Review Article| Volume 54, ISSUE 2, P154-163, February 2022

Distinctive features of hepatocellular carcinoma in non-alcoholic fatty liver disease


      Hepatocellular carcinoma (HCC) is on the rise globally, causing more than 800 thousand deaths annually, with an estimated annual percent change of 0.51 for causes other than viral hepatitis, including nonalcoholic fatty liver disease (NAFLD). The incidence of NAFLD-related HCC is peaking in several Far East regions (6–12% vs. 2–3% in Western Europe and USA), HCC risk being mainly driven by the epidemic of obesity and diabetes, both favored by an unhealthy diet and sedentary lifestyle. Under inherited susceptibility outlined by such genetic markers as variants in PNPLA3, TM6SF2 and MBOAT7, neoplastic transformation of NAFLD is driven by sublethal lipotoxicity consequent to hepatocyte lipid overload, whereas a myriad of factors spanning from subverted circadian homeostasis and gut dysbiosis to alcohol abuse and tobacco may interact as risk modifiers. At variance with viral HCC, NAFLD-HCC shows a frequent association with cardiovascular co-morbidities, absence of cirrhosis in up to half of patients and an association with persistently normal transaminase values. All these misleading features of NAFLD-related HCC account for the low uptake of surveillance and linkage to curative treatments that has been reported in patients with this cancer, a downside that could be attenuated when scores for cost-effective risk stratification become available.


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        • Estes C.
        • Anstee Q.M.
        • Arias-Loste M.T.
        • et al.
        Modeling NAFLD disease burden in China, France, Germany, Italy, Japan, Spain, United Kingdom, and United States for the period 2016-2030.
        J Hepatol. 2018; 69: 896-904
        • Dulai P.S.
        • Singh S.
        • Patel J.
        • et al.
        Increased risk of mortality by fibrosis stage in nonalcoholic fatty liver disease: systematic review and meta-analysis.
        Hepatology. 2017; 65: 1557-1565
        • Younossi Z.
        • Stepanova M.
        • Ong J.P.
        • et al.
        Nonalcoholic steatohepatitis is the fastest growing cause of hepatocellular carcinoma in liver transplant candidates.
        Clin Gastroenterol Hepatol. 2019; 17 (e3): 748-755
        • Romeo S.
        • Kozlitina J.
        • Xing C.
        • et al.
        Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease.
        Nat Genet. 2008; 40: 1461-1465
        • Chen L.Z.
        • Xia H.H.X.
        • Xin Y.N.
        • Lin Z.H.
        • Xuan S.Y.
        TM6SF2 E167K variant, a novel genetic susceptibility variant, contributing to nonalcoholic fatty liver disease.
        J Clin Transl Hepatol. 2015; 3: 265-270
        • Dongiovanni P.
        • Romeo S.
        • Valenti L.
        Genetic factors in the pathogenesis of nonalcoholic fatty liver and steatohepatitis.
        Biomed Res Int. 2015; 2015: 460190
        • Bianco C.
        • Jamialahmadi O.
        • Pelusi S.
        • et al.
        Non-invasive stratification of hepatocellular carcinoma risk in non-alcoholic fatty liver using polygenic risk scores.
        J. Hepatol. 2021; 74: 775-782
        • Calle E.E.
        • Rodriguez C.
        • Walker-Thurmond K.
        • Thun M.J.
        Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults.
        N Engl J Med. 2003; 348: 1625-1638
        • El-Serag H.B.
        • Tran T.
        • Everhart J.E.
        Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma.
        Gastroenterology. 2004; 126: 460-468
        • Zoppini G.
        • Fedeli U.
        • Gennaro N.
        • Saugo M.
        • Targher G.
        • Bonora E.
        Mortality from chronic liver diseases in diabetes.
        Am J Gastroenterol. 2014; 109: 1020-1025
        • Margini C.
        • Dufour J.F.
        The story of HCC in NAFLD: from epidemiology, across pathogenesis, to prevention and treatment.
        Liver Int. 2016; 36: 317-324
        • Kulik L.
        • El-Serag H.B.
        Epidemiology and management of hepatocellular carcinoma.
        Gastroenterology. 2019; 156: 477-491
        • Kim D.
        • Li A.A.
        • Perumpail B.J.
        • et al.
        Changing trends in etiology-based and ethnicity-based annual mortality rates of cirrhosis and hepatocellular carcinoma in the United States.
        Hepatology. 2019; 69: 1064-1074
        • Reig M.
        • Gambato M.
        • Man N.K.
        • et al.
        Should patients with NAFLD/NASH be surveyed for HCC?.
        Transplantation. 2019; 103: 39-44
      1. J.G. Stine, B.J. Wentworth, A. Zimmet, et al. Systematic review with meta-analysis: risk of hepatocellular carcinoma in non-alcoholic steatohepatitis without cirrhosis compared to other liver diseases. Aliment Pharmacol Ther. 2018;48(7):696–703.

        • Piscaglia F.
        • Svegliati-Baroni G.
        • Barchetti A.
        • et al.
        Clinical patterns of hepatocellular carcinoma in nonalcoholic fatty liver disease: a multicenter prospective study.
        Hepatology. 2016; 63: 827-838
        • Younossi Z.M.
        • Otgonsuren M.
        • Henry L.
        • et al.
        Association of nonalcoholic fatty liver disease (NAFLD) with hepatocellular carcinoma (HCC) in the United States from 2004 to 2009.
        Hepatology. 2015; 62: 1723-1730
      2. M. Alexander, D. Ansell, A. Pasqua, et al. Risks and clinical predictors of cirrhosis and hepatocellular carcinoma diagnoses in adults with diagnosed NAFLD: real-world study of 18 million patients in four European cohorts. BMC Medicine 2019;17:19.

        • Angulo P.
        • Kleiner D.E.
        • Dam-Larsen S.
        • et al.
        Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease.
        Gastroenterology. 2015; 149 (--): 389-397
        • Vilar-Gomez E.
        • Calzadilla-Bertot L.
        • Wong V W.S.
        • et al.
        Fibrosis severity as a determinant of cause-specific mortality in patients with advanced nonalcoholic fatty liver disease: a multi-national cohort study.
        Gastroenterology. 2018; 155 (--): 443-457
        • Pelusi S.
        • Cespiati A.
        • Rametta R.
        • et al.
        Prevalence and risk factors of significant fibrosis in patients with nonalcoholic fatty liver without steatohepatitis.
        Clin Gastroenterol Hepatol. 2019; 17 (--): 2310-2319
        • Simon T.G.
        • King L.Y.
        • Chong D.Q.
        • et al.
        Diabetes, metabolic comorbidities, and risk of hepatocellular carcinoma: results from two prospective cohort studies.
        Hepatology. 2018; 67: 1797-1806
        • Kanwal F.
        • Kramer J.R.
        • Li L.
        • et al.
        Effect of metabolic traits on the risk of cirrhosis and hepatocellular cancer in nonalcoholic fatty liver disease.
        Hepatology. 2020; 71: 808-819
        • Hassan M.M.
        • Kaseb A.
        • Li D.
        • et al.
        Association between hypothyroidism and hepatocellular carcinoma: a case-control study in the United States.
        Hepatology. 2009; 49: 1563-1570
        • Trépo E.
        • Valenti L.
        Update on NAFLD genetics: from new variants to the clinic.
        J Hepatol. 2020; 72: 1196-1209
        • Donati B.
        • Dongiovanni P.
        • Romeo S.
        • et al.
        MBOAT7 rs641738 variant and hepatocellular carcinoma in non-cirrhotic individuals.
        Sci Rep. 2017; 7: 4492
        • Romeo S.
        • Sanyal A.
        • Valenti L.
        Leveraging human genetics to identify potential new treatments for fatty liver disease.
        Cell Metab. 2020; 31: 35-45
        • Pelusi S.
        • Valenti L.
        Hepatic fat as clinical outcome and therapeutic target for nonalcoholic fatty liver disease.
        Liver Int. 2019; 39: 250-256
        • European Association for the Study of the Liver. Electronic address: [email protected], European Association for the Study of the Liver
        EASL clinical practice guidelines: management of hepatocellular carcinoma.
        J Hepatol. 2018; 69: 182-236
        • Liu Y.L.
        • Patman G.L.
        • Leathart J.B.S.
        • et al.
        Carriage of the PNPLA3 rs738409 C >G polymorphism confers an increased risk of non-alcoholic fatty liver disease associated hepatocellular carcinoma.
        J Hepatol. 2014; 61: 75-81
        • Anstee Q.M.
        • Liu Y.L.
        • Day C.P.
        • Reeves H.L.
        Reply to: HCC and liver disease risk in homozygous PNPLA3 p.I148M carriers approach monogenic inheritance.
        J Hepatol. 2015; 62: 982-983
        • Krawczyk M.
        • Stokes C.S.
        • Romeo S.
        • Lammert F.
        HCC and liver disease risks in homozygous PNPLA3 p.I148M carriers approach monogenic inheritance.
        J Hepatol. 2015; 62: 980-981
        • Font-Burgada J.
        • Sun B.
        • Karin M.
        Obesity and cancer: the oil that feeds the flame.
        Cell Metab. 2016; 23: 48-62
        • Ibrahim S.H.
        • Hirsova P.
        • Gores G.J.
        Non-alcoholic steatohepatitis pathogenesis: sublethal hepatocyte injury as a driver of liver inflammation.
        Gut. 2018; 67: 963-972
        • Luedde T.
        • Beraza N.
        • Kotsikoris V.
        • et al.
        Deletion of NEMO/IKKgamma in liver parenchymal cells causes steatohepatitis and hepatocellular carcinoma.
        Cancer Cell. 2007; 11: 119-132
        • Grohmann M.
        • Wiede F.
        • Dodd G.T.
        • et al.
        Obesity Drives STAT-1-Dependent NASH and STAT-3-Dependent HCC.
        Cell. 2018; 175: 1289-1306
        • Kettner N.M.
        • Voicu H.
        • Finegold M.J.
        • et al.
        Circadian homeostasis of liver metabolism suppresses hepatocarcinogenesis.
        Cancer Cell. 2016; 30: 909-924
        • Ponziani F.R.
        • Bhoori S.
        • Castelli C.
        • et al.
        Hepatocellular carcinoma is associated with gut microbiota profile and inflammation in nonalcoholic fatty liver disease.
        Hepatology. 2019; 69: 107-120
        • Boursier J.
        • Mueller O.
        • Barret M.
        • et al.
        The severity of nonalcoholic fatty liver disease is associated with gut dysbiosis and shift in the metabolic function of the gut microbiota.
        Hepatology. 2016; 63: 764-775
        • Miele L.
        • Valenza V.
        • La Torre G.
        • et al.
        Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease.
        Hepatology. 2009; 49: 1877-1887
        • Grąt M.
        • Wronka K.M.
        • Krasnodębski M.
        • et al.
        Profile of gut microbiota associated with the presence of hepatocellular cancer in patients with liver cirrhosis.
        Transplant Proc. 2016; 48: 1687-1691
        • Henao-Mejia J.
        • Elinav E.
        • Jin C.
        • et al.
        Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity.
        Nature. 2012; 482: 179-185
      3. S. Mittal, H.B. El-Serag, Y.H. Sada, et al. Hepatocellular carcinoma in the absence of cirrhosis in US veterans is associated with non-alcoholic fatty liver disease. 2016;14:124–31.

        • Natarajan Y.
        • Kramer J.R.
        • Yu X.
        • et al.
        Risk of cirrhosis and hepatocellular cancer in patients with NAFLD and normal liver enzymes.
        Hepatology. 2020; 72: 1242-1252
        • Younossi Z.M.
        • Koenig A.B.
        • Abdelatif D.
        • et al.
        Global epidemiology of nonalcoholic fatty liver disease-meta-analytic assessment of prevalence, incidence, and outcomes.
        Hepatology. 2016; 64: 73-84
        • Stine J.G.
        • Wentworth B.J.
        • Zimmet A.
        • et al.
        Systematic review with meta-analysis: risk of hepatocellular carcinoma in non-alcoholic steatohepatitis without cirrhosis compared to other liver diseases.
        Aliment Pharmacol Ther. 2018; 48: 696-703
      4. Taylor R.S., Taylor R.J., Bayliss S., et al. Association between fibrosis stage and outcomes of patients with nonalcoholic fatty liver disease: a systematic review and meta-analysis 2020;158:1611–1625.

        • Marin V.
        • Rosso N.
        • Ben M.D.
        • et al.
        An animal model for the juvenile non-alcoholic fatty liver disease and non-alcoholic steatohepatitis.
        PLoS ONE. 2016; 11: 1-15
      5. O'Hara J., Finnegan A., Dhillon H., et al. Cost of non-alcoholic steatohepatitis in Europe and the USA: the GAIN study. J HEP 2020;2(5):18. 2100142. doi:10.1016/j.jhepr.2020.100142. eCollection 2020 Oct.

      6. Tapper E.B., Hunink M.G.M., Afdhal N.H., Lai M., Sengupta al. Cost-effectiveness analysis: risk stratification of nonalcoholic fatty liver disease (NAFLD) by the primary care physician using the NAFLD fibrosis score. PLoS ONE 2016;11(2):112. e0147237. doi:10.1371/journal.pone.0147237. eCollection 2016.

        • Simon T.G.
        • Roelstraete B.
        • Sharma R.
        • Khalili H.
        • Hagström H.
        • Ludvigsson J.F.
        Cancer risk in patients with biopsy-confirmed nonalcoholic fatty liver disease: a population-based cohort study.
        Hepatology. 2021;
      7. V. Paradis, S. Zalinski, E. Chelbi, et al. Hepatocellular carcinomas in patients with metabolic syndrome often develop without significant liver fibrosis: a pathological analysis. 2009;49(3):9.

        • Burt A.D.
        • Lackner C.
        • Tiniakos D.G.
        Diagnosis and assessment of NAFLD: definitions and histopathological classification.
        Semin Liver Dis. 2015; 35: 207-220
        • Calderaro J.
        • Ziol M.
        • Paradis V.
        • Zucman-Rossi J.
        Molecular and histological correlations in liver cancer.
        J. Hepatol. 2019; 71: 616-630
        • Lee J.S.
        • Yoo J.E.
        • Kim H.
        • et al.
        Tumor stroma with senescence-associated secretory phenotype in steatohepatitic hepatocellular carcinoma.
        PLoS ONE. 2017; 12: e0171922
        • Shibahara J.
        • Ando S.
        • Sakamoto Y.
        • et al.
        Hepatocellular carcinoma with steatohepatitic features: a clinicopathological study of Japanese patients.
        Histopathology. 2014; 64: 951-962
        • Salomao M.
        • Yu W.M.
        • Brown R.S.
        • et al.
        Steatohepatitic hepatocellular carcinoma (SH-HCC): a distinctive histological variant of HCC in hepatitis C virus-related cirrhosis with associated NAFLD/NASH.
        Am J Surg Pathol. 2010; 34: 1630-1636
        • Jain D.
        Steatohepatitic hepatocellular carcinoma: a metabolic syndrome-associated carcinoma.
        Histopathology. 2015; 67: 267
        • Nascimbeni F.
        • Ballestri S.
        • Di Tommaso L.
        • et al.
        Inflammatory hepatocellular adenomatosis, metabolic syndrome, polycystic ovary syndrome and non-alcoholic steatohepatitis: chance tetrad or association by necessity?.
        Dig Liver Dis. 2014; 46: 288-289
        • Nault J.-.C.
        • Couchy G.
        • Balabaud C.
        • et al.
        Molecular classification of hepatocellular adenoma associates with risk factors, bleeding, and malignant transformation.
        Gastroenterology. 2017; 152 (e6): 880-894
        • Baumeister S.E.
        • Schlesinger S.
        • Aleksandrova K.
        • et al.
        Association between physical activity and risk of hepatobiliary cancers: a multinational cohort study.
        J Hepatol. 2019; 70: 885-892
        • Singh S.
        • Singh P.P.
        • Singh A.G.
        • et al.
        Anti-diabetic medications and risk of pancreatic cancer in patients with diabetes mellitus: a systematic review and meta-analysis.
        Am J Gastroenterol. 2013; 108 (quiz 520): 510-519
        • Strandberg T.E.
        • Pyörälä K.
        • Cook T.J.
        • et al.
        Mortality and incidence of cancer during 10-year follow-up of the scandinavian simvastatin survival study (4S).
        Lancet. 2004; 364: 771-777
        • Islam M.M.
        • Poly T.N.
        • Walther B.A.
        • Yang H.C.
        • Jack Li Y.C.
        Statin use and the risk of hepatocellular carcinoma: a meta-analysis of observational studies.
        Cancers (Basel). 2020; 12: 1-17
        • Njei B.
        • McCarty T.R.
        • Sharma P.
        • et al.
        Bariatric surgery and hepatocellular carcinoma: a propensity score-matched analysis.
        Obes Surg. 2018; 28: 3880-3889
        • Simmons O.
        • Fetzer D.T.
        • Yokoo T.
        • et al.
        Predictors of adequate ultrasound quality for hepatocellular carcinoma surveillance in patients with cirrhosis.
        Aliment Pharmacol Ther. 2017; 45: 169-177
        • Ioannou G.N.
        • Green P.
        • Lowy E.
        • Mun E.J.
        • Berry K.
        Differences in hepatocellular carcinoma risk, predictors and trends over time according to etiology of cirrhosis.
        PLoS ONE. 2018; 13 (e0204412): 1-20
        • Best J.
        • Bechmann L.P.
        • Sowa J.P.
        • et al.
        GALAD score detects early hepatocellular carcinoma in an international cohort of patients with nonalcoholic steatohepatitis.
        Clin Gastroenterol Hepatol. 2020; 18: 728-735
        • Reddy S.K.
        • Steel J.L.
        • Chen H.W.
        • et al.
        Outcomes of curative treatment for hepatocellular cancer in nonalcoholic steatohepatitis versus hepatitis C and alcoholic liver disease.
        Hepatology. 2012; 55: 1809-1819
        • Cauchy F.
        • Zalinski S.
        • Dokmak S.
        • et al.
        Surgical treatment of hepatocellular carcinoma associated with the metabolic syndrome.
        Br J Surg. 2013; 100: 113-121
        • Viganò L.
        • Conci S.
        • Cescon M.
        • et al.
        Liver resection for hepatocellular carcinoma in patients with metabolic syndrome: a multicenter matched analysis with HCV-related HCC.
        J Hepatol. 2015; 63: 93-101
        • Liang J.
        • Ariizumi S.-.I.
        • Nakano M.
        • Yamamoto M.
        Diabetes mellitus and/or nonalcoholic steatohepatitis-related hepatocellular carcinoma showed favorable surgical outcomes after hepatectomy.
        Anticancer Res. 2019; 39: 5639-5643
        • Koh Y.X.
        • Tan H.J.
        • Liew Y.X.
        • et al.
        Liver Resection for Nonalcoholic Fatty Liver Disease-Associated Hepatocellular Carcinoma.
        J Am Coll Surg. 2019; 229: 467-478
        • Yang T.
        • Hu L.Y.
        • Li Z.L.
        • et al.
        Liver resection for hepatocellular carcinoma in non-alcoholic fatty liver disease: a multicenter propensity matching analysis with HBV-HCC.
        J Gastrointest Surg. 2020; 24: 320-329
        • Wong R.J.
        • Aguilar M.
        • Cheung R.
        • et al.
        Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States.
        Gastroenterology. 2015; 148: 547-555
        • Gawrieh S.
        • Dakhoul L.
        • Miller E.
        • et al.
        Characteristics, aetiologies and trends of hepatocellular carcinoma in patients without cirrhosis: a United States multicentre study.
        Aliment Pharmacol Ther. 2019; 50: 809-821
        • Haldar D.
        • Kern B.
        • Hodson J.
        • et al.
        Outcomes of liver transplantation for non-alcoholic steatohepatitis: a European liver transplant registry study.
        J Hepatol. 2019; 71: 313-322
        • Bassaganyas L.
        • Pinyol R.
        • Esteban-Fabró R.
        • et al.
        Copy-number alteration burden differentially impacts immune profiles and molecular features of hepatocellular carcinoma.
        Clin Cancer Res. 2020; 26: 6350-6361
        • Feng G.S.
        • Hanley K.L.
        • Liang Y.
        • Lin X.
        Improving the efficacy of liver cancer immunotherapy: the power of combined preclinical and clinical studies.
        Hepatology. 2021; 73: 104-114
        • Dudek M.
        • Pfister D.
        • Donakonda S.
        • et al.
        Auto-aggressive CXCR6+ CD8 T cells cause liver immune pathology in NASH.
        Nature. 2021; 592: 444-449
        • Finn R.S.
        • Qin S.
        • Ikeda M.
        • et al.
        IMbrave150: updated overall survival (OS) data from a global, randomized, open-label phase III study of atezolizumab (atezo) + bevacizumab (bev) versus sorafenib (sor) in patients (pts) with unresectable hepatocellular carcinoma (HCC).
        JCO. 2021; 39 (–267): 267
        • Llovet J.M.
        • Kelley R.K.
        • Villanueva A.
        • et al.
        Hepatocellular carcinoma.
        Nat Rev Dis Primers. 2021; 7: 6
      8. B. Scheiner, M.M. Kirstein, F. Hucke, et al. Programmed cell death protein-1 (PD-1)-targeted immunotherapy in advanced hepatocellular carcinoma: efficacy and safety data from an international multicentre real-world cohort. Aliment Pharmacol Ther 2019;49(10):1323-1333.

        • Pinter M.
        • Scheiner B.
        • Peck-Radosavljevic M.
        Immunotherapy for advanced hepatocellular carcinoma: a focus on special subgroups.
        Gut. 2021; 70: 204-214
        • Duffy A.G.
        • Ulahannan S.V.
        • Makorova-Rusher O.
        • et al.
        Tremelimumab in combination with ablation in patients with advanced hepatocellular carcinoma.
        J Hepatol. 2017; 66: 545-551
        • Petta S.
        • Ting J.
        • Saragoni S.
        • et al.
        Healthcare resource utilization and costs of nonalcoholic steatohepatitis patients with advanced liver disease in Italy.
        Nutr Metab Cardiovasc Dis. 2020; 30: 1014-1022
        • Lazarus J.V.
        • Ekstedt M.
        • Marchesini G.
        • et al.
        A cross-sectional study of the public health response to non-alcoholic fatty liver disease in Europe.
        J Hepatol. 2020; 72: 14-24