Loneliness and Social Isolation with Risk of Incident Non-alcoholic Fatty Liver Disease, UK Biobank 2006 to 2022.

Background: Although loneliness and social isolation are proposed as important risk factors for metabolic diseases, their associations with the risk of non-alcoholic fatty liver disease (NAFLD) have not been elucidated. The aims of this study were to determine whether loneliness and social isolation are independently associated with the risk of NAFLD and to explore potential mediators for the observed associations. Methods: In this large prospective cohort analysis with 405,073 participants of the UK Biobank, the status of loneliness and social isolation was assessed through self-administrated questionnaires at study recruitment. The primary endpoint of interest was incident NAFLD. Multivariable-adjusted Cox proportional hazard regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals for the associations between loneliness, social isolation, and risk of NAFLD. Results: During a median follow-up of 13.6 years, there were 5,570 cases of NAFLD identified. In the multivariable-adjusted model, loneliness and social isolation were both statistically significantly associated with an increased risk of NAFLD (HR = 1.22 and 1.13, respectively). No significant multiplicative or additive interaction was found between loneliness and social isolation on the risk of NAFLD. The mediation analysis estimated that 30.4%, 16.2%, 5.3%, 4.1%, 10.5%, and 33.2% of the loneliness-NAFLD association was mediated by unhealthy lifestyle score, obesity, current smoking, irregular physical activity, suboptimal sleep duration, and depression, respectively. On the other hand, 25.6%, 10.1%, 15.5%, 10.1%, 8.1%, 11.6%, 9.6%, 4.8%, and 3.0% of the social isolation-NAFLD association was mediated by unhealthy lifestyle score, obesity, current smoking, irregular physical activity, suboptimal sleep duration, depression, C-reactive protein, count of white blood cells, and count of neutrophils, respectively. Conclusions: Our study demonstrated that loneliness and social isolation were associated with an elevated risk of NAFLD, independent of other important risk factors. These associations were partially mediated by lifestyle, depression, and inflammatory factors. Our findings substantiate the importance of loneliness and social isolation in the development of NAFLD.