COVID-19 and nonalcoholic fatty liver disease (NAFLD) have emerged as global pandemics affecting millions of people worldwide over the past three years. NAFLD is particularly prevalent in individuals with metabolic comorbidities, such as diabetes and obesity, which have been strongly linked to a severe course of Sars-CoV-2 infection. Recently, due to the close association between metabolic abnormalities and NAFLD, the disease has been redefined as metabolic dysfunction-associated fatty liver disease (MAFLD). This review offers an overview of the biological and cellular mechanisms by which COVID-19 can cause liver damage, with a specific focus on the influence of fatty liver in these mechanisms. Additionally, it explores how fatty liver can exacerbate a COVID-19 infection and, conversely, if the presence of COVID-19 may accelerate the development and progression of fatty liver. Finally, the review examines the existing evidence suggesting that NAFLD or MAFLD independently contributes to a heightened severity of COVID-19, while also considering other factors such as age and metabolic comorbidities that may play a role in the disease’s progression.

Aim: In males, obesity is characterized by features resembling those observed during aging, such as hypogonadism and cytokines imbalance, yet at an early age. A direct connection between the low-grade inflammatory state and sex steroid abnormalities has been proposed to explain the development of these conditions in obesity.

Methods: We evaluated the relationship between sex hormones plasma levels and metabolic and inflammatory parameters in a cohort of patients with grade III obesity (n = 24, BMI 43.4 ± 8.5 kg/m²) undergoing bariatric surgery. Furthermore, we assessed the in vitro effects of testosterone exposure on the expression of markers of adiposity such as FABP-4, PPARγ, leptin, and adiponectin in human-derived adipocytes.

Results: A direct correlation was observed between BMI and hsCRP (P < 0.05), while testosterone plasma levels showed a statistically significant inverse correlation with hsCRP, but also with HOMA index, leptin, and von Willebrand factor concentrations (P < 0.05). In human-derived adipocytes, testosterone exposure promotes a reduction in the gene expression of adiposity markers, which is inhibited by co-exposure with the antiandrogen flutamide.

Conclusion: Our study shows a relationship between testosterone plasma levels and markers of inflammation in severe obesity, with testosterone exposure affecting adiposity biomarkers expression in humans. In light of these results, hypogonadism should be promptly identified in male patients with obesity and timely treated to reduce the burden of the disease.

Here, we comment on a recent article supporting the use of the ultrasonographic fatty liver indicator (US-FLI) as a point-of-care biomarker to be used in the community to rule out nonalcoholic steatohepatitis (NASH). To this end, we discuss definitions and characteristics of US-FLI, and we critically summarize the principal studies published from 2012 to 2023. We conclude that US-FLI exhibits high reproducibility. It finds utility across both the pediatric population and the point-of-care settings. Furthermore, it demonstrates a robust correlation with metabolic derangements, and also serves as a predictive tool for varying grades of hepatic steatosis and important liver histology endpoints. Notably, it excels in its capacity to differentiate between bland steatosis and true NASH. However, US-FLI reportedly exhibits limited accuracy among patient populations with obesity. Finally, we propose a detailed agenda to advance research on US-FLI.

This commentary is devoted to a recent study by Ren and Zheng (Nutr Metab Cardiovasc Dis. 2023;33:1349-1357). These authors analyzed sex-stratified long-term outcomes relevant to all-cause and cardiovascular field outcomes among 2,627 nonalcoholic fatty liver disease (NAFLD) adults enrolled in the 2000-2014 National Health and Nutrition Examination Surveys and identified with United States Fatty Liver Index (US FLI) score. Data have shown that, compared to women, men were exposed to a significantly higher all-cause mortality and the maximal risk was seen among those who had obesity and type 2 diabetes. However, women aged ≤ 60 years had a higher risk of death owing to cardiovascular disease (CVD). Conversely, no significantly increased risk of death from CVD was observed among women over 60 years compared to men of the same age group. The study by Ren and Zheng further fosters our understanding of cardiometabolic risk factors, illustrating sex differences present in NAFLD. The distinct impact of NAFLD on CVD by sex and age suggests that cardiometabolic comorbidities may be particularly underestimated among young and middle-aged women with NAFLD. The research by Ren and Zhang may stimulate future investigations exploring the molecular and cellular grounds underlying these findings, notably including the role of fibrosing NAFLD as a strong risk modifier of CVD. In conclusion, an improved understanding of sex-specific regulation of human metabolism in the liver and other key metabolic organs is a research priority finalized for implementing precision medicine approaches in NAFLD arena.