Impact of occult hepatitis B virus infection and high-fat diet on hepatocellular carcinoma development

Abstract

In the areas where viral infections are more common, the incidence of hepatocellular carcinoma (HCC) has declined. This is largely attributed to the availability of vaccines against hepatitis B virus (HBV), antiviral treatments, and a change in diet with healthier foods. However, in the Western world, the HCC incidence rate has risen steadily, probably due to an increased prevalence of metabolic dysfunction-associated fatty liver disease (MAFLD), a condition that has increasingly been considered an important risk factor for HCC. Despite this, in 2019, 41% of HCC cases were diagnosed globally and a majority of diagnosed cases from mainland China were related to HBV. Some HCC cases tested negative for hepatitis B surface antigen (HBsAg) but tested positive for HBV-DNA in blood. This is considered an occult HBV infection (OBI). OBI is related to various mutations in the viral genome, which modifies host immunity, subsequently leading to the long-term persistence of cccDNA in the nucleus of infected hepatocytes. Many OBIs are associated with HBV variants carrying mutations in preS/S genomic regions, which occur either spontaneously or as a result of antiviral treatments. OBIs are also frequently reported in HBV-vaccinated individuals. HBV variants post-HBV vaccination carry mutations in the preS area. This review discusses the relationship between preS variant-related OBIs and the development of HCC in the context of a high-fat diet, one of the preventable behavioral risk factors for MAFLD.

Keywords

Occult HBV infection / preS mutations / hepatocellular carcinoma / high-fat diet / hepatitis B vaccination / metabolic dysfunction associated fatty liver disease

References

[1] Singal AG,Llovet JM.Global trends in hepatocellular carcinoma epidemiology: implications for screening, prevention and therapy.Nat Rev Clin Oncol2023;20:864-84

[2] Cao M,Lu L.Long term outcome of prevention of liver cancer by hepatitis B vaccine: results from an RCT with 37 years.Cancer Lett2022;536:215652

[3] Chiang CJ,You SL,Chen CJ.Thirty-year outcomes of the national hepatitis B immunization program in Taiwan.JAMA2013;310:974-6

[4] Qu C,Fan C.Efficacy of neonatal HBV vaccination on liver cancer and other liver diseases over 30-year follow-up of the Qidong hepatitis B intervention study: a cluster randomized controlled trial.PLoS Med2014;11:e1001774 PMCID:PMC4280122

[5] Sun Z,Thorgeirsson SS.Dramatic reduction of liver cancer incidence in young adults: 28 year follow-up of etiological interventions in an endemic area of China.Carcinogenesis2013;34:1800-5 PMCID:PMC3731800

[6] Tseng CH,Wu JL,El-Serag HB.Magnitude of and prediction for risk of hepatocellular carcinoma in patients with chronic hepatitis B taking entecavir or tenofovir therapy: a systematic review.J Gastroenterol Hepatol2020;35:1684-93

[7] Lockart I,Hajarizadeh B,Danta M.HCC incidence after hepatitis C cure among patients with advanced fibrosis or cirrhosis: a meta-analysis.Hepatology2022;76:139-54 PMCID:PMC9303770

[8] Zhang W,Li HL.Vegetable-based dietary pattern and liver cancer risk: results from the Shanghai women’s and men’s health studies.Cancer Sci2013;104:1353-61 PMCID:PMC3879410

[9] Shen QM,Li ZY.Sex-specific impact of dietary patterns on liver cancer incidence: updated results from two population-based cohort studies in China.Eur J Nutr2024;63:1113-24

[10] Zhao S,Jones KC.Modeling the time-variant dietary exposure of PCBs in China over the period 1930 to 2100.Environ Sci Technol2018;52:7371-9

[11] Eslam M, Sanyal AJ, George J; International Consensus Panel. MAFLD: a consensus-driven proposed nomenclature for metabolic associated fatty liver disease.Gastroenterology2020;158:1999-2014.e1

[12] Makarova-Rusher OV,McNeel TS.Population attributable fractions of risk factors for hepatocellular carcinoma in the United States.Cancer2016;122:1757-65 PMCID:PMC5548177

[13] Vitale A, Svegliati-Baroni G, Ortolani A, et al; Italian Liver Cancer (ITA.LI.CA) group. Epidemiological trends and trajectories of MAFLD-associated hepatocellular carcinoma 2002-2033: the ITA.LI.CA database.Gut2023;72:141-52

[14] Crane H,Gofton C.Global prevalence of metabolic dysfunction-associated fatty liver disease-related hepatocellular carcinoma: A systematic review and meta-analysis.Clin Mol Hepatol2024;30:436-48 PMCID:PMC11261220

[15] George J,Kawaguchi T.Furthering research on MAFLD: the APASL Metabolic fAtty lIver DiseasE coNsortium (MAIDEN).Hepatol Int2023;17:546-9 PMCID:PMC10224827

[16] Lin J,Yu H.Epidemiological characteristics of primary liver cancer in mainland China from 2003 to 2020: a representative multicenter study.Front Oncol2022;12:906778 PMCID:PMC9253580

[17] Tang X,Du J.Clinical outcome of non-alcoholic fatty liver disease: an 11-year follow-up study.BMJ Open2022;12:e054891 PMCID:PMC9237861

[18] Seeger C.Molecular biology of hepatitis B virus infection.Virology2015;479-80:672-86 PMCID:PMC4424072

[19] Polaris Observatory Collaborators. Global prevalence, cascade of care, and prophylaxis coverage of hepatitis B in 2022: a modelling study.Lancet Gastroenterol Hepatol2023;8:879-907

[20] Wang J,Liu Y.HBV genome and life cycle.Adv Exp Med Biol2020;1179:17-37

[21] Lamontagne RJ,Bouchard MJ.Hepatitis B virus molecular biology and pathogenesis.Hepatoma Res2016;2:163-86 PMCID:PMC5198785

[22] Yan H,Xu G.Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus.eLife2012;1:e00049 PMCID:PMC3485615

[23] Königer C,Marsmann M,Beck J.Involvement of the host DNA-repair enzyme TDP2 in formation of the covalently closed circular DNA persistence reservoir of hepatitis B viruses.Proc Natl Acad Sci U S A2014;111:E4244-53 PMCID:PMC4209993

[24] Qi Y,Xu G.DNA polymerase κ is a key cellular factor for the formation of covalently closed circular DNA of hepatitis B virus.PLoS Pathog2016;12:e1005893 PMCID:PMC5081172

[25] Huovila AP,Fuller SD.Hepatitis B surface antigen assembles in a post-ER, pre-Golgi compartment.J Cell Biol1992;118:1305-20 PMCID:PMC2289601

[26] Bruss V.The role of envelope proteins in hepatitis B virus assembly.Proc Natl Acad Sci U S A1991;88:1059-63 PMCID:PMC50954

[27] Liu L,Zhang Y,Cao Z.Hepatitis B virus infection combined with nonalcoholic fatty liver disease: interaction and prognosis.Heliyon2023;9:e13113 PMCID:PMC9898750

[28] Joo EJ,Yeom JS.Hepatitis B virus infection and decreased risk of nonalcoholic fatty liver disease: a cohort study.Hepatology2017;65:828-35

[29] Hu D,Wang H.Non-alcoholic hepatic steatosis attenuates hepatitis B virus replication in an HBV-immunocompetent mouse model.Hepatol Int2018;12:438-46

[30] Adams LA,St Sauver J.The natural history of nonalcoholic fatty liver disease: a population-based cohort study.Gastroenterology2005;129:113-21

[31] Yang HI, Lu SN, Liaw YF, et al; Taiwan Community-Based Cancer Screening Project Group. Hepatitis B e antigen and the risk of hepatocellular carcinoma.N Engl J Med2002;347:168-74

[32] Wang MM,Shen F,Pan Q.Hepatic steatosis is highly prevalent in hepatitis B patients and negatively associated with virological factors.Dig Dis Sci2014;59:2571-9

[33] Zheng Q,Wu Y.Systematic review with meta-analysis: prevalence of hepatic steatosis, fibrosis and associated factors in chronic hepatitis B.Aliment Pharmacol Ther2021;54:1100-9

[34] Cheng YM,Wang CC.Impact of HBV infection on clinical outcomes in patients with metabolic dysfunction-associated fatty liver disease.JHEP Rep2023;5:100836 PMCID:PMC10432217

[35] Mak LY,Fung J.Reduced hepatic steatosis is associated with higher risk of hepatocellular carcinoma in chronic hepatitis B infection.Hepatol Int2021;15:901-11

[36] Choe JW,Kim B.Influence of metabolic syndrome on cancer risk in HBV carriers: a nationwide population based study using the national health insurance service database.J Clin Med2021;10:2401 PMCID:PMC8198770

[37] Huang SC,Tseng TC.Distinct effects of hepatic steatosis and metabolic dysfunction on the risk of hepatocellular carcinoma in chronic hepatitis B.Hepatol Int2023;17:1139-49

[38] Yu MW,Liu CJ,Tseng YL.Influence of metabolic risk factors on risk of hepatocellular carcinoma and liver-related death in men with chronic hepatitis B: a large cohort study.Gastroenterology2017;153:1006-17.e5

[39] Pollicino T,Cerenzia G.Hepatitis B virus maintains its pro-oncogenic properties in the case of occult HBV infection.Gastroenterology2004;126:102-10.

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

[41] Pollicino T,Restuccia A.Impact of hepatitis B virus (HBV) preS/S genomic variability on HBV surface antigen and HBV DNA serum levels.Hepatology2012;56:434-43

[42] Raimondo G, Locarnini S, Pollicino T, Levrero M, Zoulim F, Lok AS; Taormina Workshop on Occult HBV Infection Faculty Members. Update of the statements on biology and clinical impact of occult hepatitis B virus infection.J Hepatol2019;71:397-408

[43] Xu L,Chen T.Occult HBV infection in anti-HBs-positive young adults after neonatal HB vaccination.Vaccine2010;28:5986-92

[44] Chaudhuri V,Nayak B,Panda SK.Occult hepatitis B virus infection in chronic liver disease: full-length genome and analysis of mutant surface promoter.Gastroenterology2004;127:1356-71

[45] Candotti D,Belkhiri D.Occult hepatitis B infection in blood donors from South East Asia: molecular characterisation and potential mechanisms of occurrence.Gut2012;61:1744-53

[46] Huang FY,Seto WK.Sequence variations of full-length hepatitis B virus genomes in Chinese patients with HBsAg-negative hepatitis B infection.PLoS One2014;9:e99028 PMCID:PMC4047052

[47] Loomba R.Hepatitis B reactivation associated with immune suppressive and biological modifier therapies: current concepts, management strategies, and future directions.Gastroenterology2017;152:1297-309 PMCID:PMC5501983

[48] Liu Y,Xi J.Over-gap PCR amplification to identify presence of replication-competent HBV DNA from integrated HBV DNA: an updated occult HBV infection definition.J Hepatol2019;70:557-9

[49] Liang X,Hadler S.Origins, design and implementation of the China GAVI project.Vaccine2013;31:J8-14

[50] Wang FZ,Shen LP.[Comparative analyze on hepatitis B seroepidemiological surveys among population aged 1-29 years in different epidemic regions of China in 1992 and 2014].Zhonghua Yu Fang Yi Xue Za Zhi2017;51:462-8

[51] Ni YH,Chang MH.Two decades of universal hepatitis B vaccination in taiwan: impact and implication for future strategies.Gastroenterology2007;132:1287-93

[52] Wang Y,Lu LL.Adolescent booster with hepatitis B virus vaccines decreases HBV infection in high-risk adults.Vaccine2017;35:1064-70

[53] Yang YT,Zhao Y.The prevalence of hepatitis B core antibody in vaccinated Chinese children: a hospital-based study.Vaccine2019;37:458-63

[54] Hsu HY,Ni YH.Chronologic changes in serum hepatitis B virus DNA, genotypes, surface antigen mutants and reverse transcriptase mutants during 25-year nationwide immunization in Taiwan.J Viral Hepat2017;24:645-53

[55] Mu SC,Jow GM.Occult hepatitis B virus infection in hepatitis B vaccinated children in Taiwan.J Hepatol2009;50:264-72

[56] Yan YP,Ji ZH,Pu ZS.Epidemiology of hepatitis B virus infection in china: current status and challenges.J Clin Transl Hepatol2014;2:15-22 PMCID:PMC4521251

[57] Wang R,Chen T.Neonatal hepatitis B vaccination protects mature adults from occult virus infection.Hepatol Int2021;15:328-37

[58] Qu C,Chen K.Reducing liver cancer risk beginning at birth: experiences of preventing chronic hepatitis B virus infection in China.HR2017;3:228-40

[59] Romanò L,Tozzi AE,Zanetti AR.Chronic hepatitis B infection in adolescents vaccinated at birth: an alarm bell in favor of the need for a booster?.Hepatology2014;59:349

[60] Shi Y,Wu W,Yang J.Association between occult hepatitis B infection and the risk of hepatocellular carcinoma: a meta-analysis.Liver Int2012;32:231-40

[61] Wong DK,Lai CL.Occult hepatitis B infection and HBV replicative activity in patients with cryptogenic cause of hepatocellular carcinoma.Hepatology2011;54:829-36

[62] Carman WF,Karayiannis P.Vaccine-induced escape mutant of hepatitis B virus.Lancet1990;336:325-9

[63] Fortuin M,Allison L.Breakthrough infections and identification of a viral variant in Gambian children immunized with hepatitis B vaccine.J Infect Dis1994;169:1374-6

[64] Zhu CL,Chen T.Presence of immune memory and immunity to hepatitis B virus in adults after neonatal hepatitis B vaccination.Vaccine2011;29:7835-41

[65] Liu C,Zhao F.Occult infection with hepatitis B virus PreS variants synergistically promotes hepatocellular carcinoma development in a high-fat diet context by generating abnormal ceramides.BMC Med2022;20:279 PMCID:PMC9442965

[66] Lemmer IL,Hilal N.A guide to understanding endoplasmic reticulum stress in metabolic disorders.Mol Metab2021;47:101169 PMCID:PMC7887651

[67] Turpin-Nolan SM.The role of ceramides in metabolic disorders: when size and localization matters.Nat Rev Endocrinol2020;16:224-33

[68] Vesselinovitch SD.Kinetics of diethylnitrosamine hepatocarcinogenesis in the infant mouse.Cancer Res1983;43:4253-9

[69] Zang M,He H.IL-23 production of liver inflammatory macrophages to damaged hepatocytes promotes hepatocellular carcinoma development after chronic hepatitis B virus infection.Biochim Biophys Acta Mol Basis Dis2018;1864:3759-70

[70] Grivennikov SI,Karin M.Immunity, inflammation, and cancer.Cell2010;140:883-99 PMCID:PMC2866629

[71] Colotta F,Sica A,Mantovani A.Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability.Carcinogenesis2009;30:1073-81

[72] Mridha AR,Robertson AAB.NLRP3 inflammasome blockade reduces liver inflammation and fibrosis in experimental NASH in mice.J Hepatol2017;66:1037-46 PMCID:PMC6536116

[73] Kubes P.Immune responses in the liver.Annu Rev Immunol2018;36:247-77

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

[75] Lauby-Secretan B, Scoccianti C, Loomis D, et al; International Agency for Research on Cancer Handbook Working Group. Body fatness and cancer - viewpoint of the IARC working group.N Engl J Med2016;375:794-8 PMCID:PMC6754861

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

[77] Yasui K, Hashimoto E, Komorizono Y, et al; Japan NASH Study Group, Ministry of Health, Labour, and Welfare of Japan. Characteristics of patients with nonalcoholic steatohepatitis who develop hepatocellular carcinoma.Clin Gastroenterol Hepatol2011;9:428-33

[78] Hagström H,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.Gut2018;67:1536-42

[79] Chan AWH,Chan HY.Concurrent fatty liver increases risk of hepatocellular carcinoma among patients with chronic hepatitis B.J Gastroenterol Hepatol2017;32:667-76

[80] El-Serag HB.Epidemiology of hepatocellular carcinoma in the United States: where are we? Where do we go?.Hepatology2014;60:1767-75 PMCID:PMC4211957

[81] El-Serag HB.Epidemiology of viral hepatitis and hepatocellular carcinoma.Gastroenterology2012;142:1264-73.e1 PMCID:PMC3338949

[82] Wu YL,Zhu YB,Chen WN.Hepatitis B virus x protein induces hepatic steatosis by enhancing the expression of liver fatty acid binding protein.J Virol2016;90:1729-40 PMCID:PMC4733992

[83] Kulik L.Epidemiology and management of hepatocellular carcinoma.Gastroenterology2019;156:477-91.e1 PMCID:PMC6340716

[84] Omata M,Kokudo N.Asia-Pacific clinical practice guidelines on the management of hepatocellular carcinoma: a 2017 update.Hepatol Int2017;11:317-70 PMCID:PMC5491694

[85] Marrero JA,Sirlin CB.Diagnosis, staging, and management of hepatocellular carcinoma: 2018 practice guidance by the American association for the study of liver diseases.Hepatology2018;68:723-50