Non-alcoholic Fatty Liver Disease, Liver Fibrosis Score and Cognitive Function in Middle-aged Adults

The Framingham Study

Galit Weinstein; Kendra Davis-Plourde; Jayandra J. Himali; Shira Zelber-Sagi; Alexa S. Beiser; Sudha Seshadri


Liver International. 2019;39(9):1713-1721. 

In This Article

Abstract and Introduction


Background: Non-alcoholic fatty liver disease (NAFLD) is common and has been recently related to brain health. We aimed to assess the relationships of NAFLD and its severity, using the NAFLD fibrosis score (NFS), with cognitive performance.

Methods: Framingham study Offspring and 3rd generation participants were included if they attended exams 9 (2002–2008) and 2 (2008–2011), respectively, were free of dementia and stroke, and did not have excessive alcohol intake. Between 2008 and 2011, participants underwent Multi-detector computed tomography scans of the abdomen to determine NAFLD diagnosis and the NFS was used to categorize the severity of fibrosis. Cross-sectional relationships of NAFLD and the NFS with cognitive testing of memory, abstract reasoning, visual perception, attention and executive function were assessed, while adjusting for multiple cardiometabolic variables including visceral adipose tissue, diabetes and insulin resistance.

Results: Of the 1287 participants (mean age = 61±12 years, 48% men), 378 (29%) had NAFLD. The presence of NAFLD was not associated with cognitive function. However, among those with NAFLD (mean age = 61±12 years; 58% men), high compared to low risk of advanced fibrosis was associated with poorer performance on similarities (β = −2.22 ± 0.83; P = 0.009) and trail-making B minus A (β = −0.11 ± 0.05; P = 0.028), independently of potential confounders.

Conclusions: Participants with high risk of advanced fibrosis may have poorer cognitive function compared to those with low risk, particularly in executive function and abstract reasoning. Future findings are necessary to evaluate the value of the NFS as a biomarker that predicts cognitive impairment and dementia and to explore the role of hepatic fibrosis in brain health.


Accumulating evidence suggests that liver diseases, even in precirrhotic stages, may be linked with brain ageing.[1,2] More specifically, there is a growing interest in the implications of non-alcoholic fatty liver disease (NAFLD) on brain health, as these conditions share common risk factors (e.g. cardiovascular disease, diabetes and obesity) and possibly also common pathophysiological mechanisms, including inflammation and endothelial dysfunction.[2] Recently, NAFLD has been linked with poor cognitive function[3] and with decreased brain activity.[4] In addition, a study from our group has demonstrated an association between NAFLD and low total cerebral brain volume independently of multiple cardio-metabolic factors, including diabetes, cardiovascular diseases and visceral fat.[5] These findings are important since NAFLD prevalence is high, with estimations of around 30% in the general population and 80% among the morbidly obese.[6,7] Furthermore, NAFLD is a promising target for intervention aiming to prevent cognitive impairment because it can be improved through life-style changes including exercise,[8] healthy nutrition and weight reduction.[9]

Yet, it is important to note that NAFLD comprises a wide range of liver pathologies, ranging from simple steatosis to non-alcoholic steatohepatitis (NASH) with varying stages of fibrosis, and cirrhosis.[10] Hence, it still remains to clarify whether the presence of NAFLD per se is related to cognitive ageing, or alternatively, if this association is driven by the degree of liver fibrosis.

Liver fibrosis stage is an important prognostic factor in patients with NAFLD. It is associated with end-stage liver disease and with liver-related mortality even in its initial stages, and regardless of steatosis or inflammatory status.[11] The gold standard to detect liver fibrosis is liver biopsy, with characterization of liver histology. However, this is an invasive approach, with acknowledged limitations including high cost, risk of procedure-related morbidity and mortality and the possibility of sampling error.[12] To overcome these limitations, several non-invasive approaches, including serum-based biomarkers, have been developed.[13] One of them, the NAFLD Fibrosis Score (NFS), is based on a formula which incorporates six readily available variables: age, BMI, hyperglycemia, platelet count, albumin and AST/ALT ratio.[14] In a meta-analysis of 13 studies consisting of 3064 participants, the NFS had an area under the curve (AUC), sensitivity and specificity for predicting advanced fibrosis of 0.85 (0.80-0.93), 0.90 (0.82-0.99) and 0.97 (0.94-0.99), respectively.[15] Using previously published cutoffs of the NFS to categorize probability of fibrosis severity, a large population-based cohort study showed that individuals with NAFLD who had NFS values indicative of advanced fibrosis had an increased risk of all-cause and cardiovascular mortality compared to those without indication of significant fibrosis.[16] Additionally, in the Framingham study, NAFLD with high vs low or intermediate probability of advanced fibrosis according to the NFS was related to worse vascular function as evident by lower diastolic blood pressure, wider pulse pressure and increased odds of hypertension.[17]

In this study, we aimed to assess the cross-sectional relationship of NAFLD and the NFS with cognitive performance among middle-aged community-dwelling participants of the Framingham Study.