Table Info

Table 2.

Effect of the number of CMRFs involved in the development of MASLD on the prevalence of liver steatosis and the risk of advanced liver fibrosis [62] and the incident risk of CVD [63]

Number of CMRFs	Prevalence of liver steatosis [62]	Prevalence of liver advanced fibrosis [62]	Incident risk of CVD, SHR (95% CI) [63]	P [63]
0	< 5%	0%	1.00 (reference)
1	36.0% (31.0%–41.4%)	3.5% (0.2%–6.7%)	1.41 (1.30–1.53)	< 0.001
2	53.7% (47.7%–59.6%)	10.9% (6.2–15.6%)	1.65 (1.53–1.79)	< 0.001
3	72.3% (65.3%–79.4%)	14.5% (9.7%–19.2%)	1.86 (1.72–2.02)	< 0.001
4	85.2% (81.8%–88.7%)	21.7% (15.9%–27.4%)	1.92 (1.76–2.09)	< 0.001
5	83.5% (79.8%–87.7%)	24.2% (14.9%–33.5%)	2.15 (1.95–2.37)	< 0.001

CMRFs: cardio-metabolic risk factors; CVD: cardio-vascular disease; MASLD: metabolic dysfunction-associated steatotic liver disease; SHR: subdistribution hazard ratio

Declarations

Author contributions

LEA: Conceptualization, Project administration, Methodology, Data curation, Writing—original draft. AM: Methodology, Writing—review & editing, Validation. LR: Methodology, Data curation, Writing—review & editing, Validation. RN: Methodology, Data curation, Writing—review & editing, Validation. AI: Methodology, Writing—review & editing, Validation. FCS: Methodology, Supervision, Writing—review & editing, Validation. All authors read and approved the submitted version.

Conflicts of interest

Ferdinando Carlo Sasso who is the Editorial Board Member of Exploration of Medicine had no involvement in the decision-making or the review process of this manuscript. The other authors declare that they have no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

Not applicable.

Copyright

Publisher’s note

Open Exploration maintains a neutral stance on jurisdictional claims in published institutional affiliations and maps. All opinions expressed in this article are the personal views of the author(s) and do not represent the stance of the editorial team or the publisher.

References

Rinella ME, Lazarus JV, Ratziu V, Francque SM, Sanyal AJ, Kanwal F, et al.; NAFLD Nomenclature consensus group. A multisociety Delphi consensus statement on new fatty liver disease nomenclature. Hepatology. 2023;78:1966–86. [DOI] [PubMed] [PMC]

Pipitone RM, Ciccioli C, Infantino G, Mantia CL, Parisi S, Tulone A, et al. MAFLD: a multisystem disease. Ther Adv Endocrinol Metab. 2023;14:20420188221145549. [DOI] [PubMed] [PMC]

Le P, Payne JY, Zhang L, Deshpande A, Rothberg MB, Alkhouri N, et al. Disease State Transition Probabilities Across the Spectrum of NAFLD: A Systematic Review and Meta-Analysis of Paired Biopsy or Imaging Studies. Clin Gastroenterol Hepatol. 2023;21:1154–68. [DOI] [PubMed] [PMC]

Singh S, Allen AM, Wang Z, Prokop LJ, Murad MH, Loomba R. Fibrosis progression in nonalcoholic fatty liver vs nonalcoholic steatohepatitis: a systematic review and meta-analysis of paired-biopsy studies. Clin Gastroenterol Hepatol. 2015;13:643–54.e9. [DOI] [PubMed] [PMC]

Younossi ZM, Golabi P, Paik JM, Henry A, Dongen CV, Henry L. The global epidemiology of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH): a systematic review. Hepatology. 2023;77:1335–47. [DOI] [PubMed] [PMC]

Golabi P, Paik JM, AlQahtani S, Younossi Y, Tuncer G, Younossi ZM. Burden of non-alcoholic fatty liver disease in Asia, the Middle East and North Africa: Data from Global Burden of Disease 2009-2019. J Hepatol. 2021;75:795–809. [DOI] [PubMed]

Wong VW, Ekstedt M, Wong GL, Hagström H. Changing epidemiology, global trends and implications for outcomes of NAFLD. J Hepatol. 2023;79:842–52. [DOI] [PubMed]

Le MH, Yeo YH, Zou B, Barnet S, Henry L, Cheung R, et al. Forecasted 2040 global prevalence of nonalcoholic fatty liver disease using hierarchical bayesian approach. Clin Mol Hepatol. 2022;28:841–50. [DOI] [PubMed] [PMC]

Younossi ZM, Golabi P, Price JK, Owrangi S, Gundu-Rao N, Satchi R, et al. The Global Epidemiology of Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis Among Patients With Type 2 Diabetes. Clin Gastroenterol Hepatol. 2024;22:1999–2010.e8. [DOI] [PubMed]

10.

Quek J, Chan KE, Wong ZY, Tan C, Tan B, Lim WH, et al. Global prevalence of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in the overweight and obese population: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol. 2023;8:20–30. [DOI] [PubMed]

11.

Marchesini G, Brizi M, Morselli-Labate AM, Bianchi G, Bugianesi E, McCullough AJ, et al. Association of nonalcoholic fatty liver disease with insulin resistance. Am J Med. 1999;107:450–5. [DOI] [PubMed]

12.

Friedman SL, Neuschwander-Tetri BA, Rinella M, Sanyal AJ. Mechanisms of NAFLD development and therapeutic strategies. Nat Med. 2018;24:908–22. [DOI] [PubMed] [PMC]

13.

Wang S, Yin J, Liu Z, Liu X, Tian G, Xin X, et al. Metabolic disorders, inter-organ crosstalk, and inflammation in the progression of metabolic dysfunction-associated steatotic liver disease. Life Sci. 2024;359:123211. [DOI] [PubMed]

14.

Azzu V, Vacca M, Virtue S, Allison M, Vidal-Puig A. Adipose Tissue-Liver Cross Talk in the Control of Whole-Body Metabolism: Implications in Nonalcoholic Fatty Liver Disease. Gastroenterology. 2020;158:1899–912. [DOI] [PubMed]

15.

Merli M, Dasarathy S. Sarcopenia in non-alcoholic fatty liver disease: Targeting the real culprit? J Hepatol. 2015;63:309–11. [DOI] [PubMed]

16.

Hrncir T, Hrncirova L, Kverka M, Hromadka R, Machova V, Trckova E, et al. Gut Microbiota and NAFLD: Pathogenetic Mechanisms, Microbiota Signatures, and Therapeutic Interventions. Microorganisms. 2021;9:957. [DOI] [PubMed] [PMC]

17.

Tilg H, Adolph TE, Dudek M, Knolle P. Non-alcoholic fatty liver disease: the interplay between metabolism, microbes and immunity. Nat Metab. 2021;3:1596–607. [DOI] [PubMed]

18.

Tilg H, Moschen AR. Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology. 2010;52:1836–46. [DOI] [PubMed]

19.

Petrasek J, Bala S, Csak T, Lippai D, Kodys K, Menashy V, et al. IL-1 receptor antagonist ameliorates inflammasome-dependent alcoholic steatohepatitis in mice. J Clin Invest. 2012;122:3476–89. [DOI] [PubMed] [PMC]

20.

Mridha AR, Wree A, Robertson AAB, Yeh MM, Johnson CD, Rooyen DMV, et al. NLRP3 inflammasome blockade reduces liver inflammation and fibrosis in experimental NASH in mice. J Hepatol. 2017;66:1037–46. [DOI] [PubMed] [PMC]

21.

Tilg H, Adolph TE, Tacke F. Therapeutic modulation of the liver immune microenvironment. Hepatology. 2023;78:1581–601. [DOI] [PubMed]

22.

Tardelli M, Bruschi FV, Trauner M. The Role of Metabolic Lipases in the Pathogenesis and Management of Liver Disease. Hepatology. 2020;72:1117–26. [DOI] [PubMed] [PMC]

23.

Alsamman S, Christenson SA, Yu A, Ayad NME, Mooring MS, Segal JM, et al. Targeting acid ceramidase inhibits YAP/TAZ signaling to reduce fibrosis in mice. Sci Transl Med. 2020;12:eaay8798. [DOI] [PubMed] [PMC]

24.

Iturbe-Rey S, Maccali C, Arrese M, Aspichueta P, Oliveira CP, Castro RE, et al. Lipotoxicity-driven metabolic dysfunction-associated steatotic liver disease (MASLD). Atherosclerosis. 2025;400:119053. [DOI] [PubMed]

25.

Tilg H, Hotamisligil GS. Nonalcoholic fatty liver disease: Cytokine-adipokine interplay and regulation of insulin resistance. Gastroenterology. 2006;131:934–45. [DOI] [PubMed]

26.

Cai D, Yuan M, Frantz DF, Melendez PA, Hansen L, Lee J, et al. Local and systemic insulin resistance resulting from hepatic activation of IKK-β and NF-κB. Nat Med. 2005;11:183–90. [DOI] [PubMed] [PMC]

27.

Li Y, Yang P, Ye J, Xu Q, Wu J, Wang Y. Updated mechanisms of MASLD pathogenesis. Lipids Health Dis. 2024;23:117. [DOI] [PubMed] [PMC]

28.

Hotamisligil GS. Endoplasmic reticulum stress and the inflammatory basis of metabolic disease. Cell. 2010;140:900–17. [DOI] [PubMed] [PMC]

29.

Sethi JK, Hotamisligil GS. Metabolic Messengers: tumour necrosis factor. Nat Metab. 2021;3:1302–12. [DOI] [PubMed]

30.

Hotamisligil GS. Inflammation, metaflammation and immunometabolic disorders. Nature. 2017;542:177–85. [DOI] [PubMed]

31.

Plessis Jd, Pelt Jv, Korf H, Mathieu C, Schueren Bvd, Lannoo M, et al. Association of Adipose Tissue Inflammation With Histologic Severity of Nonalcoholic Fatty Liver Disease. Gastroenterology. 2015;149:635–48.e14. [DOI] [PubMed]

32.

Musso G, Cassader M, Paschetta E, Gambino R. Bioactive Lipid Species and Metabolic Pathways in Progression and Resolution of Nonalcoholic Steatohepatitis. Gastroenterology. 2018;155:282–302.e8. [DOI] [PubMed]

33.

Sharpton SR, Schnabl B, Knight R, Loomba R. Current Concepts, Opportunities, and Challenges of Gut Microbiome-Based Personalized Medicine in Nonalcoholic Fatty Liver Disease. Cell Metab. 2021;33:21–32. [DOI] [PubMed] [PMC]

34.

Loomba R, Seguritan V, Li W, Long T, Klitgord N, Bhatt A, et al. Gut Microbiome-Based Metagenomic Signature for Non-invasive Detection of Advanced Fibrosis in Human Nonalcoholic Fatty Liver Disease. Cell Metab. 2017;25:1054–1062.e5. Erratum in: Cell Metab. 2019;30:607. [DOI] [PubMed] [PMC]

35.

Boursier J, Mueller O, Barret M, Machado M, Fizanne L, Araujo-Perez F, et al. The severity of nonalcoholic fatty liver disease is associated with gut dysbiosis and shift in the metabolic function of the gut microbiota. Hepatology. 2016;63:764–75. [DOI] [PubMed] [PMC]

36.

Mouzaki M, Comelli EM, Arendt BM, Bonengel J, Fung SK, Fischer SE, et al. Intestinal microbiota in patients with nonalcoholic fatty liver disease. Hepatology. 2013;58:120–7. [DOI] [PubMed]

37.

Carpino G, Ben MD, Pastori D, Carnevale R, Baratta F, Overi D, et al. Increased Liver Localization of Lipopolysaccharides in Human and Experimental NAFLD. Hepatology. 2020;72:470–85. [DOI] [PubMed]

38.

Kesar V, Odin JA. Toll-like receptors and liver disease. Liver Int. 2014;34:184–96. [DOI] [PubMed]

39.

Saeed H, Díaz LA, Gil-Gómez A, Burton J, Bajaj J, Romero-Gomez M, et al. Microbiome-Centered Therapies for the Management of Metabolic Dysfunction-Associated Steatotic Liver Disease. Clin Mol Hepatol. 2024;[Epub ahead of print]. [DOI] [PubMed]

40.

Tilg H, Moschen AR. Food, immunity, and the microbiome. Gastroenterology. 2015;148:1107–19. [DOI] [PubMed]

41.

Pendyala S, Walker JM, Holt PR. A high-fat diet is associated with endotoxemia that originates from the gut. Gastroenterology. 2012;142:1100–1.e2. [DOI] [PubMed] [PMC]

42.

Devkota S, Wang Y, Musch MW, Leone V, Fehlner-Peach H, Nadimpalli A, Antonopoulos DA, Jabri B, Chang EB. Dietary-fat-induced taurocholic acid promotes pathobiont expansion and colitis in Il10^-/- mice. Nature. 2012;487:104–8. [DOI] [PubMed] [PMC]

43.

Nasiri-Ansari N, Androutsakos T, Flessa C, Kyrou I, Siasos G, Randeva HS, et al. Endothelial Cell Dysfunction and Nonalcoholic Fatty Liver Disease (NAFLD): A Concise Review. Cells. 2022;11:2511. [DOI] [PubMed] [PMC]

44.

Mitten EK, Baffy G. Mechanotransduction in the pathogenesis of non-alcoholic fatty liver disease. J Hepatol. 2022;77:1642–56. [DOI] [PubMed]

45.

Mitten EK, Baffy G. Mechanobiology in the development and progression of nonalcoholic fatty liver disease: an updated review. Metab Target Organ Damage. 2023;3:2. [DOI]

46.

Shoham N, Gefen A. Mechanotransduction in adipocytes. J Biomech. 2012;45:1–8. [DOI] [PubMed]

47.

Mashek DG. Hepatic lipid droplets: A balancing act between energy storage and metabolic dysfunction in NAFLD. Mol Metab. 2021;50:101115. [DOI] [PubMed] [PMC]

48.

Scorletti E, Carr RM. A new perspective on NAFLD: Focusing on lipid droplets. J Hepatol. 2022;76:934–45. [DOI] [PubMed]

49.

Seebacher F, Zeigerer A, Kory N, Krahmer N. Hepatic lipid droplet homeostasis and fatty liver disease. Semin Cell Dev Biol. 2020;108:72–81. [DOI] [PubMed]

50.

DeLeve LD. Liver sinusoidal endothelial cells in hepatic fibrosis. Hepatology. 2015;61:1740–6. Erratum in: Hepatology. 2015;62:326. [DOI] [PubMed] [PMC]

51.

Hammoutene A, Rautou P. Role of liver sinusoidal endothelial cells in non-alcoholic fatty liver disease. J Hepatol. 2019;70:1278–91. [DOI] [PubMed]

52.

Long Y, Niu Y, Liang K, Du Y. Mechanical communication in fibrosis progression. Trends Cell Biol. 2022;32:70–90. [DOI] [PubMed]

53.

Ma H, Liu X, Zhang M, Niu J. Liver sinusoidal endothelial cells are implicated in multiple fibrotic mechanisms. Mol Biol Rep. 2021;48:2803–15. [DOI] [PubMed]

54.

Zhu C, Tabas I, Schwabe RF, Pajvani UB. Maladaptive regeneration – the reawakening of developmental pathways in NASH and fibrosis. Nat Rev Gastroenterol Hepatol. 2021;18:131–42. [DOI] [PubMed] [PMC]

55.

Chen G, Xia B, Fu Q, Huang X, Wang F, Chen Z, et al. Matrix Mechanics as Regulatory Factors and Therapeutic Targets in Hepatic Fibrosis. Int J Biol Sci. 2019;15:2509–21. [DOI] [PubMed] [PMC]

56.

Francque SMA, Dirinck E. NAFLD prevalence and severity in overweight and obese populations. Lancet Gastroenterol Hepatol. 2023;8:2–3. [DOI] [PubMed]

57.

Acierno C, Caturano A, Pafundi PC, Nevola R, Adinolfi LE, Sasso FC. Nonalcoholic fatty liver disease and type 2 diabetes: pathophysiological mechanisms shared between the two faces of the same coin. Explor Med. 2020;1:287–306. [DOI]

58.

Pirillo A, Casula M, Olmastroni E, Norata GD, Catapano AL. Global epidemiology of dyslipidaemias. Nat Rev Cardiol. 2021;18:689–700. [DOI] [PubMed]

59.

Zhang Q, Lu L. Nonalcoholic Fatty Liver Disease: Dyslipidemia, Risk for Cardiovascular Complications, and Treatment Strategy. J Clin Transl Hepatol. 2015;3:78–84. [DOI] [PubMed] [PMC]

60.

Hong S, Sun L, Hao Y, Li P, Zhou Y, Liang X, et al. From NAFLD to MASLD: When metabolic comorbidity matters. Ann Hepatol. 2024;29:101281. [DOI] [PubMed]

61.

Yang T, Yin J, Li J, Wang Q. The influence of different combinations of cardiometabolic risk factors on the prevalence of MASLD and risk of advanced fibrosis deserves attention. J Hepatol. 2024;80:e82–5. [DOI] [PubMed]

62.

He L, Qiu K, Zheng W, Kong W, Zeng T. Uric acid may serve as the sixth cardiometabolic criterion for defining MASLD. J Hepatol. 2024;80:e152–3. [DOI] [PubMed]

63.

Moon JH, Jeong S, Jang H, Koo BK, Kim W. Metabolic dysfunction-associated steatotic liver disease increases the risk of incident cardiovascular disease: a nationwide cohort study. EClinicalMedicine. 2023;65:102292. [DOI] [PubMed] [PMC]

64.

Tamaki N, Ahlholm N, Luukkonen PK, Porthan K, Sharpton SR, Ajmera V, et al. Risk of advanced fibrosis in first-degree relatives of patients with nonalcoholic fatty liver disease. J Clin Invest. 2022;132:e162513. [DOI] [PubMed] [PMC]

65.

Kleiner DE, Brunt EM, Wilson LA, Behling C, Guy C, Contos M, et al. Association of Histologic Disease Activity With Progression of Nonalcoholic Fatty Liver Disease. JAMA Netw Open. 2019;2:e1912565. [DOI] [PubMed] [PMC]

66.

Song R, Li Z, Zhang Y, Tan J, Chen Z. Comparison of NAFLD, MAFLD and MASLD characteristics and mortality outcomes in United States adults. Liver Int. 2024;44:1051–60. [DOI] [PubMed]

67.

Zhao Q, Deng Y. Comparison of mortality outcomes in individuals with MASLD and/or MAFLD. J Hepatol. 2024;80:e62–4. [DOI] [PubMed]

68.

Kim D, Wijarnpreecha K, Cholankeril G, Ahmed A. Steatotic liver disease-associated all-cause/cause-specific mortality in the United States. Aliment Pharmacol Ther. 2024;60:33–42. [DOI] [PubMed]

69.

Li M, Xie W. Are there all-cause mortality differences between metabolic dysfunction-associated steatotic liver disease subtypes? J Hepatol. 2024;80:e53–4. [DOI] [PubMed]

70.

Konyn P, Ahmed A, Kim D. Causes and risk profiles of mortality among individuals with nonalcoholic fatty liver disease. Clin Mol Hepatol. 2023;29:S43–57. [DOI] [PubMed] [PMC]

71.

Taylor RS, Taylor RJ, Bayliss S, Hagström H, Nasr P, Schattenberg JM, et al. Association Between Fibrosis Stage and Outcomes of Patients With Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis. Gastroenterology. 2020;158:1611–25.e12. [DOI] [PubMed]

72.

Li M, Chen W, Deng Y, Xie W. Impacts of cardiometabolic risk factors and alcohol consumption on all-cause mortality among MASLD and its subgroups. Nutr Metab Cardiovasc Dis. 2024;34:2085–94. [DOI] [PubMed]

73.

Zeng G, Wang PZ, Yuan JQ. Impact of different cardiometabolic risk factors in MASLD: rethinking overweight/obesity criteria. Eur J Prev Cardiol. 2024;31:i568. [DOI]

74.

Younossi ZM, Paik JM, Shabeeb RA, Golabi P, Younossi I, Henry L. Are there outcome differences between NAFLD and metabolic-associated fatty liver disease? Hepatology. 2022;76:1423–37. [DOI] [PubMed]

75.

Hagström H, Vessby J, Ekstedt M, Shang Y. 99% of patients with NAFLD meet MASLD criteria and natural history is therefore identical. J Hepatol. 2024;80:e76–7. [DOI] [PubMed]

76.

Ekstedt M, Franzén LE, Mathiesen UL, Thorelius L, Holmqvist M, Bodemar G, et al. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology. 2006;44:865–73. [DOI] [PubMed]

77.

Rafiq N, Bai C, Fang Y, Srishord M, McCullough A, Gramlich T, et al. Long-term follow-up of patients with nonalcoholic fatty liver. Clin Gastroenterol Hepatol. 2009;7:234–8. [DOI] [PubMed]

78.

Kanwal F, Kramer JR, Li L, Dai J, Natarajan Y, Yu X, et al. Effect of Metabolic Traits on the Risk of Cirrhosis and Hepatocellular Cancer in Nonalcoholic Fatty Liver Disease. Hepatology. 2020;71:808–19. [DOI] [PubMed]

79.

Fuente RAdl, Cuadrado NM, Tafur C, Gómez JJL, Cuesta SGdl, Sánchez MCG, et al. Histopathological differences in patients with biopsy-proven non-alcoholic fatty liver disease with and without type 2 diabetes. Endocrinol Diabetes Nutr (Engl Ed). 2018;65:354–60. English, Spanish. [DOI] [PubMed]

80.

Chen VL, Oliveri A, Miller MJ, Wijarnpreecha K, Du X, Chen Y, et al. PNPLA3 Genotype and Diabetes Identify Patients With Nonalcoholic Fatty Liver Disease at High Risk of Incident Cirrhosis. Gastroenterology. 2023;164:966–77.e17. [DOI] [PubMed] [PMC]

81.

Loomba R, Wong R, Fraysse J, Shreay S, Li S, Harrison S, et al. Nonalcoholic fatty liver disease progression rates to cirrhosis and progression of cirrhosis to decompensation and mortality: a real world analysis of Medicare data. Aliment Pharmacol Ther. 2020;51:1149–59. [DOI] [PubMed]

82.

Sanyal AJ, Natta MLV, Clark J, Neuschwander-Tetri BA, Diehl A, Dasarathy S, et al. Prospective Study of Outcomes in Adults with Nonalcoholic Fatty Liver Disease. N Engl J Med. 2021;385:1559–69. [DOI] [PubMed] [PMC]

83.

Huang DQ, Noureddin N, Ajmera V, Amangurbanova M, Bettencourt R, Truong E, et al. Type 2 diabetes, hepatic decompensation, and hepatocellular carcinoma in patients with non-alcoholic fatty liver disease: an individual participant-level data meta-analysis. Lancet Gastroenterol Hepatol. 2023;8:829–36. Erratum in: Lancet Gastroenterol Hepatol. 2023;8:e7. [DOI] [PubMed] [PMC]

84.

Dulai PS, Singh S, Patel J, Soni M, Prokop LJ, Younossi Z, et al. Increased risk of mortality by fibrosis stage in nonalcoholic fatty liver disease: Systematic review and meta-analysis. Hepatology. 2017;65:1557–65. [DOI] [PubMed] [PMC]

85.

Stine JG, Wentworth BJ, Zimmet A, Rinella ME, Loomba R, Caldwell SH, et al. Systematic review with meta-analysis: risk of hepatocellular carcinoma in non-alcoholic steatohepatitis without cirrhosis compared to other liver diseases. Aliment Pharmacol Ther. 2018;48:696–703. [DOI] [PubMed] [PMC]

86.

Kanwal F, Kramer JR, Mapakshi S, Natarajan Y, Chayanupatkul M, Richardson PA, et al. Risk of Hepatocellular Cancer in Patients With Non-Alcoholic Fatty Liver Disease. Gastroenterology. 2018;155:1828–37.e2. [DOI] [PubMed] [PMC]

87.

Phoolchund AGS, Khakoo SI. MASLD and the Development of HCC: Pathogenesis and Therapeutic Challenges. Cancers (Basel). 2024;16:259. [DOI] [PubMed] [PMC]

88.

Mattos ÂZ, Debes JD, Dhanasekaran R, Benhammou JN, Arrese M, Patrício ALV, et al. Hepatocellular carcinoma in nonalcoholic fatty liver disease: A growing challenge. World J Hepatol. 2021;13:1107–21. [DOI] [PubMed] [PMC]

89.

Armandi A, Rosso C, Caviglia GP, Bugianesi E. An updated overview on hepatocellular carcinoma in patients with Metabolic dysfunction-Associated Steatotic Liver Disease: Trends, pathophysiology and risk-based surveillance. Metabolism. 2025;162:156080. [DOI] [PubMed]

90.

Liu Y, Patman GL, Leathart JBS, Piguet A, Burt AD, Dufour J, et al. Carriage of the PNPLA3 rs738409 C >G polymorphism confers an increased risk of non-alcoholic fatty liver disease associated hepatocellular carcinoma. J Hepatol. 2014;61:75–81. [DOI] [PubMed]

91.

Singal AG, Manjunath H, Yopp AC, Beg MS, Marrero JA, Gopal P, et al. The effect of PNPLA3 on fibrosis progression and development of hepatocellular carcinoma: a meta-analysis. Am J Gastroenterol. 2014;109:325–34. [DOI] [PubMed] [PMC]

92.

Ioannou GN. Epidemiology and risk-stratification of NAFLD-associated HCC. J Hepatol. 2021;75:1476–84. [DOI] [PubMed]

93.

Targher G, Byrne CD, Tilg H. MASLD: a systemic metabolic disorder with cardiovascular and malignant complications. Gut. 2024;73:691–702. [DOI] [PubMed]

94.

Bilson J, Mantovani A, Byrne CD, Targher G. Steatotic liver disease, MASLD and risk of chronic kidney disease. Diabetes Metab. 2024;50:101506. [DOI] [PubMed]

95.

Hutchison AL, Tavaglione F, Romeo S, Charlton M. Endocrine aspects of metabolic dysfunction-associated steatotic liver disease (MASLD): Beyond insulin resistance. J Hepatol. 2023;79:1524–41. [DOI] [PubMed]

96.

Duell PB, Welty FK, Miller M, Chait A, Hammond G, Ahmad Z, et al.; American Heart Association Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Hypertension; Council on the Kidney in Cardiovascular Disease; Council on Lifestyle and Cardiometabolic Health; Council on Peripheral Vascular Disease. Nonalcoholic Fatty Liver Disease and Cardiovascular Risk: A Scientific Statement From the American Heart Association. Arterioscler Thromb Vasc Biol. 2022;42:e168–85. [DOI] [PubMed]

97.

Zhou X, Targher G, Byrne CD, Somers V, Kim SU, Chahal CAA, et al. An international multidisciplinary consensus statement on MAFLD and the risk of CVD. Hepatol Int. 2023;17:773–91. [DOI] [PubMed] [PMC]

98.

Lv Q, Zhao H. The association of metabolic dysfunction-associated steatotic liver disease (MASLD) with the risk of myocardial infarction: a systematic review and meta-analysis. Ann Med. 2024;56:2306192. [DOI] [PubMed] [PMC]

99.

Adams LA, Anstee QM, Tilg H, Targher G. Non-alcoholic fatty liver disease and its relationship with cardiovascular disease and other extrahepatic diseases. Gut. 2017;66:1138–53. [DOI] [PubMed]

100.

Angulo P, Kleiner DE, Dam-Larsen S, Adams LA, Bjornsson ES, Charatcharoenwitthaya P, et al. Liver Fibrosis, but No Other Histologic Features, Is Associated With Long-term Outcomes of Patients With Nonalcoholic Fatty Liver Disease. Gastroenterology. 2015;149:389–97.e10. [DOI] [PubMed] [PMC]

101.

Simon TG, Roelstraete B, Hagström H, Sundström J, Ludvigsson JF. Non-alcoholic fatty liver disease and incident major adverse cardiovascular events: results from a nationwide histology cohort. Gut. 2022;71:1867–75. [DOI] [PubMed]

102.

Wong MYZ, Yap JJL, Sultana R, Cheah M, Goh GBB, Yeo KK. Association between non-alcoholic fatty liver disease and subclinical atherosclerosis in Western and Asian cohorts: an updated meta-analysis. Open Heart. 2021;8:e001850. [DOI] [PubMed] [PMC]

103.

Kim A, Kang D, Choi SC, Sinn DH, Gwak G. Cardiometabolic risk factors and coronary atherosclerosis progression in patients with metabolic dysfunction-associated steatotic liver disease: the influential role of quantity over type. J Gastroenterol Hepatol. 2024;[Epub ahead of print]. [DOI] [PubMed]

104.

Lee SB, Park G, Lee J, Lee BU, Park JH, Kim BG, et al. Association between non-alcoholic fatty liver disease and subclinical coronary atherosclerosis: An observational cohort study. J Hepatol. 2018;68:1018–24. [DOI] [PubMed]

105.

Hu Y, Tang W, Liu Y, Zhang N, Zhu X, Tang D, et al. Temporal relationship between hepatic steatosis and blood pressure elevation and the mediation effect in the development of cardiovascular disease. Hypertens Res. 2024;47:1811–21. [DOI] [PubMed]

106.

Francque SM, Graaff Dvd, Kwanten WJ. Non-alcoholic fatty liver disease and cardiovascular risk: Pathophysiological mechanisms and implications. J Hepatol. 2016;65:425–43. [DOI] [PubMed]

107.

Stahl EP, Dhindsa DS, Lee SK, Sandesara PB, Chalasani NP, Sperling LS. Nonalcoholic Fatty Liver Disease and the Heart: JACC State-of-the-Art Review. J Am Coll Cardiol. 2019;73:948–63. [DOI] [PubMed]

108.

Qin L, Wu J, Sun X, Huang X, Huang W, Weng C, et al. The regulatory role of metabolic organ-secreted factors in the nonalcoholic fatty liver disease and cardiovascular disease. Front Cardiovasc Med. 2023;10:1119005. [DOI] [PubMed] [PMC]

109.

Takahashi Y, Iida K, Takahashi K, Yoshioka S, Fukuoka H, Takeno R, et al. Growth hormone reverses nonalcoholic steatohepatitis in a patient with adult growth hormone deficiency. Gastroenterology. 2007;132:938–43. [DOI] [PubMed]

110.

Stefan N, Schick F, Birkenfeld AL, Häring H, White MF. The role of hepatokines in NAFLD. Cell Metab. 2023;35:236–52. [DOI] [PubMed] [PMC]

111.

Dogru T, Genc H, Tapan S, Aslan F, Ercin CN, Ors F, et al. Plasma fetuin-A is associated with endothelial dysfunction and subclinical atherosclerosis in subjects with nonalcoholic fatty liver disease. Clin Endocrinol (Oxf). 2013;78:712–7. [DOI] [PubMed]

112.

Liu Y, Zhang C, Jiang J, Cheng Z, Zhou Z, Tang M, et al. Angiopoietin-like proteins in atherosclerosis. Clin Chim Acta. 2021;521:19–24. [DOI] [PubMed]

113.

Aron-Wisnewsky J, Clément K. The gut microbiome, diet, and links to cardiometabolic and chronic disorders. Nat Rev Nephrol. 2016;12:169–81. [DOI] [PubMed]

114.

Siddiqui MS, Fuchs M, Idowu MO, Luketic VA, Boyett S, Sargeant C, et al. Severity of nonalcoholic fatty liver disease and progression to cirrhosis are associated with atherogenic lipoprotein profile. Clin Gastroenterol Hepatol. 2015;13:1000–8.e3. [DOI] [PubMed] [PMC]

115.

Byrne CD, Targher G. NAFLD as a driver of chronic kidney disease. J Hepatol. 2020;72:785–801. [DOI] [PubMed]

116.

Mantovani A, Petracca G, Beatrice G, Csermely A, Lonardo A, Schattenberg JM, et al. Non-alcoholic fatty liver disease and risk of incident chronic kidney disease: an updated meta-analysis. Gut. 2022;71:156–62. [DOI] [PubMed]

117.

Chen S, Pang J, Huang R, Xue H, Chen X. Association of MAFLD with end-stage kidney disease: a prospective study of 337,783 UK Biobank participants. Hepatol Int. 2023;17:595–605. [DOI] [PubMed]

118.

Zuo G, Xuan L, Xin Z, Xu Y, Lu J, Chen Y, et al. New Nonalcoholic Fatty Liver Disease and Fibrosis Progression Associate With the Risk of Incident Chronic Kidney Disease. J Clin Endocrinol Metab. 2021;106:e3957–68. [DOI] [PubMed]

119.

Terasaka Y, Takahashi H, Amano K, Fujisaki K, Kita S, Kato K, et al. Change in Liver Fibrosis Associates with Progress of Diabetic Nephropathy in Patients with Nonalcoholic Fatty Liver Disease. Nutrients. 2023;15:3248. [DOI] [PubMed] [PMC]

120.

Koehler E, Swain J, Sanderson S, Krishnan A, Watt K, Charlton M. Growth hormone, dehydroepiandrosterone and adiponectin levels in non-alcoholic steatohepatitis: an endocrine signature for advanced fibrosis in obese patients. Liver Int. 2012;32:279–86. [DOI] [PubMed]

121.

Rufinatscha K, Ress C, Folie S, Haas S, Salzmann K, Moser P, et al. Metabolic effects of reduced growth hormone action in fatty liver disease. Hepatol Int. 2018;12:474–81. [DOI] [PubMed] [PMC]

122.

Dichtel LE, Corey KE, Misdraji J, Bredella MA, Schorr M, Osganian SA, et al. The Association Between IGF-1 Levels and the Histologic Severity of Nonalcoholic Fatty Liver Disease. Clin Transl Gastroenterol. 2017;8:e217. [DOI] [PubMed] [PMC]

123.

Tamaki N, Kimura T, Wakabayashi S, Umemura T, Izumi N, Loomba R, et al. Cardiometabolic criteria as predictors and treatment targets of liver-related events and cardiovascular events in metabolic dysfunction-associated steatotic liver disease. Aliment Pharmacol Ther. 2024;60:1033–41. [DOI] [PubMed]

124.

Nishizawa H, Iguchi G, Murawaki A, Fukuoka H, Hayashi Y, Kaji H, et al. Nonalcoholic fatty liver disease in adult hypopituitary patients with GH deficiency and the impact of GH replacement therapy. Eur J Endocrinol. 2012;167:67–74. [DOI] [PubMed]

125.

Pan CS, Weiss JJ, Fourman LT, Buckless C, Branch KL, Lee H, et al. Effect of recombinant human growth hormone on liver fat content in young adults with nonalcoholic fatty liver disease. Clin Endocrinol (Oxf). 2021;94:183–92. [DOI] [PubMed] [PMC]

126.

Zhao M, Xie H, Shan H, Zheng Z, Li G, Li M, et al. Development of Thyroid Hormones and Synthetic Thyromimetics in Non-Alcoholic Fatty Liver Disease. Int J Mol Sci. 2022;23:1102. [DOI] [PubMed] [PMC]

127.

Sinha RA, Singh BK, Yen PM. Direct effects of thyroid hormones on hepatic lipid metabolism. Nat Rev Endocrinol. 2018;14:259–69. [DOI] [PubMed] [PMC]

128.

Pagadala MR, Zein CO, Dasarathy S, Yerian LM, Lopez R, McCullough AJ. Prevalence of hypothyroidism in nonalcoholic fatty liver disease. Dig Dis Sci. 2012;57:528–34. [DOI] [PubMed] [PMC]

129.

Kim D, Kim W, Joo SK, Bae JM, Kim JH, Ahmed A. Subclinical Hypothyroidism and Low-Normal Thyroid Function Are Associated With Nonalcoholic Steatohepatitis and Fibrosis. Clin Gastroenterol Hepatol. 2018;16:123–31.e1. [DOI] [PubMed]

130.

Bohinc BN, Michelotti G, Xie G, Pang H, Suzuki A, Guy CD, et al. Repair-related activation of hedgehog signaling in stromal cells promotes intrahepatic hypothyroidism. Endocrinology. 2014;155:4591–601. [DOI] [PubMed] [PMC]

131.

Guo Z, Li M, Han B, Qi X. Association of non-alcoholic fatty liver disease with thyroid function: A systematic review and meta-analysis. Dig Liver Dis. 2018;50:1153–62. [DOI] [PubMed]

132.

Zeng X, Li B, Zou Y. The relationship between non-alcoholic fatty liver disease and hypothyroidism: A systematic review and meta-analysis. Medicine (Baltimore). 2021;100:e25738. [DOI] [PubMed] [PMC]

133.

Manka P, Bechmann L, Best J, Sydor S, Claridge LC, Coombes JD, et al. Low Free Triiodothyronine Is Associated with Advanced Fibrosis in Patients at High Risk for Nonalcoholic Steatohepatitis. Dig Dis Sci. 2019;64:2351–8. [DOI] [PubMed]

134.

Ittermann T, Khattak RM, Markus MRP, Kühn J, Kromrey M, Targher G, et al. Association between thyroid function and assessment of hepatic fat and iron contents by magnetic resonance imaging. Endocr Connect. 2022;11:e210566. [DOI] [PubMed] [PMC]

135.

Tan Y, Tang X, Mu P, Yang Y, Li M, Nie Y, et al. High-Normal Serum Thyrotropin Levels Increased the Risk of Non-Alcoholic Fatty Liver Disease in Euthyroid Subjects with Type 2 Diabetes. Diabetes Metab Syndr Obes. 2021;14:2841–9. [DOI] [PubMed] [PMC]

136.

Guo W, Qin P, Li X, Wu J, Lu J, Zhu W, et al. Free Triiodothyronine Is Associated With Hepatic Steatosis and Liver Stiffness in Euthyroid Chinese Adults With Non-Alcoholic Fatty Liver Disease. Front Endocrinol (Lausanne). 2021;12:711956. [DOI] [PubMed] [PMC]

137.

Labenz C, Kostev K, Armandi A, Galle PR, Schattenberg JM. Impact of thyroid disorders on the incidence of non-alcoholic fatty liver disease in Germany. United European Gastroenterol J. 2021;9:829–36. [DOI] [PubMed] [PMC]

138.

Punekar P, Sharma AK, Jain A. A Study of Thyroid Dysfunction in Cirrhosis of Liver and Correlation with Severity of Liver Disease. Indian J Endocrinol Metab. 2018;22:645–50. [DOI] [PubMed] [PMC]

139.

Krause C, Grohs M, Gammal ATE, Wolter S, Lehnert H, Mann O, et al. Reduced expression of thyroid hormone receptor β in human nonalcoholic steatohepatitis. Endocr Connect. 2018;7:1448–56. [DOI] [PubMed] [PMC]

140.

Harrison SA, Bashir MR, Guy CD, Zhou R, Moylan CA, Frias JP, et al. Resmetirom (MGL-3196) for the treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet. 2019;394:2012–24. [DOI] [PubMed]

141.

Asfari MM, Niyazi F, Lopez R, Dasarathy S, McCullough AJ. The association of nonalcoholic steatohepatitis and obstructive sleep apnea. Eur J Gastroenterol Hepatol. 2017;29:1380–4. [DOI] [PubMed] [PMC]

142.

Aron-Wisnewsky J, Minville C, Tordjman J, Lévy P, Bouillot J, Basdevant A, et al. Chronic intermittent hypoxia is a major trigger for non-alcoholic fatty liver disease in morbid obese. J Hepatol. 2012;56:225–33. [DOI] [PubMed]

143.

Mantovani A, Petracca G, Beatrice G, Csermely A, Tilg H, Byrne CD, et al. Non-alcoholic fatty liver disease and increased risk of incident extrahepatic cancers: a meta-analysis of observational cohort studies. Gut. 2022;71:778–88. [DOI] [PubMed]

144.

Thomas JA, Kendall BJ, Dalais C, Macdonald GA, Thrift AP. Hepatocellular and extrahepatic cancers in non-alcoholic fatty liver disease: A systematic review and meta-analysis. Eur J Cancer. 2022;173:250–62. [DOI] [PubMed]

145.

Roderburg C, Kostev K, Mertens A, Luedde T, Loosen SH. Non-alcoholic fatty liver disease (NAFLD) is associated with an increased incidence of extrahepatic cancer. Gut. 2023;72:2383–4. [DOI] [PubMed]

146.

Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature. 2008;454:436–44. [DOI] [PubMed]

147.

Cusi K, Isaacs S, Barb D, Basu R, Caprio S, Garvey WT, et al. American Association of Clinical Endocrinology Clinical Practice Guideline for the Diagnosis and Management of Nonalcoholic Fatty Liver Disease in Primary Care and Endocrinology Clinical Settings: Co-Sponsored by the American Association for the Study of Liver Diseases (AASLD). Endocr Pract. 2022;28:528–62. [DOI] [PubMed]

148.

Rinella ME, Neuschwander-Tetri BA, Siddiqui MS, Abdelmalek MF, Caldwell S, Barb D, et al. AASLD Practice Guidance on the clinical assessment and management of nonalcoholic fatty liver disease. Hepatology. 2023;77:1797–835. [DOI] [PubMed] [PMC]

149.

European Association for the Study of the Liver; European Association for the Study of Diabetes; European Association for the Study of Obesity. EASL–EASD–EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD): Executive Summary. Diabetologia. 2024;67:2375–92. Erratum in: Diabetologia. 2024;67:2608. [DOI] [PubMed] [PMC]

150.

Rigor J, Martins ME, Passos B, Oliveira R, Martins-Mendes D. Noninvasive tools for the assessment of fibrosis in metabolic dysfunction-associated steatotic liver disease. Minerva Med. 2024;115:660–70. [DOI] [PubMed]

151.

FDA Approves First Treatment for Patients with Liver Scarring Due to Fatty Liver Disease [Internet]. Silver Spring: U.S. Food and Drug Administration; [cited 2024 Sep 24]. Available from: https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-patients-liver-scarring-due-fatty-liver-disease

152.

Semmler G, Datz C, Reiberger T, Trauner M. Diet and exercise in NAFLD/NASH: Beyond the obvious. Liver Int. 2021;41:2249–68. [DOI] [PubMed] [PMC]

153.

Stine JG, Soriano C, Schreibman I, Rivas G, Hummer B, Yoo E, et al. Breaking Down Barriers to Physical Activity in Patients with Nonalcoholic Fatty Liver Disease. Dig Dis Sci. 2021;66:3604–11. [DOI] [PubMed] [PMC]

154.

Gu Y, Zhou R, Kong T, Zhang W, Chen Y, Wang C, et al. Barriers and enabling factors in weight management of patients with nonalcoholic fatty liver disease: A qualitative study using the COM-B model of behaviour. Health Expect. 2023;26:355–65. [DOI] [PubMed] [PMC]

155.

Zhou R, Gu Y, Zhang B, Kong T, Zhang W, Li J, et al. Digital Therapeutics: Emerging New Therapy for Nonalcoholic Fatty Liver Disease. Clin Transl Gastroenterol. 2023;14:e00575. [DOI] [PubMed] [PMC]

156.

Hong JS, Wasden C, Han DH. Introduction of digital therapeutics. Comput Methods Programs Biomed. 2021;209:106319. [DOI] [PubMed]

157.

Albhaisi S, Tondt J, Cyrus J, Chinchilli VM, Conroy DE, Stine JG. Digital therapeutics lead to clinically significant body weight loss in patients with metabolic dysfunction-associated steatotic liver disease: A systematic review and meta-analysis. Hepatol Commun. 2024;8:e0499. [DOI] [PubMed]

158.

Kahn CR, Wang G, Lee KY. Altered adipose tissue and adipocyte function in the pathogenesis of metabolic syndrome. J Clin Invest. 2019;129:3990–4000. [DOI] [PubMed] [PMC]

159.

Long MT, Noureddin M, Lim JK. AGA Clinical Practice Update: Diagnosis and Management of Nonalcoholic Fatty Liver Disease in Lean Individuals: Expert Review. Gastroenterology. 2022;163:764–74.e1. [DOI] [PubMed] [PMC]

160.

Malespin MH, 4th ASB, Watkins SE, Schoen C, Tincopa MA, Corbin KD, et al. Weight Loss and Weight Regain in Usual Clinical Practice: Results From the TARGET-NASH Observational Cohort. Clin Gastroenterol Hepatol. 2022;20:2393–5.e4. [DOI] [PubMed]

161.

Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L, Torres-Gonzalez A, Gra-Oramas B, Gonzalez-Fabian L, et al. Weight Loss Through Lifestyle Modification Significantly Reduces Features of Nonalcoholic Steatohepatitis. Gastroenterology. 2015;149:367–78.e5. [DOI] [PubMed]

162.

Haigh L, Kirk C, Gendy KE, Gallacher J, Errington L, Mathers JC, et al. The effectiveness and acceptability of Mediterranean diet and calorie restriction in non-alcoholic fatty liver disease (NAFLD): A systematic review and meta-analysis. Clin Nutr. 2022;41:1913–31. [DOI] [PubMed]

163.

Chen Y, Lu F, Hu Y, Xu L, Zheng M, Hu E. A systematic review and a dose-response meta-analysis of coffee dose and nonalcoholic fatty liver disease. Clin Nutr. 2019;38:2552–7. [DOI] [PubMed]

164.

Hallsworth K, Fattakhova G, Hollingsworth KG, Thoma C, Moore S, Taylor R, et al. Resistance exercise reduces liver fat and its mediators in non-alcoholic fatty liver disease independent of weight loss. Gut. 2011;60:1278–83. [DOI] [PubMed] [PMC]

165.

Hashida R, Kawaguchi T, Bekki M, Omoto M, Matsuse H, Nago T, et al. Aerobic vs. resistance exercise in non-alcoholic fatty liver disease: A systematic review. J Hepatol. 2017;66:142–52. [DOI] [PubMed]

166.

Stine JG, Long MT, Corey KE, Sallis RE, Allen AM, Armstrong MJ, et al. American College of Sports Medicine (ACSM) International Multidisciplinary Roundtable report on physical activity and nonalcoholic fatty liver disease. Hepatol Commun. 2023;7:e0108. [DOI] [PubMed] [PMC]

167.

Cuthbertson DJ, Shojaee-Moradie F, Sprung VS, Jones H, Pugh CJA, Richardson P, et al. Dissociation between exercise-induced reduction in liver fat and changes in hepatic and peripheral glucose homoeostasis in obese patients with non-alcoholic fatty liver disease. Clin Sci (Lond). 2016;130:93–104. [DOI] [PubMed]

168.

Shojaee-Moradie F, Cuthbertson DJ, Barrett M, Jackson NC, Herring R, Thomas EL, et al. Exercise Training Reduces Liver Fat and Increases Rates of VLDL Clearance But Not VLDL Production in NAFLD. J Clin Endocrinol Metab. 2016;101:4219–28. [DOI] [PubMed]

169.

Hughes A, Dahmus J, Rivas G, Hummer B, See JRC, Wright JR, et al. Exercise Training Reverses Gut Dysbiosis in Patients With Biopsy-Proven Nonalcoholic Steatohepatitis: A Proof of Concept Study. Clin Gastroenterol Hepatol. 2021;19:1723–5. [DOI] [PubMed] [PMC]

170.

Geerts A, Lefere S. Bariatric surgery for non-alcoholic fatty liver disease: Indications and post-operative management. Clin Mol Hepatol. 2023;29:S276–85. [DOI] [PubMed] [PMC]

171.

Lassailly G, Caiazzo R, Buob D, Pigeyre M, Verkindt H, Labreuche J, et al. Bariatric Surgery Reduces Features of Nonalcoholic Steatohepatitis in Morbidly Obese Patients. Gastroenterology. 2015;149:379–88. [DOI] [PubMed]

172.

Lassailly G, Caiazzo R, Ntandja-Wandji L, Gnemmi V, Baud G, Verkindt H, et al. Bariatric Surgery Provides Long-term Resolution of Nonalcoholic Steatohepatitis and Regression of Fibrosis. Gastroenterology. 2020;159:1290–301.e5. [DOI] [PubMed]

173.

Lee Y, Doumouras AG, Yu J, Brar K, Banfield L, Gmora S, et al. Complete Resolution of Nonalcoholic Fatty Liver Disease After Bariatric Surgery: A Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol. 2019;17:1040–60.e11. [DOI] [PubMed]

174.

Aminian A, Al-Kurd A, Wilson R, Bena J, Fayazzadeh H, Singh T, et al. Association of Bariatric Surgery With Major Adverse Liver and Cardiovascular Outcomes in Patients With Biopsy-Proven Nonalcoholic Steatohepatitis. JAMA. 2021;326:2031–42. [DOI] [PubMed] [PMC]

175.

Elsaid MI, Li Y, Bridges JFP, Brock G, Minacapelli CD, Rustgi VK. Association of Bariatric Surgery With Cardiovascular Outcomes in Adults With Severe Obesity and Nonalcoholic Fatty Liver Disease. JAMA Netw Open. 2022;5:e2235003. [DOI] [PubMed] [PMC]

176.

Mumtaz K, Lipshultz H, Jalil S, Porter K, Li N, Kelly SG, et al. Bariatric Surgery in Patients with Cirrhosis: Careful Patient and Surgery-Type Selection Is Key to Improving Outcomes. Obes Surg. 2020;30:3444–52. [DOI] [PubMed]

177.

Patton H, Heimbach J, McCullough A. AGA Clinical Practice Update on Bariatric Surgery in Cirrhosis: Expert Review. Clin Gastroenterol Hepatol. 2021;19:436–45. [DOI] [PubMed] [PMC]

178.

Hashem A, Khalouf A, Acosta A. Management of Obesity and Nonalcoholic Fatty Liver Disease: A Literature Review. Semin Liver Dis. 2021;41:435–47. [DOI] [PubMed] [PMC]

179.

Nevola R, Epifani R, Imbriani S, Tortorella G, Aprea C, Galiero R, et al. GLP-1 Receptor Agonists in Non-Alcoholic Fatty Liver Disease: Current Evidence and Future Perspectives. Int J Mol Sci. 2023;24:1703. [DOI] [PubMed] [PMC]

180.

Wang H, Wang L, Cheng Y, Xia Z, Liao Y, Cao J. Efficacy of orlistat in non-alcoholic fatty liver disease: A systematic review and meta-analysis. Biomed Rep. 2018;9:90–6. [DOI] [PubMed] [PMC]

181.

Loomba R, Hartman ML, Lawitz EJ, Vuppalanchi R, Boursier J, Bugianesi E, et al.; SYNERGY-NASH Investigators. Tirzepatide for Metabolic Dysfunction-Associated Steatohepatitis with Liver Fibrosis. N Engl J Med. 2024;391:299–310. [DOI] [PubMed]

182.

Ajmera V, Cepin S, Tesfai K, Hofflich H, Cadman K, Lopez S, et al. A prospective study on the prevalence of NAFLD, advanced fibrosis, cirrhosis and hepatocellular carcinoma in people with type 2 diabetes. J Hepatol. 2023;78:471–8. [DOI] [PubMed] [PMC]

183.

European Association for the Study of the Liver (EASL); European Association for the Study of Diabetes (EASD); European Association for the Study of Obesity (EASO). EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). J Hepatol. 2024;81:492–542. [DOI] [PubMed]

184.

Nevola R, Villani A, Imbriani S, Alfano M, Criscuolo L, Beccia D, et al. Sodium-Glucose Co-Transporters Family: Current Evidence, Clinical Applications and Perspectives. Front Biosci (Landmark Ed). 2023;28:103. [DOI] [PubMed]

185.

Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, et al. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest. 2001;108:1167–74. [DOI] [PubMed] [PMC]

186.

Kramer JR, Natarajan Y, Dai J, Yu X, Li L, El-Serag HB, et al. Effect of diabetes medications and glycemic control on risk of hepatocellular cancer in patients with nonalcoholic fatty liver disease. Hepatology. 2022;75:1420–8. [DOI] [PubMed] [PMC]

187.

DeFronzo RA, Chilton R, Norton L, Clarke G, Ryder REJ, Abdul-Ghani M. Revitalization of pioglitazone: the optimum agent to be combined with a sodium-glucose co-transporter-2 inhibitor. Diabetes Obes Metab. 2016;18:454–62. [DOI] [PubMed]

188.

Genua I, Iruzubieta P, Rodríguez-Duque JC, Pérez A, Crespo J. NAFLD and type 2 diabetes: A practical guide for the joint management. Gastroenterol Hepatol. 2023;46:815–25. English, Spanish. [DOI] [PubMed]

189.

Harrison SA, Bedossa P, Guy CD, Schattenberg JM, Loomba R, Taub R, et al.; MAESTRO-NASH Investigators. A Phase 3, Randomized, Controlled Trial of Resmetirom in NASH with Liver Fibrosis. N Engl J Med. 2024;390:497–509. [DOI] [PubMed]

190.

Belfort R, Harrison SA, Brown K, Darland C, Finch J, Hardies J, et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med. 2006;355:2297–307. [DOI] [PubMed]

191.

Kawaguchi-Suzuki M, Bril F, Kalavalapalli S, Cusi K, Frye RF. Concentration-dependent response to pioglitazone in nonalcoholic steatohepatitis. Aliment Pharmacol Ther. 2017;46:56–61. [DOI] [PubMed] [PMC]

192.

Musso G, Cassader M, Paschetta E, Gambino R. Thiazolidinediones and Advanced Liver Fibrosis in Nonalcoholic Steatohepatitis: A Meta-analysis. JAMA Intern Med. 2017;177:633–40. Erratum in: JAMA Intern Med. 2017;177:747. [DOI] [PubMed] [PMC]

193.

Francque SM, Bedossa P, Ratziu V, Anstee QM, Bugianesi E, Sanyal AJ, et al.; NATIVE Study Group. A Randomized, Controlled Trial of the Pan-PPAR Agonist Lanifibranor in NASH. N Engl J Med. 2021;385:1547–58. [DOI] [PubMed]

194.

Chaudhuri S, Dutta A, Chakraborty SBD. Efficacy and safety of saroglitazar in real-world patients of non-alcoholic fatty liver disease with or without diabetes including compensated cirrhosis: A tertiary care center experience. JGH Open. 2023;7:215–20. [DOI] [PubMed] [PMC]

195.

Gu Y, Sun L, He Y, Yang L, Deng C, Zhou R, et al. Comparative efficacy of glucagon-like peptide 1 (GLP-1) receptor agonists, pioglitazone and vitamin E for liver histology among patients with nonalcoholic fatty liver disease: systematic review and pilot network meta-analysis of randomized controlled trials. Expert Rev Gastroenterol Hepatol. 2023;17:273–82. [DOI] [PubMed]

196.

Harrison SA, Loomba R, Dubourg J, Ratziu V, Noureddin M. Clinical Trial Landscape in NASH. Clin Gastroenterol Hepatol. 2023;21:2001–14. [DOI] [PubMed]

197.

Kanwal F, Kramer JR, Li L, Yang Y, Cao Y, Yu X, et al. GLP-1 Receptor Agonists and Risk for Cirrhosis and Related Complications in Patients With Metabolic Dysfunction-Associated Steatotic Liver Disease. JAMA Intern Med. 2024;184:1314–23. [DOI] [PubMed] [PMC]

198.

Frías JP, Davies MJ, Rosenstock J, Manghi FCP, Landó LF, Bergman BK, et al.; SURPASS-2 Investigators. Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes. N Engl J Med. 2021;385:503–15. [DOI] [PubMed]

199.

Sinha B, Datta D, Ghosal S. Meta-analysis of the effects of sodium glucose cotransporter 2 inhibitors in non-alcoholic fatty liver disease patients with type 2 diabetes. JGH Open. 2020;5:219–27. [DOI] [PubMed] [PMC]

200.

Harrison SA, Frias JP, Neff G, Abrams GA, Lucas KJ, Sanchez W, et al.; HARMONY Study Group. Safety and efficacy of once-weekly efruxifermin versus placebo in non-alcoholic steatohepatitis (HARMONY): a multicentre, randomised, double-blind, placebo-controlled, phase 2b trial. Lancet Gastroenterol Hepatol. 2023;8:1080–93. [DOI] [PubMed]