Search Results (543)

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

Background: Metabolic-dysfunction-associated steatotic liver disease (MASLD) is a major global health concern associated with insulin resistance, metabolic syndrome, and cardiovascular morbidity. Early identification of at-risk individuals through simple, non-invasive methods is essential, particularly in working populations. Objectives: This study aimed to assess and compare the diagnostic accuracy of four widely used anthropometric and metabolic indicators—body mass index (BMI), waist-to-height ratio (WtHR), triglyceride–glucose index (TyG), and waist–triglyceride index (WTI)—in identifying individuals at risk of metabolic-dysfunction-associated steatotic liver disease (MASLD), as determined by the Fatty Liver Index (FLI) and the Lipid Accumulation Product (LAP), within a large sample of Spanish workers. Methods: A cross-sectional analysis was performed on data from 386,924 Spanish employees aged between 18 and 69 years. Standardized anthropometric and laboratory measurements were obtained as part of routine occupational medical examinations conducted from 2021 to 2023. The presence of NAFLD was inferred using two validated surrogate markers: FLI and LAP. Receiver operating characteristic (ROC) curves and area under the curve (AUC) values were used to assess the discriminatory ability of each index, stratified by sex. Results: WTI and TyG demonstrated the highest diagnostic accuracy for both FLI- and LAP-defined NAFLD, with AUC values >0.95 in both sexes. WTI showed the best overall performance, followed closely by TyG. WtHR outperformed BMI but was less accurate than the metabolic indices. Sex-stratified analyses confirmed consistent patterns, with slightly higher AUCs for TyG and WTI in women. BMI consistently yielded the lowest discriminatory performance. Conclusions: WTI and TyG are superior to BMI and WtHR for non-invasive screening of MASLD in occupational settings. Their simplicity, low cost, and strong predictive value support their integration into routine workplace health surveillance. Sex-specific thresholds and prospective validation are warranted to enhance clinical application. Full article

Background: The COVID-19 pandemic disrupted healthcare systems globally, raising concerns about its negative impact on patients with chronic liver diseases by contributing to hepatic decompensations such as acute variceal bleeding (AVB). This study aimed to evaluate the impact of the COVID-19 pandemic on clinical outcomes in cirrhotic patients with AVB in Germany. Methods: This retrospective national multicenter study compared patients with cirrhosis and AVB treated at four tertiary care centers in Germany before (2016–2020) and during the pandemic (2020–2022). The primary endpoint was 6-week mortality, and secondary outcomes included infections, transfusion requirement and rebleeding. Results: The baseline characteristics of the 247 patients were largely comparable between the two groups, however metabolic dysfunction-associated steatotic liver disease was more prevalent during the pandemic compared to the pre-pandemic period (12.5% vs. 4.8%, p = 0.048). Only one patient tested positive for SARS-CoV-2. Six-week mortality (32.2% vs. 30.1%; p = 0.767) and rebleeding rates (22.8% vs. 22.3%; p = 1.000) did not differ significantly between groups. Interestingly, intubation rates, length of stay on the intensive care unit, post AVB infection rates and types of infection were also comparable (all p >0.05), while transjugular intrahepatic portosystemic shunt placement (TIPS) after bleeding was performed more frequently during the pandemic (23.2% vs. 11.3%, p = 0.019). Conclusions: Relevant patient-related AVB outcomes were unaffected during the COVID-19 pandemic. These findings suggest the resilience of critical AVB management practices in German tertiary centers. The increased use of TIPS and MASLD prevalence during the pandemic may reflect evolving clinical practice and patient profiles warranting further investigation. Full article

Lean metabolic dysfunction-associated steatotic liver disease (lean MASLD) challenges longstanding views that link hepatic steatosis primarily to obesity. Emerging as a distinct and under-recognized clinical entity, lean MASLD affects individuals with a normal body mass index (BMI), yet carries risks of cardiovascular disease, hepatocellular carcinoma, and liver-related mortality comparable to obesity-associated MASLD. The absence of overt metabolic dysfunction complicates diagnosis, revealing critical limitations in current screening frameworks centered on BMI. This review synthesizes evolving clinical insights and epidemiological trends in lean MASLD, and delineates its unique pathophysiological mechanisms. Recent advances in metabolomics have uncovered disease-specific disruptions in lipid and amino acid metabolism, bile acid signaling, and gut microbiota-derived metabolites. By integrating evidence from metabolic, genetic, and epigenetic domains, we identified promising biomarkers, and therapeutic targets that may support earlier detection and precision-guided treatment strategies. Full article

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is defined by the presence of hepatic steatosis and at least one cardiometabolic risk factor. Differences in the incidence of MASLD between men and women are primarily due to distinct metabolic and cardiovascular profiles. The aim of this observational study was to investigate the prevalence and characteristics of MASLD in men and women. Methods: The study included patients from the Polish Gallstone Surgery Registry diagnosed with MASLD according to current criteria. Results: Among 3419 patients, MASLD was diagnosed in 24.2%. Its prevalence was significantly higher in men (29.8%) than in women (21.9%) (p < 0.0001), with the highest incidence observed in men aged 70–79 (32.1%) and women aged 70–79 (33.3%). MASLD was associated with overweight in individuals aged < 50 years (OR 1.87; 95% CI: 1.11–3.14; p < 0.0186) and in those aged ≥ 50 years (OR 1.99; 95% CI: 1.48–2.68; p < 0.001), as well as with obesity in patients aged < 50 years (OR 6.53; 95% CI: 4.08–10.47; p < 0.001) and in those aged ≥ 50 years (OR 3.9; 95% CI: 2.92–5.22; p < 0.0001). Conclusions: In this study, MASLD was diagnosed more frequently in men than in women, and its incidence showed a positive association with increasing BMI. These findings indicate that excess body weight and sex are key predictors of MASLD, highlighting the need for individualized treatment strategies. 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 steatotic liver disease (MASLD) is characterized by hepatic lipid accumulation and insulin resistance, yet effective therapies remain limited. This study evaluated the hepatoprotective effects of Desmodium caudatum (Thunb.) DC. Extract (DCE) in vitro and in vivo. In 600 μM oleic acid (OA)-challenged HepG2 cells, DCE (25, 50, and 100 μg/mL) reduced lipid accumulation, oxidative stress, and glycogen depletion by modulating lipogenic and oxidative pathways. In a MASLD mouse model induced by high-fat diet (HFD)/streptozotocin (HFD/STZ), oral administration of DCE (100 or 200 mg/kg) for six weeks improved fasting glucose, serum lipids, and hepatic injury markers. Histology confirmed reduced steatosis, while Western blotting showed downregulation of SREBP-1, HMGCR, and ACC, and upregulation of CPT-1, PPARα, and phosphorylated AMPK. Additionally, DCE enhanced insulin signaling and restored hepatic glycogen synthesis through IRS-1, AKT, and GSK3β activation. These findings suggest that DCE ameliorates MASLD by regulating lipid and glucose metabolism, supporting its potential as a plant-based therapeutic strategy. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing public health concern influenced by both genetic and metabolic factors. Polygenic risk scores (PRSs), which combine the effects of known single-nucleotide polymorphisms (SNPs), may improve early risk stratification. We conducted an observational study on 298 MASLD patients: 148 from a Hepatology Unit and 150 from a Bariatric Surgery Unit. Genotyping was performed for the PNPLA3, TM6SF2, MBOAT7, and GCKR variants. A PRS was calculated and used to stratify patients by genetic risk. Liver fibrosis was assessed using the FIB-4 index, and a subset also underwent transient elastography. Clinical, biochemical, and anthropometric data were analyzed across genetic strata. PRSs showed positive correlations with AST, ALT, and FIB-4, indicating increased liver injury and fibrosis risk with higher genetic burden. Transaminases increased significantly across PRS quartiles (p < 0.05), and individuals with PRS > 0.532 exhibited elevated AST, ALT, and borderline FIB-4. Variant-specific associations included PNPLA3 with increased AST and MBOAT7 with higher hepatic steatosis (CAP). Subgroup analyses revealed distinct genetic and phenotypic patterns between the two clinical cohorts. These findings support the additive role of genetic risk in MASLD progression and underscore the value of polygenic profiling for the early identification and personalized management of high-risk patients. Full article

Background/Objectives: The incidence of metabolic-dysfunction-associated steatotic liver disease (MASLD) is on the rise worldwide. The purpose of this paper is to review the current and emerging trends in the management and treatment of this condition. Methods: A comprehensive literature review was conducted using PubMed and GoogleScholar, focusing on articles published within the last ten years. Results: As the incidence of MASLD rises worldwide, it is becoming ever more important to call attention to disease prevention and progression. Although weight loss, diet, and exercise play a major role, certain therapies including GLP-1 receptor agonists, resmetirom, lanifibranor, and FGF-3 analogs are showing promise when treating patients with MASLD. As more drugs become available, it will be important to note how these medications change the global outlook of this disease. Conclusions: Overall, the treatment landscape of MASLD is rapidly changing. Several phase 3 trials have revealed promising data when it comes to improving liver fibrosis and histology. This shift in treatment will provide new hope for patients and clinicians when treating this challenging disease. Full article

Background/Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) represents a significant global public health issue, affecting approximately 25% of the population and currently offering limited treatment options. Trimetazidine (TMZ) serves as a metabolic modulator that shifts cellular energy metabolism from fatty acid oxidation to glucose oxidation, thereby providing a novel therapeutic strategy aimed at addressing the underlying metabolic dysfunctions that contribute to the pathogenesis of MASLD. Our study aims to assess the efficacy of trimetazidine in improving hepatic steatosis, inflammation, and various metabolic parameters. Methods: In this double-masked, randomized controlled trial, 60 patients with confirmed MASLD diagnoses were randomly assigned in a 1:1 ratio to receive either trimetazidine 20 mg three times daily or a placebo, alongside lifestyle modifications, for 24 weeks. The trial was conducted in accordance with the Declaration of Helsinki and approved by the ethics committees of both participating institutions. We measured changes in hepatic steatosis, non-invasive fibrosis scores, inflammatory markers (including interleukin-6, tumor necrosis factor-alpha, and highly sensitive C-reactive protein), liver enzymes, and lipid profiles at baseline and at the end of the 24 weeks. Results: Hepatic steatosis decreased significantly, with controlled attenuation parameter scores from 352.5 to 302 dB/m in the TMZ group compared to the control (p < 0.001). TNF-α was reduced significantly in the TMZ group compared to the control group (p = 0.001). Fibrosis to AST score decreased from 0.49 to 0.25 in the TMZ group (p < 0.001). Aspartate aminotransferase decreased significantly compared to the control group (p 0.032). Notably, TMZ also imparted cardioprotective benefits, reducing total cholesterol by 14%, LDL by 17% (both p < 0.05), and triglycerides by 16% (p = 0.176). Conclusions: This groundbreaking trial supports the potential of trimetazidine as a promising therapeutic agent for MASLD, indicating substantial improvements in hepatic steatosis, inflammation, and metabolic disturbances. These findings underscore the urgency and importance of further multicenter trials to validate trimetazidine’s efficacy as a disease-modifying therapy for MASLD. Full article

Peroxisomes are cellular organelles involved in multiple metabolic processes, including lipid oxidation, lipid synthesis, and the metabolism of reactive oxygen species. Peroxisomal disorders arise from defects in peroxisomal biogenesis or peroxisomal enzymes. Patients with severe peroxisomal disorders often present with a range of distinctive physical features and congenital malformations, such as neuronal migration defects, renal cysts, and bony stippling in the patellae and long bones. Liver disease has also been reported in some patients with peroxisomal biogenesis disorders, although the exact molecular mechanisms underlying its development remain unclear. Metabolic dysfunction-associated steatotic liver disease (MASLD) is now recognised as one of the most prevalent causes of chronic liver disease globally, due to its widespread incidence and potential for serious complications. This review aims to highlight the possible involvement of peroxisomal defects in the pathogenesis of MASLD. Full article

Background/Objectives: Metabolic (dysfunction)-associated steatotic liver disease (MASLD), the hepatic consequence of metabolic syndrome, affects 30% of the global population. Studies in animals and humans investigating the effect of fructose on MASLD present conflicting findings, while in vitro methods often fail to add meaningful evidence due to acute exposures (<72 h) and non-physiological concentrations. This study aimed to determine the effect of fructose on triglyceride (TG) accumulation in HepG2 cells following acute and chronic exposures and assess its effect on the expression of genes related to de novo lipogenesis (DNL). Methods: TG concentration was measured after 48 h in response to fructose (20 mM) or glucose (20 mM), with or without a fatty acid mixture (oleic acid/palmitic acid 110 µM/55 µM), in low (5.5 mM)- and high (25.5 mM)-glucose media. To model chronic exposure, cells were maintained in fructose, glucose, or fatty acids for 28 days and the TG concentration was determined every 7 days. The effect of fructose on DNL regulators (SREBPF1, NR1H3, FASN, and ACACA) was determined using qPCR. Results: Neither fructose nor glucose, with or without fatty acids, changed the TG levels in cells at 48 h and the media glucose concentration had no effect on this result. Similarly, fructose did not increase TG levels after 28 days. While fructose and glucose did not affect key DNL genes at 6 h, the fatty acid mixture reduced FASN by 41%. Conclusions: This study shows that fructose did not significantly impact TG synthesis or DNL gene expression in the HepG2 cell model. Future studies should consider using primary human hepatocytes or more complex in vitro models. Full article

Background/Objectives: Gut microbiota has been implicated in the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD) and cardiovascular disease (CVD). This study aimed to identify associations between gut dysbiosis and MASLD, regarding body mass index (BMI) and subclinical coronary atherosclerosis (SCA). Methods: We conducted a cross-sectional study of 202 patients with MASLD who had no previous history of CVD. The severity of MASLD was evaluated using a magnetic resonance imaging-based method, and SCA was measured by assessing coronary artery calcification (CAC). Gut microbiota was assessed in fecal specimens using sequencing targeting the V4 region of the 16S rRNA gene. Results: Our results demonstrated that gut microbial profiles between low- and high-BMI groups (<30 vs. ≥30 kg/m²) differed significantly in beta-diversity, but not in alpha-diversity indices. At the genus level, we identified Megamonas, Sutterella, Catenibacterium, and Odoribacter, enriched in the high BMI group. Compared to the low CAC group (<100 AU), MASLD patients with high CAC scores (≥100 AU) exhibited enrichment in Ruminococcus gnavus, Bacteroides, and Lachnoclostridium, along with depletion of several short-chain fatty acid (SCFA)-producing bacteria, such as Faecalibacterium. Multivariate analysis demonstrated that older age, the presence of diabetes, high BMI, fibrosis stage F3-F4, and high plasma trimethylamine oxide (TMAO) levels were independently associated with a high CAC score in patients with MASLD. Conclusions: These data indicated that gut dysbiosis and related metabolites, in association with advanced liver disease, were potential contributors to the progression of SCA in obese patients with MASLD. Full article

Background and Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) is now widely acknowledged as belonging to the broader category of metabolic disorders, being closely associated with obesity, insulin resistance, and chronic systemic inflammation. Recent evidence indicates that in MASLD, alterations in the gut–liver axis—particularly increased intestinal permeability may serve as a crucial mechanistic link between metabolic dysfunction and hepatic steatosis. Zonulin, a physiological modulator of intestinal tight junctions, has been suggested as an indicator of compromised barrier integrity; however, its specific role in MASLD remains to be fully elucidated. Materials and Methods: We conducted a prospective observational study including 52 adult patients diagnosed with MASLD. Hepatic steatosis was evaluated using the SteatoTest (FibroMax panel), while fecal zonulin levels were measured by ELISA at baseline. Clinical, anthropometric, and metabolic parameters were assessed. We used ROC curve analysis to explore zonulin’s predictive value for moderate-to-severe steatosis (≥S2). Results: Elevated fecal zonulin (>107 ng/mL) occurred in 26.9% of participants. In a binary logistic model with SteatoTest ≥ S2 as outcome, zonulin was independently associated with clinically significant steatosis (OR per 1 ng/mL = 1.017; 95% CI 1.002–1.032; p = 0.029). Discrimination for ≥S2 was AUC = 0.680 (95% CI 0.535–0.825; p = 0.015). The Youden-optimal cut-off was 57.0 ng/mL (sensitivity 68.2%, specificity 63.3%) versus 40.9%/83.3% at the manufacturer’s 107 ng/mL threshold. Conclusions: Fecal zonulin shows modest discriminatory ability for steatosis and is best used as an adjunct to non-invasive assessment; cohort-specific calibration (57.0 ng/mL) outperformed the generic 107 ng/mL threshold. Full article

Background and Objectives: This study evaluated the correlation between hyperferritinemia and markers of liver steatosis, fibrosis, and risk of liver-related events in patients with type 2 diabetes mellitus (T2DM) and Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD). Material and Methods: This study included 271 patients that underwent a comprehensive medical evaluation. Hyperferritinemia was defined by values >200 ng/mL (females) and >300 ng/mL (males). Liver fibrosis and steatosis were evaluated by several non-invasive indexes, and Liver Risk Score (LRS) was calculated to determine the risk of liver-related events. Their correlation with serum ferritin was investigated by bivariate and multiple regression analyses. Receiver Operating Characteristic (ROC) analyses were used to assess the accuracy to predict advanced fibrosis and increased LRS. Statistical significance was set at p < 0.05. Results: The median serum ferritin level was 94.4 [128.1] ng/mL. Metabolic hyperferritinemia was present in 12.54% of patients. Patients with hyperferritinemia had higher liver enzymes, HbA1c, HOMA-IR, and increased markers of liver steatosis and fibrosis, with a higher prevalence of advanced fibrosis (OR = 3.744 [1.481, 9.460], p = 0.0081). LRS was highest in patients with hyperferritinemia (7.99 ± 2.01 vs. 7.12 ± 1.32 vs. 6.54 ± 1.06, p < 0.0001). Serum ferritin levels were correlated with LRS (β = 0.190 [0.001; 0.003], p < 0.001), liver fibrosis (Fibrotic NASH Index) (β = 0.198 [0.000; 0.001], p < 0.001), and steatosis, while haptoglobin concentrations were correlated negatively with them. Serum ferritin predicted the moderate risk of liver-related outcomes with an acceptable performance (area under the ROC curve = 0.726 [0.590; 0.862], p = 0.001). Conclusions: Hyperferritinemia is associated with liver fibrosis and steatosis and a higher risk of liver-related events in patients with T2DM and MASLD. Full article