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Impact of metabolic factors on risk of cardiovascular disease in nondiabetic metabolic dysfunction-associated fatty liver disease

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Abstract

Background and aim

Changing terminology of non-alcoholic fatty liver disease (NAFLD) to metabolic dysfunction-associated fatty liver disease (MAFLD) is recently proposed by expert panels based on metabolic dysregulations. However, clinical evidences for the risk of cardiovascular disease (CVD) in MAFLD are limited. The aim of this study is evaluating the association of cardiovascular risk in these two terminology and subgroups of MAFLD.

Methods

A total of 2133 individuals who underwent ultrasound and cardiac computed tomography contemporaneously were included at a single medical checkup center. Ultrasound was used to define fatty liver, and coronary artery calcification (CAC) defined a coronary artery calcium score above 0 was used to estimate the cardiovascular risk.

Results

Overall, 911 participants were diagnosed with fatty liver. In the unadjusted analysis, NAFLD (OR = 1.4, 95% confidence interval [CI] = 1.05–1.85, p = 0.019) and MAFLD (OR = 1.55, 95% CI = 1.29–1.86, p = 0.046) were significantly associated with CAC. However, in sex and age-adjusted analyses, only MAFLD was associated with CAC (adjusted OR [aOR] = 1.38, 95% CI = 1.14–1.69, p = 0.001). Of the three subgroups of MAFLD (diabetic, nondiabetic overweight/obese, and nondiabetic normal weight/lean with at least two metabolic abnormalities), only diabetic MAFLD was associated with CAC (aOR = 2.65, 95% CI = 1.98–3.55, p < 0.001). When the minimal number of metabolic risk abnormalities increased to three, nondiabetic normal-weight/lean MAFLD was associated with CAC (aOR = 1.35, 95% CI = 1.02–1.77, p = 0.034).

Conclusion

Diabetic MAFLD predicted high-risk CVD phenotypes the best. Metabolic risk abnormalities in nondiabetic MAFLD patients were independently associated with the risk of CVD. The proposed diagnostic criteria for nondiabetic MAFLD need further investigation in terms of CVD risk.

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Data availability

The data supporting findings of this study are available from the corresponding authors upon reasonable request.

Abbreviations

ALT:

Alanine aminotransferase

APRI:

AST to platelet ratio index

AST:

Serum aspartate aminotransferase

CAC:

Coronary artery calcification

CVD:

Cardiovascular disease

FIB-4:

Fibrosis-4

FPG:

Fasting plasma glucose

HDL-C:

High-density lipoprotein cholesterol

hsCRP:

High-sensitivity C reactive protein

MAFLD:

Metabolic dysfunction-associated fatty liver disease

NAFLD:

Non-alcoholic fatty liver disease

NFS:

NAFLD fibrosis score

T2DM:

Type 2 diabetes mellitus

WC:

Waist circumference

References

  1. Kang SH, Lee HW, Yoo JJ, Cho Y, Kim SU, Lee TH, et al. KASL clinical practice guidelines: management of nonalcoholic fatty liver disease. Clin Mol Hepatol. 2021;27:363–401

    Article  PubMed  PubMed Central  Google Scholar 

  2. Muthiah MD, Sanyal AJ. Burden of disease due to nonalcoholic fatty liver disease. Gastroenterol Clin North Am. 2020;49:1–23

    Article  PubMed  Google Scholar 

  3. Toh JZK, Pan XH, Tay PWL, Ng CH, Yong JN, Xiao J, et al. A meta-analysis on the global prevalence, risk factors and screening of coronary heart disease in nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2021;20:2462–2473

    Article  PubMed  Google Scholar 

  4. Loomba R, Sanyal AJ. The global NAFLD epidemic. Nat Rev Gastroenterol Hepatol. 2013;10:686–690

    Article  CAS  PubMed  Google Scholar 

  5. Eslam M, Newsome PN, Sarin SK, Anstee QM, Targher G, Romero-Gomez M, et al. A new definition for metabolic dysfunction-associated fatty liver disease: an international expert consensus statement. J Hepatol. 2020;73:202–209

    Article  PubMed  Google Scholar 

  6. Kang SH, Cho Y, Jeong SW, Kim SU, Lee JW, Korean NSG. From nonalcoholic fatty liver disease to metabolic-associated fatty liver disease: big wave or ripple? Clin Mol Hepatol. 2021;27:257–269

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Lim GEH, Tang A, Ng CH, Chin YH, Lim WH, Tan DJH, et al. An observational data meta-analysis on the differences in prevalence and risk factors between MAFLD vs NAFLD. Clin Gastroenterol Hepatol. 2023;21(619–629): e7

  8. Nguyen VH, Le MH, Cheung RC, Nguyen MH. Differential clinical characteristics and mortality outcomes in persons with NAFLD and/or MAFLD. Clin Gastroenterol Hepatol. 2021;19(2172–2181): e2176

    Google Scholar 

  9. Ciardullo S, Perseghin G. Prevalence of NAFLD, MAFLD and associated advanced fibrosis in the contemporary United States population. Liver Int. 2021;41:1290–1293

    Article  PubMed  Google Scholar 

  10. Lee H, Lee YH, Kim SU, Kim HC. Metabolic dysfunction-associated fatty liver disease and incident cardiovascular disease risk: a nationwide cohort study. Clin Gastroenterol Hepatol. 2021;19(2138–2147): e2110

    Google Scholar 

  11. Budoff MJ, Achenbach S, Blumenthal RS, Carr JJ, Goldin JG, Greenland P, et al. Assessment of coronary artery disease by cardiac computed tomography: a scientific statement from the American heart association committee on cardiovascular imaging and intervention, council on cardiovascular radiology and intervention, and committee on cardiac imaging. Council Clin Cardiol Circ. 2006;114:1761–1791

    Google Scholar 

  12. Greenland P, Blaha MJ, Budoff MJ, Erbel R, Watson KE. Coronary Calcium score and cardiovascular risk. J Am Coll Cardiol. 2018;72:434–447

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. McEvoy JW, Blaha MJ, Defilippis AP, Budoff MJ, Nasir K, Blumenthal RS, et al. Coronary artery calcium progression: an important clinical measurement? A review of published reports. J Am Coll Cardiol. 2010;56:1613–1622

    Article  PubMed  Google Scholar 

  14. Sinn DH, Kang D, Chang Y, Ryu S, Gu S, Kim H, et al. Non-alcoholic fatty liver disease and progression of coronary artery calcium score: a retrospective cohort study. Gut. 2017;66:323–329

    Article  CAS  PubMed  Google Scholar 

  15. Oh SW. Obesity and metabolic syndrome in Korea. Diabetes Metab J. 2011;35:561–566

    Article  PubMed  PubMed Central  Google Scholar 

  16. Diagnosis and classification of diabetes mellitus. Diabetes Care 2010;33 Suppl 1:S62–69. https://doi.org/10.2337/dc10-S062.

  17. Unger T, Borghi C, Charchar F, Khan NA, Poulter NR, Prabhakaran D, et al. 2020 International society of hypertension global hypertension practice guidelines. Hypertension. 2020;75:1334–1357

    Article  CAS  PubMed  Google Scholar 

  18. Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, et al. Diagnosis and management of the metabolic syndrome: an American heart association/national heart, lung, and blood institute scientific statement. Circulation. 2005;112:2735–2752

    Article  PubMed  Google Scholar 

  19. Lin ZH, Xin YN, Dong QJ, Wang Q, Jiang XJ, Zhan SH, et al. Performance of the aspartate aminotransferase-to-platelet ratio index for the staging of hepatitis C-related fibrosis: an updated meta-analysis. Hepatology. 2011;53:726–736

    Article  PubMed  Google Scholar 

  20. Tamaki N, Kurosaki M, Huang DQ, Loomba R. Noninvasive assessment of liver fibrosis and its clinical significance in nonalcoholic fatty liver disease. Hepatol Res. 2022;52(6):497–507. https://doi.org/10.1111/hepr.13764

    Article  PubMed  PubMed Central  Google Scholar 

  21. Yamamura S, Eslam M, Kawaguchi T, Tsutsumi T, Nakano D, Yoshinaga S, et al. MAFLD identifies patients with significant hepatic fibrosis better than NAFLD. Liver Int. 2020;40:3018–3030

    Article  CAS  PubMed  Google Scholar 

  22. EASL-EASD-EASO clinical practice guidelines for the management of non-alcoholic fatty liver disease. J Hepatol 2016;64:1388–1402

  23. Chalasani N, Younossi Z, Lavine JE, Charlton M, Cusi K, Rinella M, et al. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American association for the study of liver diseases. Hepatology. 2018;67:328–357

    Article  PubMed  Google Scholar 

  24. Kim D, Choi SY, Park EH, Lee W, Kang JH, Kim W, et al. Nonalcoholic fatty liver disease is associated with coronary artery calcification. Hepatology. 2012;56:605–613

    Article  CAS  PubMed  Google Scholar 

  25. Chang Y, Ryu S, Sung KC, Cho YK, Sung E, Kim HN, et al. Alcoholic and non-alcoholic fatty liver disease and associations with coronary artery calcification: evidence from the Kangbuk Samsung Health Study. Gut. 2019;68:1667–1675

    Article  CAS  PubMed  Google Scholar 

  26. Kim SH, Park HY, Lee HS, Jung KS, Lee MH, Jhee JH, et al. Association between non-alcoholic fatty liver disease and coronary calcification depending on sex and obesity. Sci Rep. 2020;10:1025

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Tsutsumi T, Eslam M, Kawaguchi T, Yamamura S, Kawaguchi A, Nakano D, et al. MAFLD better predicts the progression of atherosclerotic cardiovascular risk than NAFLD: Generalized estimating equation approach. Hepatol Res. 2021;51:1115–1128

    Article  CAS  PubMed  Google Scholar 

  28. Lassale C, Tzoulaki I, Moons KGM, Sweeting M, Boer J, Johnson L, et al. Separate and combined associations of obesity and metabolic health with coronary heart disease: a pan-European case-cohort analysis. Eur Heart J. 2018;39:397–406

    Article  PubMed  Google Scholar 

  29. Ampuero J, Aller R, Gallego-Duran R, Banales JM, Crespo J, Garcia-Monzon C, et al. The effects of metabolic status on non-alcoholic fatty liver disease-related outcomes, beyond the presence of obesity. Aliment Pharmacol Ther. 2018;48:1260–1270

    Article  CAS  PubMed  Google Scholar 

  30. 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;71:808–819

    Article  PubMed  Google Scholar 

  31. Ekstedt M, Hagstrom H, Nasr P, Fredrikson M, Stal P, Kechagias S, et al. Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up. Hepatology. 2015;61:1547–1554

    Article  CAS  PubMed  Google Scholar 

  32. Henson JB, Simon TG, Kaplan A, Osganian S, Masia R, Corey KE. Advanced fibrosis is associated with incident cardiovascular disease in patients with non-alcoholic fatty liver disease. Aliment Pharmacol Ther. 2020;51:728–736

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Moreno-Del Castillo MC, Sanchez-Rodriguez A, Hernandez-Buen Abad JJ, Aguirre-Valadez J, Ruiz I, Garcia-Buen Abad R, et al. Importance of evaluating cardiovascular risk and hepatic fibrosis in patients with newly diagnosed nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2019;17:997–999

    Article  PubMed  Google Scholar 

  34. Baratta F, Pastori D, Angelico F, Balla A, Paganini AM, Cocomello N, et al. Nonalcoholic fatty liver disease and fibrosis associated with increased risk of cardiovascular events in a prospective study. Clin Gastroenterol Hepatol. 2020;18(2324–2331): e2324

    Article  Google Scholar 

  35. Niikura T, Imajo K, Ozaki A, Kobayashi T, Iwaki M, Honda Y, et al. Coronary artery disease is more severe in patients with non-alcoholic steatohepatitis than fatty liver. Diagnostics (Basel). 2020;10:129

    Article  CAS  PubMed  Google Scholar 

  36. Park JG, Jung J, Verma KK, Kang MK, Madamba E, Lopez S, et al. Liver stiffness by magnetic resonance elastography is associated with increased risk of cardiovascular disease in patients with non-alcoholic fatty liver disease. Aliment Pharmacol Ther. 2021;53:1030–1037

    PubMed  PubMed Central  Google Scholar 

  37. Goff DC Jr, Lloyd-Jones DM, Bennett G, Coady S, D’Agostino RB Sr, Gibbons R, et al. 2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American college of cardiology/American heart association task force on practice guidelines. J Am Coll Cardiol. 2014;63:2935–2959

    Article  PubMed  Google Scholar 

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Funding

JGP receives funding supported by the 2022 Yeungnam University Research Grant. RL receives funding support from NCATS (5UL1TR001442), NIDDK (U01DK061734, U01DK130190, R01DK106419, R01DK121378, R01DK124318, P30DK120515), NHLBI (P01HL147835), and NIAAA (U01AA029019).

Author information

Author notes

  1. Min Kyu Kang and Yu Rim Lee contributed equally to this study. Jung Gil Park and Soo Young Park are co-corresponding authors in this study.

Authors and Affiliations

  1. Department of Internal Medicine, College of Medicine, Yeungnam University, Daegu, Republic of Korea

    Min Kyu Kang & Jung Gil Park

  2. Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Republic of Korea

    Yu Rim Lee, Se Young Jang, Won Young Tak, Young Oh Kweon & Soo Young Park

  3. Department of Internal Medicine, Daegu Catholic University School of Medicine, Daegu, Republic of Korea

    Jeong Eun Song

  4. NAFLD Research Center, Division of Gastroenterology and Hepatology, Department of Medicine, University of California San Diego, La Jolla, San Diego, CA, USA

    Rohit Loomba

  5. Division of Epidemiology, Department of Family Medicine and Public Health, University of California San Diego, La Jolla, San Diego, CA, USA

    Rohit Loomba

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  1. Min Kyu Kang
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Contributions

JGP and SYP is guarantor of integrity of the entire study. JGP designed the study and partially supervised by RL. All authors except RL collected data, which were reviewed by GJP, and analyzed by GJP based on the statistical analysis plan. GJP, MKG, and YLR drafted the manuscript, which was critically revised by SYP. All authors were responsible for collecting and interpretation of the data and approved the final version of manuscript.

Corresponding authors

Correspondence to Soo Young Park or Jung Gil Park.

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Conflict of interest

RL serves as a consultant for Aardvark Therapeutics, Altimmune, Anylam/Regeneron, Amgen, Arrowhead Pharmaceuticals, AstraZeneca, Bristol-Myer Squibb, CohBar, Eli Lilly, Galmed, Gilead, Glympse bio, Hightide, Inipharm, Intercept, Inventiva, Ionis, Janssen Inc., Madrigal, Metacrine, Inc., NGM Biopharmaceuticals, Novartis, Novo Nordisk, Merck, Pfizer, Sagimet, Theratechnologies, 89 bio, and Viking Therapeutics. In addition, his institution has received grant support from Allergan, Astrazeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Eli Lilly, Galectin Therapeutics, Galmed Pharmaceuticals, Genfit, Gilead, Intercept, Inventiva, Janssen, Madrigal Pharmaceuticals, Merck, NGM Biopharmaceuticals, Pfizer, and Sonic Incytes. He is also co-founder of Liponexus, Inc.

Ethical approval

This study was performed in accordance with the ethical guidelines of the 1975 Declaration of Helsinki as revised in 2013. The study protocol was approved by the institutional review board of the study center (IRB No. KNUH-2021-07-057-001). The requirement for informed consent from the study participants was waived by the ethics committee because of the retrospective nature of this study.

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Kang, M.K., Lee, Y.R., Jang, S.Y. et al. Impact of metabolic factors on risk of cardiovascular disease in nondiabetic metabolic dysfunction-associated fatty liver disease. Hepatol Int 17, 626–635 (2023). https://doi.org/10.1007/s12072-023-10517-w

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  • DOI: https://doi.org/10.1007/s12072-023-10517-w

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