Clin Mol Hepatol > Volume 29(3); 2023 > Article
Han, Baik, and Kim: Correspondence on Letter regarding “Non-alcoholic fatty liver disease: Definition and subtypes”
Dear Editor,
We appreciate the constructive recommendation of Jeong et al. [1], which was a meaningful insight regarding fatty liver conceptualization. Fatty liver disease is characterized by fat accumulation resulting in hepatic inflammation, cirrhosis, and carcinoma. Currently, non-alcoholic fatty liver disease (NAFLD) is phenotypically considered a systemic metabolic syndrome. In metabolic syndrome, fatty liver is represented by one phenotype of a high-energy state, and various other complications resulting from this high-energy state can exist beyond the liver.
A recent review provided evidence that NAFLD is a risk factor for cerebrovascular disease (CVD) [2]. Kasper et al. [2] reported that NAFLD and CVD share a common pathophysiology, such as, PNPLA3, HSD 17B13, and PGC1a were related to genetic factors. Endothelial dysfunction, atherogenic dyslipidemia, systemic inflammation, coagulopathy, and altered gut microbiome are relevant factors. Moreover, NAFLD is reported as an independent risk factor for a CVD event, after adjusting other known risk factors. In some meta-analyses, outcomes were inconsistent; although, this may be due to the diversity in NAFLD definitions.
However, controversies regarding NAFLD as a risk factor for dementia are ongoing (Tables 1 and 2) [3-11]. In a recent study that included a large number of patients with NAFLD, the patients had a higher dementia rate, including vascular dementia [10]. This outcome is similar to that reported in a previous study [7]. However, primary care data from Germany have reported that NAFLD is not related to dementia occurrence [9]. Insulin resistance and hyperglycemia are known to cause dementia through glucose neurotoxicity and glycated end products [12]; however, they share some similarities with CVD. NAFLD is associated with arterial hypertension, atherosclerosis, coronary artery disease, and atrial fibrillation. Furthermore, NAFLD is often diagnosed at a young age and dementia at an old age; thus a limitation in revealing a direct relationship between the two diseases exists. Therefore, additional direct evidence is required. However, accumulating and updated data suggest that some mechanisms between NAFLD and brain dysfunction that result in dementia and Alzheimer’s disease are not fully investigated. This can be inferred from the fact that one author reported opposing results in 2 years.
Our review paper describes the simple, basic classification of NAFLD and its subtypes and summarizes the well-accepted contents for NAFLD. Relevance to other diseases and the latest concepts of prognosis are beyond the scope of our review. The productive opinion of Jeong et al. is also acceptable, and we hope that more evidence will be accumulated and new findings will be revealed throughout active investigations.

FOOTNOTES

Authors’ contribution
All authors contributed to the article conception and design, material preparation. The first draft of the manuscript was written by Seul Ki Han and Moon Young Kim. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Conflicts of Interest
The authors have no conflicts to disclose.

Table 1.
Published papers suggesting the correlation between NAFLD and dementia
Author Title Year
Shang et al. [3] Nonalcoholic fatty liver disease and risk of dementia: A population-based cohort study 2022
Elliott et al. [4] Functional impairment in alcoholic liver disease and non-alcoholic fatty liver disease is significant and persists over 3 years of follow-up 2013
Doward et al. [5] Development of a patient-reported outcome measure for non-alcoholic steatohepatitis (NASH-CHECK): Results of a qualitative study 2020
Kim et al. [6] Association between non-alcoholic fatty liver disease and the risk of dementia: A nationwide cohort study 2022
Jeong et al. [7] Association of non-alcoholic fatty liver disease with incident dementia later in life among elder adults 2022

NAFLD, non-alcoholic fatty liver disease.

Table 2.
Published papers that do not suggest a correlation between NAFLD and dementia
Author Title Year
Gerber et al. [8] Non-alcoholic fatty liver disease and cognitive function in middle-aged adults: the CARDIA study 2021
Labenz et al. [9] Incident dementia in elderly patients with nonalcoholic fatty liver disease in Germany 2021
Shang et al. [10] Non-alcoholic fatty liver disease does not increase dementia risk although histology data might improve risk prediction 2020
Ye [11] Association of nonalcoholic fatty liver disease with incident dementia later in life among elderly adults 2022

NAFLD, non-alcoholic fatty liver disease.

Abbreviations

NAFLD
non-alcoholic fatty liver disease
CVD
cerebrovascular disease

REFERENCES

1. Jeong S, Lim Y, Lee SK, Han HW. Subtypes of non-alcoholic fatty liver disease in terms of cardiovascular disease and dementia risks. Clin Mol Hepatol 2023 May 8;doi: 10.3350/cmh.2023.0129.

2. Kasper P, Martin A, Lang S, Kütting F, Goeser T, Demir M, et al. NAFLD and cardiovascular diseases: a clinical review. Clin Res Cardiol 2021;110:921-937.
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3. Shang Y, Widman L, Hagström H. Nonalcoholic fatty liver disease and risk of dementia: A population-based cohort study. Neurology 2022;99:e574-e582.
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4. Elliott C, Frith J, Day CP, Jones DE, Newton JL. Functional impairment in alcoholic liver disease and non-alcoholic fatty liver disease is significant and persists over 3 years of follow-up. Dig Dis Sci 2013;58:2383-2391.
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5. Doward LC, Balp MM, Twiss J, Slota C, Cryer D, Brass CA, et al. Development of a patient-reported outcome measure for nonalcoholic steatohepatitis (NASH-CHECK): Results of a qualitative study. Patient 2021;14:533-543.
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6. Kim GA, Oh CH, Kim JW, Jeong SJ, Oh IH, Lee JS, et al. Association between non-alcoholic fatty liver disease and the risk of dementia: A nationwide cohort study. Liver Int 2022;42:1027-1036.
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7. 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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8. Gerber Y, VanWagner LB, Yaffe K, Terry JG, Rana JS, Reis JP, et al. Non-alcoholic fatty liver disease and cognitive function in middle-aged adults: the CARDIA study. BMC Gastroenterol 2021;21:96.
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9. Labenz C, Kostev K, Kaps L, Galle PR, Schattenberg JM. Incident Dementia in elderly patients with nonalcoholic fatty liver disease in Germany. Dig Dis Sci 2021;66:3179-3185.
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10. Shang Y, Nasr P, Ekstedt M, Widman L, Stål P, Hultcrantz R, et al. Non-alcoholic fatty liver disease does not increase dementia risk although histology data might improve risk prediction. JHEP Rep 2020;3:100218.
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11. Ye BS. Association of nonalcoholic fatty liver disease with incident dementia later in life among elderly adults. Clin Mol Hepatol 2022;28:481-482.
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12. Hamed SA. Brain injury with diabetes mellitus: evidence, mechanisms and treatment implications. Expert Rev Clin Pharmacol 2017;10:409-428.
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