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.

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.

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.

Abbreviations

NAFLD

non-alcoholic fatty liver disease

CVD

cerebrovascular disease