Liver fibrosis as a barometer of systemic health by gauging the risk of extrahepatic disease

Abstract

This review article proposes the theory that liver fibrosis, the abnormal accumulation of excessive extracellular matrix, is not just an indicator of liver disease but also a negative reflection of overall systemic health. Liver fibrosis poses a heavy financial burden on healthcare systems worldwide and can develop due to chronic liver disease from various causes, often due to sustained inflammation. Liver fibrosis may not generate symptoms and become apparent only when it reaches the stage of cirrhosis and is associated with clinically significant portal hypertension and leads to decompensation events or promotes the development of hepatocellular carcinoma. While chronic viral hepatitis and excessive alcohol consumption were once the primary causes of chronic liver disease featuring fibrosis, this role is now increasingly taken over by metabolic dysfunction-associated steatotic liver disease (MASLD). In MASLD, endothelial dysfunction is an essential component in pathogenesis, promoting the development of liver fibrosis, but it is also present in endothelial cells of other organs such as the heart, lungs, and kidneys. Accordingly, liver fibrosis is a significant predictor of liver-related outcomes, as well as all-cause mortality, cardiovascular risk, and extrahepatic cancer. Physicians should be aware that individuals seeking medical attention for reasons unrelated to liver health may also have advanced fibrosis. Early identification of these at-risk individuals can lead to a more comprehensive assessment and the use of various treatment options, both approved and investigational, to slow or reverse the progression of liver fibrosis.

Keywords

Biomarkers / cancer / cardiovascular disease / diabetes / liver fibrosis / MASH / MASLD mortality / vibration-controlled transient elastography

References

[1] BatallerR.Liver fibrosis.J Clin Invest2005;115:209-18 PMCID:PMC546435

[2] LonardoA.Liver fibrosis: more than meets the eye.Ann Hepatol2024;29:101479

[3] RoehlenN,BaumertTF.Liver fibrosis: mechanistic concepts and therapeutic perspectives.Cells2020;9:875 PMCID:PMC7226751

[4] BallestriS,GirolamoMD,CapitelliM.Liver fibrosis in nonalcoholic fatty liver disease patients: noninvasive evaluation and correlation with cardiovascular disease and mortality.Metab Target Organ Damage2023;3:1

[5] GeertsA.History, heterogeneity, developmental biology, and functions of quiescent hepatic stellate cells.Semin Liver Dis2001;21:311-35

[6] SufleţelRT,GhebanBA,MihuCM.Hepatic stellate cells - from past till present: morphology, human markers, human cell lines, behavior in normal and liver pathology.Rom J Morphol Embryol2020;61:615-42 PMCID:PMC8112759

[7] ITOT.[Kupfer’s cells and fat storing cells in the capillary wall of human liver].Okajimas Folia Anat Jpn1952;24:243-58

[8] TanumaY,ShibasakiS.Further electron-microscope studies on the human hepatic sinusoidal wall with special reference to the fat-storing cell.Arch Histol Jpn1982;45:263-74

[9] TanumaY,ItoT.Electron microscopic studies on the sinusoidal cells in the monkey liver.Arch Histol Jpn1983;46:401-26

[10] ItoT,UkidaM.Scanning electron microscopy of Ito’s fat-storing cells in the rat liver.Acta Med Okayama1984;38:1-9

[11] FriedmanSL,BoylesJ.Hepatic lipocytes: the principal collagen-producing cells of normal rat liver.Proc Natl Acad Sci U S A1985;82:8681-5 PMCID:PMC391500

[12] RamadoriG.Portal tract fibrogenesis in the liver.Lab Invest2004;84:153-9

[13] ForbesSJ,ReyV.A significant proportion of myofibroblasts are of bone marrow origin in human liver fibrosis.Gastroenterology2004;126:955-63

[14] BatallerR,BrennerDA.Genetic polymorphisms and the progression of liver fibrosis: a critical appraisal.Hepatology2003;37:493-503

[15] MontfortI.Collagenase in experimental carbon tetrachloride cirrhosis of the liver.Am J Pathol1978;92:411-20 PMCID:PMC2018284

[16] Pérez-TamayoR.Cirrhosis of the liver: a reversible disease?.Pathol Annu1979;14:183-213

[17] HammelP,O'TooleD.Regression of liver fibrosis after biliary drainage in patients with chronic pancreatitis and stenosis of the common bile duct.N Engl J Med2001;344:418-23

[18] BatallerR.Hepatic stellate cells as a target for the treatment of liver fibrosis.Semin Liver Dis2001;21:437-51

[19] TrivellaJP,CarrionAF.Novel targeted therapies for the management of liver fibrosis.Expert Opin Emerg Drugs2020;25:59-70

[20] LanY,WengH.The burden of liver cirrhosis and underlying etiologies: results from the Global Burden of Disease study 2019.Hepatol Commun2023;7:e0026 PMCID:PMC10019239

[21] WuXN,ZhangN.Global burden of liver cirrhosis and other chronic liver diseases caused by specific etiologies from 1990 to 2019.BMC Public Health2024;24:363 PMCID:PMC10837876

[22] RinellaME.From NAFLD to MASLD: updated naming and diagnosis criteria for fatty liver disease.J Lipid Res2024;65:100485 PMCID:PMC10824973

[23] CiardulloS.From NAFLD to MAFLD and MASLD: a tale of alcohol, stigma and metabolic dysfunction.Metab Target Organ Damage2024;4:30

[24] TanD,WongZY.Global Epidemiology of cirrhosis: changing etiological basis and comparable burden of nonalcoholic steatohepatitis between males and females.Dig Dis2023;41:900-12 PMCID:PMC10716870

[25] HagströmH,HolmerM.Etiologies and outcomes of cirrhosis in a large contemporary cohort.Scand J Gastroenterol2021;56:727-32

[26] 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

[27] WeiskirchenR,TackeF.Recent advances in understanding liver fibrosis: bridging basic science and individualized treatment concepts.F1000Res2018;7:921 PMCID:PMC6024236

[28] WeiskirchenR,TackeF.Organ and tissue fibrosis: molecular signals, cellular mechanisms and translational implications.Mol Aspects Med2019;65:2-15

[29] FriedmanSL.Mechanisms of hepatic fibrogenesis.Gastroenterology2008;134:1655-69 PMCID:PMC2888539

[30] TesterinkN,HouwelingM.Replacement of retinyl esters by polyunsaturated triacylglycerol species in lipid droplets of hepatic stellate cells during activation.PLoS One2012;7:e34945 PMCID:PMC3335019

[31] DelgadoME,FarranN.Metabolic reprogramming of liver fibrosis.Cells2021;10:3604 PMCID:PMC8700241

[32] ShahV,Garcia-CardenaG.Liver sinusoidal endothelial cells are responsible for nitric oxide modulation of resistance in the hepatic sinusoids.J Clin Invest1997;100:2923-30 PMCID:PMC508500

[33] Chávez-GalánL,VesinD.Much more than M1 and M2 macrophages, there are also CD169⁺ and TCR⁺ macrophages.Front Immunol2015;6:263 PMCID:PMC4443739

[34] Duque G, Descoteaux A. Macrophage cytokines: involvement in immunity and infectious diseases.Front Immunol2014;5:491 PMCID:PMC4188125

[35] LeeUE.Mechanisms of hepatic fibrogenesis.Best Pract Res Clin Gastroenterol2011;25:195-206 PMCID:PMC3079877

[36] MittenEK.Mechanotransduction in the pathogenesis of non-alcoholic fatty liver disease.J Hepatol2022;77:1642-56

[37] BaffyG.Gut microbiota and sinusoidal vasoregulation in MASLD: a portal perspective.Metabolites2024;14:324 PMCID:PMC11205793

[38] AirdWC.Phenotypic heterogeneity of the endothelium: II. Representative vascular beds.Circ Res2007;100:174-90

[39] AugustinHG.A systems view of the vascular endothelium in health and disease.Cell2024;187:4833-58

[40] ZhangYL,GouHZ,ZhangL.The gut microbiota-bile acid axis: a potential therapeutic target for liver fibrosis.Front Cell Infect Microbiol2022;12:945368 PMCID:PMC9519863

[41] ArabJP,ShahVH.Gut microbiota in non-alcoholic fatty liver disease and alcohol-related liver disease: current concepts and perspectives.Hepatol Res2020;50:407-18 PMCID:PMC7187400

[42] CostaCFFA,AraujoR.Gut microbiome and organ fibrosis.Nutrients2022;14:352 PMCID:PMC8781069

[43] WinstonJA.Diversification of host bile acids by members of the gut microbiota.Gut Microbes2020;11:158-71 PMCID:PMC7053883

[44] LarabiAB,BäumlerAJ.Bile acids as modulators of gut microbiota composition and function.Gut Microbes2023;15:2172671 PMCID:PMC9904317

[45] BarabásiAL,LoscalzoJ.Network medicine: a network-based approach to human disease.Nat Rev Genet2011;12:56-68 PMCID:PMC3140052

[46] OuyangX,MehalWZ.Inflammasome biology in fibrogenesis.Biochim Biophys Acta2013;1832:979-88

[47] Borkham-KamphorstE.The PDGF system and its antagonists in liver fibrosis.Cytokine Growth Factor Rev2016;28:53-61

[48] SchonHT.Immunomodulatory effects of transforming growth factor-β in the liver.Hepatobiliary Surg Nutr2014;3:386-406 PMCID:PMC4273109

[49] KangH,OhYS.TGF-β activates NLRP3 inflammasome by an autocrine production of TGF-β in LX-2 human hepatic stellate cells.Mol Cell Biochem2022;477:1329-38 PMCID:PMC8989865

[50] Blas-GarcíaA.Novel therapeutic approaches to liver fibrosis based on targeting oxidative stress.Antioxidants2023;12:1567 PMCID:PMC10451738

[51] BallestriS,FontanaMC.Direct oral anticoagulants in patients with liver disease in the era of non-alcoholic fatty liver disease global epidemic: a narrative review.Adv Ther2020;37:1910-32 PMCID:PMC7467481

[52] LonardoA.Does an aspirin a day take the MASLD away?.Adv Ther2024;41:2559-75

[53] OhH,SongMS,BaekJH.The therapeutic potential of anticoagulation in organ fibrosis.Front Med2022;9:866746 PMCID:PMC9148959

[54] WeiskirchenR.The role of radiologic modalities in diagnosing nonalcoholic steatohepatitis (NASH) and fibrosis.Curr Hepatology Rep2018;17:324-35

[55] NascimbeniF,MachadoMV.Clinical relevance of liver histopathology and different histological classifications of NASH in adults.Expert Rev Gastroenterol Hepatol2018;12:351-67

[56] Ratziu V, Charlotte F, Heurtier A, et al; LIDO Study Group. Sampling variability of liver biopsy in nonalcoholic fatty liver disease. Gastroenterology 2005;128:1898-906.

[57] BallestriS,BaldelliE.Liver fibrosis biomarkers accurately exclude advanced fibrosis and are associated with higher cardiovascular risk scores in patients with NAFLD or viral chronic liver disease.Diagnostics2021;11:98 PMCID:PMC7827076

[58] SanyalAJ,WongVW.Noninvasive assessment of liver fibrosis in NAFLD.Clin Gastroenterol Hepatol2023;21:2026-39

[59] BoursierJ,CostentinC.Impact of type 2 diabetes on the accuracy of noninvasive tests of liver fibrosis with resulting clinical implications.Clin Gastroenterol Hepatol2023;21:1243-51.e12

[60] SunW,LiN.Comparison of FIB-4 index, NAFLD fibrosis score and BARD score for prediction of advanced fibrosis in adult patients with non-alcoholic fatty liver disease: a meta-analysis study.Hepatol Res2016;46:862-70

[61] XiaoG,XiaoX,YangJ.Comparison of laboratory tests, ultrasound, or magnetic resonance elastography to detect fibrosis in patients with nonalcoholic fatty liver disease: a meta-analysis.Hepatology2017;66:1486-501

[62] FerraioliG,CasteraL.Liver ultrasound elastography: an update to the world federation for ultrasound in medicine and biology guidelines and recommendations.Ultrasound Med Biol2018;44:2419-40

[63] BallestriS,LugariS,FrancicaG.A critical appraisal of the use of ultrasound in hepatic steatosis.Expert Rev Gastroenterol Hepatol2019;13:667-81

[64] de Franchis R, Bosch J, Garcia-Tsao G, Reiberger T, Ripoll C; Baveno VII Faculty. Baveno VII - renewing consensus in portal hypertension. J Hepatol 2022;76:959-74. PMCID:PMC11090185

[65] WattacherilJJ,LimJK.AGA clinical practice update on the role of noninvasive biomarkers in the evaluation and management of nonalcoholic fatty liver disease: expert review.Gastroenterology2023;165:1080-8

[66] European Association for the Study of the Liver. Electronic address: [e-mail]; Clinical Practice Guideline Panel; Chair:; EASL Governing Board representative:; Panel members:. EASL clinical practice guidelines on non-invasive tests for evaluation of liver disease severity and prognosis - 2021 update.J Hepatol2021;75:659-89

[67] NewsomePN,DeeksJJ.FibroScan-AST (FAST) score for the non-invasive identification of patients with non-alcoholic steatohepatitis with significant activity and fibrosis: a prospective derivation and global validation study.Lancet Gastroenterol Hepatol2020;5:362-73 PMCID:PMC7066580

[68] Mózes FE, Lee JA, Selvaraj EA, et al; LITMUS Investigators. Diagnostic accuracy of non-invasive tests for advanced fibrosis in patients with NAFLD: an individual patient data meta-analysis. Gut 2022;71:1006-19. PMCID:PMC8995830

[69] PatelK.Limitations of non-invasive tests for assessment of liver fibrosis.JHEP Rep2020;2:100067 PMCID:PMC7047178

[70] McPhersonS,DufourJF.Age as a confounding factor for the accurate non-invasive diagnosis of advanced NAFLD fibrosis.Am J Gastroenterol2017;112:740-51 PMCID:PMC5418560

[71] PettaS,BugianesiE.Impact of obesity and alanine aminotransferase levels on the diagnostic accuracy for advanced liver fibrosis of noninvasive tools in patients with nonalcoholic fatty liver disease.Am J Gastroenterol2019;114:916-28

[72] ZhangX,WongVW.Application of transient elastography in nonalcoholic fatty liver disease.Clin Mol Hepatol2020;26:128-41 PMCID:PMC7160347

[73] Vilar-GomezE,Wai-SunWong V.Fibrosis severity as a determinant of cause-specific mortality in patients with advanced nonalcoholic fatty liver disease: a multi-national cohort study.Gastroenterology2018;155:443-57.e17

[74] TargherG,TilgH.MASLD: a systemic metabolic disorder with cardiovascular and malignant complications.Gut2024;73:691-702

[75] TaylorRS,BaylissS.Association between fibrosis stage and outcomes of patients with nonalcoholic fatty liver disease: a systematic review and meta-analysis.Gastroenterology2020;158:1611-25.e12

[76] CianciN,HillT.Prognostic non-invasive biomarkers for all-cause mortality in non-alcoholic fatty liver disease: a systematic review and meta-analysis.World J Hepatol2022;14:1025-37 PMCID:PMC9157703

[77] DulaiPS,PatelJ.Increased risk of mortality by fibrosis stage in nonalcoholic fatty liver disease: systematic review and meta-analysis.Hepatology2017;65:1557-65 PMCID:PMC5397356

[78] CiardulloS,MuracaE,PerseghinG.Liver fibrosis, NT-ProBNP and mortality in patients with MASLD: a population-based cohort study.Nutr Metab Cardiovasc Dis2024;34:963-71

[79] CollierA,CameronL,ByrneCD.Liver fibrosis markers and all cause mortality in people with type 2 diabetes: a population based study (The Ayrshire Diabetes Outcomes Cohort (ADOC) study).Diabetes Obes Metab2023;25:2659-68

[80] ChoiSW,LeeYH,NamHS.Association of liver fibrosis biomarkers with overall and CVD mortality in the Korean population: the Dong-gu study.PLoS One2022;17:e0277729 PMCID:PMC9747044

[81] VieiraBarbosa J,FrickA.Fibrosis-4 index as an independent predictor of mortality and liver-related outcomes in NAFLD.Hepatol Commun2022;6:765-79 PMCID:PMC8948572

[82] BaikM,HeoJH.Advanced liver fibrosis predicts unfavorable long-term prognosis in first-ever ischemic stroke or transient ischemic attack.Cerebrovasc Dis2020;49:474-80

[83] CaoYX,ZhangHW.Impact of liver fibrosis score on prognosis in patients with previous myocardial infarction: a prospective cohort study.Liver Int2021;41:1294-304

[84] JinJL,CaoYX.Liver fibrosis scores and coronary atherosclerosis: novel findings in patients with stable coronary artery disease.Hepatol Int2021;15:413-23

[85] OhTJ,MoonJH,ChoNH.Liver fibrosis indices for the prediction of mortality in korean subjects: a 16-year prospective cohort study.J Endocr Soc2021;5:bvab123 PMCID:PMC8358988

[86] ChungGE,LeeKN.Combined effects of chronic kidney disease and nonalcoholic fatty liver disease on the risk of cardiovascular disease in patients with diabetes.Biomedicines2022;10:1245 PMCID:PMC9219946

[87] YanZ,LiW.Liver fibrosis scores and prognosis in patients with cardiovascular diseases: a systematic review and meta-analysis.Eur J Clin Invest2022;52:e13855

[88] MascherbauerK,KoschutnikM.Hepatic T1-time predicts cardiovascular risk in all-comers referred for cardiovascular magnetic resonance: a post-hoc analysis.Circ Cardiovasc Imaging2022;15:e014716

[89] LeeJ,ParkD,BaeJH.The association between advanced liver fibrosis and mortality is modified by dietary quality among Korean adults: results from the Korea National Health and Nutrition Examination Survey with mortality data.Nutrients2023;15:1501 PMCID:PMC10053070

[90] SeoYG,ParkKH.Fibrosis-4 index predicts long-term all-cause, cardiovascular and liver-related mortality in the adult Korean population.Clin Gastroenterol Hepatol2023;21:3322-35

[91] GuanL,ZouY,QiuL.Association between FIB-4, all-cause mortality, cardiovascular mortality, and cardiovascular disease risk among diabetic individuals: NHANES 1999-2008.Front Cardiovasc Med2023;10:1172178 PMCID:PMC10560879

[92] NakashimaM,NishiharaT.Association between cardiovascular disease and liver disease, from a clinically pragmatic perspective as a cardiologist.Nutrients2023;15:748 PMCID:PMC9919281

[93] Roca-FernandezA,Thomaides-BrearsH.Liver disease is a significant risk factor for cardiovascular outcomes - a UK Biobank study.J Hepatol2023;79:1085-95

[94] LuC,ZhangY.Liver fibrosis scores and coronary artery disease: novel findings in patients with metabolic dysfunction-associated fatty liver disease.Diabetes Metab Syndr Obes2023;16:2627-37 PMCID:PMC10474841

[95] MittenEK,BaffyG.Portal hypertension in nonalcoholic fatty liver disease: challenges and paradigms.J Clin Transl Hepatol2023;11:1201-11 PMCID:PMC10412712

[96] WanY,SlevinE.Endothelial dysfunction in pathological processes of chronic liver disease during aging.FASEB J2022;36:e22125 PMCID:PMC8782255

[97] CetinEG,SenI.The relationship between insulin resistance and liver damage in non-alcoholic fatty liver patients.Sisli Etfal Hastan Tip Bul2020;54:411-5 PMCID:PMC7751232

[98] KimGA,ChoeJ.Association between non-alcoholic fatty liver disease and cancer incidence rate.J Hepatol2017;68:140-6

[99] PelegN,IssacharA,BraunM.Noninvasive scoring systems predict hepatic and extra-hepatic cancers in patients with nonalcoholic fatty liver disease.PLoS One2018;13:e0202393 PMCID:PMC6091950

[100] LiuSS,ZhaoJ.Association between nonalcoholic fatty liver disease and extrahepatic cancers: a systematic review and meta-analysis.Lipids Health Dis2020;19:118 PMCID:PMC7262754

[101] LeeJM,YunJS.The association between nonalcoholic fatty liver disease and esophageal, stomach, or colorectal cancer: national population-based cohort study.PLoS One2020;15:e0226351 PMCID:PMC6980645

[102] VeracruzN,SaabS.The association between nonalcoholic fatty liver disease and risk of cardiovascular disease, stroke, and extrahepatic cancers.J Clin Exp Hepatol2021;11:45-81 PMCID:PMC7897860

[103] MantovaniA,BeatriceG.Non-alcoholic fatty liver disease and increased risk of incident extrahepatic cancers: a meta-analysis of observational cohort studies.Gut2022;71:778-88

[104] ThomasJA,DalaisC,ThriftAP.Hepatocellular and extrahepatic cancers in non-alcoholic fatty liver disease: a systematic review and meta-analysis.Eur J Cancer2022;173:250-62

[105] MuhamadNA,LemanFN.The global prevalence of nonalcoholic fatty liver disease and its association with cancers: systematic review and meta-analysis.Interact J Med Res2023;12:e40653 PMCID:PMC10398554

[106] XieJ,LiuC,XuC.Causal association of nonalcoholic fatty liver disease with 22 extrahepatic cancers: a Mendelian randomization study.Hepatol Res2024;54:261-71

[107] ThomasJA,El-SeragHB,MacdonaldGA.Hepatocellular and extrahepatic cancer risk in people with non-alcoholic fatty liver disease.Lancet Gastroenterol Hepatol2024;9:159-69

[108] LoriaP,NascimbeniF.Cardiovascular risk, lipidemic phenotype and steatosis. A comparative analysis of cirrhotic and non-cirrhotic liver disease due to varying etiology.Atherosclerosis2014;232:99-109

[109] BallestriS,TargherG.Nonalcoholic fatty liver disease is associated with an almost twofold increased risk of incident type 2 diabetes and metabolic syndrome. Evidence from a systematic review and meta-analysis.J Gastroenterol Hepatol2016;31:936-44

[110] MantovaniA,PetraccaG.Non-alcoholic fatty liver disease and risk of fatal and non-fatal cardiovascular events: an updated systematic review and meta-analysis.Lancet Gastroenterol Hepatol2021;6:903-13

[111] HensonJB,KaplanA,MasiaR.Advanced fibrosis is associated with incident cardiovascular disease in patients with non-alcoholic fatty liver disease.Aliment Pharmacol Ther2020;51:728-36 PMCID:PMC7069774

[112] SimonTG,HagströmH,LudvigssonJF.Non-alcoholic fatty liver disease and incident major adverse cardiovascular events: results from a nationwide histology cohort.Gut2022;71:1867-75

[113] HagströmH,EkstedtM.Cardiovascular risk factors in non-alcoholic fatty liver disease.Liver Int2019;39:197-204

[114] Park JH, Koo BK, Kim W, Kim WH; Innovative Target Exploration of NAFLD (ITEN) Consortium. Histological severity of nonalcoholic fatty liver disease is associated with 10-year risk for atherosclerotic cardiovascular disease. Hepatol Int 2021;15:1148-59.

[115] HanE,LeeJS.Fibrotic burden determines cardiovascular risk among subjects with metabolic dysfunction-associated fatty liver disease.Gut Liver2022;16:786-97 PMCID:PMC9474484

[116] AraiT,TsubotaA.Liver fibrosis is associated with carotid atherosclerosis in patients with liver biopsy-proven nonalcoholic fatty liver disease.Sci Rep2021;11:15938 PMCID:PMC8342487

[117] YiM,TengF,ChenZ.The role of noninvasive scoring systems for predicting cardiovascular disease risk in patients with nonalcoholic fatty liver disease: a systematic review and meta-analysis.Eur J Gastroenterol Hepatol2022;34:1277-84

[118] ChenS,HuangR,ZhangH.Associations of MAFLD and MAFLD subtypes with the risk of the incident myocardial infarction and stroke.Diabetes Metab2023;49:101468

[119] ParkJ,KimBS.The association between changes in hepatic steatosis and hepatic fibrosis with cardiovascular outcomes and mortality in patients with new-onset type 2 diabetes: a nationwide cohort study.Diabetes Res Clin Pract2022;194:110191

[120] CorbinKD,CannonCP.Cardiorenal outcomes by indices of liver steatosis and fibrosis in individuals with type 2 diabetes and atherosclerotic cardiovascular disease: analyses from VERTIS CV, a randomized trial of the sodium-glucose cotransporter-2 inhibitor ertugliflozin.Diabetes Obes Metab2023;25:758-66

[121] LiJ,HanJ.Retinopathy as a predictive indicator for significant hepatic fibrosis according to T2DM status: a cross-sectional study based on the national health and nutrition examination survey data.Ann Hepatol2024;29:101478

[122] TrivediHD,FrickerZ,LiJX.Type 2 diabetes complications are associated with liver fibrosis independent of hemoglobin A1c.Ann Hepatol2023;28:101087

[123] MantovaniA,SandriD.Association between non-alcoholic fatty liver disease and risk of atrial fibrillation in adult individuals: an updated meta-analysis.Liver Int2019;39:758-69

[124] ParkHE,ChoiSY,ChungGE.The risk of atrial fibrillation in patients with non-alcoholic fatty liver disease and a high hepatic fibrosis index.Sci Rep2020;10:5023 PMCID:PMC7081198

[125] WangZ,LuoF.Impact of advanced liver fibrosis on atrial fibrillation recurrence after ablation in non-alcoholic fatty liver disease patients.Front Cardiovasc Med2022;9:960259 PMCID:PMC9583404

[126] LiuX,ShaoW.Liver fibrosis scores and atrial fibrillation incidence in heart failure with preserved ejection fraction.ESC Heart Fail2022;9:3985-94 PMCID:PMC9773713

[127] MantovaniA,BenfariG,SimonTG.Risk of heart failure in patients with nonalcoholic fatty liver disease: JACC review topic of the week.J Am Coll Cardiol2022;79:180-91

[128] SalahHM,VanSpall HGC,McGarrahRW.Meta-analysis of nonalcoholic fatty liver disease and incident heart failure.Am J Cardiol2022;171:180-1

[129] IwasakiY,MatsumotoC.Correlation of the fatty liver index with the pathophysiological abnormalities associated with cardiovascular risk markers in japanese men without any history of cardiovascular disease: comparison with the fibrosis-4 score.J Atheroscler Thromb2021;28:524-34 PMCID:PMC8193774

[130] BoeckmansJ,KnackstedtC.Liver stiffness as a cornerstone in heart disease risk assessment.Liver Int2024;44:344-56

[131] LongMT,XuH.Hepatic fibrosis associates with multiple cardiometabolic disease risk factors: the framingham heart study.Hepatology2021;73:548-59 PMCID:PMC8515503

[132] TangR,HoweLD,FraserA.Non-alcoholic fatty liver and fibrosis is associated with cardiovascular structure and function in young adults.Hepatol Commun2023;7:e0087 PMCID:PMC10069841

[133] KuznetsovaA,SavochkinaA.Liver stiffness is associated with the burden of carotid and systemic atherosclerosis in an unorganized cohort of patients 40-64 years old.Diagnostics2022;12:2336 PMCID:PMC9600688

[134] SongY,WangP,RuanL.CHD is associated with higher grades of NAFLD predicted by liver stiffness.J Clin Gastroenterol2020;54:271-7 PMCID:PMC7012352

[135] Shili-MasmoudiS,HiriartJB.Liver stiffness measurement predicts long-term survival and complications in non-alcoholic fatty liver disease.Liver Int2020;40:581-9

[136] CiardulloS,MazzettiS,PerseghinG.Nonalcoholic fatty liver disease, liver fibrosis and cardiovascular disease in the adult US population.Front Endocrinol2021;12:711484 PMCID:PMC8350483

[137] PettaS,ViganòM.Monitoring occurrence of liver-related events and survival by transient elastography in patients with nonalcoholic fatty liver disease and compensated advanced chronic liver disease.Clin Gastroenterol Hepatol2021;19:806-15.e5

[138] Kleef LA, Lu Z, Ikram MA, de Groot NMS, Kavousi M, de Knegt RJ. Liver stiffness not fatty liver disease is associated with atrial fibrillation: the Rotterdam study.J Hepatol2022;77:931-938

[139] OstovanehMR,FujiT.Association of liver fibrosis with cardiovascular diseases in the general population: the Multi-Ethnic Study of Atherosclerosis (MESA).Circ Cardiovasc Imaging2018;11:e007241 PMCID:PMC5846116

[140] Tamaki N, Higuchi M, Kurosaki M, Loomba R, Izumi N; MRCH Liver Study Group. Risk difference of liver-related and cardiovascular events by liver fibrosis status in nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 2022;20:1171-73.e2. PMCID:PMC8761224

[141] LugariS,LonardoA.Metabolic primary liver cancer in adults: risk factors and pathogenic mechanisms.Metab Target Organ Damage2023;3:5

[142] HagströmH,EkstedtM.Risk for hepatic and extra-hepatic outcomes in nonalcoholic fatty liver disease.J Intern Med2022;292:177-89

[143] MantovaniA,StefanN.Metabolic dysfunction-associated steatotic liver disease and extrahepatic gastrointestinal cancers.Metabolism2024;160:156014

[144] LonardoA.Extra-hepatic cancers in metabolic fatty liver syndromes.Explor Dig Dis2023;2:11-7

[145] LonardoA.Is liver fibrosis a risk factor for gynecological cancers?.Metab Target Organ Damage2024;4:7

[146] KimMC,JangBI,LeeWK.Liver fibrosis is associated with risk for colorectal adenoma in patients with nonalcoholic fatty liver disease.Medicine2019;98:e14139 PMCID:PMC6380844

[147] ChakrabortyD.Nonalcoholic fatty liver disease and colorectal cancer: correlation and missing links.Life Sci2020;262:118507 PMCID:PMC8128156

[148] Ait-ahmedY.Novel insights into the impact of liver inflammatory responses on primary liver cancer development.Liver Research2023;7:26-34

[149] YuJ,YangX.Understanding gut dysbiosis for hepatocellular carcinoma diagnosis and treatment.Trends Endocrinol Metab2024;35:1006-20

[150] WongND,PatelR.Cardiovascular risk factor targets and cardiovascular disease event risk in diabetes: a pooling project of the atherosclerosis risk in communities study, multi-ethnic study of atherosclerosis, and jackson heart study.Diabetes Care2016;39:668-76 PMCID:PMC4839178

[151] SiniawskiD,MassonW.Residual cardiovascular risk, use of standard care treatments, and achievement of treatment goals in patients with cardiovascular disease.Int J Cardiol Cardiovasc Risk Prev2023;18:200198 PMCID:PMC10374461

[152] JamaliniaM.Perspective article: Determinants and assessment of cardiovascular risk in steatotic liver disease owing to metabolic dysfunction-addressing the challenge.Metab Target Organ Damage2024;4:23

[153] Moreno-DelCastillo MC,Hernandez-BuenAbad JJ.Importance of evaluating cardiovascular risk and hepatic fibrosis in patients with newly diagnosed nonalcoholic fatty liver disease.Clin Gastroenterol Hepatol2019;17:997-9

[154] LauridsenBK,KristensenTS.Liver fat content, non-alcoholic fatty liver disease, and ischaemic heart disease: Mendelian randomization and meta-analysis of 279 013 individuals.Eur Heart J2018;39:385-93

[155] Yeung SL, Borges MC, Wong THT, Lawlor DA, Schooling CM. Evaluating the role of non-alcoholic fatty liver disease in cardiovascular diseases and type 2 diabetes: a Mendelian randomization study in Europeans and East Asians.Int J Epidemiol2023;52:921-31 PMCID:PMC10244054

[156] RenZ,WesseliusA,BrouwersMCGJ.Relationship between NAFLD and coronary artery disease: a Mendelian randomization study.Hepatology2023;77:230-8 PMCID:PMC9970021

[157] WanlessIR.The role of vascular injury and congestion in the pathogenesis of cirrhosis: the congestive escalator and the parenchymal extinction sequence.Curr Hepatology Rep2020;19:40-53

[158] PoissonJ,BoulangerC.Liver sinusoidal endothelial cells: physiology and role in liver diseases.J Hepatol2017;66:212-27

[159] AdolphTE,MoschenAR.Liver-microbiome axis in health and disease.Trends Immunol2018;39:712-23

[160] HammouteneA.Role of liver sinusoidal endothelial cells in non-alcoholic fatty liver disease.J Hepatol2019;70:1278-91

[161] HsuCL.The gut-liver axis and gut microbiota in health and liver disease.Nat Rev Microbiol2023;21:719-33 PMCID:PMC10794111

[162] PandeyE,HarrisEN.Prominent receptors of liver sinusoidal endothelial cells in liver homeostasis and disease.Front Physiol2020;11:873 PMCID:PMC7396565

[163] StefanN,TargherG.Role of steatotic liver disease in prediction and prevention of cardiometabolic diseases.Nat Rev Gastroenterol Hepatol2024;21:136-7

[164] AlkhouriN,YerianL,ZeinNN.The inflamed liver and atherosclerosis: a link between histologic severity of nonalcoholic fatty liver disease and increased cardiovascular risk.Dig Dis Sci2010;55:2644-50

[165] ArulanandanA,BettencourtR.Association between quantity of liver fat and cardiovascular risk in patients with nonalcoholic fatty liver disease independent of nonalcoholic steatohepatitis.Clin Gastroenterol Hepatol2015;13:1513-20.e1

[166] BrilF,BacaAM.Hepatic steatosis and insulin resistance, but not steatohepatitis, promote atherogenic dyslipidemia in NAFLD.J Clin Endocrinol Metab2016;101:644-52

[167] LonardoA,MantovaniA.Hypertension, diabetes, atherosclerosis and NASH: cause or consequence?.J Hepatol2018;68:335-52

[168] JamaliniaM,NoorizadehK.Systematic review with meta-analysis: steatosis severity and subclinical atherosclerosis in metabolic dysfunction-associated steatotic liver disease.Aliment Pharmacol Ther2024;59:445-58

[169] las Heras N, Aller MA, Arias J, Lahera V. The risk association between experimental portal hypertension and an aortic atherosclerosis-like disease.Hepatology2013;57:421-2

[170] MittenEK.Mechanobiology in the development and progression of non-alcoholic fatty liver disease: an updated review.Metab Target Organ Damage2023;3:2

[171] Gracia-SanchoJ,Fernández-IglesiasA,BoschJ.New cellular and molecular targets for the treatment of portal hypertension.Hepatol Int2015;9:183-91

[172] SharptonSR.Emerging role of statin therapy in the prevention and management of cirrhosis, portal hypertension, and HCC.Hepatology2023;78:1896-906

[173] LonardoA.The “obese liver” and gastrointestinal cancer risk.Transl Gastroenterol Hepatol2020;5:44 PMCID:PMC7063505

[174] TadokoroT,MasakiT.Diagnosis and therapeutic management of liver fibrosis by microRNA.Int J Mol Sci2021;22:8139 PMCID:PMC8347497