Dysmetabolic comorbidities and non-alcoholic fatty liver disease: a stairway to metabolic dysfunction-associated steatotic liver disease

Abstract

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease. This term does not describe the pathogenetic mechanisms and complications associated with NAFLD. The new definition, Metabolic Dysfunction-associated Steatotic Liver disease (MASLD), emphasizes the relationship between NAFLD and cardiometabolic comorbidities. Cardiovascular disease features, such as arterial hypertension and atherosclerosis, are frequently associated with patients with MASLD. Furthermore, these patients have a high risk of developing neoplastic diseases, primarily hepatocellular carcinoma, but also extrahepatic tumors, such as esophageal, gastric, and pancreatic cancers. Moreover, several studies showed the correlation between MASLD and endocrine disease. The imbalance of the gut microbiota, systemic inflammation, obesity, and insulin resistance play a key role in the development of these complications. This narrative review aims to clarify the evolution from NAFLD to the new nomenclature MASLD and evaluate its complications.

Keywords

Hepatic steatosis / inflammation / cardiometabolic comorbidities / gut microbiota / obesity / carcinogenesis / liver damage

References

[1] Perazzo H,Griep RH.CollaboratorsChanging from NAFLD through MAFLD to MASLD: Similar prevalence and risk factors in a large Brazilian cohort.J Hepatol2024;80:e72-4

[2] Chalasani N,Lavine JE.American Gastroenterological AssociationAmerican Association for the Study of Liver DiseasesAmerican College of GastroenterologyhThe 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

[3] World Health Organization. No level of alcohol consumption is safe for our health. Available from: https://www.who.int/europe/news/item/04-01-2023-no-level-of-alcohol-consumption-is-safe-for-our-health [Last accessed on 28 Mar 2024]

[4] Alwahsh SM,Schultze FC.Combination of alcohol and fructose exacerbates metabolic imbalance in terms of hepatic damage, dyslipidemia, and insulin resistance in rats.PLoS One2014;9:e104220 PMCID:PMC4125190

[5] Eshraghian A,Dehghani M.Nonalcoholic steatohepatitis is the most rapidly growing indication for liver transplantation in Iranian patients.Exp Clin Transplant2022;20:487-94

[6] World Health Organization. World obesity day 2022-accelerating action to stop obesity. Available online: https://www.who.int/news/item/04-03-2022-world-obesity-day-2022-accelerating-action-to-stop-obesity [Last accessed on 23 Jan 2024]

[7] Keramat SA,Gow J.Impact of Disadvantaged neighborhoods and lifestyle factors on adult obesity: evidence from a 5-year cohort study in Australia.Am J Health Promot2021;35:28-37

[8] Sun Y,Sun X.Estimating neighbourhood-level prevalence of adult obesity by socio-economic, behavioural and built environment factors in New York City.Public Health2020;186:57-62

[9] Boutari C.A 2022 update on the epidemiology of obesity and a call to action: as its twin COVID-19 pandemic appears to be receding, the obesity and dysmetabolism pandemic continues to rage on.Metabolism2022;133:155217 PMCID:PMC9107388

[10] Ng M,Robinson M.Global, regional, and national prevalence of overweight and obesity in children and adults during 1980-2013: a systematic analysis for the global burden of disease study 2013.Lancet2014;384:766-81 PMCID:PMC4624264

[11] Angulo P,Dam-Larsen S.Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease.Gastroenterology2015;149:389-97.e10 PMCID:PMC4516664

[12] Eslam M,George J.International Consensus PanelMAFLD: a consensus-driven proposed nomenclature for metabolic associated fatty liver disease.Gastroenterology2020;158:1999-2014.e1

[13] Ramírez-Mejía MM,Abenavoli L,Eslam M.Metabolic dysfunction: The silenced connection with fatty liver disease.Ann Hepatol2023;28:101138

[14] Rinella ME,Ratziu V.NAFLD Nomenclature consensus groupA multisociety Delphi consensus statement on new fatty liver disease nomenclature.Hepatology2023;78:1966-86 PMCID:PMC10653297

[15] Alharthi J,Cua IH,Eslam M.Metabolic dysfunction-associated fatty liver disease: a year in review.Curr Opin Gastroenterol2022;38:251-60

[16] Cheng YM,Kao JH.Metabolic associated fatty liver disease better identifying patients at risk of liver and cardiovascular complications.Hepatol Int2023;17:350-6

[17] Yamamura S,Kawaguchi T.MAFLD identifies patients with significant hepatic fibrosis better than NAFLD.Liver Int2020;40:3018-30

[18] Huang SC,Kao JH.Clinical and histologic features of patients with biopsy-proven metabolic dysfunction-associated fatty liver disease.Gut Liver2021;15:451-8 PMCID:PMC8129653

[19] Lee H,Kim SU.Metabolic dysfunction-associated fatty liver disease and incident cardiovascular disease risk: a nationwide cohort study.Clin Gastroenterol Hepatol2021;19:2138-47.e10

[20] Sun DQ,Wang TY.MAFLD and risk of CKD.Metabolism2021;115:154433

[21] Kim D,Sandhu KK,Cheung AC.Metabolic dysfunction-associated fatty liver disease is associated with increased all-cause mortality in the United States.J Hepatol2021;75:1284-91

[22] Ramírez-Mejía MM,Méndez-Sánchez N.Letter to the EDITOR: THE MAFLD and MASLD conundrum: is it reinvention of the wheel?.J Hepatol2024;79:S0168-8278(24)00158

[23] Ramírez-Mejía MM,Eslam M,Méndez-Sánchez N.Breaking new ground: MASLD vs. MAFLD-which holds the key for risk stratification?.Hepatol Int2024;18:168-78

[24] Chen L,Zeng M,Xu L.Clinical and histological features under different nomenclatures of fatty liver disease: NAFLD, MAFLD, MASLD and MetALD.J Hepatol2024;80:e64-6

[25] Zhao Q.Comparison of mortality outcomes in individuals with MASLD and/or MAFLD.J Hepatol2024;80:e62-4

[26] Wang CC,Kao JH.Letter to the editor: statement of steatotic liver disease-A great leap toward the global standardization.Hepatology2024;79:E7-8

[27] Song SJ,Wong GL,Yip TC.Can we use old NAFLD data under the new MASLD definition?.J Hepatol2024;80:e54-6

[28] He L,Qiu K,Zeng T.Changing from NAFLD to MASLD: The new definition can more accurately identify individuals at higher risk for diabetes.J Hepatol2024;80:e85-7

[29] Yang A,Zhang L.Transitioning from NAFLD to MAFLD and MASLD: Consistent prevalence and risk factors in a Chinese cohort.J Hepatol2024;80:e154-5

[30] De A,Mehta M,Duseja A.Metabolic dysfunction-associated steatotic liver disease (MASLD) definition is better than MAFLD criteria for lean patients with NAFLD.J Hepatol2024;80:e61-2

[31] Hutchison AL,Romeo S.Endocrine aspects of metabolic dysfunction-associated steatotic liver disease (MASLD): Beyond insulin resistance.J Hepatol2023;79:1524-41

[32] Wang Y,Antwi SO,Yang L.Racial disparities in liver disease mortality trends among black and white populations in the United States, 1999-2020: an analysis of CDC WONDER database.Am J Gastroenterol2024;119:682-9

[33] Comitato R,Turrini A,Virgili F.Sex hormones and macronutrient metabolism.Crit Rev Food Sci Nutr2015;55:227-41 PMCID:PMC4151815

[34] Yuan Q,Gao P.Prevalence and risk factors of metabolic-associated fatty liver disease among 73,566 individuals in Beijing, China.Int J Environ Res Public Health2022;19:2096 PMCID:PMC8871878

[35] Chen YL,Li S.Prevalence of and risk factors for metabolic associated fatty liver disease in an urban population in China: a cross-sectional comparative study.BMC Gastroenterol2021;21:212 PMCID:PMC8111711

[36] Chen Q,Mei L.Association of sex hormones with hepatic steatosis in men with chronic hepatitis B.Dig Liver Dis2022;54:378-84

[37] Liu L,Li T.Gut microbiota and butyrate contribute to nonalcoholic fatty liver disease in premenopause due to estrogen deficiency.PLoS One2022;17:e0262855 PMCID:PMC8809533

[38] Eng PC,Tan T,Dhillo WS.Non-alcoholic fatty liver disease in women - Current knowledge and emerging concepts.JHEP Rep2023;5:100835 PMCID:PMC10522907

[39] Anderson WD,Innis SE.Sex differences in human adipose tissue gene expression and genetic regulation involve adipogenesis.Genome Res2020;30:1379-92 PMCID:PMC7605264

[40] Jang YS,Park YS,Jang SI.Association between smoking cessation and non-alcoholic fatty liver disease using NAFLD liver fat score.Front Public Health2023;11:1015919 PMCID:PMC9982128

[41] Cui Y,Lou C.Gender differences in cigarette smoking and alcohol drinking among adolescents and young adults in Hanoi, Shanghai, and Taipei.J Int Med Res2018;46:5257-68 PMCID:PMC6300939

[42] Vespasiani-Gentilucci U,Romeo S.Usefulness of PNPLA3 variant for predicting hepatic events in steatotic liver disease: a matter of ethnicity or baseline risk?.Liver Int2023;43:2052-4

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

[44] Wagenknecht LE,Bowden DW.Association of PNPLA3 with non-alcoholic fatty liver disease in a minority cohort: the insulin resistance atherosclerosis family study.Liver Int2011;31:412-6 PMCID:PMC3703938

[45] Huang G,Powell EE,Clark PJ.Gene variants implicated in steatotic liver disease: opportunities for diagnostics and therapeutics.Biomedicines2023;11:2809 PMCID:PMC10604560

[46] Goffredo M,Feldstein AE.Role of TM6SF2 rs58542926 in the pathogenesis of nonalcoholic pediatric fatty liver disease: a multiethnic study.Hepatology2016;63:117-25 PMCID:PMC4688225

[47] Semmler G,Wernly S.Insulin resistance and central obesity determine hepatic steatosis and explain cardiovascular risk in steatotic liver disease.Front Endocrinol2023;14:1244405 PMCID:PMC10570507

[48] Fernández-Barrena MG.Frontiers in fatty liver: recent advances in pathogenic mechanisms, assessment of patients' prognosis and pharmacotherapy: MASLD: new pathogenic mechanisms, risk assessment tools and drug therapies.J Physiol Biochem2023;79:811-3

[49] Yang T,Li J.The influence of different combinations of cardiometabolic risk factors on the prevalence of MASLD and risk of advanced fibrosis deserves attention.J Hepatol2024;80:e82-5

[50] Balogun O,Shaikh ES.Effect of combined tobacco use and type 2 diabetes mellitus on prevalent fibrosis in patients with MASLD.Hepatol Commun2023;7:e0300 PMCID:PMC10615418

[51] Forlano R,Jayawardana S.A prospective study on the prevalence of MASLD in people with type-2 diabetes in the community. Cost effectiveness of screening strategies.Liver Int2024;44:61-71

[52] Ciardullo S,Perseghin G.Nonalcoholic fatty liver disease in patients with type 2 diabetes: screening, diagnosis, and treatment.J Clin Med2023;12:5597 PMCID:PMC10488336

[53] Yang G,Rezaei S,Wan YY.Uncovering the gut-liver axis biomarkers for predicting metabolic burden in mice.Nutrients2023;15:3406 PMCID:PMC10421148

[54] Heller B,Leicht HB.Salt-intake-related behavior varies between sexes and is strongly associated with daily salt consumption in obese patients at high risk for MASLD.Nutrients2023;15:3942 PMCID:PMC10534674

[55] Pei E,Li Z,Cai L.Endoplasmic reticulum stress inhibitor may substitute for sleeve gastrectomy to alleviate metabolic dysfunction-associated steatotic liver disease.Clin Res Hepatol Gastroenterol2023;47:102229

[56] Hepburn C.Nutrition in liver disease - a review.Curr Gastroenterol Rep2023;25:242-9

[57] Zhang X,Soltero V.A study of dietary patterns derived by cluster analysis and their association with metabolic dysfunction-associated steatotic liver disease severity among Hispanic patients.Am J Gastroenterol2024;119:505-11

[58] Tamilmani P,Chandrasekaran P.Linalool attenuates lipid accumulation and oxidative stress in metabolic dysfunction-associated steatotic liver disease via Sirt1/Akt/PPRA-α/AMPK and Nrf-2/HO-1 signaling pathways.Clin Res Hepatol Gastroenterol2023;47:102231

[59] Chen VL,Suresh D,Perumalswami P.Effects of social determinants of health on mortality and incident liver-related events and cardiovascular disease in steatotic liver disease.Aliment Pharmacol Ther2023;58:537-45 PMCID:PMC10720393

[60] Kani AS,Kani HT,Sayar K.Chronotype preference, sleep quality, and night-eating behaviors in patients with metabolic dysfunction-associated steatotic liver disease: assessing the relationship with disease severity and fibrosis.Hepatol Forum2023;4:123-8 PMCID:PMC10564252

[61] Lai J,Zhou T,Ye J.Alterations in circulating bile acids in metabolic dysfunction-associated steatotic liver disease: a systematic review and meta-analysis.Biomolecules2023;13:1356 PMCID:PMC10526305

[62] García-Mateo S,Gargallo-Puyuelo CJ.Lifestyle can exert a significant impact on the development of metabolic complications and quality life in patients with inflammatory bowel disease.Nutrients2023;15:3983 PMCID:PMC10537893

[63] Martínez-Domínguez SJ,Gargallo-Puyuelo CJ.Inflammatory bowel disease is an independent risk factor for metabolic dysfunction-associated steatotic liver disease in lean individuals.Inflamm Bowel Dis2023;Online ahead of print:izad175

[64] Gomaa EZ.Human gut microbiota/microbiome in health and diseases: a review.Antonie Van Leeuwenhoek2020;113:2019-40

[65] Chen Y,Wang L.Role and mechanism of gut microbiota in human disease.Front Cell Infect Microbiol2021;11:625913 PMCID:PMC8010197

[66] Rutsch A,Ronchi F.The gut-brain Axis: how microbiota and host inflammasome influence brain physiology and pathology.Front Immunol2020;11:604179 PMCID:PMC7758428

[67] Rebersek M.Gut microbiome and its role in colorectal cancer.BMC Cancer2021;21:1325 PMCID:PMC8666072

[68] Wong SH.Gut microbiota in colorectal cancer: mechanisms of action and clinical applications.Nat Rev Gastroenterol Hepatol2019;16:690-704

[69] Shan Y,Chang EB.The gut microbiome and inflammatory bowel diseases.Annu Rev Med2022;73:455-68 PMCID:PMC10012812

[70] Laserna-Mendieta EJ,Carretero-Gomez JF.Determinants of reduced genetic capacity for butyrate synthesis by the gut microbiome in crohn's disease and ulcerative colitis.J Crohns Colitis2018;12:204-16

[71] Milano W,Di Munzio W,Capasso A.Obesity: The new global epidemic pharmacological treatment, opportunities and limits for personalized therapy.Endocr Metab Immune Disord Drug Targets2020;20:1232-43

[72] Sumida Y.Current and future pharmacological therapies for NAFLD/NASH.J Gastroenterol2018;53:362-76 PMCID:PMC5847174

[73] Chiu CC,Li YP.Nonalcoholic fatty liver disease is exacerbated in high-fat diet-fed gnotobiotic mice by colonization with the gut microbiota from patients with nonalcoholic steatohepatitis.Nutrients2017;9:1220 PMCID:PMC5707692

[74] Qiao S,Wang K.Activation of a specific gut bacteroides-folate-liver axis benefits for the alleviation of nonalcoholic hepatic steatosis.Cell Rep2020;32:108005

[75] Zafar H.Gut Bacteroides species in health and disease.Gut Microbes2021;13:1-20 PMCID:PMC7872030

[76] Choi KJ,Kim JE.Gut commensal Kineothrix alysoides mitigates liver dysfunction by restoring lipid metabolism and gut microbial balance.Sci Rep2023;13:14668 PMCID:PMC10482948

[77] Yoshida N,Yamashita T.Bacteroides vulgatus and Bacteroides dorei Reduce Gut Microbial Lipopolysaccharide Production and Inhibit Atherosclerosis.Circulation2018;138:2486-98

[78] López-Almela I,Bullich-Vilarrubias C.Bacteroides uniformis combined with fiber amplifies metabolic and immune benefits in obese mice.Gut Microbes2021;13:1-20 PMCID:PMC8018257

[79] Koh A,Kovatcheva-Datchary P.From dietary fiber to host physiology: short-chain fatty acids as key bacterial metabolites.Cell2016;165:1332-45

[80] Iruzubieta P,Fernández-López R,de la Cruz F.A role for gut microbiome fermentative pathways in fatty liver disease progression.J Clin Med2020;9:1369 PMCID:PMC7291163

[81] de la Cuesta-Zuluaga J,Álvarez-Quintero R.Higher fecal short-chain fatty acid levels are associated with gut microbiome dysbiosis, obesity, hypertension and cardiometabolic disease risk factors.Nutrients2018;11:51 PMCID:PMC6356834

[82] Wu Y,Cheng Z,Ma X.The role of neuropeptide y and peptide yy in the development of obesity via gut-brain axis.Curr Protein Pept Sci2019;20:750-8

[83] Jiao N,Chapa-Rodriguez A.Suppressed hepatic bile acid signalling despite elevated production of primary and secondary bile acids in NAFLD.Gut2018;67:1881-91

[84] Chávez-Talavera O,Lefebvre P.Bile acid control of metabolism and inflammation in obesity, type 2 diabetes, dyslipidemia, and nonalcoholic fatty liver disease.Gastroenterology2017;152:1679-94.e3

[85] Liang Y,Liu Y.Association of MAFLD with diabetes, chronic kidney disease, and cardiovascular disease: a 4.6-year cohort study in China.J Clin Endocrinol Metab2022;107:88-97 PMCID:PMC8684479

[86] Mouries J,Silvestri A.Microbiota-driven gut vascular barrier disruption is a prerequisite for non-alcoholic steatohepatitis development.J Hepatol2019;71:1216-28 PMCID:PMC6880766

[87] Sorribas M,Yilmaz B.FXR modulates the gut-vascular barrier by regulating the entry sites for bacterial translocation in experimental cirrhosis.J Hepatol2019;71:1126-40

[88] Chan WL,Chang F.Long-term clinical outcomes of adults with metabolic dysfunction-associated fatty liver disease: a single-centre prospective cohort study with baseline liver biopsy.Hepatol Int2023;17:870-81 PMCID:PMC10218774

[89] Ramírez-Mejía MM,N .What is in a name: from NAFLD to MAFLD and MASLD-unraveling the complexities and implications.Curr Hepatology Rep2023;22:221-7.

[90] Nazir S,Bender G,Rye KA.Interaction between high-density lipoproteins and inflammation: function matters more than concentration!.Adv Drug Deliv Rev2020;159:94-119

[91] Heeren J.Metabolic-associated fatty liver disease and lipoprotein metabolism.Mol Metab2021;50:101238 PMCID:PMC8324684

[92] Mantovani A,Beatrice G.Non-alcoholic fatty liver disease and increased risk of incident extrahepatic cancers: a meta-analysis of observational cohort studies.Gut2022;71:778-88

[93] Pati S,Jameel A,Shahid RK.Obesity and cancer: a current overview of epidemiology, pathogenesis, outcomes, and management.Cancers2023;15:485 PMCID:PMC9857053

[94] Umar MI,Murtaza G.The adipokine component in the molecular regulation of cancer cell survival, proliferation and metastasis.Pathol Oncol Res2021;27:1609828 PMCID:PMC8473628

[95] Jiménez-Cortegana C,Tami M.Role of leptin in non-alcoholic fatty liver disease.Biomedicines2021;9:762 PMCID:PMC8301314

[96] Deng Y,Gong R.Association between metabolic associated fatty liver disease and chronic kidney disease: a cross-sectional study from NHANES 2017-2018.Diabetes Metab Syndr Obes2021;14:1751-61 PMCID:PMC8075735

[97] Raj AS,Tran CD.Dysbiosis of the duodenal mucosal microbiota is associated with increased small intestinal permeability in chronic liver disease.Clin Transl Gastroenterol2019;10:e00068 PMCID:PMC6736223

[98] Vuik F,Lam SY.Composition of the mucosa-associated microbiota along the entire gastrointestinal tract of human individuals.United European Gastroenterol J2019;7:897-907 PMCID:PMC6683645

[99] Ruan Z,Chen Y.Association between psoriasis and nonalcoholic fatty liver disease among outpatient US adults.JAMA Dermatol2022;158:745-53 PMCID:PMC9134040

[100] Wang H,He S.Self-reported snoring is associated with nonalcoholic fatty liver disease.Sci Rep2020;10:9267 PMCID:PMC7283303

[101] Whelton PK,Aronow WS.2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: executive summary: a report of the American college of Cardiology/American heart association task force on clinical practice guidelines.Hypertension2018;71:1269-324

[102] Cruz-Jentoft AJ,Bauer J.Writing Group for the European Working Group on Sarcopenia in Older People 2 (EWGSOP2)and the Extended Group for EWGSOP2Sarcopenia: revised European consensus on definition and diagnosis.Age Ageing2019;48:16-31 PMCID:PMC6322506

[103] Kumar R,Priyadarshi RN.Sarcopenia in chronic liver disease: a metabolic perspective.J Clin Transl Hepatol2022;10:1213-22 PMCID:PMC9634780

[104] Mohammadi-Motlagh HR,Yavari N.β cell and autophagy: what do we know?.Biomolecules2023;13:649 PMCID:PMC10136307

[105] Mazzotta AD.Advancements in hepatocellular carcinoma diagnosis and treatment: liquid biopsy and surgical as precision treatment.Hepatoma Res2024;10:8

[106] Li J,Yeo YH.Prevalence, incidence, and outcome of non-alcoholic fatty liver disease in Asia, 1999-2019: a systematic review and meta-analysis.Lancet Gastroenterol Hepatol2019;4:389-98

[107] Pais R,Goumard C.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

[108] Lin L,Yan L,Yang H.Global, regional, and national cancer incidence and death for 29 cancer groups in 2019 and trends analysis of the global cancer burden, 1990-2019.J Hematol Oncol2021;14:197 PMCID:PMC8607714

[109] Stine JG,Zimmet A.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

[110] Zunica ERM,Axelrod CL.Obesity management in the primary prevention of hepatocellular carcinoma.Cancers2022;14:4051 PMCID:PMC9406638

[111] Abenavoli L,Scarpellini E.Metabolic-dysfunction-associated fatty liver disease and gut microbiota: from fatty liver to dysmetabolic syndrome.Medicina2023;59:594 PMCID:PMC10054528

[112] Norero B.Should we undertake surveillance for HCC in patients with MAFLD?.Ther Adv Endocrinol Metab2023;14:20420188231160389 PMCID:PMC10052487

[113] Fassio E,Pérez MS.Hepatocellular carcinoma in patients with metabolic dysfunction-associated fatty liver disease: Can we stratify at-risk populations?.World J Hepatol2022;14:354-71 PMCID:PMC8891669

[114] Aspichueta P.miR-21p-5p coordinates biological pathways to promote MASLD progression.Liver Int2023;43:2343-5

[115] Abenavoli L,Paravati MR,Luzza F.Gut microbiota and liver transplantation: immune mechanisms behind the rejection.Biomedicines2023;11:1792 PMCID:PMC10376769

[116] Wongjarupong N,Susantitaphong P.Non-alcoholic fatty liver disease as a risk factor for cholangiocarcinoma: a systematic review and meta-analysis.BMC Gastroenterol2017;17:149 PMCID:PMC5721586

[117] Corrao S,Argano C.Nonalcoholic fatty liver disease is associated with intrahepatic cholangiocarcinoma and not with extrahepatic form: definitive evidence from meta-analysis and trial sequential analysis.Eur J Gastroenterol Hepatol2021;33:62-8

[118] De Lorenzo S,Mazzotta A.Non-alcoholic steatohepatitis as a risk factor for intrahepatic cholangiocarcinoma and its prognostic role.Cancers2020;12:3182 PMCID:PMC7692633

[119] Pascale A,Duclos-Vallée JC.New epidemiologic trends in cholangiocarcinoma.Clin Res Hepatol Gastroenterol2023;47:102223

[120] Lurje I,Pavicevic S.Body composition is associated with disease aetiology and prognosis in patients undergoing resection of intrahepatic cholangiocarcinoma.Cancer Med2023;12:17569-80 PMCID:PMC10524050

[121] Takahashi Y,Kusano H.Pathology and Pathogenesis of metabolic dysfunction-associated steatotic liver disease-associated hepatic tumors.Biomedicines2023;11:2761 PMCID:PMC10604511

[122] Maeda S,Fujiwara H.NAFLD exacerbates cholangitis and promotes cholangiocellular carcinoma in mice.Cancer Sci2021;112:1471-80 PMCID:PMC8019203

[123] Cadamuro M,Camerotto R.Intrahepatic cholangiocarcinoma developing in patients with metabolic syndrome is characterized by osteopontin overexpression in the tumor stroma.Int J Mol Sci2023;24:4748 PMCID:PMC10003180