Emerging risk factors for nonalcoholic fatty liver disease associated hepatocellular carcinoma

Abstract

Worldwide, nonalcoholic fatty liver disease (NAFLD) has reached epidemic proportions and in parallel, hepatocellular carcinoma (HCC) has become one of the fastest growing cancers. Epidemiological studies have not only shed light on the prevalence and incidence of the disease but have also unmasked important environmental risk factors, including the role of diabetes and dyslipidemia in disease pathogenesis. Genetic association studies have identified single nucleotide polymorphisms implicated in NAFLD-HCC, many of which are part of lipid metabolism pathways. Through these clinical studies and subsequently, translational and basic research, the role of statins as a chemoprotective agent has also emerged with ongoing clinical trials assessing their utility in HCC prevention and treatment. In this review, we summarize the recent epidemiological studies describing the burden of NAFLD-HCC in different patient populations and countries. We discuss the genetic and environmental risk factors for NAFLD-HCC and highlight the chemoprotective role of statins and aspirin. We also summarize what is known about NAFLD-HCC in the cirrhosis and non-cirrhosis populations and briefly address the role of surveillance in NAFLD-HCC patients.

Keywords

Nonalcoholic fatty liver disease / nonalcoholic steatohepatitis / hepatocellular carcinoma / statins / metabolic syndrome

References

[1] Loomba R.The global NAFLD epidemic..Nat Rev Gastroenterol Hepatol2013;10:686-90

[2] Adams LA.Nonalcoholic fatty liver disease..Ann Epidemiol2007;17:863-9

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

[4] Kleiner DE,Van Natta M,Contos MJ.Design and validation of a histological scoring system for nonalcoholic fatty liver disease..Hepatology2005;41:1313-21

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

[6] Sanyal AJ.AGA technical review on nonalcoholic fatty liver disease..Gastroenterology2002;123:1705-25

[7] Estes C,Loomba R,Sanyal AJ.Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease..Hepatology2018;67:123-33 PMCID:PMC5767767

[8] Allen AM,Sangaralingham LR,McCoy RG.Healthcare cost and utilization in nonalcoholic fatty liver disease: real-world data from a large U.S. claims database..Hepatology2018;68:2230-8 PMCID:PMC6240503

[9] Younossi ZM,Bush H.Clinical and economic burden of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis..Clin Liver Dis2018;22:1-10

[10] Younossi ZM,Stepanova M,Venkatesan C.Trends in outpatient resource utilizations and outcomes for Medicare beneficiaries with nonalcoholic fatty liver disease..J Clin Gastroenterol2015;49:222-7

[11] Stine JG,Zimmet A,Loomba R.Systematic review with meta-analysis: risk of hepatocellular carcinoma in non-alcoholic steatohepatitis without cirrhosis compared to other liver diseases..Aliment Pharmacol Ther2018;48:696-703

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

[13] Lee TY,Yu SH,Wu MS.The occurrence of hepatocellular carcinoma in different risk stratifications of clinically noncirrhotic nonalcoholic fatty liver disease..Int J Cancer2017;141:1307-14

[14] Kaplan DE,Mehta R,John B.Effects of hypercholesterolemia and statin exposure on survival in a large national cohort of patients with cirrhosis..Gastroenterology2019;156:1693-706.e12

[15] Thrift AP,Liu Y.Statin use after diagnosis of hepatocellular carcinoma is associated with decreased mortality..Clin Gastroenterol Hepatol2019;17:2117-25.e3 PMCID:PMC6612541

[16] Simon TG,Ludvigsson JF,Giovannucci EL.Association between aspirin use and risk of hepatocellular carcinoma..JAMA Oncol2018;4:1683-90 PMCID:PMC6440745

[17] Simon TG,Aleman S,Nguyen LH.Lipophilic statins and risk for hepatocellular carcinoma and death in patients with chronic viral hepatitis: results from a nationwide Swedish population..Ann Intern Med2019;171:318-27

[18] Anstee QM,Kotsiliti E,Heikenwalder M.From NASH to HCC: current concepts and future challenges..Nat Rev Gastroenterol Hepatol2019;16:411-28

[19] Singal AG.Hepatocellular carcinoma from epidemiology to prevention: translating knowledge into practice..Clin Gastroenterol Hepatol2015;13:2140-51 PMCID:PMC4618036

[20] Siegel RL,Jemal A.Cancer statistics, 2017..CA Cancer J Clin2017;67:7-30

[21] Welzel TM,Quraishi S,Davila JA.Population-attributable fractions of risk factors for hepatocellular carcinoma in the United States..Am J Gastroenterol2013;108:1314-21 PMCID:PMC4105976

[22] Kanwal F,Mapakshi S,Chayanupatkul M.Risk of hepatocellular cancer in patients with non-alcoholic fatty liver disease..Gastroenterology2018;155:1828-37.e2 PMCID:PMC6279617

[23] Mittal S,El-Serag HB,Duan Z.Temporal trends of nonalcoholic fatty liver disease-related hepatocellular carcinoma in the veteran affairs population..Clin Gastroenterol Hepatol2015;13:594-601.e1 PMCID:PMC4333060

[24] Ioannou GN,Kerr KF.Models estimating risk of hepatocellular carcinoma in patients with alcohol or NAFLD-related cirrhosis for risk stratification..J Hepatol2019;71:523-33 PMCID:PMC6702126

[25] Younossi Z,Ong JP,Bugianesi E.Nonalcoholic steatohepatitis is the fastest growing cause of hepatocellular carcinoma in liver transplant candidates..Clin Gastroenterol Hepatol2019;17:748-55.e3

[26] Wong RJ,Ahmed A.Nonalcoholic steatohepatitis is the most rapidly growing indication for liver transplantation in patients with hepatocellular carcinoma in the U.S..Hepatology2014;59:2188-95

[27] Wong RJ,Cheung R,Harrison SA.Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States..Gastroenterology2015;148:547-55

[28] 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

[29] Kawamura Y,Ikeda K,Imai N.Large-scale long-term follow-up study of Japanese patients with non-alcoholic Fatty liver disease for the onset of hepatocellular carcinoma..Am J Gastroenterol2012;107:253-61

[30] Alexander M,van der Lei J,Prieto-Alhambra D.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 Med2019;17:95 PMCID:PMC6526616

[31] Haldar D,Hodson J,Adam R.Outcomes of liver transplantation for non-alcoholic steatohepatitis: a European Liver Transplant Registry study..J Hepatol2019;71:313-22 PMCID:PMC6656693

[32] Fan JG,Wong VW.New trends on obesity and NAFLD in Asia..J Hepatol2017;67:862-73

[33] Wong MCS,George J,Leung C.The changing epidemiology of liver diseases in the Asia-Pacific region..Nat Rev Gastroenterol Hepatol2019;16:57-73

[34] Cho EJ,Jang ES,Lee JH.Relative etiological role of prior hepatitis B virus infection and nonalcoholic fatty liver disease in the development of non-B non-C hepatocellular carcinoma in a hepatitis B-endemic area..Digestion2011;84:17-22

[35] Hagström H,Ekstedt M,Stål P.Risk for development of severe liver disease in lean patients with nonalcoholic fatty liver disease: a long-term follow-up study..Hepatol Commun2018;2:48-57 PMCID:PMC5776871

[36] Browning JD,Dobbins R,Horton JD.Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity..Hepatology2004;40:1387-95

[37] Caldwell SH,Patrie JT.Is NASH underdiagnosed among African Americans?.Am J Gastroenterol2002;97:1496-500

[38] Browning JD,Saboorian MH.Ethnic differences in the prevalence of cryptogenic cirrhosis..Am J Gastroenterol2004;99:292-8

[39] Schwimmer JB,Lavine JE,Campbell N.Heritability of nonalcoholic fatty liver disease..Gastroenterology2009;136:1585-92 PMCID:PMC3397140

[40] Loomba R,Chen CH,Bhatt A.Heritability of hepatic fibrosis and steatosis based on a prospective twin study..Gastroenterology2015;149:1784-93 PMCID:PMC4663110

[41] Romeo S,Xing C,Cox D.Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease..Nat Genet2008;40:1461-5 PMCID:PMC2597056

[42] Dongiovanni P,Fares R,Mancina RM.PNPLA3 I148M polymorphism and progressive liver disease..World J Gastroenterol2013;19:6969-78 PMCID:PMC3819533

[43] Smagris E,Li J,Lai KM.Pnpla3I148M knockin mice accumulate PNPLA3 on lipid droplets and develop hepatic steatosis..Hepatology2015;61:108-18 PMCID:PMC4262735

[44] Sookoian S.Meta-analysis of the influence of I148M variant of patatin-like phospholipase domain containing 3 gene (PNPLA3) on the susceptibility and histological severity of nonalcoholic fatty liver disease..Hepatology2011;53:1883-94

[45] Liu YL,Leathart JB,Burt AD.Carriage of the PNPLA3 rs738409 C >G polymorphism confers an increased risk of non-alcoholic fatty liver disease associated hepatocellular carcinoma..J Hepatol2014;61:75-81

[46] Kozlitina J,Stender S,Zhou HH.Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease..Nat Genet2014;46:352-6 PMCID:PMC3969786

[47] Falleti E,Cmet S,Toniutto P.PNPLA3 rs738409 and TM6SF2 rs58542926 variants increase the risk of hepatocellular carcinoma in alcoholic cirrhosis..Dig Liver Dis2016;48:69-75

[48] Mancina RM,Petta S,Meroni M.The MBOAT7-TMC4 variant rs641738 increases risk of nonalcoholic fatty liver disease in individuals of european descent..Gastroenterology2016;150:1219-30.e6 PMCID:PMC4844071

[49] Luukkonen PK,Hyötyläinen T,Arola J.The MBOAT7 variant rs641738 alters hepatic phosphatidylinositols and increases severity of non-alcoholic fatty liver disease in humans..J Hepatol2016;65:1263-5

[50] Donati B,Romeo S,McCain M.MBOAT7 rs641738 variant and hepatocellular carcinoma in non-cirrhotic individuals..Sci Rep2017;7:4492 PMCID:PMC5495751

[51] Pelusi S,Pietrelli A,Donati B.Rare pathogenic variants predispose to hepatocellular carcinoma in nonalcoholic fatty liver disease..Sci Rep2019;9:3682 PMCID:PMC6403344

[52] El-Serag HB,Eschbach K,Goodwin J.Epidemiology of hepatocellular carcinoma in Hispanics in the United States..Arch Intern Med2007;167:1983-9

[53] Rich NE,Odewole M,Parikh ND.Racial and ethnic differences in presentation and outcomes of hepatocellular carcinoma..Clin Gastroenterol Hepatol2019;17:551-9.e1 PMCID:PMC6274621

[54] Garske KM,Miao Z,Comenho C.Reverse gene-environment interaction approach to identify variants influencing body-mass index in humans..Nat Metab2019;1:630-42 PMCID:PMC6752726

[55] Benhammou JN,Alvarez M,Rankin C.Novel lipid long intervening noncoding RNA, oligodendrocyte maturation-associated long intergenic noncoding RNA, regulates the liver steatosis gene stearoyl-coenzyme a desaturase as an enhancer RNA..Hepatol Commun2019;3:1356-72 PMCID:PMC6771395

[56] Villanueva A,Sayols S,Hoshida Y.DNA methylation-based prognosis and epidrivers in hepatocellular carcinoma..Hepatology2015;61:1945-56

[57] Fei Q,Zhang J,Kong D.Histone methyltransferase SETDB1 regulates liver cancer cell growth through methylation of p53..Nat Commun2015;6:8651 PMCID:PMC5426523

[58] Xu RH,Krawczyk M,Luo H.Circulating tumour DNA methylation markers for diagnosis and prognosis of hepatocellular carcinoma..Nat Mater2017;16:1155-61

[59] Ng CKY,Terracciano LM.Circulating cell-free DNA in hepatocellular carcinoma: current insights and outlook..Front Med (Lausanne)2018;5:78 PMCID:PMC5880118

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

[61] Lai SW,Liao KF,Lin CC.Risk of hepatocellular carcinoma in diabetic patients and risk reduction associated with anti-diabetic therapy: a population-based cohort study..Am J Gastroenterol2012;107:46-52

[62] Chen HF,Li CY.Risk of malignant neoplasms of liver and biliary tract in diabetic patients with different age and sex stratifications..Hepatology2010;52:155-63

[63] Simon TG,Chong DQ,Ma Y.Diabetes, metabolic comorbidities, and risk of hepatocellular carcinoma: results from two prospective cohort studies..Hepatology2018;67:1797-806 PMCID:PMC5906170

[64] Cancer Prevention Study IIThe American Cancer Society Prospective Study..Stat Bull Metrop Insur Co1992;73:21-9

[65] Karagozian R,Baffy G.Obesity-associated mechanisms of hepatocarcinogenesis..Metabolism2014;63:607-17

[66] Ioannou GN,Boyko EJ,Kahn SE.Is central obesity associated with cirrhosis-related death or hospitalization? A population-based, cohort study..Clin Gastroenterol Hepatol2005;3:67-74

[67] Schlesinger S,Pischon T,Jenab M.Abdominal obesity, weight gain during adulthood and risk of liver and biliary tract cancer in a European cohort..Int J Cancer2013;132:645-57

[68] Pang Q,Song SD,Xu XS.Central obesity and nonalcoholic fatty liver disease risk after adjusting for body mass index..World J Gastroenterol2015;21:1650-62 PMCID:PMC4316109

[69] Consultation WE.Appropriate body-mass index for Asian populations and its implications for policy and intervention strategies..Lancet2004;363:157-63

[70] Welzel TM,Zeuzem S,Davila JA.Metabolic syndrome increases the risk of primary liver cancer in the United States: a study in the SEER-Medicare database..Hepatology2011;54:463-71 PMCID:PMC4141525

[71] Borena W,Lukanova A,Lindkvist B.Metabolic risk factors and primary liver cancer in a prospective study of 578,700 adults..Int J Cancer2012;131:193-200

[72] Chiang CH,Hung SH,Hung HF.Opposite association between diabetes, dyslipidemia, and hepatocellular carcinoma mortality in the middle-aged and elderly..Hepatology2014;59:2207-15

[73] Chalasani N.Statins and hepatotoxicity: focus on patients with fatty liver..Hepatology2005;41:690-5

[74] Chalasani N,Lavine JE,Brunt EM.The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology..Gastroenterology2012;142:1592-609

[75] Bays H,Chalasani N.An assessment by the Statin Liver Safety Task Force: 2014 update..J Clin Lipidol2014;8:S47-57

[76] Puri P,Cheung O,Sargeant C.The plasma lipidomic signature of nonalcoholic steatohepatitis..Hepatology2009;50:1827-38 PMCID:PMC5031239

[77] Chiappini F,Kadar H,Tran A.Metabolism dysregulation induces a specific lipid signature of nonalcoholic steatohepatitis in patients..Sci Rep2017;7:46658 PMCID:PMC5402394

[78] Walle P,Männistö V,Lankinen M.Fatty acid metabolism is altered in non-alcoholic steatohepatitis independent of obesity..Metabolism2016;65:655-66

[79] Safadi R,Mahamid M,Halpern M.The fatty acid-bile acid conjugate Aramchol reduces liver fat content in patients with nonalcoholic fatty liver disease..Clin Gastroenterol Hepatol2014;12:2085-91.e1

[80] Ajmera VH,Ramers C,Bassirian S.MRI assessment of treatment response in HIV-associated NAFLD: a randomized trial of a stearoyl-coenzyme-A-desaturase-1 inhibitor (ARRIVE Trial)..Hepatology2019;70:1531-45 PMCID:PMC7164416

[81] Kim G,Nam CM.Statin use and the risk of hepatocellular carcinoma in patients at high risk: a nationwide nested case-control study..J Hepatol2018;68:476-84

[82] Friedman GD,Fireman B.Statins and reduced risk of liver cancer: evidence for confounding..J Natl Cancer Inst2016;108: PMCID:PMC6437715

[83] Yi C,Wan M,Cheng X.Statins intake and risk of liver cancer: a dose-response meta analysis of prospective cohort studies..Medicine (Baltimore)2017;96:e7435 PMCID:PMC5502182

[84] Shi M,Nie B,Cui X.Statin use and risk of liver cancer: an update meta-analysis..BMJ Open2014;4:e005399 PMCID:PMC4166249

[85] Ogura S,Kurahashi T,Furuta K.Targeting the mevalonate pathway is a novel therapeutic approach to inhibit oncogenic FoxM1 transcription factor in human hepatocellular carcinoma..Oncotarget2018;9:21022-35 PMCID:PMC5940385

[86] Gruenbacher G.Mevalonate metabolism governs cancer immune surveillance..Oncoimmunology2017;6:e1342917 PMCID:PMC5665080

[87] Cuzick J,Baron JA,Burn J.Aspirin and non-steroidal anti-inflammatory drugs for cancer prevention: an international consensus statement..Lancet Oncol2009;10:501-7

[88] Bosetti C,La Vecchia C.Aspirin and cancer risk: a summary review to 2007..Recent Results Cancer Res2009;181:231-51

[89] Leng J,Demetris AJ,Wu T.Cyclooxygenase-2 promotes hepatocellular carcinoma cell growth through Akt activation: evidence for Akt inhibition in celecoxib-induced apoptosis..Hepatology2003;38:756-68

[90] Sahasrabuddhe VV,Graubard BI,Schwartz LM.Nonsteroidal anti-inflammatory drug use, chronic liver disease, and hepatocellular carcinoma..J Natl Cancer Inst2012;104:1808-14 PMCID:PMC3514167

[91] Schatzkin A,Thompson FE,Tangrea J.Design and serendipity in establishing a large cohort with wide dietary intake distributions : the National Institutes of Health-American Association of Retired Persons Diet and Health Study..Am J Epidemiol2001;154:1119-25

[92] Petrick JL,Chan AT,Beane-Freeman LE.NSAID use and risk of hepatocellular carcinoma and intrahepatic cholangiocarcinoma: the liver cancer pooling project..Cancer Prev Res (Phila)2015;8:1156-62 PMCID:PMC4704448

[93] Carpino G,Pastori D,Baratta F.Increased liver localization of lipopolysaccharides in human and experimental non-alcoholic fatty liver disease..Hepatology2019;Epub ahead of print. doi: 10.1002/hep.31056

[94] Paik JM,De Avila L,Racila A.Mortality related to nonalcoholic fatty liver disease is increasing in the United States..Hepatol Commun2019;3:1459-71 PMCID:PMC6824058

[95] Gill SR,Deboy RT,Turnbaugh PJ.Metagenomic analysis of the human distal gut microbiome..Science2006;312:1355-9 PMCID:PMC3027896

[96] Miele L,La Torre G,Cammarota G.Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease..Hepatology2009;49:1877-87

[97] Volynets V,Strahl S,Spruss A.Nutrition, intestinal permeability, and blood ethanol levels are altered in patients with nonalcoholic fatty liver disease (NAFLD)..Dig Dis Sci2012;57:1932-41

[98] Noverr MC.Does the microbiota regulate immune responses outside the gut?.Trends Microbiol2004;12:562-8

[99] Buzzetti E,Tsochatzis EA.The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD)..Metabolism2016;65:1038-48

[100] Mouzaki M,Bandsma R,Arendt BM.Bile acids and dysbiosis in non-alcoholic fatty liver disease..PLoS One2016;11:e0151829 PMCID:PMC4874546

[101] Henao-Mejia J,Jin C,Mehal WZ.Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity..Nature2012;482:179-85 PMCID:PMC3276682

[102] Boursier J.Implication of gut microbiota in nonalcoholic fatty liver disease..PLoS Pathog2015;11:e1004559 PMCID:PMC4308105

[103] Zhu L,Gill C,Alkhouri R.Characterization of gut microbiomes in nonalcoholic steatohepatitis (NASH) patients: a connection between endogenous alcohol and NASH..Hepatology2013;57:601-9

[104] Ley RE,Klein S.Microbial ecology: human gut microbes associated with obesity..Nature2006;444:1022-3

[105] Boursier J,Barret M,Fizanne L.The severity of nonalcoholic fatty liver disease is associated with gut dysbiosis and shift in the metabolic function of the gut microbiota..Hepatology2016;63:764-75 PMCID:PMC4975935

[106] Loomba R,Li W,Klitgord N.Gut microbiome-based metagenomic signature for non-invasive detection of advanced fibrosis in human nonalcoholic fatty liver disease..Cell Metab2019;30:607

[107] Grąt M,Krasnodębski M,Lewandowski Z.Profile of gut microbiota associated with the presence of hepatocellular cancer in patients with liver cirrhosis..Transplant Proc2016;48:1687-91

[108] Chassaing B,Gewirtz AT.Microbiota-liver axis in hepatic disease..Hepatology2014;59:328-39 PMCID:PMC4084781

[109] Ponziani FR,Castelli C,Rivoltini L.Hepatocellular carcinoma is associated with gut microbiota profile and inflammation in nonalcoholic fatty liver disease..Hepatology2019;69:107-20

[110] Roberts MS,Burczynski FJ.Enterohepatic circulation: physiological, pharmacokinetic and clinical implications..Clin Pharmacokinet2002;41:751-90

[111] Jacobs JP,Agopian V,Sundaram V.Microbiome and bile acid profiles in duodenal aspirates from patients with liver cirrhosis: the Microbiome, Microbial Markers and Liver Disease Study..Hepatol Res2018;48:1108-17 PMCID:PMC6334634

[112] Chung GE,Lee JH,Myung SJ.Ursodeoxycholic acid-induced inhibition of DLC1 protein degradation leads to suppression of hepatocellular carcinoma cell growth..Oncol Rep2011;25:1739-46

[113] Liu H,Zhang YZ,Han GQ.Ursodeoxycholic acid induces apoptosis in hepatocellular carcinoma xenografts in mice..World J Gastroenterol2015;21:10367-74 PMCID:PMC4579883

[114] Zhu L,Liu YJ,Xiao XG.Ursodeoxycholic acid induces apoptosis of hepatocellular carcinoma cells in vitro..J Dig Dis2014;15:684-93

[115] Li J,Lee N,Pihlajamäki J.Probiotics modulated gut microbiota suppresses hepatocellular carcinoma growth in mice..Proc Natl Acad Sci U S A2016;113:E1306-15 PMCID:PMC4780612

[116] Zhang HL,Yang W,Lin Y.Profound impact of gut homeostasis on chemically-induced pro-tumorigenic inflammation and hepatocarcinogenesis in rats..J Hepatol2012;57:803-12

[117] Yoshimoto S,Atarashi K,Sato S.Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome..Nature2013;499:97-101

[118] Tokushige K,Horie Y,Higuchi S.Hepatocellular carcinoma in Japanese patients with nonalcoholic fatty liver disease, alcoholic liver disease, and chronic liver disease of unknown etiology: report of the nationwide survey..J Gastroenterol2011;46:1230-7

[119] Yasui K,Komorizono Y,Arii S.Characteristics of patients with nonalcoholic steatohepatitis who develop hepatocellular carcinoma..Clin Gastroenterol Hepatol2011;9:428-33

[120] Kawada N,Kawaguchi T,Ishihara R.Hepatocellular carcinoma arising from non-cirrhotic nonalcoholic steatohepatitis..J Gastroenterol2009;44:1190-4

[121] Pais R,Goumard C,Wendum D.Temporal trends, clinical patterns and outcomes of NAFLD-related HCC in patients undergoing liver resection over a 20-year period..Aliment Pharmacol Ther2017;46:856-63

[122] Grohmann M,Dodd GT,Ooi GJ.Obesity drives STAT-1-dependent NASH and STAT-3-dependent HCC..Cell2018;175:1289-306.e20 PMCID:PMC6242467

[123] Calvisi DF,Gorden A,Conner EA.Ubiquitous activation of Ras and Jak/Stat pathways in human HCC..Gastroenterology2006;130:1117-28

[124] He G,Temkin V,Kuntzen C.Hepatocyte IKKbeta/NF-kappaB inhibits tumor promotion and progression by preventing oxidative stress-driven STAT3 activation..Cancer Cell2010;17:286-97 PMCID:PMC2841312

[125] Marrero JA,Sirlin CB,Finn RS.Diagnosis, staging, and management of hepatocellular carcinoma: 2018 practice guidance by the American Association for the Study of Liver Diseases..Hepatology2018;68:723-50

[126] European Association for the Study of the LiverCorrigendum to “EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma” [J Hepatol 69 (2018) 182-236]..J Hepatol2019;70:817

[127] Del Poggio P,Ciccarese F,Rapaccini GL.Factors that affect efficacy of ultrasound surveillance for early stage hepatocellular carcinoma in patients with cirrhosis..Clin Gastroenterol Hepatol2014;12:1927-33.e2

[128] Simmons O,Yokoo T,Yopp A.Predictors of adequate ultrasound quality for hepatocellular carcinoma surveillance in patients with cirrhosis..Aliment Pharmacol Ther2017;45:169-77 PMCID:PMC7207219

[129] Simmons O,Yokoo T,Yopp A.Editorial: ultrasound surveillance of hepatocellular carcinoma in the 21st century - authors’ reply..Aliment Pharmacol Ther2017;45:562-63

[130] Zhang E,Lepanto L,Cloutier G.Cost-utility analysis of nonalcoholic steatohepatitis screening..Eur Radiol2015;25:3282-94 PMCID:PMC4836892

[131] Khatri G,Ananthakrishnan L,Fetzer DT.Abbreviated-protocol screening MRI vs. complete-protocol diagnostic MRI for detection of hepatocellular carcinoma in patients with cirrhosis: an equivalence study using LI-RADS v2018..J Magn Reson Imaging2020;51:415-25

[132] Leerapun A,Bida JP,Sanders EL.The utility of Lens culinaris agglutinin-reactive alpha-fetoprotein in the diagnosis of hepatocellular carcinoma: evaluation in a United States referral population..Clin Gastroenterol Hepatol2007;5:394-402 PMCID:PMC1931510

[133] Liebman HA,Tong MJ,Lo KJ.Des-gamma-carboxy (abnormal) prothrombin as a serum marker of primary hepatocellular carcinoma..N Engl J Med1984;310:1427-31

[134] Best J,Sowa JP,Dechêne A.GALAD score detects early hepatocellular carcinoma in an international cohort of patients with nonalcoholic steatohepatitis..Clin Gastroenterol Hepatol2020;18:728-35.e4

[135] Loomba R,Patton H.AGA clinical practice update on screening and surveillance for hepatocellular carcinoma in patients with nonalcoholic fatty liver disease: expert review..Gastroenterology2020;158:1822-30

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

[137] Dyson J,Chattopadyhay D,Graham J.Hepatocellular cancer: the impact of obesity, type 2 diabetes and a multidisciplinary team..J Hepatol2014;60:110-7

[138] Arase Y,Suzuki F,Kawamura Y.Difference in malignancies of chronic liver disease due to non-alcoholic fatty liver disease or hepatitis C in Japanese elderly patients..Hepatol Res2012;42:264-72

[139] Shen JH,Li D,Jing L.The rs738409 (I148M) variant of the PNPLA3 gene and cirrhosis: a meta-analysis..J Lipid Res2015;56:167-75 PMCID:PMC4274064

[140] Vespasiani-Gentilucci U,Dell’Unto C,Antonelli-Incalzi R.Promoting genetics in non-alcoholic fatty liver disease: combined risk score through polymorphisms and clinical variables..World J Gastroenterol2018;24:4835-45 PMCID:PMC6250919