Metabolic primary liver cancer in adults: risk factors and pathogenic mechanisms

Abstract

Primary liver cancer (PLC) is a heterogeneous group of disorders arising with the background of chronic liver disease (CLD) owing to varying etiologies. PLC carries a high lethality rate and a substantial epidemiological, clinical, and financial burden, which is projected to escalate. The two most common PLC histotypes in adults are hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC); the latter is sub-classified as either intrahepatic CC or extrahepatic CC. Over recent decades, there has been a decline of viral CLD accompanied by an increase in dysmetabolic CLD, resulting in PLC becoming relatively more common in Western countries. Metabolic co-morbidities are risk factors and co-factors for HCC and (increasingly) CC. Complex immunological, cellular, pro-inflammatory, molecular, and genetic processes in the systemic dysmetabolic milieu increase PLC risk. Improved understanding of these mechanisms requires close surveillance and early diagnosis of at-risk patients while paving the way for personalized medicine, chemoprevention, and innovative management of metabolic PLC.

Keywords

Cholangiocarcinoma / epidemiology / hepatocellular carcinoma / metabolic syndrome / NAFLD / pathogenesis

References

[1] PetrickJL.The changing epidemiology of primary liver cancer.Curr Epidemiol Rep2019;6:104-11 PMCID:PMC6599615

[2] SharmaR.Descriptive epidemiology of incidence and mortality of primary liver cancer in 185 countries: evidence from GLOBOCAN 2018.Jpn J Clin Oncol2020;50:1370-9

[3] ValeryPC,ClarkPJ,McGlynnKA.Projections of primary liver cancer to 2030 in 30 countries worldwide.Hepatology2018;67:600-11 PMCID:PMC5832532

[4] StepanovaM,AfendyM.Direct and indirect economic burden of chronic liver disease in the united states.Clin Gastroenterol Hepatol2017;15:759-766.e5

[5] RazumilavaN.Liver transplantation for intrahepatic cholangiocarcinoma-authors’ reply.Lancet2014;384:1182-3

[6] TysonGL.Risk factors for cholangiocarcinoma.Hepatology2011;54:173-84 PMCID:PMC3125451

[7] KirsteinMM.Epidemiology and risk factors of cholangiocarcinoma.Visc Med2016;32:395-400 PMCID:PMC5290446

[8] SchizasD,RoutsiE.Combined hepatocellular-cholangiocarcinoma: an update on epidemiology, classification, diagnosis and management.Hepatobiliary Pancreat Dis Int2020;19:515-23

[9] LlovetJM,VillanuevaA.Hepatocellular carcinoma.Nat Rev Dis Primers2021;7:6

[10] HerbstDA.Risk factors for hepatocellular carcinoma.Clin Liver Dis (Hoboken)2013;1:180-2 PMCID:PMC6499296

[11] TrinchetJC,ChaffautC.ANRS CO12 CirVir GroupComplications and competing risks of death in compensated viral cirrhosis (ANRS CO12 CirVir prospective cohort).Hepatology2015;62:737-50

[12] BaeckerA,LaVecchia C.Worldwide incidence of hepatocellular carcinoma cases attributable to major risk factors.Eur J Cancer Prev2018;27:205-12 PMCID:PMC5876122

[13] FracanzaniAL,FraquelliM.Increased cancer risk in a cohort of 230 patients with hereditary hemochromatosis in comparison to matched control patients with non-iron-related chronic liver disease.Hepatology2001;33:647-51

[14] TuratiF,TalaminiR.Family history of liver cancer and hepatocellular carcinoma.Hepatology2012;55:1416-25

[15] LonardoA,ChowPKH.Sex disparity in hepatocellular carcinoma owing to NAFLD and non-NAFLD etiology: epidemiological findings and pathobiological mechanisms.HR2020;2020

[16] SongJ,BowlusCL,LeungPSC.Cholangiocarcinoma in patients with primary sclerosing cholangitis (PSC): a comprehensive review.Clin Rev Allergy Immunol2020;58:134-49

[17] CutoloC,FuscoR.Combined hepatocellular-cholangiocarcinoma: what the multidisciplinary team should know.Diagnostics (Basel)2022;12:890 PMCID:PMC9026907

[18] BeaufrèreA,ParadisV.Combined hepatocellular-cholangiocarcinoma: an update.J Hepatol2021;74:1212-24

[19] ChoiJH.Combined hepatocellular-cholangiocarcinoma: an update on pathology and diagnostic approach.Biomedicines2022;10:1826 PMCID:PMC9405224

[20] GeraS,Acosta-GonzalezG.Clinical features, histology, and histogenesis of combined hepatocellular-cholangiocarcinoma.World J Hepatol2017;9:300-9 PMCID:PMC5332419

[21] VoiculescuM.How far we are towards eradication of HBV infection.J Gastrointestin Liver Dis2015;24:473-9

[22] FungJ,SetoWK.Nucleoside/nucleotide analogues in the treatment of chronic hepatitis B.J Antimicrob Chemother2011;66:2715-25

[23] RomagnoliD.Elimination of hepatitis C virus infection in Europe: targeting the obstacles.Exploration of Medicine

[24] LonardoA.Clearing hepatitis C virus with direct antiviral agents reduces cardiovascular events in patients with prediabetes. Commentary to Sasso and colleagues.Nutr Metab Cardiovasc Dis2021;31:2354-7

[25] MoonAM,TapperEB.Contemporary epidemiology of chronic liver disease and cirrhosis.Clin Gastroenterol Hepatol2020;18:2650-66 PMCID:PMC7007353

[26] LonardoA,AlswatKA.History of nonalcoholic fatty liver disease.Int J Mol Sci2020;21:5888 PMCID:PMC7460697

[27] PiscagliaF,BarchettiA.HCC-NAFLD Italian Study GroupClinical patterns of hepatocellular carcinoma in nonalcoholic fatty liver disease: a multicenter prospective study.Hepatology2016;63:827-38

[28] LonardoF.Metabolism and cancer-select topics.Metab Target Organ Damage2022;2:8

[29] LonardoF.Cancer in individuals with obesity and metabolic disorders. A preventable epidemic?.Metab Target Organ Damage2022;2:20

[30] AhmedM,LumsdenA.Metabolic profile predicts incident cancer: a large-scale population study in the UK Biobank.Metabolism2023;138:155342

[31] TrevisaniF,SantiV,BernardiM.Hepatocellular carcinoma in non-cirrhotic liver: a reappraisal.Dig Liver Dis2010;42:341-7

[32] SchütteK,PoranzkeJ.Characterization and prognosis of patients with hepatocellular carcinoma (HCC) in the non-cirrhotic liver.BMC Gastroenterol2014;14:117 PMCID:PMC4098694

[33] GaddikeriS,WangCL.Hepatocellular carcinoma in the noncirrhotic liver.AJR Am J Roentgenol2014;203:W34-47

[34] BengtssonB,WahlinS,HagströmH.Characteristics and outcome of hepatocellular carcinoma in patients with NAFLD without cirrhosis.Liver Int2019;39:1098-108

[35] HaiderMB,ChaudharyAJ,EdhiAI.Hereditary hemochromatosis: temporal trends, sociodemographic characteristics, and independent risk factor of hepatocellular cancer - nationwide population-based study.World J Hepatol2022;14:1804-16 PMCID:PMC9521447

[36] JamwalR,KushwahaDS.Hepatocellular carcinoma in non-cirrhotic versus cirrhotic liver: a clinico-radiological comparative analysis.Abdom Radiol (NY)2020;45:2378-87

[37] ChrysavgisL,DiamantopoulouP.Non-alcoholic fatty liver disease and hepatocellular carcinoma: clinical challenges of an intriguing link.World J Gastroenterol2022;28:310-31 PMCID:PMC8771615

[38] GawriehS,MillerE.Characteristics, aetiologies and trends of hepatocellular carcinoma in patients without cirrhosis: a United States multicentre study.Aliment Pharmacol Ther2019;50:809-21

[39] StineJG,ZimmetA.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 PMCID:PMC7495494

[40] TaraoK,IkedaT.Real impact of liver cirrhosis on the development of hepatocellular carcinoma in various liver diseases-meta-analytic assessment.Cancer Med2019;8:1054-65 PMCID:PMC6434205

[41] PinyopornpanishK,SalehMA.Hepatocellular carcinoma in nonalcoholic fatty liver disease with or without cirrhosis: a population-based study.BMC Gastroenterol2021;21:394 PMCID:PMC8529782

[42] DavilaJA,ShaibY,El-SeragHB.Diabetes increases the risk of hepatocellular carcinoma in the United States: a population based case control study.Gut2005;54:533-9 PMCID:PMC1774454

[43] WelzelTM,ZeuzemS,DavilaJA.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

[44] WelzelTM,QuraishiS,DavilaJA,McGlynnKA.Population-attributable fractions of risk factors for hepatocellular carcinoma in the United States.Am J Gastroenterol2013;108:1314-21 PMCID:PMC4105976

[45] RaffEJ,BloomerJR,RasheedK.Diabetes mellitus predicts occurrence of cirrhosis and hepatocellular cancer in alcoholic liver and non-alcoholic fatty liver diseases.J Clin Transl Hepatol2015;3:9-16 PMCID:PMC4542082

[46] PangY,TurnbullI.Diabetes, plasma glucose, and incidence of fatty liver, cirrhosis, and liver cancer: a prospective study of 0.5 million people.Hepatology2018;68:1308-18 PMCID:PMC6220764

[47] YangJD,MaraKC.Diabetes is associated with increased risk of hepatocellular carcinoma in patients with cirrhosis from nonalcoholic fatty liver disease.Hepatology2020;71:907-16 PMCID:PMC6960360

[48] KramerJR,DaiJ,LiL,KanwalF.Effect of diabetes medications and glycemic control on risk of hepatocellular cancer in patients with nonalcoholic fatty liver disease.Hepatology2022;75:1420-8 PMCID:PMC9107529

[49] DoychevaI,AmjadW.Diabetes and hepatocellular carcinoma: incidence trends and impact of liver disease etiology.J Clin Exp Hepatol2020;10:296-303 PMCID:PMC7335702

[50] DetterbeckFC.Systematic flaws in the use of systematic reviews and meta-analyses.Chest2022;161:1150-2

[51] MrzljakA,GiovanardiF.The prognostic role of diabetes mellitus type 2 in the setting of hepatocellular carcinoma: a systematic review and meta-analysis.Croat Med J2022;63:176-86 PMCID:PMC9086813

[52] YangC,LuY.Associations between diabetes mellitus and the risk of hepatocellular carcinoma in Asian individuals with hepatitis B and C infection: systematic review and a meta-analysis of cohort studies.Eur J Cancer Prev2022;31:107-16

[53] VáncsaS,HegyiP.Diabetes mellitus increases the risk of hepatocellular carcinoma after direct-acting antiviral therapy: systematic review and meta-analysis.Front Med (Lausanne)2021;8:744512 PMCID:PMC8558240

[54] LiQ,SuiC.Impact of metformin use on risk and mortality of hepatocellular carcinoma in diabetes mellitus.Clin Res Hepatol Gastroenterol2022;46:101781

[55] ZhouJ,LeiX.Meta-analysis: The efficacy of metformin and other anti-hyperglycemic agents in prolonging the survival of hepatocellular carcinoma patients with type 2 diabetes.Ann Hepatol2020;19:320-8

[56] TanY,ZhangW,YangJ.Type 2 diabetes mellitus increases the risk of hepatocellular carcinoma in subjects with chronic hepatitis B virus infection: a meta-analysis and systematic review.Cancer Manag Res2019;11:705-13 PMCID:PMC6338123

[57] WangP,CaoW,LiuZ.Diabetes mellitus and risk of hepatocellular carcinoma: a systematic review and meta-analysis.Diabetes Metab Res Rev2012;28:109-22

[58] GuptaA,MajumderK.Obesity is Independently associated with increased risk of hepatocellular cancer-related mortality: a systematic review and meta-analysis.Am J Clin Oncol2018;41:874-81 PMCID:PMC5700876

[59] LiY,LiuX,HuangY.Metabolic syndrome relates to high risk in hepatocellular carcinoma: a meta-analysis.Discov Med2018;26:185-196

[60] WangC,GongG.Increased risk of hepatocellular carcinoma in patients with diabetes mellitus: a systematic review and meta-analysis of cohort studies.Int J Cancer2012;130:1639-48

[61] TsaiPC,HungCH.T-COACH Study GroupMetformin reduces hepatocellular carcinoma incidence after successful antiviral therapy in patients with diabetes and chronic hepatitis C in Taiwan.J Hepatol2023;78:281-92

[62] JunBG,ShinHS,YiSW.Impact of overweight and obesity on the risk of hepatocellular carcinoma: a prospective cohort study in 14.3 million Koreans.Br J Cancer2022;127:109-15 PMCID:PMC9276765

[63] NairS,EasonJ,PerrilloRP.Is obesity an independent risk factor for hepatocellular carcinoma in cirrhosis?.Hepatology2002;36:150-5

[64] OhataK,ToriyamaK.Hepatic steatosis is a risk factor for hepatocellular carcinoma in patients with chronic hepatitis C virus infection.Cancer2003;97:3036-43

[65] TanakaA,KuriharaH.Hepatic steatosis as a possible risk factor for the development of hepatocellular carcinoma after eradication of hepatitis C virus with antiviral therapy in patients with chronic hepatitis C.World J Gastroenterol2007;13:5180-7 PMCID:PMC4171299

[66] OhkiT,ShiinaS.Visceral fat accumulation is an independent risk factor for hepatocellular carcinoma recurrence after curative treatment in patients with suspected NASH.Gut2009;58:839-44

[67] El-SeragHB,EverhartJE.Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma.Gastroenterology2004;126:460-8

[68] TsengCH.Diabetes is not an independent risk factor for hepatocellular carcinoma.Diabetes Metab Res Rev2013;29:515-24

[69] RegimbeauJM,MognolP.Obesity and diabetes as a risk factor for hepatocellular carcinoma.Liver Transpl2004;10:S69-73

[70] WatanabeN,ImaiK.Increased levels of serum leptin are a risk factor for the recurrence of stage I/II hepatocellular carcinoma after curative treatment.J Clin Biochem Nutr2011;49:153-8 PMCID:PMC3208009

[71] JainD,SaigalS.Hepatocellular carcinoma in nonalcoholic fatty liver cirrhosis and alcoholic cirrhosis: risk factor analysis in liver transplant recipients.Eur J Gastroenterol Hepatol2012;24:840-8

[72] GuptaSP,SathianB.Elevated serum insulin is an independent risk factor for hepatocellular carcinoma: a case control study from Nepal.Asian Pac J Cancer Prev2013;14:7331-3

[73] IbrahimAA,AbdellaHM.Study of the role of insulin resistance as a risk factor in HCV related hepatocellular carcinoma.J Egypt Soc Parasitol2015;45:107-13

[74] KamachiS,OtsukaT.Sarcopenia is a risk factor for the recurrence of hepatocellular carcinoma after curative treatment.Hepatol Res2016;46:201-8

[75] AzumaS,KakinumaS.Diabetic retinopathy as a risk factor associated with the development of hepatocellular carcinoma in nonalcoholic fatty liver disease.Dig Dis2019;37:247-54

[76] Valdés-PeregrinaEN,Gamboa-DomínguezA.Metabolic syndrome instead of aflatoxin-related tp53 r249s mutation as a hepatocellular carcinoma risk factor.Rev Invest Clin2020;72

[77] OhkiT,SatoT.Obesity is an independent risk factor for hepatocellular carcinoma development in chronic hepatitis C patients.Clin Gastroenterol Hepatol2008;6:459-64

[78] KonishiI,ShigematsuS.Diabetes pattern on the 75 g oral glucose tolerance test is a risk factor for hepatocellular carcinoma in patients with hepatitis C virus.Liver Int2009;29:1194-201

[79] TakahashiH,EguchiY.Post-challenge hyperglycemia is a significant risk factor for the development of hepatocellular carcinoma in patients with chronic hepatitis C.J Gastroenterol2011;46:790-8

[80] LiX,GaoP.Diabetes Mellitus is a risk factor for hepatocellular carcinoma in patients with chronic hepatitis B virus infection in China.Med Sci Monit2018;24:6729-34 PMCID:PMC6178879

[81] KurosakiM,MatsunagaK.Hepatic steatosis in chronic hepatitis C is a significant risk factor for developing hepatocellular carcinoma independent of age, sex, obesity, fibrosis stage and response to interferon therapy.Hepatol Res2010;40:870-7

[82] JiD,NiuXX.Non-alcoholic fatty liver disease is a risk factor for occurrence of hepatocellular carcinoma after sustained virologic response in chronic hepatitis C patients: a prospective four-years follow-up study.Metabol Open2021;10:100090 PMCID:PMC8050772

[83] FanR,MaH.Chronic Hepatitis B Study ConsortiumAssociation of central obesity with hepatocellular carcinoma in patients with chronic hepatitis B receiving antiviral therapy.Aliment Pharmacol Ther2021;54:329-38

[84] ImaiK,MiwaT.Higher accumulation of visceral adipose tissue is an independent risk factor for hepatocellular carcinoma among viral hepatitis patients with non-cirrhotic livers.Cancers (Basel)2021;13:5980 PMCID:PMC8657094

[85] ZhangL,LiM,DengW.The association of leptin and adiponectin with hepatocellular carcinoma risk and prognosis: a combination of traditional, survival, and dose-response meta-analysis.BMC Cancer2020;20:1167 PMCID:PMC7708253

[86] PiñeroF,BoteonYL.Latin American Liver ResearchEducationAwareness Network (LALREAN)A changing etiologic scenario in liver transplantation for hepatocellular carcinoma in a multicenter cohort study from Latin America.Clin Res Hepatol Gastroenterol2018;42:443-52

[87] Van Iderstine M, Iluz-Freundlich D, Dolovich C, Villarin E, Minuk GY. Liver disease referrals to an urban, hospital-based hepatology outpatient clinic over the past 25 years.JGH Open2020;4:484-9

[88] ZouB,JeongD.A nationwide study of inpatient admissions, mortality, and costs for patients with cirrhosis from 2005 to 2015 in the USA.Dig Dis Sci2020;65:1520-8

[89] GuW,ErasmusHP.Trends and the course of liver cirrhosis and its complications in Germany: nationwide population-based study (2005 to 2018).Lancet Reg Health Eur2022;12:100240 PMCID:PMC8640738

[90] PaikJM,EberlyKE,HenryL.Global burden of NAFLD and chronic liver disease among adolescents and young adults.Hepatology2022;75:1204-17

[91] AhmadMI,KodaliS,BellSM.Hepatocellular carcinoma due to nonalcoholic fatty liver disease: current concepts and future challenges.J Hepatocell Carcinoma2022;9:477-96 PMCID:PMC9167599

[92] BenhammouJN,AbyES.Nonalcoholic fatty liver disease-related hepatocellular carcinoma growth rates and their clinical outcomes.Hepatoma Res2021;7:70 PMCID:PMC8713558

[93] YounossiZ,OngJP.Global Nonalcoholic Steatohepatitis CouncilNonalcoholic steatohepatitis is the fastest growing cause of hepatocellular carcinoma in liver transplant candidates.Clin Gastroenterol Hepatol2019;17:748-755.e3

[94] KuperH,MucciLA,BenetouV.Risk factors for cholangiocarcinoma in a low risk Caucasian population.Soz Praventivmed2001;46:182-5

[95] ShaibYH,DavilaJA,McGlynnKA.Risk factors of intrahepatic cholangiocarcinoma in the United States: a case-control study.Gastroenterology2005;128:620-6

[96] ChangJS,ChenLT.Medical risk factors associated with cholangiocarcinoma in Taiwan: a population-based case-control study.PLoS One2013;8:e69981 PMCID:PMC3718690

[97] LeeBS,ParkEC.Risk factors for perihilar cholangiocarcinoma: a hospital-based case-control study.Liver Int2015;35:1048-53

[98] Barner-RasmussenN,HadkhaleK.Risk factors, epidemiology and prognosis of cholangiocarcinoma in Finland.United European Gastroenterol J2021;9:1128-35 PMCID:PMC8672081

[99] WelzelTM,GloriaG.Risk factors for intrahepatic cholangiocarcinoma in a low-risk population: a nationwide case-control study.Int J Cancer2007;120:638-41

[100] PalmerWC.Are common factors involved in the pathogenesis of primary liver cancers?.J Hepatol2012;57:69-76 PMCID:PMC3804834

[101] ChaiteerakijR,HarmsenWS.Risk factors for intrahepatic cholangiocarcinoma: association between metformin use and reduced cancer risk.Hepatology2013;57:648-55 PMCID:PMC3565026

[102] AhrensW,VybergM.Risk factors for extrahepatic biliary tract carcinoma in men: medical conditions and lifestyle: results from a European multicentre case-control study.Eur J Gastroenterol Hepatol2007;19:623-30

[103] WelzelTM,El-SeragHB.Risk factors for intrahepatic and extrahepatic cholangiocarcinoma in the United States: a population-based case-control study.Clin Gastroenterol Hepatol2007;5:1221-8 PMCID:PMC2083573

[104] ZhouYM,YangJM.Risk factors for intrahepatic cholangiocarcinoma: a case-control study in China.World J Gastroenterol2008;14:632-5

[105] ZhouZ,JiangB,LvP.Risk factors for extrahepatic cholangiocarcinoma: a case-control study in China.Eur J Cancer Prev2019;28:254-7

[106] ChoiJ,PeeraphatditT.Aspirin use and the risk of cholangiocarcinoma.Hepatology2016;64:785-96

[107] PetrickJL,AltekruseSF.Risk factors for intrahepatic and extrahepatic cholangiocarcinoma in the United States: a population-based study in SEER-Medicare.PLoS One2017;12:e0186643 PMCID:PMC5648218

[108] ChungT.Up-to-date pathologic classification and molecular characteristics of intrahepatic cholangiocarcinoma.Front Med (Lausanne)2022;9:857140 PMCID:PMC9008308

[109] AishimaS.Pathogenesis and classification of intrahepatic cholangiocarcinoma: different characters of perihilar large duct type versus peripheral small duct type.J Hepatobiliary Pancreat Sci2015;22:94-100

[110] VijM,RammohanA.Pathological, molecular, and clinical characteristics of cholangiocarcinoma: a comprehensive review.World J Gastrointest Oncol2022;14:607-27 PMCID:PMC8919011

[111] ZenY.Intrahepatic cholangiocarcinoma: typical features, uncommon variants, and controversial related entities.Hum Pathol2023;132:197-207

[112] der Stroth L, Tharehalli U, Günes C, Lechel A. Telomeres and telomerase in the development of liver cancer.Cancers (Basel)2020;12:2048 PMCID:PMC7464754

[113] MangnallD,MajeedAW.The molecular physiology of liver regeneration following partial hepatectomy.Liver Int2003;23:124-38

[114] LonardoA,NascimbeniF.Telomere shortening: an innocent bystander at the crossroad of NASH with ageing and cardiometabolic risk?.Liver Int2018;38:1730-2

[115] DonatiB.Telomeres, NAFLD and chronic liver disease.Int J Mol Sci2016;17:383 PMCID:PMC4813240

[116] CalderaroJ,ParadisV.Molecular and histological correlations in liver cancer.J Hepatol2019;71:616-30

[117] KhemlinaG,KurzrockR.The biology of Hepatocellular carcinoma: implications for genomic and immune therapies.Mol Cancer2017;16:149 PMCID:PMC5577674

[118] TakaiA,WangXW.Identification of drivers from cancer genome diversity in hepatocellular carcinoma.Int J Mol Sci2014;15:11142-60 PMCID:PMC4100204

[119] NgCKY,BoldanovaT.Integrative proteogenomic characterization of hepatocellular carcinoma across etiologies and stages.Nat Commun2022;13:2436 PMCID:PMC9068765

[120] IoannouGN.Epidemiology and risk-stratification of NAFLD-associated HCC.J Hepatol2021;75:1476-84

[121] CampaniC.Molecular mechanisms of liver carcinogenesis related to metabolic syndrome.HR2022;

[122] MontellaL,AmbrosinoA.The role of immunotherapy in a tolerogenic environment: current and future perspectives for hepatocellular carcinoma.Cells2021;10:1909 PMCID:PMC8393830

[123] RingelhanM,O'ConnorT,HeikenwalderM.The immunology of hepatocellular carcinoma.Nat Immunol2018;19:222-32

[124] CrispeIN.The liver as a lymphoid organ.Annu Rev Immunol2009;27:147-63

[125] WadaY,KutamiR,KojiroM.Clinicopathological study on hepatocellular carcinoma with lymphocytic infiltration.Hepatology1998;27:407-14

[126] LeiQ,ZouH.Efficacy and safety of monotherapy and combination therapy of immune checkpoint inhibitors as first-line treatment for unresectable hepatocellular carcinoma: a systematic review, meta-analysis and network meta-analysis.Discov Oncol2022;13:95 PMCID:PMC9519826

[127] JácomeAA,VasconcelosJPS.Efficacy and safety associated with immune checkpoint inhibitors in unresectable hepatocellular carcinoma: a meta-analysis.JAMA Netw Open2021;4:e2136128

[128] WangR,MaoB.The efficacy of immune checkpoint inhibitors in advanced hepatocellular carcinoma: a meta-analysis based on 40 cohorts incorporating 3697 individuals.J Cancer Res Clin Oncol2022;148:1195-210

[129] PfisterD,PinyolR.NASH limits anti-tumour surveillance in immunotherapy-treated HCC.Nature2021;592:450-6 PMCID:PMC8046670

[130] HaberPK,CastetF.Evidence-based management of hepatocellular carcinoma: systematic review and meta-analysis of randomized controlled trials (2002-2020).Gastroenterology2021;161:879-98

[131] RuiL.Reprogramming of hepatic metabolism and microenvironment in nonalcoholic steatohepatitis.Annu Rev Nutr2022;42:91-113

[132] PeiselerM,HampeJ,HeikenwälderM.Immune mechanisms linking metabolic injury to inflammation and fibrosis in fatty liver disease - novel insights into cellular communication circuits.J Hepatol2022;77:1136-60

[133] WabitschS,KamenyevaO.Metformin treatment rescues CD8⁺ T-cell response to immune checkpoint inhibitor therapy in mice with NAFLD.J Hepatol2022;77:748-60 PMCID:PMC9391315

[134] KartsoliS,TsimihodimosV,ChristodoulouDK.Lipidomics in non-alcoholic fatty liver disease.World J Hepatol2020;12:436-50 PMCID:PMC7475773

[135] HigashiT,HoshidaY.Hepatic stellate cells as key target in liver fibrosis.Adv Drug Deliv Rev2017;121:27-42 PMCID:PMC5682243

[136] Association for the Study of the Liver. Electronic address: [e-mail]; European Association for the Study of the Liver. EASL clinical practice guidelines: management of hepatocellular carcinoma.J Hepatol2018;69:182-236

[137] MarreroJA,SirlinCB.Diagnosis, staging, and management of hepatocellular carcinoma: 2018 practice guidance by the american association for the study of liver diseases.Hepatology2018;68:723-50

[138] TsochatzisEA,BurroughsAK.Liver cirrhosis.Lancet2014;383:1749-61

[139] RiskMC,ColemanI.Differential gene expression in benign prostate epithelium of men with and without prostate cancer: evidence for a prostate cancer field effect.Clin Cancer Res2010;16:5414-23 PMCID:PMC2992073

[140] MaC,EggertT.NAFLD causes selective CD4⁺ T lymphocyte loss and promotes hepatocarcinogenesis.Nature2016;531:253-7 PMCID:PMC4786464

[141] DapitoDH,GwakGY.Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4.Cancer Cell2012;21:504-16 PMCID:PMC3332000

[142] MaC,HeinrichB.Gut microbiome-mediated bile acid metabolism regulates liver cancer via NKT cells.Science2018;360:eaan5931 PMCID:PMC6407885

[143] JiangY,HuK.Inflammatory microenvironment of fibrotic liver promotes hepatocellular carcinoma growth, metastasis and sorafenib resistance through STAT3 activation.J Cell Mol Med2021;25:1568-82 PMCID:PMC7875922

[144] QinW,LiuS.Recent advances regarding tumor microenvironment and immunotherapy in hepatocellular carcinoma.HR2020;2020

[145] LonardoA,MaurantonioM,RinaldiL.Nonalcoholic fatty liver disease: evolving paradigms.World J Gastroenterol2017;23:6571-92 PMCID:PMC5643282

[146] BalakrishnanM.Editorial: NAFLD-related hepatocellular carcinoma - increasing or not?.Aliment Pharmacol Ther2018;47:437-438

[147] LonardoA,OsnaN.Effect of cofactors on NAFLD/NASH and MAFLD. A paradigm illustrating the pathomechanics of organ dysfunction.Metab Target Organ Damage2022;2:12 PMCID:PMC9453927

[148] AvgerinosKI,MantzorosCS.Obesity and cancer risk: emerging biological mechanisms and perspectives.Metabolism2019;92:121-35

[149] DewidarB,PafiliK.Metabolic liver disease in diabetes - from mechanisms to clinical trials.Metabolism2020;111S:154299 PMCID:PMC7305712

[150] HashibaM,HyogoH.Glycemic variability is an independent predictive factor for development of hepatic fibrosis in nonalcoholic fatty liver disease.PLoS One2013;8:e76161 PMCID:PMC3819352

[151] KobayashiD,TakahashiO.Glycemic variability and subsequent malignancies among the population without diabetes.Diabetes Res Clin Pract2020;159:107987

[152] YooJJ,HanK.Glucose variability and risk of hepatocellular carcinoma in patients with diabetes: a nationwide population-based study.Cancer Epidemiol Biomarkers Prev2021;30:974-81

[153] MaoD,WuH.Risk associations of glycemic burden and obesity with liver cancer-a 10-year analysis of 15,280 patients with type 2 diabetes.Hepatol Commun2022;6:1350-60 PMCID:PMC9134801

[154] MaoD,WuH.Risk associations of long-term HbA1c variability and obesity on cancer events and cancer-specific death in 15,286 patients with diabetes - a prospective cohort study.Lancet Reg Health West Pac2022;18:100315 PMCID:PMC8669375

[155] ShinHS,YiSW.Impact of diabetes, obesity, and dyslipidemia on the risk of hepatocellular carcinoma in patients with chronic liver diseases.Clin Mol Hepatol28:773-789 PMCID:PMC9597232

[156] ZhangX,YipTC.Angiotensin-converting enzyme inhibitors prevent liver-related events in nonalcoholic fatty liver disease.Hepatology2022;76:469-82

[157] L.; Deng, C.; Lin, Z.; Giovannucci, E.; Zhang, X. Dietary fats, serum cholesterol and liver cancer risk: a systematic review and meta-analysis of prospective studies.Cancers2021;13:1580

[158] KechagiasS,BlomdahlJ.Established and emerging factors affecting the progression of nonalcoholic fatty liver disease.Metabolism2020;111S:154183

[159] GuarinoM,FelserA,Guixé-MuntetS,FotiM,St-PierreMV.Exercise attenuates the transition from fatty liver to steatohepatitis and reduces tumor formation in mice.Cancers (Basel)12:1407 PMCID:PMC7352494

[160] FagesA,StepienM.Metabolomic profiles of hepatocellular carcinoma in a European prospective cohort.BMC Med2015;13:242 PMCID:PMC4581424

[161] GaoHC,LiuX,ZhaoLC.Application of H-1 NMR-based metabonomics in the study of metabolic profiling of human hepatocellular carcinoma and liver cirrhosis. Cancer Sci. 2009;100:782-5.

[162] JiangH,WangJ,HeC.Adiponectin and the risk of gastrointestinal cancers in East Asians: mendelian randomization analysis.Cancer Med2022;11:2397-404 PMCID:PMC9189470

[163] LiuZY,FangAP,HeTT,YishakeD,LuXT,ZhuHL.High serum fibroblast growth factor 21 is associated with inferior hepatocellular carcinoma survival: a prospective cohort study.Liver Int2022;42:663-73

[164] FouassierL,AfonsoMB.Signalling networks in cholangiocarcinoma: molecular pathogenesis, targeted therapies and drug resistance.Liver Int2019;39 Suppl 1:43-62

[165] LabibPL,PereiraSP.Molecular pathogenesis of cholangiocarcinoma.BMC Cancer2019;19:185 PMCID:PMC6394015

[166] HagaH,TakahashiK,ZubairA.Tumour cell-derived extracellular vesicles interact with mesenchymal stem cells to modulate the microenvironment and enhance cholangiocarcinoma growth.J Extracell Vesicles2015;4:24900 PMCID:PMC4283029

[167] MorikawaM,MiyazonoK.TGF-β and the TGF-β family: context-dependent roles in cell and tissue physiology.Cold Spring Harb Perspect Biol2016;8:a021873 PMCID:PMC4852809

[168] FabregatI,SánchezA,DewidarB,TenDijke P.IT-LIVER ConsortiumTGF-β signalling and liver disease.FEBS J2016;283:2219-32

[169] PapoutsoglouP,CoulouarnC.Transforming growth factor-beta (TGFβ) signaling pathway in cholangiocarcinoma.Cells2019;8:960 PMCID:PMC6770250

[170] YunYR,JeonE.Fibroblast growth factors: biology, function, and application for tissue regeneration.J Tissue Eng2010;2010:218142 PMCID:PMC3042641

[171] ItohN.Fibroblast growth factors: from molecular evolution to roles in development, metabolism and disease.J Biochem2011;149:121-30 PMCID:PMC3106964

[172] WescheJ,HaugstenEM.Fibroblast growth factors and their receptors in cancer.Biochem J2011;437:199-213

[173] ChenL,YinL,HuangP,LiangG.Fibroblast growth factor receptor fusions in cancer: opportunities and challenges.J Exp Clin Cancer Res2021;40:345 PMCID:PMC8564965

[174] JinW.ErBb Family Proteins in Cholangiocarcinoma and Clinical Implications.J Clin Med2020;9:2255 PMCID:PMC7408920

[175] OnoriP,GaudioE.Secretin inhibits cholangiocarcinoma growth via dysregulation of the cAMP-dependent signaling mechanisms of secretin receptor.Int J Cancer2010;127:43-54

[176] YothaisongS,TechasenA.Increased activation of PI3K/AKT signaling pathway is associated with cholangiocarcinoma metastasis and PI3K/mTOR inhibition presents a possible therapeutic strategy.Tumour Biol2013;34:3637-48

[177] TanimizuN.Notch signaling controls hepatoblast differentiation by altering the expression of liver-enriched transcription factors.J Cell Sci2004;117:3165-74

[178] TakebeN,HarrisPJ.Targeting notch, hedgehog, and wnt pathways in cancer stem cells: clinical update.Nat Rev Clin Oncol2015;12:445-64 PMCID:PMC4520755

[179] MancarellaS,GiganteI.CD90 is regulated by notch1 and hallmarks a more aggressive intrahepatic cholangiocarcinoma phenotype.J Exp Clin Cancer Res2022;41:65 PMCID:PMC8851853

[180] O'RourkeCJ,NepalC.Identification of a pan-gamma-secretase inhibitor response signature for notch-driven cholangiocarcinoma.Hepatology2020;71:196-213 PMCID:PMC6918012

[181] PerugorriaMJ,LabianoI,MarzioniM,BujandaL.Wnt-β-catenin signalling in liver development, health and disease.Nat Rev Gastroenterol Hepatol2019;16:121-36

[182] ShenDY,ZengX.Inhibition of Wnt/β-catenin signaling downregulates P-glycoprotein and reverses multi-drug resistance of cholangiocarcinoma.Cancer Sci2013;104:1303-8 PMCID:PMC7656555

[183] WuMJ,MerrittJ,BardeesyN.Biology of IDH mutant cholangiocarcinoma.Hepatology2022;75:1322-37

[184] TsimafeyeuI.Cholangiocarcinoma: an emerging target for molecular therapy.Gastrointest Tumors2021;8:153-8 PMCID:PMC8546446

[185] LuchiniC.The roles of chromatin remodeling genes in pancreatic-biliary malignancies.Crit Rev Oncog2017;22:471-479

[186] LiuZH,DongQZ.Whole-exome mutational and transcriptional landscapes of combined hepatocellular cholangiocarcinoma and intrahepatic cholangiocarcinoma reveal molecular diversity.Biochim Biophys Acta Mol Basis Dis2018;1864:2360-8

[187] ChungT,ShimHS,ChoiGH,ParkYN.Genetic, clinicopathological, and radiological features of intrahepatic cholangiocarcinoma with ductal plate malformation pattern.Gut Liver2022;16:613-24 PMCID:PMC9289835

[188] BruixJ.American Association for the Study of Liver DiseasesManagement of hepatocellular carcinoma: an update.Hepatology2011;53:1020-2 PMCID:PMC3084991

[189] RaduP.Sonography in surveillance for HCC in NAFLD patients.Hepatoma Res2022;8:38

[190] LoombaR,PattonH.AGA clinical practice update on screening and surveillance for hepatocellular carcinoma in patients with nonalcoholic fatty liver disease: expert review.Gastroenterology2020;158:1822-30 PMCID:PMC8012107

[191] IoannouGN.Editorial: hepatocellular carcinoma in the absence of cirrhosis-a nightmare without solution.Aliment Pharmacol Ther2019;50:1062-3

[192] PlazTorres MC,FurnariM.Surveillance for hepatocellular carcinoma in patients with non-alcoholic fatty liver disease: universal or selective?.Cancers (Basel)2020;12:1422

[193] CholankerilG.Current challenges and future direction in surveillance for hepatocellular carcinoma in patients with nonalcoholic fatty liver disease.Semin Liver Dis2023;43:89-99

[194] BowlusCL,LindorKD.AGA clinical practice update on surveillance for hepatobiliary cancers in patients with primary sclerosing cholangitis: expert review.Clin Gastroenterol Hepatol2019;17:2416-22

[195] SripaB.Cholangiocarcinoma: lessons from Thailand.Curr Opin Gastroenterol2008;24:349-56 PMCID:PMC4130346

[196] SiripongsakunS,CharuswattanakulS.Ultrasound surveillance for cholangiocarcinoma in an endemic area: a prove of survival benefits.J Gastroenterol Hepatol2018;33:1383-8

[197] TovoliF,IavaroneM.Surveillance for hepatocellular carcinoma also improves survival of incidentally detected intrahepatic cholangiocarcinoma arisen in liver cirrhosis.Liver Cancer2020;9:744-55 PMCID:PMC7768136