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This article discusses the new nomenclature for nonalcoholic fatty liver disease (NAFLD) and its implications in clinical practice. The term "metabolic dysfunction-associated steatotic liver disease" (MASLD) has been proposed to replace NAFLD, as it more accurately reflects the disease's association with metabolic dysfunction. The diagnosis of MASLD is based on the presence of hepatic steatosis and at least one cardiometabolic risk factor. Additionally, a new category called "metabolic dysfunction- and alcohol-associated liver disease" (MetALD) has been created for patients with metabolic dysfunction and increased alcohol intake. The article emphasizes the need for further research to validate the findings and ensure that existing data on NAFLD can be extrapolated to MASLD. [Extracted from the article]

Non-alcoholic fatty liver disease (NAFLD) is a major health problem which is now recognized by governmental agencies. NAFLD is a spectrum of diseases including non-alcoholic fatty liver (NAFL), non-alcoholic steatohepatitis (NASH) and its complications: fibrosis, cirrhosis and hepatocellular carcinoma. Worldwide, 25% of the general population have NAFL, and 1.5 to 6.5% have NASH. These high frequencies are linked to the epidemic of overweight and obesity. As for obesity, NAFLD is a complex and heterogeneous disease. The mechanisms, the clinical occurrence, the associated diseases and the natural history imply multiple genetic and environmental factors. Insulin-resistance may play a central but not exclusive role in the occurrence of NASH. NAFLD such as obesity and type 2 diabetes is a multisystem disease associated with various complications (cardio-vascular events, hepatic and extra hepatic cancers, chronic kidney disease. . .). Advances in the knowledge of the mechanisms of NAFLD led to the development of new pharmacological or non pharmacological treatments, which are undergoing clinical trials. The management of patients with NAFLD must be well structured, particularly because the liver biopsy, which is still the gold standard, cannot be performed in all suspected subjects. There is a need to develop and validate new non-invasive tools based on analyses of serum or on physical assessment that allow reliable assessment of fibrosis, the NASH and steatosis. Their availability will allow easy screening, diagnosis and follow-up of patients. [ABSTRACT FROM AUTHOR]

Non-Alcoholic Fatty Liver Disease (NAFLD) is a spectrum of liver diseases that encompass steatosis, Non-Alcoholic Steatohepatitis (NASH) and fibrosis. It is a major public health problem due to its frequency and potential complications (cirrhosis, hepatocellular carcinoma). At present, the monitoring of patients with steatosis or NASH is not fully coded and current treatments are not very effective. Research into the genetics and epigenetics of NAFLD is booming. While genetics studies modifications into the nucleotide sequence of genes, epigenetics studies modifications in the function of a gene that cannot be explained by alterations to the gene sequence. PNPLA3, TM6SF2 and MBOAT7-TMC4 are the 3 main genes for which single nucleotide polymorphisms are associated with steatosis, NASH and hepatic fibrosis, independently of insulin resistance and metabolic syndrome. MicroRNAs (miR), small non-coding RNAs inhibit messenger RNAs and thus regulate gene expression. The expression of some miRs in the liver is modified in NAFLD: miR 122 is decreased and miR 34a is increased. Some miRs are also found in the circulation: for example, miR 122 is increased in the case of NAFLD. Finally, the methylation of target genes is modified in NAFLD resulting in changes in their expression. This is particularly the case for PPAR, a key gene for lipid metabolism. In future, it is likely that substantial genetic and epigenetic data can be obtained for each individual from a simple blood sample allowing personalized monitoring and treatment for NAFLD, as for other diseases. [ABSTRACT FROM AUTHOR]

The proteolytic cleavage of Fibronectin type III domain-containing 5 (FNDC5) generates soluble irisin. Initially described as being mainly produced in muscle during physical exercise, irisin mediates adipose tissue thermogenesis and also regulates carbohydrate and lipid metabolism. The aim of this study was to evaluate the hepatic expression of FNDC5 and its role in hepatocytes in Non-Alcoholic Fatty Liver (NAFL). Here we report that hepatic expression of FNDC5 increased with hepatic steatosis and liver injury without impacting the systemic level of irisin in mouse models of NAFLD (HFD and MCDD) and in obese patients. The increased Fndc5 expression in fatty liver resulted from its upregulation in hepatocytes and non-parenchymal cells in mice. The local production of Fndc5 in hepatocytes was influenced by genotoxic stress and p53-dependent pathways. The down-regulation of FNDC5 in human HepG2 cells and in primary mouse hepatocytes increased the expression of PEPCK , a key enzyme involved in gluconeogenesis associated with a decrease in the expression of master genes involved in the VLDL synthesis (CIDEB and APOB). These alterations in FNDC5 -silenced cells resulted to increased steatosis and insulin resistance in response to oleic acid and N -acetyl glucosamine, respectively. The downregulation of Fndc5 also sensitized primary hepatocytes to apoptosis in response to TNFα, which has been associated with decreased hepatoprotective autophagic flux. In conclusion, our human and experimental data strongly suggest that the hepatic expression of FNDC5 increased with hepatic steatosis and its upregulation in hepatocytes could dampen the development of NAFLD by negatively regulating steatogenesis and hepatocyte death. • Hepatic FNDC5 is upregulated in NAFLD without impacting systemic levels of irisin in mouse and human. • Hepatocytes and non-parenchymal cells contribute to increased FNDC5 expression in fatty livers. • Hepatic genotoxic stress and p53 pathway activation could be involved in local upregulation of FNDC5. • FNDC5 in hepatocytes limits steatosis and cytokine-mediated apoptosis. [ABSTRACT FROM AUTHOR]

Previous studies on the prognostic significance of non-invasive liver fibrosis tests in non-alcoholic fatty liver disease (NAFLD) lack direct comparison to liver biopsy. We aimed to evaluate the prognostic accuracy of fibrosis-4 (FIB4) and vibration-controlled transient elastography (VCTE), compared to liver biopsy, for the prediction of liver-related events (LREs) in NAFLD. A total of 1,057 patients with NAFLD and baseline FIB4 and VCTE were included in a multicenter cohort. Of these patients, 594 also had a baseline liver biopsy. The main study outcome during follow-up was occurrence of LREs, a composite endpoint combining cirrhosis complications and/or hepatocellular carcinoma. Discriminative ability was evaluated using Harrell's C-index. FIB4 and VCTE showed good accuracy for the prediction of LREs, with Harrell's C-indexes >0.80 (0.817 [0.768-0.866] vs. 0.878 [0.835-0.921], respectively, p = 0.059). In the biopsy subgroup, Harrell's C-indexes of histological fibrosis staging and VCTE were not significantly different (0.932 [0.910-0.955] vs. 0.881 [0.832-0.931], respectively, p = 0.164), while both significantly outperformed FIB4 for the prediction of LREs. FIB4 and VCTE were independent predictors of LREs in the whole study cohort. The stepwise FIB4-VCTE algorithm accurately stratified the risk of LREs: compared to patients with "FIB4 <1.30", those with "FIB4 ≥1.30 then VCTE <8.0 kPa" had similar risk of LREs (adjusted hazard ratio [aHR] 1.3; 95% CI 0.3–6.8), whereas the risk of LREs significantly increased in patients with "FIB4 ≥1.30 then VCTE 8.0-12.0 kPa" (aHR 3.8; 95% CI 1.3–10.9), and even more for those with "FIB4 ≥1.30 then VCTE >12.0 kPa" (aHR 12.4; 95% CI 5.1–30.2). VCTE and FIB4 accurately stratify patients with NAFLD based on their risk of LREs. These non-invasive tests are alternatives to liver biopsy for the identification of patients in need of specialized management. The amount of fibrosis in the liver is closely associated with the risk of liver-related complications in non-alcoholic fatty liver disease (NAFLD). Liver biopsy currently remains the reference standard for the evaluation of fibrosis, but its application is limited by its invasiveness. Therefore, we evaluated the ability of non-invasive liver fibrosis tests to predict liver-related complications in NAFLD. Our results show that the blood test FIB4 and transient elastography stratify the risk of liver-related complications in NAFLD, and that transient elastography has similar prognostic accuracy as liver biopsy. These results support the use of non-invasive liver fibrosis tests instead of liver biopsy for the management of patients with NAFLD. [Display omitted] • At their published cut-offs, FIB4 and VCTE stratify patients with NAFLD into subgroups with significantly different prognoses. • Compared to liver biopsy in NAFLD, VCTE has similar accuracy for the prediction of liver-related events. • With regards to clinical events, the FIB4-VCTE stepwise algorithm accurately discriminates at-risk patients with NAFLD. • This algorithm should be used in the referral pathway to a liver specialist. [ABSTRACT FROM AUTHOR]

[Display omitted] • 9/17 PFAS were detected in more than 50% of the patients. • PFDA, PFNA, PFOA, PFOS and PFHxS were detected in all patients. • Higher concentrations of PHFpA were associated with liver steatosis. • PFHpA could disturb NAFLD natural history being involved in liver steatosis. Non-alcoholic fatty liver disease (NAFLD) has become the leading cause of chronic liver disease worldwide and the determinants driving its severity remain to be elucidated. Perfluoroalkyl substances (PFAS) are synthetic chemical compounds. They are used in commonplace products and persistent in water, soil and the human body. In vitro and animal studies suggest a pathogenic role for PFAS in metabolic diseases such as NAFLD. We aimed to evaluate the association between NAFLD severity and serum PFAS concentrations in humans. One hundred biopsy-proven NAFLD patients were included with a well-balanced distribution between the different stages of severity: 25 patients with simple steatosis, 25 with early non-alcoholic steatohepatitis (NASH and F0–F1 fibrosis), 33 with fibrotic NASH (NASH and F2–F3 fibrosis), and 17 with cirrhotic NASH (NASH and F4 fibrosis). Liver histological features were evaluated according to the NASH Clinical Research Network classification. Seventeen PFAS were measured by high-performance liquid chromatography coupled with tandem mass spectrometry on serum samples stored at −80 °C. The median age was 60 years, 61 % of patients were male, 46 % had diabetes and the median body mass index (BMI) was 32 kg/m2. Long-chain PFAS were associated with steatosis grade (p = 0.03). Among the nine PFAS detected in > 50 % of the patients, Perfluoro-n-heptanoic acid (PFHpA) showed significantly higher concentrations in grade 3 steatosis versus grade 1 (p = 0.02). Perfluoro-n-dodecanoic acid (PFDoA) concentrations were higher in patients with significant fibrosis (p = 0.04) and PFHpA in patients with advanced fibrosis (p = 0.02). The association between PFHpA and steatosis grade remained significant in multivariate analysis adjusted for age, gender, BMI, diabetes presence and dyslipidemia (p = 0.004). Our study showed a significant association between PFHpA and liver steatosis in NAFLD. According to data available in the literature, PFHpA could be implicated in liver steatosis through β-oxidation and biosynthesis of fatty acids. [ABSTRACT FROM AUTHOR]

Background & Aims Cluster of differentiation (CD)44 regulates adipose tissue inflammation in obesity and hepatic leukocyte recruitment in a lithogenic context. However, its role in hepatic inflammation in a mouse model of steatohepatitis and its relevance in humans have not yet been investigated. We aimed to evaluated the contribution of CD44 to non-alcoholic steatohepatitis (NASH) development and liver injury in mouse models and in patients at various stages of non-alcoholic fatty liver disease (NAFLD) progression. Methods The role of CD44 was evaluated in CD44 −/− mice and after injections of an αCD44 antibody in wild-type mice challenged with a methionine- and choline-deficient diet (MCDD). In obese patients, hepatic CD44 (n = 30 and 5 NASH patients with a second liver biopsy after bariatric surgery) and serum sCD44 (n = 64) were evaluated. Results Liver inflammation (including inflammatory foci number, macrophage and neutrophil infiltration and CCL2/CCR2 levels), liver injury and fibrosis strongly decreased in CD44 −/− mice compared to wild-type mice on MCDD. CD44 deficiency enhanced the M2 polarization and strongly decreased the activation of macrophages by lipopolysaccharide (LPS), hepatocyte damage-associated molecular patterns (DAMPs) and saturated fatty acids. Neutralization of CD44 in mice with steatohepatitis strongly decreased the macrophage infiltration and chemokine ligand (CCL)2 expression with a partial correction of liver inflammation and injury. In obese patients, hepatic CD44 was strongly upregulated in NASH patients ( p = 0.0008) and correlated with NAFLD activity score (NAS) ( p = 0.001), ballooning ( p = 0.003), alanine transaminase ( p = 0.005) and hepatic CCL2 ( p <0.001) and macrophage marker CD68 ( p <0.001) expression. Correction of NASH was associated with a strong decrease in liver CD44 + cells. Finally, the soluble form of CD44 increased with severe steatosis ( p = 0.0005) and NASH ( p = 0.007). Conclusion Human and experimental data suggest that CD44 is a marker and key player of hepatic inflammation and its targeting partially corrects NASH. Lay summary Human and experimental data suggest that CD44, a cellular protein mainly expressed in immune cells, is a marker and key player of non-alcoholic steatohepatitis (NASH). Indeed, CD44 enhances the non-alcoholic fatty liver (NAFL) (hepatic steatosis) to NASH progression by regulating hepatic macrophage polarization (pro-inflammatory phenotype) and infiltration (macrophage motility and the MCP1/CCL2/CCR2 system). Targeting CD44 partially corrects NASH, making it a potential therapeutic strategy. [ABSTRACT FROM AUTHOR]