Non-alcoholic fatty liver disease (NAFLD) is a prevalent chronic liver condition encompassing a spectrum of pathologies from steatosis to cirrhosis and hepatocellular carcinoma (HCC). Its increasing incidence presents a significant global health challenge, exacerbated by the lack of effective pharmacological treatments. NAFLD frequently co-occurs with metabolic syndrome, characterized by disrupted glycolipid metabolism and low-grade inflammation, leading to comorbidities like type 2 diabetes mellitus (T2DM), obesity, hypertension, and dyslipidemia. Lifestyle factors, particularly sedentary behavior and high-calorie diets, are strongly linked to NAFLD development and progression. Conversely, lifestyle interventions combining physical exercise and caloric restriction have shown significant benefits in NAFLD management. Maintaining a balanced body composition, with increased free fat mass (FFM) and reduced fat mass (FM), is crucial for NAFLD prevention. The COVID-19 pandemic and subsequent lockdowns in 2020 caused widespread changes in lifestyle, including reduced physical activity and shifts in dietary habits. While the long-term effects of unhealthy lifestyle choices on NAFLD are well-established, the consequences of abrupt lifestyle changes require further investigation. This study aimed to evaluate the impact of these pandemic-related lifestyle changes on NAFLD evolution and HCC occurrence.

Extensive research highlights the strong association between unhealthy lifestyle behaviors and chronic metabolic disorders, including NAFLD. Studies have demonstrated that prolonged sitting, even in lean individuals, increases NAFLD prevalence, emphasizing the role of sedentary behavior. Conversely, lifestyle modifications involving physical activity and caloric restriction have proven effective in NAFLD prevention and management by improving insulin resistance, increasing energy expenditure, and reducing lipid overload. Maintaining a healthy body composition, with a higher proportion of FFM and lower FM, is also a key protective factor against NAFLD. However, there's a gap in understanding the impact of rapid, acute lifestyle changes on NAFLD progression. Previous studies have explored the effects of the COVID-19 pandemic on metabolic parameters, but a comprehensive analysis of the impact on NAFLD progression, considering body composition, remains limited.

This retrospective multicenter longitudinal study followed 187 NAFLD patients for four years (2018-2022), dividing the period into pre-lockdown (2018-2020) and lockdown (2020-2022) phases. Patients were assessed clinically, biochemically, and with imaging techniques. Data collected included anthropometric measurements (BMI, WHR), biochemical markers (glucose, insulin, lipids, liver enzymes), non-invasive liver fibrosis assessments (FibroScan for liver stiffness and CAP, NAFLD fibrosis score), and body composition analysis (Bioelectrical Impedance Analysis – BIA). Dietary habits (macronutrient intake), alcohol consumption (AUDIT-C), and physical activity levels were also assessed. HCC occurrence was monitored through ultrasound screenings. Statistical analyses included t-tests, Wilcoxon tests, ANOVA, Kruskal-Wallis tests, Kaplan-Meier analysis, log-rank tests, and logistic regression to compare data between time points and assess risk factors for HCC. The study was approved by the ethical committee of the University of Campania "L. Vanvitelli".

During the lockdown, significant changes in lifestyle were observed, including increased fat and carbohydrate intake and decreased physical activity. This led to a significant increase in BMI, WHR, and several metabolic parameters (total cholesterol, LDL, triglycerides, insulin, glucose, HOMA-IR, AST, ALT) while HDL levels decreased. Non-invasive assessments showed a worsening of liver fibrosis and steatosis (NFS, LSM, CAP). Body composition analysis revealed a significant increase in fat mass (FM) and a decrease in free fat mass (FFM) and body cell mass (BCM). Importantly, the incidence of both overall HCC and HCC meeting Milan-out criteria significantly increased during the lockdown period (overall HCC: HR 2.39, p=0.02; Milan-out HCC: HR 5.93, p=0.008). Logistic regression analyses revealed significant associations between body composition changes (increased FM, decreased FFM, BCM, and SMMI) and HCC occurrence during the lockdown, independent of other factors like age, sex, BMI, T2DM, and SARS-CoV-2 infection. Changes in body composition from the pre-lockdown period to the end of the lockdown (Δ values) strengthened the association between these changes and HCC outcomes. This association was not observed in the pre-lockdown period.

This study demonstrates that acute lifestyle changes, induced by the COVID-19 lockdown, significantly impacted NAFLD progression and HCC risk. The observed worsening of metabolic parameters, liver fibrosis, and steatosis, coupled with unfavorable body composition shifts, contributed to the increased HCC incidence. The study's findings highlight the importance of body composition as a critical factor influencing NAFLD outcomes, even during relatively short periods of lifestyle disruption. The lack of association between HCC and other metabolic parameters during the lockdown compared to the pre-lockdown period points towards the predominant role of body composition changes. The study confirms the need for proactive lifestyle interventions to mitigate the adverse effects of disruptions to healthy habits on NAFLD.

This study provides strong evidence that acute lifestyle changes negatively affect NAFLD progression and increase HCC risk. Body composition modifications emerged as a critical factor influencing this outcome. Future research should focus on developing targeted interventions to counteract the adverse impact of lifestyle disruptions on NAFLD, especially considering the potential for rapid body composition alterations to drive disease progression. Larger, prospective studies with longer follow-up periods are needed to further confirm these findings and explore the long-term implications.

The retrospective nature of this study is a limitation. Selection bias might have influenced the results. A prospective study with a larger and more diverse cohort would strengthen the conclusions. The assessment of sedentary behavior was not directly included, limiting the comprehensive understanding of lifestyle factors influencing NAFLD progression. Finally, although the study included data from three centers, generalizability to other populations needs to be further confirmed.