Liver fibrosis is the primary predictor of complications in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). However, there are currently no non-invasive prognostic tests to stratify patients at risk for hepatic fibrosis progression. This study aimed to explore whether plasma proteins could serve as non-invasive biomarkers for monitoring MASLD disease progression.

Blood plasma protein analysis was performed on samples from a long-term follow-up study of patients with MASLD with repeated liver biopsies. Over 1100 proteins covering a broad range of biological processes were analyzed using 13 Olink® Target 96 panels. Protein level changes were compared between the different time points and between patients with or without an increase in the liver fibrosis stage between the two biopsies.

Increased vascular endothelial growth factor A (VEGFA) plasma levels were significantly associated with liver fibrosis progression in patients with a histologically assessed increase in the fibrosis stage.

These findings suggest that the plasma protein VEGFA may be an effective biomarker for monitoring fibrosis progression in patients with MASLD.

This study aimed to explore the association between dietary fiber intake and the risk of metabolic dysfunction-associated steatotic liver disease (MASLD), as well as liver fat content, while considering genetic predispositions of MASLD, gut microbial abundance, and butyrate levels. This study analyzed data from 190,276 participants in the UK Biobank. Dietary fiber intake was assessed using 24-h dietary recall. MASLD cases were diagnosed through hospital admission records and death registries, and liver fat content was measured via magnetic resonance imaging. The genetic predispositions of MASLD, gut microbial abundance, and butyrate levels were evaluated using single nucleotide polymorphisms. Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95 % confidence intervals (CIs). Over a median follow-up of 10.49 years, 1423 MASLD cases were recorded. Elevated dietary fiber intake was associated with a reduced risk of MASLD (HR: 0.72; 95 % CI: 0.58, 0.90) and a lower level of liver fat content (β: -0.97; 95 % CI: -1.21, -0.73) (all P for trend <0.05). Restricted cubic spline analyses further confirmed the linear inverse associations between fiber intake and the risk of MASLD. Notably, the negative associations between dietary fiber intake and both MASLD and liver fat content were consistent across different genetic predispositions of gut microbial abundance and butyrate levels. Moreover, the inverse association between dietary fiber intake and liver fat was strengthened by high genetic susceptibility of MASLD and elevated body mass index (both P for interaction <0.05). Overall, increased dietary fiber consumption was associated with a lower MASLD risk and decreased liver fat content regardless of genetic predispositions of gut microbial abundance and butyrate levels.

Interleukin-22 (IL-22), a cytokine from the IL-10 family produced by T cells and innate lymphoid cells, plays a crucial role in immune responses and tissue regeneration. Its association with liver disease has garnered significant attention; however, its exact impact remains controversial. This review aims to enhance the current understanding of the dual role of IL-22 in liver disease by exploring its protective and pathogenic effects. First, we provide an overview of IL-22 biology, including its source, receptors, and signaling pathways. Subsequently, we offer a comprehensive overview of the dual function of IL-22 in non-neoplastic liver disease, emphasizing its antiapoptotic and regenerative properties. We also discuss the applicability of the conclusions drawn from studies on nonalcoholic fatty liver disease to metabolic dysfunction-associated steatotic liver disease. Furthermore, we elaborate on the intricate role of IL-22 in hepatocellular carcinoma, particularly its influence on the tumor microenvironment, proliferation, and immune evasion. In conclusion, IL-22 is paradoxical in liver disease, acting as a friend and foe. It is imperative to understand this paradox to develop targeted therapies that capitalize on the beneficial effects of IL-22 while mitigating its detrimental effects.

In recent years, the rising prevalence of obesity and metabolic syndrome has led to an increased number of individuals developing metabolic dysfunction-associated steatotic liver disease (MASLD). Furthermore, given the substantial global prevalence of chronic hepatitis B (CHB), instances of MASLD coexisting with CHB are becoming increasingly commonplace in clinical scenarios. Both conditions can lead to liver fibrosis, cirrhosis, and potentially hepatocellular carcinoma (HCC). However, the intricacies of the dual etiology, consequential outcomes, and associated risks of CHB concurrent with MASLD are still not fully understood.

A literature search was conducted on PubMed for articles published up to March 2024. The search keywords included nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, chronic hepatitis B, liver fibrosis, hepatocellular carcinoma, nuclear factor erythroid 2-related factor 2, and oxidative stress.

This review examined recent studies on the interplay between MASLD and CHB. The coexistence of these conditions may facilitate the clearance of hepatitis B surface antigen from the serum and impede hepatitis B virus (HBV) replication. Conversely, individuals with coexisting CHB tend to exhibit a lower rate of hypertriglyceridemia and reduced serum triglyceride levels compared with those only having NAFLD. Nevertheless, these observations do not necessarily indicate universally positive outcomes. Indeed, MASLD and CHB may synergistically act as "co-conspirators" to exacerbate clinical manifestations, particularly liver fibrosis and HCC.

As our understanding of the interaction between steatosis and HBV infection becomes clearer, we can better assess the risk of advanced liver disease in patients with concurrent CHB and MASLD. These insights will support the exploration of potential underlying mechanisms and may provide recommendations for improving patient outcomes.

In 2023, nonalcoholic fatty liver disease was renamed metabolic dysfunction-associated steatotic liver disease by the American and European liver associations. This new nomenclature recognizes metabolic dysfunction as the central driver of the disease, and the diagnostic criteria now require the presence of hepatic steatosis plus at least one of five cardiometabolic risk factors. B-mode ultrasonography remains the most common and practical method for detecting hepatic steatosis, although newer ultrasound techniques based on attenuation, backscatter, and speed of sound have gained traction as tools to diagnose and quantify hepatic steatosis. Additionally, ultrasound elastography is increasingly used in routine clinical practice to assess liver fibrosis, diagnose cirrhosis, and identify clinically significant portal hypertension.

This study aims to assess the performance of Steatotic Liver Disease (SLD) criteria in identifying liver steatosis compared to the NAFLD and MAFLD definitions in an agricultural population in Chile.

We performed a cross-sectional analysis on the MAUCO cohort, composed of 9,013 individuals aged 38 to 74. Health conditions, socio-demographics, anthropometrics, hepatic ultrasonography, blood pressure, and biological samples were obtained. Participants were classified as NAFLD, MAFLD, or any of the five SLD categories: Metabolic dysfunction-associated steatosis liver disease (MASLD), Metabolic and Alcohol-Associated Liver Disease (MetALD), Alcohol-Associated Liver Disease (ALD), Specific aetiologies, and Cryptogenic. The Framingham cardiovascular risk score and BARD liver fibrosis score were used to assess clinical relevance.

Liver steatosis was present in 4,082 participants (45%); SLD criteria captured an additional 176 individuals not classified under NAFLD and 103 not included under MAFLD definition. The main SLD subgroups were MASLD (95%), MetALD (1.9%) and ALD (1.3%). Individuals classified in the MetALD and ALD subgroups exhibited more severe liver steatosis and a higher cardiovascular risk. Notably, participants categorized under specific etiologies and cryptogenic subgroups were younger and had a higher risk for liver fibrosis.

The study reveals that SLD offers a more inclusive classification to identify high-risk individuals in the Chilean population, capturing cases that could be missed by NAFLD or MAFLD definitions by using the same resources.

This article synthesizes the current knowledge on the epidemiology of metabolic dysfunction-associated steatotic liver disease (MASLD), its associated risks, and its genetic determinants. The findings presented in this article can be used to develop clinical strategies to reduce MASLD's growing global burden. MASLD has become a major global health concern due to increasing rates of obesity, sedentary lifestyles, and metabolic disorders. MASLD is a leading cause of end-stage liver diseases, including cirrhosis and hepatocellular carcinoma (HCC), and MASLD also significantly increases the risk of cardiovascular disease (CVD), thereby exerting dual effects on liver and cardiovascular health. MASLD was once referred to as nonalcoholic fatty liver disease, and this change in nomenclature reflects a growing focus on its metabolic underpinnings, facilitating the more precise diagnosis and clinical management of this disease. Epidemiological studies have demonstrated that the prevalence of MASLD is increasing worldwide, although the prevalence varies across regions and populations. Noninvasive diagnostic tools such as ultrasound and fatty liver indices along with biomarkers such as alanine aminotransferase (ALT) are crucial for early detection and risk stratification. Genetic research has identified key gene variants, including PNPLA3 (rs738409) and TM6SF2 (rs58542926), that influence MASLD susceptibility and progression, and these findings have created opportunities for improving precision medicine with respect to treating MASLD. Research has revealed an association between MASLD and major adverse cardiovascular events and increased mortality, which highlights the importance of integrating cardiovascular risk management into treatment strategies for MASLD. Future research should focus on advancing noninvasive diagnostics, leveraging genetic insights to provide tailored care, and implementing population-specific interventions to address regional variations.

Previous studies on the association between non-skimmed milk consumption and non-alcoholic fatty liver disease (NAFLD) have reported inconsistent findings, with some suggesting an increased risk and others indicating a protective effect. Moreover, as the research focus has shifted globally from NAFLD to metabolic dysfunction-associated fatty liver disease (MAFLD), there remains limited evidence on the relationship between non-skimmed milk consumption and MAFLD. The objective of this cross-sectional study was to investigate this association using data from the National Health and Nutrition Examination Survey (NHANES).

In this U.S. population-based study, adults with complete information on non-skimmed milk consumption and MAFLD diagnosis from the 2017-March 2020 Pre-Pandemic NHANES were included. MAFLD was defined using the controlled attenuation parameter (CAP). The association between non-skimmed milk consumption and MAFLD was assessed using weighted multivariable logistic regression, adjusting for potential confounders. Subgroup and sensitivity analyses were conducted to evaluate effect modifications and robustness.

The study involved 3,758 participants in total, 1,423 (37.87%) of whom had MAFLD according to the diagnosis. Frequent non-skimmed milk consumption was independently associated with higher MAFLD risk. Compared to the "Rarely" group (< 1 time/week), the "Sometimes" group (≥ 1 time/week but < 1 time/day) had an odds ratio (OR) of 1.67 (95% CI: 1.32-2.12, P = 0.004), and the "Often" group (≥ 1 time/day) had an OR of 1.36 (95% CI: 1.06-1.75, P = 0.046). Stratified analysis revealed that the association was significantly modified by education level (P for interaction = 0.010), with a stronger association observed among participants with higher education levels. Sensitivity analysis yielded consistent results, further supporting the robustness of the association.

Our findings suggest a significant association between frequent non-skimmed milk consumption and risk of MAFLD, particularly in highly educated individuals. These results highlight the importance of dietary modifications, specifically reducing non-skimmed milk intake, as a potential preventive strategy for MAFLD, especially in high-risk populations.

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease (NAFLD), encompasses a spectrum of liver diseases characterized by hepatic steatosis, the presence of at least one cardiometabolic risk factor, and no other apparent cause. Metabolic syndrome (MetS) is a cluster of clinical conditions associated with increased risk of cardiovascular disease, type 2 diabetes, and overall morbidity and mortality. This narrative review summarizes the changes in the management of people with MetS and NAFLD/MASLD from screening to therapeutic strategies that have occurred in the last decades. Specifically, we underline the clinical importance of considering the different impacts of simple steatosis and advanced fibrosis and provide an up-to-date overview on non-invasive diagnostic tests (i.e., imaging and serum biomarkers), which now offer acceptable accuracy and are globally more accessible. Early detection of MetS and MASLD is a top priority as it allows for timely interventions, primarily through lifestyle modification. The liver and cardiovascular benefits of a global and multidimensional approach are not negligible. Therefore, a holistic approach to both conditions, MetS and related chronic liver disease, should be applied to improve overall health and longevity.

This review aims to summarize the current scientific understanding on the complex interplay between sterol regulatory element-binding proteins (SREBPs) and metabolic dysfunction associated steatotic liver disease (MASLD) by critically examining a few significant molecular pathways. Additionally, the review explores the potential of both natural and synthetic SREBP inhibitors as promising therapeutic candidates for MASLD.

SREBPs are central regulators of lipid homeostasis, with SREBP-1c primarily controlling fatty acid synthesis and SREBP-2 regulating cholesterol metabolism. Dysregulation of SREBP activity, often triggered by excessive caloric intake, insulin resistance, or endoplasmic reticulum (ER) stress, contributes to the development of metabolic syndrome and MASLD. SREBP-1c overexpression leads to increased de novo lipogenesis (DNL), hepatic lipid accumulation, and insulin resistance, while SREBP-2 modulates cholesterol metabolism via miRNA-33 and ABCA1 regulation leading to the pathogenesis of MASLD. The PI3K-Akt-mTORC1 pathway plays a critical role in SREBP activation, linking nutrient availability to lipid synthesis. Synthetic SREBP inhibitors, such as fatostatin and 25-hydroxycholesterol, and natural compounds, including kaempferol and resveratrol, show promise in modulating SREBP activity in vivo.

While targeting SREBP pathways presents a promising avenue for mitigating MASLD, further scientific investigation is imperative to identify and validate potential molecular targets. Although current studies on synthetic and natural SREBP inhibitors demonstrate encouraging results, rigorous pre-clinical and clinical research is warranted to translate these findings into effective MASLD treatments.

Although metabolic dysfunction-associated steatotic liver disease (MASLD) is strongly associated with obesity, around 20% of individuals with hepatic steatosis may nonetheless have normal body mass index, a condition often referred to as lean nonalcoholic fatty liver disease (NAFLD). Under the new nomenclature and definition of MASLD, lean NAFLD can be further divided into lean MASLD (when there is one or more cardiometabolic risk factors) and cryptogenic steatotic liver disease (when there is no cardiometabolic risk factor).

Current studies suggest that the at-risk PNPLA3 rs738409 variant is more common among individuals with lean NAFLD than their overweight and obese counterparts. However, even in this group, cardiometabolic risk factors are often required for the development of hepatic steatosis and liver injury. In the general population, PNPLA3 gene polymorphism is associated with an increased risk of MASLD, more severe liver histology (i.e., the presence of steatohepatitis and fibrosis) and future development of hepatocellular carcinoma and cirrhotic complications. Emerging data also suggest that individuals carrying the PNPLA3 GG genotype might have a greater reduction in hepatic steatosis and liver enzymes with lifestyle intervention and metabolic treatments, such as glucagon-like peptide-1 receptor agonists.

Studies have not specifically examined the impact of PNPLA3 in lean individuals.

Controversy remains whether the mortality risk in people with fatty liver disease (FLD) including metabolic-(dysfunction) associated steatotic liver disease (MASLD) and metabolic-(dysfunction) associated fatty liver disease (MAFLD) is higher than observed in those without FLD. We aimed to determine the mortality rate and mortality rate ratio (MRR) for these FLDs.

The study population was a randomly selected cohort of community-dwelling adults in regional Victoria, Australia between 2001 and 2003 with sufficient data evaluable for Fatty Liver Index and determination on alcohol consumption. MASLD and MAFLD were diagnosed by established criteria. The primary outcome was overall mortality and main secondary outcome was major adverse liver outcomes (MALO) (i.e., decompensated liver disease, primary liver cancer and liver-related death). Non-fatal and fatal outcomes were captured via data linkage to hospital admission, cancer registry, and death registries. MRR was calculated with non-FLD participants as the comparator.

1444 (99.3%) and 1324 (91.1%) individuals from a total of 1454 were included in the final MAFLD and MASLD analyses. The median follow-up was 19.7 years (IQR 19.1-20.1) and there were 298 deaths. The MRR for MAFLD and MASLD was 1.39 (95% CI 1.10-1.76) and 1.25 (95% CI 0.96-1.61), respectively. MAFLD persisted as a risk factor for all-cause death on multivariable models correcting for lifestyle and socioeconomic variables, but not when adjusted for metabolic risk factors. MALOs were increased in MAFLD [incidence rate ratio (IRR) 3.03, 95% CI 1.22-8.18] and MASLD (IRR 2.80, 95% CI 1.05-7.90). Metabolic risk factors increased the risk of overall mortality and MALO, and cancer (34.3-34.6%) and cardiovascular disease (30.1-33.7%) were the most common cause of death in FLD.

In this population-based longitudinal study, MAFLD but not MASLD increases the risk of overall mortality, with metabolic syndrome components key risk factors increasing risk of death.

Smoking was identified as a risk factor for the development of liver fibrosis in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). However, the association between smoking cessation history and the development of liver fibrosis remains unclear. This study was intended to analyze the association between smoking cessation history and significant liver fibrosis in adult MASLD participants in the United States.

This study utilized data from 2643 patients with MASLD from the National Health and Nutrition Examination Survey (NHANES). Significant liver fibrosis was detected based on transient elastography measurements. According to the smoking questionnaire data, patients were categorized as non-smokers, ex-smokers and current smokers. A multivariate logistic regression analysis, adjusted for weights, was performed to investigate the relationship between smoking cessation history and the presence of significant liver fibrosis in participants with MASLD.

A total of 2643 patients with MASLD were included in this study. Compared with non-smokers, ex-smokers had a slightly elevated risk of developing significant liver fibrosis (OR: 1.07, 95% CI: 1.02-1.13). Specifically, a positive correlation was observed between patients who quit smoking for < 20 years and significant liver fibrosis (OR: 1.07, 95% CI: 1.01-1.15). Furthermore, MASLD patients who started regularly smoking at an age of ≤ 20 years (OR: 1.09, 95% CI: 1.02-1.16) and had a smoking duration of ≥ 10 years before quitting (OR: 1.10, 95% CI: 1.02-1.18) were also highly correlated with an increased likelihood of developing significant liver fibrosis.

This study revealed that individuals with MASLD who have ceased smoking exhibit an elevated risk for significant liver fibrosis when compared to those who never smoked. It is highly emphasized that MASLD patients who quit smoking for < 20 years, started regularly smoking at an age of ≤ 20 years, and had a smoking duration of ≥ 10 years before quitting should be extremely vigilant regarding the risk of significant liver fibrosis.

Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) affects one-third of the global population. Despite its high prevalence, there is a lack of minimally non-invasive diagnostic methods to assess this condition. This study explores the potential of circulating microRNAs (miRNAs) as diagnostic biomarkers for MASLD after a 2-year nutritional intervention.

Fifty-five subjects with steatosis (MASLD group) from the Fatty Liver in Obesity (FLiO) study (NCT03183193) were analyzed at baseline and after 6, 12 and 24 months. Participants were classified into two groups: those who still had steatosis after the intervention (unhealthy group) and those in whom steatosis had disappeared (healthy group). Hepatic status was evaluated through magnetic resonance imaging (MRI), ultrasonography, elastography and serum transaminases. Circulating miRNA levels were measured by RT-PCR.

The dietary intervention was able to modulate the expression of circulating miRNAs after 6, 12, and 24 months. Logistic regression analyses revealed that the most effective panels for diagnosing whether MASLD has disappeared after the nutritional intervention included miR15b-3p, miR126-5p and BMI (AUC 0.68) at 6 months, miR29b-3p, miR122-5p, miR151a-3p and BMI (AUC 0.85) at 12 months and miR21-5p, miR151a-3p and BMI at 24 months (AUC 0.85).

Circulating miRNAs were useful in predicting MASLD in subjects with overweight or obesity after following a weight-loss oriented nutritional intervention. These findings highlight the potential role of miRNAs in diagnosing MASLD and underscore the importance of precision nutrition in managing and determining MASLD.

Trial registration number: NCT03183193 (www.

gov).

Metabolic dysfunction-associated steatotic liver disease (MASLD) featuring hepatic steatosis and insulin dysregulation is becoming a common cause of chronic hepatic diseases. Although the involvement of endocrine disruption in the onset and progression of MASLD is thought to be critical, there are limited effective animal models reflecting hyperinsulinemia and hepatic steatosis. Here, we propose a MASLD mouse model that combines neuropeptide effects and dietary nutrition. We employed chronic overexpression of the gene encoding neurosecretory protein GL (NPGL) in the hypothalamus of ICR mice under a low-fat/medium-sucrose diet (LFMSD). Npgl overexpression promoted fat accumulation in the white adipose tissues in 2 weeks. Basal insulin levels were increased and pancreatic islets expanded following Npgl overexpression. Histological and molecular biological approaches revealed that Npgl overexpression enhanced de novo lipogenesis, leading to hepatic steatosis. Nine-week overexpression of Npgl exacerbated obesity and hyperinsulinemia, resulting in hyperglycemia. Moreover, prolonged Npgl overexpression aggravated fat accumulation in the liver with a change in the lipid metabolic pathway. These findings suggest that Npgl overexpression readily leads to obesity with hyperinsulinemia and hepatic steatosis in ICR mice under an LFMSD.

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects > 25% of the global population, potentially leading to severe hepatic and extrahepatic complications, including metabolic dysfunction-associated steatohepatitis. Given that the pathophysiology of MASLD is incompletely understood, identifying therapeutic targets and optimizing treatment strategies are crucial for addressing this severe condition.

Mendelian randomization (MR) analysis was conducted using two genome-wide association study datasets: a European meta-analysis (8,434 cases; 770,180 controls) and an additional study (3,954 cases; 355,942 controls), identifying therapeutic targets for MASLD. Of 4302 drug-target genes, 2,664 genetic instrument variables were derived from cis-expression quantitative trait loci (cis-eQTLs). Colocalization analyses assessed shared causal variants between MASLD-associated single nucleotide polymorphisms and eQTLs. Using the drug target gene cis-eQTL of liver tissue from the genotype-tissue expression project, we performed MR and summary MR to validate the significance of the gene results of the blood eQTL MR. RNA-sequencing data from liver biopsies were validated using immunohistochemistry and quantitative polymerase chain reaction (qPCR) tests to confirm gene expression findings.

MR analysis across both datasets identified significant MR associations between MASLD and two drug targets-milk fat globule-EGF factor 8 (MFGE8) (odds ratio [OR] 0.89, 95% confidence interval [CI] 0.85-0.94; P = 2.15 × 10-6) and cluster of differentiation 33 (CD33) (OR 1.17, 95% CI 1.10-1.25; P = 1.39 × 10-6). Both targets exhibited strong colocalization with MASLD. Genetic manipulation indicating MFGE8 activation and CD33 inhibition did not increase the risk for other metabolic disorders. RNA-sequencing, qPCR, and immunohistochemistry validation demonstrated consistent differential expressions of MFGE8 and CD33 in MASLD.

CD33 inhibition can reduce MASLD risk, while MFGE8 activation may offer therapeutic benefits for MASLD treatment.

Given that cardiovascular events induced by metabolic disorders are the leading cause of death in nonalcoholic fatty liver disease (NAFLD), this study aimed to explore the heterogeneity of cardiometabolic and liver fibrosis risks among lean, overweight, and obese NAFLD individuals.

A multicenter cross-sectional study was conducted across three hospitals in Pudong from July 2022 to June 2023. Health checkup data were obtained and stratified by BMI categories. Multivariable logistic regression was performed to analyze the association between NAFLD and risk factors for cardiometabolic diseases and liver fibrosis across different BMI categories.

The study included 37,122 patients, with 25.25% diagnosed with NAFLD. Over 97% of these patients met the criteria for metabolic dysfunction-associated fatty liver disease. NAFLD detection rates were 7.72% in lean, 33.99% in overweight, and 63.56% in obese individuals. Non-obese patients had significantly lower cardiometabolic disease prevalence than obese patients (P < 0.001). All NAFLD subtypes, except lean NAFLD (negatively associated with total cholesterol) and obese NAFLD (no significant association with total triglycerides), were linked to other cardiometabolic or liver fibrosis risk factors (P < 0.05). Additioinally, only obese NAFLD demonstrated a negative correlation with age.

Non-obese NAFLD, despite a relatively better metabolic profile than obese NAFLD, still poses significant cardiometabolic and fibrosis risks. Interventions targeting cardiovascular events and liver disease progression are essential for all NAFLD subtypes, customized to their metabolic characteristics. The detection rates in this study provide a valuable reference for estimating local NAFLD prevalence.

Insulin resistance, lipotoxicity, and mitochondrial dysfunction contribute to the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD). Mitochondrial dysfunction impairs oxidative phosphorylation and increases reactive oxygen species production, leading to steatohepatitis and hepatic fibrosis. Artificial intelligence (AI) is a potent tool for disease diagnosis and risk stratification.

To investigate mitochondrial DNA polymorphisms in susceptibility to MASLD and establish an AI model for MASLD screening.

Multiplex polymerase chain reaction was performed to comprehensively genotype 82 mitochondrial DNA variants in the screening dataset (n = 264). The significant mitochondrial single nucleotide polymorphism was validated in an independent cohort (n = 1046) using the Taqman® allelic discrimination assay. Random forest, eXtreme gradient boosting, Naive Bayes, and logistic regression algorithms were employed to construct an AI model for MASLD.

In the screening dataset, only mt12361A>G was significantly associated with MASLD. mt12361A>G showed borderline significance in MASLD patients with 2-3 cardiometabolic traits compared with controls in the validation dataset (P = 0.055). Multivariate regression analysis confirmed that mt12361A>G was an independent risk factor of MASLD [odds ratio (OR) = 2.54, 95% confidence interval (CI): 1.19-5.43, P = 0.016]. The genetic effect of mt12361A>G was significant in the non-diabetic group but not in the diabetic group. mt12361G carriers had a 2.8-fold higher risk than A carriers in the non-diabetic group (OR = 2.80, 95%CI: 1.22-6.41, P = 0.015). By integrating clinical features and mt12361A>G, random forest outperformed other algorithms in detecting MASLD [training area under the receiver operating characteristic curve (AUROC) = 1.000, validation AUROC = 0.876].

The mt12361A>G variant increased the severity of MASLD in non-diabetic patients. AI supports the screening and management of MASLD in primary care settings.

Metabolic-Associated Fatty Liver Disease (MAFLD) is the most common chronic liver disease worldwide, associated with systemic metabolic dysregulation. It can progress from simple hepatic steatosis (MAFL) to more severe conditions like Metabolic-Associated Steatohepatitis (MASH), fibrosis, cirrhosis, and Hepatocellular Carcinoma (HCC). There is a critical lack of reliable non-invasive diagnostic methods and effective pharmaceutical treatments for MAFLD/MASH, emphasizing the need for further research. Extracellular vesicles (EVs) are nanoscale structures that play important roles in cell signaling by delivering bioactive molecules. However, there is a significant gap in literature regarding the roles of EVs from hosts, plants, and microbiota in MAFLD. This review explores the potential of EVs from various sources-host, plants, and microbiota-as biomarkers, therapeutic agents, drug carriers, and treatment targets for MAFLD. Firstly, the roles of host-derived extracellular vesicles (EVs) in MAFLD, with a focus on cell-type specific EVs and their components-proteins, miRNAs, and lipids-for disease diagnosis and monitoring were discussed. Moreover, it highlighted the therapeutic potential of mesenchymal stem cell (MSC)-derived EVs in reducing lipid accumulation and liver injury, and immune cell-derived EVs in mitigating inflammation and fibrosis. The review also discussed the use of host-derived EVs as drug carriers and therapeutic targets due to their ability to deliver bioactive molecules that impact disease mechanisms. Additionally, it summarized research on plant-derived EVs, which help reduce liver lipid accumulation, inflammation, and enhance gut barrier function in MAFLD. Also, the review explored microbial-derived EVs as novel therapeutic targets, particularly in relation to insulin resistance, liver inflammation, and dysfunction in MAFLD. Overall, by exploring the diverse roles of EVs from host, plant, and microbiota sources in MAFLD, this review offers valuable insights into their potential as non-invasive biomarkers and novel therapeutic strategies, which could pave the way for more effective diagnostic and treatment options for this increasingly prevalent liver disease. Notably, the challenges of translating EVs into clinical practice were also thoroughly discussed, aiming to provide possible directions and strategies for future research.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the umbrella term that comprises metabolic dysfunction-associated steatotic liver, or isolated hepatic steatosis, through to metabolic dysfunction-associated steatohepatitis, the progressive necroinflammatory disease form that can progress to fibrosis, cirrhosis and hepatocellular carcinoma. MASLD is estimated to affect more than one-third of adults worldwide. MASLD is closely associated with insulin resistance, obesity, gut microbial dysbiosis and genetic risk factors. The obesity epidemic and the growing prevalence of type 2 diabetes mellitus greatly contribute to the increasing burden of MASLD. The treatment and prevention of major metabolic comorbidities such as type 2 diabetes mellitus and obesity will probably slow the growth of MASLD. In 2023, the field decided on a new nomenclature and agreed on a set of research and action priorities, and in 2024, the US FDA approved the first drug, resmetirom, for the treatment of non-cirrhotic metabolic dysfunction-associated steatohepatitis with moderate to advanced fibrosis. Reliable, validated biomarkers that can replace histology for patient selection and primary end points in MASH trials will greatly accelerate the drug development process. Additionally, noninvasive tests that can reliably determine treatment response or predict response to therapy are warranted. Sustained efforts are required to combat the burden of MASLD by tackling metabolic risk factors, improving risk stratification and linkage to care, and increasing access to therapeutic agents and non-pharmaceutical interventions.

Accessible noninvasive screening tools for metabolic dysfunction-associated steatotic liver disease (MASLD) are needed. We aim to explore the performance of a deep learning-based artificial intelligence (AI) model in distinguishing the presence of MASLD using 12-lead electrocardiogram (ECG).

This is a retrospective study of adults diagnosed with MASLD in Olmsted County, Minnesota, between 1996 and 2019. Both cases and controls had ECGs performed within 6 years before and 1 year after study entry. An AI-based ECG model using a convolutional neural network was trained, validated, and tested in 70%, 10%, and 20% of the cohort, respectively. External validation was performed in an independent cohort from Mayo Clinic Enterprise. The primary outcome was the performance of ECG to identify MASLD, alone or when added to clinical parameters.

A total of 3468 MASLD cases and 25,407 controls were identified. The AI-ECG model predicted the presence of MASLD with an area under the curve (AUC) of 0.69 (original cohort) and 0.62 (validation cohort). The performance was similar or superior to age- and sex-adjusted models using body mass index (AUC, 0.71), presence of diabetes, hypertension or hyperlipidemia (AUC, 0.68), or diabetes alone (AUC, 0.66). The model combining ECG, age, sex, body mass index, diabetes, and alanine aminotransferase had the highest AUC: 0.76 (original) and 0.72 (validation).

This is a proof-of-concept study that an AI-based ECG model can detect MASLD with a comparable or superior performance as compared with the models using a single clinical parameter but not superior to the combination of clinical parameters. ECG can serve as another screening tool for MASLD in the nonhepatology space.

The new definition of steatotic liver disease (SLD), as a broader concept, was a step forward in the increasing recognition of the substantial overlap between alcohol and cardiometabolic risk factors (CMRFs), in a continuum way. The spectrum of pathophysiological aspects, ranging from liver steatosis to fibrosis, has similarities in MASLD and ALD. Also, there is now considerable evidence that the association of metabolic dysfunction with increased alcohol consumption impacts on the risk of severe liver disease and prognosis. The new MetALD class, as recently proposed, shows clear differences in prognosis when comparing with MASLD and ALD groups. However, there is room for improvement, such as considering the role of previous alcohol intake, fluctuations of consumption over time, including binge drinking, refinement of alcohol assessment, and better understanding of the role of biomarkers. In summary, SLD is no doubt a significant improvement, but the new classification needs to be dynamic and adapting to patients needing frequent reassessment. Furthermore, it brings opportunities for research on the interaction between alcohol consumption and CMRFs.

Recent epidemiological evidence indicates a significant rise in cirrhosis burden over the past 2 decades in all parts of the world, with cirrhosis incidence rates and related deaths escalating quickly. Women face unique risk factors and susceptibility to chronic liver diseases compared with men, underscoring the need for a sex-specific approach in early identification, reversal of causative factors, and complication prevention. This review aims to explore epidemiological trends and sex-specific factors contributing to the global epidemiology of cirrhosis among female patients today. While cirrhosis prevalence remains higher in male patients globally, the incidence rate from 2010 to 2019 grew faster among female patients. The female-to-male incidence ratio of metabolic dysfunction-associated steatotic liver disease-related cirrhosis globally in 2019 was 1.3, indicating a shifting trend toward new diagnoses among women now surpassing that of men. Alcohol-associated cirrhosis epidemiology is also changing, with trends toward an equal incidence of alcohol-associated cirrhosis between both sexes, particularly in industrialized nations with increased alcohol accessibility. Cirrhosis from viral hepatitis remains the main etiology among female patients in endemic regions. Sex differences in epidemiology are likely multifactorial, influenced by varying risk factors, susceptibility, and behaviors between sexes. Further research is necessary to better understand these disparities and to tailor sex-specific interventions toward improved management and treatment strategies, ultimately enhancing outcomes for women with cirrhosis and providing better patient-centered care.

Cocoa may have prebiotic effects and improve gut barrier function. However, it remains unclear whether dark chocolate can reduce lipopolysaccharide (LPS) levels in patients with metabolic dysfunction-associated steatohepatitis (MASH). This study aims to evaluate the effect of dark chocolate compared to milk chocolate on endotoxemia in patients with MASH.

Nineteen patients with MASH were randomly assigned in a crossover design to consume either 40 g/d of dark chocolate (>85% cocoa) or 40 g/d of milk chocolate (<35% cocoa) for 2 weeks to evaluate circulating levels of LPS and zonulin. A significant difference between treatments was observed in LPS (P = 0.04) and zonulin (P = 0.02) levels based on the ANOVA conducted on the crossover study data. Pairwise comparisons revealed that, compared to baseline, after 14 days of dark chocolate consumption, LPS levels decreased from 22 ± 4 to 19 ± 4 pg/dL (-15%), and zonulin levels decreased from 3.2 ± 0.9 to 2.5 ± 0.8 pg/mL (-20%). Linear correlation analysis indicated that the change (Δ) in LPS values before and after chocolate intake correlated with the change (Δ) in zonulin levels (R = 0.340, P = 0.03).

This study demonstrates that dark chocolate reduces circulating levels of LPS and zonulin in patients with MASH.

Metabolic-associated fatty liver disease (MAFLD) is the leading chronic liver disease globally, impacting a large segment of the population. The Zhuyu Pill (ZYP), a traditional Chinese remedy, has been clinically used for treating MAFLD, with its effectiveness demonstrated in both human patients and animal models. However, the underlying mechanisms of how ZYP addresses MAFLD still require further investigation.

This study investigated the molecular mechanism of ZYP in treating MAFLD through both in vivo and vitro methods.

A murine MAFLD model was induced by a high-fat, high-fructose diet for 12 weeks. ZYP was administered for 4 weeks, with fenofibrate serving as a positive control. Indicators of lipid metabolism in serum and liver tissue were detected by automatic biochemical analyzer and ELISA, respectively. Histopathological evaluation of liver sections was performed using HE and oil red O staining. Transcriptomics was employed to further investigate the therapeutic mechanism of ZYP in MAFLD. Additionally, macrophages and their polarization in the liver were analyzed using ELISA, flow cytometry, immunohistochemistry, and immunofluorescence (IF). Candidate proteins and pathways were validated in vivo and in vitro by western blotting and IF. Validation of the pathway was performed in vitro using inhibitors and co-culture strategies.

ZYP significantly improved obesity and hepatic steatosis in MAFLD mice, reducing body/liver weight and regulating lipid metabolism indicators in serum and liver tissue. Bioinformatics analysis of transcriptomic data highlighted lipid metabolism regulation and inflammation control as key effects of ZYP in treating MAFLD. The in vivo experimental results showed that ZYP inhibited M1 polarization of macrophages (pro-inflammatory) and promoted M2 polarization of macrophages (anti-inflammatory) in MAFLD mice. Further in vivo and vitro experiments indicated that ZYP competes with LPS to bind to Toll-like receptor 4 (TLR4), suppressing M1 polarization in liver macrophages, and improving MAFLD. The in vitro co-culture system also confirmed that ZYP reduces liver lipid deposition by modulating M1 macrophage polarization.

ZYP alleviates MAFLD by inhibiting M1 polarization of liver macrophages, indicating that ZYP may be a promising treatment for MAFLD. Its mechanism of action is to inhibit the TLR4/MyD88/TRAF6 signaling pathway, modulate macrophage polarization, and improve inflammatory response.

This meta-analysis aimed to summarize the diagnostic accuracy and cut-off values of cytokeratin (CK) 18 measurements, specifically M30 and M65, as candidate biomarkers for the pathological evaluation of biopsy specimens used to stage liver inflammation and fibrosis in patients with chronic liver diseases.

Databases were searched for studies collected up to January 11th, 2025. Pooled sensitivity, specificity, area under the receiver-operating characteristic curves, and mean cut-off values were calculated using random-effects models regardless of heterogeneity. A meta-regression analysis and subgroup analysis were performed to explore heterogeneity.

Sixty-three studies comprising 9137 patients were included. The summarized AUROC curve of CK18 M30 for the diagnosis of significant liver inflammation, fibrosis ≥F1, ≥F2, ≥F3, and =F4 according to the METAVIR score system were 0.82, 0.75, 0.78, 0.78 and 0.76, with mean cut-off values of 264.3, 188.0, 276.9, 322.8 and 169.4 U/L. For M65, the summarized AUROC curve for detecting significant liver inflammation, fibrosis ≥F1, ≥F2, and =F4 were 0.79, 0.70, 0.76, 0.64 and 0.72, with mean cut-off values of 541.1, 417.6, 500.1, 424.6 and 674.0 U/L. The subgroup analyses implied that ethnicity may be the primary factor related to heterogeneity in CK18 M30 when applied to detect significant inflammation. Asian patients had values 79.7 U/L higher than those of non-Asian patients (p = 0.0157).

CK18 M30 and M65 have clinically meaningful accuracy as alternative diagnostic tools for determining liver inflammation and fibrosis using biopsy specimens of patients with steatotic liver disease or viral hepatitis.

PROSPERO registration number: CRD42022364598.

Metabolic dysfunction-associated steatotic liver disease (MASLD; formerly known as nonalcoholic fatty liver disease) is a chronic liver disease affecting over a billion individuals worldwide. MASLD can gradually develop into more severe liver pathologies, including metabolic dysfunction-associated steatohepatitis (MASH), cirrhosis, and liver malignancy. Notably, although being a global health problem, there are very limited therapeutic options against MASLD and its related diseases. While a thyroid hormone receptor agonist (resmetirom) is recently approved for MASH treatment, other efforts to control these diseases remain unsatisfactory. Given the projected rise in MASLD and MASH incidence, it is urgent to develop novel and effective therapeutic strategies against these prevalent liver diseases. In this article, the pathogenic mechanisms of MASLD and MASH, including insulin resistance, dysregulated nuclear receptor signaling, and genetic risk factors (eg, patatin-like phospholipase domain-containing 3 and hydroxysteroid 17-β dehydrogenase-13), are introduced. Various therapeutic interventions against MASH are then explored, including approved medication (resmetirom), drugs that are currently in clinical trials (eg, glucagon-like peptide 1 receptor agonist, fibroblast growth factor 21 analog, and PPAR agonist), and those failed in previous trials (eg, obeticholic acid and stearoyl-CoA desaturase 1 antagonist). Moreover, given that the role of gut microbes in MASLD is increasingly acknowledged, alterations in the gut microbiota and microbial mechanisms in MASLD development are elucidated. Therapeutic approaches that target the gut microbiota (eg, dietary intervention and probiotics) against MASLD and related diseases are further explored. With better understanding of the multifaceted pathogenic mechanisms, the development of innovative therapeutics that target the root causes of MASLD and MASH is greatly facilitated. The possibility of alleviating MASH and achieving better patient outcomes is within reach. SIGNIFICANCE STATEMENT: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease worldwide, and it can progress to more severe pathologies, including steatohepatitis, cirrhosis, and liver cancer. Better understanding of the pathogenic mechanisms of these diseases has facilitated the development of innovative therapeutic strategies. Moreover, increasing evidence has illustrated the crucial role of gut microbiota in the pathogenesis of MASLD and related diseases. It may be clinically feasible to target gut microbes to alleviate MASLD in the future.

N6-methyladenosine (m6A) RNA modification plays a crucial role in various biological events and is implicated in various metabolic-related diseases. However, its role in MASLD remains unclear. This study aims to investigate the impact of METTL3 on MASLD through multi-omics analysis, with a focus on exploring its potential mechanisms of action.

An MASLD mouse model was established by feeding C57BL/6J mice a high-fat diet for 12 weeks. A METTL3 stable overexpression AML12 cell model was also constructed via lentiviral transfection. Subsequent transcriptomic and proteomic analyses, as well as integrated analysis between different omics datasets, were conducted.

METTL3 expression was significantly increased in the MASLD mouse model. Through our transcriptomic and proteomic analyses, we identified 848 genes with significant inconsistencies between the transcriptomic and proteomic datasets. GO/ KEGG enrichment analyses identified terms that may be involved in post-transcriptional modifications, particularly METTL3-mediated m6A modification. Subsequently, through integrated proteomic analysis of the METTL3-overexpressed AML12 cell model and the MASLD mouse model, we selected the top 20 co-upregulated and co-downregulated GO/ KEGG terms as the main biological processes influenced by METTL3 during MASLD. By intersecting with pathways obtained from previous integrated analyses, we identified GO/ KEGG terms affected by METTL3-induced m6A modification. Protein-protein interaction analysis of proteins involved in these pathways highlighted GAPDH and TPI1 as two key hub genes.

During MASLD, METTL3 regulates the glycolytic pathway through m6A modification, influencing the occurrence and development of the disease via the key hub genes GAPDH and TPI1. These findings expand our understanding of MASLD and provide strong evidence for potential therapeutic targets and drug development.

Background/Objectives: Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is commonly considered as a hepatic manifestation of metabolic syndrome, posing considerable public health and economic challenges due to its high prevalence. This study investigates the diagnostic potential of serum galectin-1 levels in MASLD patients. Methods: A total of 128 participants were analyzed for this study, comprising 68 healthy controls and 60 MASLD patients. The hepatic steatosis index (HSI) and fatty liver index (FLI) were calculated to evaluate the liver steatosis. Serum galectin-1 levels were measured using an enzyme-linked immunosorbent assay. We additionally conducted a comparative analysis of galectin-1 mRNA and protein expression levels in the liver tissue between the mouse models of MASLD, including ob/ob mice (n = 6), high-fat diet-fed C57 mice (n = 6), and the control group (n = 6). Results: Average serum galectin-1 levels significantly differed between groups, with lower values in the controls (p < 0.01). The frequency of MASLD increased with higher quartiles of galectin-1 levels (p < 0.01). The correlation analysis showed a positive relationship between serum galectin-1 and both HSI and FLI (p < 0.01). The multivariate logistic regression indicated that elevated galectin-1 was associated with an increased risk of MASLD (p < 0.01), yielding an area under the receiver operating characteristic curve for predicting MASLD at 0.745 (95% CI: 0.662-0.829). Hepatic galectin-1 levels were also elevated in the MASLD mouse model at both transcript and protein levels (p < 0.01). Conclusions: Serum galectin-1 can be used as a potential biomarker to help diagnose MASLD.

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects one-third of adults globally. Despite efforts to develop non-invasive diagnostic tools, liver biopsy remains the gold standard for diagnosing metabolic dysfunction-associated steatohepatitis (MASH) and assessing fibrosis. This study investigated RNA aptamer panels, selected using APTASHAPE technology, for non-invasive MASLD diagnosis and fibrosis stratification. Aptamer panels were selected in a cohort of individuals with MASLD (development cohort, n = 77) and tested in separate cohorts: one with MASLD (test cohort, n = 57) and one assessed for bariatric surgery (bariatric cohort, n = 62). A panel distinguishing MASLD without steatohepatitis from MASH accurately stratified individuals in the developmentcohort (AUC = 0.83) but failed in the test and bariatric cohorts. It did, however, distinguish healthy controls from individuals with MASLD, achieving an AUC of 0.72 in the test cohort. A panel for fibrosis stratification differentiated F0 from F3-4 fibrosis in the development cohort (AUC = 0.68) but not in other cohorts. Mass spectrometry identified five plasma proteins as potential targets of the discriminative aptamers, with complement factor H suggested as a novel MASLD biomarker. In conclusion, APTASHAPE shows promise as a non-invasive tool for diagnosing and staging MASLD and identifying associated plasma biomarkers.

Cigarette smoke (CS), an intricate blend comprising over 4000 compounds, induces abnormal cellular reactions that harm multiple tissues. Non-alcoholic fatty liver disease (NAFLD) is a prevalent chronic liver disease (CLD), encompassing non-alcoholic fatty liver (NAFL), non-alcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma (HCC). Recently, the term NAFLD has been changed to metabolic dysfunction-associated steatotic liver disease (MASLD), and NASH has been renamed metabolic dysfunction-associated steatohepatitis (MASH). A multitude of experiments have confirmed the association between CS and the incidence and progression of MASLD. However, the specific signaling pathways involved need to be updated with new scientific discoveries. CS exposure can disrupt lipid metabolism, induce inflammation and apoptosis, and stimulate liver fibrosis through multiple signaling pathways that promote the progression of MASLD. Currently, there is no officially approved efficacious pharmaceutical intervention in clinical practice. Therefore, lifestyle modifications have emerged as the primary therapeutic approach for managing MASLD. Smoking cessation and the application of a series of natural ingredients have been shown to ameliorate pathological changes in the liver induced by CS, potentially serving as an effective approach to decelerating MASLD development. This article aims to elucidate the specific signaling pathways through which smoking promotes MASLD, while summarizing the reversal factors identified in recent studies, thereby offering novel insights for future research on and the treatment of MASLD.

In managing metabolic dysfunction-associated steatotic liver disease, which affects over 30% of the general population, effective noninvasive biomarkers for assessing disease severity, monitoring disease progression, predicting the development of liver-related complications, and assessing treatment response are crucial. The advantage of simple fibrosis scores lies in their widespread accessibility through routinely performed blood tests and extensive validation in different clinical settings. They have shown reasonable accuracy in diagnosing advanced fibrosis and good performance in excluding the majority of patients with a low risk of liver-related complications. Among patients with elevated serum fibrosis scores, a more specific fibrosis and imaging biomarker has proved useful to accurately identify patients at risk of liver-related complications. Among specific fibrosis blood biomarkers, enhanced liver fibrosis is the most widely utilized and has been approved in the United States as a prognostic biomarker. For imaging biomarkers, the availability of vibration-controlled transient elastography has been largely improved over the past years, enabling the use of liver stiffness measurement (LSM) for accurate assessment of significant and advanced fibrosis, and cirrhosis. Combining LSM with other routinely available blood tests enhances the ability to diagnose at-risk metabolic dysfunction-associated steatohepatitis and predict liver-related complications, some reaching an accuracy comparable to that of liver biopsy. Magnetic resonance imaging-based modalities provide the most accurate quantification of liver fibrosis, though the current utilization is limited to research settings. Expanding their future use in clinical practice depends on factors such as cost and facility availability.

In light of the new nomenclature of steatotic liver disease (SLD), we aimed to enhance the existing knowledge on the epidemiology and clinical outcomes of metabolic and alcohol related/associated liver disease (MetALD).

A systematic review and meta-analysis were performed in Medline/PubMed, Embase, Scopus and Cochrane databases to evaluate the prevalence and outcomes of MetALD within the SLD population and to compare the characteristics between MetALD patients and those with metabolic dysfunction associated steatotic liver disease (MASLD) and alcohol-related liver disease (ALD). Nineteen studies from nine countries that evaluated 4,543,341 adult participants with SLD were included.

The pooled overall prevalence of MetALD among the SLD population was 10 % (95%CI:7-13 %) without significant difference between Asian and non-Asian populations. However, MetALD was more frequent in men than women (86 % vs 14 %, p < 0.01), while Asian MetALD patients, were more frequent men (92 % vs 66 %, p < 0.01) compared to non-Asians. Additionally, in terms of metabolic characteristics there were no significant differences between MetALD, MASLD and ALD patients. Regarding outcomes, patients with MetALD, compared to non-SLD, were at increased risk of all-cause [HR 1.44 (95%CI:1.24-1.66)], cardiovascular disease (CVD) [HR 1.17 (95%CI:1.12-1.21)] and cancer-related mortality [HR 2.07 (95%CI:1.32-3.25)]. Finally, patients with MetALD, had increased incidence of CVD and liver decompensating events, compared to non-SLD participants [HR 1.49 (95%CI:1.03-2.15); HR 10.55 (95%CI:3.46-32.16) respectively].

Based on the existing literature, patients with MetALD consist a significant part of the SLD population, with high all-cause, CVD and cancer-related mortality and increased risk for CVD and hepatic decompensation.

Background: To investigate the association of demographic, clinical, and metabolic factors with nonalcoholic fatty liver disease (NAFLD) in a non-overweight/obese and overweight/obese Chinese population at risk for metabolic syndrome. Patients and Method: A cross-sectional multicenter study was conducted using convenience sampling from eight selected counties/cities in Zhejiang, China, between May 2021 and September 2022. Demographics, epidemiological, anthropometric, and clinical characteristics were obtained from a questionnaire. Least absolute shrinkage and selection operator (LASSO)-logistic regression analysis was used to identify the variables associated with NAFLD. Receiver operating characteristic (ROC) curve analysis and decision curve analysis (DCA) were performed to evaluate the diagnostic value and clinical utility of the variables and models. Results: A total of 1739 patients were enrolled in the final analysis, 345 (19.8%) were non-overweight/obese and 1394 (80.2%) were overweight/obese participants. There were 114 (33.0%) and 1094 (78.5%) patients who met the criteria for NAFLD in the non-overweight/obese participants and the overweight/obese participants respectively. Older age, current smoking, higher triglyceride (TG) levels, higher AST levels, higher albumin levels, lower insulin levels, and higher controlled attenuation parameter (CAP) scores were associated with NAFLD in both non-overweight/obese and overweight/obese participants. The combination of TG+CAP scores had strong predictive values for NAFLD, especially in non-overweight/obese (Area Under Curve = 0.812, 95% confidence interval: 0.764-0.863). DCA showed a superior net benefit of the TG+CAP score over other variables or models, suggesting a better clinical utility in identifying NAFLD. Conclusions: More stringent lipid management strategies remain essential, and the convenience and efficacy of transient elastography for liver steatosis should be recognized, especially in the non-overweight/obese population.

The Life's Essential 8 (LE8) is a recently introduced assessment of cardiovascular health (CVH) by the American Heart Association (AHA). Nonalcoholic fatty liver disease (NAFLD) is currently the most common chronic liver disease and is associated with an increased risk of stroke. We aimed to explore the association of LE8 with stroke in NAFLD using a national cross-sectional study.

Eligible participants with NAFLD aged 20-85 years in NHANES 2005-2018 were included. LE8 was assessed according to AHA criteria and categorized into metabolic and behavioral factors. US Fatty Liver Index (USFLI) ≥ 30 and exclusion of other chronic liver diseases suggested NAFLD. Stroke was diagnosed according to self-report on standardized questionnaires.

After adjusting for all confounders, each point increase in LE8, LE8 metabolic factors, and LE8 behavioral factors was associated with a 4.4 %, 1.8 %, and 2.5 % reduction in stroke prevalence in NAFLD, respectively. Both moderate and high CVH assessed by LE8 and LE8 behavioral factors were associated with reduced odds of stroke compared with low CVH. Stroke prevalence declined progressively with increasing number of ideal LE8 components, with the lowest odds of stroke at 3 + ideal LE8 components for both LE8 metabolic and behavioral factors. Restricted cubic spline suggested dose-response associations. Race/ethnicity was a significant effect modifier, and this association was present only among non-Hispanic white population and other Hispanic population. FLI as a diagnostic indicator of NAFLD yielded generally consistent results.

Higher LE8 score, especially LE8 behavioral factors, was associated with reduced prevalence of stroke in NAFLD, especially among non-Hispanic white population and other Hispanic population. The odds of stroke declined progressively with increased ideal LE8 component number. These findings underscore the preventive value of adherence to high CVH for stroke prevention in NAFLD.

We aimed to compare the association of metabolic dysfunction-associated fatty liver disease (MAFLD), metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-related liver disease (ALD), metabolic dysfunction and ALD (MetALD), and MASLD with viral hepatitis (MASLD-Viral) with risks of cirrhosis, liver cancer, and mortality. The data of 464,556 adults from the UK Biobank (UKB), 13,526 adults from the National Health and Nutrition Examination Survey (NHANES), and 2554 adults from BeijngFH Health Cohort Study (FHCS) were included. Adjusted hazard ratios (aHR) and odds ratios were calculated using Cox and Logistic regression models, respectively. Compared with non-SLD, the risk of liver cancer increased from MetALD (aHR 1.70 [95% CI 1.37, 2.09]), MASLD (1.91 [1.66, 2.21]), MAFLD (2.01 [1.76, 2.29]), ALD (3.16 [2.54, 3.93]), to MASLD-Viral (22.0 [10.8, 44.4]) in a stepwise manner in the UKB; the risk of all-cause mortality increased from MetALD, MASLD, MAFLD, ALD, to MASLD-Viral in the NHANES. The odds ratio of liver fibrosis increased from MASLD, MAFLD, to MASLD-Viral in the FHCS. In patients with diabetes, metformin plus other drugs were associated with higher risks of cirrhosis, liver cancer, and all-cause mortality in MASLD or MAFLD. Prevention rather than antiglycemic treatment is important for patients with diabetic MASLD or MAFLD.

The global epidemic of metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing worldwide. People with MASLD can progress to cirrhosis and hepatocellular carcinoma and are at increased risk of developing type 2 diabetes, cardiovascular disease, chronic kidney disease, and extrahepatic cancers. Most people with MASLD die from cardiac-related causes. This outcome is attributed to the shared pathogenesis of MASLD and cardiometabolic diseases, involving unhealthy dietary habits, dysfunctional adipose tissue, insulin resistance, and subclinical inflammation. In addition, the steatotic and inflamed liver affects the vasculature and heart via increased glucose production and release of procoagulant factors, dyslipidaemia, and dysregulated release of hepatokines and microRNAs. However, there is substantial heterogeneity in the contributors to the pathophysiology of MASLD, which might influence its rate of progression, its relationship with cardiometabolic diseases, and the response to therapy. The most effective non-pharmacological treatment approaches for people with MASLD include weight loss. Paradoxically, some effective pharmacological approaches to improve liver health in people with MASLD are associated with no change in bodyweight or even with weight gain, and similar response heterogeneity has been observed for changes in cardiometabolic risk factors. In this Review, we address the heterogeneity of MASLD with respect to its pathogenesis, outcomes, and metabolism-based treatment responses. Although there is currently insufficient evidence for the implementation of precision medicine for risk prediction, prevention, and treatment of MASLD, we discuss whether knowledge about this heterogeneity might help achieving this goal in the future.

Metabolic dysfunction-associated fatty liver disease (MAFLD), formerly known as nonalcoholic fatty liver disease (NAFLD), is a common, highly heterogeneous condition that affects about a quarter of the world's population, with no approved drug therapy. Current evidence from preclinical research and a number of small clinical trials indicates that SGLT2 inhibitors could also be effective for MAFLD. MAFLD is associated with a higher risk of chronic liver disease and multiple extrahepatic events, especially cardiovascular disease (CVD) and chronic kidney disease (CKD). MAFLD is considered a more appropriate terminology than NAFLD because it captures the complex bidirectional interplay between fatty liver and metabolic dysfunctions associated with disease progression, such as obesity and type 2 diabetes mellitus (T2DM). SGLT2 inhibitors are antidiabetic drugs that block glucose reabsorption in the kidney proximal tubule. In this article, we reviewed current clinical evidence supporting the potential use of SGLT2 inhibitors as a drug therapy for MAFLD and discussed the possible cellular and molecular mechanisms involved. We also reviewed the clinical benefits of SGLT2 inhibitors against MAFLD-related comorbidities, especially CVD, CKD and cardiovascular-kidney-metabolic syndrome (CKM). The broad beneficial effects of SGLT2 inhibitors support their use, likely in combination with other drugs, as a therapy for MAFLD.