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Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease. Body mass index (BMI) is the most used obesity index but has important limitations. The weight-adjusted waist index (WWI) is a novel obesity metric and accurately reflects body composition. We explored the association of WWI with all-cause and cardiovascular disease (CVD) mortality in MASLD. Methods: Adult participants with MASLD were included from NHANES 1999-2018. WWI was calculated by dividing the waist circumference (WC) by the square root of body weight. MASLD was diagnosed by the presence of hepatic steatosis and at least one cardiometabolic risk factor in the absence of other causes of steatosis. A fatty liver index =60 suggested the presence of hepatic steatosis. Mortality data was obtained by prospectively linking to the National Death Index. Multivariate Cox proportional hazards regression analyses were used to explore these associations and multiple adjustment models were constructed including crude, partial, and fully adjusted models. Results: After adjusting for all covariates including BMI, WWI remained positively and linearly associated with all-cause and CVD mortality in MASLD (hazard ratios [HR] 1.247 and 1.218, respectively). Higher WWI was associated with a significantly increased risk of mortality (both p for trend <0.05). There was an "obesity paradox" between BMI and all-cause mortality in MASLD, with significantly lower all-cause mortality in those with overweight/obesity compared to normal BMI (HR 0.625 and 0.596, respectively, p for trend = 0.024), and no association between BMI and CVD mortality. Interaction analyses indicated that these associations were influenced by several demographic variables and disease status. Time-dependent receiver operating characteristic curves indicated that the predictive value of WWI for mortality in MASLD was higher than that of BMI, WC, and waist-to-height ratio across all follow-up durations. Conclusions: WWI was positively and linearly associated with all-cause and CVD mortality in MASLD, whereas BMI did not accurately reflect mortality risk. WWI provided the optimal predictive value for mortality compared to traditional obesity indicators. These findings emphasize the potential use of WWI as a novel obesity indicator for mortality risk assessment, stratification, and prevention in MASLD. [ABSTRACT FROM AUTHOR]

Recent evidence suggests that adaptive immune cells are important contributors to metabolic dysfunction–associated steatotic liver disease (MASLD, formerly nonalcoholic fatty liver disease, NAFLD). In liver biopsies from MASLD patients, the accumulation of intrahepatic B cells is positively correlated with the MASLD activity score. Hepatic B-cell infiltration is observed in experimental models of metabolic dysfunction-associated steatohepatitis (MASH, formerly non-alcoholic steatohepatitis, NASH). Intrahepatic B2 cells have been shown to contribute to MASLD/MASH by activating T cells, macrophages and hepatic stellate cells, and by producing pathogenic IgG antibodies. In mice fed a MASH diet, selective depletion of B2 cells reduces steatohepatitis and fibrosis. Intestinal B cells are metabolically activated in MASH and promote T-cell activation independently of TCR signaling. In addition, B cells have been shown to contribute to liver fibrosis by activating monocyte-derived macrophages through the secretion of IgA immunoglobulins. Furthermore, our recent study indicates that certain B cell subsets, very likely regulatory B cells, may play a protective role in MASLD. This review summarizes the molecular mechanisms of B cell functions and discusses future research directions on the different roles of B cells in MASLD and MASH. [ABSTRACT FROM AUTHOR]

Introduction: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the leading chronic liver disease worldwide. Emerging evidence suggests a close crosstalk between iron status and metabolic syndrome. Therefore, this cohort study aimed to investigate the relationship between serum iron status and all-cause mortality in individuals with MASLD. Methods: A total of 3393 subjects with MASLD identified by ultrasound from the Third National Health and Nutrition Examination Survey (NHANES III) were included in the analysis. Iron status indicators included serum iron, ferritin, transferrin saturation, total iron binding capacity, hemoglobin concentration, mean corpuscular hemoglobin, mean corpuscular volume, and mean corpuscular hemoglobin concentration. Cox proportional hazards models and restricted cubic spline models with adjustment for multiple confounders were applied. Stratified analyses were performed by sex and age. Results: During a median of 26.08 years of follow-up, high serum iron and transferrin saturation were significantly associated with reduced all-cause mortality in a linear pattern (P overall<0.001). Compared with the lowest quartile, individuals with serum iron and transferrin saturation in the third or fourth quartile intervals had a 20-40% reduction in long-term mortality. However, there was no independent association of serum ferritin, total iron binding capacity, and red blood cell indices with all-cause mortality in MASLD. Conclusion: This study suggests that serum iron and transferrin saturation have the potential to serve as independent biomarkers of all-cause mortality in patients with MASLD and implies the therapeutic potential of modifying iron status. [ABSTRACT FROM AUTHOR]

Summary To evaluate the relationship between serum gamma‐glutamyl transferase (GGT) levels and fatty pancreas in subjects with concurrent obesity, insulin resistance and metabolic dysfunction‐associated steatotic liver disease (MASLD) without a history of pancreatitis. From March 2019 to September 2021, 31 adult subjects with concurrent obesity and MASLD were recruited as part of the study investigating the biological impact of bariatric surgery and lifestyle modification on obesity. Chemical shift encoded MRI of the abdomen, LiverMultiScan, anthropometric, clinical and blood biochemistry analyses were performed prior to any intervention at baseline. GGT (p <.001) was significantly different between those ‘with fatty pancreas’ and ‘without fatty pancreas’ groups. GGT (p <.001) was significantly different between those ‘with both metabolic syndrome and fatty pancreas’ and those ‘with metabolic syndrome but without fatty pancreas.’ GGT (p <.001) was also significantly different between those ‘with both diabetes and fatty pancreas’ and those ‘with diabetes but without fatty pancreas’. Logistic regression analysis showed that abnormal GGT levels (p = .010) and Hypertension (p = .045) were significant independent predictors of fatty pancreas. GGT was associated with fatty pancreas by an odds ratio 7.333 (95% [CI]: 1.467–36.664), while the AUROC of GGT in determining fatty pancreas was 0.849. Elevation in serum GGT might be a potential marker to identify fatty pancreas. [ABSTRACT FROM AUTHOR]

ABSTRACT Background and Aims Methods Results Conclusions Metabolic dysfunction‐associated steatotic liver disease (MASLD) is linked to various intrahepatic and extrahepatic diseases, but its association with severe infectious disease remains to be investigated.We analysed data from the Shanghai Suburban Adult Cohort and Biobank, encompassing participants enrolled in 2016 and 2017 with available abdominal ultrasonography data, and followed them up until December 2022 (median follow‐up = 5.71 years). We categorised the participants into the MASLD group and those without steatotic liver disease (non‐SLD). Multivariable‐adjusted Cox regression was used to estimate hazard ratios (HR) for severe infections in patients with MASLD compared to the non‐SLD group. Cumulative incidences were calculated while accounting for competing risks (non‐infection‐related deaths). Mediation analyses were performed to explore the roles of cardiometabolic risk factors in the association between MASLD and severe infections.Among the 33 072 eligible participants (mean age 56.37 years; 38.20% male), 11 908 (36.01%) were diagnosed with MASLD at baseline. Severe infections occurred in 912 (7.66%) MASLD patients and 1258 (5.94%) non‐SLD. The rate of severe infections per 1000 person‐years was higher in MASLD patients (13.58) than in comparators (10.48) (fully adjusted HR 1.18, 95% CI 1.07–1.30). The most frequent infections in MASLD were respiratory (7.25/1000 person‐years) and urinary tract infections (2.61/1000 person‐years). The 5‐year cumulative incidence of severe infections was 6.79% (95% CI 6.36–7.26) in MASLD and 5.08% (95% CI 4.79–5.38) in comparators. Cardiometabolic risk factors, including waist circumference, triglycerides and HbA1C, partially mediate the association between MASLD and severe infections.Patients with MASLD were at significantly higher risk of incident severe infections compared to the non‐SLD group. Future studies are needed to elucidate the mechanisms linking MASLD to severe infections. [ABSTRACT FROM AUTHOR]

Background and Aim Methods Results Conclusions Although nonalcoholic fatty liver disease (NAFLD) and lipoprotein(a) [Lp(a)] are associated with cardiovascular diseases, existing data on Lp(a) in NAFLD are conflicting. The aim of this systematic review and meta‐analysis was to summarize and compare data on circulating Lp(a) between NAFLD patients and non‐NAFLD controls.A systematic literature search was performed in PubMed, Scopus, and Cochrane Library. This meta‐analysis included 18 studies containing data on 74 691 individuals (20 220 patients with NAFLD and 54 471 controls).Circulating Lp(a) was similar between patients with NAFLD and controls (standardized mean difference [SMD] 0.09; 95% confidence interval [95% CI] −0.21, 0.38). The heterogeneity among studies was high (I2 = 100%); no publication bias was detected (Egger's test P = 0.941). However, in subgroup analysis, Lp(a) was lower in NAFLD patients than controls, when Lp(a) was measured with nephelometry (SMD ‐0.26; 95% CI ‐0.46, −0.06), but not turbidimetry; this analysis also resulted in mild reduction of heterogeneity within the subgroup of nephelometry (I2 = 87%). The sensitivity analyses, based on the exclusion of studies with Newcastle‐Ottawa Scale score ≤6 (n = 5), studies in which liver biopsy was used for NAFLD diagnosis (n = 4) or studies that adopted the criteria of metabolic dysfunction‐associated fatty liver disease (n = 2), and meta‐regression analysis did not explain the high heterogeneity among studies.Overall, circulating Lp(a) was similar between NAFLD patients and non‐NAFLD controls; however, patients with NAFLD had lower circulating Lp(a) compared with controls, when Lp(a) was measured with nephelometry. These results should be cautiously interpreted, because of the high heterogeneity among studies. [ABSTRACT FROM AUTHOR]

Background/Objectives: The role of body composition parameters in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) with presence and severity of coronary artery calcification (CAC) is still not fully elucidated. We aimed to evaluate the impact of computed tomography (CT)-based body composition parameters in patients with MASLD with CAC severity. Methods: In this multicenter study, 1870 individuals underwent cardiac CT for the detection of CAC as well as ultrasonography for the diagnosis of hepatic steatosis. The presence of CAC was defined by a CAC score threshold of >0, while severe CAC was defined by a threshold of >300. Using the abdominal cross-sectional CT images at the L3 vertebra level, we analyzed the skeletal muscle index, visceral to subcutaneous adipose tissue ratio, and muscle density using the Hounsfield unit. Results: Of 648 patients with MASLD, the proportions of presence of CAC and severe CAC were 45.2% and 9.9%, respectively. Visceral obesity was not associated with the presence of CAC after adjustment for age, sex, smoking, statin therapy, type 2 diabetes, and advanced fibrosis (adjusted odds ratio (aOR), 1.38; 95% confidence interval (CI), 0.86–2.23; p = 0.180). However, visceral obesity was independently associated with severe CAC after adjustment for several metabolic risk factors (aOR, 3.54; 95% CI, 1.25–14.90; p = 0.039), and adjustment for atherosclerotic cardiovascular disease risk scores (aOR, 3.74; 95% CI, 1.31–15.79; p = 0.032). Conclusions: Visceral obesity may serve as a novel prognostic CT-based radiological biomarker for patients with MASLD with severe CAC. [ABSTRACT FROM AUTHOR]

Background/Objectives: Body composition (BC) affects the risk of developing metabolic dysfunction-associated steatotic liver disease (MASLD) and hypertension (HTN). Currently, dual-energy X-ray absorptiometry (DEXA) is considered the gold standard for assessing BC, even though it has some limitations, including immobility, ionizing radiation, and patient weight restrictions. The aim of the study was to evaluate the correlations of BC parameters measured by bioelectrical impedance analysis (BIA) with those measured by DEXA in patients with MASLD and HTN. Methods: Overall, 78 patients with MASLD and HTN underwent the following study procedures: compilation of an anamnesis, physical examination of a patient, laboratory tests, abdominal ultrasound, BIA, DEXA, and anthropometric measurements. Results: The agreement between BIA and DEXA in diagnosing reduced skeletal muscle mass (SMM) in patients with MASLD and HTN was moderate (kappa values were 0.440 and 0.404 in males and females, respectively). Significant strong direct correlations were found between fat mass (FM) and body fat percentage measured by BIA with corresponding measurements by DEXA (p < 0.001 for both). The area under the receiver operating characteristic curves (AUC) of SMM to body weight ratios calculated using BIA data were 0.834 and 0.929 for reduced appendicular SMM determined by DEXA in males and females with MASLD and HTN, respectively. Conclusions: In conclusion, BIA is an easy-to-use and widely available tool for assessing SMM and FM in patients with MASLD and HTN, demonstrating reliable agreement with DEXA measurement results and completely free of its limitations. [ABSTRACT FROM AUTHOR]

ABSTRACT Background and Aims Methods and Results Metabolic dysfunction‐associated steatotic liver disease (MASLD) is a heterogenous clinical and histopathological entity, where multiple metabolic co‐factors are intertwined with high interindividual variability. The impact and severity of each factor (including obesity and type 2 diabetes) define a systemic dysmetabolism that can lead to either advanced liver disease and its complication (including hepatocellular carcinoma and clinical events related to portal hypertension) or extrahepatic events: incident cardiovascular disease, chronic kidney disease and extrahepatic cancers. The balance between environmental factors and genetic susceptibility has unique implications in MASLD: the intermittent injury of metabolic co‐factors, their fluctuation over time and their specific management, are counterbalanced by the presence of gene variants that can significantly impact the disease at multiple levels. The I148M variant in the PNPLA3 gene is the most investigated genetic susceptibility that induces a more severe steatohepatitis, enhanced fibrogenesis and can shape the incidence of long‐term clinical events regardless of, or worsened by, other metabolic risk factors.In this review, we will summarise the updated evidence on the natural history of MASLD accounting for classical metabolic risk factors, the role of PNPLA3 in clinical sub‐phenotyping (e.g., ‘lean MASLD’), impact on disease severity and fibrosis progression, as well as its role for prognostication, alone or in combination with non‐invasive tools into polygenic risk scores. [ABSTRACT FROM AUTHOR]

Background/Objectives: The diverse effects of fructose and glucose on the progression of metabolic dysfunction-associated steatotic liver disease remain uncertain. This study investigated the effects, in animal models, of high-fat diets (HFDs) supplemented with either glucose or fructose. Methods: Six-week-old, male C57BL/6J mice were randomly allocated to four groups: normal diet (ND), HFD, HFD supplemented with fructose (30% w/v, HFD + Fru), and HFD supplemented with glucose (initially 30%, HFD + Glu). After 24 weeks, liver and plasma samples were gathered for analysis. In addition, 39 patients with obesity undergoing bariatric surgery with wedge liver biopsy were enrolled in the clinical study. Results: The HFD + Glu group consumed more water than did the HFD and HFD + Fru groups. Thus, we reduced the glucose concentration from 30% at baseline to 15% at week 2 and 10% starting from week 6. The HFD + Fru and HFD + Glu groups had a similar average caloric intake (p = 0.463). The HFD increased hepatic steatosis, plasma lipid levels, lipogenic enzymes, steatosis-related oxidative stress, hepatic inflammation, and early-stage liver fibrosis. Supplementation with fructose or glucose exacerbated liver damage, but no significant differences were identified between the two. The expression patterns of hepatic ceramides in HFD-fed mice (with or without supplemental fructose or glucose) were similar to those observed in patients with obesity and severe hepatic steatosis or metabolic dysfunction–associated steatohepatitis. Conclusions: Fructose and glucose similarly exacerbated liver damage when added to an HFD. Ceramides may be involved in the progression of hepatic lipotoxicity. [ABSTRACT FROM AUTHOR]

Background and Aims: Metabolic liver disease is associated with obesity, insulin resistance, cardiovascular disease, and metabolic disorders. A Mediterranean diet (MD), known for its anti-inflammatory and antioxidant properties, is effective in managing various chronic diseases, including liver diseases. This study aimed to explore the influence of adherence to the MD on the risk of chronic metabolic diseases, including steatotic liver disease (SLD), metabolic dysfunction-associated steatotic liver disease (MASLD), and alcohol-related liver diseases (ALDs). Methods: This retrospective cohort study analyzed 5395 individuals from a single center between 2020 and 2022, grouped by adherence to the MD using the Korean Mediterranean Diet Adherence Score (K-MEDAS). MASLD score, ALD, and cardiovascular risk factors were also assessed. Statistical analyses were performed using 1:1 exact matching and multiple regression to compare the less adherent (K-MEDAS 0–7) and highly adherent (K-MEDAS 8–13) groups. Results: Adjusting for confounding variables, high adherence to the MD was significantly associated with lower rates of SLD (odds ratio [OR] 0.818, 95% confidence interval [CI] 0.700–0.957, p = 0.012), MASLD (OR 0.839, 95% CI 0.714–0.986, p = 0.033), and ALD (OR 0.677, 95% CI 0.671–0.683, p < 0.001). Post-propensity score matching analysis revealed that the highly adherent group exhibited significantly lower triglyceride levels, triglyceride and glucose index, atherogenic Index of Plasma, and Framingham risk scores than the less adherent group. Conclusions: Good adherence to the MD considerably reduces the risk of SLD, MASLD, and ALD, underscoring its protective effects and potential to prevent metabolic liver diseases and their complications. [ABSTRACT FROM AUTHOR]

ABSTRACT Background Methods Results Conclusion Metabolic dysfunction‐associated steatotic liver disease is a significant driver of the increasing global burden of chronic liver disease. This study aimed to describe the temporal trends and inequalities of liver complications related to metabolic dysfunction‐associated steatotic liver disease (LC‐MASLD) by geographical region, age and sex during 1990–2021.Global Burden of Diseases Study 2021 data were analysed to assess LC‐MASLD incidence, prevalence, mortality and disability‐adjusted life years (DALYs). Temporal trends during 1990–2021 were measured by ‘estimated annual percentage change’ (EAPC). Inequalities of LC‐MASLD burden across countries were evaluated by the slope index of inequality (SII) and the relative concentration index (RCI).During 1990–2021, LC‐MASLD rose annually by 0.73% in incidence and prevalence, 0.19% in mortality and 0.16% in DALYs. In 2021, the Middle East and North Africa had the highest incidence and prevalence and Andean and Central Latin America had the highest mortality and DALY rates. While LC‐MASLD incidence was earliest in the 15–19 age group, both prevalence and DALY rates peaked at 75–79 years for both sexes. Inequalities in mortality and DALYs by countries' socioeconomic development index increased during 1990–2021, demonstrated by a decline in SII from −0.09 to −0.56 per 100 000 for mortality and from 1.41 to −7.74 per 100 000 for DALYs. RCI demonstrated similar findings.The LC‐MASLD burden is increasing globally, especially in economically disadvantaged countries, with widening disease inequalities during 1990–2021. Effective prevention and subregional interventions are crucial, with a specific focus on resource optimisation for disadvantaged populations. [ABSTRACT FROM AUTHOR]

Despite the implementation of preventive measures to counteract the obesity epidemics, the prevalence of childhood obesity is still alarming all over the world. Childhood obesity is the most common risk factor for both cardiovascular and metabolic diseases. In fact, an earlier onset of obesity can cause a greater risk of adiposity tracking across the lifespan and consequently a longer exposure to cardiometabolic risk factors. Accumulating evidence provided by prospective and intervention studies demonstrated the link between pediatric obesity and selected subclinical signs of cardiovascular damage (atherosclerosis and left ventricular hypertrophy), or fatal and not fatal cardiovascular events as early as 40 years of age. The numerous guidelines and scientific documents published in the last years demonstrate the relevance of assessing cardiometabolic risk factors in children and adolescents with OB. This Position paper, released by experts of the "Childhood Obesity study group" within the Italian Society for Pediatric Endocrinology and Diabetology, aims to review the assessment of cardiometabolic risk factors and comorbidities in children and adolescents with OW/OB on the light of the most recent scientific evidence. The main recommendations are: (a) early detection of comorbidities, including hypertension, dyslipidemia, prediabetes/type 2 diabetes, metabolic dysfunction-associated steatotic liver disease, polycystic ovary syndrome, inactivity, obstructive sleep apnea and decline in kidney function; (b) weight loss treatment, which is associated with a reduction of all cardiometabolic risk factors; (c) specific treatment of comorbidities, through lifestyle modifications or pharmacological treatment added to lifestyle for suitable individuals; d). monitoring comorbidities for mitigating future morbidity and mortality. [ABSTRACT FROM AUTHOR]

Metabolic dysfunction-associated steatotic liver disease （MASLD） is the most prevalent chronic liver disease globally, encompassing the entire spectrum of fatty liver pathogenesis. It progresses from simple steatosis to metabolic-associated steatohepatitis （MASH）, involving injury and inflammation， with or without fibrosis， ultimately leading to cirrhosis and hepatocellular carcinoma, which affects approximately a quarter of the world's population. Liver biopsy remains the gold standard for differentiating MASH from steatosis and assessing advanced fibrosis. However, its limitations, including costliness, invasiveness, and sampling bias, have spurred the development of noninvasive diagnostic techniques. In addition, there are no FDA-approved drugs for the treatment of MASLD. Enumerating noninvasive diagnostic markers that have the potential to replace liver biopsy were summarized, and the current treatment options for MASLD were discussed, with clinical trials designed to evaluate the efficacy and safety of single agents or combination therapies to halt or reverse disease progression, which could provide new insights for the clinical diagnosis and treatment of MASLD. [ABSTRACT FROM AUTHOR]

The influence of thyroid hormone (TH) on liver metabolism has attracted the attention of pharmacologists seeking new treatments for metabolic dysfunction-associated steatotic liver disease (MASLD), an increasingly common metabolic disorder. In this context, the selective induction of autophagy by TH in preclinical models has been identified as a promising mechanism. In this process, TH clears intrahepatic fat through lipophagy while protecting against inflammation and mitochondrial damage in hepatocytes via mitophagy. Furthermore, TH-induced aggrephagy may represent a protective mechanism to mitigate the development of MASLD-associated hepatocellular carcinoma. Considering the defects in autophagy observed during the progression of human MASLD, the induction of autophagy by TH, its metabolites, and its analogs represent a novel strategy to combat hepatic damage across the MASLD spectrum. [ABSTRACT FROM AUTHOR]

Simple Summary: Consumption of extra virgin olive oil (EVOO) is associated with many beneficial effects on human health as a result of its phenolic-derived compounds. This review explores the hepatoprotective properties and mechanisms of action of tyrosol and oleocanthal from extra virgin olive oil. Both compounds demonstrate antioxidant, anti-inflammatory, and modulatory effects on liver metabolism that improve chronic liver diseases, such as dysfunction-associated steatotic liver disease (MASLD) and liver fibrosis, and their progression to liver cancer. Mechanistic studies have suggested that these compounds exert their hepatoprotective effects through the regulation of multiple cellular pathways, including those involved in the antioxidant response and lipid metabolism. Understanding these mechanisms may provide valuable information for the development of therapeutic agents based on their chemical structures that are useful to improve liver health and prevent liver-related disorders. The Mediterranean diet and consumption of EVOO are associated with multiple beneficial effects for human health, e.g. reduction in cardiovascular risk and mortality, improvement in the lipid profile, and the prevention of chronic diseases, such as cancers and neurodegenerative diseases. In EVOO, more than 30 different phenolic-derived compounds have been identified, representing one of the most promising bioactive classes in olive oil. This review explores the hepatoprotective properties of two of these compounds, tyrosol and oleocanthal, focusing on their mechanisms of action. Recent studies have shown that these compounds, which share a similar chemical structure with a hydroxyl group attached to an aromatic hydrocarbon ring, can potentially mitigate chronic liver diseases, such as MASLD and liver fibrosis, as well as their progression to liver cancer. Consequently, they deserve attention for future pharmacological drug development. In vitro and in vivo studies have suggested that these compounds exert these effects through the regulation of cellular pathways involved in antioxidant response, lipid metabolism, transcription factor activity, and NF-κB signaling. Understanding the mechanisms underlying the hepatoprotective properties of tyrosol and oleocanthal may provide valuable information for the development of therapeutic agents based on their chemical structures capable of targeting chronic liver diseases. [ABSTRACT FROM AUTHOR]

Background: Chronic liver diseases (CLD), cirrhosis, and hepatocellular carcinoma (HCC) cause significant morbidity and mortality. Unfortunately, patients with CLD often go undiagnosed until progression to cirrhosis and HCC. We aimed to determine the proportion of primary care patients with severe liver disease outcomes that had missed or delayed CLD diagnoses. Methods: This retrospective cohort study evaluated primary care patients with a diagnosis of cirrhosis, HCC, or other severe liver disease outcome between 2012 and 2021. The outcomes of interest were missed and delayed diagnoses of CLD, defined as the absence of a CLD diagnosis (missed) or first appearance of CLD on the same day as the cirrhosis diagnosis (delayed). Univariate analyses were performed to describe the cohort. Multivariable logistic regression models analyzed the association of aminotransferase elevations with the outcomes of interest. Results: Of 667 patients with cirrhosis or HCC, 133 (20%) had a missed CLD diagnosis, and 243 (36%) had a delayed CLD diagnosis. Alcohol-related liver disease was the most common etiology among patients with missed/delayed diagnoses. A lower proportion of patients with missed/delayed diagnoses had an elevation in ALT or AST compared to patients with timely diagnoses (61% vs. 77%, p < 0.001). Elevated aminotransferase values were associated with lower odds of a missed/delayed diagnosis (OR 0.47; 95%CI 0.34–0.66). Conclusions: Most patients with cirrhosis or HCC had missed or delayed diagnoses of CLD in the context of probable overreliance on aminotransferase elevation for CLD detection. Enhanced screening for high prevalence CLD, especially alcohol, in primary care is needed. [ABSTRACT FROM AUTHOR]

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) and polycystic ovary syndrome (PCOS) share several pathophysiological mechanisms. While the prevalence of MASLD has been extensively studied in PCOS populations, the occurrence of PCOS among female adolescents with transient elastography (TE)-confirmed MASLD in pediatric hepatology settings remains poorly characterized. This cross-sectional study aims to address this knowledge gap and elucidate potential clinical and biochemical differences between female adolescents with MASLD and comorbid PCOS compared to those without PCOS. Methods: The study cohort included 45 female adolescents with TE-diagnosed MASLD. Comparative analyses of clinical and laboratory parameters were performed between those with (n = 19) and those without (n = 26) comorbid PCOS, diagnosed according to the Rotterdam criteria. Results: Adolescents with MASLD and comorbid PCOS exhibited significantly higher weight, lower height, and increased waist circumference compared to those without PCOS. Additionally, the prevalence of acanthosis nigricans was significantly higher in the PCOS group (68.4% versus 34.6%, p = 0.025). Regarding laboratory parameters, serum phosphorus levels and liver enzymes—including aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyl transferase—were significantly lower in adolescents with comorbid PCOS. However, no significant differences were observed in lipid profiles, glucose metabolism, or novel non-invasive biomarkers of MASLD. Conclusions: This study reveals distinct clinical and biochemical profiles in female adolescents with MASLD and comorbid PCOS compared to those without PCOS. These findings have the potential to inform and refine future screening protocols and diagnostic algorithms for these interrelated conditions, specifically tailored to pediatric hepatology settings. [ABSTRACT FROM AUTHOR]

Simple Summary: Metabolic syndrome (MetS), metabolic dysfunction-associated steatotic liver disease (MASLD), and diabetes are all linked to Cholangiocarcinoma (CCA) in various ways. MASLD may have an increased risk of intrahepatic-CCA, whereas untreated patients with shorter diabetes durations were more likely to develop biliary tract cancer (BTC). More research is needed to understand how reproductive hormones cause BTC. BTC patients may be at increased intrinsic cardiovascular risk of neoplastic/non-neoplastic cardiac complications. Therefore, early detection/prevention of chronic liver disease, as well as intervention studies, will almost certainly be required to determine whether improvements in MetS, weight loss, and diabetes therapy can reduce CCA risk and progression. BTC overall incidence is globally increasing. CCA, including its subtypes, is a form of BTC. MetS, obesity, MASLD, and diabetes are all linked to CCA in interconnected ways. The link between obesity and CCA is less well-defined in Eastern countries as compared to Western. Although more research is needed to determine the relationship between MASLD and extrahepatic CCA (eCCA), MASLD may be a concurrent risk factor for intrahepatic CCA, particularly in populations with established or unidentified underlying liver disease. Interestingly, the risk of biliary tract cancer (BTC) seemed to be higher in patients with shorter diabetes durations who were not treated with insulin. Therefore, early detection and prevention of chronic liver disease, as well as additional intervention studies, will undoubtedly be required to determine whether improvements to MetS, weight loss, and diabetes therapy can reduce the risk and progression of BTC. However, further studies are needed to understand how reproductive hormones are involved in causing BTC and to develop consistent treatment for patients. Finally, it is critical to carefully assess the cardiological risk in BTC patients due to their increased intrinsic cardiovascular risk, putting them at risk for thrombotic complications, cardiovascular death, cardiac metastasis, and nonbacterial thrombotic endocarditis. This review aimed to provide an updated summary of the relation between the abovementioned cardio-metabolic conditions and BTC. [ABSTRACT FROM AUTHOR]

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent chronic liver condition worldwide, demanding further investigation into its pathogenesis. Circular RNAs (circRNAs) are emerging as pivotal regulators in MASLD processes, yet their pathological implications in MASLD remain poorly understood. This study focused on elucidating the role of circular RNA ribonucleotide reductase subunit M2 (circRRM2) in MASLD progression. In this study, we used both in vitro and in vivo MASLD models using long-chain-free fatty acid (FFA)-treated hepatocytes and high-fat diet (HFD)-induced MASLD in mice, respectively. We determined the expression patterns of circRRM2, microRNA-142-5p (miR-142-5p), and neuregulin 1 (NRG1) in livers of MASLD-afflicted mice and MASLD hepatocytes by RT-qPCR. Dual-luciferase reporter assays verified the binding relationships among circRRM2, miR-142-5p, and NRG1. We conducted further analyses of their roles in MASLD hepatocytes and modulated circRRM2, miR-142-5p, and NRG1 expression in vitro by transfection. Our findings were validated in vivo. The results demonstrated reduced levels of circRRM2 and NRG1, along with elevated miR-142-5p expression in MASLD livers and hepatocytes. Overexpression of circRRM2 downregulated lipogenesis-related genes and decreased triglycerides accumulation in livers of MASLD mice. MiR-142-5p, which interacts with circRRM2, effectively counteracted the effects of circRRM2 in MASLD hepatocytes. Furthermore, NRG1 was identified as a miR-142-5p target, and its overexpression mitigated the regulatory impact of miR-142-5p on MASLD hepatocytes. In conclusion, circRRM2, via its role as a miR-142-5p sponge, upregulating NRG1, possibly influenced triglycerides accumulation in both in vitro and in vivo MASLD models. NEW & NOTEWORTHY: CircRRM2 expression was downregulated in free fatty acid (FFA)-challenged hepatocytes and high-fat diet (HFD) fed mice. Overexpressed circular RNA ribonucleotide reductase subunit M2 (circRRM2) attenuated metabolic dysfunction-associated steatotic liver disease (MASLD) development by suppressing FFA-induced triglycerides accumulation. CircRRM2 targeted microRNA-142-5p (miR-142-5p), which served as an upstream inhibitor of neuregulin 1 (NRG1) and collaboratively regulated MASLD progression. [ABSTRACT FROM AUTHOR]

Computational quantification reduces observer‐related variability in histological assessment of metabolic dysfunction‐associated steatotic liver disease (MASLD). We undertook stain‐free imaging using the SteatoSITE resource to generate tools directly predictive of clinical outcomes. Unstained liver biopsy sections (n = 452) were imaged using second‐harmonic generation/two‐photon excitation fluorescence (TPEF) microscopy, and all‐cause mortality and hepatic decompensation indices constructed. The mortality index had greater predictive power for all‐cause mortality (index >.14 vs. .31 vs.

Background & Aims: Metabolic dysfunction‐associated steatohepatitis (MASH) is a growing cause of chronic liver disease, characterized by fat accumulation, inflammation and fibrosis, which development depends on mitochondrial dysfunction and oxidative stress. Highly expressed in the liver during fasting, peroxisome proliferator‐activated receptor‐γ coactivator‐1α (PGC‐1α) regulates mitochondrial and oxidative metabolism. Given the relevant role of mitochondrial function in MASH, we investigated the relationship between PGC‐1α and steatohepatitis. Methods: We measured the hepatic expression of Pgc‐1α in both MASH patients and wild‐type mice fed a western diet (WD) inducing steatosis and fibrosis. We then generated a pure C57BL6/J strain loss of function mouse model in which Pgc‐1α is selectively deleted in the liver and we fed these mice with a WD supplemented with sugar water that accurately mimics human MASH. Results: We observed that the hepatic expression of Pgc‐1α is strongly reduced in MASH, in both humans and mice. Moreover, the hepatic ablation of Pgc‐1α promotes a considerable reduction of the hepatic mitochondrial respiratory capacity, setting up a bioenergetic harmful environment for liver diseases. Indeed, the lack of Pgc‐1α decreases mitochondrial function and increases inflammation, fibrosis and oxidative stress in the scenario of MASH. Intriguingly, this profibrotic phenotype is not linked with obesity, insulin resistance and lipid disbalance. Conclusions: In a MASH model the hepatic ablation of Pgc‐1α drives fibrosis independently from lipid and glucose metabolism. These results add a novel mechanistic piece to the puzzle of the specific and crucial role of mitochondrial function in MASH development. [ABSTRACT FROM AUTHOR]

Background and Aim: LIVERSTAT is an artificial intelligence‐based noninvasive test devised to screen for and provide risk stratification for metabolic dysfunction‐associated fatty liver disease (MAFLD) by using simple blood biomarkers and anthropometric measurements. We aimed to study LIVERSTAT in patients with MAFLD and to explore its role for the diagnosis of advanced fibrosis. Methods: This is a retrospective study of data from MAFLD patients who underwent a liver biopsy. Patients with type 2 diabetes who underwent transient elastography and had liver stiffness measurement (LSM) < 5 kPa were included as patients with no fibrosis. Among these patients, controlled attenuation parameter <248 dB/m was considered as no steatosis. The LIVERSTAT results were generated based on a proprietary algorithm, blinded to the histological and LSM data. Results: The data for 350 patients were analyzed (mean age 53 years, 45% male, advanced fibrosis 22%). The sensitivity, specificity, positive predictive value, negative predictive value, and misclassification rate of LIVERSTAT to diagnose advanced fibrosis were 90%, 50%, 30%, 95%, and 42%, respectively. The corresponding rates for Fibrosis‐4 score (FIB4) were 56%, 83%, 44%, 89%, and 22%, respectively. When LSM was used as a second test, the corresponding rates for LIVERSTAT were 60%, 97%, 76%, 94%, and 8%, respectively, while the corresponding rates for FIB4 were 38%, 99%, 83%, 89%, and 11%, respectively. Conclusion: LIVERSTAT had a higher negative predictive value compared with FIB4 and a lower misclassification rate compared with FIB4 when used in a two‐step approach in combination with LSM for the diagnosis of advanced fibrosis. [ABSTRACT FROM AUTHOR]

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a complex and multifactorial disease. Dark tea exhibits great potential for various bioactivities for metabolic health. In this study, we aimed to evaluate therapeutic effects and the underlying mechanisms of dark tea wine (DTW) on MASLD with obesity. A rat model of MASLD was established by high-fat diet and administered with different doses of DTW as an intervention. The biomarkers of lipid metabolism and oxidative stress in rats were tested. The weight of organs and adipose tissues and the expressions of nuclear factor erythroid 2-like 2 (Nrf2) and heme oxygenase-1 (HO-1) were investigated based on the pathology and western blot analysis. We found that DTW enhanced antioxidant capacity via activating the Nrf2/HO-1 signaling pathway, further markedly triggering inhibition of weight gain, reduction of lipid dysfunction, and improvement of pathological characteristics to ameliorate MASLD induced by high-fat diet. These results suggest that DTW is a promising functional supplement for prevention and treatment of MASLD and obesity. [ABSTRACT FROM AUTHOR]

Aim: To elucidate the effects of sleep parameters and renal function on the risk of developing new‐onset severe metabolic dysfunction‐associated steatotic liver disease (MASLD). Materials and Methods: The primary analysis involved a cohort of 305 257 participants. Multivariable Cox models were employed to calculate hazard ratios and 95% confidence intervals. Traditional mediation and two‐step Mendelian randomization (MR) analyses were conducted to assess the associations and mediating roles of renal function indicators between sleep and new‐onset severe MASLD. Results: Poor sleep score and renal function biomarker score (RFS) were associated with an increased risk of new‐onset severe MASLD (all ptrend <0.001). Participants with poor sleep patterns and the highest RFS had a 5.45‐fold higher risk of new‐onset severe MASLD, compared to those with healthy sleep patterns and the lowest RFS (p < 0.001). The RFS could explain 10.08% of the correlations between poor sleep score and risk of new‐onset severe MASLD. Additionally, MR analyses supported a causal link between insomnia and new‐onset severe MASLD and revealed a mediating role of chronic kidney disease in the connection between insomnia and new‐onset severe MASLD risk. Conclusions: This study highlights the independent and combined associations of sleep parameters and renal function indicators with new‐onset severe MASLD, underscoring the bidirectional communication of the liver–kidney axis and providing modifiable strategies for preventing MASLD. [ABSTRACT FROM AUTHOR]

Magnetic resonance elastography (MRE) is recognized as the most precise imaging technology for assessing liver fibrosis in individuals with metabolic dysfunction-associated steatotic liver disease (MASLD). We aimed to investigate the clinical factors and pathological characteristics that may impact LSM in MASLD patients. This cross-sectional study recruited 124 patients who concurrently performed MRE, MRI-PDFF, and biopsy-proven MASLD. Linear regression models, Spearman's correlation, and subgroup analysis were employed to identify the variables affecting LSM. The AUROC (95 % CI) of MRE for diagnosing fibrosis stage ≥ 1, 2, 3, and 4 was 0.80 (0.70–0.90), 0.76 (0.66–0.85), 0.92 (0.86–0.99), and 0.99 (0.99–1.00), with corresponding cutoffs of 2.56, 2.88, 3.35, and 4.76 kPa, respectively. Multivariate analyses revealed that AST was the only independent clinical variable significantly correlated with LSM. Furthermore, LSM exhibited a notable association with the grade of lobular inflammation and hepatocellular ballooning. Subgroup analysis showed that when AST ≥ 2 ULN or inflammation grade ≥ 2, LSM of patients with early fibrosis stages showed a slight but significant increase. MRE demonstrates significant diagnostic accuracy in predicting liver fibrosis stages for MASLD patients, especially for advanced liver fibrosis and cirrhosis. However, elevated AST and the severity of liver inflammation may impact its accuracy in staging early liver fibrosis. [ABSTRACT FROM AUTHOR]

Introduction: Nonalcoholic fatty liver disease (NAFLD), now termed metabolic dysfunction-associated steatotic liver disease (MASLD), is an escalating health concern linked to obesity and type 2 diabetes. Despite liver biopsy being the gold standard, its invasiveness underscores the need for noninvasive diagnostic methods. Methods: A cross-sectional study was performed to assess MASLD using the noninvasive OWLiver® serum lipidomics test in a cohort of 117 patients with severe obesity undergoing bariatric surgery, comparing outcomes with liver biopsy. Exclusions (n = 24) included insufficient data, liver disease etiology other than MASLD, corticosteroid treatment, excessive alcohol consumption, low glomerular filtration rate, and declination to participate. Comprehensive laboratory tests, demographic assessments, and liver biopsies were performed. Serum metabolites were analyzed using OWLiver®, a serum lipidomic test that discriminates between healthy liver, steatosis, metabolic dysfunction-associated steatohepatitis (MASH), and MASH with fibrosis ≥2 by means of three algorithms run sequentially. Results: Liver biopsy revealed a MASLD prevalence of 95.7%, with MASH present in 28.2% of cases. OWLiver® demonstrated a tendency to diagnose more severe cases. Body mass index (BMI), rather than the presence of type 2 diabetes, emerged as the sole independent factor linked to the probability of concordance. Therefore, the all-population concordance of 63.2% between OWLiver® and liver biopsy notably raised to 77.1% in patients with a BMI <40 kg/m2. These findings suggest a potential correlation between lower BMI and enhanced concordance between OWLiver® and biopsy. Conclusion: This study yields valuable insights into the concordance between liver biopsy and the noninvasive serum lipidomic test, OWLiver®, in severe obesity. OWLiver® demonstrated a tendency to amplify MASLD severity, with BMI values influencing concordance. Patients with BMI <40 kg/m2 may derive optimal benefits from this noninvasive diagnostic approach. [ABSTRACT FROM AUTHOR]

Metabolic dysfunction-associated fatty liver disease (MAFLD) is the liver manifestation of a metabolic syndrome and is highly prevalent in the general population. There has been significant progress in non-invasive tests for MAFLD, from the diagnosis of fatty liver and monitoring of liver fat content in response to intervention, to evaluation of liver fibrosis and its change over time, and from risk stratification of patients within the context of clinical care pathways, to prognostication. Various non-invasive tests have also been developed to assess for fibrotic metabolic dysfunction-associated steatohepatitis, which has emerged as an important diagnostic goal, particularly in the context of clinical trials. Non-invasive tests can be used to diagnose clinically significant portal hypertension so that intervention can be administered to reduce the risk of decompensation. Furthermore, the use of risk stratification algorithms can identify at-risk patients for hepatocellular carcinoma surveillance. Beyond the liver, various tests that evaluate cardiovascular disease risk, assess sarcopenia and measure patient reported outcomes, can be utilized to improve the care of patients with MAFLD. This review provides an up-to-date overview of these non-invasive tests and the limitations of liver biopsy in the management of patients with MAFLD. [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases worldwide. In recent years, a new terminology and definition of metabolic dysfunction-associated fatty liver disease (MAFLD) has been proposed. Compared to the NAFLD definition, MAFLD better emphasizes the pathogenic role of metabolic dysfunction in the development and progression of this highly prevalent condition. Metabolic disorders, including overweight/obesity, type 2 diabetes mellitus (T2DM), atherogenic dyslipidemia and hypertension, are often associated with systemic organ dysfunctions, thereby suggesting that multiple organ damage can occur in MAFLD. Substantial epidemiological evidence indicates that MAFLD is not only associated with an increased risk of liver-related complications, but also increases the risk of developing several extra-hepatic diseases, including new-onset T2DM, adverse cardiovascular and renal outcomes, and some common endocrine diseases. We have summarized the current literature on the adverse effect of MAFLD on the development of multiple extrahepatic (cardiometabolic and endocrine) complications and examined the role of different metabolic pathways and organ systems in the progression of MAFLD, thus providing new insights into the role of MAFLD as a multisystem metabolic disorder. Our narrative review aimed to provide insights into potential mechanisms underlying the known associations between MAFLD and extrahepatic diseases, as part of MAFLD as a multisystem disease, in order to help focus areas for future drug development targeting not only liver disease but also the risk of extrahepatic complications. [ABSTRACT FROM AUTHOR]

Background and aims: Non-alcoholic fatty liver disease (NAFLD) is present in lean people. However, the magnitude of the prognostic hepatic and cardiovascular risk in these patients compared to non-lean counterparts remains unclear. We aimed to investigate this topic, and to explore whether these risks change based on factors related to NAFLD severity. Methods: PubMed and Embase databases were searched for cohort studies (published through April 2024) that evaluated liver and cardiovascular (CV) outcomes in lean and non-lean individuals with NAFLD and reported unadjusted or adjusted data. We pooled risk ratios (RRs) or hazard ratios (HRs) using a random-effects modeling and performed subgroup and meta-regressions analyses. Results: We identified 22 studies with over 1 million NAFLD patients (13.0% were lean). Lean NAFLD showed a similar risk of liver-related events in unadjusted analysis (RR 1.08, 95% CI 0.79–1.49, I2 = 31%), but a higher risk in adjusted analysis (HR 1.66, 95% CI 1.17–2.36, I2 = 83%) compared to non-lean NAFLD. Lean NAFLD had a higher risk of liver-related mortality (RR 2.22, 95% CI 1.57–3.15, I2 = 0%; HR 2.26, 95% CI 1.14–4.51, I2 = 0%). For CV outcomes, lean NAFLD had a lower risk of any cardiovascular disease in unadjusted analysis (RR = 0.82, 95% CI 0.70–0.95, I2 = 88%), but similar risk in adjusted analysis (HR 0.89, 95% CI 0.77–1.02, I2 = 78%), and similar risk of cardiovascular mortality (RR 1.09, 95% CI 0.71–1.66, I2 = 85%; HR 1.26, 95% CI 0.89–1.78, I2 = 46%) compared to non-lean NAFLD. Conclusions: Lean NAFLD patients have worse liver outcomes, but similar CV outcomes compared to non-lean NAFLD patients, highlighting the importance of monitoring both groups closely. [ABSTRACT FROM AUTHOR]

Introduction: Current guidelines recommend the use of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD), especially in patients with comorbid diabetes and obesity. This study investigated the effects of GLP-1RAs on hepatic steatosis and fibrosis in patients with MASLD, as measured by changes in vibration-controlled transient elastography (VCTE) and other clinical parameters in a real-world clinical setting. Methods: We conducted a single-center, retrospective analysis of 96 patients with MASLD from a multidisciplinary care clinic who completed VCTE at baseline and follow-up within 6–24 months to compare changes in controlled attenuation parameter (CAP) and liver stiffness measurement (LSM), as well as other metabolic markers, between GLP-1RA users and nonusers using two-sample t-tests and Wilcoxon rank-sum tests. We also assessed whether improvements in hepatic steatosis, defined as a change in CAP >38 dB/m as previously described in the literature, were associated with improvement in fibrosis. Results: GLP-1RA use resulted in significant improvements in weight (−8.1 kg vs. −3.5 kg, P = 0.009), body mass index (BMI) (−2.9 kg/m2 vs. −1.3 kg/m2, P = 0.012), alanine aminotransferase (−15.0 IU/L vs. −4.0 IU/L, P = 0.017), aspartate aminotransferase (−5.0 IU/L vs. −1.0 IU/L, P = 0.021), glycated hemoglobin (HbA1c) (−0.7% vs. 0.1%, P = 0.019), and CAP (−59.9 dB/m vs. −29.1 dB/m, P = 0.016). Responders also had significant improvements in weight (−9.2 kg vs. −1.9 kg, P < 0.001), BMI (−3.3 kg/m2 vs. −0.7 kg/m2, P < 0.001), diastolic blood pressure (−6.1 mmHg vs. −0.7 mmHg, P = 0.028), HbA1c (−0.8% vs. 0.3%, P < 0.001), and LSM (−1.5 kPa vs. 0.1 kPa, P < 0.001). Conclusions: Patients with MASLD treated with GLP-1RAs showed significant improvements in hepatic steatosis and multiple other metabolic parameters, with weight loss as the proposed mechanism for this liver improvement. In addition, change in CAP >38 dB/m was associated with improvements in LSM and other metabolic parameters, suggesting the clinical utility of VCTE in the surveillance of MASLD. [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease (NAFLD), recently proposed to be renamed to metabolic dysfunction-associated steatotic liver disease (MASLD), is a major global public health concern, affecting approximately 25–30% of the adult population and possibly leading to cirrhosis, hepatocellular carcinoma, and liver transplantation. The liver is involved in the actions of sex steroids via their hepatic metabolism and production of the sex hormone-binding globulin (SHBG). Liver disease, including NAFLD, is associated with reproductive dysfunction in men and women, and the prevalence of NAFLD in patients with hypogonadism is considerable. A wide spectrum of possible pathophysiological mechanisms linking NAFLD and male/female hypogonadism has been investigated. As therapies targeting NAFLD may impact hypogonadism in men and women, and vice versa, treatments of the latter may affect NAFLD, and an insight into their pathophysiological pathways is imperative. This paper aims to elucidate the complex association between NAFLD and hypogonadism in men and women and discuss the therapeutic options and their impact on both conditions. [ABSTRACT FROM AUTHOR]

The global epidemic of metabolic diseases has led to the emergence of metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH), which pose a significant threat to human health. Despite recent advances in research on the pathogenesis and treatment of MASLD/MASH, there is still a lack of more effective and targeted therapies. Extracellular vesicles (EVs) discovered in a wide range of tissues and body fluids encapsulate different activated biomolecules and mediate intercellular communication. Recent studies have shown that EVs derived from the liver and adipose tissue (AT) play vital roles in MASLD/MASH pathogenesis and therapeutics, depending on their sources and intervention types. Besides, adipose-derived stem cell (ADSC)-derived EVs appear to be more effective in mitigating MASLD/MASH. This review presents an overview of the definition, extraction strategies, and characterisation of EVs, with a particular focus on the biogenesis and release of exosomes. It also reviews the effects and potential molecular mechanisms of liver- and AT-derived EVs on MASLD/MASH, and emphasises the contribution and clinical therapeutic potential of ADSC-derived EVs. Furthermore, the future perspective of EV therapy in a clinical setting is discussed.

Abstract Background We explored the changes in metabolic dysfunction-associated steatotic liver disease (MASLD) severity over time by analyzing data from the placebo arms of randomized controlled trials (RCTs), focusing on the presence of diabetes. Methods RCTs on MASLD that included a placebo arm were identified using a systematic search of the literature. Primary outcomes were changes in hepatic steatosis and fibrosis. Results The meta-analysis included 8 RCTs involving 386 patients without diabetes and 24 RCTs involving 637 patients with diabetes. The pooled estimate of mean change in steatosis grade was − 0.1 in patients without diabetes, and − 0.37 in patients with diabetes (P = 0.066). The mean change in fibrosis stage was 0.05 in patients without diabetes, and − 0.03 in patients with diabetes (P = 0.359). The mean change in nonalcoholic fatty liver disease activity score was − 0.55 in patients without diabetes, and − 1.50 in patients with diabetes (P = 0.100). The mean change in ALT and AST were significantly larger in patients without diabetes compared to those with diabetes (P

Abstract Objectives To explore the impact of hepatic steatosis measured by MRI-proton density fat fraction (MRI-PDFF) on liver stiffness measurement (LSM) value and its diagnostic performance for staging liver fibrosis in patients with chronic hepatitis B (CHB). Methods A total of 914 patients with CHB who underwent liver biopsy and MRI-PDFF were retrospectively reviewed. The influence of MRI-PDFF on LSM value was assessed using univariate and multivariate linear analyses. To assess the influence of liver steatosis on the diagnostic performance of LSM, a series of ROC analyses were performed and compared by stratifying patients into non-steatosis (PDFF

Abstract Background Non-Alcoholic Fatty Liver Disease, recently better recognised as Metabolic Dysfunction–Associated Steatotic Liver Disease, is the most prevalent form of chronic liver disease at present time. It is estimated to impact 32% of the world's population, hence representing a significant health burden. Aim of the work To assess the significance of plasma Lipocalin-2 (LCN2) levels in the diagnosis and prognosis of NAFLD patients. Patients and methods In this retrospective case–control study we recruited 102 subjects aged between 18 and 70 years. The included participants were split into two study groups. Group I: 51 NAFLD patients (61% men, 39% females) and Group II: 51 healthy controls (51% men and 49% females), for whom plasma LCN2 levels were assessed and correlated with NAFLD fibrosis score, FIB4 and fatty liver index. Results In this study, LCN2 levels in NAFLD patients were significantly greater compared to individuals in the control group (p

Backgrounds/Aims Transmembrane 6 superfamily member 2 (TM6SF2) E167K variant is closely associated with the occurrence and development of metabolic dysfunction-associated steatotic liver disease (MASLD). However, the role and mechanism of TM6SF2 E167K variant during MASLD progression are not yet fully understood. Methods The Tm6sf2167K knock-in (KI) mice were subjected to high-fat diet (HFD). Hepatic lipid levels of Tm6sf2167K KI mice were detected by lipidomics analysis. Thin-layer chromatography (TLC) was used to measure the newly synthesized triglyceride (TG) and phosphatidylcholine (PC). Results The TM6SF2 E167K variant significantly aggravated hepatic steatosis and injury in HFD-induced mice. Decreased polyunsaturated PC level and increased polyunsaturated TG level were found in liver tissue of HFD-induced Tm6sf2167K KI mice. Mechanistic studies demonstrated that the TM6SF2 E167K variant increased the interaction between TM6SF2 and PNPLA3, and impaired PNPLA3-mediated transfer of polyunsaturated fatty acids (PUFAs) from TG to PC. The TM6SF2 E167K variant increased the level of fatty acid-induced malondialdehyde and reactive oxygen species, and decreased fatty acid-downregulated cell membrane fluidity. Additionally, the TM6SF2 E167K variant decreased the level of hepatic PC containing C18:3, and dietary supplementation of PC containing C18:3 significantly attenuated the TM6SF2 E167K-induced hepatic steatosis and injury in HFD-fed mice. Conclusions The TM6SF2 E167K variant could promote its interaction with PNPLA3 and inhibit PNPLA3-mediated transfer of PUFAs from TG to PC, resulting in the hepatic steatosis and injury during MASLD progression. PC containing C18:3 could act as a potential therapeutic supplement for MASLD patients carrying the TM6SF2 E167K variant.

The influence of thyroid hormone (TH) on liver metabolism has attracted the attention of pharmacologists seeking new treatments for metabolic dysfunction-associated steatotic liver disease (MASLD), an increasingly common metabolic disorder. In this context, the selective induction of autophagy by TH in preclinical models has been identified as a promising mechanism. In this process, TH clears intrahepatic fat through lipophagy while protecting against inflammation and mitochondrial damage in hepatocytes via mitophagy. Furthermore, TH-induced aggrephagy may represent a protective mechanism to mitigate the development of MASLD-associated hepatocellular carcinoma. Considering the defects in autophagy observed during the progression of human MASLD, the induction of autophagy by TH, its metabolites, and its analogs represent a novel strategy to combat hepatic damage across the MASLD spectrum.

Abstract Despite the implementation of preventive measures to counteract the obesity epidemics, the prevalence of childhood obesity is still alarming all over the world. Childhood obesity is the most common risk factor for both cardiovascular and metabolic diseases. In fact, an earlier onset of obesity can cause a greater risk of adiposity tracking across the lifespan and consequently a longer exposure to cardiometabolic risk factors. Accumulating evidence provided by prospective and intervention studies demonstrated the link between pediatric obesity and selected subclinical signs of cardiovascular damage (atherosclerosis and left ventricular hypertrophy), or fatal and not fatal cardiovascular events as early as 40 years of age. The numerous guidelines and scientific documents published in the last years demonstrate the relevance of assessing cardiometabolic risk factors in children and adolescents with OB. This Position paper, released by experts of the “Childhood Obesity study group” within the Italian Society for Pediatric Endocrinology and Diabetology, aims to review the assessment of cardiometabolic risk factors and comorbidities in children and adolescents with OW/OB on the light of the most recent scientific evidence. The main recommendations are: (a) early detection of comorbidities, including hypertension, dyslipidemia, prediabetes/type 2 diabetes, metabolic dysfunction-associated steatotic liver disease, polycystic ovary syndrome, inactivity, obstructive sleep apnea and decline in kidney function; (b) weight loss treatment, which is associated with a reduction of all cardiometabolic risk factors; (c) specific treatment of comorbidities, through lifestyle modifications or pharmacological treatment added to lifestyle for suitable individuals; d). monitoring comorbidities for mitigating future morbidity and mortality.

Abstract We aimed to compare the associations of metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated fatty liver disease (MAFLD) with coronary artery calcification (CAC). Patients who simultaneously underwent ultrasonography to diagnose hepatic steatosis and cardiac computed tomography to detect CAC were included. The presence and severity of CAC were defined with CAC-score thresholds of > 0 and > 300, respectively, and patients were divided into the following groups: no MASLD or MAFLD (reference), MASLD-only, MAFLD-only, and overlapping groups. Overall, 1,060/2,773 (38.2%) patients had CAC, of which 196 (18.5%) had severe CAC. The MASLD and MAFLD prevalence rates were 32.6% and 45.2%, respectively, with an overlap of 30.7%. In an ASCVD risk score-adjusted model, both MASLD (adjusted odd ratios [aOR], 1.21; 95% confidence interval [CI], 1.02–1.44; p = 0.033) and MAFLD (aOR 1.20; 95% CI 1.01–1.42, p = 0.034) were associated with CAC, whereas only MASLD (aOR 1.38; 95% CI 1.01–1.89, p = 0.041) was associated with severe CAC. Compared to the reference group, the overlapping group showed an association with CAC (aOR 1.22; 95% CI 1.01–1.47; p = 0.038); however, the MASLD and MAFLD subgroups did not differ in their association with CAC. MASLD may predict a higher risk of ASCVD more effectively than MAFLD.

Objective: To investigate the impact of metabolic dysfunction-associated steatotic liver disease (MASLD) on the efficacy of immune checkpoint inhibitor (ICI)-based therapy in patients with chronic hepatitis B (CHB)-related hepatocellular carcinoma (HCC). Methods: A total of 155 patients with CHB-related HCC who received ICI–based therapy (in the Department of Hepatology, Tianjin Second People’s Hospital and Department of Hepatobiliary Oncology, Tianjin Medical University Cancer Institute & Hospital) between April 2021 and December 2023 were evaluated. Patients were divided into two groups: MASLD concurrent with CHB [MASLD-CHB] (n = 38), and CHB (n = 117). Results: The median progression-free survival (PFS, 6.9 months vs. 9.3 months; P = 0.001), progressive disease (57.89% vs. 37.61%; P = 0.028), and disease control rate (42.11% vs. 62.39%; P = 0. 028) in the MASLD-CHB group were significantly worse than the CHB group. The median overall survival was not attained. The percentage of CD4+PD1+ (17. 56% vs. 8.89%; P < 0.001) and CD8+PD1+ T cells (10.50% vs. 7.42%; P = 0.005) in patient samples from the MASLD-CHB group were significantly higher than the CHB group. Concurrent MASLD [hazard ratio (HR) = 1.921; 95% CI, 1.138–3.245; P = 0.015] and alpha-fetoprotein levels after 3 months of treatment (HR = 2.412; 95% CI, 1.360–4.279; P = 0.003) were independent risk factors for PFS in all patients. Conclusions: ICI-based therapy in patients with CHB-related HCC and concurrent MASLD resulted in poorer efficacy and shorter PFS compared to patients with CHB-related HCC alone.

Abstract Background Metabolic dysfunction-associated steatotic liver disease (MASLD) patients are at an elevated risk of developing severe coronavirus disease 2019 (COVID-19). The objective of this study was to assess antibody responses and safety profiles six months after the third dose of the inactivated acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine in MASLD patients. Methods This study included MASLD patients and healthy volunteers without a history of SARS-CoV-2 infection. Blood samples were collected six months after receiving the third dose of the inactivated vaccine to measure the levels of neutralizing antibodies (NAbs) and anti-spike IgG antibodies against SARS-CoV-2. Results A total of 335 participants (214 MASLD patients and 121 healthy volunteers) were enrolled. The seroprevalence of NAb was 61.7% (132 of 214) in MASLD patients and 74.4% (90 of 121) in healthy volunteers, which was a significant difference (p = 0.018). Statistically significant differences in IgG seroprevalence were also observed between MASLD patients and healthy volunteers (p = 0.004). Multivariate analysis demonstrated that the severity of MASLD (OR, 2.97; 95% CI, 1.32–6.68; p = 0.009) and age (OR, 1.03; 95% CI, 1.01–1.06; p = 0.004) were independent risk factors for NAb negativity in MASLD patients. Moderate/severe MASLD patients had a lower NAb seroprevalence than mild MASLD patients (45.0% vs. 65.5%, p = 0.016). Conclusion Lower antibody responses were observed in MASLD patients six months after their third dose of the inactivated vaccine than in healthy volunteers, providing further assistance in monitoring patients who are more vulnerable to hypo-responsiveness to SARS-CoV-2 vaccines.

Fan Zhang,1– 3 Wenjian Li1,4 1Changzhou Clinical College, Xuzhou Medical University, Changzhou, Jiangsu, People’s Republic of China; 2Department of Endocrinology, Changzhou Third People’s Hospital, Changzhou, Jiangsu, People’s Republic of China; 3Department of Clinical Nutrition, Changzhou Third People’s Hospital, Changzhou, Jiangsu, People’s Republic of China; 4Department of Urology, Changzhou Third People’s Hospital, Changzhou, Jiangsu, People’s Republic of ChinaCorrespondence: Wenjian Li, Department of Urology, Changzhou Third People’s Hospital, 300 Lanling North Road, Changzhou, Jiangsu, 213001, People’s Republic of China, Tel +86-0519-82009011, Email 760020240117@xzhmu.edu.cnObjective: This study examined the relationship between metabolic dysfunction-associated steatotic liver disease (MASLD) and urinary incontinence in adult women and evaluated the potential contribution of the fatty liver index (FLI) in this context.Methods: The study utilized data from the National Health and Nutrition Examination Survey (NHANES) database, spanning from 2001 to 2018. The study included 17,221 adult female participants. Individuals exhibiting FLI values of 60 or greater were diagnosed with hepatic steatosis. Incontinence type and MASLD status were evaluated by analyzing questionnaire data and calculating the FLI. Logistic regression models were employed to examine the correlation between FLI, MASLD, and urinary incontinence, with potential confounding variables controlled through multivariate adjustment models. Furthermore, restricted cubic spline curve (RCS) modeling and subgroup analysis were employed to elucidate the relationship between variables further.Results: The median age of participants in the MASLD group was higher than that of the non-MASLD group (53 vs 46 years, P < 0.001). The findings indicated a positive association between FLI and MASLD and the risk of urinary incontinence. Specifically, the risk of stress urinary incontinence (SUI), urgency urinary incontinence (UUI), and mixed urinary incontinence (MUI) all increased significantly with increasing quartiles of FLI (OR 2.44, 1.91, 2.30, respectively, P < 0.001). In the multivariate-adjusted model, SUI, UUI, and MUI risk was 76%, 50%, and 69% higher in patients with MASLD than those without MASLD. RCS analysis demonstrated a significant nonlinear positive correlation between FLI and the risk of SUI, UUI, and MUI, respectively.Conclusion: This study’s findings indicate a significant association between MASLD and the risk of developing urinary incontinence. Additionally, the results suggest that FLI and MASLD may act as independent risk factors for urinary incontinence.Keywords: metabolic dysfunction-associated steatotic liver disease, urinary incontinence, fatty liver index, adult women, correlation study

Abstract Metabolic dysfunction-associated steatotic liver disease (MASLD), previously termed nonalcoholic fatty liver disease (NAFLD), poses a significant global health challenge due to its increasing prevalence and strong association with cardiovascular disease (CVD). This comprehensive review summarizes the current knowledge on the MASLD-CVD relationship, compares analysis of how different terminologies for fatty liver disease affect cardiovascular (CV) risk assessment using different diagnostic criteria, explores the pathophysiological mechanisms connecting MASLD to CVD, the influence of MASLD on traditional CV risk factors, the role of noninvasive imaging techniques and biomarkers in the assessment of CV risk in patients with MASLD, and the implications for clinical management and prevention strategies. By incorporating current research and clinical guidelines, this review provides a comprehensive overview of the complex interplay between MASLD and cardiovascular health.

Abstract Metabolic dysfunction-associated steatotic liver disease (MASLD) brings heavy clinical and economic burdens to patients worldwide. High fasting plasma glucose (HFPG) was proven to be an important modifiable risk factor. However, the global burden distribution of HFPG-attributable MASLD has not been fully studied. This study aimed to describe the epidemiological distribution and trends of the burden of HFPG-attributable MASLD worldwide. The data source was the 2021 Global Burden of Disease Study. Descriptive statistics were mainly conducted using disability-adjusted life years (DALYs) and deaths of HFPG-attributable MASLD from 1990 to 2021, as well as their age-standardized rates (ASRs) and population-attributable fractions. Subgroup analyses were conducted by region, age group, and sex. We found that 213.48 thousand DALYs and 10.02 thousand deaths in MASLD were attributable to HFPG worldwide in 2021, with an increase of 2.96 and 3.32 times compared with 1990, respectively. Over the past 32 years, age-standardized DALY rates (ASDRs) have fluctuated upward, reaching 2.45 per 100,000 people in 2021, with an increase of 81.21%. The ASDRs continued to rise in low, low-middle, and high social demographic index (SDI) regions, fluctuated upward at high levels in middle SDI regions, and were relatively low in high-middle SDI regions. People aged 50–69 accounted for the largest proportion of DALYs, while people over 70 had the largest increase of 3.73 times. Men had higher ASDRs, and the sex difference has been gradually expanding over the past 32 years, peaking at the age of 45–49. In conclusion, the burden of HFPG-attributable MASLD has continued to increase globally, with differences in geographical area, age, and sex distribution. HFPG, as a modifiable risk factor, should be given more importance. The implementation of targeted health intervention strategies is recommended for each country based on trends in the burden of HFPG-attributable MASLD.

Abstract Background The Clínica Universidad de Navarra-Body Adiposity Estimator (CUN-BAE) Index, serves as an effective tool for evaluating body fat (BF) levels. This research seeks to clarify the association between the CUN-BAE Index and metabolic dysfunction-associated steatotic liver disease (MASLD) from a gender perspective. Methods The study utilized data from a comprehensive health assessment initiative known as “Human Dock”, involving 14,251 participants. MASLD was diagnosed using abdominal ultrasound, primarily evaluated based on the following sonographic features: hepatorenal echo contrast, vascular blurring, deep attenuation, liver brightness. First, we evaluated the association of MASLD with the CUN-BAE Index using multivariate logistic regression. Second, we visualized this association and estimated potential threshold effect points using the restricted cubic spline (RCS) regression model. Ultimately, we evaluated the ability of the CUN-BAE Index to detect MASLD through receiver operating characteristic (ROC) curves. Results The female-to-male ratio was 1:1.08, with a MASLD prevalence rate of 17.59%. Following the adjustment for confounding variables, an increase of one unit in the CUN-BAE Index corresponded to a 14% increase in the risk of MASLD for males and an 18% increase for females. RCS analysis revealed an S-shaped relationship between MASLD prevalence and the CUN-BAE Index for both genders, with potential threshold effect points at approximately 30 in females and 15 in males. Beyond these threshold points, the prevalence of MASLD increased rapidly. Further subgroup analyses indicated significant differences in the relationship of the CUN-BAE Index with MASLD within age and body mass index (BMI) subgroups in females, with a stronger association observed in younger and non-obese female participants. Additionally, ROC analysis revealed that the CUN-BAE Index possesses a strong ability to distinguish MASLD in both genders, especially in females. Conclusions This research is the first to identify a positive relationship between the CUN-BAE Index and MASLD. The CUN-BAE Index appears to be more suitable for early screening of MASLD in females.