Factors predicting hepatocellular carcinoma in hepatitis C infection

Abstract

Hepatitis C virus (HCV) has emerged as a leading cause of hepatocellular carcinoma (HCC). In most cases, the virus causes HCC in the presence of chronic hepatic inflammation, advanced fibrosis, and cirrhosis. A combination of viral, environmental, and genetic factors are likely to determine the host immune response to the infection as well as the progression to HCC. Clinical and epidemiologic studies have identified many of the risk factors associated with HCC development in patients with chronic hepatitis C. Male sex and older age are considered as independent risk factors for HCC, while alcohol consumption accelerates fibrosis, increasing the risk for progression to HCC. Obesity, diabetes mellitus, nonalcoholic fatty liver disease, aflatoxin exposure and occult hepatitis B infection, all contribute to a higher HCC risk. HCV patients infected with HCV genotype 3 are also more likely to develop HCC and genetic variations such as single nucleotide polymorphisms, which may also alter the risk. Sustained virological response to the antiviral therapy results in significantly more favorable long-term outcomes. The incidence of HCC after HCV eradication is similar between patients treated with peginterferon plus ribavirin and direct-acting antiviral therapy.

Keywords

Hepatitis C / hepatocellular carcinoma / risk factors / alcohol / cirrhosis / diabetes / nonalcoholic fatty liver disease / directly acting antiviral agents

References

[1] El-Serag HB.Hepatocellular carcinoma: epidemiology and molecular carcinogenesis.Gastroenterology2007;132:2557-76

[2] Mittal S.Epidemiology of hepatocellular carcinoma: consider the population.J Clin Gastroenterol2013;47 Suppl:S2-6 PMCID:PMC3683119

[3] Kim MN,Han KH.Hepatocellular carcinoma in patients with chronic hepatitis C virus infection in the Asia-Pacific region.J Gastroenterol2013;48:681-8 PMCID:PMC3698419

[4] Budhu A.The role of cytokines in hepatocellular carcinoma.J Leukoc Biol2006;80:1197-213

[5] Maki A,Gupta M,Suzuki T,Fujii H.Predictive power of biomarkers of oxidative stress and inflammation in patients with hepatitis C virus-associated hepatocellular carcinoma.Ann Surg Oncol2007;14:1182-90

[6] 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

[7] Mitchell JK,McGivern DR.How do persistent infections with hepatitis C virus cause liver cancer?.Curr Opin Virol2015;14:101-8 PMCID:PMC4628866

[8] Nagaoki Y,Aikata H,Teraoka Y,Nakamura Y,Morio R,Kan H,Kobayashi T,Ono A,Kawaoka T,Hiramatsu A,Hayes CN,Ochi H.The risks of hepatocellular carcinoma development after HCV eradication are similar between patients treated with peg-interferon plus ribavirin and direct-acting antiviral therapy.PLoS One2017;12:e0182710 PMCID:PMC5552231

[9] Matsuura K,Ikeo K,Iio E,Shimada N,Toyoda H,Namisaki T,Sakamoto N,Asahina Y,Izumi N,Kusakabe A,Itoh Y,Tamori A,Kawada N,Tomita E,Kaneko S,Suetsugu A,Watanabe H,Sakaida I,Takaguchi K,Sugihara J,Kondo Y,Kojima K,Tokunaga K.Genome-wide association study identifies TLL1 variant associated with development of hepatocellular carcinoma after eradication of hepatitis C virus infection.Gastroenterology2017;152:1383-94

[10] Chang KC,Hung CH,Lee CM,Tsai MC,Huang CM,Chen HH.Clinical-guide risk prediction of hepatocellular carcinoma development in chronic hepatitis C patients after interferon-based therapy.Br J Cancer2013;109:2481-8 PMCID:PMC3817320

[11] McMahon BJ,Townshend-Bulson L,Spradling P,Gove J,Plotnik J,Espera H,Snowball M,Bruce M.Infection with hepatitis C virus genotype 3 is an independent risk factor for end-stage liver disease, hepatocellular carcinoma, and liver-related death.Clin Gastroenterol Hepatol2017;15:431-7 PMCID:PMC5316337

[12] Huang CF,Huang CI,Tsai PC,Chan SY,Yang HI,Lu SN,Jen CL,L'Italien G,Lee MH,Chuang WL.Risk of hepatitis C virus related hepatocellular carcinoma between subjects with spontaneous and treatment-induced viral clearance.Oncotarget2017;8:43925-33

[13] Lee SH,Shin JY.Assessment of hepatocellular carcinoma risk based on peg-interferon plus ribavirin treatment experience in this new era of highly effective oral antiviral drugs.Medicine (Baltimore).2017;96:e5321 PMCID:PMC5228644

[14] Parikh ND,Rao H,Li Y,Wu E,Xing B,Lok ASF.Risk assessment of hepatocellular carcinoma in patients with hepatitis C in China and the USA.Dig Dis Sci2017;62:3243-53

[15] Rao H,Fu S,Feng B,Fei R,Lok AS.The higher prevalence of truncal obesity and diabetes in American than Chinese patients with chronic hepatitis C might contribute to more rapid progression to advanced liver disease.Aliment Pharmacol Ther2017;46:731-40

[16] Zavaglia C,Mangia A,Piazzolla V,Stigliano R,Mazzarelli C.Prognostic factors of hepatic decompensation and hepatocellular carcinoma in patients with transfusion-acquired HCV infection.Liver Int2014;34:e308-16

[17] Amr S,Nasr GR,Blancato J,Loffredo CA.Multiple pregnancies, hepatitis C, and risk for hepatocellular carcinoma in Egyptian women.BMC Cancer2014;14:893 PMCID:PMC4258798

[18] Coelho-Little ME,Bernstein DE,Reddy KR,Li X,La Rue S.Hepatitis C virus in alcoholic patients with and without clinically apparent liver disease.Alcohol Clin Exp Res1995;19:1173-6

[19] Poynard T,Opolon P.Natural history of liver fibrosis progression in patients with chronic hepatitis C.The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups. Lancet1997;349:825-32

[20] Hutchinson SJ,Goldberg DJ.Influence of alcohol on the progression of hepatitis C virus infection: a meta-analysis.Clin Gastroenterol Hepatol2005;3:1150-9

[21] Benvegnù L,Noventa F,Chemello L,Alberti A.Concurrent hepatitis B and C virus infection and risk of hepatocellular carcinoma in cirrhosis.A prospective study. Cancer1994;74:2442-8

[22] Ikeda K,Koida I,Tsubota A,Kumada H.A multivariate analysis of risk factors for hepatocellular carcinogenesis: a prospective observation of 795 patients with viral and alcoholic cirrhosis.Hepatology1993;18:47-53

[23] Monto A,Bostrom A,Pockros P,Wright TL.Risks of a range of alcohol intake on hepatitis C-related fibrosis.Hepatology2004;39:826-34

[24] Tagger A,Ribero ML,Portera G,Albertini A,Boffetta P.Case-control study on hepatitis C virus (HCV) as a risk factor for hepatocellular carcinoma: the role of HCV genotypes and the synergism with hepatitis B virus and alcohol.Brescia HCC Study. Int J Cancer1999;81:695-9

[25] McCartney EM,Helbig KJ,Jones B,Beard MR.Alcohol metabolism increases the replication of hepatitis C virus and attenuates the antiviral action of interferon.J Infect Dis2008;198:1766-75

[26] Aloman C,Wintermeyer P,Wands JR.Chronic ethanol consumption impairs cellular immune responses against HCV NS5 protein due to dendritic cell dysfunction.Gastroenterology2007;132:698-708

[27] Otani K,Beard MR,Qian T,Singh AK,Weinman SA.Hepatitis C virus core protein, cytochrome P450 2E1, and alcohol produce combined mitochondrial injury and cytotoxicity in hepatoma cells.Gastroenterology2005;128:96-107

[28] Dyal HK,Bartos G,Bhuket T,Cheung R.Diabetes mellitus increases risk of hepatocellular carcinoma in chronic hepatitis c virus patients: a systematic review.Dig Dis Sci2016;61:636-45

[29] Schlesinger S,Pischon T,Fedirko V,Overvad K,Tjønneland A,Fagherazzi G,Kaaks R,Boeing H,Pantzalis M,Mattiello A,Sacerdote C,Tumino R,Bueno-de-Mesquita HB,Quirós JR,Sánchez MJ,Ardanaz E,Nilsson P,Sund M,Khaw KT,Travis RC,Nöthlings U.Diabetes mellitus, insulin treatment, diabetes duration, and risk of biliary tract cancer and hepatocellular carcinoma in a European cohort.Ann Oncol2013;24:2449-55 PMCID:PMC3755330

[30] Khattab MA,Mousa YI,Fathy S,Abd-Aalhalim H,Sharawe MA.Association between metabolic abnormalities and hepatitis C-related hepatocellular carcinoma.Ann Hepatol2012;11:487-94

[31] Li X,Gao Y,Wang L.Diabetes mellitus increases the risk of hepatocellular carcinoma in treatment-naïve chronic hepatitis C patients in China.Medicine (Baltimore).2017;96:e6508 PMCID:PMC5380289

[32] Toyoda H,Tada T,Tanikawa M,Kanamori A,Ito T.Risk factors of hepatocellular carcinoma development in non-cirrhotic patients with sustained virologic response for chronic hepatitis C virus infection.J Gastroenterol Hepatol2015;30:1183-9

[33] Kitab B,Alaoui R,Badre W,Chemin I.Occult HBV infection in Morocco: from chronic hepatitis to hepatocellular carcinoma.Liver Int2014;34:e144-50

[34] K-Kutala B,Guedj J,Martinot-Peignoux M,Marcellin P.Patients with chronic hepatitis C without advanced fibrosis and hepatocellular carcinoma: a retrospective clinical-pathological study.Dig Liver Dis2015;47:296-302

[35] Huang YT,Liu J,Freeman JR.Mediation analysis of hepatitis B and C in relation to hepatocellular carcinoma risk.Epidemiology2016;27:14-20

[36] Goh GB,Tan CK.Changing epidemiology of hepatocellular carcinoma in Asia.Best Pract Res Clin Gastroenterol2015;29:919-28

[37] Kar P.Risk factors for hepatocellular carcinoma in India.J Clin Exp Hepatol2014;4:S34-42 PMCID:PMC4284237

[38] Palliyaguru DL.Global geographical overlap of aflatoxin and hepatitis C: controlling risk factors for liver cancer worldwide.Food Addit Contam Part A Chem Anal Control Expo Risk Assess2013;30:534-40 PMCID:PMC3581731

[39] Huang CM,Chang KC,Lu SN,Wang JH,Tsai MC,Yen YH,Cho CL.Dynamic noninvasive markers predict hepatocellular carcinoma in chronic hepatitis C patients without sustained virological response after interferon-based therapy: prioritize who needs urgent direct-acting antiviral agents.Medicine (Baltimore).2017;96:e8696 PMCID:PMC5704851

[40] Li DK,Fierer DS,Shaikh OS,Simon T,Chung RT.The short-term incidence of hepatocellular carcinoma is not increased after hepatitis C treatment with direct-acting antivirals: an ERCHIVES study.Hepatology2018;67:2244-53

[41] Innes H,Hayes PC,Dillon JF,Bathgate A,Goldberg D,Fox R(8),Bramley P.The risk of hepatocellular carcinoma in cirrhotic patients with hepatitis C and sustained viral response: role of the treatment regimen.J Hepatol2017;

[42] Chang KC,Wu CK,Tsai MC,Hu TH.Risk factors for development of hepatocellular carcinoma in patients with chronic hepatitis C without sustained response to combination therapy.J Formos Med Assos2017;

[43] Kanwal F,Ilyas J,El-Serag HB.HCV genotype 3 is associated with an increased risk of cirrhosis and hepatocellular cancer in a national sample of U.S. Veterans with HCV..Hepatology2014;60:98-105 PMCID:PMC4689301

[44] Hedenstierna M,Weiland O.Diabetes and cirrhosis are risk factors for hepatocellular carcinoma after successful treatment of chronic hepatitis C.Clin Infect Dis2016;63:723-9

[45] Noh R,Kwon BW,Kim SB.Clinical impact of viral load on the development of hepatocellular carcinoma and liver-related mortality in patients with hepatitis C virus infection.Gastroenterol Res Pract2016;

[46] Baumert TF,Ono A.Hepatitis C-related hepatocellular carcinoma in the era of new generation antivirals.BMC Med2017;15:52 PMCID:PMC5348895

[47] El-Serag HB,Richardson P.Risk of hepatocellular carcinoma after sustained virological response in Veterans with hepatitis C virus infection.Hepatology2016;64:130-7 PMCID:PMC4917456

[48] Janjua NZ,Kuo M,Wong J,Sherman M,Samji H,Yu A,Tyndall M.Long-term effect of sustained virological response on hepatocellular carcinoma in patients with hepatitis C in Canada.J Hepatol2017;66:504-13

[49] Mattos AA,Araújo FS,Tovo CV.Hepatocellular carcinoma in a non-cirrhotic patient with sustained virological response after hepatitis C treatment.Rev Inst Med Trop Sao Paulo2015;57:519-22 PMCID:PMC4727140

[50] El-Shamy A,Shoji I,Okuno T.Polymorphisms of the core, NS3, and NS5A proteins of hepatitis C virus genotype 1b associate with development of hepatocellular carcinoma.Hepatology2013;58:555-63

[51] Balasus D,Fusilli C,Morgan MY,Giannitrapani L,Agliastro R,Montalto G.The association of variants in PNPLA3 and GRP78 and the risk of developing hepatocellular carcinoma in an Italian population.Oncotarget2016;7:86791-802 PMCID:PMC5349954

[52] Fakhry AB,AbdelAlim MA.RECK gene promoter rs10814325 polymorphism in Egyptian patients with hepatocellular carcinoma on top of chronic hepatitis C viral infection.Asian Pac J Cancer Prev2016;17:2383-8

[53] ELBassuoni MA,Zaghla H.IL17A gene polymorphism, serum IL17 and total IgE in Egyptian population with chronic HCV and hepatocellular carcinoma.Immunol Lett2015;168:240-5

[54] Labib HA,Shalaby SM,Hamed EF.Genetic polymorphism of IL-23R influences susceptibility to HCV-related hepatocellular carcinoma.Cell Immunol2015;294:21-4

[55] Radwan MI,Mohamed RH,El-Khshab MN.Influence of transforming growth factor-β1 and tumor necrosis factor-α genes polymorphisms on the development of cirrhosis and hepatocellular carcinoma in chronic hepatitis C patients.Cytokine2012;60:271-6

[56] Hsu CS,Kao JH,Chao YC,Tsai PS.Interferon-based therapy decreases risks of hepatocellular carcinoma and complications of cirrhosis in chronic hepatitis C patients.PLoS One2013;8:e70458 PMCID:PMC3720923

[57] Moon C,Kim DY,Park JY,Kim SU,Han KH.Lower incidence of hepatocellular carcinoma and cirrhosis in hepatitis C patients with sustained virological response by pegylated interferon and ribavirin.Dig Dis Sci2015;60:573-81

[58] Morgan RL,Smith BD,Pitasi M.Eradication of hepatitis C virus infection and the development of hepatocellular carcinoma: a meta-analysis of observational studies.Ann Intern Med2013;158:329-37

[59] Harada N,Oze T,Yamada R,Miyazaki M,Miyagi T,Tatsumi T,Kasahara A,Mita E,Inui Y,Tamura S,Imai Y,Hayashi N.Risk factors for hepatocellular carcinoma in hepatitis C patients with normal alanine aminotransferase treated with pegylated interferon and ribavirin.J Viral Hepat2014;21:357-65

[60] Kanogawa N,Chiba T,Motoyama T,Ooka Y,Kanda T,Azemoto R,Shinozaki M,Miyazaki M.Sustained virologic response achieved after curative treatment of hepatitis C virus-related hepatocellular carcinoma as an independent prognostic factor.J Gastroenterol Hepatol2015;30:1197-204

[61] 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

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