Abstract Background Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease associated with systemic changes in immune response, which might be associated with coronavirus disease 2019 (COVID-19) severity. The aim of this study was to investigate the impact of NAFLD on COVID-19 severity and outcomes. Methods A prospective observational study included consecutively hospitalized adult patients, hospitalized between March and June 2021, with severe COVID-19. Patients were screened for fatty liver by ultrasound and subsequently diagnosed with NAFLD. Patients were daily followed until discharge, and demographic, clinical, and laboratory data were collected and correlated to clinical outcomes. Results Of the 216 patients included, 120 (55.5%) had NAFLD. The NAFLD group had higher C-reactive protein (interquartile range [IQR]) (84.7 [38.6–129.8] mg/L vs 66.9 [32.2–97.3] mg/L; P = .0340), interleukin-6 (49.19 [22.66–92.04] ng/L vs 13.22 [5.29–39.75] ng/L; P < .0001), aspartate aminotransferase (58 [40–81] IU/L vs 46 [29–82] IU/L; P = .0123), alanine aminotransferase (51 [32–73] IU/L vs 40 [23–69] IU/L; P = .0345), and lactate dehydrogenase (391 [285–483] IU/L vs 324 [247–411] IU/L; P = .0027). The patients with NAFLD had higher disease severity assessed by 7-category ordinal scale, more frequently required high-flow nasal cannula or noninvasive ventilation (26, 21.66%, vs 10, 10.42%; P = .0289), had longer duration of hospitalization (IQR) (10 [8–15] days vs 9 [6–12] days; P = .0018), and more frequently had pulmonary thromboembolism (26.66% vs 13.54%; P = .0191). On multivariable analyses, NAFLD was negatively associated with time to recovery (hazard ratio, 0.64; 95% CI, 0.48 to 0.86) and was identified as a risk factor for pulmonary thrombosis (odds ratio, 2.15; 95% CI, 1.04 to 4.46). Conclusions NAFLD is associated with higher COVID-19 severity, more adverse outcomes, and more frequent pulmonary thrombosis.

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Association of Nonalcoholic Fatty Liver Disease With COVID-19 Severity and Pulmonary Thrombosis: CovidFAT, a Prospective, Observational Cohort Study

Non-alcoholic steatohepatitis (NASH) is characterized by steatosis, lobular inflammation, and enlargement of the diameter of hepatocytes (ballooning hepatocytes), with or without fibrosis. It affects 20% of patients with non-alcoholic fatty liver disease (NAFLD). Due to liver dysfunction and the numerous metabolic changes that commonly accompany the condition (obesity, insulin resistance, type 2 diabetes, and metabolic syndrome), the secretion of organokines is modified, which may contribute to the pathogenesis or progression of the disease. In this sense, this study aimed to perform a review of the role of organokines in NASH. Thus, by combining descriptors such as NASH, organokines, oxidative stress, inflammation, insulin resistance, and dyslipidemia, a search was carried out in the EMBASE, MEDLINE-PubMed, and Cochrane databases of articles published in the last ten years. Insulin resistance, inflammation and mitochondrial dysfunction, fructose, and intestinal microbiota were factors identified as participating in the genesis and progression of NASH. Changes in the pattern of organokines secretion (adipokines, myokines, hepatokines, and osteokines) directly or indirectly contribute to aggravating the condition or compromise homeostasis. Thus, further studies involving skeletal muscle, adipose, bone, and liver tissue as endocrine organs are essential to better understand the modulation of organokines involved in the pathogenesis of NASH to advance in the treatment of this disease.

/pdf/non-alcoholic-steatohepatitis-nash-and-organokines-what-is-1a2o27xi.pdf

Non-Alcoholic Steatohepatitis (NASH) and Organokines: What Is Now and What Will Be in the Future

Insulin action is impaired in type 2 diabetes. The functions of the hormone are an integrated product of insulin secretion from pancreatic β-cells and insulin clearance by receptor-mediated endocytosis and degradation, mostly in liver (hepatocytes) and, to a lower extent, in extrahepatic peripheral tissues. Substantial evidence indicates that genetic or acquired abnormalities of insulin secretion or action predispose to type 2 diabetes. In recent years, along with the discovery of the molecular foundation of receptor-mediated insulin clearance, such as through the membrane glycoprotein CEACAM1, a consensus has begun to emerge that reduction of insulin clearance contributes to the disease process. In this review, we consider the evidence suggesting a pathogenic role for reduced insulin clearance in insulin resistance, obesity, hepatic steatosis, and type 2 diabetes. Expected final online publication date for the Annual Review of Physiology, Volume 85 is February 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

https://www.annualreviews.org/doi/pdf/10.1146/annurev-physiol-031622-043133

Insulin Clearance in Health and Disease.

The entire spectrum of nonalcoholic fatty liver disease (NAFLD) ranging from fatty liver to cirrhosis has been considered as the result of specific metabolic pathways and mediators, gut barrier function alterations and inflammatory responses. Previous studies have associated intestinal microbiota with NAFLD pathogenesis, focusing mostly on bacteria. In a recent study by Demir et al. in the Journal of Hepatology, researchers characterized the fecal mycobiome of patients with NAFLD and controls. NAFLD severity was linked to a specific fecal mycobiome signature, particularly in patients without obesity, highlighting previously undescribed aspects of the non obese phenotype of NAFLD. There has recently been a growing interest in the pathophysiology and progression of non obese NAFLD, as its actual incidence seems to be higher than previously described. Moreover, the authors demonstrated that in subjects with NAFLD and advanced fibrosis, there was an augmented systemic immune response to Candida albicans. Amphotericin B, which has been widely regarded as an antifungal with a good safety profile, low rate of resistance and high efficacy, has already been shown to prevent liver injury and steatosis in mice. Similarly in this study when germ-free mice colonized with feces from patients with NASH were fed with a Western diet, treatment with amphotericin B protected against steatohepatitis and liver fibrosis. In conclusion, this study has provided novel insights into the fecal mycobiome composition in advanced NAFLD especially in the non obese population while suggesting a role for antifungal therapy in the management of NAFLD. 

https://doi.org/10.1016/j.metop.2022.100178

Could gut mycobiome play a role in NAFLD pathogenesis? Insights and therapeutic perspectives

DRAK2-SRSF6-regulated RNA alternative splicing is a promising therapeutic target in NAFLD/NASH

Nonalcoholic Fatty Liver Disease (NAFLD) is a multifactorial metabolic disorder that was first described in 1980. It has been prevalent and on the rise for many years and is associated with other metabolic disorders such as obesity and type 2 diabetes mellitus (T2DM). NAFLD can be best described as a metabolic dysfunction that stems from insulin resistance-induced hepatic lipogenesis. This lipogenesis increases oxidative stress and hepatic inflammation and is often potentiated by genetic and gut microbiome dysfunction. As NAFLD progresses from simple steatosis to non-alcoholic steatohepatitis (NASH) and to cirrhosis and hepatocellular carcinoma (HCC), the odds of complications including cardiovascular disease (CVD), chronic kidney disease (CKD), and overall mortality increase. The aim of this review is to describe the metabolic causes and consequences of NAFLD while examining the risks that each stage of NAFLD poses. In this review, the etiology of “lean” NAFLD, the impact of obesity, T2DM, genetics, and microbiome dysbiosis on NAFLD progression are all explored. This review will also discuss the core issue behind the progression of NAFLD: insulin resistance (IR). Upon describing the causes and consequences of NAFLD, the effectiveness of diet modification, lifestyle changes, and glucagon-like peptide 1 receptor (GLP-1) agonists to retard NAFLD progression and stem the rate of complications is examined.

Michael Frenkel

Papers

Metabolic causes and consequences of nonalcoholic fatty liver disease (NAFLD)