Search Results (443)

Metabolic dysfunction-associated steatotic liver disease (MASLD) is currently the most prevalent cause of chronic liver disease worldwide. Its pathogenesis is complex and not yet fully elucidated but is commonly explained by the “multiple hit” hypothesis, which suggests that pathological behaviours interact with an unfavourable genetic background and the presence of cardiovascular comorbidities. Recent evidence has highlighted a potential role of the gut microbiota in the onset and progression of MASLD to metabolic dysfunction-associated steatohepatitis (MASH) and hepatocellular carcinoma (HCC), potentially driven by epigenetic modifications mediated by microRNAs (miRNAs). MiRNAs are small, non-coding RNAs that regulate gene expression both intra- and extracellularly. Notably, emerging data suggests a bidirectional communication between the gut microbiota and the host, mediated by miRNAs via exosomes and outer membrane vesicles. The primary aim of this review is to explore the epigenetic crosstalk between the host and the gut microbiota through miRNA expression, with the goal of identifying specific pathways involved in MASLD development and natural history. A secondary objective is to evaluate the potential applications of artificial intelligence in the analysis of these complex host–microbiota interactions, to standardize the evaluation of microbiota and to create a model of the epigenetic changes in metabolic liver disease. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) is an increasingly prevalent liver disorder driven by metabolic dysregulation and inflammation. Recent studies highlight the importance of the gut microbiome as a key contributor to this pathology through its ability to ferment dietary sugars into ethanol, a metabolite previously overlooked in MASLD. In this review, we discuss the role of the gut microbiome in MASLD, covering functional and compositional shifts observed in the disease; we dive into the different microbial pathways of ethanol synthesis, hepatic mechanisms of ethanol clearance, and pathological consequences. We also discuss the role of a healthy microbiome in the clearance of ethanol in the gut and how microbiome-based strategies could be beneficial in targeting endogenous production of ethanol, going from the traditional probiotic–prebiotic combination to discussing new approaches. Full article

Background/Objectives: Liver fibrosis is a progressive consequence of chronic liver injury that can evolve into cirrhosis, liver failure, or hepatocellular carcinoma, representing a major global health burden. Fibrogenesis is driven by hepatic stellate cell (HSC) activation, excessive extracellular matrix deposition, and structural disruption of liver tissue, with transforming growth factor-β (TGF-β) signaling and inflammatory mediators as central pathways. Current therapies primarily target the underlying causes, which may halt disease progression but rarely reverse established fibrosis. This review aims to outline current and emerging therapeutic strategies for liver fibrosis, informing both clinical practice and future research directions. Methods: A narrative synthesis of preclinical and clinical evidence was conducted, focusing on pharmacological interventions, microbiota-directed strategies, and innovative modalities under investigation for antifibrotic activity. Results: Bile acids, including ursodeoxycholic acid and derivatives, modulate HSC activity and autophagy. Farnesoid X receptor (FXR) agonists, such as obeticholic acid, reduce fibrosis but are limited by adverse effects. Fatty acid synthase inhibitors, exemplified by denifanstat, show promise in metabolic dysfunction-associated steatohepatitis (MASH). Additional strategies include renin–angiotensin system inhibitors, omega-3 fatty acids, and agents targeting the gut–liver axis. Microbiota-directed interventions—probiotics, prebiotics, symbiotics, antibiotics (e.g., rifaximin), and fecal microbiota transplantation—are emerging as potential modulators of barrier integrity, inflammation, and fibrogenesis, though larger clinical trials are required. Reliable non-invasive biomarkers and innovative trial designs, including adaptive platforms, are essential to improve patient selection and efficiently evaluate multiple agents and combinations. Conclusions: Novel modalities such as immunotherapy, gene editing, and multi-targeted therapies hold additional potential for fibrosis reversal. Continued translational efforts are critical to establish safe, effective, and accessible treatments for patients with liver fibrosis. Full article

We investigated the impact of liver damage on systemic inter-organ communication in an extensive observational case–control study of 923 patients with severe obesity and biopsy-confirmed metabolic dysfunction-associated steatotic liver disease (MASLD) or metabolic dysfunction-associated steatohepatitis (MASH) undergoing bariatric surgery. Using a comprehensive panel of circulating organokines, including fibroblast growth factor (FGF) 19, FGF21, adiponectin, galectin-3, irisin, and leptin, along with choline metabolites, we characterized metabolic signaling patterns associated with liver disease severity. Compared to controls, patients with MASLD/MASH exhibited significantly lower levels of FGF19, choline, and trimethylamine, while FGF21, galectin-3, irisin, and leptin were elevated. Sex-specific alterations in leptin and adiponectin were observed in patients with severe obesity but not in controls. Network analysis revealed a complex and individualized interplay among organokines, shaped by age, sex, and anthropometric factors. Despite this complexity, a dysregulation of the FGF21–adiponectin axis was associated with more advanced liver involvement. The large cohort and comprehensive organokine profiling studied provide valuable insights into the role of the FGF21–adiponectin axis on systemic metabolic alterations in severe obesity and their potential clinical implications. Full article

The aim of this study, as part of a collaboration between a malt house, a brewery, and a university, was to optimize the beer production process while simultaneously maintaining or even improving the quality of the beer and creating conditions for the optimization of the malting of barley grain. The Hurbanovo malt house provided 100 t of a specially prepared batch of malt for use in industrial-scale beer production at the Żywiec brewery (which produces 4.7 million hl annually). The malt, produced from barley variety Overture, was characterized by a higher extract and protein content and increased enzymatic activity. The test malt also demonstrated favorable properties such as higher friability, lower viscosity, and a two-fold shorter saccharification time. Four HGB worts were produced during production tests. Each brew used 21.5 tons of malt, yielding an average 1020 hl of wort, with an extract content of 15.5°Blg. The malt was milled in a two-roll wet mill with a capacity of 40 t per hour. Mash filtration took place in lauter tuns with a diameter of 12.4 m each. The produced worts were transferred into a fermentation tank with a capacity of 5500 hl, and then fermentation, maturation, and lagering processes were carried out. The tested batch of malt was examined in detail and compared with a standard malt blend from three different suppliers. The tests showed an increase in extract efficiency in the process, with a simultaneous reduction in extract losses (1.2%pt.). The filterability of the mash improved compared to the standard blend, and an improvement in wort quality was observed as a result of lower turbidity (by approximately 34%). The data obtained indicate an improvement in the process with the use of the specially prepared batch of malt. Full article

The incidence and prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) are increasing, and, currently, the disease affects approximately 30% of the global population. Therefore, there is a growing need for widely available, patient-friendly, and reliable diagnostic tools. Our review is focused on the presentation and discussion of emerging biomarkers for evaluation and non-invasive detection of liver fibrosis in patients with MASLD, including glycation markers (AGEs/sRAGE), lipid mediators (eicosanoids), fetuin-A, collagen turnover markers (PRO-C3, ADAPT), and omic-based technologies. As reported recently, some of these parameters revealed high diagnostic accuracy in clinical trials, so they may be incorporated as key diagnostic tools in the future MASLD approach. Employment of such biomarkers may enable correct and quick identification of MASLD and/or MASH patients, as well as better monitoring of their treatment response. The development of precision medicine, driven by multiomics and individualized profiling, promises a rearrangement from the traditional “one size fits all” to tailoring targeted care, as environmental factors may have an even more relevant impact on MASLD pathogenesis in comparison with genetic predisposition. Nevertheless, to enable their widespread clinical use, novel biomarkers require further rigorous validation and standardized implementation in healthcare settings. Full article

Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease linked to type 2 diabetes (T2D), obesity, and dyslipidaemia, which are all parts of the metabolic syndrome. In 2024, for non-cirrhotic MASH with mild to advanced fibrosis, resmetirom, a selective thyroid hormone receptor-β agonist, became the first FDA-approved treatment for this condition. By increasing β-oxidation and lipid metabolism, it minimises systemic thyroid or cardiac effects while reducing hepatic fat, inflammation, and fibrosis. Resmetirom is being developed for use in combination with lifestyle interventions, such as diet and exercise, to maximize patient benefit. Nevertheless, the lack of congruence between clinical trial populations and real-world payer criteria underscores access obstacles that necessitate policy reform. The successful delivery of screening programs depends on the education of providers from various disciplines and the establishment of uniform screening standards. Future studies should investigate the clinical application of resmetirom in combination with agents that may provide additional benefits, such as GLP-1 receptor agonists, SGLT2 inhibitors, and statins. These results are significant in light of recent long-term safety monitoring of these agents, particularly regarding the thyroid axis. Ensuring equitable uptake will be crucial, as it involves defining fair access through payer endpoints, conducting cost-effectiveness analysis, and considering patient-reported outcomes. Resmetirom represents a breakthrough in MASH management, offering potential metabolic benefits in conjunction with comprehensive clinical and lifestyle approaches. Full article

Noise barriers are commonly used to reduce the adverse effects of traffic noise in both urban and suburban settings. While conventional systems constructed from concrete and steel provide reliable acoustic and structural performance, they raise sustainability concerns due to high embodied energy and carbon emissions. Glued-laminated (glulam) timber has emerged as a sustainable alternative, offering a reduced carbon footprint, aesthetic appeal, and effective acoustic performance. However, the crashworthiness of timber-based noise wall systems remains under investigated, particularly with respect to the safety criteria established in the 2016 edition of the American Association of State Highway and Transportation Officials (AASHTO) Manual for Assessing Safety Hardware (MASH). This study presents the full-scale crash testing and evaluation of glulam rubrail and noise wall systems under MASH Test Level 3 (TL-3) impact conditions. Building on a previously tested system compliant with National Cooperative Highway Research Program (NCHRP) Report 350, modifications were made to increase rubrail dimensions to meet higher lateral design loads. Three full-scale vehicle crash tests were conducted using 1100C and 2270P vehicles at 100 km/h and 25 degrees, covering both front- and back-mounted wall configurations. All tested systems demonstrated acceptable structural performance, effective vehicle redirection, and compliance with MASH 2016 occupant risk criteria. There was no penetration or potential for debris intrusion into the occupant compartment, and all measured occupant risk values remained well below allowable thresholds. Minimal damage to structural components was observed. The results confirm that the modified glulam noise wall system meets current impact safety standards and is suitable for use along high-speed roadways. This work supports the integration of sustainable materials into roadside safety infrastructure without compromising crash performance. Full article

The progression of metabolic dysfunction-associated steatotic liver disease (MASLD) to severe forms, including metabolic dysfunction-associated steatohepatitis (MASH) and liver fibrosis, involves metabolic dysfunction, genetics, and gut dysbiosis. People with HIV (PWH) represent a high-risk group for MASLD, but the role of gut microbiota alterations in disease severity within this population remains poorly understood. We prospectively recruited PWH with MASLD, defined as the controlled attenuation parameter (CAP) ≥ 238 dB/m, and excluded those with viral hepatitis coinfection or alcohol abuse. Severe MASLD was defined as the presence of MASH (cytokeratin-18 ≥ 130.5 U/L) and/or significant liver fibrosis (liver stiffness ≥ 7.1 kPa). Stool samples were collected for 16S rRNA gene sequencing to characterize gut microbiota composition. Functional predictions were generated using PICRUSt. The differential abundance of bacterial taxa and predicted functions were analyzed using a generalized linear model with a negative binomial distribution. Among 34 PWH with MASLD, 18 (53%) met the criteria for severe MASLD. Microbiota profiling revealed significant differences in bacterial genera between the PWH with and without severe MASLD. Enrichment was observed in the Ruminococcus gnavus group, Negativibacillus, Holdemanella, Subdoligranulum, the Eubacterium hallii group, and Butyricicoccus, while depletion was seen in Prevotella, Alloprevotella, Dialister, Catenibacterium, the Christensenellaceae R 7 group, Clostridium sensu stricto, Olsenella, Oscillospiraceae UCG-005, Libanicoccus, and the Eubacterium siraeum group. Predicted functional pathways related to fatty acid degradation, folate biosynthesis, and amino acids metabolism did not differ between groups. MASLD severity in PWH is associated with a distinct gut microbiota signature, though not with functional pathway alterations. Microbial profiling may complement existing non-invasive biomarkers for risk stratification in this high-risk population. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) significantly increases the risk of steatohepatitis and cirrhosis and multiple extrahepatic complications, in particular, cardiometabolic disease, including type 2 diabetes, atherosclerotic cardiovascular disease (CVD), and heart failure, with a significant negative impact on health-related quality of life, becoming a substantial economic burden. Moreover, cardiovascular events represent the leading cause of death in MASLD patients. A timely diagnosis stratifies patient for their risk. It can facilitate early lifestyle changes or pharmacological management of dysmetabolic conditions, thereby slowing disease progression, lowering cardiovascular risk, and preventing CVD and cirrhosis. In this narrative review, we will discuss the current knowledge on MASLD and metabolic dysfunction-associated steatohepatitis (MASH) pathophysiology, emphasizing their systemic nature, the link to CVD, and available and emerging treatment strategies. Full article

Background/Objectives: The growing prevalence of metabolic-associated steatotic liver disease (MASLD)/metabolic-associated steatohepatitis (MASH) is forecasted to be over 55% by 2040, representing a significant driver of cirrhosis and highlighting demand for effective therapeutic interventions. The therapeutic landscape is evolving with agents, like glucagon-like peptide-1 receptor agonists (GLP-1 RAs), under active investigation. A common concern across emerging therapies is potentially precipitating decompensation in patients with existing cirrhosis, necessitating careful consideration in this population. Case Presentation: A 46 y.o. female with obesity and cirrhosis from MASH and alcohol who underwent a deceased-donor liver transplant developed steatohepatitis within a year post-transplant after gaining 36 kg. Transient elastography revealed controlled attenuation parameter (CAP) 400 dB/m (S3 steatosis) and liver stiffness measurement (LSM) 61.2 kPa (advanced fibrosis). Follow-up biopsy confirmed severe steatohepatitis (NAS 7/8) and advanced fibrosis (F3), attributed to metabolic dysfunction without evidence of alcohol recurrence. She decompensated with ascites and varices, leading to transplant re-enlistment at MELD-Na 29. Despite two years of intensive lifestyle modification, losing 17 kg, and recompensation, her follow-up elastography showed persistent steatosis (S3) and advanced fibrosis (F4). Subsequent allograft biopsy revealed progression to cirrhosis (F4) with ongoing steatohepatitis (NAS 3/8). Tirzepatide was initiated for the development of type 2 diabetes, attributed to steroids used for immunosuppression. After 2 years on tirzepatide, she lost 43.1 kg. Shockingly, her follow-up elastography demonstrated fibrosis regression with LSM 5.5 kPa (F1) and steatohepatitis resolution with CAP 204 dB/m (S0). Follow-up liver biopsy confirmed fibrosis regression to F2-F3 and steatohepatitis resolution (NAS 1/8). Conclusions: This case challenges the widely accepted dogma that liver MASH cirrhosis is irreversible. Using multiple liver fibrosis monitoring modalities, cirrhosis reversal was demonstrated and attributed to mechanisms of GLP-1/GIP RA therapy. This study suggests that GLP-1/GIP RA may be safe in cirrhosis and may result in fibrosis regression. Full article

Liver sinusoidal endothelial cells (LSECs) are essential for preserving liver homeostasis. Metabolic dysfunction-associated steatotic liver disease (MASLD) encompasses a category of hepatic disorders characterized by excessive fat accumulation in the liver, known as steatosis. Over time, accumulated hepatic fat can induce inflammation of the liver (hepatitis). MASLD is among the most prevalent types of chronic liver disease. Obesity and Type 2 diabetes mellitus (T2DM) are frequent etiological factors of MASLD. In the absence of therapy, MASLD can lead to more severe hepatic conditions, which can be life-threatening. MASLD is noteworthy due to its potential progression to MASH and further severe liver impairment, including cirrhosis and hepatocellular carcinoma (HCC), a neoplastic progression. This narrative review examines the distinctive functions of LSECs in regulating immunologic responses, collagenization, and drug-sensitive bioreactivity in healthy livers, MASLD, and metabolic dysfunction-associated steatohepatitis (MASH), as well as in a human primary 3D model. We found that LSECs serve as crucial regulators of immunological equilibrium in the liver by inhibiting disproportionate immunologic activation, concurrently filtering tissue antigens, and engaging with immunologic cells, such as Kupffer cells (KCs) and T lymphocytes. In chronic diseases of the liver, LSECs experience cellular dysfunction, resulting in capillarization (focal to diffuse), loss of fenestrations (fenestrae), and the activation of pro-fibrotic signaling pathways, including transforming growth factor-beta (TGF-β). Indeed, TGF-β is crucial in activating hepatic stellate cells (HSCs), a process that facilitates the progression of liver disease toward fibrosis. In addition to examining the dynamic interplay between LSECs, specifically HSCs, and other liver cells throughout the progression of fatty liver–MASH, we suggest that LSECs may become a potential therapeutic target for modifying immune responses and averting fibrosis in hepatic disorders. The limitations of animal models are also highlighted and discussed. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), are among the most prevalent causes of chronic liver disease worldwide, closely linked to the global rise in overweight and obesity, type 2 diabetes, and metabolic syndrome. Until recently, treatment options were limited to lifestyle interventions, with no approved pharmacologic therapies. Resmetirom, a liver-directed, selective thyroid hormone receptor beta (THR-β) agonist, is a promising disease-modifying agent that targets hepatic lipid metabolism, inflammation, and fibrosis. Clinical trials, including the pivotal phase 3 MAESTRO-NASH and MAESTRO-NAFLD-1 trials, have demonstrated significant improvements in liver fat reduction, lipid profiles, histological endpoints, and health-related quality of life, with a favorable safety profile. In March 2024, the FDA granted accelerated approval of resmetirom for adults with MASH and moderate-to-advanced fibrosis, marking a significant milestone in MASLD treatment. This review discusses the mechanistic rationale, preclinical data, and pivotal clinical trial outcomes supporting resmetirom’s role in MASLD/MASH management, while outlining ongoing research needs, including long-term safety, pediatric evaluation, and biomarker development for optimized patient selection. Full article

Kupffer cells (KCs) play a pivotal role in the progression of metabolic-associated steatohepatitis (MASH). This study evaluated the impact of short-term KC depletion induced by gadolinium chloride (GdCl₃) in a rat model of MASH. The intervention with GdCl₃ effectively reduced KC markers CD68 and Clec4f, together with pro-inflammatory cytokines (IL-1β, TNFα, NOS2), without affecting anti-inflammatory markers (IL-10, MRC1). Histologically, GdCl₃ reduced hepatocyte ballooning and NAS despite persistent steatosis. KC depletion was associated with decreased oxidative stress markers (TBARS, 3-nitrotyrosine) and antioxidant enzyme activity (SOD, catalase). Additionally, markers of endoplasmic reticulum stress (ATF4, GRP78, CHOP, P58^IPK) and apoptosis (BAX/BCL2 ratio, cleaved caspase-3) were diminished. Despite these improvements, GdCl₃ had no effect on lipid or glucose metabolism in the liver, associated with persistent elevation of PTP1B expression induced by SRD intake. KC depletion, however, increased FGF21 expression. GdCl₃ treatment improved systemic insulin sensitivity and reduced fasting glucose and NEFA serum levels. In white adipose tissue, the treatment decreased adipocyte size, restored insulin signaling, and inhibited lipolysis (ATGL expression) without altering macrophage infiltration (IBA) or thermogenic protein levels (UCP1) in SRD rats. These findings suggest that KC depletion modulates liver-to-adipose tissue crosstalk, potentially through FGF21 signaling, contributing to improved systemic metabolic homeostasis of SRD animals. Full article

Metabolic dysfunction-associated steatohepatitis (MASH) constitutes a significant and progressive liver disease, characterized by a complex pathogenesis that involves dysbiosis of the gut microbiota. While the multifaceted nature of MASH is widely recognized, its underlying mechanisms remain the subject of active investigation. Contemporary research highlights the critical role of the gut–liver axis, suggesting that disturbances in the gut microbiome may contribute to the progression of the disease. Probiotics have notably emerged as a promising therapeutic approach for MASH, with the potential to modulate the gut microbiome and mitigate symptoms. This review aims to examine the alterations in the gut microbiome associated with MASH pathogenesis, the interaction of probiotics with the gut–liver axis, and their significance in the development and management of MASH. By synthesizing current evidence on the mechanisms of action of probiotics, clinical trials, and comparative efficacy of different strains, as well as existing controversies, challenges, and future research directions, this review seeks to establish a scientific foundation for probiotic-based interventions as an innovative therapeutic strategy for MASH. Full article