Review of hepatocellular carcinoma: Epidemiology, etiology, and carcinogenesis

Yezaz Ahmed Ghouri, Idrees Mian, Julie H Rowe, Yezaz Ahmed Ghouri, Idrees Mian, Julie H Rowe

Abstract

Since the 1970s, the epidemic of hepatocellular carcinoma (HCC) has spread beyond the Eastern Asian predominance and has been increasing in Northern hemisphere, especially in the United States (US) and Western Europe. It occurs more commonly in males in the fourth and fifth decades of life. Among all cancers, HCC is one of the fastest growing causes of death in the US and poses a significant economic burden on healthcare. Chronic liver disease due to hepatitis B virus or hepatitis C virus and alcohol accounts for the majority of HCC cases. Incidence of nonalcoholic fatty liver disease has been on the risem and it has also been associated with the development of HCC. Its pathogenesis varies based on the underlying etiological factor although majority of cases develop in the setting of background cirrhosis. Carcinogenesis of HCC includes angiogenesis, chronic inflammation, and tumor macroenvironment and microenvironment. There is a significant role of both intrinsic genetic risk factors and extrinsic influences such as alcohol or viral infections that lead to the development of HCC. Understanding its etiopathogenesis helps select appropriate diagnostic tests and treatments.

Keywords: Carcinogenesis; epidemiology; etiology; hepatocellular carcinoma; pathogenesis.

Conflict of interest statement

There are no conflicts of interest.

References

    1. Stuver S, Trichopoulos D. Cancer of the liver and biliary tract. In: Adami HO, Hunter D, Trichopoulos D, editors. Textbook of Cancer Epidemiology. 2nd ed. New York: Oxford University Press; 2008.
    1. Stewart BW, Wild CP, editors. World Cancer Report 2014. Lyon, France: International Agency for Research on Cancer; 2014.
    1. World Health Organization, I.A.f.R.o.C. Estimated Cancer Incidence, Mortality and Prevalence Worldwide in 2012. Available from: .
    1. SEER Cancer Statistics Factsheets: Liver and Intrahepatic Bile Duct Cancer. National Cancer Institute. 2014. [Last accessed on 2017 Apr]. Available from: .
    1. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55:74–108.
    1. Kumar V, Abbas AK, Fausto N, Robbins SL, Cotran RS. Robbins and Cotran Pathologic Basis of Disease. 7th ed. Philadelphia: Elsevier Saunders; 2004.
    1. Mittal S, El-Serag HB. Epidemiology of hepatocellular carcinoma: Consider the population. J Clin Gastroenterol. 2013;47(Suppl):S2.
    1. El-Serag HB, Mason AC. Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med. 1999;340:745–50.
    1. Altekruse SF, McGlynn KA, Reichman ME. Hepatocellular carcinoma incidence, mortality, and survival trends in the United States from 1975 to 2005. J Clin Oncol. 2009;27:1485–91.
    1. Njei B, Rotman Y, Ditah I, Lim JK. Emerging trends in hepatocellular carcinoma incidence and mortality. Hepatology. 2015;61:191–9.
    1. Lang K, Danchenko N, Gondek K, Shah S, Thompson D. The burden of illness associated with hepatocellular carcinoma in the United States. J Hepatol. 2009;50:89–99.
    1. Shebl FM, Capo-Ramos DE, Graubard BI, McGlynn KA, Altekruse SF. Socioeconomic status and hepatocellular carcinoma in the United States. Cancer Epidemiol Biomarkers Prev. 2012;21:1330–5.
    1. El-Serag HB. Hepatocellular carcinoma. N Engl J Med. 2011;365:1118–27.
    1. Zhang DY, Friedman SL. Fibrosis-dependent mechanisms of hepatocarcinogenesis. Hepatology. 2012;56:769–75.
    1. Donato F, Tagger A, Gelatti U, Parrinello G, Boffetta P, Albertini A, et al. Alcohol and hepatocellular carcinoma: The effect of lifetime intake and hepatitis virus infections in men and women. Am J Epidemiol. 2002;155:323–31.
    1. Fattovich G, Stroffolini T, Zagni I, Donato F. Hepatocellular carcinoma in cirrhosis: Incidence and risk factors. Gastroenterology. 2004;127(5 Suppl 1):S35–50.
    1. Parkin DM. The global health burden of infection-associated cancers in the year 2002. Int J Cancer. 2006;118:3030–44.
    1. Beasley RP, Hwang LY, Lin CC, Chien CS. Hepatocellular carcinoma and hepatitis B virus. A prospective study of 22 707 men in Taiwan. Lancet. 1981;2:1129–33.
    1. Lavanchy D. Hepatitis B virus epidemiology, disease burden, treatment, and current and emerging prevention and control measures. J Viral Hepat. 2004;11:97–107.
    1. Huang YT, Jen CL, Yang HI, Lee MH, Su J, Lu SN, et al. Lifetime risk and sex difference of hepatocellular carcinoma among patients with chronic hepatitis B and C. J Clin Oncol. 2011;29:3643–50.
    1. Bosch FX, Ribes J, Díaz M, Cléries R. Primary liver cancer: Worldwide incidence and trends. Gastroenterology. 2004;127(5 Suppl 1):S5–16.
    1. El-Serag HB. Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology. 2012;142:1264–73.e1.
    1. Dorfman JD, Schulick R, Choti MA, Geschwind JF, Kamel I, Torbenson M, et al. Differences in characteristics of patients with and without known risk factors for hepatocellular carcinoma in the United States. World J Gastroenterol. 2007;13:781–4.
    1. Konopnicki D, Mocroft A, de Wit S, Antunes F, Ledergerber B, Katlama C, et al. Hepatitis B and HIV: Prevalence, AIDS progression, response to highly active antiretroviral therapy and increased mortality in the EuroSIDA cohort. AIDS. 2005;19:593–601.
    1. Yotsuyanagi H, Shintani Y, Moriya K, Fujie H, Tsutsumi T, Kato T, et al. Virologic analysis of non-B, non-C hepatocellular carcinoma in Japan: Frequent involvement of hepatitis B virus. J Infect Dis. 2000;181:1920–8.
    1. Chen CH, Changchien CS, Lee CM, Tung WC, Hung CH, Hu TH, et al. A study on sequence variations in pre-S/surface, X and enhancer II/core promoter/precore regions of occult hepatitis B virus in non-B, non-C hepatocellular carcinoma patients in Taiwan. Int J Cancer. 2009;125:621–9.
    1. Tatematsu K, Tanaka Y, Kurbanov F, Sugauchi F, Mano S, Maeshiro T, et al. A genetic variant of hepatitis B virus divergent from known human and ape genotypes isolated from a Japanese patient and provisionally assigned to new genotype J. J Virol. 2009;83:10538–47.
    1. Chu CJ, Keeffe EB, Han SH, Perrillo RP, Min AD, Soldevila-Pico C, et al. Hepatitis B virus genotypes in the United States: Results of a nationwide study. Gastroenterology. 2003;125:444–51.
    1. Erhardt A, Blondin D, Hauck K, Sagir A, Kohnle T, Heintges T, et al. Response to interferon alfa is hepatitis B virus genotype dependent: Genotype A is more sensitive to interferon than genotype D. Gut. 2005;54:1009–13.
    1. Sonneveld MJ, Rijckborst V, Cakaloglu Y, Simon K, Heathcote EJ, Tabak F, et al. Durable hepatitis B surface antigen decline in hepatitis B e antigen-positive chronic hepatitis B patients treated with pegylated interferon-a2b: Relation to response and HBV genotype. Antivir Ther. 2012;17:9–17.
    1. Chan HL, Tse CH, Mo F, Koh J, Wong VW, Wong GL, et al. High viral load and hepatitis B virus subgenotype ce are associated with increased risk of hepatocellular carcinoma. J Clin Oncol. 2008;26:177–82.
    1. Tanaka H, Tsukuma H, Yamano H, Oshima A, Shibata H. Prospective study on the risk of hepatocellular carcinoma among hepatitis C virus-positive blood donors focusing on demographic factors, alanine aminotransferase level at donation and interaction with hepatitis B virus. Int J Cancer. 2004;112:1075–80.
    1. Yoshizawa H. Hepatocellular carcinoma associated with hepatitis C virus infection in Japan: Projection to other countries in the foreseeable future. Oncology. 2002;62(Suppl 1):8–17.
    1. El-Serag HB, Rudolph KL. Hepatocellular carcinoma: Epidemiology and molecular carcinogenesis. Gastroenterology. 2007;132:2557–76.
    1. Bowen DG, Walker CM. Adaptive immune responses in acute and chronic hepatitis C virus infection. Nature. 2005;436:946–52.
    1. Wedemeyer H, Duberg AS, Buti M, Rosenberg WM, Frankova S, Esmat G, et al. Strategies to manage hepatitis C virus (HCV) disease burden. J Viral Hepat. 2014;21(Suppl 1):60–89.
    1. Soriano V, Vispo E, Labarga P, Medrano J, Barreiro P. Viral hepatitis and HIV co-infection. Antiviral Res. 2010;85:303–15.
    1. Clifford GM, Rickenbach M, Polesel J, Dal Maso L, Steffen I, Ledergerber B, et al. Influence of HIV-related immunodeficiency on the risk of hepatocellular carcinoma. AIDS. 2008;22:2135–41.
    1. Kruse RL, Kramer JR, Tyson GL, Duan Z, Chen L, El-Serag HB, et al. Clinical outcomes of hepatitis B virus coinfection in a United States cohort of hepatitis C virus-infected patients. Hepatology. 2014;60:1871–8.
    1. Bosch FX, Ribes J, Borràs J. Epidemiology of primary liver cancer. Semin Liver Dis. 1999;19:271–85.
    1. Hutchinson SJ, Bird SM, Goldberg DJ. Influence of alcohol on the progression of hepatitis C virus infection: A meta-analysis. Clin Gastroenterol Hepatol. 2005;3:1150–9.
    1. Farazi PA, DePinho RA. Hepatocellular carcinoma pathogenesis: From genes to environment. Nat Rev Cancer. 2006;6:674–87.
    1. Yatsuji S, Hashimoto E, Tobari M, Taniai M, Tokushige K, Shiratori K. Clinical features and outcomes of cirrhosis due to non-alcoholic steatohepatitis compared with cirrhosis caused by chronic hepatitis C. J Gastroenterol Hepatol. 2009;24:248–54.
    1. Bhala N, Angulo P, van der Poorten D, Lee E, Hui JM, Saracco G, et al. The natural history of nonalcoholic fatty liver disease with advanced fibrosis or cirrhosis: An international collaborative study. Hepatology. 2011;54:1208–16.
    1. Dam-Larsen S, Becker U, Franzmann MB, Larsen K, Christoffersen P, Bendtsen F. Final results of a long-term, clinical follow-up in fatty liver patients. Scand J Gastroenterol. 2009;44:1236–43.
    1. Jhunjhunwala S, Jiang Z, Stawiski EW, Gnad F, Liu J, Mayba O, et al. Diverse modes of genomic alteration in hepatocellular carcinoma. Genome Biol. 2014;15:436.
    1. Thorgeirsson SS, Grisham JW. Molecular pathogenesis of human hepatocellular carcinoma. Nat Genet. 2002;31:339–46.
    1. Ascha MS, Hanouneh IA, Lopez R, Tamimi TA, Feldstein AF, Zein NN. The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. Hepatology. 2010;51:1972–8.
    1. Fargion S, Mandelli C, Piperno A, Cesana B, Fracanzani AL, Fraquelli M, et al. Survival and prognostic factors in 212 Italian patients with genetic hemochromatosis. Hepatology. 1992;15:655–9.
    1. Caballería L, Parés A, Castells A, Ginés A, Bru C, Rodés J. Hepatocellular carcinoma in primary biliary cirrhosis: Similar incidence to that in hepatitis C virus-related cirrhosis. Am J Gastroenterol. 2001;96:1160–3.
    1. Yan H, Peng B, He W, Zhong G, Qi Y, Ren B, et al. Molecular determinants of hepatitis B and D virus entry restriction in mouse sodium taurocholate cotransporting polypeptide. J Virol. 2013;87:7977–91.
    1. Rabe B, Delaleau M, Bischof A, Foss M, Sominskaya I, Pumpens P, et al. Nuclear entry of hepatitis B virus capsids involves disintegration to protein dimers followed by nuclear reassociation to capsids. PLoS Pathog. 2009;5:e1000563.
    1. Bock CT, Schwinn S, Locarnini S, Fyfe J, Manns MP, Trautwein C, et al. Structural organization of the hepatitis B virus minichromosome. J Mol Biol. 2001;307:183–96.
    1. Tang H, Delgermaa L, Huang F, Oishi N, Liu L, He F, et al. The transcriptional transactivation function of HBx protein is important for its augmentation role in hepatitis B virus replication. J Virol. 2005;79:5548–56.
    1. Lewin S, Walters T, Locarnini S. Hepatitis B treatment: Rational combination chemotherapy based on viral kinetic and animal model studies. Antiviral Res. 2002;55:381–96.
    1. Imai M, Hoshi Y, Okamoto H, Matsui T, Tsurimoto T, Matsubara K, et al. Free and integrated forms of hepatitis B virus DNA in human hepatocellular carcinoma cells (PLC/342) propagated in nude mice. J Virol. 1987;61:3555–60.
    1. Wang B, Majumder S, Nuovo G, Kutay H, Volinia S, Patel T, et al. Role of microRNA-155 at early stages of hepatocarcinogenesis induced by choline-deficient and amino acid-defined diet in C57BL/6 mice. Hepatology. 2009;50:1152–61.
    1. Toh ST, Jin Y, Liu L, Wang J, Babrzadeh F, Gharizadeh B, et al. Deep sequencing of the hepatitis B virus in hepatocellular carcinoma patients reveals enriched integration events, structural alterations and sequence variations. Carcinogenesis. 2013;34:787–98.
    1. Lin CM, Wang GM, Jow GM, Chen BF. Functional analysis of hepatitis B virus pre-s deletion variants associated with hepatocellular carcinoma. J Biomed Sci. 2012;19:17.
    1. Su IJ, Wang LH, Hsieh WC, Wu HC, Teng CF, Tsai HW, et al. The emerging role of hepatitis B virus pre-S2 deletion mutant proteins in HBV tumorigenesis. J Biomed Sci. 2014;21:98.
    1. Wang WH, Hullinger RL, Andrisani OM. Hepatitis B virus X protein via the p38MAPK pathway induces E2F1 release and ATR kinase activation mediating p53 apoptosis. J Biol Chem. 2008;283:25455–67.
    1. Chung TW, Lee YC, Kim CH. Hepatitis B viral HBx induces matrix metalloproteinase-9 gene expression through activation of ERK and PI-3K/AKT pathways: Involvement of invasive potential. FASEB J. 2004;18:1123–5.
    1. Terradillos O, Billet O, Renard CA, Levy R, Molina T, Briand P, et al. The hepatitis B virus X gene potentiates c-myc-induced liver oncogenesis in transgenic mice. Oncogene. 1997;14:395–404.
    1. Benhenda S, Cougot D, Buendia MA, Neuveut C. Hepatitis B virus X protein molecular functions and its role in virus life cycle and pathogenesis. Adv Cancer Res. 2009;103:75–109.
    1. Liu CJ, Chen BF, Chen PJ, Lai MY, Huang WL, Kao JH, et al. Role of hepatitis B virus precore/core promoter mutations and serum viral load on noncirrhotic hepatocellular carcinoma: A case-control study. J Infect Dis. 2006;194:594–9.
    1. Rehermann B, Nascimbeni M. Immunology of hepatitis B virus and hepatitis C virus infection. Nat Rev Immunol. 2005;5:215–29.
    1. Hino O, Kajino K, Umeda T, Arakawa Y. Understanding the hypercarcinogenic state in chronic hepatitis: A clue to the prevention of human hepatocellular carcinoma. J Gastroenterol. 2002;37:883–7.
    1. Majumder M, Ghosh AK, Steele R, Ray R, Ray RB. Hepatitis C virus NS5A physically associates with p53 and regulates p21/waf1 gene expression in a p53-dependent manner. J Virol. 2001;75:1401–7.
    1. Seitz HK, Stickel F. Molecular mechanisms of alcohol-mediated carcinogenesis. Nat Rev Cancer. 2007;7:599–612.
    1. Abnet CC. Carcinogenic food contaminants. Cancer Invest. 2007;25:189–96.
    1. Väkeväinen S, Tillonen J, Agarwal DP, Srivastava N, Salaspuro M. High salivary acetaldehyde after a moderate dose of alcohol in ALDH2-deficient subjects: Strong evidence for the local carcinogenic action of acetaldehyde. Alcohol Clin Exp Res. 2000;24:873–7.
    1. Teufel A, Marquardt JU, Galle PR. Next generation sequencing of HCC from European and Asian HCC cohorts. Back to p53 and Wnt/ß-catenin. J Hepatol. 2013;58:622–4.
    1. Guichard C, Amaddeo G, Imbeaud S, Ladeiro Y, Pelletier L, Maad IB, et al. Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma. Nat Genet. 2012;44:694–8.
    1. Fujimoto A, Totoki Y, Abe T, Boroevich KA, Hosoda F, Nguyen HH, et al. Whole-genome sequencing of liver cancers identifies etiological influences on mutation patterns and recurrent mutations in chromatin regulators. Nat Genet. 2012;44:760–4.
    1. Li S, Mao M. Next generation sequencing reveals genetic landscape of hepatocellular carcinomas. Cancer Lett. 2013;340:247–53.
    1. Nakagawa H, Shibata T. Comprehensive genome sequencing of the liver cancer genome. Cancer Lett. 2013;340:234–40.
    1. Hernandez-Gea V, Toffanin S, Friedman SL, Llovet JM. Role of the microenvironment in the pathogenesis and treatment of hepatocellular carcinoma. Gastroenterology. 2013;144:512–27.
    1. Wu SD, Ma YS, Fang Y, Liu LL, Fu D, Shen XZ. Role of the microenvironment in hepatocellular carcinoma development and progression. Cancer Treat Rev. 2012;38:218–25.
    1. Zhu AX, Duda DG, Sahani DV, Jain RK. HCC and angiogenesis: Possible targets and future directions. Nat Rev Clin Oncol. 2011;8:292–301.

Source: PubMed

3
Abonnieren