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Kouvari, M.;  Sergi, D.;  D’cunha, N.M.;  Bulman, A.;  Panagiotakos, D.B.;  Naumovski, N. Non-Alcoholic Fatty Liver Disease and Cognition. Encyclopedia. Available online: https://encyclopedia.pub/entry/24317 (accessed on 24 April 2024).
Kouvari M,  Sergi D,  D’cunha NM,  Bulman A,  Panagiotakos DB,  Naumovski N. Non-Alcoholic Fatty Liver Disease and Cognition. Encyclopedia. Available at: https://encyclopedia.pub/entry/24317. Accessed April 24, 2024.
Kouvari, Matina, Domenico Sergi, Nathan M. D’cunha, Amanda Bulman, Demosthenes B. Panagiotakos, Nenad Naumovski. "Non-Alcoholic Fatty Liver Disease and Cognition" Encyclopedia, https://encyclopedia.pub/entry/24317 (accessed April 24, 2024).
Kouvari, M.,  Sergi, D.,  D’cunha, N.M.,  Bulman, A.,  Panagiotakos, D.B., & Naumovski, N. (2022, June 22). Non-Alcoholic Fatty Liver Disease and Cognition. In Encyclopedia. https://encyclopedia.pub/entry/24317
Kouvari, Matina, et al. "Non-Alcoholic Fatty Liver Disease and Cognition." Encyclopedia. Web. 22 June, 2022.
Non-Alcoholic Fatty Liver Disease and Cognition
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This entry is adapted from the peer-reviewed paper 10.3390/diabetology3020026

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease globally, affecting approximately 25% of the general population. NAFLD occurs in the absence of excessive alcohol consumption and is closely associated with metabolic syndrome (MetS) and its components.

cognition liver steatosis non-alcoholic fatty liver disease

1. Introduction

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease globally, affecting approximately 25% of the general population [1]. NAFLD rates are rising in parallel with the pandemics of obesity and type 2 diabetes mellitus (T2DM) [2]. NAFLD occurs in the absence of excessive alcohol consumption and is closely associated with metabolic syndrome (MetS) and its components [3]. Indeed, it represents the hepatic manifestation of the MetS. Additionally, NAFLD has metabolic and cardiovascular consequences that have been linked with metabolic complications, chronic kidney disease, cardiovascular disease (CVD), and malignancies, contributing to higher mortality. The latter is common in people with non-alcoholic steatohepatitis (NASH), which is characterised by both hepatic steatosis and inflammation [4]. All of these conditions related to NAFLD share low-grade inflammation and oxidative stress as common features, which, in turn, also play a role in extrahepatic diseases. In this context, the literature suggests an interaction between the liver and brain, adding one more indication regarding the intercorrelation between neurological and metabolic systems [5].

2. Observational Studies on the Association between NAFLD and Cognition

Within the last decade, only 11 observational studies have evaluated the association between NAFLD and cognition, with the vast majority published in the last 4 years [6][7][8][9][10][11][12][13][14][15][16][17][18][19]. The findings of these studies are summarised in Table 1. Five studies prospectively examined this association, presenting contradicting outcomes. The CARDIA study included middle-aged participants from the USA and revealed that the presence of NAFLD did not significantly affect the cognitive decline in a 5-year follow-up [7]. On the other side, a prospective study from a Chinese cohort revealed that NAFLD participants had greater cognitive decline compared with their free-of-NAFLD counterparts during a 4-year follow-up, especially within the subgroup of middle-aged individuals. Three studies in Europe—one in Italy, one in Germany, and one in Sweden—investigated the effect of NAFLD on long-term dementia risk, revealing either positive [17] or neutral [16][19] associations. However, in the case of the study from Sweden, once the histological features of liver steatosis were included in the model that predicted dementia risk, this significantly increased its predictive ability [19]. The remaining nine studies had a cross-sectional [8][9][10][11][13][15] or case-control [12][14][18] design. Only one of them, a sub-analysis in the Framingham study, revealed non-significant associations between NAFLD and cognition assessed via neuropsychological tests [9]. Four studies [6][11][12][14] evaluated the association between NAFLD and general cognitive performance using multiple neuropsychological tests. All of these studies reported that individuals with NAFLD had significantly lower cognitive performance overall, measured via different validated questionnaires. Three studies revealed significantly lower processing speed and attention in people with NAFLD compared with non-NAFLD controls [8][14][15]. Memory and learning domains were examined in three studies revealing mixed outcomes [9][14][15]. In particular, one study reported lower performance in memory and learning test scores within the NAFLD group [15], while no significant associations were identified in the other two studies. In one study [13], the association between NAFLD and the language domain of cognitive performance was evaluated, revealing lower scores in the presence of this pathophysiological condition. Three studies investigated the role of NAFLD on visuospatial perception [9][11][14]. Two out of the three studies found poorer visuospatial perception in people with NAFLD [11][14]. In addition to this, NAFLD was associated with lower scores in abstraction, figural creation, and mental flexibility, as revealed by three studies [8][9][14]. Brain aging was assessed in one study with individuals that were free of NAFLD having lower aging of the brain compared with their NAFLD counterparts [10].
Table 1. Characteristics of selected observational studies on the association between non-alcoholic fatty liver disease and cognitive function (n = 11).
Author, Year Study Name (If Any) Study Design Country Age—Category Study Sample NAFLD Diagnosis Cognitive Function Assessment Main Exposure Main Outcome Level of Association Conclusion
Liu, Q., 2022 - prospective China middle-aged and older people 1651 Abdominal ultrasonography Mini-Mental State Examination (MMSE) NAFLD presence Global cognitive function 4-year prospective association NAFLD associated with cognitive decline, especially in middle-aged and with carotid stenosis population.
Gerber, Y., 2021 CARDIA study prospective USA middle-aged 2809 Computed tomography (CT) examination Battery of 3 cognitive tests: Digit Symbol Substitution Test (DSST), the Rey Auditory Verbal Learning Test (RAVLT), and the Stroop Test NAFLD presence Scores in cognitive tests Cross-sectional/5-year prospective association NAFLD presence associated with lower cognitive performance/NAFLD presence not significantly associated with cognitive decline in 5-year follow-up.
Labenz, C., 2021 - prospective Germany older people 22,317 patients/22,317 controls ICD-10 coding Dementia NAFLD presence Dementia risk 10-year prospective association No independent association with dementia incidence was detected.
Shang, Y.,
2021		 - nested case-cohort Sweden middle aged and older people 656 Liver Biopsy Dementia NAFLD presence Dementia risk 20-year prospective association No association between NAFLD and dementia risk in an almost 20-year follow-up. Histological markers to a conventional risk model for dementia enhanced its predictive ability.
Solfrizzi, V., 2020 Italian Longitudinal Study on Aging prospective Italy older people 1061 NAFLD fibrosis score (NFS) Dementia NFS categorization Dementia risk 8-year prospective association Advanced liver fibrosis (F3-F4 NFS) could be a long-term predictor for overall dementia risk.
Weinstein, G., 2019 Framingham prospective USA middle-aged and older people 1287 Multi-detector computed tomography scans Neuropsychological test (Wechsler Memory Scale) NAFLD presence Logical Memory Delayed Recall (LMd); Visual Reproduction Delayed Recall (VRd); Trail making B minus Trail making A (TrB-TrA); Similarities test (SIM); Hooper Visual Organization test (HVOT) Cross-sectional NAFLD per se not associated with cognitive performance. Advanced fibrosis associated with poorer performance on tests assessing executive function and abstract reasoning.
Weinstein, A. A., 2018 NHANES cross-sectional USA >65 years old 1102 Fatty liver index score ≥ 60 Consortium to Establish a Registry for Alzheimer’s Disease (CERAD-WL); Animal Fluency Test; digit symbol substitution test NAFLD presence Scores in cognitive tests Cross-sectional NAFLD with or without type 2 diabetes performed significantly worse on a task that requires a combination of processing speed, sustained attention, and working memory.
Filipović, B., 2018 - cross-sectional Serbia middle-aged 76 Ultrasonography (US) MRI brain scanning combined with Montreal Cognitive Assessment (MoCA) test NAFLD presence MoCA score Cross-sectional NAFLD significantly influenced cognitive deficit and tissue volume reduction and people suffering from NAFLD had about four times higher risk of having a cognitive impairment.
Tuttolomondo, A., 2018 - case-control Italy middle-aged Control: 83/Cases: 80 Liver biopsy; ultrasonography (US); liver stiffness Mini-Mental State Examination (MMSE) NAFLD presence Global cognitive function Cross-sectional NAFLD subjects lower mean MMSE scores in comparison with control subjects without NAFLD.
Weinstein, G., 2018 Framingham prospective USA older people 766 Multi-detector computed tomography scans Brain magnetic resonance imaging NAFLD presence TCBV (years of brain aging) Cross-sectional NAFLD associated with brain aging.
Elliot, C., 2013 - nested case-cohort USA middle aged and older people 224 Histological diagnosis Cognitive Failures Questionnaire NAFLD presence frequency of cognitive slips or failures occurring in everyday
life		 Cross-sectional NAFLD patients presented worse function independently associated with
cognitive symptoms, compared with their age-matched controls.

3. Pathogenetic Mechanisms Underpinning the Development of NAFLD

NAFLD represents the hepatic manifestation of the MetS. From a pathogenetic perspective, it arises as a consequence of an imbalance between triglyceride synthesis, fatty acid supply to the liver, triglyceride export via very-low-density lipoprotein (VLDL), and fatty acid oxidative capacity by the liver. This imbalance ultimately leads to the intrahepatic accumulation of triglycerides. Remarkably, all of these processes occur in a state of systemic insulin resistance and compensatory hyperinsulinemia [20]. Indeed, in the context of obesity and MetS, the underlying state of low-grade chronic inflammation promotes insulin resistance in metabolically active tissues, including adipose tissue [21]. Adipose tissue insulin resistance leads to an increase in fatty acid spill over from adipocytes due to the disinhibition of lipolysis [22]. This contributes to fatty acid oversupply in the liver, thereby fuelling the accumulation of triglycerides as lipid droplets within the hepatocytes. In support of the importance of this process in promoting NAFLD, the knockdown of fatty acid transport protein (FATP) 5, a fatty acid transporter expressed by hepatocytes, reversed steatosis in mice [23]. Another key pathogenetic process underpinning the accumulation of intrahepatic triglycerides is enhanced de novo lipogenesis, which is also a direct consequence of insulin resistance and, particularly, the compensatory hyperinsulinemia. De novo lipogenesis is under the transcriptional control of sterol regulatory element-binding protein 1c (SREBP1c), which, in turn, is regulated by insulin. However, de novo lipogenesis is not inhibited by insulin resistance. Instead, it is enhanced by hyperinsulinemia, which explains the increased hepatic de novo lipogenesis under insulin-resistant conditions [24]. A further pathogenetic mechanism underpinning the onset and progression of NAFLD is represented by impaired fatty acid oxidation, a metabolic pathway under the control of PPARα. In support of the role of this nuclear receptor and impaired fatty acid catabolism in the pathogenesis of NAFLD, PPARα-deficient ob/ob mice manifest more severe hepatic steatosis compared to their littermates due to decreased fatty acid oxidation [25].
However, data in humans relative to the relationship between fatty acid oxidation and NAFLD is controversial, with studies reporting either an increase, a decrease, or no changes in lipid catabolism in individuals with NAFLD [26]. Nevertheless, it must not be overlooked that even when there is an increase in fatty acid oxidation, the magnitude of such an increase may not be sufficient to cope with enhanced fatty acid supply. This compensatory response marked by an increase in fatty acid oxidation promotes an increase in reactive oxygen species (ROS), which further contributes to the mitochondrial dysfunction that characterises NAFLD [27]. In turn, mitochondrial dysfunction, due to the role of these organelles in fatty acid β-oxidation, contributes to both the inability of hepatocytes to cope with increased fatty acid supply as well as ROS production [28]. Finally, defects in triglycerides exported from the liver also contribute to NAFLD. In parallel with increased fatty acid oxidation, enhanced triglyceride export as part of VLDL also represents a mechanism to decrease hepatic lipid accumulation [29]. Once produced in the endoplasmic reticulum of hepatocytes, VLDL is channelled towards the Golgi apparatus, where mature VLDL are formed.

References

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Subjects: Nutrition & Dietetics
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Matina Kouvari
,
Domenico Sergi
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Nathan M. D’Cunha
,
Amanda Bulman
,
Demosthenes B. Panagiotakos
,
Nenad Naumovski
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