In light of the latest etiologic revolution of chronic hepatopathies, the worldwide spread of metabolic-associated liver diseases and related comorbidities became one of the most important issues, that urgently needed to be addressed by the scientific community (22). The lack of approved efficient medications, even more considering the rapid evolution of the clinical picture up to HCC development, makes the NAFLD the current “hepatologist chimera”. During the last two years the population all over the world experienced a radical lifestyle change due to, from a medical point of view, the SARS-CoV-2 diffusion and the consequent governments forced rules to counteract the contagion impacting on sociality (23, 24).
On this extraordinary background, the SARS-CoV-2 European spread represented the fuse able to trigger a series of unhealthy dietary and physical activity attitudes by which the NAFLD gains an inauspicious advantage. Our NAFLD cohort was followed up continuously for two years before and two years after the approval of lockdown social restriction rules, showing deep lifestyle changes in terms of total daily caloric intake and dietary composition as well as reduction of regularity and the time per week dedicated to physical exercise. As properly identified before in other contexts, the foreseeable effect of these duties was represented by a weight gain between 0.5 and 1.8 kg (± 2.8 Kg) after just 2 months of quarantine (25). This happened particularly in specific population subsets experiencing already proven risk factors for this outcome, like increased snacking frequency, decreased water intake, emotional eating, decreased sleep quality, and being overweight/obese (25). However, how this phenomenon impacts NAFLD, fueling its evolution, isn’t already properly known, due to the need to insert it in a more complex model of risk assessment that should take into consideration also the body composition analysis and the time frame for its modification. Taken together, our findings demonstrated the worsening of several metabolic parameters at the end of lockdown, in comparison to the previous periods (T2 vs T1 & T0). In particular, we pointed out the increase of the disease staging evaluated both via LSM and NFS calculation, also highlighting the increase of CAP values. Moreover, the association of this finding with the increase of several biochemical parameters, confirmed the derangement of the clinical picture during the lockdown, reinforcing the cause-effect relationship with the reported lifestyle change.
To our knowledge, our present study is the first observation of the effects of lifestyle behavior changes caused by the lockdown on the NAFLD clinical progression and outcomes.
In a retrospective longitudinal study including 973 participants who underwent health check-ups between 2018 and 2020, Fujii et al demonstrated the independent predictors for Metabolic dysfunction-associated fatty liver disease (MAFLD) development during the pandemic observation (2019–2020), resulting in the daily alcohol intake and, particularly for < 60 years old subjects, the proportion of participants who ate 2 times per day as statistically significant (18). However, no data regarding the possible worsening of the disease in those patients presenting the diagnosis from the beginning of the observation were shown and in our setting the alcohol consumption assessment did not significantly change during the entire length of the study.
A mutual relationship between SARS-CoV-2 infection and NAFLD clinical picture has been previously demonstrated (26). In this sense, the deleterious interplay of two inflammatory pathways, the one chronically active in NAFLD and the other acutely present during COVID-19, could be considered the key pathogenetic mechanism of the liver damage observed in a subset of patients. Contemporarily, the underlying liver fibrosis might represent an additional and independent risk factor for severe SARS-CoV-2 illness, irrespective of metabolic comorbidities (27, 28). Despite the SARS-CoV-2 infection in several enrolled patients during the pandemic spread, we would like to point out that it was not significantly associated with the impairment of the evaluated study parameters, nor with negative disease outcomes like HCC development or death.
No sequential data regarding the body composition analysis of NAFLD patients across the pandemic were published before. Here we showed a huge modification of body compartments of the enrolled population, particularly emphasizing the increase of FM (percentage and Kg) and a decrease of FFM (percentage) and BCM (percentage). Azoulay et al. in a recent observational study examined the change in body composition parameters of children and adolescents during the pandemic from May 15, 2020, until December 15, 2020. In this setting, they demonstrated in most of the enrolled subjects a relatively stable muscle-to-fat ratio (MFR) z-scores, increased in underweight (p = 0.05) and normal weight subjects (p = 0.008), but not in the overweight/obesity subgroup (p = 0.169). The multivariate linear regression identified socioeconomic position, pre-pandemic BMI z-scores, pre-pandemic MFR z-scores, and physical activity levels during the pandemic as predictors for delta MFR z-scores (29). These findings shed light on the weakness, in terms of unhealthy body composition modifications, of that subset of the analyzed overweight population. Besides, the lack of dietary information and longer follow-up data in the specific NAFLD setting represent not at all negligible differences in comparison to our observation.
The prominent increase in HCC occurrence and the rate of “Milan-out” staging at the diagnosis during the lockdown in comparison to the previous study period were also highlighted.
As previously reported, the global incidence of NAFLD-related HCC before the pandemic ranged from 0.5–2.6% among patients with NASH cirrhosis and lower in non-cirrhotic NAFLD (approximately 0.1 to 1.3 per 1,000 patient-years), making the showed findings alarming (30).
For this purpose, the impaired compliance to the screening program recommended by the CPG due to the risks from potential exposure and resource reallocation seemed to be not significant in influencing the observed findings (31). On the contrary, the logistic regression model confirmed the LSM as an independent major risk factor for HCC occurrence in the pre-pandemic period, revealing the unforeseen role exerted by the body composition changes both on HCC occurrence and “Milan-out” staging at the diagnosis during the lockdown. Specifically, FM (Kg and percentage), FFM (Kg and percentage), SMMI, and BCM (Kg and percentage) were significantly associated with both the evaluated disease outcomes, independently from age, BMI, sex, T2DM, LSM, SARS-CoV-2 infection, and CAP.
Moreover, the OR values acquired even more relevance by the analysis of the delta modification (T2 vs T1) of the assessed parameters, reinforcing the association link between their worsening and the HCC. Unexpecting, the LSM during the pandemic resulted in less power in influencing the evaluated outcomes. The latter datum, however, must be carefully interpreted, because the greater part of newly diagnosed HCC during the pandemic developed in non-cACLD (n. 16/20) patients, and a prospective observational study on large cohorts could give further details.
Lastly, the chronic modification of the body composition represents an important prognostic determinant in the context of the HCC treatment in the case of systemic therapies administration like Lenvatinib or Sorafenib, as well as resective surgery and transcatheter arterial chemoembolization (32–35). In light of the results, how and how much the rapid modifications of the body composition observed in our setting could impact NAFLD natural history, complications onset, and HCC evolution, also in terms of therapeutic response, remain an unmet open question.
The retrospective nature could represent the most important study limitation and a large multicenter observational study could help to corroborate our results. A longer follow-up period could also improve the assessment of the real long-term impact of the pandemic in this context.