatment for patients with hepatitis B virus (HBV) e antigen-positive chronic HBV genotype C infection: a nationwide, multicenter, retrospective study.J Infect Dis2017;216:1407-14

[59] Bertoletti A,Durantel D.HBV infection and HCC: the 'dangerous liaisons'.Gut2017;pii:gutjnl-2017-315528

[60] Raimondo G,Brunetto MR,Chen DS,Craxì A,Ferrari C,Gerlich WH,Locarnini S,Mondelli MU,Pollicino T,Puoti M,Shouval D,Squadrito G,Villa E,Zanetti AR.Statements from the Taormina expert meeting on occult hepatitis B virus infection.J Hepatol2008;49:652-7

[61] Pollicino T,Cerenzia G,Raffa G,Farinati F,Smedile A,Villa E.Hepatitis B virus maintains its pro-oncogenic properties in the case of occult HBV infection.Gastroenterology2004;126:102-10

[62] Saitta C,Barbera A,Smedile A,Raffa G,Navarra G,Pollicino T.Hepatitis B virus (HBV) DNA integration in patients with occult HBV infection and hepatocellular carcinoma.Liver Int2015;35:2311-7

[63] Coppola N,Iodice V,Minichini C,Liorre G,Sagnelli E.Occult HBV infection in HCC and cirrhotic tissue of HBsAg-negative patients: a virological and clinical study.Oncotarget2016;7:62706-14 PMCID:PMC5308760

[64] Squadrito G,Alibrandi A,Raimondo G.Impact of occult hepatitis B virus infection on the outcome of chronic hepatitis C.J Hepatol2013;59:696-700

[65] Papatheodoridis GV,Manolakopoulos S.Incidence of hepatocellular carcinoma in chronic hepatitis B patients receiving nucleos(t)ide therapy: a systematic review.J Hepatol2010;53:348-56

[66] Wu CY,Ho HJ,Lee TY,Wu C.Association of nucleos(t)ide analogue therapy with reduced risk of hepatocellular carcinoma in patients with chronic hepatitis B: a nationwide cohort study.Gastroenterology2014;147:143-151.e5

[67] Lin D,Nguyen N,Kim Y,Le A,Nguyen V,Li J,Hsing A,Nguyen MH.Reduction of chronic hepatitis B-related hepatocellular carcinoma with anti-viral therapy, including low risk patients.Aliment Pharmacol Ther2016;44:846-55

[68] Hoang JK,Le A,Lin D,Chaung K,Trinh HN,Zhang JQ,Nguyen MH.Lower liver cancer risk with antiviral therapy in chronic hepatitis B patients with normal to minimally elevated ALT and no cirrhosis.Medicine (Baltimore)2016;95:e4433 PMCID:PMC4979821

[69] Lin D,Hoang J.Letter: should anti-viral therapy be recommended for individuals chronically infected with hepatitis B virus and at low risk of hepatocellular carcinoma? Authors' reply.Aliment Pharmacol Ther2017;45:182-3

[70] Fattovich G,Zagni I.Hepatocellular carcinoma in cirrhosis: incidence and risk factors.Gastroenterology2004;127:S35-50

[71] Cancer European Organisation for Research and Treatment of.EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma.J Hepatol2012;56:908-43

[72] Lok AS,Morgan TR,Sterling RK,Everson GT,Lee WM,Dienstag JL,Morishima C.Incidence of hepatocellular carcinoma and associated risk factors in hepatitis C-related advancedliver disease.Gastroenterology2009;136:138-48 PMCID:PMC3749922

[73] Davis GL,El-Serag H,Jennings LW.Aging of hepatitis C virus (HCV)-infected persons in the United States: a multiple cohort model of HCV prevalence and disease progression.Gastroenterology2010;138:513-21, 521.el-6

[74] Bruno S,Maisonneuve P,Silini E.Hepatitis C virus genotype 1b as a major risk factor associated with hepatocellular carcinoma in patients with cirrhosis: a seventeen-year prospective cohort study.Hepatology2007;46:1350-6

[75] Rinaldi L,Giordano M,Guerrera B,Fascione MC,Romagnoli D,Nevola R,Iuliano N,Lonardo A.Clinical features and natural history of cryptogenic cirrhosis compared to hepatitis C virus-related cirrhosis.World J Gastroenterol2017;23:1458-68 PMCID:PMC5330831

[76] Elkrief L,Bendersky N,Larroque B,Kutala B,Boyer N,Durand F,Rautou PE.Diabetes mellitus is an independent prognostic factor for major liver-related outcomes in patients with cirrhosis and chronic hepatitis C.Hepatology2014;60:823-31

[77] Cheung O.Hepatitis C infection and nonalcoholic fatty liver disease.Clin Liver Dis2008;12:573-85, viii-ix

[78] Calle EE,Walker-Thurmond K.Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med2003;348:1625-38

[79] Ko C,Berger J,Brandhagen D,Cotler SJ,McCashland TM,Gordon FD,Kowdley KV.Prevalence of hepatic iron overload and association with hepatocellular cancer in end-stage liver disease: results from the National Hemochromatosis Transplant Registry.Liver Int2007;27:1394-401

[80] Lee MH,Lu SN,Yeh SH,Chen PJ,Wang LY,Chen CJ.Hepatitis C virus seromarkers and subsequent risk of hepatocellular carcinoma: long-term predictors from a community-based cohort study.J Clin Oncol2010;28:4587-93

[81] Duvoux C,Bastie A,Soussy CJ.Low HCV replication levels in end-stage hepatitis C virus-related liver disease.J Hepatol1999;31:593-7

[82] Yates SC,Beld M,Hassan Z,Khaled H,Attia M.Hepatocellular carcinoma in Egyptians with and without a history of hepatitis B virus infection: association with hepatitis C virus (HCV) infection but not with (HCV) RNA level.Am J Trop Med Hyg1999;60:714-20

[83] Raimondi S,Mondelli MU.Hepatitis C virus genotype 1b as a risk factor for hepatocellular carcinoma development: a meta-analysis.J Hepatol2009;50:1142-54

[84] Bandiera S,Hoshida Y,Zeisel MB.Chronic hepatitis C virus infection and pathogenesis of hepatocellular carcinoma.Curr Opin Virol2016;20:99-105 PMCID:PMC5120759

[85] Koike K.Hepatitis C virus contributes to hepatocarcinogenesis by modulating metabolic and intracellular signaling pathways.J Gastroenterol Hepatol2007;22 Suppl 1:S108-11

[86] Gieseler RK,Schlattjan M,Bechmann LP,Roggendorf M,Friedman SL.Hepatocyte apoptotic bodies encasing nonstructural HCV proteins amplify hepatic stellate cell activation: implications for chronic hepatitis C.J Viral Hepat2011;18:760-7 PMCID:PMC2995835

[87] Matsuzaki K,Yoshida K,Uemura Y,Kaibori M,Nishizawa M,Okazaki K.Chronic inflammation associated with hepatitis C virus infection perturbs hepatic transforming growth factor beta signaling, promoting cirrhosis and hepatocellular carcinoma.Hepatology2007;46:48-57

[88] Mesri EA,Munger K.Human viral oncogenesis: a cancer hallmarks analysis.Cell Host Microbe2014;15:266-82 PMCID:PMC3992243

[89] Zemel R,Greif H,Birk Y,Kunin M,Benhar I.Cell transformation induced by hepatitis C virus NS3 serine protease.J Viral Hepat2001;8:96-102

[90] Arima N,Licht T,Sasaguri Y.Modulation of cell growth by the hepatitis C virus nonstructural protein NS5A.J Biol Chem2001;276:12675-84

[91] Fukutomi T,Kawai S,Wands JR.Hepatitis C virus core protein stimulates hepatocyte growth: correlation with upregulation of wnt-1 expression.Hepatology2005;41:1096-105

[92] Zhao LJ,Ren H,Li L,Qi ZT.Hepatitis C virus E2 protein promotes human hepatoma cell proliferation through the MAPK/ERK signaling pathway via cellular receptors.Exp Cell Res2005;305:23-32

[93] Lai CK,Machida K,Lai MM.Hepatitis C virus NS3/4A protein interacts with ATM, impairs DNA repair and enhances sensitivity to ionizing radiation.Virology2008;370:295-309

[94] Okuda M,Beard MR,Scholle F,Weinman SA.Mitochondrial injury, oxidative stress, and antioxidant gene expression are induced by hepatitis C virus core protein.Gastroenterology.2002;122:366-75

[95] Fujinaga H,Yotsuyanagi H,Koike K.Hepatocarcinogenesis in hepatitis C: HCV shrewdly exacerbates oxidative stress by modulating both production and scavenging of reactive oxygen species.Oncology2011;81 Suppl 1:11-7

[96] Moriya K,Santa T,Fujie H,Tsutsumi T,Ishibashi K,Imai K,Kimura S.Oxidative stress in the absence of inflammation in a mouse model for hepatitis C virus-associated hepatocarcinogenesis.Cancer Res2001;61:4365-70

[97] Machida K,Liu JC,Govindarajan S,Akira S.c-Jun mediates hepatitis C virus hepatocarcinogenesis through signal transducer and activator of transcription 3 and nitric oxide-dependent impairment of oxidative DNA repair.Hepatology2010;52:480-92 PMCID:PMC3107125

[98] Tsutsumi T,Moriya K,Shintani Y,Matsuura Y,Koike K.Alteration of intrahepatic cytokine expression and AP-1 activation in transgenic mice expressing hepatitis C virus core protein.Virology2002;304:415-24

[99] Tsutsumi T,Moriya K,Fujie H,Matsuura Y,Miyamura T.Hepatitis C virus core protein activates ERK and p38 MAPK in cooperation with ethanol in transgenic mice.Hepatology2003;38:820-8

[100] Alisi A,Cupelli F,Fontemaggi G,Balsano C.Physical and functional interaction between HCV core protein and the different p73 isoforms.Oncogene2003;22:2573-80

[101] Moriya K,Shintani Y,Tsutsumi T,Matsuura Y,Miyamura T.The core protein of hepatitis C virus induces hepatocellular carcinoma in transgenic mice.Nat Med1998;4:1065-7

[102] Tovar V,Villanueva A,Chiang DY,Thung S,Toffanin S,Cabellos L,Schwartz M,Bruix J.IGF activation in a molecular subclass of hepatocellular carcinoma and pre-clinical efficacy of IGF-1R blockage.J Hepatol2010;52:550-9 PMCID:PMC3662876

[103] Aytug S,Sapiro LE,Begum N.Impaired IRS-1/PI3-kinase signaling in patients with HCV: a mechanism for increased prevalence of type 2 diabetes.Hepatology2003;38:1384-92

[104] Desbois AC.Diabetes mellitus, insulin resistance and hepatitis C virus infection: a contemporary review.World J Gastroenterol2017;23:1697-1711 PMCID:PMC5340821

[105] Irshad M,Irshad K.Molecular basis of hepatocellular carcinoma induced by hepatitis C virus infection.World J Hepatol2017;9:1305-14 PMCID:PMC5756719

[106] Elkrief L,Bendersky N,Larroque B,Kutala B,Boyer N,Durand F,Rautou PE.Diabetes mellitus is an independent prognostic factor for major liver-related outcomes in patients with cirrhosis and chronic hepatitis C.Hepatology2014;60:823-31

[107] Ikeda A,Matsumoto Y,Eso Y,Mizuguchi A,Hatano E,Chiba T.Leptin receptor somatic mutations are frequent in HCV-infected cirrhotic liver and associated with hepatocellular carcinoma.Gastroenterology2014;146:222-32.e35

[108] Rehermann B.Pathogenesis of chronic viral hepatitis: differential roles of T cells and NK cells.Nat Med2013;19:859-68 PMCID:PMC4482132

[109] van der Meer AJ,Feld JJ,Dufour JF,Duarte-Rojo A,Manns MP,Zeuzem S,de Knegt RJ,Janssen HL.Association between sustained virological response and all-cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis.JAMA2012;308:2584-93

[110] Innes HA,Dillon JF,Hayes PC,Mills PR,Wilks D,Fox R,Kennedy N,Fraser A,Bramley P.Toward a more complete understanding of the association between a hepatitis C sustained viralresponse and cause-specific outcomes.Hepatology2015;62:355-64

[111] Nahon P,Layese R,Cagnot C,Guyader D,Larrey D,Ouzan D,Roulot D,Bronowicki JP,Leroy V,Calès P,Alric L,Mathurin P,Blanc JF,Serfaty L,Grangé JD,Bacq Y,Dao T,Pilette C,Christidis C,Bernard-Chabert B,Di Martino V,Salmon D,Sutton A,Roudot-Thoraval F.Eradication of hepatitis C virus infection in patients with cirrhosis reduces risk of liver and non-liver complications.Gastroenterology2017;152:142-156.e2

[112] Roche B,Duclos-Vallee JC.The impact of treatment of hepatitis C with DAAs on the occurrence of HCC.Liver Int2018;38 Suppl 1:139-45

[113] Waziry R,Grebely J,Law M,George J.Hepatocellular carcinoma risk following direct-acting antiviral HCV therapy: a systematic review, meta-analyses, and meta-regression.J Hepatol2017;67:1204-12

[114] Ioannou GN,Berry K.HCV eradication induced by direct-acting antiviral agents reduces the risk of hepatocellular carcinoma.J Hepatol2017;pii:S0168-8278(17)32273

[115] Kanwal F,Asch SM,Cao Y.Risk of hepatocellular cancer in HCV patients treated with direct-acting antiviral agents.Gastroenterology2017;153:996-1005.e1

[116] Ramadori P,Liedtke C,Nevzorova YA.Alcohol and hepatocellular carcinoma: adding fuel to the flame.Cancers (Basel)2017;9. pii:E130 PMCID:PMC5664069

[117] Blonski W,Forde KA.Non-viral causes of hepatocellular carcinoma.World J Gastroenterol2010;16:3603-15 PMCID:PMC2915420

[118] Mancebo A,Cadahía V,Pérez R,Sotorríos NG,Rodrigo L.Annual incidence of hepatocellular carcinoma among patients with alcoholic cirrhosis and identification of risk groups.Clin Gastroenterol Hepatol11:95-101

[119] Marot A,Knebel JF,Deltenre P.Alcoholic liver disease confers a worse prognosis than HCV infection and non-alcoholic fatty liver disease among patients with cirrhosis: An observational study.PLoS One2017;12:e0186715 PMCID:PMC5659599

[120] Donato F,Gelatti U,Boffetta P,Decarli A,Ribero ML,Porru S.Alcohol and hepatocellular carcinoma: the effect of lifetime intake and hepatitis virus infections in men and women.Am J Epidemiol2002;155:323-31

[121] Persson EC,Park Y,Hollenbeck AR,Freedman ND.Alcohol consumption, folate intake, hepatocellular carcinoma, and liver disease mortality.Cancer Epidemiol Biomarkers Prev2013;22:415-21 PMCID:PMC3596467

[122] Matsuhashi T,Shinzawa H.Effect of alcohol on tumor growth of hepatocellular carcinoma with type C cirrhosis.Intern Med1996;35:443-8

[123] Poynard T,Lai CL,Poupon R,Myers RP,Ratziu V,Vogel A,Chedid A.A comparison of fibrosis progression in chronic liver diseases.J Hepatol2003;38:257-65

[124] Heckley GA,Asamoah BO.How the risk of liver cancer changes after alcohol cessation: a review and meta-analysis of the current literature.BMC Cancer2011;11:446 PMCID:PMC3229519

[125] Joshi K,Manch R.Alcoholic liver disease: high risk or low risk for developing hepatocellular carcinoma?.Clin Liver Dis2016;20:563-80

[126] Galati G,Vespasiani-Gentilucci U,Gallo P,Picardi A.Hepatocellular carcinoma in alcoholic liver disease: current management and recent advances.Rev Recent Clin Trials2016;11:238-52

[127] Salameh H,Erwin A,Nischalke HD,Burza MA,Romeo S,Corradini SG,Spengler U,Day CP,Singal AK.PNPLA3 gene polymorphism is associated with predisposition to and severity of alcoholic liver disease.Am J Gastroenterol2015;110:846-56

[128] Nahon P.Constitutional and functional genetics of human alcohol-related hepatocellular carcinoma.Liver Int2017;37:1591-1601

[129] Purohit V,Kwon OS.Roles of alcohol and tobacco exposure in the development of hepatocellular carcinoma.Life Sci2013;92:3-9 PMCID:PMC3822918

[130] Loomba R,Su J,Barrett-Connor E,Chen CJ.Synergism between obesity and alcohol in increasing the risk of hepatocellular carcinoma: a prospective cohort study.Am J Epidemiol2013;177:333-42 PMCID:PMC3626057

[131] Grewal P.Liver cancer and alcohol.Clin Liver Dis2012;16:839-50

[132] Hassan MM,Hatten CJ,Li D,Beasley P.Risk factors for hepatocellular carcinoma: synergism of alcohol with viral hepatitis and diabetes mellitus.Hepatology2002;36:1206-13

[133] Yasui K,Komorizono Y,Arii S,Shima T,Saibara T,Kawata S,Takami S,Takamura T,Okanoue T,Labour.Characteristics of patients with nonalcoholic steatohepatitis who develop hepatocellular carcinoma.Clin Gastroenterol Hepatol2011;9:428-33

[134] N'Kontchou G,Htar MT,Costentin L,Trinchet JC.Risk factors for hepatocellular carcinoma in patients with alcoholic or viral C cirrhosis.Clin Gastroenterol Hepatol2006;4:1062-8

[135] Torisu Y,Kobayashi M,Sezaki H,Kawamura Y,Suzuki F,Arase Y.Diabetes mellitus increases the risk of hepatocarcinogenesis in patients with alcoholic cirrhosis: a preliminary report.Hepatol Res2007;37:517-23

[136] Yuan JM,Arakawa K.Synergism of alcohol, diabetes, and viral hepatitis on the risk of hepatocellular carcinoma in blacks and whites in the U.S. Cancer2004;101:1009-17

[137] Lin CW,Mo LR,Perng DS,Lo GH,Yen YC,Yu ML,Lin JT.Heavy alcohol consumption increases the incidence of hepatocellular carcinoma in hepatitis B virus-related cirrhosis.J Hepatol2013;58:730-5

[138] Chung NS,Park CH,Cho GH,Kim GH,Ko KI,Kwon KA,Choi DJ.A comparative cross-sectional study of the development of hepatocellular carcinoma in patients with liver cirrhosis caused by hepatitis B virus, alcohol, or combination of hepatitis b virus and alcohol.Korean J Gastroenterol2007;49:369-75

[139] Kwon OS,Bae KS,Kim SG,Lee JI,Kim YS.Anti-hepatitis B core positivity as a risk factor for hepatocellular carcinoma in alcoholic cirrhosis: a case-control study.Alcohol2012;46:537-41

[140] Uetake S,Itoh S,Takeda K.Analysis of risk factors for hepatocellular carcinoma in patients with HBs antigen- and anti-HCV antibody-negative alcoholic cirrhosis: clinical significance of prior hepatitis B virus infection.Alcohol Clin Exp Res2003;27(8 Suppl):47S-51S

[141] Aizawa Y,Takagi I,Toda G.Analysis of factors affecting the appearance of hepatocellular carcinoma in patients with chronic hepatitis C.A long term follow-up study after histologic diagnosis. Cancer2000;89:53-9

[142] Tsutsumi M,Takada A.Relative risk for the development of hepatocellular carcinoma in alcoholic patients with cirrhosis: a multiple logistic-regression coefficient analysis.Alcohol Clin Exp Res1996;20:758-62

[143] Fletcher LM,Purdie DM,Crawford DH.Excess alcohol greatly increases the prevalence of cirrhosis in hereditary hemochromatosis.Gastroenterology2002;122:281-9

[144] Zhao C,Xiao J,Chen S,McClain CJ,Feng W.FGF21 mediates alcohol-induced adipose tissue lipolysis by activation of systemic release of catecholamine in mice.J Lipid Res2015;56:1481-91 PMCID:PMC4513989

[145] Mahli A.Alcohol and obesity: a dangerous association for fatty liver disease.Dig Dis2016;34 Suppl 1:32-9

[146] Kong L,Li W,Mi H,Zhang Y,Nan Y.Activation of peroxisome proliferator activated receptor alpha ameliorates ethanol induced steatohepatitis in mice.Lipids Health Dis2011;10:246 PMCID:PMC3278384

[147] Zhang W,Zhong W,Zhou Z.Hepatic peroxisome proliferator-activated receptor gamma signaling contributes to alcohol-induced hepatic steatosis and inflammation in mice.Alcohol Clin Exp Res2016;40:988-99 PMCID:PMC5742869

[148] Testino G,Borro P.Alcohol and hepatocellular carcinoma: a review and a point of view.World J Gastroenterol2014;20:15943-54 PMCID:PMC4239482

[149] Ramadori P,Liedtke C,Nevzorova YA.Alcohol and hepatocellular carcinoma: adding fuel to the flame.Cancers (Basel)2017;9:pii: E130 PMCID:PMC5664069

[150] Kohgo Y,Ikuta K,Hosoki Y,Kato J.Iron accumulation in alcoholic liver diseases.Alcohol Clin Exp Res2005;29 (11 Suppl):189S-93S

[151] Eid N,Otsuki Y.Ethanol-induced hepatic autophagy: friend or foe?.World J Hepatol2015;7:1154-6 PMCID:PMC4438490

[152] Lambert MP,Vaissière T,Zoulim F,Hainaut P,Scoazec JY,Herceg Z.Aberrant DNA methylation distinguishes hepatocellular carcinoma associated with HBV and HCV infection and alcohol intake.J Hepatol2011;54:705-15

[153] Mandrekar P.Signalling pathways in alcohol-induced liver inflammation.J Hepatol2009;50:1258-66 PMCID:PMC3342816

[154] Uthaya Kumar DB,Liu JC,Sher LS,DiNorcia J,Naini BV,Agopian VG,Machida K.TLR4 signaling via NANOG cooperates with STAT3 to activate Twist1 and promote formation of tumor-initiating stem-like cells in livers of mice.Gastroenterology2016;150:707-19 PMCID:PMC4766021

[155] Chen CL,Punj V,Sher L,Hess S.NANOG metabolically reprograms tumor-initiating stem-like cells through tumorigenic changes in oxidative phosphorylation and fatty acid metabolism.Cell Metab2016;23:206-19 PMCID:PMC4715587

[156] Dapito DH,Gwak GY,Jang MK,Caviglia JM,Adeyemi A,Lefkowitch JH,Friedman R,Rabadan R.Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4.Cancer Cell2012;21:504-16 PMCID:PMC3332000

[157] Pavanello S,Dioni L,Snenghi R,Ferrara SD,Baccarelli A.Shortened telomeres in individuals with abuse in alcohol consumption.Int J Cancer2011;129:983-92 PMCID:PMC3125427

[158] Farazi PA.Hepatocellular carcinoma pathogenesis: from genes to environment.Nat Rev Cancer2006;6:674-87

[159] Wang XD,Chung J,Seitz HK.Chronic alcohol intake reduces retinoic acid concentration and enhances AP-1 (c-Jun and c-Fos) expression in rat liver.Hepatology1998;28:744-50

[160] Napoli JL.Effects of ethanol on physiological retinoic acid levels.IUBMB Life2011;63:701-6

[161] Ishijima N,Shimizu H.Activation of AMP-activated protein kinase by retinoic acid sensitizes hepatocellular carcinoma cells to apoptosis induced by sorafenib.Cancer Sci2015;106:567-75 PMCID:PMC4452157

[162] Ascha MS,Lopez R,Feldstein AF.The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis.Hepatology2010;51:1972-8

[163] Ertle J,Sowa JP,Herzer K,Schlaak JF,Syn WK.Non-alcoholic fatty liver disease progresses to hepatocellular carcinoma in the absence of apparent cirrhosis.Int J Cancer2011;128:2436-43

[164] Paradis V,Chelbi E,Degos F,Bedossa P.Hepatocellular carcinomas in patients with metabolic syndrome often develop without significant liver fibrosis: a pathological analysis.Hepatology2009;49:851-9

[165] Baffy G,Caldwell SH.Hepatocellular carcinoma in non-alcoholic fatty liver disease: an emerging menace.J Hepatol2012;56:1384-91

[166] White DL,El-Serag HB.Association between nonalcoholic fatty liver disease and risk for hepatocellular cancer, based on systematic review.Clin Gastroenterol Hepatol2012;10:1342-59.e2 PMCID:PMC3501546

[167] Mittal S,Sada YH,Duan Z,May SB,Richardson PA.Hepatocellular carcinoma in the absence of cirrhosis in United States veterans is associated with nonalcoholic fatty liver disease.Clin Gastroenterol Hepatol2016;14:124-31.e1 PMCID:PMC4690789

[168] Piscaglia F,Barchetti A,Marinelli S,Bellentani S.Clinical patterns of hepatocellular carcinoma in nonalcoholic fatty liver disease: a multicenter prospective study.Hepatology2016;63:827-38

[169] Said A.Epidemic of non-alcoholic fatty liver disease and hepatocellular carcinoma.World J Clin Oncol2017;8:429-36 PMCID:PMC5740098

[170] Than NN,Hodson J,Coldham C,Manas D,Newsome PN,Shetty S.Comparing clinical presentations, treatments and outcomes of hepatocellular carcinoma due to hepatitis C and non-alcoholic fatty liver disease.QJM2017;110:73-81

[171] Larsson SC.Overweight, obesity and risk of liver cancer: a meta-analysis of cohort studies.Br J Cancer2007;97:1005-8 PMCID:PMC2360408

[172] Raff EJ,Bloomer JR,Rasheed K.Diabetes mellitus predicts occurrence of cirrhosis and hepatocellular cancer in alcoholic liver and non-alcoholic fatty liver diseases.J Clin Transl Hepatol2015;3:9-16 PMCID:PMC4542082

[173] Davila JA,Shaib Y,El-Serag HB.Diabetes increases the risk of hepatocellular carcinoma in the United States: a population based case control study.Gut2005;54:533-9 PMCID:PMC1774454

[174] Polesel J,Montella M,Crispo A,Serraino D,Talamini R.The impact of obesity and diabetes mellitus on the risk of hepatocellular carcinoma.Ann Oncol2009;20:353-7

[175] Starley BQ,Harrison SA.Nonalcoholic fatty liver disease and hepatocellular carcinoma: a weighty connection.Hepatology2010;51:1820-32

[176] Adinolfi LE,Guerrera B,Marrone A,Zampino R.NAFLD and NASH in HCV infection: prevalence and significance in hepatic and extrahepatic manifestations.Int J Mol Sci.2016;17:pii:E803 PMCID:PMC4926337

[177] Weinmann A,Koch S,Düber C,Otto G,Marquardt JU,Wörns MA.Treatment and survival of non-alcoholic steatohepatitis associated hepatocellular carcinoma.BMC Cancer2015;15:210 PMCID:PMC4407550

[178] Giannini EG,Savarino V,di Nolfo MA,Benvegnù L,Zoli M,Caturelli E.Hepatocellular carcinoma in patients with cryptogenic cirrhosis.Clin Gastroenterol Hepatol2009;7:580-5

[179] White DL,El-Serag HB.Association between nonalcoholic fatty liver disease and risk for hepatocellular cancer, based on systematic review.Clin Gastroenterol Hepatol2012;10:1342-1359.e2 PMCID:PMC3501546

[180] Singal AG,Gupta S,Halm EA,Nehra M,Marrero JA.Failure rates in the hepatocellular carcinoma surveillance process.Cancer Prev Res (Phila)2012;5:1124-30 PMCID:PMC3435471

[181] Younes R.Should we undertake surveillance for HCC in patients with NAFLD?.J Hepatol2018;68:326-334

[182] Uppot RN,Hahn PF,Mueller PR.Impact of obesity on medical imaging and image-guided intervention.AJR Am J Roentgenol2007;188:433-40

[183] Singal AG,Yopp AC,Marrero JA,Waljee AK.The effect of PNPLA3 on fibrosis progression and development of hepatocellular carcinoma: a meta-analysis.Am J Gastroenterol2014;109:325-34 PMCID:PMC5610907

[184] Gangarapu V,Ince AT.Role of gut microbiota: obesity and NAFLD.Turk J Gastroenterol2014;25:133-40

[185] Borrelli A,Tuccillo FM,Evans JL,Mancini A.Role of gut microbiota and oxidative stress in the progression of non-alcoholic fatty liver disease to hepatocarcinoma: current and innovative therapeutic approaches.Redox Biol2018;15:467-79 PMCID:PMC5975181

[186] Yang S,Hwang J,Diehl AM.Hepatic hyperplasia in noncirrhotic fatty livers: is obesity-related hepatic steatosis a premalignant condition?.Cancer Res2001;61:5016-23

[187] El-Serag HB,Javadi F.The association between diabetes and hepatocellular carcinoma: a systematic review of epidemiologic evidence.Clin Gastroenterol Hepatol2006;4:369-80

[188] Tilg H.Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis.Hepatology2010;52:1836-46

[189] Takaki A,Yamamoto K.Multiple hits, including oxidative stress, as pathogenesis and treatment target in non-alcoholic steatohepatitis (NASH).Int J Mol Sci2013;14:20704-28 PMCID:PMC3821639

[190] Lonardo A,Maurantonio M,Rinaldi L.Nonalcoholic fatty liver disease: evolving paradigms.World J Gastroenterol2017;23:6571-92 PMCID:PMC5643282

[191] Perumpail RB,Wong RJ,Harrison SA.Pathogenesis of hepatocarcinogenesis in non-cirrhotic nonalcoholic fatty liver disease: Potential mechanistic pathways.World J Hepatol2015;7:2384-8 PMCID:PMC4598608

[192] Stickel F.Non-alcoholic fatty liver disease as a risk factor for hepatocellular carcinoma: mechanisms and implications.Gut2010;59:1303-7

[193] Gu J,Yao D,Yang X.Nonalcoholic lipid accumulation and hepatocyte malignant transformation.J Clin Transl Hepatol2016;4:123-30 PMCID:PMC4913080

[194] Page JM.NASH and HCC.Clin Liver Dis2009;13:631-47

[195] Vinciguerra M,Veyrat-Durebex C,Buhler LH.Unsaturated fatty acids inhibit the expression of tumor suppressor phosphatase and tensin homolog (PTEN) via microRNA-21 up-regulation in hepatocytes.Hepatology2009;49:1176-84

[196] Hu W,Eveleigh J,Pan J,Chung FL.The major lipid peroxidation product, trans-4-hydroxy-2-nonenal, preferentially forms DNA adducts at codon 249 of human p53 gene, a unique mutational hotspot in hepatocellular carcinoma.Carcinogenesis2002;23:1781-9

[197] Angulo P,Petrovic LM,Lindor KD.Leptin, insulin resistance, and liver fibrosis in human nonalcoholic fatty liver disease.J Hepatol2004;41:943-9

[198] Fenton JI,Perkins SN.Interleukin-6 production induced by leptin treatment promotes cell proliferation in an Apc (Min/+) colon epithelial cell line.Carcinogenesis2006;27:1507-15

[199] Saxena NK,Ding X,Marra F,Anania FA.Concomitant activation of the JAK/STAT, PI3K/AKT, and ERK signaling is involved in leptin-mediated promotion of invasion and migration of hepatocellular carcinoma cells.Cancer Res2007;67:2497-507 PMCID:PMC2925446

[200] Watanabe N,Imai K,Naiki T,Moriwaki H.Increased levels of serum leptin are a risk factor for the recurrence of stage I/II hepatocellular carcinoma after curative treatment.J Clin Biochem Nutr2011;49:153-8 PMCID:PMC3208009

[201] Jiang CM,Hou YH,Alanazy M.Non alcoholic steatohepatitis a precursor for hepatocellulae carcinoma developmant.World J Gastroenterol2014;20:16464-73 PMCID:PMC4248189

[202] Dalamaga M,Mantzoros CS.The role of adiponectin in cancer: a review of current evidence.Endocr Rev2012;33:547-94 PMCID:PMC3410224

[203] Yang L,Fu S,Hotamisligil GS.Defective hepatic autophagy in obesity promotes ER stress and causes insulin resistance.Cell Metab2010;11:467-78 PMCID:PMC2881480

[204] Wolf MJ,Piotrowitz K,Boege Y,Ringelhan M,Egger M,Lorentzen A,Schultz S,Protzer U,Zischka H,Tschöp M,Haller D,Karin M,Knolle P,Heikenwalder M.Metabolic activation of intrahepatic CD8+ T cells and NKT cells causes nonalcoholic steatohepatatis and liver cancer via cross-talk with hepatocytes.Cancer Cell2014;26:549-64