Clin Mol Hepatol > Volume 29(3); 2023 > Article
Jeong, Lim, Lee, and Han: Letter regarding “Non-alcoholic fatty liver disease: Definition and subtypes”
Dear Editor,
We read with great interest the study by Han et al. [1], which reviewed the basic definition of non-alcoholic fatty liver disease (NAFLD) and its subtypes, including non-alcoholic fatty liver (NAFL), NAFL with inflammation, and non-alcoholic steatohepatitis (NASH). Conventional classification of NAFLD subtypes, classification by severity, and classification using scoring systems, such as the NAFLD activity score or fibrosis score, have provided an in-depth understanding of the disease status and the risk of liver cirrhosis and hepatocellular carcinoma [2,3]. However, none of the classifications targeted the risk of cardiovascular disease (CVD) and dementia according to NAFLD status.
In recent years, NAFLD has been found to increase the risk of several extrahepatic diseases, including CVD and dementia [4,5]. Previously, we used the Korean National Health and Nutrition Examination Survey-derived NAFLD (K-NAFLD) score, which was externally validated in an independent population using FibroScan, to evaluate the risk of CVD. We found that low-intermediate and high hepatic steatosis were associated with 30% and 55% higher risk of CVD, respectively [6,7]. Furthermore, high steatosis with at least two forms of metabolic dysfunction was associated with a 71% higher risk of CVD compared to high steatosis without metabolic dysfunction. Therefore, the use of the K-NAFLD score, along with metabolic dysfunction, may be useful in classifying NAFLD in terms of CVD risk.
NAFLD has also been found to be a risk factor for the development of dementia [5,8]. After independent propensity score matching between the low-intermediate and intermediatehigh fatty liver index (FLI) groups, we found a 4% lower and 5% higher risk of dementia for the low FLI group (FLI<30) and high FLI group (FLI≥60), respectively, compared with the intermediate FLI group (FLI≥30 and <60). Additionally, in a preclinical study, NAFLD-induced chronic hepatic inflammation was associated with the pathogenesis of Alzheimer’s disease through the induction of neurodegeneration [9]. Lipocalin-2, an adipokine that is exclusively produced in NASH liver and circulates in the bloodstream, has also been found to activate pro-inflammatory processes and weaken the blood-brain barrier [10,11]. Therefore, the severity of steatosis and the presence of NASH may be useful in classifying patients who are at higher NAFLD-associated risk of dementia.
Taken together, clinicians need to consider NAFLD-associated non-liver comorbidities as an important aspect of the management and classification of the disease [12]. The use of NAFLD scoring systems, metabolic dysfunction, and the severity of steatosis or the presence of NASH may provide insight into the development of NAFLD subtypes in terms of CVD and dementia risk.


Authors’ contribution
Conception or design of the work: Seogsong Jeong. Drafting the article: Seogsong Jeong. Critical revision of the article: All authors. Final approval of the version to be published: All authors.
Conflicts of Interest
The authors have no conflicts to disclose.


non-alcoholic fatty liver disease
non-alcoholic fatty liver
non-alcoholic steatohepatitis
cardiovascular disease
Korean National Health and Nutrition Examination Survey-derived NAFLD
fatty liver index


1. Han SK, Baik SK, Kim MY. Non-alcoholic fatty liver disease: Definition and subtypes. Clin Mol Hepatol 2023;29(suppl):S5-S16.
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2. 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.
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3. Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 2005;41:1313-1321.
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4. Jeong S, Oh YH, Choi S, Chang J, Kim SM, Son JS, et al. Metabolic dysfunction-associated fatty liver disease better predicts incident cardiovascular disease. Gut Liver 2022;16:589-598.
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5. Jeong S, Oh YH, Choi S, Chang J, Kim SM, Son JS, et al. Association of non-alcoholic fatty liver disease with incident dementia later in life among elder adults. Clin Mol Hepatol 2022;28:510-521.
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6. Jeong S, Kim K, Chang J, Choi S, Kim SM, Son JS, et al. Development of a simple nonalcoholic fatty liver disease scoring system indicative of metabolic risks and insulin resistance. Ann Transl Med 2020;8:1414.
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7. Jeong S, Park SJ, Na SK, Park SM, Song BC, Oh YH. Validity of fatty liver prediction scores for diagnosis of fatty liver by Fibroscan. Hepatobiliary Pancreat Dis Int 2023 Feb 24;doi: 10.1016/j.hbpd.2023.02.009.
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8. Lu LY, Wu MY, Kao YS, Hung CH. Non-alcoholic fatty liver disease and the risk of dementia: A meta-analysis of cohort studies. Clin Mol Hepatol 2022;28:931-932.
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9. Kim DG, Krenz A, Toussaint LE, Maurer KJ, Robinson SA, Yan A, et al. Non-alcoholic fatty liver disease induces signs of Alzheimer’s disease (AD) in wild-type mice and accelerates pathological signs of AD in an AD model. J Neuroinflammation 2016;13:1.
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10. Ye D, Yang K, Zang S, Lin Z, Chau HT, Wang Y, et al. Lipocalin-2 mediates non-alcoholic steatohepatitis by promoting neutrophil-macrophage crosstalk via the induction of CXCR2. J Hepatol 2016;65:988-997. Erratum in: J Hepatol 2017;66:669.

11. Mondal A, Bose D, Saha P, Sarkar S, Seth R, Kimono D, et al. Lipocalin 2 induces neuroinflammation and blood-brain barrier dysfunction through liver-brain axis in murine model of nonalcoholic steatohepatitis. J Neuroinflammation 2020;17:201.
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12. Manikat R, Nguyen MH. Nonalcoholic fatty liver disease and non-liver comorbidities. Clin Mol Hepatol 2023;29(Suppl):s86-s102.
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