Keywords
Cardiovascular disease
Liver-heart axis
Hepatic fibrosis
Cardiometabolic risk
How to Cite
Abstract
Introduction: Metabolically-dysfunction-associated steatotic liver disease (MASLD) represents a paradigm shift emphasizing the metabolic underpinnings of hepatic steatosis and its systemic consequences. MASLD carries a substantial cardiovascular burden. This review examines the clinical implications of the MASLD redefinition for internists, with particular focus on the liver-heart axis.
Methods: We conducted a narrative review synthesizing evidence through December 2024. Literature searches were performed in PubMed, EMBASE, and Cochrane Library using terms including "MASLD," "nonalcoholic fatty liver disease," "metabolic dysfunction-associated steatohepatitis, "cardiovascular disease," and "cardiometabolic risk." Priority was given to systematic reviews, meta-analyses, and large prospective cohort studies.
Results: MASLD is associated with increased risks of coronary artery disease, myocardial infarction, heart failure with preserved ejection fraction, atrial fibrillation, and cardiovascular mortality. These associations are mediated through insulin resistance, chronic inflammation, oxidative stress, atherogenic dyslipidemia, hepatokine dysregulation, gut-derived metabolites, and genetic determinants — though substantial residual confounding by shared cardiometabolic risk factors remains. Hepatic fibrosis stage emerges as a critical amplifier of cardiovascular risk. Integrated management requires systematic case-finding, fibrosis risk stratification using validated noninvasive tools, comprehensive cardiovascular assessment, intensive lifestyle intervention, and pharmacotherapy including incretin-based therapies, sodium-glucose cotransporter-2 inhibitors, and statins.
Conclusions: Internists must adopt integrated approaches addressing both hepatic and cardiovascular manifestations of MASLD. The liver-heart axis requires recognition as an interconnected system, with cardiovascular risk management prioritized alongside hepatic care. While the MASLD nomenclature is intended to improve disease recognition and patient engagement, prospective validation of these anticipated benefits remains needed.
References
1. Rinella ME, Lazarus JV, Ratziu V, Francque SM, Sanyal AJ, Kanwal F, Romero D, Abdelmalek MF, Anstee QM, Arab JP, Arrese M, Bataller R, Beuers U, Boursier J, Bugianesi E, Byrne CD, Castro Narro GE, Chowdhury A, Cortez-Pinto H, Cryer DR, Cusi K, El-Kassas M, Klein S, Eskridge W, Fan J, Gawrieh S, Guy CD, Harrison SA, Kim SU, Koot BG, Korenjak M, Kowdley KV, Lacaille F, Loomba R, Mitchell-Thain R, Morgan TR, Powell EE, Roden M, Romero-Gomez M, Silva M, Singh SP, Sookoian SC, Spearman CW, Tiniakos D, Valenti L, Vos MB, Wong VW, Xanthakos S, Yilmaz Y, Younossi Z, Hobbs A, Villota-Rivas M, Newsome PN, group NNc. A multisociety Delphi consensus statement on new fatty liver disease nomenclature. J Hepatol. 2023: 1542 [PMID: 37364790, https://doi.org/10.1016/j.jhep.2023.06.003]
2. Rinella ME, Sookoian S. From NAFLD to MASLD: updated naming and diagnosis criteria for fatty liver disease. J Lipid Res. 2024: 100485 [PMID: 38103785, https://doi.org/10.1016/j.jlr.2023.100485]
3. Rinella ME. Examining the Nomenclature Change From NAFLD and NASH to MASLD and MASH. Gastroenterol Hepatol (N Y). 2023: 697 [PMID: 38405223,
4. Eslam M, Sanyal AJ, George J, International Consensus P. MAFLD: A Consensus-Driven Proposed Nomenclature for Metabolic Associated Fatty Liver Disease. Gastroenterology. 2020: 1999 [PMID: 32044314, https://doi.org/10.1053/j.gastro.2019.11.312]
5. Bertolotti M, Lonardo A, Mussi C, Baldelli E, Pellegrini E, Ballestri S, Romagnoli D, Loria P. Nonalcoholic fatty liver disease and aging: epidemiology to management. World J Gastroenterol. 2014: 14185 [PMID: 25339806, https://doi.org/10.3748/wjg.v20.i39.14185]
6. European Association for the Study of the L, European Association for the Study of D, European Association for the Study of O. EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). J Hepatol. 2024: 492 [PMID: 38851997, https://doi.org/10.1016/j.jhep.2024.04.031]
7. Younossi ZM, Golabi P, Paik JM, Henry A, Van Dongen C, Henry L. The global epidemiology of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH): a systematic review. Hepatology. 2023: 1335 [PMID: 36626630, https://doi.org/10.1097/HEP.0000000000000004]
8. Targher G, Byrne CD, Tilg H. MASLD: a systemic metabolic disorder with cardiovascular and malignant complications. Gut. 2024: 691 [PMID: 38228377, https://doi.org/10.1136/gutjnl-2023-330595]
9. Ratti C, Malaguti M, Emanuele D, Bellasi A, Sanna G. Understanding MASLD - from molecular pathogenesis to cardiovascular risk: A concise review for the clinical cardiologist. Atherosclerosis. 2025: 120495 [PMID: 40876178, https://doi.org/10.1016/j.atherosclerosis.2025.120495]
10. Mantovani A, Csermely A, Petracca G, Beatrice G, Corey KE, Simon TG, Byrne CD, Targher G. Non-alcoholic fatty liver disease and risk of fatal and non-fatal cardiovascular events: an updated systematic review and meta-analysis. Lancet Gastroenterol Hepatol. 2021: 903 [PMID: 34555346, https://doi.org/10.1016/S2468-1253(21)00308-3]
11. Byrne CD, Targher G. NAFLD as a driver of chronic kidney disease. J Hepatol. 2020: 785 [PMID: 32059982, https://doi.org/10.1016/j.jhep.2020.01.013]
12. Targher G, Corey KE, Byrne CD, Roden M. The complex link between NAFLD and type 2 diabetes mellitus - mechanisms and treatments. Nat Rev Gastroenterol Hepatol. 2021: 599 [PMID: 33972770, https://doi.org/10.1038/s41575-021-00448-y]
13. Cusi K, Isaacs S, Barb D, Basu R, Caprio S, Garvey WT, Kashyap S, Mechanick JI, Mouzaki M, Nadolsky K, Rinella ME, Vos MB, Younossi Z. 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: 528 [PMID: 35569886, https://doi.org/10.1016/j.eprac.2022.03.010]
14. Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW, Ferrell LD, Liu YC, Torbenson MS, Unalp-Arida A, Yeh M, McCullough AJ, Sanyal AJ, Nonalcoholic Steatohepatitis Clinical Research N. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005: 1313 [PMID: 15915461, https://doi.org/10.1002/hep.20701]
15. Eslam M, Newsome PN, Sarin SK, Anstee QM, Targher G, Romero-Gomez M, Zelber-Sagi S, Wai-Sun Wong V, Dufour JF, Schattenberg JM, Kawaguchi T, Arrese M, Valenti L, Shiha G, Tiribelli C, Yki-Jarvinen H, Fan JG, Gronbaek H, Yilmaz Y, Cortez-Pinto H, Oliveira CP, Bedossa P, Adams LA, Zheng MH, Fouad Y, Chan WK, Mendez-Sanchez N, Ahn SH, Castera L, Bugianesi E, Ratziu V, George J. A new definition for metabolic dysfunction-associated fatty liver disease: An international expert consensus statement. J Hepatol. 2020: 202 [PMID: 32278004, https://doi.org/10.1016/j.jhep.2020.03.039]
16. Younossi ZM, Rinella ME, Sanyal AJ, Harrison SA, Brunt EM, Goodman Z, Cohen DE, Loomba R. From NAFLD to MAFLD: Implications of a Premature Change in Terminology. Hepatology. 2021: 1194 [PMID: 32544255, https://doi.org/10.1002/hep.31420]
17. Mendez-Sanchez N, Cruz-Ramon VC, Ramirez-Perez OL, Hwang JP, Barranco-Fragoso B, Cordova-Gallardo J. New Aspects of Lipotoxicity in Nonalcoholic Steatohepatitis. Int J Mol Sci. 2018: [PMID: 30011790, https://doi.org/10.3390/ijms19072034]
18. Song SJ, Lai JC, Wong GL, Wong VW, Yip TC. Can we use old NAFLD data under the new MASLD definition? J Hepatol. 2024: e54 [PMID: 37541393, https://doi.org/10.1016/j.jhep.2023.07.021]
19. Zou H, Ma X, Pan W, Xie Y. Comparing similarities and differences between NAFLD, MAFLD, and MASLD in the general U.S. population. Front Nutr. 2024: 1411802 [PMID: 39040926, https://doi.org/10.3389/fnut.2024.1411802]
20. Le MH, Yeo YH, Li X, Li J, Zou B, Wu Y, Ye Q, Huang DQ, Zhao C, Zhang J, Liu C, Chang N, Xing F, Yan S, Wan ZH, Tang NSY, Mayumi M, Liu X, Liu C, Rui F, Yang H, Yang Y, Jin R, Le RHX, Xu Y, Le DM, Barnett S, Stave CD, Cheung R, Zhu Q, Nguyen MH. 2019 Global NAFLD Prevalence: A Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol. 2022: 2809 [PMID: 34890795, https://doi.org/10.1016/j.cgh.2021.12.002]
21. Lazarus JV, Mark HE, Anstee QM, Arab JP, Batterham RL, Castera L, Cortez-Pinto H, Crespo J, Cusi K, Dirac MA, Francque S, George J, Hagstrom H, Huang TT, Ismail MH, Kautz A, Sarin SK, Loomba R, Miller V, Newsome PN, Ninburg M, Ocama P, Ratziu V, Rinella M, Romero D, Romero-Gomez M, Schattenberg JM, Tsochatzis EA, Valenti L, Wong VW, Yilmaz Y, Younossi ZM, Zelber-Sagi S, Consortium NC. Advancing the global public health agenda for NAFLD: a consensus statement. Nat Rev Gastroenterol Hepatol. 2022: 60 [PMID: 34707258, https://doi.org/10.1038/s41575-021-00523-4]
22. Paik JM, Golabi P, Younossi Y, Mishra A, Younossi ZM. Changes in the Global Burden of Chronic Liver Diseases From 2012 to 2017: The Growing Impact of NAFLD. Hepatology. 2020: 1605 [PMID: 32043613, https://doi.org/10.1002/hep.31173]
23. Mantovani A, Petracca G, Beatrice G, Tilg H, Byrne CD, Targher G. Non-alcoholic fatty liver disease and risk of incident diabetes mellitus: an updated meta-analysis of 501 022 adult individuals. Gut. 2021: 962 [PMID: 32938692, https://doi.org/10.1136/gutjnl-2020-322572]
24. Ballestri S, Zona S, Targher G, Romagnoli D, Baldelli E, Nascimbeni F, Roverato A, Guaraldi G, Lonardo A. 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 Hepatol. 2016: 936 [PMID: 26667191, https://doi.org/10.1111/jgh.13264]
25. Ye Q, Zou B, Yeo YH, Li J, Huang DQ, Wu Y, Yang H, Liu C, Kam LY, Tan XXE, Chien N, Trinh S, Henry L, Stave CD, Hosaka T, Cheung RC, Nguyen MH. Global prevalence, incidence, and outcomes of non-obese or lean non-alcoholic fatty liver disease: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol. 2020: 739 [PMID: 32413340, https://doi.org/10.1016/S2468-1253(20)30077-7]
26. Kim D, Kim WR. Nonobese Fatty Liver Disease. Clin Gastroenterol Hepatol. 2017: 474 [PMID: 27581063, https://doi.org/10.1016/j.cgh.2016.08.028]
27. 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: 643 [PMID: 24768810, https://doi.org/10.1016/j.cgh.2014.04.014]
28. Taylor RS, Taylor RJ, Bayliss S, Hagstrom H, Nasr P, Schattenberg JM, Ishigami M, Toyoda H, Wai-Sun Wong V, Peleg N, Shlomai A, Sebastiani G, Seko Y, Bhala N, Younossi ZM, Anstee QM, McPherson S, Newsome PN. Association Between Fibrosis Stage and Outcomes of Patients With Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis. Gastroenterology. 2020: 1611 [PMID: 32027911, https://doi.org/10.1053/j.gastro.2020.01.043]
29. Dulai PS, Singh S, Patel J, Soni M, Prokop LJ, Younossi Z, Sebastiani G, Ekstedt M, Hagstrom H, Nasr P, Stal P, Wong VW, Kechagias S, Hultcrantz R, Loomba R. Increased risk of mortality by fibrosis stage in nonalcoholic fatty liver disease: Systematic review and meta-analysis. Hepatology. 2017: 1557 [PMID: 28130788, https://doi.org/10.1002/hep.29085]
30. Paik JM, Henry L, De Avila L, Younossi E, Racila A, Younossi ZM. Mortality Related to Nonalcoholic Fatty Liver Disease Is Increasing in the United States. Hepatol Commun. 2019: 1459 [PMID: 31701070, https://doi.org/10.1002/hep4.1419]
31. 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: 1138 [PMID: 28314735, https://doi.org/10.1136/gutjnl-2017-313884]
32. Targher G, Byrne CD, Lonardo A, Zoppini G, Barbui C. Non-alcoholic fatty liver disease and risk of incident cardiovascular disease: A meta-analysis. J Hepatol. 2016: 589 [PMID: 27212244, https://doi.org/10.1016/j.jhep.2016.05.013]
33. Petersen MC, Shulman GI. Mechanisms of Insulin Action and Insulin Resistance. Physiol Rev. 2018: 2133 [PMID: 30067154, https://doi.org/10.1152/physrev.00063.2017]
34. Yoshino J, Baur JA, Imai SI. NAD(+) Intermediates: The Biology and Therapeutic Potential of NMN and NR. Cell Metab. 2018: 513 [PMID: 29249689, https://doi.org/10.1016/j.cmet.2017.11.002]
35. Meex RCR, Watt MJ. Hepatokines: linking nonalcoholic fatty liver disease and insulin resistance. Nat Rev Endocrinol. 2017: 509 [PMID: 28621339, https://doi.org/10.1038/nrendo.2017.56]
36. Stefan N, Haring HU. The role of hepatokines in metabolism. Nat Rev Endocrinol. 2013: 144 [PMID: 23337953, https://doi.org/10.1038/nrendo.2012.258]
37. Hill MA, Yang Y, Zhang L, Sun Z, Jia G, Parrish AR, Sowers JR. Insulin resistance, cardiovascular stiffening and cardiovascular disease. Metabolism. 2021: 154766 [PMID: 33766485, https://doi.org/10.1016/j.metabol.2021.154766]
38. From AM, Leibson CL, Bursi F, Redfield MM, Weston SA, Jacobsen SJ, Rodeheffer RJ, Roger VL. Diabetes in heart failure: prevalence and impact on outcome in the population. Am J Med. 2006: 591 [PMID: 16828631, https://doi.org/10.1016/j.amjmed.2006.05.024]
39. Jia G, Hill MA, Sowers JR. Diabetic Cardiomyopathy: An Update of Mechanisms Contributing to This Clinical Entity. Circ Res. 2018: 624 [PMID: 29449364, https://doi.org/10.1161/CIRCRESAHA.117.311586]
40. Tilg H, Moschen AR. Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology. 2010: 1836 [PMID: 21038418, https://doi.org/10.1002/hep.24001]
41. Schuster S, Cabrera D, Arrese M, Feldstein AE. Triggering and resolution of inflammation in NASH. Nat Rev Gastroenterol Hepatol. 2018: 349 [PMID: 29740166, https://doi.org/10.1038/s41575-018-0009-6]
42. Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, Fonseca F, Nicolau J, Koenig W, Anker SD, Kastelein JJP, Cornel JH, Pais P, Pella D, Genest J, Cifkova R, Lorenzatti A, Forster T, Kobalava Z, Vida-Simiti L, Flather M, Shimokawa H, Ogawa H, Dellborg M, Rossi PRF, Troquay RPT, Libby P, Glynn RJ, Group CT. Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. N Engl J Med. 2017: 1119 [PMID: 28845751, https://doi.org/10.1056/NEJMoa1707914]
43. Hansson GK, Hermansson A. The immune system in atherosclerosis. Nat Immunol. 2011: 204 [PMID: 21321594, https://doi.org/10.1038/ni.2001]
44. Byrne CD, Targher G. NAFLD: a multisystem disease. J Hepatol. 2015: S47 [PMID: 25920090, https://doi.org/10.1016/j.jhep.2014.12.012]
45. Lonardo A, Nascimbeni F, Mantovani A, Targher G. Hypertension, diabetes, atherosclerosis and NASH: Cause or consequence? J Hepatol. 2018: 335 [PMID: 29122390, https://doi.org/10.1016/j.jhep.2017.09.021]
46. Sunny NE, Bril F, Cusi K. Mitochondrial Adaptation in Nonalcoholic Fatty Liver Disease: Novel Mechanisms and Treatment Strategies. Trends Endocrinol Metab. 2017: 250 [PMID: 27986466, https://doi.org/10.1016/j.tem.2016.11.006]
47. Ore A, Akinloye OA. Oxidative Stress and Antioxidant Biomarkers in Clinical and Experimental Models of Non-Alcoholic Fatty Liver Disease. Medicina (Kaunas). 2019: [PMID: 30682878, https://doi.org/10.3390/medicina55020026]
48. Bhatia L, Scorletti E, Curzen N, Clough GF, Calder PC, Byrne CD. Improvement in non-alcoholic fatty liver disease severity is associated with a reduction in carotid intima-media thickness progression. Atherosclerosis. 2016: 13 [PMID: 26748347, https://doi.org/10.1016/j.atherosclerosis.2015.12.028]
49. Chen CH, Nien CK, Yang CC, Yeh YH. Association between nonalcoholic fatty liver disease and coronary artery calcification. Dig Dis Sci. 2010: 1752 [PMID: 19688595, https://doi.org/10.1007/s10620-009-0935-9]
50. Schulze PC, Drosatos K, Goldberg IJ. Lipid Use and Misuse by the Heart. Circ Res. 2016: 1736 [PMID: 27230639, https://doi.org/10.1161/CIRCRESAHA.116.306842]
51. Nakamura M, Sadoshima J. Mechanisms of physiological and pathological cardiac hypertrophy. Nat Rev Cardiol. 2018: 387 [PMID: 29674714, https://doi.org/10.1038/s41569-018-0007-y]
52. Bril F, Cusi K. Management of Nonalcoholic Fatty Liver Disease in Patients With Type 2 Diabetes: A Call to Action. Diabetes Care. 2017: 419 [PMID: 28223446, https://doi.org/10.2337/dc16-1787]
53. Adiels M, Taskinen MR, Packard C, Caslake MJ, Soro-Paavonen A, Westerbacka J, Vehkavaara S, Hakkinen A, Olofsson SO, Yki-Jarvinen H, Boren J. Overproduction of large VLDL particles is driven by increased liver fat content in man. Diabetologia. 2006: 755 [PMID: 16463046, https://doi.org/10.1007/s00125-005-0125-z]
54. Donnelly KL, Smith CI, Schwarzenberg SJ, Jessurun J, Boldt MD, Parks EJ. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Invest. 2005: 1343 [PMID: 15864352, https://doi.org/10.1172/JCI23621]
55. Kotronen A, Westerbacka J, Bergholm R, Pietilainen KH, Yki-Jarvinen H. Liver fat in the metabolic syndrome. J Clin Endocrinol Metab. 2007: 3490 [PMID: 17595248, https://doi.org/10.1210/jc.2007-0482]
56. Bhatia LS, Curzen NP, Calder PC, Byrne CD. Non-alcoholic fatty liver disease: a new and important cardiovascular risk factor? Eur Heart J. 2012: 1190 [PMID: 22408036, https://doi.org/10.1093/eurheartj/ehr453]
57. Targher G, Bertolini L, Padovani R, Rodella S, Zoppini G, Zenari L, Cigolini M, Falezza G, Arcaro G. Relations between carotid artery wall thickness and liver histology in subjects with nonalcoholic fatty liver disease. Diabetes Care. 2006: 1325 [PMID: 16732016, https://doi.org/10.2337/dc06-0135]
58. Albillos A, de Gottardi A, Rescigno M. The gut-liver axis in liver disease: Pathophysiological basis for therapy. J Hepatol. 2020: 558 [PMID: 31622696, https://doi.org/10.1016/j.jhep.2019.10.003]
59. Boursier J, Mueller O, Barret M, Machado M, Fizanne L, Araujo-Perez F, Guy CD, Seed PC, Rawls JF, David LA, Hunault G, Oberti F, Cales P, Diehl AM. The severity of nonalcoholic fatty liver disease is associated with gut dysbiosis and shift in the metabolic function of the gut microbiota. Hepatology. 2016: 764 [PMID: 26600078, https://doi.org/10.1002/hep.28356]
60. Loomba R, Seguritan V, Li W, Long T, Klitgord N, Bhatt A, Dulai PS, Caussy C, Bettencourt R, Highlander SK, Jones MB, Sirlin CB, Schnabl B, Brinkac L, Schork N, Chen CH, Brenner DA, Biggs W, Yooseph S, Venter JC, Nelson KE. Gut Microbiome-Based Metagenomic Signature for Non-invasive Detection of Advanced Fibrosis in Human Nonalcoholic Fatty Liver Disease. Cell Metab. 2017: 1054 [PMID: 28467925, https://doi.org/10.1016/j.cmet.2017.04.001]
61. Caussy C, Tripathi A, Humphrey G, Bassirian S, Singh S, Faulkner C, Bettencourt R, Rizo E, Richards L, Xu ZZ, Downes MR, Evans RM, Brenner DA, Sirlin CB, Knight R, Loomba R. A gut microbiome signature for cirrhosis due to nonalcoholic fatty liver disease. Nat Commun. 2019: 1406 [PMID: 30926798, https://doi.org/10.1038/s41467-019-09455-9]
62. Miele L, Valenza V, La Torre G, Montalto M, Cammarota G, Ricci R, Masciana R, Forgione A, Gabrieli ML, Perotti G, Vecchio FM, Rapaccini G, Gasbarrini G, Day CP, Grieco A. Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease. Hepatology. 2009: 1877 [PMID: 19291785, https://doi.org/10.1002/hep.22848]
63. Carpino G, Del Ben M, Pastori D, Carnevale R, Baratta F, Overi D, Francis H, Cardinale V, Onori P, Safarikia S, Cammisotto V, Alvaro D, Svegliati-Baroni G, Angelico F, Gaudio E, Violi F. Increased Liver Localization of Lipopolysaccharides in Human and Experimental NAFLD. Hepatology. 2020: 470 [PMID: 31808577, https://doi.org/10.1002/hep.31056]
64. Pais R, Charlotte F, Fedchuk L, Bedossa P, Lebray P, Poynard T, Ratziu V, Group LS. A systematic review of follow-up biopsies reveals disease progression in patients with non-alcoholic fatty liver. J Hepatol. 2013: 550 [PMID: 23665288, https://doi.org/10.1016/j.jhep.2013.04.027]
65. Wang CW, Huang JF, Yu ML, Chuang WL. Hepatitis C virus and cardiovascular disease: Current knowledge and unmet needs. Tzu Chi Med J. 2025: 371 [PMID: 41180511, https://doi.org/10.4103/tcmj.tcmj_101_25]
66. Ekstedt M, Hagstrom H, Nasr P, Fredrikson M, Stal P, Kechagias S, Hultcrantz R. Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up. Hepatology. 2015: 1547 [PMID: 25125077, https://doi.org/10.1002/hep.27368]
67. Hagstrom H, Nasr P, Ekstedt M, Hammar U, Stal P, Hultcrantz R, Kechagias S. Fibrosis stage but not NASH predicts mortality and time to development of severe liver disease in biopsy-proven NAFLD. J Hepatol. 2017: 1265 [PMID: 28803953, https://doi.org/10.1016/j.jhep.2017.07.027]
68. Vilar-Gomez E, Calzadilla-Bertot L, Wai-Sun Wong V, Castellanos M, Aller-de la Fuente R, Metwally M, Eslam M, Gonzalez-Fabian L, Alvarez-Quinones Sanz M, Conde-Martin AF, De Boer B, McLeod D, Hung Chan AW, Chalasani N, George J, Adams LA, Romero-Gomez M. Fibrosis Severity as a Determinant of Cause-Specific Mortality in Patients With Advanced Nonalcoholic Fatty Liver Disease: A Multi-National Cohort Study. Gastroenterology. 2018: 443 [PMID: 29733831, https://doi.org/10.1053/j.gastro.2018.04.034]
69. Simon TG, Roelstraete B, Khalili H, Hagstrom H, Ludvigsson JF. Mortality in biopsy-confirmed nonalcoholic fatty liver disease: results from a nationwide cohort. Gut. 2021: 1375 [PMID: 33037056, https://doi.org/10.1136/gutjnl-2020-322786]
70. Targher G, Tilg H, Byrne CD. Non-alcoholic fatty liver disease: a multisystem disease requiring a multidisciplinary and holistic approach. Lancet Gastroenterol Hepatol. 2021: 578 [PMID: 33961787, https://doi.org/10.1016/S2468-1253(21)00020-0]
71. Francque SM, van der Graaff D, Kwanten WJ. Non-alcoholic fatty liver disease and cardiovascular risk: Pathophysiological mechanisms and implications. J Hepatol. 2016: 425 [PMID: 27091791, https://doi.org/10.1016/j.jhep.2016.04.005]
72. Eslam M, Valenti L, Romeo S. Genetics and epigenetics of NAFLD and NASH: Clinical impact. J Hepatol. 2018: 268 [PMID: 29122391, https://doi.org/10.1016/j.jhep.2017.09.003]
73. Friedman SL, Neuschwander-Tetri BA, Rinella M, Sanyal AJ. Mechanisms of NAFLD development and therapeutic strategies. Nat Med. 2018: 908 [PMID: 29967350, https://doi.org/10.1038/s41591-018-0104-9]
74. Rinella ME, Neuschwander-Tetri BA, Siddiqui MS, Abdelmalek MF, Caldwell S, Barb D, Kleiner DE, Loomba R. AASLD Practice Guidance on the clinical assessment and management of nonalcoholic fatty liver disease. Hepatology. 2023: 1797 [PMID: 36727674, https://doi.org/10.1097/hep.0000000000000323]
75. Targher G, Day CP, Bonora E. Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease. N Engl J Med. 2010: 1341 [PMID: 20879883, https://doi.org/10.1056/NEJMra0912063]
76. Wu S, Wu F, Ding Y, Hou J, Bi J, Zhang Z. Association of non-alcoholic fatty liver disease with major adverse cardiovascular events: A systematic review and meta-analysis. Sci Rep. 2016: 33386 [PMID: 27633274, https://doi.org/10.1038/srep33386]
77. Mantovani A, Petracca G, Beatrice G, Csermely A, Tilg H, Byrne CD, Targher G. Non-alcoholic fatty liver disease and increased risk of incident extrahepatic cancers: a meta-analysis of observational cohort studies. Gut. 2022: 778 [PMID: 33685968, https://doi.org/10.1136/gutjnl-2021-324191]
78. Sookoian S, Pirola CJ. Non-alcoholic fatty liver disease is strongly associated with carotid atherosclerosis: a systematic review. J Hepatol. 2008: 600 [PMID: 18672311, https://doi.org/10.1016/j.jhep.2008.06.012]
79. Oni ET, Agatston AS, Blaha MJ, Fialkow J, Cury R, Sposito A, Erbel R, Blankstein R, Feldman T, Al-Mallah MH, Santos RD, Budoff MJ, Nasir K. A systematic review: burden and severity of subclinical cardiovascular disease among those with nonalcoholic fatty liver; should we care? Atherosclerosis. 2013: 258 [PMID: 24075754, https://doi.org/10.1016/j.atherosclerosis.2013.07.052]
80. Pisto P, Santaniemi M, Bloigu R, Ukkola O, Kesaniemi YA. Fatty liver predicts the risk for cardiovascular events in middle-aged population: a population-based cohort study. BMJ Open. 2014: e004973 [PMID: 24650811, https://doi.org/10.1136/bmjopen-2014-004973]
81. VanWagner LB, Wilcox JE, Ning H, Lewis CE, Carr JJ, Rinella ME, Shah SJ, Lima JAC, Lloyd-Jones DM. Longitudinal Association of Non-Alcoholic Fatty Liver Disease With Changes in Myocardial Structure and Function: The CARDIA Study. J Am Heart Assoc. 2020: e014279 [PMID: 32067588, https://doi.org/10.1161/JAHA.119.014279]
82. Mantovani A, Mingolla L, Rigolon R, Pichiri I, Cavalieri V, Zoppini G, Lippi G, Bonora E, Targher G. Nonalcoholic fatty liver disease is independently associated with an increased incidence of cardiovascular disease in adult patients with type 1 diabetes. Int J Cardiol. 2016: 387 [PMID: 27768965, https://doi.org/10.1016/j.ijcard.2016.10.040]
83. VanWagner LB, Wilcox JE, Colangelo LA, Lloyd-Jones DM, Carr JJ, Lima JA, Lewis CE, Rinella ME, Shah SJ. Association of nonalcoholic fatty liver disease with subclinical myocardial remodeling and dysfunction: A population-based study. Hepatology. 2015: 773 [PMID: 25914296, https://doi.org/10.1002/hep.27869]
84. Mantovani A, Petracca G, Beatrice G, Csermely A, Lonardo A, Schattenberg JM, Tilg H, Byrne CD, Targher G. Non-alcoholic fatty liver disease and risk of incident chronic kidney disease: an updated meta-analysis. Gut. 2022: 156 [PMID: 33303564, https://doi.org/10.1136/gutjnl-2020-323082]
85. Mantovani A, Petracca G, Csermely A, Beatrice G, Bonapace S, Rossi A, Tilg H, Byrne CD, Targher G. Non-alcoholic fatty liver disease and risk of new-onset heart failure: an updated meta-analysis of about 11 million individuals. Gut. 2022: [PMID: 35879047, https://doi.org/10.1136/gutjnl-2022-327672]
86. Kim G, Yu TY, Jee JH, Bae JC, Kang M, Kim JH. Association between nonalcoholic fatty liver disease and left ventricular diastolic dysfunction: A 7-year retrospective cohort study of 3,380 adults using serial echocardiography. Diabetes Metab. 2024: 101534 [PMID: 38608865, https://doi.org/10.1016/j.diabet.2024.101534]
87. Lee YH, Kim KJ, Yoo ME, Kim G, Yoon HJ, Jo K, Youn JC, Yun M, Park JY, Shim CY, Lee BW, Kang SM, Ha JW, Cha BS, Kang ES. Association of non-alcoholic steatohepatitis with subclinical myocardial dysfunction in non-cirrhotic patients. J Hepatol. 2018: 764 [PMID: 29175242, https://doi.org/10.1016/j.jhep.2017.11.023]
88. Trovato FM, Martines GF, Catalano D, Musumeci G, Pirri C, Trovato GM. Echocardiography and NAFLD (non-alcoholic fatty liver disease). Int J Cardiol. 2016: 275 [PMID: 27404689, https://doi.org/10.1016/j.ijcard.2016.06.180]
89. Iacobellis G, Corradi D, Sharma AM. Epicardial adipose tissue: anatomic, biomolecular and clinical relationships with the heart. Nat Clin Pract Cardiovasc Med. 2005: 536 [PMID: 16186852, https://doi.org/10.1038/ncpcardio0319]
90. Manco M, Putignani L, Bottazzo GF. Gut microbiota, lipopolysaccharides, and innate immunity in the pathogenesis of obesity and cardiovascular risk. Endocr Rev. 2010: 817 [PMID: 20592272, https://doi.org/10.1210/er.2009-0030]
91. Karajamaki AJ, Patsi OP, Savolainen M, Kesaniemi YA, Huikuri H, Ukkola O. Non-Alcoholic Fatty Liver Disease as a Predictor of Atrial Fibrillation in Middle-Aged Population (OPERA Study). PLoS One. 2015: e0142937 [PMID: 26571029, https://doi.org/10.1371/journal.pone.0142937]
92. Targher G, Valbusa F, Bonapace S, Bertolini L, Zenari L, Rodella S, Zoppini G, Mantovani W, Barbieri E, Byrne CD. Non-alcoholic fatty liver disease is associated with an increased incidence of atrial fibrillation in patients with type 2 diabetes. PLoS One. 2013: e57183 [PMID: 23451184, https://doi.org/10.1371/journal.pone.0057183]
93. El Amrousy D, El Ashry H, Maher S, Elsayed Y, Elkashlan K, Abdelhai D, Mawlana W, Hasan S. Increased inter-atrial and intra-atrial conduction times in pediatric patients with non-alcoholic fatty liver disease. Eur J Pediatr. 2024: 5489 [PMID: 39438332, https://doi.org/10.1007/s00431-024-05809-8]
94. Wijarnpreecha K, Boonpheng B, Thongprayoon C, Jaruvongvanich V, Ungprasert P. The association between non-alcoholic fatty liver disease and atrial fibrillation: A meta-analysis. Clin Res Hepatol Gastroenterol. 2017: 525 [PMID: 28866089, https://doi.org/10.1016/j.clinre.2017.08.001]
95. Jaiswal V, Ang SP, Huang H, Momi NK, Hameed M, Naz S, Batra N, Ishak A, Doshi N, Gera A, Sharath M, Waleed MS, Raj N, Aguilera Alvarez VH. Association between nonalcoholic fatty liver disease and atrial fibrillation and other clinical outcomes: a meta-analysis. J Investig Med. 2023: 591 [PMID: 37002665, https://doi.org/10.1177/10815589231164777]
96. Parikh NS, Kumar S, Rosenblatt R, Zhao C, Cohen DE, Iadecola C, Kamel H. Association between liver fibrosis and cognition in a nationally representative sample of older adults. Eur J Neurol. 2020: 1895 [PMID: 32503086, https://doi.org/10.1111/ene.14384]
97. Dearborn JL, Schneider AL, Sharrett AR, Mosley TH, Bezerra DC, Knopman DS, Selvin E, Jack CR, Coker LH, Alonso A, Wagenknecht LE, Windham BG, Gottesman RF. Obesity, Insulin Resistance, and Incident Small Vessel Disease on Magnetic Resonance Imaging: Atherosclerosis Risk in Communities Study. Stroke. 2015: 3131 [PMID: 26451022, https://doi.org/10.1161/STROKEAHA.115.010060]
98. Hamaguchi M, Hashimoto Y, Obora A, Kojima T, Fukui M. Non-alcoholic fatty liver disease with obesity as an independent predictor for incident gastric and colorectal cancer: a population-based longitudinal study. BMJ Open Gastroenterol. 2019: e000295 [PMID: 31275587, https://doi.org/10.1136/bmjgast-2019-000295]
99. Mahfood Haddad T, Hamdeh S, Kanmanthareddy A, Alla VM. Nonalcoholic fatty liver disease and the risk of clinical cardiovascular events: A systematic review and meta-analysis. Diabetes Metab Syndr. 2017: S209 [PMID: 28017631, https://doi.org/10.1016/j.dsx.2016.12.033]
100. Kim D, Konyn P, Sandhu KK, Dennis BB, Cheung AC, Ahmed A. Metabolic dysfunction-associated fatty liver disease is associated with increased all-cause mortality in the United States. J Hepatol. 2021: 1284 [PMID: 34380057, https://doi.org/10.1016/j.jhep.2021.07.035]
101. Targher G, Byrne CD, Tilg H. NAFLD and increased risk of cardiovascular disease: clinical associations, pathophysiological mechanisms and pharmacological implications. Gut. 2020: 1691 [PMID: 32321858, https://doi.org/10.1136/gutjnl-2020-320622]
102. Younossi Z, Anstee QM, Marietti M, Hardy T, Henry L, Eslam M, George J, Bugianesi E. Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol. 2018: 11 [PMID: 28930295, https://doi.org/10.1038/nrgastro.2017.109]
103. Angulo P, Kleiner DE, Dam-Larsen S, Adams LA, Bjornsson ES, Charatcharoenwitthaya P, Mills PR, Keach JC, Lafferty HD, Stahler A, Haflidadottir S, Bendtsen F. Liver Fibrosis, but No Other Histologic Features, Is Associated With Long-term Outcomes of Patients With Nonalcoholic Fatty Liver Disease. Gastroenterology. 2015: 389 [PMID: 25935633, https://doi.org/10.1053/j.gastro.2015.04.043]
104. Younossi ZM, Stepanova M, Ong J, Trimble G, AlQahtani S, Younossi I, Ahmed A, Racila A, Henry L. Nonalcoholic Steatohepatitis Is the Most Rapidly Increasing Indication for Liver Transplantation in the United States. Clin Gastroenterol Hepatol. 2021: 580 [PMID: 32531342, https://doi.org/10.1016/j.cgh.2020.05.064]
105. Hernaez R, Lazo M, Bonekamp S, Kamel I, Brancati FL, Guallar E, Clark JM. Diagnostic accuracy and reliability of ultrasonography for the detection of fatty liver: a meta-analysis. Hepatology. 2011: 1082 [PMID: 21618575, https://doi.org/10.1002/hep.24452]
106. Dasarathy S, Dasarathy J, Khiyami A, Joseph R, Lopez R, McCullough AJ. Validity of real time ultrasound in the diagnosis of hepatic steatosis: a prospective study. J Hepatol. 2009: 1061 [PMID: 19846234, https://doi.org/10.1016/j.jhep.2009.09.001]
107. Sasso M, Beaugrand M, de Ledinghen V, Douvin C, Marcellin P, Poupon R, Sandrin L, Miette V. Controlled attenuation parameter (CAP): a novel VCTE guided ultrasonic attenuation measurement for the evaluation of hepatic steatosis: preliminary study and validation in a cohort of patients with chronic liver disease from various causes. Ultrasound Med Biol. 2010: 1825 [PMID: 20870345, https://doi.org/10.1016/j.ultrasmedbio.2010.07.005]
108. Karlas T, Petroff D, Sasso M, Fan JG, Mi YQ, de Ledinghen V, Kumar M, Lupsor-Platon M, Han KH, Cardoso AC, Ferraioli G, Chan WK, Wong VW, Myers RP, Chayama K, Friedrich-Rust M, Beaugrand M, Shen F, Hiriart JB, Sarin SK, Badea R, Jung KS, Marcellin P, Filice C, Mahadeva S, Wong GL, Crotty P, Masaki K, Bojunga J, Bedossa P, Keim V, Wiegand J. Individual patient data meta-analysis of controlled attenuation parameter (CAP) technology for assessing steatosis. J Hepatol. 2017: 1022 [PMID: 28039099, https://doi.org/10.1016/j.jhep.2016.12.022]
109. Reeder SB, Cruite I, Hamilton G, Sirlin CB. Quantitative Assessment of Liver Fat with Magnetic Resonance Imaging and Spectroscopy. J Magn Reson Imaging. 2011: 729 [PMID: 22025886, https://doi.org/10.1002/jmri.22775]
110. Imajo K, Kessoku T, Honda Y, Tomeno W, Ogawa Y, Mawatari H, Fujita K, Yoneda M, Taguri M, Hyogo H, Sumida Y, Ono M, Eguchi Y, Inoue T, Yamanaka T, Wada K, Saito S, Nakajima A. Magnetic Resonance Imaging More Accurately Classifies Steatosis and Fibrosis in Patients With Nonalcoholic Fatty Liver Disease Than Transient Elastography. Gastroenterology. 2016: 626 [PMID: 26677985, https://doi.org/10.1053/j.gastro.2015.11.048]
111. Park SH, Kim PN, Kim KW, Lee SW, Yoon SE, Park SW, Ha HK, Lee MG, Hwang S, Lee SG, Yu ES, Cho EY. Macrovesicular hepatic steatosis in living liver donors: use of CT for quantitative and qualitative assessment. Radiology. 2006: 105 [PMID: 16484355, https://doi.org/10.1148/radiol.2391050361]
112. Pickhardt PJ, Park SH, Hahn L, Lee SG, Bae KT, Yu ES. Specificity of unenhanced CT for non-invasive diagnosis of hepatic steatosis: implications for the investigation of the natural history of incidental steatosis. Eur Radiol. 2012: 1075 [PMID: 22138733, https://doi.org/10.1007/s00330-011-2349-2]
113. Ratziu V, Charlotte F, Heurtier A, Gombert S, Giral P, Bruckert E, Grimaldi A, Capron F, Poynard T, Group LS. Sampling variability of liver biopsy in nonalcoholic fatty liver disease. Gastroenterology. 2005: 1898 [PMID: 15940625, https://doi.org/10.1053/j.gastro.2005.03.084]
114. Brunt EM, Janney CG, Di Bisceglie AM, Neuschwander-Tetri BA, Bacon BR. Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions. Am J Gastroenterol. 1999: 2467 [PMID: 10484010, https://doi.org/10.1111/j.1572-0241.1999.01377.x]
115. Kanwal F, Shubrook JH, Adams LA, Pfotenhauer K, Wai-Sun Wong V, Wright E, Abdelmalek MF, Harrison SA, Loomba R, Mantzoros CS, Bugianesi E, Eckel RH, Kaplan LM, El-Serag HB, Cusi K. Clinical Care Pathway for the Risk Stratification and Management of Patients With Nonalcoholic Fatty Liver Disease. Gastroenterology. 2021: 1657 [PMID: 34602251, https://doi.org/10.1053/j.gastro.2021.07.049]
116. European Association for the Study of the L, European Association for the Study of D, European Association for the Study of O. EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J Hepatol. 2016: 1388 [PMID: 27062661, https://doi.org/10.1016/j.jhep.2015.11.004]
117. Crossan C, Tsochatzis EA, Longworth L, Gurusamy K, Davidson B, Rodriguez-Peralvarez M, Mantzoukis K, O'Brien J, Thalassinos E, Papastergiou V, Burroughs A. Cost-effectiveness of non-invasive methods for assessment and monitoring of liver fibrosis and cirrhosis in patients with chronic liver disease: systematic review and economic evaluation. Health Technol Assess. 2015: 1 [PMID: 25633908, https://doi.org/10.3310/hta19090]
118. McPherson S, Hardy T, Dufour JF, Petta S, Romero-Gomez M, Allison M, Oliveira CP, Francque S, Van Gaal L, Schattenberg JM, Tiniakos D, Burt A, Bugianesi E, Ratziu V, Day CP, Anstee QM. Age as a Confounding Factor for the Accurate Non-Invasive Diagnosis of Advanced NAFLD Fibrosis. Am J Gastroenterol. 2017: 740 [PMID: 27725647, https://doi.org/10.1038/ajg.2016.453]
119. Sterling RK, Lissen E, Clumeck N, Sola R, Correa MC, Montaner J, M SS, Torriani FJ, Dieterich DT, Thomas DL, Messinger D, Nelson M, Investigators AC. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology. 2006: 1317 [PMID: 16729309, https://doi.org/10.1002/hep.21178]
120. Shah AG, Lydecker A, Murray K, Tetri BN, Contos MJ, Sanyal AJ, Nash Clinical Research N. Comparison of noninvasive markers of fibrosis in patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2009: 1104 [PMID: 19523535, https://doi.org/10.1016/j.cgh.2009.05.033]
121. Angulo P, Hui JM, Marchesini G, Bugianesi E, George J, Farrell GC, Enders F, Saksena S, Burt AD, Bida JP, Lindor K, Sanderson SO, Lenzi M, Adams LA, Kench J, Therneau TM, Day CP. The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology. 2007: 846 [PMID: 17393509, https://doi.org/10.1002/hep.21496]
122. Musso G, Gambino R, Cassader M, Pagano G. Meta-analysis: natural history of non-alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease severity. Ann Med. 2011: 617 [PMID: 21039302, https://doi.org/10.3109/07853890.2010.518623]
123. Wong VW, Vergniol J, Wong GL, Foucher J, Chan HL, Le Bail B, Choi PC, Kowo M, Chan AW, Merrouche W, Sung JJ, de Ledinghen V. Diagnosis of fibrosis and cirrhosis using liver stiffness measurement in nonalcoholic fatty liver disease. Hepatology. 2010: 454 [PMID: 20101745, https://doi.org/10.1002/hep.23312]
124. Castera L, Friedrich-Rust M, Loomba R. Noninvasive Assessment of Liver Disease in Patients With Nonalcoholic Fatty Liver Disease. Gastroenterology. 2019: 1264 [PMID: 30660725, https://doi.org/10.1053/j.gastro.2018.12.036]
125. Guha IN, Parkes J, Roderick P, Chattopadhyay D, Cross R, Harris S, Kaye P, Burt AD, Ryder SD, Aithal GP, Day CP, Rosenberg WM. Noninvasive markers of fibrosis in nonalcoholic fatty liver disease: Validating the European Liver Fibrosis Panel and exploring simple markers. Hepatology. 2008: 455 [PMID: 18038452, https://doi.org/10.1002/hep.21984]
126. Xiao G, Zhu S, Xiao X, Yan L, Yang J, Wu G. Comparison of laboratory tests, ultrasound, or magnetic resonance elastography to detect fibrosis in patients with nonalcoholic fatty liver disease: A meta-analysis. Hepatology. 2017: 1486 [PMID: 28586172, https://doi.org/10.1002/hep.29302]
127. Mozes FE, Lee JA, Selvaraj EA, Jayaswal ANA, Trauner M, Boursier J, Fournier C, Staufer K, Stauber RE, Bugianesi E, Younes R, Gaia S, Lupsor-Platon M, Petta S, Shima T, Okanoue T, Mahadeva S, Chan WK, Eddowes PJ, Hirschfield GM, Newsome PN, Wong VW, de Ledinghen V, Fan J, Shen F, Cobbold JF, Sumida Y, Okajima A, Schattenberg JM, Labenz C, Kim W, Lee MS, Wiegand J, Karlas T, Yilmaz Y, Aithal GP, Palaniyappan N, Cassinotto C, Aggarwal S, Garg H, Ooi GJ, Nakajima A, Yoneda M, Ziol M, Barget N, Geier A, Tuthill T, Brosnan MJ, Anstee QM, Neubauer S, Harrison SA, Bossuyt PM, Pavlides M, Investigators L. Diagnostic accuracy of non-invasive tests for advanced fibrosis in patients with NAFLD: an individual patient data meta-analysis. Gut. 2022: 1006 [PMID: 34001645, https://doi.org/10.1136/gutjnl-2021-324243]
128. Srivastava A, Gailer R, Tanwar S, Trembling P, Parkes J, Rodger A, Suri D, Thorburn D, Sennett K, Morgan S, Tsochatzis EA, Rosenberg W. Prospective evaluation of a primary care referral pathway for patients with non-alcoholic fatty liver disease. J Hepatol. 2019: 371 [PMID: 30965069, https://doi.org/10.1016/j.jhep.2019.03.033]
129. Chalasani N, Younossi Z, Lavine JE, Charlton M, Cusi K, Rinella M, Harrison SA, Brunt EM, Sanyal AJ. The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2018: 328 [PMID: 28714183, https://doi.org/10.1002/hep.29367]
130. National Guideline C. National Institute for Health and Care Excellence: Guidelines. Non-Alcoholic Fatty Liver Disease: Assessment and Management. London: National Institute for Health and Care Excellence (NICE)
Copyright © National Institute for Health and Care Excellence 2016.; 2016.
131. Arnett DK, Blumenthal RS, Albert MA, Buroker AB, Goldberger ZD, Hahn EJ, Himmelfarb CD, Khera A, Lloyd-Jones D, McEvoy JW, Michos ED, Miedema MD, Munoz D, Smith SC, Jr., Virani SS, Williams KA, Sr., Yeboah J, Ziaeian B. 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2019: 1376 [PMID: 30894319, https://doi.org/10.1016/j.jacc.2019.03.009]
132. Mach F, Baigent C, Catapano AL, Koskinas KC, Casula M, Badimon L, Chapman MJ, De Backer GG, Delgado V, Ference BA, Graham IM, Halliday A, Landmesser U, Mihaylova B, Pedersen TR, Riccardi G, Richter DJ, Sabatine MS, Taskinen MR, Tokgozoglu L, Wiklund O, Group ESCSD. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2020: 111 [PMID: 31504418, https://doi.org/10.1093/eurheartj/ehz455]
133. Romero-Gomez M, Zelber-Sagi S, Trenell M. Treatment of NAFLD with diet, physical activity and exercise. J Hepatol. 2017: 829 [PMID: 28545937, https://doi.org/10.1016/j.jhep.2017.05.016]
134. Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L, Torres-Gonzalez A, Gra-Oramas B, Gonzalez-Fabian L, Friedman SL, Diago M, Romero-Gomez M. Weight Loss Through Lifestyle Modification Significantly Reduces Features of Nonalcoholic Steatohepatitis. Gastroenterology. 2015: 367 [PMID: 25865049, https://doi.org/10.1053/j.gastro.2015.04.005]
135. Promrat K, Kleiner DE, Niemeier HM, Jackvony E, Kearns M, Wands JR, Fava JL, Wing RR. Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis. Hepatology. 2010: 121 [PMID: 19827166, https://doi.org/10.1002/hep.23276]
136. Musso G, Cassader M, Rosina F, Gambino R. Impact of current treatments on liver disease, glucose metabolism and cardiovascular risk in non-alcoholic fatty liver disease (NAFLD): a systematic review and meta-analysis of randomised trials. Diabetologia. 2012: 885 [PMID: 22278337, https://doi.org/10.1007/s00125-011-2446-4]
137. Lassailly G, Caiazzo R, Ntandja-Wandji LC, Gnemmi V, Baud G, Verkindt H, Ningarhari M, Louvet A, Leteurtre E, Raverdy V, Dharancy S, Pattou F, Mathurin P. Bariatric Surgery Provides Long-term Resolution of Nonalcoholic Steatohepatitis and Regression of Fibrosis. Gastroenterology. 2020: 1290 [PMID: 32553765, https://doi.org/10.1053/j.gastro.2020.06.006]
138. Sheka AC, Adeyi O, Thompson J, Hameed B, Crawford PA, Ikramuddin S. Nonalcoholic Steatohepatitis: A Review. JAMA. 2020: 1175 [PMID: 32207804, https://doi.org/10.1001/jama.2020.2298]
139. Ryan MC, Itsiopoulos C, Thodis T, Ward G, Trost N, Hofferberth S, O'Dea K, Desmond PV, Johnson NA, Wilson AM. The Mediterranean diet improves hepatic steatosis and insulin sensitivity in individuals with non-alcoholic fatty liver disease. J Hepatol. 2013: 138 [PMID: 23485520, https://doi.org/10.1016/j.jhep.2013.02.012]
140. Esposito K, Maiorino MI, Bellastella G, Chiodini P, Panagiotakos D, Giugliano D. A journey into a Mediterranean diet and type 2 diabetes: a systematic review with meta-analyses. BMJ Open. 2015: e008222 [PMID: 26260349, https://doi.org/10.1136/bmjopen-2015-008222]
141. Abdelmalek MF, Suzuki A, Guy C, Unalp-Arida A, Colvin R, Johnson RJ, Diehl AM, Nonalcoholic Steatohepatitis Clinical Research N. Increased fructose consumption is associated with fibrosis severity in patients with nonalcoholic fatty liver disease. Hepatology. 2010: 1961 [PMID: 20301112, https://doi.org/10.1002/hep.23535]
142. Jensen T, Abdelmalek MF, Sullivan S, Nadeau KJ, Green M, Roncal C, Nakagawa T, Kuwabara M, Sato Y, Kang DH, Tolan DR, Sanchez-Lozada LG, Rosen HR, Lanaspa MA, Diehl AM, Johnson RJ. Fructose and sugar: A major mediator of non-alcoholic fatty liver disease. J Hepatol. 2018: 1063 [PMID: 29408694, https://doi.org/10.1016/j.jhep.2018.01.019]
143. Zelber-Sagi S, Buch A, Yeshua H, Vaisman N, Webb M, Harari G, Kis O, Fliss-Isakov N, Izkhakov E, Halpern Z, Santo E, Oren R, Shibolet O. Effect of resistance training on non-alcoholic fatty-liver disease a randomized-clinical trial. World J Gastroenterol. 2014: 4382 [PMID: 24764677, https://doi.org/10.3748/wjg.v20.i15.4382]
144. Hallsworth K, Fattakhova G, Hollingsworth KG, Thoma C, Moore S, Taylor R, Day CP, Trenell MI. Resistance exercise reduces liver fat and its mediators in non-alcoholic fatty liver disease independent of weight loss. Gut. 2011: 1278 [PMID: 21708823, https://doi.org/10.1136/gut.2011.242073]
145. Musso G, Gambino R, Cassader M, Pagano G. A meta-analysis of randomized trials for the treatment of nonalcoholic fatty liver disease. Hepatology. 2010: 79 [PMID: 20578268, https://doi.org/10.1002/hep.23623]
146. Omer Z, Cetinkalp S, Akyildiz M, Yilmaz F, Batur Y, Yilmaz C, Akarca U. Efficacy of insulin-sensitizing agents in nonalcoholic fatty liver disease. Eur J Gastroenterol Hepatol. 2010: 18 [PMID: 19667999, https://doi.org/10.1097/MEG.0b013e32832e2baf]
147. Armstrong MJ, Gaunt P, Aithal GP, Barton D, Hull D, Parker R, Hazlehurst JM, Guo K, team Lt, Abouda G, Aldersley MA, Stocken D, Gough SC, Tomlinson JW, Brown RM, Hubscher SG, Newsome PN. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet. 2016: 679 [PMID: 26608256, https://doi.org/10.1016/S0140-6736(15)00803-X]
148. Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, Nissen SE, Pocock S, Poulter NR, Ravn LS, Steinberg WM, Stockner M, Zinman B, Bergenstal RM, Buse JB, Committee LS, Investigators LT. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2016: 311 [PMID: 27295427, https://doi.org/10.1056/NEJMoa1603827]
149. Newsome PN, Buchholtz K, Cusi K, Linder M, Okanoue T, Ratziu V, Sanyal AJ, Sejling AS, Harrison SA, Investigators NN. A Placebo-Controlled Trial of Subcutaneous Semaglutide in Nonalcoholic Steatohepatitis. N Engl J Med. 2021: 1113 [PMID: 33185364, https://doi.org/10.1056/NEJMoa2028395]
150. Kuchay MS, Krishan S, Mishra SK, Farooqui KJ, Singh MK, Wasir JS, Bansal B, Kaur P, Jevalikar G, Gill HK, Choudhary NS, Mithal A. Effect of Empagliflozin on Liver Fat in Patients With Type 2 Diabetes and Nonalcoholic Fatty Liver Disease: A Randomized Controlled Trial (E-LIFT Trial). Diabetes Care. 2018: 1801 [PMID: 29895557, https://doi.org/10.2337/dc18-0165]
151. McMurray JJV, Solomon SD, Inzucchi SE, Kober L, Kosiborod MN, Martinez FA, Ponikowski P, Sabatine MS, Anand IS, Belohlavek J, Bohm M, Chiang CE, Chopra VK, de Boer RA, Desai AS, Diez M, Drozdz J, Dukat A, Ge J, Howlett JG, Katova T, Kitakaze M, Ljungman CEA, Merkely B, Nicolau JC, O'Meara E, Petrie MC, Vinh PN, Schou M, Tereshchenko S, Verma S, Held C, DeMets DL, Docherty KF, Jhund PS, Bengtsson O, Sjostrand M, Langkilde AM, Committees D-HT, Investigators. Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. N Engl J Med. 2019: 1995 [PMID: 31535829, https://doi.org/10.1056/NEJMoa1911303]
152. Belfort R, Harrison SA, Brown K, Darland C, Finch J, Hardies J, Balas B, Gastaldelli A, Tio F, Pulcini J, Berria R, Ma JZ, Dwivedi S, Havranek R, Fincke C, DeFronzo R, Bannayan GA, Schenker S, Cusi K. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med. 2006: 2297 [PMID: 17135584, https://doi.org/10.1056/NEJMoa060326]
153. Cusi K, Orsak B, Bril F, Lomonaco R, Hecht J, Ortiz-Lopez C, Tio F, Hardies J, Darland C, Musi N, Webb A, Portillo-Sanchez P. Long-Term Pioglitazone Treatment for Patients With Nonalcoholic Steatohepatitis and Prediabetes or Type 2 Diabetes Mellitus: A Randomized Trial. Ann Intern Med. 2016: 305 [PMID: 27322798, https://doi.org/10.7326/M15-1774]
154. Athyros VG, Tziomalos K, Gossios TD, Griva T, Anagnostis P, Kargiotis K, Pagourelias ED, Theocharidou E, Karagiannis A, Mikhailidis DP, Group GSC. Safety and efficacy of long-term statin treatment for cardiovascular events in patients with coronary heart disease and abnormal liver tests in the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) Study: a post-hoc analysis. Lancet. 2010: 1916 [PMID: 21109302, https://doi.org/10.1016/S0140-6736(10)61272-X]
155. Dongiovanni P, Petta S, Mannisto V, Mancina RM, Pipitone R, Karja V, Maggioni M, Kakela P, Wiklund O, Mozzi E, Grimaudo S, Kaminska D, Rametta R, Craxi A, Fargion S, Nobili V, Romeo S, Pihlajamaki J, Valenti L. Statin use and non-alcoholic steatohepatitis in at risk individuals. J Hepatol. 2015: 705 [PMID: 25980762, https://doi.org/10.1016/j.jhep.2015.05.006]
156. Cannon CP, Blazing MA, Giugliano RP, McCagg A, White JA, Theroux P, Darius H, Lewis BS, Ophuis TO, Jukema JW, De Ferrari GM, Ruzyllo W, De Lucca P, Im K, Bohula EA, Reist C, Wiviott SD, Tershakovec AM, Musliner TA, Braunwald E, Califf RM, Investigators I-I. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. N Engl J Med. 2015: 2387 [PMID: 26039521, https://doi.org/10.1056/NEJMoa1410489]
157. Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, Kuder JF, Wang H, Liu T, Wasserman SM, Sever PS, Pedersen TR, Committee FS, Investigators. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med. 2017: 1713 [PMID: 28304224, https://doi.org/10.1056/NEJMoa1615664]
158. Li Y, Zhao D, Qian M, Liu J, Pan C, Zhang X, Duan X, Zhang Y, Jia W, Wang L. Amlodipine, an anti-hypertensive drug, alleviates non-alcoholic fatty liver disease by modulating gut microbiota. Br J Pharmacol. 2022: 2054 [PMID: 34862599, https://doi.org/10.1111/bph.15768]
159. Zisis M, Chondrogianni ME, Androutsakos T, Rantos I, Oikonomou E, Chatzigeorgiou A, Kassi E. Linking Cardiovascular Disease and Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): The Role of Cardiometabolic Drugs in MASLD Treatment. Biomolecules. 2025: [PMID: 40149860, https://doi.org/10.3390/biom15030324]
160. Harrison SA, Bashir MR, Guy CD, Zhou R, Moylan CA, Frias JP, Alkhouri N, Bansal MB, Baum S, Neuschwander-Tetri BA, Taub R, Moussa SE. Resmetirom (MGL-3196) for the treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet. 2019: 2012 [PMID: 31727409, https://doi.org/10.1016/S0140-6736(19)32517-6]
161. Harrison SA, Bedossa P, Guy CD, Schattenberg JM, Loomba R, Taub R, Labriola D, Moussa SE, Neff GW, Rinella ME, Anstee QM, Abdelmalek MF, Younossi Z, Baum SJ, Francque S, Charlton MR, Newsome PN, Lanthier N, Schiefke I, Mangia A, Pericàs JM, Patil R, Sanyal AJ, Noureddin M, Bansal MB, Alkhouri N, Castera L, Rudraraju M, Ratziu V. A Phase 3, Randomized, Controlled Trial of Resmetirom in NASH with Liver Fibrosis. N Engl J Med. 2024: 497 [PMID: 38324483, https://doi.org/10.1056/NEJMoa2309000]
162. Neuschwander-Tetri BA, Loomba R, Sanyal AJ, Lavine JE, Van Natta ML, Abdelmalek MF, Chalasani N, Dasarathy S, Diehl AM, Hameed B, Kowdley KV, McCullough A, Terrault N, Clark JM, Tonascia J, Brunt EM, Kleiner DE, Doo E, Network NCR. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet. 2015: 956 [PMID: 25468160, https://doi.org/10.1016/S0140-6736(14)61933-4]
163. Younossi ZM, Ratziu V, Loomba R, Rinella M, Anstee QM, Goodman Z, Bedossa P, Geier A, Beckebaum S, Newsome PN, Sheridan D, Sheikh MY, Trotter J, Knapple W, Lawitz E, Abdelmalek MF, Kowdley KV, Montano-Loza AJ, Boursier J, Mathurin P, Bugianesi E, Mazzella G, Olveira A, Cortez-Pinto H, Graupera I, Orr D, Gluud LL, Dufour JF, Shapiro D, Campagna J, Zaru L, MacConell L, Shringarpure R, Harrison S, Sanyal AJ, Investigators RS. Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2019: 2184 [PMID: 31813633, https://doi.org/10.1016/S0140-6736(19)33041-7]
164. Tai CM, Huang CK, Tu HP, Hwang JC, Chang CY, Yu ML. PNPLA3 genotype increases susceptibility of nonalcoholic steatohepatitis among obese patients with nonalcoholic fatty liver disease. Surg Obes Relat Dis. 2015: 888 [PMID: 25240529, https://doi.org/10.1016/j.soard.2014.07.016]
165. Loomba R, Noureddin M, Kowdley KV, Kohli A, Sheikh A, Neff G, Bhandari BR, Gunn N, Caldwell SH, Goodman Z, Wapinski I, Resnick M, Beck AH, Ding D, Jia C, Chuang JC, Huss RS, Chung C, Subramanian GM, Myers RP, Patel K, Borg BB, Ghalib R, Kabler H, Poulos J, Younes Z, Elkhashab M, Hassanein T, Iyer R, Ruane P, Shiffman ML, Strasser S, Wong VW, Alkhouri N. Combination Therapies Including Cilofexor and Firsocostat for Bridging Fibrosis and Cirrhosis Attributable to NASH. Hepatology. 2021: 625 [PMID: 33169409, https://doi.org/10.1002/hep.31622]
166. Younossi ZM, Zelber-Sagi S, Henry L, Gerber LH. Lifestyle interventions in nonalcoholic fatty liver disease. Nat Rev Gastroenterol Hepatol. 2023: 708 [PMID: 37402873, https://doi.org/10.1038/s41575-023-00800-4]
167. Portillo-Sanchez P, Bril F, Maximos M, Lomonaco R, Biernacki D, Orsak B, Subbarayan S, Webb A, Hecht J, Cusi K. High Prevalence of Nonalcoholic Fatty Liver Disease in Patients With Type 2 Diabetes Mellitus and Normal Plasma Aminotransferase Levels. J Clin Endocrinol Metab. 2015: 2231 [PMID: 25885947, https://doi.org/10.1210/jc.2015-1966]
168. Targher G, Corey KE, Byrne CD. NAFLD, and cardiovascular and cardiac diseases: Factors influencing risk, prediction and treatment. Diabetes Metab. 2021: 101215 [PMID: 33296704, https://doi.org/10.1016/j.diabet.2020.101215]
169. Mantovani A, Byrne CD, Bonora E, Targher G. Nonalcoholic Fatty Liver Disease and Risk of Incident Type 2 Diabetes: A Meta-analysis. Diabetes Care. 2018: 372 [PMID: 29358469, https://doi.org/10.2337/dc17-1902]
170. Williamson RM, Price JF, Glancy S, Perry E, Nee LD, Hayes PC, Frier BM, Van Look LA, Johnston GI, Reynolds RM, Strachan MW, Edinburgh Type 2 Diabetes Study I. Prevalence of and risk factors for hepatic steatosis and nonalcoholic Fatty liver disease in people with type 2 diabetes: the Edinburgh Type 2 Diabetes Study. Diabetes Care. 2011: 1139 [PMID: 21478462, https://doi.org/10.2337/dc10-2229]
171. Lean ME, Leslie WS, Barnes AC, Brosnahan N, Thom G, McCombie L, Peters C, Zhyzhneuskaya S, Al-Mrabeh A, Hollingsworth KG, Rodrigues AM, Rehackova L, Adamson AJ, Sniehotta FF, Mathers JC, Ross HM, McIlvenna Y, Stefanetti R, Trenell M, Welsh P, Kean S, Ford I, McConnachie A, Sattar N, Taylor R. Primary care-led weight management for remission of type 2 diabetes (DiRECT): an open-label, cluster-randomised trial. Lancet. 2018: 541 [PMID: 29221645, https://doi.org/10.1016/S0140-6736(17)33102-1]
172. Gerstein HC, Colhoun HM, Dagenais GR, Diaz R, Lakshmanan M, Pais P, Probstfield J, Riesmeyer JS, Riddle MC, Ryden L, Xavier D, Atisso CM, Dyal L, Hall S, Rao-Melacini P, Wong G, Avezum A, Basile J, Chung N, Conget I, Cushman WC, Franek E, Hancu N, Hanefeld M, Holt S, Jansky P, Keltai M, Lanas F, Leiter LA, Lopez-Jaramillo P, Cardona Munoz EG, Pirags V, Pogosova N, Raubenheimer PJ, Shaw JE, Sheu WH, Temelkova-Kurktschiev T, Investigators R. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet. 2019: 121 [PMID: 31189511, https://doi.org/10.1016/S0140-6736(19)31149-3]
173. Hagstrom H, Nasr P, Ekstedt M, Hammar U, Stal P, Hultcrantz R, Kechagias S. Risk for development of severe liver disease in lean patients with nonalcoholic fatty liver disease: A long-term follow-up study. Hepatol Commun. 2018: 48 [PMID: 29404512, https://doi.org/10.1002/hep4.1124]
174. Leung JC, Loong TC, Wei JL, Wong GL, Chan AW, Choi PC, Shu SS, Chim AM, Chan HL, Wong VW. Histological severity and clinical outcomes of nonalcoholic fatty liver disease in nonobese patients. Hepatology. 2017: 54 [PMID: 27339817, https://doi.org/10.1002/hep.28697]
175. Young S, Tariq R, Provenza J, Satapathy SK, Faisal K, Choudhry A, Friedman SL, Singal AK. Prevalence and Profile of Nonalcoholic Fatty Liver Disease in Lean Adults: Systematic Review and Meta-Analysis. Hepatol Commun. 2020: 953 [PMID: 32626829, https://doi.org/10.1002/hep4.1519]
176. Frith J, Day CP, Henderson E, Burt AD, Newton JL. Non-alcoholic fatty liver disease in older people. Gerontology. 2009: 607 [PMID: 19690397, https://doi.org/10.1159/000235677]
177. McPherson S, Hardy T, Henderson E, Burt AD, Day CP, Anstee QM. Evidence of NAFLD progression from steatosis to fibrosing-steatohepatitis using paired biopsies: implications for prognosis and clinical management. J Hepatol. 2015: 1148 [PMID: 25477264, https://doi.org/10.1016/j.jhep.2014.11.034]
178. Koehler EM, Plompen EP, Schouten JN, Hansen BE, Darwish Murad S, Taimr P, Leebeek FW, Hofman A, Stricker BH, Castera L, Janssen HL. Presence of diabetes mellitus and steatosis is associated with liver stiffness in a general population: The Rotterdam study. Hepatology. 2016: 138 [PMID: 26171685, https://doi.org/10.1002/hep.27981]
179. Abdou HA, Awny S. Antibody-Drug Conjugates in Solid Tumors: Mechanisms, Clinical Advances, and Emerging Resistance Patterns. ASIDE Oncology. 2026: 13 https://doi.org/10.71079/ASIDE.Onc.012026464]
180. Arab JP, Arrese M, Trauner M. Recent Insights into the Pathogenesis of Nonalcoholic Fatty Liver Disease. Annu Rev Pathol. 2018: 321 [PMID: 29414249, https://doi.org/10.1146/annurev-pathol-020117-043617]
181. Eslam M, Sarin SK, Wong VW, Fan JG, Kawaguchi T, Ahn SH, Zheng MH, Shiha G, Yilmaz Y, Gani R, Alam S, Dan YY, Kao JH, Hamid S, Cua IH, Chan WK, Payawal D, Tan SS, Tanwandee T, Adams LA, Kumar M, Omata M, George J. The Asian Pacific Association for the Study of the Liver clinical practice guidelines for the diagnosis and management of metabolic associated fatty liver disease. Hepatol Int. 2020: 889 [PMID: 33006093, https://doi.org/10.1007/s12072-020-10094-2]
This work is licensed under a Creative Commons Attribution 4.0 International License.
Copyright (c) 2026 Hassan A. Abdou, Saied A. Omar